Docetaxel, Cisplatin, and Fluorouracil Followed By Cetuximab and Radiation Therapy in Treating Patients With Locally Advanced Head and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as docetaxel, cisplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with cetuximab and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving docetaxel, cisplatin, and fluorouracil together with cetuximab and radiation therapy works in treating patients with locally advanced head and neck cancer.

Detailed Description
-----------------
OBJECTIVES: Primary Evaluate the progression-free survival of patients with locally advanced squamous cell carcinoma of the head and neck treated with induction chemotherapy comprising docetaxel, cisplatin, and fluorouracil followed by concurrent cetuximab and radiotherapy. Secondary Assess the objective response rate in patients treated with this regimen. Assess the best overall response rate, overall survival, local-regional control, and distant failure in patients treated with this regimen. Assess the acute and long-term toxicity associated with this regimen in these patients. Assess quality of life and swallowing in patients treated with this regimen. Determine the accuracy of PET/CT scan in evaluating objective response; in detecting residual disease at primary sites and nodes; in guiding the recommendation for salvage surgery or for neck dissection; and in early detection of recurrent or metastatic disease. OUTLINE: Patients are stratified according to nodal status (N2b-c or N3 vs N0-2a), tumor characteristics of invasiveness (present vs absent), human papilloma virus (HPV) status (positive vs negative), and primary tumor site (hypopharynx vs larynx vs oropharynx). Patients receive induction chemotherapy comprising docetaxel IV over 1 hour and cisplatin IV over 1 hour on day 1 and fluorouracil IV continuously on days 1-4. Treatment repeats every 3 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Beginning 3-4 weeks after completion of induction chemotherapy, patients receive cetuximab IV once weekly for 7 weeks. Beginning 1 week after the first dose of cetuximab, patients undergo concurrent intensity-modulated radiotherapy or conventional 3-dimensional radiotherapy once or twice daily 5-6 days a week for up to 6 weeks. Patients with persistent disease undergo salvage resection of the primary tumor and/or neck dissection approximately 3 months after the completion of radiotherapy. Patients undergo quality of life and swallowing evaluations periodically. Patients undergo PET/CT scan at baseline, before beginning radiotherapy, at 6-8 weeks after completion of study treatment, every 6 months for 5 years, and then annually thereafter. After completion of study treatment, patients are followed at 4 and 8 weeks, every 2 months for 2 years, every 3 months for 1 year, and then every 6 months thereafter.

Official Title
-----------------
Phase II Study to Evaluate the Efficacy and Toxicity of Multimodality Treatment With Induction Taxotere/Cisplatin?5-FU (TPF) Chemotherapy Followed by Concomitant Cetuximab and Radiation Therapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Conditions
-----------------
Head and Neck Cancer

Intervention / Treatment
-----------------
* Biological: cetuximab
* Drug: cisplatin
* Drug: docetaxel
* Drug: fluorouracil
* Procedure: computed tomography
* Procedure: positron emission tomography
* Procedure: quality-of-life assessment
* Radiation: 3-dimensional conformal radiation therapy
* Radiation: intensity-modulated radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion: Histologically confirmed (from primary lesion and/or lymph nodes) squamous cell carcinoma (SCC) of the head and neck, including the following subtypes: Oropharynx Hypopharynx Larynx Primary site of tumor must not include any of the following: Nasopharynx Sinuses Salivary glands Stage III or IV disease that is unresectable (oropharynx, larynx, or hypopharynx) OR that is resectable with organ-sparing goal (oropharynx or hypopharynx) Measurable disease by CT scan or MRI No definitive evidence of distant metastasis ECOG performance status 0-1 ANC ≥ 1,500/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 8 g/dL Total bilirubin ≤ normal Except in the case where the elevated total bilirubin is not a sign of liver disease (i.e., Gilbert syndrome), in which case a total bilirubin ≤ 2 times upper limit of normal (ULN) is allowed provided direct bilirubin is ≤ ULN AST, ALT, and alkaline phosphate (AP) meeting the following criteria: AP normal AND AST or ALT ≤ 5 times upper limit of normal (ULN) AP ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN AP ≤ 5 times ULN AND AST or ALT normal Creatinine ≤ 1.5 mg/dL Negative pregnancy test (for women of childbearing potential) Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment Willing to undergo laryngoscopy with biopsy of residual tumor at primary site (as part of a comprehensive evaluation of tumor response after completion of the induction chemotherapy portion of study treatment) Exclusion: History of severe hypersensitivity reaction to docetaxel or to other drugs formulated with polysorbate 80 Other invasive malignancy within the past 3 years, except nonmelanoma skin cancer Prior allergic reaction to the study drug(s) Concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Psychiatric illness/social situation that would limit compliance with study requirements Significant history of uncontrolled cardiac disease, including any of the following: Uncontrolled hypertension Unstable angina Myocardial infarction within the past 6 months Uncontrolled congestive heart failure Cardiomyopathy with decreased left ventricular ejection fraction (i.e., LVEF < 45%) Uncontrolled condition that, in the opinion of the investigator, would interfere in the safe and timely completion of study procedures History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on screening chest CT scan HIV positivity Pregnant or nursing Prior chemotherapy for the study cancer Prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields Prior chemotherapy, biological therapy, or hormone therapy within the last one year Prior initial surgical treatment, except diagnostic biopsy of the primary site or nodal sampling of neck disease Prior radical or modified neck dissection Prior therapy that specifically and directly targets the EGFR pathway Concurrent investigational agents

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPFChemotherapy + Concomitant Cetuximab & RT<br>Taxotere/Cisplatinum/5-Fluorouracil (TPF) Chemotherapy Followed by Concomitant Cetuximab & Radiation Therapy | Biological: cetuximab<br> <br> Drug: cisplatin<br> <br> Drug: docetaxel<br> <br> Drug: fluorouracil<br> <br> Procedure: computed tomography<br> <br> Procedure: positron emission tomography<br> <br> Procedure: quality-of-life assessment<br> <br> Radiation: 3-dimensional conformal radiation therapy<br> <br> Radiation: intensity-modulated radiation therapy<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival |  | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Will be measured by CT scan /MRI of the head and neck with corroborative results of direct biopsy of any residual tumor at primary site. | up to 2 years | 
| Best Overall Response Rate | Defined as rate of complete and partial responses (at least 30% decrease in the sum of the longest diameter of target lesions), measured by CT scan or MRI of the head and neck after completion of multimodality treatment with induction TPF (Docetaxel, cisplatin and fluorouracil) chemotherapy followed by combined ERT. We will use RECIST (Response Evaluation Criteria In Solid Tumors) (Therasse et al, 2000) for evaluation of response. | up to 2 years | 
| Overall Survival |  | up to 2 years | 
| Number of Participants With Distant Metastasis |  | up to 2 years | 
| Quality of Life - Functional Assessment of Cancer Therapy - General (FACT-G) | Four subscales: physical well-being (PWB; 7-items, score range 0-28), social/family well-being (SWB; 7-items, score range 0-28), emotional well-being (EWB; 6-items, score range 0-24), and functional well-being (FWB; 7-items, score range 0-28). Items are rated on a five-point scale: 0-not at all, 1- a little bit, 2-somewhat, 3- quite a bit and 4-very much. Overall quality of life is the sum of the core items of the FACT-G possible range of 0-108 points. The higher the score the better the quality life. This interval includes 0, we will conclude that there is not conclusive statistical evidence that there is an improvement or worsening. If the interval does not include 0 we can determine whether there was a significant improvement (or worsening) depending on which side of the 0 the interval is on. The total outcome index score (possible range 0-108 points) is the sum of the physical and functional well being and additional concerns categories from the FACT-G. | Baseline, pre-radiation therapy and post-radiation therapy, up to 2 years | 
| Number of Participants With Local-Regional Control |  | up to 2 years | 
| Performance Status Scale for Head and Neck Cancer | Consists of assessment of three functions (subscales): Normalcy of diet, eating in public, and understandability of speech. The interviewer rates the patient on each scale based on the patient's responses to targeted questions. Scores range from 0-100 (Full performance (100 score), moderate or severe impairment (≤ 50 score)). The higher the score, the better the ability of the patient to function. | Baseline, pre-radiation therapy and post-radiation therapy, up to 2 years | 
| MD Anderson Dysphagia Inventory | The MD Anderson Dysphasia Inventory (MDADI) is a survey specifically designed to assess dysphasia. It contains 20 questions directly addressing the swallowing function and several other general questions. The questionnaire asks for participants views about their swallowing ability at baseline, pre-radiation therapy and post-radiation therapy. All questions except for E7 and F2: Strongly Agree = 1 point, Agree = 2 points, No Opinion = 3 points, Disagree = 4 points, Strongly Disagree. E7 and F2: Strongly agree = 5 points, Agree = 4 points, no opinion = 3 points, disagree = 2 points, strongly disagree = 1 point. Scores range from 20 (extremely low-functioning) to 100 (high-functioning). | Baseline, pre-radiation therapy and post-radiation therapy, up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, stage III squamous cell carcinoma of the hypopharynx, stage IV squamous cell carcinoma of the hypopharynx, stage III squamous cell carcinoma of the larynx, stage III verrucous carcinoma of the larynx, stage IV squamous cell carcinoma of the larynx, stage IV verrucous carcinoma of the larynx