Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Transoral Surgery Followed by Low-Dose or Standard-Dose Radiation Therapy with or without Chemotherapy in Treating Patients with HPV Positive Stage III-IVA Oropharyngeal Cancer

Protocol: ECOG-E3311

Full Title

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

Purpose

This randomized phase II trial studies how well transoral surgery followed by low-dose or standard-dose radiation therapy works in treating patients with human papilloma virus (HPV) positive stage III-IVA oropharyngeal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving radiation therapy with chemotherapy may kill any tumor cells that remain after surgery. It is not yet known how much extra treatment needs to be given after surgery.

Study Objective

PRIMARY OBJECTIVES:

I. Accrual, risk distribution, and surgical quality will be used to determine the feasibility of a prospective multi-institutional study of transoral surgery for HPV positive (+) oropharynx cancer followed by risk-adjusted adjuvant therapy.

II. 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 progression free survival (PFS) rate will be examined.

SECONDARY OBJECTIVES:

I. To estimate the patient distribution with various histologic risk features.

II. To assess and compare early and late toxicities associated with transoral surgery (TOS) and the different doses of adjuvant postoperative radiotherapy (PORT).

III. To evaluate swallowing function before and after TOS and risk-adjusted adjuvant therapy.

IV. To evaluate quality of life (QOL), swallowing perception and performance, voice outcomes, and head and neck symptoms.

TERTIARY OBJECTIVES:

I. 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 oropharyngeal squamous cell carcinoma (OPSCC) after the above treatments.

II. To evaluate radiation resistance markers, including ERCC1 single nucleotide polymorphism and protein expression, and correlate them with treatment efficacy.

III. 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 deoxyribonucleic acid (DNA).

OUTLINE: Patients are classified by risk status (low risk, intermediate risk, or high risk) and assigned to the appropriate treatment group. Patients classified as intermediate risk are randomized to 1 or 2 treatment arms.

ARM A (low risk): Patients undergo transoral surgical resection of the oropharyngeal tumor.

ARM B (intermediate risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo low-dose intensity modulated radiation therapy (IMRT) once daily (QD) five days a week for 5 weeks.

ARM C (intermediate or unknown risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo standard-dose IMRT QD five days a week for 6 weeks.

ARM D (high risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo standard-dose IMRT QD five days a week for 6-7 weeks. Patients also receive cisplatin intravenously (IV) over 60 minutes or carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.

After completion of study treatment, patients are followed up every 6 months for 3 years, and then every 12 months for 2 years.

Are you eligible?

Inclusion Criteria:

REGISTRATION TO SURGERY (ARM S)

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Patients must register to Step 1 prior to surgery

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 American Joint Committee on Cancer (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 registration) and complete neck exam from the skull base to the clavicles; the following imaging is required: computed tomography (CT) scan with IV contrast or magnetic resonance imaging (MRI); the primary tumor should be cT1 or T2 and cervical nodes cN1, N2a, or N2b based on clinical or radiographic criteria

Patients must have biopsy-proven cyclin-dependent kinase inhibitor 2A (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 immunohistochemistry (IHC) (as surrogate for HPV) status from either the primary tumor or metastatic lymph node

Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression using immunohistochemistry (IHC) performed by a Clinical Laboratory Improvement Amendments (CLIA) approved laboratory; using p16 antibody obtained from Roche mtm laboratories AG (CINtec, clone E6H4) is recommended

No 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

Patients with the following within the last 6 months prior to registration must be evaluated by a cardiologist and/or neurologist prior to entry into the study

Patients must not have evidence of extensive or “matted/fixed” pathologic adenopathy on preoperative imaging

Absolute neutrophil count >= 1,500/mm^3

Platelets >= 100,000/mm^3

Total bilirubin =< the upper limit of normal (ULN)

Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula

Women must not be pregnant or breast-feeding; 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: has not undergone a hysterectomy or bilateral oophorectomy; or 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)

Patient must not have an intercurrent illness likely to interfere with protocol therapy or prevent surgical resection

Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to registration

REGISTRATION/RANDOMIZATION TO STEP 2 - ARMS A, B, C AND D

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])

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 (> 3 mm) 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” (> 1 mm) ECE, OR >= 5 metastatic lymph nodes (regardless of primary tumor margin status)

Intermediate risk: any of the following features: one or more “close” (< 3 mm) margin(s), OR “minimal” (=< 1 mm) ECE, OR N2a (1 or more lymph node > 3 cm in diameter), OR N2b (2-4 lymph nodes positive, any diameter < 6 cm), 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
  • Patients not categorized into the appropriate risk category will be considered ineligible for the study

Patient must be registered/randomized to Step 2 within a maximum of 7 weeks following surgery

Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception

Oropharyngeal Cancer Head & Neck Cancers