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Combined preoperative treatment with cobalt and bleomycin in patients with head and neck carcinoma--a controlled clinical study. A Prospective Randomized Trial Comparing Harmonic Scalpel versus Electrocautery for Pectoralis Major Myocutaneous Flap Dissection Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: a randomized phase III study. Induction chemotherapy in head and neck cancer: Results of a phase III trial Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head-and-neck carcinoma. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. Randomized scheduling feasibility study of S-1 for adjuvant chemotherapy in advanced head and neck cancer Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. Intra‐arterial preoperative cytostatic treatment versus preoperative irradiation Comparison of preoperative and postoperative radiation therapy for patients with carcinoma of the head and neck. Interim report. Concurrent chemo-radiotherapy with mitomycin C compared with porfiromycin in squamous cell cancer of the head and neck: final results of a randomized clinical trial. Improved survival with perilymphatic interleukin 2 in patients with resectable squamous cell carcinoma of the oral cavity and oropharynx Prospective investigation of the cigarette smoking–head and neck cancer association by sex Neoadjuvant combination of carboplatin and 5-FU in head and neck cancer: a randomized study. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma [Preliminary results of a prospective randomized study of primary chemotherapy in carcinoma of the oral cavity and pharynx]. Effect of Induction Chemotherapy on Changes of Laminin and Syndecan Expression in Oral Squamous Cell Carcinomas: A Prospective, Randomized, Clinicopathologic and Immunohistochemical Study The Utility of the Harmonic Scalpel in Selective Neck Dissection The effects of epoetin alfa on transfusion requirements in head and neck cancer patients: a prospective, randomized, placebo-controlled study. Prospective randomized study of post-operative chemotherapy with levamisole and UFT for head and neck carcinoma. Adjuvant methotrexate escalated to toxicity for resectable stage III and IV squamous head and neck carcinomas--a prospective, randomized study. The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. The influence of beam energy on the outcome of postoperative radiotherapy in head and neck cancer patients: secondary analysis of RTOG 85-03. 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A prospective, multicentric, randomized DOSAK study of advanced squamous cell carcinoma of the oral cavity and the oropharynx (a 3-year follow-up). Randomized Phase II Trial of Concomitant Chemoradiotherapy Using Weekly Carboplatin or Daily Low‐Dose Cisplatin for Squamous Cell Carcinoma of the Head and Neck Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Prospidin combined to preoperative irradiation in head and neck cancer. Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73-03 of the Radiation Therapy Oncology Group. Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study. [Immunologic study on patients with head and neck cancer treated with thymopentin associated with surgery, chemotherapy and radiotherapy]. 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Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03.
PURPOSE Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus ( HPV ) infection , but empirical evidence is lacking . PATIENTS AND METHODS HPV status was determined for all 271 oropharyngeal cancers ( 1984 - 2004 ) collected by the three population -based cancer registries in the Surveillance , Epidemiology , and End Results ( SEER ) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping ( Inno-LiPA ) , HPV16 viral load , and HPV16 mRNA expression . Trends in HPV prevalence across four calendar periods were estimated by using logistic regression . Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonr and om selection and to calculate incidence trends . Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses . RESULTS HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay ( P trend < .05 ) . For example , HPV prevalence by Inno-LiPA  increased from 16.3 % during 1984 to 1989 to 71.7 % during 2000 to 2004 . Median survival was significantly longer for HPV-positive than for HPV-negative patients ( 131 v 20 months ; log-rank P < .001 ; adjusted hazard ratio , 0.31 ; 95 % CI , 0.21 to 0.46 ) . Survival significantly increased across calendar periods for HPV-positive ( P = .003 ) but not for HPV-negative patients ( P = .18 ) . Population -level incidence of HPV-positive oropharyngeal cancers increased by 225 % ( 95 % CI , 208 % to 242 % ) from 1988 to 2004 ( from 0.8 per 100,000 to 2.6 per 100,000 ) , and incidence for HPV-negative cancers declined by 50 % ( 95 % CI , 47 % to 53 % ; from 2.0 per 100,000 to 1.0 per 100,000 ) . If recent incidence trends continue , the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020 . CONCLUSION Increases in the population -level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection BACKGROUND Elective treatment of the neck in oral squamous cell carcinoma has changed over the last 20 years . The main object of this report is to present the results of a multi-institutional prospect i ve study design ed to compare st and ard treatment with modified radical classical neck dissection ( MRND ) to supraomohyoid neck dissection ( SOH ) in the management of the clinical ly negative neck in oral cancer patients . PATIENTS AND METHODS A total of 148 patients were included in the trial . All patients had previously untreated T2 to T4 N0 squamous cell carcinoma of the oral tongue ( 62 cases ) , floor of the mouth ( 49 cases ) , inferior gingiva ( 12 cases ) , or retromolar trigone ( 25 cases ) . Tumor stages were T2 , 91 ; T3 , 27 ; and T4 , 30 . There were no significant imbalances between groups . RESULTS The false-negative rate was 28 % , and most positive nodes were sited at level II and III . Complications were seen in 41 % of MRND patients and in 25 % of SOH patients ( P = 0.043 ) . Median total duration of hospitalization was 9 days in MRND patients and 7 days in the SOH group . To date , 19 and 16 patients presented with local and neck recurrences , respectively . The 60-month actuarial survival rates were 63 % in the MRND group and 67 % in the SOH group ( P = 0.7150 ) . CONCLUSIONS This study demonstrates that the recurrence and survival rates were similar in both groups . SOH neck dissection can be recommended as st and ard elective treatment for patients with T2-T4 oral squamous cell carcinomas Background Oral cancer is a major health problem worldwide . The 5-year survival rate ranges from 30 - 60 % , and has remained unchanged in the past few decades . This is mainly due to late diagnosis and high recurrence of the disease . Of the patients who receive treatment , up to one third suffer from a recurrence or a second primary tumor . It is apparent that one major cause of disease recurrence is clinical ly unrecognized field changes which extend beyond the visible tumor boundary . We have previously developed an approach using fluorescence visualization ( FV ) technology to improve the recognition of the field at risk surrounding a visible oral cancer that needs to be removed and preliminary results have shown a significant reduction in recurrence rates . Method / Design This paper describes the study design of a r and omized , multi-centre , double blind , controlled surgical trial , the COOLS trial . Nine institutions across Canada will recruit a total of 400 patients with oral severe dysplasia or carcinoma insitu ( N = 160 ) and invasive squamous cell carcinoma ( N = 240 ) . Patients will be stratified by participating institution and histology grade and r and omized equally into FV-guided surgery ( experimental arm ) or white light-guided surgery ( control arm ) . The primary endpoint is a composite of recurrence at or 1 cm within the previous surgery site with 1 ) the same or higher grade histology compared to the initial diagnosis ( i.e. , the diagnosis used for r and omization ) ; or 2 ) further treatment due to the presence of severe dysplasia or higher degree of change at follow-up . This is the first r and omized , multi-centre trial to vali date the effectiveness of the FV-guided surgery . Discussion In this paper we described the strategies , novelty , and challenges of this unique trial involving a surgical approach guided by the FV technology . The success of the trial requires training , coordination , and quality assurance across multiple sites within Canada . The COOLS trial , an example of translational research , may result in reduced recurrence rates following surgical treatment of early-stage oral cancer with significant impacts on survival , morbidity , patients ' quality of life and the cost to the health care system . Trial Registration Clinical trials.gov PURPOSE The purpose of simultaneous chemoradiotherapy is to increase local tumor control and to decrease the incidence of distant metastases .  Platinum-based chemotherapy regimens are widely accepted as st and ard treatment in advanced head and neck cancer . Due to their remarkable activity as well as radiosensitizing effects , taxanes play in increasing role in multimodality treatment concepts of solid tumors . MATERIAL AND METHODS Since 1989 a total of 85 patients with advanced squamous cell carcinoma of the oral cavity and oropharynx were recruited to participate in two different prospect i ve clinical trials of preoperative chemoradiation . Both treatment concepts ( study A : cisplatin 12.5 mg/m(2 ) plus radiation 36 Gy vs study B : Taxol 40 mg/m(2)/carboplatin AUC 1.5 plus radiation 40 Gy ) were compared and further statistical analysis including descriptive analysis as well as univariate and multivariate analysis was performed . RESULTS At the time of the analysis a total of 47 patients ( 55.3 % ) were alive , 38 patients ( 44.7 % ) died from tumor-related causes . The overall survival for both patient groups at 5 years was 45.1 % ( study A ) and 84.9 % ( study B ) and after 10 years 32.4 % for study group A. A comparative analysis of both groups revealed a highly significant survival benefit at 4 years for study B ( p=0.0015 ) . In various calculation models of the multivariate analysis the regimen containing Taxol/carboplatin ( study B ) was superior to the cisplatin regimen ( study A ) . CONCLUSION Based on a retrospective analysis of two different concepts of preoperative chemoradiation and supported by recent data from the literature it is justified to conclude that taxane-based combination regimens are more effective compared to cisplatin-based regimens PURPOSE To determine whether , in the postoperative setting , accelerated fractionation ( AF ) radiotherapy ( RT ) yields a superior locoregional control rate compared with conventional fractionation ( CF ) RT in locally advanced squamous cell carcinomas of the oral cavity , oropharynx , larynx , or hypopharynx . METHODS AND MATERIAL S Patients from four institutions with one or more high-risk features ( pT4 , positive resection margins , pN > 1 , perineural/lymphovascular invasion , extracapsular extension , subglottic extension ) after surgery were r and omly assigned to either RT with one daily session of 2 Gy up to 60 Gy in 6 weeks or AF . Accelerated fractionation consisted of a " biphasic concomitant boost " schedule , with the boost delivered during the first and last weeks of treatment , to deliver 64 Gy in 5 weeks . Informed consent was obtained . The primary endpoint of the study was locoregional control . Analysis was on an intention-to-treat basis . RESULTS From March 1994 to August 2000 , 226 patients were r and omized . At a median follow-up of 30.6 months ( range , 0 - 110 months ) , 2-year locoregional control estimates were 80 % + /- 4 % for CF and 78 % + /- 5 % for AF ( p = 0.52 ) , and 2-year overall survival estimates were 67 % + /- 5 % for CF and 64 % + /- 5 % for AF ( p = 0.84 ) . The lack of difference in outcome between the two treatment arms was confirmed by multivariate analysis . However , interaction analysis with median values as cut-offs showed a trend for improved locoregional control for those patients who had a delay in starting RT and who were treated with AF compared with those with a similar delay but who were treated with CF ( hazard ratio = 0.5 , 95 % confidence interval 0.2 - 1.1 ) . Fifty percent of patients treated with AF developed confluent mucositis , compared with only 27 % of those treated with CF ( p = 0.006 ) . However , mucositis duration was not different between arms . Although preliminary , actuarial Grade 3 + late toxicity estimates at 2 years were 18 % + /- 4 % and 27 % + /- 6 % for CF and AF , respectively ( p = 0.10 ) . CONCLUSION Accelerated fractionation does not seem to be worthwhile for squamous cell carcinoma of the head and neck after resection ; however , AF might be an option for patients who delay starting RT One hundred patients with stage II and stage III cancer of the oropharynx and hypopharynx were treated under a protocol in which they were r and omly selected for treatment by surgery alone or by combined preoperative radiotherapy and surgery . The schedule of preoperative radiation therapy chosen was 2,000 rads from a cobalt 60 machine delivered in five days . Eighty-six of the patients were evaluable at three years ; there was no difference in the outcome of the treatment of the two groups . A similar study is urgently needed to determine the value of postoperative radiotherapy in the management of similar cancers From 1971 to 1975 , 100 patients with glottic , supraglottic , and oral cavity lesions were prospect ively r and omized between primary radiation treatment  and primary surgery .  Local control and survival were similar with either treatment for lesions of the oral cavity or supraglottic larynx . Comparison between radiation alone and surgery alone for T1 and T2 glottic laryngeal lesions showed local control rates of 76 % and 100 % ( P=0.32 ) ; after secondary salvage attempts , local control rates were 82 % and 100 % , respectively ( P= 0.52 ) . Neither result approached statistical significance . Successful radiation for early glottic larynx lesions result ed in superior deglutition and equivalent voice function compared to successful primary treatment with conservation laryngectomy . For oral cavity lesions , swallowing was impaired in the same percentage of radiated and operated patients , but fewer primary radiation patients had articulation difficulties . Among the patients with supraglottic larynx lesions , aspiration was not a problem with either radiation or surgery , but successful radiation perhaps maintained a slightly better voice quality A prospect i ve , r and omized trial was carried out to assess the value of elective versus therapeutic neck dissection in early squamous cell carcinoma of the oral tongue .  Disease-free survival ( median follow-up 20 months ) was 52 percent versus 63 percent in patients who underwent hemiglossectomy alone  and those who underwent hemiglossectomy and radical neck dissection  , respectively ( difference not statistically significant ) . Patients with a tumor depth of less than 4 mm did significantly better than those with a tumor depth of greater than 4 mm ; they were also more likely to have uninvolved nodes at elective radical neck dissection compared with those with a tumor depth of greater than 4 mm . However , when the survival rates of patients in the two treatment groups were compared with respect to a tumor depth of 4 mm , there was no significant difference between the hemiglossectomy and the hemiglossectomy and radical neck dissection groups . A policy of interval elective radical neck dissection only in those with a tumor depth of greater than 4 mm may optimize cure rates and avoid neck dissection in those unlikely to develop neck recurrence 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 The long term results and patterns of failure in patients with squamous cell head and neck carcinoma ( SCHNC ) treated in a prospect i ve r and omized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin ( CRT ) was compared with radiotherapy only ( RT ) , were analyzed . PATIENTS AND METHODS Between March 1997 and December 2001 , 114 eligible patients with Stage III or IV SCHNC were r and omized .  Primary surgical treatment was performed with curative intent in all patients . Patients in both groups were postoperatively irradiated to the total dose of 56 - 70 Gy . Chemotherapy included Mitomycin C 15 mg/m2 after 10 Gy and 5 mg of Bleomycin twice weekly during irradiation . Median follow-up was 76 months ( 48 - 103 months ) . RESULTS At 5 years in the RT and CRT arms , the locoregional control was 65 % and 88 % ( p = 0.026 ) , disease-free survival 33 % and 53 % ( p = 0.035 ) , and overall survival 37 % and 55 % ( p = 0.091 ) respectively . Patients who benefited from chemotherapy were those with high-risk factors . The probability of distant metastases was 22 % in RT and 20 % in CRT arm ( p = 0.913 ) , of grade III or higher late toxicity 19 % in RT and 26 % in CRT arm ( p = 0.52 ) and of thyroid dysfunction 36 % in RT and 56 % in CRT arm ( p = 0.24 ) . The probability to develop a second primary malignancy ( SPM ) was 34 % in the RT and 8 % in the CRT arm ( p = 0.023 ) . One third of deaths were due to infection , but there was no difference between the 2 groups . CONCLUSION With concomitant radiochemotherapy , locoregional control and disease free survival were significantly improved . Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent . The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation If chemotherapy is effectively controlling microscopic distant metastases , then a reduced number of patients would experience treatment failure at distant sites . This study has used a group of 175 patients on a phase 3 Southwest Oncology Group trial for resectable advanced stage disease to test this hypothesis . In the group that failed , 52 % of the st and ard group failed at distant sites as opposed to only 30 % of the experimental group . This difference approaches statistical significance . These findings suggest that chemotherapy , although demonstrating some activity against microscopic distant disease , has not substantially altered the usual patterns of treatment failure for head and neck cancer . However , the assumption that the clinical responses noted with chemotherapy are having a positive influence on the frequency of occult distant disease was supported by our results In 1986 , we initiated a multicenter , r and omized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment ( surgery and radiotherapy or radiotherapy alone ) with locoregional treatment alone in patients with head and neck squamous cell carcinoma . Here we report the long-term results of the trial . A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were r and omly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment ( group A ) or locoregional treatment alone ( group B ) . Among all patients , overall survival at 5 and 10 years was 23 % ( 95 % confidence interval [ CI ] = 15.3 % to 30.9 % ) and 19 % ( 95 % CI = 11.6 % to 26.4 % ) , respectively , for those in group A and 16 % ( 95 % CI = 9.6 % to 23.4 % ) and 9 % ( 95 % CI = 3.5 % to 14.7 % ) , respectively , for those in group B ( P = .13 ) . Among operable patients , we observed no difference between group A and group B in overall survival at 5 and 10 years ( group A , 31 % [ 95 % CI = 14.9 % to 47.3 % ] and 22.7 % [ 95 % CI = 7.1 % to 38.3 % ] , respectively ; group B , 43.3 % [ 95 % CI = 25.6 % to 61.0 % ] and 14.2 % [ 95 % CI = 0.1 % to 28.3 % ] , respectively ; P = .73 ) . Among inoperable patients , overall survival at 5 and 10 years was 21 % ( 95 % CI = 12.3 % to 30.1 % ) and 16 % ( 95 % CI = 7.7 % to 23.9 % ) , respectively , for group A and 8 % ( 95 % CI = 1.5 % to 12.3 % ) and 6 % ( 95 % CI = 0.1 % to 9.1 % ) , respectively , for group B ( log-rank P = .04 ) . Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease We describe the correlations between the clinical and histologic findings in an initial series of 60 patients with T2 - 4 , N0 - 3 , M0 squamous cell carcinoma ( SCC ) of the oral cavity or oropharynx enrolled in a r and omized trial set up to evaluate whether the disease-free interval and survival are extended when perilymphatic injections of recombinant interleukin-2 ( rIL-2 ) are combined with routine surgery and radiotherapy .  Twenty-nine patients were operated on only ( controls ) . The other 31 received two daily injections of 2,500 U rIL-2 , one near the mastoid process on the same side as the tumor and the other under the chin , for 10 days before surgery , and further injections on the nonoperated-on side on a monthly basis for 1 year starting 4 weeks after surgery ( or radiotherapy , where necessary ) in an effort to upregulate the immune system and delay recurrence . Their surgical specimens displayed a significantly greater inflammatory reaction , larger areas of necrosis , and more intense sclerosis . The inflammatory tumor infiltration consisted of eosinophils , plasma cells , and CD25 + and human leukocyte antigen (HLA)-DR+ lymphocytes . However , no correlations were apparent with regard to the intensity of necrosis , eosinophil infiltration , and the number of DR+ cells and the clinical outcome . By contrast , the correlation between CD25 + cells and a significantly longer disease-free survival suggests that induction of T-cell reactivity , and perhaps specific immunity , is the only important aspect of rIL-2-induced antitumor reactivity Abstract A clinical study of preoperative irradiation was established as a result of experimental studies which indicated that local recurrence and metastases could essentially be eliminated by administering preoperative irradiation . Using a single 2,000 or 1,500 r dose twenty-four hours before surgery , there was a high incidence of complications . Seventy-nine patients were then studied in a carefully controlled double-blind study using 1,000 r preoperatively . All lesions were squamous cell cancers of the oral pharyngolaryngeal area and were excised by st and ard but aggressive surgical procedures . The postoperative complications were significantly increased in the patients with irradiation . Although there was a definite trend toward the decrease of local recurrence with preoperative irradiation , there was no statistically significant decrease in the local recurrence rate in the operative wound , nor was there any tendency toward the decrease in incidence of metastases ; neither was patient survival prolonged . A carefully controlled and double-blind clinical study gave results which again indicated that tumors in human subjects do not necessarily behave as expected on the basis of studies of experimental tumor systems The aim of the study was to assess the diagnostic value of the sentinel node method in patients suffering from squamous cell carcinoma of the upper aerodigestive tract . In 50 patients with oral , pharyngeal or laryngeal carcinomas staged N0 up to 50 MBq technetium-99 m colloid were injected  peritumorally . Sentinel nodes were localised using a γ-probe in the setting of an elective neck dissection . Pathological findings of sentinel nodes and corresponding neck specimens were compared . In 46 patients  sentinel nodes were detected . Of these 34 patients were free of metastatic disease in the sentinel nodes and in the neck specimens . In 12 patients clinical ly occult metastases were found in the sentinel nodes . Three metastases were detected only after additional sectioning of the sentinel nodes . In four patients , a sentinel lymph node could not be localised . Our results support the sentinel node concept in head and neck cancer and a definition of the sentinel nodes as the three nodes with the highest activity . Careful clinical staging of the neck and thorough pathological evaluation of the sentinel nodes are necessary to avoid false-negative results Based on a 4-year- study the use of ultrasound and preoperative treatment of the neck area is evaluated . The results suggest that there is no indication for radical neck dissection . The therapeutic approach described result ed in a considerable increase in the survival rate during the first 4 years as against the figures published by the DOSAK in 1988 Surgeons have a reputation for decisiveness and self‐confidence , which suggests that they may tolerate uncertainty poorly and therefore be less capable than other doctors of experiencing clinical equipoise . Their ‘ typical ’ behaviour is characteristic of the stable extrovert personality and so they may prefer spontaneous clinical judgement over r and omized trials . The aim of this study was to compare personality dimensions and tolerance of uncertainty among surgeons and hospital physicians , to determine whether differences in either property might help to explain the apparently poor performance of surgeons in conducting r and omized controlled  trials OBJECTIVE To determine whether cricopharyngeal myotomy can improve dysphagia associated with head and neck cancer surgery . DESIGN Prospect i ve , r and omized , multicenter trial . SETTING Twelve clinical sites across the United States . PATIENTS Between 1989 and 1994 , 125 patients undergoing combined modality therapy for head and neck cancer , including resection of the tongue base or supraglottic larynx , were prospect ively entered into the trial . INTERVENTION Cricopharyngeal myotomy on a r and omized basis . MAIN OUTCOME MEASURES Videofluoroscopic examination to determine oropharyngeal swallowing efficiency , which is defined as the ratio of percentage of the bolus swallowed to total swallowing time using 3 different bolus consistencies . RESULTS No significant difference in oropharyngeal swallowing efficiency between myotomy vs no myotomy was seen at 6 months of follow-up regardless of bolus consistency . CONCLUSIONS In this prospect i ve test of cricopharyngeal myotomy , the procedure fails to significantly improve dysphagia associated with head and neck cancer surgery . The efficacy of this surgical procedure in other disease entities should also be rigorously explored This study concerns 75 patients with squamous cell carcinoma of the oral cavity who were patients at the Gustave‐Roussy Institute between December 1966 and July 1973 . These patients were divided into two groups . The first group was comprised of 39 patients who underwent elective radical neck dissection ;  nodal involvement was present in 49 % with capsular rupture in 13 % . In the second group of 36 , neck disease appeared during follow up in 19 cases . Therapeutic radical neck dissection was carried out in 17 ; the nodes were histologically positive in 15 , 9 of which had a capsular rupture . In 2 cases , local or general conditions did not permit operative intervention . In this group , the involvement rate was 47 % with a 25 % capsular rupture rate . However , the comparison of the survival curves by the log‐rank test did not reveal any differences , even though histologic prognostic factors were taken into account . These findings led to the conclusion that in squamous cell carcinoma of the oral cavity staged T1N0 , T2N0 , or T3N0 ( from AJC 's and UICC 's clinical staging system ) , it seems possible , without risk , to delay neck dissection until a node is detectable , although it is reasonable to perform elective neck dissection in those cases in which the patient is unavailable for regular followup OBJECTIVE To determine the incidence of minor and major complications in patients with squamous cell carcinoma of the upper aerodigestive tract who require surgical salvage or planned neck dissection after an initial treatment regimen with radiotherapy or concurrent chemoradiotherapy for organ preservation . DESIGN The medical records of 100 patients treated in a phase 3 trial comparing radiotherapy alone with concurrent chemoradiotherapy for stage III and IV head and neck squamous cell carcinoma were review ed . Fifty-four patients underwent 59 surgical procedures . Twenty-nine planned neck dissections were performed for persistent neck disease or initial stage N2 or greater . For persistent or recurrent disease at the primary site , 30 salvage operations were performed . SETTING Academic tertiary care referral center . RESULTS Complications occurred in 15 ( 46 % ) of the 33 procedures in the radiation-only group and 12 ( 46 % ) of the 26 procedures in the chemoradiotherapy group . Major complications occurred in 4 ( 12 % ) of the procedures in the radiation-only group and 3 ( 12 % ) of the procedures in the chemoradiotherapy group . The incidence of minor complications was 33 % and 35 % in the radiation-only and chemoradiotherapy groups , respectively . The major complication rate for salvage operations did not differ between the radiation-only and chemoradiotherapy groups ( 16 % and 27 % , respectively ; P=.79 by chi2 test ) . The incidence of major complications in planned neck dissections was 7 % of the radiation-only group and 0 % of the chemoradiotherapy group . CONCLUSIONS After radiation or concurrent chemoradiotherapy , surgery can be performed with an acceptable rate of major complications . Adding chemotherapy did not increase the incidence of surgical complications . These results differ from other reports in the literature The ability of surgery and radiotherapy to control advanced squamous cell carcinoma of the head and neck has reached its maximal potential . We initiated a r and omized , prospect i ve , stratified study of adjuvant chemotherapy .  Patients with stage II disease of the pyrlform sinus and stage III and IV disease of the oral cavity , larynx , hypopharynx , oropharynx , nasopharynx , and paranasal sinuses were eligible . Patients were r and omized to receive either st and ard therapy alone or two courses of 5-fluorouracil ( B-CMF ) chemotherapy prior to and two courses after the completion of st and ard therapy . St and ard therapy consisted of preoperative irradiation followed by radical surgery . Of 133 patients with advanced disease , 83 were included In the study —43 In the chemotherapy group and 40 In the control group .  Rates of residual and recurrent disease , as well as distant metastases , were similar for the two groups . The survival rates of patients without persistent disease at the end of treatment showed no significant difference for the two groups . The study has been discontinued because statistical analysis Indicated that the addition of more patients would not material ly Increase the statistical significance of the study The survival time of patients with squamous cell carcinoma of the oral cavity is similar to what it was 30 years ago . Despite more radical surgery , new chemotherapeutic agents , and improvements in radiotherapy , no significant changes have taken place . The 5-year survival rates vary between 37 % , as stated by Byers ( 1985 ) , and 51 % , as stated by Ackermann et al. ( 1985 ) . A survival rate of 41%–42 % would appear to be more realistic , as shown by Platz and Hudec ( 1986 ) in two German-Austrian-Swiss Association for Head and Neck Tumors ( DOSAK ) studies between 1952 and 1985 with a total of 2507 patients Forty-six patients with squamous cell carcinoma of the head and neck region were r and omized to either irradiation or irradiation plus bleomycin . If possible , the patients later underwent radical surgery . In the bleomycin group , significantly fewer patients had remaining tumour cells in the tissue removed at operation , and a longer time elapsed before recurrences occurred . However , bleomycin had no significant effect on the 3- and 5-year survival rates , and it did not significantly reduce the incidence of local recurrences In a controlled prospect i ve study of 90 patients with locally advanced but operable epidermoid carcinomas ( T2/T3N0 - 3M0 ) of the tongue and the floor of the mouth underwent 3 types of preoperative radiation : 1.5 x 5 Gy ; 2.15 x 2 Gy and 3.5 x 2.5 Gy . The preoperative radiation led to a marked decrease of local recidives and to a lengthening of the recidive-free interval respectively . The type of preoperative radiation 5 x 5 Gy seemed to have the most favourable results . Otherwise the preoperative radiation had no advantages in regard to a better prevention of regional metastases and because of that there is no indication for it Abstract A r and omised and controlled clinical study comparing cobalt plus bleomycin ( 3000 rad/180 mg bleomycin ) with cobalt plus placebo has been carried out in 29 patients with moderately to highly differentiated squamous cell carcinomas of the head and neck . The treatment was given prior to radical surgery and all specimens examined histologically after serial section . No differences iin side-effects , operative difficulties or delayed healing were encountered between the groups . Tumour response based on clinical and histological criteria was clearly in favour of preoperative treatment with cobalt plus bleomycin compared to cobalt plus placebo . However , by histological examination in serial sections of the operative specimen residual tumour was present in a rather high proportion in both groups . The histological findings also throw doubt on the specificity of the previously reported histological changes following bleomycin treatment . The necessity of radical surgery in addition to preoperative treatment with cobalt plus bleomycin is stressed Background : Conventionally , the pectoralis major myocutaneous flap is raised using electrocautery and /or other sharp instruments . The reported morbidity rate using conventional techniques of flap dissection varies from 16 to 63 percent . The purpose of this study was to consider the feasibility of myocutaneous flap dissection using the harmonic scalpel and to compare operative time , blood loss , drainage volume , and morbidity between patients undergoing flap dissection with the harmonic scalpel  and those being treated with electrocautery .  Methods : Thirty patients with oral cancer , for whom resection and reconstruction using a pectoralis major myocutaneous flap was planned , were recruited in a prospect i ve , r and omized two-arm trial . Patients in arm I ( n = 15 ) had flap dissection using electrocautery and patients in arm II ( n = 15 ) had flap dissection using the harmonic scalpel . Results : The mean operative duration for flap dissection ( 84 versus 47 minutes ) , blood loss ( 129 versus 36 ml ) , and total drainage volume ( 551 versus 302 ml ) were found to be significantly less in the harmonic scalpel group . Conclusion : The results of the study indicate that it is feasible to dissect pectoralis major myocutaneous flaps using the harmonic scalpel with less operative time , blood loss , drainage volume , and morbidity in comparison with electrocautery BACKGROUND AND PURPOSE In 1986 a prospect i ve , r and omized , multi-centre trial for evaluation of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in the treatment of advanced squamous cell carcinoma of the head and neck was initiated . As survival in this group of patients is poor the purpose was to find a possible survival benefit of the chemotherapy in addition to radiotherapy compared to radiotherapy only . METHODS Four-hundred sixty-one patients from Denmark , Norway and Sweden with tumors in oral cavity , oropharynx , hypopharynx and larynx were r and omized to receive either st and ard treatment ( radiotherapy or radiotherapy followed by surgery ) or neoadjuvant chemotherapy followed by st and ard treatment . Chemotherapy included three courses of cisplatin 100 mg/m2 i.v . infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v . infusion for 120 hours . Radiotherapy 64 - 70 Gy in 2 Gy per fraction , 5 times/week , was given to patients in both treatment arms . RESULTS Response rate was 71 % for patients r and omized to chemotherapy-radiotherapy and 66 % for patients r and omized to st and ard treatment ( not statistically significant ) . Residual tumors were excised if possible . After surgery 62 % of the patients r and omized to chemotherapy-radiotherapy and 60 % of the patients in the st and ard treatment group were clinical ly tumor free . CONCLUSIONS No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy . Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment Between December 1982 and October 1986 , 131 patients with stage II‐III‐IV squamous cell carcinoma of the oropharynx or oral cavity were r and omized to induction chemotherapy , consisting of bleomycin ( 10 mg/m2/day in continuous infusion from day 1 to day 5 ) , methotrexate ( 120 mg/m2 on day 2 ) followed by folinic acid , 5‐fluorouracil ( 5 FU ) ( 600 mg/m2 on day 2 ) , and cisplatin ( 120 mg/m2 on day 4 ) every 4 weeks for a total of three cycles followed by definitive locoregional treatment versus locoregional treatment alone . The modalities of definitive treatment ( radiotherapy ± surgery ) were chosen prior to r and omization . A total of 116 patients were evaluable . Of 55 patients in the chemotherapy arm , four ( 7 % ) had a complete response ( CR ) and 23 ( 42 % ) a partial response ( PR ) following the induction regimen . At the completion of locoregional treatment , 76 % ( 42 of 55 ) of patients in the experimental group were in CR compared to 89 % ( 54 of 61 ) in the control group . There was no difference in survival , cause‐specific survival , and pattern of relapse between both groups . The median survival was 22 months in the chemotherapy group and 29 months in the control group . Responders to chemotherapy did not fare better than nonresponders . Chemotherapy‐related toxicities were few and most of them related to cisplatin which was reduced to 100 mg/m2 for 35 patients . There were no treatment‐related deaths and , in the experimental arm of the trial , no increased morbidity from locoregional treatment . This induction regimen does not offer any advantages over st and ard treatment PURPOSE In a prospect i ve r and omized clinical study , simultaneous postoperative application of irradiation ( RT ) , mitomycin C , and bleomycin was tested in a group of patients with operable advanced head- and -neck carcinoma . It was expected that the planned combined postoperative therapy would reduce the number of locoregional recurrences and prolong survival . METHODS AND MATERIAL S A total of 114 eligible patients with Stage III or IV squamous cell head- and -neck carcinoma were r and omized to receive  postoperative RT alone ( Group 1 ) or RT combined with simultaneous mitomycin C and bleomycin ( Group 2 ) . Patients were stratified according to the stage and site of the primary tumor and the presence or absence of high-risk prognostic factors . Primary surgical treatment was performed with curative intent in all patients . Patients in both groups were postoperatively irradiated to the total dose of 56 - 70 Gy . Chemotherapy included mitomycin C 15 mg/m(2 ) after 10 Gy and 5 mg of bleomycin twice a week during RT to the planned total dose of 70 mg . RESULTS At 2 years , patients in the radiochemotherapy group had better locoregional control ( 86 % ) than those in the RT alone group ( 69 % ; p = 0.037 ) . Disease-free survival and overall survival was also better in the radiochemotherapy group compared with the RT-alone group ( 76 % vs. 60 % , p = 0.099 ; and 74 % vs. 64 % , p = 0.036 , respectively ) . Patients who benefited from chemotherapy were those with high-risk factors . CONCLUSION The results of the present study indicate that concomitant postoperative radiochemotherapy with mitomycin C and bleomycin improves locoregional control and survival in patients with advanced head- and -neck carcinoma . The patients who benefited from chemotherapy were those with high-risk factors 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 The purpose of this study was to determine the feasible adjuvant therapy administration schedule of S-1 for locoregionally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . Patients receiving definitive treatments were r and omly assigned to either arm A ( 51 cases ) receiving oral S-1 of 2-week administration followed by 1-week rest for 6 months , or arm B receiving S-1 of 4-week administration followed by 2-week rest for 6 months . Planned treatment was given in 40 % of patients in arm A and 29 % in arm B. The cumulative rates of the relative total administration dose of S-1 at 100 % were 54.9 % ( 95 % CI : 40.1–69.7 % ) in arm A and 34.3 % ( 95 % CI : 21.1–47.4 % ) in arm B , respectively ( P=0.054 ) . Adverse events were recorded in 41 patients ( 82.0 % ) in arm A and 48 patients ( 94.1 % ) in arm B ( P=0.060 ) . The incidences of diarrhoea ( 10 vs 28 % ; P<0.05 ) and skin toxicities ( 18 vs 37 % ; P<0.05 ) were significantly higher in arm B. One-year disease-free survival was similar in both arms : arm A 81.2 % ( 95 % CI : 70.0–92.4 % ) ; arm B 77.0 % ( 95 % CI : 65.0–89.0 % ) . The schedule of 2-week administration followed by 1-week rest seems to be more feasible for oral 6-month administration of S-1 in adjuvant chemotherapy of locoregionally advanced SCCHN BACKGROUND Radiotherapy is often the primary treatment for advanced head and neck cancer , but the rates of locoregional recurrence are high and survival is poor . We investigated whether hyperfractionated irradiation plus concurrent chemotherapy ( combined treatment ) is superior to hyperfractionated irradiation alone . METHODS Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily , for a total of 7500 cGy . Patients in the combined-treatment group received 125 cGy twice daily , for a total of 7000 cGy , and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation . Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy . RESULTS Of 122 patients who underwent r and omization , 116 were included in the analysis . Most patients in both treatment groups had unresectable disease . The median follow-up was 41 months ( range , 19 to 86 ) . At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group ( P=0.07 ) . The relapse-free survival rate was higher in the combined-treatment group ( 61 percent vs. 41 percent , P=0.08 ) . The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group ( P=0.01 ) . Confluent mucositis developed in 77 percent and 75 percent of the two groups , respectively . Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group . CONCLUSIONS Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone For several decades , both preoperative intra‐arterial chemotherapy and preoperative irradiation have been accepted treatments for patients with tumors of the head and neck . Unfortunately , arguments have often been put forward in favor of one or other of the two methods , but without the performance of an objective , r and omized investigation . To resolve this situation , the authors have carried out a multicenter , r and omized prospect i ve study of selected patients with a view to deciding which method affords better results in complex tumor therapy from the aspects of survival and postoperative quality of life Three hundred and fifty-four patients with squamous cell carcinoma of the oral cavity , oropharynx , supraglottic larynx , hypopharynx or maxillary sinus have been r and omized for preoperative radiation therapy and surgery versus surgery and postoperative radiation therapy plus , in the case of patients with lesions of the oral cavity and oropharynx , radical radiation therapy . Data have been analyzed on 320 patients in this interim report . In the supraglottic larynx group local-regional control is significantly better for  surgery and postoperative radiation therapy .  The treatment differences in local-regional control in the oral cavity oropharynx and hypopharynx groups are not statistically significant . No statistically significant treatment differences exist for survival in all sites or in any site ; continued follow-up is necessary to make definite treatment comparisons PURPOSE Previous r and omized trials have shown a benefit with concurrent use of the hypoxic cell cytotoxin mitomycin C ( MC ) and radiation ( RT ) in the management of squamous cell cancer of the head and neck ( SCCHN ) . We conducted a r and omized trial comparing MC with porfiromycin ( POR ) in combination with RT in the management of SCCHN . METHODS AND MATERIAL S Between 1992 and 1999 , 128 patients with SCCHN were enrolled in this prospect i ve r and omized trial . Patients were stratified by management intent , and balanced with respect to stage and site of disease . They were r and omized to receive MC ( 15 mg/M(2 ) ) or POR ( 40 mg/M(2 ) ) on Days 5 and 47 ( or last day ) of RT . Of 121 evaluable patients , 61 were r and omized to MC and 60 to POR . Patients were treated with st and ard daily RT to a total median dose of 64 Gy over 47 days . Patients were well balanced with respect to management intent , stage , site , age , sex , hemoglobin levels , tumor grade , radiation dose , and days on treatment . RESULTS There were no significant differences between the two arms with respect to acute hematologic or nonhematologic toxicities . As of January 2003 with a median follow-up of 6.3 years , there have been 19 local relapses ( 4 MC vs. 15 POR ) , 21 regional relapses ( 7 MC vs. 14 POR ) , 24 distant metastases ( 11 MC vs. 13 POR ) , and 66 deaths ( 33 MC vs. 33 POR ) . MC was superior to POR with respect to 5-year local relapse-free survival ( 91.6 % vs. 72.7 % , p = 0.01 ) , local-regional relapse-free survival ( 82 % vs. 65.3 % , p = 0.05 ) , and disease-free survival ( 72.8 % vs. 52.9 % , p = 0.026 ) . There were no significant differences between the two arms with respect to overall survival ( 49.2 % vs. 54.4 % ) or distant metastasis-free rate ( 79.9 % vs. 75.9 % ) . CONCLUSIONS Despite promising pre clinical data , and an acceptable toxicity profile , POR was inferior to MC as an adjunct to RT in the management of SCCHN . This r and omized trial emphasizes the need for r and omized studies to evaluate new agents in the management of SCCHN The current r and omized , multicenter , Phase III trial was conducted to determine whether the disease free interval and overall survival of patients with T2–T4,N0–N3,M0 squamous cell carcinoma ( SCC ) of the oral cavity or oropharynx could be extended through the combination of surgery ( and radiotherapy , if required ) with perilymphatic recombinant IL‐2 ( rIL‐2 ) 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 A prospect i ve , r and omized , multicenter study of patients with oropharyngeal and pharyngolaryngeal tumors compared locoregional treatment alone with neoadjuvant chemotherapy with carboplatin/5-fluorouracil ( 5-FU ) followed by locoregional treatment . The aim of the study was to evaluate the role of chemotherapy on survival and on the need for mutilating surgery . Since 1988 , 219 patients ( 105 with oropharyngeal and 114 with pharyngolaryngeal tumors ) have entered the study . All patients r and omized to neoadjuvant chemotherapy  received three cycles of carboplatin 400 mg/m2 day 1 and 5-FU 1 g/m2/d as a continuous infusion days 1 through 5 every 3 weeks . Neoadjuvant chemotherapy was given to 108 patients . The 268 evaluable courses induced a low rate of grade 3 or 4 toxicity . Four patients ( 3.6 % ) died of major complications . The complete response ( CR ) rate was 31 % , which represented a decrease in mutilating surgery of 30 % . ( Patients with CRs had radiotherapy alone instead of radiosurgical treatment as originally planned . ) The objective response rate was 61 % . Survival curves for the chemotherapy and chemotherapy-naive groups were not significantly different . The rate of nodal recurrence was significantly higher in the chemotherapy group , however , and chemotherapy did not decrease the rate of second primary tumors or distant metastases . Thus , the justification for neoadjuvant chemotherapy may be a decreased rate of mutilating surgery . These preliminary results are encouraging , but follow-up is as yet too short to allow definite conclusions The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer . Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric r and omized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy . The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone . Three cycles of chemotherapy consisting of Cisplatin ( 100 mg/m2 ) on day 1 followed by a 24-hour i.v . infusion of fluorouracil ( 1000 mg/m2/day ) for 5 days were delivered every 21 days . 2–3 weeks after the end of chemotherapy , local treatment was performed . The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou ( GETTEC ) . A total of 318 patients were enrolled in the study between 1986 and 1992 .  Overall survival was significantly better ( P = 0.03 ) in the neoadjuvant chemotherapy group than in the control group , with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group . The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance ( P = 0.11 ) . Stratification of the results on the type of local treatment , surgery plus radiotherapy or radiotherapy alone , did not reveal any heterogeneity in the effect of chemotherapy . © 2000 Cancer Research Campaign Although induction chemotherapie given prior to local therapy produces encouraging initial response rates in head and neck cancer , r and omized studies have failed to demonstrate an advantage in survival . All r and omized studies have included only patients with far advanced stage III and IV disease . To us this is the main reason for the low rate of complete responses demonstrated ( maximum , 18 % ) . Frei et al. estimate that 40 - 50 % complete responders are necessary before improved survival benefit will occur . To date , such complete response rates with induction chemotherapy are only attainable in resectable T2-T3 , N0-N2 disease . Therefore , we started a prospect i ve r and omized trial that included only patients with earlier disease . Patients were r and omized to receive either induction chemotherapy with 3 cycles of carboplatin/5-fluorouracil prior to surgery and radiotherapy  ( arm A , 49 patients ) or st and ard treatment with surgery and radiotherapy  ( arm B , 48 patients ) . Patients were stratified by primary tumor site and neck disease . After a follow-up of 12 - 48 months , overall survival was 72 % in arm A and 53 % in arm B , but this difference was not significant . Considering only the results in patients with cancer of the oral cavity and tonsils , overall survival was 87 % in arm A and 45 % in arm B ( p < 0.04 ) . At present , the numbers of patients with cancers of the tongue base and hypopharynx are too small for a statistically significant statement . However , preliminary data indicate a better overall and disease-free survival without chemotherapy in these patients . Therefore , we now recommend induction chemotherapy in all patients with stage T2-T3 and N0-N2 carcinomas of the oral cavity and tonsils prior to surgery but not in patients with cancers of the hypopharynx and base of tongue Sixty patients with tumors of the floor of the mouth or of the tongue ( T2N0 - 1 - 2M0 ) were r and omized into three treatment groups . The first two groups participated in low-dose inductive chemotherapy , surgery , and then radiotherapy , whereas the third control group underwent only surgery and radiotherapy . In all three groups , studies were made of the stage , grade , sex , localization , extents of expression of the pretreatment laminin and syndecan-1 and the cancer specific survival rate , and the correlations among these . The response to neoadjuvant chemotherapy was assessed by means of a method that we developed , involving measurement of the degree of histologic regression observed in response to chemotherapy . Immunohistochemical methods were applied to investigate the changes in degree of expression of laminin and syndecan-1 in response to the medication and their correlations with the survival . As concerns the overall tumorfree survival rate , a significant difference was not found between the two chemotherapeutic groups . However , there was a significant difference between the survival indices of those who participated in cytostatic treatment ( 70 % ) and the control group ( 40 % ) . In the clinical and immunohistochemical examinations , the initial laminin and syndecan-1 levels obtained from biopsy sample s could be used as prognostic factors . Our model measuring the extent of histologic regression clearly demonstrated that the survival indices of the patients who responded to the neoadjuvant cytostatic treatment with adequate tissue regression were better than those of the patients who responded to the treatment to only a decreased extent or not at all . The changes in the expressions of laminin and syndecan-1 in response to cystostatic treatment proved to be important predictive factors . The increase or stagnation of these clearly forecast a good prognosis , whereas their decrease was a definite indication of poor prognosis Objectives . To determine the impact of the harmonic scalpel on intraoperative blood loss and operative time in selective neck dissection ( SND ) ( levels I-IV ) for head and neck squamous cell carcinoma ( HNSCC ) . Study Design . Prospect i ve r and omized controlled trial . Setting . A single , tertiary care institution ( Foothills Medical Centre ) in Calgary , Alberta , Canada . Subjects . A total of 31 patients ( 36 neck dissections ) were prospect ively enrolled between January 2009 and March 2010 . Methods . Patients were r and omized to receive a neck dissection with either the harmonic scalpel or the traditional technique of using electrocautery and sharp dissection . The study included adult patients older than age 18 years diagnosed with HNSCC and who required an SND ( levels I-IV ) . Study exclusion criteria included previous treatment for head and neck cancer and all patients unwilling or unable to provide informed consent . Primary clinical outcomes were intraoperative blood loss and operative time . Secondary outcomes included intraoperative complications and surgical drain output . Results . Intraoperative blood loss was significantly lower in the harmonic scalpel group compared to the traditional group ( 158 vs 61 mL , P = .02 ) . There was no difference in operative time ( 81 minutes harmonic vs 85 minutes traditional ) or total drain output ( at both 48 hours and 1 week ) between the groups . There were no intraoperative complications reported in either group . Conclusions . Results from this study suggest that the harmonic scalpel can reduce blood loss during SND for HNSCC . The harmonic scalpel had no impact on operative time , postoperative drain output , or complication rate OBJECTIVE To evaluate the efficacy of perioperative recombinant human erythropoietin ( r-HuEPO , epoetin alfa ) in stimulating hematopoiesis and reducing allogeneic blood transfusion requirements in major head and neck cancer surgery . STUDY DESIGN Double-blinded , placebo-controlled , r and omized , prospect i ve clinical trial . METHODS Fifty-eight patients undergoing surgical resection of head and neck tumors at the University of Iowa hospitals completed this study . Patients were required to have a pre- study hemoglobin > /=10.0 g/dL and < /=13.5 g/dL. Group 1 ( 29 patients ) received three doses of 600 IU/kg epoetin alfa before surgery . Group 2 ( 29 patients ) received a placebo . All patients received oral iron supplementation ( 150 mg FeSO4 twice per day ) . RESULTS The epoetin alfa group demonstrated a significant increase in baseline to day-of-surgery mean hemoglobin ( 0.57 g/dL , P = .016 ) , hematocrit ( 2.04 % , P = .015 ) , and reticulocyte count ( 95.3 x 103 cells/mm3 , P = < .001 ) , whereas there was no significant change in these hematologic variables in the placebo group . The percent of patients who avoided transfusion in the epoetin alfa group was 34.5 % versus 17.2 % in the placebo group . Patients requiring allogeneic blood transfusions received an average of 3.16 units in the epoetin alfa group and 4.12 units in the placebo group . CONCLUSION In this single institution study , we demonstrated a significant improvement in hematopoietic parameters and a trend toward decreased transfusion requirements using perioperative epoetin alfa in a head and neck cancer patient population . Further studies may delineate additional benefits in treating qualified patients with epoetin alfa during therapy for head and neck malignancies AIMS A prospect i ve r and omized study was conducted to evaluate the benefit of adjuvant levamisole/UFT ( futraful and uracil ) chemotherapy in head and neck squamous cell carcinoma . METHODS Sixty-five patients with stage III and IV squamous cell carcinomas of oral cavity , oropharynx , hypopharynx and larynx with no distant metastasis were r and omized for the chemotherapy study . Thirty-one patients were r and omized for chemotherapy  and two of them were subsequently excluded . In this study , a total of 29 patients on levamisole/UFT therapy and 34 patients on the control group were analysed . The main outcome was measured by the 5-year disease-free actuarial survival rate . RESULTS The rates of distant metastasis were 10 % for chemotherapy group and 32 % for control group ( P=0.06 ) . The 5-year disease-free actuarial survival rates for patients with and without adjuvant chemotherapy were 57 % and 39 % respectively ( P=0.207 ) . CONCLUSIONS A trend of better distant control in head and neck cancer patients with post-operative adjuvant oral chemotherapy was observed . The side effects were minimal . However , there was no statistically significant improvement in the overall long-term survival . It may be of value to conduct a large-scale multi-centre prospect i ve r and omized study to verify the efficacy of levamisole and UFT as post-operative adjuvant chemotherapy for the control of distant metastasis in high-risk population To determine if adjuvant methotrexate ( MTX ) , escalated weekly to toxicity , could improve disease-free survival ( DFS ) and overall survival by preventing recurrent disease , 60 patients with potentially resectable stage III or IV squamous head and neck carcinomas were stratified by primary site , stage , and nutritional status , then r and omized by pairs to receive or not receive adjuvant MTX . All received st and ard surgery and postoperative radiation therapy .  Five patients were taken off study because of unresectability at the time of surgery , leaving 55 evaluable patients . There were no statistically significant imbalances in known prognostic factors between the two treatment arms . MTX was begun at 40 mg/m2 and escalated 10 mg/m2 weekly ( four doses preoperatively ; four doses postoperatively , preradiation therapy ; eight doses postradiation therapy ) to  mucosal or hematologic toxicity .  The median peak MTX dose achieved was 80 mg/m2 . Although three patients were hospitalized with MTX toxicity , none died of MTX toxicity . No patient receiving MTX had disease progression during treatment , and there was no increase in postoperative complications . Thirty-two patients died ( median survival , 19 months ) ; 23 patients are alive with median follow-up of 43 months . There was no statistically significant difference in actuarial DFS ( P = 1.0 ) or overall survival ( P = .61 ) . Although patients on the MTX arm appeared to have less local and regional recurrences at first recurrence ( thus more distant metastases ) , this did not reach statistical significance ( P = .06 ) . There was no significant difference between the sites of recurrence at death or last follow-up ( P = .38 ) The effect of an adjuvant mistletoe extract treatment was tested in a prospect i ve , r and omised controlled clinical trial involving 477 patients with head and neck squamous cell carcinoma . The patients were stratified into two treatment groups that underwent surgery or surgery followed by radiotherapy and both groups were r and omised for additional treatment with mistletoe extract . Patients treated with a mistletoe lectin-1 ( ML-1 ) st and ardised mistletoe preparation had no lower risk of local/locoregional recurrences , distant metastases or second primaries . In the main analysis based on 202 patients treated with surgery and 275 patients treated with surgery and radiotherapy the adjusted hazard ratio for the disease-free survival ( DFS ) was 0.959 ( 95 % confidence interval ( CI ) 0.725 - 1.268 ) . The 5-year survival rates of patients from the mistletoe group were no better than the survival rates of patients from the control group . Furthermore , no significant changes in the cellular immune reaction or in quality of life could be detected . We conclude that the used mistletoe preparation has no indication in the adjuvant treatment of patients with head and neck cancer 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 Two hundred forty-eight patients with primary epidermoid carcinoma of the oral cavity , oropharynx , and hypopharynx , stages II , III , and IV were entered into a prospect i ve r and omized clinical trial of preoperative irradiation therapy ( 700 rads X 2 ) and surgery versus surgery alone . At 5 years both groups had a similar survival when analyzed according to stage of disease , primary site , or lymph node status . However , the group of patients receiving preoperative irradiation showed a lower incidence of local recurrence ( 22 % versus 36 % ) preoperative irradiation showed a lower incidence of local recurrence ( 22 % versus 36 % ) ( P = 0.02 ) . From this study we conclude that preoperative irradiation in this dose schedule has little influence on the ultimate outcome after surgical treatment of head and neck cancer BACKGROUND Treating the neck after organ-preservation treatment with radiotherapy or chemoradiotherapy can be problematic . METHODS To develop management guidelines , we review ed the results of a 100-patient phase-3 trial that had compared outcome after radiotherapy alone with outcome after chemoradiotherapy for head and neck cancer . Patients were r and omly assigned to receive radiotherapy alone or concurrent chemoradiotherapy . After completing therapy , patients were reassessed , and surgery was recommended for persistent disease at the primary site or neck and for all patients with stage N2 - 3 neck nodes regardless of clinical response . RESULTS Of the 47 patients with stage NO-1 , 43 had a complete response ( CR ) ;  of the 18 N1 patients , all but 4 had a CR . One of these 4 , as well as 5 others among the NO-1 patients , underwent neck dissection ( n = 6 ) . No disease was found on pathologic examination , and no patient had neck recurrence . Of the remaining 41 N0 - 1 patients , 3 had disease progression and received no further therapy . Of the 38 others , 4 had neck recurrence , with 3 recurring at the primary site . Of the 53 with stage N2 - 3 , 23 had less than a complete response ( < CR ) , and 30 had a CR . In 35 N2 - 3 patients , neck dissection was performed as planned . Of these 35 , 18 had a CR in the neck ; 4 had positive nodes on pathologic examination . The other 17 had a < CR in the neck ; 8 had positive nodes on pathologic examination . One patient in this group of 17 had regional recurrence after a pathologically negative neck dissection . Of the 18 N2 - 3 patients who did not undergo planned neck dissection , 6 had tumor progression and had no further therapy . The other 12 , all with a CR in the neck , were followed , and 3 had neck recurrence ; none successfully salvaged . Despite a CR in 30 N2 - 3 patients , 7 had persistent disease or eventual neck recurrence . Adding neck dissection minimized neck recurrence ( p = .05 ) . In N2 - 3 patients , disease-specific survival was significantly better in patients with a CR in the neck ( p = .002 ) . Disease-specific survival was not affected by neck dissection ( p = .40 ) but was significantly affected by viable tumor in the specimen ( p = .03 ) . CONCLUSION Based on these results and the realization that it is difficult to follow patients for recurrent neck cancer , that salvage is often unsuccessful , and that patients dying from uncontrollable neck disease have an extremely poor quality of life , we recommend neck dissection for all N2 - 3 patients regardless of the neck response and for N1 patients without a CR To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region , a r and omized clinical trial was conducted under the auspices of the Head and Neck Intergroup ( Radiation Therapy Oncology Group , Southwest Oncology Group , Eastern Oncology Group , Cancer and Leukemia Group B , Northern California Oncology Group , and Southeast Group ) . Eligible patients had completely resected tumors of the oral cavity , oropharynx , hypopharynx , or larynx . They were then r and omized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy ( CT/RT ) or postoperative radiotherapy alone ( RT ) . Patients were categorized as having either " low-risk " or " high-risk " treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm , there was extracapsular nodal extension , and /or there was carcinoma-in-situ at the surgical margins . Radiation doses of 50 - 54 Gy were given to " low-risk " volumes and 60 Gy were given to " high-risk " volumes . A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis . The 4-year actuarial survival rate was 44 % on the RT arm and 48 % on the CT/RT arm ( p = n.s . ) . Disease-free survival at 4 years was 38 % on the RT arm compared to 46 % on the CT/RT arm ( p = n.s . ) . At 4 years the local/regional failure rate was 29 % vs. 26 % for the RT and CT/RT arms , respectively ( p = n.s . ) . The incidence of first failure in the neck nodes was 10 % on the RT arm compared to 5 % on the CT/RT arm ( p = 0.03 without adjusting for multiple testing ) and the overall incidence of distant metastases was 23 % on the RT arm compared to 15 % on the CT/RT arm ( p = 0.03 ) . Treatment related toxicity is discussed in detail , but , in general , the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy . Implication s for future clinical trials are discussed To evaluate the efficacy of adjuvant chemotherapy for patients with advanced head and neck squamous cancer , the Head and Neck Contracts Program conducted a three-arm study comparing st and ard surgery and radiation , induction chemotherapy ( cisplatin and bleomycin ) plus st and ard therapy , and induction chemotherapy plus st and ard therapy followed by maintenance cisplatin for 6 months . As previously reported , this trial of 462 patients demonstrated no significant difference in disease-free survival or survival , but a significantly lower metastatic rate in the maintenance arm . To determine whether particular subgroups may have benefited from adjuvant therapy , we evaluated results based on primary site , and tumor ( T ) and node ( N ) stage . Of the 192 patients with oral cavity cancer , those on the maintenance arm had a significantly improved 3-year disease-free survival ( 67 % ) compared with the st and ard arm ( 49 % ) or induction arm ( 44 % ) ( overall P = .05 ) . For hypopharyngeal and laryngeal cancers there was no marked overall benefit . For the 106 patients with T1 plus T2 disease , there was marginal improvement in disease-free survival for the maintenance group ( 72 % ) compared with the st and ard group ( 47 % ) or induction group ( 43 % ) ( overall P = .09 ) . There was no advantage for patients with T3 and T4 disease . There was superior disease-free survival for patients with N1 disease on the maintenance arm ( 70 % ) compared with the st and ard arm ( 42 % ) ( P = .024 ) . The same was true for disease-free survival in 109 patients with N2 disease : st and ard ( 52 % ) , induction ( 30 % ) , maintenance ( 84 % ) ( overall P less than .001 ) . There was no benefit for N3 disease . A significant survival advantage with  maintenance chemotherapy  was only seen for N2 disease ( overall P = .04 ) . Since head and neck cancer patients are a heterogeneous group , there may be particular sites and stages for which adjuvant chemotherapy would be advantageous , and subset analysis can help indicate directions for new trials BACKGROUND AND PURPOSE The subm and ibular gl and s produce most of the unstimulated saliva output and are the key in prevention of radiation-related xerostomia . We investigated whether sparing of the subm and ibular function is feasible with intensity modulated radiotherapy ( IMRT ) . PATIENTS AND METHODS Thirty-six patients diagnosed with head and neck cancer were treated with IMRT and had at least one parotid gl and excluded from the planning target volume . In a subset , of these patients ( n=18 ) where the risk of cancer recurrence in the contralateral subm and ibular region was judged low , the contralateral subm and ibular gl and was spared from full-dose irradiation . The total unstimulated and stimulated salivary flow rates and adverse effects were monitored . RESULTS Twelve months following IMRT  mean unstimulated saliva flow was 60 % of the baseline value among patients who had one subm and ibular gl and spared and 25 % among those who did not ( P=0.006 ) . Patients whose contralateral subm and ibular was spared reported less grade two or three xerostomia ( 4 vs. 11 ; P=0.018 ) , and used less saliva substitutes . No cancer recurrences were detected at the vicinity of the spared gl and s during a median follow-up time of 31 months . CONCLUSIONS Subm and ibular gl and sparing with IMRT is safe in selected patients treated for head and neck cancer . It is effective in prevention of radiation-associated xerostomia BACKGROUND Amifostine has reduced toxicities associated with radiation therapy and platinum-based chemotherapy . In a phase II r and omized trial , we investigated the ability of amifostine to reduce the toxicity of carboplatin plus radiotherapy ( RCT ) in patients with head and neck cancer . PATIENTS AND METHODS Thirty-nine patients with stage III or IV squamous cell carcinomas of the head and neck received RCT  ( following surgery or as primary treatment ) . Radiotherapy was given five days per week with daily fractions of 2 Gy , up to a total dose of 60 Gy in conjunction with carboplatin 70 mg/m2 on days 1 through 5 and days 21 through 26 . Eligible patients were r and omised to receive RCT alone or preceded by a rapid infusion of amifostine ( 500 mg ) on the days when carboplatin was administered . RESULTS Patients receiving amifostine + RCT ( n = 25 ) had significantly reduced mucositis ( P = 0.0001 ) and xerostomia ( P = 0.0001 ) in comparison with patients receiving RCT alone ( n = 14 ) . Additionally , patients receiving amifostine + RCT had significantly less thrombocytopenia ( P = 0.001 ) and leukopenia ( P = 0.001 ) . At 12 months following therapy , 79 % of patients receiving amifostine + RCT had no evidence of disease compared with 64 % of those receiving RCT alone . CONCLUSIONS Amifostine reduces the  RCT -induced toxicities in patients with head and neck cancer and has no negative impact on antitumour efficacy BACKGROUND Recent studies in patients with previously untreated T1 and T2 squamous cell carcinoma ( SCC ) of the tongue and floor of the mouth have shown a relationship between tumor thickness , neck metastasis , and survival . Our study was conducted to determine the indication of elective neck dissection in patients with early oral cavity SCC . PATIENTS AND METHODS Sixty-seven patients were stratified by stage ( T1 and T2 NO ) , and those in each stage were r and omized to receive one of two types of treatment ; resection alone ( RA ) or resection plus elective supraomohyoid neck dissection ( RSOND ) .  Fifty-two patients ( 78 % ) were men and 15 ( 22 % ) were women . The median age was 57 years old ( range 34 to 95 ) . RESULTS Twenty-six ( 39 % ) patients had tumor in the floor of the mouth and 41 ( 61 % ) , in the tongue . Using the criteria of the Union Internationale Contre le Cancer ( UICC ) , 1987 , we classified 31 tumors ( 46 % ) as T1 lesions and 36 ( 54 % ) as T2 lesions . Thirty patients had a tumor thickness < or = 4 mm and 37 had a tumor thickness > 4 mm . Thirty-three ( 49 % ) patients were treated with RA , and 34 patients ( 51 % ) were treated with RSOND . Seven ( 21 % ) patients of the RSOND group had occult cervical metastasis . There were recurrences in 14 ( 42 % ) patients of the RA group and 8 ( 24 % ) patients of the RSOND group . The disease-free survival rates at 3.5 years for RA and RSOND patients were 49 % , and 72 % , respectively . The impact of sex , age , site , cancer stage , and tumor thickness was assessed by the Mantel-Haenszel chi-square procedure . Later stage ( P = 0.05 ) and increased tumor thickness ( P = 0.005 ) were significantly associated with treatment failures . CONCLUSION Neck dissection remains m and atory in the early stage of oral SCC , because of better survival rates compared to RA and the poor salvage rate . In particular , patients with tumor thickness > 4 mm treated with RSOND had significant benefit on disease-free survival Squamous cell carcinoma of the buccal mucosa is a common cancer in India . We are referred a large number of locally advanced lesions where curative surgery is still possible . The objective of this study is to determine the role of post-operative radiotherapy in enhancing disease-free survival .  Patients with stages III and IV cancer of the buccal mucosa potentially curable by surgery were r and omized to surgery only or post-operative radiotherapy . Patients were followed up for 3 years . The clinico-pathological features in both arms were comparable . Disease-free survival at the end of the study was found to be 38 % and 68 % ( P<0.005 ) respectively . Post-operative radiotherapy was thus seen to improve disease-free survival in squamous cell carcinoma of the buccal mucosa Between February 1978 and January 1984 , 222 eligible patients were r and omised in a multicentre trial of preoperative intra-arterial chemotherapy in the treatment of oral cavity and oropharynx carcinoma . Patients were r and omised between either surgery or preoperative chemotherapy .  This latter group received vincristine and bleomycin for 12 days . Patients were stratified according to the primary site : floor of the mouth ( FM ) versus posterior oral cavity or oropharynx ( POC ) and institution . The FM group received postoperative radiotherapy depending upon quality of the margins and lymph-node pathological involvement , when it was systematic ally applied in the POC group . Tumour regression after chemotherapy either complete ( CR ) or partial ( PR greater than 50 % ) was observed in 48 % in the FM group and 41 % in the POC group , and lymph-node regression ( CR + PR ) was respectively 15 % and 23 % . Some discrepancies appeared between clinical regression and pathological response , and the number of cases without histological response was clearly higher than the number of cases without clinical response . The overall survival showed a statistically significant difference ( P = 0.048 ) between FM and POC groups . In the FM group , median survival in the chemotherapy arm was estimated at 7 years compared with 3 years in the surgery arm . In the POC group , median survival was estimated at 3 years in both treatment arms . Chemotherapy lowered the uncontrolled disease and local recurrence in the FM group . These differences do not exist in the POC group , which may be due to the systematic ally postoperative radiotherapy Fifty-four previously untreated patients with locally advanced resectable squamous cell carcinoma of the head and neck ( SCCHN ) were enrolled into a prospect i ve r and omized controlled trial to evaluate whether induction chemotherapy improves the disease-free survival compared to the st and ard treatment ( surgery + radiation ) . Thirty patients received chemotherapy , which consisted of cisplatin 20 mg/m2 day 1 - 5 , bleomycin 10 mg/m2 , continuous infusion from day 3 - 7 , and methotrexate 40 mg/m2 given on day 15 and day 22 . The cycle was repeated on day 29 for two cycles . Twenty patients completed chemotherapy courses . Overall response rate was 77 % ( 23 of 30 ) . No survival improvement was observed . Kaplan-Meier analysis indicated survival ( and 95 % confidence interval ) at 3 years was 57 % ( 29%-84 % ) for the control group and 60 % ( 34%-87 % ) for the chemotherapy group , and 57 % ( 29%-84 % ) and 45 % ( 12%-78 % ) at 4 years ( P = 0.736 ) . However , patients who had a complete response were significantly better in terms of long-term survivors ( 5 of 7 patients were still alive ) , in contrast to patients who had partial responses among whom only 4 of 16 were alive . Toxicities of this induction protocol are tolerable ; one chemotherapy-related death occurred from profound thrombocytopenia . If efforts in determining a chemotherapy-sensitive patient were successfully established , along with a better sequence and the discovery of new and safer drugs , survival of SCCHN should be much improved Fifty-five selected patients with previously untreated squamous cell carcinoma of the head and neck regions were studied in a r and omized , prospect i ve manner . The three treatment categories were primary radiation ( Gp R ) , primary surgery ( Gp S ) , and preoperative radiation of 4000 rads in four weeks ( Gp R/S ) . The local control rates for the 44 evaluable patients with a two-year minimum followup were 24 % , 39 % , and 43 % respectively . Further treatment attempts in patients failing initial therapy yielded local control rates of 35 % , 39 % , and 43 % for Gp R , Gp S , and Gp R/S , respectively . None of the local control rates nor the corresponding survival curves were significantly different at P less than 0.10 . However , the group sizes were sufficiently small that true differences might not have been detected . Postoperative complications were higher in the primary radiation failures subsequently operated upon compared to the primary surgery group ( P = 0.07 ) PURPOSE To report the final results of a prospect i ve r and omized trial that aim ed to evaluate efficacy and toxicity of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV squamous cell carcinoma of the head and neck and histological evidence of extracapsular spread of tumor in lymph node metastase(s ) . METHODS AND MATERIAL S Radiotherapy was delivered using a daily dose of 1.7 Gy for the first 54 Gy and 1.8 to 2 Gy until the completion of the treatment . Cisplatin 50 mg i.v . with forced hydratation was given or not every week ( i.e. , seven to nine cycles ) concurrently with radiotherapy . A total of 44 patients were treated by irradiation only ( RT group ) and 39 by irradiation with chemotherapy ( CM group ) . RESULTS The RT group displayed a higher rate of loco-regional failures as compared to CM group ( 41 vs. 23 % ; p = 0.08 ) . The overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival were better in CM group as compared to RT group with statistically significant differences . Survival without loco-regional treatment failure was better in the CM group , the difference being close to the level of significance ( p = 0.05 ) . Survival without distant metastases were comparable in the two therapeutic groups . Ten severe late complications were observed , four in the RT group ( 17 % ) and six in the CM group ( 22 % ) . Cox univariate analysis confirmed the importance of the therapeutic modality in predicting the overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival . CONCLUSIONS The present final report of this phase III study confirms preliminary results . The concomitant use of 50 mg weekly Cisplatin infusion and postoperative radiation improved loco-regional control and survival . No significant increase of late radiation complications was observed in the CM group In 1980 , the Southwest Oncology Group instituted a multi-institutional , prospect i ve , r and omized phase III trial to evaluate whether inductive chemotherapy improved survival in patients with advanced stage resectable squamous cell carcinoma of the head and neck . From a group of 158 eligible patients , 76 were r and omized to conventional treatment  ( surgery and postoperative radiotherapy ) , and 82 were assigned to experimental treatment  ( induction chemotherapy , surgery , postoperative radiotherapy ) . Median follow-up for living patients was approximately 5 years . These analyses include chemotherapy responses and toxicities , surgical complications , radiotherapy toxicities , patient compliance , survival time , and patterns of treatment failure . Overall chemotherapy response was 0.70 ( 0.19 CR , 0.51 PR ) . The median survival time for conventional treatment was longer than the time for patients receiving preoperative chemotherapy , although the survival time differences were not statistically significant . This final analysis demonstrates no benefit in survival using preoperative chemotherapy for advanced stage , resectable head and neck squamous cell carcinoma A preliminary report is made of a r and omized double-blind study comparing levamisole with placebo as surgical adjuvant treatment of patients with squamous cancer of the head and neck . The study groups were comparable according to the prognostic factors of type ( primary or recurrent ) , site ( oral cavity , pharynx , larynx ) , and stage of disease and were also similar in pretreatment immune function and in radiation exposure . Of 65 evaluable patients , 31 were treated with levamisole and 34 received placebo . Although there was no difference in the distribution of the time to recurrence of the overall treatment group , there was a difference of borderline significance in favor of levamisole in the primary disease patients ( P less than 0.006 ) . Further analysis of subgroups in the primary disease category showed decreased recurrence rates in patients receiving levamisole who had cancer of the oral cavity P less than 0.01 or who had stage II disease , P less than 0.02 . Considering site and stage simultaneously , the only significant difference was in stage II patients with oral cancer . The above results , though encouraging , must be viewed with caution due to small sample sizes and relatively short follow-up of most patients A prospect i ve clinical trial was design ed to evaluate efficacy , toxicity , and patient compliance of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV S.C.C. of the head and neck and histological evidence of extra-capsular spread of tumor in lymph node metastase(s ) .  Cisplatin 50 mg IV with forced hydration was given or not every week ( i.e. , 7 to 9 cycles ) concurrently with radiotherapy .  Between 1984 and 1988 , 83 patients were r and omized : 44 were treated by irradiation without chemotherapy ( RT group ) and 39 by the combined modality ( CM group ) . There was no significant difference between the two groups in terms of patient characteristics , primary sites , tumor differentiation , T.N. stages , or postoperative prognostic factors . All patients completed the planned radiotherapy . There were seven severe toxicities ( greater than grade 3 ) in the RT group . In the CM group , 30 severe toxicities occurred in 16/39 ( 41 % ) patients but none was life-threatening . Seven of 39 ( 18 % ) patients received less than two-thirds of the scheduled Cisplatin courses because of intolerance , mainly nausea and vomiting . Preliminary results show a better disease-free survival for the CM group ( 65 % at 24 months ) than for the RT group ( 41 % at 24 months ) . This significant difference is largely due to increased loco-regional control in the CM group ( 79 % vs 59 % ) , the actuarial distant metastasis rates in patients controlled above the clavicles not being statistically different in the two groups TWO COURSES OF PREOPERATIVE CHEMOTHERAPY ( methotrexate , bleomycin , cisplatin ) were combined with split-course irradiation ( 2,000 rad/10 preop . , 4,000 rad/20 postop . ) and prospect ively compared with st and ard therapy ( surgery and /or irradiation alone ) for locally advanced or recurrent oral/pharyngeal squamous cancer . The chemoradiotherapy arm ( Ch-XRT ) had 31 patients ; the st and ard therapy arm 28 r and omized ( RC ) and 20 concomitantly-treated ( CC ) patients . Treatment-related mortality was 17 % for Ch-XRT ; 10 % for RC + CC . Number of patients NED at completion of treatment was 74 % for Ch-XRT ; 83 % for RC + CC ( NS ) . Median survival , however , was 17 months for Ch-XRT , 9 months for CC , and 12 months for RC . In addition , survival at 40 + months was 45 % for Ch-XRT versus 21–22 % for RC and CC ( p < 0.05 ) . Thus , Ch-XRT seems to have promise in advanced oral/pharyngeal cancer , but needs revision to decrease toxicity BACKGROUND The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma ( HNSCC ) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospect i ve clinical trial . METHODS We prospect ively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group ( ECOG ) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and st and ard fractionation radiation therapy .  The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction ( PCR ) and in situ hybridization . Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis . The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age , ECOG performance status , stage , and other covariables was estimated by use of a multivariable Cox proportional hazards model . All statistical tests were two-sided . RESULTS Genomic DNA of oncogenic HPV types 16 , 33 , or 35 was located within tumor cell nuclei of 40 % ( 95 % confidence interval [ CI ] = 30 % to 50 % ) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR . Compared with patients with HPV-negative tumors , patients with HPV-positive tumors had higher response rates after induction chemotherapy ( 82 % vs 55 % , difference = 27 % , 95 % CI = 9.3 % to 44.7 % , P = .01 ) and after chemoradiation treatment ( 84 % vs 57 % , difference = 27 % , 95 % CI = 9.7 % to 44.3 % , P = .007 ) . After a median follow-up of 39.1 months , patients with HPV-positive tumors had improved overall survival ( 2-year overall survival = 95 % [ 95 % CI = 87 % to 100 % ] vs 62 % [ 95 % CI = 49 % to 74 % ] , difference = 33 % , 95 % CI = 18.6 % to 47.4 % , P = .005 , log-rank test ) and , after adjustment for age , tumor stage , and ECOG performance status , lower risks of progression ( hazard ratio [ HR ] = 0.27 , 95 % CI = 0.10 to 0.75 ) , and death from any cause ( HR = 0.36 , 95 % CI = 0.15 to 0.85 ) than those with HPV-negative tumors . CONCLUSION For patients with HNSCC of the oropharynx , tumor HPV status is strongly associated with therapeutic response and survival A prospect i ve r and omized trial was performed in patients with advanced squamous cell carcinomas ( SCC ) of the oral cavity , larynx , and pharynx to examine the effect of adjuvant postoperative radiation therapy on locoregional recurrence and survival following " curative " resection . Fifty-one patients with stage III or IV SCC treated from 1981 through 1984 were r and omized to receive either surgery alone ( n = 27 ) or surgery with postoperative radiation ( n = 24 ) . Five patients were excluded from the study after r and omization because of in eligibility or protocol violations . Overall recurrence rates of 55.6 % and 36.8 % were noted in the surgery and surgery with adjuvant radiotherapy arms , respectively ( p = NS ) . This trend towards a higher recurrence rate in the surgery only arm was in part due to the development of lymph node metastases in the contralateral , nonoperated neck . Thus far , no significant differences in either locoregional or overall survival have been noted between the two treatment arms . In this preliminary analysis , adjuvant postoperative radiotherapy does not appear to improve disease-free or overall survival 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 PURPOSE To evaluate induction chemotherapy with docetaxel , cisplatin , and fluorouracil ( TPF ) followed by surgery and postoperative radiotherapy versus up-front surgery and postoperative radiotherapy in patients with locally advanced resectable oral squamous cell carcinoma ( OSCC ) . PATIENTS AND METHODS A prospect i ve open-label phase III trial was conducted . Eligibility criteria included untreated stage III or IVA locally advanced resectable OSCC . Patients received two cycles of TPF induction chemotherapy ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by radical surgery and postoperative radiotherapy ( 54 to 66 Gy ) versus up-front radical surgery and postoperative radiotherapy . The primary end point was overall survival ( OS ) . Secondary end points included local control and safety . RESULTS Of the 256 patients enrolled onto this trial , 222 completed the full treatment protocol . There were no unexpected toxicities , and induction chemotherapy did not increase perioperative morbidity . The clinical response rate to induction chemotherapy was 80.6 % . After a median follow-up of 30 months , there was no significant difference in OS ( hazard ratio [ HR ] , 0.977 ; 95 % CI , 0.634 to 1.507 ; P = .918 ) or disease-free survival ( HR , 0.974 ; 95 % CI , 0.654 to 1.45 ; P = .897 ) between patients treated with and without TPF induction . Patients in the induction chemotherapy arm with a clinical response or favorable pathologic response ( ≤ 10 % viable tumor cells ) had superior OS and locoregional and distant control . CONCLUSION Our study failed to demonstrate that TPF induction chemotherapy improves survival compared with up-front surgery in patients with resectable stage III or IVA OSCC 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 BACKGROUND The st and ard treatment for advanced ( stage III and IV ) head and neck squamous cell carcinoma ( i.e. , surgery with postoperative radiotherapy  in operable patients and radiotherapy alone in inoperable patients ) has had poor results . A series of r and omized trials of induction chemotherapy have up to now failed to demonstrate an improvement in survival . PURPOSE This trial was design ed to determine whether intensive induction chemotherapy administered before loco-regional treatment would improve survival of patients with advanced disease . METHODS Patients had previously untreated , advanced nonmetastatic ( stages III and IV ) squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , and paranasal sinuses . The study design was a r and omized , multi-institutional , phase III trial . Eligible patients ( n = 237 ) were r and omly assigned to receive either initial chemotherapy ( cisplatin and infusional fluorouracil ) followed by loco-regional treatment ( group A , n = 118 ) or loco-regional treatment alone ( group B , n = 119 ) . For operable patients ( group A , n = 34 ; group B , n = 32 ) , loco-regional treatment included resection followed by adjuvant radiotherapy . For inoperable patients , radical irradiation was performed with a planned dose of 65 - 70 Gy to involved areas . A dose of 45 - 50 Gy was also planned to the uninvolved neck or postoperatively . The statistical ( log-rank ) test was performed no earlier than 2 years after the r and omization of the last patient . RESULTS Seventy-one patients ( 60 % ) in group A and 67 patients ( 56 % ) in group B were considered free of disease after they completed the treatment sequence . The analysis of time to distant metastases showed an advantage for group A patients . ( Respective 2- and 3-year values for inoperable patients were 15 % and 24 % for group A versus 36 % and 42 % for group B , P = .04 ; only one operable group A patient had distant metastases after 49 months versus 26 % [ 2 years ] and 31 % [ 3 years ] for operable group B patients , P = .01 . ) For inoperable patients , the combined treatment was significantly associated with an increase in complete remission rate ( group A , 44 % ) as compared with radiotherapy alone ( group B , 30 % ) ( P = .037 ) . Inoperable patients also benefitted from induction chemotherapy in terms of disease-free survival ( 49 % and 34 % for group A versus 28 % and 26 % for group B ; P = .06 ) and of overall survival ( 30 % and 24 % for group A versus 19 % and 10 % for group B ; P = .04 ) . CONCLUSIONS When all 237 r and omly assigned patients were analyzed , there were no significant differences in the two treatment strategies in loco-regional failure or in disease-free or overall survival , although the development of distant metastases was reduced . For operable patients , the only benefit from neoadjuvant chemotherapy was a significant reduction in the incidence of distant metastases . For inoperable patients , neoadjuvant chemotherapy improved local control , decreased the incidence of distant metastases , and improved the complete remission rate and overall survival . IMPLICATION S Confirmatory studies with effective chemotherapy regimens delivered for an adequate number of cycles are required A r and omized , prospect i ve trial utilizing cisplatin and fluorouracil as neoadjuvant chemotherapy in the treatment of advanced squamous cell carcinomas of the upper aerodigestive tract was initiated in January 1983 . Sixty patients were stratified by site ( oral cavity , 19 ; larynx , 14 ; hypopharynx , 14 ; oropharynx , 11 ; nasopharynx , one ; and paranasal sinuses , one ) and by stage ( III , 19 ; IV , 41 ) , and then r and omized to receive either st and ard treatment ( defined as preoperative irradiation followed by radical excision or irradiation alone ) or adjuvant chemotherapy followed by st and ard treatment .  An additional three patients were entered into the study , but withdrew . Chemotherapy consisted of three cycles for those patients in whom an objective tumor response was observed ; nonresponders received st and ard treatment .  Response to chemotherapy was complete in five and partial ( greater than 50 % ) in 18 patients , for an overall response rate of 85 % . The follow-up for surviving patients was a minimum of 24 months and a maximum of 44 months . Survival was compared for patients in both treatment groups according to the method of Lee and Desu . Despite excellent tumor response , actuarial survival was 70 % in the st and ard treatment group as opposed to 56 % in the experimental group . It was therefore evident that the high response rates reported in previous pilot studies do not necessarily result in improved survival in these cancers Fifty-six patients with locally advanced head and neck squamous cell carcinoma were subjected to adjuvant radiotherapy after radical surgery with r and omisation to either conventional fractionation ( CF ) , comprising 50 Gy/25 F/5 weeks , or to accelerated hyperfractionation ( AHF ) to a dose of 42 Gy/30 F/11 days ( 3 F/day ) , a dose/F of 1.4 Gy and an interfraction interval of 4 h. The in vitro [3H]thymidine labelling index ( TLI ) was determined as an indicator of tumour proliferation . Early mucosal reactions were somewhat more severe after AHF than after CF and the peak was attained earlier . The actuarial 3-year complication rate was significantly lower in the AHF ( 64 % ) than in the CF group ( 87 % ) . This is probably related to a smaller fraction size and a lower total dose . The overall 3-year disease-free survival amounted to 46 + /- 7 % . Sex , the anatomical site , the nodal status , the performance status and TLI have been shown to be significant prognostic factors , but only the latter two proved to be independent covariates . Overall , the type of fractionation did not seem to influence survival . However , AHF seemed to offer higher survival probabilities in fast growing tumours and this attained a significant level for tumours with TLI > 10.4 % ( Tpot < 4.5 days ) . However , CF and AHF were associated with similar survival rates in slowly growing tumours . The relative effectiveness of the CF and AHF schedules is predictable on the basis of the linear-quadratic system . In the case of tumour response , a time factor has to be included assuming that accelerated re population of microscopic residues occurs from the outset . ( ABSTRACT TRUNCATED AT 250 WORDS We examined the records of two cohorts of patients who were seen from 1960 to 1999 with a diagnosis of squamous cell carcinoma ( SCC ) of the mouth and throat , one series being retrospective ( n=400 ) and the other prospect i ve ( n=213 ) to find out about delays in diagnosis . The median delay in both cohorts was 3 months and the patients were responsible for the delay in most cases ( n=319 , 81 % and n=160 , 78 % , respectively ) . Half the patients in each cohort had delayed diagnoses ( n=217 , 54 % and n=119 , 56 % , respectively ) and similar percentages ( n=110 , 53 % and n=172 , 47 % ) presented with advanced disease ( stage III or IV ) . These were not the same patients for there was no correlation between delay and stage or survival . Logistic regression analysis showed that non-white race ( p=0.01 ) and high- grade histology ( p=0.002 ) predicted advanced disease . The proportion of patients presenting with advanced disease had not changed in 40 years despite public education . We suggest that some tumours may be silent and that initial symptoms do not reliably predict early disease Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a r and omized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy . In addition , following regional therapy , patients r and omized to  chemotherapy  were to receive similar methotrexate courses every three months for one year . Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin ( Adria Laboratories , Columbus , Ohio ) and cisplatin every three weeks for four cycles after the first 35 patients had been entered . Nine cases were ineligible and four lacked any follow-up data , leaving 82 analyzable cases . Using Cox regression analysis , no differences in the percentage of patients achieving disease control , the relapse-free survival , or the overall survival were identified between any treatment group . As has been described in many pilot studies of induction chemotherapy of head and neck cancer , chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy . However , correcting for imbalances in the expected three year disease-free survival of these patients , based on their disease site and stage , erased this difference , indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome . The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups , given the multiple site-stage combinations within the upper aerodigestive tract . The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival The treatment of patients with squamous cell carcinoma ( SCC ) of the oropharynx remains controversial . No r and omized trial has addressed adequately the question of whether surgery ( S ) , radiation therapy ( RT ) , or combined treatment is most effective Quality of life evaluation is an important measure of outcome following the treatment of head and neck cancer . The aim of this study was to evaluate the quality of life of patients undergoing primary surgery for oral and oropharyngeal squamous cell carcinoma . 50 consecutive patients with previously untreated oral cancer were assessed using two question naires , the Medical Outcomes Short Form 36 ( SF-36 ) and University of Washington Head and Neck Question naire ( UW-QOL ) at four time intervals ; pretreatment , and 3 , 6 , 12 months . At the time of presentation , patients with oral cancer scored lower than norms , particularly for physical role limitation , mental role limitation , and social functioning . At 3 months following surgery , there was a considerable deterioration in physical functioning , limitation of physical role , energy and general health perception . By 12 months postoperatively patients approached pretreatment scores . The SF-36 and UW-QOL provide outcome information suitable for international comparison Treatment of patients with advanced squamous head and neck tumors demonstrates even with best surgical and x-ray techniques only five year survival rats between 10 and 30 % . Chemotherapy in addition seems to improve these results . From July 79 to January 80 21 patients with advanced squamous-cell carcinoma at the head and neck region were treated in a controlled pilot study with Cisplatinum/Bleomycin or Methotrexate/vindesine . 6 patients were primarily treated with chemotherapy , all other secondary progressive disease after surgical and x-ray procedure . Without respect to the generally cell tolerated therapy modality on overall remission induction rate of 50 and 70 % was observed . In a subsequent r and omized controlled multicentric study both regimes will be compared concerning remission , survival and toxicity Although induction chemotherapy prior to local therapy produces encouraging initial response rates in head and neck cancer , r and omized studies have failed to demonstrate an advantage in survival . All r and omized studies included only patients with far advanced stage III and IV disease which appears to be the main reason for the low rate of complete responses ( max . 18 % ) in these trials . According to statistical considerations nearly 50 % complete responders are necessary before improved survival benefit can be expected . Until now , such complete response rates are only achieved with induction chemotherapy in resectable T2-T3 , N0-N2 disease . Therefore , we started a prospect i ve r and omized trial including only patients with these stages of disease . Patients were stratified by primary tumor site and neck node status and were r and omized to receive either induction chemotherapy with three cycles of carboplatin/5-FU prior to surgery and radiotherapy  ( arm A , 49 patients ) or st and ard treatment with surgery and radiotherapy  ( arm B , 47 patients ) . Patients were stratified by primary tumor site and neck disease . After a follow-up of 12 - 48 months overall survival was 72 % in arm A and 53 % in arm B ( n.s . ) . Considering only the patients with cancer of the oral cavity and the tonsil  overall survival was 88 % in arm A and 44 % in arm B ( p<0.05 ) . As of today , the number of patients with carcinomas of the hypopharynx and base of tongue is too small for a statistically significant statement , but preliminary data indicate a better overall and disease-free survival without chemotherapy in these patients . Therefore , we recommend controlled trials with induction chemotherapy in patients with primary resectable carcinomas of the oral cavity and the tonsil , stages T2-T3 and N0-N2 , prior to surgery but not in patients with cancer of the hypopharynx and base of the tongue A multicentric , r and omized study of squamous cell carcinoma ( SCC ) of the oral cavity and the oropharynx has been undertaken by DOSAK . The results after radical surgery alone have been compared with the results of combined preoperative radiochemotherapy followed by radical surgery .  Patients with primary ( biopsy proven ) SCC of the oral cavity or the oropharynx with tumor nodes metastasis ( TNM ) stages T2 - 4 , N0 - 3 , M0 were included in the study . A total of 141 patients were treated by radical surgery alone , whereas 127 patients were treated by radical surgery preceded by preoperative radiochemotherapy .  The preoperative treatment consisted of conventionally fractioned irradiation on the primary and the regional lymph nodes with a total dose of 36 Gy ( 5 x 2 Gy per week ) and low-dose cisplatin chemotherapy with 5 x 12.5 mg cisplatin per m2 of body surface during the first week of treatment . Radical surgery according to the DOSAK definitions ( DOSAK , 1982 ) was performed after a delay of 10 - 14 days . During the follow-up period , 28.2 % of all patients suffered from locoregional recurrence , and 27.2 % of the patients died . The percentages were higher after radical surgery alone for locoregional recurrence ( 31 % and 15.6 % ) and for death ( 28 % and 18.6 % ) . The life-table analysis showed improved survival rates of 4.5 % after 1 year and 8.3 % after 2 years in the group of patients treated with combined therapy . The demonstrated improvement appeared to be significant with the Gehan-Wilcoxon test as well as with the log rank test below a P value of 5 % PURPOSE This r and omized , phase II study aim ed to compare concomitant Chemoradiotherapy using weekly carboplatin or daily low-dose cisplatin as a treatment for squamous cell carcinoma of the head and neck . PATIENTS AND METHODS One hundred nineteen patients with moderate-to advanced-stage disease were eligible for the study . Fifty-three patients had stage II disease , 28 had stage III , and the remaining 38 had stage IV disease . Primary tumor sites included the larynx ( N = 63 ) , oropharynx ( N = 30 ) , hypopharynx ( N = 23 ) , and oral cavity ( N = 3 ) . Each patient received either a weekly carboplatin dose ( 100 mg/m2 ) in one arm or daily cisplatin ( 4 mg/m2 ) in the other arm for the initial 4 weeks of radiotherapy . The radiotherapy dose of 65 Gy was given in 26 fractions over 45 days , dependent on a good tumor response at 40 Gy . Forty-nine ( 81.7 % ) of 60 patients treated with carboplatin and 41 ( 69.5 % ) of 59 patients treated with cisplatin received the full dose of radiotherapy . Surgical resection was optionally used for the remaining patients . RESULTS The median follow-up time was 63 months . The local control rate at 5 years was 56.2 % for the carboplatin-treated arm and 35.5 % for the cisplatin-treated arm , respectively . The 5-year overall survival rate did not significantly differ between treatments : 71.4 % for carboplatin and 66.0 % for cisplatin .  Hematologic toxicity was more frequent in the carboplatin-treated arm . No difference was observed in surgical complications or in radiation-related adverse effects . DISCUSSION These findings suggest that weekly carboplatin treatment is preferable to daily low-dose cisplatin . This could be because the total dose of cisplatin was too low to be effective Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were r and omly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil ( 5-fluorouracil ) . There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers . In the group of patients with unresectable cancers , however , there was a statistically significant advantage to the addition of chemotherapy , both in terms of disease-free survival and date to progression Twenty-seven patients with operable squamous cell cancer of head and neck were r and omized into the study . Twelve patients received Prospidin combined to preoperative radiotherapy and fourteen patients were treated with preoperative radiotherapy alone . The daily dose of the drug was from 0.70 mg/kg to 2 mg/kg and the total dose during preoperative radiotherapy was between 1800 mg and 2250 mg with a mean of 2073 mg . The recurrence rate was in patients receiving Prospidin three out of twelve and in patients treated with irradiation alone four out of fourteen during the observation time of 33 months . In the present study Prospidin combined with preoperative radiotherapy had no advantage as compared to irradiation alone Between March 1973 and June 1979 , patients with advanced operable squamous cell carcinoma of the supraglottic larynx or hypopharynx were r and omly allocated to receive either preoperative radiation therapy ( 5,000 rad ) or postoperative radiation therapy ( 6,000 rad ) . Patients with oral cavity or oropharynx lesions were r and omly assigned either preoperative radiation , postoperative radiation , or definitive radiation therapy ( 6,500 - 7,000 rad ) , with surgery reserved for salvage if residual disease was present 6 weeks after completion of irradiation . Three hundred twenty patients were evaluable with a median follow-up of 60 months . Based on results in 277 patients across all four regions combined , locoregional control was significantly better for patients assigned to receive postoperative radiation therapy ( 65 % ) compared with those assigned to receive preoperative radiation therapy ( 48 % , P = 0.04 ) . This was due to a higher rate of both persistent and recurrent local and regional disease in the preoperative group . Survival also showed a trend to be better in the postoperative group ( 38 % ) compared with the preoperative group ( 33 % , P = 0.10 ) . Rates of severe surgical and radiation therapy complications were similar overall . Forty-three patients were evaluable for each of the three treatment regimens assigned to patients with oral cavity or oropharynx lesions . Due to the small number of patients available for this portion of the trial , the observed differences for overall survival ( 4-year percentage 33 % overall ; 30 % preoperative , 36 % postoperative , 33 % definitive radiation therapy ) and for locoregional control ( 45 % overall ; 43 % preoperative , 52 % postoperative , 38 % definitive radiation therapy ) were not statistically significant . The use of definitive radiation therapy with surgical rescue as an ethically justified alternative treatment for these tumors remains a question for further research Patients who are cured from head and neck carcinomas remain at high risk for developing a second primary in the head and neck area . It is now clear that retinoids exert a prophylactic action on the development of epithelial cancers when tested on laboratory animals and on human premalignant lesions . They are now used in the chemoprevention of epithelial cancers in r and omised trials evaluating their efficacy . We prospect ively studied 316 patients who developed squamous cell carcinoma of the head and neck , classified as T1/T2 , N0/N1 < or 3 cm , M0 according to the UICC TNM classification . Patients were r and omly assigned to receive orally , either etretinate ( a loading dose of 50 mg/day for the first month , followed by a dose of 25 mg/day in the following months ) or a placebo for 24 months . Adjuvant treatment began no later than 15 days after surgery and /or the initiation of radiotherapy . The 5-year survival rate and disease-free survival rate are similar in the two groups . There are no significant differences regarding either local , regional and distant relapses . After a median follow-up of 41 months ( range 0 - 81 ) , 28 patients in the etretinate group and 29 in the placebo group developed a second cancer with , respectively , 12 and 13 in the head and neck region . Adjuvant treatment was definitively discontinued mainly due to toxicity in 33 % of patients in the etretinate group versus 23 % in the placebo group ( P < 0.05 ) . Etretinate , a second-generation retinoid , does not prevent second primary tumours in patients who have been treated for squamous cell carcinoma of the oral cavity and oropharynx Patients with H&N tumours treated with surgery , chemo- and radiotherapy  also underwent an immunologic therapy with timopentina to evaluate clinic and immunologic efficacy during a 1-year follow-up . Twenty-five patients were recorded in this study divided at r and om into two groups . In group A the patients were administered timopentina ( 50 mg/3 times per week/6 weeks ) subcutaneously in 4 o 5 cycles during the year . Group B were not administered timopentina . The immunologic state was assessed through investigation of the following : Evaluation of PBL and their T and B cell sub population s Phagocytosis and blastigenesis Surface receptor and soluble receptor of IL2 NK activity IL1 production . The immunologic values of the two groups were correlated against a control group of twenty non-neoplastic patients . Our study revealed a better immunologic conditions at the end of follow-up in patients treated with timopentina  compared to the other patients A r and omized prospect i ve clinical trial was carried out to assess the usefulness of the addition of mitomycin C to radiation therapy used alone or in combination with surgery for the treatment of squamous cell carcinoma of the head and neck region . One hundred and twenty patients with biopsy proven tumor of the oral cavity , oropharynx , larynx , hypopharynx , and nasopharynx were r and omly assigned to receive or not receive mitomycin C ; all other aspects were similar in the two treatment groups . One hundred and seventeen patients were evaluable with a median follow-up time of greater than 5 years .  Acute and chronic normal tissue radiation reactions were equivalent in the two treatment groups . Hematologic and pulmonary toxicity were observed in the drug treated patients . Actuarial disease-free survival at 5 years was 49 % in the radiation therapy group and 75 % in the radiation therapy plus mitomycin C group , p less than 0.07 . Local recurrence-free survival was 66 % in the radiation therapy group and 87 % in the radiation therapy plus mitomycin C group , p less than 0.02 . The findings demonstrate that mitomycin C can be administered safely as an adjunct to radiation therapy in the treatment of head and neck cancer . The drug improves local tumor control without enhancing normal tissue radiation reactions A r and omized prospect i ve study of 5 fluorouracil ( 5-FU ) and Cis platin preceding definitive local treatment for squamous cell carcinoma of the head and neck region was initiated in September 1986 . Seventy-five patients were stratified by site ( oral cavity-12 , oropharynx-28 , larynx-16 , hypopharynx-19 ) , and by Stage ( Stage II-20 , Stage III-43 , Stage IV-12 ) and r and omized to receive definitive local treatment ( surgery and post-operative radiation or radiation alone ) or chemotherapy followed by definitive local treatment . Chemotherapy consisted of three cycles of 120 hr 5-FU infusion 1 g/m2/day plus Cis platin 100 mg/m2 on day 1 on each cycle . Response to chemotherapy was complete in 17 patients ( 46 % ) for an overall response rate of 68 % . All the patients have completed therapy with a median follow-up of more than 12 months . After local treatment , the complete response rate is 84 % for the control group and 86 % in the chemotherapy group . Actuarial disease-free survival at 1 year is 61 % in the control group and 73 % in the chemotherapy group ( p = 0.25 ) . These preliminary results show that in spite of initial tumor response , neoadjuvant chemotherapy does not improve long-term control and survival Results from experimental systems suggest that the combination of methotrexate ( MTX ) and 5-fluorouracil ( 5-FU ) produces synergistic cytotoxic effects that are dependent on the sequence of drug administration . Biochemical studies have demonstrated plausible mechanisms of a synergistic effect when MTX precedes 5-FU . A variety of phase I and phase II studies have employed this sequential combination with promising but inconclusive results . In this study , 79 evaluable patients with squamous cell head and neck cancer were r and omized to receive MTX ( 200 mg/m2 IV ) and 5-FU ( 600 mg/m2 IV ) either simultaneously or sequentially with MTX preceding 5-FU by one hour . All patients were ambulatory and patients were stratified as to whether they presented with primary disease or with recurrence after prior radiation and /or surgical therapy . The overall response rate was superior for simultaneous therapy ( 62 % ) compared with sequential therapy ( 38 % ) ( p less than 0.06 ) . Among patients with primary head and neck cancer , the stage of the disease influenced the response rate . Eight of nine stage III patients who received simultaneous therapy responded while none of the four patients who received sequential therapy responded ( p less than 0.01 ) . This study demonstrates that one-hour sequential MTX plus 5-FU is not superior to simultaneous treatment in patients with squamous cell head and neck cancer In a prospect i ve evaluation , two preoperative courses of methotrexate , bleomycin , and cisplatin combined with 2,000 rad/10 fractions ( " chemo-radiotherapy " ) yielded 78 % responses rates in previously untreated advanced head and neck cancer . Similarly staged patients receiving preoperative irradiation of 5,000 rad alone had a 67 % response rate . Treatment-related mortality in the chemo-radiotherapy patients was equal to that seen with st and ard combinations of surgery and preoperative or postoperative irradiation . At 24 months , disease-free survival is 47 % with chemo-radiotherapy vs 33 % with st and ard therapy ; however , patients benefiting most from the former approach were those with T4 primary lesions or N3a neck nodes Four regimens of prophylactic antibiotics were utilized in 122 consecutive patients of stages III and IV carcinoma of the upper aero-digestive tract undergoing major resections in a r and omized single-blind study . Ampicillin , gentamicin , cephalexin and metronidazole were used in different combinations for periods of 5 or 10 days . A cephalexin-metronidazole protocol for 10 days was associated with lowest post-operative infection rate . Oral-oropharyngeal resection and use of pectoralis major myocutaneous flap were the most important factors contributing to infection Since January 1974 , 95 patients with anterior tongue and floor of the mouth cancers were included in a r and omized trial . After stratification according to staging and initial treatment , one-third of the patients received chemotherapy for 2 years ( methotrexate 400 mg followed by citrovorum factor 100 mg + bleomycin 60 mg/week , during the first 15 weeks ) , one-third of the patients received immunotherapy with weekly C. parvum injections during 2 years , while the remaining third did not receive any treatment . If adjuvant treatment seems to delay recurrence it did not significantly decrease the recurrence rate . Survival is also not signigicantly modified by adjuvant treatment and was better for patients with small tumors . Patients who previously received radiotherapy did not benefit from adjuvant therapy Patients with primary squamous cell epitheliomas of the oral cavity , pharynx , and larynx were stratified according to stage and site and r and omized to receive either intratumoral immunotherapy with Corynebacterium parvum followed 2 weeks later by surgery and postoperative C parvum for 2 years or surgery alone . There were 209 patients entered into the trial and 176 were fully evaluable . All prognostic variables were similar between the two groups . There was no difference in disease-free survival or absolute survival between the two groups of patients . In addition , there was no difference noted for any stage and /or site . The only difference in sequential immunologic testing was that chemokinesis was increased following intratumoral C parvum , but neither this nor any other immunologic test correlated with ultimate recurrence or survival . These data demonstrate that immunotherapy using preoperative , intralesional C parvum and postoperative , subcutaneous C parvum is ineffective when used as an adjuvant to surgery for primary cancers arising in the oral cavity , pharynx , and larynx This is an interim report of a study of perioperative adjuvant chemotherapy following radical surgery for oral cancer , based on the hypothesis of Goldie and Coleman . 135 patients of alveolobuccal carcinoma , clinical ly stage III and IV , were entered on the protocol . After a curative resection , they were r and omized . The test arm received methotrexate 50 mg/m2 on the 3rd , 10th , and 17th postoperative days . The control arm was only observed . This analysis at 12 months showed a disease free survival of 71 % in the test arm vs. 45 % in the control arm , which is statistically highly significant ( P less than 0.01 ) . Analysis of recurrence pattern showed that recurrence at the primary site was dramatically reduced during the first 6 postoperative months ( P less than 0.01 ) . Our study provided further clinical evidence in support of the concepts of Goldie and Coleman that the timing of chemotherapeutic drugs is very critical for a successful end result This paper presents the first report of an ongoing prospect i ve r and omised clinical trial in early T1T2N0 carcinoma of the oral tongue . The problems of regular follow-up in an indigent population from the vast rural expanse of India has been successfully overcome in this trial by close personal follow-up . The trial addresses itself specifically to prophylactic vs. therapeutic surgical management of the neck  in T1T2N0 patients with cancer of the oral tongue .  Overall disease , free survival ( median follow-up 22 months ) is higher ( 64 % vs. 47 % ) in the group receiving prophylactic neck dissection .  Disease-free survival for those with positive nodes at prophylactic neck dissection was twice that of those who underwent a subsequent therapeutic neck dissection ( 57 % vs. 28 % ) . Contralateral neck node metastasis has been identified as a significant factor in neck failures in those patients undergoing simultaneous prophylactic neck dissection PURPOSE Clinical trials demonstrated the efficacy and safety of intravenous ( i.v . ) or subcutaneous ( s.c . ) amifostine for reducing xerostomia and mucositis after radiotherapy or radiochemotherapy for head- and -neck cancer . This r and omized , double-blinded , placebo-controlled , phase III study evaluated the efficacy and safety of i.v . amifostine during radiochemotherapy for head- and -neck cancer . METHODS AND MATERIAL S Patients from European and American study centers received i.v . amifostine 300 mg/m2 ( n = 67 ) or placebo ( n = 65 ) before carboplatin 70 mg/m2 and radiotherapy on Days 1 to 5 and 21 to 25 , and i.v . amifostine 200 mg/m2 or placebo before radiotherapy on other days . RESULTS Toxicity incidences were ( amifostine , placebo , p value ) : Grade 2 or higher acute xerostomia ( 39 % , 34 % , 0.715 ) , Grade 3 or higher acute mucositis ( 39 % , 22 % , 0.055 ) , Grade 2 or higher late xerostomia ( 37 % , 24 % , 0.235 ) , and Grade 3 or higher treatment-related adverse events ( 42 % , 20 % , 0.008 ) . One-year rates of locoregional failure , progression-free survival , and overall survival were not significantly different between treatments . CONCLUSIONS The used amifostine doses were not able to reduce the toxicity of simultaneous radiochemotherapy for head- and -neck cancer . The safety of amifostine and the lack of tumor protection were consistent with previous studies PURPOSE This study was undertaken to assess the benefit of mitomycin C as an adjunct to postoperative radiation therapy in patients with operable squamous cell carcinoma of the head and neck . METHODS AND MATERIAL S Between May 1980 and May 1991 , 182 patients have been enrolled in two consecutive r and omized clinical trials testing mitomycin C as an adjunct to radiation therapy in squamous cell carcinoma of the head and neck . In both trials , patients were stratified by stage , disease site and intent of therapy . This subset analysis includes 113 patients entered into these two r and omized trials treated with surgery and postoperative radiation therapy . In the first trial , patients were r and omized to receive st and ard postoperative radiation therapy alone compared with postoperative radiation therapy with concomitant mitomycin C. In the second trial , patients were r and omized to postoperative radiation therapy or postoperative radiation therapy with concomitant mitomycin C plus dicoumarol . RESULTS As of November 1991 , the 113 patients treated with surgery and postoperative radiation therapy in both trials had a median follow-up of 93 months . There have been a total of 12 local recurrences in the radiation therapy alone arm compared to 0 local recurrences in the radiation therapy/mitomycin C arm . There were eight regional recurrences in the radiation therapy alone arm compared with five regional recurrences in the mitomycin C arm . Patients in the mitomycin C arm experienced a superior 5-year actuarial local regional control rate ( 87 % vs. 67 % , p < .015 ) and a statistically significant disease-free survival benefit ( 67 % vs. 44 % , p < .03 ) . Overall survival difference between the two arms ( 56 % vs. 41 % ) has not reached statistical significance . CONCLUSIONS We conclude from these prospect ively design ed r and omized clinical trials that in patients with operable head and neck cancer treated with surgery  and postoperative radiation therapy  , concomitant administration of mitomycin C with radiation therapy will result in a statistically significant disease-free survival and local regional control benefit . We are currently investigating the value of other bioreductive alkylating agents as adjuncts to radiation therapy in patients with squamous cell carcinoma of the head and neck Despite modern advances in the treatment of head and neck cancer , the survival rate fails to improve . Considering the different treatment modalities involved , quality of life has been thought of as an additional end point criterion for use in clinical trials . A Nordic protocol to measure the quality of life of head and neck cancer patients before , during , and after treatment was established . Before the study , a pilot study was done with this protocol . The main purpose of this pilot study was to find out whether this cancer population would answer  quality -pf-life question naires repeatedly ( six times ) over a 1-year period and whether the chosen question naires — a core question naire ( European Organisation for Research and Treatment of Cancer Core Quality of Life Question naire ( EORTC QLQ-C30 ) ) , a tumor-specific question naire , and a psychological distress measure ( Hospital Anxiety and Depression scale (HAD))—were sensitive for changes to functions and symptoms during the study year . The results presented in this article all refer to the pilot study . Forty-eight consecutive patients agreed to participate in the study . The most common tumor locations were the oral cavity ( 17 ) and the larynx ( 12 ) . Almost all patients received combined treatment : 45 of 48 radiation therapy , 18 of 48 chemotherapy , and 17 of 48 surgery . After the primary treatment , 40 patients had complete tumor remission . Four of the 48 patients did not answer any question naires and were therefore excluded from the study . Of the remaining 44 patients , 3 died during the study year , and another 6 withdrew for various reasons . Thirty-five ( 85 % ) of the 41 patients alive at the 1-year follow-up answered all six question naires and thus completed the study . Mailed question naires were used throughout the study . All question naires were well accepted and found to be sensitive to changes during the study year . The greatest variability was found for symptoms and functions related specifically to head and neck cancer . The symptoms were swallowing difficulties , hoarse voice , sore mouth , dry mouth , and problems with taste . They all showed the same pattern , with an increase of symptoms during and just after finishing the treatment . The HAD scale revealed a high level of psychological distress , with 21 % probable cases of psychiatric morbidity at diagnosis . In conclusion , it was shown that the study design and question naires were feasible for the forthcoming prospect i ve quality -of-life assessment of Swedish and Norwegian head and neck cancer patients Two hundred and ninety-eight patients with squamous cell carcinoma of the oral cavity , oropharynx , supraglottic larynx , hypopharynx or maxillary sinus have been r and omized for preoperative radiation therapy and surgery vs. surgery and postoperative radiation therapy plus , in the case of patients with lesions of the oral cavity and oropharynx , radical radiation therapy . Data have been analyzed on 243 patients in this interim report . The differences between the three groups with respect to local control and survival are not statistically significant at this time . Additional accrual and continued follow-up are necessary to make definite treatment comparisons A group of 222 consecutive patients admitted with squamous cell carcinoma of the upper aero-digestive tract were studied in a prospect ively r and omized and stratified clinical trial . One-half of the patients received bleomycin injected intramuscularly 1 hour before the radiation treatment daily for 5 days a week ; the other half received radiation therapy without the added chemotherapy . The total dose of radiation in both groups was about the same , and was given with curative intent even to the patients with advanced tumors who constituted the majority in both groups . Interstitial radiation as boost therapy or surgery was added in patients with residual tumor if the lesions were considered operable and the patient 's condition would allow surgery . The addition of bleomycin did not increase the combined local and regional tumor control rates nor did it improve the survival , but did significantly increase the morbidity and the complication rate The problem of which antibiotic to choose and the optimal duration of its administration in the prophylaxis of otorhinolaryngological surgery for cancer has not been satisfactorily resolved . Subjects suffering from cancer of the upper airways or digestive tract , who are often smokers and drinkers , have a population of Gram-positive or Gram-negative anaerobes and Gram-negative aerobes ( predominantly Pseudomonas , Proteus and Escherichia coli ) in addition to their usual oropharyngeal flora .  Antibacterial monotherapy has little chance of success against all of these organisms , which are liable to become pathogenic in the event of surgery . Drug combinations would be costly and could result in selection of resistant strains . Accordingly , it is generally recommended that either monotherapy with a newer 13-lactam or a combination of a penicillin and imidazole be used , knowing that not all of the potential pathogens will be covered , but that the most resistant anaerobes in the postoperative period will be effectivelyerased and that a second antibiotic can be used in the event of the sudden occurrence of a specific infection . The optimum duration of antibiotic administration has not been determined for this area of surgery ; 8 days ' treatment is excessively long and 24 hours ( the usual duration of st and ard prophylaxis ) is insufficient because one is dealing with a highly infectious type of surgery in a very septic medium . Tumours are often necrosed in an environment which already has an abundance of potentially pathogenic organisms ; surgery is long ( average duration is 4 hours ) and exposes a large operation area to contamination : i.e. the neck and frontal thorax if a musculo-cutaneous flap has been prepared . Third generation cephalosporins similar to cefotaxime have already been the subject of studies as antibiotic prophylaxis in this indication ( Gehanno & Moisy in press ; Johnson et al. 1983 ) . The aim of the present multicentre study was to determine the optimum duration of administration of cefotaxime One hundred and thirty-four patients ( 118 males and 16 females ) with epidermoid carcinoma of the head and neck were studied . After treatment of the primary lesion , they were r and omized into two groups : 69 received levamisole , 150 mg/day orally for 3 consecutive days every other week , and 65 received placebo .  Immune status was also evaluated . Positive reactions to dinitrochlorobenzene increased significantly after primary tumor therapy in both levamisole- and placebo-treated patients . There were no significant differences in immune responses between the two groups , except in recall antigen reactivity , which was decreased in both groups overall recurrence and death rates at 36 months did not differ between the two groups of patients . However , stage I and II patients treated with levamisole had a significantly higher incidence of recurrence than the placebo-treated patients ( P less than 0.02 ) , while there was some evidence that levamisole-treated stage IV patients did better . It is concluded that the overall outcome in patients with squamous cell carcinoma controlled locally by surgery or radiation was not favorably affected by levamisole in the dose and schedule used in this protocol Tumours of the oral cavity/oropharynx occur relatively infrequently in the UK . The management of such lesions , especially the squamous cell carcinomas , is still a little controversial . Some centres advocate radiotherapy while others adopt surgery and radiotherapy . In an attempt to resolve the question of which approach gives the better results , a multicentre r and omized trial was established to compare surgery plus postoperative radiotherapy with radical radiotherapy alone . It was anticipated that 350 patients would be required to give a statistically significant result , but , after 35 patients had been entered , the trial was closed prematurely with a marked difference in overall survival in favour of the combination arm ( P = 0.0006 ) . At this analysis , carried out 23 months after trial closure , the survival difference between the two arms remains statistically significant for all causes of mortality ( P = 0.001 ; relative death rate = 0.24 ; 95 % CI 0.10 - 0.59 ) In the final report of a prospect i ve , r and omized controlled clinical trial , we report the results of using adjuvant perioperative chemotherapy in patients with oral cancer . Our study is based on the hypothesis of Goldie and Coldman . A total of 135 patients with alveolobuccal carcinoma , classified as clinical ly stage III and IV , were entered on the protocol . After a curative resection , they were r and omized . The patients in the test arm of the study received methotrexate 50 mg/m2 on the 3rd , 10th , and 17th postoperative days . The patients in the control arm underwent observation . This analysis at 24 months showed a disease-free survival rate of 61 % in the test arm versus 37 % in the control arm , which is statistically highly significant ( P < 0.01 ) . Analysis of the recurrence pattern showed that recurrence at the primary site was dramatically reduced during the first 6 postoperative months ( P = 0.002 ) . Our study provided further clinical evidence in support of the concepts of Goldie and Coldman that the timing of chemotherapeutic drugs is critical for a successful end result Patient compliance with the increasingly complex adjuvant therapy protocol s has always been of concern , particularly in the head and neck cancer population . The Head and Neck Intergroup recently concluded a phase III prospect i ve r and omized trial testing the addition of three courses of cisplatinum containing combination chemotherapy to st and ard treatment defined as surgery and postoperative radiotherapy for advanced stage III and IV squamous cell carcinoma . The chemotherapy was administered following the surgery prior to the postoperative radiotherapy .  Variation from protocol is ranked retrospectively as minor acceptable , major acceptable , and major unacceptable . The incidence of major unacceptable variation from the protocol for radiotherapy immediately following the surgery was 15 % vs. 19 % in the population that completed all three courses of the chemotherapy ( P < 0.10 ) . However , for those patients that completed less than the three courses of chemotherapy , the incidence of major unacceptable variation in radiotherapy was 33 % ( P < 0.001 ) . This observation was controlled for site , stage , performance status , age , sex , surgical margins and experience of participating institution . We conclude that compliance with a multicourse adjuvant chemotherapy regimen is predictive of subsequent compliance to radiotherapy  in the head and neck cancer population This is a report of a 10-year median follow-up of a r and omized , prospect i ve study investigating the optimal sequencing of radiation therapy ( RT ) in relation to surgery for operable advanced head and neck cancer . In May 1973 , the Radiation Therapy Oncology Group ( RTOG ) began a Phase III study of preoperative radiation therapy ( 50.0 Gy ) versus postoperative radiation therapy ( 60.0 Gy ) for supraglottic larynx and hypopharynx primaries . Of 277 evaluable patients , duration of follow-up is 9 - 15 years , with 7.6 % patients lost to follow-up before 7 years .  Loco-regional control was significantly better for 141 postoperative radiation therapy patients than for 136 preoperative radiation therapy patients ( p = 0.04 ) , but absolute survival was not affected ( p = 0.15 ) . When the analysis was restricted to supraglottic larynx primaries ( 60 postoperative radiation therapy patients versus 58 preoperative radiation therapy patients ) , the difference for loco-regional control was highly significant ( p = .007 ) , but not for survival ( p = 0.18 ) . In considering only supraglottic larynx , 78 % of loco-regional failures occurred in the first 2 years . Thirty-one percent ( 18/58 ) of preoperative patients failed locally within 2 years versus 18 % ( 11/60 ) of postoperative patients . After 2 years , distant metastases and second primaries became the predominant failure pattern , especially in postoperative radiation therapy patients . This shift in the late failure pattern along with the increased number of unrelated deaths negated any advantage in absolute survival for postoperative radiation therapy patients . The rates of severe surgical and radiation therapy complications were similar between the two arms . Because of an increased incidence of late distant metastases and secondary primaries , additional therapeutic intervention is required beyond surgery and postoperative irradiation to impact significantly upon survival
BACKGROUND Surgery is an important part of the management of oral cavity cancer with regard to both the removal of the primary tumour and removal of lymph nodes in the neck .
Surgery is less frequently used in oropharyngeal cancer .
Surgery alone may be treatment for early stage disease or surgery may be used in combination with radiotherapy , chemotherapy and immunotherapy/biotherapy .
There is variation in the recommended timing and extent of surgery in the overall treatment regimens of people with these cancers .
OBJECTIVES To determine which surgical treatment modalities for oral cavity and oropharyngeal cancers result in increased overall survival , disease free survival , progression free survival and reduced recurrence .