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Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Fast neutrons in the treatment of head and neck cancers: the results of a multi-centre randomly controlled trial. Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation The Saudi experience with neutron therapy in locally advanced head and neck cancers. [Chemotherapy of advanced head and neck tumors. A prospective randomized study comparing the effectiveness of chemotherapy alone to a chemo-radiotherapy procedure]. The Edinburgh experience of fast neutron therapy. Irradiation twenty-four hours preoperatively. Adjuvant chemotherapy in stage III and IV squamous cell carcinoma of the head and neck. 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Comparison of preoperative and postoperative radiation therapy for patients with carcinoma of the head and neck. Interim report. Long-Term Results of Conventional Radiotherapy versus Accelerated Hyperfractionated Radiotherapy versus Concomitant Radiotherapy and Chemotherapy in Locoregionally Advanced Carcinoma of the Oropharynx Randomized clinical trial on accelerated 7 days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity. Carcinomas of the oropharynx treated with hyperfractionated radiation therapy on Radiation Therapy Oncology Group Protocol 8313. Concomitant cisplatin and radiotherapy in a conventional and modified fractionation schedule in locally advanced head and neck cancer: a randomised phase II EORTC trial. interruptions adversely affect local control and survival with hyperfractionated radiation therapy of carcinomas of the upper respiratory and digestive tracts new evidence for accelerated proliferation from radiation therapy oncology group protocol 8313 Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts: preliminary report of radiation therapy oncology group protocol 83-13. 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Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. Fast-neutron therapy in advanced head and neck cancer: a collaborative international randomized trial. Hyperfractionated photon radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx, and sinuses, using radiation therapy as the only planned modality: (preliminary report) by the Radiation Therapy Oncology Group (RTOG). Fast neutron therapy for squamous cell carcinoma in the head and neck region: results of a randomized trial. Preoperative irradiation for head and neck cancer: results of a prospective study. Conventional vs accelerated fractionation in head and neck cancer. Protocol variations and their influence on the final outcome: critical review of the split-course base of tongue study of the RTOG. 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Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial. Immediate results of weekly fractionation in external radiotherapy. 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. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. Second report on results of a randomised clinical trial of fast neutrons compared with chi or gamma rays in treatment of advanced tumours of head and neck. Split-course radiation therapy of carcinoma of the base of the tongue: results of a prospective national collaborative clinical trial conducted by the Radiation Therapy Oncology Group. Multimodality treatment in stage IV squamous cell carcinoma of the head and neck. A long-term follow-up. Randomized phase I/II trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: results of RTOG 88-09. Evaluation of a Neutron Boost in Head and Neck Cancer Results of the Randomized RTOG Trial 78–08 Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach. Randomized trial of postoperative reirradiation combined with chemotherapy after salvage surgery compared with salvage surgery alone in head and neck carcinoma. 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From April 1986 to May 1989 , 112 patients seen at a single institution with previously untreated squamous cell oropharynx carcinoma , Stages III and IV , were r and omly assigned to 66 Gy in 33 fractions of 2 Gy each ( conventional RT ) versus 70.4 Gy in 64 fractions of 1.1 Gy given twice a day with a minimal interfraction interval of 6 hours ( hyperfractionated RT ) . The overall time for both arms was 6 1/2 weeks . Patients were stratified by site ( base of the tongue vs others ) , T stage ( T1/T2 vs T3 vs T4 ) , N stage ( N0/N1 vs N2 vs N3 ) , and lymphnode size ( less than 6 cm vs greater than 6 cm ) . As of January 1990 , an analysis was performed in 98 patients ( 8 patients in the conventional arm and 6 in the hyperfractionation not included ) . The groups were balanced by age , performance status , stage , and site of the primary disease . The median follow-up time was 25 months . The probability of complete loco-regional response was 62 % in the hyperfractionation arm and 52 % for the conventional fractionation ( p = 0.28 ) . There was no difference in the control of lymphnodal disease ( hyperfractionated = 55 % , conventional = 57 % ; p = 0.92 ) , but the disease control in the oropharynx only was significantly improved in the hyperfractionation arm ( 84 % vs 64 % , p = 0.02 ) . Overall survival rate at 42 months was 27 % for the hyperfractionation arm and 8 % for the conventional ( p = 0.03 ) . Survival rates for hyperfractionated versus conventional RT were 40 % versus 18 % ( p = 0.06 ) , respectively , for Stage III patients and 16 % versus 0 % ( p = 0.15 ) , respectively , for Stage IV . There was significant improvement in survival in favor of the hyperfractionation arm in patients with lesions outside the base of the tongue ( 31 % vs 15 % , p = 0.02 ) , for those with a 50 - 70 % Karnofsky status ( 19 % vs 0 % , p = 0.006 ) and for patients with N0/N1 disease ( 38 % vs 15 % , p = 0.03 ) . Acute toxicities were of similar magnitude , although both skin and mucosal reactions appeared earlier on the hyperfractionation scheme . To date , no differences in late toxicity have been observed . We conclude that in a subset group of patients with locally advanced carcinoma of the oropharynx , hyperfractionated radiotherapy appears to provide improved survival without adding to increased toxicity The European Organization for Research on Treatment of Cancer ( EORTC ) Cooperative Group of Radiotherapy started phase II and III trials on modified fractionation schemes in 1980 . As of June 1 , 1992 , 2006 patients have entered eight trials . This short overview will only concentrate on two phase III trials of hyperfractionation ( EORTC trial 22791 ) and accelerated fractionation ( trial 22851 ) Summary The r and omized multicentre trial of continuous hyperfractionated accelerated radiotherapy ( CHART ) versus conventional radiotherapy in patients with advanced head and neck cancer showed no good evidence of a difference in any of the major clinical outcomes of survival , freedom from metastases , loco-regional control and disease-free survival . Therefore an assessment of the effect of treatment on physical and psychological symptoms is vital to balance the costs and benefits of the two treatments . A total of 615 patients were asked to complete a Rotterdam Symptom Checklist and the Hospital Anxiety and Depression Scale , which cover a variety of physical and psychological symptoms , at a total of ten time points . The data consisted of short-term data ( the initial 3 months ) and long-term data ( 1 and 2 years ) . The short-term data was split into an exploratory data set and a confirmatory data set , and analysed using subject-specific and group-based methods . Differences were only cl aim ed if hypotheses generated in the exploratory data set were confirmed in the confirmatory data set . The long-term data was not split into two data sets and was analysed using a group-based approach . There was evidence of significantly worse symptoms of pain at day 21 in those treated with CHART and significantly worse symptoms of cough and hoarseness at 6 weeks in those treated conventionally . There was also evidence to suggest a higher degree of decreased sexual interest at 1 year and sore muscles at 2 years in those treated with conventional radiotherapy . There is no clear indication that one regimen is superior to the other in terms of ‘ quality of life ’ , generally the initially more severe reaction in the CHART group being offset by the longer duration of symptoms in the conventionally treated group PURPOSE To evaluate tumour and normal tissues 3-year response to 7-day-a-week continuous accelerated irradiation ( CAIR ) compared to a conventional treatment ( 5 days per week ) in a r and omized trial . MATERIAL S AND METHODS One hundred patients with squamous cell carcinoma of the head and neck in stage T(2 - 4)N(0 - 1)M(0 ) were entered into the trial between December 1 , 1993 and June 30 , 1996 . Dose per fraction of 2.0 Gy ( to the end of 1994 ) , and 1.8 Gy ( since January 1 , 1995 ) was the same in both arms and delivered once a day at regular 24-h intervals to total dose in the range of 66 - 72 Gy ( depending on tumour stage ) . The only difference was overall treatment time being 5 weeks in the CAIR and 7 weeks in control arm . RESULTS Actuarial 3-year local tumour control was 82 % in the CAIR and 37 % in the control group ( P<0.0001 ) with reduction in local recurrence rate of 83 % . Actuarial 3-year overall survival was 78 and 32 % ( P<0.0001 ) , respectively . Confluent mucositis was significantly more severe and lasted longer in the CAIR than in control arm . After 2.0 Gy fractions five of 23 patients ( 22 % ) in the CAIR developed early necroses over a period of 2 - 4 months of follow-up which can be considered as a consequential to severe protracted acute mucosal reactions ( CLE ) . For this reason dose per fraction was lowered to 1 . 8 Gy and the CLE was not observed again until now . Thus the overall rate of CLE decreased to 10 % . CONCLUSIONS The gain in tumour control is likely the effect of shortening of overall treatment time by 14 days and regular continuous dose delivery during the whole course of radiation therapy including weekends . A 7-day schedule produces more severe acute mucosal reactions lasting longer than in conventional fractionation , however tolerable by patients . Relatively high rate ( 22 % ) of CLE in the 7-day arm observed during the first year of the study was eliminated by decreasing dose per fraction from 2.0 Gy to 1.8 Gy 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 EORTC protocol 22791 compared once daily fractionation ( CF ) of 70 Gy in 35 - 40 fractions in 7 - 8 weeks , to pure hyperfractionation ( HF ) of 80.5 Gy in 70 fractions in 7 weeks using 2 fractions of 1.15 Gy per day , in T2-T3 oropharyngeal carcinoma ( excluding base of tongue ) , N0,N1 of less than 3 cm . From 1980 to 1987 , 356 patients were entered . In the final analysis ( June 1990 ) , the local control was significantly higher ( p = 0.02 log-rank ) after HF compared with CF . At 5 years , 59 % of patients are local disease-free in the HF arm compared to 40 % in the CF arm . The superiority of HF was demonstrated in patients staged T3N0,T3N1 but not in T2 . The Cox model confirmed that the treatment regimen was an independent significant prognostic factor for locoregional control ( p = 0.007 log-rank ) . This improvement of locoregional control was responsible for a trend to an improved survival ( p = 0.08 log-rank ) . There was no difference in late normal tissue damage between the two treatment modalities The results are presented of a multi-centre r and omly controlled trial of fast neutron irradiation and mega-voltage X-rays in the treatment of patients with locally advanced squamous cell carcinoma of the head and neck region . No significant difference was observed in local tumour control rates . Salvage  surgery  was performed in a similar number of patients in the two groups . Late morbidity was also similar in the two treatment groups . Patients in a subgroup with cancer of the larynx treated by photons had a significantly better survival than those in the neutron treated group Based on the assumption that an accelerated proliferation process prevails in tumour cell residues after surgery , the possibility that treatment acceleration would offer a therapeutic advantage in postoperative radiotherapy of locally advanced head and neck cancer was investigated . The value of Tpot in predicting the treatment outcome and in selecting patients for accelerated fractionation was tested . Seventy patients with ( T2/N1–N2 ) or ( T3 - 4/any N ) squamous cell carcinoma of the oral cavity , larynx and hypopharynx who underwent radical surgery , were r and omized to either ( a ) accelerated hyperfractionation : 46.2 Gy per 12 days , 1.4 Gy per fraction , three fractions per day with 6 h interfraction interval , treating 6 days per week or ( b ) Conventional fractionation : 60 Gy per 6 weeks , 2 Gy per fraction , treating 5 days per week . The 3-year locoregional control rate was significantly better in the accelerated hyperfractionation ( 88±4 % ) than in the CF ( 57±9 % ) group , P=0.01 ( and this was confirmed by multivariate analysis ) , but the difference in survival ( 60±10 % vs 46±9 % ) was not significant ( P=0.29 ) . The favourable influence of a short treatment time was further substantiated by demonstrating the importance of the gap between surgery and radiotherapy and the overall treatment time between surgery and end of radiotherapy . Early mucositis progressed more rapidly and was more severe in the accelerated hyperfractionation group ; reflecting a faster rate of dose accumulation . Xerostomia was experienced by all patients with a tendency to be more severe after accelerated hyperfractionation . Fibrosis and oedema also tended to be more frequent after accelerated hyperfractionation and probably represent consequential reactions . Tpot showed a correlation with disease-free survival in a univariate analysis but did not prove to be an independent factor . Moreover , the use of the minimum and corrected P-values did not identify a significant cut-off . Compared to conventional fractionation , accelerated hyperfractionation did not seem to offer a survival advantage in fast tumours though a better local control rate was noted . This limits the use of Tpot as a guide for selecting patients for accelerated hyperfractionation . For slowly growing tumours , tumour control and survival probabilities were not significantly different in the conventional fractionation and accelerated hyperfractionation groups . A rapid tumour growth was associated with a higher risk of distant metastases ( P=0.01 ) . In conclusion , tumour cell re population seems to be an important determinant of postoperative radiotherapy of locally advanced head and neck cancer despite lack of a definite association between Tpot and treatment outcome . In fast growing tumours accelerated hyperfractionation provided an improved local control but without a survival advantage . To gain a full benefit from treatment acceleration , the surgery-radiotherapy gap and the overall treatment time should not exceed 6 and 10 weeks respectively The neutron therapy program at King Faisal Specialist Hospital and Research Center conducted a phase II study to evaluate the toxicity and efficacy of neutrons against conventional external megavoltage irradiation in patients with locally advanced head and neck malignancy . One hundred and nineteen patients were allocated to receive either photons ( 46/119 ) or neutrons ( 73/119 ) . Radiation effects were scored according to the EORTC/RTOG criteria ; data was collected weekly during treatment , once a month for the first year and at 6-month intervals subsequently . While acute effects were scored in all patients , only 59 were evaluable for late effects and locoregional control . A composite of the average reaction results were obtained using this information , to compare them in time , for acute and late effects in both arms of the study . The maximum acute reactions in the two groups were similar . In the majority of the patients ( 80 % ) acute skin and mucosal reactions occurred during the last week of treatment . The changes in the subcutaneous tissues and salivary gl and s became clinical ly apparent at 3 months or later . Salivary gl and toxicity was more severe in the photon arm and the difference was statistically significant at 3 months ( P = 0.04 ) but this was lost at 12 months . Late effects for skin and subcutaneous tissues were significantly more severe in the neutron arm with P values of 0.04 and 0.01 respectively . Three patients in the neutron arm died of grade 4 radiation complications . The local control and survival were similar in both groups One of the most difficult problems of cancer treatment is the management of advanced squamous cell carcinomas of the upper respiratory tract . For several reasons the surgical resection of the primary lesion and the observed neck node metastases are limited to earlier tumour stages . Advanced and not resectable tumours of T3 - 4-N2 - 3-stages have very poor cure rates . Their treatment is based traditionally on radiotherapy and in recent years on combination chemotherapy programmes . 75 patients were entered into this prospect i ve r and omised study . 33 of these were treated with two cycles of chemotherapy followed by radiotherapy and 42 patients received three cycles of chemotherapy alone . Both therapy modalities induced tumour response rates of up to 75 % but have done little to improve survival . The role of combined radiotherapy and chemotherapy in advanced squamous tumours is not yet well defined . In our group only patients who showed tumour response after chemotherapy actually benefited from radiotherapy Abstract The Edinburgh experience is based on a d(15 + Be neutron beam generated by a compact CS 30 Cyclotron . The facility has an iso-center treatment head providing 240 ° of rotation . The most important limitation of the beam is its poor penetrating quality . We have compared neutron therapy alone given in 20 daily fractions over four weeks with photon therapy given in the same fractionation schedule . Since clinical studies began in March , 1977 , over 500 patients have been treated by fast neutrons . Almost all patients are now admitted to r and omly controlled trials . In the head and neck trial conducted in collaboration with colleagues in Amsterdam and Essen,192 patients are available for analysis . Most patients had T3 lesions and about 50 % had involved nodes . The cumulative regression rate at six months is similar after neutrons and photons ( 75 % ) . Later recurrence rates ( 36 % ) are also similar . The early radiation morbidity is similar in both groups , but the late reactions are greater after neutrons ( 15 % ) than photons ( 6 % ) . Overall survival is better after photon therapy . A trial of patients with glioblastoma has also shown a better survival after photon therapy . Neutron therapy was associated with demelinization in three of 18 patients . Patients with transitional cell cancer of the bladder have also been the subject of study . Local tumor control was similar ( 53 % ) after neutrons and photons .  Late radiation morbidity was much greater after neutrons ( 20 % ) , compared with photons ( 2 % ) . In a trial of advanced carcinoma of the rectum , the local tumor control was also similar after neutrons and photons ( 30 % ) , but morbidity was greater after neutrons . Soft tissue sarcomas have shown response rates ( 37 % ) that may be expected after photon therapy . Salivary gl and tumors have shown a similar experience , although slow growing tumors such as adenoid cystic carcinoma may respond better to neutrons . The response of malignant melanoma also requires further evaluation . No qualitative advantage of neutrons in relation to tumor responses has been determined , while increased late radiation morbidity has been demonstrated following the dose-time schedules used 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 Initial combination drug regimen containing cisplatin in patients with stage III and IV head and neck cancer produced a high percentage of clinical response . This trial was initiated to assess the role of multimodality treatment ( chemotherapy plus radiotherapy ) versus chemotherapy alone .  Ninety-six patients entered into this study ; 80 patients were evaluable at time of analysis ( Table I ) . Patients were r and omized between chemotherapy and radiotherapy ( group I ) and  chemotherapy alone ( group II ) . The chemotherapy administered consisted of cisplatin , bleomycin and methotrexate and was given in 2 cycles over 35 days . Local radiotherapy followed . In group II 3 cycles of chemotherapy were given without radiotherapy . The overall tumour response after chemotherapy rose up to 75 per cent . After radiotherapy in group II the response rate sank to 59 per cent . In both regimes the remission duration was very short . Patients receiving only two cycles of chemotherapy do not have a statistically shorter survival than patients , who were treated by chemotherapy plus radiotherapy , or by a 3rd cycle of chemotherapy While radiotherapy is proceeding , tumour cells may proliferate . The use of small individual doses reduces late morbidity .  Continuous hyperfractionated accelerated radiation therapy ( CHART ) , which reduces overall treatment from 6 - 7 weeks to 12 days and gives 36 small fractions , has now been tested in multicentre r and omised controlled clinical trials . The trial in non-small-cell lung cancer included 563 patients and showed improvement in survival ; 30 % of the CHART patients were alive at 2 years compared with 20 % in the control group ( P = 0.006 ) . In the 918 head and neck cases , there was only a small , non-significant improvement in the disease-free interval . In this interim analysis there was a trend for those with more advanced disease ( T3 and T4 ) to show advantage ; this will be subject to further analysis when the data are more mature . The early mucosal reactions appeared sooner and were more troublesome with CHART , however they quickly settled ; so far no difference in long-term morbidity has emerged . These results support the hypothesis that tumour cell re population can occur during a conventional course of radiotherapy and be a cause of treatment failure BACKGROUND AND PURPOSE Radiation therapy is often the primary treatment for advanced cases of head and neck cancers not considered suitable for radical surgery . In these cases locoregional tumour control rates are low and has warranted innovative treatment modifications , such as altered fractionation schedules and combination with chemotherapy . PATIENTS AND METHODS From October 1990 to December 1997 , 239 patients with squamous cell cancers originating in the head and neck region were r and omized to one of three treatment options . St and ard therapy consisting of conventional fractionation with 70 Gy in 7 weeks in 35 fractions ( CF ) . The second treatment option consisted of a continuous hyperfractionated accelerated radiotherapy delivering a total dose of 55.3 Gy in 33 fractions over 17 consecutive days ( V-CHART ) . The third study arm had identical fractionation and dose as the above accelerated treatment , with the additional administration of 20 mg/m(2 ) mitomycin C ( MMC ) on day 5 of treatment ( V-CHART+MMC ) . RESULTS Main toxicity result ed from accelerated fractionation in confluent mucositis ( Grade 3 - 4 in 95 % ) requiring nasogastral tube feeding , analgetics and antiphlogistics in the majority of cases . Haematological toxicity Grade 3 - 4 was seen after MMC administration in 18 % . MMC administration did not influence mucosal reaction . Overall duration of mucositis was not different in the three treatment groups . Loco-regional tumour control was 31 % after CF , 32 % after V-CHART and 48 % after V-CHART+MMC , respectively ( P<0.05 ) . Overall crude survival was 24 % after CF , 31 % following V-CHART and 41 % after V-CHART+MMC , respectively ( P<0.05 ) . Median follow up was 48 months ( assessment performed in February 1999 ) . CONCLUSION Following shortening overall treatment time from 7 weeks to 17 consecutive days and dose of radiotherapy from 70 to 55.3 Gy the results in the radiotherapy only treated patients are identical . A significant improvement regarding local tumour control and survival was seen following administration of MMC to the accelerated fractionated treatment Initial combination drug regimens containing Cisplatin in patients with stage III and IV head and neck cancer produce a high percentage of clinical response . We initiated the current trial to assess the role of multimodality treatment ( CT plus RT ) versus CT alone in eliciting tumour response rates , and the duration of tumour free survival . Patients were r and omised to CT followed by RT ( arm A : 36 patients ) or CT alone ( arm B : 44 patients ) . Of 96 patients entered into this study 80 are evaluable at the time of analysis . There were 13 women and 67 men with a median age of 52 years and a median performance status of 90 % . All of them presented measurable stage T4N0 - 3M0 - 1 or T3N2 - 3M0 - 1 carcinomas . The chemotherapy consisted of Cisplatinum , Bleomycin and Methotrexate and was given in 2 cycles over 35 days . Local radiotherapy with 6,000 rad followed . In arm B , 3 cycles of chemotherapy were given without radiotherapy . The overall tumour responses after CT were 75 % in arm B , and 70 % in arm A. After RT the tumour response fell to 59 % . Median tumour remission was 4 months and median survival 11 months . Toxic effects were mild mainly consisting of alopecia , nausea and vomiting . Myelotoxicity was moderate , but significant renal or ototoxic side effects did not occur . 10 cases of Bleomycin related pulmonary fibrosis were found . Our main findings show that patients receiving 2 cycles of CT do not have a statistically shorter survival compared to those who were treated by CT plus RT 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 BACKGROUND Although head and neck cancer can be cured by radiotherapy , the optimum treatment time for locoregional control is unclear . We aim ed to find out whether shortening of treatment time by use of six instead of five radiotherapy fractions per week improves the tumour response in squamous-cell carcinoma . METHODS We did a multicentre , controlled , r and omised trial . Between January , 1992 , and December , 1999 , of 1485 patients treated with primary radiotherapy alone , 1476 eligible patients were r and omly assigned five ( n=726 ) or six ( n=750 ) fractions per week at the same total dose and fraction number ( 66 - 68 Gy in 33 - 34 fractions to all tumour sites except well-differentiated T1 glottic tumours , which were treated with 62 Gy ) . All patients , except those with glottic cancers , also received the hypoxic radiosensitiser nimorazole . Analysis was by intention to treat . FINDINGS More than 97 % of the patients received the planned total dose . Median overall treatment times were 39 days ( six-fraction group ) and 46 days ( five-fraction group ) . Overall 5-year locoregional control rates were 70 % and 60 % for the six-fraction and five-fraction groups , respectively ( p=0.0005 ) . The whole benefit of shortening of treatment time was seen for primary tumour control ( 76 vs 64 % for six and five fractions , p=0.0001 ) , but was non-significant for neck-node control . Six compared with five fractions per week improved preservation of the voice among patients with laryngeal cancer ( 80 vs 68 % , p=0.007 ) . Disease-specific survival improved ( 73 vs 66 % for six and five fractions , p=0.01 ) but not overall survival . Acute morbidity was significantly more frequent with six than with five fractions , but was transient . INTERPRETATION The shortening of overall treatment time by increase of the weekly number of fractions is beneficial in patients with head and neck cancer . The six-fractions-weekly regimen has become the st and ard treatment in Denmark The primary purpose of the present analysis was to assess the feasibility and acute toxicity of a pure accelerated fractionation regimen in a cooperative group setting . This analysis included the first 320 patients entered on to the Trans-Tasman Radiation Oncology Group ( TROG ) r and omized controlled trial which compared accelerated radiotherapy ( ART ) with conventional radiotherapy ( CRT ) in stage III and IV squamous cell carcinoma ( SCC ) of the head and neck . Patients were r and omized to either 59.4 Gy in 33 fractions over 24 days ( ART )  or to 70 Gy 35 fractions over 49 days ( CRT ) after being stratified for site and stage . Accrual began in 1991 and the trial was closed on 3 April 1998 with the targeted 350 patients . The 3-year survival for the whole group was 54 % , and the 3-year disease-free survival was 41 % . Toxicity data were available on 303 patients ( 148 ART ; 155 CRT ) . Mucosal toxicity was worse in the accelerated arm , and it peaked approximately 3 weeks earlier than the conventional arm . Skin toxicity was equivalent but occurred approximately 7 days earlier in the accelerated arm . Acute effects in both arms healed completely . Hospitalization was more common in the ART arm ( 71 vs 52 patients ; P = 0.01 ) but the total bed days in hospital was not greatly different ( 1707 bed days for ART and 1607 bed days for CRT ) . Patients were more likely to require nasogastric ( NG ) feeding in the ART arm ( 49 vs 33 patients ; P = 0.02 ) . There were 1157 NG feeding days for ART and 1154 NG feeding days for CRT . The average cost of radiation treatment per patient including hospitalization , NG feeding and accommodation was $ 11,750 in the ART arm and $ 11,587 in the CRT arm . The accelerated arm has been shown to be a tolerable , practical and cost-equivalent regimen . The assessment of the therapeutic ratio of this accelerated protocol ( ART ) will be determined when the analysis of late effects and loco-regional control is made when the data are more mature 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 Aims and Background To compare conventional fractionation ( CF ) radiation therapy ( RT ) , arm A , versus a split-course accelerated hyperfractionated schedule ( S-AHF ) , arm B , versus CFRT plus concomitant chemotherapy ( CT ) , arm C , in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx . Methods and Study Design Between January 1993 and June 1998 , 192 previously untreated patients with stage III and IV oropharyngeal carcinoma ( excluding T1N1 and T2N1 ) were enrolled in a multicenter r and omized phase III trial ( ORO 93 - 01 ) . In arms A and C , 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks . In arm B , the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day , five days a week , with a planned two-week split at 38.4 Gy . In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil ( CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v . on days 1 to 4 every 28 days ) . Results No statistically significant difference was found in five-year overall survival ( P = 0.39 ) : 21 % for arm A , 21 % for arm B , and 40 % for arm C. Similarly , there was no statistically significant difference in terms of five-year relapse-free survival : 15 % for arm A , 17 % for arm B , and 36 % for arm C. There was a slight trend towards better five-year locoregional control ( P = 0.07 ) for the combined arm : patients without locoregional relapse were 48 % in arm C , 21 % in arm A and 18 % in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined ( P = 0.02 ; arm A+B 20 % ; arm C 48 % ) . Distant metastases were fairly balanced in the three arms ( A : 14 ; B : 9 ; C : 11 ) , with a tendency towards more frequent isolated distant metastasis development in arm C ( 8 of 11 [ 72 % ] versus 7 of 23 [ 30 % ] in arms A+B ) . Five-year second-tumor-free survival was 85 % . The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption ( five lung , two esophagus , two oral cavity , one larynx , one pancreas , one hepatocarcinoma , one myeloma ) . Arm C showed slightly more G3 + late side effects involving subcutaneous tissues and mucosa , although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient . The occurrence of persistent G3 xerostomia was comparable in the three treatment arms . Conclusions The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance , but combined treatment almost doubled the five-year overall survival , relapse-free survival and locoregional control rate .  Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy . The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death PURPOSE Toxicity of an accelerated 7 days per week fractionation schedule ( arm A ) was evaluated and compared with a conventional 5 days per week treatment ( arm B ) in a r and omized trial . MATERIAL S AND METHODS Forty-four patients with squamous cell carcinoma of the head and neck in stage T2 - 4Nzero-1Mzero were included in the study . Total dose and dose per fraction of 2.0 Gy given once-a-day at 24 h intervals were the same in both arms of the trial . The only difference was the overall treatment time being 5 weeks in arm A and 7 weeks in arm B. RESULTS Analysis of severe mucosal reactions shows significant difference between arm A and B , with regard to both maximum score and duration of severe mucositis . Confluent mucositis ( score > 15 according to the Dische system ) lasting longer than 3 weeks developed in 48 % of patients in arm A and only in 5 % in arm B. In group A seven ( 30 % ) late effects ( osteo- and soft tissue necrosis ) occurred during 7 - 12 month follow-up with two reactions ( 10 % ) in group B being suspected as late effects . There was significant association between acute reactions and late effects in arm A , suggesting that the late effects are consequential . CONCLUSION The high incidence of severe acute reactions and consequential late effects suggests that the accelerated treatment in arm A ( using daily fractions of 2.0 Gy , 7 days per week ) gives unacceptable toxicity Squamous cell carcinomas of the oropharynx are among the sites within the upper aerodigestive tract most consistently treated with radiation therapy . The ability to observe directly the response to radiation therapy and to document local-regional control and failure result in their being excellent sites to investigate modifiers of radiation effects A r and omised phase II trial was initiated to explore the feasibility of concomitant cisplatin and radiotherapy with conventional fractionation ( CF ) or multiple fractions per day ( MFD ) for patients with locally advanced head and neck malignancies . The MFD schedule was design ed to achieve higher tumour concentrations of cisplatin at the time of irradiation by reducing the number of radiation treatment weeks from 7 to 3 , allowing recovery from side-effects of both irradiation and cystostatic drugs during the rest periods , while keeping the same total dose and overall treatment time . Patients were r and omised between a conventional fractionation scheme ( CF ) of 70 Gy in 7 weeks with 2 Gy per fraction with a daily dose of 6 mg/m(2 ) cisplatin and a modified fractionation scheme ( MFD ) delivering three fractions of 1.6 Gy per day , in weeks 1 , 4 and 7 , keeping the same overall treatment time and total dose . In the modified treatment regime , a daily dose of 10 mg/m(2 ) cisplatin was administered . 53 patients were entered in this trial and radiotherapy was given according to the schedule to all patients in both treatment arms . Cisplatin was given during the whole course of radiotherapy to only one quarter of the patients in the CF arm , stopping mostly after 5 - 6 weeks due to bone marrow depression and kidney toxicity , while patients in the MFD arm received it according to schedule . No difference was observed in acute and late toxicity in both treatment arms , while a similar or even better tumour response was obtained with MFD . A 67 % higher daily dose of cisplatin concomitant with irradiation could be given in a 3-week multiple fractionation per day schedule , as opposed to the cisplatin given in the conventional daily fractionation schedule of 7 weeks with the same total radiation dose . Similar acute and late toxicities were seen in both treatment arms Hyperfractionated radiation therapy ( HFX ) attempts to overcome tumor proliferation during treatment by permitting higher total doses in the same overall time as st and ard fractionation . Whereas interruptions , including splits , reduce local control with st and ard fractionation in carcinoma of the upper respiratory and digestive tracts , HFX might compensate for interruptions . Patients were r and omized to receive total doses of 6720 , 7200 , 7680 , and 8160 cGy , using 120 cGy twice daily , 5 days per week . Those analyzed received ± 4 % of assigned total dose and lived 90 days or more . Treatment was completed within 5 days of the time specified for each treatment arm in 233 patients ; 48 , 80 , and 131 patients had delays 14 , 10 , and 5 days or more , respectively . Locoregional control and survival were significantly ( P ≤ 0.03 ) reduced with delays of 5 days or more when corrected for prognostic factors . Late effects of radiation therapy were not affected by interruptions . These data support the hypothesis that proliferation ( possibly accelerated ) of tumor clonogens during treatment influences the outcome . Cancer 1992 ; 69:2744‐2748 A prospect i ve , r and omized Phase Ilate/II trial of hyperfractionated radiation therapy was conducted : 1.2 Gy minimum tumor dose was administered twice daily with a minimum interval of 4 hr , 5 days per week . Patients with Stage III and IV carcinomas of the oral cavity , oropharynx , nasopharynx , hypopharynx , and supraglottic larynx were stratified by site , presence or absence of nodal metastases , and performance status . They were assigned to four total doses between 67.2 Gy and 81.6 Gy to all known tumors . The highest dose arm was opened after preliminary assessment indicated acceptable late morbidity rates with the three lower doses . Of 479 patients entered , 260 patients were r and omized to the three lower total doses and 237 were analyzed for this preliminary report : 63 were assigned to receive 67.2 Gy , 58 to 72.0 Gy , and 116 to 76.8 Gy . Estimates of grade 4 necrosis at 2 years were 10.0 % , 5.1 % , and 13.9 % , respectively , for patients who received total doses of 67.2 Gy , 72.0 Gy , and 76.8 Gy . There was a suggestion of a trend toward increased local control at 24 months ( Kaplan-Meier estimates of 25 % for 67.2 Gy , 37 % for 72.0 Gy , and 42 % for 76.8 Gy ) ( p = .08 ) . No difference was observed in survival . Assessment of the results using Cox regression models to correct for slight inequalities of pretreatment prognostic variables supported a total dose-tumor control relationship ( p = .054 ) . Results for the lowest dose arm were comparable to previous RTOG studies of common fractionation with similar total doses . The higher local control rates with 72.0 and 76.8 Gy using hyperfractionated radiation therapy suggest an improvement in outcome with radiation therapy for advanced carcinomas of the upper aerodigestive tracts . These preliminary findings have led to a Phase III comparison of hyperfractionated radiation therapy with 1.2 Gy b.i.d . with st and ard fractionation Three hundred and twenty-seven patients with inoperable squamous cell carcinomas of the head and neck were entered on a r and omized study comparing a mixture of neutron and photon ( " mixed beam " ) radiation therapy with photon/electron radiation therapy . Neutron treatment was delivered with fixed-beam , physics-laboratory-based equipment . Patients with histologically proven tumors of T-stage T2 , T3 , or T4 and any N-stage were eligible for r and omization . Primary tumor sites were limited to cancers originating in the oral cavity , oropharynx , supraglottic larynx , or hypopharynx . Patients entered on this study now have a minimum at-risk follow-up period of 6 years . Study results reveal no significant differences in overall loco-regional tumor control rates or survival . Subgroup analysis reveals significant differences based on whether or not patients presented with positive lymph nodes . Loco-regional tumor control rates for patients presenting with positive lymph nodes were 30 % for mixed-beam-treated patients versus 18 % for photon-treated patients ( p = 0.05 ) . Loco-regional tumor control rates for patients presenting without positive lymph nodes were 64 % for photon-treated patients and 33 % for mixed-beam-treated patients ( p = 0.004 ) . Control of tumor located in the nodal sites favored mixed beam over photons by a margin of 45 % ( 49/109 ) to 26 % ( 23/87 ) with a significance of p = 0.004 . Possible explanations for these contradictory findings are discussed The Radiation Therapy Oncology Group conducted a prospect i ve comparison of a compensated split course radiotherapy technique ( 300 cGy x 10 , 3 weeks rest , 300 cGy X 10 ) . versus continuous radiotherapy ( 200–220 cGy up to 6000–6600 cGy ) , in 137 evaluable patients . The complete response ( CR ) was 57 % in 63 patients , treated with the split-technique vs 61 % in 74 patients su bmi tted to continuous course radiotherapy . The completion of therapy as planned was better in the split-technique , but acute and late tissue reactions were the same . Locoregional control of tumor at 5 years was 25 % for split and 28 % for continuous therapy . At 7 years this was 25 % and 24 % , respectively . Absolute survival in the split-course patients tended to be lower than in the continuous group , but when the sample of patients was enlarged by the addition of cases from similar trials of nasopharynx and base of tongue lesions , the survival difference was eliminated . On the basis of the results of this study we conclude that the stated compensated split-course technique gives equal clinical results as conventional continuous therapy , with the advantage of requiring fewer radiation fractions , and less burden on the patient and therapy facilities 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 The need for new methods of treatment to be compared with others by objective means is stressed . R and omized clinical trials are markedly superior to retrospective or to nonr and omized comparisons . Despite the difficulties , patients with tumours of the same stage , histology and site should be r and omized between the new treatment and the best alternative in order to assess the real value of treatments as quickly as possible . Such a prospect ively r and omized clinical trial has been completed on 126 patients with advanced squamous cell carcinomas of the head and neck in which treatments with 7.5 MeV fast neutrons were compared with radiation from X or gamma rays ( photons ) . The neutron treated patients received the st and ard dose of 1560 rads given in 12 treatments over 4 weeks and all were treated on the MRC Cyclotron  at Hammersmith Hospital . Forty per cent of the photon patients were treated at Hammersmith and the rest at the collaborating hospitals . The doses ranged from 4540 to 6840 rads in periods of 4 - 6 weeks . The proportion of patients whose tumours clinical ly completely regressed was nearly twice as great in the neutron series ( 77 % ) as in the photon series ( 43 % ) and only one tumour recurred in the neutron series compared with 15 in the photon group . The benefit to the neutron treated patients was most marked in the buccal cavity ( p = 0.001 ) , the oropharynx ( p = 0.004 ) and cervical nodes ( p = 0.01 ) . Neutrons gave the least advantage to tumours in the hypopharynx , persisting control being seen in 9 neutron and 3 photon patients ( p = 0.10 ) . There were 4  neutron complications compared with one in the photon series and the one  neutron recurrence was in this site . There were also more complications in the neutron treated oropharyngeal tumours and these were mostly aspiration following regression of large tumours which had already caused extensive damage . The actuarial percentages surviving at 1 year were 53 % ( neutron ) and 42 % ( photon ) and at 2 years these figures were 28 % and 15 % respectively . These differences are not statistically significant . Fifteen neutron treated patients , and 14 of those receiving photons , underwent surgery because they had signs of residual or recurrent tumour after the course of radiation . There were 4 fatal complications in the neutron series and 3 in the photon series ; healing was normal in 8 and 9 respectively . However tumour was present in only 5 of the neutron specimens compared with 13 in the photon treated patients . Three of the 4 fatal complications in the neutron series occurred after operations where the specimen removed showed no malignancy PURPOSE To up date 5-year results of a previously published study on special 7-days-a-week fractionation continuous accelerated irradiation ( CAIR ) for head- and -neck cancer patients . METHODS AND MATERIAL S One hundred patients with squamous cell carcinoma of head and neck in Stage T(2 - 4)N(0 - 1)M(0 ) were r and omized between two definitive radiation treatments : accelerated fractionation 7 days a week including weekends ( CAIR ) and conventional 5 days a week ( control ) . Hence the overall treatment time was 2 weeks shorter in CAIR . RESULTS Five-year local tumor control was 75 % in the CAIR group and 33 % in the control arm ( p < 0.00004 ) . Tumor-cure benefit corresponded with significant improvement in disease-free survival and overall survival rates . Confluent mucositis was the main acute toxicity , with the incidence significantly higher in CAIR patients than in control ( respectively , 94 % vs. 53 % ) . When 2.0-Gy fractions were used , radiation necrosis developed in 5 patients ( 22 % ) in the CAIR group as a consequential late effect ( CLE ) , but when fraction size was reduced to 1.8 Gy no more CLE occurred . Actuarial 5-year morbidity-free survival rate was similar for both treatments . CONCLUSIONS Selected head- and -neck cancer patients could be treated very effectively with 7-days-a-week radiation schedule with no compromise of total dose and with slight 10 % reduction of fraction dose ( 2 Gy-1.8 Gy ) , which article gives 1 week reduction of overall treatment time compared with st and ard 70 Gy in 35 fractions over 47 - 49 days . Although this report is based on the relatively small group of patients , its results have encouraged us to use CAIR fractionation in a st and ard radiation treatment for moderately advanced head- and -neck cancer patients PURPOSE Accelerated re population of tumor cells during radiotherapy has been suggested as an important cause of treatment failure in squamous cell carcinoma of the head and neck . Due to tumor heterogeneity , not all tumors may benefit from accelerated radiotherapy at the expense of a lower total dose . This analysis evaluates the impact of histological differentiation on loco-regional control in relation to treatment duration . PATIENTS AND METHODS A total of 501 patients with advanced supraglottic and pharyngeal squamous cell carcinoma with known histopathological grading were treated with planned split-course ( 191 patients ) or continuous radiotherapy ( 310 patients ) in two consecutive r and omized controlled trials . Irradiation was given 2 Gy per fraction , 5 fractions per week to a dose of 66 - 68 Gy in 9.5 or 6.5 weeks , respectively . RESULTS Overall , split-course and continuous treatment result ed in a 5-year loco-regional control of 30 % and 41 % ( P = 0.007 ) , respectively . However , the detrimental effects of split-course were only found in moderately and well-differentiated tumors , where the 5-year tumor controls were 38 % and 21 % after continuous and split-course treatment , respectively ( P = 0.001 ) . In contrast , in poorly differentiated tumors loco-regional control was obtained in 44 % of the cases for continuous and 40 % for split-course treatment ( P = 0.63 ) . CONCLUSIONS It is suggested that the ability to accelerate re population may be lost by dedifferentiation , and that prolongation of the overall treatment time only lead to reduced loco-regional control in well to moderately differentiated tumors PURPOSE To define further the role of concurrent chemoradiotherapy for patients with advanced squamous carcinoma of the head and neck . PATIENTS AND METHODS The Radiation Therapy Oncology Group developed this three-arm r and omized phase II trial . Patients with stage III or IV squamous carcinoma of the oral cavity , oropharynx , or hypopharynx were eligible . Each of three arms proposed a radiation schedule of 70 Gy in 35 fractions . Patients on arm 1 were to receive cisplatin 10 mg/m(2 ) daily and fluorouracil ( FU ) 400 mg/m(2 ) continuous infusion ( CI ) daily for the final 10 days of treatment . Treatment on arm 2 consisted of hydroxyurea 1 g every 12 hours and FU 800 mg/m(2)/d CI delivered with each fraction of radiation . Arm 3 patients were to receive weekly paclitaxel 30 mg/m(2 ) and cisplatin 20 mg/m(2 ) . Patients r and omly assigned to arms 1 and 3 were to receive their treatments every week ; patients on arm 2 were to receive their therapy every other week . RESULTS Between 1997 and 1999 , 241 patients were entered onto study ; 231 were analyzable . Ninety-two percent , 79 % , and 83 % of patients on arms 1 , 2 , and 3 , respectively , were able to complete their radiation as planned or with an acceptable variation . Fewer than 10 % of patients had unacceptable deviations or incomplete chemotherapy in the three arms . Estimated 2-year disease-free and overall survival rates were 38.2 % and 57.4 % for arm 1 , 48.6 % and 69.4 % for arm 2 , and 51.3 % and 66.6 % for arm 3 . CONCLUSION We have demonstrated that three different approaches of concurrent multiagent chemotherapy and radiation were feasible and could be delivered to patients in a multi-institutional setting with high compliance rates PURPOSE To compare the efficacy of fast-neutron radiotherapy with that of conventionally fractionated photon therapy in the management of patients with locally advanced squamous cell carcinoma of the head and neck . METHODS AND MATERIAL S Patients with Stage III or IV disease were r and omized to receive either 20.4 Gy/12 fractions/4 weeks of neutrons or 70 Gy/35 fractions/7 weeks of photons ( control ) .  Between April 1986 and March 1991 , 178 patients were entered , 169 of whom were eligible for analysis . The treatment arms were balanced for age , stage , and performance status , but not for primary site of origin . RESULTS Complete response occurred in 70 and 52 % with neutrons and photons , respectively ( p = 0.006 ) . Local regional failure at 3 years for all patients was 63 % for neutrons and 68 % for photons .  Actuarial overall survival curves were virtually identical in both study arms , falling to 27 % at 3 years . Acute toxicity was similar in the two arms , but late grade 3 - 5 toxicity was 40 % with neutrons compared to 18 % with photons ( p = 0.008 ) . CONCLUSION Although the initial response rate was higher with neutrons , permanent local control and survival were not improved , and the incidence of late normal tissue toxicity was increased . As a result , fast-neutron therapy for advanced squamous cell carcinoma of the head and neck can only be recommended for patients in whom the logistic benefit of treatment in 12 sessions over 4 weeks outweighs the increased risk of late toxicity From August 1979 to June 1983 , the RTOG conducted a prospect i ve Phase III study that compared a st and ard schedule with five fractions per week of 180 to 200 cGy per day to a total dose of 6600 - 7380 cGy , with a hyperfractionation regimen consisting of two fractions of 120 cGy per day , separated by a rest period of 3 to 6 hours for a total of 6000 cGy . A total of 210 patients were entered , of which 187 are analyzed .  Complete initial tumor clearance in the head and neck was achieved by radiotherapy in 61 % of the patients assigned to the st and ard schedules and in 59 % of those assigned to the continuous hyperfractionation schedule ; surgical salvage contributed towards achieving complete response in 5 % and 7 % of patients , respectively . The Kaplan-Meier estimates for loco-regional control of tumor at 1 and 2 years was 39 % and 29 % for the st and ard schedules , and 43 % and 30 % for the hyperfractionation schedule . The endpoints examined to evaluate therapeutic effects do not indicate that the stated hyperfractionation schedule is different than the st and ard RTOG treatment schedule for head and neck cancer . Acute normal tissue reactions appear to be more severe with the hyperfractionation schedule but the incidence of late reactions is similar in both groups . There is a tendency toward more severe acute reactions when the interval between the two fractions per day is 4.5 hrs or less in comparison to intervals longer than 4.5 hrs A r and omized trial of fast neuron therapy compared with 4MV photons for patients with head and neck cancer is reported . One hundred and sixty-eight patients were recruited between 1977 and 1984 . The minimum follow-up is 2 years . Three patients were withdrawn before treatment began . Eighty-five were allocated to neutron therapy and 80 to receive photon therapy .  All patients had squamous cell cancers in one of four primary sites : oral cavity , oropharynx , larynx , and hypopharynx . Local tumor control was similar in both groups : 44.7 % after neutrons and 45.0 % after photons . Salvage surgery was performed on 18 patients in each treatment group for residual or recurrent cancer . Acute radiation reactions of the mucous membranes were significantly more severe after photons . The number of patients with serious late reactions was greater after neutron therapy but the difference was not statistically significant . There were six deaths related to late morbidity after neutron therapy but none after photon therapy .  Survival was better after photon therapy but the difference compared with the neutron group failed to reach statistical significance . When intercurrent deaths are excluded , the difference is less marked . Photon therapy was clearly better in terms of disease-free survival giving a 2-year local disease-free rate of 41.3 % ( s.e . 5.5 % ) compared with 29.4 % ( s.e . 4.9 % ) after neutrons 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 From October 1990 to March 1994 , 90 patients entered a prospect ively r and omised trial in head and neck cancer . All patients had verified squamous cell carcinoma and were referred for primary radiation therapy .  Tumours originated in the oral cavity in 25 , oropharynx in 37 , larynx in 15 and hypopharynx in 13 cases . Patients ' stages were predominantely T3 and T4 ( 71/90 ) and had lymph node metastases ( 60/90 ) . Seventy-nine male patients and 11 female patients , with a median age of 57 years ( range 37 - 76 years ) were treated . Patients were r and omised to one of three treatment options : conventional fractionation ( CF ) consisting of 70 Gy in 35 fractions over 7 weeks or continuous hyperfractionated accelerated radiation therapy ( Vienna-CHART ) or Vienna-CHART with administration of a single dose of mitomycin C on day 5 of treatment ( V-CHART + MMC ) . By the accelerated regimen a total dose of 55.3 Gy was given in 33 fractions within 17 consecutive days . Acute mucositis was the main toxicity recorded in those patients treated by accelerated fractionation , although the overall duration of mucosal reaction did not differ in the three treatment groups . There was no influence on local toxicity if MMC was added to radiation therapy or not . Those patients treated with additional MMC experienced a grade III/IV haematological toxicity in 4/28 cases . Complete remission ( CR ) was recorded in 48 % following CF , 79 % after Vienna-CHART ( P < 0.05 ) and 71 % after Vienna-CHART + MMC . The overall local failure rates were 73 % , 59 % and 42 % ( P = NS ) for patients treated by CF , Vienna-CHART and Vienna-CHART + MMC respectively A critical review of the protocol variations in an RTOG prospect i ve r and omized multi-institutional clinical trial has been conducted . The objective of the review was to identify variables that might have affected the results of the study . Compliance with general guidelines and specific technical treatment parameters of the Split-Course Radiation Therapy Protocol for Carcinoma of the Base of the Tongue ( RTOG # 71 - 02 ) was analyzed . A + /- 5 % variation of the time-dose-fractionation factors , using the NSD and TDF formulae and their respective protocol ratios ( ratio between actual case NSD and TDF level and what the protocol recommended ) , has been defined as fully acceptable . Seventy-two percent of the 141 study cases were within this category . Minor variation has been defined as one result ing in a + /- 6 % to + /- 15 % deviation from the study values ( 15.3 % of cases ) . Major and unacceptable variation was a deviation of + /- 16 % or more from the research plan ( 12.7 % of cases ) . After identifying the different variations and correlating them with the clinical results , we conclude that these deviations did not affect the final results to a significant or identifiable degree A prospect ively r and omized clinical trial was undertaken to compare conventionally fractionated radiation therapy and high fractional dose irradiation in the treatment of advanced , surgically unresectable head and neck squamous cell carcinoma . Sixty-four patients were entered into the study between 1973 and 1979 and were r and omized to receive either 200 rad daily to total tumor doses of 6000 - 7000 rad in 6 - 7 weeks , or 400 rad daily to a total of approximately 4400 rad in 2 - 3 weeks . The distribution of patients between the two fractionation schedules was comparable regarding site of the primary tumor , extent of disease , degree of histologic differentiation and performance status . Twenty-nine of 31 ( 94 % ) patients in the 200 rad group and 29 of 33 ( 88 % ) in the 400 rad group has Stage IV disease . Twenty-six in the former group and 30 in the latter completed radiation therapy as planned . Acute skin and mucosal reactions occurred earlier in patients treated with 400 rad daily , but were of equivalent intensity and well within acceptable levels in both groups . No increase in late adverse effects was seen with high daily doses . Palliation of tumor-related symptoms and extent of tumor control were comparable in the two groups . Actuarial five year disease-free survival rates were approximately 10 % in both treatment groups with a mean follow-up period of 5 1/2 years . We conclude that high fractional dose irradiation is equivalent to conventionally fractionated radiation therapy in the treatment of advanced head and neck cancer A prospect i ve , r and omized , multi-institutional , Phase I(LE)/II trial of HFX was conducted by the RTOG between 1983 and 1987 . Patients with histologically proven , inoperable squamous cell carcinoma of the upper respiratory and digestive tracts stratified by site , nodal status , and performance status , were assigned to one of three arms , were assigned to one of three arms , 67.2 Gy , 72.0 Gy , or 76.8 Gy . Fractions of 1.2 Gy were given twice daily , 5 days per week : intervals of 4 to 8 hours were permitted between fractions . After acceptable rates of acute normal tissue effects were found , the r and omization was changed to evaluate a new higher total dose , 81.6 Gy . Of 479 patients entered , 447 were analyzed , 63 on 67.2 Gy , 129 on 72.0 Gy , 117 on 76.8 Gy , and 138 on 81.6 Gy . The treatment arms were well balanced with respect to pretreatment characteristics . Acute reactions consisted almost entirely of pseudomembranous inflammation . " Severe " ( Grade 3 ) acute reactions were reported in 33 % to 41 % and grade 4 reactions were found in 0 to 3 % of patients , with no differences in frequencies among the four arms . Toxicities that developed or persisted beyond 90 days after the first treatment ( 408 patients evaluable greater than 90 days ) did not differ among arms : grade 3 + reactions occurred in 10 % to 14 % , and grade 4 + effects ( necroses ) were reported in 5 % at 67.2 Gy , 3 % at 72.0 Gy , 7 % at 76.8 Gy , and 2 % at 81.6 Gy . Grade 3 + acute reactions occurred in 40 % of patients when the interfraction interval was less than or equal to 4.5 hours versus 31 % with greater than 4.5 hours ( p = .03 ) . Interfraction intervals less than or equal to 4.5 hours were associated with higher frequencies of grade 4 + late effects in all four arms , 8 % of 197 patients with less than or equal to 4.5 hours versus 1 % of 211 patients with greater than 4.5 hours . Estimates of late toxicity at 1 , 2 , and 3 years were 5.5 % , 9.8 % , and 15.4 % with intervals less than or equal to 4.5 hours , versus 1.7 % at all three periods for greater than 4.5 hours ( p = .006 ) . Local-regional control at 2 years was 25 % for the assigned dose of 67.2 Gy compared to 43 % to 45 % for the three higher doses ( p = .01 ) , but a similar comparison for survival showed no significant difference ( p = .35 ) . There was no evidence for an effect of interfraction interval on either local-regional control ( p = .38 ) or survival ( p = .28 ) . ( ABSTRACT TRUNCATED AT 400 WORDS 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 PURPOSE The objective of this study was to examine the incidence of late effects of hyperfractionated radiotherapy for head and neck cancer as a function of the dose delivered , as well as the daily interfraction interval . In addition , we wished to examine the influence of other prognostic factors including age , gender , primary site , T- and N-stage , and overall stage on the late effects of hyperfractionated radiotherapy . METHODS AND MATERIAL S Between 1983 and 1987 , 479 patients with advanced head and neck cancer were entered on a Phase ILE/II dose escalation trial of hyperfractionated radiotherapy . They were r and omly assigned to receive a dose of 67.2 , 72.0 , 76.8 , or 81.6 Gy , delivered at 1.2 Gy/fraction , twice a day ( BID ) , 5 days/week . Of the 451 analyzable patients , 399 patients who received > or = 64.8 Gy and had a follow-up > 90 days were eligible for this study .  Acute and late effects were scored with the RTOG/EORTC late radiation morbidity scoring scheme . For this analysis , patients were subclassified by the actual doses delivered and by an average daily interfraction interval of < or = 4.5 h or > 4.5 h. The incidence of late effects was estimated using a cumulative incidence approach . RESULTS Fifty-nine patients received 67.2 + /- 2.4 Gy , 119 received 72.0 + /- 2.4 Gy , 98 received 76.8 + /- 2.4 Gy , and 123 received 81.6 + /- 2.4 Gy . The proportion of patients treated with a daily interfraction interval of > 4.5 h was 32 , 50 , 43 , and 71 % , respectively . The four treatment groups were well balanced with respect to pretreatment characteristics . The median follow-up was 1.71 years ( range : 0.24 - 9.6 ) for all evaluable patients and 6.12 years for 85 alive patients . There was no significant difference in the incidence of late effects between the different dose levels . At 5 years , the cumulative incidence of late effects was 17 , 14 , 20 , and 13 % for grade 3 , and 7 , 3 , 7 , and 5 % for grade 4 . However , the incidence of late effects differed significantly with respect to daily interfraction interval . The cumulative incidence of grade 4 late effects increased from 6.3 % at 2 years to 7.5 % at 3 years to 8.0 % at 4 years and 8.6 % at 5 years with an interval of < or = 4.5 h , while it remained at a constant of 2.0 % with an interval of > 4.5 h during the same period ( p = 0.0036 ) . Multivariate analysis showed that among the prognostic factors examined , daily interfraction interval of < or = 4.5 h was the only significant independent prognostic factor for the development of grade 3 + or grade 4 late effects ( p = 0.0167 and p = 0.0013 , respectively ) . CONCLUSION Results of this r and omized Phase ILE/II trial of hyperfractionated radiotherapy in head and neck cancer showed no apparent dose-response relationship for late effects within the range of 67.2 - 81.6 Gy . Daily interfraction interval was a significant independent factor for the development of late effects in a multivariate analysis Purpose Radiotherapy ( RTx ) has been considered as the treatment for locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . However , with only conventional fractionation ( Cfx ) , response rates are relatively low . In this study , we report the results of hyperfractionation ( Hfx ) RTx with concurrent docetaxel , cisplatin and 5-fluorouracil ( TPF ) chemotherapy ( CTx ) in patients with locally advanced SCCHN and compare Hfx and Cfx RTx with concurrent TPF CTx . Methods Fifty patients with previously untreated stage III – IV SCCHN were entered into this study . Eligible patients received RTx delivered using arm 1 : Hfx at 1.2 Gy/fraction , twice daily , 5 days/week to 76.8 Gy/64 fractions , and arm 2 : Cfx at 2 Gy/fraction/day , 5 days/week to 70 Gy/35 fractions . Patients received 2 cycles CTx every 4 weeks . The doses were docetaxel 50 mg/m2 ( day 1 ) , cisplatin 60 mg/m2 ( day 4 ) , and 5-FU 600 mg/m2/day ( days 1–5 ) . Results The overall clinical response rate and the pathological CR were 100 % ( 25/25 ) and 84 % ( 21/25 ) in arm 1 , and 100 % ( 25/25 ) and 80 % ( 20/25 ) in arm 2 . Local – regional control was better significant in arm 1 than arm 2 ( P = 0.048 ) . There were also trend toward improved disease-free survival ( P = 0.059 ) and overall survival ( P = 0.078 ) in arm 1 . Mucositis was significantly more frequent in arm 1 ( P = 0.048 ) . Conclusion There were trend toward improved local – regional control , disease-free survival and overall survival in Hfx RTx with concurrent TPF CTx , compared to Cfx RTx with concurrent TPF CTx 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 PURPOSE To evaluate long-term late adverse events and treatment outcome of a r and omized , multicenter Phase III trial of continuous , hyperfractionated , accelerated radiotherapy ( CHART ) compared with conventional radiotherapy ( CRT ) in 918 patients with advanced squamous cell carcinomas of the head and neck . METHODS AND MATERIAL S Survival estimates were obtained for locoregional relapse-free survival , local relapse-free survival , overall survival , disease-specific survival , disease-free survival and for late adverse events . RESULTS The 10-year estimates ( + /-1 st and ard error ) for locoregional relapse-free survival , overall survival , disease-free survival , and disease-specific survival were 43 % + /- 2 % for CHART and 50 % + /- 3 % with CRT ( log-rank p = 0.2 ) ; 26 % + /- 2 % and 29 % + /- 3 % ( p = 0.4 ) , respectively ; 41 % + /- 2 % and 46 % + /- 3 % ( p = 0.3 ) , respectively ; and 56 % + /- 3 % and 58 % + /- 3 % ( p = 0.5 ) , respectively . There was a small but significant reduction in the incidence of slight or worse and moderate or worse epidermal adverse events with CHART ( p = 0.002 to 0.05 ) . Severe xerostomia , laryngeal edema , and mucosal necrosis were also significantly lower with CHART ( p = 0.02 to 0.05 ) . CONCLUSIONS Despite the reduction in total dose from 66 Gy to 54 Gy , control of locoregional disease and survival with CHART were similar to those with CRT . These findings , together with the low incidence of long-term severe adverse events , suggest that CHART is a treatment option for patients with low-risk disease and for those unable to withst and the toxicity of concurrent chemoradiotherapy Results of the first r and omized clinical trial to compare the effects of fast neutrons and those of x or gamma rays ( photons ) in treating patients with advanced tumours of the head and neck are reported . In 37 out of 52 patients treated with neutrons and 16 out of 50 treated with photons the local tumour completely regressed ; the tumour later recurred in nine of the 16 photon patients but in none of the 37 neutron patients . The advantages to the neutron-treated patients were seen in tumours of well and poorly differentiated histology and in each site . Complications after treatment did not differ significantly between the groups . Despite these substantial differences in local control of the tumour there were no significant differences in mortality between the series . A detailed study of the effective doses and the response of tumours and normal tissue in each series indicated that the improved results from neutron therapy were due to differences in the biological quality of the beam and not to the rather higher average effective dose in the neutron series . To assess the long-term effects of neutron treatment patients in earlier stages of disease and with smaller tumours should be included in the next phase of the trial Inoperable cases of advanced squamous cell carcinomas in the head and neck area which have a very poor prognosis are often treated by a combined radio- and chemotherapy . Tumor remissions up to 70 % are induced by both radiotherapy and chemotherapy alone ; an increase of the survival time is not reported . The present r and omized study investigates the efficacy of two therapy schemes , i.e. chemotherapy alone and chemotherapy combined with irradiation .  Tumor remissions of 75 % were achieved in 80 evaluable patients , the median remission period was four months and the median survival period eleven months . The survival curves do not show any dependence of the survial time on the size of tumor or metastases . Only responders had a significantly longer survival time than non-responders From January 1978 to January 1988 , 859 patients with T3-T4 , NO-3 , MO were r and omly allocated to receive either : Group A--60Co 60 , 60 Gy in 30 fractions ; Group B--60Co , 70.4 Gy in 64 fractions ; Group C--60Co , 60 Gy in 30 fractions plus chemotherapy ( 5 Fu , 250 mg/m2/IV every 2 days ) . Chemotherapy and radiotherapy were combined simultaneously . The average age was 56 years ; the male/female ratio was 802/57 . Median performance status ( ECOG scale ) was 1 ( range 0 - 2 ) . The TNM distribution as UICC criteria was T3 529 patients ; T4 330 patients ; No 217 patients ; N1 52 patients ; N2 319 patients ; and N3 271 patients . The primary sites were nasopharynx 92 , oral cavity 252 , hypopharynx 119 , larynx 310 , and others ( sinuses and unknown primary ) 86 . Complete response was achieved in 188/277 patients in Group A ( 67.8 % ) , 254/282 patients in Group B ( 90 % ) , and 289/300 in Group C ( 96.3 % ) . All patients were followed and statistical analysis shows a significant improvement in median duration of response , as well as survival for Groups B and C compared with Group A. No significant differences were seen between Group B and C. The acute toxicity was mucositis , skin toxicity , bone marrow depression . A mean temporary weight loss of 4.9 Kg was observed with a range of 2.3 - 10.5 Kg Short-course , high fractional dose radiation therapy was compared with the conventional protracted radiation schedule in the treatment of advanced ( stages III and IV ) head and neck cancer . Sixty-four patients with surgically unresectable squamous cell carcinoma were r and omized to receive either 6,000 to 7,000 rad in six to seven weeks or 4,000 to 4,800 rad in two to three weeks . The palliative benefits of irradiation were comparable in the two treatment arms , and complete tumor regression was observed in the majority of patients in both groups . There was no difference between the groups with regard to either short-term normal tissue radiation reaction or long-term complications .  High fractional dose irradiation appears to yield results equivalent to those of conventionally fractionated radiation therapy in advanced head and neck cancer and deserves further study both as primary treatment and in combination with surgery 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 AIMS To test the efficacy of an accelerated fractionation schedule ( concomitant boost ) against st and ard conventional fractionation in squamous cell carcinomas of the head and neck region in our patient population . MATERIAL S AND METHODS Patients were r and omised to receive either conventional radiotherapy with 2 Gy/fraction/day , to a dose of 66 Gy in 33 fractions over 6.5 weeks or accelerated radiotherapy in the form of concomitant boost to a dose of 67.5 Gy/40 fractions over 5 weeks ( phase 1 : 45 Gy/25 fractions/5 weeks and phase 2 : 22.5 Gy/15 fractions/3 weeks as a second daily fraction after a 6h gap ) . The primary and secondary end points were disease-free survival and locoregional control respectively . RESULTS The compliance was 97.2 % and 96.5 % in the concomitant boost and conventional arms , respectively . Patients treated with concomitant boost had a better 2-year disease-free survival ( 71.7 % vs 52.17 % , P=0.0007 ) and locoregional control rates ( 73.6 % vs 54.5 % , P=0.0006 ) than with conventional fractionation . On exploratory subgroup analysis , the oropharynx ( P<0.001 ) , T4 lesions ( P=0.017 ) , N+ disease ( P<0.001 ) and stage IV disease ( P<0.001 ) were statistically significant prognostic variables in favour of the concomitant boost arm . Grade 3 mucositis was seen in 35 % of patients in the concomitant boost arm , whereas in the conventional arm only 19 % of patients had grade 3 mucositis ( P=0.01 ) . The median radiotherapy duration in the concomitant boost arm was 36 days ( range 36 - 53 days ) , whereas in the conventional arm it was 46 days ( range 46 - 64 days ) . The mean gap in radiation treatment in the concomitant boost arm was 1.68 days ( range 0 - 14 days ) , whereas the mean gap in the conventional arm was 1.58 days ( range 0 - 14 days ) . CONCLUSIONS Concomitant boost is a therapeutically superior and logistically feasible accelerated radiotherapy regimen in advanced head and neck cancers , especially in the setting of a developing country BACKGROUND AND PURPOSE Fractionation strategies delivered over 4 weeks are of clinical and radiobiological interest because treatment is completed before radiotherapy ( RT ) induced clonogen proliferation commences in earnest approximately 3 to 4 weeks into a course of RT . We wished to test the clinical hypothesis that an increased total dose delivered over 4 weeks with smaller than st and ard doses per fraction in locally advanced squamous cell carcinoma ( SCC ) may result in relative protection of late responding tissues and an increased tumor control compared to a conventional daily course in the same overall time . MATERIAL S AND METHODS Between 1988 and 1995 a r and omized controlled trial employing RT alone was undertaken at the Princess Margaret Hospital that included 331 eligible patients with T3 or T4 N0 or any N-positive oropharynx , hypopharynx , or larynx primary SCC . RT was r and omly assigned to one of two 4 week schedules , either 51 Gy in 20 equal daily fractions , termed conventional fractionation ( CF ) , or 58 Gy in 40 equal fractions given twice per day as a hyperfractionated ( HF ) experimental arm . RESULTS The 5-year local relapse rate was reduced in the HF ( 41 % ) compared to the CF arm ( 49 % ) . This difference was marginally not significant ( p=0.082 ) when the effect was not adjusted . When the effect of the treatment was adjusted by Cox model for clinical factors that included N-category , ECOG performance status , site of disease , T-category , age , hemoglobin , and gender the HF achieved a significant effect ( p=0.02 ) . Survival ( 40 % vs. 30 % ) was also improved with HF compared to CF arm . This difference was only marginally not significant ( p=0.069 ) but again achieved statistical significance when the model was adjusted for clinical factors ( p=0.01 ) . Similar results were observed for disease free survival . Although reversible acute toxicity was increased with HF , the overall 5-year rate of grade 3 and 4 late toxicity for the CF was 10.5 % compared to 7.7 % in the higher dose HF arm . CONCLUSIONS HF delivered in 4 weeks permits enhanced RT doses achieving improved tumor control , without increased late toxicity , compared to daily fractionated radiotherapy in the same overall time PURPOSE With the aim to increase the dose intensity of radiation therapy ( RT ) , and subsequently the locoregional control rate , a very accelerated RT regimen was compared with conventional RT in a series of patients with head and neck squamous cell carcinoma ( HNSCC ) . PATIENTS AND METHODS Between 1994 and 1998 , 268 patients with T3 or T4 , N0 to N3 HNSCC ( staged by 1997 International Union Against Cancer criteria ) that was not eligible for surgery were r and omly assigned to receive either conventional RT , delivering 70 Gy in 7 weeks to the primary tumor and 35 fractions of 2 Gy over 49 days , or to receive very accelerated RT , delivering 62 to 64 Gy in 31 to 32 fractions of 2 Gy over 22 to 23 days ( 2 Gy/fraction bid ) . RESULTS The most common tumor site was the oropharynx and most of the patients ( 70 % ) had T4 and N1 to N3 tumors in 72 % of patients . The main patient and tumor characteristics were well-balanced between the two arms . The median total doses were 63 Gy ( accelerated ) and 70 Gy ( conventional ) , with a median overall time of 22 days and 48 days , respectively . Acute mucositis was markedly increased in the accelerated-RT arm ( P < .001 ) . The locoregional control rate was improved by 24 % at 6 years with accelerated RT . In contrast , disease-free survival and overall survival were not significantly different between the two arms . There was no difference in late effects between the two arms . CONCLUSION The very accelerated RT regimen was feasible and provided a major benefit in locoregional control but had a modest effect on survival BACKGROUND AND PURPOSE Continuous , hyperfractionated , accelerated radiotherapy ( CHART ) has shown promise of improved tumour control and reduced late morbidity in pilot studies and has now been tested in a multicentre r and omised controlled clinical trial . MATERIAL AND METHODS Patients with squamous cell cancer in the main sites within the head and neck region with the general exception of early T1 N0 tumours were entered into the study by 11 centres . There was a 3:2 r and omisation to either CHART , where a dose of 54 Gy was given in 36 fractions over 12 days , or to conventional therapy where 66 Gy was given in 33 fractions over 6.5 weeks . A total of 918 patients were included over a 5 year period from March 1990 . RESULTS ACUTE MORBIDITY : Acute radiation mucositis was more severe with CHART , occurred earlier but settled sooner and was in nearly all cases healed by 8 weeks in both arms . Skin reactions were less severe and settled more quickly in the CHART treated patients . TUMOUR CONTROL AND SURVIVAL : Life table analyses of loco-regional control , primary tumour control , nodal control , disease-free interval , freedom from metastasis and survival showed no evidence of differences between the two arms . In exploratory subgroup analyses there was evidence of a greater response to  CHART  in younger patients ( P = 0.041 ) and poorly differentiated tumours appeared to fare better with conventional radiotherapy ( P = 0.030 ) . In the larynx there was evidence of a trend towards increasing benefit with more advanced T stage ( P = 0.002 ) . LATE TREATMENT RELATED MORBIDITY : Osteoradionecrosis occurred in 0.4 % of patients after CHART and 1.4 % of patients after conventional radiotherapy . The incidence of chondritis or cartilage necrosis was similar in both arms . Life table analysis showed evidence of reduced severity in a number of late morbidities in favour of CHART . These were most striking for skin telangiectasia , superficial and deep ulceration of the mucosa and laryngeal oedema . CONCLUSION Similar local turnout control was achieved by CHART as compared with conventional radiotherapy despite the reduction in total dose from 66 to 54 Gy supporting the importance of re population as a cause of radiation failure . The effects seen in advanced laryngeal cancer and those related to histological differentiation need further study . Reduced late morbidity is a factor which together with patient preference should be considered in the decision as to the programme of radiotherapy to employ in the curative treatment of head and neck cancer 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 AND PURPOSE To analyse acute mucosal reactions in patients treated with continuous accelerated postoperative irradiation ( p-CAIR )  compared to  conventionally fractionated postoperative radiotherapy ( p-CF ) .  PATIENTS AND METHODS The patients were r and omly assigned to receive 63 Gy in 1.8 Gy fractions 7-days-a-week given over a period of 5 weeks ( n=88 ) , or 63 Gy in 1.8 Gy fractions given 5-days-a-week over 7 weeks ( n=87 ) . It represents 65 % of an overall trial size . Acute mucosal reactions were scored using modified Dische system . Polychotomous logistic regression was used to estimate the influence of the selected variables on maximum grade of mucositis , and percent of the body weight loss during radiotherapy . RESULTS The average maximum Dische score and percent of the patients with confluent mucositis were higher in patients treated with p-CAIR , compared to p-CF ( 13.3 vs. 10.8 and 54 vs. 27 % ) . Polychotomous logistic regression analysis revealed that fractionation scheme and tumour site have significantly influenced maximum Dische score . Tumour site ( laryngeal vs. other ) had even stronger influence on maximum Dische score than fractionation scheme . The average residual Dische score 8 weeks after radiotherapy was higher in p-CAIR compared to p-CF ( 2.1 vs. 1.4 ) , and was , most frequently , related to persistent mucosal erythema ( 70 vs. 57 % of pts . ) . No severe consequential toxicity of radiotherapy was observed , so far , in the trial . CONCLUSIONS While the incidence , intensity and duration of mucosal reactions was higher in p-CAIR than in p-CF the accelerated treatment can be considered tolerable with respect to acute toxicity . In both arms of the trial slight or moderate mucosal erythema was the most frequent acute side effect , which did not completely subside within 8 weeks after irradiation 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 PURPOSE To compare conventional fractionation radiation therapy ( RT ) , Arm A , vs. split-course accelerated hyperfractionated RT ( S-AHF ) , Arm B , vs. conventional fractionation RT plus concomitant chemotherapy ( CT ) , Arm C , in terms of survival and toxicity for advanced , unresectable epidermoid tumors of oropharynx . METHODS AND MATERIAL S Between January 1993 and June 1998 , 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma ( excluding T1N1 and T2N1 ) were accrued in a multicenter , r and omized Phase III trial ( ORO 93 - 01 ) . For Arms A and C , 66 - 70 Gy in 33 - 35 fractions , 5 days a week , were administered in 6.5 - 7 weeks to tumor and positive nodes . In Arm B , the dose delivered to tumor and involved nodes was 64 - 67.2 Gy , giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h , 5 days a week . At 38.4 Gy , a 2-week split was planned ; after the split , RT was resumed with the same modality . In Arm C , CT regimen consisted of carboplatin and 5-fluorouracil ( CBDCA 75 mg/m(2 ) , Days 1 - 4 ; 5-FU 1,000 mg/m(2 ) i.v . over 96 h , Days 1 - 4 , recycling every 28 days ( at 1st , 5th , and 9th week ) . RESULTS No statistically significant difference was detected in overall survival ( p = 0.129 ) : 40 % Arm A vs. 37 % Arm B vs. 51 % Arm C were alive at 24 months . Similarly , there was no statistically significant difference in terms of event-free survival ( p = 0.196 ) : 20 % for Arm A , 19 % for Arm B , and 37 % for Arm C were event free at 24 months . On the contrary , the 2-year disease-free survival was significantly different among the three arms ( p = 0.022 ) , with a superiority for Arm C. At 24 months , the proportion of patients without relapse was 42 % for Arm C vs. 23 % for Arm A and 20 % for Arm B. Patients in Arm A less frequently developed G3 + acute mucositis than their counterparts in Arm B or C ( 14.7 % vs. 40.3 % vs. 44 % ) . Regarding the CT-related acute toxicity , apart from 1 case of fatal nephrotoxicity , only hematologic G3 + ( Grade 3 or higher ) acute sequelae were observed ( World Health Organization scale ) , most commonly leukopenia ( 22.7 % ) . Arm C showed slightly more G3 + skin , s.c . tissue , and mucosal late side effects ( RTOG scale ) , although significant sequelae were relatively uncommon , and mucosal sequelae were most commonly transient . The occurrence of persistent G3 xerostomia was comparable in all three treatment arms . CONCLUSIONS The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas , by increasing disease-free survival . This improvement , however , did not translate into an overall survival improvement , and was associated with a higher incidence of acute morbidity The feasibility of using large fractions at weekly intervals in external radiotherapy was studied to try to reduce work load on the only /sup 60/CO teletherapy unit at the Cancer Hospital , Indore , India . Using the nominal st and ard dose ( NSD ) formula of Ellis , for six fractions at weekly intervals we decided to use 670 rad per fraction in patients with advanced disease . The responses were satisfactory and the treatment was tolerated well by patients . A r and omized clinical trial was conducted from May 1975 to June 1976 to evaluate this treatment schedule . Cancers of head and neck region , esophagus , breast , and uterine cervix were included in the trial . One hundred and sixty four patients were treated in the control group with conventional shedules and 177 in the trial group with weekly fractionation .  In all the sites the immediate responses of local lesions and lymph nodes and the normal tissue reactions were comparable in the control and trial groups . The weekly fractionation was tolerated better by the patients 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 BACKGROUND We aim ed to examine deficiencies in established methods of summarising adverse events , and to create a new reporting system ( TAME ) for summarising the toxicity burden of cancer treatment . TAME consoli date s traditional adverse-event data into three risk domains : short-term ( acute ) Toxicity ( T ) , Adverse long-term ( late ) effects ( A ) , and Mortality risk ( M ) generated by a treatment programme ( E = End results ) ; and assigns treatments to risk classes for each risk domain . METHODS We examined formally an established method for summarising adverse events ( the max- grade method ) in five trials of patients with head and neck cancer done between September , 1991 , and August , 2000 , by the Radiation Therapy Oncology Group ( RTOG ) that involved 13 treatment groups ( 2304 patients ) . We calculated TAME summary metrics that included time and multiplicity factors in the same patient groups . We compared relative T values with relative values for toxic effects from the max- grade approach . We also calculated the range of individual patient T scores in two groups from one of the trials ( the laryngeal-preservation trial ) . RESULTS The max- grade method systematic ally excluded 29 - 70 % of total reported high- grade ( grade 3 - 4 ) acute adverse events , contained progressive bias , and favoured higher toxicity programmes . Relative T values in the 13 treatment programmes tested showed an increase of almost 500 % in acute toxicity burden ( 100 - 590 ) between treatment groups compared with a 170 % increase ( 100 - 270 ) between treatment groups by use of the max- grade method . The difference between these two summary systems was statistically significant ( mean difference -102 [ 95 % CI -167 to -37 ] , p=0.005 , t test for paired differences ) . Four risk classes were design ated for acute and relative late effects : low ( 100 - 140 ) , moderate ( 150 - 390 ) , high ( 400 - 490 ) , and extreme ( > or=500 ) . The distribution of individual patient T scores showed that 82 ( 60 % ) patients who received concurrent platinum-radiotherapy for larynx preservation reported two or more high- grade events , and 34 ( 20 % ) reported four or more high- grade events ; these findings differed significantly from the distribution of individual patient T scores for patients who received radiotherapy alone , in which 32 ( 19 % ) reported two or more high- grade events and 3 ( 3 % ) reported four or more high- grade events ( p<0.0001 ) . The max- grade method also systematic ally excluded 26 - 48 % of high- grade ( grade 3 - 4 ) late adverse events . However , less variation was noted in the relative risk of late events ( 100 - 270 ) by the TAME method for late effects . INTERPRETATION Traditional methods for summarising adverse events systematic ally exclude important data , giving an inaccurate impression of the toxicity burden in complex multimodality trials . By contrast , T values use data on all high- grade adverse events . T values are proportional to the intensity of treatment , showing a 500 % increase between treatment groups in acute toxicity burden in RTOG trials of head and neck cancer done during this study interval . TAME reporting provides a concise and uniform method to compare relative risk among treatment options . Future studies should include testing the performance of the TAME system in additional data sets ( from different research organisations and disease sites ) , prospect i ve correlation of TAME endpoints with predefined outcome measures , and assessment of its usefulness in clinical decision making BACKGROUND In 1992 , we reported the first analysis of a r and omized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck . The results of that 3-year analysis indicated that the combined treatment had superior efficacy . PURPOSE After an additional 2 years of follow-up , we again compared the efficacy of the two treatment regimens , with attention paid to differences in overall survival , progression-free survival , and locoregional relapse-free survival . METHODS One hundred fifty-seven patients with untreated , unresectable squamous cell carcinoma of the head and neck were r and omly assigned to receive either chemotherapy ( four courses of cisplatin [ 20 mg/m2 ] and fluorouracil [ 200 mg/m2 ] , given daily for 5 consecutive days during weeks 1 , 4 , 7 , and 10 ) plus radiotherapy ( three courses of 20 Gy each , given in fractions of 2 Gy per day during weeks 2 - 3 , 5 - 6 , and 8 - 9 ) or radiotherapy alone ( 70 Gy total dose , given in fractions of 2 Gy per day , 5 days per week ) . Eighty patients received the combined therapy , and 77 were treated with radiotherapy alone . Responses , failures , and toxic effects associated with the two treatment regimens were compared . Overall survival , progression-free survival , and locoregional relapse-free survival were calculated according to the Kaplan-Meier method ; the logrank test was used to compare survival parameters between the two patient groups . Reported P values are two-sided . RESULTS As reported previously , toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects ; however , the incidence and severity of mucositis were nearly identical among patients in the two treatment arms . The combined treatment was associated with a statistically significant increase in the frequency of complete response ( i.e. , the disappearance of clinical ly detectable disease for at least 4 weeks ) ( 43 % for the combined-treatment group compared with 22 % for the radiotherapy-only group ; P = .037 , chi-squared test ) . Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24 % ( 95 % confidence interval [ CI ] = 14%-40 % ) and 10 % ( 95 % CI = 4%-24 % ) , respectively ( P = .01 , logrank test ) . The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21 % ( 95 % CI = 11%-37 % ) and 9 % ( 95 % CI = 3%-22 % ) , respectively ( P = .008 , logrank test ) . Finally , the 5-year estimates of locoregional relapse-free survival were 64 % ( 95 % CI = 36%-84 % ) in the combined-treatment group and 32 % ( 95 % CI = 10%-65 % ) in the radiotherapy-only group ( P = .038 , logrank test ) . CONCLUSIONS AND IMPLICATION S The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years . However , additional trials must be conducted before considering the combined approach as st and ard therapy for it . Since wholemeal Manitoba flour contains 3 - 8 to 3 - 9 mg iron/ 100 g , compared with 1 mg/100 g , in unsupplemented white bread , the amounts of iron absorbed from both types of bread are similar ( 0 11 mg/100 g from wholemeal and 0 09 mg/100 g from white flour ) . Further isotopic studies are needed to determine whether supplementation of white bread with elemental iron increases the absorption of iron . We suggest that supplementation of white bread with iron may be unnecessary as the higher iron absorption compensates for the lower iron content One hundred forty-one patients with carcinoma of the base of tongue were r and omized to receive either continuous course radiotherapy ( 6600 rad in 30/33 fractions over 7 - 8 weeks ) or split course therapy ( 3000 rad in 10 fractions over 2 weeks , a three-week rest , 3000 rad in 10 fractions over 2 weeks ) . Both treatment groups tolerated the treatment well , but the continuous course group required more treatment modifications . The results of therapy , as judged by control of primary tumor , control of metastatic lymph nodes , time to failure and overall survival were comparable in the two treatment groups We treated 114 patients with advanced inoperable head and neck cancer with a combined-modality protocol that included two cycles of chemotherapy followed by radiotherapy or three chemotherapy and in 18 patients with a radiosensitizing agent . At the beginning of the treatment all but one patient presented with a stage IV cancer . With a follow-up of 42 - 58 months , four patients are alive ( three from the radiosensitizing group and one of the chemotherapy group ) . Complete response after the radiosensitizing agent correlated with superior prolonged disease-free survival in comparison to complete responses after chemotherapy at the level of p less than 0.009 PURPOSE To establish the feasibility of performing split-course accelerated hyperfractionation ( AHFX-S ) and concomitant boost accelerated fractionation radiotherapy ( AFX-C ) for advanced head and neck cancer in a multi-institutional cooperative trial setting and to evaluate the tumor clearance rate and acute and late toxicity of these fractionation schedules . METHODS AND MATERIAL S Between February 1989 and January 1990 , 75 patients with Stage III or IV squamous cell carcinoma of the head and neck were r and omized to receive : ( a ) AHFX-S : 1.6 Gy/fraction , twice daily ( 6-h interval ) , 5 days/week , to a total dose of 67.2 Gy/42 fractions/6 weeks , with a 2-week rest after 38.4 Gy ; or ( b ) AFX-C : 1.8 Gy/fraction/day , 5 daily fractions/week to 54 Gy/30 fractions/6 weeks to a large field and 1.5 Gy/fraction/day to a boost field , 6 h after large field treatment during the last 11 treatment days , to a total dose of 70.5 Gy/41 fractions/6 weeks . Acute and late toxicities were scored according to the RTOG normal tissue reaction scales and tumor clearance was evaluated at completion of therapy and at regular intervals thereafter . RESULTS Of the 70 analyzable patients , 38 received AHFX-S and 32 received AFX-C. The two arms were balanced with respect to sex , age , T-stage , and Karnofsky Performance Status ( KPS ) . However , the AHFX-S arm had a higher proportion of oropharyngeal primaries ( 63 % vs. 44 % ) , and Stage IV disease ( 82 % vs. 50 % ) and lower proportion of oral cavity lesions ( 3 % vs. 22 % ) and N0 disease ( 16 % vs. 31 % ) than the AFX-C arm . The median follow-up was 2 years ( range : 0.03 - 4.87 years ) . Tolerance of both variants of accelerated fractionated radiotherapy was satisfactory . There was no significant difference in local-regional control , disease-free survival , or survival between the two arms . The 2-year local-regional failure rate , survival , and disease-free survival was 50 , 50 , and 40 % , respectively , for the entire group of patients . Acute radiation mucositis was increased in both arms . There was no significant difference in the incidence of grade 3 acute toxicities ( 63 % vs. 56 % ) and grade 3 ( 14 % vs. 14 % ) or grade 4 ( 6 % vs. 17 % ) late toxicities . Permanent grade 4 late toxicity was observed in 6 and 7 % of the patients , respectively . CONCLUSION Results of this r and omized Phase I/II trial showed that the two accelerated fractionated schedules studied can be successfully given in a multi-institutional cooperative trial . There was no significant difference in acute or late toxicities , local-regional control , disease-free survival , or survival in this small scale study . Therefore , a Phase III trial comparing the relative efficacy of these two accelerated fractionation schedules against st and ard fractionation and hyperfractionation has been activated Patients with untreated squamous cell cancer of the head and neck region were r and omized to receive either a boost of 25–30 Gy using photon-beam irradiation ( photons ) or an equivalent boost using neutron-beam irradiation ( neutrons ) . All patients received an initial 45–50 Gy of wide-field photon irradiation . A total of 57 patients was evaluable on the neutron arm and 58 were evaluable on the photon arm . The proportion of patients with complete responses was 60 and 64 % on the neutron and photon arms , respectively . The locally disease-free proportion at 2 years was estimated to be 20 and 31 % , and the 2-year survival was estimated to be 32 and 41 % , respectively . These differences are not statistically significant . There was a higher rate of severe complications on the neutron arm , 16 versus 7 % . Thus , there was no evidence that a neutron boost produces better initial tumor clearance , local tumor control , or survival than a photon boost , and it may produce more complications Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing chemotherapy ( DDP + bleomycin ) alone , multiple daily fractionated radiation therapy , and multimodality therapy consisting of chemotherapy plus multiple fractionated radiation therapy . Multimodal therapy gave a significantly higher response rate ( 69 % ) than either single-treatment modality . The use of a multiple daily dose fractionation allowed radiation therapy to be completed over 10 treatment days , and the addition of chemotherapy to the radiation treatment did not significantly increase toxicity . Patients receiving multimodal therapy also survived significantly longer ( median 50 weeks ) than those receiving single-modality therapy ( median 24 weeks ) PURPOSE Full-dose reirradiation combined with chemotherapy has been shown to be feasible after salvage surgery with acceptable toxicity . The Groupe d'Etude des Tumeurs de la Tête et du Cou and Groupe d'Oncologie Radiothérapie Tête Et Cou groups performed a r and omized study to assess its efficacy . PATIENTS AND METHODS Between 1999 and 2005 , 130 patients with head and neck cancer were treated with salvage surgery and r and omly assigned to full-dose reirradiation combined with chemotherapy ( RT arm ) or to observation ( a " wait and see " approach ; WS arm ) . Eligibility criteria were recurrence or a second primary tumor in a previously irradiated area , no major sequelae result ing from the first radiotherapy , good general condition , no distant metastasis , and salvage surgery with macroscopic complete resection . Patients in the RT arm received 60 Gy over 11 weeks combined with concomitant fluorouracil and hydroxyurea . RESULTS Sixty-five patients were r and omly assigned to each arm . There was no imbalance in the distribution of the main tumor and patients characteristics . The most serious acute toxicity in the RT arm was mucositis , attaining grade 3 or 4 in 28 % of patients . At 2 years , 39 % of patients in the RT arm and 10 % in the WS arm experienced grade 3 or 4 late toxicity according to Radiation Therapy Oncology Group criteria ( P = .06 ) . Disease-free survival ( DFS ) was significantly improved in the RT arm , with a hazard ratio of 1.68 ( 95 % CI , 1.13 to 2.50 ; P = .01 ) , but overall survival ( OS ) was not statistically different . CONCLUSION Full-dose reirradiation combined with chemotherapy after salvage surgery significantly improved DFS , but had no significant impact on OS . An increase in both acute and late toxicity was observed 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 A r and omized clinical trial was performed from 1964 to 1967 to compare the therapeutic results of split-course external beam radiotherapy with those of continuously fractionated treatment .  Altogether 439 consecutive patients with carcinoma of larynx , nasopharynx , hypopharynx , oropharynx , oral cavity , oesophagus and urinary bladder were included in the series . 227 patients received split-course treatment and 212 were treated by the continuous-course method .  In the split-course treatment there was a 2 - 3 weeks ' interruption after 25 - 30 Gy . This break was compensated by a 10 % increase in the total dose . For each tumour site local control and failure rates for the 2 treatment techniques were similar . No significant differences in 5- and 10-year survival were noted . Acute side effects were milder in all patients treated with split-course . The occurrence of late reactions was similar in both treatment groups . However , severe late reactions in the urinary bladder were somewhat more frequent in patients treated with split-course technique ; the difference was not statistically significant . We conclude that there were no significant differences in local control , long-term survival and late normal tissue reactions between the treatment groups . The acute normal tissue reactions were milder in the split-course treated groups . We still regard split-course as a useful treatment modality provided the interruption is compensated with about 10 % increase in total dose . However , more studies are needed to show which tumours proliferate during prolonged radiotherapy To evaluate quality ‐adjusted survival ( QAS ) of patients with locally advanced squamous cell carcinoma of the head and neck treated with 4 different radiation fractionation schedules Between January 1977 and February 1980 , 95 patients with inoperable squamous carcinomas of the head and neck were treated in a two-armed r and omized clinical trial comparing 1 ) mixed schedule irradiation using two neutron and three photon fractions per week and 2 ) st and ard photon irradiation .  Complete tumor regression was achieved in 80 % of patients treated with mixed-schedule irradiation , and in 68 % of patients treated with photons . The local control rate was 44 % in patients treated with mixed-schedule irradiation and 41 % in patients treated with photons . There were four complications of treatment in each treatment arm . Absolute survival was 20 % with mixed-schedule treatment and 17 % in photons . Actuarial analysis shows superior local control and survival rates with mixed-schedule irradiation over photons only in the first two years PURPOSE The aims of this analysis were to determine the effect of anaemia on loco-regional control , relapse-free survival , cause-specific survival , overall survival , and acute and late radiation therapy toxicity in patients with Stage III and IV squamous cell carcinoma of the head and neck treated with radiotherapy .  PATIENTS AND METHODS Between 1991 and 1998 , 350 patients were r and omly assigned to either conventional radiotherapy , ( 70 Gy in 35 fractions in 49 days ) or to accelerated radiotherapy ( 59.4 Gy in 33 fractions in 24 days ) . Patients were divided into two groups according to their haemoglobin level : a normal haemoglobin group ( > /=13 g/dl in males , > /=12 g/dl in females ) and a low haemoglobin group ( < 13 g/dl in males , < 12 g/dl in females ) . The influence of anaemia on cause-specific survival and the development of confluent mucositis independent of other variables was tested using Cox proportional hazards model . RESULTS Of 350 patients recruited to the trial , 238 had haemoglobin measurements and were eligible for inclusion in this secondary analysis . One hundred and ninety-three were considered to have normal haemoglobin , and 45 patients were considered to be anaemic . There were significant differences between the groups in loco-regional control , relapse-free survival , cause-specific survival and overall survival , with hazards ratios of 0.56 ( 95 % confidence interval ( CI ) 0.34 - 0.94 ) , 0.57 ( 95 % CI 0.35 - 0.92 ) , 0.49 ( 95 % CI 0.29 - 0.85 ) and 0.43 ( 95 % CI 0.26 - 0.70 ) in favour of the normal haemoglobin group . Using Cox proportional hazards modelling , haemoglobin level was a significant predictor of cause-specific survival in addition to disease site , stage , and Eastern Cooperative Oncology Group status . There were no statistically significant differences between the groups in the development of acute or late reactions . CONCLUSION Significant reductions in loco-regional control , disease-free survival , cause-specific survival and overall survival occur in the presence of anaemia . No significant differences in normal tissue toxicity have been identified in this analysis Abstract Between October 1972 and April 1979 , 187 patients with locally advanced head and neck tumors were treated with 50 MeV d→Be neutrons or with conventional treatment in the M. D. And erson Hospital-Texas A & M University variable energy cyclotron ( MDAH-TAMVEC ) program . Of these , 114 patients were treated in pilot studies and 73 in a r and omized clinical trial . In the pilot studies , 49 patients were treated with neutrons alone , 25 with mixed-beam irradiation ( two neutron and three photon fractions per week ) , and 40 with conventional treatment ( surgery , photons , or combined surgery and photons ) . There was no appreciable difference among patients in these studies with regard to local tenor control or servival . However , the patients in the conventional-treatment pilot study had less advanced disease than those in either of the other studies . The complication rates in the neutrons-only and conventional-treatment studies were significantly greater than the complication rate observed in the mixed-beam pilot study . In the r and omized clinical trial , 41 patients were treated with mixed-beam irradiation and 32 with photon irradiation . The preliminary results of this trial show a slight superiority with mixed-beam irradiation . In the mixed-beam group , 61 % had local tumor control , 7 % developed major complications , and 4996 were alive at the time of analysis ; whereas in the photon group , 47 % had local tumor control , 3 % developed major complications , and 25 % were alive at the time of analysis 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 ) PURPOSE This study was design ed to determine in a prospect i ve r and omized trial the optimal dose of conventionally fractionated postoperative radiotherapy for advanced head and neck cancer in relation to clinical and pathologic risk factors . METHODS AND MATERIAL S Between January 1983 and March 1991 , 302 patients were enrolled on the study . This analysis is based on the first 240 patients entered through September 1989 , of whom 221 ( 92 % ) had AJC Stage III or IV cancers of the oral cavity , oropharynx , hypopharynx , or larynx . The patients were stratified by postulated risk factors and r and omized to one of three dose levels ranging between 52.2 Gy and 68.4 Gy , all given in daily doses of 1.8 Gy . Patients receiving > 57.6 Gy had a field reduction at this dose level such that boosts were only given to sites of increased risk . RESULTS The overall crude and actuarial 2-year local-regional recurrence rates were 25.4 % and 26 % , respectively . Patients who received a dose of < or = 54 Gy had a significantly higher primary failure rate than those receiving > or = 57.6 Gy ( p = 0.02 ) . No significant dose response could be demonstrated above 57.6 Gy except for patients with extracapsular nodal disease in the neck in whom the recurrence rate was significantly higher at 57.6 Gy than at > or = 63 Gy . Analysis of prognostic factors predictive of local-regional recurrence showed that the only variable of independent significance was extracapsular nodal disease . However , clusters of two or more of the following risk factors were associated with a progressively increased risk of recurrence : oral cavity primary , mucosal margins close or positive , nerve invasion , > or = 2 positive lymph nodes , largest node > 3 cm , treatment delay greater than 6 weeks , and Zubrod performance status > or = 2 . Moderate to severe complications of combined treatment occurred in 7.1 % of patients ; these were more frequent in patients who received > or = 63 Gy . CONCLUSION With daily fractions of 1.7 Gy , a minimum tumor dose of 57.6 Gy to the whole operative bed should be delivered with a boost of 63 Gy being given to sites of increased risk , especially regions of the neck where extracapsular nodal disease is present . Treatment should be started as soon as possible after surgery . Dose escalation above 63 Gy at 1.8 Gy per day does not appear to improve the therapeutic ratio PURPOSE To evaluate the normal tissue reactions and loco-regional control rates ( LRC ) in patients treated with 7-days-a-week postoperative continuous irradiation ( p-CAIR ) compared to conventionally fractionated 5-days-a-week postoperative radiotherapy ( CF ) . MATERIAL S/ METHODS Between 2001 and 2004 , 279 patients with high-risk squamous cell cancer of the larynx ( 158 pts . ) or cancer of the oral cavity/oropharynx ( 121 pts . ) were enrolled . They were stratified according to the primary cancer site ( larynx vs. others ) and the treating center and r and omized to receive 63 Gy in fractions of 1.8 Gy given 5-days-a-week ( 140 pts : CF ) or 7-days-a-week ( 139 pts : p-CAIR ) . RESULTS The acute and late toxicity was considered acceptable , although the proportion of patients with confluent mucositis was higher in p-CAIR compared to CF ( 60.0 vs. 33.3 % ) . The actuarial 3-year LRC were 64 vs. 70 % for CF and p-CAIR , respectively , p=0.32 . A statistically significant improvement in 3-year LRC in p-CAIR arm appeared in a subset of the patients with cancer of the oropharynx/oral cavity ( 74 % p-CAIR vs. 53 % CF , p=0.02 ) . By contrast , there was no improvement in LRC in a subset of the patients with cancer of the larynx ( p=0.46 ) . CONCLUSION An improvement in LRC attributable to acceleration of postoperative radiotherapy appeared restricted to the patients with cancer of the oropharynx/oral cavity . In patients with cancer of the larynx acceleration of postoperative radiotherapy did not have any beneficial effect BACKGROUND Relationships between normal tissue reactions and tumor response to radiotherapy have generally been investigated in retrospective studies , with the attendant difficulties such as different times of treatment and lack of st and ard scales for scoring of normal tissue reactions . This study analyses the correlation between normal tissue reactions and tumor response in a r and omized trial of hyperfractionation versus conventional radiotherapy . MATERIAL S AND METHODS EORTC trial 22791 , which accrued 325 T2 - 3 , N0 - 1 and M0 oropharynx squamous cell carcinomas , compared conventional radiotherapy ( 70 Gy in 7 weeks ) to a hyperfractionated regime ( two daily irradiations of 1.15 Gy up to 80.5 Gy in 7 weeks ) . Acute and late toxicities were assessed according to the RTOG/EORTC scales . The variables were tumor regression at treatment completion , tumor control for unlimited follow-up , severity of acute mucosal reactions ( grade of the peak reaction , time to onset of grade 2 mucositis , or duration of acute reactions of grade 3 ) and severity of late effects in normal tissues ( late ulceration , cervical edema secondary to lymphatic drainage damage , late muscular fibrosis , or late mucosal necrosis as consequential damage ) . Kendall 's rank correlation was used to assess the levels of significance of the correlation . The 95 % confidence interval ( 95 % CI ) was calculated for each correlation tau-b coefficient . RESULTS Irradiation doses and overall treatment times were consistent between the treatment arms . The time to onset of patchy mucosal reactions was inversely correlated to tumor regression at treatment completion in the hyperfractionated arm ( arm 2 ) but not in the conventional fractionation arm ( arm 1 ) . The other significant correlations were restricted to the following pairs of end-points and patient subgroups : acute mucositis of grade 3 versus tumor regression at the end of treatment in arm 2 for T2 tumors , late ulceration versus tumor control in arm 2 and acute mucosal reactions versus late effects in normal tissues in arm 2 for T3 tumors . By and large , the 95 % CIs for Kendall 's tau-b included zero and did not include 0.5 , an indication that the comparison had sufficient power to detect a difference , if indeed one existed . CONCLUSIONS These results do not represent clinical evidence strong enough to demonstrate that individual differences in sensitivity influence the response of tumors to radiation Three hundred and twenty-two patients with inoperable squamous cell carcinomas of the head and neck were entered on a r and omized study comparing " mixed beam " radiation therapy with photon radiation therapy .  Patients with histologically proven tumors of T-stage T2 , T3 , or T4 and any N-stage originating in the oral cavity , oropharynx , supraglottic larynx , or hypopharynx were eligible . One hundred forty-five patients were r and omized to photon treatment  and 177 were r and omized to mixed beam treatment . No significant differences could be demonstrated between the experimental and control groups for primary tumor control or overall survival , although there was an advantage for mixed beam treatment over photon treatment for patients with metastatic cervical adenopathy ( 69 vs. 55 % complete response rate in the nodes , p = .024 ) . It is concluded that mixed beam radiation therapy does not offer a significant advantage over photon radiation therapy for patients with advanced squamous cell carcinomas of the head and neck 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 PURPOSE Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle , with most cells in the G(1 ) phase in the morning and M phase at night , we hypothesized that morning radiotherapy ( RT ) would lead to less oral mucositis than afternoon RT . METHODS AND MATERIAL S A total of 216 patients were r and omized to morning ( 8 - 10 AM ) vs. afternoon ( 4 - 6 PM ) RT  and stratified by radiation dose , smoking status , and center . Patients receiving primary or postoperative RT alone were eligible .  Oral mucositis was scored using the Radiation Therapy Oncology Group ( RTOG ) criteria and a vali date d scoring system . RESULTS Of 205 evaluable patients , 52.9 % vs. 62.4 % developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT , respectively ( p = 0.17 ) . Morning RT was also associated with significantly less weight loss after 5 months ( p = 0.024 ) . In a subgroup of 111 patients treated to a dose of 66 - 70 Gy in 33 - 35 fractions , exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT ( 44.6 % vs. 67.3 % , p = 0.022 ) and a longer interval to the development of Grade 3 or greater mucositis ( median , > 7.9 vs. 5.6 weeks , p = 0.033 ) . In 53 patients , who smoked during therapy , a significant reduction was found in Grade 3 or greater mucositis with morning RT ( 42.9 % vs. 76 % , p = 0.025 ) . CONCLUSION In this proof of principle study , morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving > /=66 Gy and in patients who smoked during therapy
BACKGROUND The management of advanced oral cavity and oropharyngeal cancers is problematic and has traditionally relied on surgery and radiotherapy , both of which are associated with substantial adverse effects .
Radiotherapy has been in use since the 1950s and has traditionally been given as single daily doses .
This method of dividing up the total dose , or fractionation , has been modified over the years and a variety of approaches have been developed with the aim of improving survival whilst maintaining acceptable toxicity .
OBJECTIVES To determine which radiotherapy regimens for oral cavity and oropharyngeal cancers result in increased overall survival , disease free survival , progression free survival and locoregional control .