Stereotactic Ablative Radiotherapy in Synchronous and Metachronous Oligo-Metastatic Non Small Cell Lung Cancer

Targeted Therapies and Immunotherapy have fundamentally changed the treatment of metastatic non-small cell lung cancer (NSCLC). There is an increasing interest in the use of stereotactic ablative radiotherapy (SABR) for oligo-metastatic (oligo-M) NSCLC patients. It is postulated that definitive treatment of the primary as well as regional node/s and oligo-M in these patients may improve their overall survival (OS). Oligo-M is considered an intermediate state between local and poly-metastatic disease and is commonly defined as 1-5 metastatic lesions, in keeping with the recent European Society of Radiotherapy and Oncology (ESTRO) and American Society for Radiation Oncology (ASTRO) consensus. If discovered within 4-6months of diagnosis, they are termed synchronous oligo-M. Alternatively, should oligo-M develop following definitive treatment of the primary tumour, this is termed metachronous oligo-M. Multiple clinical trials have demonstrated prolonged survival following SABR treatment to all sites of oligo-M, particularly in NSCLC. Targeted therapies (TT) and Immunotherapy (IT) have transformed the landscape of NSCLC treatment by improving OS in metastatic setting. However, most SABR trials for oligo-M patients were conducted in the pre-TT and pre-IT era. How SABR and TT or IT should be integrated in the treatment of oligo-M NSCLC therefore remains an active area of investigation. Oligo-M is considered a clinically distinct from poly-metastatic disease, presenting a unique therapeutic window during which the treatment of all oligo-M may result in long-term disease control and possibly cure in select cases. SABR offers the advantages of being non-invasive, safe, and well-tolerated, even by frail patients. It ablates multiple targets simultaneously achieving good rates of local control. The objectives of treating oligo-M using SABR include: 1. ablating all sites of visible disease to reduce tumor burden 2. preventing progression to a poly-metastatic disease state 3. relieving morbidity associated with metastases without a decline in quality of life (QoL) 4. delaying the start of systemic therapy Reasons to support SABR in oligo-M NSCLC: 1. Systemic treatment alone does not eradicate the presence of all oligo-M disease. SABR may improve local control at the sites of oligo-M decreasing the risk of poly-metastatic widespread by reducing the burden of proliferative malignant cells 2. SABR is a histology-agnostic ablative technique which can eradicate systemic therapy-resistant disease. So, SABR optimizes local control at the sites of oligo-M, thereby delaying the need to start a new systemic therapy or eliminating the morbidity and potential mortality associated with local and eventually distant progression of disease. * Targeted therapies (TT) or Immunotherapy (IT) (chemotherapy) will be combined with early SABR of all cancer sites in patients with synchronous oligo-M NSCLC: primary tumour (T), regional node/s (N) and oligo-metastases (M). Eradication of all macroscopic cancer sites at the time of primary diagnosis by combined modality treatment is expected to decrease the risk of resistance development with only microscopic disease potentially remaining. This will result in improvement of progression free survival (PFS), QoL, delayed change of therapy and OS without added high-grade (\>G3) toxicity. Synchronous oligo-M NSCLC patients will be enrolled to SABR and TT or IT. * Targeted therapies or Immunotherapy (chemotherapy) will be combined with SABR of all cancer residual sites in patients with oligo-persistence, oligo-progressive or oligo- induced oligo-M NSCLC: primary tumour (T), regional node/s (N) and oligo-M. Eradication of all macroscopic cancer sites at the time of oligo-persistence or oligo- progression by combined modality treatment is expected to delay the initiation of a new systemic therapy. This will result in improvement of PFS and QoL, delayed change of therapy and OS without added high-grade (\>G3) toxicity. Metachronous oligo-M NSCLC patients will be enrolled to SABR including maintenance TT or IT. * Patients unfit for systemic therapy with synchronous or metachronous oligo-M NSCLC will be enrolled to receive SABR alone in all sites of disease. Eradication of all macroscopic cancer sites is expected to delay the widespread and/or symptomatic disease. This will result in improvement of OS and QoL without added high-grade (\>G3) toxicity.