Dose Escalation Versus Standard in Laryngopharyngeal Cancers

Study Overview
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Brief Summary
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The primary objective of the study is to establish the safety of using a moderate escalation of radiotherapy dose in advanced/poor prognosis OPC and LH cancers receiving curative radiotherapy. The study will also explore the efficacy (improvement in complete response rates at 2 years) of dose escalation in intermediate and high risk OPC and LH cancers patients.

Detailed Description
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Patients with locally advanced Laryngeal, Hypopharyngeal (LH) or oropharyngeal (OPC) head and neck squamous cell carcinomas have 5 year survival ranging between 25-45%. 60% of all LH cancers occur in the developing world and its incidence in India ranges from 1.8-8.8 per 1,00,000 population . Local control outcomes of OPC patients with stage III and IV OPC has been modest with reported loco-regional control rates of 50-60% at 5 years. For patients with locally advanced LH a 60-70% 2 year survival is seen and loco-regional control rates of 70% have been reported . Majority of locally advanced OPC and LH cancers are treated with a combination of chemotherapy and radiotherapy (CRT) with organ and function preserving approach. Identifying the area of tumour involvement in the OPC and LH could be challenging on CECT scans, requiring metabolic imaging with PET-CT for more precise definition of radiation target. Improvements in radiation treatment delivery techniques have enabled clinicians to explore the possibility of improving tumour control probability (TCP) and reduce normal tissue complication probability . This allows us to explore the role of escalating dose in the above group of patients to assess the safety and efficacy of the regime. Tumours treated in the standard dose arm will receive radiotherapy @ 220 cGy per fraction for 30 fractions whilst those in the escalated dose arm will receive @ 245 cGy per fraction for 30 fractions using IMRT techniques. Patients in both arms will receive weekly platinum based chemotherapy concurrent with radiotherapy.

Official Title
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Intensifying Radiation Treatment in Advanced/ Poor Prognosis Laryngeal, Hypopharyngeal (LH) and Oropharyngeal Cancers (OPC) Using PET -CT Based Dose Escalation Strategies ( INTELHOPE)

Conditions
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Malignant Neoplasm of Oropharynx Stage III, Malignant Neoplasm of Larynx Stage III, Malignant Neoplasm of Hypopharynx Stage III, Malignant Neoplasm of Oropharynx Stage IVa, Malignant Neoplasm of Oropharynx Stage IVb, Malignant Neoplasm of Larynx Stage IV, Malignant Neoplasm of Hypopharynx Stage IVa, Malignant Neoplasm of Hypopharynx Stage IVb

Intervention / Treatment
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* Radiation: Escalated Dose
* Radiation: Standard Dose


Participation Criteria
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Eligibility Criteria
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LH Inclusion Criteria ALL of the following inclusion criteria must be met Histologically confirmed squamous cell cancer of the larynx or hypopharynx Radiotherapy with concomitant chemotherapy as primary therapy Induction chemotherapy is permitted TNM Stage T3-4, N0-3, M0 or T1/2 with N2-3 disease (Stage III or IV a/b) disease WHO performance status of 0 or 1 Creatinine clearance of more than 50ml/min All patients must be suitable to attend regular follow up OPC inclusion criteria ALL of the following inclusion criteria must be met Histologically confirmed squamous cell cancer of the oropharynx Radiotherapy with concomitant chemotherapy as primary therapy Induction chemotherapy is permitted WHO performance status of 0 or 1 Creatinine clearance of more than 50ml/min All patients must be suitable to attend regular follow up And any of the stage of disease as seen below HPV (p16) negative: TNM Stage T2-T4, any N stage, M0 disease HPV (p16) Positive: more than 10 pack year history and N2b or N3 disease LH Exclusion Criteria The patient is ineligible if ANYONE of the following exclusion criteria is met Previous radiotherapy to the head and neck region Previous malignancy except non-melanoma skin cancer and early stage cancer in remission for at least 5 years following treatment Previous or concurrent illness, which in the investigator's opinion would interfere with either completion of therapy or follow-up Pre-existing previous speech or swallowing problems unrelated to the diagnosis of cancer Patients with locally advanced LH tumours where organ preservation is unrealistic Patients with metastatic carcinoma OPC Exclusion Criteria The patient is ineligible if ANYONE of the following exclusion criteria is met Previous radiotherapy to the head and neck region Previous malignancy except non-melanoma skin cancer and early stage cancer in remission for at least 5 years following treatment Previous or concurrent illness, which in the investigator's opinion would interfere with either completion of therapy or follow-up Pre-existing previous speech or swallowing problems unrelated to the diagnosis of cancer Patients with locally advanced LH or OPC tumours where organ preservation is unrealistic Patients with metastatic carcinoma Low risk OPC: HPV p16 positive T1-2 with N0-N2a disease or less than 10 pack year history

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
Interventional Model Description: It is a radiation dose escalation study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard dose<br>Patients receive a radiation dose of 66Gy in 30 fractions to the planning target volume 1 (PTV1) and 54 Gy in 30 fractions to the PTV2 concurrent with platinum chemotherapy weekly | Radiation: Standard Dose<br>* CTV 1 includes 6mm isotropic margin around the entire PET-CT avid (thresholding at 40% of SUV max) larynx/ hypopharynx /oropharynx and 5mm isotropic margin around nodes. CTV 2: This (CTV 2) includes the area around the primary or nodal levels at risk of harbouring microscopic primary or microscopic nodal involvement, or at risk nodal areas, and not already included in CTV1. Planning Target Volume: PTV - A margin of 5mm will be added to each of the CTV to obtain the PTV. PTV 1 receives 66Gy in 30 fractions. PTV 2 receives 54 Gy in 30 fractions. All patients receive concurrent platinum chemotherapy.<br>|
| Experimental: Escalated dose<br>Patients receive a radiation dose of 73.5 Gy in 30 fractions to the boost target volume (BTV), 63Gy in 30 fractions to PTV1 and 54 Gy in 30 fractions to PTV2 concurrent with platinum chemotherapy weekly | Radiation: Escalated Dose<br>* Boost Target Volume (BTV): The PET CT GTV (thresholding at 40% of SUV max) with a 3mm margin will form the BTV. CTV1: A 3mm area around the BTV avid primary or 2mm area around the node will form the CTV1. CTV 2: This (CTV 2) includes the area around the primary or nodal levels at risk of harbouring microscopic primary or microscopic nodal metastatic disease and not already included in CTV1. Planning Target Volume: PTV - A margin of 5mm will be added to each of the CTV to obtain the PTV. BTV receives 73.5Gy in 30 fractions. PTV 1 receives 63Gy in 30 fractions. PTV 2 receives 54 Gy in 30 fractions. All patients receive concurrent platinum chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with Grade 3 through grade 5 adverse events that are related to dose escalation, graded according to NCI CTCAE version 4.0 | In addition: Interim assessment for early stoppage is if 35% or more patients in the intervention arm has Grade 4 mucositis or dysphagia | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy (improvement in complete response rates at 2 years) of dose escalation in intermediate and high risk Oropharyngeal cancer (OPC) patients and in node positive, locally advanced Laryngeal and Hypopharyngeal cancer patients. |  | 2 years |