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. Tirapazamine, Cisplatin, and Radiation versus Fluorouracil, Cisplatin, and Radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. Adjuvant therapy with cetuximab for locally advanced squamous cell carcinoma of the oropharynx: results from a randomized, phase II prospective trial. Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin. 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 Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival, surgery, and organ preservation. Induction chemotherapy with cisplatin/docetaxel versus cisplatin/5-fluorouracil for locally advanced squamous cell carcinoma of the head and neck: a randomised phase II study. 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 trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. Gemcitabine concurrent with radiation therapy for locally advanced head and neck carcinomas. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study. Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: A Randomized Phase II 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. Randomized phase II study of cisplatin and 5-FU continuous infusion (PF) versus cisplatin, UFT and vinorelbine (UFTVP) as induction chemotherapy in locally advanced squamous cell head and neck cancer (LA-SCHNC) Concurrent chemo-radiotherapy with mitomycin C compared with porfiromycin in squamous cell cancer of the head and neck: final results of a randomized clinical trial. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. Randomized clinical trial of post-operative radiotherapy versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck cancer: results of the IAEA multicentre randomised trial. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. Concomitant chemoradiotherapy using low-dose weekly gemcitabine versus low-dose weekly paclitaxel in locally advanced head and neck squamous cell carcinoma: a phase III study 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. Prospective randomized study of post-operative chemotherapy with levamisole and UFT for head and neck carcinoma. 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). Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. A comparative study of a monoclonal antibody against EGFR (nimotuzumab) used in combination with chemoradiation versus chemoradiation alone in the treatment of locally advanced inoperable squamous cell carcinoma of the head and neck. 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. 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). Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. 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 phase II trial of cetuximab-based induction chemotherapy followed by concurrent cetuximab, 5-FU, hydroxyurea, and hyperfractionated radiation (CetuxFHX), or cetuximab, cisplatin, and accelerated radiation with concomitant boost (CetuxPX) in patients with locoregionally advanced head and Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. 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. Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients. Systemic therapy in the curative treatment of head-and-neck squamous cell cancer: Cancer Care Ontario clinical practice guideline. Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity. Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial Relationship between radiation treatment time and overall survival after induction chemotherapy for locally advanced head-and-neck carcinoma: a subset analysis of TAX 324. 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. Two-year results from a Swedish study on conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma--the ARTSCAN study.
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 PURPOSE To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma ( SCC ) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial . PATIENTS AND METHODS One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were r and omized to receive definitive radiotherapy ( 70 Gy in 7 weeks ) concurrently with either cisplatin ( 75 mg/m(2 ) ) plus tirapazamine ( 290 mg/m(2)/d ) on day 2 of weeks 1 , 4 , and 7 , and tirapazamine alone ( 160 mg/m(2)/d ) on days 1 , 3 , and 5 of weeks 2 and 3 ( TPZ/CIS ) , or cisplatin ( 50 mg/m(2 ) ) on day 1 and infusional fluorouracil ( 360 mg/m(2)/d ) on days 1 through 5 of weeks 6 and 7 ( chemoboost ) . RESULTS Three-year failure-free survival rates were 55 % with TPZ/CIS ( 95 % CI , 39 % to 70 % ) and 44 % with chemoboost ( 95 % CI , 30 % to 60 % ; log-rank P = .16 ) . Three-year locoregional failure-free rates were 84 % in the TPZ/CIS arm ( 95 % CI , 71 % to 92 % ) and 66 % in the chemoboost arm ( 95 % CI , 51 % to 79 % ; P = .069 ) . More febrile neutropenia and grade 3 or 4 late mucous membrane toxicity were observed with TPZ/CIS , while acute skin radiation reaction was more severe and prolonged with chemoboost . Compliance with protocol treatment was satisfactory on both arms . CONCLUSION Both regimens are feasible and are associated with significant but acceptable toxicity profiles in the cooperative group setting . Based on the promising efficacy seen in this trial , TPZ/CIS is being evaluated in a large phase III trial 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 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 PURPOSE The long term results and patterns of failure in patients with squamous cell head and neck carcinoma ( SCHNC ) treated in a prospect i ve r and omized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin ( CRT ) was compared with radiotherapy only ( RT ) , were analyzed . PATIENTS AND METHODS Between March 1997 and December 2001 , 114 eligible patients with Stage III or IV SCHNC were r and omized .  Primary surgical treatment was performed with curative intent in all patients . Patients in both groups were postoperatively irradiated to the total dose of 56 - 70 Gy . Chemotherapy included Mitomycin C 15 mg/m2 after 10 Gy and 5 mg of Bleomycin twice weekly during irradiation . Median follow-up was 76 months ( 48 - 103 months ) . RESULTS At 5 years in the RT and CRT arms , the locoregional control was 65 % and 88 % ( p = 0.026 ) , disease-free survival 33 % and 53 % ( p = 0.035 ) , and overall survival 37 % and 55 % ( p = 0.091 ) respectively . Patients who benefited from chemotherapy were those with high-risk factors . The probability of distant metastases was 22 % in RT and 20 % in CRT arm ( p = 0.913 ) , of grade III or higher late toxicity 19 % in RT and 26 % in CRT arm ( p = 0.52 ) and of thyroid dysfunction 36 % in RT and 56 % in CRT arm ( p = 0.24 ) . The probability to develop a second primary malignancy ( SPM ) was 34 % in the RT and 8 % in the CRT arm ( p = 0.023 ) . One third of deaths were due to infection , but there was no difference between the 2 groups . CONCLUSION With concomitant radiochemotherapy , locoregional control and disease free survival were significantly improved . Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent . The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation 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 We conducted a multinational , r and omized study to compare radiotherapy alone with radiotherapy plus cetuximab , a monoclonal antibody against the epidermal growth factor receptor , in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck . METHODS Patients with locoregionally advanced head and neck cancer were r and omly assigned to treatment with high-dose radiotherapy alone ( 213 patients ) or high-dose radiotherapy plus weekly cetuximab  ( 211 patients ) at an initial dose of 400 mg per square meter of body-surface area , followed by 250 mg per square meter weekly for the duration of radiotherapy . The primary end point was the duration of control of locoregional disease ; secondary end points were overall survival , progression-free survival , the response rate , and safety . RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone ( hazard ratio for locoregional progression or death , 0.68 ; P=0.005 ) . With a median follow-up of 54.0 months , the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone ( hazard ratio for death , 0.74 ; P=0.03 ) . Radiotherapy plus cetuximab significantly prolonged progression-free survival ( hazard ratio for disease progression or death , 0.70 ; P=0.006 ) . With the exception of acneiform rash and infusion reactions , the incidence of grade 3 or greater toxic effects , including mucositis , did not differ significantly between the two groups . CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck . ( Clinical Trials.gov number , NCT00004227 . BACKGROUND Locally advanced laryngeal and hypopharyngeal cancers ( LHC ) represent a group of cancers for which surgery , laryngectomy-free survival ( LFS ) , overall survival ( OS ) , and progression-free survival ( PFS ) are clinical ly meaningful end points . PATIENTS AND METHODS These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324 , a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil ( TPF ) against cisplatin and fluorouracil ( PF ) , followed by chemoradiotherapy . RESULTS Among 501 patients enrolled in TAX 324 , 166 had LHC ( TPF , n = 90 ; PF , n = 76 ) . Patient characteristics were similar between subgroups . Median OS for TPF was 59 months [ 95 % confidence interval ( CI ) : 31-not reached ] versus 24 months ( 95 % CI : 13 - 42 ) for PF [ hazard ratio ( HR ) for death : 0.62 ; 95 % CI : 0.41 - 0.94 ; P = 0.024 ] . Median PFS for TPF was 21 months ( 95 % CI : 12 - 59 ) versus 11 months ( 95 % CI : 8 - 14 ) for PF ( HR : 0.66 ; 95 % CI : 0.45 - 0.97 ; P = 0.032 ) . Among operable patients ( TPF , n = 67 ; PF , n = 56 ) , LFS was significantly greater with TPF ( HR : 0.59 ; 95 % CI : 0.37 - 0.95 ; P = 0.030 ) . Three-year LFS with TPF was 52 % versus 32 % for PF . Fewer TPF patients had surgery ( 22 % versus 42 % ; P = 0.030 ) . CONCLUSIONS In locally advanced LHC , sequential therapy with induction TPF significantly improved survival and PFS versus PF . Among operable patients , TPF also significantly improved LFS and PFS . These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC A combination of cisplatin and 5-fluorouracil ( PF ) is considered the st and ard induction chemotherapy regimen for squamous cell carcinoma of the head and neck ( SCCHN ) . The present study compares the efficacy and safety of a new combination of cisplatin/docetaxel versus the PF regimen . A total of 83 chemotherapy-naive patients with locally advanced SCCHN were r and omised to receive every 21 d ( i ) docetaxel 85 mg/m2 i.v . on day 1 and cisplatin 40 mg/m2 i.v . on days 1 and 2 ( arm A ) or ( ii ) cisplatin 100 mg/m2 i.v . on day 1 followed by 5-fluorouracil 1000 mg/m2 in 24 h continuous infusion for 5 d ( arm B ) . A total of 287 cycles ( range 1 - 3 per patient ) were administered . Among 76 patients evaluable for response , the overall response rate in arm A was 70 % ( complete response ( CR ) 26 % , partial response ( PR ) 44 % ) and in arm B 69 % ( CR 16 % , PR 54 % ) , respectively . Median survival in arm A was 7.6 months ( 95 % CI : 5.8 - 11.1 ) and 9.9 months ( 95 % CI : 7.4 - 14.6 ) for arm B. The most frequent grade 3/4 toxicity in arm A was neutropaenia ( 34.1 % ) and diarrhoea ( 9.8 % ) versus mucositis ( 29.3 % ) and neutropaenia ( 19.5 % ) in arm B. Both schedules present a similar efficacy , with different but acceptable toxicity patterns 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 BACKGROUND Chemotherapy with cisplatin ( P ) and 5-fluorouracil ( F ) followed by radiotherapy in patients who respond to chemotherapy  is an alternative to total laryngectomy for patients with locally advanced larynx and hypopharynx cancer . Data suggest that docetaxel ( T ) may add to the efficacy of PF . The objective of this trial was to determine whether adding T to PF could increase the larynx preservation rate . METHODS Patients who had larynx and hypopharynx cancer that required total laryngectomy were r and omly assigned to receive three cycles of TPF or PF . Patients who responded to chemotherapy received radiotherapy with or without additional chemotherapy . Patients who did not respond to chemotherapy underwent total laryngectomy followed by radiotherapy with or without additional chemotherapy . The primary endpoint was 3-year larynx preservation rate . Secondary endpoints included acute toxicities and overall response . All statistical tests were two-sided . RESULTS Baseline patient and tumor characteristics were well balanced between the  TPF ( n = 110 ) and PF ( n = 103 ) groups . With a median follow-up of 36 months , the 3-year actuarial larynx preservation rate was 70.3 % with TPF vs 57.5 % with PF ( difference = 12.8 % ; P = .03 ) . Patients in the TPF group had more grade 2 alopecia , grade 4 neutropenia , and febrile neutropenia , whereas patients in the PF group had more grade 3 and 4 stomatitis , thrombocytopenia , and grade 4 creatinine elevation . The overall response was 80.0 % in the TPF group vs 59.2 % in the PF group ( difference = 20.8 % ; P = .002 ) . CONCLUSIONS In patients with advanced larynx and hypopharynx carcinomas , TPF induction chemotherapy was superior to the PF regimen in terms of overall response rate . These results suggest that larynx preservation could be achieved for a higher proportion of patients BACKGROUND Management of advanced head and neck carcinoma is a challenging proposition . Presently concomitant chemo-irradiation has become the st and ard of care in such patients . Many chemotherapeutic drugs have shown radio-sensitising effects when used concomitantly along with radiation . The present study was carried out with the objective of assessing the feasibility and efficacy of low dose gemcitabine as radiosensitizer when used during radical radiotherapeutic management of patients with locally advanced head and neck carcinomas . PATIENTS AND METHODS From November 2000 to March 2003 , eighty histopathologically proven cases of squamous cell head and neck carcinoma were included in this trial , 40 patients were r and omly assigned to receive radiotherapy alone and 40 patients to receive gemcitabine along with radiotherapy .  RESULTS All patients were assessable for toxicity and response . Severe mucositis ( WHO level 5 reactions were observed in 67 % patients in the CT/RT group vs 16 % patients in the RT only group . No severe hematological toxicity was seen . The rates of complete and partial responses were 42.5 % & 57.5 % respectively for RT only and 62.5 % & 37.5 % , respectively for CT/RT group . There was no significant difference in the response rates at the end of treatment but disease free survival at three years was better in the CT/RT group ( 63.3 % vs 20 % ) . Nine of the 17 patients with complete response in the radiation only group developed relapse while no relapses were seen in CT/RT group . CONCLUSION In the present study the combination of gemcitabine and radiotherapy has not shown any statistical difference in locoregional control but survival advantage was seen as compared to radiotherapy alone . At the same time more mucosal and skin toxicity was encountered when Gemcitabine is given concurrently with radiation BACKGROUND Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer . We report results of the r and omized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer . METHODS Patients with resectable advanced squamous cell carcinoma of the larynx ( tumor stage T3-T4 ) or hypopharynx ( T2-T4 ) , with regional lymph nodes in the neck staged as N0-N2 and with no metastasis , were r and omly assigned to treatment in the sequential ( or control ) or the alternating ( or experimental ) arm . In the sequential arm , patients with a 50 % or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles , followed by radiotherapy ( 70 Gy total ) . In the alternating arm , a total of four cycles of cisplatin and 5-fluorouracil ( in weeks 1 , 4 , 7 , and 10 ) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles ( 60 Gy total ) . All nonresponders underwent salvage surgery and postoperative radiotherapy . The Kaplan-Meier method was used to obtain time-to-event data . RESULTS The 450 patients were r and omly assigned to treatment ( 224 to the sequential arm and 226 to the alternating arm ) . Median follow-up was 6.5 years . Survival with a functional larynx was similar in sequential and alternating arms ( hazard ratio of death and /or event = 0.85 , 95 % confidence interval = 0.68 to 1.06 ) , as were median overall survival ( 4.4 and 5.1 years , respectively ) and median progression-free interval ( 3.0 and 3.1 years , respectively ) . Grade 3 or 4 mucositis occurred in 64 ( 32 % ) of the 200 patients in the sequential arm who received radiotherapy and in 47 ( 21 % ) of the 220 patients in the alternating arm . Late severe edema and /or fibrosis was observed in 32 ( 16 % ) patients in the sequential arm and in 25 ( 11 % ) in the alternating arm . CONCLUSIONS Larynx preservation , progression-free interval , and overall survival were similar in both arms , as were acute and late toxic effects BACKGROUND We design ed a r and omized clinical trial to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV ( i.e. , advanced oropharynx carcinoma ) . METHODS A total of 226 patients have been entered in a phase III multicenter , r and omized trial comparing radiotherapy alone ( arm A ) with radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B , patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin ( 70 mg/m(2 ) per day ) and 5-fluorouracil ( 600 mg/m(2 ) per day ) by continuous infusion . The two arms were equally balanced with regard to age , sex , stage , performance status , histology , and primary tumor site . RESULTS Radiotherapy compliance was similar in the two arms with respect to total dose , treatment duration , and treatment interruption . The rate of grade s 3 and 4 mucositis was statistically significantly higher in arm B ( 71 % ; 95 % confidence interval [ CI ] = 54%-85 % ) than in arm A ( 39 % ; 95 % CI = 29%-56 % ) . Skin toxicity was not different between the two arms . Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were , respectively , 51 % ( 95 % CI = 39%-68 % ) versus 31 % ( 95 % CI = 18%-49 % ) and 42 % ( 95 % CI = 30%-57 % ) versus 20 % ( 95 % CI = 10%-33 % ) for patients treated with combined modality versus radiation therapy alone ( P = .02 and .04 , respectively ) . The locoregional control rate was improved in arm B ( 66 % ; 95 % CI = 51%-78 % ) versus arm A ( 42 % ; 95 % CI = 31%-56 % ) . CONCLUSION The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx BACKGROUND Concomitant chemoradiotherapy ( CT/RT ) is the st and ard treatment of locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . We evaluated the efficacy of induction docetaxel ( Taxotere ) , cisplatin , and 5-fluorouracil ( TPF ) before CT/RT versus CT/RT alone . PATIENTS AND METHODS Patients with stage III-IVM0 SCCHN , Eastern Cooperative Oncology Group performance status of zero to one , were r and omly assigned to receive CT/RT alone ( arm A : two cycles of cisplatin 20 mg/m(2 ) , days1 - 4 , plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , during weeks 1 and 6 of radiotherapy ) or three cycles of TPF ( arm B : docetaxel 75 mg/m(2 ) and cisplatin 80 mg/m(2 ) , day 1 , and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , every 3 weeks ) followed by the same CT/RT . The primary end point was the rate of radiologic complete response ( CR ) at 6 - 8 weeks after the end of CT/RT . RESULTS A total of 101 patients were r and omly allocated to the study ( 51 arm A ; 50 arm B ) . CR rates were 21.2 % ( arm A ) versus 50 % ( arm B ) . Median progression-free survival and overall survival were , respectively , 19.7 and 33.3 months ( arm A ) and 30.4 and 39.6 months ( arm B ) . Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms . CONCLUSION Induction TPF followed by CT/RT was associated with higher radiologic CR  in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility 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 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 Objectives We conducted a multicentric r and omized phase II trial comparing 5-FU continuous infusion ( PF ) and cisplatin , UFT and vinorelbine ( UFTVP ) as induction chemotherapy ( IC ) in locally advanced squamous cell head and neck cancer ( LA-SCHNC ) . Primary objective was complete response ( CR ) to IC and overall survival ( OS ) was a secondary objective . Material s and methods PF : cisplatin 100 mg/m2 i.v . Day 1 ( D1 ) and 5-FU 1,000 mg/m2 per day i.v . continous infusion D1–D5 , every 21 days . UFTVP : cisplatin 100 mg/m2 i.v . D1 ; UFT 200 mg/m2 per day p.o . D1–D21 and vinorelbine 25 mg/m2 i.v . D1 and D8 , every 21 days . Four IC courses were planned in both arms . Results A total of 206 patients ( pts ) were included ( PF/UFTVP : 99/107 ) : oral cavity : 8%/10 % , oropharynx : 20%/25 % , hypopharynx : 17%/14 % , larynx : 54%/50 % . Stage ( TNM , 2002 ) : III : 41%/35 % , IVA : 23%/27 % , IVB : 35%/38 % . Complete response to IC : PF:36%/UFTVP:31 % ( P : no significative ( NS ) ) . G 3–4 toxicity ( PF/UFTVP ) : neutropenia : 52%/72 % ; febrile neutropenia : 3%/20 % ( P < 0.001 ) ; anaemia:1%/14 % ( P < 0.001 ) ; trombocytopenia : 5%/0 % ( P = 0.02 ) ; mucositis : 15%/7 % ( P < 0.001 ) . Deaths during IC : 2(2%)/3(3 % ) . IC with UFTVP was associated with a favourable OS in the Cox analysis ( actuarial 5 year OS : 49 % vs. 34 % ; HR : 0.67 , 95 % CI : 0.47–0.95 , P : 0.03 ) . Conclusions Although clinical response is equal in both arms , overall survival ( Cox ) is better in the UFTVP arm . Febrile neutropenia and anaemia were more frequent with UFTVP while mucositis and trombocytopenia were more severe with PF PURPOSE Previous r and omized trials have shown a benefit with concurrent use of the hypoxic cell cytotoxin mitomycin C ( MC ) and radiation ( RT ) in the management of squamous cell cancer of the head and neck ( SCCHN ) . We conducted a r and omized trial comparing MC with porfiromycin ( POR ) in combination with RT in the management of SCCHN . METHODS AND MATERIAL S Between 1992 and 1999 , 128 patients with SCCHN were enrolled in this prospect i ve r and omized trial . Patients were stratified by management intent , and balanced with respect to stage and site of disease . They were r and omized to receive MC ( 15 mg/M(2 ) ) or POR ( 40 mg/M(2 ) ) on Days 5 and 47 ( or last day ) of RT . Of 121 evaluable patients , 61 were r and omized to MC and 60 to POR . Patients were treated with st and ard daily RT to a total median dose of 64 Gy over 47 days . Patients were well balanced with respect to management intent , stage , site , age , sex , hemoglobin levels , tumor grade , radiation dose , and days on treatment . RESULTS There were no significant differences between the two arms with respect to acute hematologic or nonhematologic toxicities . As of January 2003 with a median follow-up of 6.3 years , there have been 19 local relapses ( 4 MC vs. 15 POR ) , 21 regional relapses ( 7 MC vs. 14 POR ) , 24 distant metastases ( 11 MC vs. 13 POR ) , and 66 deaths ( 33 MC vs. 33 POR ) . MC was superior to POR with respect to 5-year local relapse-free survival ( 91.6 % vs. 72.7 % , p = 0.01 ) , local-regional relapse-free survival ( 82 % vs. 65.3 % , p = 0.05 ) , and disease-free survival ( 72.8 % vs. 52.9 % , p = 0.026 ) . There were no significant differences between the two arms with respect to overall survival ( 49.2 % vs. 54.4 % ) or distant metastasis-free rate ( 79.9 % vs. 75.9 % ) . CONCLUSIONS Despite promising pre clinical data , and an acceptable toxicity profile , POR was inferior to MC as an adjunct to RT in the management of SCCHN . This r and omized trial emphasizes the need for r and omized studies to evaluate new agents in the management of SCCHN BACKGROUND The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear . The PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel , cisplatin , and fluorouracil ( TPF ) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer . METHODS Adult patients with previously untreated , non-metastatic , newly diagnosed head and neck cancer were eligible . Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage ( 3 or 4 ) or regional-node stage ( 2 or 3 , except T1N2 ) , or if they were a c and i date for organ preservation . Patients were r and omly assigned ( in a 1:1 ratio ) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin . A computer-generated r and omisation schedule using minimisation was prepared and the treatment assignment was done central ly at one of the study sites . Patients , study staff , and investigators were not masked to group assignment . Stratification factors were WHO performance status , primary disease site , and stage . The primary endpoint was overall survival . Analysis was by intention to treat . Patient accrual was terminated in December , 2008 , because of slow enrolment . The trial is registered with Clinical Trials.gov , number NCT00095875 . FINDINGS Between Aug 24 , 2004 , and Dec 29 , 2008 , we enrolled 145 patients across 16 sites . After a median follow-up of 49 months ( IQR 39 - 63 ) , 41 patients had died-20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy  alone group . 3-year overall survival was 73 % ( 95 % CI 60 - 82 ) in the induction therapy followed by chemoradiotherapy group and 78 % ( 66 - 86 ) in the chemoradiotherapy alone group ( hazard ratio 1·09 , 95 % CI 0·59 - 2·03 ; p=0·77 ) . More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group ( 16 patients ) than in the chemoradiotherapy alone group ( one patient ) . INTERPRETATION Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone . We can not rule out the possibility of a difference in survival going undetected due to early termination of the trial . Clinicians should still use their best judgment , based on the available data , in the decision of how to best treat patients . The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure . FUNDING Sanofi-Aventis 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 AND PURPOSE Post-operative radiotherapy is indicated for the treatment of head and neck cancers . In vitro , chemotherapy potentiates the cytotoxic effects of radiation . We report the results of a r and omized trial testing post-operative radiotherapy alone versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement . MATERIAL S AND METHODS The study involved patients undergoing curative-intent surgery for head and neck cancers with histological evidence of lymph node involvement . Patients were r and omly assigned to receive radiotherapy alone ( 54 - 72Gy , 30 - 40 fractions , 6 - 8 weeks ) or identical treatment plus concomitant Carboplatin ( 50mg/m(2 ) administered by IV infusion twice weekly ) . RESULTS Between February 1994 and June 2002 , 144 patients were included . With a median follow-up of 106 months ( 95 % confidence interval ( CI ) [ 92 - 119 ] ) , the 2-year rate of loco-regional control was 73 % ( 95 % CI : 0.61 - 0.84 ) in the combined treatment group and 68 % ( 95 % CI : 0.57 - 0.80 ) in the radiotherapy group ( p=0.26 ) . Overall survival did not differ significantly between groups ( hazard ratio for death , 1.05 ; 95 % CI : 0.69 - 1.60 ; p=0.81 ) . CONCLUSIONS Twice-weekly administration of carboplatin concomitant to post-operative radiotherapy did not improve local control or overall survival rates in this population of patients with node-positive head and neck cancers 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 BACKGROUND AND PURPOSE Single agent mitomycin c ( MMC ) has been shown to improve the outcome of radiotherapy in single institution trials . In order to confirm these findings in a broader worldwide setting , the International Atomic Energy Agency ( IAEA ) initiated a multicentre trial r and omising between radiotherapy alone versus radiotherapy plus MMC . MATERIAL AND METHODS Patients with advanced head and neck cancer were treated with primary curative radiotherapy ( 66 Gy in 33 fractions with five fractions per week ) + /-a single injection ( 15 mg/m(2 ) ) of MMC at the end of the first week of radiotherapy . Stratification parameters were tumour localization , T-stage , N-stage , and institution . A total of 558 patients were recruited in the trial from February 1996 to December 1999 . Insufficient accrual and reporting led to the exclusion of three centres . The final study population consisted of 478 patients from seven centres . Patients had stage III ( n=223 ) or stage IV ( n=255 ) squamous cell carcinoma of the oral cavity ( n=230 ) , oropharynx ( n=140 ) , hypopharynx ( n=65 ) or larynx ( n=43 ) . Prognostic factors like age , gender , site , size , differentiation and stage were well balanced between the two arms . RESULTS The haematological side effects of  MMC  were very modest ( < 5 % grade 3 - 4 ) and did not require any specific interventions . Furthermore , MMC did not enhance the incidence or severity of acute and late radiation side effects . Confluent mucositis and dry skin desquamation was common , occurring in 56 % and 62 % of patients , respectively . The overall 3-year primary locoregional tumour control , disease-specific and overall survival rates were 19 , 36 and 30 % , respectively . Gender , haemoglobin drop , tumour site , tumour and nodal stage were significant parameters for loco-regional tumour control . There was no significant effect of MMC on locoregional control or survival , except for the 161 N0 patients , where MMC result ed in a better loco-regional control ( 3-year estimate 16 % vs. 29 % , P=0.01 ) . CONCLUSIONS The study did not show any major influence of MMC on loco-regional tumour control , survival or morbidity after primary radiotherapy in stage III-IV head and neck cancer except in N0 patients where loco-regional control was significantly improved The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer . Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric r and omized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy . The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone . Three cycles of chemotherapy consisting of Cisplatin ( 100 mg/m2 ) on day 1 followed by a 24-hour i.v . infusion of fluorouracil ( 1000 mg/m2/day ) for 5 days were delivered every 21 days . 2–3 weeks after the end of chemotherapy , local treatment was performed . The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou ( GETTEC ) . A total of 318 patients were enrolled in the study between 1986 and 1992 .  Overall survival was significantly better ( P = 0.03 ) in the neoadjuvant chemotherapy group than in the control group , with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group . The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance ( P = 0.11 ) . Stratification of the results on the type of local treatment , surgery plus radiotherapy or radiotherapy alone , did not reveal any heterogeneity in the effect of chemotherapy . © 2000 Cancer Research Campaign PURPOSE To report results of a r and omized phase II trial ( Radiation Therapy Oncology Group RTOG-0234 ) examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with squamous cell carcinoma of the head and neck ( SCCHN ) with high-risk pathologic features . PATIENTS AND METHODS Eligibility required pathologic stage III to IV SCCHN with gross total resection showing positive margins and /or extracapsular nodal extension and /or two or more nodal metastases . Patients were r and omly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m(2 ) or docetaxel 15 mg/m(2 ) once per week . RESULTS Between April 2004 and December 2006 , 238 patients were enrolled . With a median follow-up of 4.4 years , 2-year overall survival ( OS ) was 69 % for the cisplatin arm and 79 % for the docetaxel arm ; 2-year disease-free survival ( DFS ) was 57 % and 66 % , respectively . Patients with p16-positive oropharynx tumors showed markedly improved survival outcome relative to patients with p16-negative oropharynx tumors . Grade 3 to 4 myelosuppression was observed in 28 % of patients in the cisplatin arm and 14 % in the docetaxel arm ; mucositis was observed in 56 % and 54 % , respectively . DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial ( Phase III Intergroup Trial of Surgery Followed by Radiotherapy Versus Radiochemotherapy for Resectable High Risk Squamous Cell Carcinoma of the Head and Neck ) , which had a hazard ratio of 0.76 for the cisplatin arm versus control ( P = .05 ) and 0.69 for the docetaxel arm versus control ( P = .01 ) , reflecting absolute improvement in 2-year DFS of 2.5 % and 11.1 % , respectively . CONCLUSION The delivery of postoperative chemoradiotherapy and cetuximab to patients with SCCHN is feasible and tolerated with predictable toxicity . The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial BACKGROUND Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the st and ard alternative to total laryngectomy for patients with locally advanced laryngeal cancer . The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown . METHODS We r and omly assigned patients with locally advanced cancer of the larynx to one of three treatments : induction cisplatin plus fluorouracil followed by radiotherapy , radiotherapy with concurrent administration of cisplatin , or radiotherapy alone . The primary end point was preservation of the larynx . RESULTS A total of 547 patients were r and omly assigned to one of the three study groups . The median follow-up period was 3.8 years . At two years , the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin ( 88 percent ) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy ( 75 percent , P=0.005 ) or radiotherapy alone ( 70 percent , P<0.001 ) . The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin ( 78 percent , vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone ) . Both of the chemotherapy-based regimens suppressed distant metastases and result ed in better disease-free survival than radiotherapy alone . However , overall survival rates were similar in all three groups . The rate of high- grade toxic effects was greater with the chemotherapy-based regimens ( 81 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin , vs. 61 percent with radiotherapy alone ) . The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy . CONCLUSIONS In patients with laryngeal cancer , radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control The objective of this study was to compare concomitant chemoradiotherapy based on weekly low-dose gemcitabine versus weekly low-dose paclitaxel in locally advanced head and neck squamous cell carcinoma . Previously , untreated patients with locally advanced squamous cell carcinoma of the head and neck were r and omly assigned to one of the two concomitant chemoradiation regimens : ( 1 ) weekly gemcitabine at a dose of 100 mg/m2 over 30 min 1–2 h before radiotherapy and ( 2 ) weekly paclitaxal at a dose of 20 mg/m2 over 60 min 4–6 h before radiotherapy . The planned radiotherapy dose was 65 Gy over 6.5 weeks in 32 setting s. Two hundred and sixteen patients were r and omly divided into 2 groups : group A ( 110 patients ) and group B ( 106 patients ) who received concomitant weekly low-dose gemcitabine and low-dose paclitaxal , respectively , with the radiotherapy protocol . The hematological toxicity was generally mild . On the contrary , non-hematologic toxicities were severe . Grade III mucositis occurred in 36 % in group A and in 24 % in group B ( P = 0.04 ) . Moreover , grade III dermatitis were encountered in 24 % in group A and 13 % in group B ( P = 0.049 ) . Thirty-two ( 29 % ) of group A and 18(17 % ) of group B patients required enteral or parenteral feeding ( P = 0.01 ) . Sixteen ( 15 % ) of group A and 6 ( 6 % ) of group B required enteral or parenteral feeding that lasted for 6 months ( P = 0.03 ) . Regarding the late effect on swallowing , 8 % of patients in group A and 2 % of patients in group B required enteral or parenteral feeding for more than 6 months ( P = 0.035 ) . Response rates were 78 and 89 % in groups A and B , respectively ( P = 0.038 ) . The 2-year progression-free survival figures were 54 and 64 % of groups A and B , respectively ; however , the 2-year overall survival figures were 56 and 67 % , respectively . On the other h and , the 3-year progression-free survival figures were 39 and 48 % for groups A and B , respectively , while the 3-year overall survival figures were 45 and 49 % , respectively ( P = 0.05 ) . Both concomitant chemoradiotherapy regimens were easily given in the outpatient clinic . The regimen based on paclitaxel was significantly more tolerable and effective ; however , the difference was not enormous 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 AIMS A prospect i ve r and omized study was conducted to evaluate the benefit of adjuvant levamisole/UFT ( futraful and uracil ) chemotherapy in head and neck squamous cell carcinoma . METHODS Sixty-five patients with stage III and IV squamous cell carcinomas of oral cavity , oropharynx , hypopharynx and larynx with no distant metastasis were r and omized for the chemotherapy study . Thirty-one patients were r and omized for chemotherapy  and two of them were subsequently excluded . In this study , a total of 29 patients on levamisole/UFT therapy and 34 patients on the control group were analysed . The main outcome was measured by the 5-year disease-free actuarial survival rate . RESULTS The rates of distant metastasis were 10 % for chemotherapy group and 32 % for control group ( P=0.06 ) . The 5-year disease-free actuarial survival rates for patients with and without adjuvant chemotherapy were 57 % and 39 % respectively ( P=0.207 ) . CONCLUSIONS A trend of better distant control in head and neck cancer patients with post-operative adjuvant oral chemotherapy was observed . The side effects were minimal . However , there was no statistically significant improvement in the overall long-term survival . It may be of value to conduct a large-scale multi-centre prospect i ve r and omized study to verify the efficacy of levamisole and UFT as post-operative adjuvant chemotherapy for the control of distant metastasis in high-risk population 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 report the final results of a prospect i ve r and omized trial that aim ed to evaluate efficacy and toxicity of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV squamous cell carcinoma of the head and neck and histological evidence of extracapsular spread of tumor in lymph node metastase(s ) . METHODS AND MATERIAL S Radiotherapy was delivered using a daily dose of 1.7 Gy for the first 54 Gy and 1.8 to 2 Gy until the completion of the treatment . Cisplatin 50 mg i.v . with forced hydratation was given or not every week ( i.e. , seven to nine cycles ) concurrently with radiotherapy . A total of 44 patients were treated by irradiation only ( RT group ) and 39 by irradiation with chemotherapy ( CM group ) . RESULTS The RT group displayed a higher rate of loco-regional failures as compared to CM group ( 41 vs. 23 % ; p = 0.08 ) . The overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival were better in CM group as compared to RT group with statistically significant differences . Survival without loco-regional treatment failure was better in the CM group , the difference being close to the level of significance ( p = 0.05 ) . Survival without distant metastases were comparable in the two therapeutic groups . Ten severe late complications were observed , four in the RT group ( 17 % ) and six in the CM group ( 22 % ) . Cox univariate analysis confirmed the importance of the therapeutic modality in predicting the overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival . CONCLUSIONS The present final report of this phase III study confirms preliminary results . The concomitant use of 50 mg weekly Cisplatin infusion and postoperative radiation improved loco-regional control and survival . No significant increase of late radiation complications was observed in the CM group 51 Background : To determine the efficacy , safety and tolerability of concurrent nimotuzumab ( monoclonal antibody against epidermal growth factor receptor ) used in combination with chemoradiation versus chemoradiation ( CRT ) alone in advanced inoperable squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS 56 patients were r and omly assigned to either of the two treatment arms , nimotuzumab + CRT arm and CRT alone arm . Both arms received concurrent Cisplatin 30 mg/m2 repeated weekly for 6 - 7 cycles along with external beam radiotherapy 64 - 70 Gy ( 200cGy/day for 5 days a week for 6 - 7 weeks ) . Nimotuzumab arm additionally received nimotuzumab 200 mg weekly for 6 - 7 cycles . The patients were followed for 6 months after completion of CRT . The study end points were tumor response evaluation according to the RECIST Criteria version 1.1 and safety analysis using RTOG Acute Radiation Morbidity Scoring Criteria . Patients were evaluated weekly with hematologic tests and for adverse events like mucositis and dermatitis during the CRT . Tumor assessment was performed with clinical and endoscopic methods regularly during the CRT and then at 1 month , 3 months , and 6 months intervals after CRT . One MR imaging was done before starting the CRT to evaluate the baseline tumor characteristics , and another was done after the completion of CRT either at 3 months or 6 months or at both the intervals . RESULTS 25 patients each were evaluable in both the arms who completed the 6-month study . The overall response rate ( complete response + partial response ) was 96 % in nimotuzumab + CRT arm , whereas it was only 72 % in CRT alone arm after 6 months of completion of CRT , which is statistically significant ( p value = 0.0206 by Chi Square test ) . Additionally , nimotuzumab did not potentiate toxicities of CRT , and there was no significant difference in the acute radiation mucositis , dermatitis , or hematological toxicities in both the groups ( p value>>0.05 ) . CONCLUSIONS Nimotuzumab can be safely added to the st and ard CRT treatment for advanced inoperable SCCHN , to achieve better tumor response without potentiating toxicity 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 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 BACKGROUND Despite the use of resection and postoperative radiotherapy , high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed . We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control . METHODS Between September 9 , 1995 , and April 28 , 2000 , 459 patients were enrolled . After undergoing total resection of all visible and palpable disease , 231 patients were r and omly assigned to receive radiotherapy alone  ( 60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks ) and 228 patients to receive the identical treatment plus concurrent cisplatin ( 100 mg per square meter of body-surface area intravenously on days 1 , 22 , and 43 ) . RESULTS After a median follow-up of 45.9 months , the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( hazard ratio for local or regional recurrence , 0.61 ; 95 percent confidence interval , 0.41 to 0.91 ; P=0.01 ) . The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group , as compared with 72 percent in the radiotherapy group . Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group ( hazard ratio for disease or death , 0.78 ; 95 percent confidence interval , 0.61 to 0.99 ; P=0.04 ) , but overall survival was not ( hazard ratio for death , 0.84 ; 95 percent confidence interval , 0.65 to 1.09 ; P=0.19 ) . The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group ( P<0.001 ) . Four patients who received combined therapy died as a direct result of the treatment . CONCLUSIONS Among high-risk patients with resected head and neck cancer , concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival . However , the combined treatment is associated with a substantial increase in adverse effects 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 5519 Background : Cetuximab is commonly used in combination with either chemotherapy or radiation in the treatment of HNC , although the optimal way to integrate cetuximab with concurrent chemoradiation ( CRT ) remains unclear . We explored the addition of cetuximab to induction chemotherapy and two established CRT platforms in a r and omized phase II trial . METHODS Patients with locoregionally advanced HNC were treated with cetuximab , carboplatin , paclitaxel induction chemotherapy for 2 cycles . Patients were r and omized to A : cetuximab , 5-FU , hydroxyurea , and hyperfractionated week-on week-off RT ( 72 - 74Gy ) ( CetuxFHX ) , or B : cetuximab , cisplatin , accelerated radiation with concomitant boost (CetuxPX)(72Gy ) . Primary endpoints were 1- and 2-year progression-free ( PFS ) , and overall survival ( OS ) . RESULTS 110 patients with locoregionally advanced HNC ( 108 with Stage IV ) were enrolled . 57.3 % of patients had oropharyngeal ( OP ) primaries ( A : 49 % , B : 66 % , p16 staining is pending ) . Induction response rate was 91.8 % . 99.1 % of patients developed a rash ( ≥ grade 3 in 16.4 % ) ; ≥ grade 3 neutropenia developed in 36.3 % of patients . Overall 1- and 2-year survival rates were 98.3 % and 89.5 % in CetuxFHX , and 94.2 % and 91.4 % in CetuxPX arm , with 21.1months median follow-up ( not statistically significant , p=0.27 , logrank test ) . Progression free survival at 1 and 2 years was 86.0 % and 82.3 % in CetuxFHX , and 95.9 % and 89.7 % in CetuxPX ( p=0.18 ) . Grade ≥3 mucositis was present in 91.1%(A ) and 94.3%(B ) of patients ; grade ≥3 dermatitis in 82.1 % and 50.9 % of patients . 95 % of patients completed therapy . Treatment failures occurred in both OP and non-OP tumors . CONCLUSIONS Cetuximab-based induction chemotherapy is well tolerated and active . Cetuximab can safely be integrated with both FHX and cisplatin based CRT with acceptable toxicities . Survival is favorable on both study arms suggesting that either platform could be investigated further . Data on HPV versus non-HPV-related tumors will be available PURPOSE In this r and omized , phase III study , quality of life ( QoL ) was assessed in patients with locoregionally advanced squamous cell carcinoma of the head and neck ( SCCHN ) after high-dose radiotherapy alone or in combination with cetuximab .  PATIENTS AND METHODS Patients with stage III or IV nonmetastatic and measurable squamous cell carcinoma of the oropharynx , hypopharynx , or larynx were eligible .  QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ( EORTC QLQ-C30 ) and EORTC QLQ Head and Neck Cancer-Specific Module at baseline , week 4 , and at months 4 , 8 , and 12 postbaseline . RESULTS In this study , one of the largest conducted in a population of patients with locoregionally advanced SCCHN , 424 patients received radiotherapy alone ( 213 patients ) or radiotherapy plus cetuximab ( 211 patients ) .  Radiotherapy/cetuximab significantly improved locoregional control ( P = .005 ) and overall survival ( P = .03 ) compared with radiotherapy alone , without significantly increasing radiotherapy-associated adverse events . The current analysis focused on the impact of cetuximab on the QoL. Compliance with completion of QoL question naires was high in both arms . QoL worsened during treatment and improved after cessation of treatment , reaching baseline levels at 12 months . There were no significant differences in QoL scores between the treatment arms . This was particularly notable for global health status/QoL , social functioning , social eating , and social contact . Pretreatment global health status/QoL was identified as a significant prognostic variable in these patients . CONCLUSION The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting 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 OBJECTIVE Overexpression of epidermal growth factor receptor ( EGFR ) in many cancers makes it an attractive therapeutic target . This study evaluated the clinical utility of nimotuzumab , a monoclonal anti-EGFR antibody , used concurrently with radiotherapy ( RT ) and chemoradiotherapy ( CRT ) in squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS This open-label study r and omized 92 treatment-naïve patients ( 1:1 ) with advanced SCCHN into chemoradiation ( CRT ± nimotuzumab ) or radiation ( RT ± nimotuzumab ) group by investigator 's discretion ; these were further r and omized into CRT + nimotuzumab or CRT and RT + nimotuzumab or RT groups , respectively . Treatment included 6 cycles each of cisplatin ( 50 mg/week ) , nimotuzumab ( 200 mg/week ) , and RT ( total dose , 60 - 66 Gy ) . Response ( tumor size reduction ) was assessed at Month 6 post-treatment and survival , at Month 60 . RESULTS Forty and 36 patients in the chemoradiation and radiation groups , respectively ( intent-to-treat population ) were evaluated . Overall response at Month 6 post-treatment was 100 % with CRT + nimotuzumab , 70 % with CRT , 76 % with RT + nimotuzumab , and 37 % with RT . At Month 60 , overall survival was 57 % with CRT + nimotuzumab , 26 % with CRT ( P = 0.03 ) , 39 % with RT + nimotuzumab , and 26 % with RT ( P > 0.05 ) . Median overall survival was not reached for CRT + nimotuzumab ; it was 21.94 months for CRT ( P = 0.0078 ) , 14.36 months for RT + nimotuzumab , and 12.78 months for RT ( P = 0.45 ) . Risk of death was 64 % lower with CRT + nimotuzumab than with CRT ( 95%CI : 0.37 , 1.56 ) , and 24 % lower with RT + nimotuzumab than with RT ( 95%CI : 0.16 , 0.79 ) . Thus nimotuzumab was safe and well tolerated with few mild to moderate self-limiting adverse events . CONCLUSION Concurrent use of nimotuzumab with CRT/RT is safe and provides long-term survival benefit OBJECTIVE The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation ( rt ) or surgery , or both , for cure or organ preservation , or both , in patients with locally advanced nonmetastatic ( stages iii-ivb ) squamous cell carcinoma of the head and neck ( lascchn ) . METHODS The Meta- analysis of Chemotherapy in Head and Neck Cancer ( mach-nc ) reports have , de facto , guided practice since 2000 , and so we search ed the literature for systematic review s published from January 2000 to February 2015 in reference to five research questions . A search was also conducted up to February 2015 for r and omized trials ( rcts ) not included in the meta-analyses . Recommendations were constructed using the Cancer Care Ontario Program in Evidence -Based Care practice guidelines development cycle . RESULTS In addition to up date d mach-nc reports , five additional meta-analyses and thirty rcts were identified . Five recommendations for lascchn treatment were generated based on those data . Concurrent chemoradiation ( ccrt ) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment . The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence . For lascchn patients who are c and i date s for organ preservation strategies and would otherwise require total laryngectomy , either ccrt or induction chemotherapy , followed by rt or surgery based on tumour response is recommended . The addition of cetuximab to intensified rt ( concomitant boost or hyperfractionated schedule ) is an alternative to ccrt . Routine use of induction chemotherapy to improve overall survival is not recommended . CONCLUSIONS We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn . A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx . One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting . Concurrent chemoradiation provides one strategy for larynx preservation , but the best strategy is unclear . Use of induction chemotherapy does not improve overall survival , and its use should be limited to patients requiring immediate tumour downsizing before local therapy PURPOSE We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost ( AFX-C ) versus st and ard fractionation ( SFX ) in locally advanced head and neck carcinoma ( LA-HNC ) . PATIENTS AND METHODS Patients had stage III to IV carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx .  Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks ( SFX ) or 72 Gy in 42 fractions over 6 weeks ( AFX-C ) . Cisplatin doses were 100 mg/m(2 ) once every 3 weeks for two ( AFX-C ) or three ( SFX ) cycles . Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria . Overall survival ( OS ) and progression-free survival ( PFS ) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test . Locoregional failure ( LRF ) and distant metastasis ( DM ) rates were estimated by using the cumulative incidence method and Gray 's test . RESULTS In all , 721 of 743 patients were analyzable ( 361 , SFX ; 360 , AFX-C ) . At a median follow-up of 7.9 years ( range , 0.3 to 10.1 years ) for 355 surviving patients , no differences were observed in OS ( hazard ratio [ HR ] , 0.96 ; 95 % CI , 0.79 to 1.18 ; P = .37 ; 8-year survival , 48 % v 48 % ) , PFS ( HR , 1.02 ; 95 % CI , 0.84 to 1.24 ; P = .52 ; 8-year estimate , 42 % v 41 % ) , LRF ( HR , 1.08 ; 95 % CI , 0.84 to 1.38 ; P = .78 ; 8-year estimate , 37 % v 39 % ) , or DM ( HR , 0.83 ; 95 % CI , 0.56 to 1.24 ; P = .16 ; 8-year estimate , 15 % v 13 % ) . For oropharyngeal cancer , p16-positive patients had better OS than p16-negative patients ( HR , 0.30 ; 95 % CI , 0.21 to 0.42 ; P < .001 ; 8-year survival , 70.9 % v 30.2 % ) . There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status . CONCLUSION When combined with cisplatin , AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC . Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification 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 PURPOSE To analyze the relationship between overall survival ( OS ) and radiation treatment time ( RTT ) and overall treatment time ( OTT ) in a well-described sequential therapy paradigm for locally advanced head- and -neck carcinoma ( LAHNC ) . METHODS AND MATERIAL S TAX 324 is a Phase III study comparing TPF ( docetaxel , cisplatin , and fluorouracil ) with PF ( cisplatin and fluorouracil ) induction chemotherapy ( IC ) in LAHNC patients ; both arms were followed by carboplatin-based chemoradiotherapy ( CRT ) . Prospect i ve radiotherapy quality assurance was performed . This analysis includes all patients who received three cycles of IC and a radiation dose of ≥70 Gy . Radiotherapy treatment time was analyzed as binary ( ≤8 weeks vs. longer ) and continuous ( number of days beyond 8 weeks ) functions . The primary analysis assessed the relationship between RTT , OTT , and OS , and the secondary analysis explored the association between treatment times and locoregional recurrence ( LRR ) . RESULTS A total of 333 ( of 501 ) TAX 324 patients met the criteria for inclusion in this analysis . There were no significant differences between the treatment arms in baseline or treatment characteristics . On multivariable analysis , PF IC , World Health Organization performance status of 1 , non-oropharynx site , T3/4 stage , N3 status , and prolonged RTT ( hazard ratio 1.63 , p=0.006 ) were associated with significantly inferior survival . Performance status , T3/4 disease , and prolonged RTT ( odds ratio 1.68 , p=0.047 ) were independently and negatively related to LRR on multivariable analysis , whereas PF was not . Overall treatment time was not independently associated with either OS or LRR . CONCLUSIONS In this secondary analysis of the TAX 324 trial , TPF IC remains superior to PF IC after controlling for radiotherapy delivery time . Even with optimal IC and concurrent chemotherapy , a non-prolonged RTT is a crucial determinant of treatment success . Appropriate delivery of radiotherapy after IC remains essential for optimizing OS in LAHNC 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 AND PURPOSE Studies on accelerated fractionation ( AF ) in head and neck cancer have shown increased local control and survival compared with conventional fractionation ( CF ) , while others have been non-conclusive . In 1998 a national Swedish group decided to perform a r and omised controlled clinical study of AF . MATERIAL S AND METHODS Patients with verified squamous cell carcinoma of the oral cavity , oropharynx , larynx ( except glottic T1-T2 , N0 ) and hypopharynx were included . Patients with prior chemotherapy or surgery were excluded . Patients were r and omised to either CF ( 2Gy/day , 5days/week for 7 weeks , total dose 68Gy ) or to AF ( 1.1Gy+2.0Gy/day , 5days/week for 4.5weeks , total dose 68Gy ) . An extensive quality assurance protocol was followed throughout the study . The primary end point was loco-regional tumour control ( LRC ) at two years after treatment . RESULTS The study was closed in 2006 when 750 patients had been r and omised . Eighty-three percent of the patients had stages III-IV disease . Forty eight percent had oropharyngeal , 21 % laryngeal , 17 % hypopharyngeal and 14 % oral cancers . There were no significant differences regarding overall survival ( OS ) or LRC between the two regimens . The OS at two years was 68 % for AF and 67 % for CF . The corresponding figures for LRC were 71 % and 67 % , respectively . There was a trend towards improved LRC for oral cancers treated ( p=0.07 ) and for large tumours ( T3-T4 ) ( p=0.07 ) treated with AF . The AF group had significantly worse acute reactions , while there was no significant increase in late effects . CONCLUSION Overall the AF regimen did not prove to be more efficacious than CF . However , the trend towards improved results in AF for oral cancers needs to be further investigated
Objective To review the available evidence and make recommendations regarding use of systemically administered drugs in combination or in sequence with radiation ( RT ) and /or surgery for cure and /or organ preservation in patients with locally advanced nonmetastatic ( Stage III to IVB ) squamous cell carcinoma of the head and neck ( LASCCHN ) .
High-dose cisplatin was most commonly studied .