Study of Chemotherapy Prior to Radiotherapy and Chemotherapy in Patients With HPV Associated Cancer of the Oral Cavity

Induction Chemotherapy TPF induction chemotherapy will be administered as published from the
TAX 323 phase III trial. Specifically, each cycle will consist of docetaxel at a dose of 75
mg per square meter, administered as a 1-hour infusion on day 1, followed by cisplatin at a
dose of 75 mg per square meter, administered as a 1-hour infusion on day 1, and fluorouracil
at a dose of 750 mg per square meter per day, administered by continuous infusion on days 1
to 5. Induction chemotherapy will be given every 3 weeks for three cycles, unless there is
distant disease progression, unacceptable toxic effects, or withdrawal of consent by the
patient. All patients will be required to have a continuous venous access device such as a
PICC line or Infusaport type device. This is standard of care for continuous infusion
fluorouracil. Response assessment by examination, contrast-enhanced CT imaging and whole body
PET-CT will be performed after the third treatment cycle. Radiotherapy or chemoradiotherapy
will commence within 3-4 weeks from the conclusion of the induction program.

Selection for Radiation Alone vs. Chemoradiotherapy For CR/PR patients with CR at primary
site following induction chemotherapy, locoregional therapy will be risk-adjusted according
to baseline tumor stage/characteristics. Local therapy will be 1) radiotherapy as a single
modality for Tx (T1-2), T0-1 or exophytic T2, N0-2a disease, or will be 2) concomitant
chemoradiotherapy for Tx (T3), endophytic T2, T3, N2b-c disease. Patients with PR at primary
site will receive concurrent chemotherapy and reduced dose radiation.

All SD/PD patients will receive concurrent chemotherapy and full dose radiation. Patients
catalogued with disease progression on the basis of new distant metastatic disease spread
(DM) during induction chemotherapy will be taken off protocol for consideration of palliative
therapy.

Concurrent Chemotherapy Concurrent chemotherapy will consist of cisplatin given at 35 mg/m2
weekly for six cycles OR carboplatin given at AUC 1.5 weekly for six cycles. Concurrent
chemotherapy will start during the first week of radiation treatment. Selection of either
schedule will be left to the discretion of the attending medical oncologist. Concurrent
chemotherapy will be held for a platelet count of <100,000 or an absolute neutrophil count of
< 1000 per cubic mm.

IMRT doses Primary Target (residual gross disease): 66 Gy called CTV1 (2.2 Gy/fraction in 30
fractions).

Intermediate-Risk Target: 57 Gy called CTV2 (1.9 Gy/fraction in 30 fractions). Prophylactic
Target Coverage: 54 Gy called CTV3 (1.8 Gy/fraction in 30 fractions).

IMRT planning Treatment planning CT scans will be required to define target volumes. The
treatment planning CT scan should be acquired with the patient in the same position and
immobilization device as for treatment. All tissues to be irradiated must be included in the
CT scan. MRI or whole body PET/CT scans may be included to assist in definition of target
volumes, especially when primary or retropharyngeal nodal disease extends near the base of
skull. The immobilization device should include neck and shoulder immobilization. GTV, CTVs,
PTVs, and normal tissues must be outlined on all CT slices in which these structures exist.

Primary Target CTV1: All regions of GTV-R in PR patients will receive 66 Gy in 30 fractions,
with no attempt to cover remainder of initial GTV. There will be no CTV1 in CR patients.

Intermediate-Risk Target CTV2: This volume encompasses all initial primary and nodal GTV
volumes, regions adjacent to GTV (e.g. contralateral base of tongue), as well as complete
anatomic coverage of involved cervical neck levels. This will receive 57 Gy in 30 fractions.

Prophylactic Target Coverage CTV3: This volume covers all uninvolved at-risk nodal basins.
This will receive 54 Gy in 30 fractions.

Low Neck Conventional Field Treatment: Bilateral low neck/supraclavicular fossae will
initially be treated with a beam-split AP field to 40 Gy in 20 fractions with a 3x3 cm larynx
block matched at central axis with the inferior edge of IMRT treatment fields. Treatment will
then continue to 50 Gy with a midline cord block over 5 daily fractions. Cone-down AP mid
neck boosting to 56 Gy will be administered to low neck CTV2, down to the superior edge of
the clavicle. Treatment will continue to 64 Gy for low neck CTV1 volumes, respecting brachial
plexus dose limitations.

Dose specification The prescription dose is the isodose which encompasses at least 95% of the
PTV. No more than 20% of any PTV will receive >110% of its prescribed dose. No more than 1%
of any PTV will receive <93% of its prescribed dose. No more than 1% or 1 cc of the tissue
outside the PTVs will receive >110% of the dose prescribed to the primary PTV.

Fractionation and treatment duration Treatment will be delivered once daily, 5 fractions per
week, over 6 weeks. All targets will be treated simultaneously. Breaks in treatment should be
minimized. Break in treatment time of more than 5 days will be considered a major variation
and requires documentation underlying the specific reasons for the treatment break (ex.
related to study drug and/or chemotherapy and/or RT).

Functional Quality-of-Life Assessments Clinical Assessment of Treatment-Related Symptoms, and
Dietary Status: MDASI-HN and MDADI instruments will be self-administered by all study
subjects at baseline, treatment completion, and at routine post-radiation surveillance
appointments over the subsequent 24 months. At these time points, nutritional status will
also be assessed by weight, normalcy of diet score based on the results of the PSS-HN, and
feeding tube dependence for any amount of nutritional intake (yes/no). The radiation oncology
research nurse will oversee subject completion of these instruments.

MD Anderson Dysphagia Inventory (MDADI): The MDADI measures swallowing-related quality of
life (QOL) in patients with swallowing dysfunction. It evaluates the patient's physical,
emotional, and functional perceptions of swallowing dysfunction, and has been validated in
head and neck cancer patients.

Performance Status Scale for Head and Neck Cancer Patients (PSS-H&N): The PSS-H&N is a
clinician rated instrument consisting of three subscales: 1) normalcy of diet, 2) public
eating, and 3) understandability of speech. The radiation oncology research nurse or
speech-language pathologist will complete the PSS-H&N.

Modified Barium Swallow (MBS) Study: Patients will undergo MBS testing at baseline, 4-6, 12,
and 24 months after the completion of ART. Studies will be performed using standard
radiographic systems with a videofluoroscope focused on the patient's lips anteriorly, the
posterior pharyngeal wall posteriorly, the hard palate superiorly, and the upper esophageal
segment inferiorly. The order of bolus presentation will include: two 5-ml Varibar thin
liquid boluses, two 10-ml Varibar thin liquid boluses, two 20-ml Varibar thin liquid boluses,
two cup sips of Varibar thin liquid, two pureed/Varibar pudding boluses, two solid boluses
consisting of ¼ of a shortbread cookie or cracker coated with Varibar pudding, and 2 trials
of the most difficult consistency in the A-P plane. The following measures will be used to
quantify MBS findings: (1) Penetration-Aspiration Scale (PAS) - The PAS is a clinician rated
8-point, ordinal scale used to describe penetration and aspiration events. Scores are
determined by depth of bolus invasion into the airway and the patient's response; a higher
score is assumed to be a more severe sign of dysphagia. Intra- and interjudge reliability has
been established in head and neck cancer patients. (2) Oropharyngeal swallow efficiency -
(OPSE) is a global measure of swallow function defined as the ratio of the percent swallowed
into the esophagus divided by oropharyngeal transit time. Thus, a higher OPSE score indicates
a safer and more efficient oropharyngeal swallow. The continuous score obtained has been
found to correlate with the degree of oropharyngeal dysphagia in head and neck cancer
patients. (3) National Institutes of Health Swallowing Safety Scale (NIH-SSS) - The NIH-SSS
provides a continuous numeric score to quantify swallowing safety using 7 dysphagia symptoms,
residue, penetration, aspiration, response to aspiration, esophageal entry, regurgitation,
and multiple swallows. The scale demonstrates high reliability (intra- and interrater
intraclass correlation coefficient >.95) and validity in dysphagic patients. We are
concurrently evaluating its utility in patients with head and neck cancer. The speech
pathologist will complete the PAS, OPSE, and NIH-SSS during analysis of the MBS study.

Salivary Flow Quantification: For unstimulated resting sialometry, each patient will be
instructed to first clear the mouth by swallowing. With the head held slightly forward, the
patient will be instructed not to swallow during the 5-minute collection, but to allow saliva
to collect in the floor of mouth. The patient will expectorate the accumulated saliva into a
pre-weighed 100 mL vial after 60 seconds. The patient will repeat this procedure 4 more times
for a total collection time of 5 minutes. At the end of the 5 minutes, the collection vial
will be promptly sealed and weighed. For each collection, the actual clock time at the start
and end of the collection will be recorded as well as the vial weight before and after the
collection of the sample. Stimulated sialometry will then be performed. Patients will rest
for 5 minutes prior to collection. The exogenous stimulant will be 20 mL of citric acid
solution held in the mouth for 1 minute. After the patient expectorates this solution,
5-minute saliva collection will take place as described above. These measurements will be
done by the radiation oncology research nurse.

Inclusion Criteria:

- Tumor tissue available from primary or nodal metastasis for histological analysis.

- High p16 tumor expression by IHC, or indeterminate p16 expression by IHC and
definitively positive detection of high-risk HPV infection by ISH.

- T-stage = T1-3 or post-tonsillectomy Tx (T1-3).

- N-stage = N1-2 or Nx (N1-2).

- Biopsy-confirmed oropharyngeal primary site.

- Histology = squamous cell carcinoma, basaloid-squamous carcinoma, nasopharyngeal-type
squamous carcinoma, adenosquamous carcinoma, or papillary squamous carcinoma.

- Age > 17 years old.

- Patients should have adequate bone marrow function defined as an absolute peripheral
granulocyte count (AGC at least 1500 cells/mm3 and platelet count at least 100,000
cells/mm3); adequate hepatic function with bilirubin less than 1.5x ULN (excluding
Gilbert's disease); SGOT, SGPT and alkaline phosphatase must be within the normal
range to be eligible for study.

- Creatinine clearance at least 70 ml/min determined by 24 hour collection or nomogram:
CrCl male = (140 - age) x (wt in kg)/serum Cr x 72; CrCl female = 0.85 x (CrCl male).

- Patients must have an untransfused hemoglobin of at least 9.0 grams/dL.

- Patients should have no serious acute or chronic co-morbid condition, or acute
infection, which in the judgment of the attending physician would affect
administration of the induction chemotherapy regimens.

- Patients must sign a study-specific informed consent form.

- All of the above lab criteria must be verified within 28days of registration.

Exclusion Criteria:

- Low p16 expressing tumor by IHC, or indeterminate p16 expression by IHC and negative
or weak detection of high-risk HPV infection by ISH.

- TxNx without residual measurable disease, T4, or N3 disease.

- Significant cigarette smoking history, defined as >10 pack-years total lifetime
exposure. Pack years is calculated as # packs smoked per day x # years smoking.

- Histology other than squamous cell carcinoma.

- Proven distant metastases (below the clavicle) by clinical or radiographic measures.

- Karnofsky performance status < 80 or ECOG >1.

- Prior chemotherapy, within the previous 3 years.

- Prior radiotherapy to the head and neck.

- Initial surgical resection rendering the patient clinically and radiologically disease
free.

- Simultaneous primary invasive cancers, excluding superficial non-melanoma skin
cancers.

- Patients with a history of another malignancy (excluding non melanoma skin cancers,
and cancers treated > 3 years prior for which patient remains continuously disease
free).

- Men and women of childbearing potential (WOCBP) unwilling to consent to using
effective contraception while on treatment and for at least 3 months thereafter. Note:
WOCBP must be using an adequate method of contraception to avoid pregnancy throughout
the study and for 3 months after the study in such a manner that the risk of pregnancy
is minimized.