Chemotherapy and Radiation Therapy With or Without Surgery in Treating Patients With Head and Neck Cancer

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy (RT) uses high-energy x-rays to damage tumor cells. Giving radiation therapy in different ways and combining it with chemotherapy before surgery may kill more tumor cells. It is not yet known which radiation therapy regimen combined with chemotherapy with or without surgery is more effective for head and neck cancer. PURPOSE: Randomized phase III trial to compare two different radiation therapy regimens combined with cisplatin with or without surgery in treating patients who have stage III or stage IV head and neck cancer.

Detailed Description
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OBJECTIVES: Primary Compare overall survival of patients with stage III or IV squamous cell carcinoma of the head and neck treated with conventional vs accelerated radiotherapy and concurrent cisplatin with or without surgical resection. Secondary Compare local-regional control of disease and disease-free rates in patients treated with these regimens. Compare the acute and late toxicity of these regimens in these patients. Compare quality of life, perception of side effects, and performance status of patients treated with these regimens. Determine whether epidermal growth factor receptor and cyclo-oxygenase-2 expressions are independent prognostic markers in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor site (larynx vs other), nodal stage (N0 vs N1 or N2a or N2b vs N2c or N3), and Zubrod performance status (0 vs 1). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo standard fractionation radiotherapy 5 days a week for 7 weeks. Patients also receive cisplatin IV on days 1, 22, and 43. Arm II: Patients undergo accelerated fractionation radiotherapy 5 days a week for 3.5 weeks and then twice a day, 5 days a week, for 2.5 weeks. Patients also receive cisplatin IV on days 1 and 22. Patients with biopsy-proven relapsed disease more than 3 months after completion of therapy undergo surgical resection of the primary tumor. Quality of life is assessed at baseline, during one of the last 2 weeks of treatment, at 3 and 12 months, and then annually for 4 years. Patients are followed at 6-8 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 720 patients (360 per treatment arm) will be accrued for this study within 3 years.

Official Title
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A Phase III Trial of Concurrent Radiation and Chemotherapy for Advanced Head and Neck Carcinomas

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: cisplatin
* Radiation: Standard fractionation RT
* Radiation: Accelerated fractionation radiation therapy
* Procedure: Conventional surgery for select patients


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx Stage III or IV (T2, N2-3, M0 or T3-4, any N, M0) No metastases below the clavicle or more distant by clinical exam or radiology PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-1 Life expectancy Not specified Hematopoietic Absolute granulocyte count at least 2,000/mm^3 Platelet count at least 100,000/mm^3 Hepatic Bilirubin no greater than 1.5 mg/dL Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) no greater than 2 times upper limit of normal Renal Creatinine no greater than 1.5 mg/dL Creatinine clearance at least 50 mL/min Calcium normal Cardiovascular No symptomatic coronary artery disease (angina) No myocardial infarction within the past 6 months Other No other invasive malignancy within the past 3 years except nonmelanoma skin cancer No simultaneous primary tumors Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior chemotherapy Endocrine therapy Not specified Radiotherapy No prior radiotherapy to the head and neck except radioactive iodine therapy Surgery No prior surgery to the primary tumor or nodes except diagnostic biopsy or nodal sampling of neck disease No radical or modified neck dissection

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 |
| --- | --- |
| Other: Standard fractionation RT + cisplatin<br>Standard fractionation radiation therapy with concurrent cisplatin followed by conventional surgery for select patients. | Drug: cisplatin<br>* 100 mg/m^2 intravenously on days 1, 22<br>Radiation: Standard fractionation RT<br>* Radiation will be delivered in 2 Gy per fraction, five fractions a week. The primary tumor and clinically/radiologically involved nodes will receive 70 Gy in 7 weeks and uninvolved nodes will receive 50 Gy in 5 weeks. The anterior lower neck field will be treated with 2 Gy per fraction at 3-cm depth to a total dose of 50 Gy.<br>Procedure: Conventional surgery for select patients<br>* Surgical removal (salvage resection) of the primary tumor should be performed if biopsy-proven cancer remains more than three months after completion of therapy. The nature of the surgical resection should be dictated by the extent of tumor at the initial evaluation. The operation should be conducted using accepted criteria for primary surgical treatment of the cancer. A planned neck dissection for patients with multiple neck nodes or with lymph nodes exceeding 3 cm in diameter (N2a, N2b, N3) is mandatory, regardless of the clinical and/or radiographic response. A neck dissection is required for patients with N1 disease if a palpable or worrisome radiographic abnormality persists in the neck six weeks after completion of therapy. Surgery should be performed within 2 weeks once the decision for neck dissection is made.<br>|
| Experimental: Accelerated fractionation RT + cisplatin<br>Accelerated fractionation radiation therapy by concomitant boost with concurrent cisplatin followed by conventional surgery for select patients. | Drug: cisplatin<br>* 100 mg/m^2 intravenously on days 1, 22<br>Radiation: Accelerated fractionation radiation therapy<br>* Radiation to the initial target volume encompassing the gross and subclinical disease sites will be delivered in 1.8 Gy per fraction, five fractions a week to 54 Gy in 30 fractions over 6 weeks. At 32.4 Gy/18 Fx (i.e., latter part of week 4), the boost volume covering gross tumor and clinically/radiologically involved nodes will receive boost irradiation of 1.5 Gy/Fx as second daily fraction (at least 6 h interval) for a total of 12 treatment days (18 Gy total). The primary tumor and clinically/radiologically involved nodes will receive 72 Gy in 42 fractions over 6 weeks and uninvolved nodes will receive 54 Gy in 6 weeks. Clinically/radiologically negative posterior neck should receive a minimum dose of 50.4 Gy at 3 cm. The anterior lower neck field will be treated with 1.8 Gy per fraction at 3-cm depth to a total dose of 50.4 Gy in 28 fractions in 5.6 weeks.<br>Procedure: Conventional surgery for select patients<br>* Surgical removal (salvage resection) of the primary tumor should be performed if biopsy-proven cancer remains more than three months after completion of therapy. The nature of the surgical resection should be dictated by the extent of tumor at the initial evaluation. The operation should be conducted using accepted criteria for primary surgical treatment of the cancer. A planned neck dissection for patients with multiple neck nodes or with lymph nodes exceeding 3 cm in diameter (N2a, N2b, N3) is mandatory, regardless of the clinical and/or radiographic response. A neck dissection is required for patients with N1 disease if a palpable or worrisome radiographic abnormality persists in the neck six weeks after completion of therapy. Surgery should be performed within 2 weeks once the decision for neck dissection is made.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Percentage of Participants Alive) | Overall survival time is defined as time from randomization to the date of death (failure) or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. The full distribution is the outcome of interest, and the protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Three-year estimates are provided as a summary of the distributions. Analysis was planned to occur after 309 deaths had been reported. | From randomization to last follow-up. Follow-up schedule from end of treatment: 6-8 weeks, every 3 mo. for 2 yr., then every 6 mo. for 3 yr., then yearly. Maximum follow-up at time of analysis was 6.5 years. Three-year rates are reported here. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local-regional Failure (Percentage of Participants With Local-regional Failure) | Local-regional failure time is defined as time from randomization to persistent disease in the primary tumor or regional nodes (considered an event at day 1), relapse/progression in either of those sites (considered an event at the time of relapse/progression), death (competing event), or last follow-up (censored). Progression is defined as an estimated increase in the size of the tumor of greater than 25% or appearance of new areas of malignant disease. The full distribution is the outcome of interest, and the protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Three-year estimates are provided as a summary of the distributions. Analysis was planned to occur after 309 deaths had been reported. | From randomization to last follow-up. Follow-up schedule from end of treatment: 6-8 weeks, every 3 mo. for 2 yr., then every 6 mo. for 3 yr., then yearly. Maximum follow-up at time of analysis was 6.5 years. Three-year rates are reported here. | 
| Local-regional Failure (Alternate Definition) [Percentage of Participants With Local-regional Failure] | Local-regional failure time is defined as time from randomization to relapse/progression in the primary tumor or regional nodes (event), death due to study cancer or unknown causes (event), death due to other causes (competing event), distant metastasis (competing event), or last follow-up (censored). Progression is defined as an estimated increase in the size of the tumor of greater than 25% or appearance of new areas of malignant disease. The full distribution is the outcome of interest, and the protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Three-year estimates are provided as a summary of the distributions. Analysis was planned to occur after 309 deaths had been reported. | From randomization to last follow-up. Follow-up schedule from end of treatment: 6-8 weeks, every 3 mo. for 2 yr., then every 6 mo. for 3 yr., then yearly. Maximum follow-up at time of analysis was 6.5 years. Three-year rates are reported here. | 
| Disease-free Survival (Percentage of Participants Alive Without Disease) | Disease-free survival time is defined as time from randomization to persistent disease in the primary tumor or regional nodes (considered an event at day 1), relapse/progression in either of those sites (considered an event at the time of relapse/progression), distant metastasis (event), second primary tumor (event), death (event), or last follow-up (censored). Progression is defined as an estimated increase in the size of the tumor of greater than 25% or appearance of new areas of malignant disease. The full distribution is the outcome of interest, and the protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Three-year estimates are provided as a summary of the distributions. Analysis was planned to occur after 309 deaths had been reported. | From randomization to last follow-up. Follow-up schedule from end of treatment: 6-8 weeks, every 3 mo. for 2 yr., then every 6 mo. for 3 yr., then yearly. Maximum follow-up at time of analysis was 6.5 years. Three-year rates are reported here. | 
| Progression-free Survival (Alternate Definition of Disease-free Survival) [Percentage of Participants Alive Without Progression] | Progression-free survival time is defined as time from randomization to relapse/progression in the primary site or regional nodes (event), distant metastasis (event), death (event), or last follow-up (censored). Progression is defined as an estimated increase in the size of the tumor of greater than 25% or appearance of new areas of malignant disease. The full distribution is the outcome of interest, and the protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Three-year estimates are provided as a summary of the distributions. Analysis was planned to occur after 309 deaths had been reported. | From randomization to last follow-up. Follow-up schedule from end of treatment: 6-8 weeks, every 3 mo. for 2 yr., then every 6 mo. for 3 yr., then yearly. Maximum follow-up at time of analysis was 6.5 years. Three-year rates are reported here. | 
| Percentage of Participants With Toxicity Grade 3 or Higher | Acute radiation therapy toxicities (within 90 days from start of radiation therapy) and systemic effects at any time were scored using Common Toxicity Criteria (CTC) version 2.0. Late RT toxicities (> 90 days from start of radiation therapy) were scored by the Radiation Therapy Oncology Group (RTOG)/European Organisation for. Research and Treatment of Cancer (EORTC) criteria. Both criteria grades toxicity severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event/toxicity data. | From randomization to last follow-up. Follow-up schedule from end of treatment: 6-8 weeks, every 3 mo. for 2 yr., then every 6 mo. for 3 yr., then yearly. Maximum follow-up at time of analysis was 6.5 years. | 
| Performance Status Scale for Head and Neck Cancer (PSS-HN) Normalcy of Diet Score - Area Under the Curve (AUC) at One Year | The PSS-HN is a clinician-rated evaluation conducted as an unstructured interview format that assesses three functions: Normalcy of Diet (this outcome measure), Public Eating, and Understandability of Speech. Each function is scored from 0 to 100 and analyzed separately. Higher scores indicate better performance status. Treatment effect was analyzed as time-weighted average between baseline (pre-treatment) and one year calculated by use of area under the curve (AUC). | Baseline (pretreatment), sometime during the last two weeks of treatment, three months from start of treatment, and one year from start of treatment. | 
| PSS-HN Public Eating Score - AUC at One Year | The Performance Status Scale for Head and Neck Cancer (PSS-HN) is a clinician-rated evaluation conducted as an unstructured interview format that assesses three functions: Normalcy of Diet , Public Eating (this outcome measure), and Understandability of Speech. Each function is scored from 0 to 100 and analyzed separately. Higher scores indicate better performance status. Treatment effect was analyzed as time-weighted average between baseline (pretreatment) and one year calculated by use of area under the curve (AUC). | Baseline (pretreatment), sometime during the last two weeks of treatment, three months from start of treatment, and one year from start of treatment. | 
| PSS-HN Understandability of Speech Score - AUC at One Year | The Performance Status Scale for Head and Neck Cancer (PSS-HN) is a clinician-rated evaluation conducted as an unstructured interview format that assesses three functions: Normalcy of Diet , Public Eating, and Understandability of Speech (this outcome measure). Each function is scored from 0 to 100 and analyzed separately. Higher scores indicate better performance status. Treatment effect was analyzed as time-weighted average between baseline (pretreatment) and one year calculated by use of area under the curve (AUC). | Baseline (pretreatment), sometime during the last two weeks of treatment, three months from start of treatment, and one year from start of treatment. | 
| Head and Neck Radiotherapy Questionnaire (HNRQ) - AUC at One Year | The HNRQ is a patient-reported questionnaire administrated through a paper format; it measures radiation-related side effects and the overall well-being of head and neck cancer patients in the past week. The overall score is the mean of the 22 questions, with a range of 1 to 7. Higher scores indicate better quality of life. Treatment effect was analyzed as time-weighted average between baseline (pre-treatment) and 1 year calculated by use of area under the curve (AUC). | Baseline (pretreatment), sometime during the last two weeks of treatment, three months from start of treatment, and one year from start of treatment. | 
| Correlation of Epidermal Growth Factor Receptor(EGFR) With Outcomes |  | From randomization to date of death or last follow-up | 
| Correlation of COX-2 With Outcomes |  | From randomization to date of death or last follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III squamous cell carcinoma of the hypopharynx, stage III squamous cell carcinoma of the larynx, stage III squamous cell carcinoma of the lip and oral cavity, stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the hypopharynx, stage IV squamous cell carcinoma of the larynx, stage IV squamous cell carcinoma of the lip and oral cavity, stage IV squamous cell carcinoma of the oropharynx