Phase II Treatment Stratification Trial Using Neck Dissection-Driven Selection to Improve Quality of Life for Low Risk Patients With HPV+ Oropharyngeal Squamous Cell Cancer

Investigators will determine whether a treatment paradigm of up-front neck dissection, to more accurately pathologically stage patients, minimizing the number of treatment modalities in patients with low risk oropharyngeal squamous cell carcinoma, can improve quality of life.

After enrollment, all patients will undergo neck dissection and primary site biopsy. Pathology will be reviewed, and patients will proceed into one of three standard-of-care (SOC) treatment groups. The treatments themselves are not the focus of this study; the focus of this study is quality of life in this population, after a pathology-based treatment plan, to assess the utility of the investigational "neck dissection first" paradigm. The SOC treatment plans are as follows:

1. Patients with a single lymph node that measures less than six centimeters, have no extracapsular extension in the lymph node, and have no perineural or perivascular invasion of the primary biopsy will undergo transoral surgery of the primary site.
2. Patients who have 2 positive nodes with no extracapsular extension, or have perineural or perivascular invasion of the primary biopsy will undergo radiation.
3. Patients who have extracapsular extension in any number of lymph nodes or in those patients in whom negative margins are unable to be obtained after the completion of transoral surgery will undergo chemoradiation.

After completion of therapy (surgical, radiation, or combined modality) patients will be followed closely on an outpatient basis including regular exams, quality of life questionnaires, and interval surveillance imaging as clinically indicated. Swallowing function will also be addressed by videofluoroscopy one year after completion of therapy. Blood/plasma and oral rinses for correlative studies will be collected at 3-month intervals during 3 years of follow up.

This study was initially registered as if it were an inter-group comparison; however, the original and consistent intent has been to determine whether a treatment paradigm of neck dissection guided staging as a whole can minimize the number of standard treatment methods used, leading to improved quality of life in low risk patients with HPV+ oropharyngeal squamous cell cancer. Though certain groups are expected to need multimodal definitive treatment downstream of the experimental "neck dissection first" paradigm, the population must be assessed as one group in this trial to assess the utility of the paradigm.

Eligibility Criteria:
Inclusion Criteria:

* Patients must have pathologically-confirmed, previously untreated, p16-positive oropharyngeal squamous cell carcinoma
* Patients must have pretreatment neck and chest imaging
* Tumors must be potentially surgically resectable via a transoral approach, at the discretion of the treating surgeon
* Patients with T stage T1-3
* Patients with N stage N0-N2c
* ECOG (Eastern Cooperative Oncology Group Performance Status: an attempt to quantify cancer patients' general well-being and activities of daily life. The score ranges from 0 to 5 where 0 is asymptomatic and 5 is death.) Performance status 0-2
* Patients are adults (Age \>18)
* Patients must agree to biospecimen submission for tissue and serum processing and storage for secondary biomarker studies
* Patients must give documented informed consent to participate in this study.
* Patients must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of chemoradiation (treatment) and for 3 months after discontinuing treatment. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to starting treatment.
* Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 30 days after study treatment. Women not of childbearing potential will be defined as all women older than age 50 and anovulatory for 12 months.
* Sexually active males must use a condom during intercourse while receiving chemoradiation and for 90 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Likewise, male subjects should not donate sperm during the time they are receiving chemoradiation and for 90 days after stopping treatment.

Exclusion Criteria:

* Prior head and neck radiation or prior chemotherapy for HNSCC (Head and Neck Squamous Cell Carcinoma)
* Patients with T4 disease
* Patients with N3 disease
* FNA evidence of squamous cell carcinoma involving 3 or more lymph nodes
* Patients with matted lymph nodes, defined as three nodes abutting one another with loss of intervening fat plane that is a replaced with radiologic evidence of extracapsular spread
* Patients with an outside primary site biopsy showing perineural or perivascular invasion
* Documented evidence of distant metastases.
* Active infection
* Patients residing in prison.
* Age \< 18 years
* Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
* Unstable angina or a history of myocardial ischemia within prior 6 months
* Patients with any of the following laboratory values at baseline:

  * Absolute neutrophil count (ANC) \< 1,000/mm3
  * Platelets \< 75,000/mm3
  * Hemoglobin \< 9.0 gm/dL
  * Calculated or measured creatinine clearance (method determined by the prescribing physicians) \< 50 ml/min
  * Bilirubin \> 1.5 x ULN (Upper Limit of Normal), except for patients with known Gilbert syndrome who are excluded if total bilirubin \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN
  * Aspartate transaminase (AST) \> 3.0 x ULN
  * Alanine transaminase (ALT) \> 3.0 x ULN
* Pregnancy or breastfeeding female.
* Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation