Dose Escalation Using Hypoxia-adjusted Radiotherapy

Study Overview
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Brief Summary
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DE-HyART is a phase II clinical trial aimed at understanding the effects of escalating radiation doses to hypoxic sub-volumes inherent to squamous cell head and neck cancer. The study is aimed at assessing locoregional control, feasibility, and acceptable toxicity with such a strategy.

Detailed Description
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DE-HyART is a randomized, non-blinded study that assesses the effects of combining IMRT (using SIB-Sequential planning) with dose-escalation to hypoxic sub-volume delineated using [18-F] FMISO. The treatment protocol will also include concurrent chemotherapy with cisplatin at standard uniform dosing. Patients with HNSCC whose cancer is determined to originate from the oral cavity, oropharynx, larynx, and hypopharynx will be selected. The included patients will be subjected to [18F] FMISO scan, labeled as baseline FMISO. Depending upon the result of the baseline FMISO, the patient will be either hypoxic or anoxic. Patients exhibiting no hypoxia in their tumor will be labeled as Arm 1 and act as an external cohort. Patients with hypoxia will be randomized (1:1) into two arms - Arms 2 and 3. Both arms will be subjected to chemoradiation by IMRT and concurrent chemotherapy with cisplatin at 40mg/m2. In Arm 3, the trial arm will receive an additional 10 Gy @ 2 Gy per fraction in phase II (total 80 Gy) to the HSV + 5mm isotropic margin. One twenty-four patients will recruited in a 1:1 fashion between Arm 3 and Arm 2. The primary endpoint will be locoregional control and its possible increase in control.

Official Title
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A Phase II Randomised Controlled Study Assessing the Role of Dose Escalation Using [18F] FMISO PET CT in Head and Neck Cancer: The DE-HyART (Dose Escalation Using Hypoxia-adjusted Radiotherapy) Protocol

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Radiation: DE-HyART
* Radiation: Standard Arm
* Drug: Cisplatin injection
* Radiation: Standard fractionation (Radiation Oncology preference)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18 - 70 years Willingness to sign informed consent (written/video documentation) Performance status: ECOG 0 - 2 Histology proved - squamous cell carcinoma Any grade, gender Tumour sites: Oral Cavity, Oropharynx, Hypopharynx and Larynx Sufficient bone marrow reserve within the last 14 days. Hb: > 10g/dl (corrected) TLC: > 4,000 per cumm Platelet: >1.5Lakh per cumm Liver functions and kidney functions within normal limits Nutritional and dental assessment before inclusion into the study Exclusion Criteria: HPV (p16) positive tumours Prior surgery and/or radiation therapy given for any HNC T1/T2 Glottis Metastatic disease or disease not amenable for definitive locoregional treatment. Medical co-morbidity hampering the administration of radiation and/or chemotherapy (cisplatin) Pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Arm 3 - DE-HyART<br>The radiation dose will be similar to 'arm 2'. In addition, the HSV identified on baseline FMISO scans will be contoured, and an isotropic margin of 5 mm will be given. This volume will be boosted in phase II to a total dose of 80 Gy. (Addition of 30 Gy in 3 Gy daily fraction added in phase II as a simultaneous integrated boost - SIB). | Radiation: DE-HyART<br>* The HSV delineation will be done for patients in arm 3 using baseline FMISO. The HSV will be contoured and adjusted according to the second FMISO scan done between the 4th - the 5th week of radiation treatment. A planning CT will also be repeated at the time for adjusting the HSV to account for temporal changes. The Biological Target Volume thus generated after adequate margins will be prescribed 30 Gy in 10 fractions over and above the standard fractination.<br>* Other names: FMISO;Drug: Cisplatin injection<br>* Concurrent chemotherapy, weekly Inj Cisplatin 40mg/m2. This will be given if clinically indicated<br>|
| Active Comparator: Arm 2 - Hypoxic Comparator Arm<br>The prescribed radiotherapy dose will be 70 Gy in 2 Gy per fraction daily. The elective volume will be treated with 50 Gy in 2 Gy per fraction daily till the first 5 weeks. The entire treatment will be delivered in a phased mannered using sequential planning. | Radiation: Standard Arm<br>* The prescribed radiotherapy dose will be 70 Gy in 2 Gy per fraction daily. The elective volume will be treated with 50 Gy in 2 Gy per fraction daily till the first 5 weeks. The entire treatment will be delivered in a phased mannered using sequential planning.<br>* Other names: Standard Sequential fractionation without dose escalation;Drug: Cisplatin injection<br>* Concurrent chemotherapy, weekly Inj Cisplatin 40mg/m2. This will be given if clinically indicated<br>|
| Placebo Comparator: Arm 1 - Non-hypoxic arm<br>The patients will be treated with a standard of care where the treatment will not be controlled, and these patients will act as external control representing clinical practice. However, these patients will be discussed in the head and neck multispeciality clinic and follow the institutional approach. They will be subjected to treatment similar to 'arm 2' but are allowed protocol deviation as per treating radiation oncology discretion. | Drug: Cisplatin injection<br>* Concurrent chemotherapy, weekly Inj Cisplatin 40mg/m2. This will be given if clinically indicated<br>Radiation: Standard fractionation (Radiation Oncology preference)<br>* Standard institutional practice is detailed before starting the patient. Doses 66-70 Gy over 6-7 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional Control (LRC) | The duration of LRC was defined from the date of randomisation to the first histopathologically proven relapse of locoregional disease. If there is no proven recurrence, the LRC duration will be cut-off at the analysis point. | Disease recurrence locally or analysis cut-off point. The analysis cut off pint is 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The duration of OS was defined from the date of surgery to death from any cause. Therefore, if there is no death (for any reason), the OS duration will be cut-off at the analysis. | Death during following up or analysis cut-off point. The analysis cut off pint is 24 months |