Stereotactic Boost and Short-course Radiation Therapy for Oropharynx Cancer

Study Overview
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Brief Summary
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This is a randomized clinical trial comparing the outcomes of short-course chemoradiation consisting in stereotactic boost to the gross tumor and de-esclalated chemoradiation to the elective neck in human papilloma associated oropharynx cancer vs. the current standard 7-week course chemoradiation.

Detailed Description
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Concurrent platinum-based chemoradiation remains the standard of care in locally advanced head and neck cancer. The current standard radiation regimen consists in a 7-week course of conventionally fractionated radiotherapy to the gross tumor volume (GTV), along with bilateral prophylactic neck irradiation to an elective dose of   50 Gy in 2 Gy per fraction. In addition to being cumbersome, the current protracted daily radiation course is associated with high rates of acute and late toxicities and significant deterioration of patients' quality of life. In the light of the remarkably improved prognosis of the distinct subgroup of HPV-OPC, there is growing interest for treatment de-intensification strategies in contemporaneous OPC cohorts. Stereotactic ablative radiotherapy (SABR) allows for ultra-precise delivery of ablative radiation dose over a small number of fractions, by combining sharp dose gradients with use of optimal image guidance. The increased conformity and reduced margins used in SABR can substantially reduce the dose to surrounding organs at risk and could therefore reduce toxicity. In addition, previous work has shown that an elective dose of 40 Gy in 2 Gy per fraction, in conjunction with chemotherapy, is sufficient for microscopic sterilisation of cancer cells and can translate into a reduction of toxicities. The goal of this trial is to compare the efficacy and safety of short-course chemoradiation consisting in stereotactic boost to the gross tumor of 14 Gy in 2 fractions followed by de-esclalated chemoradiation (40 Gy in 20 fractions and concurrent 2 cycles of Cisplatin 100mg/m2) in human papilloma associated oropharynx cancer vs. the current standard 7-week course chemoradiation (70 Gy in 33 fractions with 2-3 cycles of Cisplatin 100mg/m2). This is an open label randomized phase II trial with 2 planned interim safety (toxicity) analysis and 1 futility (locoregional control) analysis with go/no go decision to pursue the study based on probabilities of toxicities and LRC (Bayesian adaptive design). Patients will be randomized using a 1:1 ratio between the standard and the experimental arm and will be stratified by tumor stage. At the significance level of 0.2 and assuming the LRC rate of 90% for both experimental and control arms, 80% for the non-inferiority test with the margin of 10%, and 6% attrition rate, a total of 106 patients will be enrolled.

Official Title
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Stereotactic Boost and SHOrt-course Radiation Therapy for HPV-associated OroPharynx Cancer Trial: A Randomized Multicentric Phase II Trial

Conditions
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Head and Neck Cancer, Oropharynx Cancer, Human Papilloma Virus

Intervention / Treatment
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* Radiation: SABR boost and de-escalated chemoradiation
* Radiation: Standard chemoradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Ability to provide written informed consent. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Biopsy proven diagnosis of squamous cell carcinoma of the oropharynx. Positive for HPV by p16 immunohistochemistry (IHC) or HPV in-situ hybridization (ISH) Clinical stage T1-3, N1 M0 (Stage I-II) as per AJCC 8th edition. Primary tumor < 30 cc Planned for curative chemoradiation For females of child-bearing age, a negative pregnancy test Exclusion Criteria: Previous irradiation of the head and neck (HNC) region Previous surgery of the HNC region (except for incisional or excisional biopsies) Pregnancy or breastfeeding Connective tissue disease Any medical condition that could, in the opinion of the investigator, prevent follow-up after radiotherapy. Non-Cisplatin concurrent chemotherapy Prior induction 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: SABR boost and de-escalated chemoradiation<br>SABR boost of 14 Gy in 2 fractions to the GTV, immediately followed by de-escalated chemoradiation. De-escalated chemoradiation will consist in 40 Gy in 20 fractions with concurrent high dose Cisplatin (3-weekly, 100 mg/m2) for 2 cycles, aiming for a cumulative dose of 200 mg/m2. | Radiation: SABR boost and de-escalated chemoradiation<br>* Stereotactic body radiotherapy boost to the gross tumor volume to a dose of 14 Gy in 2 fractions, followed by cisplatin-based chemoradiation to a dose of 40 Gy in 20 fractions<br>|
| Active Comparator: Standard chemoradiation<br>The standard arm will consist of conventionally radiation to a dose of 70 Gy in 33 fractions concurrently with high dose Cisplatin (3-weekly, 100 mg/m2) for 2-3 cycles, aiming for a cumulative dose of ≥ 200 mg/m2. | Radiation: Standard chemoradiation<br>* Standard Cisplatin-based chemoradiation to a dose of 70 Gy in 33 fractions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional control | Patient alive with locoregional control at 2 years after the end of chemoradiation | 2 years after the end of chemoradiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subacute toxicity | Rate of grade ≥ 3 subacute toxicity | Between 2 and 6 months after the end of chemoradiation | 
| Acute toxicity | Rate of grade ≥ 3 acute toxicity | Less than 2 months after the end of chemoradiation | 
| Late toxicity | Rate of grade ≥ 3 late toxicity | Between 6 months and 5-years after the end of chemoradiation | 
| OS | Overall survival | At 2- and 5-years after the end of chemoradiation | 
| PFS | Progression free survival | At 2- and 5-years after the end of chemoradiation | 
| Head and neck symptom burden | Patient-reported head and neck symptom burden as measured by the MD Anderson Symptom Inventory Head and Neck Cancer Module. The core and head and neck cancer specific symptoms are rated on a 0-10 scale to indicate the presence and severity of the symptoms. Lower scores represent better functioning and quality of life. | At baseline, and 1-, 3-, 6-, 12- months post-treatment, and yearly from years 2-5 after the end of chemoradiation | 
| Dysphagia | Patient-reported dysphagia as measured by the MD Anderson Dysphagia Index. Overall score ranges from 0 to 100, with higher score representing better functioning and quality of life. | At baseline, and 1-, 3-, 6-, 12- months post-treatment, and yearly from years 2-5 after the end of chemoradiation | 
| Time from treatment start to return to work | Time from first day of treatment start to first day of return to work. | Measured in days and reported at 2-years post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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head and neck cander, Oropharynx cancer, Human papilloma virus, Radiotherapy, Stereotactic body radiotherapy, Chemotherapy, De-intensification