Assessing the Efficacy and Safety of Selective Metabolically Adaptive Radiation Dose Escalation in Locally Advanced Non-Small Cell Lung Cancer Receiving Definitive Chemoradiotherapy

Study Overview
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Brief Summary
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A randomized phase II trial to assess the efficacy and safety of selective metabolically adaptive radiation dose escalation in locally advanced non-small cell lung cancer receiving definitive chemoradiotherapy. Eligible and consenting patients will be randomized to receive conventional chemoradiotherapy or chemoradiotherapy with a radiation (RT) integrated boost. All patients will receive a fludeoxyglucose-positron emission tomography (FDG-PET) scan within two weeks prior to starting treatment. The primary outcome is to determine if dose escalation to metabolically active tumor subvolumes will reduce local-regional failure rate at 2 years.

Official Title
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A Randomized Phase II Trial to Assess the Efficacy and Safety of Selective Metabolically Adaptive Radiation Dose Escalation in Locally Advanced Non-Small Cell Lung Cancer Receiving Definitive Chemoradiotherapy

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Radiation: Chemoradiotherapy
* Radiation: Chemoradiotherapy with Integrated Boost Dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are at least 18 years old and are able to consent Patients who will undergo Chemo-RT as primarily modality of treatment Patients with a primary tumor or node measuring at least 10mm on CT scan Patients with a PET avid tumor having Standardized Uptake Values (SUV) > 4 Patients with Eastern Cooperative Oncology Group (ECOG) status 0-2 within 4 weeks of randomization Exclusion Criteria: Trimodality patients who have surgery as part of curative treatment Previous radiotherapy to intended treatment volumes Active invasive malignancy other than lung cancer Active pregnancy Poor respiratory function (Forced Expiratory Volume < 1.0 or Diffusing Capacity < 50% age-adjusted normal) ECOG status > 2 Pre-treatment complete blood count/differential showing inadequate bone marrow reserve (absolute neutrophil count < 1800 cells/mm3 or platelets < 100 000 cells/mm3 or hemoglobin < 90g/L), measured within 4 weeks of registration AST, ALT or total bilirubin > 2.5 times the upper limit of normal, measured within 4 weeks of registration Unintentional weight loss >10% over 3 months within 4 weeks of registration Severe active co-morbidity defined by: Significant history of uncontrolled cardiac disease; i.e. uncontrolled hypertension, unstable angina, myocardial infarction within the last 6 months, uncontrolled congestive heart failure, cardiomyopathy with decreased ejection fraction Transmural myocardial infection requiring intravenous antibiotics at the time of registration Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization Acquired immune deficiency syndrome (AIDS) based on the current Centre for Disease Control definition; note, however, that HIV testing is not required for entry into this protocol

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 |
| --- | --- |
| Active Comparator: Chemoradiotherapy<br>Patients randomized to the standard arm will receive radiotherapy (5x per week) of 60 gray (Gy) in 30 fractions with concurrent cisplatin and etoposide chemotherapy. | Radiation: Chemoradiotherapy<br>* Patients will receive radiotherapy of 60Gy in 30 fractions (5x per week) with concurrent cisplatin and etoposide chemotherapy.<br>|
| Experimental: Chemoradiotherapy with Integrated Boost Dose<br>Patients randomized to the experimental arm will receive radiotherapy (5x per week) with an integrated boost dose of up to 85Gy in 30 fractions to tumor subvolumes, with concurrent cisplatin and etoposide chemotherapy. | Radiation: Chemoradiotherapy with Integrated Boost Dose<br>* Patients will receive an RT integrated boost to tumor subvolumes (max boost dose of 85Gy) in 30 fractions (5x per week) with concurrent cisplatin and etoposide chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of local-regional failure rate | Primary outcome of the trial is to determine if dose escalation to metabolically active subvolumes will reduce local-regional failure rate | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | Determine if dose escalation to metabolically active subvolumes will improve progression-free survival at 2 years | 2 years | 
| Overall Survival | Determine if dose escalation to metabolically active subvolumes will improve overall survival at 2 years | 2 years | 
| Grade 3-5 Toxicity Rate | Determine if dose escalation to metabolically active subvolumes will increase the rate of grade 3-5 toxicities | 2 years | 
| Quality of Life FACT-L | Compare the quality of life in the two arms using Functional Assessment of Cancer Therapy-Lung (FACT-L) instrument | 2 years | 
| Quality of Life EQ-5D | Compare the quality of life in the two arms using EuroQol Quality of Life-5 Dimensions (EQ-5D) instrument | 2 years | 
| Dose-Response Characterization | Characterize the tumor dose-response relationship in the experimental arm and create a tumor control probability model for local-regional failure at 2 years | 2 years | 
| Dose Escalation Feasibility | Explore the feasibility of adaptive dose escalation based on PET response at week 2 | 2 weeks | 
| Imaging Use | Explore the use of Week 0 and Week 2 PET images for prognostication and response assessment for local-regional failure at 2 years | 2 years |