Radiation Therapy with or without Cetuximab in Treating Patients Who Have Undergone Surgery for Locally Advanced Head and Neck Cancer
This randomized phase III trial studies radiation therapy alone to see how well it works compared with radiation therapy and cetuximab in treating patients who have undergone surgery for head and neck cancer that has spread to nearby tissues or organs. Radiation therapy uses high-energy x-rays to kill tumor cells. Using a 3-dimensional (3-D) image of the tumor to help focus the radiation directly onto the tumor, and giving the radiation in higher doses over a shorter period of time, may kill more tumor cells and cause fewer side effects. Monoclonal antibodies, such as cetuximab, may block tumor growth by targeting certain cells. It is not yet known whether radiation therapy is more effective when given alone or together with cetuximab in treating patients with head and neck cancer that has been removed by surgery.
- Pathologically (histologically) proven diagnosis of squamous cell carcinoma (including variants such as verrucous carcinoma, spindle cell carcinoma, carcinoma not otherwise specified [NOS], etc.) of the head/neck (oral cavity, oropharynx or larynx); note: hypopharynx primaries are excluded
- Clinical stage T1, N1-2 or T2-4a, N0-2, M0 including no distant metastases, based upon the following minimum diagnostic workup: * General history and physical examination by a radiation oncologist and/or medical oncologist within 8 weeks prior to registration * Examination by an ear, nose and throat (ENT) or head & neck surgeon, within 8 weeks prior to registration; a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is recommended but not required * Chest x-ray (at a minimum) or chest computed tomography (CT) scan (with or without contrast) or CT/positron emission tomography (PET) of chest (with or without contrast) within 8 weeks prior to registration
- Gross total resection of the primary tumor with curative intent must be completed within 7 weeks of registration with surgical pathology demonstrating one or more of the following “intermediate” risk factors: * Perineural invasion * Lymphovascular invasion * Single lymph node > 3 cm or >= 2 lymph nodes (all < 6 cm) (no extracapsular extension) * Close margin(s) of resection, defined as cancer extending to within 5 mm of a surgical margin, and/or an initially focally positive margin that is subsequently superseded by intraoperative negative margins; similarly, patients whose tumors had focally positive margins in the main specimen but negative margins from re-excised samples in the region of the positive margin are eligible; for questions or ambiguities about an individual case, contact Dr. Machtay and/or Dr. Holsinger prior to enrolling the patient * Pathologically confirmed T3 or T4a primary tumor; for questions or ambiguities about an individual case, contact Dr. Machtay and/or Dr. Holsinger prior to enrolling the patient * T2 oral cavity cancer with > 5 mm depth of invasion
- Zubrod performance status 0-1
- Absolute granulocyte count (AGC) >= 1,500/mm³
- Platelet count >= 100,000/mm³
- Hemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)
- Total bilirubin < 2 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x institutional ULN
- Serum creatinine < 2 x institutional ULN or; creatinine clearance (CC) >= 50 mL/min determined by 24-hour collection or estimated by Cockcroft-Gault formula
- Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential
- The following assessments are required within 2 weeks prior to the start of registration: sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg), and albumin; note: patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may receive corrective magnesium supplementation but should continue to receive either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g., magnesium oxide) at the investigator’s discretion
- Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control
- Patients must provide study specific informed consent prior to study entry, including consent for mandatory tissue submission for EGFR and for oropharyngeal patients, HPV analyses
- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; noninvasive cancers (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) are permitted even if diagnosed and treated < 3 years ago; patients with simultaneous primaries or bilateral tumors are excluded, with the exception of patients with bilateral tonsil cancers or patients with primary tumor (T)1-2, nearby lymph nodes (N)0, metastasis (M)0 resected differentiated thyroid carcinoma, who are eligible
- Per the operative and/or pathology report, positive margin(s) (defined as tumor present at the cut or inked edge of the tumor), nodal extracapsular extension, and/or gross residual disease after surgery; note: patients whose tumors had focally positive margins in the main specimen but negative margins from re-excised samples in the region of the positive margin are eligible; for questions or ambiguities about an individual case, contact Dr. Machtay and/or Dr. Holsinger prior to enrolling the patient
- Prior systemic chemotherapy or anti-EGF therapy for the study cancer; note: prior chemotherapy or anti-EGF therapy for a different cancer is allowable
- Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
- Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization within 6 months prior to registration * Transmural myocardial infarction within 6 months prior to registration * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration * Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to registration * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol * Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note: human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients * Grade 3-4 electrolyte abnormalities (CTCAE, v. 4): ** Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5 mg/dl (> 3.1 mmol/L) despite intervention to normalize levels ** Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14 mmol/L) ** Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite intervention to normalize levels ** Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels ** Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels
- Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
- Prior allergic reaction to cetuximab
Locations & Contacts
Contact: Bahman Emami
Contact: Mitchell Machtay
Phone: 800-641-2422 Email: email@example.com
Status: Temporarily closed to accrual
Contact: Tapan Roy
Phone: 888-823-5923 Email: firstname.lastname@example.org
Trial Objectives and Outline
I. Test whether the addition of cetuximab to radiation therapy will improve overall survival (OS) in postoperative patients with intermediate risk following surgery.
I. Assess the impact of the addition of cetuximab to postoperative radiation therapy on disease-free survival (DFS).
II. Assess the impact of the addition of cetuximab to postoperative radiation therapy on acute dysphagia, dry mouth, skin toxicity, and other toxicities (Common Terminology Criteria for Adverse Events [CTCAE], version [v.] 4) and their relationships to patient-reported outcomes at 3 months.
III. Assess the impact of the addition of cetuximab to postoperative radiation therapy on late dysphagia, dry mouth, skin toxicity, and other toxicities (CTCAE, v. 4) and their relationships to patient-reported outcomes at 12 and 24 months.
IV. Tumor analysis of epidermal growth factor receptor (EGFR), specifically extent of EGFR overexpression by immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) analysis, EGFR variant III (EGFRvIII) expression, as well as association of these assay data with OS and DFS.
V. Tumor analysis of human papillomavirus (HPV) infection (as defined by in situ hybridization), specifically, within the cohort of patients with oropharynx cancer, to perform an exploratory analysis of the impact of HPV on DFS and OS in this patient subset.
VI. Tumor deoxyribonucleic acid (DNA) analyses of tumor protein 53 (TP53) mutations for response prediction to cetuximab and prognosis.
VII. Germline DNA analyses of polymorphic variants in EGFR intron repeats for response prediction to cetuximab.
I. Assess the impact of the addition of cetuximab to postoperative radiation therapy on local-regional control.
II. Assess the impact of the addition of cetuximab to postoperative radiation therapy on patient-reported quality of life (QOL), swallowing, xerostomia, and skin toxicity based on head and neck specific instruments, including the Performance Status Scale for Head and Neck Cancer (PSS-HN), the Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N), the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS), and the Dermatology Life Quality Index (DLQI).
III. Assess the impact of the addition of cetuximab to postoperative radiation therapy on cost-utility analysis using the EuroQol (EQ-5D).
IV. To evaluate the utility of image-guided radiotherapy (IGRT) as a means of enhancing the efficacy (i.e., local-regional control) of intensity-modulated radiation therapy (IMRT) while reducing the acute and/or late toxicity (particularly xerostomia) and improving patient-reported outcomes (particularly XeQOLS scores).
V. To retrospectively compare the local regional control rate for patients treated with IMRT alone (no IGRT or cetuximab) with similar patients treated with external beam radiotherapy alone in the postoperative trial Radiation Therapy Oncology Group (RTOG) 95-01.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients undergo IMRT once daily (QD) for a total of 30 fractions in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo IMRT as in arm I. Patients also receive cetuximab intravenously (IV) over 60-120 minutes once weekly beginning at least 5 days prior to the start of IMRT for 11 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 1 and 3 months, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Trial Phase & Type
Secondary IDs NCI-2011-00878, CDR0000651536, NCT01311063
Clinicaltrials.gov ID NCT00956007