Trial of De-Intensified Post-operative Chemoradiation Following Robotic Surgery for HPV-positive Oropharyngeal Cancer

This is a single arm phase II study that will enroll patients with HPV-associated oropharyngeal cancer, undergoing resection through trans-oral robotic surgery (TORS) of all gross visible disease at the primary site and in the lymph nodes. A total of 36 patients at Cedars-Sinai Medical Center and its affiliates (Tower Hematology-Oncology, Torrance Memorial Physician Network) who have had or will require surgery to remove cancer cells prior to starting chemoradiation may be enrolled. All eligible patients will receive de-intensified cisplatin-based chemoradiation, with high-risk patients receiving a higher dose and longer treatment period than other patients on the study. The treatment period will last 3 to 5 weeks depending on whether the patient is considered high-risk or not. The study will assess whether a de-intensified version of standard chemoradiation treatment will be just as effective in treating HPV-associated oropharyngeal cancer while causing less side effects than standard dosing.

Inclusion criteria

• AJCC 8th edition T0-3N0-2 p16-positive oropharyngeal (tonsil, base of tongue, glossotonsillar sulcus, soft palate, oropharyngeal wall) squamous cell carcinoma or squamous cell carcinoma of unknown primary involving the cervical lymph nodes. Cytologic diagnosis from a cervical lymph node is sufficient for diagnosis in the presence of clinical evidence of a primary tumor in the oropharynx.
• For patients with pT0 tumors (unknown primary), there must be at least one metastatic lymph node present in cervical level II.
• p16 should be strongly and diffusely positive in the nuclear and cytoplasmic component in greater than 70% of the tumor cells.
• Have undergone or will undergo gross total resection of all known disease in the head and neck via transoral robotic surgery. For patients with unknown primary tumors, a minimum of an ipsilateral tonsillectomy and base of tongue resection is required.
• Have undergone or will undergo neck dissection.
• Have at least one of the following after surgery:

• Pathologic stage T3
• 2 or more positive lymph nodes
• At least one lymph node >3cm
• Lymphovascular invasion
• Perineural invasion
• Extranodal extension
• Close/positive margins: Close margins are considered <3mm from the peripheral margins and <1mm from the deep margin on the en bloc specimen, unless the area of close margin is re-resected and without carcinoma.
• Age ≥ 18 years old
• ECOG performance status 0 or 1 within 56 days of start of chemoradiation.
• Women of childbearing potential require a negative serum or urine pregnancy test within 28 days prior to start of chemoradiation.
• Written informed consent obtained from subject and ability for subject to comply with the requirements of the study.
• Adequate hematologic and renal function within 30 days of start of chemoradiation, defined as:

• Hemoglobin ≥ 9.0 g/dL
• Platelets ≥ 100, 000 cells/mm3
• ANC ≥ 1.5 X 109/L
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase/alanine aminotransferase ≤ 3.0 x upper limit of normal (ULN)
• Serum creatinine ≤1.5 x upper limit of normal (ULN) OR a calculated creatinine clearance ≥60 mL/min

Exclusion criteria

• AJCC 8th edition pT4 or cN3 disease.
• Radiologic or clinical evidence of distant metastasis.
• Recurrent disease.
• Inability to achieve gross total resection at time of surgery.
• Greater than 56 days (8 weeks) after surgical resection of the primary site.
• Prior radiation to the head and neck > 30 Gy.
• Prior active invasive (not in situ) malignancy within the prior 2 years, excluding cutaneous basal cell or squamous cell carcinoma, low or intermediate risk prostate cancer, papillary thyroid cancer, AJCC 8th edition stage I-II breast cancer, or low grade non-Hodgkin lymphoma
• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
• Transmural myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
• Hepatic insufficiency resulting in clinical jaundice and/or known coagulation defects
• Uncontrolled Acquired Immune Deficiency Syndrome (AIDS), defined as a CD4 count < 200 at screening or an AIDS-defining opportunistic infection within the last 6 months.
• Moderate to severe hearing loss.
• Active connective tissue disease (e.g. systemic lupus erythematous, scleroderma) requiring immunosuppression.
• Pregnant or breast-feeding women.
• Prior allergic reaction to cisplatin.
• Live vaccines within 30 days prior to the first dose of chemoradiation. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral vaccine). Season influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.