RTOG 1216 RANDOMIZED PHASE II/III TRIAL OF SURGERY AND POSTOPERATIVE RADIATION DELIVERED WITH CONCURRENT CISPLATIN VERSUS DOCETAXEL VERSUS DOCETAXEL AND CETUXIMAB FOR HIGH-RISK SQUAMOUS CELL CANCER OF THE HEAD AND NECK

Summary

The proposed randomized phase ii-iii trial will address several important issues in head and neck cancer. approximately 50% of head and neck cancer patients undergo primary surgery for their malignancy. For those with high-risk clinical and pathologic features (eg bone destruction, extracapsular nodal extension, tumor involving resection margins) [Peters 1993; ang 2001;Bernier 2005), the local-regional failure rates remain high and efforts to reduce recurrence include the use of postoperative radiation, and more recently, postoperative chemoradiation. The beneficial impact of adding cisplatin chemotherapy to radiation in the high-risk setting is modest and is accompanied by significant incremental toxicity (including ototoxicity, nephrotoxicity, neutropenia, nausea, and other). a substantial cohort of head and neck cancer patients do not tolerate and cannot successfully complete the regimen of 100 mg/m2 cisplatin every 3 weeks during radiation. Meanwhile, the RToG has conducted several phase ii studies testing the optimal regimen delivered with radiation in the postoperative setting and have identified the docetaxel-cetuximab regimen as the most promising to date.
This study will therefore address the question whether docetaxel alone is as active as docetaxel and cetuximab combination and whether either taxane-based regimen is better than cisplatin monotherapy given to this high-risk group of patients with concurrent radiation. The less toxic weekly cisplatin regimen is selected to enhance compliance in the control arm and to parallel to weekly regimen proposed for the 2 experimental arms. if positive, this study will provide a new standard of care with a non-cisplatin regimen for patients with high-risk head and neck squamous cell carcinoma in the postop setting.

Translational Research
This trial enrolls advanced stage head and neck cancer patients who are treated with primary
surgical resection. This affords a critical opportunity to collect valuable tissue specimens for
correlative biomarker analyses to test specific hypotheses. The proposed correlative studies for
the proposed trial will assist in the development of tissue-based biomarkers to identify patients
who would benefit from each treatment regimen and those who are at high risk for relapse for
future treatment intensification.
We plan to: 1) utilize archival formalin fixed paraffin embedded (FFPe) tumor tissues (either as
tumor blocks, tumor cores or tumor section) that are collected at the time of surgical resection to
construct tissue microarrays (TMas) and for p53 mutational analysis 2) obtain plasma and
serum samples from all participating patients prior to starting radiation (RT). Since the blood
samples will be obtained after removal of all gross disease, they are unlikely to provide useful
biomarkers for prognosis. However, they will be important for addressing future questions on
normal tissue toxicity, once such markers are identified from other studies.

Participant Eligibility

For questions concerning eligibility, contact RTOG DATA Management (via the RTOG contact list on the RTOG web site) or the Co-Principal Investigators, Dr.s Harari and Rosenthal (see the title page of the protocol for contact information)

3.1 Conditions for Patient Eligibility (2/19/13)
3.1.1 Pathologically (histologically or cytologically) proven diagnosis of head and neck squamous cell carcinoma (HNSCC) involving the oral cavity, oropharynx (p16 negative), larynx, or hypopharynx
within 49 days of registration;
3.1.2 Patients must have undergone gross total surgical resection of high-risk oral cavity, oropharynx (p16 negative), larynx, or hypopharynx within 49 days prior to registration.
Note: Patients may
have biopsy under general anesthesia in an operating room followed by definitive ablative cancer
surgery representing gross total resection. The gross total resection has to be done within 49
days prior to registration. If, however, patients have ablative resection but shortly recur or are
determined to have persisting disease requiring re-resection to achieve gross total resection, then
the patient is not eligible.
3.1.3 Patients must have at least 1 of the following high-risk pathologic features: extracapsular nodal extension or invasive cancer seen within 3 mm of the primary tumor resection margins.
3.1.4 Pathologic stage III or IV HNSCC, including no distant metastases, based upon the following
minimum diagnostic workup:

* General history and physical examination by a Radiation Oncologist and/or Medical
Oncologist within 84 days prior to registration;

* Examination by an ENT or Head & Neck Surgeon, prior to surgery; a
laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) if appropriate is recommended but
not required. Intra-operative examination is acceptable documentation

* Pre-op Imaging within 63 days of registration: Either a CT (with contrast) or CT/PET and/or an MRI (T1 with Gadolinium and T2) of the neck within 84 days prior to registration; note: this imaging data (diagnostic pre-operative scan showing gross
disease) is to be submitted on a CD in DICOM format to RTOG Headquarters, Attention
RTQA, with the report; see Section 11.2.

* Chest CT scan (with or without contrast) or CT/PET of chest (with or without contrast) within
84 days prior to registration.
3.1.5 Zubrod Performance Status of 0-1 within 14 days prior to registration;
3.1.6 Age >= 18;
3.1.7 CBC/differential obtained within 28 days prior to registration on study, with adequate bone
marrow function defined as follows:

* Absolute granulocyte count (AGC) >= 1,500 cells/mm3;

* Platelets >= 100,000 cells/mm3;

* Hemoglobin >= 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb >=
8.0 g/dl is acceptable).
3.1.8 Adequate hepatic function, defined as follows:

* Total bilirubin < 2 x institutional ULN within 14 days prior to registration;

* AST or ALT < 3 x institutional ULN within 14 days prior to registration.
3.1.9 Adequate renal function, defined as follows:

* Serum creatinine institutional ULN within 14 days prior to registration or;
creatinine clearance (CC) >= 50 ml/min within 14 days prior to registration determined by 24-
hour collection or estimated by Cockcroft-Gault formula:

CCr male = [(140 x age) x (wt in kg)]
[(Serum Cr mg/dl) x (72)]

CCr female = 0.85 x (CrCl male)
3.1.10 Negative urine or serum pregnancy test within 14 days prior to registration for women of childbearing
potential;
3.1.11 The following assessments are required within 14 days prior to registration: Na, K, Cl, glucose,
Ca, Mg, and albumin. Note: Patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may
receive corrective magnesium supplementation but should continue to receive either prophylactic
weekly infusion of magnesium and/or oral magnesium supplementation (eg, magnesium oxide) at
the investigator[Single Quote]s discretion.
3.1.12 Patients with feeding tubes are eligible for the study.
3.1.13 Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control;
3.1.14 Patient must provide study specific informed consent prior to study entry, including consent for mandatory tissue submission for EGFR analysis and for oropharyngeal cancer patients, HPV
analysis.