De-intensification of Radiation and Chemotherapy for Low-Risk HPV-related Oropharyngeal SCC: Follow-up Study

Study Overview
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Brief Summary
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The purpose of this research study is to learn about the effectiveness of using lower-intensity radiation and chemotherapy to treat human papillomavirus (HPV) associated low-risk oropharyngeal and/or unknown primary squamous cell carcinomas of the head and neck. The cure rate for this type of cancer is estimated to be high, > 90%. The standard treatment for this cancer is 7 weeks of radiation with 3 high doses of cisplatin. Sometimes surgery is performed afterwards. This standard regimen causes a lot of side effects and long term complications. This study is evaluating whether a lower dose of radiation and chemotherapy may provide a similar cure rate as the longer, more intensive standard regimen. Patients in this study will receive 1 less week of radiation and a lower weekly dose of chemotherapy.

Detailed Description
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The proposed study is a follow-up study to NCT01530997. In NCT01530997, patients with HPV positive and/or p16 positive low-risk oropharyngeal squamous cell carcinoma (OPSCC) received de-intensified chemoradiotherapy (CRT) followed by a limited surgical evaluation. The primary endpoint of NCT01530997 was the rate of pathological complete response (pCR) after CRT. Power computations were performed for N=40 and were based on the null hypothesis (H0) that the pCR for de-intensified chemoradiotherapy is at least 87%, the historical rate. The type 1 error for this calculation was 14.2%. 43 patients enrolled and 38 were evaluable for the primary endpoint. The observed pCR rate was 89% (34/38). Since the observed pCR rate was excellent in NCT01530997 and was in concordance with the expected rate, in the proposed study we will not mandate a post-CRT surgical evaluation. Instead a PET/CT 10 to 16 weeks post-CRT will be used to determine whether a surgical evaluation is needed.

Official Title
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De-intensification of Radiation and Chemotherapy for Low-Risk HPV-related Oropharyngeal Squamous Cell Carcinoma

Conditions
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Carcinoma, Squamous Cell, Head and Neck Neoplasms, Oropharyngeal Neoplasms

Intervention / Treatment
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* Radiation: Intensity Modulated Radiotherapy (IMRT)
* Drug: Cisplatin (or alternative)
* Procedure: Assessment for surgical evaluation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age (no upper age limit) T0-3, N0 to N2c, M0 squamous cell carcinoma of the oropharynx Biopsy proven squamous cell carcinoma that is HPV and/or p16 positive ≤ 10 pack-years smoking history or ≤ 30 pack-years smoking history WITH ≥ 5 years abstinence from smoking Radiologic confirmation of the absence of hematogenous metastasis within 12 weeks prior to treatment ECOG Performance Status 0-1 CBC/differential obtained within 8 weeks prior to treatment, with adequate bone marrow function defined as follows: Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl. Adequate renal and hepatic function within 4 weeks prior to registration, defined as follows: Serum creatinine < 2.0 mg/dl; Total bilirubin < 2 x the institutional ULN; AST or ALT < 3 x the institutional ULN. Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential Women of childbearing potential and male participants who are sexually active must practice adequate contraception during treatment and for 6 weeks following treatment. Patients must be deemed able to comply with the treatment plan and follow-up schedule. Patients must provide study specific informed consent prior to study entry Exclusion Criteria: Prior history of radiation therapy to the head and neck Prior history of head and neck cancer. Unresectable disease (e.g. immobile node on physical exam, nodal disease that radiographically involves the carotid arteries, nerves) Currently taking Disease Modifying Rheumatoid Drugs (DMRDs) Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects (Note, however, coagulation parameters are not required for entry into this protocol); Pre-existing ≥ grade 2 neuropathy; Prior organ transplant; Systemic lupus; Psoriatic arthritis. Known HIV positive.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: De-escalated Radiation and Chemotherapy<br>Patients will receive Intensity Modulated Radiotherapy Treatments (IMRT), 60 Gy at 2 Gy/fx. The acceptable weekly chemotherapy regimens are Cisplatin 30 to 40 mg/m2 (first choice), Cetuximab 250mg/m2 (second choice), Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 (third choice), Carboplatin AUC 3 (fourth choice). Chemotherapy will be given intravenously weekly during IMRT, 6 total doses. Chemotherapy will not be given to patients with T0-2 N0-1 disease, ≤ 10 pack years smoking history. Decision for surgical evaluation will be based on the results of the PET/CT and clinical exam 10-16 weeks after CRT. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon. Patients with a negative PET/CT scan will be observed. | Radiation: Intensity Modulated Radiotherapy (IMRT)<br>* All patients will receive Intensity Modulated Radiotherapy Treatments (IMRT). Dose painting IMRT will be used and all doses will be specified to the planning target volume (PTV). The high risk planning target volume (PTV-HR) and standard risk planning target volume (PTV-SR) will be treated to the following respective total doses: 60 Gy and 54 Gy. The dose per fraction to the PTV-HR and PTV-SR will be 2 Gy per day and 1.8 Gy per day respectively. The PTV-HR will include the gross tumor and the PTV-SR will include areas at risk for harboring subclinical microscopic disease.<br>Drug: Cisplatin (or alternative)<br>* Cisplatin is the preferred mandated first choice chemotherapy, however alternative weekly regimens are permissible. Justification for not using cisplatin must be documented. Chemotherapy will be given intravenously weekly during IMRT. 6 total doses will be given. It is preferred that the doses be administered on days 1, 8, 15, 22, 29, and 36; however, this is not mandatory. Chemotherapy will not be given to patients with T0-2 N0-1 disease, ≤ 10 pack years smoking history.<br>Procedure: Assessment for surgical evaluation<br>* Decisions for surgical evaluation will be based on the results of the PET/CT 10 to 16 weeks after CRT and clinical exam (including fiberoptic laryngoscopy) at that time. Other optional imaging studies may be performed. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon, with the goal being to remove any suspected residual tumor with a negative resection margin while maintaining organ preservation. This may include biopsies and/or oncological resections of the primary tumor and lymph node metastases. Patients with a negative PET/CT scan will be observed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2 Year Progression Free Survival After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC) | Progression Free Survival (PFS) was defined as the time from the beginning of treatment to cancer progression or death. The outcome measure will be reported as the proportion of patients with PFS at 2 years post-treatment. | Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2 Year Local Control (LC) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC) | The outcome measure will be reported as the proportion of patients with LC at 2 years post-treatment. | Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks). | 
| 2 Year Regional Control (RC) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC) | The outcome measure will be reported as the proportion of patients with RC at 2 years post-treatment. | Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks). | 
| 2 Year Local-regional Control (LRC) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC) | The outcome measure will be reported as the proportion of patients with LRC at 2 years post-treatment. | Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks). | 
| 2 Year Distant Metastasis Free Survival (DMFS) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC) | The outcome measure will be reported as the proportion of patients with DMFS at 2 years post-treatment. | Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks). | 
| 2 Year Overall Survival (OS) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC) | The outcome measure will be reported as the proportion of patients who are still alive (overall survival) at 2 years post-treatment. | Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks). | 
| Head and Neck Quality of Life Assessments |  | Within 2 weeks prior to CRT, weekly during CRT, 10-16 weeks after CRT, follow-up visits every 2 months after CRT for 2 years, then every 6 months for 3 years, then yearly, up to 10 years. | 
| Speech and Swallowing Function |  | Within 2 weeks prior to CRT, 6-8 weeks after CRT, 6 months after CRT (MBS); Within 2 weeks prior to CRT, 10-16 weeks after CRT, follow-up visits every 2 months after CRT for 2 years, then every 6 months for 3 years, then yearly (EAT-10), up to 10 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Papillomavirus, Oropharynx, Oropharyngeal Squamous Cell Carcinoma, Squamous Cell Carcinoma, Radiation Therapy, Chemotherapy, p16