Daily Adaptive Radiation Therapy: An Individualized Approach for Stage III Lung Cancer

Study Overview
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Brief Summary
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This is a prospective multi-center randomized clinical trial designed to demonstrate that daily online adaptive radiotherapy with concomitant chemotherapy for stage III non-small cell lung cancer (NSCLC) will result in decreased acute respiratory and esophageal toxicity compared with non-adaptive radiotherapy with concomitant chemotherapy. The timepoint for this assessment will be 1 month following the end of radiotherapy and will use the Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Official Title
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Daily Adaptive vs Non-Adaptive External Beam Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung)

Conditions
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Stage III Non-small Cell Lung Cancer

Intervention / Treatment
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* Device: Adaptive Radiotherapy
* Device: Non-Adaptive Radiotherapy
* Drug: Chemotherapy
* Drug: Immunotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form. Histologically confirmed NSCLC Clinical stage IIIA-IIIB (AJCC v8) disease who are either: Patients classified as non-operable by the treatment team Patients who refuse surgery Clinical stage IIIC due to contralateral mediastinal lymph node involvement only (e.g., no contralateral hilar or any supraclavicular/cervical lymph node metastases). Mediastinal stations 2R and 4R are considered contralateral for patients whose primary tumor is within the left lung. Mediastinal stations 2L, 4L, 5, and 6 are considered contralateral for patients whose primary tumor is in the right lung. Completed evaluation for metastatic disease with no distant metastases identified. Evaluation must include the following: History and physical examination within 30 days prior to enrollment. Whole body FDG PET-CT for staging within 60 days prior to enrollment Brain MRI or contrast enhanced CT within 60 days prior to enrollment. ECOG performance status 0-2 and deemed clinically fit for chemoradiotherapy. Age ≥18 years (or at least the local age of consent) Patients must have normal organ and marrow function. Serum creatinine ≤1.5 mg/dL within 60 days prior to enrollment. Measurable disease must be present. Negative urine or serum pregnancy test within 14 days prior to enrollment for women of childbearing potential. Exclusion Criteria: Contralateral hilar or any supraclavicular/cervical lymph nodes. Baseline grade ≥3 dyspnea, or cough, or dysphagia. Prior invasive non-skin malignancy unless disease free for a minimum of 3 years. History of prior RT to the thorax. Severe imaging artifact that, in the view of the local investigator, would preclude accurate identification of the thoracic anatomy and tumor targets on the cone beam CT (e.g., artifact created implanted cardiac device in proximity to the targets). Evidence of malignant pleural effusion, defined as either FDG PET avidity within effusion fluid or presence of malignant cells identified by cytology of thoracentesis fluid. Severe active chronic obstructive pulmonary disease or respiratory illness other than NSCLC precluding study therapy. Hospitalization for chronic obstructive pulmonary disease or respiratory illness other than NSCLC within 1 year prior to study enrollment. Women of childbearing potential and sexually active women not willing or able to use contraception.

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: Adaptive Arm<br>Subjects in this arm will receive their external beam radiotherapy on the Ethos Radiotherapy System, with daily online adaptation of their radiation dosimetry plan to account for day-to-day changes in the tumor and surrounding anatomical structures. All subjects will received standard concurrent chemotherapy and may receive adjuvant immunotherapy, if indicated. | Device: Adaptive Radiotherapy<br>* Standard fractionation external beam radiotherapy (60-66 Gy in 2 Gy/fraction) with daily online adaptation.<br>Drug: Chemotherapy<br>* Concomitant chemotherapy per NCCN or other national guidelines.<br>Drug: Immunotherapy<br>* Adjuvant immunotherapy per national or institutional guidelines.<br>|
| Active Comparator: Non-Adaptive Arm<br>Subjects in this arm will receive their radiotherapy using standard image-guided radiation therapy (IMRT) techniques. All subjects will received standard concurrent chemotherapy and may receive adjuvant immunotherapy, if indicated. | Device: Non-Adaptive Radiotherapy<br>* Standard fractionation external beam radiotherapy (60-66 Gy in 2 Gy/fraction) with daily image guidance.<br>Drug: Chemotherapy<br>* Concomitant chemotherapy per NCCN or other national guidelines.<br>Drug: Immunotherapy<br>* Adjuvant immunotherapy per national or institutional guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute toxicity | Composite rate of grade 3 or worse cough, dyspnea, or dysphagia using PRO-CTCAE | From randomization to 30 days after completion of chemoradiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung cancer specific quality of life | Results from the FACT-L questionnaire | From randomization to 12 months after completion of chemoradiotherapy | 
| Global quality of life | Results from the EQ-5D-5L questionnaire | From randomization to 12 months after completion of chemoradiotherapy | 
| Normal lung tissue radiation exposure | The percentage of normal lung tissue volume that receives radiation of 20 Gy or more over the course of radiation treatment. | End of external beam radiation treatment (approximately 2 months from randomization) | 
| Mean normal tissue doses | Mean dose delivered to the heart, esophagus and normal lung tissue over the course of radiation treatment. | End of external beam radiation treatment (approximately 2 months from randomization) | 
| Overall response rate | Frequency of complete and partial tumor response as determined on chest imaging using RECIST v1.1 | 3 months, 6 months and 12 months after completion of chemoradiotherapy | 
| Local progression | Physician report of progression determined by imaging or clinical evaluation | 12 months after completion of chemoradiotherapy | 
| Radiation pneumonitis | CTCAE v.5.0 grade 2+ pneumonitis | 12 months after completion of chemoradiotherapy |