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BACKGROUND To know the effectiveness and tolerance of weekly cisplatin added to radiotherapy ( RT ) in advanced carcinoma of oropharynx and nasopharynx . PATIENTS AND METHODS Stage II-IV cancer patients were r and omly assigned to either radical RT , 70 Gy/35 fractions over 7 weeks ( RT arm ) , or chemoradiotherapy ( CRT ) , cisplatin 40 mg/m² weekly for seven doses plus RT . Primary end points were ( i ) the responses , ( ii ) toxicity profile , and ( iii ) overall survival ( OS ) in two groups . Study period was from June 2003 to July 2005 . RESULTS One hundred and fifty-three patients were r and omly allocated to the study , 76 in RT arm and 77 in CRT arm . Seventy-one in each arm completed the planned treatment ; complete response ( CR ) : 67.1 % versus 80.5 % in RT and CRT arms ( P = 0.04 ) . Grade III and IV toxicity were 16 % and 40 % in RT and CRT arms , respectively ( P = 0.01 ) . There were frequent treatment interruptions ( 9.3 % versus 28.9 % ; P = 0.003 ) and hospitalization ( 20 % versus 40.8 % ) in the CRT group . OS was superior in the CRT arm ( P = 0.02 ) : 27 months [ 95 % confidence interval ( CI ) 15.2 - 36.8 ] for RT versus not reached for CRT . Three-year OS was 42 % for RT and 62 % for CRT group . CRT and CR were independent prognostic factors . CONCLUSION This trial on Indian head and neck squamous cell carcinoma patients confirms that the use of weekly cisplatin is safe and CRT is superior to RT alone result ing in higher OS Aim and background Radiotherapy is the conventional treatment for locally advanced inoperable head and neck squamous cell carcinoma . However , the poor therapeutic results justify the development of radiochemotherapy combinations . In an attempt to improve local control and survival in patients with stage III and IV unresectable head and neck squamous cell carcinoma and based on the results of our previous dose escalation study , we undertook a prospect i ve multicentric r and omized trial . Material s and methods From November 1992 through December 1995 , a total of 164 patients were r and omized to receive radiotherapy alone ( arm I ) or combined ( arm II ) with daily low-dose carboplatin . Results The 3 , 5 and 10-year local-regional recurrence-free survival rates were better in arm II(21.7 % , 15.1 % and 15.1 % , respectively ) than in arm I ( 15 % , 10.7 % and 10.7 % ) , but without statistical significance ( P = 0.11 ) . The 3 , 5 and 10-year disease-free survival rates showed the same positive trend for arm II ( 16 % , 6.8 % and 6.8 % vs 9 % , 5.5 % and 5.5 % , in arm I , respectively ) , again without statistical significance ( P = 0.09 ) . Instead , a statistical advantage was found in overall survival rates at 3 , 5 and 10-years ( 28.9 % , 9 % and 5.5 % in arm II and 11.1 % , 6.9 % and 6.9 % in arm I , respectively ) ( P = 0.02 ) . The 3 , 5 and 10-year local-regional recurrence-free survival rates in stage IV disease were statistically better in arm II ( 21.5 % , 15.9 % and 15.9 % ) than in arm I ( 12.8 % , 7.7 % and 7.7 % , respectively ) ( P = 0.04 ) . Conclusions Long-term results in both treatment arms of the trial appear less positive than most published series . However , our findings do not exclude that carboplatin may be beneficial , but the benefit in local control must be lower than the 15 % assumed to dimension the trial BACKGROUND Single-modality radiotherapy is still considered st and ard treatment for patients with locally advanced unresectable cancer of the head and neck . As treatment outcome is poor , attempts to integrate chemotherapy into the overall management of these patients are ongoing . PATIENTS AND METHODS A r and omized study was undertaken to compare a sequential with a simultaneous chemoradiotherapy program . Between February 1986 and February 1991 , 93 eligible patients with locally advanced unresectable cancer of the head and neck were stratified by WHO PS , T and N class and primary site and then r and omized to receive either three courses of neoadjuvant chemotherapy with cisplatin ( 100 mg/m2 i.v . d 1 ) and 5-fluorouracil 1000 mg/m2/days 1 - 5 by continuous i.v . infusion every 3 weeks prior to definitive conventional radiotherapy of 65 - 70 Gy ( sequential treatment ) , or cisplatin 100 mg/m2 on days 1 , 22 , 43 given simultaneously for the duration of the same conventional radiotherapy ( simultaneous treatment ) . RESULTS At the end of the entire treatment 18 complete responses ( 47 % ) in the sequential-treatment arm and 18 ( 41 % ) in the simultaneous treatment arm were obtained . No statistically significant differences in the 5-yr progression-free survival , in the median time to loco-regional and distant progression and in the 5-yr overall survival were observed . Leukopenia was more frequent in the simultaneous than in the sequential arm ( p = 0.03 ) , whereas alopecia ( p = 0.008 ) and phlebitis ( p < 0.0001 ) were more frequent in the sequential-treatment arm . A better compliance was associated with the concomitant treatment , with 87 % of the patients completing the entire radiotherapy program versus 63 % of those in the sequential arm ( p = 0.01 ) . CONCLUSIONS In the present study , the two treatment arms showed similar activity ( complete response , progression-free and overall survival rates ) . Compliance to treatment was better in the concomitant arm . These data suggest that concomitant chemo-radiation therapy might be considered an option in unresectable locally advanced cancer of the head and neck . Phase III studies are needed in order to establish the superiority of this combination of cisplatin and radiotherapy versus radiotherapy alone The r and omization of 155 patients with advanced head and neck carcinomas into 5 subgroups related to the site of origin result ed in 2 comparable groups suitable for study . One group was treated with external radiation alone , the second group was treated with external radiation plus concomitant systemic 5-FU . The improved cure rate and average survival of the entire group was statistically significant ; however , the tabulated results indicated that the better results in the combination treated group were present in the lesions originating in the oral cavity or oropharynx . All of these lesions were squamous cell carcinomas . The 106 lesions which were r and omized in these 2 areas demonstrated an impressive advantage for the combination therapy .  Reactions to therapy with the combination group are slightly more severe but are certainly within tolerable limits . We have not demonstrated a greater long-term number of complications . The results of the study indicate a need for a similar cooperative study in an effort t Between January 1996 and November 1998 38 patients were treated with induction chemotherapy .  Patients were distributed in two r and omized groups , 19 - 19 patients in each , receiving ( group N ) either bleomycin , vincristine and methotrexate ( BVM ) or the previous medication plus cisplatin ( BVCM ) chemotherapy ( group C ) . Side effects were low and reversible during the treatments . The clinical regression rate ( RR ) of the cases was 87 % including complete regression 24 % . There was no difference between the two groups . There was no difference in the pathological macroscopic regression , however group C was better in microscopic regression . During the 27.5 months of average follow-up time , group N had a significantly better result in the tumor-free survival , with a lower rate of metastatic recidives ( N/C = 2/9 ) . There was no significant difference in the overall survival rate , due to the radical neck dissections of recidive metastases . According to our experience we recommend the use of cisplatin in conjunction with neck radiotherapy In a r and omized double-blind trial hydroxyurea was compared to placebo in conjunction with radiotherapy of head and neck cancer .  Chemotherapy was given orally twice a week ( 80 mg∕kg ) concurrently with irradiation . Comparison of the 2 groups for primary tumor regression , cervical node response , and early survival fails to show statistically significant differences . Combined treatment may be useful in massive node metastases . Increased local radiation reactions were frequent in the hydroxyurea group and severe with interstitial implants . The drug was generally well tolerated . Complications of treatment and an apparently higher incidence of distant metastases are discussed Two hundred and forty-one patients , with advanced squamous cell carcinoma of head and neck , were r and omized to receive three courses of  induction chemotherapy . The chemotherapy regimens were delivered every 3 weeks , and consisted in 1 ) cisplatin , 80 mg/m2 given alone ( CDDP regimen ) , or 2 ) in combination with vincristine , 1 mg , d 1 , methotrexate 10 mg/m2 d 1 , 2 , 3 , and bleomycin 10 mg/m2 , d 1 , 2 , and 3 ( MOB-P ) . Tolerance was significantly better with the CDDP regimen ( p less than 0.05 ) ; severe side effects , affecting mainly digestive tract , and bone marrow , were encountered in 7 % of the patients in the CDDP group , vs 15 % in the MOB-P group , without death related to pancytopenia . Short-term results were better for patients treated by the MOB-P regimen , with a 42 % response rate ( including 9 complete responses ) vs 22 % with the CDDP regimen ( p = 0.01 ) . A superiority of combination chemotherapy was more significant for primary sites than regional lymph nodes . The relapse-free survival was not statistically different in the 2 groups , as well as the 2 years overall survival . Among responders , the survival was found highly correlated with a good initial general status ( p less than 0.01 ) , and with the highest total doses of cisplatin ( p less than 0.02 ) . ( ABSTRACT TRUNCATED AT 250 WORDS PURPOSE To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma ( SCC ) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial . PATIENTS AND METHODS One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were r and omized to receive definitive radiotherapy ( 70 Gy in 7 weeks ) concurrently with either cisplatin ( 75 mg/m(2 ) ) plus tirapazamine ( 290 mg/m(2)/d ) on day 2 of weeks 1 , 4 , and 7 , and tirapazamine alone ( 160 mg/m(2)/d ) on days 1 , 3 , and 5 of weeks 2 and 3 ( TPZ/CIS ) , or cisplatin ( 50 mg/m(2 ) ) on day 1 and infusional fluorouracil ( 360 mg/m(2)/d ) on days 1 through 5 of weeks 6 and 7 ( chemoboost ) . RESULTS Three-year failure-free survival rates were 55 % with TPZ/CIS ( 95 % CI , 39 % to 70 % ) and 44 % with chemoboost ( 95 % CI , 30 % to 60 % ; log-rank P = .16 ) . Three-year locoregional failure-free rates were 84 % in the TPZ/CIS arm ( 95 % CI , 71 % to 92 % ) and 66 % in the chemoboost arm ( 95 % CI , 51 % to 79 % ; P = .069 ) . More febrile neutropenia and grade 3 or 4 late mucous membrane toxicity were observed with TPZ/CIS , while acute skin radiation reaction was more severe and prolonged with chemoboost . Compliance with protocol treatment was satisfactory on both arms . CONCLUSION Both regimens are feasible and are associated with significant but acceptable toxicity profiles in the cooperative group setting . Based on the promising efficacy seen in this trial , TPZ/CIS is being evaluated in a large phase III trial PURPOSE To exp and on our experience with the combination of paclitaxel , fluorouracil , hydroxyurea , and twice daily irradiation ( T-FHX ) and to assess the impact of weekly administration of erythropoietin ( r-HuEpo ) on transfusion requirements , we conducted a Phase II multi-institutional trial with a simplified 1-h paclitaxel infusion schedule and r and omized patients to receive weekly doses of r-HuEpo . PATIENTS AND METHODS A total of 90 patients with locally advanced head and neck cancers ( stage IV , 96 % ; N(2)/N(3 ) , 66 % ) were treated on a regimen of 1-h infusion of paclitaxel ( 100 mg/m(2)/day , day 1 ) , 120-h infusion of 5-fluorouracil ( 600 mg/m(2)/day , days 0 - 5 ) ; hydroxyurea 500 mg p.o . every 12 h for 11 doses ; and radiation 150cGy bid , days 1 - 5 of each 14-day cycle repeated for five cycles over 10 weeks ( 7200 - 7500 cGy ) . Before initiating therapy , patients were r and omized to receive r-HuEpo 40,000 IU s.c . once weekly . RESULTS At median follow-up of 40 months , 3-year progression-free survival is 62 % , locoregional control is 84 % , and systemic control is 79 % . Overall survival is 59 % . Anemia , leucopenia , dermatitis , and mucositis were the most frequent grade 3 or 4 toxicities . Patients r and omized to erythropoietin experienced less grade 2/3 anemia ( 52 versus 77 % ; P = 0.02 ) , but transfusion requirements were not significantly different . CONCLUSIONS T-FHX is an active and tolerable regimen inducing local tumor control and promising survival with organ preservation in high-risk patients . One h infusion of paclitaxel simplified the regimen without compromising efficacy . Addition of erythropoietin does not reduce the need for transfusion with this nonplatinum-containing regimen . T-FHX should be advanced to a r and omized trial and compared with a cisplatin-based concomitant regimen BACKGROUND A r and omized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil ( TPF ) with cisplatin and fluorouracil ( PF ) , followed by chemoradiotherapy . METHODS We r and omly assigned 501 patients ( all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were c and i date s for organ preservation ) to receive either TPF or PF induction chemotherapy  , followed  by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week . The primary end point was overall survival . RESULTS With a minimum of 2 years of follow-up ( > or =3 years for 69 % of patients ) , significantly more patients survived in the TPF group than in the PF group ( hazard ratio for death , 0.70 ; P=0.006 ) . Estimates of overall survival at 3 years were 62 % in the TPF group and 48 % in the PF group ; the median overall survival was 71 months and 30 months , respectively ( P=0.006 ) . There was better locoregional control in the TPF group than in the PF group ( P=0.04 ) , but the incidence of distant metastases in the two groups did not differ significantly ( P=0.14 ) . Rates of neutropenia and febrile neutropenia were higher in the TPF group ; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group . CONCLUSIONS Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy . ( Clinical Trials.gov number , NCT00273546 [ Clinical Trials.gov ] . ) From 1979 to 1980 , 52 patients with Stage III-IV squamous cell carcinoma of the head and neck were included in a prospect i ve r and omized study on hyperfractionated radiotherapy with or without misonidazole . The radiotherapeutic schedule consisted of two weeks of treatment split by a rest-period of one month , 6 X 1.1 Gy fractions per day for 5 consecutive days ( total dose : 2 X 33 Gy/30 f/5 d ) . Total dose of misonidazole was 12 g/m2 administered daily in 1.2 g/m2 fractions . The overall tolerance of misonidazole  was good , with a neuropathy rate of 5.7 % . Local control , recurrence and 3 year survival rates did not statistically differ between the two groups . The r and omized trials published at the present time , including our own , suggest that misonidazole has no beneficial effect with classical , concentrated or multiple fractions per day radiotherapy In a prospect i ve , r and omized , multicenter study , neoadjuvant chemotherapy ( CT ) with carboplatin and 5-fluorouracil ( 5-FU ) followed by locoregional treatment ( LRT ) was compared with locoregional treatment alone in the treatment of patients with head and neck cancer . This study , which includes 324 patients , was conducted from January 1988 to July 1991 . The aim of this study was to evaluate the impact of the carboplatin/5-FU regimen both on the incidence of mutilating surgery and on the survival rate .  Chemotherapy consisted of three cycles of carboplatin 400 mg/m2 day 1 and 5-FU 1 g/m2 days 1 - 5 , repeated every 3 weeks . Patients with a complete tumor response then received radiotherapy alone , instead of the treatment planned initially . Three hundred patients were analyzed : 79 had tumors of the oral cavity , 106 oropharyngeal tumors , and 115 pharyngolaryngeal tumors . One hundred fifty patients underwent CT+LRT ; 150 patients had LRT alone .  Grade 3 and 4 toxicity rates were minimal in the CT+LRT group ; toxicity was mainly hematologic ( 24 % neutropenia , 19 % thrombocytopenia ) . There were 3 toxic deaths ( 2 % ) , 2 due to septicemia and 1 due to cardiac toxicity .  One hundred forty-three patients were evaluable for efficacy . The tumor objective response rate was 63 % and complete response rate was 31 % ( 35 % for oropharyngeal , 34 % for pharyngolaryngeal tumors , 22.5 % for oral cavity tumors ) , which led to a 29 % decrease in the rate of mutilating surgery . Conservative treatment was performed in 57 % of patients in the CT+LRT group vs. 24 % in the LRT group ( p = 0.001 ) . There was no significant difference between survival curves in the CT+LRT and LRT groups . At 4 years , overall survival rates were 56 and 46 % ; disease-free survival rates were 33 and 30 % in the CT+LRT and the LRT groups , respectively . The survival rates were not significantly different in the two groups . The locoregional recurrence rates were 35 % in the CT+LRT arm and 25 % in the LRT arm ( p = 0.04 ) , with median follow-up of 25 months . The rates of secondary localization and distant metastasis were not significantly different in the two groups This study was design ed to ascertain whether a prior reduction of tumor size by drugs could affect the final outcome of tumors treated with radiation . 142 patients with head and neck cancer ( oropharynx , maxillary antrum and intra-oral ) were r and omized for the study . In 72 cases , irradiation was preceded by a continuous intra-arterial infusion of 3 - 5 mg/day methotrexate to a total dose of 90 - 120 mg ; the other 70 patients were treated with radiotherapy alone . Chemotherapy , given prior to radiotherapy , caused a shift in the tumor stage ( i.e. a reduction in tumor size ) in more than one third of the cases . The overall 5-year survival was 43 % in the combined treatment group and 25 % in the group treated with radiation alone ( statistical difference : p less than .05 ) . However , when analysed separately the difference was statistically significant only in oral cavity tumors ( 5-year survival of 54 % in the combined modality group vs. 27 % in the control group ) , although local control rates after both single and combined modalities were not statistically different from those of oropharynx and maxillary antrum tumors . In these last lesions , however , the dissemination of disease was more frequent ; therefore , the lack of improvement of cure rate with the combined modality in these cases seems to be related to both the higher tendency of these tumors to disseminate and the low effectiveness of intra-arterial chemotherapy in controlling distant metastases . Mild and transient local and systemic toxicities were observed during chemotherapy infusion , but no radiosensitising effect on normal skin and mucosa was seen during radiotherapy in patients who had received pre-irradiation chemotherapy Abstract 50 patients of advanced squamous cell carcinoma of the head and neck were r and omised cither to receive  chemotherapy followed by radiation therapy or chemoimmunotherapy followed by radiotherapy . In the chemoimmunotherapy arm , the patients received recombinant interferon alpha 2b 3 M.U. subcutaneously , thrice a week on alterante days for 5 weeks from Day 1 , Cisplatinum 70 mg/ m2 on Day 1 and 21 , and 5 — flurouracil 1000mg/m2 on Day 1 , 2 , 3 and Day 21 , 22 , 23 , followed by from Dav 36 , radiotherapy'by Co bait 60 to a tumour dose of 65 Gy in 30 # over 6 weeks . In the control arm , patiens received Cisplatitnum 70 mg/ m2 on Day 1 and Day 21 , 5 flurouracil 1000 mg/ m2 on Dav 1 , 2 , 3 and Day 21 , 22 , 23 followed by radiotherapy by Cobalt 60 to a tumour dose of 65 Gy in 30 # over 6 weeks from Day 36 . Only Grade II and III toxicity was observed in the two arms which were manageable Patients treated with chemoimmunotherapy followed by radiotherapy showed 60 % complete response , 20 % partial response and 12 % no change/ progressive disease ; while the patients on the control arm treated with chemotherapy and radiotherapy showed 12 % complete response 44 % Partial response and 32 % no change “ progressive disease . This trial concludes that chemoimmunotherapy followed by radiotherapy is an excellent alternative therapeutic strategy for the management of advanced head and neck cancers with manageable toxicity A significant link between 5-fluorouracil ( 5FU ) plasma concentration and its therapeutic activity has been demonstrated in colon and head and neck cancer patients for 5FU used as a continuous infusion . Dose adjustment based on pharmacokinetic follow-up has been proposed to decrease hematological and digestive toxicities , but the clinical impact of this approach has not yet been demonstrated . A r and omized multicentric study was conducted to evaluate the clinical interest of 5FU dose adaptation guided by pharmacokinetics . One hundred twenty-two head and neck cancer patients were r and omly assigned to receive induction chemotherapy with cisplatin ( 100 mg/m2 , day 1 ) and 5FU ( 96-h continuous infusion ) , either at st and ard dose ( St-arm ; 4 g/m2 ) or at a dose adjusted according to the 5FU area under the curve ( AUC0 - 48h ; PK-arm ) . In total , 106 patients were evaluable for toxicity and response .  In the PK-arm ( n = 49 ) ,  5FU doses and area under the curve were significantly reduced during cycle 2 and cycle 3 ( P < 0.001 ) as compared with the St-arm ( n = 57 ) . Grade 3 - 4 neutropenia and thrombopenia were significantly more frequent in the St-arm as compared with the PK-arm ( 17.5 % versus 7.6 % , respectively ; P = 0.013 ) . No grade 3 - 4 mucositis occurred in the PK-arm , whereas 5.1 % was observed in the St-arm ( P < 0.01 ) . The objective response rate was comparable in the two treatment arms : 77.2 % in the St-arm versus 81.7 % in the PK-arm . The present study is the first to demonstrate , in a r and omized design , the clinical interest of an individual 5FU dose adaptation based on pharmacokinetic survey , in terms of therapeutic index improvement PURPOSE To report the results and corresponding acute and late reactions of a prospect i ve , r and omized , clinical study in locally advanced head and neck cancer comparing concurrent fluorouracil ( FU ) and mitomycin ( MMC ) chemotherapy and hyperfractionated accelerated radiation therapy ( C-HART ; 70.6 Gy ) to hyperfractionated accelerated radiation therapy alone ( HART ; 77.6 Gy ) . PATIENTS AND METHODS Three hundred eighty-four stage III ( 6 % ) and IV ( 94 % ) oropharyngeal ( 59.4 % ) , hypopharyngeal ( 32.3 % ) , and oral cavity ( 8.3 % ) cancer patients were r and omly assigned to receive either 30 Gy ( 2 Gy every day ) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU ( 600 mg/m(2 ) , 120 hours continuous infusion ) days 1 through 5 and MMC ( 10 mg/m(2 ) ) on days 5 and 36 ( C-HART ) or 14 Gy ( 2 Gy every day ) followed by 1.4 Gy bid to a total dose of 77.6 Gy ( HART ) . The data were analyzed on an intent-to-treat basis . RESULTS At 5 years , the locoregional control and overall survival rates were 49.9 % and 28.6 % for C-HART versus 37.4 % and 23.7 % for HART , respectively ( P = .001 and P = .023 , respectively ) . Progression-free and freedom from metastases rates were 29.3 % and 51.9 % for C-HART versus 26.6 % and 54.7 % for HART , respectively ( P = .009 and P = .575 , respectively ) . For C-HART , maximum acute reactions of mucositis , moist desquamation , and erythema were lower than with HART , whereas no differences in late reactions and overall rates of secondary neoplasms were observed . CONCLUSION C-HART ( 70.6 Gy ) is superior to dose-escalated HART ( 77.6 Gy ) with comparable or less acute reactions and equivalent late reactions , indicating an improvement of the therapeutic ratio The authors report the results of a multicentric r and omised trial assessing the effects on survival of neoadjuvant chemotherapy with cisplatin ( 100 mg/m2 , D1 ) and fluorouracil ( 1 g/m2 , D2 - 4 ) delivered before regional treatment in patients with squamous cell carcinoma of hypopharynx and base of tongue . 133 patients were enrolled in the study , and 121 were included in the analysis , 64 in group A ( regional treatment alone ) and 27 in group B ( chemotherapy followed by regional treatment ) . Despite a high objective response rate to chemotherapy ( primary tumour : 85 % , 24 % complete ; nodes : 63 % ) , overall survival was not significantly higher in group B than in group If chemotherapy is effectively controlling microscopic distant metastases , then a reduced number of patients would experience treatment failure at distant sites . This study has used a group of 175 patients on a phase 3 Southwest Oncology Group trial for resectable advanced stage disease to test this hypothesis . In the group that failed , 52 % of the st and ard group failed at distant sites as opposed to only 30 % of the experimental group . This difference approaches statistical significance . These findings suggest that chemotherapy , although demonstrating some activity against microscopic distant disease , has not substantially altered the usual patterns of treatment failure for head and neck cancer . However , the assumption that the clinical responses noted with chemotherapy are having a positive influence on the frequency of occult distant disease was supported by our results One of the most difficult problems of cancer treatment is the management of advanced squamous cell carcinomas of the upper respiratory tract . For several reasons the surgical resection of the primary lesion and the observed neck node metastases are limited to earlier tumour stages . Advanced and not resectable tumours of T3 - 4-N2 - 3-stages have very poor cure rates . Their treatment is based traditionally on radiotherapy and in recent years on combination chemotherapy programmes . 75 patients were entered into this prospect i ve r and omised study . 33 of these were treated with two cycles of chemotherapy followed by radiotherapy and 42 patients received three cycles of chemotherapy alone . Both therapy modalities induced tumour response rates of up to 75 % but have done little to improve survival . The role of combined radiotherapy and chemotherapy in advanced squamous tumours is not yet well defined . In our group only patients who showed tumour response after chemotherapy actually benefited from radiotherapy In 1986 , we initiated a multicenter , r and omized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment ( surgery and radiotherapy or radiotherapy alone ) with locoregional treatment alone in patients with head and neck squamous cell carcinoma . Here we report the long-term results of the trial . A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were r and omly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment ( group A ) or locoregional treatment alone ( group B ) . Among all patients , overall survival at 5 and 10 years was 23 % ( 95 % confidence interval [ CI ] = 15.3 % to 30.9 % ) and 19 % ( 95 % CI = 11.6 % to 26.4 % ) , respectively , for those in group A and 16 % ( 95 % CI = 9.6 % to 23.4 % ) and 9 % ( 95 % CI = 3.5 % to 14.7 % ) , respectively , for those in group B ( P = .13 ) . Among operable patients , we observed no difference between group A and group B in overall survival at 5 and 10 years ( group A , 31 % [ 95 % CI = 14.9 % to 47.3 % ] and 22.7 % [ 95 % CI = 7.1 % to 38.3 % ] , respectively ; group B , 43.3 % [ 95 % CI = 25.6 % to 61.0 % ] and 14.2 % [ 95 % CI = 0.1 % to 28.3 % ] , respectively ; P = .73 ) . Among inoperable patients , overall survival at 5 and 10 years was 21 % ( 95 % CI = 12.3 % to 30.1 % ) and 16 % ( 95 % CI = 7.7 % to 23.9 % ) , respectively , for group A and 8 % ( 95 % CI = 1.5 % to 12.3 % ) and 6 % ( 95 % CI = 0.1 % to 9.1 % ) , respectively , for group B ( log-rank P = .04 ) . Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease Thirty-eight patients with advanced , inoperable squamous cell carcinoma of the head and neck were r and omized to receive methotrexate alone or methotrexate with Bacillus Calmette-Guérin . The response rates with methotrexate ( 3 of 19 ) and methotrexate plus B. Calmette-Guérin ( 4 of 16 ) were similar , as was the duration of response and survival of the two groups . The results of in vitro immunological studies of lymphocytes were assessed . Marked weight loss , poor performance status , and distant metastases were the most important prognostic factors . The presence of anergy was significantly correlated with weight loss . This study also indicated that a large tumor burden is a frequent occurrence in advanced head and neck cancer and may account for the lack of efficacy of B. Calmette-Guérin PURPOSE We report the 5-year survival and late toxicity results of a r and omized clinical trial , which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma , using concomitant radiochemotherapy ( arm B ) , compared with st and ard radiotherapy ( arm A ) . PATIENTS AND METHODS A total of 226 patients were entered onto a phase III multicenter r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions ; arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil ; arm B ) . Prognostic factors were evaluated by univariate and multivariate analysis . Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity , hearing , taste , m and ibula , and teeth damage , and Radiation Therapy Oncology Group toxicity criteria for skin , salivary gl and , and mucosa . RESULTS Five-year overall survival , specific disease-free survival , and locoregional control rates were 22 % and 16 % ( log-rank P = .05 ) , 27 % and 15 % ( P = .01 ) , and 48 % and 25 % ( P = .002 ) , in arm B and arm A , respectively . Stage IV , hemoglobin level lower than 125 g/L , and st and ard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis . One or more grade 3 to 4 complications occurred in 56 % of the patients in arm B , compared with 30 % in arm A ( P was not significant ) . CONCLUSION Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity . Anemia was the most important prognostic factor for survival in both arms OBJECTIVES This single-institution study evaluates the feasibility of accelerated fractionation radiotherapy ( AF ) with and without mitomycin C ( MMC ) in the treatment of locally advanced head and neck cancer . PATIENTS AND METHODS Between May 1998 and October 2001 , sixty patients with locally advanced stage III and IV of head and neck cancer were r and omized into three treatment arms : ( 1 ) conventional fractionation radiotherapy ( CF ) ( 5 fractions per week ) ; ( 2 ) accelerated fractionation radiotherapy ( AF ) ( 6 fractions per week ) ; and ( 3 ) AF plus Mitomycin C ( MMC ) . RESULTS The 2-year overall survival ( OS ) of the whole group was 21 % . The OS according to treatment arm was 23 % , 20 % , and 28 % in CF , AF , and AF+MMC arms respectively ( p<0.19 ) . The 2-year loco-regional control ( LC ) rate was 22 % for the whole group of patients . The LC was 10 % , 25 % , and 30 % for the CF , AF , and AF+MMC respectively ( p=0.27 ) . The only significant parameters for OS and LC were performance status and pre-treatment hemoglobin level . Mucositis grade s 3 & 4 occurred in 70 % and 90 % of the patients in the AF and AF+MMC arm respectively compared to 55 % of patients in the CF arm ( p=0.04 ) . However the addition of MMC did not significantly increase the incidence or severity of mucositis between AF and AF+MMC ( p=0.13 ) . Hematological toxicity grade s 3 & 4 were significantly higher after MMC ( occurred in 40 % of patients versus 10 % and 5 % in CF and AF arms respectively , p=0.04 ) . There was no statistically significant difference in the incidence of grade 3 dryness of mouth ( p=0.06 ) , fibrosis ( p=0.6 ) , or lymphoedema ( p=0.39 ) among the three arms . CONCLUSION There was a trend for improvement of LC and OS rates with the use of AF and the addition of MMC to AF compared to CF radiotherapy , although the difference was not statistically significant . The small number of the patients in each treatment arm and the inclusion of multiple tumor sites may contribute to these statistically insignificant results . Accordingly we advise 85 to continue the trial with inclusion of a larger number of patients and restrict tumor sites to one major site One hundred eligible patients with inoperable , locally advanced or metastatic squamous cell carcinoma of the head and neck region following prior therapy were r and omized to receive i m methotrexate ( 50 patients ) or iv cisplatin ( 50 patients ) . Methotrexate produced a complete plus partial response rate of 16.0 % and cisplatin produced a partial response rate of 8.0 % , with median duration s of response of 18 and 8 weeks , respectively . The corresponding median survival times were 20 and 18 weeks . Methotrexate responders survived 60 weeks , versus 17 weeks for nonresponders . The corresponding survival times for cisplatin-treated patients were 38 and 18 weeks . Good pretreatment performance status had a significantly positive effect on survival ( P = 0.04 ) , but prior therapy did not . Toxicity secondary to either agent occurred with the expected frequency . The two agents examined showed comparable antitumor activity in patients with squamous cell carcinoma of the head and neck who had not previously received chemotherapy PURPOSE Promising results in a r and omized phase II trial with the hypoxic cytotoxin tirapazamine ( TPZ ) combined with cisplatin ( CIS ) and radiation led to this phase III trial . PATIENTS AND METHODS Patients with previously untreated stage III or IV ( excluding T1 - 2N1 and M1 ) squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx were r and omly assigned to receive definitive radiotherapy ( 70 Gy in 7 weeks ) concurrently with either CIS ( 100 mg/m(2 ) ) on day 1 of weeks 1 , 4 , and 7 or CIS ( 75 mg/m(2 ) ) plus TPZ ( 290 mg/m(2)/d ) on day 1 of weeks 1 , 4 , and 7 and TPZ alone ( 160 mg/m(2)/d ) on days 1 , 3 , and 5 of weeks 2 and 3 ( TPZ/CIS ) . The primary end point was overall survival ( OS ) . The planned sample size was 850 , estimated to result in 334 deaths , which would provide 90 % power to detect a difference in 2-year survival rates of 60 % v 70 % for CIS versus TPZ/CIS , respectively ( hazard ratio = 0.69 ) . RESULTS Eight hundred sixty-one patients were accrued from 89 sites in 16 countries . In an intent-to-treat analysis , the 2-year OS rates were 65.7 % for CIS and 66.2 % for TPZ/CIS ( TPZ/CIS -- CIS : 95 % CI , -5.9 % to 6.9 % ) . There were no significant differences in failure-free survival , time to locoregional failure , or quality of life as measured by Functional Assessment of Cancer Therapy-Head and Neck . CONCLUSIONS We found no evidence that the addition of TPZ to chemoradiotherapy , in patients with advanced head and neck cancer not selected for the presence of hypoxia , improves OS The therapeutic effectivity of two administration schedules of DDP were compared . The dose was either 100 mg/m2 infused for 4 h or 20 mg/m2 infused for 1 h on 5 consecutive days . The combined objective remission rate of the two regimens were 37/53 ( 23 % CR + + 44 % PR ) for ovarian cancer and 8/35 ( 9 % CR + 14 % PR ) for head and neck cancer . WHO Grade 1 - 2 myelo- and nephrotoxicity was observed in 26 % and 20 % , respectively , out of the 105 cases evaluable for toxicity in the two groups . Nausea and vomiting was moderate to severe . Neither the remission rate nor the toxicity of the two schedules were significantly different BACKGROUND Phase 2 studies suggest that the st and ard regimen of cisplatin and fluorouracil ( PF ) plus docetaxel ( TPF ) improves outcomes in squamous-cell carcinoma of the head and neck . We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced , unresectable disease . METHODS We r and omly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF ( docetaxel and cisplatin , day 1 ; fluorouracil by continuous infusion , days 1 to 5 ) or PF every 3 weeks for four cycles . Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy . The primary end point was progression-free survival . RESULTS A total of 358 patients underwent r and omization , with 177 assigned to the TPF group and 181 to the PF group . At a median follow-up of 32.5 months , the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group ( hazard ratio for disease progression or death in the TPF group , 0.72 ; P=0.007 ) . Treatment with TPF result ed in a reduction in the risk of death of 27 % ( P=0.02 ) , with a median overall survival of 18.8 months , as compared with 14.5 months in the PF group . There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia , nausea , vomiting , stomatitis , and hearing loss in the PF group . The rates of death from toxic effects were 2.3 % in the TPF group and 5.5 % in the PF group . CONCLUSIONS As compared with the st and ard regimen of cisplatin and fluorouracil , induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00003888 [ Clinical Trials.gov ] . ) Initial combination drug regimen containing cisplatin in patients with stage III and IV head and neck cancer produced a high percentage of clinical response . This trial was initiated to assess the role of multimodality treatment ( chemotherapy plus radiotherapy ) versus chemotherapy alone .  Ninety-six patients entered into this study ; 80 patients were evaluable at time of analysis ( Table I ) . Patients were r and omized between chemotherapy and radiotherapy ( group I ) and  chemotherapy alone ( group II ) . The chemotherapy administered consisted of cisplatin , bleomycin and methotrexate and was given in 2 cycles over 35 days . Local radiotherapy followed . In group II 3 cycles of chemotherapy were given without radiotherapy . The overall tumour response after chemotherapy rose up to 75 per cent . After radiotherapy in group II the response rate sank to 59 per cent . In both regimes the remission duration was very short . Patients receiving only two cycles of chemotherapy do not have a statistically shorter survival than patients , who were treated by chemotherapy plus radiotherapy , or by a 3rd cycle of chemotherapy BACKGROUND We conducted a multinational , r and omized study to compare radiotherapy alone with radiotherapy plus cetuximab , a monoclonal antibody against the epidermal growth factor receptor , in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck . METHODS Patients with locoregionally advanced head and neck cancer were r and omly assigned to treatment with high-dose radiotherapy alone ( 213 patients ) or high-dose radiotherapy plus weekly cetuximab  ( 211 patients ) at an initial dose of 400 mg per square meter of body-surface area , followed by 250 mg per square meter weekly for the duration of radiotherapy . The primary end point was the duration of control of locoregional disease ; secondary end points were overall survival , progression-free survival , the response rate , and safety . RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone ( hazard ratio for locoregional progression or death , 0.68 ; P=0.005 ) . With a median follow-up of 54.0 months , the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone ( hazard ratio for death , 0.74 ; P=0.03 ) . Radiotherapy plus cetuximab significantly prolonged progression-free survival ( hazard ratio for disease progression or death , 0.70 ; P=0.006 ) . With the exception of acneiform rash and infusion reactions , the incidence of grade 3 or greater toxic effects , including mucositis , did not differ significantly between the two groups . CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck . ( Clinical Trials.gov number , NCT00004227 . Forty‐eight patients with locally confined ( MO ) squamous cell head and neck cancer were prospect ively r and omized to receive either simultaneous ( SIM ) or sequential ( SEQ ) combined technique therapy with a 5‐fluorouracil infusion , a cisplatin bolus injection , and radiation therapy .  Patients with residual resectable disease underwent surgery after induction therapy , whereas those achieving a complete response to induction did not require surgery . Patients on the two treatment arms were equivalent in all measured variables , including disease extent . Toxicities of the SIM and SEQ arms also were equivalent except for mucositis and the result ant weight loss , which were more severe on the SIM arm ( P = 0.002 ) . With a follow‐up time ranging from 9 to 41 months , seven of the 24 SIM patients and 14 of the 24 SEQ patients are considered treatment failures . The relapse‐free survival is significantly better on the SIM arm ( P = 0.03 ) , although an overall survival advantage has not yet been demonstrated ( P = 0.13 ) . The achievement of a complete response after induction therapy correlates with both the relapse‐free ( P = 0.0005 ) and overall ( P = 0.05 ) survival , and the likelihood of an induction complete response also is significantly better for those treated with the SIM schedule ( P = 0.02 ) . Eighteen patients did not require surgery after achieving an induction complete response . Relapse‐free survival does not appear to be compromised in this patient subset The authors discuss the results of 3 studies of their group reflecting the possible role of amifostine in simultaneous radiochemotherapy ( RCT ) of advanced head and neck cancer . In a controlled phase II trial ( 1995 through 1996 ) , 39 patients were included in this pilot investigation . A control group ( n = 14 ) received simultaneous RCT of the head and neck region with an irradiation dose of 60 Gy and 2 cycles of carboplatin ( 700 mg/m(2 ) cumulative dose ) . Twenty-five patients received the same basic therapy and an additional 500-mg dose of amifostine before each chemotherapy . Amifostine was administered less than 45 minutes before the end of radiotherapy . The authors observed a dramatic reduction of typical radiotherapy-associated toxicities ( mucositis , xerostomia , loss of taste , dysphagia ) . The hematologic side effects ( leukocytopenia , anemia , thrombocytopenia ) also were decreased significantly . The overall survival rate and locoregional control of both groups were comparable after 12 months . In a controlled intensification trial ( 1997 through 1999 ) , the authors included 76 consecutive patients ( 69 men , 7 women ) with pharyngeal cancer ( oropharynx , n = 33 ; hypopharynx , n = 43 ) . The tumors were characterized as unresectable and locally advanced without distant metastasis . All patients received a conventional radiotherapy ( 2-Gy single dose , daily fractionation ) up to doses of 60 Gy and an additional 10 Gy as a boost in the tumor-infiltrated region . A dose of carboplatin , 70 mg/m(2 ) , was given to a group of 45 patients on days 1 through 5 and 29 through 33 of radiotherapy ( RCT arm ) . The result ing cumulative dose was 700 mg/m(2 ) . A group of 31 patients ( RCT intens arm ) received the same dose of carboplatin on days 1 through 5 , 22 through 26 , and 43 through 47 or 1 through 5 , 15 through 19 , 29 through 33 , and 43 through 47 of radiotherapy ( cumulative dose 1.05 to 1.40 mg/m(2 ) ) . All patients received 500 mg of amifostine before each carboplatin administration . If the tumor volume was less than 20 cm(3 ) , we observed an increased 1-year overall survival rate ( 91 % v 71 % ) and time to progression ( 17 months v 10 months ) . If the tumor volume was greater than 20 cm(3 ) , we observed comparable treatment results in both groups ( 1-year survival rate , 60 % v 61 % ; time to progression , 13 months v 12 months ) . In a long-term follow-up investigation ( 1999 through 2000 ) , 531 patients ( 89 women , 442 men ) were analyzed according to their toxicities during regular follow-up investigations at our outpatient facility . All patients were treated by surgery or radio(chemo)therapy because of an advanced head and neck cancer . A total of 218 of 531 patients received the antineoplastic therapy without cytoprotection . An additional 313 patients received their RCT  combined with amifostine administration before administration of the radiosensitizer . A significant influence of cytoprotection was registered in the following toxicities : xerostomia , fibrosis , loss of taste , and dysphagia . No impact was seen on the development of interstitial lymph edema and esophageal stenosis .  Amifostine could be integrated in simultaneous radiochemotherapy of advanced head and neck cancer patients . The authors favor the administration of amifostine before chemotherapeutics alone . Selective cytoprotection could decrease the main acute toxicities ( mucositis , xerostomia , dysphagia ) as well as late side effects ( xerostomia , loss of taste , fibrosis ) of this form of combined treatment . The enhanced therapeutic index may be changed into a prognostic benefit for selected patients with unresectable tumors , if the volume is smaller than 20 cm(3 ) OBJECTIVE To determine the incidence of minor and major complications in patients with squamous cell carcinoma of the upper aerodigestive tract who require surgical salvage or planned neck dissection after an initial treatment regimen with radiotherapy or concurrent chemoradiotherapy for organ preservation . DESIGN The medical records of 100 patients treated in a phase 3 trial comparing radiotherapy alone with concurrent chemoradiotherapy for stage III and IV head and neck squamous cell carcinoma were review ed . Fifty-four patients underwent 59 surgical procedures . Twenty-nine planned neck dissections were performed for persistent neck disease or initial stage N2 or greater . For persistent or recurrent disease at the primary site , 30 salvage operations were performed . SETTING Academic tertiary care referral center . RESULTS Complications occurred in 15 ( 46 % ) of the 33 procedures in the radiation-only group and 12 ( 46 % ) of the 26 procedures in the chemoradiotherapy group . Major complications occurred in 4 ( 12 % ) of the procedures in the radiation-only group and 3 ( 12 % ) of the procedures in the chemoradiotherapy group . The incidence of minor complications was 33 % and 35 % in the radiation-only and chemoradiotherapy groups , respectively . The major complication rate for salvage operations did not differ between the radiation-only and chemoradiotherapy groups ( 16 % and 27 % , respectively ; P=.79 by chi2 test ) . The incidence of major complications in planned neck dissections was 7 % of the radiation-only group and 0 % of the chemoradiotherapy group . CONCLUSIONS After radiation or concurrent chemoradiotherapy , surgery can be performed with an acceptable rate of major complications . Adding chemotherapy did not increase the incidence of surgical complications . These results differ from other reports in the literature A prospect i ve r and omized trial was conducted at Wayne State University , Detroit , Michigan , to compare the efficacy of the combination of high‐dose cis‐diamminodichloroplatinum , Oncovin ( vincristine ) and bleomycin ( COB ) to that of weekly methotrexate ( MTX ) in the induction and maintenance of remission in patients with previously treated advanced squamous cell carcinoma of the head and neck .  Complete response ( CR ) was observed in 11.1 % of patients treated with COB and in 8.3 % of patients treated with weekly methotrexate . The overall response rate ( PR + CR ) was 33.3 % to methotrexate versus 40.7 % to COB . This difference was not significant , nor was the survival of patients treated by either modality . Important variables affecting survival in this study proved to be good performance status ( ⩾70 ) and response to therapy . Nausea and vomiting were the more common side effects of COB ( 56 % ) , while hematologic toxicity was more frequent and more severe in the methotrexate arm ( 75 % ) . Combination chemotherapy with COB is not more effective in producing response or prolonging survival than weekly methotrexate in patients with advanced head and neck carcinoma when both regimens are compared in a r and omized study Purpose To assess the survival rate , the probability of local control , the patterns of relapse and late sequelae including self-reported quality of life in patients treated with hyperfractionated radiotherapy ( RT ) and simultaneous CDDP chemotherapy for stage-III to stage-IV carcinomas of the head and neck . Methods From 1988 to 1994 , 64 patients ( median age 55.5 years ) with carcinomas of different subsites , excluding the nasopharynx , were treated in a pilot study with 1.2 Gy bid ( 6 h interval ; total dose 74.4 Gy ) and simultaneous CDDP ( 20 mg/m2 daily , 5 days in week 1 and 5 ) and followed at regular intervals . Overall survival and local control , as well as the rates of late toxicity , were estimated using the actuarial method . Median follow-up was 3.3 years for all and 5.2 years for surviving patients . To assess the quality of life , the EORTC QLQ-C 30 question naire and the H&N35 module question naire were sent to the patients surviving with no evidence of disease or second primary tumors ; they were answered by 15/23 ( 67 % ) . Results Overall survival was 37 % at 5 years , whereas disease-specific survival was 59 % . Twenty-three patients died from uncontrolled head and neck cancer . Second primary tumors were observed in 13 patients , most frequently in the lung . Local control without salvage surgery was 74 % at 5 years for all subsites and stages , and loco-regional disease-free survival was 72 % . Eleven patients developed distant metastases , which was the only site of failure in 6 cases . Salvage surgery was successful in 2 cases . The actuarial estimates of ≥ grade -3 late toxicity was 4 % for the m and ibular bone and 23 % for dysphagia , and 50 % of the patients experienced a permanent xerostomy . Self-reported global quality of life in surviving patients was good ( mean 68 points on a scale 0 to 100 ) ; consequences of impaired salivary function had most impact on nutritional and social aspects . Conclusions Hyperfractionated RT with concomitant CDDP is well tolerated and highly efficient in controlling moderately advanced to advanced cancers of the head and neck . Second primary tumors are the main cause of death after 3 years and were observed outside of the irradiated area , most frequently in the lung . Even after RT of large volumes to a high dose , salvage surgery can be successfully performed in individual cases . Self-reported quality of life of surviving patients is good , despite xerostomy-associated nutritional difficulties . ZusammenfassungZielAnalyse der Überlebensrate , des krankheitsspezifischen Überlebens , des Rezidivmusters , der Spättoxizität sowie der subjektiven Lebensqualität nach hyperfraktionierter Radiotherapie ( RT ) und gleichzeitiger Cisplatin-Chemotherapie ( CDDP ) bei Patienten mit mindestens zwei Jahren Beobachtungszeit i m Rahmen einer prospektiven Phase-II-Studie . Patienten und Method eIm Rahmen einer Pilotstudie ( 1988 bis 1994 ) wurden 64 Patienten ( medianes Alter 55,5 Jahre ) mit Stadium III oder IV kombiniert beh and elt :  RT 1,2 Gy zweimal täglich bis 74,4 Gy , CDDP 20 mg/m2 täglich an den Tagen 1 bis 5 der ersten und fünften Woche . Die Überlebenskurven sowie die Toxizität wurden aktuariell berechnet . Die mediane Beobachtungszeit war 3,3 Jahre für alle respektive 5,2 Jahre für die überlebenden Patienten . Zur Einschätzung der Lebensqualität wurden 23 tumorfrei überlebende Patienten angefragt , den EORTC-QLQ-C30-Fragebogen sowie das ergänzende Modul für Kopf-Hals-Tumoren H&N35 auszufüllen . ErgebnisseDas Gesamtüberleben betrug nach fünf Jahren 37 % , während das krankheitsspezifische Überleben mit 59 % deutlich höher lag . 23 Patienten sind am Tumor verstorben . Zweittumoren , hauptsächlich Lungenkarzinome ( n=8 ) , wurden bei 13 Patienten registriert und waren die hauptsächliche Todesursache nach über drei Jahren . Die lokale Tumorkontrolle ohne zusätzliche Chirurgie betrug 74 % nach fünf Jahren und war für alle Lokalisationen und Stadien gleich ; die lokoregionäre Tumorkontrollrate lag bei 64 % . Fernmetastasen ohne ein lokoregionäres Therapieversagen wurden bei sechs Patienten gesehen . Eine „ Rettungschirurgie ” wurde in zwei Fällen erfolgreich durchgeführt . Die aktuarielle Spätkomplikationsrate ≥ Grad 3 betrug 4 % für den Kieferknochen und 23 % für Dysphagie ; 50 % der Patienten hatten eine bleibende komplette Xerostomie . Die globale Lebensqualität war gut ( i m Mittel 68 Punkte auf einer Skala von 0 bis 100 ) . Folgen der gestörten Speichelsekretion hatten die größte Auswirkung auf die funktionelle Behinderung der Ernährung sowie der sozialen Kontakte . SchlußfolgerungenDie hyperfraktionierte RT mit gleichzeitiger CDDP-Gabe wird hinsichtlich Spättoxizität gut toleriert und ist effizient zur Beh and lung fortgeschrittener Kopf-Hals-Tumoren . I m Gegensatz zu chirurgischen Serien treten Zweitkarzinome praktisch nur außerhalb des ursprünglichen Tumorbereichs auf . Eine „ Rettungschirurgie ” nach initialem Therapieversagen ist auch nach RT mit 74,4 Gy in Einzelfällen erfolgreich . Die selbstrapportierte Lebensqualität bei den Langzeitüberlebenden ist generell gut trotz gewisser , vorwiegend xerostomiebedingter Einschränkungen BACKGROUND AND PURPOSE Radiation therapy is often the primary treatment for advanced cases of head and neck cancers not considered suitable for radical surgery . In these cases locoregional tumour control rates are low and has warranted innovative treatment modifications , such as altered fractionation schedules and combination with chemotherapy . PATIENTS AND METHODS From October 1990 to December 1997 , 239 patients with squamous cell cancers originating in the head and neck region were r and omized to one of three treatment options . St and ard therapy consisting of conventional fractionation with 70 Gy in 7 weeks in 35 fractions ( CF ) . The second treatment option consisted of a continuous hyperfractionated accelerated radiotherapy delivering a total dose of 55.3 Gy in 33 fractions over 17 consecutive days ( V-CHART ) . The third study arm had identical fractionation and dose as the above accelerated treatment , with the additional administration of 20 mg/m(2 ) mitomycin C ( MMC ) on day 5 of treatment ( V-CHART+MMC ) . RESULTS Main toxicity result ed from accelerated fractionation in confluent mucositis ( Grade 3 - 4 in 95 % ) requiring nasogastral tube feeding , analgetics and antiphlogistics in the majority of cases . Haematological toxicity Grade 3 - 4 was seen after MMC administration in 18 % . MMC administration did not influence mucosal reaction . Overall duration of mucositis was not different in the three treatment groups . Loco-regional tumour control was 31 % after CF , 32 % after V-CHART and 48 % after V-CHART+MMC , respectively ( P<0.05 ) . Overall crude survival was 24 % after CF , 31 % following V-CHART and 41 % after V-CHART+MMC , respectively ( P<0.05 ) . Median follow up was 48 months ( assessment performed in February 1999 ) . CONCLUSION Following shortening overall treatment time from 7 weeks to 17 consecutive days and dose of radiotherapy from 70 to 55.3 Gy the results in the radiotherapy only treated patients are identical . A significant improvement regarding local tumour control and survival was seen following administration of MMC to the accelerated fractionated treatment Size and extent of a primary tumor strongly influences its response to irradiation . In order to investigate the relevance of this statement a r and omized study was carried out in which irradiation of advanced carcinoma of head and neck was compared with a combined treatment where preirradiation intraarterial chemotherapy was administered in order to reduce the extent of the tumor . Intra‐arterial chemotherapy ( MTX 3–5 mg/day for 25–35 days ) was given to 72 cases with lesions in the oral cavity , the oropharynx and maxillary antrum . Depending on response the patients were restaged and su bmi tted to radiotherapy . In 68 other cases r and omly allocated , radiotherapy only was given with the same modality and technique . After chemotherapy 21 cases with intraoral and 14 cases with maxillary antrum and oropharynx cancers were classified Stage I and II ( 0 and 23 , respectively , before treatment ) . Results after 4 years follow up showed both local control and survival statistically better in the combined treatment in intraoral cancer where irradiation was delivered by a combination of external and interstitial technique . In the other cases no statistically significant difference was found . Amelioration of the results in the oral cavity could be ascribed to the greater use of interstitial irradiation due to the tumor shrinkage obtained with preirradiation chemotherapy more than to some synergistic effect between drug and irradiation . In 8 cases tumor cell kinetics were performed and the nuclear DNA content measured , but none of the kinetic parameters could be correlated with the response to treatment , even when the cancers were grouped according to their clinical growth characteristics . Late results in the irradiation of head and neck cancer probably depends on the presence of some resistant component which can not be predicted by the cell kinetic or nuclear DNA content . Surgical excision or a second course of chemotherapy must be considered as a part of the multimodality treatment The ability of surgery and radiotherapy to control advanced squamous cell carcinoma of the head and neck has reached its maximal potential . We initiated a r and omized , prospect i ve , stratified study of adjuvant chemotherapy .  Patients with stage II disease of the pyrlform sinus and stage III and IV disease of the oral cavity , larynx , hypopharynx , oropharynx , nasopharynx , and paranasal sinuses were eligible . Patients were r and omized to receive either st and ard therapy alone or two courses of 5-fluorouracil ( B-CMF ) chemotherapy prior to and two courses after the completion of st and ard therapy . St and ard therapy consisted of preoperative irradiation followed by radical surgery . Of 133 patients with advanced disease , 83 were included In the study —43 In the chemotherapy group and 40 In the control group .  Rates of residual and recurrent disease , as well as distant metastases , were similar for the two groups . The survival rates of patients without persistent disease at the end of treatment showed no significant difference for the two groups . The study has been discontinued because statistical analysis Indicated that the addition of more patients would not material ly Increase the statistical significance of the study Combination chemotherapy with CDDP and 5-FU is one of the effective regimens for head and neck cancer . We studied the difference in the effects and adverse effects between two kinds of schedules of CDDP administration for CDDP-5-FU combination chemotherapy . For 13 patients , CDDP was administered on 5 consecutive days from day 1 to day 5 at a daily dose of 16 mg/m2 ( Regimen A ) . For 14 patients  CDDP was administered 80 mg on day 1 ( Regimen B ) . 5-FU was administered 700 mg/m2/ day as a continuous drip infusion for 120 hours from day 1 to day 5 . For regimen A , the response rate was 77 % ; for regimen B , it was 64 % . The pattern of adverse effects showed a difference . Regimen B was more toxic for renal function than regimen A. But regimen A showed toxicity for bone marrow function . Acute phase nausea and vomit appeared more frequently in regimen B. The difference in the adverse effect pattern , which depends on the schedule of CDDP administration , seems important in order to apply this regimen for head and neck cancer patients safely . The schedule of CDDP administration should be changes depending on the renal and bone marrow function of patients . In order to evaluate the efficacy of UFT as adjuvant chemotherapy , UFT was administered p.o . to patients with maxillary sinus carcinoma for more than one year after definitive treatment with surgery or radiotherapy . Fifteen patients with UFT adjuvant chemotherapy  showed significantly better survival rates than patients without adjuvant chemotherapy . We also studied adjuvant chemotherapy with CBDCA and FT for patients with advanced head and neck cancer . Administration with UFT ( 600 mg/day ) from day 1 to day 14 with CBDCA 350 mg/m2 at day 7 was repeated more than twice . This regimen showed low toxicity and better survival for nasopharyngeal cancer patients . More clinical trials with this regimen for adjuvant chemotherapy are needed From March 1983 to June 1986 , 100 patients with locally advanced squamous cell carcinoma of the head and neck were r and omized to receive either two courses of chemotherapy prior to local therapy ( group A ) , or local therapy alone ( group B ) . Local treatment consisted of primary radiotherapy in all patients . When a poor response was observed after 55 Gy , surgery was performed . The chemotherapy regimen was a combination of cisplatinum , bleomycin , vindesine , and mitomycin C. The response rate to induction chemotherapy ( group A ) was 50 % for the primary tumor ( CR : 10 % and PR : 40 % ) . At the end of radiotherapy , the overall tumor response rates in the two groups A and B , were 77 % and 79 % respectively . Complete disappearance of the primary tumor occurred more often than that of the lymph node metastases . The response rate to  induction chemotherapy  for lymph node metastases was 27.1 % ( CR : 9 % and PR : 18.1 % ) . An initial major response to chemotherapy predicted subsequent efficacy of irradiation on 90 % of the cases , while a failure of chemotherapy had no predictive value in this respect . The survival rates in groups A and B were 66.5 % vs. 65.1 % at 1 year and 35 % vs. 46.2 % at 2 years . Local disease-free and disease-free intervals were similar in both groups . A Cox 's multi-step regression analysis revealed two significant independant prognostic factors : size of primary tumor and nodal status . After adjustment for these factors , the chemotherapy did not seem to improve the effectiveness of the local treatment in terms of loco-regional control and survival Initial combination drug regimens containing Cisplatin in patients with stage III and IV head and neck cancer produce a high percentage of clinical response . We initiated the current trial to assess the role of multimodality treatment ( CT plus RT ) versus CT alone in eliciting tumour response rates , and the duration of tumour free survival . Patients were r and omised to CT followed by RT ( arm A : 36 patients ) or CT alone ( arm B : 44 patients ) . Of 96 patients entered into this study 80 are evaluable at the time of analysis . There were 13 women and 67 men with a median age of 52 years and a median performance status of 90 % . All of them presented measurable stage T4N0 - 3M0 - 1 or T3N2 - 3M0 - 1 carcinomas . The chemotherapy consisted of Cisplatinum , Bleomycin and Methotrexate and was given in 2 cycles over 35 days . Local radiotherapy with 6,000 rad followed . In arm B , 3 cycles of chemotherapy were given without radiotherapy . The overall tumour responses after CT were 75 % in arm B , and 70 % in arm A. After RT the tumour response fell to 59 % . Median tumour remission was 4 months and median survival 11 months . Toxic effects were mild mainly consisting of alopecia , nausea and vomiting . Myelotoxicity was moderate , but significant renal or ototoxic side effects did not occur . 10 cases of Bleomycin related pulmonary fibrosis were found . Our main findings show that patients receiving 2 cycles of CT do not have a statistically shorter survival compared to those who were treated by CT plus RT 5522 Background : The EORTC 24971 trial compared the efficacy and safety of two neoadjuvant regimens in the treatment of stage III or IV , M0 SCCHN . Eligible patients ( pts ) with primary tumor sites in the oral cavity , oropharynx , hypopharynx , and larynx and WHO performance status ( PS ) ≤1 ) were r and omized to 2 - 4 cycles  of cisplatin ( P ) 100 mg/m2 day 1 , followed by a continuous infusion of 5-fluorouracil ( F ) 1000 mg/m2/day from days 1- 5 ( PF ) , or T 75 mg/m2 + P 75 mg/m2 day 1 then F 750 mg/m2/day from days 1 - 5 ( TPF ) , followed by locoregional radiation therapy ( RT ) . The impact of the two regimens on QoL was a secondary endpoint . METHODS QoL was assessed at baseline , at cycles 2 and 4 , and 6 and 9 months after RT using the EORTC QLQ-C30 question naire to obtain the Global Health Status/ Quality of Life ( GHS/QoL ) score , and the Head and Neck Performance Status Scale ( PSS-HN ) to assesses the normality of diet , eating in public , and underst and ability of speech on a scale of 0 to 100 . The EORTC QLQ-HN35 question naire was also administered at those time-points . RESULTS 358 pts were r and omized to PF ( 181 pts ) or TPF ( 177 pts ) .  Baseline ( BL ) characteristics of the pts were well balanced between groups . TPF was superior to PF in terms of response rate , progression-free survival ( primary endpoint ) , overall survival , and tolerability . Compliance with the QLQ-C30 question naire was good ranging from 96 % at BL to 41 % at 9 months post RT , and was similar between the treatment arms . GHS/QoL scores were comparable at BL between the two arms ( p = 0.54 ) and improved in both arms on starting treatment . Over time this score remained stable with TPF , but decreased after RT with PF ( treatment-time interaction : p = 0.009 ) . Evolution of the PSS-H&N score was better on TPF ( normality of diet p= 0.0064 ; eating in public p = 0.0004 ; underst and ability of speech p = 0.0003 ) . Moreover , TPF was associated with a 30 % reduction in  the risk of WHO PS deterioration ( p = 0.0158 ) Conclusions : The use of docetaxel in neoadjuvant treatment of SCCHN improves efficacy without deleterious effects on QoL and functional outcomes . [ Table : see text ] From January 1981 through December 1983 , 49 untreated patients with locally advanced head and neck cancers were r and omized in two groups to receive different radiochemotherapy regimens . Group A , including 29 cases , received 4 cycles of induction chemotherapy with Bleomycin , Methotrexate and Hydroxyurea before definitive external radiotherapy ( 60 Gy ) ; group B , including 20 patients , received the same total dose of radiotherapy but the 4 cycles of chemotherapy , as described above , were administered between the 20- and the 40-Gy doses . Both groups were compared with a control group treated in the same period with radiotherapy ( 60 Gy ) alone . The response to treatment was evaluated at the end of chemotherapy or radiotherapy alone and at the end of combined regimens . Long-term survival rates were analyzed for all groups relative to complete tumor response , disease-free interval and time to disease progression . In our experience the radio-chemotherapy combination , according to the described schedules , failed to improve both local control and overall survival ; the comparison with the control group does not suggest that induction or intercalated chemotherapy can increase long-term survival even if initial complete and partial response rates are high 44 patients with advanced squamous cell carcinoma of the head and neck were r and omized and treated preoperatively either with arm " A " : cis-DDP ( 3 mg/kg iv day 1 ) and BLM ( 15 - 20 mg iv continuously day 2 - 6 ) or arm " B " : MTX ( 30 mg/m2 iv day 1 + 6 ) and VDS ( 3 mg/m2 iv day 2 + 7 ) . Treatment with arm " A " was superior producing 73 % complete and partial remissions ( CR + PR ) compared to 40 % for arm " B " ( p = 0,05 ) . The number of patients with CR could be increased from 2 to 26 by surgery and /or radiotherapy . The median survival for patients with chemotherapeutically induced CR and PR was 16 months but this did not differ significantly from the median survival ( 13 months ) of non responders ( p = 0.25 ) . For patients with CR and PR achieved by surgery and /or x-ray therapy the median survival point has not yet been reached , and this is significant compared to the non responders ( p = 0.001 ) . Five of 26 patients with CR died after 39 months of observation and 6 are living with recurrence . In addition to clinical trials , chemotherapy is indicated for patients with inoperable tumours .  The value of chemotherapy can only be answered by r and omized trials comparing chemotherapy combined with st and ard procedures against surgery and radiotherapy alone A combination of cisplatin and 5-fluorouracil ( PF ) is considered the st and ard induction chemotherapy regimen for squamous cell carcinoma of the head and neck ( SCCHN ) . The present study compares the efficacy and safety of a new combination of cisplatin/docetaxel versus the PF regimen . A total of 83 chemotherapy-naive patients with locally advanced SCCHN were r and omised to receive every 21 d ( i ) docetaxel 85 mg/m2 i.v . on day 1 and cisplatin 40 mg/m2 i.v . on days 1 and 2 ( arm A ) or ( ii ) cisplatin 100 mg/m2 i.v . on day 1 followed by 5-fluorouracil 1000 mg/m2 in 24 h continuous infusion for 5 d ( arm B ) . A total of 287 cycles ( range 1 - 3 per patient ) were administered . Among 76 patients evaluable for response , the overall response rate in arm A was 70 % ( complete response ( CR ) 26 % , partial response ( PR ) 44 % ) and in arm B 69 % ( CR 16 % , PR 54 % ) , respectively . Median survival in arm A was 7.6 months ( 95 % CI : 5.8 - 11.1 ) and 9.9 months ( 95 % CI : 7.4 - 14.6 ) for arm B. The most frequent grade 3/4 toxicity in arm A was neutropaenia ( 34.1 % ) and diarrhoea ( 9.8 % ) versus mucositis ( 29.3 % ) and neutropaenia ( 19.5 % ) in arm B. Both schedules present a similar efficacy , with different but acceptable toxicity patterns Summary A phase III 2x2 factorial trial of cisplatinum and bleomycin in 116 patients with recurrent or advanced squamous cell carcinoma of the head and neck is reported . Thirty percent of patients proved to be unfit for chemotherapy , and of those treated progression of tumour was the commonest “ response ” . However , 25 % of patients achieved a partial or complete response , with no significant difference in response rates between the treated arms . The median number of courses received was 1 ( range 0–6 ) and the commonest causes for discontinuation of treatment were renal toxicity and death .  Bleomycin  reduced survival , but not significantly so , whereas cisplatinum  prolonged median survival significantly by 10 weeks . Significant predictors of survival , in addition to treatment by cisplatinum , were age , performance status , N status , number of courses and response of the tumor Forty-six patients with squamous cell carcinoma of the head and neck region were r and omized to either irradiation or irradiation plus bleomycin . If possible , the patients later underwent radical surgery . In the bleomycin group , significantly fewer patients had remaining tumour cells in the tissue removed at operation , and a longer time elapsed before recurrences occurred . However , bleomycin had no significant effect on the 3- and 5-year survival rates , and it did not significantly reduce the incidence of local recurrences 5515 Background : we have previously reported that ICT plus CRT is more active than CRT alone in pts with unresectable LAHNC ( Hitt et al : ASCO 2005 , abstract 5578 ) . Here we present new data of efficacy and time to progression ( TTP ) in this trial . METHODS Patients : eligible pts included those with unresectable LAHNC , measurable disease , adequate organ function and ECOG 0 - 1 . Pts were stratified according to primary tumor site . TREATMENT Induction chemotherapy regimens ( 3 cycles ) : PF : P 100 mg/m2 day ( d ) 1 , then F 1000 mg/m2 c.i . d1 - 5 q 21d ; TPF : T 75 mg/m2 d1 , P 75 mg/m2 d1 , F 750 mg/m2 c.i . d 1 - 5 q 21 d plus G-CSF and ciprofloxacin . Chemoradiotherapy : conventional RT up to 70 Gy plus P 100 mg/m2 d 1 - 22 - 43 Results : Patients : a total of 310 pts have been accrued . Pts/tumor characteristics ( ECOG , age , primary site , T/N stage ) were well balanced among the three arms . T/N stage : T3 - 4 ( 88 % ) ; N2 - 3 ( 63 % ) ; pharynx-oropharynx site ( 62 % ) . TREATMENT Median number of cycles of ICT : 3 ; median dose of RT : 70 Gy , median number of cycles of P during RT in three arms : 3 . EFFICACY Complete Response : 70 % ( ICT + CRT ) vs. 49 % ( CRT alone ) ( p = 0.01 ) . The response rate was similar between TPF and PF . Time to progression ( TTP ) in months : 16 ( TPF + CRT ) ; 12 ( PF + CRT ) vs 8 ( CRT alone ) ( log-Rank= 0.02 ) . G 3/4 toxicity ( NCI criteria ): Febrile neutropenia : 21 % ( TPF ) ; mucositis : 10 % ( PF ) . Mucositis was observed in 55 % ( TPF + CRT ) , 60 % ( PF + CRT ) and 36 % ( CRT alone ) of the pts , respectively Conclusions : The results of the present r and omised clinical trial demonstrate that the combination of ICT + CRT significantly increases the complete response rate and prolongs TTP when compared to CRT alone in patients with unresectable LAHNC . No significant financial relationships to disclose The aim of this pilot study was to explore the prognostic relevance of cell kinetics parameters on the local control of patients affected by head and neck squamous cell carcinoma ( HN-SCC ) , r and omly assigned to receive either alternating chemoradiotherapy or partly accelerated radiotherapy . Between 1992 and 1995 , 40 patients with HN-SCC at stages III and IV entered the study . Multiple primary tumor biopsies were obtained 6 h after in vivo infusion of bromodeoxyuridine , an analogue of thymidine that is incorporated in DNA-synthesizing cells . In vivo S-phase fraction labeling index ( LI ) , duration of S-phase ( TS ) , and potential doubling time ( Tpot ) were obtained by analysis of the flow cytometric content of bromodeoxyuridine and DNA . Twenty patients were treated by alternating chemotherapy and conventional radiotherapy ( arm A ) , whereas 20 other matching patients received partly accelerated radiotherapy alone ( arm B ) . Univariate local control analysis showed that LI , TS , and Tpot were not prognostically significant in either arm . However , local control probability at 2 years for fast growing tumors , characterized by a LI of 9 % , was higher for patients treated with alternating chemoradiotherapy than it was for those treated with partly accelerated radiotherapy alone ( 68 versus 39 % ) . Conversely , local control probabilities for slow proliferating tumors ( LI , < 9 % ) treated in the two arms were similar . These results suggest a potential role for alternating chemotherapy and radiotherapy in HN-SCC patients with fast growing tumors Abstract A r and omised and controlled clinical study comparing cobalt plus bleomycin ( 3000 rad/180 mg bleomycin ) with cobalt plus placebo has been carried out in 29 patients with moderately to highly differentiated squamous cell carcinomas of the head and neck . The treatment was given prior to radical surgery and all specimens examined histologically after serial section . No differences iin side-effects , operative difficulties or delayed healing were encountered between the groups . Tumour response based on clinical and histological criteria was clearly in favour of preoperative treatment with cobalt plus bleomycin compared to cobalt plus placebo . However , by histological examination in serial sections of the operative specimen residual tumour was present in a rather high proportion in both groups . The histological findings also throw doubt on the specificity of the previously reported histological changes following bleomycin treatment . The necessity of radical surgery in addition to preoperative treatment with cobalt plus bleomycin is stressed BACKGROUND AND PURPOSE In 1986 a prospect i ve , r and omized , multi-centre trial for evaluation of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in the treatment of advanced squamous cell carcinoma of the head and neck was initiated . As survival in this group of patients is poor the purpose was to find a possible survival benefit of the chemotherapy in addition to radiotherapy compared to radiotherapy only . METHODS Four-hundred sixty-one patients from Denmark , Norway and Sweden with tumors in oral cavity , oropharynx , hypopharynx and larynx were r and omized to receive either st and ard treatment ( radiotherapy or radiotherapy followed by surgery ) or neoadjuvant chemotherapy followed by st and ard treatment . Chemotherapy included three courses of cisplatin 100 mg/m2 i.v . infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v . infusion for 120 hours . Radiotherapy 64 - 70 Gy in 2 Gy per fraction , 5 times/week , was given to patients in both treatment arms . RESULTS Response rate was 71 % for patients r and omized to chemotherapy-radiotherapy and 66 % for patients r and omized to st and ard treatment ( not statistically significant ) . Residual tumors were excised if possible . After surgery 62 % of the patients r and omized to chemotherapy-radiotherapy and 60 % of the patients in the st and ard treatment group were clinical ly tumor free . CONCLUSIONS No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy . Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment A prospect i ve r and omized study was conducted in 77 patients with stages III and IV epidermoid carcinomas of the buccal cavity , oropharynx , and pharyngolaryngeal regions to compare effects of two induction chemotherapy regimens : cisplatinum , methotrexate , bleomycin , and oncovin , methotrexate , bleomycin .  Tumoral response and complications were analyzed as a function of the regimen , the tumoral site , and the stage . Chemotherapy including cisplatinum provided a tumoral response in 58.8 p.cent of stage III pharyngolaryngeal epitheliomas as against 38.4 p.cent with oncovin , methotrexate , bleomycin , but with a higher frequency of complications Combination chemotherapy with CDDP and 5-FU is one of the most effective regimens for head and neck cancer . Recent studies have focused on biochemical modulation in the combination of CDDP and 5-FU . We studied the difference in effectiveness and adverse effects between two CDDP administration schedules for CDDP-5-FU combination chemotherapy . For regimen A , CDDP was administered on 5 consecutive days from day 1 to day 5 , with a daily dose of 16 mg/m2 . For regimen B , CDDP was administered at 80 mg/m2 on day 1 . 5-FU was administered at 600 mg/m2/day in a continuous drip infusion for 120 hours from day 1 to day 5 for regimens A and B. Twenty-seven patients with head and neck squamous cell carcinoma were included in this study , and received either regimen A or B. Thirteen patients were given regimen A and 14 regimen B. With regimen A , 3 patients showed CR and the response rate was 76.9 % . With regimen B , 3 patients showed CR and the response rate was 64.3 % . The rates of efficacy were not different between regimen A and B. In contrast , a difference was seen with organ toxicity . Regimen B was more toxic for renal function than regimen A , while regimen A showed greater toxicity to bone marrow function . Acute nausea and vomiting were observed more frequently with regimen B. The difference in organs and symptoms of adverse effects , according to the schedule of CDDP administration would seem to be important in the treatment of head and neck cancer patients . The schedule of CDDP administration should be adjusted depending on the renal and bone marrow functions of the patients . Because multiple infusion of CDDP proved to be efficacious , low-dose CDDP and 5-FU will have a role for patients with head and neck squamous cell carcinoma . We also introduce other reports on the efficacy of low-dose CDDP and 5-FU Between December 1982 and October 1986 , 131 patients with stage II‐III‐IV squamous cell carcinoma of the oropharynx or oral cavity were r and omized to induction chemotherapy , consisting of bleomycin ( 10 mg/m2/day in continuous infusion from day 1 to day 5 ) , methotrexate ( 120 mg/m2 on day 2 ) followed by folinic acid , 5‐fluorouracil ( 5 FU ) ( 600 mg/m2 on day 2 ) , and cisplatin ( 120 mg/m2 on day 4 ) every 4 weeks for a total of three cycles followed by definitive locoregional treatment versus locoregional treatment alone . The modalities of definitive treatment ( radiotherapy ± surgery ) were chosen prior to r and omization . A total of 116 patients were evaluable . Of 55 patients in the chemotherapy arm , four ( 7 % ) had a complete response ( CR ) and 23 ( 42 % ) a partial response ( PR ) following the induction regimen . At the completion of locoregional treatment , 76 % ( 42 of 55 ) of patients in the experimental group were in CR compared to 89 % ( 54 of 61 ) in the control group . There was no difference in survival , cause‐specific survival , and pattern of relapse between both groups . The median survival was 22 months in the chemotherapy group and 29 months in the control group . Responders to chemotherapy did not fare better than nonresponders . Chemotherapy‐related toxicities were few and most of them related to cisplatin which was reduced to 100 mg/m2 for 35 patients . There were no treatment‐related deaths and , in the experimental arm of the trial , no increased morbidity from locoregional treatment . This induction regimen does not offer any advantages over st and ard treatment PURPOSE In a prospect i ve r and omized clinical study , simultaneous postoperative application of irradiation ( RT ) , mitomycin C , and bleomycin was tested in a group of patients with operable advanced head- and -neck carcinoma . It was expected that the planned combined postoperative therapy would reduce the number of locoregional recurrences and prolong survival . METHODS AND MATERIAL S A total of 114 eligible patients with Stage III or IV squamous cell head- and -neck carcinoma were r and omized to receive  postoperative RT alone ( Group 1 ) or RT combined with simultaneous mitomycin C and bleomycin ( Group 2 ) . Patients were stratified according to the stage and site of the primary tumor and the presence or absence of high-risk prognostic factors . Primary surgical treatment was performed with curative intent in all patients . Patients in both groups were postoperatively irradiated to the total dose of 56 - 70 Gy . Chemotherapy included mitomycin C 15 mg/m(2 ) after 10 Gy and 5 mg of bleomycin twice a week during RT to the planned total dose of 70 mg . RESULTS At 2 years , patients in the radiochemotherapy group had better locoregional control ( 86 % ) than those in the RT alone group ( 69 % ; p = 0.037 ) . Disease-free survival and overall survival was also better in the radiochemotherapy group compared with the RT-alone group ( 76 % vs. 60 % , p = 0.099 ; and 74 % vs. 64 % , p = 0.036 , respectively ) . Patients who benefited from chemotherapy were those with high-risk factors . CONCLUSION The results of the present study indicate that concomitant postoperative radiochemotherapy with mitomycin C and bleomycin improves locoregional control and survival in patients with advanced head- and -neck carcinoma . The patients who benefited from chemotherapy were those with high-risk factors Summary Treatment results of irradiation as a single treatment for advanced stage IV unresectable head and neck cancer remains uniformly poor and apparently has not changed with the most recent improvements in oncological care . Despite several negative results of r and omized studies , neoadjuvant or concomitant chemotherapy and radiotherapy seems to improve the number of complete responses and also the duration of disease-free survival . The present study was design ed to determine the feasibility , potential risks and benefits of the two methods of combined treatment and radiotherapy alone on the management of advanced unresectable squamous cell carcinoma of the upper respiratory and digestive system . From 1983 to 1986 , 90 patients entered the trial . Thirty patients were r and omized to each study group : radiotherapy alone ( 70 Gy ) ; neoadjuvant chemotherapy ( vinblastine , mitomycin , cisplatin , and bleomycin ) and radiotherapy ; concomitant chemotherapy ( cisplatin and bleomycin ) and radiotherapy . An increased frequency of complete responses ( 33 % ) was seen in patients treated with the two different combinations of chemotherapy and irradiation compared to irradiation alone ( 10 % ) . However , toxicity was more common in patients treated with the two modalities of combined treatment and there were no differences in overall survival rates ( P = 0.706 ) BACKGROUND We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer . METHODS After undergoing surgery with curative intent , 167 patients were r and omly assigned to receive radiotherapy alone ( 66 Gy over a period of 6 1/2 weeks ) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1 , 22 , and 43 of the radiotherapy regimen . RESULTS After a median follow-up of 60 months , the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( P=0.04 by the log-rank test ; hazard ratio for disease progression , 0.75 ; 95 percent confidence interval , 0.56 to 0.99 ) , with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent , respectively . The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group ( P=0.02 by the log-rank test ; hazard ratio for death , 0.70 ; 95 percent confidence interval , 0.52 to 0.95 ) , with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent , respectively . The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group ( P=0.007 ) . The estimated five-year cumulative incidence of local or regional relapses ( considering death from other causes as a competing risk ) was 31 percent after radiotherapy and 18 percent after combined therapy .  Severe ( grade 3 or higher ) adverse effects were more frequent after combined therapy ( 41 percent ) than after radiotherapy ( 21 percent , P=0.001 ) ; the types of severe mucosal adverse effects were similar in the two groups , as was the incidence of late adverse effects . CONCLUSIONS Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications Seventy-two patients with advanced squamous-cell carcinomas of the head and neck were r and omised to receive weekly intravenous methotrexate at doses of either 50 mg/m2 ( low dose ) , 500 mg/m2 ( medium dose ) , or 5 g/m2 ( high dose ) . Patients who failed to respond after four treatments at their initial dose were given four further treatments at the next higher dose . There were two complete responses and 21 partial responses to the initial dose -- in 10 out of 22 patients given the high dose , seven out of 27 given the medium dose , six out of 23 given the low dose . A further five out of 16 patients responded after crossing over to a higher dose . Toxicity was more severe with the high-dose regimen . Responders survived significantly longer than non-responders ( p less than 0.05 ) , but there was no significant difference in duration s of survival among the three treatment groups . Analysis of patients who completed the first four treatments indicated an improved response rate and duration of survival for the high-dose group . Because of toxicity associated with high-dose methotrexate this treatment produces no overall greater benefit than low-dose regimens BACKGROUND Management of advanced head and neck carcinoma is a challenging proposition . Presently concomitant chemo-irradiation has become the st and ard of care in such patients . Many chemotherapeutic drugs have shown radio-sensitising effects when used concomitantly along with radiation . The present study was carried out with the objective of assessing the feasibility and efficacy of low dose gemcitabine as radiosensitizer when used during radical radiotherapeutic management of patients with locally advanced head and neck carcinomas . PATIENTS AND METHODS From November 2000 to March 2003 , eighty histopathologically proven cases of squamous cell head and neck carcinoma were included in this trial , 40 patients were r and omly assigned to receive radiotherapy alone and 40 patients to receive gemcitabine along with radiotherapy .  RESULTS All patients were assessable for toxicity and response . Severe mucositis ( WHO level 5 reactions were observed in 67 % patients in the CT/RT group vs 16 % patients in the RT only group . No severe hematological toxicity was seen . The rates of complete and partial responses were 42.5 % & 57.5 % respectively for RT only and 62.5 % & 37.5 % , respectively for CT/RT group . There was no significant difference in the response rates at the end of treatment but disease free survival at three years was better in the CT/RT group ( 63.3 % vs 20 % ) . Nine of the 17 patients with complete response in the radiation only group developed relapse while no relapses were seen in CT/RT group . CONCLUSION In the present study the combination of gemcitabine and radiotherapy has not shown any statistical difference in locoregional control but survival advantage was seen as compared to radiotherapy alone . At the same time more mucosal and skin toxicity was encountered when Gemcitabine is given concurrently with radiation BACKGROUND We design ed a r and omized clinical trial to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV ( i.e. , advanced oropharynx carcinoma ) . METHODS A total of 226 patients have been entered in a phase III multicenter , r and omized trial comparing radiotherapy alone ( arm A ) with radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B , patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin ( 70 mg/m(2 ) per day ) and 5-fluorouracil ( 600 mg/m(2 ) per day ) by continuous infusion . The two arms were equally balanced with regard to age , sex , stage , performance status , histology , and primary tumor site . RESULTS Radiotherapy compliance was similar in the two arms with respect to total dose , treatment duration , and treatment interruption . The rate of grade s 3 and 4 mucositis was statistically significantly higher in arm B ( 71 % ; 95 % confidence interval [ CI ] = 54%-85 % ) than in arm A ( 39 % ; 95 % CI = 29%-56 % ) . Skin toxicity was not different between the two arms . Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were , respectively , 51 % ( 95 % CI = 39%-68 % ) versus 31 % ( 95 % CI = 18%-49 % ) and 42 % ( 95 % CI = 30%-57 % ) versus 20 % ( 95 % CI = 10%-33 % ) for patients treated with combined modality versus radiation therapy alone ( P = .02 and .04 , respectively ) . The locoregional control rate was improved in arm B ( 66 % ; 95 % CI = 51%-78 % ) versus arm A ( 42 % ; 95 % CI = 31%-56 % ) . CONCLUSION The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx The purpose of this study was to determine the feasible adjuvant therapy administration schedule of S-1 for locoregionally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . Patients receiving definitive treatments were r and omly assigned to either arm A ( 51 cases ) receiving oral S-1 of 2-week administration followed by 1-week rest for 6 months , or arm B receiving S-1 of 4-week administration followed by 2-week rest for 6 months . Planned treatment was given in 40 % of patients in arm A and 29 % in arm B. The cumulative rates of the relative total administration dose of S-1 at 100 % were 54.9 % ( 95 % CI : 40.1–69.7 % ) in arm A and 34.3 % ( 95 % CI : 21.1–47.4 % ) in arm B , respectively ( P=0.054 ) . Adverse events were recorded in 41 patients ( 82.0 % ) in arm A and 48 patients ( 94.1 % ) in arm B ( P=0.060 ) . The incidences of diarrhoea ( 10 vs 28 % ; P<0.05 ) and skin toxicities ( 18 vs 37 % ; P<0.05 ) were significantly higher in arm B. One-year disease-free survival was similar in both arms : arm A 81.2 % ( 95 % CI : 70.0–92.4 % ) ; arm B 77.0 % ( 95 % CI : 65.0–89.0 % ) . The schedule of 2-week administration followed by 1-week rest seems to be more feasible for oral 6-month administration of S-1 in adjuvant chemotherapy of locoregionally advanced SCCHN BACKGROUND Radiotherapy is often the primary treatment for advanced head and neck cancer , but the rates of locoregional recurrence are high and survival is poor . We investigated whether hyperfractionated irradiation plus concurrent chemotherapy ( combined treatment ) is superior to hyperfractionated irradiation alone . METHODS Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily , for a total of 7500 cGy . Patients in the combined-treatment group received 125 cGy twice daily , for a total of 7000 cGy , and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation . Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy . RESULTS Of 122 patients who underwent r and omization , 116 were included in the analysis . Most patients in both treatment groups had unresectable disease . The median follow-up was 41 months ( range , 19 to 86 ) . At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group ( P=0.07 ) . The relapse-free survival rate was higher in the combined-treatment group ( 61 percent vs. 41 percent , P=0.08 ) . The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group ( P=0.01 ) . Confluent mucositis developed in 77 percent and 75 percent of the two groups , respectively . Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group . CONCLUSIONS Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone From March 1983 to December 1989 , 208 patients with locally advanced squamous cell carcinoma of the head and neck were successively included into two r and omized induction chemotherapy trials . The chemotherapy regimen of the first trial , which included 100 patients , consisted of two cycles of a combination of cisplatin , bleomycin , vindesine and mitomycin C ; while that of the second trial , which included 108 patients , consisted of three cycles of a combination cisplatin , 5-fluorouracil by continuous infusion and vindesine . Local treatment was the same in the two trials : primary radiotherapy in all patients . The response was then evaluated ; in the case of a poor response at 55 Grays surgery was performed ; otherwise , radiotherapy was continued to full doses ( possibly followed by salvage surgery ) . The tumor and lymph node responses to chemotherapy  ( complete and partial response ) were higher in the second trial than in the first : 70 % versus 50 % for primary lesions , 47 % versus 25 % for lymph nodes . The toxicity of the two chemotherapy regimens was minimal . In the two trials , an initial major response to chemotherapy predicted subsequent efficacy of irradiation in 80 % of the patients . The significance of the complete response at the end of the irradiation varies with the previous response to the chemotherapy . With a median follow-up of 60 months with the first chemotherapy regimen and 30 months with the second , overall survival and disease-free interval were very similar in the two groups . The incidence of distant metastasis was significantly reduced ( p less than 0.03 ) with chemotherapy . This trial suggests the need to test new chemotherapy protocol s according to new schemes of treatment , with chemotherapy given concurrently with or following the completion of st and ard treatment by means of multicenter r and omized trials For several decades , both preoperative intra‐arterial chemotherapy and preoperative irradiation have been accepted treatments for patients with tumors of the head and neck . Unfortunately , arguments have often been put forward in favor of one or other of the two methods , but without the performance of an objective , r and omized investigation . To resolve this situation , the authors have carried out a multicenter , r and omized prospect i ve study of selected patients with a view to deciding which method affords better results in complex tumor therapy from the aspects of survival and postoperative quality of life BACKGROUND Concomitant chemoradiotherapy ( CT/RT ) is the st and ard treatment of locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . We evaluated the efficacy of induction docetaxel ( Taxotere ) , cisplatin , and 5-fluorouracil ( TPF ) before CT/RT versus CT/RT alone . PATIENTS AND METHODS Patients with stage III-IVM0 SCCHN , Eastern Cooperative Oncology Group performance status of zero to one , were r and omly assigned to receive CT/RT alone ( arm A : two cycles of cisplatin 20 mg/m(2 ) , days1 - 4 , plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , during weeks 1 and 6 of radiotherapy ) or three cycles of TPF ( arm B : docetaxel 75 mg/m(2 ) and cisplatin 80 mg/m(2 ) , day 1 , and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , every 3 weeks ) followed by the same CT/RT . The primary end point was the rate of radiologic complete response ( CR ) at 6 - 8 weeks after the end of CT/RT . RESULTS A total of 101 patients were r and omly allocated to the study ( 51 arm A ; 50 arm B ) . CR rates were 21.2 % ( arm A ) versus 50 % ( arm B ) . Median progression-free survival and overall survival were , respectively , 19.7 and 33.3 months ( arm A ) and 30.4 and 39.6 months ( arm B ) . Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms . CONCLUSION Induction TPF followed by CT/RT was associated with higher radiologic CR  in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility Three hundred and fifty-four patients with squamous cell carcinoma of the oral cavity , oropharynx , supraglottic larynx , hypopharynx or maxillary sinus have been r and omized for preoperative radiation therapy and surgery versus surgery and postoperative radiation therapy plus , in the case of patients with lesions of the oral cavity and oropharynx , radical radiation therapy . Data have been analyzed on 320 patients in this interim report . In the supraglottic larynx group local-regional control is significantly better for  surgery and postoperative radiation therapy .  The treatment differences in local-regional control in the oral cavity oropharynx and hypopharynx groups are not statistically significant . No statistically significant treatment differences exist for survival in all sites or in any site ; continued follow-up is necessary to make definite treatment comparisons Summary Retinoids , the analogs of vitamin A , are active in vitro and in vivo against squamous cell carcinoma in animals and against certain epithelial precancers and cancers in humans . These data led us to design a prospect i ve , multi-institutional , r and omized phase II trial of isotretinoin in advanced head and neck squamous cell carcinoma . We r and omly assigned 40 patients to receive isotretinoin or methotrexate , the best-studied and most active single agent for this disease . Overall , the study patients had extremely poor prognoses , i.e. , low performance statuses and recurring disease after surgery and /or irradiation . Three objective responses ( 16 % ) , including one complete response , occurred in the 19 evaluable isotretinoin-treated patients . Only one minor response ( 5 % ) occurred in the methotrexate-treated group . Toxicity occurred with both drugs , but was manageable and never life threatening in the retinoid group . These results and the established activity of retinoids in oral leukoplakia ( a precursor of head and neck cancer ) indicate the need for further study of this class of drugs in head and neck cancer A clinical trial comparing Bleomycin ( BLM ) plus radiation against radiation alone is reported . One hundred and fifty-seven previously untreated T3 and T4 and N0 , N1 or N2 buccal squamous cell carcinomas were entered . Eighty-four of these received the combined therapy and 73 were controls .  Cobalt-60 teletherapy using two opposing fields was employed . BLM was administered intra-arterially in 42 patients , intravenously in 22 patients and intramuscularly in 20 patients . The 73 controls received physiological saline as a placebo .  Total clinical healing of the lesion within the volume of irradiation eight weeks after the end of radiotherapy was termed a favourable response . Anything else was a failure . Five-year recurrence-free rates and disease-free survival were also evaluated . The favourable response rate in the study group was 78.6 % and in the control 19.1 % . The corresponding recurrence-free rates and five-year survival rates were 71.8 % and 17 % , and 65.5 and 23.5 % respectively . The main toxic features were acute mucositis , pneumonitis and dermatitis 5518 Background : Concomitant CT/RT is the st and ard treatment for LASCCHN . Induction chemotherapy followed by CT/RT vs CT/RT alone have not yet been compared . The feasibility of TPF followed by CT/RT has been evaluated in a previous study ( Int J Rad Oncol Biol Phys 2004 , 59:481 ) . METHODS Pts with inoperable stage III-IVa , PS 0 - 1 , were r and omized to CT/RT  [ 2 cycles of Cisplatin 20 mg/sqm days 1 - 4 , 5FU 800 mg/sqm 96 hours c.i . weeks 1 and 6 during RT ( 66 - 70 Gy ) ] ( Arm A ) or 3 cycles of neoadjuvant TPF ( Docetaxel 75mg/sqm day1 , Cisplatin 80mg/sqm day1 , 5FU 800mg/sqm 96 hours c.i ) followed by the same CT/RT ( Arm B ) . Pts were stratified according to tumor site , T stage and nodal status . Neck dissection was performed in N2-N3 patients with pathological CR on primary tumor . The planned sample size was 96 pts to detect a difference in CR ( primary endpoint ) up to 15 % in favour of arm B. The radiological responses were evaluated by an internal committee according to RECIST criteria . RESULTS Preliminary data are available for 84/96 r and omized pts ( 42 arm A , 42 arm B ) . Pts/tumor characteristics are well balanced in the two arms . Toxicities during induction TPF consisted primarily of G3 - 4 granulocytopenia 56 % ( febrile neutropenia : 7.5 % ) . Grade 3 - 4 toxicities during CT/RT in arm A and B were mucositis ( 42 % and 26 % ) , dysphagia ( 20 % and 9 % ) , skin reaction ( 12 % and 8.6 % ) , asthenia ( 5 % and 3 % ) ; G3 weight loss ( 2 % and 3 % ) , G3 dry-mouth ( 0 % and 3 % ) . Duration of CT/RT  was equivalent : 6.1 wks ( 4.2 - 8.7 ) in arm A and 6.3 wks ( 3.8 - 9.5 ) in arm B. At the end of CT/RT , in the 82 pts evaluable for efficacy , radiological CR were 20 % ( 95 % CI 8 - 37 % ) in arm A and 64 % ( 95 % CI 45 - 80 % ) in arm B. CONCLUSIONS Three cycles of neoadjuvant TPF are feasible and do n't compromise subsequent concomitant CT/RT with comparable toxicity pattern . At the end of the treatment sequence serious adverse events were 31 % in arm A and 34 % in arm B. The difference in CR of 40 % in favour of arm B justifies the following phase III study . Final results including pCR and DFS will be presented at the meeting . [ Table : see text ] PURPOSE To determine the prophylactic properties of amifostine against acute and late toxicities from radiochemotherapy in patients with head- and -neck cancer . METHODS AND MATERIAL S Fifty patients were r and omized to receive conventional radiotherapy ( RT ) ( 2-Gy fractions , 5 days weekly , to a total of 60 - 74 Gy , depending on the tumor localization and TNM classification ) and carboplatin ( 90 mg/m(2 ) infusion once per week before RT ) . Amifostine ( 300 mg/m(2 ) ) was administered in the study group only 15 - 30 min before RT for 6 - 7.5 weeks . The primary study end point was the grading of acute and late nonhematologic toxicities ( mucositis , dysphagia , xerostomia ) induced by radiochemotherapy . Secondary end points included treatment duration , hematologic toxicity , and clinical outcome . RESULTS The treatment duration was significantly shorter in the amifostine-treated group ( p = 0.013 ) , because treatment interruptions were more frequent in the control group . Acute toxicities ( mucositis and dysphagia ) were less severe in the amifostine-treated group . By Week 3 , all in the control group experienced Grade 2 mucositis compared with only 9 % in the amifostine-treated group ( p < 0.0001 ) . By Week 5 , 52.2 % of the patients in the control group experienced Grade 4 mucositis compared with 4.5 % in the amifostine-treated group ( p = 0.0006 ) . Similar results were obtained for dysphagia . At 3 months of follow-up , only 27 % of patients in the study group experienced Grade 2 xerostomia compared with 73.9 % in the control group ( p = 0.0001 ) . Eighteen months after cessation of therapy , the proportion of patients with Grade 2 xerostomia was 4.5 % vs. 30.4 % for each respective treatment group ( p = 0.047 ) . Cytoprotection with amifostine did not affect treatment outcome , with 90.9 % complete responses in the amifostine-treated group compared with 78.3 % in the control group ( p = 0.414 ) . CONCLUSION Amifostine was effective in reducing mucositis and dysphagia result ing from radiochemotherapy in patients with head- and -neck cancer . Furthermore , amifostine reduced the severity of late xerostomia , a side effect of RT with long-lasting consequences . Amifostine treatment did not affect the clinical outcome Aims and Background To compare conventional fractionation ( CF ) radiation therapy ( RT ) , arm A , versus a split-course accelerated hyperfractionated schedule ( S-AHF ) , arm B , versus CFRT plus concomitant chemotherapy ( CT ) , arm C , in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx . Methods and Study Design Between January 1993 and June 1998 , 192 previously untreated patients with stage III and IV oropharyngeal carcinoma ( excluding T1N1 and T2N1 ) were enrolled in a multicenter r and omized phase III trial ( ORO 93 - 01 ) . In arms A and C , 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks . In arm B , the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day , five days a week , with a planned two-week split at 38.4 Gy . In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil ( CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v . on days 1 to 4 every 28 days ) . Results No statistically significant difference was found in five-year overall survival ( P = 0.39 ) : 21 % for arm A , 21 % for arm B , and 40 % for arm C. Similarly , there was no statistically significant difference in terms of five-year relapse-free survival : 15 % for arm A , 17 % for arm B , and 36 % for arm C. There was a slight trend towards better five-year locoregional control ( P = 0.07 ) for the combined arm : patients without locoregional relapse were 48 % in arm C , 21 % in arm A and 18 % in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined ( P = 0.02 ; arm A+B 20 % ; arm C 48 % ) . Distant metastases were fairly balanced in the three arms ( A : 14 ; B : 9 ; C : 11 ) , with a tendency towards more frequent isolated distant metastasis development in arm C ( 8 of 11 [ 72 % ] versus 7 of 23 [ 30 % ] in arms A+B ) . Five-year second-tumor-free survival was 85 % . The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption ( five lung , two esophagus , two oral cavity , one larynx , one pancreas , one hepatocarcinoma , one myeloma ) . Arm C showed slightly more G3 + late side effects involving subcutaneous tissues and mucosa , although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient . The occurrence of persistent G3 xerostomia was comparable in the three treatment arms . Conclusions The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance , but combined treatment almost doubled the five-year overall survival , relapse-free survival and locoregional control rate .  Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy . The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death Two hundred and nine patients , with locoregional or metastatic recurrences of head and neck epidermoid carcinoma , were r and omized to receive a palliative chemotherapy .  The chemotherapy regimens were delivered every 3 weeks , and consisted in ( 1 ) cisplatin , 80 mg/m2 given alone ( CDDP regimen ) , or ( 2 ) in combination with vincristine , 1 mg , methotrexate 10 mg/m2 d 1 , 2 , 3 , and bleomycin 10 mg/m2 , d 1 , 2 and 3 ( 1040 regimen ) . Short-term results were better for patients treated by the 1040 regimen , with a 30 % response rate ( including 4 complete responses ) vs 15 % with the CDDP regimen ( P = 0.01 ) . A superiority of combination chemotherapy was found for all tumoral sites , but was particularly significant for pulmonary and cutaneous metastases , in previously un irradiated areas ( P = 0.001 ) . Tolerance was significantly better with the CDDP regimen ( P = 0.001 ) ; severe side effects , affecting mainly general status , digestive tract and bone marrow were encountered in 5 % of the patients in the CDDP group , vs 21 % in the 1040 group , with one death related to pancytopenia . The median duration of remissions was not statistically different in the 2 groups , as well as the 2 years overall survival . Among responders , the survival was slightly better in those treated with CDDP alone ; moreover , the quality of long term results was found highly correlated with a good initial general status , and with low levels of side effects . Those results confirm recent data of the literature , and lead to the following conclusions : ( 1 ) combination chemotherapy with CDDP give a better response rate than CDDP alone , ( 2 ) response rate does n't influence overall duration of survival , ( 3 ) tolerance to treatment is crucial to preserve quality of life , and thus , ( 4 ) palliative chemotherapy in head and neck cancer should be efficient but also as short of intensity as possible Between 1978 and 1981 , 85 patients with advanced squamous cell carcinoma of the head and neck were r and omized to receive induction VBM followed by radiotherapy , or radiotherapy alone . The shortest follow-up is thus 6 years . The median survival of patients receiving induction chemotherapy was 46 weeks , that of the radiotherapy group alone was 75 weeks . As the two groups were not balanced despite r and omization , multivariate methods ( GLIM ) were used to identify significant prognostic factors . These were : response to radiotherapy  ( P less than 0.001 ) , nodal status ( P less than 0.001 ) , age ( P less than 0.01 ) , and histological grade ( P less than 0.01 ) . Neither treatment with , nor response to , chemotherapy had a significant effect on survival PURPOSE To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone . METHODS AND MATERIAL S Between March 1991 and December 1993 , 64 patients with inoperable head and neck carcinoma ( 41 with oropharyngeal site ) were r and omized to radiotherapy alone ( group A ) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin ( group B ) . In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66 - 70 Gy . The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy . To enhance the effect of these two drugs , patients received also nicotinamide , chlorpromazine , and dicoumarol . Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma , the study was closed and such patients were after December 1993 routinely treated with the combined therapy ( as in arm B ) . Until October 1996 , we treated and followed up 48 such consecutive patients . RESULTS Median follow-up of our study patients is 42 months . Complete remission ( CR ) rate in group A was 31 % and in group B 59 % ( p = 0.04 ) ; disease-free survival ( DFS ) in group A was 8 % and in group B 37 % ( P = 0.01 ) ; and overall survival ( OS ) was 7 % in group A and 26 % in group B ( p = 0.08 ) . CR rate for patients with oropharyngeal carcinoma was 29 % in group A ( N = 21 ) and 75 % in group B ( N = 20 ) ( p = 0.007 ) ; DFS in group A was 10 % and in group B 48 % ( p = 0.001 ) ; and the OS was 10 % in group A and 38 % in group B ( p = 0.019 ) . In patients with inoperable oropharyngeal carcinoma treated after December 1993 , complete remission was achieved in 32/48 ( 67 % , 95 % CI : 52%-80 % ) . DFS at the median follow-up of 14 months was 60 % ( 95 % CI 43 - 77 % ) and OS 58 % ( 95 % CI 42 - 74 % ) . CONCLUSION From the results of our study it seems that the concomitant treatment significantly improves CR rate , DFS , and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone The purpose of the present study was to determine the safety and efficacy of induction chemotherapy followed by concomitant chemoradiotherapy .  Thirty-eight patients were r and omised to receive induction chemotherapy , consisting of cyclophosphamide and methotrexate followed by concomitant 5-fluorouracil and irradiation ( study group ) or irradiation alone ( control group ) . There were non-significant differences in the initial tumor clearance rates in the two groups . Median disease-free survival ( in complete responders ) was 17 months ( 6 - 60 + ) vs 11 months ( 5 - 60 + ) ( p = 0.407 ) and overall survival 11 months ( 1 - 60 + ) vs 14 months ( 2 - 60 + ) ( p = 0.428 ) in the study and control groups respectively . Acute morbidity and deaths during intervention were higher in the study group ( p = 0.007 ) . This study suggests that induction along with concomitant chemoradiotherapy is too toxic for routine use and also fails to provide a survival benefit The study , which compares DDP to DDP+FU , was planned to detect an increase by 60 % in efficacy and by 5 % in toxicity ( 2a = B = 5 % ) for DDP+FU . In a previous trial DDP produced 15 % of responders and 5 % of high‐level toxic manifestations . The eligible patients with an advanced head and neck cancer were paired off successively on the basis of the tumour site and the UICC stage .  DDP ( 100 mg/m2 ; day 1 ) was administered with hyperhydration , alone in the first protocol and followed by a 5‐day continuous infusion of 5‐FU ( 1 g/m2 ) in the second one . Courses were repeated every three weeks . Assessment was carried out after three courses or two , in cases of toxic manifestations . Seventy‐four patients , who were paired off , entered the trial . The median age was 55 years and the median Karnofsky index was 90 . The tumor site was as follows : 28 hypopharynx , 28 oropharynx , 8 oral cavity , and 10 multiple primary cancers . According to the UICC stage , there were 14 T1/T2 N3 , 60 T3/T4 with among them 45 N3 , and they were all MO . Comparisons were made through sequential closed plans . The combination chemotherapy was more efficacious  than DDP with a difference that could be appreciated by the sequential analysis as high as 60 % ( 95 % confidence interval , 38 % to 82 % ) . The high‐level toxicity appeared more significant ( + 25 % ) for the association . After radiation therapy 11 of 37 patients ( 30 % ) achieved a complete response in the arm with DDP versus 18 of 37 ( 49 % ) in that with DDP+FU . The median survival times were 9 and 11.5 months , respectively , and were not statistically different PURPOSE To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel , cisplatin , and fluorouracil ( FU ; PCF ) versus st and ard cisplatin and FU ( CF ) , both followed by chemoradiotherapy ( CRT ) , in locally advanced head and neck cancer ( HNC ) . PATIENTS AND METHODS Eligibility criteria included biopsy-proven , previously untreated , stage III or IV locally advanced HNC . Patients received either CF ( cisplatin 100 mg/m2 on day 1 plus FU 1000 [ corrected ] mg/m2 continuous infusion on days 1 through 5 ) or PCF ( paclitaxel 175 mg/m2 on day 1 , cisplatin 100 mg/m2 on day 2 , and FU 500 mg/m2 continuous infusion on days 2 through 6 ) ; both regimens were administered for three cycles every 21 days . Patients with complete response ( CR ) or partial response of greater than 80 % in primary tumor received additional CRT ( cisplatin 100 mg/m2 on days 1 , 22 , and 43 plus 70 Gy ) . RESULTS A total of 382 eligible patients were r and omly assigned to CF ( n = 193 ) or PCF ( n = 189 ) . The CR rate was 14 % in the CF arm v 33 % in the PCF arm ( P < .001 ) . Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm ( log-rank test , P = .006 ; Tarone-Ware , P = .003 ) . PCF patients had a trend to longer overall survival ( OS ; 37 months in CF arm v 43 months in PCF arm ; log-rank test , P = .06 ; Tarone-Ware , P = .03 ) . This difference was more evident in patients with unresectable disease ( OS : 26 months in CF arm v 36 months in PCF arm ; log-rank test , P = .04 ; Tarone-Ware , P = .03 ) . CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients ( 53 % v 16 % , respectively ; P < .001 ) . CONCLUSION Induction chemotherapy with PCF was better tolerated and result ed in a higher CR rate than CF . However , new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospect ively controlled study comparing high-dose infusion methotrexate with leucovorin against st and ard-dose methotrexate without leucovorin .  Patients were stratified for prior treatment and hematogenous metastases prior to r and omization . Patients received either methotrexate ( 1,500 mg/m2 ) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly . Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity . After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly . One patient was ineligible and four had inadequate follow-up to assess response ( less than two weeks ) . Forty-two patients were evaluable for survival and 37 for response .  Six of 19 patients ( 32 % ) treated with high-dose infusion responded ( one complete response ) and four of 18 patients ( 22 % ) receiving st and ard dosage responded ( P = .52 ) . Treatment with high-dose methotrexate result ed in an improved duration of disease control over st and ard dosage with the respective median times to progression of 11 weeks and five weeks ( P = .04 ) . These differences were most marked in good performance status patients ( P = .007 ) and those without hematogenous dissemination ( P = .02 ) . Toxicity , however , was also significantly worse in the high-dose treatment group ( P = .01 ) and survival was identical between treatments ( 4.2 months ) . The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival . Good performance status patients may benefit from more aggressive therapy A r and omized prospect i ve clinical trial involved 259 cases of advanced recurrent Stage III and IV epidermoid cancers of the head and neck . The cases were r and omized among three treatment programs evaluating two dose schedules and a combination treatment of methotrexate . The treatments consisted of : weekly methotrexate , biweekly methotrexate with leucovorin rescue ( ML ) , and biweekly ML combined with cyclophosphamide and cytosine arabinoside ( MLCC ) . Equivalent overall drug‐related toxicity was produced with a 5 % drug‐related fatality rate . Methotrexate alone produced significantly more skin and mucosal toxicity , and the combination ( MLCC ) result ed in more hematologic toxicity than other treatments . Complete and partial objective responses were achieved in 26 % , 24 % , and 18 % by each treatment . Methotrexate alone produced a median duration of response of 105 days compared with 42 and 49 days from the other treatments . Duration of response was significantly longer and survival was better in the methotrexate‐alone group . Response was markedly stage dependent ; 40 % of Stage III patients achieved response , whereas only 17 % of Stage IV patients responded . Presence of visceral metastases decreased response rates and the likelihood of response was particularly compromised by pulmonary metastatic spread ; only seven of 54 such patients responded . Decreased survival was related to non‐ambulatory performance status , disease‐free intervals of less than one year and weight loss . Survival differences between Stage III and IV patients could not be shown . This study demonstrates the therapeutic superiority of weekly i.v . treatment with methotrexate but failed to support cl aims of an improved therapeutic index for high‐dose methotrexate with leucovorin rescue . As the only r and omized prospect i ve clinical trial of chemotherapy in advanced head and neck cancer , this study reinforces the weekly i.v . schedule of methotrexate as the st and ard against which other drug schedules and drug combinations should be compared PURPOSE Previous r and omized trials have shown a benefit with concurrent use of the hypoxic cell cytotoxin mitomycin C ( MC ) and radiation ( RT ) in the management of squamous cell cancer of the head and neck ( SCCHN ) . We conducted a r and omized trial comparing MC with porfiromycin ( POR ) in combination with RT in the management of SCCHN . METHODS AND MATERIAL S Between 1992 and 1999 , 128 patients with SCCHN were enrolled in this prospect i ve r and omized trial . Patients were stratified by management intent , and balanced with respect to stage and site of disease . They were r and omized to receive MC ( 15 mg/M(2 ) ) or POR ( 40 mg/M(2 ) ) on Days 5 and 47 ( or last day ) of RT . Of 121 evaluable patients , 61 were r and omized to MC and 60 to POR . Patients were treated with st and ard daily RT to a total median dose of 64 Gy over 47 days . Patients were well balanced with respect to management intent , stage , site , age , sex , hemoglobin levels , tumor grade , radiation dose , and days on treatment . RESULTS There were no significant differences between the two arms with respect to acute hematologic or nonhematologic toxicities . As of January 2003 with a median follow-up of 6.3 years , there have been 19 local relapses ( 4 MC vs. 15 POR ) , 21 regional relapses ( 7 MC vs. 14 POR ) , 24 distant metastases ( 11 MC vs. 13 POR ) , and 66 deaths ( 33 MC vs. 33 POR ) . MC was superior to POR with respect to 5-year local relapse-free survival ( 91.6 % vs. 72.7 % , p = 0.01 ) , local-regional relapse-free survival ( 82 % vs. 65.3 % , p = 0.05 ) , and disease-free survival ( 72.8 % vs. 52.9 % , p = 0.026 ) . There were no significant differences between the two arms with respect to overall survival ( 49.2 % vs. 54.4 % ) or distant metastasis-free rate ( 79.9 % vs. 75.9 % ) . CONCLUSIONS Despite promising pre clinical data , and an acceptable toxicity profile , POR was inferior to MC as an adjunct to RT in the management of SCCHN . This r and omized trial emphasizes the need for r and omized studies to evaluate new agents in the management of SCCHN PURPOSE To evaluate the effect of mitomycin C to an accelerated hyperfractionated radiation therapy . The aim was to test a very short schedule with/without mitomycin C ( MMC ) with conventional fractionation in histologically verified squamous cell carcinoma of the head and neck region . METHODS AND MATERIAL S From October 1990 to December 1996 , 188 patients entered the trial . Tumors originated in the oral cavity in 54 , oropharynx in 82 , larynx in 20 , and hypopharynx in 32 cases , respectively . Patients ' stages were predominantly T3 and T4 ( 158/188 , 84 % ) and most patients had lymph node metastases ( 144/188 , 77 % ) at diagnosis . Only 22 patients were female , 166 were male , the median age of patients was 57 years ( range 34 to 76 years ) . Patients were r and omized to one of the following three treatment options : conventional fractionation ( CF ) consisting of 70 Gy in 35 fractions over 7 weeks ( 65 patients ) or continuous hyperfractionated accelerated radiation therapy ( V-CHART ; 62 patients ) or continuous hyperfractionated accelerated radiation therapy with 20 mg/sqm MMC on day 5 ( V-CHART + MMC ; 61 patients ) . By the accelerated regimens , the total dose of 55.3 Gy was delivered within 17 consecutive days , by 33 fractions . On day 1 , a single dose of 2.5 Gy was given , from day 2 to 17 a dose of 1.65 Gy was delivered twice : the interfraction interval was 6 hours or more . RESULTS Mucositis was very intense after accelerated therapy , most patients experiencing a grade III/IV reaction . The mucosal reaction did not differ whether MMC was administered or not . Patients treated by accelerated fractionation experienced a confluent mucosal reaction 12 - 14 days following start of therapy and recovered ( no reaction ) within 6 weeks . The skin reaction was not considered different in the three treatment groups . Those patients treated with additional chemotherapy experienced a grade III/IV hematologic toxicity in 12/61 patients . Initial complete response ( CR ) was recorded in 43 % following CF , 58 % after V-CHART , and 67 % after V-CHART + MMC , respectively ( p < 0.05 ) . Actuarial survival ( Kaplan-Meier ) was significantly improved in the combined treated patients . Local tumor control was 28 % , 32 % , and 56 % following CF , V-CHART , and V-CHART + MMC , respectively ( p < 0.05 ) . CONCLUSION We conclude that our continuous hyperfractionated accelerated radiation therapy regimen is equal to conventional fractionation , suggesting that by shortening the overall treatment time from 7 weeks to 17 days a reduction in dose from 70 Gy to 55.3 Gy is possible , with maintenance of local tumor control rates . The administration of MMC to the accelerated regimen is tolerable and improves the outcome for patients significantly We studied the usefulness and safety of long-term administration of uracil and tegafur ( UFT )  after primary therapy of the malignant tumor in jaw and oral cavity regions r and omized controlled trial . 112 cases were totallized 6 institutes belonging to the Oral Surgery Malignant Tumor Research Association in Kanto Kohshinetsu District during 2 years and 10 months , beginning in September 1986 . After completing the primary therapy , treatment was not performed in group A and 400 mg/day of UFT was orally administered in group B for 1 year . A variation was observed in the stages of background factors such as sex and age ( more than 30 years old and less than 80 years old ) , while no such discrepancy was observed in other stages . No significant difference of 1-year-survival ratio and non-recurrence ratio was noted in either group , while the non-recurrence ratio was more favorable in group B than group A , and the usefulness of UFT for adjuvant chemotherapy was suggested . The incidence of side effects in group B was 42.6 % , and no serious side effect was observed Eighty-six previously untreated patients with advanced squamous-cell carcinoma of the head and neck were entered into a prospect i ve r and omised controlled trial to evaluate whether the addition of a kinetically based chemotherapy regimen before and after radiotherapy would improve survival compared with radiotherapy alone .  Survival at 30 months showed there was no evidence that the addition of chemotherapy to  radiotherapy  improved survival and that the chance of obtaining a significant result in favour of adjuvant chemotherapy was remote . We make a strong plea that all chemotherapy regimens for the treatment of squamous-cell carcinoma of the head and neck regions should be subjected to controlled prospect i ve trials before they are widely adopted BACKGROUND AND PURPOSE Post-operative radiotherapy is indicated for the treatment of head and neck cancers . In vitro , chemotherapy potentiates the cytotoxic effects of radiation . We report the results of a r and omized trial testing post-operative radiotherapy alone versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement . MATERIAL S AND METHODS The study involved patients undergoing curative-intent surgery for head and neck cancers with histological evidence of lymph node involvement . Patients were r and omly assigned to receive radiotherapy alone ( 54 - 72Gy , 30 - 40 fractions , 6 - 8 weeks ) or identical treatment plus concomitant Carboplatin ( 50mg/m(2 ) administered by IV infusion twice weekly ) . RESULTS Between February 1994 and June 2002 , 144 patients were included . With a median follow-up of 106 months ( 95 % confidence interval ( CI ) [ 92 - 119 ] ) , the 2-year rate of loco-regional control was 73 % ( 95 % CI : 0.61 - 0.84 ) in the combined treatment group and 68 % ( 95 % CI : 0.57 - 0.80 ) in the radiotherapy group ( p=0.26 ) . Overall survival did not differ significantly between groups ( hazard ratio for death , 1.05 ; 95 % CI : 0.69 - 1.60 ; p=0.81 ) . CONCLUSIONS Twice-weekly administration of carboplatin concomitant to post-operative radiotherapy did not improve local control or overall survival rates in this population of patients with node-positive head and neck cancers Abstract A r and omized study was conducted to evaluate the protective activity of amifostine ( A ) against the dose-limiting toxicities of radiochemotherapy ( RCT ) .  Patients with head and neck cancer received radiotherapy  ( 2 Gy/day 5 days a week up to 60 Gy ) with carboplatin 70 mg/m2 on days 1–5 and 21–25 inclusive . Patients either received RCT alone ( n=14 ) or RCT + A at a dose of 500 mg prior to treatment with carboplatin ( n=25 ) . There was a significant reduction in the incidence of grade 3/4 mucositis ( P<0.0001 ) , acute grade 2 xerostomia ( P<0.0001 ) and grade 3/4 thrombocytopenia ( P=0.012 ) in these patients who received A. The incidence of grade 2 late xerostomia at 12 months is 16.7 % and the incidence of loss of taste is 0 % in patients treated with A , as opposed to 54.5 % and 63.6 % in patients who received RCT alone . There were 18 ( 72 % ) complete responses ( CR ) and 6 ( 24 % ) partial responses ( PR ) in patients who received A , compared with 6 ( 43 % ) CR and 6 PR ( 43 % ) in patients treated with RCT alone . The disease-free survival at 12 months is 85.7 % in the RCT + A arm and 78.6 % in the RCT alone arm . The use of amifostine reduces the incidence and severity of acute and late toxicities associated with RCT whilst preserving antitumour activity Men are approximately 3 times more likely to develop squamous cancers of the head and neck ( oral cavity , pharynx , and larynx ) than women . Very few prospect i ve studies have examined the association between cigarette smoking and cancers of the head and neck in women , even though the rates of smoking in women are increasing rapidly worldwide BACKGROUND AND PURPOSE Single agent mitomycin c ( MMC ) has been shown to improve the outcome of radiotherapy in single institution trials . In order to confirm these findings in a broader worldwide setting , the International Atomic Energy Agency ( IAEA ) initiated a multicentre trial r and omising between radiotherapy alone versus radiotherapy plus MMC . MATERIAL AND METHODS Patients with advanced head and neck cancer were treated with primary curative radiotherapy ( 66 Gy in 33 fractions with five fractions per week ) + /-a single injection ( 15 mg/m(2 ) ) of MMC at the end of the first week of radiotherapy . Stratification parameters were tumour localization , T-stage , N-stage , and institution . A total of 558 patients were recruited in the trial from February 1996 to December 1999 . Insufficient accrual and reporting led to the exclusion of three centres . The final study population consisted of 478 patients from seven centres . Patients had stage III ( n=223 ) or stage IV ( n=255 ) squamous cell carcinoma of the oral cavity ( n=230 ) , oropharynx ( n=140 ) , hypopharynx ( n=65 ) or larynx ( n=43 ) . Prognostic factors like age , gender , site , size , differentiation and stage were well balanced between the two arms . RESULTS The haematological side effects of  MMC  were very modest ( < 5 % grade 3 - 4 ) and did not require any specific interventions . Furthermore , MMC did not enhance the incidence or severity of acute and late radiation side effects . Confluent mucositis and dry skin desquamation was common , occurring in 56 % and 62 % of patients , respectively . The overall 3-year primary locoregional tumour control , disease-specific and overall survival rates were 19 , 36 and 30 % , respectively . Gender , haemoglobin drop , tumour site , tumour and nodal stage were significant parameters for loco-regional tumour control . There was no significant effect of MMC on locoregional control or survival , except for the 161 N0 patients , where MMC result ed in a better loco-regional control ( 3-year estimate 16 % vs. 29 % , P=0.01 ) . CONCLUSIONS The study did not show any major influence of MMC on loco-regional tumour control , survival or morbidity after primary radiotherapy in stage III-IV head and neck cancer except in N0 patients where loco-regional control was significantly improved In the first study by the " Kinki Head and Neck Tumor Study Group , " we performed a comparative study to investigate intergroup difference between a  control group consisting of patients given radical treatment only , and a HCFU group consisting of patients receiving long-term administration of HCFU after radical treatment .  We earlier reported that subsequent observations by stratification revealed a favorable tendency in the cumulative disease-free rate in Stage II and Stage III patients in the HCFU group . In the second study , the same methods of treatment as in the first study were compared in a prospect i ve control study . No differences were found between the two groups in Stage II patients . In Stage III patients , however , the disease-free rate tended to increase significantly in the HCFU group as in the first study A prospect i ve , r and omized , multicenter study of patients with oropharyngeal and pharyngolaryngeal tumors compared locoregional treatment alone with neoadjuvant chemotherapy with carboplatin/5-fluorouracil ( 5-FU ) followed by locoregional treatment . The aim of the study was to evaluate the role of chemotherapy on survival and on the need for mutilating surgery . Since 1988 , 219 patients ( 105 with oropharyngeal and 114 with pharyngolaryngeal tumors ) have entered the study . All patients r and omized to neoadjuvant chemotherapy  received three cycles of carboplatin 400 mg/m2 day 1 and 5-FU 1 g/m2/d as a continuous infusion days 1 through 5 every 3 weeks . Neoadjuvant chemotherapy was given to 108 patients . The 268 evaluable courses induced a low rate of grade 3 or 4 toxicity . Four patients ( 3.6 % ) died of major complications . The complete response ( CR ) rate was 31 % , which represented a decrease in mutilating surgery of 30 % . ( Patients with CRs had radiotherapy alone instead of radiosurgical treatment as originally planned . ) The objective response rate was 61 % . Survival curves for the chemotherapy and chemotherapy-naive groups were not significantly different . The rate of nodal recurrence was significantly higher in the chemotherapy group , however , and chemotherapy did not decrease the rate of second primary tumors or distant metastases . Thus , the justification for neoadjuvant chemotherapy may be a decreased rate of mutilating surgery . These preliminary results are encouraging , but follow-up is as yet too short to allow definite conclusions The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer . Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric r and omized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy . The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone . Three cycles of chemotherapy consisting of Cisplatin ( 100 mg/m2 ) on day 1 followed by a 24-hour i.v . infusion of fluorouracil ( 1000 mg/m2/day ) for 5 days were delivered every 21 days . 2–3 weeks after the end of chemotherapy , local treatment was performed . The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou ( GETTEC ) . A total of 318 patients were enrolled in the study between 1986 and 1992 .  Overall survival was significantly better ( P = 0.03 ) in the neoadjuvant chemotherapy group than in the control group , with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group . The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance ( P = 0.11 ) . Stratification of the results on the type of local treatment , surgery plus radiotherapy or radiotherapy alone , did not reveal any heterogeneity in the effect of chemotherapy . © 2000 Cancer Research Campaign PURPOSE A r and omized trial was design ed to compare cisplatin ( CDDP ) and fluorouracil ( FU ) versus carboplatin ( CBDCA ) and FU as neoadjuvant treatment in stage IV-M0 head and neck cancer to assess whether CBDCA-FU is better than CDDP-FU with regard to response and toxicity . PATIENTS AND METHODS Patients were r and omized to receive CDDP 100 mg/m2 intravenously on day 1 and FU 5,000 mg/m2 over a 120-hour continuous infusion , or CBDCA 400 mg/m2 over a 24-hour continuous infusion on day 1 and FU with the same schedule . Both regimens were repeated every 21 days . The patients received three courses of chemotherapy , excluding those who failed to achieve a partial response ( PR ) after the second course . Complete responders were treated with radiotherapy . The remaining patients underwent surgery if the tumor was resectable . RESULTS Interim analysis was performed when 95 patients were included . The trial was stopped due to significantly better results in the control arm . Differences in response ( P = .04 ) were favorable to CDDP-FU .  Hematologic toxicity predominated in the CBDCA-FU arm ( P < .001 ) . Mucositis and vomiting predominated in the CDDP-FU arm ( P = .03 , P < .001 , respectively ) . Favorable outcomes ( complete response [ CR ] plus any grade of toxicity and PR plus grade 0 to 3 toxicity ) predominated in the CDDP-FU arm ( P = .02 ) . Only the treatment assigned was associated with response ( P = .02 ) and favorable outcomes ( P = .009 ) in the logistic regression analysis . In the CDDP-FU arm , disease-free and overall survival were significantly better . Cox regression analysis showed that only treatment association with disease-free survival remains significant . CONCLUSION Our results indicate that CDDP-FU is more effective than CBDCA-FU as neoadjuvant treatment in stage IV-M0 head and neck cancer 136 patients with previously untreated stage III or IV squamous cell carcinoma of the head and neck entered a prospect i ve r and omized trial to compare the efficacy and toxicity of DDP vs DDP-VP 16 213 ( Etoposide ) . 69 patients ( group A ) were given three courses of DDP 100 mg/m2 administered on day 1 , while 67 patients ( group B ) were given three courses of a combination of Etoposide 100 mg/m2 per os administered on days 1 to 5 and DDP 100 mg/m2 on day 4 . Objective response rate appeared to be low in both groups : in group A ( 60 evaluated patients ) CR = 1 , PR = 9 ; CR + PR = 14.5 % , and in group B ( 57 evaluated patients ) CR = 3 , PR = 8 ; CR + PR = 16.4 % ( p greater than 0.4 ) . One drug-related death occurred in each group . There was no difference in toxicity between the two treatments with regard to leukopenia , thrombopenia , vomiting and nephrotoxicity . Thus this schedule of oral Etoposide does not seem to increase either the efficacy or the toxicity of DDP Although induction chemotherapie given prior to local therapy produces encouraging initial response rates in head and neck cancer , r and omized studies have failed to demonstrate an advantage in survival . All r and omized studies have included only patients with far advanced stage III and IV disease . To us this is the main reason for the low rate of complete responses demonstrated ( maximum , 18 % ) . Frei et al. estimate that 40 - 50 % complete responders are necessary before improved survival benefit will occur . To date , such complete response rates with induction chemotherapy are only attainable in resectable T2-T3 , N0-N2 disease . Therefore , we started a prospect i ve r and omized trial that included only patients with earlier disease . Patients were r and omized to receive either induction chemotherapy with 3 cycles of carboplatin/5-fluorouracil prior to surgery and radiotherapy  ( arm A , 49 patients ) or st and ard treatment with surgery and radiotherapy  ( arm B , 48 patients ) . Patients were stratified by primary tumor site and neck disease . After a follow-up of 12 - 48 months , overall survival was 72 % in arm A and 53 % in arm B , but this difference was not significant . Considering only the results in patients with cancer of the oral cavity and tonsils , overall survival was 87 % in arm A and 45 % in arm B ( p < 0.04 ) . At present , the numbers of patients with cancers of the tongue base and hypopharynx are too small for a statistically significant statement . However , preliminary data indicate a better overall and disease-free survival without chemotherapy in these patients . Therefore , we now recommend induction chemotherapy in all patients with stage T2-T3 and N0-N2 carcinomas of the oral cavity and tonsils prior to surgery but not in patients with cancers of the hypopharynx and base of tongue PURPOSE To define further the role of concurrent chemoradiotherapy for patients with advanced squamous carcinoma of the head and neck . PATIENTS AND METHODS The Radiation Therapy Oncology Group developed this three-arm r and omized phase II trial . Patients with stage III or IV squamous carcinoma of the oral cavity , oropharynx , or hypopharynx were eligible . Each of three arms proposed a radiation schedule of 70 Gy in 35 fractions . Patients on arm 1 were to receive cisplatin 10 mg/m(2 ) daily and fluorouracil ( FU ) 400 mg/m(2 ) continuous infusion ( CI ) daily for the final 10 days of treatment . Treatment on arm 2 consisted of hydroxyurea 1 g every 12 hours and FU 800 mg/m(2)/d CI delivered with each fraction of radiation . Arm 3 patients were to receive weekly paclitaxel 30 mg/m(2 ) and cisplatin 20 mg/m(2 ) . Patients r and omly assigned to arms 1 and 3 were to receive their treatments every week ; patients on arm 2 were to receive their therapy every other week . RESULTS Between 1997 and 1999 , 241 patients were entered onto study ; 231 were analyzable . Ninety-two percent , 79 % , and 83 % of patients on arms 1 , 2 , and 3 , respectively , were able to complete their radiation as planned or with an acceptable variation . Fewer than 10 % of patients had unacceptable deviations or incomplete chemotherapy in the three arms . Estimated 2-year disease-free and overall survival rates were 38.2 % and 57.4 % for arm 1 , 48.6 % and 69.4 % for arm 2 , and 51.3 % and 66.6 % for arm 3 . CONCLUSION We have demonstrated that three different approaches of concurrent multiagent chemotherapy and radiation were feasible and could be delivered to patients in a multi-institutional setting with high compliance rates BACKGROUND For patients with advanced , unresectable squamous-cell carcinoma of the head and neck , radiotherapy is the st and ard treatment but has poor results . We therefore design ed a r and omized trial to determine whether alternating chemotherapy with radiotherapy would improve the survival of such patients . METHODS Patients in the trial had biopsy-confirmed unresectable , previously untreated Stage III or IV , squamous-cell carcinoma of the oral cavity , pharynx , or larynx . They were r and omly assigned to chemotherapy consisting of four cycles of intravenous cisplatin ( 20 mg per square meter of body-surface area per day for five consecutive days ) and fluorouracil ( 200 mg per square meter per day for five consecutive days ) alternating with radiotherapy in three two-week courses ( 20 Gy per course ; 2 Gy per day , five days per week ) , or to radiotherapy alone ( up to 70 Gy ; 2 Gy per day , five days per week ) . RESULTS The 80 patients given chemotherapy alternating with radiotherapy and the 77 given radiotherapy alone were comparable in terms of age , sex , performance status , disease stage , and site of the primary tumor . Complete responses were obtained in 42 percent of the patients in the combined-therapy group and 22 percent of those in the radiotherapy group ( P = 0.037 ) . The median survival was 16.5 months in the combined-therapy group and 11.7 months in the radiotherapy group ( P less than 0.05 ) ; the 3-year survival was 41 percent and 23 percent , respectively . Severe mucositis occurred in 19 percent of the patients in the combined-therapy group and 18 percent of those in the radiotherapy group . CONCLUSIONS In patients with advanced unresectable squamous-cell carcinoma of the head and neck , chemotherapy alternating with radiotherapy increases the median survival and doubles the probability of survival for three years as compared with radiotherapy alone . However , since local disease can not be controlled in over half the patients who receive the combined treatment and since almost two thirds die within three years , further improvements in management are necessary From November 1981 to February 1983 , 64 patients with advanced head and neck squamous carcinoma were r and omly treated with either high-dose ( 120 mg/m2 ) or low-dose ( 60 mg/m2 ) cisplatin . Of the 62 eligible patients , 59 were evaluable : the response rate observed in patients receiving high-dose and low-dose cisplatin was 16.1 % and 17.8 % , respectively . Survival was superimposable in the two treatment arms . No evidence of dose dependency of cisplatin activity in advanced head and neck squamous carcinoma was noted in this r and omized trial 135 cases of oral cancer have been treated by two fractions per week , and the results are compared with 115 approximately identical cases treated by conventional five days a week schedule with other parameters being identical . Radical irradiation was done by 6000 and 6500 rd in 6 - -6 1/2 weeks ( NSD 1800 - -1900 ret ) and palliative dose was 4500 R/4 weeks ( NSD 1532 ret ) . Tumour regression was found markedly superior by conventional regime in radically irradiated cases but much less superior for palliative treatment . Acute and late reaction as well as tumour control at 1 year was better with daily treatment , more so in cases treated for radical cure , while in palliative treatment , the superiority of daily regime was less marked . Our study provides evidence that only for palliation in advanced cases , radiation therapy by 2 fractions a week can be alternatively used Objectives : To compare locoregional control with alternating chemo radiation and radiation alone in patients with locally advanced head and neck carcinoma . Study Design : A prospect i ve r and omized study . Setting : Tertiary academic referral center . Patients : 50 patients of biopsy proven locally-advanced carcinoma of head and neck . Intervention : 25 patients were kept in Group I or study group ( i.e. alternating chemo-radiation ) and 25 patients in Group II or control group ( i.e. radiation alone ) . In the study group , patients were given 3 cycles of chemotherapy ( Cisplatin 20 mg/m[2 ] and Inj . 5-FU 200mg/m[2 ] from day 1–5 of each week ) during weeks 1,5 and 9 alternated with radiation dose of 10Gy/week was given during weeks 2,3,4 and 6,7,8 . In the control group , patients were given a total dose of 60Gy in 6 weeks . Outcome measures : The response rate at the primary site and nodal site was better in study group as compared to control group . Results : On comparing the response at the primary and nodal site together , 72 % ( 18/25 ) patients of group I and 44 % ( 11/25 ) patients of group II showed CR . PR was seen in 28 % ( 7/25 ) and 36 % ( 9/25 ) patients in group I and II respectively . No response was seen in 5/25 ( 20 % ) of patients in Group II . Conclusion : Our study has revealed that alternating/ sequential chemoradiation is a promising and feasible approach for patients in advanced head and neck cancer In order to evaluate the efficacy of HCFU as an adjuvant chemotherapy agent for squamous cell carcinoma of the head and neck areas , a r and omized comparative study was performed with cooperative facilities . 191 patients who had undergone radical therapy were r and omly assigned to the following two groups : Group A was the control group , which underwent radical therapy only , and Group B was a group which received long-term HCFU administration ( 300 - 600 mg/day x 12 weeks or more ) . In the comparison of non-recurrence rate in both groups , Group B had better results among patients who were at the advanced clinical stages such as N1 through N3 , Stage II ( p = 0.0583 ) and Stage III ( p = 0.0970 ) . The adverse reactions to HCFU included pollakiuria , feverishness , and digestive symptoms , but these were mild and the recovery was possible The objective of this article was to report the results from a r and omized trial that evaluated the efficacy and toxicity of adding tirapazamine ( TPZ ) to chemoradiotherapy in the treatment of patients with head and neck squamous cell carcinomas ( HNSCC ) This study was aim ed at assessing whether c-DDP administration immediately before radiotherapy could increase frequency and duration of objective responses , as well as survival , in patients affected with locally advanced stages of squamous carcinomas of the head and neck . All patients had already undergone two induction cycles according to the CABO schedule . Ninety-six of 108 treated patients could be evaluated . Treatment schedule consisted in : 1 ) r and omized distribution of patients into two groups before induction chemotherapy ; 2 ) two cycles of induction chemotherapy according to the CABO schedule in all patients ; 3 ) radiation therapy : the patients in group A were given 5 mg/mq of i.v . cisplatin , 30 - 60 minutes before each session . The results from the two groups were compared and no significant differences were observed regarding objective response ( 82.5 % in group A vs. 86 % in group B ) , response duration and overall survival rates . Even though toxicity was higher in the patients in group A , therapeutic protocol never needed be modified PURPOSE The purpose of this study was to develop and vali date an instrument for clinical trials to measure radiation-related acute morbidity and quality of life from the perspective of patients with head and neck cancer ( HNC ) treated with radiotherapy . METHODS The Head and Neck Radiotherapy Question naire ( HNRQ ) was developed by a panel of health care workers and patients , was pretested in a pilot study of HNC patients , and was vali date d in a r and omized double-blind trial of concomitant fluorouracil ( FUra ) infusional therapy ( 1.2 g/m2 per 24 hours ) or saline placebo administered for 72 hours in the first and third weeks of a 6 1/2-week course of radiation therapy . The HNRQ was vali date d against existing toxicity and performance status indices , all of which were measured weekly for the 6 1/2 weeks of treatment and for 4 weeks posttreatment . RESULTS There were three a priori constructs : ( 1 ) that the HNRQ scores would conform to a shallow U-shaped pattern to reflect declining quality of life ( increasing morbidity ) during radiation and recovery posttreatment ; ( 2 ) that the HNRQ would correlate with existing toxicity indices ( World Health Organization [ WHO ] stomatitis , Byfield stomatitis , WHO skin toxicity , Eastern Cooperative Oncology Group [ ECOG ] and Karnofsky performance status ) ; and ( 3 ) that the HNRQ would discriminate between FUra and placebo groups . The HNRQ and its domain scores all showed a change from baseline reflecting increased morbidity during radiation ( analysis of variance [ ANOVA ] , P < .00001 ) . The HNRQ correlated well with all other indices ( r > or = .60 ) , and domain scores correlated best with other indices that assess the same symptom complex ( eg , HNRQ skin domain and WHO skin toxicity index , r = .77 ) . There was a significant difference in HNRQ scores between the FUra and placebo groups during radiation ( ANOVA , P = .0007 ) , and all HNRQ domains also discriminated between the treatment groups . CONCLUSION The HNRQ is a valid measure of acute morbidity due to radiation therapy in patients with locally advanced HNC , and may be useful as an outcome measure for future clinical trials of radiation treatment strategies This trial of treatment for head and neck carcinoma was initiated in 1973 by the European Organization for Research and Treatment of Cancer . Its purpose was to investigate the value of single-agent chemotherapy with bleomycin ( BLM ) given during the course of a conventional treatment by external radiotherapy ( RT ) compared to treatment by external RT alone . In this r and omized study , we compared treatment results in 2 groups of patients with squamous cell carcinoma of the oropharynx ( T2 , T3 , and T4 ; International Union Against Cancer classification ) . One group of 92 patients was treated by RT  at the prescribed dose of 70 Gy  . The other group of 107 patients received radiation according to the same protocol and simultaneously received i m injection of BLM at a dose of 15 mg twice a week , 2 hours prior to the session of RT , for a total dose of 150 mg in 5 weeks . The occurrence of local toxic effects ( i.e. , mucositis and epidermatitis ) was significantly greater in the RT-BLM group ( RT-BLM , 72 % , vs. RT , 21 % ) . Primary tumor response 6 weeks after completion of RT was the same in both arms of the study ( RT , 68 % , vs. RT-BLM , 67 % ) . The 6-year survival rate was 24 % ( RT-BLM ) versus 22 % ( RT ) . Long-term analysis ( 10 yr ) is given AIMS A prospect i ve r and omized study was conducted to evaluate the benefit of adjuvant levamisole/UFT ( futraful and uracil ) chemotherapy in head and neck squamous cell carcinoma . METHODS Sixty-five patients with stage III and IV squamous cell carcinomas of oral cavity , oropharynx , hypopharynx and larynx with no distant metastasis were r and omized for the chemotherapy study . Thirty-one patients were r and omized for chemotherapy  and two of them were subsequently excluded . In this study , a total of 29 patients on levamisole/UFT therapy and 34 patients on the control group were analysed . The main outcome was measured by the 5-year disease-free actuarial survival rate . RESULTS The rates of distant metastasis were 10 % for chemotherapy group and 32 % for control group ( P=0.06 ) . The 5-year disease-free actuarial survival rates for patients with and without adjuvant chemotherapy were 57 % and 39 % respectively ( P=0.207 ) . CONCLUSIONS A trend of better distant control in head and neck cancer patients with post-operative adjuvant oral chemotherapy was observed . The side effects were minimal . However , there was no statistically significant improvement in the overall long-term survival . It may be of value to conduct a large-scale multi-centre prospect i ve r and omized study to verify the efficacy of levamisole and UFT as post-operative adjuvant chemotherapy for the control of distant metastasis in high-risk population To determine if adjuvant methotrexate ( MTX ) , escalated weekly to toxicity , could improve disease-free survival ( DFS ) and overall survival by preventing recurrent disease , 60 patients with potentially resectable stage III or IV squamous head and neck carcinomas were stratified by primary site , stage , and nutritional status , then r and omized by pairs to receive or not receive adjuvant MTX . All received st and ard surgery and postoperative radiation therapy .  Five patients were taken off study because of unresectability at the time of surgery , leaving 55 evaluable patients . There were no statistically significant imbalances in known prognostic factors between the two treatment arms . MTX was begun at 40 mg/m2 and escalated 10 mg/m2 weekly ( four doses preoperatively ; four doses postoperatively , preradiation therapy ; eight doses postradiation therapy ) to  mucosal or hematologic toxicity .  The median peak MTX dose achieved was 80 mg/m2 . Although three patients were hospitalized with MTX toxicity , none died of MTX toxicity . No patient receiving MTX had disease progression during treatment , and there was no increase in postoperative complications . Thirty-two patients died ( median survival , 19 months ) ; 23 patients are alive with median follow-up of 43 months . There was no statistically significant difference in actuarial DFS ( P = 1.0 ) or overall survival ( P = .61 ) . Although patients on the MTX arm appeared to have less local and regional recurrences at first recurrence ( thus more distant metastases ) , this did not reach statistical significance ( P = .06 ) . There was no significant difference between the sites of recurrence at death or last follow-up ( P = .38 ) The aim of the study was to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV oropharynx carcinoma . A total of 226 patients have been entered in a phase III multicentric r and omized trial comparing radiotherapy alone ( arm A ) to radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B patients received simultaneously 3 cycles of a four-day regimen containing carboplatin ( 70 mg/m2/d ) and 5 fluorouracil ( 600 mg/m2/d ) continuous infusion . The two arms were equally balanced regarding to age , gender , stage , performance status , histology , and primary tumor site . Radiotherapy compliance was similar in the two arms regarding to total dose , treatment duration and treatment interruption . Grade 3 and 4 mucositis rate was significantly higher in arm B ( 67 % versus 36 % ) . Skin toxicity was not different . Haematologic toxicity was higher in arm B on neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were respectively 51 % versus 31 % and 42 % versus 20 % for patients treated with combined modality versus radiation alone ( p = 0.022 and 0.043 ) . Local and regional control rate has been improved in arm B ( 66 % versus 42 % ) . The statistically significant improvement in overall survival obtained support the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx PURPOSE The Head and Neck Intergroup conducted a phase III r and omized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer . PATIENTS AND METHODS Eligible patients were r and omly assigned between arm A ( the control ) , single daily fractionated radiation ( 70 Gy at 2 Gy/d ) ; arm B , identical radiation therapy with concurrent bolus cisplatin , given on days 1 , 22 , and 43 ; and arm C , a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy , 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle . Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and , if necessary , as salvage therapy on all three treatment arms . Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test . RESULTS Between 1992 and 1999 , 295 patients were entered on this trial . This did not meet the accrual goal of 362 patients and result ed in premature study closure . Grade 3 or worse toxicity occurred in 52 % of patients enrolled in arm A , compared with 89 % enrolled in arm B ( P < .0001 ) and 77 % enrolled in arm C ( P < .001 ) . With a median follow-up of 41 months , the 3-year projected overall survival for patients enrolled in arm A is 23 % , compared with 37 % for arm B ( P = .014 ) and 27 % for arm C ( P = not significant ) . CONCLUSION The addition of concurrent high-dose , single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival , although it also increases toxicity . The loss of efficacy result ing from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery PURPOSE Two consecutive r and omized trials were run at our institution using the bioreductive alkylating agent mitomycin as an adjunct to radiation therapy in an effort to improve outcome in patients with squamous cell carcinoma of the head and neck . METHODS Between 1980 and 1992 , two consecutive r and omized trials using mitomycin ( trial 1 ) and mitomycin with dicumarol ( trial 2 ) as an adjunct to radiation therapy in patients with squamous cell carcinoma of the head and neck were conducted at our institution . The patients were stratified by intent of therapy , extent of disease , and primary tumor site . Within each strata , patients were r and omized to receive radiation therapy with or without mitomycin ( trial 1 ) or mitomycin/dicumarol ( trial 2 ) . RESULTS A total of 203 patients were enrolled onto both trials , 195 of whom were eligible for analysis . Patients were equally balanced with respect to sex , age , extent of disease , primary site , radiation dose , and total duration of radiation treatment . Hematologic toxicities were more frequently noted in the drug-treated arms , but were acceptable with no drug-related treatment deaths . Nonhematologic toxicities were acceptable and not significantly different between the two arms . As of September 1995 , with a median follow-up of 138 months , a statistically significant benefit occurred in the mitomycin arms with respect to cause-specific survival ( 0.74 + /- 0.05 v 0.51 + /- 0.05 ; P = .005 ) , local recurrence-free survival ( 0.85 + /- 0.04 v 0.66 + /- 0.05 ; P = .002 ) , and local regional recurrence-free survival ( 0.76 + /- 0.05 v 0.54 + /- 0.05 ; P = .003 ) . No statistically significant difference in overall survival was obtained ( 0.48 + /- 0.05 mitomycin arms v 0.42 + /- 0.05 radiation alone ) . CONCLUSION The bioreductive alkylating agent mitomycin is a safe and effective adjunct to radiation therapy in the treatment of squamous cell carcinoma of the head and neck . The statistically and clinical ly significant improvement in local regional relapse and cause-specific survival obtained support the use of mitomycin as an adjunct to radiation therapy in the management of squamous cell carcinoma of the head and neck A cooperative r and omized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment , arm A , with an alternation of chemotherapy and radiotherapy ( three courses of 20 Gy in ten daily fractions ) , arm B. The same chemotherapy was used in both arms : 6 mg/m2 , vinblastine , hour 0 ; 30 mg , bleomycin , hour 6 ; 200 mg , methotrexate , hours 24 to 26 ; 45 mg , leucovorin , hour 48 .  One hundred sixteen patients entered the study , 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck ( SCCHN ) . Forty-five patients had stage III and 71 had stage IV disease . The two arms were fully comparable . As of April 1986 , 116 patients were evaluable for survival , while 112 were evaluable for toxicity and 105 for response .  Response analysis shows that there were 14 complete responses ( CR ) and 11 partial responses ( PR ) , for an overall response rate ( ORR ) of 52 % in arm A , and 30 CRs and seven PRs , for an ORR of 64.9 % in arm B. The difference in terms of CR between the two arms was statistically significant ( P less than .03 ) . Progression-free survival ( PFS ) was also statistically different , with an advantage for arm B ( P less than .05 ) , but without differences in overall survival . Arm B correlates with a significant increase in mucositis compared with arm A ( P less than .001 ) PURPOSE To determine whether any difference in toxicity or efficacy occurs when head and neck cancer patients are treated postoperatively with (60)C0 , 4 MV , or 6 MV photon beam . METHODS AND MATERIAL S This is a secondary analysis of the Intergroup Study 0034 . Three hundred ninety-two patients were evaluable for comparison between treatment with (60)C0 , 4 MV , or 6 MV photon beam .  All patients had advanced but operable squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx . Patients were r and omized following surgical resection  to receive treatment with either postoperative irradiation alone , or postoperative irradiation plus three cycles of cisplatin and 5-fluorouracil . Patients were categorized as having either " low risk " or " high risk " treatment volumes based on whether the surgical margin was 5 mm or less , presence of extra capsular nodal extension , and /or carcinoma in situ at the surgical margins . Low-risk volumes received 50 - 54 Gy , and high-risk volumes were given 60 Gy . Patients were compared in regards to acute and late radiotherapy toxicities as well as overall survival and loco-regional control according to the beam energy used . RESULTS One-hundred fifty-seven , 140 , and 95 patients were treated by (60)C0 , 4 MV , and 6 MV , respectively . No differences were seen in acute or late toxicity among treatment groups . Locoregional control was achieved in 75 % , 79 % , and 80 % of patients treated with (60)C0 , 4 MV , or 6 MV ( p = 0.61 ) . Patients treated with 6 MV had a higher incidence of ipsilateral neck failure as first event ( 13 % ) than patients treated by (60)C0 and 4 MV ( 9 % ) . This difference was not statistically significant . CONCLUSION No differences in outcome , acute , or late toxicity were discernible in patients with advanced head and neck cancer treated with (60)C0 , 4 MV , or 6 MV . This result should be interpreted with caution as increased incidence , albeit nonsignificant , of ipsilateral neck recurrence was observed in patients treated with 6 MV and the power of the study to detect a statistically significant difference is small Several phase II studies have shown that concurrent chemotherapy and radiotherapy ( RT ) improves the response rates and locoregional control in patients with advanced , unresectable squamous-cell carcinoma of the head and neck ( H&N ) . However , it is still unclear which is the drug of choice to be given with RT . We therefore conducted a r and omized comparison of cisplatin (CDDP)-RT versus carboplatin (CRP)-RT in such patients . The two platinum compounds were given at equitoxic doses . The primary objective of the study was to compare the side effects and the response rates of the two regimens . Radiotherapy was given at conventional dosages , 2 Gy for 5 days every week for a total dose of 64 Gy with CDDP 80 mg/m2 or CRP 375 mg/m2 for three cycles on days 1 , 21 and 42 . At present 53 patients are entered in the study : 27 in the CDDP arm and 26 in the CRP .  The two arms were balanced for all the pre-treatment characteristics . Both the schedules were well tolerated . However , incidence of nausea and vomiting ( p=0.0045 ) ; anemia ( p=0.032 ) and peripheral neuropathy ( p=0.032 ) was significantly greater with CDDP-RT as compared to CRP-RT . On the other h and , CRP-RT gives a significantly higher incidence of stomatitis ( p=0.0067 ) and a marginally worse thrombocytopenia ( p=0.09 ) . The complete response ( CR ) rates were similar in the two arms ( 55.5 % in the CDDP-RT versus 61.5 % in that CRP-RT , respectively ) as well as the overall response rates ( 92.5 % versus 84.5 % , respectively ; p=0.36 ) . The estimated 1 - and 2 year overall and disease-free survival rates were not significantly different in the two arms . In both the groups logistic-regression models showed that those patients with a CR ( p=0.017 ) ; stage III ( p=0.011 ) ; smaller primary ( p=0.025 ) and limited node-involvement ( p<0.001 ) had a significant better survival . We conclude that concurrent chemo-radiotherapy is an effective and safe treatment for patients with locally advanced H&N cancer . The combination CRP-RT possess a similar activity but a different , and perhaps a more favorable , spectrum of toxicity when compared to the CDDP-RT therapy . Survival results need to be assessed in a larger series and followed for a more prolonged time Either intra-arterial infusions of MTX ( 500 mg over 10 days ) or intra-arterial infusions of BLM ( 95 mg over 13 days ) were administered as initial treatment to 85 patients with untreated squamous cell carcinomas of the oral cavity . Tumour regression was assessed 10 - 15 days after the end of chemotherapy . A sequential analysis was used , and BLM demonstrated a significantly greater local efficacy after the 32nd matched pair was assessed . The same results were observed when tumour response rates were compared , ignoring the matching , on the 85 patients , ( P less than 0.001 ) . The response rate for patients with neck nodes was low ( 10/38 ) . Catheter management problems , toxic effects and lethal reactions were 2.5 times more frequent in the MTX group PURPOSE To compare two published schedules of cisplatin plus fluorouracil ( 5-FU ) infusion and radiation as either sequential or concomitant treatment for toxicity and efficacy in patients with unresectable head and neck cancer . PATIENTS AND METHODS This was a r and omized trial between cisplatin 100 mg/m2 over 15 minutes on day 1 plus 5-FU 1.0 g/m2 by continuous infusion on days 1 to 5 , repeated every 3 weeks for three cycles , followed by 70 Gy of radiation in 7 to 8 weeks , versus cisplatin 60 mg/m2 over 15 minutes on day 1 plus 5-FU 800 mg/m2 by continuous infusion on days 1 to 5 plus radiation 2 Gy on days 1 to 5 , repeated every other week for seven cycles . Unresectable head and neck squamous cancer patients not previously treated with radiation or chemotherapy and with a performance status of 0 to 2 were stratified by tumor ( T ) and node ( N ) groupings and performance status and r and omized . RESULTS Two hundred fifteen patients were entered and 214 analyzed , 107 on each arm . After all treatment , overall response rates were different ( P = .003 ) , with similar complete response rates , but more partial responses and fewer patients with no change or progression with concomitant treatment . Cox regression analysis for progression-free survival identified concomitant treatment ( P = .003 ) , Radiation Therapy Oncology Group ( RTOG ) stage III grouping ( P < .0001 ) , performance status ( P = .0002 ) , concomitant treatment ( P = .003 ) , and treating institution ( P = .006 ) as significant . The sequential and concomitant treatments showed similar distant failure patterns ( 10 % and 7 % , respectively ) , but divergent regional failure rates ( 55 % and 39 % ) . Severe and worse toxic events were similar between the treatment programs , but radiation-induced mucositis combined with cisplatin-induced water-losing nephropathy , in the concomitant arm only , dem and ed more supportive care . Survival duration was similar between the treatment arms , but significantly more patients in the sequential arm died of their cancer ( P = .011 ) . CONCLUSION Concomitant treatment offered improved disease control , predominantly of regional disease , but benefit was dependent on the experience of the treating institution . Translation of this benefit into improved survival is not yet evident , with an excess of deaths from other causes in the concomitant arm To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region , a r and omized clinical trial was conducted under the auspices of the Head and Neck Intergroup ( Radiation Therapy Oncology Group , Southwest Oncology Group , Eastern Oncology Group , Cancer and Leukemia Group B , Northern California Oncology Group , and Southeast Group ) . Eligible patients had completely resected tumors of the oral cavity , oropharynx , hypopharynx , or larynx . They were then r and omized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy ( CT/RT ) or postoperative radiotherapy alone ( RT ) . Patients were categorized as having either " low-risk " or " high-risk " treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm , there was extracapsular nodal extension , and /or there was carcinoma-in-situ at the surgical margins . Radiation doses of 50 - 54 Gy were given to " low-risk " volumes and 60 Gy were given to " high-risk " volumes . A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis . The 4-year actuarial survival rate was 44 % on the RT arm and 48 % on the CT/RT arm ( p = n.s . ) . Disease-free survival at 4 years was 38 % on the RT arm compared to 46 % on the CT/RT arm ( p = n.s . ) . At 4 years the local/regional failure rate was 29 % vs. 26 % for the RT and CT/RT arms , respectively ( p = n.s . ) . The incidence of first failure in the neck nodes was 10 % on the RT arm compared to 5 % on the CT/RT arm ( p = 0.03 without adjusting for multiple testing ) and the overall incidence of distant metastases was 23 % on the RT arm compared to 15 % on the CT/RT arm ( p = 0.03 ) . Treatment related toxicity is discussed in detail , but , in general , the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy . Implication s for future clinical trials are discussed To evaluate the efficacy of adjuvant chemotherapy for patients with advanced head and neck squamous cancer , the Head and Neck Contracts Program conducted a three-arm study comparing st and ard surgery and radiation , induction chemotherapy ( cisplatin and bleomycin ) plus st and ard therapy , and induction chemotherapy plus st and ard therapy followed by maintenance cisplatin for 6 months . As previously reported , this trial of 462 patients demonstrated no significant difference in disease-free survival or survival , but a significantly lower metastatic rate in the maintenance arm . To determine whether particular subgroups may have benefited from adjuvant therapy , we evaluated results based on primary site , and tumor ( T ) and node ( N ) stage . Of the 192 patients with oral cavity cancer , those on the maintenance arm had a significantly improved 3-year disease-free survival ( 67 % ) compared with the st and ard arm ( 49 % ) or induction arm ( 44 % ) ( overall P = .05 ) . For hypopharyngeal and laryngeal cancers there was no marked overall benefit . For the 106 patients with T1 plus T2 disease , there was marginal improvement in disease-free survival for the maintenance group ( 72 % ) compared with the st and ard group ( 47 % ) or induction group ( 43 % ) ( overall P = .09 ) . There was no advantage for patients with T3 and T4 disease . There was superior disease-free survival for patients with N1 disease on the maintenance arm ( 70 % ) compared with the st and ard arm ( 42 % ) ( P = .024 ) . The same was true for disease-free survival in 109 patients with N2 disease : st and ard ( 52 % ) , induction ( 30 % ) , maintenance ( 84 % ) ( overall P less than .001 ) . There was no benefit for N3 disease . A significant survival advantage with  maintenance chemotherapy  was only seen for N2 disease ( overall P = .04 ) . Since head and neck cancer patients are a heterogeneous group , there may be particular sites and stages for which adjuvant chemotherapy would be advantageous , and subset analysis can help indicate directions for new trials This study compared the activity and toxicity of fluorouracil (5-FU)/ cisplatin with the combination tegafur and uracil (UFT)/cisplatin in the neoadjuvant treatment of locally advanced-stage III or IV (MO)-head and neck cancer . A total of 67 patients were r and omly assigned to treatment with cisplatin 100 mg/m2 on day 1 followed by either a continuous infusion of 5-FU 1,000 mg/m2/day on days 2 through 6 ( group 1 ) or oral administration of UFT 300 mg/m2/day on days 2 through 20 ( group 2 ) . Both treatments were repeated every 21 days for four cycles . Responding patients received locoregional st and ard radiotherapy ( 50 to 70 Gy ) after chemotherapy .  Group 1 was comprised of 34 patients , 30 of whom were men , with a median age of 57.5 years ; 79 % of this group had a Karnofsky performance status of 90 % to 100 % ; 70 % had a squamous and 29 % an undifferentiated histology . The majority ( 85 % ) had stage IV disease . Of the 33 patients in group 2 , 29 were men . The median age was 56 years . Most ( 88 % ) had a performance status of 90 % to 100 % . More patients had a squamous than an undifferentiated histology ( 82 % vs 18 % ) and most ( 88 % ) had stage IV disease . Overall response in group 1 was 73 % ( 21 % complete ) compared with 79 % ( 18 % complete ) in group 2 . At a median follow-up of 84 months , no significant differences have emerged in overall survival , 15 vs 37 months , or time to progression , 8.5 vs 14.5 months , for groups 1 and 2 , respectively . Toxicity was also similar , except for phlebitis , which occurred significantly more often in group 1 ( 71 % vs 9 % ) . Cisplatin/UFT was as effective as the classic cisplatin/5-FU regimen and has the advantages of outpatient oral administration and a lower incidence of phlebitis BACKGROUND Amifostine has reduced toxicities associated with radiation therapy and platinum-based chemotherapy . In a phase II r and omized trial , we investigated the ability of amifostine to reduce the toxicity of carboplatin plus radiotherapy ( RCT ) in patients with head and neck cancer . PATIENTS AND METHODS Thirty-nine patients with stage III or IV squamous cell carcinomas of the head and neck received RCT  ( following surgery or as primary treatment ) . Radiotherapy was given five days per week with daily fractions of 2 Gy , up to a total dose of 60 Gy in conjunction with carboplatin 70 mg/m2 on days 1 through 5 and days 21 through 26 . Eligible patients were r and omised to receive RCT alone or preceded by a rapid infusion of amifostine ( 500 mg ) on the days when carboplatin was administered . RESULTS Patients receiving amifostine + RCT ( n = 25 ) had significantly reduced mucositis ( P = 0.0001 ) and xerostomia ( P = 0.0001 ) in comparison with patients receiving RCT alone ( n = 14 ) . Additionally , patients receiving amifostine + RCT had significantly less thrombocytopenia ( P = 0.001 ) and leukopenia ( P = 0.001 ) . At 12 months following therapy , 79 % of patients receiving amifostine + RCT had no evidence of disease compared with 64 % of those receiving RCT alone . CONCLUSIONS Amifostine reduces the  RCT -induced toxicities in patients with head and neck cancer and has no negative impact on antitumour efficacy PURPOSE To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and /or node-positive nonmetastatic carcinomas of the head and neck , compared with hyperfractionated radiotherapy alone . PATIENTS AND METHODS From July 1994 to July 2000 , 224 patients with squamous cell carcinomas of the head and neck ( excluding nasopharynx and paranasal sinus ) were r and omly assigned to hyperfractionated radiotherapy ( median dose , 74.4 Gy ; 1.2 Gy twice daily ) or the same radiotherapy combined with two cycles of concomitant cisplatin ( 20 mg/m2 on 5 days of weeks 1 and 5 ) . The primary end point was time to any treatment failure ; secondary end points were locoregional failure , metastatic relapse , overall survival , and late toxicity . RESULTS There was no difference in radiotherapy between both treatment arms ( 74.4 Gy in 44 days ) . The full cisplatin dose was applied in 93 % and 71 % of patients during the first and second treatment cycles , respectively . Acute toxicity was similar in both arms . Median time to any treatment failure was not significantly different between treatment arms ( 19 months for combined treatment and 16 months for radiotherapy only , respectively ) and the failure-free rate at 2.5 years was 45 % and 33 % , respectively . Locoregional control and distant disease-free survival were significantly improved with cisplatin ( log-rank test , P = .039 and .011 , respectively ) . The difference in overall survival did not reach significance ( log-rank test , P = .147 ) . Late toxicity was comparable in both treatment groups . CONCLUSION The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin A phase III r and omized comparison of radiotherapy alone versus combination chemotherapy and concurrent continuous‐course radiotherapy was performed at the Clevel and Clinic Foundation Between August 1983 and December 1986 , 116 previously untreated patients with squamous cell carcinoma of the head and neck were r and omized to receive induction chemotherapy followed by radiotherapy given in conventional fractions ( 55 patients , arm A ) or an alternating chemotherapy and radiotherapy ( 3 courses of 20 Gy , 10 daily fractions each ; 61 patients , arm B ) . The same chemotherapy was used in both arms : 6 mg/m2 vinblastine sulfate , hour 0 ; 30 mg bleomycin , hour 6 ; 200 mg methotrexate , hours 24 to 26 ; 45 mg leucovorin , hour 48 .  Forty-five patients had stage III disease and 71 had stage IV disease . All patients were evaluated for  survival ,  112 for  toxicity , and 105 for analyses of response and time from the start of treatment until progression of disease . At the end of the combined treatment , we observed an overall response rate of 52 % in arm A and an overall response rate of 64.9 % in arm B. The incidence of mucositis was more relevant in arm B compared to arm A ( P less than .00004 ) . The difference in complete response , progression-free survival , and survival was statistically significant , with an advantage for arm B ( P less than .03 , P less than .02 , and P less than .03 , respectively ) . The analysis at a median follow-up of 36 months ( range = 19 to 59 ) demonstrates a higher effectiveness for the alternating program Between February 1978 and January 1984 , 222 eligible patients were r and omised in a multicentre trial of preoperative intra-arterial chemotherapy in the treatment of oral cavity and oropharynx carcinoma . Patients were r and omised between either surgery or preoperative chemotherapy .  This latter group received vincristine and bleomycin for 12 days . Patients were stratified according to the primary site : floor of the mouth ( FM ) versus posterior oral cavity or oropharynx ( POC ) and institution . The FM group received postoperative radiotherapy depending upon quality of the margins and lymph-node pathological involvement , when it was systematic ally applied in the POC group . Tumour regression after chemotherapy either complete ( CR ) or partial ( PR greater than 50 % ) was observed in 48 % in the FM group and 41 % in the POC group , and lymph-node regression ( CR + PR ) was respectively 15 % and 23 % . Some discrepancies appeared between clinical regression and pathological response , and the number of cases without histological response was clearly higher than the number of cases without clinical response . The overall survival showed a statistically significant difference ( P = 0.048 ) between FM and POC groups . In the FM group , median survival in the chemotherapy arm was estimated at 7 years compared with 3 years in the surgery arm . In the POC group , median survival was estimated at 3 years in both treatment arms . Chemotherapy lowered the uncontrolled disease and local recurrence in the FM group . These differences do not exist in the POC group , which may be due to the systematic ally postoperative radiotherapy Fifty-four previously untreated patients with locally advanced resectable squamous cell carcinoma of the head and neck ( SCCHN ) were enrolled into a prospect i ve r and omized controlled trial to evaluate whether induction chemotherapy improves the disease-free survival compared to the st and ard treatment ( surgery + radiation ) . Thirty patients received chemotherapy , which consisted of cisplatin 20 mg/m2 day 1 - 5 , bleomycin 10 mg/m2 , continuous infusion from day 3 - 7 , and methotrexate 40 mg/m2 given on day 15 and day 22 . The cycle was repeated on day 29 for two cycles . Twenty patients completed chemotherapy courses . Overall response rate was 77 % ( 23 of 30 ) . No survival improvement was observed . Kaplan-Meier analysis indicated survival ( and 95 % confidence interval ) at 3 years was 57 % ( 29%-84 % ) for the control group and 60 % ( 34%-87 % ) for the chemotherapy group , and 57 % ( 29%-84 % ) and 45 % ( 12%-78 % ) at 4 years ( P = 0.736 ) . However , patients who had a complete response were significantly better in terms of long-term survivors ( 5 of 7 patients were still alive ) , in contrast to patients who had partial responses among whom only 4 of 16 were alive . Toxicities of this induction protocol are tolerable ; one chemotherapy-related death occurred from profound thrombocytopenia . If efforts in determining a chemotherapy-sensitive patient were successfully established , along with a better sequence and the discovery of new and safer drugs , survival of SCCHN should be much improved Purpose Radiotherapy ( RTx ) has been considered as the treatment for locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . However , with only conventional fractionation ( Cfx ) , response rates are relatively low . In this study , we report the results of hyperfractionation ( Hfx ) RTx with concurrent docetaxel , cisplatin and 5-fluorouracil ( TPF ) chemotherapy ( CTx ) in patients with locally advanced SCCHN and compare Hfx and Cfx RTx with concurrent TPF CTx . Methods Fifty patients with previously untreated stage III – IV SCCHN were entered into this study . Eligible patients received RTx delivered using arm 1 : Hfx at 1.2 Gy/fraction , twice daily , 5 days/week to 76.8 Gy/64 fractions , and arm 2 : Cfx at 2 Gy/fraction/day , 5 days/week to 70 Gy/35 fractions . Patients received 2 cycles CTx every 4 weeks . The doses were docetaxel 50 mg/m2 ( day 1 ) , cisplatin 60 mg/m2 ( day 4 ) , and 5-FU 600 mg/m2/day ( days 1–5 ) . Results The overall clinical response rate and the pathological CR were 100 % ( 25/25 ) and 84 % ( 21/25 ) in arm 1 , and 100 % ( 25/25 ) and 80 % ( 20/25 ) in arm 2 . Local – regional control was better significant in arm 1 than arm 2 ( P = 0.048 ) . There were also trend toward improved disease-free survival ( P = 0.059 ) and overall survival ( P = 0.078 ) in arm 1 . Mucositis was significantly more frequent in arm 1 ( P = 0.048 ) . Conclusion There were trend toward improved local – regional control , disease-free survival and overall survival in Hfx RTx with concurrent TPF CTx , compared to Cfx RTx with concurrent TPF CTx 5532 Background : In 1986 , the Gruppo di Studio sui Tumori Testa e Collo ( GSTTC ) started a multicenter r and omized trial comparing induction CT with Cisplatin and 5Fluorouracil 120h c.i . ( PF ) followed by locoregional treatment ( Surgery+RT or RT alone ) ( Group A ) versus locoregional therapy ( LRT ) alone ( Group B ) in resectable or unresectable stage III-IVM0 H&N Squamous Cell Carcinoma . Our previous report ( J Natl Cancer Inst 86 : 265 - 72,1994 ) , showed that 4 cycles of PF before LRT improved local control , decreased the incidence of distant metastases and increased Disease-Free-Survival ( DFS ) and Overall Survival ( OS ) in the subgroup of inoperable patients . METHODS From March 1986 to February 1990 , 237 patients with stage III-IVM0 were r and omized to 4 neoadjuvant PF followed by LRT or LRT alone . After a minimum follow-up of 10 years , the two treatments were compared in univariate and multivariate analysis for OS . RESULTS Of the 237 patients , 118 group A and 119 group B , 92 % and 90 % respectively were male , 25 % and 28 % hypopharynx , 59 % and 54 % oropharynx , 15 % and 16 % oral cavity . KPS ≥70 in 95 % and 92 % ; stage III 35 % and 37 % . Inoperable 71 % and 73 % . The OS for the entire group of patients at 5 and 10 years was 23 % and 19 % for Group A and 16 % and 9 % for Group B ( p=0.13 ) . No difference was observed in operable patients . In inoperable patients , the OS at 5 and 10 years was 21 % and 16 % for Group A and 8 % and 6 % for RT arm ( p=0.04 ) . With Cox analysis applied to all r and omized patients , the HR and p values were respectively 1.251 and 0.292 for site ; 3.28 and 0.002 for T ; 1.66 and 0.036 for N ; 0.92 and 0.56 for treatment arm . CONCLUSION The analyses at 10 years has confirmed all the previously reported data . Four cycles of neoadjuvant CT remains a promising approach for advanced H&N cancer with a significant OS advantage in inoperable patients . No significant financial relationships to disclose PURPOSE To report the final results of a prospect i ve r and omized trial that aim ed to evaluate efficacy and toxicity of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV squamous cell carcinoma of the head and neck and histological evidence of extracapsular spread of tumor in lymph node metastase(s ) . METHODS AND MATERIAL S Radiotherapy was delivered using a daily dose of 1.7 Gy for the first 54 Gy and 1.8 to 2 Gy until the completion of the treatment . Cisplatin 50 mg i.v . with forced hydratation was given or not every week ( i.e. , seven to nine cycles ) concurrently with radiotherapy . A total of 44 patients were treated by irradiation only ( RT group ) and 39 by irradiation with chemotherapy ( CM group ) . RESULTS The RT group displayed a higher rate of loco-regional failures as compared to CM group ( 41 vs. 23 % ; p = 0.08 ) . The overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival were better in CM group as compared to RT group with statistically significant differences . Survival without loco-regional treatment failure was better in the CM group , the difference being close to the level of significance ( p = 0.05 ) . Survival without distant metastases were comparable in the two therapeutic groups . Ten severe late complications were observed , four in the RT group ( 17 % ) and six in the CM group ( 22 % ) . Cox univariate analysis confirmed the importance of the therapeutic modality in predicting the overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival . CONCLUSIONS The present final report of this phase III study confirms preliminary results . The concomitant use of 50 mg weekly Cisplatin infusion and postoperative radiation improved loco-regional control and survival . No significant increase of late radiation complications was observed in the CM group In 1980 , the Southwest Oncology Group instituted a multi-institutional , prospect i ve , r and omized phase III trial to evaluate whether inductive chemotherapy improved survival in patients with advanced stage resectable squamous cell carcinoma of the head and neck . From a group of 158 eligible patients , 76 were r and omized to conventional treatment  ( surgery and postoperative radiotherapy ) , and 82 were assigned to experimental treatment  ( induction chemotherapy , surgery , postoperative radiotherapy ) . Median follow-up for living patients was approximately 5 years . These analyses include chemotherapy responses and toxicities , surgical complications , radiotherapy toxicities , patient compliance , survival time , and patterns of treatment failure . Overall chemotherapy response was 0.70 ( 0.19 CR , 0.51 PR ) . The median survival time for conventional treatment was longer than the time for patients receiving preoperative chemotherapy , although the survival time differences were not statistically significant . This final analysis demonstrates no benefit in survival using preoperative chemotherapy for advanced stage , resectable head and neck squamous cell carcinoma To determine the efficacy of adjuvant chemotherapy in patients with advanced head and neck squamous carcinoma , the National Cancer Institute initiated a multi-institutional , prospect i ve r and omized trial termed the Head and Neck Contracts Program . Between 1978 and 1982 , 462 patients with resectable Stage III or IV cancers of the oral cavity , larynx , or hypopharynx were r and omly assigned to receive one of three treatment options : induction chemotherapy consisting of a single course of cisplatin and bleomycin followed by st and ard therapy ( surgery and postoperative radiotherapy ) ; induction chemotherapy and st and ard therapy followed by maintenance chemotherapy which consisted of six cycles of monthly cisplatin ; or st and ard therapy alone .  Toxicity from the chemotherapy regimens was minimal . Induction therapy result ed in an overall complete response of 3 % and a partial response in 34 % of patients . With a median follow-up of 61 months , overall survival and disease-free survival were not markedly different among the three groups ( P = 0.86 and P = 0.16 , respectively ) . The incidence of distant relapse was reduced in the maintenance group compared to st and ard or induction groups ( P = 0.025 and P = 0.021 , respectively ) and time to first distant relapse was prolonged ( P = 0.032 and P = 0.022 , respectively ) . The results confirm the feasibility of administering chemotherapy prior to surgery or radiation in patients with head and neck cancer but fail to demonstrate a significant impact of one cycle of induction chemotherapy  on clinical outcome . The suggestion that distant relapse rates may be reduced with the addition of maintenance chemotherapy supports the need to test traditional adjuvant approaches in patients with advanced head and neck cancer Chemoradiation is the preferred treatment for advanced stage IV head and neck cancer . Higher doses of chemotherapy yielded promising results in vitro and vivo , confirmed by intra‐arterial ( IA ) cisplatin‐based chemoradiation in phase 2 studies A prospect i ve r and omized trial was performed in 67 institutions for the purpose to evaluate the efficacy of adjuvant chemotherapy after radical treatment of head and neck carcinoma . A comparison was made between the following two groups ; one-year oral administration of UFT , 300 mg/day , after radical treatment ( UFT group ) ; and a non-treatment group .  Patients were classified under the following three categories ; 1 ) stage II-IV , receiving radical surgery ; 2 ) stage II , receiving radical radiotherapy ; and 3 ) nasopharyngeal cancer . The numbers of cases were 424 , 111 and 25 , respectively , and they were r and omized into two groups . The numbers of eligible cases were 398 , 105 and 25 , respectively . Statistical analysis was performed in the cases receiving radical surgery and in those receiving radical radiotherapy . As the results , in cases receiving radical surgery no significant difference was observed in 3-year survival rates ( 77.9 % for UFT group vs 72.9 % for non-treatment group ) or 3-year relapse-free rates ( 73.4 % for UFT group vs 66.2 % for non-treatment group ) between the two groups . However , the distant relapse rate was significantly lower in the UFT group than in the non-treatment group ( 7.9 % vs 14.6 % ; p = 0.034 ) . In the cases receiving radical radiotherapy , no significant differences was observed in either 3-year survival rates or 3-year relapse-free rates . Thus it was suggested that UFT maintenance therapy might suppress the distant metastasis after radical surgery . We considered a further confirmative trial for patients at high risk of distant metastasis after radical surgery  to be advisable In 1961 , a r and omized study was begun at the University of Wisconsin Medical Center in which the treatment of advanced squamous cell carcinoma of the head and neck with  radiation therapy was compared with combined treatment with radiation therapy and 5-Fluorouracil .  One hundred and thirty-six patients with primary lesions in the oral cavity , the base of the tongue , and the oropharynx were analyzed . Both local control and survival were better in the combined treatment group than in the group with radiation therapy alone . However , in only the oral cavity patient population was the difference statistically significant . Both acute and late complications were also increased in this group of patients who received combined treatment The current study presents mature results from a Phase III r and omized trial comparing radiation therapy and concurrent chemoradiotherapy in patients with resectable American Joint Committee on Cancer Stage III and IV disease Between 1975 and 1978 , 23 patients with Stage IV , unresectable , squamous cell carcinoma of the head and neck were r and omized to receive radiotherapy ( RT , 11 patients ) , or radiotherapy‐chemotherapy ( RT & CT , 12 patients ) . The response rate for the 12 RT & CT patients was four complete remissions ( CR ) and four partial remissions ( PR ) ; the 11 RT patients had one CR and three PR . The presence of a responses ( CR or PR ) significantly enhanced the median survival ( 14 vs. 5 months ; P = 0.005 ) . The duration of objectives remission was longer among the RT & CT patients when compared with RT patients ( 6 vs. 2.3 months , P = 0.18 ) . The median survival of the RT & CT group was 12 months compared with 5.6 months for the RT group ( P = 0.13 ) . One RT & CT patient remains alive with disease at 44 months , one RT patient remains alive without disease at 30 months . The present chemotherapy regimen did not modify the pattern of failure and only marginally increased patient survival . It did , however , increase the response rate . The authors plan to reactivate the trial with modification in the induction chemotherapy and the addition of postradiation maintenance CT consisting of sequential bleomycin and cis‐platinum BACKGROUND Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis . Following a previous phase II study , this phase III multicenter trial was conducted between November 1997 and March 2002 . METHODS Nontreated , strictly unresectable cases were eligible .  Twice-daily radiation : two fractions of 1.2 Gy/day , 5 days per week , with no split ( D1 - ->D46 ) . Total tumor doses : 80.4 Gy/46 day ( oropharynx ) , 75.6 Gy/44 day ( hypopharynx ) . Chemotherapy ( arm B ) : Cisplatin 100 mg/m2 ( D1 , D22 , D43 ) ; 5FU , continuous infusion ( D1 - ->D5 ) , 750 mg/m2/day cycle 1 ; 430 mg/m2/day cycles 2 and 3 . RESULTS A total of 163 evaluable patients .  Grade 3 - 4 acute mucositis 82.6 % arm B/69.5 % arm A ( NS ) ; Grade 3 - 4 neutropenia 33.3 % arm B/2.4 % arm A ( p < 0.05 ) . Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months ( p < 0.01 ) . At 24 months , overall survival ( OS ) , disease-free survival ( DFS ) , and specific survival ( SS ) were significantly better in arm B. OS : 37.8 % arm B vs. 20.1 % arm A ( p = 0.038 ) ; DFS : 48.2 % vs. 25.2 % ( p = 0.002 ) ; SS : 44.5 % vs. 30.2 % ( p = 0.021 ) . No significant difference between the two arms in the amount of side effects at 1 and 2 years . CONCLUSION For these unresectable cases , chemoradiation provides better outcome than radiation alone , even with an " aggressive " dose-intensity radiotherapy schedule BACKGROUND The role of postoperative radiotherapy and carboplatin in squamous cell carcinoma of the head and neck ( SCCHN ) has not been established . METHODS Patients with macroscopically resected stage III/IV SCCHN with high-risk pathologic features ( > or =3 lymph nodes , extracapsular extension , perineural or angiolymphatic invasion , or involved margins ) were r and omized to receive postoperative radiotherapy alone ( arm A ) or the same radiotherapy plus carboplatin 100 mg/m intravenously once weekly during radiation ( arm B ) . The primary endpoint was 2-year disease-free survival . RESULTS Seventy-six patients were r and omized , of whom 72 were eligible and analyzable ( 36 in each arm ) . The study was prematurely closed because of slow accrual . With a median follow-up of 5.3 years , the disease-free survival at 2 and 5 years was 71 % and 53 % in arm B versus 58 % ( P = .27 ) and 49 % ( P = .72 ) in arm A. The overall survival at 2 and 5 years was 74 % and 47 % in arm B versus 51 % ( P = .04 ) and 41 % ( P = .61 ) in arm A. Serious toxicities were infrequent in both arms . CONCLUSIONS We could not demonstrate a benefit with the addition of carboplatin to postoperative radiotherapy , possibly because of insufficient sample size A prospect i ve clinical trial was design ed to evaluate efficacy , toxicity , and patient compliance of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV S.C.C. of the head and neck and histological evidence of extra-capsular spread of tumor in lymph node metastase(s ) .  Cisplatin 50 mg IV with forced hydration was given or not every week ( i.e. , 7 to 9 cycles ) concurrently with radiotherapy .  Between 1984 and 1988 , 83 patients were r and omized : 44 were treated by irradiation without chemotherapy ( RT group ) and 39 by the combined modality ( CM group ) . There was no significant difference between the two groups in terms of patient characteristics , primary sites , tumor differentiation , T.N. stages , or postoperative prognostic factors . All patients completed the planned radiotherapy . There were seven severe toxicities ( greater than grade 3 ) in the RT group . In the CM group , 30 severe toxicities occurred in 16/39 ( 41 % ) patients but none was life-threatening . Seven of 39 ( 18 % ) patients received less than two-thirds of the scheduled Cisplatin courses because of intolerance , mainly nausea and vomiting . Preliminary results show a better disease-free survival for the CM group ( 65 % at 24 months ) than for the RT group ( 41 % at 24 months ) . This significant difference is largely due to increased loco-regional control in the CM group ( 79 % vs 59 % ) , the actuarial distant metastasis rates in patients controlled above the clavicles not being statistically different in the two groups Inoperable cases of advanced squamous cell carcinomas in the head and neck area which have a very poor prognosis are often treated by a combined radio- and chemotherapy . Tumor remissions up to 70 % are induced by both radiotherapy and chemotherapy alone ; an increase of the survival time is not reported . The present r and omized study investigates the efficacy of two therapy schemes , i.e. chemotherapy alone and chemotherapy combined with irradiation .  Tumor remissions of 75 % were achieved in 80 evaluable patients , the median remission period was four months and the median survival period eleven months . The survival curves do not show any dependence of the survial time on the size of tumor or metastases . Only responders had a significantly longer survival time than non-responders Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing radical radiation therapy to the primary tumour and associated lymph node areas with a combination of radiation therapy plus chemotherapy . The distribution of tumour types and stages was similar in the two treatment groups . The response rates to radiation therapy alone ( 50 % complete plus parital response ) and to radiation therapy plus chemotherapy ( 60 % complete plus partial response ) were not significantly different . However , a significant difference in survival was found between the two groups . The median duration of survival for the patients treated by means of radiation therapy alone was 18 weeks ; that for the combined therapy was 36 weeks . The combination of radical radiation therapy plus intermittent high-dose chemotherapy was well tolerated and appears to be an approach that warrants further trial From January 1978 to January 1988 , 859 patients with T3-T4 , NO-3 , MO were r and omly allocated to receive either : Group A--60Co 60 , 60 Gy in 30 fractions ; Group B--60Co , 70.4 Gy in 64 fractions ; Group C--60Co , 60 Gy in 30 fractions plus chemotherapy ( 5 Fu , 250 mg/m2/IV every 2 days ) . Chemotherapy and radiotherapy were combined simultaneously . The average age was 56 years ; the male/female ratio was 802/57 . Median performance status ( ECOG scale ) was 1 ( range 0 - 2 ) . The TNM distribution as UICC criteria was T3 529 patients ; T4 330 patients ; No 217 patients ; N1 52 patients ; N2 319 patients ; and N3 271 patients . The primary sites were nasopharynx 92 , oral cavity 252 , hypopharynx 119 , larynx 310 , and others ( sinuses and unknown primary ) 86 . Complete response was achieved in 188/277 patients in Group A ( 67.8 % ) , 254/282 patients in Group B ( 90 % ) , and 289/300 in Group C ( 96.3 % ) . All patients were followed and statistical analysis shows a significant improvement in median duration of response , as well as survival for Groups B and C compared with Group A. No significant differences were seen between Group B and C. The acute toxicity was mucositis , skin toxicity , bone marrow depression . A mean temporary weight loss of 4.9 Kg was observed with a range of 2.3 - 10.5 Kg TWO COURSES OF PREOPERATIVE CHEMOTHERAPY ( methotrexate , bleomycin , cisplatin ) were combined with split-course irradiation ( 2,000 rad/10 preop . , 4,000 rad/20 postop . ) and prospect ively compared with st and ard therapy ( surgery and /or irradiation alone ) for locally advanced or recurrent oral/pharyngeal squamous cancer . The chemoradiotherapy arm ( Ch-XRT ) had 31 patients ; the st and ard therapy arm 28 r and omized ( RC ) and 20 concomitantly-treated ( CC ) patients . Treatment-related mortality was 17 % for Ch-XRT ; 10 % for RC + CC . Number of patients NED at completion of treatment was 74 % for Ch-XRT ; 83 % for RC + CC ( NS ) . Median survival , however , was 17 months for Ch-XRT , 9 months for CC , and 12 months for RC . In addition , survival at 40 + months was 45 % for Ch-XRT versus 21–22 % for RC and CC ( p < 0.05 ) . Thus , Ch-XRT seems to have promise in advanced oral/pharyngeal cancer , but needs revision to decrease toxicity PURPOSE To prove an expected benefit of concurrent radiochemotherapy ( RCT ) , a two-arm r and omized multicentric study was performed . In a subgroup analysis the influence of pretherapeutical hemoglobin level ( p-Hb ) on survival under locoregional control ( SLC ) was tested . PATIENTS AND METHODS The study included primarily untreated Stage III/IV ( International Union Against Cancer [ UICC ] ) oropharyngeal and hypopharyngeal carcinomas . Patients were r and omized to receive either hyperfractionated ( hf ) and accelerated ( acc ) RCT with two cycles 5-fluorouracil ( 600 mg/m(2)/day ) and carboplatin ( 70 mg/m(2)/day ) on Days 1 - 5 and 29 - 33 or hf-acc radiotherapy ( RT ) alone . Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique . RESULTS After a median follow-up time of 57 months , SLC is significantly better in RCT than in RT ( p = 0.01 ) , with median SLC of 17 months and 11 months , respectively . Also overall survival ( OS ) shows a benefit for RCT ( p = 0.016 ) , with a median survival of 23 months for RCT and 16 months for RT . However , the benefit in SLC and OS is not seen in hypopharyngeal carcinomas . In a multivariate analysis of oropharyngeal cancer patients , p-Hb levels lower than 12.7 g/dL result ed in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels > 13.8 g/dL did not further improve SLC . CONCLUSIONS Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas . P-Hb levels > 13.8 g/dL do not further improve SLC Two regimens of neoadjuvant chemotherapy for previously untreated patients with locally advanced head and neck cancer were compared with the goal of identifying a regimen with a greater than 50 % complete response ( CR ) rate . Patients with a performance status of 0 to 2 and normal end‐organ function were r and omized to receive either four cycles of neoadjuvant methotrexate , cisplatin , and continuous infusion 5‐fluorouracil ( 5‐FU ) ( MPF ) ( arm A ) , or four cycles of bleomycin , cisplatin , and methotrexate ( PBM ) alternating with cisplatin and 5‐FU ( PF ) ( arm B ) . Patients with a performance status of greater than 2 or a carbon monoxide diffusion capacity of less than 50 % of the predicted value were assigned to the arm A regimen but were analyzed separately ( arm C ) . Local therapy consisted of surgery ( for patients with resectable disease ) or radiation therapy followed by two cycles of adjuvant chemotherapy with the regimen that was administered initially . of the 42 patients who were evaluated , 16 were r and omized to arm A , 13 to arm B , and 13 to arm C. The clinical CR rate was 19 % on arm A ( 95 % confidence interval , 0 % to 38 % ) , 39 % on arm B ( 95 % confidence interval , 12 % to 66 % ) ( P = 0.41 ) , and 54 % on arm C ( 95 % confidence interval , 27 % to 81 % ) . At a median follow‐up time of 35 months , the 2‐year actuarial survival rate was 61 % on arm A , 69 % on arm B ( the P value was not significant ) , and 38 % on arm C. The 2‐year survival rate for all 42 patients who were treated was 57 % and the median survival time was 31 months . Toxicities of neoadjuvant chemotherapy on all arms consisted of mild to moderate myelosuppression and renal toxicity . The incidence of moderate to severe mucositis was significantly higher on arm A than arm B ( P = 0.02 ) . Two cycles of adjuvant chemotherapy were administered to only 11 of 42 patients due to patient refusal or cumulative toxicity . in conclusion , both neoadjuvant chemotherapy regimens result ed in similar response and survival rates , but mucositis was more severe with arm A. However , since neither regimen was likely to cause a CR rate of greater than 50 % , this study was closed to further patient accrual PURPOSE To determine the response rate , survival and toxicity of infusional cisplatin plus fluorouracil ( CF ) versus cisplatin plus paclitaxel ( CP ) in patients with incurable squamous cell cancer of the head and neck , with the hypothesis that CP is superior . PATIENTS AND METHODS Two hundred eighteen patients with locally advanced , recurrent , or metastatic disease were r and omly assigned to CF ( cisplatin 100 mg/m2 day 1 and fluorouracil 1,000 mg/m2/24 hours by continuous intravenous infusion day 1 through 4 ) or CP ( cisplatin 75 mg/m2 day 1 and paclitaxel 175 mg/m2 over 3 hours on day 1 ) . Cycles were repeated every 3 weeks until progression or a minimum of 6 cycles with complete response or stable disease . The primary outcome was overall survival . Secondary outcomes included response rate and toxicity . RESULTS No significant difference in overall survival or response rate was seen . Estimated median survival was 8.7 months in the CF group and 8.1 month in the CP group . Objective response rate ( complete response plus partial response ) was 27 % in the CF group and 26 % in the CP group . Toxicity was similar between groups , with the most frequent including myelosuppression , thrombocytopenia , anemia , nausea , vomiting , and stomatitis . A total of 12 deaths occurred ( CF , seven ; CP , five ) during treatment ; eight from infection , two from hemorrhage , one from cardiac causes and one from unknown causes . Gastrointestinal and hematologic toxicities were more common in the CF group , whereas neurotoxicity was equivalent between groups . CONCLUSION This phase III , r and omized , multicenter trial showed no difference in survival between patients treated with CF or CP The value of a combination of methotrexate , bleomycin and hydroxyurea with vs. without cisplatin was r and omly examined in 62 evaluable patients with previously untreated ( 44 patients ) and recurrent ( 18 patients ) squamous cell carcinoma of the head and neck .  Methotrexate ( 30 mg/m2 ) and bleomycin ( 15 mg ) were given intravenously weekly , hydroxyurea ( 1000 mg/m2 ) per os 3 times per week for 4 weeks . Cisplatin ( 60 mg/m2 ) was added on Day 1 every month . A higher overall response rate was observed with the cisplatin-containing regimen ( 66 % , included 17 % complete ) as compared with 27 % ( 3 % complete ) with the 3-drug combination ( P value 0.0025 ) . The cisplatin-containing regimen was more active in both previously untreated patient group and in the group recurrent patients . Toxicity was more pronounced in the cisplatin regimen and necessitated frequently reduced drug dosages . No survival difference was observed between the treatment groups . Median survival in previously untreated patients was 16.2 months and 7.2 months in patients who failed conventional local treatment . It is concluded that a cisplatin-containing regimen is more effective in advanced head and neck carcinoma than the same combination without cisplatin BACKGROUND The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma ( HNSCC ) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospect i ve clinical trial . METHODS We prospect ively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group ( ECOG ) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and st and ard fractionation radiation therapy .  The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction ( PCR ) and in situ hybridization . Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis . The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age , ECOG performance status , stage , and other covariables was estimated by use of a multivariable Cox proportional hazards model . All statistical tests were two-sided . RESULTS Genomic DNA of oncogenic HPV types 16 , 33 , or 35 was located within tumor cell nuclei of 40 % ( 95 % confidence interval [ CI ] = 30 % to 50 % ) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR . Compared with patients with HPV-negative tumors , patients with HPV-positive tumors had higher response rates after induction chemotherapy ( 82 % vs 55 % , difference = 27 % , 95 % CI = 9.3 % to 44.7 % , P = .01 ) and after chemoradiation treatment ( 84 % vs 57 % , difference = 27 % , 95 % CI = 9.7 % to 44.3 % , P = .007 ) . After a median follow-up of 39.1 months , patients with HPV-positive tumors had improved overall survival ( 2-year overall survival = 95 % [ 95 % CI = 87 % to 100 % ] vs 62 % [ 95 % CI = 49 % to 74 % ] , difference = 33 % , 95 % CI = 18.6 % to 47.4 % , P = .005 , log-rank test ) and , after adjustment for age , tumor stage , and ECOG performance status , lower risks of progression ( hazard ratio [ HR ] = 0.27 , 95 % CI = 0.10 to 0.75 ) , and death from any cause ( HR = 0.36 , 95 % CI = 0.15 to 0.85 ) than those with HPV-negative tumors . CONCLUSION For patients with HNSCC of the oropharynx , tumor HPV status is strongly associated with therapeutic response and survival PURPOSE To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck . PATIENTS AND METHODS Two hundred ten patients with locally advanced , recurrent , or metastatic disease were r and omly placed in either Arm A , paclitaxel 200 mg/m(2 ) ( 24-hour infusion ) + cisplatin 75mg/m(2 ) + granulocyte colony-stimulating factor , or Arm B , paclitaxel 135 mg/m(2 ) ( 24-hour infusion ) + cisplatin 75 mg/m(2 ) . Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses . Primary outcomes were event-free and overall survival . RESULTS No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens . The estimated median survival was 7.3 months ( 95 % confidence interval , 6.0 to 8.6 ) . The 1-year survival rate was 29 % , and event-free survival was 4.0 months . The objective response rate ( complete response plus partial response ) was 35 % for the high-dose patients and 36 % for the low-dose patients . Myelosuppression was the most frequent toxicity : grade 3 or 4 granulocytopenia , 70 % of patients in Arm A and 78 % in Arm B ; febrile neutropenia , 27 % of patients in Arm A and 39 % in Arm B. Grade 5 toxicities occurred in 22 patients ( 10.5 % ) . Treatment was terminated early in 31 % because of excessive toxicity or patient refusal . CONCLUSION This phase III multicenter trial showed ( 1 ) no advantage for high-dose paclitaxel and ( 2 ) excessive hematologic toxicity associated with both regimens . Therefore , neither of the paclitaxel regimens evaluated in this trial can be recommended BACKGROUND AND PURPOSE Fractionation strategies delivered over 4 weeks are of clinical and radiobiological interest because treatment is completed before radiotherapy ( RT ) induced clonogen proliferation commences in earnest approximately 3 to 4 weeks into a course of RT . We wished to test the clinical hypothesis that an increased total dose delivered over 4 weeks with smaller than st and ard doses per fraction in locally advanced squamous cell carcinoma ( SCC ) may result in relative protection of late responding tissues and an increased tumor control compared to a conventional daily course in the same overall time . MATERIAL S AND METHODS Between 1988 and 1995 a r and omized controlled trial employing RT alone was undertaken at the Princess Margaret Hospital that included 331 eligible patients with T3 or T4 N0 or any N-positive oropharynx , hypopharynx , or larynx primary SCC . RT was r and omly assigned to one of two 4 week schedules , either 51 Gy in 20 equal daily fractions , termed conventional fractionation ( CF ) , or 58 Gy in 40 equal fractions given twice per day as a hyperfractionated ( HF ) experimental arm . RESULTS The 5-year local relapse rate was reduced in the HF ( 41 % ) compared to the CF arm ( 49 % ) . This difference was marginally not significant ( p=0.082 ) when the effect was not adjusted . When the effect of the treatment was adjusted by Cox model for clinical factors that included N-category , ECOG performance status , site of disease , T-category , age , hemoglobin , and gender the HF achieved a significant effect ( p=0.02 ) . Survival ( 40 % vs. 30 % ) was also improved with HF compared to CF arm . This difference was only marginally not significant ( p=0.069 ) but again achieved statistical significance when the model was adjusted for clinical factors ( p=0.01 ) . Similar results were observed for disease free survival . Although reversible acute toxicity was increased with HF , the overall 5-year rate of grade 3 and 4 late toxicity for the CF was 10.5 % compared to 7.7 % in the higher dose HF arm . CONCLUSIONS HF delivered in 4 weeks permits enhanced RT doses achieving improved tumor control , without increased late toxicity , compared to daily fractionated radiotherapy in the same overall time One hundred seventeen patients with advanced squamous cell carcinoma of the head and neck were treated and placed r and omly between two combination protocol s , one with adriamycin and the other without . Responses ( more than 50 % tumor regression ) were 67 % overall with 63 % responding to the combination without adriamycin and 82 % responding to the protocol containing it . The increase in the response rate seen with the addition of adriamycin was not statistically significant . The degree of response to chemotherapy was reduced by prior radiotherapy BACKGROUND We report the results of a multicenter r and omized phase III study , assessing quality of life ( QOL ) in intra-arterial ( IA ) versus st and ard intravenous ( IV ) chemoradiation in advanced head and neck cancer . METHODS Two hundred seven patients with inoperable stage IV disease-152 men and 55 women ; mean age , 55 years-were included in this study . The patients were treated with st and ard radiotherapy with 4 weekly IA or 3 weekly IV cisplatin infusions . The QOL assessment s carried out were EORTC-C30 , H&N35 , and trial-specific question naires . RESULTS Overall QOL deteriorated in all patients during treatment , is gradually improving over 1 year . IA patients showed significantly less nausea and vomiting at week 7 ( p < .001 ) . IV patients were significantly more fatigued ( p < .006 ) . At 1 year , no significant difference in tube feeding was found . Voice quality slightly exceeded the pretreatment values at 1 year . Forty-two of 62 employed patients returned to work . CONCLUSION During treatment , significantly fewer problems with nausea and vomiting occurred in IA than in IV patients . Both groups showed improved voicing and oral intake during follow-up , often exceeding pretreatment values at 1 year Long-term follow-up for patients who receive chemoradiation for head and neck cancer is lacking from most studies reported in the literature . This report gives a 15-year review of the use of concomitant methotrexate and radiation in advanced head and neck cancer . Although there has not been any significant benefit in overall survival , the primary control rate is higher in patients who received methotrexate in addition to radiotherapy .  However , in those with oropharyngeal cancer , both primary control and survival were significantly improved when chemotherapy was used . The other most significant benefit from chemoradiation is the much lower rate of salvage operations for primary recurrence . The addition of methotrexate failed to show any effect on the development of metastatic neck nodes . The rate of block dissection of the neck was similar in both arms of the study and is comparable with the historical data collected at this institute . There has not been any significant increase in serious late morbidity . The timing of the methotrexate with radiotherapy has a significant influence on primary control and survival in head and neck cancer Between January 1988 and December 1991 , 159 patients with Stage III/IV ( M0 ) squamous cell carcinoma of the head and neck were r and omized to receive st and ard fraction RT ( 70 Gy ) ( group I ) or the same RT plus either 6 mg/m2 of cisplatin ( CDPP ) ( group II ) or 25 mg/ m2 of carboplatin ( CBDCA ) both given daily during RT ( group III ) . Patients in groups II and III had significantly higher overall response rates then those in group I ( P = 0.011 and P = 0.0025 , respectively ) with no difference between groups II and III ( P = 0.60 ) . They also had significantly longer median survival time ( MST ) and higher 5-year survival rates than those in group I ( MST , 32 months ( 32 % ) and 30 months ( 29 % ) versus 16 months ( 15 % ) , respectively ; P = 0.011 and P = 0.019 , respectively ) , with no difference between the two RT/CHT groups . Median time to local recurrence ( MTLR ) and 5-year local recurrence-free survival ( LRFS ) were significantly higher for both RT/CHT when compared to RT alone ( MTLR , not attained yet and 30 months versus 10 months , respectively ; 5-year LRFS , 51 % and 48 % versus 27 % , respectively ; P = 0.018 and P = 0.040 , respectively ) with no difference between the two RT/CHT groups . There was no difference between the three treatment groups regarding regional lymph node and distant metastasis control . Apart from acute high grade ( > or =3 ) hematological toxicity that was significantly more frequent in the two RT/CHT groups and no different between the two RT/CHT groups , other acute high grade toxicity was similar between the three treatment groups . Late high grade toxicity was infrequent and similar between the three treatment groups The purpose of this study was to analyze long‐term follow‐up of a single institution 's experience with a regimen of concomitant cisplatin/fluorouracil ( 5‐FU ) infusion and radiation given every  other week . This analysis was stimulated by results of a r and omized trial showing superiority for this regimen over induction cisplatin/5‐FU chemotherapy followed by radiotherapy , especially in regional disease control BACKGROUND Despite the use of resection and postoperative radiotherapy , high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed . We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control . METHODS Between September 9 , 1995 , and April 28 , 2000 , 459 patients were enrolled . After undergoing total resection of all visible and palpable disease , 231 patients were r and omly assigned to receive radiotherapy alone  ( 60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks ) and 228 patients to receive the identical treatment plus concurrent cisplatin ( 100 mg per square meter of body-surface area intravenously on days 1 , 22 , and 43 ) . RESULTS After a median follow-up of 45.9 months , the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( hazard ratio for local or regional recurrence , 0.61 ; 95 percent confidence interval , 0.41 to 0.91 ; P=0.01 ) . The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group , as compared with 72 percent in the radiotherapy group . Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group ( hazard ratio for disease or death , 0.78 ; 95 percent confidence interval , 0.61 to 0.99 ; P=0.04 ) , but overall survival was not ( hazard ratio for death , 0.84 ; 95 percent confidence interval , 0.65 to 1.09 ; P=0.19 ) . The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group ( P<0.001 ) . Four patients who received combined therapy died as a direct result of the treatment . CONCLUSIONS Among high-risk patients with resected head and neck cancer , concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival . However , the combined treatment is associated with a substantial increase in adverse effects Ninety-six patients with advanced squamous cell carcinoma of the head and neck were r and omized to treatment with intravenous methotrexate followed by radical irradiation or radiotherapy alone . No significant differences were demonstrated in local disease control or actuarial survival rates at three and five years . Some patients with local treatment failure were surgically salvaged PURPOSE To determine whether the addition of infusional fluorouracil ( I-FU ) to st and ard radiotherapy improves survival at acceptable toxicity in patients with locally advanced squamous cell head and neck cancer ( SCHNC ) . PATIENTS AND METHODS Consenting patients with an Eastern Cooperative Oncology Group ( ECOG ) performance status < or = 2 ; with stage III or IV SCHNC of the oral cavity , oropharynx , hypopharynx , or larynx ; and who were recommended for radiotherapy with curative intent received  66 Gy of radiation therapy  delivered in 2-Gy fractions once daily 5 days per week for 6 1/2 weeks . Those in the experimental arm received I-FU 1.2 g/m2/d , as a 72-hour infusion in the first and third weeks of radiation . Saline infusions were used in the placebo arm . RESULTS One hundred seventy-five patients were r and omized ( 88 to I-FU and 87 to placebo ) , and the treatment arms were well balanced . The complete response rate was 68 % for I-FU and 56 % for placebo ( P = .04 ) . The overall median survival duration was 33 months for I-FU and 25 months for placebo ( P = .08 ) . Progression-free survival also favored I-FU ( P = .06 ) . Toxicity was greater in I-FU patients , but did not interfere with the scheduled delivery or completion of radiation . CONCLUSION The addition of I-FU to st and ard radiation in SCHNC improved the complete response rate and was associated with beneficial trends in progression-free and overall survival compared with radiation alone . I-FU patients also experienced greater morbidity , but this did not compromise delivery of radiotherapy Fifty-eight patients with advanced squamous cell cancer of the head and neck have been r and omized on a study comparing three different weekly methotrexate ( MTX ) dose levels followed at 24 hours by st and ardized folinic acid rescue . Eighteen patients received MTX 5 g/m2 , 24 patients received 500 mg/m2 , and 16 patients received 50 mg/m2 . The initial response rate according to treatment were 50 % , 21 % and 31 % , respectively . Six patients crossed from low- to medium-dose MTX after failing to respond ( four ) or relapsing , and one in each group had a tumor response . Eleven patients crossed over from initial medium-dose to high-dose MTX after failing to respond ( ten ) or relapsing , and one in each group had a tumor response . The median time to maximum response was 3.5 weeks . There were only two complete responders , and one is disease free more than 19 months after starting treatment and more than 15 months after stopping treatment . The high-dose MTX treatment was significantly more toxic than lower doses , and there were four drug-related deaths ( three in the high-dose group ) . The preliminary results of this study support the notion of a dose-response relationship to MTX in advanced squamous cell cancer of the head and neck BACKGROUND AND PURPOSE To analyse acute mucosal reactions in patients treated with continuous accelerated postoperative irradiation ( p-CAIR )  compared to  conventionally fractionated postoperative radiotherapy ( p-CF ) .  PATIENTS AND METHODS The patients were r and omly assigned to receive 63 Gy in 1.8 Gy fractions 7-days-a-week given over a period of 5 weeks ( n=88 ) , or 63 Gy in 1.8 Gy fractions given 5-days-a-week over 7 weeks ( n=87 ) . It represents 65 % of an overall trial size . Acute mucosal reactions were scored using modified Dische system . Polychotomous logistic regression was used to estimate the influence of the selected variables on maximum grade of mucositis , and percent of the body weight loss during radiotherapy . RESULTS The average maximum Dische score and percent of the patients with confluent mucositis were higher in patients treated with p-CAIR , compared to p-CF ( 13.3 vs. 10.8 and 54 vs. 27 % ) . Polychotomous logistic regression analysis revealed that fractionation scheme and tumour site have significantly influenced maximum Dische score . Tumour site ( laryngeal vs. other ) had even stronger influence on maximum Dische score than fractionation scheme . The average residual Dische score 8 weeks after radiotherapy was higher in p-CAIR compared to p-CF ( 2.1 vs. 1.4 ) , and was , most frequently , related to persistent mucosal erythema ( 70 vs. 57 % of pts . ) . No severe consequential toxicity of radiotherapy was observed , so far , in the trial . CONCLUSIONS While the incidence , intensity and duration of mucosal reactions was higher in p-CAIR than in p-CF the accelerated treatment can be considered tolerable with respect to acute toxicity . In both arms of the trial slight or moderate mucosal erythema was the most frequent acute side effect , which did not completely subside within 8 weeks after irradiation It is often suggested that tumors will respond to induction chemotherapy and result in improved survival for patients with squamous cell carcinoma of the head and neck . Two regimens of induction chemotherapy were studied in separate r and omized , prospect i ve trials over the last 6 years . Eighty-three patients with advanced disease were entered into the first study ( 43/chemotherapy ; 40/control ) , and 60 into the second ( 27/chemotherapy ; 33/control ) . Patient r and omization was stratified by stage ( III/IV ) and site ( oral cavity , oropharynx , nasopharynx , hypopharynx , larynx , paranasal sinuses ) . The first study utilized bleomycin , Cytoxan , methotrexate and 5-fluorouracil in two cycles ( one cycle if no tumor response ) , followed by st and ard treatment which consisted of combined irradiation and surgery or , in some instances , primary irradiation alone . The second study utilized cisplatin and 5-fluorouracil in three cycles prior to st and ard treatment . An objective tumor response to chemotherapy was observed in 68 % in the first study and 85 % in the second . The patient survival in both studies ( at 24 months in the first ; at 19 in the second ) was better in the control than that in the experimental groups ( 43 % to 31 % ; 69 % to 46 % ) . In the second study , the average length of delay of st and ard treatment was longer than in the first study ( 95 days vs. 66 days ; P less than .02 ) . Results combining the P-values of both studies indicate that the relative risk of having persistent disease was 2.9 times greater for patients who received chemotherapy . While toxicity to chemotherapy was not a factor in survival , the number of patients who withdrew from the studies and those who did not comply with treatment were greater in the chemotherapy groups . Except for new drug regimens of exceptional promise , it is recommended that future studies be design ed so that chemotherapy is given concurrent with , or following the completion of st and ard treatment Abstract This report culminates a 4-year study on the benefits attained by intravenous Methotrexate adjuvant and prior to definitive irradiation of advanced head and neck cancers . Three hundred twenty-six patients were r and omized to receive definitive radiotherapy alone while 312 similar patients first received intravenous Methotrexate  , 25 mgm every third day for 5 doses , followed immediately by full-course irradiation . Population characteristics by specific disease site , stage ( T and N ) , age , and sex were similar between the two patient population s ; no significant bias was demonstrated . Eligibility included advanced primary ( T3 4 ) and /or nodal stage disease . The number of annual deaths among the two r and omized categories was essentially equal during the first 5 years of follow-up . Nearly one-half occurred in the first year ( 146 for radiation alone and 143 in the chemotherapy plus irradiation groups ) . Median metastasis-free survival was between 12–13 months in both categories . The unadjusted 5 year survivals were in the 11–22 % range for oral cavity , oropharynx , and supraglottic larynx and 3–9 % for hypopharynx primaries . Although several variables did exert an impact upon survival , primary ( T ) and lymph node ( N ) stage seem to be of paramount importance and Methotrexate of minor consideration . Median and 5-year survivals within the various anatomic regions ( oral cavity , supraglottic larynx , and hypopharynx ) were consistently better when Methotrexate was given . However , these improvements were minimal ( 1–4 mos . median or 2–6 % at 5 yrs ) and depended upon whether comparisons were performed on adjusted or unadjusted survival figures . Any “ real ” gain achieved directly by Methotrexate is conjecture , since several uncontrolled biases were identified among these various categories . In view of the modest benefits attained by using this Methotrexate regimen the authors suggest that other adjuvant programs be investigated and that this schedule not be adopted for routine clinical usage PURPOSE The goal of the present analyses is to assess the association between different therapeutic approaches and both the probability of achieving a complete response and the risk of death in patients with stage III-IV , inoperable , squamous cell carcinoma of the head and neck ( SCC-HN ) . PATIENTS AND METHODS Between August 1983 and December 1990 , 273 patients with stage III-IV , previously untreated , unresectable SCC of the oral cavity , pharynx and larynx , were included into two consecutive r and omized multi-institutional trials ( HN-7 and HN-8 protocol s ) coordinated by the National Institute for Cancer Research ( NICR ) of Genoa . The HN-7 protocol compared neo-adjuvant chemotherapy ( four cycles of vinblastine , 6 mg/m2 i.v . followed by bleomycin , 30 IU i.m . six hours later , day 1 ; methotrexate , 200 mg i.v . , day 2 ; leucovorin , 45 mg orally , day 3 ) ( VBM ) followed by st and ard radiotherapy ( 70 - 75 Gy in 7 - 8 weeks ) ( 55 patients ) to alternating chemoradiotherapy based on four cycles of the same chemotherapy alternated with three splits of radiation , 20 Gy each ( 61 patients ) . In the HN-8 protocol st and ard radiotherapy ( 77 patients ) was compared to the same alternating program as the one used in the previous protocol but employing cisplatin , 20 mg/m2/day and fluorouracil , 200 mg/m2/day , bolus , both given for five consecutive days ( CF ) instead of VBM ( 80 patients ) . A single data base was created with the patients on the two protocol s. Age at diagnosis , gender , site of the primary tumor , size of the primary , nodal involvement , performance status and treatment approach were analyzed by the multiple logistic regression model and the Cox regression method . The analyses were repeated including the treating institutions as a covariate ( coordinating center versus others ) . RESULTS The multiple logistic regression analysis indicates that treatment ( alternating more so than others , regardless of the chemotherapy regimen used ) ( P = 0.0001 ) is more likely to be associated with complete response . In addition , size of the primary tumor ( P = 0.004 ) , nodal involvement ( P = 0.02 ) and performance status ( P = 0.009 ) are prognostic variables affecting the probability of achieving a complete response . The Cox regression analysis indicates that treatment , performance status , size of the primary tumor , nodal involvement and , marginally , site of the primary tumor , are independent prognostic variables affecting the risk of death . When the radiation-alone therapy is adopted as the reference treatment , the relative risk of death is 0.58 ( 95 % confidence interval ( CI ) 0.40 - 0.84 ) for alternating CF and radiation , 0.79 ( 95 % CI 0.53 - 1.16 ) for alternating VBM and radiation and 1.30 ( 95 % CI 0.89 - 1.92 ) for sequential VBM and radiation . When the treating institution is included in the model , a 34 % increased risk of death ( P = 0.04 ) is observed for patients treated outside the coordinating center . CONCLUSION In our series of patients with advanced , unresectable SCC-HN , treatment with cisplatin and fluorouracil alternating with radiation was associated with a more favourable prognosis . The role of the treating institution in the modulation of the treatment outcomes was also relevant PURPOSE A prospect i ve r and omized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy ( CT ) and radiotherapy ( RT ) in previously untreated patients with unresectable stage III/IV head and neck cancer . PATIENTS AND METHODS Patients with locoregionally advanced head and neck cancer were treated either with RT alone ( arm A ) or simultaneous RT plus CT ( RCT ; arm B ) . RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily . During one course , from day 3 to 11 , 23.4 Gy was delivered . In arm B , cisplatin ( CDDP ) 60 mg/m2 , fluorouracil ( 5-FU ) 350 mg/m2 by intravenous ( i.v . ) bolus , and leucovorin ( LV ) 50 mg/m2 by i.v . bolus were given on day 2 , and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5 . Treatment was repeated on days 22 and 44 ; a total RT dose of 70.2 Gy was administered . Treatment breaks were scheduled from days 12 to 21 and days 34 to 43 . RESULTS From 1989 to 1993 , 298 patients were enrolled and 270 patients were assessable .  Acute mucositis grade 3 or 4 was more frequent in arm B ( 38 % ) than in arm A ( 16 % ) ( P < .001 ) . Total treatment time was significantly longer in arm B than in arm A ( P < .001 ) due to prolonged breaks . According to hematologic toxicity , scheduled drug doses were given in 74 % of patients for the second course and 46 % for the third course . The 3-year overall survival rate was 24 % in arm A and 48 % in arm B ( P < .0003 ) . The 3-year locoregional control rate was 17 % in arm A and 36 % in arm B ( P < .004 ) . Both arms showed similar distant failure patterns ( arm A , 13 of 140 ; arm B , 12 of 130 ) . Serious late side effects were not significantly different between treatment arms ( arm A , 6.4 % ; arm B , 10 % ; not significant ) . CONCLUSION Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients . Due to increased acute toxicity , more supportive care is dem and ed when CT is given simultaneously . Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen BACKGROUND The st and ard treatment for advanced ( stage III and IV ) head and neck squamous cell carcinoma ( i.e. , surgery with postoperative radiotherapy  in operable patients and radiotherapy alone in inoperable patients ) has had poor results . A series of r and omized trials of induction chemotherapy have up to now failed to demonstrate an improvement in survival . PURPOSE This trial was design ed to determine whether intensive induction chemotherapy administered before loco-regional treatment would improve survival of patients with advanced disease . METHODS Patients had previously untreated , advanced nonmetastatic ( stages III and IV ) squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , and paranasal sinuses . The study design was a r and omized , multi-institutional , phase III trial . Eligible patients ( n = 237 ) were r and omly assigned to receive either initial chemotherapy ( cisplatin and infusional fluorouracil ) followed by loco-regional treatment ( group A , n = 118 ) or loco-regional treatment alone ( group B , n = 119 ) . For operable patients ( group A , n = 34 ; group B , n = 32 ) , loco-regional treatment included resection followed by adjuvant radiotherapy . For inoperable patients , radical irradiation was performed with a planned dose of 65 - 70 Gy to involved areas . A dose of 45 - 50 Gy was also planned to the uninvolved neck or postoperatively . The statistical ( log-rank ) test was performed no earlier than 2 years after the r and omization of the last patient . RESULTS Seventy-one patients ( 60 % ) in group A and 67 patients ( 56 % ) in group B were considered free of disease after they completed the treatment sequence . The analysis of time to distant metastases showed an advantage for group A patients . ( Respective 2- and 3-year values for inoperable patients were 15 % and 24 % for group A versus 36 % and 42 % for group B , P = .04 ; only one operable group A patient had distant metastases after 49 months versus 26 % [ 2 years ] and 31 % [ 3 years ] for operable group B patients , P = .01 . ) For inoperable patients , the combined treatment was significantly associated with an increase in complete remission rate ( group A , 44 % ) as compared with radiotherapy alone ( group B , 30 % ) ( P = .037 ) . Inoperable patients also benefitted from induction chemotherapy in terms of disease-free survival ( 49 % and 34 % for group A versus 28 % and 26 % for group B ; P = .06 ) and of overall survival ( 30 % and 24 % for group A versus 19 % and 10 % for group B ; P = .04 ) . CONCLUSIONS When all 237 r and omly assigned patients were analyzed , there were no significant differences in the two treatment strategies in loco-regional failure or in disease-free or overall survival , although the development of distant metastases was reduced . For operable patients , the only benefit from neoadjuvant chemotherapy was a significant reduction in the incidence of distant metastases . For inoperable patients , neoadjuvant chemotherapy improved local control , decreased the incidence of distant metastases , and improved the complete remission rate and overall survival . IMPLICATION S Confirmatory studies with effective chemotherapy regimens delivered for an adequate number of cycles are required Porfiromycin ( methyl mitomycin C ) has been shown in laboratory studies to have increased preferential cytotoxicity to hypoxic cells and therefore may provide enhanced therapeutic efficacy over mitomycin C when used in combination with radiation therapy ( RT ) . The purpose of the two clinical studies reported here is to evaluate the concomitant use of porfiromycin with RT in the management of squamous cell carcinoma of the head and neck . Between October 1989 and July 1992 , 21 patients presenting with locally advanced stage III/IV squamous cell carcinoma of the head and neck were entered into a phase I toxicity trial evaluating porfiromycin as an adjunct to RT .  Patients were eligible if they had biopsy documented squamous cell carcinoma of the head and neck with a low probability of cure by conventional means . Patients were treated with st and ard fractionated daily RT to a total median dose of 63 Gy , with porfiromycin administered on days 5 and 47 of the course of RT . Upon completion of this phase I trial , a phase III trial was initiated in November 1992 r and omizing patients with squamous cell carcinoma of the head and neck to RT with mitomycin C vs. RT with porfiromycin . There is no radiation only arm in this current trial . To date , 75 patients have been entered on this trial and acute toxicity data are available on 67 patients ( 34 porfiromycin , 31 mitomycin C ) who have completed their entire course of treatment . Median follow-up of the 21 patients enrolled in the phase I porfiromycin trial is 58.5 months . Of the 21 patients , 5 were treated at a dose of 50 mg/M2 , 4 at 45 mg/M2 , and the final 12 at 40 mg/M2 , which appeared to result in acceptable acute hematological and nonhematological toxicities . As of December 1995 , 14 of the 21 patients have died with disease and 7 remain alive and free of disease , result ing in a 5-year actuarial survival of 32 % . Of the patients enrolled to date in the phase III r and omized trial of mitomycin C vs. porfiromycin , there have been no statistically significant differences between the two arms with respect to white blood cell count ( WBC ) , platelet , or hemoglobin nadirs . Acute nonhematological toxicities including mucositis , epidermitis , odynophagia , and nausea have also been comparable . Two patients in this current r and omized trial died during treatment , apparently of nondrug-related causes . We conclude that the bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date . Final analysis of the phase I trial , which revealed a 5-year no evidence of disease survival rate of 32 % in patients with locally advanced disease and a low probability of cure , appears encouraging . We anticipate completion of the current ongoing trial comparing mitomycin C to porfiromycin in the next 2 years . Further investigations , including large-scale multiinstitutional trials employing bioreductive alkylating agents or other hypoxic cell cytotoxins as adjuncts to RT , are warranted A r and omized , prospect i ve trial utilizing cisplatin and fluorouracil as neoadjuvant chemotherapy in the treatment of advanced squamous cell carcinomas of the upper aerodigestive tract was initiated in January 1983 . Sixty patients were stratified by site ( oral cavity , 19 ; larynx , 14 ; hypopharynx , 14 ; oropharynx , 11 ; nasopharynx , one ; and paranasal sinuses , one ) and by stage ( III , 19 ; IV , 41 ) , and then r and omized to receive either st and ard treatment ( defined as preoperative irradiation followed by radical excision or irradiation alone ) or adjuvant chemotherapy followed by st and ard treatment .  An additional three patients were entered into the study , but withdrew . Chemotherapy consisted of three cycles for those patients in whom an objective tumor response was observed ; nonresponders received st and ard treatment .  Response to chemotherapy was complete in five and partial ( greater than 50 % ) in 18 patients , for an overall response rate of 85 % . The follow-up for surviving patients was a minimum of 24 months and a maximum of 44 months . Survival was compared for patients in both treatment groups according to the method of Lee and Desu . Despite excellent tumor response , actuarial survival was 70 % in the st and ard treatment group as opposed to 56 % in the experimental group . It was therefore evident that the high response rates reported in previous pilot studies do not necessarily result in improved survival in these cancers Two dose schedules of methyl CCNU were compared for drug effect and toxicity .  One hundred thirteen patients were stratified by tumor site , performance status , and prior chemotherapy and r and omized to 100 mg/m2 q 3 wk or 200 mg/m2 q 6 wk orally . Response rates were similar ( 12 % vs. 18 % , respectively , in the major tumor sub‐types studied ) and survival was equivalent . Hematologic toxicity , however , was significantly different , with earlier time to the most severe blood count depressions , more frequent occurrence of severe depression , and a larger percentage of patients requiring dosage reduction on the 6‐week regimen . We conclude that the 3‐week regimen is superior due to its improved tolerance and is recommended especially for combination drug therapy From 1987 to 1989 , 42 patients with locally advanced squamous cell carcinoma of the head and neck ( Stages III-IV , Mo ) were r and omized to receive radiotherapy ( Group A ) or three courses of induction chemotherapy followed by radiotherapy ( Group B ) . There were 36 evaluable patients , 17 in Group A and 19 in Group B. The radiotherapy regimen was the same for both groups , 66 - 74 Gy total tumor doses with st and ard fractionation scheme of 2 Gy/day . The chemotherapy regimen was a combination of carboplatin 400 mg/m2 by intravenous bolus injection on day 1 , and Ftorafur 1,000 mg/m2 orally once a day for 14 days . Cycles were given every 4 weeks . The complete response rate in Group A was 65 % ; in group B it was 31.5 % after induction chemotherapy and 84 % after radiotherapy . The 42-month actuarial overall survival rates were 34 % for Group A and 47 % for Group B ( P = NS ) . Patients from both groups with a complete response had a significantly longer survival time than those with a partial response ( P less than 0.001 ) . No significant differences in disease-free survival were found between the two treated groups . The chemotherapy regimen was well tolerated , with moderate hematologic and gastrointestinal toxicity . Increased in radiation toxicity by chemotherapy was not observed In a r and omized prospect i ve study of patients with advanced squamous cell carcinoma of the head and neck , treatment with MTX plus BCG and with MTX plus BCG plus INH produced no better response rate or survival time than treatment with MTX alone We examined the records of two cohorts of patients who were seen from 1960 to 1999 with a diagnosis of squamous cell carcinoma ( SCC ) of the mouth and throat , one series being retrospective ( n=400 ) and the other prospect i ve ( n=213 ) to find out about delays in diagnosis . The median delay in both cohorts was 3 months and the patients were responsible for the delay in most cases ( n=319 , 81 % and n=160 , 78 % , respectively ) . Half the patients in each cohort had delayed diagnoses ( n=217 , 54 % and n=119 , 56 % , respectively ) and similar percentages ( n=110 , 53 % and n=172 , 47 % ) presented with advanced disease ( stage III or IV ) . These were not the same patients for there was no correlation between delay and stage or survival . Logistic regression analysis showed that non-white race ( p=0.01 ) and high- grade histology ( p=0.002 ) predicted advanced disease . The proportion of patients presenting with advanced disease had not changed in 40 years despite public education . We suggest that some tumours may be silent and that initial symptoms do not reliably predict early disease Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a r and omized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy . In addition , following regional therapy , patients r and omized to  chemotherapy  were to receive similar methotrexate courses every three months for one year . Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin ( Adria Laboratories , Columbus , Ohio ) and cisplatin every three weeks for four cycles after the first 35 patients had been entered . Nine cases were ineligible and four lacked any follow-up data , leaving 82 analyzable cases . Using Cox regression analysis , no differences in the percentage of patients achieving disease control , the relapse-free survival , or the overall survival were identified between any treatment group . As has been described in many pilot studies of induction chemotherapy of head and neck cancer , chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy . However , correcting for imbalances in the expected three year disease-free survival of these patients , based on their disease site and stage , erased this difference , indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome . The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups , given the multiple site-stage combinations within the upper aerodigestive tract . The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival To test the hypothesis that sequential scheduling of methotrexate ( MTX ) and fluorouracil ( FU ) produces a synergistic antitumor effect , we r and omized 113 patients with recurrent or locally advanced squamous cell carcinoma of the head and neck to receive MTX-FU either 18 hours apart or simultaneously , with leucovorin rescue . There were 100 patients with locally advanced newly presenting disease and 13 patients with recurrence .  Excessive toxicity was observed in the first 11 patients who received MTX 250 mg/m2 administered intravenously ( IV ) and leucovorin at 36 hours , therefore all subsequent patients received MTX 200 mg/m2 administered IV and leucovorin at 24 hours . FU 600 mg/m2 IV was administered to all patients , and treatment was given on days 1 and 8 of 21-day cycles . The treatment groups were well balanced for known prognostic variables . The response rate was 47.3 % ( 26 of 55 ) for simultaneous v 44.8 % ( 26 of 58 ) for sequential therapy . These results exclude a 20 % difference in response rate favoring sequential therapy at P = .04 . There was no observed difference in survival between the two treatment arms ( P = .55 ) with a minimum follow-up of 8 months . Toxicity was greater in patients who received sequential therapy , and the difference was confined to the gastrointestinal ( GI ) tract . A comparison of the distribution in maximum Eastern Cooperative Oncology Group ( ECOG ) toxicity scores during chemotherapy for the two treatment groups showed greater stomatitis ( P = .001 ) , diarrhea ( P = .04 ) , and overall toxicity ( P = .02 ) for sequential treatment without an observed difference in bone marrow toxicity . The results of this trial indicate that sequential MTX-FU is not superior to simultaneous therapy for the treatment of patients with head and neck cancer . Biochemical modulation of MTX-FU by drug scheduling may occur in vivo and may be organ specific PURPOSE To compare conventional fractionation radiation therapy ( RT ) , Arm A , vs. split-course accelerated hyperfractionated RT ( S-AHF ) , Arm B , vs. conventional fractionation RT plus concomitant chemotherapy ( CT ) , Arm C , in terms of survival and toxicity for advanced , unresectable epidermoid tumors of oropharynx . METHODS AND MATERIAL S Between January 1993 and June 1998 , 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma ( excluding T1N1 and T2N1 ) were accrued in a multicenter , r and omized Phase III trial ( ORO 93 - 01 ) . For Arms A and C , 66 - 70 Gy in 33 - 35 fractions , 5 days a week , were administered in 6.5 - 7 weeks to tumor and positive nodes . In Arm B , the dose delivered to tumor and involved nodes was 64 - 67.2 Gy , giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h , 5 days a week . At 38.4 Gy , a 2-week split was planned ; after the split , RT was resumed with the same modality . In Arm C , CT regimen consisted of carboplatin and 5-fluorouracil ( CBDCA 75 mg/m(2 ) , Days 1 - 4 ; 5-FU 1,000 mg/m(2 ) i.v . over 96 h , Days 1 - 4 , recycling every 28 days ( at 1st , 5th , and 9th week ) . RESULTS No statistically significant difference was detected in overall survival ( p = 0.129 ) : 40 % Arm A vs. 37 % Arm B vs. 51 % Arm C were alive at 24 months . Similarly , there was no statistically significant difference in terms of event-free survival ( p = 0.196 ) : 20 % for Arm A , 19 % for Arm B , and 37 % for Arm C were event free at 24 months . On the contrary , the 2-year disease-free survival was significantly different among the three arms ( p = 0.022 ) , with a superiority for Arm C. At 24 months , the proportion of patients without relapse was 42 % for Arm C vs. 23 % for Arm A and 20 % for Arm B. Patients in Arm A less frequently developed G3 + acute mucositis than their counterparts in Arm B or C ( 14.7 % vs. 40.3 % vs. 44 % ) . Regarding the CT-related acute toxicity , apart from 1 case of fatal nephrotoxicity , only hematologic G3 + ( Grade 3 or higher ) acute sequelae were observed ( World Health Organization scale ) , most commonly leukopenia ( 22.7 % ) . Arm C showed slightly more G3 + skin , s.c . tissue , and mucosal late side effects ( RTOG scale ) , although significant sequelae were relatively uncommon , and mucosal sequelae were most commonly transient . The occurrence of persistent G3 xerostomia was comparable in all three treatment arms . CONCLUSIONS The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas , by increasing disease-free survival . This improvement , however , did not translate into an overall survival improvement , and was associated with a higher incidence of acute morbidity Although induction chemotherapy prior to local therapy produces encouraging initial response rates in head and neck cancer , r and omized studies have failed to demonstrate an advantage in survival . All r and omized studies included only patients with far advanced stage III and IV disease which appears to be the main reason for the low rate of complete responses ( max . 18 % ) in these trials . According to statistical considerations nearly 50 % complete responders are necessary before improved survival benefit can be expected . Until now , such complete response rates are only achieved with induction chemotherapy in resectable T2-T3 , N0-N2 disease . Therefore , we started a prospect i ve r and omized trial including only patients with these stages of disease . Patients were stratified by primary tumor site and neck node status and were r and omized to receive either induction chemotherapy with three cycles of carboplatin/5-FU prior to surgery and radiotherapy  ( arm A , 49 patients ) or st and ard treatment with surgery and radiotherapy  ( arm B , 47 patients ) . Patients were stratified by primary tumor site and neck disease . After a follow-up of 12 - 48 months overall survival was 72 % in arm A and 53 % in arm B ( n.s . ) . Considering only the patients with cancer of the oral cavity and the tonsil  overall survival was 88 % in arm A and 44 % in arm B ( p<0.05 ) . As of today , the number of patients with carcinomas of the hypopharynx and base of tongue is too small for a statistically significant statement , but preliminary data indicate a better overall and disease-free survival without chemotherapy in these patients . Therefore , we recommend controlled trials with induction chemotherapy in patients with primary resectable carcinomas of the oral cavity and the tonsil , stages T2-T3 and N0-N2 , prior to surgery but not in patients with cancer of the hypopharynx and base of the tongue A series of 79 patients with locally inoperable squamous cell carcinoma of the head and neck region were treated from June 1979 to December 1982 . The status of inoperability was based on a surgical evaluation indicating that the tumor and /or regional nodes could not be totally resected with curative intent . The aim of this study was to compare an aggressive regimen against a mild one Forty-five patients with epidermoid cancer of the head and neck were either treated with cisplatin and bleomycin ( DDP-BLM ) or with vincristine , bleomycin and methotrexate ( VBM ) as neoadjuvant chemotherapy before radical radiation therapy ( XRT ) . Chemotherapy with DDP-BLM provided a tumoral response of 80 % [ 20 % complete response ( CR ) , 60 % partial response ( PR ) ] ; VBM showed a response of 60 % ( 12 % CR , 48 % PR ) . At the end of XRT-program ( 65 Gy total dose , 2 - 2.5 Gy dose per fraction , 5 times a week ) complete response rates were similar in VBM-pretreated group ( 52.5 % ) and DDP-BLM pretreated group ( 50 % ) . Analysis of survival shows no significant difference between the two inductive schemes : 8 % vs 7.5 % at 72 months . Our study suggests an increased initial response rate but no advantage in survival with combined therapy in comparison with st and ard XRT : long-term benefits were not apparent in these two groups of patients Between 1983 and 1986 , the National Institute for Cancer Research in Genoa and affiliated institutions conducted a r and omized study to compare two different ways of combining chemotherapy ( CT ) and radiation therapy ( RT ) .  One hundred sixteen patients were r and omized to receive neoadjuvant CT followed by definitive RT ( treatment arm A ) or alternating CT and RT . In treatment arm A , RT consisted of 70 Gy to the involved areas and 50 Gy to the uninvolved neck at 2 Gy/fraction , five fractions per week . In treatment arm B , RT consisted of 60 Gy to involved areas and 50 Gy to the uninvolved neck in three courses of 20 Gy each , 2 Gy/fraction , ten fractions/2 weeks alternated with four courses of CT . CT consisted of vinblastine 6 mg/m2 intravenously followed 6 hours later by bleomycin 30 IU intramuscularly , day 1 ; methotrexate 200 mg intravenously , day 2 ; leucovorin rescue , day 3 . CT was repeated every 2 weeks up to four courses . The same CT was used in both treatment arms of the study . Fifty‐five patients were entered in treatment arm A and 61 in treatment arm B.  Complete responses were 7/48 and 19/57 in treatment arms A and B , respectively ( P < 0.03 ) . Four‐year progression‐free survival was 4 % in treatment arm A and 12 % in treatment arm B ( P < 0.02 ) , and four‐year survival was 10 % in A and 22 % in B ( P < 0.02 ) . Mucosal tolerance was significantly worse in treatment arm B ( P < 0.00004 ) . The subgroup analysis shows the major improvement of alternating CT and RT in patients with the worst prognostic characteristics A prospect i ve , r and omized trial of induction chemotherapy in advanced squamous cell carcinomas of the upper aerodigestive tract ( UAD ) was conducted between July 1979 and September 1982 . Eighty-three patients with locally advanced Stage III-IV tumors received  st and ard treatment ( STD RX ; defined as preoperative irradiation and radical excision or irradiation alone ) , or induction chemotherapy ( CTX ) followed by STD RX . Chemotherapy consisted of two cycles of bleomycin ( 30 units/day by continuous infusions Days 1 - 4 ) , cyclophosphamide ( 200 mg/m2 IV Days 1 - 5 ) , methotrexate ( 30 mg/m2 Days 1 + 5 ) , and 5-fluorouracil ( 400 mg/m2 IV Days 1 - 5 ) . Response to CTX was complete in 2 and partial ( greater than 50 % reduction ) in 27 ; the overall response rate was 68 % . Tumor clearance was documented in 30/40 STD RX patients at completion of irradiation and /or surgery and in 24/43 CTX patients ( 17/29 responders , 7/14 non-responders ) . Freedom from local-regional disease was noted at 2 years in 53 % STD RX and 35 % CTX patients ( p less than .06 ) . CTX patients had a higher proportion of local-regional persistence and recurrence . The difference was apparent only in the subset of patients treated with primary irradiation ; local-regional control following irradiation and surgery was equal in STD RX and CTX groups . Survival at 2 years was 43 % STD RX and 31 % CTX . Disease-free survival in those with clearance was 64 % STD RX and 59 % CTX . Induction chemotherapy did not improve tumor clearance or survival in this series . Caution regarding local-regional control with CTX and primary irradiation is noted The r and omized Radiation Therapy Oncology Group ( RTOG ) Methotrexate trial in advanced squamous cancers of the head and neck has reported no control or survival benefits when the chemotherapy adjuvant was administered to patients just prior to definitive irradiation . The required data collection and outcome reporting among 146 patients bearing oral cavity primaries and 354 patients with oropharyngeal cancers has allowed a multi-variate approach seeking answers to many unresolved questions . As anticipated , the ability to control these squamous cancers is largely a function of size ( T & N stage ) with a superior clearance among T3 - 4 primaries of the oropharynx ( 66 % ) contrasted to identically staged oral cavity tumors ( 48 % ) . Adjusted median survival is more than doubled to 26.6 months or 19.8 months among oral cavity and oropharynx patients respectively , when compared to the 8 month median survival when neither primary nor cervical nodes are controlled . Lymph node deposits also impact upon survival , especially among oropharynx patients where the 17.6 month adjusted median survival among N0 patients declines to 11.0 months when the primaries are associated with N3 nodes . Surprisingly , the ability to control nodel deposits of all sizes ( N1 , N2 , or N3 ) is superior among oropharynx patients when compared with identical oral cavity metastases ( e.g. 71.4 % adjusted clearance in N3 oropharyngeal deposits versus 46.1 % in N3 nodes secondary to oral cavity primaries ) . Adjustments for maldistribution of advanced N-stages in association with T-4 primary stage eliminated an apparent T-stage effect upon nodal clearance within both anatomic regions . Finally , the association of T and N-stage upon distant metastases was investigated , with the surprising conclusion that neither initial T nor N-stage exerts any apparent influence on the observed 10 - 12 % occurrence . The interrelationship of these various prognostic variables is explored using the Cox and logistic models Three hundred and thirteen patients with squamous cell cancer of the head and neck were entered in a r and omised clinical trial to determine whether the addition of methotrexate during the course of irradiation improved the rate of primary control and subsequent survival . The overall primary control ( P = 0.016 ) and survival ( P = 0.075 ) for the patients receiving methotrexate was better than the patients treated by radiotherapy alone . The improvement in primary control ( P = 0.0019 ) and survival ( P = 0.0089 ) in patients with oropharyngeal cancers who had methotrexate in addition to radiotherapy  is statistically significant . The treatment was well tolerated and there has been no increase of late morbidity A multicentric , r and omized study of squamous cell carcinoma ( SCC ) of the oral cavity and the oropharynx has been undertaken by DOSAK . The results after radical surgery alone have been compared with the results of combined preoperative radiochemotherapy followed by radical surgery .  Patients with primary ( biopsy proven ) SCC of the oral cavity or the oropharynx with tumor nodes metastasis ( TNM ) stages T2 - 4 , N0 - 3 , M0 were included in the study . A total of 141 patients were treated by radical surgery alone , whereas 127 patients were treated by radical surgery preceded by preoperative radiochemotherapy .  The preoperative treatment consisted of conventionally fractioned irradiation on the primary and the regional lymph nodes with a total dose of 36 Gy ( 5 x 2 Gy per week ) and low-dose cisplatin chemotherapy with 5 x 12.5 mg cisplatin per m2 of body surface during the first week of treatment . Radical surgery according to the DOSAK definitions ( DOSAK , 1982 ) was performed after a delay of 10 - 14 days . During the follow-up period , 28.2 % of all patients suffered from locoregional recurrence , and 27.2 % of the patients died . The percentages were higher after radical surgery alone for locoregional recurrence ( 31 % and 15.6 % ) and for death ( 28 % and 18.6 % ) . The life-table analysis showed improved survival rates of 4.5 % after 1 year and 8.3 % after 2 years in the group of patients treated with combined therapy . The demonstrated improvement appeared to be significant with the Gehan-Wilcoxon test as well as with the log rank test below a P value of 5 % PURPOSE This r and omized , phase II study aim ed to compare concomitant Chemoradiotherapy using weekly carboplatin or daily low-dose cisplatin as a treatment for squamous cell carcinoma of the head and neck . PATIENTS AND METHODS One hundred nineteen patients with moderate-to advanced-stage disease were eligible for the study . Fifty-three patients had stage II disease , 28 had stage III , and the remaining 38 had stage IV disease . Primary tumor sites included the larynx ( N = 63 ) , oropharynx ( N = 30 ) , hypopharynx ( N = 23 ) , and oral cavity ( N = 3 ) . Each patient received either a weekly carboplatin dose ( 100 mg/m2 ) in one arm or daily cisplatin ( 4 mg/m2 ) in the other arm for the initial 4 weeks of radiotherapy . The radiotherapy dose of 65 Gy was given in 26 fractions over 45 days , dependent on a good tumor response at 40 Gy . Forty-nine ( 81.7 % ) of 60 patients treated with carboplatin and 41 ( 69.5 % ) of 59 patients treated with cisplatin received the full dose of radiotherapy . Surgical resection was optionally used for the remaining patients . RESULTS The median follow-up time was 63 months . The local control rate at 5 years was 56.2 % for the carboplatin-treated arm and 35.5 % for the cisplatin-treated arm , respectively . The 5-year overall survival rate did not significantly differ between treatments : 71.4 % for carboplatin and 66.0 % for cisplatin .  Hematologic toxicity was more frequent in the carboplatin-treated arm . No difference was observed in surgical complications or in radiation-related adverse effects . DISCUSSION These findings suggest that weekly carboplatin treatment is preferable to daily low-dose cisplatin . This could be because the total dose of cisplatin was too low to be effective Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were r and omly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil ( 5-fluorouracil ) . There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers . In the group of patients with unresectable cancers , however , there was a statistically significant advantage to the addition of chemotherapy , both in terms of disease-free survival and date to progression A synergism between cisplatin and radiotherapy has been demonstrated in in vitro and in vivo studies . To improve the locoregional control of disease and the survival rate in patients affected by locally advanced or recurrent squamous cell carcinoma of the head and neck , we planned a Phase II study of concurrent radiotherapy , 2 Gy for 5 days every week for a total dose of 60–70 Gy with cisplatin 80 mg/m2 every 21 days for 2 or 3 doses ( on days 1,21 , 42 ) . Fifty-one patients were entered in the study ; 48 were evaluable for response and toxicity ; 18 ( 37.5 % ) had untreated Stage III disease ; 25 ( 52 % ) had Stage IV disease ; 5 ( 10.5 % ) had recurrent disease .  The complete response rate in Stage III-IV patients was 63 % ( 27 of 43 ) with 95 % confidence limits from 48 to 77 % ( ±14.5 % ) . In the group of five patients with recurrent disease , only one ( 20 % ) achieved a complete response . In patients with Stage III-IV disease , a significantly higher complete response rate was observed for those younger than 58.5 years ( p = 0.05 ) . The overall estimated 1− and 2-year survival was 59 % and 37 % , respectively , and a significantly better survival was observed in complete responders compared to partial responses or patients with stable disease ( p = 0.037 ) . Disease-free survival was 46 % and 36 % at 1 and 2 years , respectively . Distant failure occurred only in 12.5 % of the patients . Overall , the treatment was well tolerated , and only three patients refused to complete the planned therapy . Gastrointestinal and hematological toxicity were the most common side effects . Data from present trial were compared with that of 50 patients with comparable characteristics treated with radiotherapy alone from 1985 to 1987 as a historical control . The complete response rate , the disease-free survival , and the overall survival appear to be better in the patients treated with chemoradiotherapy . It was concluded that the combination of chemoradiotherapy in patients with Stage III-IV head and neck squamous cell carcinoma is an effective and safe treatment with an apparent better locoregional control than radiotherapy alone . Survival results need to be evaluated in a Phase III r and omized trial A r and omized prospect i ve trial was performed to study the toxicity and efficacy of the hypoxic cell sensitizer , misonidazole ( MISO ) , used as an adjunct to high fractional dose radiotherapy in the management of unresectable Stage III and IV squamous cell carcinomas of the oral cavity , oropharynx and hypopharynx . From June 1979 to February 1983 , 42 patients were r and omized with 40 patients available for analysis . In the radiotherapy  ( RT ) only group , 19 patients received a short course of high fractional dose radiotherapy with 400 rad per day , 5 days per week , to a total of 4400 to 5200 rad . In the radiotherapy plus misonidazole group ( RT + MISO ) 21 patients received the same radiotherapy plus 1.5 gm/m2 of misonidazole 3 times a week for a total of 7 doses . The observed side effects associated with misonidazole were : persistent numbness and paresthesia ( 1 patient ) , transient peripheral nerve paresis and persistent paresthesia ( 1 patient ) , and nausea and vomiting ( 2 patients ) . The treatment related morbidities were similar in both groups . Acute mucositis was seen in 4 of 19 patients in the RT group and 3 of 21 patients in the RT + MISO group . Acute airway obstruction requiring tracheotomy was seen in 2 patients with massive tumor in the base of tongue ( 1 in each group ) . Severe dysphagia requiring NG tube feeding was seen in 3 patients in the RT + MISO group and 3 patients in the RT group . The initial complete response rate in the RT group was 53 % , versus 48 % in the RT + MISO group . The estimated 2-year loco-regional control rates were 10 % for RT alone and 17 % for RT + MISO ( no significancy ) . These results indicate that the addition of misonidazole does not improve the efficacy of high fractional dose radiotherapy for management of unresectable head and neck carcinomas . However , high fractional dose radiotherapy can be administered for the management of advanced head and neck carcinomas with acceptable morbidity and thus , is a useful regimen for future clinical trials of hyperbaric oxygen or new hypoxic cell sensitizers Between 1978 and 1984 , the Northern California Oncology Group ( NCOG ) conducted a r and omized trial to study the efficacy of combined radiotherapy ( RT ) and chemotherapy ( CT ) for stage III or IV inoperable head and neck cancer . One hundred four patients were r and omized to receive : ( 1 ) RT alone  , or ( 2 ) RT plus CT . RT consisted of 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction , five fractions/wk . CT consisted of bleomycin , 5 U intravenously ( IV ) , twice weekly during RT , followed by bleomycin , 15 U IV , and methotrexate , 25 mg/m2 IV weekly for 16 weeks after completion of RT . Fifty-one patients in the RT alone group and 45 in the combined treatment group were evaluable . The local-regional complete response ( CR ) rate was 45 % v 67 % ( P = .056 ) ; the 2-year local-regional control rate , including salvage surgery , was 26 % v 64 % ( P = .001 ) ; and the incidence of distant metastasis was 24 % v 38 % ( P greater than .25 ) , for the RT alone and RT plus CT groups , respectively . The relapse-free survival curves were significantly different ( P = .041 ) , favoring the combined treatment . However , the survival curves were not significantly different ( P = .16 ) . Patient compliance to maintenance CT was poor . Bleomycin significantly increased the acute radiation mucositis , although the difference in late normal tissue toxicity was not statistically significant . Thus , bleomycin and concurrent RT produced a more favorable CR rate , local-regional control rate , and relapse-free survival , but the difference in survival was not statistically significant Patients who are cured from head and neck carcinomas remain at high risk for developing a second primary in the head and neck area . It is now clear that retinoids exert a prophylactic action on the development of epithelial cancers when tested on laboratory animals and on human premalignant lesions . They are now used in the chemoprevention of epithelial cancers in r and omised trials evaluating their efficacy . We prospect ively studied 316 patients who developed squamous cell carcinoma of the head and neck , classified as T1/T2 , N0/N1 < or 3 cm , M0 according to the UICC TNM classification . Patients were r and omly assigned to receive orally , either etretinate ( a loading dose of 50 mg/day for the first month , followed by a dose of 25 mg/day in the following months ) or a placebo for 24 months . Adjuvant treatment began no later than 15 days after surgery and /or the initiation of radiotherapy . The 5-year survival rate and disease-free survival rate are similar in the two groups . There are no significant differences regarding either local , regional and distant relapses . After a median follow-up of 41 months ( range 0 - 81 ) , 28 patients in the etretinate group and 29 in the placebo group developed a second cancer with , respectively , 12 and 13 in the head and neck region . Adjuvant treatment was definitively discontinued mainly due to toxicity in 33 % of patients in the etretinate group versus 23 % in the placebo group ( P < 0.05 ) . Etretinate , a second-generation retinoid , does not prevent second primary tumours in patients who have been treated for squamous cell carcinoma of the oral cavity and oropharynx A r and omized prospect i ve clinical trial was carried out to assess the usefulness of the addition of mitomycin C to radiation therapy used alone or in combination with surgery for the treatment of squamous cell carcinoma of the head and neck region . One hundred and twenty patients with biopsy proven tumor of the oral cavity , oropharynx , larynx , hypopharynx , and nasopharynx were r and omly assigned to receive or not receive mitomycin C ; all other aspects were similar in the two treatment groups . One hundred and seventeen patients were evaluable with a median follow-up time of greater than 5 years .  Acute and chronic normal tissue radiation reactions were equivalent in the two treatment groups . Hematologic and pulmonary toxicity were observed in the drug treated patients . Actuarial disease-free survival at 5 years was 49 % in the radiation therapy group and 75 % in the radiation therapy plus mitomycin C group , p less than 0.07 . Local recurrence-free survival was 66 % in the radiation therapy group and 87 % in the radiation therapy plus mitomycin C group , p less than 0.02 . The findings demonstrate that mitomycin C can be administered safely as an adjunct to radiation therapy in the treatment of head and neck cancer . The drug improves local tumor control without enhancing normal tissue radiation reactions 226 patients with an operable epidermoid carcinoma of the pyriform sinus were entered in this clinical trial ; 187 cases were considered evaluable , they were distributed as follows : 16 T2 , 171 T3 , 44 N0 , 103 N1 and 40 N3 ( UICC TNM Classification 1979 ) . The 89 patients of the chemotherapy group received a 3 day course of Vincristine ( 1.5 mg/m2 ) , Bleomycin ( 15 mg ) , Methotrexate ( 80 mg ) . Both the  chemotherapy group and the 98 patients of the control group went through the surgical procedure of total laryngectomy with pharyngectomy and radical neck dissection . Radiotherapy was administered postoperatively according to tumor margins and nodal involvement . On examination of the surgical specimen , no evidence of tumor regression was observed in the chemotherapy group . The 3 and 5 year survivals are respectively 45 % and 35 % in both groups . Node metastasis was studied after N size , N status , capsular rupture ( PR + ) and revealed early and extensive nodal involvement with 25 % capsular ruptures in N0 patients , up to 70 % rate in N3 . Capsular rupture is also associated with a significantly lower survival and a higher incidence of distant metastases PURPOSE Pre clinical studies showed lonidamine to potentiate the effects of x-irradiation by inhibiting the repair of potentially lethal damage . This Phase III double blind , placebo-controlled study was performed to evaluate whether lonidamine can increase the tumor control of radiotherapy in the treatment of advanced head and neck cancer without any synergistic toxic effects on the exposed normal tissues . METHODS AND MATERIAL S Ninety-seven patients with Stages II-IV squamous cell carcinoma of the head and neck were enrolled . Separate analyses were done on the 96 eligible patients and the 90 patients who completed the prescribed treatment regimen . Patients received radiotherapy up to a planned total of 60 - 66 Gy , in 2 daily fractions of 1.5 Gy each and either lonidamine ( 450 mg p.o . in three divided daily doses ) or placebo , given continuously for 3 months or up to 1 month after the end of radiotherapy . RESULTS The rate of tumor clearance was 66 % ( 32/48 ) in the lonidamine group and 65 % ( 31/48 ) in the placebo group , while the subsequent failure rate was 50 % and 77 % , respectively ( p < 0.05 ) . The 3 and 5 year locoregional control rates in the adequately treated patients achieving complete tumor clearance were 66 % and 63 % for lonidamine vs. 41 % and 37 % for placebo . The disease-free survival in adequately treated patients was significantly better in the lonidamine group ( p < 0.03 ) , with 3 and 5 year rates of 44 % and 40 % , respectively , vs. 23 % and 19 % in the placebo group . The overall survival rate for all eligible patients at both 3 and 5 years was 44 % in the lonidamine group and 44 % and 31 % , respectively , in the placebo group . Both acute and late radiation reactions were similar in the two groups . Myalgia and testicular pain were the most frequent side effects of lonidamine with an incidence of 8.5 % and 4.2 % , respectively . CONCLUSION The addition of lonidamine to hyperfractionated radiotherapy was correlated with a statistically and clinical ly significant proportion of long-term disease-free patients . The toxicity of radiotherapy was not aggravated by the drug and the overall tolerance of the combined regimen was acceptable A r and omized prospect i ve study of 5 fluorouracil ( 5-FU ) and Cis platin preceding definitive local treatment for squamous cell carcinoma of the head and neck region was initiated in September 1986 . Seventy-five patients were stratified by site ( oral cavity-12 , oropharynx-28 , larynx-16 , hypopharynx-19 ) , and by Stage ( Stage II-20 , Stage III-43 , Stage IV-12 ) and r and omized to receive definitive local treatment ( surgery and post-operative radiation or radiation alone ) or chemotherapy followed by definitive local treatment . Chemotherapy consisted of three cycles of 120 hr 5-FU infusion 1 g/m2/day plus Cis platin 100 mg/m2 on day 1 on each cycle . Response to chemotherapy was complete in 17 patients ( 46 % ) for an overall response rate of 68 % . All the patients have completed therapy with a median follow-up of more than 12 months . After local treatment , the complete response rate is 84 % for the control group and 86 % in the chemotherapy group . Actuarial disease-free survival at 1 year is 61 % in the control group and 73 % in the chemotherapy group ( p = 0.25 ) . These preliminary results show that in spite of initial tumor response , neoadjuvant chemotherapy does not improve long-term control and survival Results from experimental systems suggest that the combination of methotrexate ( MTX ) and 5-fluorouracil ( 5-FU ) produces synergistic cytotoxic effects that are dependent on the sequence of drug administration . Biochemical studies have demonstrated plausible mechanisms of a synergistic effect when MTX precedes 5-FU . A variety of phase I and phase II studies have employed this sequential combination with promising but inconclusive results . In this study , 79 evaluable patients with squamous cell head and neck cancer were r and omized to receive MTX ( 200 mg/m2 IV ) and 5-FU ( 600 mg/m2 IV ) either simultaneously or sequentially with MTX preceding 5-FU by one hour . All patients were ambulatory and patients were stratified as to whether they presented with primary disease or with recurrence after prior radiation and /or surgical therapy . The overall response rate was superior for simultaneous therapy ( 62 % ) compared with sequential therapy ( 38 % ) ( p less than 0.06 ) . Among patients with primary head and neck cancer , the stage of the disease influenced the response rate . Eight of nine stage III patients who received simultaneous therapy responded while none of the four patients who received sequential therapy responded ( p less than 0.01 ) . This study demonstrates that one-hour sequential MTX plus 5-FU is not superior to simultaneous treatment in patients with squamous cell head and neck cancer BACKGROUND In 1992 , we reported the first analysis of a r and omized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck . The results of that 3-year analysis indicated that the combined treatment had superior efficacy . PURPOSE After an additional 2 years of follow-up , we again compared the efficacy of the two treatment regimens , with attention paid to differences in overall survival , progression-free survival , and locoregional relapse-free survival . METHODS One hundred fifty-seven patients with untreated , unresectable squamous cell carcinoma of the head and neck were r and omly assigned to receive either chemotherapy ( four courses of cisplatin [ 20 mg/m2 ] and fluorouracil [ 200 mg/m2 ] , given daily for 5 consecutive days during weeks 1 , 4 , 7 , and 10 ) plus radiotherapy ( three courses of 20 Gy each , given in fractions of 2 Gy per day during weeks 2 - 3 , 5 - 6 , and 8 - 9 ) or radiotherapy alone ( 70 Gy total dose , given in fractions of 2 Gy per day , 5 days per week ) . Eighty patients received the combined therapy , and 77 were treated with radiotherapy alone . Responses , failures , and toxic effects associated with the two treatment regimens were compared . Overall survival , progression-free survival , and locoregional relapse-free survival were calculated according to the Kaplan-Meier method ; the logrank test was used to compare survival parameters between the two patient groups . Reported P values are two-sided . RESULTS As reported previously , toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects ; however , the incidence and severity of mucositis were nearly identical among patients in the two treatment arms . The combined treatment was associated with a statistically significant increase in the frequency of complete response ( i.e. , the disappearance of clinical ly detectable disease for at least 4 weeks ) ( 43 % for the combined-treatment group compared with 22 % for the radiotherapy-only group ; P = .037 , chi-squared test ) . Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24 % ( 95 % confidence interval [ CI ] = 14%-40 % ) and 10 % ( 95 % CI = 4%-24 % ) , respectively ( P = .01 , logrank test ) . The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21 % ( 95 % CI = 11%-37 % ) and 9 % ( 95 % CI = 3%-22 % ) , respectively ( P = .008 , logrank test ) . Finally , the 5-year estimates of locoregional relapse-free survival were 64 % ( 95 % CI = 36%-84 % ) in the combined-treatment group and 32 % ( 95 % CI = 10%-65 % ) in the radiotherapy-only group ( P = .038 , logrank test ) . CONCLUSIONS AND IMPLICATION S The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years . However , additional trials must be conducted before considering the combined approach as st and ard therapy Three regimes of combined treatment for intraoral and oropharyngeal cancer were compared . In group A , cisplatin 6 mg/m2 was given intravenously , daily ; group B--40 mg/m2 , weekly ; group C--100 mg/m2 , once in 3 weeks . All patients simultaneously received distant radiation therapy in a st and ard fractionated dose of 2 Gy per fraction , 5 times a week , up to TTD of 68 - 70 Gy . Among relatively frequent side-effects were granulocytopenia , asthenia and stomatitis . Overall immediate effectiveness was : group A--100 % , group B--96 % and group C--100 % . The rates of complete tumor resorption were : group A--27.3 % , group B--19.2 % and group C--16.7 % There were 79 patients with squamous cell head and neck cancer r and omized to receive simultaneous or 1 hour sequential methotrexate-5 fluorouracil ( MTX--5-FU ) chemotherapy :  47 patients were previously untreated and 32 patients had recurrent disease . The treatment groups were comparable for important prognostic features . The median survival for the 47 newly presenting patients was 22 months and for recurrent disease patients was 14 months . No difference could be detected in the survival of patients who received simultaneous versus sequential chemotherapy . When only chemotherapy responders were compared , no difference in survival was detected for those who received sequential versus simultaneous therapy . Subsequently , 19 chemotherapy responders received radical radiation therapy , and 15 were rendered disease-free whereas only 4 of 17 chemotherapy nonresponders were rendered disease-free by subsequent radiation ( P = .002 ) . The survival of the 19 chemotherapy responders was 34 months compared with 16 months for the 17 chemotherapy nonresponders treated with radiation . We conclude that there is no therapeutic advantage for 1 hour sequential MTX-5 FU chemotherapy compared with simultaneous use of these drugs in squamous cell head and neck cancer . Chemotherapy responders are more likely to respond to radiation therapy This Head and Neck Intergroup ( Radiation Therapy Oncology Group , Southwest Oncology Group , Eastern Cooperative Oncology Group , Cancer and Leukemia Group B , Northern California Oncology Group , and Southeastern Cancer Study Group ) phase 3 r and omized prospect i ve trial was opened for registration January 1985 . It is an evaluation of the role of chemotherapy for previously untreated advanced stage resectable squamous cell carcinoma of the head and neck . As of March 1 , 1988 , there has been a total of 535 patients registered . There are 266 patients analyzable with 133 in each treatment group . The surgical , chemotherapy , and radiation therapy toxic reactions are in the tolerable range with the worst toxic reactions reported in those patients receiving both surgery and radiation therapy .  Compliance continues to be a major challenge to patient accrual . The most common cause for cases not being r and omized involves positive margins of surgical resection . Patient refusal or surgical complications are other common reasons We treated 114 patients with advanced inoperable head and neck cancer with a combined-modality protocol that included two cycles of chemotherapy followed by radiotherapy or three chemotherapy and in 18 patients with a radiosensitizing agent . At the beginning of the treatment all but one patient presented with a stage IV cancer . With a follow-up of 42 - 58 months , four patients are alive ( three from the radiosensitizing group and one of the chemotherapy group ) . Complete response after the radiosensitizing agent correlated with superior prolonged disease-free survival in comparison to complete responses after chemotherapy at the level of p less than 0.009 In a prospect i ve evaluation , two preoperative courses of methotrexate , bleomycin , and cisplatin combined with 2,000 rad/10 fractions ( " chemo-radiotherapy " ) yielded 78 % responses rates in previously untreated advanced head and neck cancer . Similarly staged patients receiving preoperative irradiation of 5,000 rad alone had a 67 % response rate . Treatment-related mortality in the chemo-radiotherapy patients was equal to that seen with st and ard combinations of surgery and preoperative or postoperative irradiation . At 24 months , disease-free survival is 47 % with chemo-radiotherapy vs 33 % with st and ard therapy ; however , patients benefiting most from the former approach were those with T4 primary lesions or N3a neck nodes The primary objective of the present r and omized phase III trial was to compare the 3-yr survival rate of patients treated with  st and ard fractionated radiotherapy ( RT ) alone or with the same RT concomitantly with cisplatin ( DDP ) or carboplatin ( Cb ) . From January 1995 until July 1999 , 124 patients with histologically proven locally advanced non-nasopharyngeal head and neck cancer ( HNC ) were r and omized to receive either RT monotherapy ( 70Gy , Group A ) or the same RT concomitantly with DDP ( 100 mg/m2 on d 2 , 22 , 42 , Group B ) or Cb ( 7 AUC on d 2 , 22 , 42 , Group C ) . There were no significant differences in complete response rates between patients treated with RT alone or combined chemoradiotherapy . However , median time to progression ( TTP ) and overall survival ( OS ) were significantly longer in patients treated with concomitant chemoradiotherapy . Thus , median TTP was 6.3 , 45.2 , and 17.7 mo in groups A , B , and C respectively ( p=0.0002 ) . Similarly , median OS was 12.2 , 48.6 , and 24.5 mo , respectively ( p=0.0003 ) . At 3 yr follow-up , 17.5 % of patients in group A were alive compared to 52 % in group B and 42 % in group C ( p<0.001 ) . Patients treated with concomitant chemoradiotherapy experienced more frequently severe hematological toxicity . Also , severe nausea/vomiting was more pronounced in group B , as expected . The present study clearly demonstrated that concomitant chemoradiotherapy with platinum analogs significantly prolongs 3-yr survival and median OS in patients with locally advanced HNC compared to conventional RT alone This prospect i ve r and omised study was undertaken to assess the effects and effectiveness of cisplatin in a pre-operative setting . Thirty-eight patients were treated with stage II-IVa ( AJCC ) squamous cell cancer of the oral cavity and oropharynx . Nineteen patients received a combination of bleomycin , vincristine , methotrexate ( BVM ; group I. ) , 19 received BVM and cisplatin ( group II ) . Patients underwent surgery within 3 weeks after chemotherapy . Biopsy and surgical specimens were compared . A clinical complete response was seen in five patients in group I ( 26.3 % ) and in four patients in group II ( 21.1 % ) . Partial response was noted in 11 patients in group I ( 57.8 % ) and in 13 patients in group II ( 68.4 % ) . There was no statistical difference in clinical response between the two groups . Microscopic response was better in the cisplatin treated group . Median follow up of patients is 52 ( 36 - 70 ) months . Disease free survival showed a significant difference , favouring the no cisplatin group ( P = 0.03 ) . There was no significant difference in overall survival ( P > 0.6 ) . Cisplatin in combination with BVM showed significantly higher levels of microscopic response , but the lower disease free survival is mostly due to a higher rate of regional neck failure Abstract The authors report the results of a sequential trial demonstrating the superiority , in terms of tumor regression , of a treatment with high dose methotrexate ( 50 mg per day , in 10 -hr infusion ) over a treatment with low dose methotrexate in advanced cancers of the oral cavity and oropharynx PURPOSE To demonstrate the efficacy of radiochemotherapy ( RCT ) as the first choice of treatment for advanced unresectable head- and -neck cancer . To prove an expected benefit of simultaneously given chemotherapy , a two-arm r and omized study with hyperfractionated accelerated radiochemotherapy ( HF-ACC- RCT ) vs. hyperfractionated accelerated radiotherapy ( HF-ACC-RT ) was initiated . The primary endpoint was 1-year survival with local control ( SLC ) . METHODS AND MATERIAL S Patients with Stage III and IV ( UICC ) unresectable oro- and hypopharyngeal carcinomas were r and omized for HF-ACC- RCT with 2 cycles of 5-FU ( 600 mg/m(2)/day)/carboplatinum ( 70 mg/m(2 ) ) on days 1 - -5 and 29 - -33 ( arm A ) or HF-ACC-RT alone ( arm B ) . In both arms , there was a second r and omization for testing the effect of prophylactically given G-CSF ( 263 microg , days 15 - -19 ) on mucosal toxicity . Total RT dose in both arms was 69.9 Gy in 38 days , with a concomitant boost regimen ( weeks 1 - -3 : 1.8 Gy/day , weeks 4 and 5 : b.i.d . RT with 1.8 Gy/1.5 Gy ) . Between July 1995 and May 1999 , 263 patients were r and omized ( median age 56 years ; 96 % Stage IV tumors , 4 % Stage III tumors ) . RESULTS This analysis is based on 240 patients : 113 patients with RCT and 127 patients with RT , qualified for protocol and starting treatment . There were 178 oropharyngeal and 62 hypopharyngeal carcinomas . Treatment was tolerable in both arms , with a higher mucosal toxicity after RCT . Restaging showed comparable nonsignificant different CR + PR rates of 92.4 % after RCT and 87.9 % after RT ( p = 0.29 ) . After a median observed time of 22.3 months , l- and 2-year local-regional control ( LRC ) rates were 69 % and 51 % after RCT and 58 % and 45 % after RT ( p = 0.14 ) . There was a significantly better 1-year SLC after RCT ( 58 % ) compared with RT ( 44 % , p = 0.05 ) . Patients with oropharyngeal carcinomas showed significantly better SLC after RCT ( 60 % ) vs. RT ( 40 % , p = 0.01 ) ; the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT ( p = 0.84 ) . For both tumor locations , prophylactically given G-CSF was a poor prognostic factor ( Cox regression ) , and result ed in reduced LRC ( log-rank test : + /- G-CSF , p = 0.0072 ) . CONCLUSION With accelerated radiotherapy , the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to st and ard fractionated RT . Oropharyngeal carcinomas showed better LRC after HF-ACC- RCT vs. HF-ACC-RT ; hypopharyngeal carcinomas did not . Prophylactic G-CSF result ed in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication Since January 1974 , 95 patients with anterior tongue and floor of the mouth cancers were included in a r and omized trial . After stratification according to staging and initial treatment , one-third of the patients received chemotherapy for 2 years ( methotrexate 400 mg followed by citrovorum factor 100 mg + bleomycin 60 mg/week , during the first 15 weeks ) , one-third of the patients received immunotherapy with weekly C. parvum injections during 2 years , while the remaining third did not receive any treatment . If adjuvant treatment seems to delay recurrence it did not significantly decrease the recurrence rate . Survival is also not signigicantly modified by adjuvant treatment and was better for patients with small tumors . Patients who previously received radiotherapy did not benefit from adjuvant therapy Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing chemotherapy ( DDP + bleomycin ) alone , multiple daily fractionated radiation therapy , and multimodality therapy consisting of chemotherapy plus multiple fractionated radiation therapy . Multimodal therapy gave a significantly higher response rate ( 69 % ) than either single-treatment modality . The use of a multiple daily dose fractionation allowed radiation therapy to be completed over 10 treatment days , and the addition of chemotherapy to the radiation treatment did not significantly increase toxicity . Patients receiving multimodal therapy also survived significantly longer ( median 50 weeks ) than those receiving single-modality therapy ( median 24 weeks ) A total of 185 eligible patients with advanced inoperable squamous cell carcinoma of the head and neck were r and omized into two groups ; the cisplatin , methotrexate , bleomycin , and vincristine ( CABO ) group received cisplatin ( 50 mg/m2 ; day 4 ) , methotrexate ( 40 mg/m2 ; days 1 , 15 ) , bleomycin ( 10 mg ; days 1 , 8 , and 15 ) , and vincristine ( 2 mg ; days 1 , 8 , and 15 ) and the ABO group received methotrexate , bleomycin and vincristine in the same doses on days 1 , 8 , and 15 . After three courses , patients in both arms received weekly methotrexate as maintenance therapy ; those 34 patients with previously untreated locoregional disease went off the study because of subsequent locoregional treatment in form of radiotherapy — surgery . The complete response rate was 16 % in patients receiving CABO , compared with 5 % among patients given ABO . The corresponding overall response rates were 50 % and 28 % , respectively ( P = 0.003 ) . Among patients with recurrent or metastatic disease , progression was delayed in patients receiving CABO ( median , 18 weeks ) compared to those receiving ABO ( median , 14 weeks ) ( P = 0.07 ) , but there was no difference in survival time . Myelosuppression consisted mostly of leukopenia , which was seen in 67 % of the CABO patients versus 47 % in the other arm . Myelosuppression‐associated infection and hemorrhage led to death in two patients in the CABO treatment group and six patients in the ABO treatment group . Nausea and vomiting , mostly of grade s 1 or 2 , occurred in 93 % of the patients given CABO and 44 % of those receiving ABO . Other toxic effects — neuropathy , alopecia , stomatitis , constipation , fever/chills , diarrhea , cutaneous alterations , and renal impairment — occurred equally in the two treatment groups . This study underlines the role of cisplatin in head and neck cancer , although no impact on survival could be demonstrated . It also supports indirectly the superiority of combination chemotherapy over single‐agent treatment for this disease The purpose of this r and omized trial was to verify some experimental and clinical data suggesting a possible potentiating effect of bleomycin when used concomitantly with radiotherapy . Out of 220 patients with a biopsy proven epidermoid carcinoma of the oropharynx , 186 evaluable cases are reported here . One group of 87 patients was treated with radiotherapy alone ( Cobalt 60 ∼ 6400 rad ∼ 7–8.5 weeks ) , the other group of 99 patients received radiotherapy combined with bleomycin , the latter administered at the dose of 15 mg i.m . twice a week for 5 weeks ( total dose : 150 mg ) . Analysis of the treatment groups showed their comparability with regard to the most important prognostic factors ( TNM , sites of primary , sex , age … ) . Complication rates of mucositis and epidermitis were significantly increased ( 71 % ) in the radiotherapy + bleomycin group and were considered responsible of frequent denutrition and weight loss in this group . Such side effects necessitated a delay of radiotherapy in 22 % of patients and definitive interruption in 5 % in the combined treatment group whereas in the radiotherapy alone group no interruption of treatment was recorded and only 5 treatments ( 6 % ) were postponed . Considering tumor regressions measured 6 weeks after completion of radiation therapy , total regression rates were not significantly different in both groups as far as primary tumor ( 67.9–67 % ) or neck nodes ( 49–62 % ) are concerned . Survival curves obtained by the actuarial method showed the same 50 % survival in both groups at 15 months of follow-up R and omized studies on the efficacy of two courses of different types of chemotherapy , including cisplatin and 5-fluorouracil ( 5-FU ) , were performed on 130 previously untreated cases with advanced squamous cell carcinomas of the head and neck .  Cisplatin , followed by 120-hr continuous 5-FU infusion given in the conventional way , was administered to 60 patients ( Group A ) , while cisplatin was administered 72 hr after the initiation of continuous 5-FU infusion in 70 other patients ( Group B ) . The overall response rates ( complete response plus partial response ) were 58 % in group A and 69 % in group B , respectively . A superior complete response rate was obtained in cases receiving modified chemotherapy ( 10 % in group A vs 20 % in group B ) . There was no significant difference in the incidence of side effects between the two groups . These findings indicate that the modified cisplatin plus 5-FU combination chemotherapy tested here is more efficacious regimen than that of the conventional one to achieve high complete response rate and subsequently , to improve the survival of advanced carcinoma cases of the head and neck Abstract We carried out an open , r and omized , phase III , multicenter clinical trial to compare , in neo-adjuvant setting , the clinical response and toxicity of the combination chemotherapy cisplatin + 5-FU with the same combination plus s.c . recombinant interleukin-2 ( rIL-2 ) in patients with advanced ( stage III – IV ) head and neck squamous-cell carcinoma ( HNSCC ) . Regimen A was the classical Al Sarraf treatment : 100 mg/m2 cisplatin i.v . on day 1 plus 1000 mg m−2 day−1 5-FU on days 1–5 as a continuous infusion . Regimen B was the same as regimen A plus 4.5 MIU/day rIL-2 s.c . on days 8–12 and 15–19 . Treatment was repeated every 3 weeks for three cycles . A total of 33 patients were enrolled in the study ; 30 were evaluable for toxicity and 28 for response . Seventeen patients were assigned to group A and 16 were assigned to group B. Three patients ( 20 % ) of group A and 4 ( 31 % ) of group B had a complete response , 9 patients ( 60 % ) of group A and 6 ( 46 % ) of group B had a partial response , with an overall response rate of 12 patients ( 80 % ) for group A and 10 patients ( 77 % ) for group B. Two patients ( 13 % ) of group A and 3 patients ( 23 % ) group B had stable disease ; 1 patient ( 7 % ) of group A had progressive disease . Thus , there was not a statistically significant difference in response rate between the two groups and therefore there was no benefit from the addition of immunotherapy with rIL-2 to the st and ard chemotherapy . Both regimens were well tolerated . There were 2 toxic deaths ( 6.7 % ) , 1 from hematological causes in group A and 1 from cardiac causes in group B. Myelosuppression and gastrointestinal toxicity , mainly nausea/vomiting and stomatitis , were the most frequent toxicities . The calculated number of patients for the sample has not yet been reached ; however , the projection of our present results suggests that it is highly improbable that a clinical ly significant difference between the two treatment groups will be observed even if the calculated patient sample size is achieved This is an interim report of a study of perioperative adjuvant chemotherapy following radical surgery for oral cancer , based on the hypothesis of Goldie and Coleman . 135 patients of alveolobuccal carcinoma , clinical ly stage III and IV , were entered on the protocol . After a curative resection , they were r and omized . The test arm received methotrexate 50 mg/m2 on the 3rd , 10th , and 17th postoperative days . The control arm was only observed . This analysis at 12 months showed a disease free survival of 71 % in the test arm vs. 45 % in the control arm , which is statistically highly significant ( P less than 0.01 ) . Analysis of recurrence pattern showed that recurrence at the primary site was dramatically reduced during the first 6 postoperative months ( P less than 0.01 ) . Our study provided further clinical evidence in support of the concepts of Goldie and Coleman that the timing of chemotherapeutic drugs is very critical for a successful end result The authors previously have found that in patients with locally advanced squamous cell carcinoma of the head and neck ( SCC‐HN ) , alternating chemoradiotherapy ( ALT ) was superior to low‐total‐dose conventional radiotherapy alone . The purpose of this r and omized trial was to compare the same chemoradiotherapy approach with high‐total‐dose partly accelerated radiotherapy In a r and omized multicenter trial , 151 patients , with advanced epidermoid carcinoma of the head , neck and oesophagus , were treated with an association of vincristin , methotrexate , bleomycin and cis-platin ( group I ) or detorubicin ( group II ) . Prognostic factors were equally distributed for the both groups . Partial or complete responses were obtained in 22 patients of group I ( 29 p. cent ) and 9 in group II ( 12 p. cent , p less than 0.05 ) . Objective response rates were higher in untreated patients or those in good condition but the difference was not statistically significant . Five probably treatment induced deaths ( 3 p. cent ) were observed . Treatment was stopped in 2 patients ( 15 p. cent ) for haematological , general or digestive toxicity . This trial confirms the efficacy of vincristin , methotrexate , bleomycin and cis-platin for advanced head and neck carcinomas We investigated a phase III r and omized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16 , both given intravenously in patients with unresectable advanced head and neck cancer . The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage . Comparisons were made through sequential closed plans . In 179 patients , tumor beds and cervical lymph nodes were irradiated , and 20 patients underwent salvage surgical procedures . Cisplatin plus 5-fluorouracil showed a response ( CR + PR ) rate of 15 % greater than that observed with cisplatin plus etoposide ( alpha=0.05 , power 70 % ) . Complete responses played a major role in the CDDP + 5-FU regimen . Furthermore , we noted a higher cervical node regression with this chemotherapy combination . Because radiotherapy was administered after chemotherapy , we could not analyze the mean duration response for each protocol . No significant difference in survival existed between the two groups . Myelosuppression was the most frequent sign of toxicity observed , especially with the CDDP + VP16 regimen . Mucositis was rare with allopurinol protection . In the CDDP + 5-FU group , one patient had grade 4 cardiac dysfunction , and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage . Thirteen patients died , with 8 cases related to septic shock ( 5 CPPP + VP16 and 3 CDDP + 5-FU ) . Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16 , with caution to patients with a cardiac or vascular history . Although we could not show a benefit in survival with the CDDP + 5-FU protocol , this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck Purpose : Induction chemotherapy has shown to provide consistent benefit for local control in primary treatment of advanced oropharyngeal cancer . The beneficial role of chemoradiation following induction chemotherapy over concurrent chemoradiation has not been evaluated . Present study evaluates the same prospect ively . Method : Out of 135 patients of locally advanced oropharyngeal carcinoma , 105 patients were found eligible and r and omized to treat either with induction chemotherapy consisting of 2 - 3 cycles of cisplatin and 5- Florouracil followed by low dose weekly cisplatin based chemoradiotherapy ( treatment arm : n=48 ) or chemoradiotherapy only ( control arm : n=57 ) . The primary tumor and regional lymph drainage areas received 66 - 70 Gy in 6.5 to 7 weeks by fractionated dose schedule . Results : The response rate and acute toxicity ( primary end points ) in both the arms were found to be similar ( P>0.05 ) The points disease free survival and overall survival ( secondary end points ) were significantly ( PURPOSE To prospect ively assess 5-year late toxicity in patients treated by concomitant radiochemotherapy for locally advanced oropharynx carcinoma using three different toxicity scales . METHODS AND MATERIAL S A total of 226 patients were entered in a Phase III multicenter , r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions : Arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen containing carboplatin and 5-fluorouracil : Arm B ) . Five living patients , free of local or distant recurrences , could not be evaluated for late toxicity .  Forty-four patients were eligible for late toxicity with a median follow-up of 5 years .  Late toxicity was evaluated by the radiation oncologist using a large question naire containing 120 mixed items of three scales ( NCI-CTC , LENT/SOMA , and RTOG ) . The data were then transposed on separate scales using corresponding grade s. RESULTS The 5-year overall survival rate was 22 % in Arm B and 16 % in Arm A ( p = 0.05 ) . The 5-year locoregional control rate was 48 % in Arm B and 25 % in Arm A ( p = 0.002 ) . The spinal cord was not affected by the concomitant adjunct of chemotherapy , and no deaths were caused by late toxicity . Using the three late toxicity scales , 100 % of the patients treated with the combined modality ( Arm B ) developed one or more late complications vs. 94 % in the radiotherapy-alone arm ( Arm A ) . The difference was not statistically significant . The most commonly damaged organs ( all Grade 1 - 4 ) were the salivary gl and s ( 100 % in Arm B vs. 82 % in Arm A , p < 0.05 ) , skin ( 78 % vs. 47 % , p < 0.05 ) , teeth ( 67 % vs. 18 % , p < 0.05 ) , mucosa ( 59 % vs. 63 % p = not significant ) , and m and ible ( 44 % vs. 12 % , p < 0.05 ) . One or more Grade 3 - 4 complications occurred in 82 % of the patients in Arm B vs. 47 % in Arm A ( p = 0.02 ) but concerned only the teeth . The correlation between the RTOG and LENT/SOMA scale and between the NCI-CTC and LENT/SOMA scale were low for Grade 1 - 4 toxicity ( near 30 % ) . The transposability of a patient 's symptoms was significantly greater using the LENT/SOMA or RTOG/EORTC scaling systems than using the NCI-CTC system . CONCLUSION Concomitant radiochemotherapy increased overall survival and locoregional control rates . The difference between the two treatment groups for Grade 3 - 4 complications was only significant for the teeth . The late toxicity assessment of a treatment may depend on the toxicity scale used . The LENT/SOMA scale seems to be the most accurate scale , but most of the score results were not concordant with those obtained with other scales . The results of this study confirm the necessity of using a common late toxicity scale in clinical trials Forty patients with end-stage carcinoma of the head and neck were admitted to a r and omized double blind trial with cisplatinum  in one arm and cisplatinum + nifedipine in the other . Nifedipine , a calcium channel blocking drug , inhibits the effect of acquired multidrug resistance in animal models . In the present study the addition of this agent had no effect on either response rate or survival in end-stage carcinoma of the head and neck .  It is concluded that adding nifedipine to cisplatinum serves no useful purpose in the treatment of end-stage carcinoma of the head and neck The value of misonidazole in advanced head and neck cancer was examined in 3 ways and the preliminary results are reported in a r and omized study with large fractions of irradiation , when misonidazole appeared to confer no advantage ; whereas in previously ( partially ) treated patients  misonidazole was possibly useful . The combination of hyperbaric oxygen and misonidazole did not appear to be toxic PURPOSE Clinical trials demonstrated the efficacy and safety of intravenous ( i.v . ) or subcutaneous ( s.c . ) amifostine for reducing xerostomia and mucositis after radiotherapy or radiochemotherapy for head- and -neck cancer . This r and omized , double-blinded , placebo-controlled , phase III study evaluated the efficacy and safety of i.v . amifostine during radiochemotherapy for head- and -neck cancer . METHODS AND MATERIAL S Patients from European and American study centers received i.v . amifostine 300 mg/m2 ( n = 67 ) or placebo ( n = 65 ) before carboplatin 70 mg/m2 and radiotherapy on Days 1 to 5 and 21 to 25 , and i.v . amifostine 200 mg/m2 or placebo before radiotherapy on other days . RESULTS Toxicity incidences were ( amifostine , placebo , p value ) : Grade 2 or higher acute xerostomia ( 39 % , 34 % , 0.715 ) , Grade 3 or higher acute mucositis ( 39 % , 22 % , 0.055 ) , Grade 2 or higher late xerostomia ( 37 % , 24 % , 0.235 ) , and Grade 3 or higher treatment-related adverse events ( 42 % , 20 % , 0.008 ) . One-year rates of locoregional failure , progression-free survival , and overall survival were not significantly different between treatments . CONCLUSIONS The used amifostine doses were not able to reduce the toxicity of simultaneous radiochemotherapy for head- and -neck cancer . The safety of amifostine and the lack of tumor protection were consistent with previous studies PURPOSE This study was undertaken to assess the benefit of mitomycin C as an adjunct to postoperative radiation therapy in patients with operable squamous cell carcinoma of the head and neck . METHODS AND MATERIAL S Between May 1980 and May 1991 , 182 patients have been enrolled in two consecutive r and omized clinical trials testing mitomycin C as an adjunct to radiation therapy in squamous cell carcinoma of the head and neck . In both trials , patients were stratified by stage , disease site and intent of therapy . This subset analysis includes 113 patients entered into these two r and omized trials treated with surgery and postoperative radiation therapy . In the first trial , patients were r and omized to receive st and ard postoperative radiation therapy alone compared with postoperative radiation therapy with concomitant mitomycin C. In the second trial , patients were r and omized to postoperative radiation therapy or postoperative radiation therapy with concomitant mitomycin C plus dicoumarol . RESULTS As of November 1991 , the 113 patients treated with surgery and postoperative radiation therapy in both trials had a median follow-up of 93 months . There have been a total of 12 local recurrences in the radiation therapy alone arm compared to 0 local recurrences in the radiation therapy/mitomycin C arm . There were eight regional recurrences in the radiation therapy alone arm compared with five regional recurrences in the mitomycin C arm . Patients in the mitomycin C arm experienced a superior 5-year actuarial local regional control rate ( 87 % vs. 67 % , p < .015 ) and a statistically significant disease-free survival benefit ( 67 % vs. 44 % , p < .03 ) . Overall survival difference between the two arms ( 56 % vs. 41 % ) has not reached statistical significance . CONCLUSIONS We conclude from these prospect ively design ed r and omized clinical trials that in patients with operable head and neck cancer treated with surgery  and postoperative radiation therapy  , concomitant administration of mitomycin C with radiation therapy will result in a statistically significant disease-free survival and local regional control benefit . We are currently investigating the value of other bioreductive alkylating agents as adjuncts to radiation therapy in patients with squamous cell carcinoma of the head and neck From July 1987 to July 1990 , 374 patients were r and omized in a multicenter trial coordinated by the Gustave-Roussy Institute . Patients were treated either by radiotherapy alone ( RT ) or by combined etanidazole with radiotherapy ( ETA ) . The same radiotherapy protocol was used in both arms . Major deviations from the protocol occurred in 16 % of the patients . Etanidazole was given at a dose of 2 g/m2 , 3 times per week , for a total of 30 - 34 g/m2 . Seventeen percent of the patients received less than 14 injections ( 4 % refused , 12 % presented a toxicity , 1 % died before beginning ) . The rate of neuropathy was 28 % in the ETA arm and 3 % in the RT arm . Acute radiotherapy reactions occurred in similar proportions in both arms . The 3-month rates of complete regression are presently 75.3 % in the RT alone group and 77.6 % in the ETA group ; this difference is not significant . No definitive results are presently available and we must wait for the two-year survival results . In addition , if a meta- analysis could be performed with the parallel RTOG study , the results would be more valid A concurrent r and omised controlled clinical trial to evaluate a combination of Bleomycin and radiation  as against radiation only in the treatment of advanced oral cancer has been conducted at the Cancer Institute , Madras , since 1971 . All T3 and T4 previously untreated oral squamous cell carcinomas with N0 , N1 and N2 regional nodes , or N3 nodes confined to the subm and ibular region , without systemic metastases or gross infiltration of the temporal and infratemporal fossa producing total trismus , and in decent general health were eligible for the trial . Patients with gross active pulmonary tuberculosis were excluded , as were recurrent carcinomas . Age , external fungation of growth or radiological bone invasion were no bar . R and omisation was done by the sealed envelope technique . The study group received concurrent fractionated cobalt 60 teletherapy using two opposing fields and 10 - 15 mg of Intra-arterial or Intravenous Bleomycin . The controls received fractionated cobalt teletherapy and i.v . or i.m . distilled water on the same protocol as the Bleomycin cases . All cases were evaluated double blind 8 weeks after the end of radiation therapy , and were classified as ' favourable response ' or ' failure ' . The criterion of ' favourable response ' was ' total clinical healing of the tumour within the volume of irradiation with no subsequent recurrence within that volume , whatever the length of follow up ' . Anything else was reported as a failure . A long term follow up of 3 years is also available . 136 cases have completed the trial . The favourable response in the study group was 77 % as against 20.9 % in the control group . The differential response is statistically significant . The present study is the fourth in the series of combined therapeutic trials conducted in advanced oral squamous cell carcinoma since 1958 . ( Krishnamurthi and Shanta , 1963 , 1965 , 1967 and 1971 ) . A concurrent r and omised controlled clinical trial to evaluate the combination of Bleomycin and radiation as against radiation  only in treatment of advanced oral cancer has been conducted at the Cancer Institute , Madras since 1971 PURPOSE Prognosis of patients with advanced oral cavity cancer is worth improving . Chemotherapy has been reported to be especially active in oral cavity tumors . Here we repeat the results of a r and omized , multicenter trial enrolling patients with a resectable , stage T2-T4 ( > 3 cm ) , N0-N2 , M0 untreated , squamous cell carcinoma of the oral cavity . PATIENTS AND METHODS Patients were r and omly assigned to three cycles of cisplatin and fluorouracil followed by surgery ( chemotherapy arm ) or surgery alone ( control arm ) . In both arms , postoperative radiotherapy was reserved to high-risk patients , and surgery was modulated depending on the tumor 's closeness to the m and ible . Patients ' accrual was opened in 1989 and closed in 1999 . It included 195 patients . RESULTS In the chemotherapy arm , three toxic deaths were recorded . No significant difference in overall survival was found . Five-year overall survival was , for both arms , 55 % . Postoperative radiotherapy  was administered in 33 % of patients in the chemotherapy arm , versus 46 % in the control arm . A m and ible resection was performed in 52 % of patients in the control arm , versus 31 % in the chemotherapy arm . CONCLUSION The addition of primary chemotherapy to st and ard surgery was unable to improve survival . However , in this study , primary chemotherapy seemed to play a role in reducing the number of patients who needed to undergo m and ibulectomy and /or radiation therapy . Variations in the criteria used to select patients for these treatment options may make it difficult to generalize these results , but there appears to be room for using preoperative chemotherapy to spare destructive surgery or radiation therapy in patients with advanced , resectable oral cavity cancer From March 1983 to December 1989 , 208 patients with locally advanced squamous cell carcinoma of the head and neck were successively included into two trials r and omizing induction chemotherapy versus no pre-irradiation treatment . The chemotherapy regimen of the first trial , which included 100 patients , consisted of two cycles of a combination of cisplatin , bleomycin , vindesine , mitomycin C ; while that of the second trial , which included 108 patients , consisted of three cycles of a combination cisplatin , 5-fluorouracil ( continuous infusion ) and vindesine . Local treatment was the same in two trials : ' primary ' radiotherapy in all patients . The response was then evaluated at 55 Gy ; in the case of poor response , surgery was performed , otherwise radiotherapy was continued to full doses ( possibly followed by salvage surgery ) . The tumor and lymph node responses to chemotherapy  ( complete and partial response ) were higher in the second trial and in the first one : 70 % versus 50 % for primary lesions , 47 % versus 25 % for lymph nodes . The toxicity of the two chemotherapy regimens was minimal . In the two trials , an initial major response to chemotherapy predicted subsequent efficacy of irradiation in 80 % of the patients . Complete response rate at the end of irradiation correlates with the previous response to the chemotherapy . With a median follow-up of 60 months with the first chemotherapy regimen and 30 months with the second , overall survival and disease-free interval did not significantly differ in the two groups of patients , with or without chemotherapy . The incidence of distant metastasis was significantly reduced ( P < 0.03 ) in the chemotherapy arms . This negative trial encourages the design of new chemotherapy protocol s according to new schemes of treatment . For advanced stages of head and neck cancers ( T3 , T4 , N2 , N3 ) , we recently launched a pilot study combining platinum and irradiation , but according to a concomitant schedule Abstract Ninety patients with salivary gl and or squamous cell tumours of the head and neck region presenting to two centres were included in a double blind controlled clinical trial of radiation plus razoxane versus radiation plus placebo . The patients were paired according to treatment centre , sex , tumour site and tumour stage , one member of a pair receiving razoxane and one placebo  during radiotherapy .  The dose of razoxane administered was 125 mg in the morning and 62.5 mg in the evening of each day of radiation . The treatments were assessed by comparing the tumour response of pairs of patients and the preferences for treatment type analyzed sequentially on the plan described by Bross . Of the 18 pairs eligible for analysis at the completion of the trial , one showed a preference for the treatment radiation plus razoxane , nine for the treatment radiation plus placebo , four showed no preference for either treatment and four had not been assessed . The conclusion drawn from the sequential analysis of the results is that razoxane , in the dose and schedule employed , has a deleterious effect on the response of head and neck tumours to radiation . Excluding a positive placebo action , the possibility of a radioprotective effect of razoxane is discussed and the importance of reconsidering the dose and timing of administration of the drug in future clinical studies is emphasized A group of 222 consecutive patients admitted with squamous cell carcinoma of the upper aero-digestive tract were studied in a prospect ively r and omized and stratified clinical trial . One-half of the patients received bleomycin injected intramuscularly 1 hour before the radiation treatment daily for 5 days a week ; the other half received radiation therapy without the added chemotherapy . The total dose of radiation in both groups was about the same , and was given with curative intent even to the patients with advanced tumors who constituted the majority in both groups . Interstitial radiation as boost therapy or surgery was added in patients with residual tumor if the lesions were considered operable and the patient 's condition would allow surgery . The addition of bleomycin did not increase the combined local and regional tumor control rates nor did it improve the survival , but did significantly increase the morbidity and the complication rate Because of biochemical and tissue culture evidence casting doubt on the physiologic relevance of reported synergy afforded by sequential administration of methotrexate ( MTX ) followed by 5-fluorouracil ( 5-FU ) , a r and omized controlled clinical trial was conducted in 108 patients with advanced cancer , including 70 with squamous cell carcinoma ( SCC ) of the head and neck , nine with SCC of other primary sites , 24 with colorectal , and five with gastric adenocarcinomas . Patients were r and omized to receive weekly therapy consisting of MTX followed one hour later by 5-FU , or 5-FU followed one hour later by MTX . There was a trend to higher tumor response rates in patients treated with MTX before 5-FU ( 45 % v 33 % overall ; 65 % v 39 % in patients with previously untreated head and neck cancer ) , but these differences were not significant , either by chi-square test or by multivariate stepwise logistic regression . The trend in survival favoring the reverse sequence of 5-FU before MTX was not significant in univariate analyses . Stepwise multivariate Cox model analysis showed that Eastern Cooperative Oncology Group performance status at study entry was the major prognostic factor for survival ( P less than 0.001 ) , but among the 70 patients with head and neck cancer , the sequence of drug administration was the only other significant prognostic factor for survival , and favored the sequence of 5-FU followed by MTX ( P less than 0.025 ) With the aim of reducing the side-effects in the surrounding healthy tissues , and /or improving the local control rate , radiotherapy combined with chemotherapy has been used to treat carcinoma of the esophagus , of the tongue , and of the paranasal sinuses . In the treatment of esophageal cancer , a dose of bleomycin too small to demonstrate clinical activity on its own is shown to potentiate the action of radiation with an enhancement ratio lying between 1.3 and 1.7 ( Table 1 ) . From the concept of ' therapeutic ratio ' a ' two-phase ' treatment modality ( Table 2 ) was proposed , because many anticancer drugs or radiosensitizers available today influence not only the tumor tissue but also the surrounding healthy tissues . ' Two-phase ' treatment was applied to cancer of the tongue ( Table 3 ) and to cancer of the paranasal sinuses ( Table 4 ) . The appearance of the chronical complications such as the osteoradionecrosis of the m and ible and the cataract of the lens could be prevented by the use of bleomycin or BUdR combined with radiotherapy PURPOSE To investigate the impact of pretreatment and treatment-related factors on local-regional control and overall survival rates in advanced ( III and IV stage ) head and neck cancer patients treated with alternating chemoradiotherapy , a selected group of 115 patients who had PS < or = 1 and received a total dose of radiotherapy ( RT ) within + /- 5 % of that planned , was analyzed . METHODS AND MATERIAL S Patients were planned to receive 4 cycles of chemotherapy ( cisplatin and 5-fluorouracil ) alternated with radiotherapy ( 60 Gy/30 fractions ) . However , mainly due to systemic toxicity , about 30 % of the patients received less than 90 % of the planned combined chemotherapy total dose ( CCTD ) . Based on differences in treatment planning and delivery , patients were divided into two groups . For living patients , median follow-up is 34 months ( range : 24 - 111 months ) . RESULTS At multivariate analysis , RT technique ( p = 0.008 ) , N stage ( p = 0.010 ) and CCTD ( p = 0.027 ) were independent predictors of LRC . Compared to each favorable subset ( RR = 1 ) , the relative risks of LRC failure were 2.18 ( 95 % CI : 1.21 - 3.91 ) , 2.23 ( 95 % CI : 1.11 - 4.50 ) and 2.23 ( 95 % CI : 1.15 - 4.31 ) for patients without improved dose distribution and treatment delivery , with bilateral nodes or nodes greater than 6 cm , and with a CCTD lower than 90 % , respectively . Regarding overall survival , only RT treatment was found to be an independent predictor ( p = 0.037 ) , with an RR of 1.61 ( 95 % CI : 1.02 - 2.53 ) for patients without improved dose distribution and treatment delivery . CONCLUSION Optimal delivery of RT dose is crucial in patients with advanced head and neck tumors , even if they receive chemotherapy as part of their treatment . This study also suggests that chemotherapy total dose may play a role in patient outcome , but this must be confirmed prospect ively In the final report of a prospect i ve , r and omized controlled clinical trial , we report the results of using adjuvant perioperative chemotherapy in patients with oral cancer . Our study is based on the hypothesis of Goldie and Coldman . A total of 135 patients with alveolobuccal carcinoma , classified as clinical ly stage III and IV , were entered on the protocol . After a curative resection , they were r and omized . The patients in the test arm of the study received methotrexate 50 mg/m2 on the 3rd , 10th , and 17th postoperative days . The patients in the control arm underwent observation . This analysis at 24 months showed a disease-free survival rate of 61 % in the test arm versus 37 % in the control arm , which is statistically highly significant ( P < 0.01 ) . Analysis of the recurrence pattern showed that recurrence at the primary site was dramatically reduced during the first 6 postoperative months ( P = 0.002 ) . Our study provided further clinical evidence in support of the concepts of Goldie and Coldman that the timing of chemotherapeutic drugs is critical for a successful end result Patient compliance with the increasingly complex adjuvant therapy protocol s has always been of concern , particularly in the head and neck cancer population . The Head and Neck Intergroup recently concluded a phase III prospect i ve r and omized trial testing the addition of three courses of cisplatinum containing combination chemotherapy to st and ard treatment defined as surgery and postoperative radiotherapy for advanced stage III and IV squamous cell carcinoma . The chemotherapy was administered following the surgery prior to the postoperative radiotherapy .  Variation from protocol is ranked retrospectively as minor acceptable , major acceptable , and major unacceptable . The incidence of major unacceptable variation from the protocol for radiotherapy immediately following the surgery was 15 % vs. 19 % in the population that completed all three courses of the chemotherapy ( P < 0.10 ) . However , for those patients that completed less than the three courses of chemotherapy , the incidence of major unacceptable variation in radiotherapy was 33 % ( P < 0.001 ) . This observation was controlled for site , stage , performance status , age , sex , surgical margins and experience of participating institution . We conclude that compliance with a multicourse adjuvant chemotherapy regimen is predictive of subsequent compliance to radiotherapy  in the head and neck cancer population Prospect i ve studies of dose adaptation of continuous 5FU infusion combined with cisplatin have shown that pharmacologically guided dosing was feasible in the treatment of head and neck carcinomas . Adaptative dosing results in reduced haematological toxicity , but few data are available for clinical response rate . Preliminary results ( 38 patients ) of a r and omized trial comparing st and ard dose of 5FU  ( 20 patients ) and monitoring of 5FU based on pharmacokinetic information ( half-cycle area under the curve , 18 patients ) indicate that haematological tolerance and complete response rate were improved . Severe ( GIII-GIV ) thrombocytopenia and neutropenia were significantly reduced during cycle 2 ( 0 % versus 11.1 % and 5.5 % versus 27.7 % respectively , p < 0.01 ) and cycle 3 ( 0 % versus 27.7 % and 6.6 % versus 33.3 % respectively , p < 0.001 ) . The complete response rate was increased in the group with monitoring of 5FU doses ( 55.5 % versus 40.0 % , p < 0.001 ) . These interesting results will be confirmed at the end of the trial , which is expected to include 126 patients One hundred and seventeen patients with advanced squamous cell carcinoma of the head and neck were r and omised between two combination schedules , one with and the other without adramycin . Responses ( more than 50 % tumor regression ) were 67 % overall with 63 % responding to the combination without adriamycin and 82 % responding to the schedule containing it . The increase in response rate seen with the addition of adriamycin is not statistically significant . Prior radiotherapy reduced the likelihood of response to chemotherapy Summary Background Between 1990 and 2000 , we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy . We aim ed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy , or both , affected clinical outcome . Here we report survival and recurrence after 10 years of follow-up . Methods Between Jan 15 , 1990 , and June 20 , 2000 , 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey . Patients with locally advanced head and neck cancer , and who had not previously undergone surgery , were r and omly assigned to one of four groups in a 3:2:2:2 ratio , stratified by centre and chemotherapy regimen : radical radiotherapy alone ( n=233 ) ; radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy ( SIM alone ; n=166 ) ; or 14 and 28 days after completing radiotherapy ( SUB alone , n=160 ) ; or both ( SIM+SUB ; n=154 ) . Chemotherapy was either methotrexate alone , or vincristine , bleomycin , methotrexate , and fluorouracil .  Patients who had previously undergone radical surgery to remove their tumour were only r and omised to radiotherapy alone ( n=135 ) or SIM alone ( n=118 ) , in a 3:2 ratio . The primary endpoints were overall survival ( from r and omisation ) , and event-free survival ( EFS ; recurrence , new tumour , or death ; whichever occurred first ) among patients who were disease-free 6 months after r and omisation . Analyses were by intention to treat . This trial is registered at www . Clinical trials.gov , number NCT00002476 . Findings All 966 patients were included in the analyses . Among patients who did not undergo surgery , the median overall survival was 2·6 years ( 99 % CI 1·9–4·2 ) in the radiotherapy alone group , 4·7 ( 2·6–7·8 ) years in the SIM alone group , 2·3 ( 1·6–3·5 ) years in the SUB alone group , and 2·7 ( 1·6–4·7 ) years in the SIM+SUB group ( p=0·10 ) . The corresponding median EFS were 1·0 ( 0·7–1·4 ) , 2·2 ( 1·1–6·0 ) , 1·0 ( 0·6–1·5 ) , and 1·0 ( 0·6–2·0 ) years ( p=0·005 ) , respectively . For every 100 patients given SIM alone , there are 11 fewer EFS events ( 99 % CI 1–21 ) , compared with 100 given radiotherapy , 10 years after treatment . Among the patients who had previously undergone surgery  , median overall survival was 5·0 ( 99 % CI 1·8–8·0 ) and 4·6 ( 2·2–7·6 ) years in the radiotherapy alone and SIM alone groups ( p=0·70 ) , respectively , with corresponding median EFS of 3·7 ( 99 % CI 1·1–5·9 ) and 3·0 ( 1·2–5·6 ) years ( p=0·85 ) , respectively . The percentage of patients who had a significant toxicity during treatment were : 11 % ( radiotherapy alone , n=25 ) , 28 % ( SIM alone , n=47 ) , 12 % ( SUB alone , n=19 ) , and 36 % ( SIM+SUB , n=55 ) among patients without previous surgery ; and 9 % ( radiotherapy alone , n=12 ) and 20 % ( SIM alone , n=24 ) among those who had undergone previous surgery . The most common toxicity during treatment was mucositis . The percentage of patients who had a significant toxicity at least 6 months after r and omisation were : 6 % ( radiotherapy alone , n=13 ) , 6 % ( SIM alone , n=10 ) , 4 % ( SUB alone , n=7 ) , and 6 % ( SIM+SUB , n=9 ) among patients who had no previous surgery ; and 7 % ( radiotherapy alone , n=10 ) and 11 % ( SIM alone , n=13 ) among those who had undergone previous surgery . The most common toxicity 6 months after treatment was xerostomia , but this occurred in 3 % or less of patients in each group . Interpretation Concurrent non-platinum chemoradiotherapy  reduces recurrences , new tumours , and deaths in patients who have not undergone previous surgery , even 10 years after starting treatment . Chemotherapy given after radiotherapy ( with or without concurrent chemotherapy ) is ineffective . Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy . Funding Cancer Research UK , with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre
BACKGROUND Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer .
Treatment of oral cavity cancer is generally surgery followed by radiotherapy , whereas oropharyngeal cancers , which are more likely to be advanced at the time of diagnosis , are managed with radiotherapy or chemoradiation .
Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects , notably impaired ability to eat , drink and talk .
The development of new chemotherapy agents , new combinations of agents and changes in the relative timing of surgery , radiotherapy , and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients .
OBJECTIVES To determine whether chemotherapy , in addition to radiotherapy and /or surgery for oral cavity and oropharyngeal cancer results in improved survival , disease free survival , progression free survival , locoregional control and reduced recurrence of disease .
To determine which regimen and time of administration ( induction , concomitant or adjuvant ) is associated with better outcomes .