Combination Chemotherapy and Radiation in Treating Patients With Stage III or IV Head and Neck Cancer (Paradigm Trial)

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as docetaxel, cisplatin, fluorouracil, and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy with radiation therapy may kill more tumor cells. It is not yet known which regimen of chemotherapy and radiation therapy is most effective in treating head and neck cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of two different regimens of chemotherapy and radiation therapy in treating patients who have stage III or stage IV head and neck cancer.

Detailed Description
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OBJECTIVES: Primary Compare 3-year survival of patients with previously untreated stage III or IV squamous cell carcinoma of the head and neck treated with induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil followed by radiotherapy and carboplatin or docetaxel vs radiotherapy and cisplatin only. Secondary Compare 2-year progression-free status in patients treated with these regimens. Compare 5-year survival of patients treated with these regimens. Compare 3- and 5-year progression-free survival of patients treated with these regimens. Compare the complete response rate in patients treated with these regimens. Compare tumor site-specific survival in patients treated with these regimens. Compare functional organ preservation in patients treated with these regimens. Compare the toxicity of these regimens in these patients. Compare the quality of life of patients treated with these regimens. Correlate tissue and germline markers with response, local/regional control, and the development of distant metastases in patients treated with these regimens. OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. Arm II: Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. Quality of life is assessed at baseline and then at 3, 12, and 24 months. Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1 year, and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 330 patients will be accrued for this study.

Official Title
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A Randomized Phase III Comparing Sequential Therapy With TPF/Chemoradiation (ST) To Cisplatinum-Based Chemoradiotherapy [PARADIGM TRIAL]

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: cisplatin
* Drug: docetaxel
* Drug: fluorouracil


Participation Criteria
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Eligibility Criteria
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List of Inclusion Criteria: Histologically or cytologically confirmed squamous cell carcinoma of the head and neck Stage III or IV* disease One of the following primary tumor sites: Oral cavity No mandible invasion Oropharynx Hypopharynx Larynx The following primary tumor sites are excluded: Nasal cavity Paranasal cavity Nasopharynx NOTE: *No evidence of distant metastases by chest x-ray, abdominal ultrasound, or CT scan (for patients with liver function test abnormalities) or bone scan (for patients with local symptoms) At least 1 uni- or bi-dimensionally measurable lesion PATIENT CHARACTERISTICS: Age Over 18 Performance status WHO 0-1 Life expectancy Not specified Hematopoietic Neutrophil count > 1,500/mm^3 Platelet count > 100,000/mm^3 Hemoglobin > 10 g/dL Hepatic Bilirubin normal AST or ALT within eligibility range Alkaline phosphatase within eligibility range Renal Creatinine clearance > 60 mL/min Cardiovascular No unstable cardiac disease despite treatment No myocardial infarction within the past 6 months Pulmonary No chronic obstructive pulmonary disease, defined as requiring hospitalization for pneumonia or respiratory decompensation within the past year Obstruction caused by the tumor allowed Neurologic No symptomatic peripheral neuropathy > grade 2 No symptomatic altered hearing > grade 2 No history of significant neurologic or psychiatric disorders, including dementia or seizures Other No active drug addiction, including alcohol, cocaine, or intravenous drugs within the past 6 months No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, or other cancer curatively treated by surgery alone No active, clinically significant, uncontrolled infection No autoimmune disease requiring therapy No unhealed or clinically active peptic ulcer disease No hypercalcemia No other serious illness or medical condition No involuntary weight loss > 25% of body weight within the past 2 months HIV negative Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 3 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior chemotherapy Endocrine therapy Not specified Radiotherapy No prior radiotherapy Surgery No prior organ transplantation No prior surgery for this cancer Biopsy allowed Other More than 30 days since prior participation in another investigational study No other concurrent anticancer therapy

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: Arm I<br>Patients receive induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil. Treatment repeats every 21 days for 3 courses. Patients achieving a pathologic complete response at the primary site and a clinical complete response in the neck then receive carboplatin once weekly and undergo concurrent radiotherapy once daily, 5 days a week, for 7 weeks. Patients with a partial response at the primary site (i.e., positive biopsy), stable disease, or radiographic evidence of persistent disease in the neck receive docetaxel once weekly for 4 weeks and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. | Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: cisplatin<br>* Given IV<br>* Other names: Platinol;Drug: docetaxel<br>* Given IV<br>* Other names: Taxotere;Drug: fluorouracil<br>* Given IV<br>* Other names: Efudex;|
| Experimental: Arm II<br>Patients receive cisplatin IV on weeks 1 and 4 and undergo concurrent radiotherapy once or twice daily, 5 days a week, for 6 weeks. | Drug: cisplatin<br>* Given IV<br>* Other names: Platinol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | To compare the 3-year survival achieved by docetaxel/cisplatin/5-FU based sequential therapy with platinum based chemo radiotherapy in patients with locally advanced SCCHN. Overall survival is defined as the time from date of randomisation to death from any cause. Patients alive at the time of current analysis were censored at the date last known to be alive.Kaplan-Meier method was used to estimate overall survival | 3-years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival and Disease-specific Survival as Assessed by Disease Progression or Death and Log Rank Tests at the Median, and 2, 3, and 5 Years | Progression free survival was defined as the time from date of randomisation to disease progression or death from any cause without progression whichever occurred first; otherwise, patients were censored at the date last known to be free of progression. | 5 years | 

 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