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

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)

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

Eligibility Criteria:
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