Evaluation of De-escalated Adjuvant Radiation Therapy for Human Papillomavirus (HPV)-Associated Oropharynx Cancer

Study Overview
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Brief Summary
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This study is designed for patients with a cancer of the oropharynx (tonsils or base of tongue) caused by the HPV virus. Traditional treatment involves surgery followed by six weeks of daily radiation therapy. This study investigates a less intense radiation treatment following surgery that uses half the dose of radiation given over two weeks rather than six weeks. Patients will be randomly assigned to receive the less intense treatment versus the traditional treatment by coin flip. Patients are twice as likely to receive the less intense treatment during randomization.

Detailed Description
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Recent studies suggest that tumors in the oropharynx (tonsils or base of tongue) caused by the HPV virus are much more sensitive to radiation and chemotherapy. Standard treatment for HPV associated oropharynx tumor after surgery involves six weeks of radiation therapy and has many long term side effects and complications. Mayo Clinic recently piloted a study investigating whether patients with HPV-associated oropharynx tumors can receive less radiation and chemotherapy after surgery when compared with the standard treatment. The investigators current study will compare the new, shorter treatment course (2 weeks of treatment) with the standard course of treatment (six weeks). Patients will be randomized to either the less intense or standard treatment arm. Patients will be twice as likely to receive the less intense treatment during randomization.

Official Title
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DART-HPV: A Phase III Evaluation of De-escalated Adjuvant Radiation Therapy for HPV-Associated Oropharynx Cancer

Conditions
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Oropharynx Cancer

Intervention / Treatment
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* Radiation: Adjuvant Radiation Therapy
* Drug: Docetaxel
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Histological confirmation of HPV+ squamous cell carcinoma of the oropharynx. HPV positivity will be defined as positive staining for p16 on immunohistochemistry (IHC). Gross total surgical resection with curative intent of the primary tumor and at least unilateral neck dissection within 7 weeks of registration. ECOG Performance Status (PS) 0 or 1 Absence of distant metastases on standard diagnostic work-up ≤ 10 weeks prior to registration. (Chest CT, Chest x-ray (CXR), or PET/CT.) Must have one of the following risk factors: Lymph node > 3 cm 2 or more positive lymph nodes Perineural invasion Lymphovascular space invasion T3 or T4 primary disease Lymph node extracapsular extension The following laboratory values obtained ≥14 days prior to registration. Absolute neutrophil count (ANC) ≥1500/mm3 Platelet count ≥100,000/mm3 Hemoglobin ≥8.0g/dL Creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min Total bilirubin < 2 x institutional upper limit of normal (ULN) AST or ALT < 3 x institutional ULN Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only. Ability to complete questionnaire(s) by themselves or with assistance. Provide informed written consent. Willingness to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study). Exclusion Criteria: Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. Immunocompromised patients and patients known to be HIV positive. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm. Other active malignancy ≤ 5 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer. Prior history of radiation therapy to the affected site. History of connective tissue disorders such as rheumatoid arthritis, lupus, or Sjogren's disease. Presence of any of the following risk factors after surgery: Any positive surgical margin. Adenopathy below the clavicles Prior systemic chemotherapy. Receiving any medications or substances which in the opinion of the investigators would interfere with treatment. Examples could include strong inhibitors of CYP3A4 at oncologist discretion (see Appendix IV). Severe pre-existing ototoxicity or neuropathy that would, in the opinion of the investigator, preclude the use of cisplatin chemotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: De-escalated Adjuvant Radiation Therapy<br>Docetaxel 15 mg/m2 days 1, 8 + Radiation Therapy (RT) 30 Gy/1.5 Gy fractions twice daily (b.i.d.) days 1-12 only (intermediate risk) or 36 Gy/1.8 Gy b.i.d. fractions (high risk) | Radiation: Adjuvant Radiation Therapy<br>* 60 Gy / 2 Gy fractions (standard arm) 30 - 36 Gy / 1.5 - 1.8 Gy b.i.d. fractions (experimental arm)<br>Drug: Docetaxel<br>* 15 mg/m2. Experimental arm only.<br>* Other names: Taxotere;|
| Active Comparator: Standard of Care Treatment<br>RT 60 Gy/2 Gy fractions daily (qday) days 1-40. For high risk, add weekly Cisplatin 40 mg/m2 (Around days 1, 8, 15, 22, 29, 36) | Radiation: Adjuvant Radiation Therapy<br>* 60 Gy / 2 Gy fractions (standard arm) 30 - 36 Gy / 1.5 - 1.8 Gy b.i.d. fractions (experimental arm)<br>Drug: Cisplatin<br>* 40 mg/m2. Standard arm only.<br>* Other names: cisplatinum;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Rate | To compare rate of late grade 3-5 toxicities between de-escalated adjuvant radiation therapy (DART) and standard adjuvant therapy. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local/regional control | Local/regional failure as assessed by imaging or physical exam at 2 years after study registration for patients treated with DART vs standard therapy. | 2 years | 
| Quality of Life between DART and standard adjuvant therapy | To compare the overall QOL between DART and standard adjuvant therapy at 1-year post-treatment as measured by FACT H&N questionnaire. | 1 year | 
| Quality of Life between DART and standard adjuvant therapy | To compare the overall QOL between DART and standard adjuvant therapy at 1-year post-treatment as measured by the EORTC H&N quality of life questionnaire (QLQ) 35. | 1 year | 
| Overall Survival |  | 2 years | 
| Disease-free survival |  | 2 years | 
| Distant failure associated with DART vs standard treatment |  | 2 years |