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Head and Neck Cancer


Table 2: Efficacy Outcomes in a Phase III Study Comparing High-dose Radiotherapy With or Without Concomitant Cetuximab


Parameter


3-year Data Duration of locoregional control


(median, months) Duration of progression-free survival


(median, months) Duration of overall survival


(median, months) Response rate (complete response and partial response) (%)


5-year Data Duration of overall survival (median, months)


High-dose Radiotherapy Only (n=213)


14.9 12.4 29.3 64


High-dose Radiotherapy plus Cetuximab (n=211)


24.4 17.1 49 74 Hazard Ratio* (95% Confidence Interval) 0.68 (0.52–0.89) 0.70 (0.54–0.90) 0.74 (0.57–0.97) 0.57 (0.36–0.90)*** 0.005 0.006 0.03 0.02**** p-value**


29.3


49


0.73 (0.56–0.95)


0.018


*The hazard ratio is for the outcome in the group assigned to radiotherapy plus cetuximab compared with the group assigned to radiotherapy alone. Outcomes were as follows: progression of locoregional disease or death (in the analysis of locoregional control), progression of disease or death (in the analysis of progression-free survival) and death (in the analysis of overall survival); **p-values were calculated by the log-rank test; ***Odds ratios are given for differences in response rate; ****p-value was calculated by Cochran–Mantel–Haenszel test. Source: Bonner et al., 200630


and 2010.31


response, 31% had stable disease and 5% showed disease progression. There was one case of grade 5 neutropenic fever that was attributed to treatment (although the publication did not specify which component of the treatment was considered to be the specific cause). Among 65 evaluable patients in this study, 97% showed some form of grade >3 toxicity, including neutropenia (26%), fatigue (23%), acneiform rash (28%) and radiation dermatitis (15%). Other grade 3 or higher events included mucositis (54%) and hyponatraemia (20%). Overall, these results indicated that weekly cetuximab with concurrent cisplatin and full-dose radiotherapy is a potential treatment for otherwise fit patients with unresectable LA SCCHN. The authors commented that longer follow-up is needed to determine locoregional control and survival end-points.


22 patients with LA SCCHN at a treatment centre in New York, US, received concomitant boost radiotherapy (1.8Gy/day in weeks one to six with a 1.6Gy/day boost, to a total dose of 70Gy) with cisplatin 100mg/m2 in weeks one and four and cetuximab 400mg/m2 in week one, followed by 250mg/m2 in weeks two to 10. The three-year overall survival rate, progression-free survival and locoregional control rates were 76, 56 and 71%, respectively. The toxicities were typical of those expected with definitive concurrent cisplatin and delayed, accelerated radiotherapy for SCCHN.34 Common grade 3 or 4 toxicities included mucositis, skin toxicity, nausea, vomiting, fever, dehydration, metabolic abnormalities and constipation. This study, however, was stopped due to two patient deaths (pneumonia and unknown cause), and three events from which the patients recovered (myocardial infarction, bacteraemia and atrial fibrillation). There was no indication that cetuximab was the cause of these events.


In another study,34


A small single-arm phase II study in Italy showed the benefit of combining weekly cetuximab with a regimen of alternating radiotherapy and chemotherapy (AlteRCC trial).35


Radiotherapy


(2Gy/day to a total dose of 70Gy) was administered as a single daily fraction, from days one to five, in weeks two and three, five and six and eight to 10. Chemotherapy (cisplatin 20mg/m2/day and bolus 5-FU 200mg/m2/day) was delivered daily, on days one to five of weeks one, four and seven. In addition to chemoradiation, cetuximab was delivered weekly, on day one of each week, at an initial dose of


20


400mg/m2 (in week one) followed by a dose of 250mg/m2 (in weeks two to 10). After three months of treatment, in 16 evaluable patients, there was a complete response in 11 patients and a partial response in five patients. Two of the patients with partial responses received salvage surgery to make them disease-free. After a maximum follow-up of 15 months, 16/20 patients were alive and 16/20 were progression-free. Toxicity was evaluable in 20 patients. Grade 3 or 4 toxicities included diarrhoea (20%), febrile neutropenia (20%), hypomagnesaemia (10%) and mucositis (60%). Skin toxicity, starting as desquamating moist dermatitis and confined at the irradiated field, occurred in 18 patients.


Two large-scale phase III trials using concurrent cetuximab with chemoradiotherapy regimens for treating unresectable tumours are currently in progress. One of these, the Radiation Therapy Oncology Group (RTOG) 0522 study (NCT00265941),36


has completed the planned


recruitment of 945 patients with LA SCCHN, at multiple centres in the US. Patients were randomised to receive concurrent cisplatin 100mg/m2 and radiotherapy (1.8Gy/day in weeks one to six with a boost of 1.5Gy/day to a total dose of 72Gy) with or without cetuximab (initial dose of 400mg/m2 and thereafter 250mg/m2/week). The study aims to compare the effect of the two regimens on disease-free survival and overall survival and to investigate any associations between outcome parameters and positron emission tomography (PET) scan findings of the tumour sites. In the other ongoing study, patients with LA SCCHN at treatment centres in France (planned recruitment of 406 patients) are being randomised to receive cetuximab (initial 400mg/m2 dose followed by 250mg/m2/week) plus radiotherapy (70Gy over seven weeks) with or without carboplatin (70mg/m2/day) and 5-FU (600mg/m2/day) (NCT00609284).37


This study


aims to evaluate the effect of adding cetuximab to an existing chemoradiotherapy regimen compared with cetuximab and radiotherapy on progression-free survival and locoregional control over three years in patients with LA SCCHN (stages III–IV).


Clinical Studies Using Cetuximab as Induction and/or Post-induction Therapy for LA SCCHN Cetuximab in Post-induction Therapy Only The Radiotherapy With Cisplatin Versus Radiotherapy With Cetuximab After Induction Chemotherapy for Larynx Preservation (TREMPLIN)


EUROPEAN ONCOLOGY & HAEMATOLOGY


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