Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. Radiotherapy Alone or with Concomitant Daily Low-Dose Carboplatin in Locally Advanced, Unresectable Head and Neck Cancer: Definitive Results of a Phase III Study with a Follow-Up Period of up to Ten Years A randomized phase II study comparing sequential versus simultaneous chemo-radiotherapy in patients with unresectable locally advanced squamous cell cancer of the head and neck. Adjuvant therapy with cetuximab for locally advanced squamous cell carcinoma of the oropharynx: results from a randomized, phase II prospective trial. Combined radiation and drugs: the effect of intra-arterial chemotherapy followed by radiotherapy in head and neck cancer. Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. A randomized study of accelerated fractionation radiotherapy with and without mitomycin C in the treatment of locally advanced head and neck cancer. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck Combination of direct and indirect evidence in mixed treatment comparisons. Docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by chemoradiotherapy or chemoradiotherapy alone in stage III–IV unresectable head and neck cancer Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: a randomized phase III study. A randomized trial of neoadjuvant vs concomitant chemotherapy vs radiotherapy alone in the treatment of stage IV head and neck squamous cell 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. Combined bleomycin and radiotherapy in oral cancer. Long-Term Results of Conventional Radiotherapy versus Accelerated Hyperfractionated Radiotherapy versus Concomitant Radiotherapy and Chemotherapy in Locoregionally Advanced Carcinoma of the Oropharynx Induction VBM plus radiotherapy, versus radiotherapy alone for advanced head and neck cancer: long-term results. Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial. Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. Feasibility of non-cisplatin-based induction chemotherapy and concurrent chemoradiotherapy in advanced head and neck cancer. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. 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. Ten-year results of randomized trial comparing radiotherapy and concomitant bleomycin to radiotherapy alone in epidermoid carcinomas of the oropharynx: experience of the European Organization for Research and Treatment of Cancer. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group (E2382). Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study. A randomized comparison of radiotherapy with a radiotherapy–chemotherapy combination in stage IV carcinoma of the head and neck French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC). Treatment of advanced head and neck cancer by means of radiation therapy plus chemotherapy--a randomised trial. Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. 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). Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. A Randomized, Multicenter, Phase II Study of Cetuximab With Docetaxel and Cisplatin as Induction Chemotherapy in Unresectable, Locally Advanced Head and Neck Cancer. Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach. A prospective comparision of sequential chemoradiation vs concurrent chemoradiation in locally advanced oropharyngeal carcinomas Randomized phase III trial comparing induction chemotherapy followed by radiotherapy to concomitant chemoradiotherapy for laryngeal preservation in T3M0 pyriform sinus carcinoma Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial Randomised Phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease.
PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival ( OS ) of patients with stage III or IV head and neck carcinoma ( HNC ) .  Cetuximab plus platinum regimens also increase OS in metastatic HNC . The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival ( PFS ) . PATIENTS AND METHODS Eligible patients with stage III or IV HNC were r and omly assigned to receive radiation and cisplatin without ( arm A ) or with ( arm B ) cetuximab .  Acute and late reactions were scored using Common Terminology Criteria for Adverse Events ( version 3 ) . Outcomes were correlated with patient and tumor features and markers . RESULTS Of 891 analyzed patients , 630 were alive at analysis ( median follow-up , 3.8 years ) . Cetuximab plus cisplatin-radiation , versus cisplatin-radiation alone , result ed in more frequent interruptions in radiation therapy ( 26.9 % v. 15.1 % , respectively ) ; similar cisplatin delivery ( mean , 185.7 mg/m2 v. 191.1 mg/m2 , respectively ) ; and more grade 3 to 4 radiation mucositis ( 43.2 % v. 33.3 % , respectively ) , rash , fatigue , anorexia , and hypokalemia , but not more late toxicity . No differences were found between arms A and B in 30-day mortality ( 1.8 % v. 2.0 % , respectively ; P = .81 ) , 3-year PFS ( 61.2 % v. 58.9 % , respectively ; P = .76 ) , 3-year OS ( 72.9 % v. 75.8 % , respectively ; P = .32 ) , locoregional failure ( 19.9 % v. 25.9 % , respectively ; P = .97 ) , or distant metastasis ( 13.0 % v. 9.7 % , respectively ; P = .08 ) . Patients with p16-positive oropharyngeal carcinoma ( OPC ) , compared with patients with p16-negative OPC , had better 3-year probability of PFS ( 72.8 % v. 49.2 % , respectively ; P < .001 ) and OS ( 85.6 % v. 60.1 % , respectively ; P < .001 ) , but tumor epidermal growth factor receptor ( EGFR ) expression did not distinguish outcome . CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely . PFS and OS were higher in patients with p16-positive OPC , but outcomes did not differ by EGFR expression Aim and background Radiotherapy is the conventional treatment for locally advanced inoperable head and neck squamous cell carcinoma . However , the poor therapeutic results justify the development of radiochemotherapy combinations . In an attempt to improve local control and survival in patients with stage III and IV unresectable head and neck squamous cell carcinoma and based on the results of our previous dose escalation study , we undertook a prospect i ve multicentric r and omized trial . Material s and methods From November 1992 through December 1995 , a total of 164 patients were r and omized to receive radiotherapy alone ( arm I ) or combined ( arm II ) with daily low-dose carboplatin . Results The 3 , 5 and 10-year local-regional recurrence-free survival rates were better in arm II(21.7 % , 15.1 % and 15.1 % , respectively ) than in arm I ( 15 % , 10.7 % and 10.7 % ) , but without statistical significance ( P = 0.11 ) . The 3 , 5 and 10-year disease-free survival rates showed the same positive trend for arm II ( 16 % , 6.8 % and 6.8 % vs 9 % , 5.5 % and 5.5 % , in arm I , respectively ) , again without statistical significance ( P = 0.09 ) . Instead , a statistical advantage was found in overall survival rates at 3 , 5 and 10-years ( 28.9 % , 9 % and 5.5 % in arm II and 11.1 % , 6.9 % and 6.9 % in arm I , respectively ) ( P = 0.02 ) . The 3 , 5 and 10-year local-regional recurrence-free survival rates in stage IV disease were statistically better in arm II ( 21.5 % , 15.9 % and 15.9 % ) than in arm I ( 12.8 % , 7.7 % and 7.7 % , respectively ) ( P = 0.04 ) . Conclusions Long-term results in both treatment arms of the trial appear less positive than most published series . However , our findings do not exclude that carboplatin may be beneficial , but the benefit in local control must be lower than the 15 % assumed to dimension the trial BACKGROUND Single-modality radiotherapy is still considered st and ard treatment for patients with locally advanced unresectable cancer of the head and neck . As treatment outcome is poor , attempts to integrate chemotherapy into the overall management of these patients are ongoing . PATIENTS AND METHODS A r and omized study was undertaken to compare a sequential with a simultaneous chemoradiotherapy program . Between February 1986 and February 1991 , 93 eligible patients with locally advanced unresectable cancer of the head and neck were stratified by WHO PS , T and N class and primary site and then r and omized to receive either three courses of neoadjuvant chemotherapy with cisplatin ( 100 mg/m2 i.v . d 1 ) and 5-fluorouracil 1000 mg/m2/days 1 - 5 by continuous i.v . infusion every 3 weeks prior to definitive conventional radiotherapy of 65 - 70 Gy ( sequential treatment ) , or cisplatin 100 mg/m2 on days 1 , 22 , 43 given simultaneously for the duration of the same conventional radiotherapy ( simultaneous treatment ) . RESULTS At the end of the entire treatment 18 complete responses ( 47 % ) in the sequential-treatment arm and 18 ( 41 % ) in the simultaneous treatment arm were obtained . No statistically significant differences in the 5-yr progression-free survival , in the median time to loco-regional and distant progression and in the 5-yr overall survival were observed . Leukopenia was more frequent in the simultaneous than in the sequential arm ( p = 0.03 ) , whereas alopecia ( p = 0.008 ) and phlebitis ( p < 0.0001 ) were more frequent in the sequential-treatment arm . A better compliance was associated with the concomitant treatment , with 87 % of the patients completing the entire radiotherapy program versus 63 % of those in the sequential arm ( p = 0.01 ) . CONCLUSIONS In the present study , the two treatment arms showed similar activity ( complete response , progression-free and overall survival rates ) . Compliance to treatment was better in the concomitant arm . These data suggest that concomitant chemo-radiation therapy might be considered an option in unresectable locally advanced cancer of the head and neck . Phase III studies are needed in order to establish the superiority of this combination of cisplatin and radiotherapy versus radiotherapy alone 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 This study was design ed to ascertain whether a prior reduction of tumor size by drugs could affect the final outcome of tumors treated with radiation . 142 patients with head and neck cancer ( oropharynx , maxillary antrum and intra-oral ) were r and omized for the study . In 72 cases , irradiation was preceded by a continuous intra-arterial infusion of 3 - 5 mg/day methotrexate to a total dose of 90 - 120 mg ; the other 70 patients were treated with radiotherapy alone . Chemotherapy , given prior to radiotherapy , caused a shift in the tumor stage ( i.e. a reduction in tumor size ) in more than one third of the cases . The overall 5-year survival was 43 % in the combined treatment group and 25 % in the group treated with radiation alone ( statistical difference : p less than .05 ) . However , when analysed separately the difference was statistically significant only in oral cavity tumors ( 5-year survival of 54 % in the combined modality group vs. 27 % in the control group ) , although local control rates after both single and combined modalities were not statistically different from those of oropharynx and maxillary antrum tumors . In these last lesions , however , the dissemination of disease was more frequent ; therefore , the lack of improvement of cure rate with the combined modality in these cases seems to be related to both the higher tendency of these tumors to disseminate and the low effectiveness of intra-arterial chemotherapy in controlling distant metastases . Mild and transient local and systemic toxicities were observed during chemotherapy infusion , but no radiosensitising effect on normal skin and mucosa was seen during radiotherapy in patients who had received pre-irradiation chemotherapy In 1986 , we initiated a multicenter , r and omized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment ( surgery and radiotherapy or radiotherapy alone ) with locoregional treatment alone in patients with head and neck squamous cell carcinoma . Here we report the long-term results of the trial . A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were r and omly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment ( group A ) or locoregional treatment alone ( group B ) . Among all patients , overall survival at 5 and 10 years was 23 % ( 95 % confidence interval [ CI ] = 15.3 % to 30.9 % ) and 19 % ( 95 % CI = 11.6 % to 26.4 % ) , respectively , for those in group A and 16 % ( 95 % CI = 9.6 % to 23.4 % ) and 9 % ( 95 % CI = 3.5 % to 14.7 % ) , respectively , for those in group B ( P = .13 ) . Among operable patients , we observed no difference between group A and group B in overall survival at 5 and 10 years ( group A , 31 % [ 95 % CI = 14.9 % to 47.3 % ] and 22.7 % [ 95 % CI = 7.1 % to 38.3 % ] , respectively ; group B , 43.3 % [ 95 % CI = 25.6 % to 61.0 % ] and 14.2 % [ 95 % CI = 0.1 % to 28.3 % ] , respectively ; P = .73 ) . Among inoperable patients , overall survival at 5 and 10 years was 21 % ( 95 % CI = 12.3 % to 30.1 % ) and 16 % ( 95 % CI = 7.7 % to 23.9 % ) , respectively , for group A and 8 % ( 95 % CI = 1.5 % to 12.3 % ) and 6 % ( 95 % CI = 0.1 % to 9.1 % ) , respectively , for group B ( log-rank P = .04 ) . Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease PURPOSE We report the 5-year survival and late toxicity results of a r and omized clinical trial , which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma , using concomitant radiochemotherapy ( arm B ) , compared with st and ard radiotherapy ( arm A ) . PATIENTS AND METHODS A total of 226 patients were entered onto a phase III multicenter r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions ; arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil ; arm B ) . Prognostic factors were evaluated by univariate and multivariate analysis . Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity , hearing , taste , m and ibula , and teeth damage , and Radiation Therapy Oncology Group toxicity criteria for skin , salivary gl and , and mucosa . RESULTS Five-year overall survival , specific disease-free survival , and locoregional control rates were 22 % and 16 % ( log-rank P = .05 ) , 27 % and 15 % ( P = .01 ) , and 48 % and 25 % ( P = .002 ) , in arm B and arm A , respectively . Stage IV , hemoglobin level lower than 125 g/L , and st and ard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis . One or more grade 3 to 4 complications occurred in 56 % of the patients in arm B , compared with 30 % in arm A ( P was not significant ) . CONCLUSION Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity . Anemia was the most important prognostic factor for survival in both arms OBJECTIVES This single-institution study evaluates the feasibility of accelerated fractionation radiotherapy ( AF ) with and without mitomycin C ( MMC ) in the treatment of locally advanced head and neck cancer . PATIENTS AND METHODS Between May 1998 and October 2001 , sixty patients with locally advanced stage III and IV of head and neck cancer were r and omized into three treatment arms : ( 1 ) conventional fractionation radiotherapy ( CF ) ( 5 fractions per week ) ; ( 2 ) accelerated fractionation radiotherapy ( AF ) ( 6 fractions per week ) ; and ( 3 ) AF plus Mitomycin C ( MMC ) . RESULTS The 2-year overall survival ( OS ) of the whole group was 21 % . The OS according to treatment arm was 23 % , 20 % , and 28 % in CF , AF , and AF+MMC arms respectively ( p<0.19 ) . The 2-year loco-regional control ( LC ) rate was 22 % for the whole group of patients . The LC was 10 % , 25 % , and 30 % for the CF , AF , and AF+MMC respectively ( p=0.27 ) . The only significant parameters for OS and LC were performance status and pre-treatment hemoglobin level . Mucositis grade s 3 & 4 occurred in 70 % and 90 % of the patients in the AF and AF+MMC arm respectively compared to 55 % of patients in the CF arm ( p=0.04 ) . However the addition of MMC did not significantly increase the incidence or severity of mucositis between AF and AF+MMC ( p=0.13 ) . Hematological toxicity grade s 3 & 4 were significantly higher after MMC ( occurred in 40 % of patients versus 10 % and 5 % in CF and AF arms respectively , p=0.04 ) . There was no statistically significant difference in the incidence of grade 3 dryness of mouth ( p=0.06 ) , fibrosis ( p=0.6 ) , or lymphoedema ( p=0.39 ) among the three arms . CONCLUSION There was a trend for improvement of LC and OS rates with the use of AF and the addition of MMC to AF compared to CF radiotherapy , although the difference was not statistically significant . The small number of the patients in each treatment arm and the inclusion of multiple tumor sites may contribute to these statistically insignificant results . Accordingly we advise 85 to continue the trial with inclusion of a larger number of patients and restrict tumor sites to one major site 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 Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed Purpose Concurrent chemoradiotherapy ( CRT ) is the st and ard treatment for advanced head and neck squamous cell carcinoma . In this phase II r and omized study , the efficacy and toxicity of docetaxel , cisplatin and 5-fluorouracil induction chemotherapy ( ICT ) followed by concurrent CRT was compared with those after st and ard CRT alone in patients with locally advanced , unresectable head and neck cancer . Patients and methods Between January 2007 and June 2009 , 66 patients with advanced ( stage III or IV ) unresectable squamous cell carcinoma of the head and neck ( oral cavity , oropharynx , hypopharynx , and larynx ) were r and omly assigned to two groups : one receiving two cycles of docetaxel , cisplatin , and 5-fluorouracil ICT followed by CRT with three cycles of cisplatin and one treated by CRT alone . Response rate , local tumor control ( LTC ) , locoregional tumor control ( LRTC ) , overall survival ( OS ) , progression-free survival ( PFS ) , and toxicity results were assessed . Results Three patients from the ICT + CRT group did not appear at the first treatment , so a total of 63 patients were evaluated in the study ( 30 ICT + CRT group and 33 CRT group ) . Three patients died of febrile neutropenia after ICT . The median follow-up time for surviving patients was 63 months ( range 53–82 months ) . The rate of radiologic complete response was 63 % following ICT + CRT , whereas 70 % after CRT alone . There were no significant differences in the 3-year rates of LTC ( 56 vs. 57 % ) , LRTC ( 42 vs. 50 % ) , OS ( 43 vs. 55 % ) , and PFS ( 41 vs. 50 % ) in the ICT + CRT group and in the CRT group , respectively . The rate of grade 3–4 neutropenia was significantly higher in the ICT + CRT group than in the CRT group ( 37 and 12 % ; p = 0.024 ) . Late toxicity ( grade 2 or 3 xerostomia ) developed in 59 and 42 % in the ICT + CRT and CRT groups , respectively . Conclusion The addition of ICT to CRT did not show any advantage in our phase II trial , while the incidence of adverse events increased . The three deaths as a consequence of ICT call attention to the importance of adequate patient selection if ICT is considered . ZusammenfassungHintergrundSimultane Chemoradiotherapie ( CRT ) ist eine St and ardtherapie beim fortgeschrittenen Plattenepithelkarzinom i m Kopf-Hals-Bereich . In dieser r and omisierten Phase-II-Studie wurden die Wirksamkeit und Toxizität einer Induktionschemotherapie ( ICT ) mit Docetaxel , Cisplatin und 5-Fluorouracil gefolgt von simultaner CRT mit der CRT allein bei Patienten mit lokal fortgeschrittenen , irresektablen Kopf-Hals-Tumoren verglichen . Patienten und Method enZwischen Januar 2007 und Juni 2009 wurden 66 Patienten mit fortgeschrittenem ( Stadium III oder IV ) , inoperablem Plattenepithelkarzinom i m Kopf-Hals-Bereich ( Mundhöhle , Oropharynx , Hypopharynx , Larynx ) nach dem Zufallsprinzip in 2 Gruppen eingeteilt . Die eine Gruppe erhielt 2 Zyklen der Docetaxel- , Cisplatin- und 5-Fluorouracil-ICT gefolgt von CRT mit 3 Zyklen Cisplatin , die and ere Gruppe erhielt nur CRT . Ansprechrate , lokale Tumorkontrolle ( LTC ) , lokoregionale Tumorkontrolle ( LRTC ) , Gesamtüberleben ( OS ) , progressionsfreies Überleben ( PFS ) und toxischer Effekt wurden verglichen . ErgebnisseDrei Patienten der Gruppe mit ICT + CRT erschienen bei der ersten Beh and lung nicht , so dass insgesamt 63 Patienten in der Studie ausgewertet wurden ( 30 in der Gruppe ICT + CRT , 33 in der CRT-Gruppe ) . Drei Patienten starben an febriler Neutropenie nach ICT . Die mediane Nachbeobachtungszeit der überlebenden Patienten betrug 63 Monate ( Spanne 53–82 Monate ) . Die Rate des radiologischen vollständigen Ansprechens war 63 % nach ICT + CRT vs. 70 % nach CRT allein . Es gab keinen signifikanten Unterschied in der 3-Jahres-Rate bei LTC ( 56 vs. 57 % ) , LRTC ( 42 vs. 50 % ) , OS ( 43 vs. 55 % ) und PFS ( 41 vs. 50 % ) zwischen der Gruppe mit ICT + CRT und den mit CRT beh and elten Patienten . Die Rate von Neutropenie mit einem Grad 3–4 lag in der Gruppe mit ICT + CRT deutlich höher als in der CRT-Gruppe ( 37 und 12 % ; p = 0,024 ) . Späte Toxizität ( Grad-2- und Grad-3-Xerostomie ) ereignete sich in der Gruppe mit ICT + CRT und in der CRT-Gruppe in jeweils 59 vs. 42 % .SchlussfolgerungDie Kombination von ICT und CRT erbrachte in unserer Phase-II-Studie keine Vorteile , wobei die Gesamtinzidenz der unerwünschten Ereignisse stieg . Die 3 Todesfälle infolge ICT weisen auf die Wichtigkeit der Patientenauswahl i m Falle einer ICT-Beh and lung hin BACKGROUND AND PURPOSE In 1986 a prospect i ve , r and omized , multi-centre trial for evaluation of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in the treatment of advanced squamous cell carcinoma of the head and neck was initiated . As survival in this group of patients is poor the purpose was to find a possible survival benefit of the chemotherapy in addition to radiotherapy compared to radiotherapy only . METHODS Four-hundred sixty-one patients from Denmark , Norway and Sweden with tumors in oral cavity , oropharynx , hypopharynx and larynx were r and omized to receive either st and ard treatment ( radiotherapy or radiotherapy followed by surgery ) or neoadjuvant chemotherapy followed by st and ard treatment . Chemotherapy included three courses of cisplatin 100 mg/m2 i.v . infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v . infusion for 120 hours . Radiotherapy 64 - 70 Gy in 2 Gy per fraction , 5 times/week , was given to patients in both treatment arms . RESULTS Response rate was 71 % for patients r and omized to chemotherapy-radiotherapy and 66 % for patients r and omized to st and ard treatment ( not statistically significant ) . Residual tumors were excised if possible . After surgery 62 % of the patients r and omized to chemotherapy-radiotherapy and 60 % of the patients in the st and ard treatment group were clinical ly tumor free . CONCLUSIONS No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy . Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment Summary Treatment results of irradiation as a single treatment for advanced stage IV unresectable head and neck cancer remains uniformly poor and apparently has not changed with the most recent improvements in oncological care . Despite several negative results of r and omized studies , neoadjuvant or concomitant chemotherapy and radiotherapy seems to improve the number of complete responses and also the duration of disease-free survival . The present study was design ed to determine the feasibility , potential risks and benefits of the two methods of combined treatment and radiotherapy alone on the management of advanced unresectable squamous cell carcinoma of the upper respiratory and digestive system . From 1983 to 1986 , 90 patients entered the trial . Thirty patients were r and omized to each study group : radiotherapy alone ( 70 Gy ) ; neoadjuvant chemotherapy ( vinblastine , mitomycin , cisplatin , and bleomycin ) and radiotherapy ; concomitant chemotherapy ( cisplatin and bleomycin ) and radiotherapy . An increased frequency of complete responses ( 33 % ) was seen in patients treated with the two different combinations of chemotherapy and irradiation compared to irradiation alone ( 10 % ) . However , toxicity was more common in patients treated with the two modalities of combined treatment and there were no differences in overall survival rates ( P = 0.706 ) 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 A clinical trial comparing Bleomycin ( BLM ) plus radiation against radiation alone is reported . One hundred and fifty-seven previously untreated T3 and T4 and N0 , N1 or N2 buccal squamous cell carcinomas were entered . Eighty-four of these received the combined therapy and 73 were controls .  Cobalt-60 teletherapy using two opposing fields was employed . BLM was administered intra-arterially in 42 patients , intravenously in 22 patients and intramuscularly in 20 patients . The 73 controls received physiological saline as a placebo .  Total clinical healing of the lesion within the volume of irradiation eight weeks after the end of radiotherapy was termed a favourable response . Anything else was a failure . Five-year recurrence-free rates and disease-free survival were also evaluated . The favourable response rate in the study group was 78.6 % and in the control 19.1 % . The corresponding recurrence-free rates and five-year survival rates were 71.8 % and 17 % , and 65.5 and 23.5 % respectively . The main toxic features were acute mucositis , pneumonitis and dermatitis Aims and Background To compare conventional fractionation ( CF ) radiation therapy ( RT ) , arm A , versus a split-course accelerated hyperfractionated schedule ( S-AHF ) , arm B , versus CFRT plus concomitant chemotherapy ( CT ) , arm C , in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx . Methods and Study Design Between January 1993 and June 1998 , 192 previously untreated patients with stage III and IV oropharyngeal carcinoma ( excluding T1N1 and T2N1 ) were enrolled in a multicenter r and omized phase III trial ( ORO 93 - 01 ) . In arms A and C , 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks . In arm B , the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day , five days a week , with a planned two-week split at 38.4 Gy . In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil ( CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v . on days 1 to 4 every 28 days ) . Results No statistically significant difference was found in five-year overall survival ( P = 0.39 ) : 21 % for arm A , 21 % for arm B , and 40 % for arm C. Similarly , there was no statistically significant difference in terms of five-year relapse-free survival : 15 % for arm A , 17 % for arm B , and 36 % for arm C. There was a slight trend towards better five-year locoregional control ( P = 0.07 ) for the combined arm : patients without locoregional relapse were 48 % in arm C , 21 % in arm A and 18 % in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined ( P = 0.02 ; arm A+B 20 % ; arm C 48 % ) . Distant metastases were fairly balanced in the three arms ( A : 14 ; B : 9 ; C : 11 ) , with a tendency towards more frequent isolated distant metastasis development in arm C ( 8 of 11 [ 72 % ] versus 7 of 23 [ 30 % ] in arms A+B ) . Five-year second-tumor-free survival was 85 % . The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption ( five lung , two esophagus , two oral cavity , one larynx , one pancreas , one hepatocarcinoma , one myeloma ) . Arm C showed slightly more G3 + late side effects involving subcutaneous tissues and mucosa , although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient . The occurrence of persistent G3 xerostomia was comparable in the three treatment arms . Conclusions The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance , but combined treatment almost doubled the five-year overall survival , relapse-free survival and locoregional control rate .  Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy . The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death Between 1978 and 1981 , 85 patients with advanced squamous cell carcinoma of the head and neck were r and omized to receive induction VBM followed by radiotherapy , or radiotherapy alone . The shortest follow-up is thus 6 years . The median survival of patients receiving induction chemotherapy was 46 weeks , that of the radiotherapy group alone was 75 weeks . As the two groups were not balanced despite r and omization , multivariate methods ( GLIM ) were used to identify significant prognostic factors . These were : response to radiotherapy  ( P less than 0.001 ) , nodal status ( P less than 0.001 ) , age ( P less than 0.01 ) , and histological grade ( P less than 0.01 ) . Neither treatment with , nor response to , chemotherapy had a significant effect on survival 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 efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone . METHODS AND MATERIAL S Between March 1991 and December 1993 , 64 patients with inoperable head and neck carcinoma ( 41 with oropharyngeal site ) were r and omized to radiotherapy alone ( group A ) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin ( group B ) . In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66 - 70 Gy . The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy . To enhance the effect of these two drugs , patients received also nicotinamide , chlorpromazine , and dicoumarol . Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma , the study was closed and such patients were after December 1993 routinely treated with the combined therapy ( as in arm B ) . Until October 1996 , we treated and followed up 48 such consecutive patients . RESULTS Median follow-up of our study patients is 42 months . Complete remission ( CR ) rate in group A was 31 % and in group B 59 % ( p = 0.04 ) ; disease-free survival ( DFS ) in group A was 8 % and in group B 37 % ( P = 0.01 ) ; and overall survival ( OS ) was 7 % in group A and 26 % in group B ( p = 0.08 ) . CR rate for patients with oropharyngeal carcinoma was 29 % in group A ( N = 21 ) and 75 % in group B ( N = 20 ) ( p = 0.007 ) ; DFS in group A was 10 % and in group B 48 % ( p = 0.001 ) ; and the OS was 10 % in group A and 38 % in group B ( p = 0.019 ) . In patients with inoperable oropharyngeal carcinoma treated after December 1993 , complete remission was achieved in 32/48 ( 67 % , 95 % CI : 52%-80 % ) . DFS at the median follow-up of 14 months was 60 % ( 95 % CI 43 - 77 % ) and OS 58 % ( 95 % CI 42 - 74 % ) . CONCLUSION From the results of our study it seems that the concomitant treatment significantly improves CR rate , DFS , and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone The purpose of the present study was to determine the safety and efficacy of induction chemotherapy followed by concomitant chemoradiotherapy .  Thirty-eight patients were r and omised to receive induction chemotherapy , consisting of cyclophosphamide and methotrexate followed by concomitant 5-fluorouracil and irradiation ( study group ) or irradiation alone ( control group ) . There were non-significant differences in the initial tumor clearance rates in the two groups . Median disease-free survival ( in complete responders ) was 17 months ( 6 - 60 + ) vs 11 months ( 5 - 60 + ) ( p = 0.407 ) and overall survival 11 months ( 1 - 60 + ) vs 14 months ( 2 - 60 + ) ( p = 0.428 ) in the study and control groups respectively . Acute morbidity and deaths during intervention were higher in the study group ( p = 0.007 ) . This study suggests that induction along with concomitant chemoradiotherapy is too toxic for routine use and also fails to provide a survival benefit PURPOSE To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel , cisplatin , and fluorouracil ( FU ; PCF ) versus st and ard cisplatin and FU ( CF ) , both followed by chemoradiotherapy ( CRT ) , in locally advanced head and neck cancer ( HNC ) . PATIENTS AND METHODS Eligibility criteria included biopsy-proven , previously untreated , stage III or IV locally advanced HNC . Patients received either CF ( cisplatin 100 mg/m2 on day 1 plus FU 1000 [ corrected ] mg/m2 continuous infusion on days 1 through 5 ) or PCF ( paclitaxel 175 mg/m2 on day 1 , cisplatin 100 mg/m2 on day 2 , and FU 500 mg/m2 continuous infusion on days 2 through 6 ) ; both regimens were administered for three cycles every 21 days . Patients with complete response ( CR ) or partial response of greater than 80 % in primary tumor received additional CRT ( cisplatin 100 mg/m2 on days 1 , 22 , and 43 plus 70 Gy ) . RESULTS A total of 382 eligible patients were r and omly assigned to CF ( n = 193 ) or PCF ( n = 189 ) . The CR rate was 14 % in the CF arm v 33 % in the PCF arm ( P < .001 ) . Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm ( log-rank test , P = .006 ; Tarone-Ware , P = .003 ) . PCF patients had a trend to longer overall survival ( OS ; 37 months in CF arm v 43 months in PCF arm ; log-rank test , P = .06 ; Tarone-Ware , P = .03 ) . This difference was more evident in patients with unresectable disease ( OS : 26 months in CF arm v 36 months in PCF arm ; log-rank test , P = .04 ; Tarone-Ware , P = .03 ) . CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients ( 53 % v 16 % , respectively ; P < .001 ) . CONCLUSION Induction chemotherapy with PCF was better tolerated and result ed in a higher CR rate than CF . However , new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment PURPOSE Induction chemotherapy ( IC ) before radiotherapy lowers distant failure ( DF ) rates in locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . The goal of this phase III trial was to determine whether IC before chemoradiotherapy ( CRT ) further improves survival compared with CRT alone in patients with N2 or N3 disease . PATIENTS AND METHODS Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were r and omly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) . The primary end point was overall survival ( OS ) . Secondary end points included DF-free survival , failure pattern , and recurrence-free survival ( RFS ) . RESULTS A total of 285 patients were r and omly assigned . The most common grade 3 to 4 toxicities during IC were febrile neutropenia ( 11 % ) and mucositis ( 9 % ) ; during CRT ( both arms combined ) , they were mucositis ( 49 % ) , dermatitis ( 21 % ) , and leukopenia ( 18 % ) . Serious adverse events were more common in the IC arm ( 47 % v 28 % ; P = .002 ) . With a minimum follow-up of 30 months , there were no statistically significant differences in OS ( hazard ratio , 0.91 ; 95 % CI , 0.59 to 1.41 ) , RFS , or DF-free survival . CONCLUSION IC did not translate into improved OS compared with CRT alone . However , the study was underpowered because it did not meet the planned accrual target , and OS was higher than predicted in both arms . IC can not be recommended routinely in patients with N2 or N3 locally advanced SCCHN BACKGROUND Concurrent chemoradiotherapy ( CCRT ) is the st and ard treatment for patients with unresectable , nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) . This r and omized , open-label , phase III clinical trial compared the efficacy between st and ard CCRT and two different induction chemotherapy ( ICT ) regimens followed by CCRT . PATIENTS AND METHODS Patients with untreated LASCCHN were r and omly assigned to ICT ( three cycles ) , with either docetaxel ( Taxotere ) , cisplatin and 5-fluorouracil ( TPF arm ) or cisplatin and 5-fluorouracil ( PF arm ) , followed by CCRT [ 7 weeks of radiotherapy ( RT ) with cisplatin 100 mg/m(2 ) on days 1 , 22 and 43 ] ; or 7 weeks of CCRT alone . The primary end points were progression-free survival ( PFS ) and time-to-treatment failure ( TTF ) . RESULTS In the intention-to-treat ( ITT ) population ( n = 439 ) , the median PFS times were 14.6 ( 95 % CI , 11.6 - 20.4 ) , 14.3 ( 95 % CI , 11.8 - 19.3 ) and 13.8 months ( 95 % CI , 11.0 - 17.5 ) at TPF-CCRT , PF-CCRT and CCRT arms , respectively ( log-rank P = 0.56 ) . The median TTF were 7.9 ( 95 % CI , 5.9 - 11.8 ) , 7.9 ( 95 % CI , 6.5 - 11.8 ) and 8.2 months ( 95 % CI , 6.7 - 12.6 ) for TPF-CCRT , PF-CCRT and CCRT alone , respectively ( log-rank P = 0.90 ) . There were no statistically significant differences for overall survival ( OS ) . Toxic effects from ICT-CCRT were manageable . CONCLUSION Overall , this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN 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 This trial of treatment for head and neck carcinoma was initiated in 1973 by the European Organization for Research and Treatment of Cancer . Its purpose was to investigate the value of single-agent chemotherapy with bleomycin ( BLM ) given during the course of a conventional treatment by external radiotherapy ( RT ) compared to treatment by external RT alone . In this r and omized study , we compared treatment results in 2 groups of patients with squamous cell carcinoma of the oropharynx ( T2 , T3 , and T4 ; International Union Against Cancer classification ) . One group of 92 patients was treated by RT  at the prescribed dose of 70 Gy  . The other group of 107 patients received radiation according to the same protocol and simultaneously received i m injection of BLM at a dose of 15 mg twice a week , 2 hours prior to the session of RT , for a total dose of 150 mg in 5 weeks . The occurrence of local toxic effects ( i.e. , mucositis and epidermatitis ) was significantly greater in the RT-BLM group ( RT-BLM , 72 % , vs. RT , 21 % ) . Primary tumor response 6 weeks after completion of RT was the same in both arms of the study ( RT , 68 % , vs. RT-BLM , 67 % ) . The 6-year survival rate was 24 % ( RT-BLM ) versus 22 % ( RT ) . Long-term analysis ( 10 yr ) is given PURPOSE The Head and Neck Intergroup conducted a phase III r and omized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer . PATIENTS AND METHODS Eligible patients were r and omly assigned between arm A ( the control ) , single daily fractionated radiation ( 70 Gy at 2 Gy/d ) ; arm B , identical radiation therapy with concurrent bolus cisplatin , given on days 1 , 22 , and 43 ; and arm C , a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy , 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle . Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and , if necessary , as salvage therapy on all three treatment arms . Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test . RESULTS Between 1992 and 1999 , 295 patients were entered on this trial . This did not meet the accrual goal of 362 patients and result ed in premature study closure . Grade 3 or worse toxicity occurred in 52 % of patients enrolled in arm A , compared with 89 % enrolled in arm B ( P < .0001 ) and 77 % enrolled in arm C ( P < .001 ) . With a median follow-up of 41 months , the 3-year projected overall survival for patients enrolled in arm A is 23 % , compared with 37 % for arm B ( P = .014 ) and 27 % for arm C ( P = not significant ) . CONCLUSION The addition of concurrent high-dose , single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival , although it also increases toxicity . The loss of efficacy result ing from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery BACKGROUND Panitumumab is a fully human monoclonal antibody that targets EGFR . We aim ed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( three cycles of cisplatin 100 mg/m(2 ) ) or panitumumab plus chemoradiotherapy ( three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2 ) ) using stratified r and omisation with a block size of five . All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for sub clinical disease with st and ard fractionation . The primary endpoint was local-regional control at 2 years , analysed in all r and omised patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This trial is registered with Clinical Trials.gov , number NCT00500760 . FINDINGS Between Oct 26 , 2007 , and March 26 , 2009 , 153 patients were enrolled and 150 received treatment ( 63 in the  chemoradiotherapy  group and 87 in the panitumumab plus chemoradiotherapy group ) .  Local-regional control at 2 years was 68 % ( 95 % CI 54 - 78 ) in the chemoradiotherapy group and 61 % ( 50 - 71 ) in the panitumumab plus chemoradiotherapy group . The most frequent grade 3 - 4 adverse events were dysphagia ( 17 [ 27 % ] of 63 patients in the chemoradiotherapy group vs 35 [ 40 % ] of 87 in the panitumumab plus chemoradiotherapy group ) , mucosal inflammation ( 15 [ 24 % ] vs 48 [ 55 % ] ) , and radiation skin injury ( eight [ 13 % ] vs 27 [ 31 % ] ) . Serious adverse events were reported in 20 ( 32 % ) of 63 patients in the chemoradiotherapy group and in 37 ( 43 % ) of 87 patients in the panitumumab plus chemoradiotherapy group . INTERPRETATION In patients with locally advanced squamous-cell carcinoma of the head and neck , the addition of panitumumab to st and ard fractionation radiotherapy and cisplatin did not confer any benefit , and the role of EGFR inhibition in these patients needs to be reassessed . FUNDING Amgen PURPOSE To investigate the impact of treatment-related toxicity on health-related quality of life ( HRQoL ) among patients with head and neck squamous cell carcinoma treated with radiotherapy either alone or in combination with chemotherapy or surgery .  PATIENTS AND METHODS The study sample was composed of 425 disease-free patients .  Toxicity was scored according to the European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group ( RTOG ) late radiation-induced morbidity scoring system . HRQoL was assessed using the EORTC Quality of Life Question naire C30 . These assessment s took place at 6 , 12 , 18 , and 24 months after completion of radiotherapy . The analysis was performed using a multivariate analysis of variance . RESULTS Of the six RTOG scales investigated , two significantly affected self-reported HRQoL , salivary gl and ( RTOG(xerostomia ) ) and esophagus/pharynx ( RTOG(swallowing ) ) . Although RTOG(xerostomia ) was reported most frequently , HRQoL was most affected by RTOG(swallowing ) , particularly in the first 18 months after completion of radiotherapy . CONCLUSION Late radiation-induced toxicity , particularly RTOG(swallowing ) and RTOG(xerostomia ) , has a significant impact on the more general dimensions of HRQoL. These findings suggest that the development of new radiation-induced delivery techniques should not only focus on reduction of the dose to the salivary gl and s , but also on anatomic structures that are involved in swallowing PURPOSE The Head and Neck Intergroup conducted a Phase III r and omized trial to determine whether the addition weekly cisplatin to daily radiation therapy ( RT ) would improve survival in patients with unresectable squamous cell head- and -neck carcinoma . METHODS AND MATERIAL S Eligible patients were r and omized to RT ( 70 Gy at 1.8 - 2 Gy/day ) or to the identical RT with weekly cisplatin dosed at 20 mg/m(2 ) .  Failure-free survival ( FFS ) and overall survival ( OS ) curves were estimated with the Kaplan-Meier method and compared with the log rank test . RESULTS Between 1982 and 1987 , 371 patients were accrued , and 308 patients were found eligible for analysis . Median follow-up was 62 months . The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups , respectively ( p = 0.30 ) . The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS ( compared to a p = 0.30 in univariate analysis ) . Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities . Late toxicities were not significantly different except for significantly more esophageal ( 9 % vs. 3 % , p = 0.03 ) and laryngeal ( 11 % vs. 4 % , p = 0.05 ) late toxicities in the RT + cisplatin group . CONCLUSION The addition of concurrent weekly cisplatin at 20 mg/m(2 ) to daily radiation did not improve survival , although there was evidence of activity . Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications PURPOSE To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and /or node-positive nonmetastatic carcinomas of the head and neck , compared with hyperfractionated radiotherapy alone . PATIENTS AND METHODS From July 1994 to July 2000 , 224 patients with squamous cell carcinomas of the head and neck ( excluding nasopharynx and paranasal sinus ) were r and omly assigned to hyperfractionated radiotherapy ( median dose , 74.4 Gy ; 1.2 Gy twice daily ) or the same radiotherapy combined with two cycles of concomitant cisplatin ( 20 mg/m2 on 5 days of weeks 1 and 5 ) . The primary end point was time to any treatment failure ; secondary end points were locoregional failure , metastatic relapse , overall survival , and late toxicity . RESULTS There was no difference in radiotherapy between both treatment arms ( 74.4 Gy in 44 days ) . The full cisplatin dose was applied in 93 % and 71 % of patients during the first and second treatment cycles , respectively . Acute toxicity was similar in both arms . Median time to any treatment failure was not significantly different between treatment arms ( 19 months for combined treatment and 16 months for radiotherapy only , respectively ) and the failure-free rate at 2.5 years was 45 % and 33 % , respectively . Locoregional control and distant disease-free survival were significantly improved with cisplatin ( log-rank test , P = .039 and .011 , respectively ) . The difference in overall survival did not reach significance ( log-rank test , P = .147 ) . Late toxicity was comparable in both treatment groups . CONCLUSION The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin In 1961 , a r and omized study was begun at the University of Wisconsin Medical Center in which the treatment of advanced squamous cell carcinoma of the head and neck with  radiation therapy was compared with combined treatment with radiation therapy and 5-Fluorouracil .  One hundred and thirty-six patients with primary lesions in the oral cavity , the base of the tongue , and the oropharynx were analyzed . Both local control and survival were better in the combined treatment group than in the group with radiation therapy alone . However , in only the oral cavity patient population was the difference statistically significant . Both acute and late complications were also increased in this group of patients who received combined treatment Between 1975 and 1978 , 23 patients with Stage IV , unresectable , squamous cell carcinoma of the head and neck were r and omized to receive radiotherapy ( RT , 11 patients ) , or radiotherapy‐chemotherapy ( RT & CT , 12 patients ) . The response rate for the 12 RT & CT patients was four complete remissions ( CR ) and four partial remissions ( PR ) ; the 11 RT patients had one CR and three PR . The presence of a responses ( CR or PR ) significantly enhanced the median survival ( 14 vs. 5 months ; P = 0.005 ) . The duration of objectives remission was longer among the RT & CT patients when compared with RT patients ( 6 vs. 2.3 months , P = 0.18 ) . The median survival of the RT & CT group was 12 months compared with 5.6 months for the RT group ( P = 0.13 ) . One RT & CT patient remains alive with disease at 44 months , one RT patient remains alive without disease at 30 months . The present chemotherapy regimen did not modify the pattern of failure and only marginally increased patient survival . It did , however , increase the response rate . The authors plan to reactivate the trial with modification in the induction chemotherapy and the addition of postradiation maintenance CT consisting of sequential bleomycin and cis‐platinum BACKGROUND Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis . Following a previous phase II study , this phase III multicenter trial was conducted between November 1997 and March 2002 . METHODS Nontreated , strictly unresectable cases were eligible .  Twice-daily radiation : two fractions of 1.2 Gy/day , 5 days per week , with no split ( D1 - ->D46 ) . Total tumor doses : 80.4 Gy/46 day ( oropharynx ) , 75.6 Gy/44 day ( hypopharynx ) . Chemotherapy ( arm B ) : Cisplatin 100 mg/m2 ( D1 , D22 , D43 ) ; 5FU , continuous infusion ( D1 - ->D5 ) , 750 mg/m2/day cycle 1 ; 430 mg/m2/day cycles 2 and 3 . RESULTS A total of 163 evaluable patients .  Grade 3 - 4 acute mucositis 82.6 % arm B/69.5 % arm A ( NS ) ; Grade 3 - 4 neutropenia 33.3 % arm B/2.4 % arm A ( p < 0.05 ) . Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months ( p < 0.01 ) . At 24 months , overall survival ( OS ) , disease-free survival ( DFS ) , and specific survival ( SS ) were significantly better in arm B. OS : 37.8 % arm B vs. 20.1 % arm A ( p = 0.038 ) ; DFS : 48.2 % vs. 25.2 % ( p = 0.002 ) ; SS : 44.5 % vs. 30.2 % ( p = 0.021 ) . No significant difference between the two arms in the amount of side effects at 1 and 2 years . CONCLUSION For these unresectable cases , chemoradiation provides better outcome than radiation alone , even with an " aggressive " dose-intensity radiotherapy schedule Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing radical radiation therapy to the primary tumour and associated lymph node areas with a combination of radiation therapy plus chemotherapy . The distribution of tumour types and stages was similar in the two treatment groups . The response rates to radiation therapy alone ( 50 % complete plus parital response ) and to radiation therapy plus chemotherapy ( 60 % complete plus partial response ) were not significantly different . However , a significant difference in survival was found between the two groups . The median duration of survival for the patients treated by means of radiation therapy alone was 18 weeks ; that for the combined therapy was 36 weeks . The combination of radical radiation therapy plus intermittent high-dose chemotherapy was well tolerated and appears to be an approach that warrants further trial From January 1978 to January 1988 , 859 patients with T3-T4 , NO-3 , MO were r and omly allocated to receive either : Group A--60Co 60 , 60 Gy in 30 fractions ; Group B--60Co , 70.4 Gy in 64 fractions ; Group C--60Co , 60 Gy in 30 fractions plus chemotherapy ( 5 Fu , 250 mg/m2/IV every 2 days ) . Chemotherapy and radiotherapy were combined simultaneously . The average age was 56 years ; the male/female ratio was 802/57 . Median performance status ( ECOG scale ) was 1 ( range 0 - 2 ) . The TNM distribution as UICC criteria was T3 529 patients ; T4 330 patients ; No 217 patients ; N1 52 patients ; N2 319 patients ; and N3 271 patients . The primary sites were nasopharynx 92 , oral cavity 252 , hypopharynx 119 , larynx 310 , and others ( sinuses and unknown primary ) 86 . Complete response was achieved in 188/277 patients in Group A ( 67.8 % ) , 254/282 patients in Group B ( 90 % ) , and 289/300 in Group C ( 96.3 % ) . All patients were followed and statistical analysis shows a significant improvement in median duration of response , as well as survival for Groups B and C compared with Group A. No significant differences were seen between Group B and C. The acute toxicity was mucositis , skin toxicity , bone marrow depression . A mean temporary weight loss of 4.9 Kg was observed with a range of 2.3 - 10.5 Kg PURPOSE To prove an expected benefit of concurrent radiochemotherapy ( RCT ) , a two-arm r and omized multicentric study was performed . In a subgroup analysis the influence of pretherapeutical hemoglobin level ( p-Hb ) on survival under locoregional control ( SLC ) was tested . PATIENTS AND METHODS The study included primarily untreated Stage III/IV ( International Union Against Cancer [ UICC ] ) oropharyngeal and hypopharyngeal carcinomas . Patients were r and omized to receive either hyperfractionated ( hf ) and accelerated ( acc ) RCT with two cycles 5-fluorouracil ( 600 mg/m(2)/day ) and carboplatin ( 70 mg/m(2)/day ) on Days 1 - 5 and 29 - 33 or hf-acc radiotherapy ( RT ) alone . Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique . RESULTS After a median follow-up time of 57 months , SLC is significantly better in RCT than in RT ( p = 0.01 ) , with median SLC of 17 months and 11 months , respectively . Also overall survival ( OS ) shows a benefit for RCT ( p = 0.016 ) , with a median survival of 23 months for RCT and 16 months for RT . However , the benefit in SLC and OS is not seen in hypopharyngeal carcinomas . In a multivariate analysis of oropharyngeal cancer patients , p-Hb levels lower than 12.7 g/dL result ed in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels > 13.8 g/dL did not further improve SLC . CONCLUSIONS Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas . P-Hb levels > 13.8 g/dL do not further improve SLC BACKGROUND The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma ( HNSCC ) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospect i ve clinical trial . METHODS We prospect ively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group ( ECOG ) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and st and ard fractionation radiation therapy .  The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction ( PCR ) and in situ hybridization . Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis . The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age , ECOG performance status , stage , and other covariables was estimated by use of a multivariable Cox proportional hazards model . All statistical tests were two-sided . RESULTS Genomic DNA of oncogenic HPV types 16 , 33 , or 35 was located within tumor cell nuclei of 40 % ( 95 % confidence interval [ CI ] = 30 % to 50 % ) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR . Compared with patients with HPV-negative tumors , patients with HPV-positive tumors had higher response rates after induction chemotherapy ( 82 % vs 55 % , difference = 27 % , 95 % CI = 9.3 % to 44.7 % , P = .01 ) and after chemoradiation treatment ( 84 % vs 57 % , difference = 27 % , 95 % CI = 9.7 % to 44.3 % , P = .007 ) . After a median follow-up of 39.1 months , patients with HPV-positive tumors had improved overall survival ( 2-year overall survival = 95 % [ 95 % CI = 87 % to 100 % ] vs 62 % [ 95 % CI = 49 % to 74 % ] , difference = 33 % , 95 % CI = 18.6 % to 47.4 % , P = .005 , log-rank test ) and , after adjustment for age , tumor stage , and ECOG performance status , lower risks of progression ( hazard ratio [ HR ] = 0.27 , 95 % CI = 0.10 to 0.75 ) , and death from any cause ( HR = 0.36 , 95 % CI = 0.15 to 0.85 ) than those with HPV-negative tumors . CONCLUSION For patients with HNSCC of the oropharynx , tumor HPV status is strongly associated with therapeutic response and survival 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 Between January 1988 and December 1991 , 159 patients with Stage III/IV ( M0 ) squamous cell carcinoma of the head and neck were r and omized to receive st and ard fraction RT ( 70 Gy ) ( group I ) or the same RT plus either 6 mg/m2 of cisplatin ( CDPP ) ( group II ) or 25 mg/ m2 of carboplatin ( CBDCA ) both given daily during RT ( group III ) . Patients in groups II and III had significantly higher overall response rates then those in group I ( P = 0.011 and P = 0.0025 , respectively ) with no difference between groups II and III ( P = 0.60 ) . They also had significantly longer median survival time ( MST ) and higher 5-year survival rates than those in group I ( MST , 32 months ( 32 % ) and 30 months ( 29 % ) versus 16 months ( 15 % ) , respectively ; P = 0.011 and P = 0.019 , respectively ) , with no difference between the two RT/CHT groups . Median time to local recurrence ( MTLR ) and 5-year local recurrence-free survival ( LRFS ) were significantly higher for both RT/CHT when compared to RT alone ( MTLR , not attained yet and 30 months versus 10 months , respectively ; 5-year LRFS , 51 % and 48 % versus 27 % , respectively ; P = 0.018 and P = 0.040 , respectively ) with no difference between the two RT/CHT groups . There was no difference between the three treatment groups regarding regional lymph node and distant metastasis control . Apart from acute high grade ( > or =3 ) hematological toxicity that was significantly more frequent in the two RT/CHT groups and no different between the two RT/CHT groups , other acute high grade toxicity was similar between the three treatment groups . Late high grade toxicity was infrequent and similar between the three treatment groups PURPOSE A prospect i ve r and omized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy ( CT ) and radiotherapy ( RT ) in previously untreated patients with unresectable stage III/IV head and neck cancer . PATIENTS AND METHODS Patients with locoregionally advanced head and neck cancer were treated either with RT alone ( arm A ) or simultaneous RT plus CT ( RCT ; arm B ) . RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily . During one course , from day 3 to 11 , 23.4 Gy was delivered . In arm B , cisplatin ( CDDP ) 60 mg/m2 , fluorouracil ( 5-FU ) 350 mg/m2 by intravenous ( i.v . ) bolus , and leucovorin ( LV ) 50 mg/m2 by i.v . bolus were given on day 2 , and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5 . Treatment was repeated on days 22 and 44 ; a total RT dose of 70.2 Gy was administered . Treatment breaks were scheduled from days 12 to 21 and days 34 to 43 . RESULTS From 1989 to 1993 , 298 patients were enrolled and 270 patients were assessable .  Acute mucositis grade 3 or 4 was more frequent in arm B ( 38 % ) than in arm A ( 16 % ) ( P < .001 ) . Total treatment time was significantly longer in arm B than in arm A ( P < .001 ) due to prolonged breaks . According to hematologic toxicity , scheduled drug doses were given in 74 % of patients for the second course and 46 % for the third course . The 3-year overall survival rate was 24 % in arm A and 48 % in arm B ( P < .0003 ) . The 3-year locoregional control rate was 17 % in arm A and 36 % in arm B ( P < .004 ) . Both arms showed similar distant failure patterns ( arm A , 13 of 140 ; arm B , 12 of 130 ) . Serious late side effects were not significantly different between treatment arms ( arm A , 6.4 % ; arm B , 10 % ; not significant ) . CONCLUSION Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients . Due to increased acute toxicity , more supportive care is dem and ed when CT is given simultaneously . Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen BACKGROUND Previous results from our phase 3 r and omised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) at 3 years . Here we report the 5-year survival data , and investigate the relation between cetuximab-induced rash and survival . METHODS Patients with LASCCHN of the oropharynx , hypopharynx , or larynx with measurable disease were r and omly allocated in a 1:1 ratio to receive either  comprehensive head and neck radiotherapy alone  for 6 - 7 weeks or radiotherapy plus weekly doses of cetuximab : 400 mg/m(2 ) initial dose , followed by seven weekly doses at 250 mg/m(2 ) . R and omisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score , T stage , N stage , and radiation fractionation . The trial was un-blinded . The primary endpoint was locoregional control , with a secondary endpoint of survival . Following discussion s with the US Food and Drug Administration , the data set was locked , except for queries to the sites about overall survival , before our previous report in 2006 , so that an independent review could be done . Analyses were done on an intention-to-treat basis . Following completion of treatment , patients underwent physical examination and radiographic imaging every 4 months for 2 years , and then every 6 months thereafter . The trial is registered at www . Clinical Trials.gov , number NCT00004227 . FINDINGS Patients were r and omly assigned to receive radiotherapy with ( n=211 ) or without ( n=213 ) cetuximab , and all patients were followed for survival . Up date d median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months ( 95 % CI 32.8 - 69.5 ) versus 29.3 months ( 20.6 - 41.4 ) in the radiotherapy-alone group ( hazard ratio [ HR ] 0.73 , 95 % CI 0.56 - 0.95 ; p=0.018 ) . 5-year overall survival was 45.6 % in the cetuximab-plus-radiotherapy group and 36.4 % in the radiotherapy-alone group . Additionally , for the patients treated with cetuximab , overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash ( HR 0.49 , 0.34 - 0.72 ; p=0.002 ) . INTERPRETATION For patients with LASCCHN , cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone , confirming cetuximab plus radiotherapy as an important treatment option in this group of patients . Cetuximab-treated patients with prominent cetuximab-induced rash ( grade 2 or above ) have better survival than patients with no or grade 1 rash . FUNDING ImClone Systems , Merck KGaA , and Bristol-Myers Squibb BACKGROUND At a minimum follow-up of 2 years , the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel , cisplatin , and fluorouracil ( TPF ) versus cisplatin and fluorouracil ( PF ) in locally advanced head and neck cancer . We report the long-term results at 5 years ' minimum follow-up . METHODS TAX 324 was a r and omised , open-label phase 3 trial comparing three cycles of TPF induction chemotherapy ( docetaxel 75 mg/m(2 ) , followed by intravenous cisplatin 100 mg/m(2 ) and fluorouracil 1000 mg/m(2 ) per day , administered as a continuous 24-h infusion for 4 days ) with three cycles of PF ( intravenous cisplatin 100 mg/m(2 ) , followed by fluorouracil 1000 mg/m(2 ) per day as a continuous 24-h infusion for 5 days ) in patients with stage III or IV squamous-cell carcinoma of the head or neck . Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin . R and omisation was done central ly with the use of a biased-coin minimisation technique . At study entry , patients were stratified according to the site of the primary tumour , nodal status ( N0 or N1 vs N2 or N3 ) , and institution . For this long-term analysis , data as of Dec 1 , 2008 , were gathered retrospectively from patients ' medical records .  Overall and progression-free survival were the primary endpoints . Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity . The intention-to-treat analysis included data from all 501 patients ( 255 TPF , 246 PF ) ; data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up . TAX 324 was registered at Clinical Trials.gov , NCT00273546 . FINDINGS Median follow-up was 72·2 months ( 95 % CI 68·8 - 75·5 ) . Overall survival was significantly better after treatment with TPF versus PF ( hazard ratio [ HR ] 0·74 , 95 % CI 0·58 - 0·94 ) , with an estimated 5-year survival of 52 % in patients treated with TPF and 42 % in those receiving PF . Median survival was 70·6 months ( 95 % CI 49·0 - 89·0 ) in the TPF group versus 34·8 months ( 22·6 - 48·0 ) in the PF group ( p=0·014 ) . Progression-free survival was also significantly better in patients treated with TPF ( median 38·1 months , 95 % CI 19·3 - 66·1 , vs 13·2 months , 10·6 - 20·7 ; HR 0·75 , 95 % CI 0·60 - 0·94 ) . We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups . In the TPF group , three ( 3 % ) of 91 patients remained feeding-tube dependent , compared with eight ( 11 % ) of 71 patients in the PF group . Six ( 7 % ) of 92 patients had tracheostomies in the TPF group , versus eight ( 11 % ) of 71 in the PF group . INTERPRETATION Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer . Patients who are c and i date s for induction chemotherapy should be treated with TPF . FUNDING Sanofi-Aventis BACKGROUND We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy ( CCRT ) in patients with locally advanced head and neck squamous cell carcinoma . METHODS Patients were r and omized to receive three cycles of docetaxel and cisplatin ( TP regimen ) with or without cetuximab ( TP plus cetuximab [ CTP ] vs. TP ) as induction chemotherapy . Patients in the CTP arm received CCRT with cetuximab and cisplatin , whereas patients in the TP arm received cisplatin alone . The primary endpoint was the objective response rate ( ORR ) after induction chemotherapy . RESULTS Overall , 92 patients were enrolled . The ORRs for induction chemotherapy in the CTP and TP arms were not different ( 81 % vs. 82 % ) . Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and result ed in more frequent dose reductions of the induction chemotherapy , although this did not reach statistical significance . In the CTP and TP arms , respectively , the 3-year progression-free survival ( PFS ) rates were 70 % and 56 % ( p = .359 ) , and the overall survival ( OS ) rates were 88 % and 74 % ( p = .313 ) . When limited to patients who completed induction chemotherapy , 3-year PFS rates of 78 % and 59 % ( p = .085 ) and OS rates of 94 % and 73 % ( p = .045 ) were observed in the CTP and TP arms , respectively . CONCLUSION Adding cetuximab to sequential treatment did not increase the treatment efficacy and result ed in greater toxicity . In the intent-to-treat population , neither PFS nor OS was improved by the addition of cetuximab to sequential treatment ; however , a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were r and omly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil ( 5-fluorouracil ) . There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers . In the group of patients with unresectable cancers , however , there was a statistically significant advantage to the addition of chemotherapy , both in terms of disease-free survival and date to progression The primary objective of the present r and omized phase III trial was to compare the 3-yr survival rate of patients treated with  st and ard fractionated radiotherapy ( RT ) alone or with the same RT concomitantly with cisplatin ( DDP ) or carboplatin ( Cb ) . From January 1995 until July 1999 , 124 patients with histologically proven locally advanced non-nasopharyngeal head and neck cancer ( HNC ) were r and omized to receive either RT monotherapy ( 70Gy , Group A ) or the same RT concomitantly with DDP ( 100 mg/m2 on d 2 , 22 , 42 , Group B ) or Cb ( 7 AUC on d 2 , 22 , 42 , Group C ) . There were no significant differences in complete response rates between patients treated with RT alone or combined chemoradiotherapy . However , median time to progression ( TTP ) and overall survival ( OS ) were significantly longer in patients treated with concomitant chemoradiotherapy . Thus , median TTP was 6.3 , 45.2 , and 17.7 mo in groups A , B , and C respectively ( p=0.0002 ) . Similarly , median OS was 12.2 , 48.6 , and 24.5 mo , respectively ( p=0.0003 ) . At 3 yr follow-up , 17.5 % of patients in group A were alive compared to 52 % in group B and 42 % in group C ( p<0.001 ) . Patients treated with concomitant chemoradiotherapy experienced more frequently severe hematological toxicity . Also , severe nausea/vomiting was more pronounced in group B , as expected . The present study clearly demonstrated that concomitant chemoradiotherapy with platinum analogs significantly prolongs 3-yr survival and median OS in patients with locally advanced HNC compared to conventional RT alone Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing chemotherapy ( DDP + bleomycin ) alone , multiple daily fractionated radiation therapy , and multimodality therapy consisting of chemotherapy plus multiple fractionated radiation therapy . Multimodal therapy gave a significantly higher response rate ( 69 % ) than either single-treatment modality . The use of a multiple daily dose fractionation allowed radiation therapy to be completed over 10 treatment days , and the addition of chemotherapy to the radiation treatment did not significantly increase toxicity . Patients receiving multimodal therapy also survived significantly longer ( median 50 weeks ) than those receiving single-modality therapy ( median 24 weeks ) Purpose : Induction chemotherapy has shown to provide consistent benefit for local control in primary treatment of advanced oropharyngeal cancer . The beneficial role of chemoradiation following induction chemotherapy over concurrent chemoradiation has not been evaluated . Present study evaluates the same prospect ively . Method : Out of 135 patients of locally advanced oropharyngeal carcinoma , 105 patients were found eligible and r and omized to treat either with induction chemotherapy consisting of 2 - 3 cycles of cisplatin and 5- Florouracil followed by low dose weekly cisplatin based chemoradiotherapy ( treatment arm : n=48 ) or chemoradiotherapy only ( control arm : n=57 ) . The primary tumor and regional lymph drainage areas received 66 - 70 Gy in 6.5 to 7 weeks by fractionated dose schedule . Results : The response rate and acute toxicity ( primary end points ) in both the arms were found to be similar ( P>0.05 ) The points disease free survival and overall survival ( secondary end points ) were significantly ( Conclusions . Conventional radiotherapy with concurrent cisplatin is significantly superior to induction cisplatin fluorouracil chemotherapy followed by radiotherapy in terms of laryngeal preservation in patients with T3 hypopharyngeal carcinoma . Despite a high rate of laryngeal preservation no survival benefit was recorded in this selected population . Objectives . To compare conventional radiotherapy with concurrent cisplatin to induction chemotherapy with cisplatin fluorouracil followed by conventional radiotherapy . The primary end point was the preservation of the larynx . The secondary end points included toxicity , causes of death , and survival rates . Patients and methods . Seventy-one adult patients with previously untreated resectable T3 pyriform sinus squamous cell carcinoma were enrolled in the multicenter prospect i ve r and omized phase III trial . They were evaluated for organ preservation , survival rates , and toxic reactions . Results . The rates of laryngeal preservation at 2 years were 68 % for the induction chemotherapy ( IC ) group and 92 % for the chemoradiotherapy ( CR ) group ( p = 0.016 ) . At 2 years , the event-free survival rates were 36 % and 41 % for the IC group and CR group , respectively PURPOSE The combination of cisplatin and radiotherapy is a st and ard treatment for patients with locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) .  Cetuximab-radiotherapy is superior to radiotherapy alone in this population , validating epidermal growth factor receptor ( EGFR ) as a target . Erlotinib is a small-molecule inhibitor of EGFR . Adding EGFR inhibition to st and ard cisplatin-radiotherapy may improve efficacy . PATIENTS AND METHODS Patients with locally advanced SCCHN were r and omly assigned to receive cisplatin 100 mg/m(2 ) on days 1 , 22 , and 43 combined with 70 Gy of radiotherapy ( arm A ) or the same chemoradiotherapy with erlotinib 150 mg per day , starting 1 week before radiotherapy and continued to its completion ( arm B ) . The primary end point was complete response rate ( CRR ) , evaluated by central review . The secondary end point was progression-free survival ( PFS ) . Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization . RESULTS Between December 2006 and October 2011 , 204 patients were r and omly assigned . Arms were well balanced for all patient characteristics including p16 , with the exception of more women on arm A. Patients on arm B had more rash , but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities . Arm A had a CRR of 40 % and arm B had a CRR of 52 % ( P = .08 ) when evaluated by central review . With a median follow-up time of 26 months and 54 progression events , there was no difference in PFS ( hazard ratio , 0.9 ; P = .71 ) . CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS Summary Background Between 1990 and 2000 , we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy . We aim ed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy , or both , affected clinical outcome . Here we report survival and recurrence after 10 years of follow-up . Methods Between Jan 15 , 1990 , and June 20 , 2000 , 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey . Patients with locally advanced head and neck cancer , and who had not previously undergone surgery , were r and omly assigned to one of four groups in a 3:2:2:2 ratio , stratified by centre and chemotherapy regimen : radical radiotherapy alone ( n=233 ) ; radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy ( SIM alone ; n=166 ) ; or 14 and 28 days after completing radiotherapy ( SUB alone , n=160 ) ; or both ( SIM+SUB ; n=154 ) . Chemotherapy was either methotrexate alone , or vincristine , bleomycin , methotrexate , and fluorouracil .  Patients who had previously undergone radical surgery to remove their tumour were only r and omised to radiotherapy alone ( n=135 ) or SIM alone ( n=118 ) , in a 3:2 ratio . The primary endpoints were overall survival ( from r and omisation ) , and event-free survival ( EFS ; recurrence , new tumour , or death ; whichever occurred first ) among patients who were disease-free 6 months after r and omisation . Analyses were by intention to treat . This trial is registered at www . Clinical trials.gov , number NCT00002476 . Findings All 966 patients were included in the analyses . Among patients who did not undergo surgery , the median overall survival was 2·6 years ( 99 % CI 1·9–4·2 ) in the radiotherapy alone group , 4·7 ( 2·6–7·8 ) years in the SIM alone group , 2·3 ( 1·6–3·5 ) years in the SUB alone group , and 2·7 ( 1·6–4·7 ) years in the SIM+SUB group ( p=0·10 ) . The corresponding median EFS were 1·0 ( 0·7–1·4 ) , 2·2 ( 1·1–6·0 ) , 1·0 ( 0·6–1·5 ) , and 1·0 ( 0·6–2·0 ) years ( p=0·005 ) , respectively . For every 100 patients given SIM alone , there are 11 fewer EFS events ( 99 % CI 1–21 ) , compared with 100 given radiotherapy , 10 years after treatment . Among the patients who had previously undergone surgery  , median overall survival was 5·0 ( 99 % CI 1·8–8·0 ) and 4·6 ( 2·2–7·6 ) years in the radiotherapy alone and SIM alone groups ( p=0·70 ) , respectively , with corresponding median EFS of 3·7 ( 99 % CI 1·1–5·9 ) and 3·0 ( 1·2–5·6 ) years ( p=0·85 ) , respectively . The percentage of patients who had a significant toxicity during treatment were : 11 % ( radiotherapy alone , n=25 ) , 28 % ( SIM alone , n=47 ) , 12 % ( SUB alone , n=19 ) , and 36 % ( SIM+SUB , n=55 ) among patients without previous surgery ; and 9 % ( radiotherapy alone , n=12 ) and 20 % ( SIM alone , n=24 ) among those who had undergone previous surgery . The most common toxicity during treatment was mucositis . The percentage of patients who had a significant toxicity at least 6 months after r and omisation were : 6 % ( radiotherapy alone , n=13 ) , 6 % ( SIM alone , n=10 ) , 4 % ( SUB alone , n=7 ) , and 6 % ( SIM+SUB , n=9 ) among patients who had no previous surgery ; and 7 % ( radiotherapy alone , n=10 ) and 11 % ( SIM alone , n=13 ) among those who had undergone previous surgery . The most common toxicity 6 months after treatment was xerostomia , but this occurred in 3 % or less of patients in each group . Interpretation Concurrent non-platinum chemoradiotherapy  reduces recurrences , new tumours , and deaths in patients who have not undergone previous surgery , even 10 years after starting treatment . Chemotherapy given after radiotherapy ( with or without concurrent chemotherapy ) is ineffective . Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy . Funding Cancer Research UK , with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre BACKGROUND This r and omised Phase II study assessed the activity and safety of concurrent chemoradiotherapy ( CRT ) and lapatinib followed by maintenance treatment in locally advanced , unresected stage III/IVA/IVB head and neck cancer . PATIENTS AND METHODS Patients were r and omised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib .  Treatment continued until disease progression or study withdrawal . Primary end-point was complete response rate ( CRR ) by independent review 6 months post-CRT . RESULTS Sixty-seven patients ( median age 56 years ; 97 % Eastern Cooperative Oncology Group performance status ≤1 ; 82 % stage IV ) were recruited . CRT dose intensities were unaffected by lapatinib : median radiation dose 70 Gy ( lapatinib , placebo ) , duration 49 ( lapatinib ) and 50 days ( placebo ) ; median cisplatin dose 260 mg/m(2 ) ( lapatinib ) and 280 mg/m(2 ) ( placebo ) . Lapatinib combined with CRT was well-tolerated . Grade 3/4 toxicities during CRT were balanced between arms , with the exception of an excess of grade 3 diarrhoea ( 6 % versus 0 % ) and rash ( 9 % versus 3 % ) and two grade 4 cardiac events in the lapatinib arm . CRR at 6 months post-CRT was 53 % with lapatinib versus 36 % with placebo in the intent-to-treat population . The progression-free survival ( PFS ) and overall survival rates at 18 months were 55 % versus 41 % and 68 % versus 57 % for the lapatinib and placebo arms , respectively . The difference between study arms was greatest in p16-negative disease ( median PFS > 20.4 months [ lapatinib ] versus 10.9 [ placebo ] ) . CONCLUSION Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease
OBJECTIVES The current st and ard therapy for locally advanced squamous cell carcinoma of the head and neck ( LASCCHN ) is platinum-based chemotherapy plus concurrent radiotherapy ( CRT ) , but several systemic therapies have been evaluated .
We performed a Bayesian network meta- analysis ( NMA ) with r and om effects to enable direct and indirect comparisons of all existing treatment modalities for LASCCHN simultaneously .