Cetuximab Plus Radiotherapy Versus Cisplatin Plus Radiotherapy in Locally Advanced Head and Neck Cancer

Study Overview
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Brief Summary
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BACKGROUND: Concomitant radiotherapy and cisplatin (CDDP) based chemotherapy is the standard treatment for LA-NHSCC. This combined modality treatment is linked with considerable acute local and systemic toxicity.EGFR is overexpressed in 90-100% of the HNSCC cases and is considered an unfavourable prognostic marker. EGFR costitutive activation is linked with HNSCC pathogenesis. Cetuximab is a monoclonal anti-EGFR antibody blocking the activation of the receptor and signal transduction. Cetuximab combined with radiotherapy is superior to radiotherapy only in the treatment of LA-HNSCC and is characterized by an acceptable toxicity profile. RATIONALE: A direct comparison between concomitant chemoradiotherapy with Cisplatin and the concomitant treatment with radiotherapy associated to cetuximab does not exist. STUDY DESIGN: Arm A: Radical radiotherapy (doses and volumes) concomitant with chemotherapy with Cisplatin (40 mg/mq/week) Arm B: Radical radiotherapy (doses and volumes) concomitant with therapy with the monoclonal antibody Cetuximab (400 mg/m2 [loading dose] and subsequently 250 mg /m2/week)

Detailed Description
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PRIMARY OBJECTIVES: Evaluation and comparison of the compliance of the two treatments; SECONDARY OBJECTIVES: Evaluation and comparison of the grade and incidence of acute toxicity; Evaluation and comparison of local control; Evaluation and comparison of event free survival (both local control and distant metastases); Evaluation and comparison of cause specific and overall survival. INCLUSION/EXCLUSION CRITERIA Histologically confirmed squamous cell carcinoma (biopsy obtained from the tumor and/or from its lymphnodal metastases) originating from oral cavity, oropharynx, hypopharinx, supraglottic larynx; Locally advanced disease, defined by one of the following criteria: every T, N+, M0 ( T1, N1 cases excluded); T3-4, N0, M0; Not a nasopharynx, paranasal sinuses, salivary glands tumor; General conditions and concomitant diseases not considered a contraindication for chemotherapy or curative radiotherapy; No other surgical, chemotherapeutic or radiotherapic treatments for ENT region tumors or for tumors of other anatomical sites (with the exception of non-melanoma cutaneous tumors and of the carcinoma in situ of the uterine cervix and of other solid tumors whose primary treatment has been completed more than 3 years before the accrual in this study and never relapsed since primary treatment (the patient having been since then continuously disease- free); Availability for follow-up; Signed informed consent; An interval of maximum 3 weeks between staging procedures for local disease and randomization An interval of maximum 2 weeks between randomization and the onset of the treatment

Official Title
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Multiinstitutional Open Label Randomized Phase II Study Comparing Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy as Firstline Treatment for Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LA-NHSCC)

Conditions
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Head and Neck Neoplasms, Laryngeal Neoplasms, Mouth Neoplasms, Pharyngeal Neoplasms

Intervention / Treatment
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* Drug: cetuximab
* Drug: cisplatin (associated to radiotherapy)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed squamous cell carcinoma (with biopsy on the primary and / or lymph node metastases) of the oral cavity, oropharynx, hypopharynx, larynx supraglottix; Locally advanced disease, defined by one of the following criteria: any T, N +, M0 (excluding T1, N1), T3-4, N0, M0; Not cancer nasopharynx or paranasal sinuses or salivary glands; General conditions and associated diseases which does not allow to perform chemotherapy or radiotherapy in a radical view; No other surgical treatments, chemotherapy or radiotherapy for cancer of head and neck or elsewhere, except non-melanoma skin cancer or in situ cervical cancer and other solid tumors for which radical treatment has been completed > three years prior to enrollment in the study and for which the patient has remained continuously free of disease; Accessibility to follow-up; Signing of informed consent; Interval between examinations of local staging and randomization, maximum 3 weeks Interval between randomization and initiation of treatment, maximum 2 weeks Exclusion Criteria: Age <18 years ECOG performance status > 0-1 Hemoglobin <9 g / dL Counts of granulocytes, total <1.5 x 10 ^ 9 / L Platelet count <100 x 10 ^ 9 / L Bilirubin> 1.5 times upper limit of normal (ULN) AST or ALT> 3 times ULN Creatinine clearance > 50 mL/min Mg > 0.5 mmol/L Pregnancy or lactation Presence of allergy to study drug or to the excipients used in their formulation Peripheral neuropathy ≥ grade 2 (CTCAE v3.0) Hearing loss / tinnitus ≥ grade 3 (CTCAE v3.0) One of the following conditions: Myocardial infarction within 12 months prior to randomization Severe congestive heart failure Unstable angina Cardiomyopathy in act Ventricular arrhythmia uncontrolled hypertension Severe psychotic disorders in act Severe infection in act Any other serious illness that could interfere with the administration of the therapy provided by the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cetuximab plus radiotherapy<br>Cetuximab given one week before radiotherapy (loading dose, 400 mg/m2) plus weekly (250 mg/m2), concomitant with radiotherapy (7O Gy on clinically involved sites). | Drug: cetuximab<br>* Cetuximab is given according to the standard mode of administration: loading dose : 400 mg/m2 one week before the start of radiotherapy (week -1), followed by a weekly dose of 250 mg/m2 during the weeks of the treatment with radiotherapy. Radiotherapy: Doses: Clinical sites of disease (T e N) : total dose of 70 Gy given with a fractional dose of 2 Gy/day; prophylactic nodal volume (N) : total dose of 50 Gy given with a fractional dose of 2 Gy/day ; Treatment technique: conformal 3D. Intensity modulated radiotherapy (IMRT), also with simultaneous boost (SIB), is allowed.<br>* Other names: Erbitux;|
| Active Comparator: cisplatin plus radiotherapy<br>CDDP 40 mg/mq in a single weekly 1-hour infusion concomitant to radiotherapy: (70 Gy to clinically involved sites) | Drug: cisplatin (associated to radiotherapy)<br>* CDDP dose: 40 mg/mq in a single weekly 1-hour infusion preceded by adequate hydration, diuretics e antiemetic premedication. Radiotherapy: Doses: Clinical sites of disease (T e N) : total dose of 70 Gy given with a fractional dose of 2 Gy/day; prophylactic nodal volume (N) : total dose of 50 Gy given with a fractional dose of 2 Gy/day ; Treatment technique: conformal 3D. Intensity modulated radiotherapy (IMRT), also with simultaneous boost (SIB), is allowed.<br>* Other names: Cisplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance | Evaluation and comparison of the compliance of the two treatments arms | weekly during treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| event free survival | Evaluation and comparison of the event free survival (both local control and distant metastases) | bimonthly for two years, every 6 months thereafter | 
| acute toxicity | Evaluation and comparison of the grade and incidence of acute toxicity. | Weekly during treatment. | 
| Local control | Evaluation and comparison of local control | bimonthly for two years after treatment, every six months thereafter | 
| cause specific survival | Evualation and comparison of cause specific survival | bimonthly after treatment for two years, then every 6 months | 
| overall survival | evaluation and comperison of overall survival | bimonthly after treatment for two years, then every 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Head and Neck Cancer, Radiotherapy, Cetuximab, Cisplatin