Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. Radiotherapy Alone or with Concomitant Daily Low-Dose Carboplatin in Locally Advanced, Unresectable Head and Neck Cancer: Definitive Results of a Phase III Study with a Follow-Up Period of up to Ten Years Accelerated versus conventional fractionated postoperative radiotherapy for advanced head and neck cancer: results of a multicenter Phase III study. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II–III trial Adjuvant therapy with cetuximab for locally advanced squamous cell carcinoma of the oropharynx: results from a randomized, phase II prospective trial. Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. A randomized study of accelerated fractionation radiotherapy with and without mitomycin C in the treatment of locally advanced head and neck cancer. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers. Docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by chemoradiotherapy or chemoradiotherapy alone in stage III–IV unresectable head and neck cancer Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. Randomized phase III trial of concurrent chemoradiotherapy vs accelerated hyperfractionation radiotherapy in locally advanced head and neck cancer Long-Term Results of Conventional Radiotherapy versus Accelerated Hyperfractionated Radiotherapy versus Concomitant Radiotherapy and Chemotherapy in Locoregionally Advanced Carcinoma of the Oropharynx Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial. Concomitant cisplatin and radiotherapy in a conventional and modified fractionation schedule in locally advanced head and neck cancer: a randomised phase II EORTC trial. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Comparison of concomitant boost radiotherapy against concurrent chemoradiation in locally advanced oropharyngeal cancers: a phase III randomised trial. Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group (E2382). Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC). Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. Five year results of a randomized trial comparing hyperfractionated to conventional radiotherapy over four weeks in locally advanced head and neck cancer. Concomitant cisplatin and hyperfractionated radiotherapy in locally advanced head and neck cancer: 10-year follow-up of a randomized phase III trial (SAKK 10/94). Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial. Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. A Randomized, Multicenter, Phase II Study of Cetuximab With Docetaxel and Cisplatin as Induction Chemotherapy in Unresectable, Locally Advanced Head and Neck Cancer. Conventional radiotherapy versus concurrent chemoradiotherapy versus accelerated radiotherapy in locoregionally advanced carcinoma of head and neck: Results of a prospective randomized trial. Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Alternating chemoradiotherapy versus partly accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck A prospective comparision of sequential chemoradiation vs concurrent chemoradiation in locally advanced oropharyngeal carcinomas Randomized phase III trial comparing induction chemotherapy followed by radiotherapy to concomitant chemoradiotherapy for laryngeal preservation in T3M0 pyriform sinus carcinoma Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. Hyperfractionated accelerated radiation therapy (HART) of 70.6 Gy with concurrent 5-FU/Mitomycin C is superior to HART of 77.6 Gy alone in locally advanced head and neck cancer: long-term results of the ARO 95-06 randomized phase III trial. Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial Randomised Phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease.
PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival ( OS ) of patients with stage III or IV head and neck carcinoma ( HNC ) .  Cetuximab plus platinum regimens also increase OS in metastatic HNC . The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival ( PFS ) . PATIENTS AND METHODS Eligible patients with stage III or IV HNC were r and omly assigned to receive radiation and cisplatin without ( arm A ) or with ( arm B ) cetuximab .  Acute and late reactions were scored using Common Terminology Criteria for Adverse Events ( version 3 ) . Outcomes were correlated with patient and tumor features and markers . RESULTS Of 891 analyzed patients , 630 were alive at analysis ( median follow-up , 3.8 years ) . Cetuximab plus cisplatin-radiation , versus cisplatin-radiation alone , result ed in more frequent interruptions in radiation therapy ( 26.9 % v. 15.1 % , respectively ) ; similar cisplatin delivery ( mean , 185.7 mg/m2 v. 191.1 mg/m2 , respectively ) ; and more grade 3 to 4 radiation mucositis ( 43.2 % v. 33.3 % , respectively ) , rash , fatigue , anorexia , and hypokalemia , but not more late toxicity . No differences were found between arms A and B in 30-day mortality ( 1.8 % v. 2.0 % , respectively ; P = .81 ) , 3-year PFS ( 61.2 % v. 58.9 % , respectively ; P = .76 ) , 3-year OS ( 72.9 % v. 75.8 % , respectively ; P = .32 ) , locoregional failure ( 19.9 % v. 25.9 % , respectively ; P = .97 ) , or distant metastasis ( 13.0 % v. 9.7 % , respectively ; P = .08 ) . Patients with p16-positive oropharyngeal carcinoma ( OPC ) , compared with patients with p16-negative OPC , had better 3-year probability of PFS ( 72.8 % v. 49.2 % , respectively ; P < .001 ) and OS ( 85.6 % v. 60.1 % , respectively ; P < .001 ) , but tumor epidermal growth factor receptor ( EGFR ) expression did not distinguish outcome . CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely . PFS and OS were higher in patients with p16-positive OPC , but outcomes did not differ by EGFR expression Aim and background Radiotherapy is the conventional treatment for locally advanced inoperable head and neck squamous cell carcinoma . However , the poor therapeutic results justify the development of radiochemotherapy combinations . In an attempt to improve local control and survival in patients with stage III and IV unresectable head and neck squamous cell carcinoma and based on the results of our previous dose escalation study , we undertook a prospect i ve multicentric r and omized trial . Material s and methods From November 1992 through December 1995 , a total of 164 patients were r and omized to receive radiotherapy alone ( arm I ) or combined ( arm II ) with daily low-dose carboplatin . Results The 3 , 5 and 10-year local-regional recurrence-free survival rates were better in arm II(21.7 % , 15.1 % and 15.1 % , respectively ) than in arm I ( 15 % , 10.7 % and 10.7 % ) , but without statistical significance ( P = 0.11 ) . The 3 , 5 and 10-year disease-free survival rates showed the same positive trend for arm II ( 16 % , 6.8 % and 6.8 % vs 9 % , 5.5 % and 5.5 % , in arm I , respectively ) , again without statistical significance ( P = 0.09 ) . Instead , a statistical advantage was found in overall survival rates at 3 , 5 and 10-years ( 28.9 % , 9 % and 5.5 % in arm II and 11.1 % , 6.9 % and 6.9 % in arm I , respectively ) ( P = 0.02 ) . The 3 , 5 and 10-year local-regional recurrence-free survival rates in stage IV disease were statistically better in arm II ( 21.5 % , 15.9 % and 15.9 % ) than in arm I ( 12.8 % , 7.7 % and 7.7 % , respectively ) ( P = 0.04 ) . Conclusions Long-term results in both treatment arms of the trial appear less positive than most published series . However , our findings do not exclude that carboplatin may be beneficial , but the benefit in local control must be lower than the 15 % assumed to dimension the trial 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 BACKGROUND A r and omized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil ( TPF ) with cisplatin and fluorouracil ( PF ) , followed by chemoradiotherapy . METHODS We r and omly assigned 501 patients ( all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were c and i date s for organ preservation ) to receive either TPF or PF induction chemotherapy  , followed  by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week . The primary end point was overall survival . RESULTS With a minimum of 2 years of follow-up ( > or =3 years for 69 % of patients ) , significantly more patients survived in the TPF group than in the PF group ( hazard ratio for death , 0.70 ; P=0.006 ) . Estimates of overall survival at 3 years were 62 % in the TPF group and 48 % in the PF group ; the median overall survival was 71 months and 30 months , respectively ( P=0.006 ) . There was better locoregional control in the TPF group than in the PF group ( P=0.04 ) , but the incidence of distant metastases in the two groups did not differ significantly ( P=0.14 ) . Rates of neutropenia and febrile neutropenia were higher in the TPF group ; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group . CONCLUSIONS Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy . ( Clinical Trials.gov number , NCT00273546 [ Clinical Trials.gov ] . ) Background Platinum-based chemoradiation ( CCRT ) is the st and ard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma ( LAHNSCC ) .  Cetuximab/RT ( CET/RT ) is an alternative treatment option to CCRT . The efficacy of induction chemotherapy ( IC ) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in r and omized clinical trials . The goals of this phase II-III trial were to assess : ( i ) the overall survival ( OS ) of  IC  versus no-induction ( no-IC  ) and ( ii ) the Grade 3 - 4 in-field mucosal toxicity of CCRT versus CET/RT . The present paper focuses on the analysis of efficacy . Material s and methods Patients with LAHNSCC were r and omized to receive concomitant treatment alone [ CCRT ( Arm A1 ) or CET/RT ( Arm A2 ) ] , or three cycles of induction docetaxel/cisplatin/5 fluorouracil ( TPF ) followed by CCRT ( Arm B1 ) or followed by CET/RT ( Arm B2 ) . The superiority hypothesis of OS comparison of IC versus no-IC ( Arms B1 + B2 versus A1 + A2 ) required 204 deaths to detect an absolute 3-year OS difference of 12 % ( HR 0.675 , with 80 % power at two-sided 5 % significance level ) . Results 414 out of 421 patients were finally analyzed : 206 in the IC and 208 in the no-IC arm . Six patients were excluded because of major violation and one because of metastatic disease at diagnosis . With a median follow-up of 44.8 months , OS was significantly higher in the IC arm ( HR 0.74 ; 95 % CI 0.56 - 0.97 ; P = 0.031 ) . Complete Responses ( P = 0.0028 ) , Progression Free Survival ( P = 0.013 ) and the Loco-regional Control ( P = 0.036 ) were also significantly higher in the IC arm . Compliance to concomitant treatments was not affected by induction TPF . Conclusions IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments . The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy . Clinical Trial Number NCT01086826 , www . clinical trials.gov BACKGROUND Cetuximab combined with radiotherapy ( RT ) is a treatment option for head and neck cancer . The objectives of this r and omized , phase II trial were to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer . PATIENTS AND METHODS Ninety-one patients with stage III-IV M0 oropharyngeal tumors were r and omly assigned to the treatment with accelerated concomitant boost RT ( 69.9 Gy ) + cetuximab or the same treatment with the addition of 12 consecutive weeks of cetuximab maintenance therapy . The primary end point was locoregional control ( LRC ) at 1 year . RESULTS LRC at 1 year was superior among patients in the experimental arm , treated with cetuximab maintenance ( 59 % versus 47 % ) . However , LRC was similar between both arms after 2 years of follow-up , as a result of increased locoregional recurrences after the first year in the maintenance group . Patients treated with adjuvant cetuximab do recover very soon from toxic effect after combined treatment . CONCLUSIONS Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year . This improvement is not maintained after the second year suggesting that epidermal growth factor receptor blockade is not sufficient to completely eliminate the minimal residual disease In 1986 , we initiated a multicenter , r and omized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment ( surgery and radiotherapy or radiotherapy alone ) with locoregional treatment alone in patients with head and neck squamous cell carcinoma . Here we report the long-term results of the trial . A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were r and omly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment ( group A ) or locoregional treatment alone ( group B ) . Among all patients , overall survival at 5 and 10 years was 23 % ( 95 % confidence interval [ CI ] = 15.3 % to 30.9 % ) and 19 % ( 95 % CI = 11.6 % to 26.4 % ) , respectively , for those in group A and 16 % ( 95 % CI = 9.6 % to 23.4 % ) and 9 % ( 95 % CI = 3.5 % to 14.7 % ) , respectively , for those in group B ( P = .13 ) . Among operable patients , we observed no difference between group A and group B in overall survival at 5 and 10 years ( group A , 31 % [ 95 % CI = 14.9 % to 47.3 % ] and 22.7 % [ 95 % CI = 7.1 % to 38.3 % ] , respectively ; group B , 43.3 % [ 95 % CI = 25.6 % to 61.0 % ] and 14.2 % [ 95 % CI = 0.1 % to 28.3 % ] , respectively ; P = .73 ) . Among inoperable patients , overall survival at 5 and 10 years was 21 % ( 95 % CI = 12.3 % to 30.1 % ) and 16 % ( 95 % CI = 7.7 % to 23.9 % ) , respectively , for group A and 8 % ( 95 % CI = 1.5 % to 12.3 % ) and 6 % ( 95 % CI = 0.1 % to 9.1 % ) , respectively , for group B ( log-rank P = .04 ) . Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease PURPOSE We report the 5-year survival and late toxicity results of a r and omized clinical trial , which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma , using concomitant radiochemotherapy ( arm B ) , compared with st and ard radiotherapy ( arm A ) . PATIENTS AND METHODS A total of 226 patients were entered onto a phase III multicenter r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions ; arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil ; arm B ) . Prognostic factors were evaluated by univariate and multivariate analysis . Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity , hearing , taste , m and ibula , and teeth damage , and Radiation Therapy Oncology Group toxicity criteria for skin , salivary gl and , and mucosa . RESULTS Five-year overall survival , specific disease-free survival , and locoregional control rates were 22 % and 16 % ( log-rank P = .05 ) , 27 % and 15 % ( P = .01 ) , and 48 % and 25 % ( P = .002 ) , in arm B and arm A , respectively . Stage IV , hemoglobin level lower than 125 g/L , and st and ard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis . One or more grade 3 to 4 complications occurred in 56 % of the patients in arm B , compared with 30 % in arm A ( P was not significant ) . CONCLUSION Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity . Anemia was the most important prognostic factor for survival in both arms OBJECTIVES This single-institution study evaluates the feasibility of accelerated fractionation radiotherapy ( AF ) with and without mitomycin C ( MMC ) in the treatment of locally advanced head and neck cancer . PATIENTS AND METHODS Between May 1998 and October 2001 , sixty patients with locally advanced stage III and IV of head and neck cancer were r and omized into three treatment arms : ( 1 ) conventional fractionation radiotherapy ( CF ) ( 5 fractions per week ) ; ( 2 ) accelerated fractionation radiotherapy ( AF ) ( 6 fractions per week ) ; and ( 3 ) AF plus Mitomycin C ( MMC ) . RESULTS The 2-year overall survival ( OS ) of the whole group was 21 % . The OS according to treatment arm was 23 % , 20 % , and 28 % in CF , AF , and AF+MMC arms respectively ( p<0.19 ) . The 2-year loco-regional control ( LC ) rate was 22 % for the whole group of patients . The LC was 10 % , 25 % , and 30 % for the CF , AF , and AF+MMC respectively ( p=0.27 ) . The only significant parameters for OS and LC were performance status and pre-treatment hemoglobin level . Mucositis grade s 3 & 4 occurred in 70 % and 90 % of the patients in the AF and AF+MMC arm respectively compared to 55 % of patients in the CF arm ( p=0.04 ) . However the addition of MMC did not significantly increase the incidence or severity of mucositis between AF and AF+MMC ( p=0.13 ) . Hematological toxicity grade s 3 & 4 were significantly higher after MMC ( occurred in 40 % of patients versus 10 % and 5 % in CF and AF arms respectively , p=0.04 ) . There was no statistically significant difference in the incidence of grade 3 dryness of mouth ( p=0.06 ) , fibrosis ( p=0.6 ) , or lymphoedema ( p=0.39 ) among the three arms . CONCLUSION There was a trend for improvement of LC and OS rates with the use of AF and the addition of MMC to AF compared to CF radiotherapy , although the difference was not statistically significant . The small number of the patients in each treatment arm and the inclusion of multiple tumor sites may contribute to these statistically insignificant results . Accordingly we advise 85 to continue the trial with inclusion of a larger number of patients and restrict tumor sites to one major site PURPOSE Promising results in a r and omized phase II trial with the hypoxic cytotoxin tirapazamine ( TPZ ) combined with cisplatin ( CIS ) and radiation led to this phase III trial . PATIENTS AND METHODS Patients with previously untreated stage III or IV ( excluding T1 - 2N1 and M1 ) squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx were r and omly assigned to receive definitive radiotherapy ( 70 Gy in 7 weeks ) concurrently with either CIS ( 100 mg/m(2 ) ) on day 1 of weeks 1 , 4 , and 7 or CIS ( 75 mg/m(2 ) ) plus TPZ ( 290 mg/m(2)/d ) on day 1 of weeks 1 , 4 , and 7 and TPZ alone ( 160 mg/m(2)/d ) on days 1 , 3 , and 5 of weeks 2 and 3 ( TPZ/CIS ) . The primary end point was overall survival ( OS ) . The planned sample size was 850 , estimated to result in 334 deaths , which would provide 90 % power to detect a difference in 2-year survival rates of 60 % v 70 % for CIS versus TPZ/CIS , respectively ( hazard ratio = 0.69 ) . RESULTS Eight hundred sixty-one patients were accrued from 89 sites in 16 countries . In an intent-to-treat analysis , the 2-year OS rates were 65.7 % for CIS and 66.2 % for TPZ/CIS ( TPZ/CIS -- CIS : 95 % CI , -5.9 % to 6.9 % ) . There were no significant differences in failure-free survival , time to locoregional failure , or quality of life as measured by Functional Assessment of Cancer Therapy-Head and Neck . CONCLUSIONS We found no evidence that the addition of TPZ to chemoradiotherapy , in patients with advanced head and neck cancer not selected for the presence of hypoxia , improves OS BACKGROUND Phase 2 studies suggest that the st and ard regimen of cisplatin and fluorouracil ( PF ) plus docetaxel ( TPF ) improves outcomes in squamous-cell carcinoma of the head and neck . We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced , unresectable disease . METHODS We r and omly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF ( docetaxel and cisplatin , day 1 ; fluorouracil by continuous infusion , days 1 to 5 ) or PF every 3 weeks for four cycles . Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy . The primary end point was progression-free survival . RESULTS A total of 358 patients underwent r and omization , with 177 assigned to the TPF group and 181 to the PF group . At a median follow-up of 32.5 months , the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group ( hazard ratio for disease progression or death in the TPF group , 0.72 ; P=0.007 ) . Treatment with TPF result ed in a reduction in the risk of death of 27 % ( P=0.02 ) , with a median overall survival of 18.8 months , as compared with 14.5 months in the PF group . There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia , nausea , vomiting , stomatitis , and hearing loss in the PF group . The rates of death from toxic effects were 2.3 % in the TPF group and 5.5 % in the PF group . CONCLUSIONS As compared with the st and ard regimen of cisplatin and fluorouracil , induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00003888 [ Clinical Trials.gov ] . ) The prognosis of patients with advanced head and neck cancer remain dismal . For this tumor type , elevated levels of EGFR are associated with a shorter disease free survival and time to treatment failure , reflecting a more aggressive phenotype . Nimotuzumab is a humanized monoclonal antibody that recognizes domain III of the extracellular region of the EGFR , within an area that overlaps with both the surface patch recognized by cetuximab and the binding site for EGF . In order to assess the efficacy of nimotuzumab in combination with radiotherapy , a controlled , double blind , r and omized clinical trial was conducted in 106 advanced squamous cell carcinoma of the head and neck patients , mostly , unfit for chemo-radiotherapy . Control patients received a placebo and radiotherapy . Treatment was safe and the most frequent adverse events consisted on grade I or II asthenia , fever , headache and chills . No skin rash was detected . A significant complete response rate improvement was found in the group of patients treated with nimotuzumab as compared to the placebo . In the intent to treat analysis , a trend towards survival benefit for nimotuzumab treated subjects was found . The survival benefit became significant when applying the Harrington-Fleming test , a weighted log-rank that underscores the detection of differences deferred on time . In addition , a preliminary biomarker investigation showed a significant survival improvement for nimotuzumab treated patients as compared to controls for subjects with EGFR positive tumors . All patients showed a quality of life improvement and a reduction of the general and specific symptoms of the disease 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 Purpose Concurrent chemoradiotherapy ( CRT ) is the st and ard treatment for advanced head and neck squamous cell carcinoma . In this phase II r and omized study , the efficacy and toxicity of docetaxel , cisplatin and 5-fluorouracil induction chemotherapy ( ICT ) followed by concurrent CRT was compared with those after st and ard CRT alone in patients with locally advanced , unresectable head and neck cancer . Patients and methods Between January 2007 and June 2009 , 66 patients with advanced ( stage III or IV ) unresectable squamous cell carcinoma of the head and neck ( oral cavity , oropharynx , hypopharynx , and larynx ) were r and omly assigned to two groups : one receiving two cycles of docetaxel , cisplatin , and 5-fluorouracil ICT followed by CRT with three cycles of cisplatin and one treated by CRT alone . Response rate , local tumor control ( LTC ) , locoregional tumor control ( LRTC ) , overall survival ( OS ) , progression-free survival ( PFS ) , and toxicity results were assessed . Results Three patients from the ICT + CRT group did not appear at the first treatment , so a total of 63 patients were evaluated in the study ( 30 ICT + CRT group and 33 CRT group ) . Three patients died of febrile neutropenia after ICT . The median follow-up time for surviving patients was 63 months ( range 53–82 months ) . The rate of radiologic complete response was 63 % following ICT + CRT , whereas 70 % after CRT alone . There were no significant differences in the 3-year rates of LTC ( 56 vs. 57 % ) , LRTC ( 42 vs. 50 % ) , OS ( 43 vs. 55 % ) , and PFS ( 41 vs. 50 % ) in the ICT + CRT group and in the CRT group , respectively . The rate of grade 3–4 neutropenia was significantly higher in the ICT + CRT group than in the CRT group ( 37 and 12 % ; p = 0.024 ) . Late toxicity ( grade 2 or 3 xerostomia ) developed in 59 and 42 % in the ICT + CRT and CRT groups , respectively . Conclusion The addition of ICT to CRT did not show any advantage in our phase II trial , while the incidence of adverse events increased . The three deaths as a consequence of ICT call attention to the importance of adequate patient selection if ICT is considered . ZusammenfassungHintergrundSimultane Chemoradiotherapie ( CRT ) ist eine St and ardtherapie beim fortgeschrittenen Plattenepithelkarzinom i m Kopf-Hals-Bereich . In dieser r and omisierten Phase-II-Studie wurden die Wirksamkeit und Toxizität einer Induktionschemotherapie ( ICT ) mit Docetaxel , Cisplatin und 5-Fluorouracil gefolgt von simultaner CRT mit der CRT allein bei Patienten mit lokal fortgeschrittenen , irresektablen Kopf-Hals-Tumoren verglichen . Patienten und Method enZwischen Januar 2007 und Juni 2009 wurden 66 Patienten mit fortgeschrittenem ( Stadium III oder IV ) , inoperablem Plattenepithelkarzinom i m Kopf-Hals-Bereich ( Mundhöhle , Oropharynx , Hypopharynx , Larynx ) nach dem Zufallsprinzip in 2 Gruppen eingeteilt . Die eine Gruppe erhielt 2 Zyklen der Docetaxel- , Cisplatin- und 5-Fluorouracil-ICT gefolgt von CRT mit 3 Zyklen Cisplatin , die and ere Gruppe erhielt nur CRT . Ansprechrate , lokale Tumorkontrolle ( LTC ) , lokoregionale Tumorkontrolle ( LRTC ) , Gesamtüberleben ( OS ) , progressionsfreies Überleben ( PFS ) und toxischer Effekt wurden verglichen . ErgebnisseDrei Patienten der Gruppe mit ICT + CRT erschienen bei der ersten Beh and lung nicht , so dass insgesamt 63 Patienten in der Studie ausgewertet wurden ( 30 in der Gruppe ICT + CRT , 33 in der CRT-Gruppe ) . Drei Patienten starben an febriler Neutropenie nach ICT . Die mediane Nachbeobachtungszeit der überlebenden Patienten betrug 63 Monate ( Spanne 53–82 Monate ) . Die Rate des radiologischen vollständigen Ansprechens war 63 % nach ICT + CRT vs. 70 % nach CRT allein . Es gab keinen signifikanten Unterschied in der 3-Jahres-Rate bei LTC ( 56 vs. 57 % ) , LRTC ( 42 vs. 50 % ) , OS ( 43 vs. 55 % ) und PFS ( 41 vs. 50 % ) zwischen der Gruppe mit ICT + CRT und den mit CRT beh and elten Patienten . Die Rate von Neutropenie mit einem Grad 3–4 lag in der Gruppe mit ICT + CRT deutlich höher als in der CRT-Gruppe ( 37 und 12 % ; p = 0,024 ) . Späte Toxizität ( Grad-2- und Grad-3-Xerostomie ) ereignete sich in der Gruppe mit ICT + CRT und in der CRT-Gruppe in jeweils 59 vs. 42 % .SchlussfolgerungDie Kombination von ICT und CRT erbrachte in unserer Phase-II-Studie keine Vorteile , wobei die Gesamtinzidenz der unerwünschten Ereignisse stieg . Die 3 Todesfälle infolge ICT weisen auf die Wichtigkeit der Patientenauswahl i m Falle einer ICT-Beh and lung hin PURPOSE Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months , the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head- and -neck carcinomas . With a minimum of 10 years of follow-up potentially now available for all patients , these results are up date d here to examine long-term outcomes . METHODS AND MATERIAL S A total of 410 analyzable patients who had high-risk resected head- and -neck cancers were prospect ively r and omized to receive either radiation therapy ( RT : 60 Gy in 6 weeks ) or identical RT plus cisplatin , 100 mg/m(2)i.v . on days 1 , 22 , and 43 ( RT + CT ) . RESULTS At 10 years , the local-regional failure rates were 28.8 % vs 22.3 % ( P=.10 ) , disease-free survival was 19.1 % vs 20.1 % ( P=.25 ) , and overall survival was 27.0 % vs 29.1 % ( P=.31 ) for patients treated by RT vs RT + CT , respectively . In the unplanned subset analysis limited to patients who had microscopically involved resection margins and /or extracapsular spread of disease , local-regional failure occurred in 33.1 % vs 21.0 % ( P=.02 ) , disease-free survival was 12.3 % vs 18.4 % ( P=.05 ) , and overall survival was 19.6 % vs 27.1 % ( P=.07 ) , respectively . CONCLUSION At a median follow-up of 9.4 years for surviving patients , no significant differences in outcome were observed in the analysis of all r and omized eligible patients . However , analysis of the subgroup of patients who had either microscopically involved resection margins and /or extracapsular spread of disease showed improved local-regional control and disease-free survival with concurrent administration of chemotherapy . The remaining subgroup of patients who were enrolled only because they had tumor in 2 or more lymph nodes did not benefit from the addition of CT to RT BACKGROUND We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer . METHODS After undergoing surgery with curative intent , 167 patients were r and omly assigned to receive radiotherapy alone ( 66 Gy over a period of 6 1/2 weeks ) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1 , 22 , and 43 of the radiotherapy regimen . RESULTS After a median follow-up of 60 months , the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( P=0.04 by the log-rank test ; hazard ratio for disease progression , 0.75 ; 95 percent confidence interval , 0.56 to 0.99 ) , with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent , respectively . The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group ( P=0.02 by the log-rank test ; hazard ratio for death , 0.70 ; 95 percent confidence interval , 0.52 to 0.95 ) , with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent , respectively . The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group ( P=0.007 ) . The estimated five-year cumulative incidence of local or regional relapses ( considering death from other causes as a competing risk ) was 31 percent after radiotherapy and 18 percent after combined therapy .  Severe ( grade 3 or higher ) adverse effects were more frequent after combined therapy ( 41 percent ) than after radiotherapy ( 21 percent , P=0.001 ) ; the types of severe mucosal adverse effects were similar in the two groups , as was the incidence of late adverse effects . CONCLUSIONS Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications The aim of this study was to compare the efficacy and safety of concurrent chemoradiotherapy ( CCRT ) vs accelerated hyperfractionation with concomitant boost ( CCB ) as a primary treatment for patients with Stage III – IV squamous cell carcinoma of head and neck ( SCCHN ) . A total of 85 non-metastatic advanced SCCHN patients were accrued from January 2003 to December 2007 . Of these , 48 and 37 patients received CCRT and CCB , respectively . The patients were r and omized to receive either three cycles of carboplatin and 5-fluorouracil plus conventional radiotherapy ( CCRT , 66 Gy in 6.5 weeks ) or hybrid accelerated radiotherapy ( CCB , 70 Gy in 6 weeks ) . The primary endpoint was determined by locoregional control rate . The secondary endpoints were overall survival and toxicity . With a median follow-up of 43 months ( range , 3–102 ) , the 5-year locoregional control rate was 69.6 % in the CCRT arm vs 55.0 % in the CCB arm ( P = 0.184 ) . The 5-year overall survival rate was marginally significantly different ( P = 0.05 ) : 76.1 % in the CCRT arm vs 63.5 % in the CCB arm . Radiotherapy treatment interruptions of more than three days were 60.4 % and 40.5 % in the CCRT arm and CCB arm , respectively . The median total treatment time was 55.5 days in the CCRT arm and 49 days in the CCB arm . The rate of Grade 3–4 acute mucositis was significantly higher in the CCB arm ( 67.6 % vs 41.7 % , P = 0.01 ) , but no high grade hematologic toxicities were found in the CCB arm ( 27.2 % vs 0 % ) . CCRT has shown a trend of improving outcome over CCB irradiation in locoregionally advanced head and neck cancer 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 No r and omized trials have been conducted to directly compare radiotherapy ( RT ) with concomitant cisplatin ( CDDP ) versus concomitant cetuximab ( CTX ) as first-line treatment of locally advanced squamous cell carcinoma of the head and neck . In this r and omized trial , we compared these two treatment regimens in terms of compliance , toxicity , and efficacy . PATIENTS AND METHODS Eligible patients were r and omly assigned in a 1:1 ratio to receive either CDDP 40 mg/m(2 ) once per week or CTX 400 mg/m(2 ) as loading dose followed by CTX 250 mg/m(2 ) once per week concomitant to radical RT . For primary end points , compliance to treatment was defined as number of days of treatment discontinuation and drug dosage reduction . The acute toxicity rate was defined according to the National Cancer Institute Common Toxicity Criteria . Efficacy end points were local recurrence-free survival , metastasis-free survival , cancer-specific survival , and overall survival . RESULTS The study was discontinued early because of slow accrual after the enrollment of 70 patients .  RT discontinuation for more than 10 days occurred in 13 % of patients given CTX and 0 % given CDDP ( P = .05 ) . Drug dosage reduction occurred in 34 % given CTX and 53 % given CDDP ( difference not significant ) . Toxicity profiles differed between the two arms , with hematologic , renal , and GI toxicities more frequent in the CDDP arm , and cutaneous toxicity and the need for nutritional support more frequent in the CTX arm . Serious adverse events related to treatment , including four versus one toxic deaths , were higher in the CTX arm ( 19 % v 3 % , P = .044 ) . Locoregional control , patterns of failure , and survivals were similar between the treatment arms . CONCLUSION CTX concomitant to RT lowered compliance and increased acute toxicity rates . Efficacy outcomes were similar in both arms . These results raise the issue of appropriately selecting patients with head and neck cancer who can benefit from CTX in combination with RT 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 PURPOSE To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel , cisplatin , and fluorouracil ( FU ; PCF ) versus st and ard cisplatin and FU ( CF ) , both followed by chemoradiotherapy ( CRT ) , in locally advanced head and neck cancer ( HNC ) . PATIENTS AND METHODS Eligibility criteria included biopsy-proven , previously untreated , stage III or IV locally advanced HNC . Patients received either CF ( cisplatin 100 mg/m2 on day 1 plus FU 1000 [ corrected ] mg/m2 continuous infusion on days 1 through 5 ) or PCF ( paclitaxel 175 mg/m2 on day 1 , cisplatin 100 mg/m2 on day 2 , and FU 500 mg/m2 continuous infusion on days 2 through 6 ) ; both regimens were administered for three cycles every 21 days . Patients with complete response ( CR ) or partial response of greater than 80 % in primary tumor received additional CRT ( cisplatin 100 mg/m2 on days 1 , 22 , and 43 plus 70 Gy ) . RESULTS A total of 382 eligible patients were r and omly assigned to CF ( n = 193 ) or PCF ( n = 189 ) . The CR rate was 14 % in the CF arm v 33 % in the PCF arm ( P < .001 ) . Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm ( log-rank test , P = .006 ; Tarone-Ware , P = .003 ) . PCF patients had a trend to longer overall survival ( OS ; 37 months in CF arm v 43 months in PCF arm ; log-rank test , P = .06 ; Tarone-Ware , P = .03 ) . This difference was more evident in patients with unresectable disease ( OS : 26 months in CF arm v 36 months in PCF arm ; log-rank test , P = .04 ; Tarone-Ware , P = .03 ) . CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients ( 53 % v 16 % , respectively ; P < .001 ) . CONCLUSION Induction chemotherapy with PCF was better tolerated and result ed in a higher CR rate than CF . However , new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment PURPOSE Induction chemotherapy ( IC ) before radiotherapy lowers distant failure ( DF ) rates in locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . The goal of this phase III trial was to determine whether IC before chemoradiotherapy ( CRT ) further improves survival compared with CRT alone in patients with N2 or N3 disease . PATIENTS AND METHODS Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were r and omly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) . The primary end point was overall survival ( OS ) . Secondary end points included DF-free survival , failure pattern , and recurrence-free survival ( RFS ) . RESULTS A total of 285 patients were r and omly assigned . The most common grade 3 to 4 toxicities during IC were febrile neutropenia ( 11 % ) and mucositis ( 9 % ) ; during CRT ( both arms combined ) , they were mucositis ( 49 % ) , dermatitis ( 21 % ) , and leukopenia ( 18 % ) . Serious adverse events were more common in the IC arm ( 47 % v 28 % ; P = .002 ) . With a minimum follow-up of 30 months , there were no statistically significant differences in OS ( hazard ratio , 0.91 ; 95 % CI , 0.59 to 1.41 ) , RFS , or DF-free survival . CONCLUSION IC did not translate into improved OS compared with CRT alone . However , the study was underpowered because it did not meet the planned accrual target , and OS was higher than predicted in both arms . IC can not be recommended routinely in patients with N2 or N3 locally advanced SCCHN BACKGROUND Concurrent chemoradiotherapy ( CCRT ) is the st and ard treatment for patients with unresectable , nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) . This r and omized , open-label , phase III clinical trial compared the efficacy between st and ard CCRT and two different induction chemotherapy ( ICT ) regimens followed by CCRT . PATIENTS AND METHODS Patients with untreated LASCCHN were r and omly assigned to ICT ( three cycles ) , with either docetaxel ( Taxotere ) , cisplatin and 5-fluorouracil ( TPF arm ) or cisplatin and 5-fluorouracil ( PF arm ) , followed by CCRT [ 7 weeks of radiotherapy ( RT ) with cisplatin 100 mg/m(2 ) on days 1 , 22 and 43 ] ; or 7 weeks of CCRT alone . The primary end points were progression-free survival ( PFS ) and time-to-treatment failure ( TTF ) . RESULTS In the intention-to-treat ( ITT ) population ( n = 439 ) , the median PFS times were 14.6 ( 95 % CI , 11.6 - 20.4 ) , 14.3 ( 95 % CI , 11.8 - 19.3 ) and 13.8 months ( 95 % CI , 11.0 - 17.5 ) at TPF-CCRT , PF-CCRT and CCRT arms , respectively ( log-rank P = 0.56 ) . The median TTF were 7.9 ( 95 % CI , 5.9 - 11.8 ) , 7.9 ( 95 % CI , 6.5 - 11.8 ) and 8.2 months ( 95 % CI , 6.7 - 12.6 ) for TPF-CCRT , PF-CCRT and CCRT alone , respectively ( log-rank P = 0.90 ) . There were no statistically significant differences for overall survival ( OS ) . Toxic effects from ICT-CCRT were manageable . CONCLUSION Overall , this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN PURPOSE To test the toxicity and efficacy of concomitant boost radiotherapy alone against concurrent chemoradiation ( conventional fractionation ) in locally advanced oropharyngeal cancer in our patient population . METHODS AND MATERIAL S In this open-label , r and omised trial , 216 patients with histologically proven Stage III-IVA oropharyngeal cancer were r and omly assigned between June 2006 and December 2010 to receive either chemoradiation ( CRT ) to a dose of 66 Gy in 33 fractions over 6.5 weeks with concurrent cisplatin ( 100 mg/m(2 ) on days 1 , 22 and 43 ) or accelerated radiotherapy with concomitant boost ( CBRT ) to a dose of 67.5 Gy in 40 fractions over 5 weeks . The compliance , toxicity and quality of life were investigated . Disease-free survival ( DFS ) and overall survival ( OS ) curves were estimated with the Kaplan-Meier method and compared using log rank test . RESULTS The compliance to radiotherapy was superior in concomitant boost with lesser treatment interruptions ( p=0.004 ) . Expected acute toxicities were significantly higher in CRT , except for grade 3/4 mucositis which was seen more in CBRT arm ( 39 % and 55 % in CRT and CBRT , respectively ; p=0.02 ) . Late toxicities like Grade 3 xerostomia were significantly high in CRT arm than CBRT arm ( 33 % versus 18 % ; p<0.0001 ) . The quality of life was significantly poor in CRT arm at all follow up visits ( p<0.0001 ) . The rates of 2 year disease-free survival were similar with 56 % in the chemoradiotherapy group and 61 % in CBRT group ( p=0.2 ; HR-0.81 , 95%CI-0.53 - 1.2 ) . Subgroup analysis revealed that patients with nodal size > 2 cm had significantly better DFS with CRT ( p=0.05 ; HR-1.59 , 95%CI-0.93 - 2.7 ) . CONCLUSION In selected patients of locally advanced oropharyngeal cancer , concomitant boost offers a better compliance , toxicity profile and quality of life with similar disease control , than chemoradiation BACKGROUND We aim ed to compare panitumumab , a fully human monoclonal antibody against EGFR , plus radiotherapy with chemoradiotherapy in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( two cycles of cisplatin 100 mg/m(2 ) during radiotherapy ) or to radiotherapy plus panitumumab ( three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy ) using a stratified r and omisation with a block size of five . All patients received 70 - 72 Gy to gross tumour and 54 Gy to areas of sub clinical disease with accelerated fractionation radiotherapy . The primary endpoint was local-regional control at 2 years , analysed in all r and omly assigned patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This study is registered with Clinical Trials.gov , number NCT00547157 . FINDINGS Between Nov 30 , 2007 , and Nov 16 , 2009 , 152 patients were enrolled , and 151 received treatment ( 61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group ) . Local-regional control at 2 years was 61 % ( 95 % CI 47 - 72 ) in the chemoradiotherapy group and 51 % ( 40 - 62 ) in the radiotherapy plus panitumumab group . The most frequent grade 3 - 4 adverse events were mucosal inflammation ( 25 [ 40 % ] of 62 patients in the chemoradiotherapy group vs 37 [ 42 % ] of 89 patients in the radiotherapy plus panitumumab  group ) , dysphagia ( 20 [ 32 % ] vs 36 [ 40 % ] ) , and radiation skin injury ( seven [ 11 % ] vs 21 [ 24 % ] ) . Serious adverse events were reported in 25 ( 40 % ) of 62 patients in the chemoradiotherapy group and in 30 ( 34 % ) of 89 patients in the radiotherapy plus panitumumab group . INTERPRETATION Panitumumab can not replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck , and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed . FUNDING Amgen PURPOSE The Head and Neck Intergroup conducted a phase III r and omized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer . PATIENTS AND METHODS Eligible patients were r and omly assigned between arm A ( the control ) , single daily fractionated radiation ( 70 Gy at 2 Gy/d ) ; arm B , identical radiation therapy with concurrent bolus cisplatin , given on days 1 , 22 , and 43 ; and arm C , a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy , 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle . Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and , if necessary , as salvage therapy on all three treatment arms . Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test . RESULTS Between 1992 and 1999 , 295 patients were entered on this trial . This did not meet the accrual goal of 362 patients and result ed in premature study closure . Grade 3 or worse toxicity occurred in 52 % of patients enrolled in arm A , compared with 89 % enrolled in arm B ( P < .0001 ) and 77 % enrolled in arm C ( P < .001 ) . With a median follow-up of 41 months , the 3-year projected overall survival for patients enrolled in arm A is 23 % , compared with 37 % for arm B ( P = .014 ) and 27 % for arm C ( P = not significant ) . CONCLUSION The addition of concurrent high-dose , single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival , although it also increases toxicity . The loss of efficacy result ing from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery BACKGROUND Panitumumab is a fully human monoclonal antibody that targets EGFR . We aim ed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( three cycles of cisplatin 100 mg/m(2 ) ) or panitumumab plus chemoradiotherapy ( three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2 ) ) using stratified r and omisation with a block size of five . All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for sub clinical disease with st and ard fractionation . The primary endpoint was local-regional control at 2 years , analysed in all r and omised patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This trial is registered with Clinical Trials.gov , number NCT00500760 . FINDINGS Between Oct 26 , 2007 , and March 26 , 2009 , 153 patients were enrolled and 150 received treatment ( 63 in the  chemoradiotherapy  group and 87 in the panitumumab plus chemoradiotherapy group ) .  Local-regional control at 2 years was 68 % ( 95 % CI 54 - 78 ) in the chemoradiotherapy group and 61 % ( 50 - 71 ) in the panitumumab plus chemoradiotherapy group . The most frequent grade 3 - 4 adverse events were dysphagia ( 17 [ 27 % ] of 63 patients in the chemoradiotherapy group vs 35 [ 40 % ] of 87 in the panitumumab plus chemoradiotherapy group ) , mucosal inflammation ( 15 [ 24 % ] vs 48 [ 55 % ] ) , and radiation skin injury ( eight [ 13 % ] vs 27 [ 31 % ] ) . Serious adverse events were reported in 20 ( 32 % ) of 63 patients in the chemoradiotherapy group and in 37 ( 43 % ) of 87 patients in the panitumumab plus chemoradiotherapy group . INTERPRETATION In patients with locally advanced squamous-cell carcinoma of the head and neck , the addition of panitumumab to st and ard fractionation radiotherapy and cisplatin did not confer any benefit , and the role of EGFR inhibition in these patients needs to be reassessed . FUNDING Amgen PURPOSE The Head and Neck Intergroup conducted a Phase III r and omized trial to determine whether the addition weekly cisplatin to daily radiation therapy ( RT ) would improve survival in patients with unresectable squamous cell head- and -neck carcinoma . METHODS AND MATERIAL S Eligible patients were r and omized to RT ( 70 Gy at 1.8 - 2 Gy/day ) or to the identical RT with weekly cisplatin dosed at 20 mg/m(2 ) .  Failure-free survival ( FFS ) and overall survival ( OS ) curves were estimated with the Kaplan-Meier method and compared with the log rank test . RESULTS Between 1982 and 1987 , 371 patients were accrued , and 308 patients were found eligible for analysis . Median follow-up was 62 months . The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups , respectively ( p = 0.30 ) . The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS ( compared to a p = 0.30 in univariate analysis ) . Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities . Late toxicities were not significantly different except for significantly more esophageal ( 9 % vs. 3 % , p = 0.03 ) and laryngeal ( 11 % vs. 4 % , p = 0.05 ) late toxicities in the RT + cisplatin group . CONCLUSION The addition of concurrent weekly cisplatin at 20 mg/m(2 ) to daily radiation did not improve survival , although there was evidence of activity . Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications PURPOSE To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and /or node-positive nonmetastatic carcinomas of the head and neck , compared with hyperfractionated radiotherapy alone . PATIENTS AND METHODS From July 1994 to July 2000 , 224 patients with squamous cell carcinomas of the head and neck ( excluding nasopharynx and paranasal sinus ) were r and omly assigned to hyperfractionated radiotherapy ( median dose , 74.4 Gy ; 1.2 Gy twice daily ) or the same radiotherapy combined with two cycles of concomitant cisplatin ( 20 mg/m2 on 5 days of weeks 1 and 5 ) . The primary end point was time to any treatment failure ; secondary end points were locoregional failure , metastatic relapse , overall survival , and late toxicity . RESULTS There was no difference in radiotherapy between both treatment arms ( 74.4 Gy in 44 days ) . The full cisplatin dose was applied in 93 % and 71 % of patients during the first and second treatment cycles , respectively . Acute toxicity was similar in both arms . Median time to any treatment failure was not significantly different between treatment arms ( 19 months for combined treatment and 16 months for radiotherapy only , respectively ) and the failure-free rate at 2.5 years was 45 % and 33 % , respectively . Locoregional control and distant disease-free survival were significantly improved with cisplatin ( log-rank test , P = .039 and .011 , respectively ) . The difference in overall survival did not reach significance ( log-rank test , P = .147 ) . Late toxicity was comparable in both treatment groups . CONCLUSION The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin BACKGROUND Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis . Following a previous phase II study , this phase III multicenter trial was conducted between November 1997 and March 2002 . METHODS Nontreated , strictly unresectable cases were eligible .  Twice-daily radiation : two fractions of 1.2 Gy/day , 5 days per week , with no split ( D1 - ->D46 ) . Total tumor doses : 80.4 Gy/46 day ( oropharynx ) , 75.6 Gy/44 day ( hypopharynx ) . Chemotherapy ( arm B ) : Cisplatin 100 mg/m2 ( D1 , D22 , D43 ) ; 5FU , continuous infusion ( D1 - ->D5 ) , 750 mg/m2/day cycle 1 ; 430 mg/m2/day cycles 2 and 3 . RESULTS A total of 163 evaluable patients .  Grade 3 - 4 acute mucositis 82.6 % arm B/69.5 % arm A ( NS ) ; Grade 3 - 4 neutropenia 33.3 % arm B/2.4 % arm A ( p < 0.05 ) . Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months ( p < 0.01 ) . At 24 months , overall survival ( OS ) , disease-free survival ( DFS ) , and specific survival ( SS ) were significantly better in arm B. OS : 37.8 % arm B vs. 20.1 % arm A ( p = 0.038 ) ; DFS : 48.2 % vs. 25.2 % ( p = 0.002 ) ; SS : 44.5 % vs. 30.2 % ( p = 0.021 ) . No significant difference between the two arms in the amount of side effects at 1 and 2 years . CONCLUSION For these unresectable cases , chemoradiation provides better outcome than radiation alone , even with an " aggressive " dose-intensity radiotherapy schedule PURPOSE To prove an expected benefit of concurrent radiochemotherapy ( RCT ) , a two-arm r and omized multicentric study was performed . In a subgroup analysis the influence of pretherapeutical hemoglobin level ( p-Hb ) on survival under locoregional control ( SLC ) was tested . PATIENTS AND METHODS The study included primarily untreated Stage III/IV ( International Union Against Cancer [ UICC ] ) oropharyngeal and hypopharyngeal carcinomas . Patients were r and omized to receive either hyperfractionated ( hf ) and accelerated ( acc ) RCT with two cycles 5-fluorouracil ( 600 mg/m(2)/day ) and carboplatin ( 70 mg/m(2)/day ) on Days 1 - 5 and 29 - 33 or hf-acc radiotherapy ( RT ) alone . Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique . RESULTS After a median follow-up time of 57 months , SLC is significantly better in RCT than in RT ( p = 0.01 ) , with median SLC of 17 months and 11 months , respectively . Also overall survival ( OS ) shows a benefit for RCT ( p = 0.016 ) , with a median survival of 23 months for RCT and 16 months for RT . However , the benefit in SLC and OS is not seen in hypopharyngeal carcinomas . In a multivariate analysis of oropharyngeal cancer patients , p-Hb levels lower than 12.7 g/dL result ed in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels > 13.8 g/dL did not further improve SLC . CONCLUSIONS Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas . P-Hb levels > 13.8 g/dL do not further improve SLC PURPOSE To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91 - 11 study evaluating the contribution of chemotherapy added to radiation therapy ( RT )  for larynx preservation . PATIENTS AND METHODS Patients with stage III or IV glottic or supraglottic squamous cell cancer were r and omly assigned to induction cisplatin/fluorouracil ( PF ) followed by RT ( control arm ) , concomitant cisplatin/RT , or RT alone . The composite end point of laryngectomy-free survival ( LFS ) was the primary end point . RESULTS Five hundred twenty patients were analyzed . Median follow-up for surviving patients is 10.8 years . Both chemotherapy regimens significantly improved LFS compared with RT alone ( induction chemotherapy v RT alone : hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59 to 0.95 ; P = .02 ; concomitant chemotherapy v RT alone : HR , 0.78 ; 95 % CI , 0.78 to 0.98 ; P = .03 ) . Overall survival did not differ significantly , although there was a possibility of worse outcome with concomitant relative to induction chemotherapy ( HR , 1.25 ; 95 % CI , 0.98 to 1.61 ; P = .08 ) . Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT ( HR , 0.58 ; 95 % CI , 0.37 to 0.89 ; P = .0050 ) and over RT alone ( P < .001 ) , whereas induction PF followed by RT was not better than treatment with RT alone ( HR , 1.26 ; 95 % CI , 0.88 to 1.82 ; P = .35 ) . No difference in late effects was detected , but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy ( 30.8 % v 20.8 % with induction chemotherapy and 16.9 % with RT alone ) . CONCLUSION These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS . Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone . New strategies that improve organ preservation and function with less morbidity are needed 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 To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer . METHODS AND MATERIAL S From July 1994 to July 2000 , a total of 224 patients with squamous cell carcinoma of the head and neck were r and omized to receive either hyperfractionated radiotherapy alone ( median total dose , 74.4 Gy ; 1.2 Gy twice daily ; 5 days per week ) or the same radiotherapy combined with two cycles of cisplatin ( 20 mg/m(2 ) for 5 consecutive days during weeks 1 and 5 ) . The primary endpoint was the time to any treatment failure ; secondary endpoints were locoregional failure , metastatic failure , overall survival , and late toxicity assessed according to Radiation Therapy Oncology Group criteria . RESULTS Median follow-up was 9.5 years ( range , 0.1 - 15.4 years ) . Median time to any treatment failure was not significantly different between treatment arms ( hazard ratio [ HR ] , 1.2 [ 95 % confidence interval { CI } , 0.9 - 1.7 ; p = 0.17 ] ) . Rates of locoregional failure-free survival ( HR , 1.5 [ 95 % CI , 1.1 - 2.1 ; p = 0.02 ] ) , distant metastasis-free survival ( HR , 1.6 [ 95 % CI , 1.1 - 2.5 ; p = 0.02 ] ) , and cancer-specific survival ( HR , 1.6 [ 95 % CI , 1.0 - 2.5 ; p = 0.03 ] ) were significantly improved in the combined-treatment arm , with no difference in major late toxicity between treatment arms . However , overall survival was not significantly different ( HR , 1.3 [ 95 % CI , 0.9 - 1.8 ; p = 0.11 ] ) . CONCLUSIONS After long-term follow-up , combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control , distant metastasis-free survival , and cancer-specific survival compared to that of hyperfractionated radiotherapy alone , with no difference in major late toxicity 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 PURPOSE To test whether altered radiation fractionation schemes ( hyperfractionation [ HFX ] , accelerated fractionation , continuous [ AFX-C ] , and accelerated fractionation with split [ AFX-S ] ) improved local-regional control ( LRC ) rates for patients with squamous cell cancers ( SCC ) of the head and neck when compared with st and ard fractionation ( SFX ) of 70 Gy . METHODS AND MATERIAL S Patients with stage III or IV ( or stage II base of tongue ) SCC ( n=1076 ) were r and omized to 4 treatment arms : ( 1 ) SFX , 70 Gy/35 daily fractions/7 weeks ; ( 2 ) HFX , 81.6 Gy/68 twice-daily fractions/7 weeks ; ( 3 ) AFX-S , 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy ; and ( 4 ) AFX-C , 72 Gy/42 fractions/6 weeks . The 3 experimental arms were to be compared with SFX . RESULTS With patients censored for LRC at 5 years , only the comparison of HFX with SFX was significantly different : HFX , hazard ratio ( HR ) 0.79 ( 95 % confidence interval 0.62 - 1.00 ) , P=.05 ; AFX-C , 0.82 ( 95 % confidence interval 0.65 - 1.05 ) , P=.11 . With patients censored at 5 years , HFX improved overall survival ( HR 0.81 , P=.05 ) . Prevalence of any grade 3 , 4 , or 5 toxicity at 5 years ; any feeding tube use after 180 days ; or feeding tube use at 1 year did not differ significantly when the experimental arms were compared with SFX . When 7-week treatments were compared with 6-week treatments , accelerated fractionation appeared to increase grade 3 , 4 or 5 toxicity at 5 years ( P=.06 ) . When the worst toxicity per patient was considered by treatment only , the AFX-C arm seemed to trend worse than the SFX arm when grade 0 - 2 was compared with grade 3 - 5 toxicity ( P=.09 ) . CONCLUSIONS At 5 years , only HFX improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity BACKGROUND Previous results from our phase 3 r and omised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) at 3 years . Here we report the 5-year survival data , and investigate the relation between cetuximab-induced rash and survival . METHODS Patients with LASCCHN of the oropharynx , hypopharynx , or larynx with measurable disease were r and omly allocated in a 1:1 ratio to receive either  comprehensive head and neck radiotherapy alone  for 6 - 7 weeks or radiotherapy plus weekly doses of cetuximab : 400 mg/m(2 ) initial dose , followed by seven weekly doses at 250 mg/m(2 ) . R and omisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score , T stage , N stage , and radiation fractionation . The trial was un-blinded . The primary endpoint was locoregional control , with a secondary endpoint of survival . Following discussion s with the US Food and Drug Administration , the data set was locked , except for queries to the sites about overall survival , before our previous report in 2006 , so that an independent review could be done . Analyses were done on an intention-to-treat basis . Following completion of treatment , patients underwent physical examination and radiographic imaging every 4 months for 2 years , and then every 6 months thereafter . The trial is registered at www . Clinical Trials.gov , number NCT00004227 . FINDINGS Patients were r and omly assigned to receive radiotherapy with ( n=211 ) or without ( n=213 ) cetuximab , and all patients were followed for survival . Up date d median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months ( 95 % CI 32.8 - 69.5 ) versus 29.3 months ( 20.6 - 41.4 ) in the radiotherapy-alone group ( hazard ratio [ HR ] 0.73 , 95 % CI 0.56 - 0.95 ; p=0.018 ) . 5-year overall survival was 45.6 % in the cetuximab-plus-radiotherapy group and 36.4 % in the radiotherapy-alone group . Additionally , for the patients treated with cetuximab , overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash ( HR 0.49 , 0.34 - 0.72 ; p=0.002 ) . INTERPRETATION For patients with LASCCHN , cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone , confirming cetuximab plus radiotherapy as an important treatment option in this group of patients . Cetuximab-treated patients with prominent cetuximab-induced rash ( grade 2 or above ) have better survival than patients with no or grade 1 rash . FUNDING ImClone Systems , Merck KGaA , and Bristol-Myers Squibb BACKGROUND At a minimum follow-up of 2 years , the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel , cisplatin , and fluorouracil ( TPF ) versus cisplatin and fluorouracil ( PF ) in locally advanced head and neck cancer . We report the long-term results at 5 years ' minimum follow-up . METHODS TAX 324 was a r and omised , open-label phase 3 trial comparing three cycles of TPF induction chemotherapy ( docetaxel 75 mg/m(2 ) , followed by intravenous cisplatin 100 mg/m(2 ) and fluorouracil 1000 mg/m(2 ) per day , administered as a continuous 24-h infusion for 4 days ) with three cycles of PF ( intravenous cisplatin 100 mg/m(2 ) , followed by fluorouracil 1000 mg/m(2 ) per day as a continuous 24-h infusion for 5 days ) in patients with stage III or IV squamous-cell carcinoma of the head or neck . Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin . R and omisation was done central ly with the use of a biased-coin minimisation technique . At study entry , patients were stratified according to the site of the primary tumour , nodal status ( N0 or N1 vs N2 or N3 ) , and institution . For this long-term analysis , data as of Dec 1 , 2008 , were gathered retrospectively from patients ' medical records .  Overall and progression-free survival were the primary endpoints . Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity . The intention-to-treat analysis included data from all 501 patients ( 255 TPF , 246 PF ) ; data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up . TAX 324 was registered at Clinical Trials.gov , NCT00273546 . FINDINGS Median follow-up was 72·2 months ( 95 % CI 68·8 - 75·5 ) . Overall survival was significantly better after treatment with TPF versus PF ( hazard ratio [ HR ] 0·74 , 95 % CI 0·58 - 0·94 ) , with an estimated 5-year survival of 52 % in patients treated with TPF and 42 % in those receiving PF . Median survival was 70·6 months ( 95 % CI 49·0 - 89·0 ) in the TPF group versus 34·8 months ( 22·6 - 48·0 ) in the PF group ( p=0·014 ) . Progression-free survival was also significantly better in patients treated with TPF ( median 38·1 months , 95 % CI 19·3 - 66·1 , vs 13·2 months , 10·6 - 20·7 ; HR 0·75 , 95 % CI 0·60 - 0·94 ) . We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups . In the TPF group , three ( 3 % ) of 91 patients remained feeding-tube dependent , compared with eight ( 11 % ) of 71 patients in the PF group . Six ( 7 % ) of 92 patients had tracheostomies in the TPF group , versus eight ( 11 % ) of 71 in the PF group . INTERPRETATION Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer . Patients who are c and i date s for induction chemotherapy should be treated with TPF . FUNDING Sanofi-Aventis BACKGROUND We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy ( CCRT ) in patients with locally advanced head and neck squamous cell carcinoma . METHODS Patients were r and omized to receive three cycles of docetaxel and cisplatin ( TP regimen ) with or without cetuximab ( TP plus cetuximab [ CTP ] vs. TP ) as induction chemotherapy . Patients in the CTP arm received CCRT with cetuximab and cisplatin , whereas patients in the TP arm received cisplatin alone . The primary endpoint was the objective response rate ( ORR ) after induction chemotherapy . RESULTS Overall , 92 patients were enrolled . The ORRs for induction chemotherapy in the CTP and TP arms were not different ( 81 % vs. 82 % ) . Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and result ed in more frequent dose reductions of the induction chemotherapy , although this did not reach statistical significance . In the CTP and TP arms , respectively , the 3-year progression-free survival ( PFS ) rates were 70 % and 56 % ( p = .359 ) , and the overall survival ( OS ) rates were 88 % and 74 % ( p = .313 ) . When limited to patients who completed induction chemotherapy , 3-year PFS rates of 78 % and 59 % ( p = .085 ) and OS rates of 94 % and 73 % ( p = .045 ) were observed in the CTP and TP arms , respectively . CONCLUSION Adding cetuximab to sequential treatment did not increase the treatment efficacy and result ed in greater toxicity . In the intent-to-treat population , neither PFS nor OS was improved by the addition of cetuximab to sequential treatment ; however , a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy BACKGROUND The purpose of this study was to report the results of a phase III , 3-arm , r and omized trial comparing conventional radiotherapy ( RT ) to concurrent chemoradiotherapy ( CRT ) and accelerated RT in advanced head and neck squamous cell carcinoma ( HNSCC ) . METHODS One hundred eighty-six of 750 planned patients were r and omized to receive one of the following treatment plans : RT ( 66 - 70 Gy/2 Gy fraction/5 fractions weekly ; CRT of weekly cisplatin ( 30 mg/m(2 ) ) with the same RT dose ; or accelerated RT alone of 66 to 70 Gy/2 Gy fraction/6 fractions weekly were available for analysis . The primary endpoint was locoregional control at 5 years . RESULTS The mean follow-up was 54 months . Among the 3 arms , CRT showed superior locoregional control ( 49 % ; p = .049 ) . RT had lower grade ≥3 mucositis and late toxicity . CONCLUSION CRT is associated with significantly better locoregional control as compared to RT and accelerated RT with higher but acceptable acute and late toxicities The primary objective of the present r and omized phase III trial was to compare the 3-yr survival rate of patients treated with  st and ard fractionated radiotherapy ( RT ) alone or with the same RT concomitantly with cisplatin ( DDP ) or carboplatin ( Cb ) . From January 1995 until July 1999 , 124 patients with histologically proven locally advanced non-nasopharyngeal head and neck cancer ( HNC ) were r and omized to receive either RT monotherapy ( 70Gy , Group A ) or the same RT concomitantly with DDP ( 100 mg/m2 on d 2 , 22 , 42 , Group B ) or Cb ( 7 AUC on d 2 , 22 , 42 , Group C ) . There were no significant differences in complete response rates between patients treated with RT alone or combined chemoradiotherapy . However , median time to progression ( TTP ) and overall survival ( OS ) were significantly longer in patients treated with concomitant chemoradiotherapy . Thus , median TTP was 6.3 , 45.2 , and 17.7 mo in groups A , B , and C respectively ( p=0.0002 ) . Similarly , median OS was 12.2 , 48.6 , and 24.5 mo , respectively ( p=0.0003 ) . At 3 yr follow-up , 17.5 % of patients in group A were alive compared to 52 % in group B and 42 % in group C ( p<0.001 ) . Patients treated with concomitant chemoradiotherapy experienced more frequently severe hematological toxicity . Also , severe nausea/vomiting was more pronounced in group B , as expected . The present study clearly demonstrated that concomitant chemoradiotherapy with platinum analogs significantly prolongs 3-yr survival and median OS in patients with locally advanced HNC compared to conventional RT alone BACKGROUND Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma ( HNSCC ) . We aim ed to assess the efficacy and safety of a combination of these approaches . METHODS In our open-label phase 3 r and omised trial , we enrolled patients with locally advanced , stage III and IV ( non-metastatic ) HNSCC and an Eastern Cooperative Oncology Group performance status of 0 - 2 . We r and omly allocated patients central ly with a computer program ( with centre , T stage , N stage , and localisation as minimisation factors ) in a 1:1:1 ratio to receive conventional chemoradiotherapy ( 70 Gy in 7 weeks plus three cycles of 4 days ' concomitant carboplatin-fluorouracil ) , accelerated radiotherapy-chemotherapy ( 70 Gy in 6 weeks plus two cycles of 5 days ' concomitant carboplatin-fluorouracil ) , or very accelerated radiotherapy alone ( 64·8 Gy [ 1·8 Gy twice daily ] in 3·5 weeks ) . The primary endpoint , progression-free survival ( PFS ) , was assessed in all enrolled patients . This trial is completed . The trial is registered with Clinical Trials.gov , number NCT00828386 . FINDINGS Between Feb 29 , 2000 , and May 9 , 2007 , we r and omly allocated 279 patients to receive conventional chemoradiotherapy , 280 to accelerated radiotherapy-chemotherapy , and 281 to very accelerated radiotherapy .  Median follow-up was 5·2 years ( IQR 4·9 - 6·2 ) ; rates of chemotherapy and radiotherapy compliance were good in all groups . Accelerated radiotherapy-chemotherapy offered no PFS benefit  compared with conventional chemoradiotherapy ( HR 1·02 , 95 % CI 0·84 - 1·23 ; p=0·88 ) or very accelerated radiotherapy ( 0·83 , 0·69 - 1·01 ; p=0·060 ) ; conventional chemoradiotherapy  improved PFS compared with very accelerated radiotherapy ( 0·82 , 0·67 - 0·99 ; p=0·041 ) . 3-year PFS was 37·6 % ( 95 % CI 32·1 - 43·4 ) after conventional chemoradiotherapy , 34·1 % ( 28·7 - 39·8 ) after accelerated radiotherapy-chemotherapy , and 32·2 % ( 27·0 - 37·9 ) after very accelerated radiotherapy . More patients in the very accelerated radiotherapy  group had RTOG grade 3 - 4 acute mucosal toxicity ( 226 [ 84 % ] of 268 patients ) compared with accelerated radiotherapy-chemotherapy ( 205 [ 76 % ] of 271 patients ) or conventional chemoradiotherapy ( 180 [ 69 % ] of 262 ; p=0·0001 ) . 158 ( 60 % ) of 265 patients in the conventional chemoradiotherapy group , 176 ( 64 % ) of 276 patients in the accelerated radiotherapy-chemotherapy group , and 190 ( 70 % ) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment ( p=0·045 ) . INTERPRETATION Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy can not compensate for the absence of chemotherapy . We noted the most favourable outcomes for conventional chemoradiotherapy , suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules . FUNDING French Ministry of Health The authors previously have found that in patients with locally advanced squamous cell carcinoma of the head and neck ( SCC‐HN ) , alternating chemoradiotherapy ( ALT ) was superior to low‐total‐dose conventional radiotherapy alone . The purpose of this r and omized trial was to compare the same chemoradiotherapy approach with high‐total‐dose partly accelerated radiotherapy Purpose : Induction chemotherapy has shown to provide consistent benefit for local control in primary treatment of advanced oropharyngeal cancer . The beneficial role of chemoradiation following induction chemotherapy over concurrent chemoradiation has not been evaluated . Present study evaluates the same prospect ively . Method : Out of 135 patients of locally advanced oropharyngeal carcinoma , 105 patients were found eligible and r and omized to treat either with induction chemotherapy consisting of 2 - 3 cycles of cisplatin and 5- Florouracil followed by low dose weekly cisplatin based chemoradiotherapy ( treatment arm : n=48 ) or chemoradiotherapy only ( control arm : n=57 ) . The primary tumor and regional lymph drainage areas received 66 - 70 Gy in 6.5 to 7 weeks by fractionated dose schedule . Results : The response rate and acute toxicity ( primary end points ) in both the arms were found to be similar ( P>0.05 ) The points disease free survival and overall survival ( secondary end points ) were significantly ( Conclusions . Conventional radiotherapy with concurrent cisplatin is significantly superior to induction cisplatin fluorouracil chemotherapy followed by radiotherapy in terms of laryngeal preservation in patients with T3 hypopharyngeal carcinoma . Despite a high rate of laryngeal preservation no survival benefit was recorded in this selected population . Objectives . To compare conventional radiotherapy with concurrent cisplatin to induction chemotherapy with cisplatin fluorouracil followed by conventional radiotherapy . The primary end point was the preservation of the larynx . The secondary end points included toxicity , causes of death , and survival rates . Patients and methods . Seventy-one adult patients with previously untreated resectable T3 pyriform sinus squamous cell carcinoma were enrolled in the multicenter prospect i ve r and omized phase III trial . They were evaluated for organ preservation , survival rates , and toxic reactions . Results . The rates of laryngeal preservation at 2 years were 68 % for the induction chemotherapy ( IC ) group and 92 % for the chemoradiotherapy ( CR ) group ( p = 0.016 ) . At 2 years , the event-free survival rates were 36 % and 41 % for the IC group and CR group , respectively PURPOSE The combination of cisplatin and radiotherapy is a st and ard treatment for patients with locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) .  Cetuximab-radiotherapy is superior to radiotherapy alone in this population , validating epidermal growth factor receptor ( EGFR ) as a target . Erlotinib is a small-molecule inhibitor of EGFR . Adding EGFR inhibition to st and ard cisplatin-radiotherapy may improve efficacy . PATIENTS AND METHODS Patients with locally advanced SCCHN were r and omly assigned to receive cisplatin 100 mg/m(2 ) on days 1 , 22 , and 43 combined with 70 Gy of radiotherapy ( arm A ) or the same chemoradiotherapy with erlotinib 150 mg per day , starting 1 week before radiotherapy and continued to its completion ( arm B ) . The primary end point was complete response rate ( CRR ) , evaluated by central review . The secondary end point was progression-free survival ( PFS ) . Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization . RESULTS Between December 2006 and October 2011 , 204 patients were r and omly assigned . Arms were well balanced for all patient characteristics including p16 , with the exception of more women on arm A. Patients on arm B had more rash , but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities . Arm A had a CRR of 40 % and arm B had a CRR of 52 % ( P = .08 ) when evaluated by central review . With a median follow-up time of 26 months and 54 progression events , there was no difference in PFS ( hazard ratio , 0.9 ; P = .71 ) . CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS PURPOSE To report the long-term results of the ARO 95 - 06 r and omized trial comparing hyperfractionated accelerated chemoradiation with mitomycin C/5-fluorouracil ( C-HART ) with hyperfractionated accelerated radiation therapy ( HART ) alone in locally advanced head and neck cancer . PATIENTS AND METHODS The primary endpoint was locoregional control ( LRC ) . Three hundred eighty-four patients with stage III ( 6 % ) and IV ( 94 % ) oropharyngeal ( 59.4 % ) , hypopharyngeal ( 32.3 % ) , and oral cavity ( 8.3 % ) cancer were r and omly assigned to 30 Gy/2 Gy daily followed by twice-daily 1.4 Gy to a total of 70.6 Gy concurrently with mitomycin C/5-FU ( C-HART ) or 16 Gy/2 Gy daily followed by twice-daily 1.4 Gy to a total dose of 77.6 Gy alone ( HART ) . Statistical analyses were done with the log-rank test and univariate and multivariate Cox regression analyses . RESULTS The median follow-up time was 8.7 years ( 95 % confidence interval [ CI ] : 7.8 - 9.7 years ) . At 10 years , the LRC rates were 38.0 % ( C-HART ) versus 26.0 % ( HART , P=.002 ) . The cancer-specific survival and overall survival rates were 39 % and 10 % ( C-HART ) versus 30.0 % and 9 % ( HART , P=.042 and P=.049 ) , respectively . According to multivariate Cox regression analysis , the combined treatment was associated with improved LRC ( hazard ratio [ HR ] : 0.6 [ 95 % CI : 0.5 - 0.8 ; P=.002 ] ) . The association between combined treatment arm and increased LRC appeared to be limited to oropharyngeal cancer ( P=.003 ) as compared with hypopharyngeal or oral cavity cancer ( P=.264 ) . CONCLUSIONS C-HART remains superior to HART in terms of LRC . However , this effect may be limited to oropharyngeal cancer patients Summary Background Between 1990 and 2000 , we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy . We aim ed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy , or both , affected clinical outcome . Here we report survival and recurrence after 10 years of follow-up . Methods Between Jan 15 , 1990 , and June 20 , 2000 , 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey . Patients with locally advanced head and neck cancer , and who had not previously undergone surgery , were r and omly assigned to one of four groups in a 3:2:2:2 ratio , stratified by centre and chemotherapy regimen : radical radiotherapy alone ( n=233 ) ; radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy ( SIM alone ; n=166 ) ; or 14 and 28 days after completing radiotherapy ( SUB alone , n=160 ) ; or both ( SIM+SUB ; n=154 ) . Chemotherapy was either methotrexate alone , or vincristine , bleomycin , methotrexate , and fluorouracil .  Patients who had previously undergone radical surgery to remove their tumour were only r and omised to radiotherapy alone ( n=135 ) or SIM alone ( n=118 ) , in a 3:2 ratio . The primary endpoints were overall survival ( from r and omisation ) , and event-free survival ( EFS ; recurrence , new tumour , or death ; whichever occurred first ) among patients who were disease-free 6 months after r and omisation . Analyses were by intention to treat . This trial is registered at www . Clinical trials.gov , number NCT00002476 . Findings All 966 patients were included in the analyses . Among patients who did not undergo surgery , the median overall survival was 2·6 years ( 99 % CI 1·9–4·2 ) in the radiotherapy alone group , 4·7 ( 2·6–7·8 ) years in the SIM alone group , 2·3 ( 1·6–3·5 ) years in the SUB alone group , and 2·7 ( 1·6–4·7 ) years in the SIM+SUB group ( p=0·10 ) . The corresponding median EFS were 1·0 ( 0·7–1·4 ) , 2·2 ( 1·1–6·0 ) , 1·0 ( 0·6–1·5 ) , and 1·0 ( 0·6–2·0 ) years ( p=0·005 ) , respectively . For every 100 patients given SIM alone , there are 11 fewer EFS events ( 99 % CI 1–21 ) , compared with 100 given radiotherapy , 10 years after treatment . Among the patients who had previously undergone surgery  , median overall survival was 5·0 ( 99 % CI 1·8–8·0 ) and 4·6 ( 2·2–7·6 ) years in the radiotherapy alone and SIM alone groups ( p=0·70 ) , respectively , with corresponding median EFS of 3·7 ( 99 % CI 1·1–5·9 ) and 3·0 ( 1·2–5·6 ) years ( p=0·85 ) , respectively . The percentage of patients who had a significant toxicity during treatment were : 11 % ( radiotherapy alone , n=25 ) , 28 % ( SIM alone , n=47 ) , 12 % ( SUB alone , n=19 ) , and 36 % ( SIM+SUB , n=55 ) among patients without previous surgery ; and 9 % ( radiotherapy alone , n=12 ) and 20 % ( SIM alone , n=24 ) among those who had undergone previous surgery . The most common toxicity during treatment was mucositis . The percentage of patients who had a significant toxicity at least 6 months after r and omisation were : 6 % ( radiotherapy alone , n=13 ) , 6 % ( SIM alone , n=10 ) , 4 % ( SUB alone , n=7 ) , and 6 % ( SIM+SUB , n=9 ) among patients who had no previous surgery ; and 7 % ( radiotherapy alone , n=10 ) and 11 % ( SIM alone , n=13 ) among those who had undergone previous surgery . The most common toxicity 6 months after treatment was xerostomia , but this occurred in 3 % or less of patients in each group . Interpretation Concurrent non-platinum chemoradiotherapy  reduces recurrences , new tumours , and deaths in patients who have not undergone previous surgery , even 10 years after starting treatment . Chemotherapy given after radiotherapy ( with or without concurrent chemotherapy ) is ineffective . Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy . Funding Cancer Research UK , with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre BACKGROUND This r and omised Phase II study assessed the activity and safety of concurrent chemoradiotherapy ( CRT ) and lapatinib followed by maintenance treatment in locally advanced , unresected stage III/IVA/IVB head and neck cancer . PATIENTS AND METHODS Patients were r and omised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib .  Treatment continued until disease progression or study withdrawal . Primary end-point was complete response rate ( CRR ) by independent review 6 months post-CRT . RESULTS Sixty-seven patients ( median age 56 years ; 97 % Eastern Cooperative Oncology Group performance status ≤1 ; 82 % stage IV ) were recruited . CRT dose intensities were unaffected by lapatinib : median radiation dose 70 Gy ( lapatinib , placebo ) , duration 49 ( lapatinib ) and 50 days ( placebo ) ; median cisplatin dose 260 mg/m(2 ) ( lapatinib ) and 280 mg/m(2 ) ( placebo ) . Lapatinib combined with CRT was well-tolerated . Grade 3/4 toxicities during CRT were balanced between arms , with the exception of an excess of grade 3 diarrhoea ( 6 % versus 0 % ) and rash ( 9 % versus 3 % ) and two grade 4 cardiac events in the lapatinib arm . CRR at 6 months post-CRT was 53 % with lapatinib versus 36 % with placebo in the intent-to-treat population . The progression-free survival ( PFS ) and overall survival rates at 18 months were 55 % versus 41 % and 68 % versus 57 % for the lapatinib and placebo arms , respectively . The difference between study arms was greatest in p16-negative disease ( median PFS > 20.4 months [ lapatinib ] versus 10.9 [ placebo ] ) . CONCLUSION Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease
BACKGROUND There are still many unresolved questions in the management of locally advanced Head and Neck Cancer ( HNC ) .
Many chemotherapeutic drugs and radiotherapy fractionation schemes are available and not all have been evaluated in head-to-head clinical trials .
This systematic review and Bayesian network meta- analysis aims to compare the available treatment strategies and chemotherapeutic options for locally advanced HNC .
Altered fractionation increases the risk of developing grade 3 - 4 mucositis compared to conventional RT ( OR 3.74 95 % 1.64 - 8.67 ) INTERPRETATION : CCRT with cisplatin remains the gold st and ard of treatment .