Integration of Stereotactic Body Radiation Therapy With Tyrosine Kinase Inhibitors in Stage IV Oncogene-Driven Lung Cancer

Abstract

Genotype-based selection of patients for targeted therapies has had a substantial impact on the treatment of non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs) directed at cancers driven by oncogenes, such as epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, often achieve dramatic responses and result in prolonged survival compared with chemotherapy. However, TKI resistance invariably develops. Disease progression can be limited to only one or a few sites and might not be symptomatic, raising the important question of whether this type of oligoprogression warrants a change in systemic therapy or consideration of local treatment. Recent clinical observations suggest a growing role for stereotactic body radiation therapy (SBRT) in the treatment of oligoprogressive and perhaps even oligopersistent disease (primary and/or metastases) in oncogene-driven NSCLC. SBRTmight allow patients to continue with existing TKI treatments longer and delay the need to switch to other systemic options. We review the current data with regard to the use of SBRT for metastatic NSCLC and particularly oncogene-driven disease. Although there is great promise in the marriage of targeted therapies with SBRT, prospective data are urgently needed. In the meantime, such strategies are being used in carefully selected patients, with risk-adapted SBRT dose-fractionation regimens used to optimize the therapeutic index. The Oncologist 2016; 21:964-973 Implications for Practice: Stereotactic body radiation therapy (SBRT) or SBRT-like treatments are increasingly being used for oligoprogression in patients with oncogene-driven non-small cell lung cancer.This approach allows patients to extend the duration of tyrosine kinase inhibitor therapy and has the potential to prolong survival times. Careful patient selection and risk-adapted radiation dosing is of critical importance to minimize toxicity and preserve patient quality of life.

Non–Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology

“…213 After development of acquired resistance in patients with lung adenocarcinoma and sensitizing EGFR mutations, erlotinib, gefitinib, or afatinib may be continued, but osimertinib is also an option for select patients; local therapy should be considered (eg, stereotactic radiosurgery to brain metastases or other sites, SABR for thoracic disease). [214][215][216][217] The NCCN panel recommends continuing erlotinib, gefitinib, or afatinib and considering local therapy in patients with asymptomatic progression; however, treatment varies for patients with symptomatic progression (see NSCL-19, page 508). [218][219][220] For the 2017 updates (Versions 1 and 4), the NCCN panel revised the recommendations for patients with sensitizing EGFR mutations whose disease has progressed on erlotinib, gefitinib, or afatinib.…”

Targeting ALK: Precision Medicine Takes on Drug Resistance

“…While most patients develop systemic, multisite progression requiring a change in systemic therapy, a subset of patients develop progression limited to only one or a few anatomic sites, with the remaining disease sites continuing to be controlled by the TKI. This phenomenon has been termed “oligoprogression” (155, 156). In the case of oligoprogressive disease, local ablative therapy (LAT) using surgery or radiation may serve as a strategy that offers several advantages (Figure 4).…”

“…Taken one step further, patients may achieve an overall tumor response to a TKI but continue to have a few sites of persistent, residual disease (“oligopersistent disease”) (155). Similar to the oligoprogressive situation, these sites of oligopersistent disease may serve as a reservoir of residual, TKI-insensitive tumor cells that can eventually drive systemic therapy failure (159).…”

Efficacy and Safety of Metastasis Directed Stereotactic Radiotherapy in NSCLC Patients Progressing Under Targeted- or Immunotherapy.

“…This analysis of stage IV NSCLC patients receiving MDT for progressive or persistent metastases under targeted-, or immunotherapy showed survival rates in the OPD group that appear promising compared to literature on patients receiving TT/IT alone [15][16][17]. The concept of targeting OPD while continuing systemic therapy beyond progression is increasingly performed [18,19]. This is based on the observation that 1) further lines of systematic treatment are characterized by a worse therapeutic effect, 2) MDT obtains good results with limited toxicity in the primary oligometastatic situation [7][8][9], and 3) whole genomic sequencing studies showing that through parallel evolution, subpopulations of metastatic clones are capable to metastasize themselves [20].…”