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 treatment stratification by 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 be stratified into one of three treatment

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.

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