Randomized Phase II Study of DCE-MRI-based Dose Escalation for Poor-prognosis and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
This study aims to improve locoregional control of poor prognosis Head and Neck Cancer (HNC) patients by selectively escalating the radiotherapy dose to subvolumes of tumor likely to be resistant to standard Radiation Therapy (RT) using DCE-MRI (Dynamic Contrast Enhanced Magnetic Resonance Imaging). Standard doses of radiotherapy to the rest of the tissues and surrounding normal tissues will be maintained.

Official Title
-----------------
Randomized Phase II Study of DCE-MRI-based Dose Escalation for Poor-prognosis and Neck Cancer

Conditions
-----------------
Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
-----------------
* Drug: Cisplatin
* Drug: Carboplatin
* Radiation: IMRT (Intensity-Modulated Radiation Therapy)
* Radiation: Boost Radiation to Hypoperfused Volumes


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have pathologically-confirmed, non-metastatic locally/regionally advanced squamous cell carcinoma of the head and neck, stage III/IV, referred for definitive chemo-RT, and meet one of the following six criteria: Primary tumor (T4) with or without metastatic lymph nodes. Tumor or nodes are: unresectable, resection is considered by the treating surgeon or patient to result in unacceptable functional or oncological results, patient refuses surgery, or surgery is not possible due to comorbidities. HPV(-) (Human Papillomavirus) or p16(-) locally/regionally advanced (T3-4 or N2-3) oropharyngeal cancer. HPV(+) or p16(+) locally/regionally advanced (T4 or N3) oropharyngeal cancer. T3 or T4 laryngeal or hypopharyngeal cancer that is locally advanced, bulky (>40 cc*), unresectable, or patient declines surgery. Stage III/IV oral cavity or paranasal sinus cancers in patients who refuse surgery or are unfit for surgery. Locally/regionally advanced (stage T3-4 and/or N3) nasopharyngeal cancer which is EBV (-) (Epstein-Barr Virus). KPS (Karnofsky Performance Status: A measure of general well being and activities of daily living; scores range from 0 to 100 where 100 represents perfect health) >70 (see Appendix A) within two weeks of enrollment. Pre-treatment laboratory criteria within four weeks of enrollment: WBC (White Blood Cell) > 3500/ul, granulocyte > 1500/ul. Platelet count > 100,000/ul. Total Bilirubin < 1.5 X ULN. AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) < 2.5 X ULN. Estimated Creatinine clearance >30cc/min. Patients must be able to receive protocol chemotherapy in the judgment of the treating Medical Oncologist. Patients are adults (Age ≥18). All patients must be informed of the investigational nature of this study and given written informed consent in accordance with institutional and federal guidelines. Exclusion Criteria: EBV (+) Nasopharyngeal Carcinoma in the protocol treated tumor. Prior head and neck radiation. Documented evidence of distant metastases. Patients with active infection. Pregnant women. Patients should have no contraindications to having a contrast enhanced MRI scan. These contraindications will be assessed at the time of enrollment using the guidelines set up and in clinical use by the Institutional Standard Practice.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Arm<br>Standard chemotherapy (Cisplatin or Carboplatin) and IMRT (Intensity-Modulated Radiation Therapy) | Drug: Cisplatin<br>* Cisplatin 40mg/m2 administered as an IV infusion prior to radiotherapy on day 1 of each week of chemo-irradiation<br>Drug: Carboplatin<br>* Patients considered medically unfit to receive Cisplatin as determined by the prescribing physician, will receive Carboplatin via IV infusion on day 1 of each week of chemo-irradiation<br>Radiation: IMRT (Intensity-Modulated Radiation Therapy)<br> <br> |
| Experimental: Boost Arm<br>Boost radiation to hypoperfused/low-diffusion volumes in addition to standard chemotherapy (Cisplatin or Carboplatin) and IMRT (Intensity-Modulated Radiation Therapy) | Drug: Cisplatin<br>* Cisplatin 40mg/m2 administered as an IV infusion prior to radiotherapy on day 1 of each week of chemo-irradiation<br>Drug: Carboplatin<br>* Patients considered medically unfit to receive Cisplatin as determined by the prescribing physician, will receive Carboplatin via IV infusion on day 1 of each week of chemo-irradiation<br>Radiation: IMRT (Intensity-Modulated Radiation Therapy)<br> <br> Radiation: Boost Radiation to Hypoperfused Volumes<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DSF) time | Kaplan-Meier curves with point-wise 90% confidence intervals will be generated for each treatment arm, overall and by strata. Estimates with confidence intervals will be generated from these curves for the usual summary statistics, including median DFS times and DFS at 1, 2, and 3 years. | 3 years post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local-regional control rate | Compare local-regional control rates between the two arms at 1, 2 and 3 years. Local-regional control is defined as the absence of local-regional progression. | 3 years post-treatment | 
| Proportion of patients in which hypoperfused/low-diffusion subvolumes overlap with recurrence volumes |  | 3 years post treatment | 
| Number of patients with adverse events | Acute and late toxicities will be summarized descriptively by grade and type for each treatment group. The proportion of patients experiencing certain toxicity types will be calculated with score based confidence intervals. Chi-square tests will be used to test whether the proportion of patients with toxicity differs between treatment groups. | 3 years post treatment | 
| Correlation coefficient between continuous dose and perfusion summary measures | Pearson or Spearman rank based correlation between the continuous dose and perfusion summary measures | 2 weeks post Radiation Therapy (RT) |