Cancer esearch roup ev. 6/14, 2/15, 1/16 Step 2 Schema 5 Arm A: (7 weeks) Step 1 1,2 N Accrual: 515 S Arm S ransoral esection dissections S A N D M Z 4 ntermediate isk 7 Stratify: = 10 pk-yr vs. > 10 pk-yr Unknown isk 9 High isk 6 Arm B: (5-7 weeks) adiotherapy M 50 y/25 Fx 3 Arm C: (5-7 weeks) adiotherapy M 60 y/30 Fx 3 Arm D: (5-7 weeks) adiotherapy M 66 y/33 Fx + 3 CDDP 40 mg/m 2 weekly M F W - U P 1. esectable oropharynx carcinoma, p16 + by HC, PS 0-1 2. Credentialing of surgeon required as part of site participation, neck levels dissected and nodal yield (> nodes/neck) 3. adiotherapy will be given with an intensity modulated radiotherapy (M) technique. Standard C credentialing through QAC will be required. 4. Stratify by current/former smoking history(< 10pk-yr vs. > 10pk-yr) 5. ow isk: 1-2, N0-N1 AND clear (> 3mm) margins, AND no C or PN/V. 6. High isk: Any of the following features: one or more positive margin(s) with any stage, xtensive (> 1mm) C, > 5 metastatic lymph nodes (regardless of primary tumor margin status). 7. ntermediate isk: Any of the following features: one or more "close" (< 3mm) margin(s), "Minimal" (< 1mm) C, N2a (1 or more lymph node >3cm in diameter), N2b (2-4 lymph nodes positive, any diameter < 6cm), with perineural invastion or lymphovascular invasion. 8. f = 2 events are observed among the first ten patients registered on Arm A within one year, currently enrolled and subsequently enrolled low risk patients who have not progressed will be treated with M 50 y 9. Patients found to have N2c (bilateral nodes), N3 (>6cm node) disease on final pathologic analysis. 6
Cancer esearch roup 3. Selection of Patients ach of the criteria in the checklist that follows must be met in order for a patient to be considered eligible for this study. Use the checklist to confirm a patient s eligibility. For each patient, this checklist must be photocopied, completed and maintained in the patient s chart. n calculating days of tests and measurements, the day a test or measurement is done is considered Day 0. herefore, if a test is done on a Monday, the Monday four weeks later would be considered Day 28. Patient. Patient s nitials (, F, M) Physician Signature and Date N: All questions regarding eligibility should be directed to the study chair or study chair liaison. N: nstitutions may use the eligibility checklist as source documentation if it has been reviewed, signed, and dated prior to registration/randomization by the treating physician. 3.1 egistration to Surgery (Arm S) _ 3.1.1 Age >/= 18 years. _ 3.1.2 C performance status of 0 or 1. ev. 2/15 _ 3.1.3 Patients must register to Step 1 prior to surgery. ev. 2/15 _ 3.1.4 _ 3.1.5 Patients must have newly diagnosed, histologically or cytologically confirmed squamous cell carcinoma or undifferentiated carcinoma of the oropharynx. Patients must have been determined to have resectable oropharyngeal disease. Patients with primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not eligible Patients must have AJCC NM tumor stage, V a, or V b (with no evidence of distant metastases) as determined by imaging studies (performed < 30 days prior to pre-registration) and complete neck exam, from the skull base to the clavicles. he following imaging is required: C scan with V contrast or M. AJCC NM tumor stage, V a, or V b? Stage Date scans performed C scan with V contrast or M? he primary tumor should be c1 or 2 and cervical nodes cn1, N2a, or N2b based on clinical or radiographic criteria. ev. 6/14 _ 3.1.6 Patients must have biopsy-proven p16+ oropharynx cancer; the ev. 2/15 histologic evidence of invasive squamous cell carcinoma may have been obtained from the primary tumor or metastatic lymph node. t is required that patients have a positive p16 HC (as surrogate for HPV) status from either the primary tumor or metastatic lymph node. 24
ev. 1/16 Cancer esearch roup _ 3.1.7 _ 3.1.8 _ 3.1.9 _ 3.1.10 _ 3.1.11 Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression using immunohistochemistry (HC) performed by a CA approved laboratory. Using p16 antibody obtained from oche mtm laboratories A (CNtec, clone 6H4) is recommended. Confirmed p16 + disease? prior radiation above the clavicles. Patients with a history of a curatively treated malignancy must be disease-free for at least two years except for carcinoma in situ of cervix, melanoma in-situ (if fully resected), and/or non-melanomatous skin cancer. History of curatively treated malignancy? f yes, disease-free for at least two years? Patients with the following within the last 6 months prior to preregistration must be evaluated by a cardiologist and/or neurologist prior to entry into the study. Congestive heart failure > NYHA Class? Date CVA/A? Date Unstable angina? Date Myocardial infarction? (with or without S elevation) Date Patients must not have evidence of extensive or matted/fixed pathologic adenopathy on preoperative imaging. _ 3.1.12 Patients must have acceptable renal and hepatic function within 4 weeks prior to registration as defined below: Absolute neutrophil count 1,500/mm 3 ANC Date of est Platelets 100,000/mm 3 Platelets Date of est otal bilirubin the upper limit of normal (UN) otal bilirubin Date of est nstitutional UN 25
Cancer esearch roup _ 3.1.13 _ 3.1.14 _ 3.1.15 Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-ault formula : (140-age)*wt(kg)/([Cr]*72). For women the calculation may be multiplied by 0.85 Creatinine clearance Date of est Women must not be pregnant or breast-feeding due to the teratogenicity of chemotherapy. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Female of child bearing potential? Date of blood test or urine study: ( or ) Patient must not have an intercurrent illness likely to interfere with protocol therapy or prevent surgical resection. ntercurrent illness? Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to pre-registration. Uncontrolled diabetes? Date Uncontrolled infection? Date Uncontrolled hypertension? Date ev. 6/14 3.2 egistration/andomization to Step 2 - Arms A, B, C, and D _ 3.2.1 Histopathologic assessment of surgical pathology must include examination for perineural invasion (PN) and lymphovascular invasion (V) and reported as absent or present. he absence or presence of extracapsular extension (C) requires gross and microscopic assessment and is defined to be: absent (negative or nodal metastasis with smooth/rounded leading edge confined to thickened capsule/pseudocapsule), present - minimal (tumor extends 1 mm beyond the lymph node capsule), or present - extensive (ross, tumor extends >1 mm beyond the lymph node capsule (includes soft tissue metastasis) 26
Cancer esearch roup ev. 2/15 _ 3.2.2 Patient must be stratified/classified into one of the following risk ev. 1/16 categories: ev. 1/16 ev. 2/15 _ 3.2.3 _ 3.2.4 he highest risk feature assessed pathologically will determine the patient's category/treatment arm assignment. ow isk: 1-2, N0-N1 AND clear ( 3mm) margins, AND no C or PN/V. High isk: Any of the following features: one or more positive margin(s) with any stage, xtensive (> 1mm) C, 5 metastatic lymph nodes (regardless of primary tumor margin status). ntermediate isk: Any of the following features: one or more close (< 3mm) margin(s), Minimal ( 1mm) C, N2a (1 or more lymph node > 3cm in diameter), N2b (2-4 lymph nodes positive, any diameter 6cm), with perineural invasion or lymphovascular invasion. Unknown isk: Patients found to have N2C or N3 disease on final pathologic analysis are at unknown risk for recurrence, but are not candidates for deintensified adjuvant therapy in this trial. hese patients will be treated on Arm C. Patients not categorized into the appropriate risk category will be considered ineligible for the study. Patient must be registered/randomized to Step 2 within 5-7 weeks following surgery. Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception 27