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Cetuximab in the Treatment of Locally Advanced Head and Neck Cancer


study was a randomised phase II trial that was conducted in France.38 Patients were required to be previously untreated and to have resectable LA laryngeal or hypopharyngeal tumours. Induction chemotherapy consisted of three cycles of docetaxel, cisplatin (both 75mg/m2) and 5-FU (750mg/m2/day). Patients showing ≥50% response were randomised to receive radiotherapy (70Gy) with either cisplatin (100mg/m2) (arm A) or cetuximab (400mg/m2 initial dose followed by 250mg/m2 weekly) (arm B). Preliminary results showed that out of 115 patients randomised, after three months of treatment there was no significant difference in larynx preservation (the primary end-point of the trial) between the two groups (93% in arm A and 96% in arm B). Induction therapy followed by radiotherapy with concurrent cetuximab appeared better tolerated than induction therapy followed by radiotherapy with concurrent cisplatin. It was noteworthy that among patients who received cisplatin and radiotherapy in this study (arm A), 16% had permanent renal failure, which would preclude them from receiving any further platinum-containing compounds as part of subsequent treatment regimens.38


Cetuximab in Induction Therapy or in Induction and Post-induction Therapy


A trial conducted in Sweden included 68 patients with LA SCCHN (56 with stage IV disease) who received two cycles of docetaxel and cisplatin (both 75mg/m2) and 5-FU (1,000mg/m2) followed by radiotherapy (68Gy/4.5 weeks) and cetuximab (initial dose of 400mg/m2 and 250mg/m2/week thereafter).39


Thirty patients were


followed beyond six weeks and were evaluated for response and early toxicity. Preliminary results showed that after treatment with docetaxel, cisplatin and 5-FU there was a complete response in one patient, a partial response in 15 patients and stable disease in 14 patients. After radiotherapy with cetuximab there was a complete response in 10 patients, a partial response in 18 patients, and stable disease in one patient. Dermatitis in the irradiated neck (with accelerated fractionation) was problematic but did not interrupt treatment and healed rapidly. It was concluded that the TPF combination followed by radiotherapy concomitant with cetuximab is feasible, with manageable toxicities.39


Several trials have evaluated the use of cetuximab during both induction and post-induction therapy in combination with radiotherapy and chemotherapy medications. An example is a phase II single-arm study of 50 patients with unresectable LA SCCHN conducted in Spain.40 Induction treatment comprised docetaxel 75mg/m2 on day one, cisplatin 75mg/m2 on day one, 5-FU 750mg/m2 on days one to five and cetuximab 250mg/m2 on days one, eight and 15 (initial dose 400mg/m2 on cycle one, day one) and repeated every 21 days for four cycles. Patients then received accelerated radiotherapy with a concomitant boost (69.9Gy) and cetuximab 250mg/m2 weekly. The results showed that the addition of cetuximab to the induction regimen resulted in a good response rate (mainly a complete response). After two and four cycles of treatment, a complete response was seen in six (12%) and 10 (20%) patients, respectively, and a partial response was seen in 31 (62%) and 25 (50%) patients, respectively. Serious grade 3/4 adverse events included: neutropenia (24%), neutropenic fever (20%), diarrhoea (12%) and infection (6%). Grade 3 adverse events included mucositis (6%), renal failure (4%), asthenia (4%), rash (4%) and hypotension (4%). In addition, there were two adverse-event-related deaths (hepatic insufficiency, in a patient with previously unknown liver cirrhosis, and febrile neutropenia). The authors concluded that the cetuximab/chemotherapy combination should be given to


EUROPEAN ONCOLOGY & HAEMATOLOGY


LA SCCHN patients who have good performance status with specialised support.40


In another phase II study, 74 patients with resectable LA SCCHN at medical centres in the US received cetuximab as part of both induction and post-induction therapy.41


Patients received induction


chemotherapy (weekly cetuximab 250mg/m2, paclitaxel 90mg/m2, carboplatin [area under the curve (AUC)] = 2). Patients showing a clinical response had a staging primary site biopsy at week eight; patients with positive biopsy (or persistent tumour) had a restaging biopsy at week 14 after chemoradiation (cetuximab 250mg/m2, paclitaxel 30mg/m2, carboplatin [AUC=1] and 50Gy). If the primary site biopsy was negative, patients completed their radiotherapy (68–72Gy) and continued chemotherapy (cetuximab 250mg/m2, paclitaxel 30mg/m2, carboplatin [AUC = 1]). If the primary site biopsy was positive at 14 weeks, salvage surgery was required. At week eight, 26 out of 40 patients (65%) who had a primary-site restaging biopsy had a complete pathological response. At week 14, 28 out of 28 patients (100%) who had a restaging biopsy had a complete pathological response. Grade 3 and 4 toxicities in this study included acneiform rash (12%), leukopenia/neutropenia (32/24%), dysphagia (29%) and stomatitis (82%).41


There was one grade 5 adverse event (death from encephalopathy). These results showed that the addition of cetuximab to both induction therapy and post-induction therapy is potentially effective and well tolerated. Long-term progression data or this study are yet to be published.


Quality of Life


LA SCCHN has an extremely deleterious effect on quality of life (QoL). Symptoms occurring at this stage of disease can include difficulties swallowing and speaking, and surgical procedures to remove tumours in LA SCCHN can also be disfiguring.42,43


These symptoms often severely


inhibit social interaction and diminish self-esteem. The treatments used for LA SCCHN can also negatively affect QoL since they can result in acute episodes of mucositis44


and xerostomia.45 Chemoradiotherapy


has well-documented toxic effects including nausea and vomiting, diarrhoea, asthenia, hair loss and may necessitate the use of a feeding tube. These treatments therefore have the potential to substantially diminish QoL and may cause many patients to prematurely stop taking medication, resulting in treatment failure.46,47


A QoL analysis of a phase III trial comparing high-dose radiotherapy with or without concomitant cetuximab48


concluded that the addition of


cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without having any significant effects on QoL. In this study, compliance with completing QoL questionnaires was high and the data are therefore considered to be reliable. For both treatment groups, the scores for most of the QoL scales decreased during treatment, indicating a worsening of symptoms, but then returned to scores comparable with baseline levels by month 12. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC QLQ Head and Neck (H&N) Cancer-Specific Module were used in this study and would be expected to indicate any adverse effect of the acne-like rash on patient QoL. However, there was no difference between the treatment groups in QoL. The lack of difference between radiotherapy alone and radiotherapy plus cetuximab was particularly notable for global health status/QoL, social functioning, social eating and social contact. Pre-treatment global health status/QoL was identified as a significant prognostic variable in this study population. Parameters


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