Induction Chemotherapy Followed By Cetuximab and Radiation in HPV-Associated Resectable Stage III/IV Oropharynx Cancer
- Conditions
- Precancerous ConditionHead and Neck Cancer
- Interventions
- Biological: cetuximabRadiation: intensity-modulated radiation therapy (IMRT)
- Registration Number
- NCT01084083
- Lead Sponsor
- Eastern Cooperative Oncology Group
- Brief Summary
RATIONALE: Drugs used in chemotherapy, such as paclitaxel and cisplatin, 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 paclitaxel, cisplatin, and cetuximab together with radiation therapy may kill more tumor cells.
PURPOSE: This phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy in treating patients with HPV-associated stage III or stage IV cancer of the oropharynx that can be removed by surgery.
- Detailed Description
OBJECTIVES:
Primary
* To evaluate the efficacy of induction therapy comprising paclitaxel, cisplatin, and cetuximab followed by cetuximab in combination with low-dose or standard-dose intensity-modulated radiotherapy, as measured by 2-year progression-free survival (PFS), in patients with human papillomavirus(HPV)-associated resectable stage III-IVB squamous cell carcinoma of the oropharynx.
Secondary
* To assess overall survival.
* To evaluate the objective response, local control, and metastatic rate.
* To evaluate early and late toxicities of treatment.
Tertiary
* To evaluate quality of life and speech and swallowing function as measured by Functional Assessment of Cancer Therapy - General (FACT-G), Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), and Vanderbilt Head and Neck Symptom Survey (VHNSS).
* To assess the effect of treatment-induced fatigue on general physical functioning in patients with head and neck cancer.
* To correlate functional decline with clinical, physical, and biologic correlatives.
* To evaluate radiation-resistance markers, including ERCC1 single nucleotide polymorphism and protein expression, and to correlate them with treatment efficacy.
* To demonstrate the usefulness of biomarkers, including ERCC1, epidermal growth factor receptor (EGFR), cytokine and chemokine markers, and plasma transforming growth factor alpha (TGFA) and transforming growth factor beta (TGFB) levels, in predicting progression-free survival (PFS) and other outcome parameters.
* To evaluate the correlation between the efficacy of cetuximab and polymorphisms in FcγR-receptors.
* To evaluate functional outcome and biological parameters, including telomere length, angiotensin-converting enzyme polymorphism, and C-reactive protein level.
OUTLINE: This is a multicenter study.
* Induction therapy: Patients receive cisplatin intravenously (IV) over 1 hour on day 1 and paclitaxel IV over 3 hours and cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for 3 courses. Patients then undergo evaluation of response to induction therapy. Patients with a clinical complete response (CR) at the primary tumor site proceed to group 1 of concurrent radiotherapy and cetuximab. Patients with a clinical partial response (PR) or stable disease (SD) at the primary tumor site or those with grossly positive disease at the primary tumor site proceed to group 2 of concurrent radiotherapy and cetuximab.
* Concurrent radiotherapy and cetuximab: Treatment begins 14-21 days after the last day of induction therapy.
* Group 1 (CR): Patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 6 weeks.
* Group 2 (PR, SD, or grossly positive disease): Patients undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 7 weeks.
Patients complete questionnaires assessing fatigue, physical function, weight loss, quality of life, head and neck symptom burden, and speech and swallowing function at baseline and at 1, 6, 12, and 24 months after completion of study treatment.
Tumor tissue and serum samples may be collected periodically for correlative laboratory studies.
After completion of study treatment, patients are followed up periodically for 3 years.
PROJECTED ACCRUAL: 83 patients
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 90
-
Histologically or cytologically confirmed squamous cell carcinoma of the oropharynx as determined by Hematoxylin and eosin (H&E) staining
- Newly diagnosed disease
- Resectable disease OR disease that is expected to become resectable after study treatment
- Stage III, IVA, or IVB disease as determined by imaging studies (computed tomography (CT) scan with IV contrast or magnetic resonance imaging (MRI) required) and a complete head and neck exam
-
Paraffin-embedded tumor specimen available for central confirmation of HPV-associated disease as determined by H&E staining and in-situ hybridization (ISH) for HPV-16 and immunohistochemistry (IHC) for p16
- HPV-associated disease is defined as p16 IHC-positive and/or HPV-16 ISH-positive
- Non-HPV-associated disease is defined as p16 IHC-negative
- NOTE: If there is limited tumor material, p16 IHC will be performed before HPV-16 ISH
-
Measurable disease of the primary tumor or nodes by clinical and radiographic methods, defined as a lesion that is ≥ 2 cm in at least one dimension by clinical exam AND by radiographic exam with CT scan or MRI (or a lesion that is ≥ 1 cm in at least one dimension if the radiographic exam utilizes spiral CT scan)
-
No primary tumor or nodal metastasis fixed to the carotid artery, skull base, or cervical spine
-
No evidence of distant metastases
-
Eastern Cooperative Oncology Group performance status 0-1
-
Granulocytes ≥ 1,000/mm^3
-
Platelet count ≥ 100,000/mm^3
-
Total serum bilirubin ≤ 1.5 mg/dL
-
Creatinine clearance ≥ 60 mL/min
-
Negative pregnancy test
-
Fertile patients must use effective contraception
-
No history of another malignancy (except for carcinoma in situ of the cervix and/or nonmelanomatous skin cancer) unless it has been curatively treated and the patient has been disease-free for ≥ 2 years
-
Patients with any of the following within the past 6 months are eligible provided they have been evaluated by a cardiologist and/or neurologist before study entry:
- New York Heart Association (NYHA) class III-IV congestive heart failure
- Cerebrovascular accident or transient ischemic attack
- Unstable angina
- Myocardial infarction (with or without ST elevation)
- Prior chemotherapy
- Prior radiotherapy above the clavicles
- Prior surgery with curative intent for this disease (complete head and neck exam with biopsy allowed)
- Prior therapy specifically and directly targeting the EGFR pathway
- Prior severe infusion reaction to a monoclonal antibody
- Uncontrolled diabetes, uncontrolled infection despite antibiotics, or uncontrolled hypertension within the past 30 days
- Concurrent illness likely to interfere with study therapy or to prevent surgical resection
- Pregnant or nursing
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Group 2 intensity-modulated radiation therapy (IMRT) After induction therapy with Paclitaxel and Cisplatin, patients undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 7 weeks. Group 1 intensity-modulated radiation therapy (IMRT) After induction therapy with Paclitaxel and Cisplatin, patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 6 weeks. Group 1 cetuximab After induction therapy with Paclitaxel and Cisplatin, patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 6 weeks. Group 2 cetuximab After induction therapy with Paclitaxel and Cisplatin, patients undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 7 weeks. Group 1 Cisplatin After induction therapy with Paclitaxel and Cisplatin, patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 6 weeks. Group 1 Paclitaxel After induction therapy with Paclitaxel and Cisplatin, patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 6 weeks. Group 2 Paclitaxel After induction therapy with Paclitaxel and Cisplatin, patients undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 7 weeks. Group 2 Cisplatin After induction therapy with Paclitaxel and Cisplatin, patients undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 7 weeks.
- Primary Outcome Measures
Name Time Method 24-month Progression-free Survival assessed within 14 days after delivery of the third cycle of induction therapy, and 8 weeks and 6 months after completion of concurrent therapy, then every 6 months until progression or until 3 years from study entry 24-month progression-free survival is defined as the proportion of patients who were alive and progression-free at 24 months post registration. The primary study population for this endpoint is patients who were confirmed post-induction clinical complete response (CR) at their primary sites and subsequently received 5400 cGy radiation therapy to their primary sites.
- Secondary Outcome Measures
Name Time Method 24-months Overall Survival assessed within 14 days after delivery of the third cycle of induction therapy, and 8 weeks and 6 months after completion of concurrent therapy, then every 6 months until progression or until 3 years from study entry OS was defined as the time from registration to death, or censored at last date known alive. Kaplan-Meier method was used to estimate the overall survival rate at 24 months.
Primary Clinical Response Rate assessed within 14 days after delivery of the third cycle of induction therapy Primary clinical response rate is defined as the proportion of patients with complete response or partial response at their primary sites after induction therapy. Response status for the primary site was classified by clinical examination using endoscopy. If, however, the clinical response status of the primary was unclear based on endoscopy, then the CT or MRI (required at the end of induction) was used to determine status of the primary. If clinical and radiological evaluation of the primary was unclear, a biopsy was considered at the discretion of the treating physician.
Trial Locations
- Locations (121)
Northwest Ohio Oncology Center
🇺🇸Maumee, Ohio, United States
McKee Medical Center
🇺🇸Loveland, Colorado, United States
Hope Cancer Care Center at Longmont United Hospital
🇺🇸Longmont, Colorado, United States
St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center
🇺🇸Grand Junction, Colorado, United States
Exempla Lutheran Medical Center
🇺🇸Wheat Ridge, Colorado, United States
Minnesota Oncology Hematology, PA - Maplewood
🇺🇸Maplewood, Minnesota, United States
CCOP - MeritCare Hospital
🇺🇸Fargo, North Dakota, United States
Penrose Cancer Center at Penrose Hospital
🇺🇸Colorado Springs, Colorado, United States
North Colorado Medical Center
🇺🇸Greeley, Colorado, United States
St. Mary - Corwin Regional Medical Center
🇺🇸Pueblo, Colorado, United States
Sky Ridge Medical Center
🇺🇸Lone Tree, Colorado, United States
Willmar Cancer Center at Rice Memorial Hospital
🇺🇸Willmar, Minnesota, United States
Fergus Falls Medical Group, PA
🇺🇸Fergus Falls, Minnesota, United States
Front Range Cancer Specialists
🇺🇸Fort Collins, Colorado, United States
CCOP - Metro-Minnesota
🇺🇸Saint Louis Park, Minnesota, United States
Regions Hospital Cancer Care Center
🇺🇸Saint Paul, Minnesota, United States
Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
🇺🇸Robbinsdale, Minnesota, United States
St. Francis Cancer Center at St. Francis Medical Center
🇺🇸Shakopee, Minnesota, United States
North Suburban Medical Center
🇺🇸Thornton, Colorado, United States
George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus
🇺🇸New Britain, Connecticut, United States
CCOP - Christiana Care Health Services
🇺🇸Newark, Delaware, United States
Tunnell Cancer Center at Beebe Medical Center
🇺🇸Lewes, Delaware, United States
Community Cancer Center of Monroe
🇺🇸Monroe, Michigan, United States
Mercy Memorial Hospital - Monroe
🇺🇸Monroe, Michigan, United States
Swedish Medical Center
🇺🇸Englewood, Colorado, United States
Waukesha Memorial Hospital Regional Cancer Center
🇺🇸Waukesha, Wisconsin, United States
UAB Comprehensive Cancer Center
🇺🇸Birmingham, Alabama, United States
St. Anthony Central Hospital
🇺🇸Denver, Colorado, United States
Porter Adventist Hospital
🇺🇸Denver, Colorado, United States
Presbyterian - St. Luke's Medical Center
🇺🇸Denver, Colorado, United States
St. Joseph Hospital
🇺🇸Denver, Colorado, United States
CCOP - Colorado Cancer Research Program
🇺🇸Denver, Colorado, United States
Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
🇺🇸Minneapolis, Minnesota, United States
Hennepin County Medical Center - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
Lawrence Memorial Hospital
🇺🇸Lawrence, Kansas, United States
Cancer Center of Kansas, PA - Liberal
🇺🇸Liberal, Kansas, United States
Cancer Center of Kansas, PA - Kingman
🇺🇸Kingman, Kansas, United States
Cancer Center of Kansas, PA - Parsons
🇺🇸Parsons, Kansas, United States
Cancer Center of Kansas, PA - Pratt
🇺🇸Pratt, Kansas, United States
Cancer Center of Kansas, PA - Salina
🇺🇸Salina, Kansas, United States
Cancer Center of Kansas, PA - Wellington
🇺🇸Wellington, Kansas, United States
Cancer Center of Kansas, PA - Winfield
🇺🇸Winfield, Kansas, United States
Hickman Cancer Center at Bixby Medical Center
🇺🇸Adrian, Michigan, United States
Fairview Southdale Hospital
🇺🇸Edina, Minnesota, United States
Mercy and Unity Cancer Center at Mercy Hospital
🇺🇸Coon Rapids, Minnesota, United States
Minnesota Oncology Hematology, PA - Woodbury
🇺🇸Woodbury, Minnesota, United States
Mary Bird Perkins Cancer Center - Baton Rouge
🇺🇸Baton Rouge, Louisiana, United States
Fairview Ridges Hospital
🇺🇸Burnsville, Minnesota, United States
Stony Brook University Cancer Center
🇺🇸Stony Brook, New York, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Borgess Medical Center
🇺🇸Kalamazoo, Michigan, United States
Union Hospital of Cecil County
🇺🇸Elkton, Maryland, United States
Bronson Methodist Hospital
🇺🇸Kalamazoo, Michigan, United States
Mercy and Unity Cancer Center at Unity Hospital
🇺🇸Fridley, Minnesota, United States
West Michigan Cancer Center
🇺🇸Kalamazoo, Michigan, United States
Hutchinson Area Health Care
🇺🇸Hutchinson, Minnesota, United States
Wood County Oncology Center
🇺🇸Bowling Green, Ohio, United States
Ridgeview Medical Center
🇺🇸Waconia, Minnesota, United States
Flower Hospital Cancer Center
🇺🇸Sylvania, Ohio, United States
Park Nicollet Cancer Center
🇺🇸Saint Louis Park, Minnesota, United States
Cancer Institute of New Jersey at Cooper - Voorhees
🇺🇸Voorhees, New Jersey, United States
United Hospital
🇺🇸Saint Paul, Minnesota, United States
North Coast Cancer Care - Clyde
🇺🇸Clyde, Ohio, United States
Lima Memorial Hospital
🇺🇸Lima, Ohio, United States
St. Charles Mercy Hospital
🇺🇸Oregon, Ohio, United States
Hematology Oncology Center
🇺🇸Elyria, Ohio, United States
Fisher-Titus Medical Center
🇺🇸Norwalk, Ohio, United States
Fredericksburg Oncology, Incorporated
🇺🇸Fredericksburg, Virginia, United States
Holy Family Memorial Medical Center Cancer Care Center
🇺🇸Manitowoc, Wisconsin, United States
Bay Area Cancer Care Center at Bay Area Medical Center
🇺🇸Marinette, Wisconsin, United States
St. Vincent Mercy Medical Center
🇺🇸Toledo, Ohio, United States
Fox Chase Cancer Center - Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Medical University of Ohio Cancer Center
🇺🇸Toledo, Ohio, United States
Vanderbilt-Ingram Cancer Center - Cool Springs
🇺🇸Franklin, Tennessee, United States
Fulton County Health Center
🇺🇸Wauseon, Ohio, United States
Toledo Clinic, Incorporated - Main Clinic
🇺🇸Toledo, Ohio, United States
Vanderbilt-Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
St. Vincent Hospital Regional Cancer Center
🇺🇸Green Bay, Wisconsin, United States
St. Nicholas Hospital
🇺🇸Sheboygan, Wisconsin, United States
Natalie Warren Bryant Cancer Center at St. Francis Hospital
🇺🇸Tulsa, Oklahoma, United States
Toledo Clinic - Oregon
🇺🇸Oregon, Ohio, United States
Mercy Hospital of Tiffin
🇺🇸Tiffin, Ohio, United States
North Coast Cancer Care, Incorporated
🇺🇸Sandusky, Ohio, United States
St. Anne Mercy Hospital
🇺🇸Toledo, Ohio, United States
UPMC Cancer Centers
🇺🇸Pittsburgh, Pennsylvania, United States
Aurora Presbyterian Hospital
🇺🇸Aurora, Colorado, United States
Butler Memorial Hospital
🇺🇸Butler, Pennsylvania, United States
California Cancer Care, Incorporated - Greenbrae
🇺🇸Greenbrae, California, United States
Veterans Affairs Medical Center - Palo Alto
🇺🇸Palo Alto, California, United States
Stanford Cancer Center
🇺🇸Stanford, California, United States
Boulder Community Hospital
🇺🇸Boulder, Colorado, United States
Rose Medical Center
🇺🇸Denver, Colorado, United States
Poudre Valley Hospital
🇺🇸Fort Collins, Colorado, United States
Medical Oncology and Hematology Associates - West Des Moines
🇺🇸Clive, Iowa, United States
Siouxland Hematology-Oncology Associates, LLP
🇺🇸Sioux City, Iowa, United States
Cancer Center of Kansas, PA - Chanute
🇺🇸Chanute, Kansas, United States
Cancer Center of Kansas, PA - Dodge City
🇺🇸Dodge City, Kansas, United States
Cancer Center of Kansas, PA - El Dorado
🇺🇸El Dorado, Kansas, United States
Community Cancer Center
🇺🇸Elyria, Ohio, United States
CCOP - Toledo Community Hospital
🇺🇸Toledo, Ohio, United States
Regional Cancer Center at Oconomowoc Memorial Hospital
🇺🇸Oconomowoc, Wisconsin, United States
Mercy Medical Center - Sioux City
🇺🇸Sioux City, Iowa, United States
Evanston Hospital
🇺🇸Evanston, Illinois, United States
St. Luke's Regional Medical Center
🇺🇸Sioux City, Iowa, United States
MBCCOP - LSU Health Sciences Center
🇺🇸New Orleans, Louisiana, United States
Medical Center of Louisiana - New Orleans
🇺🇸New Orleans, Louisiana, United States
CCOP - Iowa Oncology Research Association
🇺🇸Des Moines, Iowa, United States
Mercy Cancer Center at Mercy Medical Center - Des Moines
🇺🇸Des Moines, Iowa, United States
John Stoddard Cancer Center at Iowa Lutheran Hospital
🇺🇸Des Moines, Iowa, United States
Cancer Center of Kansas, PA - Medical Arts Tower
🇺🇸Wichita, Kansas, United States
Cancer Center of Kansas, PA - Wichita
🇺🇸Wichita, Kansas, United States
CCOP - Wichita
🇺🇸Wichita, Kansas, United States
Medical Oncology and Hematology Associates at John Stoddard Cancer Center
🇺🇸Des Moines, Iowa, United States
Medical Oncology and Hematology Associates at Mercy Cancer Center
🇺🇸Des Moines, Iowa, United States
Via Christi Cancer Center at Via Christi Regional Medical Center
🇺🇸Wichita, Kansas, United States
Associates in Womens Health, PA - North Review
🇺🇸Wichita, Kansas, United States
John Stoddard Cancer Center at Iowa Methodist Medical Center
🇺🇸Des Moines, Iowa, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
HealthEast Cancer Care at St. John's Hospital
🇺🇸Maplewood, Minnesota, United States
Toledo Hospital
🇺🇸Toledo, Ohio, United States
Cancer Center of Kansas, PA - Newton
🇺🇸Newton, Kansas, United States