Details

Details

Title Phase II Randomized Trial of Transoral Surgical Resection followed by Low-dose or Standard-dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer

IRB E3311

CC 14-485

Hospital Main Campus

Stage Stage 3, Stage 4

Phase Phase 2

Disease Head and Neck

Description

Description

Primary Objective
  1. Accrual, risk distribution, and surgical quality will be used to determine the feasibility of a prospective multi-institutional study of transoral surgery for HPV+ oropharynx cancer followed by risk-adjusted adjuvant therapy.
  2. To assess the oncologic efficacy following transoral resection and adjuvant therapy in patients determined to be at "intermediate risk" after surgical excision, the 2-year PFS rate will be examined.
Secondary Objectives
  1. To estimate the patient distribution with various histologic risk features.
  2. To assess and compare early and late toxicities associated with TOS and the different doses of adjuvant PORT.
  3. To evaluate swallowing function before and after TOS and risk-adjusted adjuvant therapy.
  4. To evaluate QOL, swallowing perception and performance, voice outcomes, and head and neck symptoms.
Laboratory Research Objectives:
  1. To correlate tumor TP53 mutation and other associated mutation profile with pathologic findings, with PFS and other outcome parameters in patients with resectable HPV-associated OPSCC after the above treatments.
  2. To evaluate radiation resistance markers, including ERCC1 single nucleotide polymorphism and protein expression, and correlate them with treatment efficacy.
  3. To investigate the usefulness of biomarkers in predicting progression free survival and biomarkers, including tumor ERCC1, EGFR, plasma cytokine/chemokines, cellular immunity to HPV, and oral HPV DNA
Inclusion Criteria

Inclusion Criteria

  1. Age ≥ 18 years.
  2. ECOG performance status of 0 or 1.
  3. Patients must register to Step 1 prior to surgery.
  4. 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
  5. Patients must have AJCC TNM tumor stage III, IV a, or IV 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. The following imaging is required: CT scan with IV contrast or MRI. The primary tumor should be cT1 or T2 and cervical nodes cN1, N2a, or N2b based on clinical or radiographic criteria.
  6. Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of invasive squamous cell carcinoma may have been obtained from the primary tumor or metastatic lymph node. It is required that patients have a positive p16 IHC (as surrogate for HPV) status from either the primary tumor or metastatic lymph node.
  7. Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression using immunohistochemistry (IHC) performed by a CLIA approved laboratory. Using p16 antibody obtained from Roche mtm laboratories AG (CINtec, clone E6H4) is recommended.
  8. No prior radiation above the clavicles.
  9. 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.
  10. Patients with the following within the last 6 months prior to pre-registration must be evaluated by a cardiologist and/or neurologist prior to entry into the study.
  11. Patients must not have evidence of extensive or "matted/fixed" pathologic adenopathy on preoperative imaging.
  12. Patients must have acceptable renal and hepatic function within 4 weeks prior to registration as defined below:
    • Absolute neutrophil count ≥1,500/mm3
    • Platelets ≥ 100,000/mm3
    • Total bilirubin ≤ the upper limit of normal (ULN)
    • Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula: (140-age) x wt(kg)/([Cr] x 72). For women the calculation may be multiplied by 0.85
  13. 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).
  14. Patient must not have an intercurrent illness likely to interfere with protocol therapy or prevent surgical resection.
  15. Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to pre-registration.

Registration/Randomization to Step 2 - Arms A, B, C, and D

  1. Histopathologic assessment of surgical pathology must include examination for perineural invasion (PNI) and lymphovascular invasion (LVI) and reported as absent or present. The absence or presence of extracapsular extension (ECE) 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 (Gross, tumor extends >1 mm beyond the lymph node capsule (includes soft tissue metastasis)
  2. Patient must be stratified/classified into one of the following risk categories:The highest risk feature assessed pathologically will determine the patient's category/treatment arm assignment.
    • Low Risk: T1-T2, N0-N1 AND clear (>3mm) margins, AND no ECE or PNI/LVI.
    • High Risk: Any of the following features: one or more positive margin(s) with any T stage, OR 'Extensive' (>1mm) ECE, OR ≥ 5 metastatic lymph nodes (regardless of primary tumor margin status).
    • Intermediate Risk: Any of the following features: one or more 'close' (<3mm) margin(s), OR 'Minimal' (≤1mm) ECE, OR 2-4 metastatic lymph nodes (regardless of primary tumor margin status), OR with perineural invasion or lymphovascular invasion.
    • Unknown Risk: 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. These patients will be treated on Arm C.
  3. Patient must be registered/randomized to Step 2 within 5-7 weeks following surgery.
  4. Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception
Exclusion Criteria

Exclusion Criteria

Exclusion Criteria Not Available