Radiation for Oligometastatic Lung Cancer in the Era of Immunotherapy: What Do We (Need to) Know?

Abstract

Oligometastatic cancer is recognized as a separate entity within the spectrum of metastatic disease. It was suggested that patients with oligometastatic disease can obtain long-term survival by giving local ablative therapy (LAT) to all visible disease locations. However, the true extent from which metastatic cancer should be called “oligometastatic” is unknown, although a consensus definition for oligometastatic disease is proposed by research organizations, such as the EORTC (maximum of five metastases in three organs). Different states of the oligometastatic disease are defined, such as synchronous vs. metachronous, oligopersistent vs. oligoprogressive disease. All clinical trials including patients with non-small cell lung cancer (NSCLC) are small and most are not randomized. Two small randomized phase II trials on synchronous disease showed an improvement in progression free survival, with the addition of LAT, and one also demonstrated an overall survival benefit. Immune checkpoint inhibitors (ICI) were not part of the treatment in these trials, while ICI significantly improved long-term outcomes of patients with metastatic NSCLC. Radiotherapy might improve the prognosis of patients treated with ICI because of its immunostimulatory effects and the possibility to eradicate metastatic deposits. Here, we summarize the data for adding ablative radiotherapy to the treatment of oligometastatic NSCLC, especially in the ICI era, and discuss the challenges of combined treatment.

Immunotherapy resistance in non-small-cell lung cancer: From mechanism to clinical strategies

“…Local radiation therapy on oligo-metastases improves immunotherapy response for NSCLC patients without multiple progression after primary systemic therapy. Radiotherapy might improve the response to immunotherapy in patients treated with ICI through its immunostimulatory effects and eradicating metastatic deposits (127). Radiation-killing tumor cells promote releasing and presenting tumor antigens, up-regulating PD-L1 expression on tumor cells, increasing TME infiltration of CD8 + T cells, and enhancing T cell-mediated immune response, contributing to improved antitumor immune response (128)(129)(130).…”

“…However, there are still many issues to be explored, such as the optimum patient selection, the radiotherapy scheme or fractionated dose selection, the number and location selection of radiation treating metastases, the selection of specific checkpoint inhibitors, and the sequence of radiotherapy combined with immunotherapy. There are many ongoing prospective trials about the effect of radiotherapy combined with immunotherapy in NSCLC patients with limited metastases or who oligo-progressed on ICI treatment or and we are looking forward to awaiting the outcome (127,133,134). The current clinical strategies and future perspectives in NSCLC patients after immunotherapy resistance.…”

Efficacy of stereotactic ablative radiotherapy (SABR) during anti-PD-1 in oligoprogressive non-small cell lung cancer and melanoma—a prospective multicenter observational study pointing out new unmet needs

“…The pooled results of the PEMBRO-RT and MDACC trial showed that 12.5 Gy in 4 fx, with an EQD2 (α/β=3) of 155, gave the best out-of-field response (13), which is significantly higher compared to the 7 Gy in 5 fx used. However, as stated by a recent review of the literature on this topic, a lack of evidence prevents us from understanding the best fractionation schedule and it might be questionable if there is only one optimal fractionation schedule as the effect might be dependent on the specific drug or on other patient-related factors (16).…”

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy

“…However, the exploration of LCT's clinical value in immunotherapy-treated metastatic NSCLC with ORD remains unreported. Notably, radiotherapy-induced cell death can trigger immunogenic effects, potentially synergizing with immunotherapy [17][18][19]. Consequently, radiotherapy-based LCT might play pivotal roles, such as enhancing systemic anti-tumor immune responses and fostering long-term survival, in patients treated with PD-1/PD-L1 inhibitors for metastatic NSCLC with ORD, meriting further examination.…”