Reduced Radiotherapy With Pac/Cis vs Standard Radiotherapy With 5-FU/Cis in Locally Advanced Head and Neck Cancer

Study Overview
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Brief Summary
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Reduced RT with Pac/Cis vs. standard RCT with 5-FU/Cis

Detailed Description
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Standard treatment for patients with advanced, unresectable head and neck cancer is a platin-based simultaneous radiochemotherapy (RCT) (Pignon JP et al., Lancet 2000;355:949-955). However, irradiation dose is still debatable regarding local tumor control and late toxicity. Moreover, it is still unclear which combination of different drugs might be more effective. In recent years, new drugs have been introduced in the field of head and neck cancer. The Taxanes, namely Docetaxel and Paclitaxel, have been investigated in several phase I/II-studies, and showed promising results concerning locoregional control rates and survival data. The RTOG 97-03 trial (Garden et al., J Clin Oncol 2004; 22:2856-64) compared a RCT either with Cisplatin/5-FU or Cisplatin/Paclitaxel. In this phase II-study an improvement of local tumor control and disease free survival of 15-20% in favour of the Cisplatin/Paclitaxel treatment arm was seen. Therefore, our phase III-trial compares a standard RCT (70.6 Gy) with Cisplatin/5-FU to a RCT with Cisplatin/Paclitaxel and reduced irradiation dose (63.6 Gy). Primary endpoint is to proof superiority of the experimental Cisplatin/Paclitaxel treatment arm concerning disease-free-survival. Secondary endpoints are locoregional tumor control, overall survival and quality of life.

Official Title
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Randomised Phase-III-trial of Simultaneous Radiochemotherapy (RCT) of Locally Advanced Head and Neck Cancer in the Stages III and IV A-B: Comparing Dose Reduced Radiotherapy (63,6 Gy) With Paclitaxel/Cisplatin to Standard Radiotherapy (70,2 Gy) With 5-Fluorouracil/Cisplatin

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: Paclitaxel/Cisplatin
* Radiation: Reduced RT
* Drug: 5-FU/Cisplatin
* Radiation: Standard RT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven, locally advanced stage III-IV A-B (UICC 2002) primary squamous cell carcinoma of the oral cavity, the oropharynx, the hypopharynx, the supraglottic larynx Age ≥ 18 Written informed consent for the participation in the clinical trial Exclusion Criteria: Inadequate hepatic function: Bilirubin > 2,0 mg/dl, SGOT, SGPT, AP, Gamma-GT > 3 x ULN Inadequate bone marrow function: leukocytes < 3,5 x 10^9/l, platelets < 100 x 10^9/l or neutrophils < 1,5 x 10^9/l Serum creatinine > 1,5 mg/dl, creatinine clearance < 60ml/min Uncontrolled severe somatic or psychological disease: e.g. unstable angina pectoris; myocardial infarction during the last 6 months; significant cardial rhythm disorders; apoplexy; high grade stenosis of the carotis; neurological or psychiatric disorders including convulsive disorders; dementia; psychosis; active uncontrolled infection or sepsis; liver cirrhosis; Child stage B,C; severe liver function disorders; marginal changes in the blood count; severe kidney damage; HIV-infection Acute infections Fertile women without adequate contraception during and up to 6 months after therapy (the method of contraception has to be high effective as described in the Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (CPMP/ICH/286/95 mod) and it has to be discussed with the investigator) Pregnant or breast feeding women Men, who are not willing to use adequate contraception during and up to 6 months after therapy, that is discussed with the investigator ECOG-Status > 1 Reduced hearing function (especially higher frequencies) Exsiccosis Neuropathy, caused by cisplatin Concurrent malignancies, with exception of adequately treated basal cell carcinoma of the skin or in situ carcinoma or the cervix Prior radiotherapy of the neck or chemotherapy Distant metastasis Recurrent carcinoma in the head and neck region Prior neck-dissection or surgical intervention exceeding an exploratory excision Known intolerance to 5-Fluorouracil Known deficit of Dihydropyrimidine dehydrogenase (DPD) Simultaneous therapy with Brivudin or other inhibitors of DPD Known intolerance to Cisplatin or other substances that contain platin Known intolerance to Paclitaxel or one of the included substances, especially to Poly(oxyethylene)Rhizinusöl/Macrogolglycerol ricinoleate

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: Reduced RT + Pacitaxel/Cisplatin<br>63,6 Gy accelerated hyperfractionated radiotherapy with Paclitaxel (20mg/m^2/d) on days 2, 5, 8, 11 and 25, 30, 33, 36) and Cisplatin (20mg/m^2/d) on days 1-4 and 29-32, followed by a salvage operation or neck dissection if there is persisting tumor | Drug: Paclitaxel/Cisplatin<br>* Experimental: Paclitaxel (20mg/m^2/d) on days 2, 5, 8, 11 and 25, 30, 33, 36) and Cisplatin (20mg/m^2/d) on days 1-4 and 29-32,<br>Radiation: Reduced RT<br>* Experimental: 63,6 Gy accelerated hyperfractionated radiotherapy<br>|
| Active Comparator: Standard RT + 5-Fluorouracil/Cisplatin<br>70,6 Gy accelerated hyperfractionated radiotherapy with 5-Fluorouracil(600mg/m^2/d) on days 1-5 and 29-33) and Cisplatin (20mg/m^2/d) on days 1-5 and 29-33, followed by a salvage operation or neck dissection if there is persisting tumor | Drug: 5-FU/Cisplatin<br>* Active Comparator: 5-Fluorouracil(600mg/m^2/d) on days 1-5 and 29-33) and Cisplatin (20mg/m^2/d) on days 1-5 and 29-33<br>Radiation: Standard RT<br>* Active Comparator: 70,6 Gy accelerated hyperfractionated radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | 3 years | 
| Distant metastasis free survival |  | 3 years | 
| Local control |  | 3 years | 
| Acute and Late Toxicity |  | 4 years | 
| Life Quality |  | 4 years | 
| HPV/p16-Status |  | End of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiochemotherapy, head and neck cancer, Paclitaxel, Cisplatin, 5-FU