Stereotactic Ablative Radiotherapy in Locally Advanced Non Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
This is a prospective, non-randomized, single arm, single institution phase II trial to evaluate the safety and effectiveness of stereoractic ablative radiotherapy (SABR) in selected unresectable newly diagnosed and recurrent locally advanced (LA) non-small cell lung cancer (NSCLC) patients unfit for concurrent chemo-radiotherapy (ChT-RT). Patients unfit for concurrent ChT-RT but fit for chemotherapy will be enrolled to sequential ChT-SABR; patients unfit for ChT will be enrolled to exclusive SABR.

Detailed Description
-----------------
Current standard of care for fit patients with unresectable LA-NSCLC is concurrent chemo-radiotherapy (ChT-RT) which consists of 6 weeks of radiation and chemotherapy. Unfortunately many LA NSCLC patients, particularly the elderly, are unfit for concurrent ChT-RT because of their poor performance status and co-morbidities. Sequential ChT-RT and/or exclusive RT are options available for patients not suitable for concomitant approaches. Median progression-free survival among patients receiving concurrent ChT-RT is poor and no more than 15% of cases are alive at 5 years. This study is evaluating SABR in unresectable LA-NSCLC. Hypofractionated regimens of RT have emerged as a possible approach in LA-NSCLC, not only because prolonged treatments may discourage a proportion of elderly patients (20-30%) who are forced to give up treatment due to distance from the Radiotherapy Centre, but also for radiobiological reasons. Recent technological advances in RT, first of all stereotactic body radiotherapy (SBRT), have made hypofractionation widely applicable with the possibility to administer few (5 to 8) fractions of high external beam doses to the tumor, sparing the surrounding healthy tissues by a rapid fall of dose outside the target. LA-NSCLC patients will be discussed at the multidisciplinary lung cancer group and will be judged unfit for surgery and concurrent ChT-RT (e.g. elderly patients and/or large volume of disease and/or cardiovascular comorbidities) but suitable for RT. Neoadjuvant ChT will be evaluated case by case and will be prescribed only in fit patients. Starting from the standard radical conventionally administered dose for LA-NSCLC (equivalent to at least 54-60 Gy in 27-30 fractions), the investigators decided to prescribe an ablative dose of at least 35-40 Gy in 5 fractions. The SABR dose will be increased, case by case, respecting the maximum tolerance dose of healthy structures. The purpose of this study is to explore SABR in the treatment of unresectable LA-NSCLC.

Official Title
-----------------
STereotactic Ablative RadioTherapy in NEWly Diagnosed and Recurrent Locally Advanced Non-small Cell Lung Canter Patients Unfit for concurrEnt RAdio-chemotherapy

Conditions
-----------------
Locally Advanced Lung Non-Small Cell Carcinoma

Intervention / Treatment
-----------------
* Radiation: Stereotactic Ablative Radiotherapy in Unresectable Locally Advanced Non-Small Cell Lung Cancer


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age ≥18 years Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Histologically or cytologically confirmed non-small cell lung cancer LA-NSCLC at the first diagnosis or recurrent LA-NSCLC after previous surgery Stage II-III disease as determined by PET/CT and TC/MRI Brain (American Joint Committee on Cancer 7th or 8th Edition) oligo-metastatic LA-NSCLC with metastasis suitable to local treatment in the primary and metastatic site Participant is not eligible for surgical resection as determined by the multidisciplinary lung cancer group Participant is not eligible for concurrent chemotherapy as determined by the multidisciplinary lung cancer group Ability to understand and the willingness to sign an IRB-approved informed consent document (either directly or via a legally authorized representative). Exclusion Criteria: LA-NSCLC patients eligible for surgical resection ECOG performance status 3 or more Inability to safely treat target lesions Pregnant women are excluded from this study because radiation therapy has known potential for teratogenic or abortifacient effects.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SABR in unresectable LA-NSCLC<br>Patients fit for chemotherapy will be enrolled to sequential chemotherapy-stereotactic ablative radiotherapy (SABR), while patients unfit for chemotherapy will be enrolled to exclusive stereotactic ablative radiotherapy (SABR). | Radiation: Stereotactic Ablative Radiotherapy in Unresectable Locally Advanced Non-Small Cell Lung Cancer<br>* The prescribed dose of stereotactic ablative radiotherapy (SABR) will be of at least 35-40 Gy in 5 fractions. The dose of SABR will be increased, case by case, respecting the maximum tolerance dose of the healthy structures. Participants will SABR once a day for 5 days, Monday through Friday (around 1 week).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local control | A lack of progression (i.e., any response and stable disease) of the treated volume according to RECIST and PERCIST. Local recurrence (LR) was defined as tumor progression within the radiation field (95% of the recurrence volume within the original 80% isodose of SABR). Local recurrence-free survival (LR-FS) was defined as the interval between treatment and radiological evidence of LR. | 1 year, 2 years and 3 years | 
| Proportion of Participants Experiencing Grade 3 or Higher Toxicities | SABR will be considered safe if no grade (G) 3 or higher toxicities appears. Toxicity, graded according to Common Terminology Criteria for Adverse Events (CTCAE v3.0) will be assessed during SABR and at all follow-up intervals. Toxicity will be recorded as acute when occurred during SABR or within 3 months after completion of treatment. When the time interval will be longer than 3 months, toxicity will be defined late. | 6 months and 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thoracic nodal-recurrence free survival | The interval between treatment and radiological evidence of any nodal recurrence outside the treated nodes and anyway outside the original isodose of 80% | 1 year, 2 years and 3 years | 
| Distant progression free-survival | The interval between treatment and radiological evidence of systemic disease progression | 1 year, 2 years and 3 years | 
| Overall Survival | The overall survival will be calculated from treatment to patient death or last follow-up | 1 year, 2 years, 3 years and 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
LA-NSCLC; SABR