Hypofractionated Radiation Therapy Followed by Surgery in Treating Patients With Advanced Squamous Cell Carcinoma of the Oral Cavity

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studies how well hypofractionated radiation therapy followed by surgery works in treating patients with squamous cell carcinoma of the oral cavity that has spread to other places in the body. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving hypofractionated radiation therapy before surgery may shrink the tumor making it easier to be removed, may reduce the risk of the cancer coming back, and may be a better treatment for squamous cell carcinoma of the oral cavity.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. 2 year locoregional control for advanced oral cavity squamous cell carcinoma (SCC) treated with preoperative hypofractionated radiation followed by surgical resection. SECONDARY OBJECTIVES: I. Rate of pathologic complete response after preoperative hypofractionated radiation at both the primary site and lymph nodes (LN). II. Rate of radiologic complete and partial response (computed tomography [CT] neck with intravenous [IV] contrast performed before and after radiation therapy, judged per Response Evaluation Criteria In Solid Tumors [RECIST] 1.1 criteria). III. Grade III/IV/V toxicity both short term (from start of radiation to 60 days after surgery) and long term (more than 60 days after surgery). IV. Rate of flap complications: Rate of flap revisions, and complete revisions required. V. Molecular correlates. VI. Quantitative imaging correlates. OUTLINE: Patients undergo hypofractionated intensity-modulated radiation therapy (IMRT) every other day for up to 5 treatments. Patients then undergo surgery 7-14 days after the last radiation treatment. After completion of study treatment, patients are followed up every 3 months for 2 years.

Official Title
-----------------
Preoperative Hypofractionated Radiation Followed by Surgery in Advanced Oral Cavity Squamous Cell Carcinoma

Conditions
-----------------
Tongue Cancer, Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage III Verrucous Carcinoma of the Oral Cavity, Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVA Verrucous Carcinoma of the Oral Cavity, Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVB Verrucous Carcinoma of the Oral Cavity

Intervention / Treatment
-----------------
* Radiation: hypofractionated radiation therapy
* Radiation: intensity-modulated radiation therapy
* Procedure: therapeutic conventional surgery
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient is willing to sign study specific informed consent Pathologically proven (histologically or cytologically) diagnosis of squamous cell carcinoma (including histological variants like papillary squamous cell carcinoma and basaloid squamous cell carcinoma) Advanced stage but not metastatic SCC of the oral cavity (III or IVa, b); sites in the oral cavity include oral tongue, floor of mouth, hard palate, gingiva, buccal mucosa, retromolar trigone; often, head & neck tumors may involve other adjacent sites, such as the oropharynx- in these cases, the criteria is that the tumor must appear to have originated in the oral cavity per ear, nose, and throat (ENT)/radiation oncology Patient is deemed to be a surgical candidate by ENT Karnofsky performance status (KPS) 0-2 For women of childbearing potential, a negative serum pregnancy test completed prior to any radiation therapy Patients with human immunodeficiency virus (HIV) infection are not automatically excluded, but must meet the following criteria: cluster of differentiation 4 (CD4) count is > 499/cu mm and their viral load is < 50 copies/ml; use of highly active antiretroviral therapy (HAART) is allowed Patient is free of any prior invasive malignancy (except non-melanomatous skin cancer) for a minimum of the past 3 years Exclusion Criteria: Metastatic disease beyond the neck or supraclavicular area as demonstrated by positron emission tomography (PET)/CT or biopsy KPS 3 or worse Gross disease in the retrostyloid (high level II) or retropharyngeal lymph node regions by CT or PET/CT Patients may not have received previous therapy for their head and neck SCC, including chemotherapy, radiation therapy, or surgery beyond biopsy Second primary malignancy; exceptions are 1) patient had a second primary malignancy but has been treated and disease free for at least 3 years, 2) in situ carcinoma (e.g. in situ carcinoma of the cervix), 3) non-melanomatous carcinoma of the skin Serious concomitant systemic disorders (including active infections) that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator; this includes scleroderma Women who are pregnant; women of childbearing age must agree to undergo a urine pregnancy test prior to therapy and to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 6 months after; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Patient is deemed to not be a surgical candidate by ENT

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Preoperative hypofractionated radiation followed by surgical resection
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (hypofractionated IMRT, surgery)<br>Patients undergo hypofractionated IMRT every other day for up to 5 treatments. Patients then undergo surgery 7-14 days after the last radiation treatment. | Radiation: hypofractionated radiation therapy<br>* Undergo hypofractionated IMRT<br>Radiation: intensity-modulated radiation therapy<br>* Undergo hypofractionated IMRT<br>* Other names: IMRT;Procedure: therapeutic conventional surgery<br>* Undergo surgery<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional control | Will be assessed using both clinical and radiographic means, and recurrence will be confirmed by biopsy. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of pathologic complete response after preoperative hypofractionated radiation at both the primary site and lymph nodes |  | Up to 2 years | 
| Rate of complete and partial response per imaging, judged per RECIST 1.1 criteria | CT neck with IV contrast will be performed before and after radiation therapy. | Up to 2 years | 
| Incidence of short term grade III/IV/V toxicity, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 | Interim analysis will be used for grade IV toxicity (death). | Up to 60 days post-surgery | 
| Incidence of long term grade III/IV/V toxicity, graded according to the NCI CTCAE, version 4.0 |  | Up to 2 years | 
| Rate of flap complications (rate of flap revisions and flap complete revisions required) |  | Up to 2 years | 
| Expression of molecular markers | Will correlate molecular markers (especially those relating to radioresitance such as B-cell lymphoma 2 or autophagy markers to locoregional control). | Up to 24 hours after initial radiation treatment | 
| Quantitative imaging characteristics in the pre-treatment PET/CT | Includes max/peak/total/mean standard uptake value, the metabolic tumor volume, and the total lesion glycolysis. These imaging findings will be correlated to clinical outcomes such as pathological response and locoregional control. | Baseline | 
| Changes from CT to CT (after radiation), such as changes in tumor volume or longest tumor diameter | These imaging findings will be correlated to clinical outcomes such as pathological response and locoregional control. | Baseline to up to 2 years |