[Randomized trial of initial chemotherapy with cisplatin alone or in combination in 241 advanced carcinomas of the upper respiratory and digestive tract]. Neoadjuvant chemotherapy with carboplatin/5-fluorouracil in head and neck cancer. Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German  Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. 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Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. Induction chemotherapy in advanced head and neck tumors: results of two randomized trials. [A randomized study comparing cisplatin alone or combined in the palliative treatment of carcinoma of the head and neck. Analysis of a series of 209 patients]. Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer. Prospective investigation of the cigarette smoking–head and neck cancer association by sex Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck cancer: results of the IAEA multicentre randomised trial. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer. A phase III of cisplatinum versus cisplatinum-etoposide for previously untreated squamous cell carcinoma of the head and neck. The Head and Neck Radiotherapy Questionnaire: a morbidity/quality-of-life instrument for clinical trials of radiation therapy in locally advanced head and neck cancer. Ten-year results of randomized trial comparing radiotherapy and concomitant bleomycin to radiotherapy alone in epidermoid carcinomas of the oropharynx: experience of the European Organization for Research and Treatment of Cancer. Prospective randomized study of post-operative chemotherapy with levamisole and UFT for head and neck carcinoma. [Stage III and IV cancers of the oropharynx: results of a randomized study of Gortec comparing radiotherapy alone with concomitant chemotherapy]. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. 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Alternating chemoradiotherapy versus partly accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. [Role of neoadjuvant chemotherapy in the treatment of advanced head and neck tumors. Results of two randomized therapeutical trials conducted at the Institut Curie on 208 patients]. Chemotherapy as predictor of compliance.
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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
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 .