Adjuvant Radiotherapy in Early Stage Oral Cancers

Study Overview
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Brief Summary
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This study will assess the benefit of postoperative adjuvant radiotherapy in patients with an early oral squamous cell carcinoma (OSCC) having tumor thickness more than or equal to 5mm. The study population will consist of patients who have been treated by surgery for early stage oral tongue cancers. Patients with a close or positive margin (</= 5mm) and or with metastatic neck node(s) will be excluded. Selected patients will be randomized into two groups. The group I will be observed after surgery and group II will receive adjuvant radiotherapy as per protocol.

Detailed Description
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The aim of this study is to assess the benefit of postoperative adjuvant radiotherapy in patients with an early oral squamous cell carcinoma (OSCC) having a tumor depth of invasion more than or equal to 5mm. Primary objective: To determine the impact of postoperative adjuvant radiotherapy on locoregional recurrence-free survival in patients with early-stage oral tongue cancer with tumor thickness ≥ 5 mm. Secondary objectives: To compare disease-free survival and overall survival between the two groups. To assess and compare the quality of life changes between the two groups. To assess the acute and long-term radiation toxicity. We will be conducting a Phase III Open-Label Prospective Randomized Controlled Trial using stratified randomization. Patients will be randomized into two groups: Group I: Control arm (Observation only) Group II: Study arm (Postoperative adjuvant radiotherapy) Patients will be stratified on the following factors Presence of Perineural Invasion (PNI)/Lympho-Vascular Emboli (LVE) Histological grade (well-differentiated/moderately differentiated vs poorly differentiated) Tongue/Floor of Mouth vs Buccal Mucosa. Study procedures: The study population will consist of patients who have been treated by surgery for early-stage oral cancers. Patients satisfying the inclusion-exclusion criteria will be included in the study after obtaining a valid, written and informed consent. The depth of invasion will be assessed microscopically by measuring the maximum vertical bulk of the tumor from the normal mucosal surface to the deepest point of invasion. After reviewing the histopathological report, patients will be randomized to one of the 2 arms. Patients belonging to study arm (Group II) will receive adjuvant radiotherapy 60 Gray, 30 fractions for 30 days over 6 weeks as routinely prescribed at Tata Memorial Center (TMC) and will receive the treatment within or by 6 weeks after surgery. Both the groups (Group I and Group II) will be under regular follow-up with 3 monthly intervals for the first 2 years and 6 monthly for the next 3 years and once a year thereafter. At each follow-up, patients will be evaluated clinically for evidence of locoregional tumor recurrence. The locoregional recurrence-free survival will be calculated based on the difference between the date of randomization and the date of biopsy-proven recurrence. We will also record the overall survival in both groups. The quality of life will be assessed at each follow-up regular intervals using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ H&N-35 ) and EORTC QLQ-C 30. The radiation toxicity will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

Official Title
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Adjuvant Radiotherapy in Early Stage Oral Cancers (AREST)

Conditions
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Cancer of Mouth, Cancer of the Tongue, Cancer of the Head and Neck, Buccal Mucosa Cancer, Floor of Mouth Carcinoma

Intervention / Treatment
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* Radiation: Post-operative adjuvant radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post-operative early stage squamous cell carcinoma of the oral cavity (Oral Tongue, Buccal Mucosa, Floor of mouth). (pT1, pT2, N0 as defined in the AJCC Classification 8th edition. Adequate surgery (Defined as wide local excision of the primary tumor with tumor-free margin ≥ 5mm and ipsilateral selective neck dissection addressing levels I-III at minimum.) Written informed consent. Age ≥18 years Eastern Co-operative Oncology Group (ECOG) Performance Status 0-2 The depth of invasion (DOI) ≥ 5 mm. Compliance to therapy and follow-up The interval from surgery to adjuvant radiotherapy ≤ 6 weeks Exclusion Criteria: pT3/pT4 (as specified in the AJCC 8th edition). Depth of invasion < 5mm. Any neck nodal metastasis with or without extra nodal extension Tumor-free margin < 5 mm Non-squamous histology Pregnant woman Prior h/o any other malignancy in the last five years Prior therapeutic irradiation of the head and neck.

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 |
| --- | --- |
| No Intervention: Control arm<br>Patients in this arm will be observed and kept under active follow-up after surgery for the primary. | |
| Experimental: Study arm<br>Intervention in the study arm will be in the form of post-operative adjuvant radiotherapy starting within 6-weeks after primary surgery. | Radiation: Post-operative adjuvant radiotherapy<br>* Conventional treatment planning, as well as intensity-modulated radiation therapy (IMRT) planning, would be allowed on the study with patients being stratified on the RT technique. Treatment would be delivered on telecobalt unit (gamma-rays/linear accelerator (6MV photons). All fields would be treated daily. Phase I: 46 Gray(Gy) in 23 fractions over 4.5 weeks Phase II: 14Gray in 7 fractions over 1.5 weeks For IMRT, inverse planning would be done on a commercial TPS configured to deliver IMRT using 6MV photons. Patients shall be treated using the simultaneous integrated boost (SIB) technique with 5 fractions being delivered every week.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| loco-regional recurrence free survival | Measures the number of local or regional recurrences in both arm over a defined time frame. | Date of randomization to loco regional recurrence (date of proven biopsy date) or at the end of 36 months after recruitment of the last participant. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival | time from the beginning of an intervention until patient experiences a recurrence, a new primary cancer or death. | Calculated as difference of date of randomization to date of first documented recurrence or relapse, second primary or death or at the end of 36 months after recruitment of the last participant. | 
| Overall survival | Date of Randomization to death from any cause | Date of randomization to death from any cause or at the end of 36 months after recruitment of the last participant. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer of the Mouth, Tongue cancer, Buccal Mucosa cancer, Head and Neck, Oral Cancer, Adjuvant Radiotherapy, Depth of Invasion