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. Phase II Study of Cetuximab Plus Concomitant Boost Radiotherapy in Japanese Patients with Locally Advanced Squamous Cell Carcinoma 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. Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer. Cisplatin-based chemoradiation plus cetuximab in locally advanced head and neck cancer: a phase II clinical study. Induction cetuximab, paclitaxel, and carboplatin followed by chemoradiation with cetuximab, paclitaxel, and carboplatin for stage III/IV head and neck squamous cancer: a phase II ECOG-ACRIN trial (E2303). Weekly cetuximab concurrent with IMRT aggravated radiation-induced oral mucositis in locally advanced nasopharyngeal carcinoma: Results of a randomized phase II study. Using the Skindex-16 and Common Terminology Criteria for Adverse Events to assess rash symptoms: results of a pooled-analysis (N0993) Acute toxicity in 14 patients with locally advanced head and neck squamous cell carcinoma treated with concurrent cetuximab and radiotherapy Concurrent Radiotherapy with Carboplatin and Cetuximab for the Treatment of Medically Compromised Patients with Locoregionally Advanced Head and Neck Squamous Cell Carcinoma IMRT with simultaneous integrated boost and concurrent chemotherapy for locoregionally advanced squamous cell carcinoma of the head and neck. Feasibility of 6-month maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck Differential outcome of concurrent radiotherapy plus epidermal growth factor receptor inhibitors versus radiotherapy plus cisplatin in patients with human papillomavirus-related head and neck cancer Phase II study evaluating the addition of cetuximab to the concurrent delivery of weekly carboplatin, paclitaxel, and daily radiotherapy for patients with locally advanced squamous cell carcinomas of the head and neck. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. Cisplatin-Based Chemotherapy versus Cetuximab in Concurrent Chemoradiotherapy for Locally Advanced Head and Neck Cancer Treatment Cetuximab, Paclitaxel, Carboplatin, and Radiation For Head and Neck Cancer: A Toxicity Analysis Grade 3/4 dermatitis in head and neck cancer patients treated with concurrent cetuximab and IMRT. Stereotactic Body Radiotherapy as Primary Treatment for Elderly Patients with Medically Inoperable Head and Neck Cancer Radiochemoimmunotherapy with intensity-modulated concomitant boost: interim analysis of the REACH trial Prospective phase II trial of cetuximab plus VMAT-SIB in locally advanced head and neck squamous cell carcinoma Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial. Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study. Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. A Phase 2 Open Label, Single-Arm Trial to Evaluate the Combination of Cetuximab Plus Taxotere, Cisplatin, and 5-Flurouracil as an Induction Regimen in Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck. Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab. A phase II study of concurrent cetuximab-cisplatin and intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma. Concurrent Cetuximab With Stereotactic Body Radiotherapy for Recurrent Squamous Cell Carcinoma of the Head and Neck: A Single Institution Matched Case-Control Study Efficacy and feasibility of induction chemotherapy and radiotherapy plus cetuximab in head and neck cancer. Reirradiation with cetuximab in locoregional recurrent and inoperable squamous cell carcinoma of the head and neck: feasibility and first efficacy results. Cetuximab, Paclitaxel, Carboplatin, and Radiation for Head and Neck Cancer: A Survival Analysis of a Brown University Oncology Group Phase II Study Induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced squamous cell carcinoma of the head and neck. Phase 2 trial of concurrent 5‐fluorouracil, hydroxyurea, cetuximab, and hyperfractionated intensity‐modulated radiation therapy for locally advanced head and neck cancer Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results. 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. Prognostic significance of p16 in locoregionally advanced head and neck cancer treated with concurrent 5-fluorouracil, hydroxyurea, cetuximab and intensity-modulated radiation therapy. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. Toxicity and efficacy of cetuximab associated with several modalities of IMRT for locally advanced head and neck cancer. Radiochemotherapy with cetuximab, cisplatin, and amifostine for locally advanced head and neck cancer: a feasibility study. Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. A retrospective, multicenter study of the tolerance of induction chemotherapy with docetaxel, Cisplatin, and 5-Fluorouracil followed by radiotherapy with concomitant cetuximab in 46 cases of squamous cell carcinoma of the head and neck. A phase 2 trial of induction nab‐paclitaxel and cetuximab given with cisplatin and 5‐fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck A retrospective study of induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiotherapy with cetuximab in locally advanced head and neck cancer. Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer. Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionated-accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck. Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III-IVB head and neck squamous cell carcinoma (HNSCC). Phase I study of C-TPF in patients with locally advanced squamous cell carcinoma of the head and neck. Cetuximab plus radiotherapy in patients with unresectable locally advanced squamous cell carcinoma of head and neck region--a open labelled single arm phase II study.
PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival ( OS ) of patients with stage III or IV head and neck carcinoma ( HNC ) .  Cetuximab plus platinum regimens also increase OS in metastatic HNC . The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival ( PFS ) . PATIENTS AND METHODS Eligible patients with stage III or IV HNC were r and omly assigned to receive radiation and cisplatin without ( arm A ) or with ( arm B ) cetuximab .  Acute and late reactions were scored using Common Terminology Criteria for Adverse Events ( version 3 ) . Outcomes were correlated with patient and tumor features and markers . RESULTS Of 891 analyzed patients , 630 were alive at analysis ( median follow-up , 3.8 years ) . Cetuximab plus cisplatin-radiation , versus cisplatin-radiation alone , result ed in more frequent interruptions in radiation therapy ( 26.9 % v. 15.1 % , respectively ) ; similar cisplatin delivery ( mean , 185.7 mg/m2 v. 191.1 mg/m2 , respectively ) ; and more grade 3 to 4 radiation mucositis ( 43.2 % v. 33.3 % , respectively ) , rash , fatigue , anorexia , and hypokalemia , but not more late toxicity . No differences were found between arms A and B in 30-day mortality ( 1.8 % v. 2.0 % , respectively ; P = .81 ) , 3-year PFS ( 61.2 % v. 58.9 % , respectively ; P = .76 ) , 3-year OS ( 72.9 % v. 75.8 % , respectively ; P = .32 ) , locoregional failure ( 19.9 % v. 25.9 % , respectively ; P = .97 ) , or distant metastasis ( 13.0 % v. 9.7 % , respectively ; P = .08 ) . Patients with p16-positive oropharyngeal carcinoma ( OPC ) , compared with patients with p16-negative OPC , had better 3-year probability of PFS ( 72.8 % v. 49.2 % , respectively ; P < .001 ) and OS ( 85.6 % v. 60.1 % , respectively ; P < .001 ) , but tumor epidermal growth factor receptor ( EGFR ) expression did not distinguish outcome . CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely . PFS and OS were higher in patients with p16-positive OPC , but outcomes did not differ by EGFR expression Background We investigated the tolerability of cetuximab plus radiotherapy in Japanese patients with untreated locally advanced squamous cell carcinoma of the head and neck . Methods Patients with epidermal growth factor receptor-expressing locally advanced squamous cell carcinoma of the head and neck received cetuximab ( 400 mg/m2 initial dose then 250 mg/m2 weekly ) for 7 weeks plus concomitant boost radiotherapy ( weeks 2–7 : once daily [ 1.8 Gy ] for 3.6 weeks , then twice daily [ 1.8 Gy morning and 1.5 Gy afternoon ] for 2.4 weeks ) . The primary endpoint was treatment completion rate ( the rate of treated patients completing ≥70 % of the planned cetuximab dose and the full dose of radiotherapy within 2 weeks over the planned schedule ) . Results Twenty-two patients were evaluable . The treatment completion rate was 100 % ( 95 % confidence interval 85–100 ) . The response rate 8 weeks post-radiotherapy was 82 % ( 95 % confidence interval 60–95 ) . The most common grade 3/4 treatment-emergent adverse events were mucosal inflammation ( 73 % ) ; dermatitis ( 27 % ) ; and infection , radiation skin injury and stomatitis ( 23 % each ) . Conclusions Cetuximab plus concomitant boost radiotherapy can be safely administered to Japanese patients with locally advanced squamous cell carcinoma of the head and neck . Tolerability and efficacy were in line with those reported in the Phase III Bonner trial in a Western population of patients with locally advanced squamous cell carcinoma of the head and neck 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 BACKGROUND We studied the combination of pemetrexed , a multi-targeted antifolate , and cetuximab , an mAb against the epidermal growth factor receptor , with radiotherapy in poor prognosis head and neck cancer . PATIENTS AND METHODS Patients received pemetrexed on days 1 , 22 , and 43 on a dose-escalation scheme with starting level ( 0 ) 350 mg/m(2 ) ( level -1 , 200 mg/m(2 ) ; level + 1 , 500 mg/m(2 ) ) with concurrent radiotherapy ( 2 Gy/day ) and cetuximab in two separate cohorts , not previously irradiated ( A ) and previously irradiated ( B ) , who received 70 and 60 - 66 Gy , respectively . Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated . RESULTS Thirty-two patients were enrolled . The maximum tolerated dose of pemetrexed was 500 mg/m(2 ) in cohort A and 350 mg/m(2 ) in cohort B. Prophylactic antibiotics were required . In cohort A , two dose-limiting toxicities ( DLTs ) occurred ( febrile neutropenia ) , one each at levels 0 and + 1 . In cohort B , two DLTs occurred at level + 1 ( febrile neutropenia ; death from perforated duodenal ulcer and sepsis ) . Grade 3 mucositis was common . No association of gene polymorphisms with toxicity or efficacy was evident . CONCLUSION The addition of pemetrexed 500 mg/m(2 ) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients BACKGROUND Intensification of chemoradiation for advanced head and neck squamous cell carcinoma ( HNSCC ) is unlikely due to toxicity . Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic profile with positive results in both combinations . Therefore , cetuximab could intensify chemoradiation without worsening toxicity . We conducted a phase II study of chemoradiation and cetuximab . PATIENTS AND METHODS Eligible patients had stage III-IV M0 HNSCC . Treatment consisted of three cycles of cisplatin ( 20 mg/m(2)/day × 5 days ) and fluorouracil ( 200 mg/m(2)/day × 5 days ) rapidly alternated to three split courses of radiotherapy up to 70 Gy and concurrent weekly cetuximab . The primary end point of the study was complete response ( CR ) rate . Secondary end points were toxicity , progression-free survival ( PFS ) and overall survival ( OS ) . RESULTS Fourty-five patients were enrolled : median age was 56 years , 38 had stage IV disease and 40 nodal involvement .  CR occurred in 32 patients ( 71 % ) . PFS and OS was 21 + months and 32.6 + , respectively . Acute grade 3 - 4 toxic effects were in the expected range , but grade 3 radiodermatitis occurred in 33 patients . CONCLUSIONS The combination of cetuximab , cisplatin , fluorouracil and radiotherapy leads to a very high proportion of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy . The only unexpected toxicity was skin toxicity : grade 3 radiodermatitis occurred in 73 % of the patients BACKGROUND E2303 evaluated cetuximab , paclitaxel , and carboplatin used as induction therapy and concomitant with radiation therapy in patients with stage III/IV head and neck squamous cell carcinoma ( HNSCC ) determining pathologic complete response ( CR ) , event-free survival ( EFS ) , and toxicity . PATIENTS AND METHODS Patients with resectable stage III/IV HNSCC underwent induction therapy with planned primary site restaging biopsies ( at week 8 in clinical complete responders and at week 14 if disease persisted ) . Chemoradiation ( CRT ) began week 9 . If week 14 biopsy was negative , patients completed CRT ( 68 - 72 Gy ) ; otherwise , resection was carried out . p16 protein expression status was correlated with response/survival . RESULTS Seventy-four patients were enrolled ; 63 were eligible . Forty-four ( 70 % ) were free of surgery to the primary site , progression , and death 1-year post-treatment . Following induction , 41 ( 23 CR ) underwent week 8 primary site biopsy and 24 ( 59 % ) had no tumor ( pathologic CR ) . Week 14 biopsy during chemoradiation ( 50 Gy ) in 34 ( 15 previously positive biopsy ; 19 no prior biopsy ) was negative in 33 . Thus 90 % of eligible patients completed CRT . Overall survival and EFS were 78 % and 55 % at 3 years , respectively . Disease progression in 23 patients ( 37 % ) was local only in 10 ( 16 % ) , regional in 5 ( 8 % ) , local and regional in 2 ( 3 % ) , and distant in 5 patients ( 8 % ) . There were no treatment-related deaths . Toxicity was primarily hematologic or radiation-related . p16 AQUA score was not associated with response/survival . CONCLUSIONS Induction cetuximab , paclitaxel , and carboplatin followed by the same drug CRT is safe and induces high primary site response and promising survival . CLINICAL TRIALS NUMBER NCT 00089297 BACKGROUND To evaluate the clinical efficacies and toxicities of induction chemotherapy followed by concomitant cisplatin-chemoradiotherapy ( CRT ) or cetuximab-radiotherapy ( ERT ) in locally advanced nasopharyngeal carcinoma ( NPC ) . METHODS Previously untreated patients with stage III-IVb NPC were eligible . They were r and omized to CRT arm : intensity modulated radiation therapy ( IMRT ) with weekly cisplatin ( 30 mg/m(2)/w ) or ERT arm : IMRT with weekly cetuximab ( loading dose of 400 mg/m(2 ) followed by weekly doses of 250 mg/m(2 ) ) . Two cycles of induction chemotherapy ( docetaxel 75 mg/m(2 ) d1 and cisplatin 80 mg/m(2 ) d1 ) were administered to both arms . Endpoints were survivals , toxicities and quality of life ( QoL ) . RESULTS Because of the unexpectedly high rates of grade 3/4 mucositis observed in the ERT arm , the study was closed ahead of schedule . A total of 44 patients ( 23 in CRT arm and 21 in ERT arm ) were enrolled . All patients completed the scheduled induction chemotherapy and radical radiotherapy . The results showed better compliance ( P<0.001 ) with more oral mucositis , acneiform rash and dysphagia ( P<0.05 ) of cetuximab . The 3-year disease-free survival ( DFS ) were achieved as 78.3 % and 85.7 % ( P=0.547 ) in CRT and ERT arm , respectively . In the analysis of QoL , the addition of cetuximab to radiotherapy temporarily increased the adverse symptoms but did not result in long-term dysfunction . CONCLUSIONS ERT was not more efficacious than CRT but was more likely to cause acute adverse events in LA NPC . The recommended treatment modality was still concurrent cisplatin-IMRT . The combination of TP induction chemotherapy and concurrent cetuximab-radiotherapy should only be used in selected patients Background Historically , skin toxicity has been assessed in prospect i ve clinical trials using the clinician-reported National Cancer Institute Common Terminology Criteria for Adverse Events ( CTCAE ) . The patient-reported Skindex-16 measures symptoms and perceptions of toxicity . This study was design ed to compare information provided by these two measures . Methods Data were compiled from three placebo-controlled North Central Cancer Treatment Group studies ( N06C4 , N03CB , N05C4 ) having rash prevention as the primary objective . All used the Skindex-16 and CTCAE at baseline , weekly during treatment and during a minimum 2-week follow-up period . Statistical procedures , including Pearson correlations , were utilized to determine relationships between adverse event ( AE ) grade s and Skindex-16 scores . Results Four hundred and twelve individual patients provided data ( median age , 61 ; 134 male ) . Patients ' Skindex-16 score  results show a 0.9 overall mean ( range 0–6 with 6 being worse symptoms ) , a 0.4 baseline mean ( range , 0–4.3 ) and a 1.3 end-of-treatment mean ( range , 0–5.9 ) . Ninety-three , 142 and 177 patients experienced a grade 0 , 1 and 2 + CTCAE skin toxicity , respectively . Baseline Skindex-16 scores had relatively low correlation with CTCAE grade s. The correlation of rash grade with Skindex-16 scores ranged from r = 0.49 with the function subscale to r = 0.62 with the symptom subscale . The highest correlations of the maximum grade of any dermatological AE with the Skindex-16 were r = 0.48 for the total score and r = 0.55 for the symptom subscale . Conclusions The data reported support the decision to include both measures in a clinical trial to assess the patient experience , as each measure may specifically target varying symptoms and intensities Purpose The authors report acute toxicity in 14 patients with locally advanced head and neck squamous cell carcinoma treated with radiotherapy and cetuximab .  Material s and methods Data collection was performed prospect ively on patients treated from September 2007 to March 2009 . Treatment consisted of 64.8–70 Gy radiotherapy in conventional fractions and cetuximab . Results Two out of 14 patients did not complete the planned combined treatment ; radiotherapy was temporarily suspended in six other patients . Seven of 12 patients received cetuximab until the end of radiotherapy . Treatment breaks were principally due to severe acute cutaneous or mucous toxicity . Any grade acneiform rash occurred in all patients . In-field G3 - 4 cutaneous toxicity occurred in five ( 36 % ) patients and G3 - 4 mucous toxicity in seven ( 50 % ) . One patient died of sepsis . Conclusions In our experience , severe acute toxic reactions are common in patients treated with radiotherapy and concurrent cetuximab  , result ing in frequent breaks or incomplete treatment with potential reduction in disease control . RiassuntoObiettivoScopo del nostro lavoro è stato riportare i dati relativi alla tossicità acuta in 14 pazienti affetti da carcinoma squamoso localmente avanzato del distretto testa-collo trattati con radioterapia e cetuximab in contemporanea . Material i e metodiLa raccolta dei dati è stata effettuata in modo prospettico relativamente ai pazienti trattati da settembre 2007 a marzo 2009 . Lo schema di trattamento consisteva nella radioterapia per una dose totale di 64,8–70 Gy con frazionamento convenzionale associata al cetuximab . RisultatiIn 2 dei 14 pazienti il trattamento combinato pianificato non è stato completato ; la radioterapia è stata temporaneamente interrotta in altri 6 pazienti . In 7 dei 12 pazienti che hanno ricevuto la terapia combinata il cetuximab è stato somministrato fino al termine della radioterapia . Le interruzioni sono state principalmente imputabili all’insorgenza di tossicità cutanea o mucosa severa . In tutti i pazienti è comparso rash cutaneo di tipo acneiforme ; tossicità cutanea di grado 3–4 si è verificata in 5 ( 36 % ) pazienti mentre tossicità mucosa di grado 3–4 si è avuta in 7 ( 50 % ) pazienti ; un paziente è deceduto per sepsi . Conclusion iNella nostra esperienza gli effetti tossici acuti di entità severa nei pazienti trattati con radioterapia e cetuximab concomitante sono stati comuni implic and o interruzioni frequenti della terapia o l’impossibilità di completare il trattamento con potenziale minor efficacia sul controllo della malattia Background : Cetuximab ( Cx ) + radiation therapy ( RT ) is well-tolerated and has improved survival in patients ( pts ) with locoregionally advanced head and neck squamous cell carcinomas ( LA-HNSCC ) . However , its efficacy when compared to HD-DDP + RT has been question ed . At our institution , low-dose weekly carboplatin is added to Cx + RT for patients unsuitable for HD-DDP . Methods : We review ed records of 16 patients with LA-HNSCC treated with definitive Cx + carboplatin + RT at the University of Miami from 2007 to 2011 . Median follow-up was 24 months ( range : 1–69 months ) . Results : Median age : 71.5 years ( range : 57–90 years ) ; 15 male , 1 female . ECOG PS 0 = 15 , 1 = 1 . TNM staging was : T1 = 1 , T2 = 5 , T3 = 8 , T4 = 2 ; N stage : N0 = 8 , N1 = 5 , N2a = 2 , N2b = 1 . All patients received weekly carboplatin ( AUC 1.5–2 ) , Cx given conventionally and daily conventionally fractionated RT . Median total weeks of concurrent systemic therapy = 7 ( range : 3–8 weeks ) . RT was delivered to a median total dose of 70 Gy ( range 30–74 Gy ) . Of the 15 evaluable patients , there were : 12 CR , 2 PR , and 1 PD . There were three local in-field failures , two regional failures , and three distant failures . At last follow-up , 8/15 patients remained with NED . Three-year locoregional recurrence was 28.3 % ( 95 % CI : 7.7–53.9 % ) . Mean percentage of weight loss was 14 % ( range : 6–26 % ) . Two patients required systemic therapy dose reduction . Three patients experienced a treatment delay and three did not finish RT as planned including a patient who received only 30 Gy due to death secondary to MI during treatment . Conclusion : In this small retrospective series , carboplatin/Cx/RT was well-tolerated and efficacious in patients unsuitable for HD-DDP having LA-HNSCC . Acute toxicities were similar to Cx + RT , likely due to the non-overlapping toxicity profiles of the two systemic agents . We hypothesize that the addition of a well-tolerated cytotoxic chemotherapy agent may improve the therapeutic ratio of Cx + RT in patients who are poor c and i date s for more aggressive therapies and warrants evaluation in a prospect i ve manner PURPOSE To evaluate the efficacy and toxicity of accelerated radiotherapy with concurrent chemotherapy in advanced head- and -neck squamous cell carcinoma . METHODS AND MATERIAL S Between April 2003 and May 2008 , 43 consecutive patients with advanced head- and -neck squamous cell carcinoma received accelerated chemoradiation with concurrent cisplatin or cetuximab . The doses for intensity-modulated radiotherapy with simultaneous integrated boost were 67.5 , 60.0 , and 54 Gy in 30 daily fractions of 2.25 , 2.0 , and 1.8 Gy to the planning target volumes for gross disease , high-risk nodes , and low-risk nodes , respectively . RESULTS Of the patients , 90.7 % completed chemoradiotherapy as prescribed . The median treatment duration was 43 days ( range , 38 - 55 days ) . The complete response rate was 74.4 % . With median follow-up of 36.7 months ( range , 16.8 - 78.1 months ) in living patients , the estimated 1- , 2- , and 5-year locoregional control , overall survival , and disease-free survival rates were 82 % , 82 % , and 82 % ; 73 % , 65 % , and 61 % ; and 73 % , 73 % , and 70 % , respectively . One treatment-related death occurred from renal failure . Grade 3 mucositis and dermatitis occurred in 13 patients ( 30.2 % ) and 3 patients ( 6.9 % ) , respectively . Grade 2 xerostomia occurred in 12 patients ( 27.9 % ) . In patients with adequate follow-up , 82 % were feeding tube free by 6 months after therapy ; 13 % remained feeding tube dependent at 1 year . Grade 3 soft-tissue fibrosis , esophageal stricture , osteoradionecrosis , and trismus occurred in 3 patients ( 6.9 % ) , 5 patients ( 11.6 % ) , 1 patient ( 2.3 % ) , and 3 patients ( 6.9 % ) , respectively . CONCLUSIONS Our results show that intensity-modulated radiotherapy with simultaneous integrated boost with concurrent chemotherapy improved local and regional control . Acute and late toxicities were tolerable and acceptable . A prospect i ve trial of this fractionation regimen is necessary for further assessment of its efficacy and toxicity compared with other approaches Background Close resection margins < 5 mm ( CM ) or extra capsular extent at the lymph nodes ( ECE ) impair the prognosis of patients with squamous cell cancer of the head and neck ( SCCHN ) scheduled for adjuvant radiochemotherapy .  We conducted a multicenter phase II study to investigate toxicity and efficacy of additional cetuximab administered concomitantly and as maintenance for the duration of 6 months following adjuvant radiochemotherapy . , Ppreliminary results on feasibility and acute toxicity on skin and mucosa are presented in this article . Methods Patients with SCCHN following CM resection or with ECE were eligible for the study . In all , 61.6 Gy ( 1.8/2.0/2.2 Gy , days 1–36 ) were administered using an integrated boost intensity-modulated radiotherapy ( IMRT ) technique . Cisplatin ( 20 mg/m2 , days 1–5 and days 29–33 ) and 5-fluorouracil ( 5-FU ) as continuous infusion ( 600 mg/m2 , days 1–5 + days 29–33 ) were given concurrently . Cetuximab was started 7 days prior to radiochemotherapy at 400 mg/m2 followed by weekly doses of 250 mg/m2 . Maintenance cetuximab began after radiochemotherapy at 500 mg/m2 every 2 weeks for 6 months . Results Of the 55 patients ( 46 male , 9 female , mean age 55.6 , range 29–70 years ) who finished radiochemotherapy , 50 were evaluable for acute toxicity concerning grade III/IV toxicities of skin and mucosa . Grade 3–4 ( CTC 3.0 ) mucositis , radiation dermatitis , and skin reactions outside the radiation portals were documented for 46 , 28 , and 14 % of patients , respectively . One toxic death occurred ( peritonitis at day 57 ) . Cetuximab was terminated in 5 patients due to allergic reactions after the first application . In addition , 22 % of patients discontinued cetuximab within the last 2 weeks or at the end of radiochemotherapy . Of patients embarking on maintenance treatment , 80 % were still on cetuximab at 3 months and 63 % at 5 months . Concurrent and maintenance treatment with cetuximab could be administered as scheduled in 48 % of patients . Conclusion Adjuvant radiochemotherapy with concomitant and maintenance cetuximab is feasible and acute toxicities are within the expected range . Compliance within the first 3–5 months is moderate . ZusammenfasssungHintergrundDie Prognose von Patienten mit Plattenepithelkarzinomen i m Kopf-Hals-Bereich ( SCCHN , „ squamous cell cancer of the head and neck “ ) nach adjuvanter Radiochemotherapie ist weiterhin unbefriedigend , sofern < 5 mm i m Gesunden reseziert wurde oder an den Lymphknoten ein extrakapsuläres Wachstum ( ECE ) nachweisbar war . Aus diesem Grund führten wir eine multizentrische Phase-II-Studie zur Untersuchung der Toxizitäten und der Wirksamkeit der adjuvanten Radiotherapie in Kombination mit Cisplatin , 5-Fluorouracil ( 5-FU ) und Cetuximab gefolgt von einer Erhaltungstherapie mit Cetuximab für 6 Monate durch . In dieser Publikation präsentieren wir eine Interimsanalyse zur Durchführbarkeit und Akuttoxizität an Haut und Schleimhäuten . Method ikPatienten , mit Plattenepithelkarzinomen i m Kopf-Hals-Bereich , die operiert wurden und bei denen ein hohes Risiko für ein Lokalrezidiv best and ( Resektionsr and < 5 mm ; ECE ) , wurden in die Studie eingeschlossen . Die Strahlentherapie erfolgte mit integrierter Boost-IMRT-Technik ( 1,8/2,0/2,2 Gy , Tage 1–36 ) bis zu einer Gesamtdosis von 61,6 Gy . Als Chemotherapie wurden Cisplatin ( 20 mg/m2 Tag 1–5 und Tag 29–33 ) und 5-Fluouracil ( 5-FU ) als kontinuierliche Infusion ( 600 mg/m2 Tag 1–5 plus Tag 29–33 ) simultan zur adjuvanten Radiochemotherapie gegeben . Die Gabe von Cetuximab begann 7 Tage vor Start der Radiochemotherapie mit einer Dosierung von 400 mg/m2 durch wöchentliche Cetuximab-Gaben ( 250 mg/m2 ) während der kombinierten Radiochemotherapie . Die Cetuximab – Erhaltungstherapie betrug nach Abschluss der Radiochemotherapie 500 mg/m2 alle 2 Wochen über einen Zeitraum von 6 Monaten . ErgebnisseVon 55 Patienten ( 46 Männer , 9 Frauen , Durchschnittsalter 55,6 Jahre , Spanne 29–70 Jahre ) , die die kombinierte Therapie ( Radiochemotherapie + Cetuximab ) beendeten , konnten bei 50 Patienten die Akuttoxizitäten Grad 3–4 an Haut und Schleimhaut anh and der CTC-3.0-Kriterien augewertet werden . Simultan zur kombinierten Radiochemotherapie war bei 46 % der Patienten eine Mukositis vom Grad 3–4 , bei 28 % der Patienten eine Hautreaktion vom Grad 3–4 i m Bestrahlungsfeld und bei 14 % der Patienten eine Hautreaktion außerhalb des Bestrahlungsfeldes vom Grad 3–4 zu verzeichnen . Ein Patient verstarb an einer Peritonitis am Tag 57 . Bei 10 % der Patienten wurde die Cetuximab-Gabe nach der ersten Anwendung ( allergische Reaktionen ) beendet . Die Cetuximab-Therapie wurde von 22 % aller Patienten vor Abschluss der Radiochemotherapie beendet . Von allen Patienten , die mit der Cetuximab-Erhaltungstherapie begonnen haben , erhielten 80 % Cetuximab noch nach 3 Monaten , 63 % noch nach 5 Monaten und 48 % beendeten die komplette Cetuximab-Erhaltungstherapie nach 6 Monaten . SchlussfolgerungDie adjuvante Radiochemotherapie mit Cetuximab gefolgt von einer Cetuximab-Erhaltungstherapie ist durchführbar und nicht mit unerwartet hohen Nebenwirkungen verbunden . Die Compliance bei der Erhaltungstherapie mit Cetuximab ist innerhalb der ersten 3–5 Monate befriedigend Background Human papillomavirus (HPV)-related head and neck cancer has been associated with an improved prognosis in patients treated with radiotherapy ( RT ) + /− chemotherapy ( CT ) ;  however , RT combined with epidermal growth factor receptor ( EGFR ) inhibitors has not been fully studied in this group of patients . Methods Immunohistochemical expression of p16 and PCR of HPV16 DNA were retrospectively analyzed in tumor blocks from 108 stage III/IV head and neck cancer patients treated with RT+CT ( 56 ) or RT+EGFR inhibitors ( 52 )  . Disease-free survival ( DFS ) and overall survival ( OS ) were analyzed by the Kaplan-Meier method . Results DNA of HPV16 was found in 12 of 108 tumors ( 11 % ) and p16 positivity in 18 tumors ( 17 % ) , with similar rates in both arms of treatment . After a median follow-up time of 35 months ( range 6–135 ) , p16-positive patients treated with RT+EGFR inhibitors showed improved survival compared with those treated with RT+CT ( 2-year OS 88 % vs. 60 % , HR 0.18 ; 95 % CI 0.04 to 0.88 ; p = 0.01 ; and 2-year DFS 75 % vs. 47 % , HR 0.17 ; 95 % CI 0.03 to 0.8 ; p = 0.01 ) . However , no differences were observed in p16-negative patients ( 2-year OS 56 % vs. 53 % , HR 0.97 ; 95 % CI 0.55 to 1.7 ; p = 0.9 ; and 2-year DFS 43 % vs. 45 % , HR 0.99 ; 95 % CI 0.57 to 1.7 ; p = 0.9 ) . Conclusions This is the first study to show that p16-positive patients may benefit more from RT+EGFR inhibitors than conventional RT+CT . These results are hypothesis-generating and should be confirmed in prospect i ve trials PURPOSE To report the mature data of a prospect i ve Phase II trial design ed to evaluate the efficacy of an epidermal growth factor receptor inhibitor cetuximab ( CTX ) added to the concurrent therapy of weekly paclitaxel/carboplatin ( PC ) and daily radiation therapy ( RT ) . METHODS AND MATERIAL S From 2005 to 2009 , a total of 43 patients were enrolled in the study . The median follow-up was 31 months ( range , 9 - 59 months ) . All patients had Stage III/IV disease at presentation , and 67 % had oropharyngeal primaries . The weekly IV dose schedules were CTX 250 mg/m(2 ) ( 400 mg/m(2 ) IV loading dose 1 week before RT ) , paclitaxel 40 mg/m(2 ) , and carboplatin AUC 2 . RT was given at 1.8 Gy per day to 70.2 Gy . Intensity-modulated RT was used in 70 % of cases . RESULTS All patients completed the planned RT dose , 74 % without any treatment breaks . The planned CTX and PC cycles were completed in 70 % ( 91 % with at least seven of planned nine cycles ) and 56 % ( 93 % with at least seven of planned eight cycles ) of patients , respectively . Toxicity included Grade 3 mucositis ( 79 % ) , rash ( 9 % ) , leucopenia ( 19 % ) , neutropenia ( 19 % ) , and RT dermatitis ( 16 % ) . The complete response ( CR ) rate at the completion of therapy was 84 % . The estimated 3-year local regional control rate was 72 % . Six patients with an initial CR subsequently experienced a local recurrence , 10 patients experienced distant progression . The median overall survival and disease-free survivals have not been reached . The 3-year actuarial overall survival and disease-free survival were 59 % and 58 % , respectively . CONCLUSIONS The addition of CTX to weekly PC and daily RT was well tolerated and result ed in encouraging local control and survival rates BACKGROUND We conducted a multinational , r and omized study to compare radiotherapy alone with radiotherapy plus cetuximab , a monoclonal antibody against the epidermal growth factor receptor , in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck . METHODS Patients with locoregionally advanced head and neck cancer were r and omly assigned to treatment with high-dose radiotherapy alone ( 213 patients ) or high-dose radiotherapy plus weekly cetuximab  ( 211 patients ) at an initial dose of 400 mg per square meter of body-surface area , followed by 250 mg per square meter weekly for the duration of radiotherapy . The primary end point was the duration of control of locoregional disease ; secondary end points were overall survival , progression-free survival , the response rate , and safety . RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone ( hazard ratio for locoregional progression or death , 0.68 ; P=0.005 ) . With a median follow-up of 54.0 months , the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone ( hazard ratio for death , 0.74 ; P=0.03 ) . Radiotherapy plus cetuximab significantly prolonged progression-free survival ( hazard ratio for disease progression or death , 0.70 ; P=0.006 ) . With the exception of acneiform rash and infusion reactions , the incidence of grade 3 or greater toxic effects , including mucositis , did not differ significantly between the two groups . CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck . ( Clinical Trials.gov number , NCT00004227 . Background and Purpose . This study aim ed to analyze survival , clinical responses , compliance , and adverse effects in locally advanced head and neck cancer ( LAHNC ) patients treated with split-dose cisplatin-based concurrent chemoradiation therapy ( SD-CCRT ) or cetuximab with concurrent radiation therapy ( BioRT ) .  Material s and Methods . We retrospectively evaluated 170 LAHNC patients diagnosed between January 1 , 2009 , and July 31 , 2012 : 116 received CCRT and 54 received BioRT .  Results . Complete response rates were similar in the SD-CCRT and BioRT groups ( 63.8 % versus 59.3 % ; P = 0.807 ) , and locoregional relapse rates were 18.1 % and 13.0 % , respectively ( P = 0.400 ) . The 3-year relapse-free survival rate was 65.8 % in the SD-CCRT group and 65.5 % in the BioRT group , respectively ( P = 0.647 ) . The 3-year overall survival rate was 78.5 % in the SD-CCRT group and 70.9 % in the BioRT group , respectively ( P = 0.879 ) . Hematologic side effects were significantly more frequent in the SD-CCRT than in the BioRT group . Mucositis frequency was similar . Conclusions . Primary SD-CCRT and BioRT both showed good clinical response and survival . Hematologic toxicities were more frequent , but tolerable , in the SD-CCRT group . Both groups showed good compliance Objective : To determine the feasibility and toxicity of the addition of cetuximab to paclitaxel , carboplatin , and concurrent radiation for patients with head and neck cancer . Material s and Methods : Patients with stage III or IV locally advanced squamous cell cancer of the head and neck , without distant organ metastases , were eligible . Patients received 4 weeks of induction cetuximab followed by weekly cetuximab , paclitaxel , carboplatin , and concurrent radiation . Results : Thirty-two patients were assessable for  chemoradiation toxicities . Grade 3 and grade 4 mucositis occurred in 53 % and 16 % of patients , respectively . Grade 3 and grade 4 radiation dermatitis occurred in 44 % and 9 % of patients , respectively . Grade 3/4 radiation dermatitis was associated with the use of intensity modulated radiation therapy ( 64 % vs.14 % , respectively , P < 0.0001 ) . Grade 3 and grade 4 cetuximab associated acneiform rash developed in 6 % and 3 % of patients . Overall 21 patients ( 66 % ) had any grade 3 toxicity and 10 patients ( 31 % ) had any grade 4 toxicity . The percentages of the intended total dose delivered of carboplatin , cetuximab , paclitaxel , and radiation were 86 % , 89 % , 89 % , and 96 % , respectively . Conclusion : Cetuximab , when combined with paclitaxel , carboplatin and intensity modulated radiation therapy , increases dermatologic toxicity but does not increase mucosal toxicity as compared with previous Brown University Oncology Group studies of paclitaxel , carboplatin , and conventional radiation for patients with head and neck cancer PURPOSE To assess the rate of serious ( > Grade 2 , CTCAE 3.0 ) dermatitis in our head- and -neck cancer ( HNC ) patients undergoing simultaneous integrated boost intensity-modulated radiotherapy with concomitant cetuximab ( SIB-IMRT-cetuximab ) .  We hypothesized a positive association between the radiation dose to the skin and the degree of dermatitis in patients receiving cetuximab .  METHODS AND MATERIAL S Between April 2006 and December 2009 , 99 HNC patients underwent SIB-IMRT-cetuximab .  In 69/99 ( 70 % ) , systemic treatment consisted of concomitant cetuximab only , whereas 30 ( 30 % ) were switched from concomitant cisplatin to concomitant cetuximab .  Treatment-related dermatitis was prospect ively monitored . Ninety-nine patients treated with four to seven concomitant cycles of cisplatin  only served as an internal control group . The radiation dose delivered to the skin was measured and related to dermal reactions . RESULTS Grade 3/4 dermatitis developed in 34 % of the cetuximab cohort , which was substantially higher than in the control cohort ( 3 % , p<0.01 ) . No cases of skin necrosis or other fatal events related to cetuximab have occurred so far . A significantly larger mean skin area was found exposed to high radiation doses in patients with severe cetuximab-related dermatitis , compared with those without ( p<0.01 ) . CONCLUSION Concomitant cetuximab result ed in a ∼10-fold increase in the rate of severe transient dermatitis compared with the use of concomitant cisplatin . We found a positive association between the incidence of Grade 3/4 dermatitis and the radiation dose delivered to the skin in patients receiving cetuximab Purpose : With a growing elderly population , elderly patients with head and neck cancers represent an increasing challenge with limited prospect i ve data to guide management . The complex interplay between advanced age , associated co-morbidities , and conventional local therapies , such as surgery and external beam radiotherapy ± chemotherapy , can significantly impact elderly patients ’ quality of life ( QoL ) . Stereotactic body radiotherapy ( SBRT ) is a well-established curative strategy for medical-inoperable early-stage lung cancers even in elderly population s ; however , there is limited data examining SBRT as primary therapy in head and neck cancer . Material / methods : Twelve patients with medically inoperable head and neck cancer treated with SBRT ± cetuximab from 2002 to 2013 were retrospectively review ed .  SBRT consisted of primarily 44 Gy in five fractions delivered on alternating days over 1–2 weeks . Concurrent cetuximab was administered at a dose of 400 mg/m2 on day −7 followed by 250 mg/m2 on day 0 and + 7 in n = 3 ( 25 % ) . Patient-reported quality of life ( PRQoL ) was prospect ively recorded using the previously vali date d University of Washington quality of life revised ( UW-QoL-R ) . Results : Median clinical follow-up was 6 months ( range : 0.5–29 months ) . The 1-year actuarial local progression-free survival , distant progression-free survival , progression-free survival , and overall survival for definitively treated patients were 69 , 100 , 69 , and 64 % , respectively . One patient ( 8 % ) experienced acute grade 3 dysphagia and one patient ( 8 % ) experienced late grade 3 mucositis ; there were no grade 4–5 toxicities . Prospect i ve collection of PRQoL as assessed by UW-QoL-R was preserved across domains . Conclusion : Stereotactic body radiotherapy shows encouraging survival and relatively low toxicity in elderly patients with unresectable head and neck cancer , which may provide an aggressive potentially curative local therapy while maintaining Purpose To evaluate efficacy and toxicity clinical in the intensified treatment of locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) with the combination of  chemotherapy , the EGFR antibody cetuximab , and intensity-modulated radiation therapy ( IMRT ) in a concomitant boost concept . Methods REACH is a prospect i ve , bi-centric phase II trial of carboplatin/5-FU and cetuximab weekly combined with IMRT . Primary endpoint is locoregional control , secondary endpoints include acute radiation effects and adverse events . Evaluation of disease response is carried out according to the Response Evaluation Criteria in Solid Tumors ( RECIST ) ; toxicity is assessed using NCI CTC v 3.0 . Results Treatment was tolerated moderately well , acneiforme erythema occurred in 74.1 % ( grade II/III ) , mucositis grade III in 28.6 % , and radiation dermatitis grade III in 14.3 % . Higher- grade side-effects resolved quickly until the first follow-up post treatment . Objective response rates were promising with 28.6 % CR at first follow-up and 92.9 % thereafter . Conclusion The combination of st and ard carboplatin/5-FU and cetuximab is feasible and results in promising objective response rates . The use of an IMRT concomitant boost is practicable in a routine clinical setting result ing in only moderate overall toxicity of the regimen . Trial Registration NumberIS RCT N87356938 Introduction Cetuximab plus radiotherapy ( RT ) may be an effective alternative to chemoradiation in locally advanced head and neck squamous cell carcinoma ( LASCCHN ) patients . We analyzed a group of patients treated at our institute with cetuximab plus volumetric modulation arc therapy ( VMAT )  with the RapidArc technique in a simultaneous integrated boost ( SIB ) regime . The primary end point was the assessment of acute toxicity and the feasibility of the combined approach . Material s and methods Between December 2008 and March 2010 , 22 patients were su bmi tted to IMRT-SIB plus cetuximab for radical intent in case of LASCCHN . None of the patients was suitable for chemotherapy because of important comorbidities ( the majority suffered of heart chronic diseases ) . All patients underwent planning CT ( additional image modalities were acquired for contouring purpose s in the same treatment position : MRI in 12 and FDG-PET in 4 out of 22 patients ) . VMAT , by means of RapidArc , and SIB with two dose levels of 54.45 Gy and 69.96 Gy in 33 fractions were adopted . All patients included in the analysis were concomitantly treated with cetuximab : administration of the drug was initiated 1 week before RT at a loading dose of 400 mg/m2 body surface area over a period of 120 min , follow by a weekly 60 min infusion of 250 mg/m2 for the duration of RT . Patients were assessed for toxicities according to the Radiation Therapy Oncology Group ( RTOG ) criteria . Results All but 2 patients completed treatment and achieved the minimum follow-up of 12 months after the end of the treatment . Of the 22 patients , 18 % ( 4 patients ) showed grade 1 , 36 % ( 8 patients ) grade 2 , and 36 % ( 8 patients ) showed grade 3 dermatitis , while 9 % ( 2 patients ) had grade 1 , 36 % ( 8 patients ) grade 2 , and 45 % ( 10 patients ) had grade 3 mucositis/stomatitis . No grade 4 toxicities were recorded . Considering blood parameters , 3 cases of grade 1 anemia and 1 case of grade 2 thrombocytopenia were observed . Nobody required feeding tube placement during treatment . Conclusion The here reported toxicity data are promising and encouraging in regard to the adoption of moderate hypofractionation with VMAT-SIB techniques , when cetuximab is concomitantly administered . ZusammenfassungEinführungCetuximab und Radiotherapie ( RT ) kann für Patienten mit lokal fortgeschrittenen Kopf-Hals-Plattenepithelkarzinomen ( LASCCHN ) eine effektive Alternative zur Radiochemotherapie darstellen . Wir haben eine Gruppe von Patienten analysiert , die in unserer Klinik mit Cetuximab und RapidArc ® , einer volumetrisch modulierten Arc-Therapie ( VMAT ) , beh and elt wurden . Dabei haben wir das simultan integrierte Boost- (SIB-)Verfahren verwendet . Primärer Endpunkt waren die Akutoxizität und die Realisierbarkeit dieses kombinierten Vorgehens . Patienten und Method enZwischen Dezember 2008 und März 2010 wurden 22 LASCCHN-Patienten der IMRT-SIB- und Cetuximab-Beh and lung in kurativer Absicht zugeführt . Aufgrund relevanter Komorbidität ( die Mehrheit litt an chronischen Herzerkrankungen ) war keiner dieser Patienten für eine Chemotherapie geeignet . Für alle Patienten wurde ein Planungs-CT erstellt ; in derselben Beh and lungsposition wurden bei 12 von 22 Patienten zusätzlich ein MRT und bei 4 von 22 Patienten ein FDG-PET erstellt . Eine VMAT-Beh and lung , in diesem Fall RapidArc mit SIB in 2 Dosierungen ( 54,45 Gy und 69,96 Gy in 33 Fraktionen ) , wurde durchgeführt . Gleichzeitig wurden alle Patienten in dieser Studie mit Cetuximab beh and elt . Die Verabreichung des Medikaments begann eine Woche vor der Strahlentherapie ; dabei wurde eine Dosis von 400 mg/m2 über 120 min gegeben . Danach wurde über die gesamte Dauer der Strahlentherapie wöchentlich 250 mg/m2 über 60 min als Infusion verabreicht . Die Toxizität wurde anh and der Kriterien der „ Radiation Therapy Oncology Group “ ( RTOG ) beurteilt . ErgebnisseMit Ausnahme von 2 Patienten beendeten alle Patienten die Beh and lung und erreichten nach Abschluss der Therapie ein Follow-up von mindestens 12 Monaten . 18 % ( 4/22 ) der Patienten zeigten eine G1- , 36 % ( 8/22 ) eine G2- und 36 % ( 8/22 ) eine G3-Dermatitis . Bei 9 % ( 2/22 ) der Patienten entwickelte sich eine G1- , bei 36 % ( 8/22 ) eine G2- und bei 45 % ( 10/22 ) eine G3-Mukositis/Stomatitis . Es wurden keine G4-Toxizitäten festgestellt . Bei den Blutwerten wiesen 3 Patienten eine G1-Anämie und ein Patient eine G2-Thrombozytopenie auf . Kein Patient benötigte während der Beh and lung eine künstliche Ernährung . ZusammenfassungDie hier gezeigten Toxizitäts date n sind vielversprechend und ermutigend hinsichtlich des Einsatzes einer hypofraktionierten VMAT-SIB-Beh and lungstechnik bei gleichzeitiger Gabe von Cetuximab PURPOSE To compare the efficacy and safety of induction chemotherapy ( ICT ) followed by chemoradiotherapy ( CRT ) or bioradiotherapy ( BRT ) for larynx preservation ( LP ) . PATIENTS AND METHODS Previously untreated patients with stage III to IV larynx/hypopharynx squamous cell carcinoma received three cycles of ICT-docetaxel and cisplatin 75 mg/m(2 ) each on day 1 and fluorouracil 750 mg/m(2 ) per day on days 1 through 5 . Poor responders ( < 50 % response ) underwent salvage surgery . Responders ( ≥ 50 % response ) were r and omly assigned to conventional radiotherapy ( RT ; 70 Gy ) with concurrent cisplatin 100 mg/m(2 ) per day on days 1 , 22 , and 43 of RT ( arm A ) or concurrent cetuximab 400 mg/m(2 ) loading dose and 250 mg/m(2 ) per week during RT ( arm B ) . Primary end point was LP at 3 months . Secondary end points were larynx function preservation ( LFP ) and overall survival ( OS ) at 18 months . RESULTS Of the 153 enrolled patients , 116 were r and omly assigned after ICT ( 60 , arm A ; 56 , arm B ) . Overall toxicity of both CRT and BRT was substantial following ICT . However , treatment compliance was higher in the BRT arm . In an intent-to-treat analysis , there was no significant difference in LP at 3 months between arms A and B ( 95 % and 93 % , respectively ) , LFP ( 87 % and 82 % , respectively ) , and OS at 18 months ( 92 % and 89 % , respectively ) . There were fewer local treatment failures in arm A than in arm B ; salvage surgery was feasible in arm B only . CONCLUSION There is no evidence that one treatment was superior to the other or could improve the outcome reported with ICT followed by RT alone ( French Groupe Oncologie Radiothérapie Tête et Cou [ GORTEC ] 2000 - 01 trial [ Induction CT by Cisplatin , 5FU With or Without Docetaxel in Patients With T3 and T4 Larynx and Hypopharynx Carcinoma ] ) . The protocol that can best compare with RT alone after ICT is still to be determined 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 report results of a r and omized phase II trial ( Radiation Therapy Oncology Group RTOG-0234 ) examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with squamous cell carcinoma of the head and neck ( SCCHN ) with high-risk pathologic features . PATIENTS AND METHODS Eligibility required pathologic stage III to IV SCCHN with gross total resection showing positive margins and /or extracapsular nodal extension and /or two or more nodal metastases . Patients were r and omly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m(2 ) or docetaxel 15 mg/m(2 ) once per week . RESULTS Between April 2004 and December 2006 , 238 patients were enrolled . With a median follow-up of 4.4 years , 2-year overall survival ( OS ) was 69 % for the cisplatin arm and 79 % for the docetaxel arm ; 2-year disease-free survival ( DFS ) was 57 % and 66 % , respectively . Patients with p16-positive oropharynx tumors showed markedly improved survival outcome relative to patients with p16-negative oropharynx tumors . Grade 3 to 4 myelosuppression was observed in 28 % of patients in the cisplatin arm and 14 % in the docetaxel arm ; mucositis was observed in 56 % and 54 % , respectively . DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial ( Phase III Intergroup Trial of Surgery Followed by Radiotherapy Versus Radiochemotherapy for Resectable High Risk Squamous Cell Carcinoma of the Head and Neck ) , which had a hazard ratio of 0.76 for the cisplatin arm versus control ( P = .05 ) and 0.69 for the docetaxel arm versus control ( P = .01 ) , reflecting absolute improvement in 2-year DFS of 2.5 % and 11.1 % , respectively . CONCLUSION The delivery of postoperative chemoradiotherapy and cetuximab to patients with SCCHN is feasible and tolerated with predictable toxicity . The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial PURPOSE The aim of this study was to investigate prospect ively the weekly volume changes in the target volumes and organs at risk and the result ing dosimetric changes during induction chemotherapy followed by chemoradiotherapy with intensity-modulated radiation therapy ( C-IMRT ) for head- and -neck cancer patients . METHODS AND MATERIAL S Patients receiving C-IMRT for head- and -neck cancer had repeat CT scans at weeks 2 , 3 , 4 , and 5 during radiotherapy .  The volume changes of clinical target volume 1 ( CTV1 ) and CTV2 and the result ing dosimetric changes to planning target volume 1 ( PTV1 ) and PTV2 and the organs at risk were measured . RESULTS The most significant volume differences were seen at week 2 for CTV1 and CTV2 . The reductions in the volumes of CTV1 and CTV2 at week 2 were 3.2 % and 10 % , respectively ( p = 0.003 and p < 0.001 ) . The volume changes result ed in a significant reduction in the minimum dose to PTV1 and PTV2 ( 2 Gy , p = 0.002 , and 3.9 Gy , p = 0.03 , respectively ) and an increased dose range across PTV1 and PTV2 ( 2.5 Gy , p < 0.001 , and 5.1 Gy , p = 0.008 , respectively ) . There was a 15 % reduction in the parotid volumes by week 2 ( p < 0.001 ) and 31 % by week 4 ( p < 0.001 ) . There was a statistically significant increase in the mean dose to the ipsilateral parotid only at week 4 ( 2.7 Gy , p = 0.006 ) . The parotid gl and s shifted medially by an average of 2.3 mm ( p < 0.001 ) by week 4 . CONCLUSION The most significant volumetric changes and dosimetric alterations in the tumor volumes and organs at risk during a course of C-IMRT occur by week 2 of radiotherapy . Further adaptive radiotherapy with replanning , if appropriate , is recommended PURPOSE To report toxicity data from the first 13 consecutive patients with locally advanced head and neck squamous cell carcinoma ( LAHNSCC ) , ineligible for cisplatin , treated with concurrent cetuximab and radiotherapy ( RT ) at our institution . MATERIAL S AND METHODS Data were collected prospect ively between August 2007 and May 2008 . Planned treatment consisted of a cetuximab loading dose ( 400mg/m(2 ) ) via intravenous infusion 1 week prior and then weekly ( 250mg/m(2 ) ) with 70Gy in 35 daily fractions over 7 weeks . RESULTS Median age was 68 years ( range 52 - 82 years ) . The predominant primary sites were hypopharyngeal ( 5 ) and oropharyngeal ( 5 ) . In eligibility for cisplatin consisted of renal impairment ( 5 ) , hearing impairment ( 4 ) and of other major co-morbidities ( 4 ) . Of the 13 patients , 10 ( 77 % ) had grade 3/4 skin reactions and 10 ( 77 % ) grade 3/4 mucositis . Six ( 46 % ) patients required admission for management of severe skin reactions and /or mucositis with 4 ( 31 % ) requiring a treatment break , median 10 days ( 9 - 15days ) . Only 4 ( 31 % ) patients managed to complete the planned 8 cycles of cetuximab . Of the 9 patients with 12-week post-therapy data , 7 ( 78 % ) achieved a complete response . CONCLUSIONS Our early experience with cetuximab/RT has demonstrated a higher rate of toxicity compared with the recently reported r and omised trial , result ing in low treatment compliance and delays in completing RT PURPOSE Despite treatment , prognosis of unresectable squamous cell carcinoma of the head and neck ( SCCHC ) is dismal . Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile . We design ed a phase 2 trial to evaluate the efficacy of docetaxel , cisplatin , and 5-fluorouracil ( TPF ) plus cetuximab ( C-TPF ) as an induction regimen in patients with unresectable SCCHN . METHODS AND MATERIAL S A single-arm phase 2 trial was conducted . Eligible patients included those with untreated unresectable SCCHC , World Health Organization performance status of 0 to 1 , 18 to 70 years of age . Treatment consisted of four 21-day cycles of TPF ( docetaxel , 75 mg/m(2 ) day 1 ; cisplatin , 75 mg/m(2 ) day 1 ; 5-fluorouracil [ 5-FU ] , 750 mg/m(2 ) day 1 - 5 ) and cetuximab , 250 mg/m(2 ) weekly ( loading dose of 400 mg/m(2 ) ) . Prophylactic granulocyte colony-stimulating factor and antibiotic support were given . After induction , sequential accelerated radiation therapy with concomitant boost ( 69.9 Gy ) and weekly cetuximab therapy were delivered in the absence of disease progression . The primary endpoint was objective response rate ( ORR ) to C-TPF . RESULTS Fifty patients were enrolled across 8 centers . Median age was 54 years ; disease was stage IV ; oropharynx and hypopharynx were the most common primary sites . Eighty-two percent received 4 cycles of C-TPF , and 86 % started sequential treatment based on radiation therapy and cetuximab .  ORR after C-TPF was 86 % ( 95 % confidence interval [ CI ] : 73%-94 % ) and 24 % had complete response ( CR ) . With a median follow-up of 40.7 months , median overall survival ( OS ) was 40.7 months . The 2-year actuarial locoregional control ( LRC ) rate was 57 % . The most common drug-related grade 3 or 4 toxicities during induction were neutropenia ( 24 % ) , neutropenic fever ( 24 % ) , and diarrhea ( 20 % ) . There were 3 treatment-related deaths ( 6 % ) . CONCLUSIONS C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN . However , hematologic toxicity is too high to recommend this regimen at the current dose PURPOSE We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus ( HPV ) and p16 protein expression status with outcomes in patients with oropharyngeal carcinoma ( OPC ) receiving radiotherapy ( RT ) plus cetuximab or RT alone .  PATIENTS AND METHODS In the IMCL-9815 study , patients were r and omly allocated to receive RT plus weekly cetuximab or RT alone . A sub population of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control ( LRC ) , overall survival ( OS ) , and progression-free survival ( PFS ) . Evaluable sample s from patients with p16-positive OPC were also tested for HPV DNA . RESULTS Tumor p16 status  was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study ; 41 % were p16 positive . When treated with RT alone or RT plus cetuximab , p16-positive patients had a longer OS than p16-negative patients ( hazard ratio , 0.40 ; 95 % CI , 0.21 to 0.74 and hazard ratio , 0.16 ; 95 % CI , 0.07 to 0.36 , respectively ) . The addition of cetuximab to RT increased LRC , OS , and PFS in both patients with p16-positive OPC and those with p16-negative disease . Interaction tests for LRC , OS , and PFS did not demonstrate any significant interaction between p16 status and treatment effect ( P = .087 , .085 , and .253 , respectively ) . Similar trends were observed when patients with p16-positive/HPV-positive OPC ( n = 49 ) and those with p16-positive/HPV-negative OPC ( n = 14 ) were compared . CONCLUSION p16 status was strongly prognostic for patients with OPC . The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone BACKGROUND Based on our previous work on the clinical activity of cetuximab in recurrent nasopharyngeal carcinoma ( NPC ) , we evaluated the feasibility of adding cetuximab to concurrent cisplatin and intensity-modulated radiotherapy ( IMRT ) in locoregionally advanced NPC . PATIENTS AND METHODS Patients with American Joint Committee on Cancer stage III-IVB NPC were given an initial dose of cetuximab ( 400 mg/m(2 ) ) 7 - 10 days before receiving concurrent IMRT , weekly cisplatin ( 30 mg/m(2)/week ) and cetuximab ( 250 mg/m(2)/week ) . RESULTS Thirty patients ( median age of 45 years ) with stage III ( 67 % ) , IVA ( 30 % ) and IVB ( 3 % ) nonkeratinizing NPC were enrolled .  Grade 3 - 4 oropharyngeal mucositis occurred in 26 ( 87 % ) patients and 10 ( 33 % ) patients required short-term nasogastric feeding . Grade 3 radiotherapy-related dermatitis occurred in six patients ( 20 % ) and three patients ( 10 % ) had grade 3 cetuximab-related acneiform rash . These grade 3 - 4 skin and mucosal toxic effects were manageable and reversible . At a median follow-up of 31.8 months [ 95 % confidence interval ( CI ) 26.2 - 32.1 months ] , the 2-year progression-free survival was 86.5 % ( 95 % CI 74.3 % to 98.8 % ) . CONCLUSIONS Concurrent administration of cetuximab , weekly cisplatin and IMRT is a feasible strategy against locoregionally advanced NPC . Preliminary survival data compare favorably with historic data and further follow-up is warranted Purpose : Locally recurrent head and neck squamous cell carcinoma can be treated with curative intent by surgical salvage or reirradiation with or without chemotherapy . We have previously demonstrated the feasibility and safety of stereotactic body reirradiation at our institution ; however , efficacy has been unsatisfactory . Based on the successful combination of cetuximab with radiotherapy in locally-advanced squamous cell carcinoma of the head and neck , we compared stereotactic body radiotherapy alone with combination therapy , using concomitant cetuximab with stereotactic body radiotherapy , to enhance clinical efficacy while minimizing toxicity . Methods : In a retrospective-matched cohort study , we compared 2 groups of patients treated over a 6-year period with stereotactic body radiation therapy alone ( n = 35 ) or with weekly cetuximab infusion during stereotactic body radiotherapy ( n = 35 ) , and evaluated clinical response , local control , overall survival , and toxicity . Cox proportional hazard models were used to assess independent prognostic factors . Results : The median follow-ups for patients alive at last contact were 21.3 months and 24.8 months for stereotactic body radiotherapy only ( n = 13 ) and stereotactic body radiotherapy plus cetuximab ( n = 22 ) , respectively . Our results indicate that cetuximab conferred an overall survival advantage ( 24.5 vs. 14.8 months ) when compared with the stereotactic body radiotherapy alone arm , without a significant increase in grade 3/4 toxicities . This survival advantage was also observed in the subgroup that had received cetuximab therapy during their prior therapeutic regimen . Conclusions : Our results suggest an overall survival benefit of concomitant cetuximab with stereotactic body radiotherapy in locally recurrent head and neck squamous cell carcinoma , and suggest a role in this setting . Concomitant cetuximab with stereotactic body radiotherapy is a reasonable approach for unresectable recurrent squamous cell carcinoma of the head and neck , and should be tested in prospect i ve r and omized trials to vali date its clinical efficacy BACKGROUND To determine the potential activity and tolerability of sequential treatment in head and neck cancer , we conducted a phase II trial based on induction chemotherapy of two cycles of taxotere , cisplatin and 5-fluorouracil followed by radiotherapy plus weekly cetuximab . PATIENTS AND METHODS Thirty-six patients with stage III or IV squamous cell carcinoma of the oral cavity , larynx , oropharynx and hypopharynx were treated and evaluated for response and acute toxicity . RESULTS Eighty-one percent of patients had stage IV disease and 42 % had hypopharyngeal and oral cavity primaries . The overall response rate was 81.8 % , with 60.6 % complete response and 33.3 % partial response . Severe toxicities were febrile neutropenia ( 6 % ) during induction chemotherapy and dermatitis ( 48 % ) , mucositis ( 33 % ) and dysphagia ( 12 % ) during the concurrent phase . CONCLUSION Our protocol proved to be feasible , effective and well tolerated . This sequential strategy should be further investigated PURPOSE To report our experience with a prospect i ve protocol of external beam reirradiation ( Re-RT ) combined with cetuximab for patients with inoperable , recurrent squamous cell carcinoma of the head and neck ( SCCHN ) . PATIENTS AND METHODS Between August 2008 and June 2010 , 18 patients with inoperable recurrence of SCCHN after adjuvant or definitive radiotherapy ( RT ) and simultaneous or sequential cisplatin-based chemotherapy for primary SCCHN were enrolled .  Acute and late toxicity from the experimental regimen were recorded every week during RT and every 3 months thereafter . Efficacy was assessed with repeated imaging using response evaluation criteria in solid tumors and clinical examinations 8 - 12 weeks after completion of the treatment and every 3 months thereafter . RESULTS Median follow-up time for all patients was 9.4 ( range : 3.85 - 31.7 ) months and for patients alive 30.4 ( range : 15.7 - 31.7 ) months . Acute toxicity was generally mild or moderate . Five patients developed a grade 3 acneiform rash related to cetuximab . Late toxicity occurred as grade 3 trismus in five and as grade 3 abacterial salivary gl and inflammation in one patient , respectively . Overall response rate was 47 % . Median overall and progression-free survival for all patients was 8.38 months and 7.33 months , respectively . The overall survival rate was 44 % at 1 year , with a 1 year local control rate of 33 % . CONCLUSION Notwithst and ing the limitations of our preliminary data Re-RT combined with cetuximab for recurrent and inoperable SCCHN is feasible and the integration of newer targeted agents seems to be less toxic compared to conventional chemotherapy with encouraging response rates at least for a subset of patients Objectives : To assess the effect on progression-free and overall survival from the addition of cetuximab to paclitaxel-based chemoradiation for patients with squamous cell head and neck cancer from Brown University Oncology Group studies . Methods : BrUOG HN-204 patients with stage III or IV locally advanced squamous cell cancer of the head and neck without distant organ metastases received 4 weeks of induction cetuximab followed by weekly cetuximab , paclitaxel , carboplatin , and concurrent radiation .  Recurrence and survival data were compared with previous Brown University studies utilizing the same paclitaxel-based chemoradiation with and without induction chemotherapy . Results : The progression-free survival and overall survival at 3 years for all 37 patients initiating chemoradiation was 54 % and 57 % , respectively . All surviving patients were followed for at least 3 years and the median follow-up is 4.4 years . Of 14 patients who recurred within 3 years , 7 patients recurred locally only , 5 had a systemic recurrence , and 2 recurred both locally and systemically . Conclusions : The addition of cetuximab to paclitaxel , carboplatin , and radiation achieves overall survival that is virtually identical to prior Brown University Oncology Group studies of paclitaxel-based chemoradiation without cetuximab . Improvements in locoregional control are needed despite the use of 3 agents to enhance the effects of radiation PURPOSE To determine the efficacy and feasibility of induction chemotherapy ( ICT ) with docetaxel , cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab ( C ) in patients with locally advanced head and neck cancer . PATIENTS AND METHODS Forty-nine previously untreated patients with local advanced stage III and IV squamous cell carcinoma of the head and neck ( SCCHN ) received three courses of ICT consisting of docetaxel 75mg/m(2 ) day 1 , cisplatin 75mg/m(2 ) day 1 and infusional 5-fluorouracil 750mg/m(2)/day on days 1 - 5 followed by radiotherapy plus C at 250mg/m(2)/week ( after an initial loading dose of 400mg/m(2 ) ) . RESULTS After completion of ICT 44 of 49 patients received radiotherapy plus C. Three months after therapy completion tumour response was observed in 33 patients and after two years , 25 patients were in complete remission ( CR ) . The most common grade 4 toxicity during the whole treatment period was dermatitis ( 30 % ) , followed by mucositis ( 27 % ) and neutropenia ( 17 % ) without fever . One toxic related death was observed during ICT . Two-year progression-free survival ( PFS ) rate was 59 % and two-year overall survival ( OS ) rate was 63 % , respectively . CONCLUSION Concurrent radiotherapy plus C after three courses of ICT was feasible and was associated with promising CR , PFS and OS rates . Further optimisation of dose and sequence is warranted The objective of this phase 2 study was to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated‐boost ( SIB ) , intensity‐modulated radiation therapy ( IMRT ) into a well described 5‐fluorouracil ( 5‐FU ) and hydroxyurea (HU)‐based chemoradiation regimen AIMS To assess whether routine mid-treatment replanning in head and neck squamous cell carcinoma patients results in meaningful improvements in target or normal tissue dosimetry and to assess which patients derive the greatest benefit . MATERIAL S AND METHODS Twenty patients treated with either postoperative chemoradiotherapy or definitive chemoradiotherapy with primary or nodal disease ≥3 cm in size were included in this prospect i ve pilot study . Seven patients received adjuvant chemoradiotherapy and 13 received definitive chemoradiotherapy . Patients were planned and treated on a helical tomotherapy system . All patients had a second computed tomography scan after 15 fractions and a new plan based on this was initiated from fraction 20 . RESULTS Relative volume changes between computed tomography scans were : GTV 29 % ; CTV60 ( adjuvant patients ) 4 % ; parotid volume 17.5 % ; median reduction in neck separation 6 - 7 mm ; weight loss 3 % . For the group overall and for the definitively treated patient cohort , respectively , adapted plans result ed in reductions in PTV66 D(1 ) ( 0.3Gy , P=0.01 and 0.5Gy , P=0.01 ) ; PTV54 D(1 ) ( 0.6Gy , P<0.0001 and 0.9Gy , P=0.0002 ) ; spinal cord maximum ( 0.5Gy , P=0.004 and 0.6Gy , P=0.04 ) and volume of skin receiving ≥50Gy ( 16 cm(2 ) , P=0.01 and 19 cm(2 ) , P=0.001 ) . Definitively treated patients also had a reduction in mean parotid dose ( 0.6Gy , P=0.046 ) and volume of normal tissue receiving ≥50Gy ( 67 cm(3 ) , P=0.02 ) . Patients with nasopharyngeal carcinoma received the greatest benefits with treatment adaptation with reduction in spinal cord maximum 1.2Gy , mean parotid dose 1.2Gy and parotid V(26 ) 6.3 % . There was no significant benefit for adjuvant patients . Other factors associated with greater benefits were greater weight loss and greater reduction in neck separation and higher T stage . CONCLUSIONS There is minimal benefit to routine adaptive replanning in unselected patients , and no benefit in adjuvantly treated patients . Patients with nasopharyngeal carcinoma or with greater weight loss or reduction in neck separation  did have clinical ly significant benefits . These patients should be targeted for adaptive strategies 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 A phase II trial was conducted to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated boost intensity-modulated radiation therapy ( SIB-IMRT ) into a well-described 5-fluorouracil ( 5-FU ) and hydroxyurea (HU)-based chemoradiation regimen . Patients with stage IVa-IVb or high-risk stage III squamous cell carcinomas were enrolled . Prior organ-conserving surgery or induction chemotherapy was allowed . IMRT was administered in 1.5 Gy fractions twice daily on days 1 - 5 of weeks 1 , 3 , 5 , 7±9 for a total dose of 60 - 73.5 Gy . Concurrent systemic therapy consisted of 5-FU ( 600 mg/m2 ) , HU ( 500 mg BID ) and cetuximab ( 250 mg/m2 )  .  p16INK4A expression was assessed by immunohistochemistry . From January 2007 to January 2010 , 65 patients ( 61 with stage IV disease ; 31 with oropharyngeal primaries ) were enrolled . At a median follow-up of 28 months , 2-year locoregional control , distant control , progression-free survival , event-free survival and overall survival were 79 , 83 , 72 , 63 and 80 % , respectively . In 48 patients with available pre-treatment tissue , p16 overexpression was associated with significantly increased distant control ( p=0.03 ) , progression-free survival ( p=0.02 ) , event-free survival ( p=0.007 ) and overall survival ( p=0.03 ) . The most common grade 3 - 4 toxicities were mucositis ( 46 % ) , leukopenia ( 18 % ) , anemia ( 18 % ) and dermatitis ( 17 % ) . Concurrent 5-FU , HU , cetuximab and SIB-IMRT is a highly active regimen , particularly in patients with p16-positive disease PURPOSE Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor . Cetuximab has activity in squamous cell carcinoma and enhances both chemotherapy and radiotherapy . We conducted a pilot phase II study of a new combined-modality paradigm of targeted therapy ( cetuximab ) with chemoradiotherapy . PATIENTS AND METHODS Eligible patients had stage III or IV , M0 , squamous cell head and neck cancer . Treatment included concomitant boost radiotherapy ( 1.8 Gy/d weeks 1 to 6 ; boost : 1.6 Gy 4 to 6 hours later weeks 5 to 6 ; 70 Gy total to gross disease ) , cisplatin ( 100 mg/m2 intravenously weeks 1 and 4 ) , and cetuximab ( 400 mg/m2 intravenously week 1 , followed by 250 mg/m2 weeks 2 to 10 ) . RESULTS Twenty-two patients were enrolled ( median age , 57 years ; range , 41 to 72 years ; median Karnofsky status , 90 % ; range , 70 % to 90 % ; oropharynx primary tumor , 59 % of patients ; T4 , 36 % ; N2/3 , 77 % ; stage IV disease , 86 % ) . One patient did not receive study treatment because of an ineligible diagnosis . The severity of expected , acute toxicities was typical of concurrent cisplatin and radiotherapy alone . Grade 3 or 4 cetuximab-related toxicities included acne-like rash ( 10 % ) and hypersensitivity ( 5 % ) . However , the study was closed for significant adverse events , including two deaths ( one pneumonia and one unknown cause ) , one myocardial infa rct ion , one bacteremia , and one atrial fibrillation . With a median follow-up of 52 months , the 3-year overall survival rate is 76 % , the 3-year progression-free survival rate is 56 % , and the 3-year locoregional control rate is 71 % . CONCLUSION This regimen is not currently recommended outside of the clinical trial setting . Further investigation of its safety profile is needed . However , preliminary efficacy is encouraging , and further development of this targeted combined-modality paradigm is warranted PURPOSE Intensity-modulated radiation therapy ( IMRT ) has shown its interest for head and neck cancer treatment . In parallel , cetuximab has demonstrated its superiority against exclusive radiotherapy . The objective of this study was to assess the acute toxicity , local control and overall survival of cetuximab associated with different IMRT modalities compared to platinum-based chemotherapy and IMRT in the ARTORL study ( NCT02024035 ) . PATIENTS AND METHOD This prospect i ve , multicenter study included patients with epidermoid or undifferentiated nasopharyngeal carcinoma , epidermoid carcinoma of oropharynx and oral cavity ( T1-T4 , M0 , N0-N3 ) .  Acute toxicity , local control and overall survival were compared between groups ( patients receiving cetuximab or not ) . Propensity score analysis at the ratio 1:1 was undertaken in an effort to adjust for potential bias between groups due to non-r and omization . RESULTS From the 180 patients included in the ARTORL study , 29 patients receiving cetuximab and 29 patients treated without cetuximab  were matched for the analysis . Ten patients ( 34.5 % ) reported acute dermal toxicity of grade 3 in the cetuximab group versus three ( 10.3 % ) in the non-cetuximab group obtained after matching ( P=0.0275 ) . Cetuximab was not significantly associated with more grade 3 mucositis ( P=0.2563 ) . There were no significant differences in cutaneous or oral toxicity for patients treated with cetuximab between the different IMRT modalities ( P=1.000 and P=0.5731 , respectively ) . There was no significant difference in local relapse-free survival ( P=0.0920 ) or overall survival ( P=0.4575 ) between patients treated with or without cetuximab . CONCLUSION Patients treated with cetuximab had more cutaneous toxicities , but oral toxicity was similar between groups . The different IMRT modalities did not induce different toxicity profiles PURPOSE Radiotherapy ( RT ) combined with cisplatin or cetuximab is the st and ard of care for patients with locally advanced head/neck cancer ( LA-HNC ) . The feasibility of radiochemotherapy with cisplatin and cetuximab , supported with amifostine , was herein investigated . METHODS AND MATERIAL S Forty-three patients with LA-HNC were recruited .  Conformal hypofractionated/accelerated RT with amifostine cytoprotection ( 2.7 Gy/fraction , 21 fractions in 4 weeks ) was combined with cisplatin ( 30 mg/m(2)/week ) and cetuximab ( st and ard weekly regimen ) therapy . The dose of amifostine was individualized according to tolerance . RESULTS A high daily amifostine dose ( 750 - 1,000 mg ) was tolerated by 41.8 % of patients , and a st and ard dose ( 500 mg ) was tolerated by 34.9 % of patients . A high amifostine dose was linked to reduced RT delays ( p = 0.0003 ) . Grade 3 to 4 ( 3 - 4 ) mucositis occurred in 7/43 ( 16.2 % ) patients , and fungal infections occurred in 18/43 ( 41.8 % ) patients . Radiation dermatitis was not aggravated . Interruption of cetuximab due to acneiform rash was necessary in 23.3 % of patients , while amifostine-related fever and rash were not observed . Severe late radiation sequelae consisted of laryngeal edema ( 9 % laryngeal cases ) and cervical strictures ( 33 % of hypopharyngeal cases ) . Good salivary function was preserved in 6/11 ( 54.5 % ) nasopharyngeal cancer patients . The complete response rate was 68.5 % , reaching 77.2 % in patients with minor radiotherapy delays . The 24-month local control and survival rates were 72.3 % and 91 % , respectively ( median follow-up was 13 months . ) . CONCLUSIONS In this feasibility study , weekly administration of cisplatin and cetuximab was safely combined with accelerated RT , supported with amifostine , at the cost of a high incidence of acneiform rash but a reduced incidence of amifostine-related fever/rash . A high daily dose of amifostine allows completion of therapy with minor delays PURPOSE In this r and omized , phase III study , quality of life ( QoL ) was assessed in patients with locoregionally advanced squamous cell carcinoma of the head and neck ( SCCHN ) after high-dose radiotherapy alone or in combination with cetuximab .  PATIENTS AND METHODS Patients with stage III or IV nonmetastatic and measurable squamous cell carcinoma of the oropharynx , hypopharynx , or larynx were eligible .  QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ( EORTC QLQ-C30 ) and EORTC QLQ Head and Neck Cancer-Specific Module at baseline , week 4 , and at months 4 , 8 , and 12 postbaseline . RESULTS In this study , one of the largest conducted in a population of patients with locoregionally advanced SCCHN , 424 patients received radiotherapy alone ( 213 patients ) or radiotherapy plus cetuximab ( 211 patients ) .  Radiotherapy/cetuximab significantly improved locoregional control ( P = .005 ) and overall survival ( P = .03 ) compared with radiotherapy alone , without significantly increasing radiotherapy-associated adverse events . The current analysis focused on the impact of cetuximab on the QoL. Compliance with completion of QoL question naires was high in both arms . QoL worsened during treatment and improved after cessation of treatment , reaching baseline levels at 12 months . There were no significant differences in QoL scores between the treatment arms . This was particularly notable for global health status/QoL , social functioning , social eating , and social contact . Pretreatment global health status/QoL was identified as a significant prognostic variable in these patients . CONCLUSION The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting PURPOSE To investigate , in a multicenter study , the tolerance of induction chemotherapy ( ICT ) and external radiotherapy ( ERT ) with concomitant cetuximab in the treatment of patients with squamous cell carcinoma of the head and neck ( SCCHN ) . PATIENTS AND METHODS Clinical data from 46 patients with Stage III or IV nonmetastatic SCCHN who received docetaxel , cisplatin , and 5-fluorouracil as ICT , followed by ERT with concomitant cetuximab  , were retrospectively analyzed . Clinical safety ( weight , allergy , mucositis , and dermatitis ) and para clinical safety ( levels of hemoglobin , polynuclear neutrophils , and creatinine clearance ) were studied . The primary objective was the proportion of patients who completed the protocol . RESULTS The percentage of patients completing ICT was 73.9 % , ERT 93.5 % , and cetuximab 69.6 % . Induction chemotherapy was better tolerated than that previously reported . The rates of temporary suspensions of radiation ( 39.1 % , mean duration of 13 days ) and hospitalization ( 26.1 % ) during ERT with concomitant cetuximab were high . Weight loss during treatment ( 21.4 % of patients lost > 10 % of their body weight ) , radiodermatitis , and radiomucositis were the main causes of temporary suspension of treatment , although Grade 4 dermatitis was not experienced . There were no allergic reactions to cetuximab . CONCLUSION The completed protocol rate for SCCHN patients receiving ICT and ERT with concomitant cetuximab is high and the toxicity acceptable . Future improvements to protocol will be possible through early action and systematic implementation of nutritional support coupled with antibiotic treatment upon the first signs of radiodermatitis . These data could be useful for prospect i ve studies on the safety and efficacy of this protocol Complete response ( CR ) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF ( cisplatin and 5‐fluorouracil [ 5‐FU ] ) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck . In most series , the rate of CR at the primary site after induction PF was 20 % to 30 % . This study evaluated the efficacy and feasibility  of induction nab‐paclitaxel and cetuximab given with PF ( ACPF ) followed by definitive chemoradiation ( CRT ) in a phase 2 trial BACKGROUND The objective was to study the results of induction chemotherapy followed by external beam radiation therapy with concurrent cetuximab in the treatment of locally advanced head and neck cancer . METHODS Seventeen patients with stage III or IV squamous cell carcinomas of the head and neck who received docetaxel , cisplatinum , and 5-fluorouracil followed by radiation therapy with concurrent cetuximab were retrospectively analyzed . All radiation was delivered with image-guided intensity-modulated radiation treatments . Primary end points analyzed were local control and overall survival . RESULTS With a median follow-up of 17 months , the approximate 2-year local control was 85 % , with overall survival being 91 % . At time of last follow-up , only 1 death was observed , with the cause of death unknown . Two local failures were observed , and the patients were under active management for their recurrences at time of last follow-up . No distant metastatic failures were noted among the patients . CONCLUSIONS Induction chemotherapy with docetaxel , cisplatinum , and 5-fluorouracil followed by concurrent radiation with cetuximab provides for excellent locoregional control of disease . Future prospect i ve studies can better establish the efficacy of this treatment regimen to current favored protocol PURPOSE Recurrent head and neck cancer is associated to a poor survival prognosis . A high toxicity rate is demonstrated when surgery and /or radiotherapy and /or chemotherapy are combined . Furthermore , the duration of treatment is often not ethically compatible with the expected survival ( median survival<1year ) . Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy ( SBRT ) could offer precise irradiation while sparing healthy tissues . After completion of a feasibility study , results of a multicentric study ( Lille , Nancy & Nice ) using SBRT with cetuximab are reported . The aim of the study was to deliver non toxic short course SBRT ( 2weeks ) in order to get the same local control as the one demonstrated with longer protocol s. METHODS AND MATERIAL S Patients with inoperable recurrent , or new primary tumor in a previously irradiated area , were included ( WHO<3 ) .  Reirradiation ( RT ) dose was 36Gy in six fractions of 6Gy to the 85 % isodose line covering 95 % of the PTV with 5 injections of concomitant cetuximab ( CT ) .  All patients had previous radiotherapy , 85 % had previous surgery and 48 % previous chemotherapy .  RESULTS Between 11/2007 and 08/2010 , 60 were included ( 46 men and 14 women ) , 56 received CT+RT , 3 were not treated and 1 received only CT . Median age was 60 ( 42 - 87 ) ) and all 56 patients had squamous carcinoma and received concomitant cetuximab .  Mean time between previous radiotherapy and the start of SBRT was 38months . Cutaneous toxicity was observed for 41 patients . There was one toxic death from hemorrhage and denutrition . Median follow-up was 11.4months . At 3months , response rate was 58.4 % ( 95 % CI : 43.2 - 72.4 % ) and disease control rate was 91.7 % ( 95 % CI : 80.0 - 97.7 % ) . The one-year OS rate was 47.5 % ( 95 % CI : 30.8 - 62.4 ) . CONCLUSION These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC . Treatment is feasible and , with appropriate care to limiting critical structure , acute toxicities are acceptable . This combination may be the reference treatment is this population BACKGROUND Cetuximab is active in the treatment of squamous cell carcinoma of the head and neck ( SCCHN ) , enhancing both radiotherapy and chemotherapy effects . This phase I study was design ed to investigate the safety and tolerability of combining weekly cisplatin treatment with cetuximab and hyperfractionated-accelerated radiotherapy ( HART ) for locally advanced SCCHN . PATIENTS AND METHODS Patients with unresectable stage III or IVA/B SCCHN were treated with cetuximab , 400 mg/m² initial dose on day -7 of HART , followed by 250 mg/m² weekly during the administration of HART , which started with 2.0 Gy/day ( 5 days/week ) for 3 weeks followed by 1.4 Gy/twice-daily ( Monday to Friday ) for another 3 weeks , result ing in a total dose of 70.6 Gy . Cisplatin was administered weekly starting on the first day of radiotherapy until week 6 . Cisplatin was dose escalated of four dose levels from 20 to 40 mg/m² using a classical 3 + 3 dose escalation algorithm . RESULTS Eighteen patients were enrolled . Sixteen patients were eligible for toxicity , and 15 for response .  No maximum tolerated dose was reached for cisplatin . One of six patients of dose level 4 had grade 4 neutropenia . This patient died 1 week after the end of the study treatment . The most common types of grade 3 + adverse events were mucositis ( 9 of 16 patients ) , in-field dermatitis ( 6 of 16 patients ) and neutropenia ( 4 of 16 patients ) . Cetuximab-related hypersensitivity was observed in 1 out of 18 patients . Six weeks after the end of the study treatment , 5 complete responses , 8 partial responses and 1 progressive disease ( at distant sites ) were documented in a total of 15 patients ( objective response rate 87 % ) . CONCLUSIONS The combination of cisplatin with cetuximab and HART is active , well tolerated and merits additional investigation . The recommended weekly dose of cisplatin for phase II studies is 40 mg/m² BACKGROUND There is a clinical need to improve the efficacy of st and ard cetuximab + concurrent intensity-modulated radiation therapy ( IMRT ) for patients with locally and /or regionally advanced HNSCC . Taxanes have radiosensitizing activity against HNSCC , and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes . PATIENTS AND METHODS This was a single-institution phase I study with a modified 3 + 3 design . Four dose levels ( DLs ) of weekly nab-paclitaxel were explored ( 30 , 45 , 60 , and 80 mg/m(2 ) ) , given with st and ard weekly cetuximab ( 450 mg/m(2 ) loading dose followed by 250 mg/m(2 ) weekly ) and concurrent IMRT ( total dose , 70 Gy ) . RESULTS Twenty-five eligible patients ( 20 M , 5 F ) enrolled , with median age 58 years ( range , 46 - 84 years ) . Primary tumor sites were oropharynx , 19 ( 10 human papillomavirus [ HPV ] pos , 8 HPV neg , 1 not done ) ; neck node with unknown primary , 2 ; larynx 2 ; and oral cavity and maxillary sinus , 1 each . Seven patients had received prior induction chemotherapy .  Maximum tolerated dose ( MTD ) was exceeded at DL4 ( nab-paclitaxel , 80 mg/m(2 ) ) with three dose-limiting toxicities ( DLTs ) ( grade 3 neuropathy , grade 3 dehydration , with grade 3 mucositis grade 3 anemia ) among five assessable patients . There was only one DLT ( grade 3 supraventricular tachycardia ) among six patients at DL3 ( nab-paclitaxel , 60 mg/m(2 ) ) , and this was deemed the MTD . Among 23 assessable patients , the most common ≥ g3 AEs were lymphopenia 100 % , functional mucositis 65 % , and pain in throat/oral cavity 52 % . At a median follow-up of 33 months , 2-year failure-free survival ( FFS ) is 65 % [ 95 % confidence interval ( CI ) 42 % to 81 % ] and 2-year overall survival ( OS ) is 91 % ( 95 % CI 69 - 97 ) . CONCLUSION The recommended phase II dose for nab-paclitaxel is 60 mg/m(2 ) weekly when given st and ard weekly cetuximab and concurrent IMRT . This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone . CLINICAL TRIALSGOV ID NCT00736619 PURPOSE Phase I study to determine the maximum tolerated dose ( MTD ) of fluorouracil ( FU ) in the docetaxel/cisplatin/FU ( TPF ) regimen when combined with cetuximab ( C ) for induction treatment of locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . PATIENTS AND METHODS Patients with previously untreated SCCHN were enrolled . FU cohorts were 700 , 850 , and 1,000 mg/m(2)/d for 4 days via continuous infusion . TPF given every 3 weeks for three cycles and C was given weekly for a total of 9 weeks , starting on day 1 of TPF . All patients received chemoradiotherapy after C-TPF . RESULTS A total of 30 patients were enrolled and 28 were assessable . The median age was 57 years , 92 % had stage 4 disease , 71 % were oropharynx , and 100 % had a performance status of 0 . No dose-limiting toxicity ( DLT ) was encountered on dose levels 1 and 2 . At dose level 3 of 1000 mg/m(2 ) , one DLT was encountered and three more patients were enrolled with no DLTs . In the expansion cohort at the MTD , three DLT 's were encountered . The decision was made to decrease the FU from 1,000 mg/m(2 ) to dose level 2 of 850 mg/m(2 ) . A total of 13 patients were enrolled at the MTD of 850 mg/m(2 ) . The number of average weeks that  C  was delivered was seven of nine planned . CONCLUSION C-TPF appears to be safe and feasible as given in this study . GI toxicity ( mucositis , enteritis , and diarrhea ) appears to be the major combined DLT . Reducing the FU in TPF to 850 mg/m(2 ) reduces GI toxicity and is the recommended phase II dose PURPOSE To evaluate feasibility , safety and outcome of cetuximab concurrent with radiotherapy in locally advanced head-neck cancer . MATERIAL S AND METHODS Between March 2007 and January 2008 eligible cases of locally advanced unresectable ( Stage IV ) squamous cell carcinoma of head and neck were enrolled in this single arm , open labeled phase II Study . They were treated with cetuximab for a duration of 8 weeks and concomitant RT for 7 weeks ( starting one week after initiating Cetuximab ) . RESULTS A total of 19 eligible patients were enrolled . The median age of patients was 53 years , all patients happening to be male . The performance status of the patients was 0/1 . The location of the primary tumor was oropharynx in 12 cases , oral cavity in 4 , larynx in 2 , and hypopharynx in one case . The overall response rate ( ORR ) was 68.42 % and the overall survival at 2 year was 84 % . All 13 patients who completed two years follow-up after completion of study treatment continued to be alive with no evidence of disease progression . One patient also remained alive with progressive disease . CONCLUSIONS Cetuximab concurrent with radiotherapy is a safe and effective option in advanced head-neck cancer patients
PURPOSE Radiotherapy plus cetuximab is an effective combination therapy for locally advanced head and neck squamous cell carcinoma .
The aim of our study was to determine the frequency of skin toxicity in patients receiving the combined treatment .