International consensus on radiotherapy in metastatic non-small cell lung cancer

Introduction

Lung cancer is the leading cause of cancer-related death worldwide. It is estimated 2.2 million new lung cancer cases were diagnosed globally in 2021 and 1.8 million people will die from this disease (1). Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, accounting for approximately 85% of all cases (2), and as most patients are diagnosed at an advanced stage, the prognosis is poor (2). Systemic therapy is the main treatment of metastatic NSCLC, while radiotherapy is conventionally used to alleviate symptoms and mitigate oncological emergencies. However, with considerable advances in radiotherapy technology and the continued development of cutting-edge systemic therapies, such as targeting agents and immune checkpoint inhibitors (ICIs), the role and scope of radiotherapy in metastatic NSCLC are evolving.

The last two decades have brought remarkable advances in the medical treatments of NSCLC, such as targeted therapy and immunotherapy. These methods not only greatly improve patient survival, but also increase the role of radiotherapy in metastatic disease (3). For example, timely radiotherapy may improve the general condition of patients with primary severe symptoms caused by tumor emergencies or metastases, rendering them eligible for subsequent aggressive therapeutic approaches.

Although the term “oligo-metastasis” was first coined by Hellman and Weichselbaum in the 1990s, a common definition for this clinical entity remains a matter of debate (4-7). Accumulating data has demonstrated superior survival in patients with oligo-metastatic disease compared to multi-metastatic disease (8-10). Consolidative stereotactic body radiotherapy (SBRT) following induction and prior to maintenance chemotherapy could triple progression-free survival (PFS) in patients with oligo-metastatic disease compared with maintenance chemotherapy alone (11). Similarly, in patients with three or fewer metastases, consolidative radiotherapy or surgery extended the median PFS from 4.4 to 14.2 months and median overall survival (OS) from 17.0 to 41.2 months (12). Although these results are appealing, the role of radiotherapy in oligo-metastatic NSCLC warrants validation in prospective clinical trials (13).

Radiotherapy has long been the standard of care for NSCLC patients with central nervous system (CNS) metastasis due its efficacy and the poor penetrance of cytotoxic agents through the blood brain barrier (BBB). The introduction of tyrosine kinase inhibitors (TKIs) and ICIs has resulted in impressive improvement in survival outcomes for patients with CNS metastasis (14-17), although the mechanisms underlying their synergistic anti-tumor effect with radiotherapy have not been elucidated (18-20). The clinical value, optimal timing, and technology of cranial radiotherapy (CRT) for CNS metastasis remains to be established.

The treatment paradigm for metastatic NSCLC has been rapidly transformed by the advent of ICI’s, which have become a new standard of care in first-line settings (21-23). The synergistic anti-tumor effect of radiation and immunotherapy has formed the basis of several prospective trials evaluating the safety and efficacy of this combination therapeutic strategy (13,24-28). As different dose-fractionation regimens have been found to result in heterogeneous immunologic effects, it is of clinical importance to explore the optimal regimen to maximize the efficacy of combined radiotherapy and ICI therapy.

The role of radiotherapy has shifted from palliative care alone to therapy with curative intent in a subgroup of patients with metastatic NSCLC. In the era of precision medicine, the formulation of individualized radiotherapy strategies incorporating both clinical expertise and patient values poses a significant challenge to radiation oncologists. Herein, we invited multiple international lung cancer experts to weigh in and address these important issues. The resultant group consensuses are presented below and summarized in Table 1.

Palliative radiotherapy

Consensus 1.1: Palliative radiotherapy is a safe and effective approach for patients who present with oncologic emergencies or cancer-related severe symptoms

Radiotherapy is known to have beneficial effects in the palliative treatment of metastatic NSCLC, and some data suggest potential survival improvement (29). Despite the increasing use of chemotherapy in the palliative setting, local radiotherapy is an established option to achieve rapid, effective symptom control with few side effects and expedient improvement in overall patient status. Oncologic emergencies and cancer-related severe symptoms are two clinical scenarios in which the employment of timely radiotherapy is crucial.

Among patients diagnosed with malignancies, some will experience an acute condition caused by cancer or its treatment and require rapid intervention to avoid death or severe permanent damage, termed an oncological emergency (30,31). The manifestations are diverse, ranging from mechanical obstruction due to tumor growth to metabolic derangements due to abnormal tumor secretions. Local radiotherapy is conventionally employed in structural and obstructive oncologic emergencies, such as superior vena cava syndrome (SVCS), metastatic spinal cord compression (MSCC), hemoptysis, malignant airway obstruction (MAO), and brain metastases (BMs) with impending herniation. Previous data show a high incidence of oncological emergencies in metastatic NSCLC. At diagnosis, SVCS is present in 1.7% of NSCLC cases (32) and approximately 28% of patients with metastatic NSCLC develop MSCC (33). Hemoptysis and MAO are present in more than 20–30% of NSCLC patients, respectively (34,35). In addition to oncologic emergencies, the occurrence of cancer-related severe symptoms such as pain, cough, or hemoptysis, commonly due to loco-regional progression of primary or metastatic tumor burden, is another indication for radiotherapy (36). Once these oncologic emergencies or cancer-related severe symptoms occur, performance status (PS) is immediately adversely impacted, which prohibits the use of aggressive treatment for metastatic NSCLC. However, the timely intervention of palliative radiotherapy can prevent and reduce this barrier by offering fast, efficient symptom relief, after which the general condition of the patient can be optimized for subsequent treatment approaches.

A wealth of studies has evaluated the efficacy and safety of palliative radiotherapy (37-40). A recent meta-analysis including 14 randomized controlled studies and 3,576 patients assessed the effects of different regimens on improving thoracic symptoms and prolonging the survival of patients (36). The results showed a symptom response rate ranging from 43% to 86%, median OS ranging from 5.9 to 8.5 months, and 1-year survival rate ranging from 20.0% to 40.0%. In addition, a retrospective study reviewed the records of 140 patients treated with split-course palliative thoracic radiotherapy (PTR), and symptomatic relief was observed in 52–84% of patients, with no grade 3 to 5 toxicities (41). Pain relief was experienced by approximately 86% of patients treated with palliative radiotherapy for painful local recurrence (42), and this treatment has been proven to be cost-effective (43). In patients who developed SVCS, a symptom relief rate could be achieved in 63.0% patients with palliative radiotherapy (44). For patients with MSCC, SBRT provided a significant rate of pain relief and objective local control of over 80%, with a low (<1%) incidence of myelopathy (45). A recent study evaluated the effect of palliative external beam radiotherapy (EBRT) on MAO in 75 patients with lung cancer and analyzed the influencing factors (46). Dyspnea was improved in 61.3% of the participants, and tumor size was partially decreased in 52%. Symptom improvement was observed in most participants and was significantly related to the time taken to initiate EBRT, which indicates the importance of timely radiotherapy intervention. In addition to short-term palliation, appropriate intervention with radiotherapy provided better survival by improving PS and allowing the viability of future aggressive treatment options. Despite the median survival of 4.6 months reported in patients treated with PTR near the end of life, a longer median survival of 9.8 months was observed in those with bone metastases also treated by radiotherapy. Additionally, timely radiotherapy for bone metastasis was identified as a significant, independent, and favorable prognostic factor (47,48). In a prospective study of short-course palliative radiotherapy, 73% of participants (including those with initially poor PS) experienced an improved PS score, which was the only factor influencing survival (P=0.0289) (49). In a large-scale retrospective study, over 2% (23/963) of cases survived at least 5 years after palliative radiotherapy, with approximately 74% free of disease (50). All these data suggest palliative radiotherapy may provide long-term survival or even cure in some cases.

Oligo-focal disease states

The “oligo-metastatic disease” hypothesis describes an intermediate state between loco-regionally confined disease and diffuse metastatic disease. This idea has gained significant traction over the decades following its proposal by Hellman and Weichselbaum in 1995 (51), and supported by data and evidence from numerous clinical trials, the term has been incorporated into the American Joint Committee on Cancer (AJCC) 8^th edition staging system for NSCLC (52). Systemic therapy remains the mainstream treatment, while local therapy (LT) is playing an increasingly important role in combination therapy. At present, there is great interest in defining which patient subgroups can be expected to benefit most from radiotherapy, optimal radiotherapy timing, and the appropriate radiotherapy technology. Taking inspiration from “oligo-metastatic disease”, the terms “oligo-residual disease” and “oligo-progressive disease” have generally been used to describe stage IV patients harboring limited residual and progressive disease after a period of active systemic therapy, respectively.

Consensus 2.1: Oligo-focal disease states, which manifest as oligo-metastatic disease, oligo-residual disease, or oligo-progressive disease, are characterized by limited tumor lesions and relatively favorable oncologic outcomes

Since the “seed and soil” hypothesis was first postulated, much has been learned about the distant metastatic process (53). The metastatic cascade has various steps, including loss of cellular adhesion, increased motility and invasiveness of the primary tumor, entry into and survival in the circulation, and adhesion to the blood vessel wall followed by extravasation and colonization of new organs (54). Numerous studies have demonstrated primary tumors consist of heterogeneous subpopulations of clonogens with varying metastatic potential that can give rise to further metastases (54-57). This evidence supports the de novo phenotypes of oligo-metastatic, oligo-residual, and oligo-progressive disease, and provides a theoretically sound rationale for local radiotherapy.

Oligo-metastatic NSCLC was first defined as a maximum of five metastases and three organs, and mediastinal lymph nodes were not considered a metastatic site (58). However, the inclusion criteria across different clinical trials have been heterogenous, and based on an ESTRO-ASTRO consensus document, oligo-metastatic disease is currently defined as one–five metastatic lesions, with a controlled primary tumor being optional, but all metastatic sites must be safely treatable (5). For these patients, radiotherapy plays a role of synchronous therapy. Slightly distinct from the concept of oligo-metastatic disease, oligo-residual disease refers to the persistence of polymetastases at the onset rendered oligo-metastatic (generally one–three lesions remaining) by a period of treatment (59). In patients with oligo-residual disease, local consolidation radiotherapy may treat the remaining lesions before any progression occurs, and importantly, such treatment can be delivered safely, with minimal toxicity, in carefully selected patients (60). The term oligo-progressive disease was first introduced to describe a clinical scenario where only a few tumor lesions progressed and most of the disease was under control, with an upper limit for the number of progressive lesions instead of that of metastases (61). In this setting, the utility of radiotherapy as salvage therapy may eradicate the drug-resistant lesions and extend the duration of systemic therapy, resulting in better survival outcomes.

Consensus 2.2: PET/CT should be considered and encouraged in the process of identifying patients with oligo-focal disease states

Positron emission tomography/computed tomography (PET/CT) is a well-established molecular imaging platform enabling non-invasive quantification of the relevant biological tumor characteristics (62). Technological improvements combined with the development of new radiotracers over the past decades have extended the possibilities for disease characterization using PET/CT.

Fluorodeoxyglucose PET/CT (FDG-PET) is recommended as a first-line staging modality due to its excellent diagnostic accuracy (63). For patients with oligo-metastatic NSCLC, PET/CT can offer a higher sensitivity for global disease assessment at baseline, and evidence indicates primary tumor and oligo-metastatic lesions can be detected at an earlier stage using FDG-PET as compared with CT measurements (64). According to the European Organization for Research and Treatment of Cancer Lung Cancer Group survey on questions involving synchronous oligometastatic (sOM) NSCLC, 98% of physicians completed sOM staging with PET/CT, highlighting its role in the process of identifying patients in an oligo-metastatic state (65). Presently, clinical trials conducted in the setting of an oligo-metastatic disease state frequently require participants to undergo PET/CT before randomization and contrast-enhanced CT-scans on follow-up (66-70). It is generally believed that, compared to CT, PET/CT with its superior diagnostic accuracy will more accurately filter patients not meeting the inclusion criteria and enable better stratification of oligo-metastatic and polymetastatic disease (71). A systematic review focusing on sOM NSCLC found PET/CT was used for accurate disease staging in 81% (17/21) of the eligible articles (72).

Currently, FDG-PET using traditional standardized uptake value (SUV)-derived indices is used for early response assessment to chemotherapy and radiotherapy. Several studies have demonstrated the potential to monitor treatment effects based on SUVs on serial FDG-PET imaging of the primary tumor, and recently, the efficacy of the initial response to nivolumab was compared in metastatic NSCLC patients between CT-based criteria and ¹⁸F-FDG PET response criteria in a clinical trial (NCT02475382) (73). Despite a low concordance between the two criteria, the PET-based response demonstrated prognostic significance in patients classified as having progressive disease, indicating its potential in improving therapeutic decision making, especially in the setting of oligo-residual and oligo-progressive disease.

Consensus 2.3: Concurrent radiotherapy in combination with optimal systemic therapy for suitable patients could provide additional survival benefit for NSCLC patients with oligo-metastatic disease

A single-center retrospective study showed approximately 26% of patients with stage IV NSCLC present with oligo-metastatic disease at diagnosis as detected by PET/CT and brain magnetic resonance imaging (MRI) (74). For such patients, concurrent radiotherapy in combination with appropriate systemic therapy could provide additional survival benefit. Based on previous studies, SBRT, a metastatic radiotherapy technique with high local tumor control rates and low toxicity, boosted the 2-year local control rate to over 90% in malignancies with limited metastatic burden (75,76). A meta-analysis of 21 studies with a total of 924 oligo-metastatic NSCLC patients found both OS [hazard ratio (HR) =0.44, 95% confidence interval (CI): 0.32 to 0.6, P<0.001] and PFS (HR =0.42, 95% CI: 0.33 to 0.55, P<0.001) were significantly improved with the addition of concurrent thoracic radiotherapy to the primary tumor (77). Similarly, a survival benefit has been observed from the addition of concurrent radiotherapy to TKIs in epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-mutated patients with oligo-metastatic disease (78).

In addition to the findings of retrospective studies, the results of several prospective clinical trials have provided convincing evidence demonstrating the efficacy of radiotherapy in oligo-metastatic NSCLC (79). According to Gomez et al., local consolidative radiotherapy or surgery could offer an obvious survival benefit in patients with three or fewer metastases, extending median PFS from 4.4 to 14.2 months and improving median OS from 17.0 to 41.2 months (12,80). The interim reports of a randomized phase III, open-label clinical trial (SINDAS) showed the combination of EGFR-TKI and concurrent SBRT significantly extended the PFS (20.2 vs. 12.5 months) and OS (25.5 vs. 17.4 months) in patients harboring EGFR mutation when compared to EGFR-TKI alone (81). In a phase II study where most (17/29) participants received SBRT after induction chemotherapy, the overall metabolic response rate was 60%, with a median PFS and OS of 11.2 and 23 months, respectively (68). All these results demonstrate the critical role of concurrent radiotherapy in combination with proper systemic therapy in oligo-metastatic NSCLC.

Consensus 2.4: Consolidative radiotherapy may improve survival for patients with oligo-residual disease after systemic therapy

Despite the favorable response rate and survival outcomes produced by TKIs in oncogene-addicted patients, progression inevitably develops in most cases after 1–2 years of treatment (82-87). For patients who receive initial systemic therapy and have oligo-residual disease, local consolidative radiotherapy outside the CNS is strongly suggested for several reasons. Firstly, disease progression at the original site is the predominant pattern of failure for patients treated with first-line systemic therapy (88). Secondly, as tumor growth follows a sigmoidal pattern and the effect of systemic therapy is proportional to the rate of tumor growth, consolidative radiotherapy may move the tumor growth curve back to a state of exponential growth and augment the antitumor activity of systemic therapy (89). Thirdly, local consolidative radiotherapy might serve as a means of eliminating an evolutionary reservoir of resistant subclones and help extend the use of systemic therapy (90). The results from a pattern of failure analysis in metastatic NSCLC indicated approximately 20% of patients were considered consolidative SBRT candidates based on the extent of disease at the time of maximum response to TKI therapy (91). Similarly, Guo et al. analyzed the serial imaging of patients with TKI-treated oligo-residual NSCLC and identified 26.8% patients as candidates for consolidative SBRT at the time of maximal response (92).

Accumulating evidence suggests local consolidative radiotherapy could improve survival in patients with metastatic NSCLC (93). A multicenter, retrospective study reviewed 84 cases of stage IV NSCLC treated with systemic therapy and found the OS was significantly higher in patients undergoing local consolidative radiotherapy than in those who did not (13 vs. 7 months, P=0.002) (94). The survival benefit of consolidative radiotherapy is more apparent in highly selected patients, and in patients with limited metastatic NSCLC without EGFR- or ALK-mutations, SBRT prior to maintenance chemotherapy nearly tripled PFS to 9.7 months compared with maintenance therapy alone, with no difference in toxic effects (11). Similar results have been reported by several prospective studies, including the ATOM trial, where the efficacy of preemptive SBRT was assessed in patients with oligo-residual disease after TKI therapy, and a 1-year PFS rate of 68.8% and median OS of 43.3 months were reported, with no occurrence of grade 3 or higher SBRT-related toxicities (67). In the same trial, the risk of progression was lower in participants receiving preemptive SBRT compared with those unfit for SBRT due to screen failure (HR =0.41, P=0.0097). More recently, prolongation of PFS and OS by local consolidative SBRT was seen in patients with oligo-metastatic NSCLC without progression after front-line therapy (70).

Consensus 2.5: For patients who develop oligo-progressive disease after acquired resistance to targeted therapy or ICIs, salvage radiotherapy could prolong the time to treatment failure and potentially improve OS

Oligo-progression is a common phenomenon in TKI-treated oncogene-addicted NSCLC (95-97), and is increasingly encountered in patients treated with ICIs (98-100). Once acquired resistance (AR) is identified, systemic treatment options include next generation TKIs or other ICIs, introduction of other biological agents targeting bypass signaling pathways leading to AR, and chemotherapy. Although a subset of patients might benefit from these approaches, further development of resistance or lack of tolerability eventually results in discontinuation of treatment. In this instance, the use of radiotherapy as a salvage approach to eradicate TKI- or ICI-resistant subpopulations, extend the duration of systemic therapy, and result in improved OS, is of great clinical significance.

Clinical observations suggest a growing role of salvage radiotherapy in the treatment of oligo-progression. The proportion of oligo-progression cases ranged from 15% to 47% during first-generation TKI treatment and increased to approximately 70% with third-generation TKI (101-103). Intracranial oligo-progression is a frequent and serious phenomenon in patients treated with TKIs due to their inadequate ability to penetrate the BBB. A retrospective study of 232 patients treated with first-generation TKIs showed the site of first disease progression was the CNS in 16% of patients (104), and among those with ALK rearrangements, 20–46% developed isolated CNS metastases at the time of progression after TKI treatment (105). In a study of patients with extra-cranial oligo-progression, 49% were considered suitable for local radiotherapy or surgery (106). In terms of survival benefit, the results from a retrospective study showed the addition of LT to TKIs resulted in a significantly longer median PFS (13.9 vs. 9.2 months, P=0.007) and OS (28.3 vs. 17.1 months, P=0.011) in the oligo-progressive cohort and locoregional recurrence was the major pattern of failure in the switching chemotherapy group (107).

A growing body of evidence demonstrates the efficacy of radiotherapy in oligo-progression after ICI treatment. In a retrospective study of 26 patients with AR to programmed cell death protein-1 (PD-1) axis inhibitor therapy, 88% of cases had recurrence limited to one (54%) or two (35%) sites of disease, and among the 15 patients who went on to receive salvage systemic therapy, the median survival time and 2-year survival rate from AR were 27 months and 69% (95% CI: 0.48 to 1), respectively (108). A total of 15 patients received LT to sites of AR, 11 of whom continued respective PD-1 axis inhibitor after LT, and among the 15, the median survival time from AR was not reached, and the 2-year survival rate from AR was 92% (95% CI: 0.77 to 1). The superior survival in patients who received LT (including radiotherapy) indicates local radiotherapy to oligo-progression with continuation of ICIs should be considered. Similarly, a significantly longer PFS (12.9 vs. 10.0 months, P=0.006) and OS (26.3 vs. 18.5 months, P=0.001) with local radiotherapy plus continued immunotherapy were seen in patients with oligo-progression from ICI treatment, compared with the survival in patients not receiving local radiotherapy (109). All these data indicate the potential role of salvage radiotherapy in oligo-progressive NSCLC from ICI treatment, and an ongoing study by Alliance (USA; NCT04929041) will directly address the role of SBRT in programmed death ligand 1 (PD-L1)-negative patients.

Consensus 2.6: Multisite SBRT targeting oligo-focal tumor lesions could provide additional clinical benefit for selected patients

Although the oligo-metastatic phenotype may arise de novo in patients with NSCLC, it may also be rendered by tailored systemic therapies, in which it is termed oligo-residual disease. Additionally, advances in diagnostic imaging have led to greater sensitivity in identifying patients with oligo-focal disease states. These factors predict a future increase in the incidence of oligo-metastatic, oligo-residual, and oligo-progressive NSCLC, and it is of great importance to administrate the optimal therapeutic strategy in this highly selected group of patients.

The SBRT procedure is an advanced radiotherapy technique which precisely delivers high radiation doses over a limited number (fraction) of treatments. With the accurate delivery of multiple small radiation fields, radiation damage can be minimized outside of the target lesions (organs at-risk). Although the precise dose-response relationship at high doses per fraction is controversial, the proportion of cells killed appears to increase at least exponentially with dose and may involve destruction of the vascular endothelium (110,111). Thus, the dose-fraction relationship of SBRT may be far more effective at killing tumor cells than the equivalent total dose conventionally given over many smaller fractions. A wealth of clinical studies have demonstrated SBRT can produce high tumor control rates along with a favorable toxicity profile delivered to one–three metastatic sites (75,112-114). However, it can still be a significant challenge to deliver SBRT to patients with more than three metastases or those with two metastases in close proximity. As the number of metastases increases, treatment-related toxicity may increase because of the interval and the cumulative radiation dose to the surrounding organs. Additionally, the prior radiotherapy may limit further dosing to surrounding normal tissues, magnifying the difficulty in delivering multiple courses of SBRT.

Due to the rapid refinement of SBRT techniques, there is growing interest in exploring its utility in patients with multiple metastases. The NRG-BR001 phase I trial was performed to evaluate the safety of SBRT in patients with three–four metastases or two metastases in close proximity (≤5 cm) to each other. The starting dose schedule was 50 Gy in five fractions (central lung and mediastinal/cervical lymph node), 45 Gy in three fractions (peripheral lung, abdominal-pelvic, and liver), and 30 Gy in three fractions (bone and spinal/paraspinal). Among the 39 patients evaluable for dose-limiting toxicity (DLT), no protocol-defined DLTs were observed, and the safety profile of SBRT treatment for multiple metastases was shown to be similar to that reported from the treatment of single metastases and primary tumors (11,80,115-117). These findings suggest up to four separate metastatic sites can be safely treated with curative-intent SBRT doses. Ongoing phase II/III National Cancer Institute-sponsored trials (NRG-BR002, NRG-LU002) will further assess the efficacy of treatment with SBRT for multiple metastases.

CNS metastases

Approximately 20–40% of patients diagnosed with NSCLC develop BMs during the course of the disease (118), and the management of BMs is an age-old problem in real-world clinical practice. Due to the presence of the BBB and the poor passage of traditional cytotoxic agents across it, limited therapeutic options have been available beyond LT, including surgical resection and radiotherapy. However, in recent years, the role of systemic therapy in the management of BM has been dramatically reinforced due to the advent of new-generation highly CNS-penetrant TKIs (e.g., osimertinib and alectinib) and immunotherapeutic agents, which have demonstrated promising activity in the CNS. The ever-growing therapeutic armamentarium for BM also raises key questions about the role of CRT in multidisciplinary care, including the appropriate choice of radiation techniques, optimal sequence of systemic therapy and radiotherapy administration, and ideal candidates for this combination treatment strategy.

Consensus 3.1: For oncogene-addicted NSCLC with baseline BM, upfront CRT in combination with corresponding TKIs may provide additional survival benefit among selected patients with favorable profiles (especially oligo-metastatic BM). Otherwise, next-generation TKIs with stronger potency against BM should be preferred as first-line treatment, and upfront whole brain radiotherapy may be deferred

In the era of first-generation TKIs, the role of CRT for patients with oncogene-driven NSCLC with BM has been investigated in numerous studies (119-122). In a retrospective analysis of 93 patients with metastatic ALK-rearranged NSCLC treated with crizotinib, Ni et al. observed CRT before crizotinib could alter the disease recurrence patterns and prolong PFS for patients with baseline BM (119). A meta-analysis of published studies also reported a longer PFS among patients with BM harboring EGFR or ALK mutations treated with the combination of TKIs plus radiotherapy compared with TKI alone (18.6 vs. 13.6 months, P=0.06). However, no significant OS benefit was observed with the addition of CRT to TKIs (120). In contrast, a retrospective study involving 571 patients with EGFR-mutated NSCLC-BM treated with TKIs reported a significant difference in OS between patients treated with and without intracranial local radiotherapy (23.6 vs. 17.0 months, P=0.0008) (121). The divergent conclusions derived from various studies on combination TKIs and CRT in oncogene-driven NSCLC may be attributable to the heterogeneity of the patient populations and treatment modalities across studies.

Further studies with more detailed patient stratification and classification of LT have lent credence to the crucial role of CRT for patients with oncogene-driven NSCLC with BMs. A retrospective analysis of patients with ALK-rearranged or EGFR-mutant NSCLC with multiple (≥4) BM reported single and multiple courses of radiosurgery without whole brain radiation therapy (WBRT) were well tolerated and could be an effective treatment strategy for these patients (123). Another retrospective analysis of patients treated with WBRT+TKI, stereotactic radiosurgery (SRS) +TKI, or TKI alone for ALK-rearranged or EGFR-mutant NSCLC suggested a prolongation of time to intracranial progression in those treated with WBRT+TKI, with no significant differences in OS between the three groups (124). This study provided preliminary evidence for the use of TKI+SRS or TKI alone in selected patients on active surveillance for intracranial recurrence. Yomo et al. investigated the impact of concurrent or post-SRS EGFR-TKI use on the efficacy and toxicity of SRS for lung adenocarcinoma with BM in propensity score-matched cohorts, and found the use of TKIs was associated with a longer median OS (25.5 vs. 11.0 months, HR 0.60, 95% CI: 0.48 to 0.75, P<0.001). Moreover, previous literature has suggested the safety profile of combined EGFR-TKI and SRS is acceptable, with no significant increase in severe adverse event rates observed in relation to this combination treatment (125-127). Of note, the risk of radiation necrosis was found to increase when SRS was performed after development of TKI resistance (128).

The appropriate sequence of TKIs administration and CRT has also been explored in various studies. A retrospective analysis using data from a multi-institutional cohort of 351 patients with EGFR-mutant NSCLC reported those who received SRS followed by TKI had a longer OS than those who underwent WBRT followed by TKI or TKI followed by SRS or WBRT (129). Similarly, Lee et al. reported the median survival times for patients with brain-metastatic EGFR-mutant NSCLC treated with immediate WBRT, immediate SRS, delayed radiotherapy upon intracranial progression, and no CRT were 18.5, 55.7, 21.1, and 18.2 months, respectively (P=0.008). Moreover, immediate SRS and fewer extracranial lesions have been associated with improved survival (130). Miyawaki et al. evaluated the clinical value of upfront LT in a retrospective study involving 176 patients with EGFR-mutant NSCLC, with a particular focus on the efficacy of upfront cranial radiotherapy (uCRT) in subgroups of patients stratified by the number of BM (1–4 vs. >4) (131). Among all participants, 107 (61%) received upfront TKI and 69 (39%) received upfront LT, and of the latter group, most (82%) of those with >4 BM received WBRT, while all patients with 1–4 BMs received SRS. The beneficial effects of upfront LT in terms of PFS and OS were more prominent in patients with 1–4 BMs (median PFS, 14 vs. 9.1 months; HR, 0.57; 95% CI: 0.34 to 0.91; P=0.02; median OS, 35 vs. 23 months; HR 0.54; 95% CI: 0.32 to 0.90; P=0 .02) than in patients with >4 BM, among whom no significant benefit was observed in PFS and OS (median PFS, 8.4 vs. 7.4 months; HR 1.13; 95% CI: 0.70 to 1.80; P=0.61; median OS, 22 vs. 27 months; HR 1.08; 95% CI: 0.64 to 1.81; P=0.76). These findings suggest personalized therapeutic strategies should be carefully tailored to individual patients depending on their general condition and characteristics of BM.

Recently, the promising efficacy of new generation targeted therapies in patients with ALK rearranged or EGFR mutant NSCLC with BM has been reported in numerous prospective and retrospective studies, with impressive response rates and notable improvements in CNS-PFS and OS (132-134). The approval of new generation TKIs (e.g., osimertinib and alectinib) with better BBB penetration compared with earlier generations for oncogene-addicted NSCLC raises questions of immense clinical interest regarding the role of CRT. The results of the exploratory analyses of two phase II trials showed alectinib-treated patients with ALK-positive NSCLC and baseline BM progressed at a higher rate in the CNS, as suggested by a higher cumulative incidence rate of CNS progression than non-CNS progression at 24 months (43.9% vs. 31.0%) (135). Another exploratory analysis of CNS efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive NSCLC also suggested patients were at a higher risk of CNS progression than non-CNS progression, even if they received a selective CNS-active ALK inhibitor (136). In a secondary analysis of the phase III ALEX study, the 12-month cumulative incidence of CNS progression was lower in patients with baseline BM treated with both radiotherapy and alectinib compared with those who had not received previous radiotherapy (8.6% vs. 20.5%, no P value given) (137). This suggests the addition of radiotherapy, especially SRS, to alectinib may provide long-term intracranial disease control compared with ALK-targeted therapy alone.

For patients with EGFR mutant NSCLC, subgroup analyses from a phase II trial of 160 mg osimertinib in EGFR T790M-positive NSCLC with BMs who progressed on prior TKI therapy demonstrated those who had previously undergone radiotherapy had a longer PFS than radiotherapy-naïve patients (138). A Bayesian network meta-analysis demonstrated the combination of TKIs (gefitinib/erlotinib) and SRS/WBRT ranked first in terms of OS, followed by third-generation TKIs (osimertinib), suggesting the addition of cranial radiation to targeted therapies may provide the greatest survival benefit (127). A recent retrospective study involving 135 first-generation EGFR-TKI-resistant NSCLC patients with an acquired EGFR T790M mutation included 54 patients with BM (139), and found those who received osimertinib combined with CRT had a median OS of 53 months versus 40 months for those treated with osimertinib alone (P=0.014). These findings suggest the combination of new generation TKIs and CRT could have a positive impact on patient outcomes over TKIs alone. Furthermore, a recent multi-institutional retrospective study of patients with NSCLC-BM conducted by Yu et al. provided valuable insight into the clinical value of uCRT via a detailed analysis of patterns of recurrence on osimertinib and the impact of uCRT on patient outcomes stratified by the number of BM (140). Patterns of recurrence analysis revealed 40.2% of the initial progression on osimertinib involved the brain and most (76.9%) of intracranial progression occurred at the original BM sites, providing a rationale for uCRT before progression occurs. Additionally, in the propensity-score matching oligo-BM cohort, the uCRT group demonstrated improved OS compared with the non-uCRT group, and no significant differences in OS were reported in the subgroup of patients with multiple BM. More mature data on the efficacy of this combination treatment strategy are needed to provide a benchmark for individualized treatment in the future.

Consensus 3.2: CRT in combination with ICIs could be safe and provide additional clinical values in selected patients with driver mutation-negative NSCLC. However, evaluation on a case-by-case basis is warranted

The advent of ICIs has revolutionized the treatment approach for metastatic lung cancer. The approval of PD-1/PD-L1 inhibitors for metastatic NSCLC also raises questions about the interaction of CRT in relation to anti-PD-1/PD-L1 therapy for patients with BM. The current body of clinical data suggest combining ICI treatment with CRT for the management of NSCLC-BM could be superior to radiotherapy alone or exclusively systemic therapy in terms of local tumor response and survival outcomes, presumably due to the immunologic effects of radiotherapy in the tumor microenvironment (141-147). Shepard et al. observed the combination of ICI and SRS resulted in an increased rate of complete response (CR) in the CNS for NSCLC-BM treated with SRS according to the Response Assessment in Neuro-Oncology (RANO) criteria compared with SRS alone, with a shorter median time to BM regression (143). Chen et al. retrospectively analyzed the survival outcomes of patients with NSCLC, melanoma, and renal cell carcinoma (RCC) with BM treated with concurrent SRS and ICI (145), and reported a superior median OS relative to those who underwent non-concurrent SRS/SRT and ICI (24.7 vs. 14.5 months; P=0.006) or SRS/SRT alone (24.7 vs. 12.9 months; P=0.002). These observations echo those of other recent studies (148-150), which suggest concurrent SRS and ICI is the preferred therapeutic strategy to sequential SRS and ICI to maximize the synergy between ICI and radiotherapy for the treatment of patients with BMs. Schapira et al. reported patients who underwent concurrent SRS and anti-PD-1 therapy (defined as the receipt of SRS within 1 month of anti-PD-1 therapy) had improved local control and OS compared with those treated with SRS before or after anti-PD-1 therapy (150).

Clinical safety is an obvious concern when combining ICIs and CRT for the treatment of patients with NSCLC-BM. The short-term safety profile of combining the two seems to be acceptable, with no significant increase in immune- or radiotherapy-related adverse events (145,146,149-151). However, some studies have raised the concern that ICI treatment may increase the risk of radiation necrosis (152-154), and it is worth noting current data regarding the combination of ICI and CRT in the management of NSCLC-BM is limited to retrospective studies. The appropriate therapeutic index of combining CRT with ICI and the toxicities of this combination strategy, especially regarding long-term neurological and cognitive sequelae, remains to be clarified. The combination of CRT and ICIs seems to be safe, and holds promise to provide extra clinical values in selected patients. However, until more robust clinical trial data are published, caution is warranted with the addition of CRT. The decision regarding the use of CRT and timing relative to immunotherapy should be made by a multidisciplinary thoracic tumor board, on a case-by-case basis depending on the patient’s PS, PD-L1 expression status, neurological symptoms, corticosteroid use, tumor location, number of lesions, and size characteristics of metastatic brain lesions.

Consensus 3.3: The decision to use SRS or WBRT should be individualized based on clinical expertise, patient values, and logistical considerations

Historically, WBRT has been the mainstay local treatment modality for BM. However, this treatment paradigm has been challenged over the past decade by growing concerns over neurocognitive dysfunction following treatment which have arisen from the results of prospective trials evaluating the safety and efficacy of SRS plus WBRT versus SRS alone for the treatment of BM (155,156). Due to the superior preservation of neurocognitive function with no compromise in survival outcomes with the use of SRS alone compared with WBRT, SRS has now become the most widely used local treatment modality for selected patients with limited [1–4] BM (157,158).

More recently, technological advances in SRS have enabled the management of patients with larger numbers of BMs, and the role of SRS for multiple (>4) BM is rapidly evolving (159). A multi-institutional prospective observational study from the Japanese Leksell Gamma Knife Society demonstrated no significant differences in OS among patients with 2–4 BM treated with SRS compared with those with 5–10 BM (160). Similarly, Hughes et al. reported patients undergoing initial SRS for 5–15 BM had similar OS compared to those with 2–4 BM (161). These findings suggest SRS may be an effective treatment modality in selected patients with multiple BM, and the decision to use SRS or WBRT should not depend solely on the number of BM. Another retrospective analysis of 64 patients undergoing SRS for ≥5 BM showed a Karnofsky performance scale (KPS) score of ≥80, rather than the number of metastatic brain lesions, was predictive of an improved survival outcome (160). Several other studies have shown cumulative intracranial tumor volume might have more prognostic impact than the total number of BM (162,163). Therefore, the choice of SRS or WBRT should be individualized to each case based on clinical expertise, patient values, and logistical considerations. Several ongoing randomized clinical trials (NCT03550391, NCT01592968, NCT03775330, NCT03075072) are investigating the efficacy of SRS in patients with ≤20 BM.

Consensus 3.4: CRT is generally not recommended for improving survival in patients with leptomeningeal metastasis

Leptomeningeal metastasis (LM) is another serious CNS complication whereby cancer cells spread to the subarachnoid space. It remains a devastating clinical problem historically associated with poor prognosis, with a median survival of 3.0 months (164).

Management of LM includes approaches such as WBRT, craniospinal irradiation (CSI), and the elimination of focal lesions by SRS and SRT, although controversy exists regarding the efficacy of WBRT for LM. In a retrospective analysis of 149 NSCLC patients with LM conducted by Lee et al., WBRT was one of the positive prognostic factors for OS on multivariate analysis (165). However, studies have also suggested WBRT provides no benefit in OS. Morris et al. reported data from 125 NSCLC patients with LM, of whom 46 received WBRT, and observed no significant differences in survival between patients treated with and without WBRT (164). Similarly, Li et al. retrospectively analyzed a series of 109 consecutive EGFR-mutant NSCLC patients with LM and reported that compared with TKIs alone, TKIs plus WBRT did not confer any survival benefit (166).

For most patients with LM, multiple lines of treatment can weaken the immune system and affect overall PS. Thus, caution is warranted with CSI for LM, as the former can cause serious treatment-related side effects, leading to aggravation of clinical symptoms. The safety and efficacy of CSI in patients with LM from breast cancer (n=9), lung cancer (n=3), and other cancers (n=3) were investigated in a retrospective study in which patients with lung cancer experienced no improvement in neurological symptoms, the median OS added up to 3 months, and there were six cases of grades 3 and 4 toxicity and three treatment-associated deaths (167). While several studies have suggested SRS may be particularly useful in appropriately selected cases with focal lesions in the salvage setting (168,169), future studies are necessary to explore its safety and efficacy for patients with focal leptomeningeal disease.

In summary, while cranial radiotherapy (RT) is generally not recommended for patients with LM, WBRT can still be considered for symptom palliation. The efficacy of WBRT for NSCLC patients with LM is still uncertain, and caution is warranted for the use of CSI for LM. Identification of prognostic factors that predict patients likely to derive benefit from cranial RT, and the combination of cranial RT with immunotherapies and targeted therapies for the management of LM, are worthy of further clinical research.

Combining radiation and ICIs

The use of ICIs has revolutionized oncology practice for metastatic NSCLC, with responses often durable to several years in a subset of patients. Currently, PD-1/PD-L1 inhibitors, such as pembrolizumab, nivolumab, and atezolizumab, have demonstrated impressive efficacy in prospective randomized trials and are approved by the Food and Drug Authority (FDA) for patients with metastatic NSCLC (170-172). However, despite the encouraging outcomes achieved with ICIs, the objective response rate (ORR) of ICI monotherapy is still unsatisfactory, and AR inevitably occurs in most patients. Given the profound immune-modulatory effects of radiation, combining radiotherapy and ICIs to improve the therapeutic ratio for metastatic NSCLC is currently a burgeoning area of preclinical and clinical research.

Consensus 4.1: Appropriate radiation therapy can enhance the efficacy of ICIs with manageable toxicities in patients with metastatic NSCLC

To date, pre-clinical and clinical evidence have provided a strong rationale for the combination of radiotherapy and ICIs. Mechanistically, radiation can, via various mechanisms, increase tumor cell susceptibility to immune-mediated killing. For example, radiation can induce immunogenic cell death (ICD) and trigger the release of tumor antigens and the production of type I interferons (IFN) (173). Moreover, the radiation-induced local release of pro-inflammatory cytokines [e.g., tumor necrosis factor (TNF) and interleukin-1β (IL-1β)] and damage-associated molecular patterns trigger the infiltration and activation of immune cells, resulting in a favorable tumor microenvironment for anti-tumor immunity (174-176). Apart from the local immunologic effects in the tumor microenvironment, radiation also enhances a systemic anti-tumor response, which manifests as an out of field “abscopal” effect (177), and growing evidence suggests an in situ vaccine effect of radiation underscores this effect (178). Notably, radiation-induced upregulation of PD-L1 on tumor cells also triggers detrimental immunologic effects (179), and targeting these with the addition of ICIs can overcome adaptive immune resistance and augment the efficacy of radiotherapy.

The current body of clinical data suggests radiotherapy can enhance the efficacy of ICIs with an acceptable safety profile in patients with metastatic NSCLC (26,142,180). A secondary analysis of the KEYNOTE-001 trial conducted by Shaverdian et al. suggested a prolongation of PFS and OS in patients who received both thoracic radiotherapy and pembrolizumab compared with those with no previous thoracic radiotherapy, and no statistically significant differences in the incidence of pulmonary toxicity of any grade were observed between the two groups (63% vs. 40%, P=0.052) (142). A recent retrospective study involving 269 metastatic NSCLC patients treated with nivolumab or pembrolizumab included 102 patients who underwent radiotherapy within 3 months of initiation of anti-PD-1 therapy or subsequently during anti-PD-1 therapy (180), and the addition of radiotherapy to anti-PD-1 therapy was not associated with increased toxicity. The efficacy and safety of ICIs in combination with radiation has also been explored in several prospective trials. The results from recently published safety run-in data of a multicenter, single-arm, phase II trial of sintilimab, SBRT, and granulocyte-macrophage colony stimulating factor as second-line therapy for metastatic NSCLC have demonstrated this combination strategy was safe, with manageable treatment-related adverse events (181). In addition, the results of a phase I/II study, the MDACC trial, demonstrated concurrent pembrolizumab and radiotherapy was safe, with few high-grade adverse events (182). Moreover, exploratory findings have demonstrated that for patients with low PD-L1 expression, median PFS was significantly improved with the combination of radiotherapy and pembrolizumab versus pembrolizumab alone (20.8 vs. 4.6 months, P=0.004). The phase II PEMBRO-RT study randomized patients with metastatic NSCLC to receive pembrolizumab either alone or after radiotherapy to a single tumor site. This study demonstrated no significant increase in treatment-related toxicity between the two arms, and ORR at 12 weeks and median PFS and OS were improved with the addition of radiotherapy (26). The results from a pooled analysis of the PEMBRO-RT trial and the MDACC trial demonstrated both OS (median 19.2 vs. 8.7 months, P=0.0004) and PFS (median 9.0 vs. 4.4 months; P=0.045) were improved with the addition of radiotherapy (27), and adding radiotherapy to pembrolizumab significantly increased the best abscopal response rate compared with pembrolizumab alone (41.7% vs. 19.7%, P=0.0039). Additionally, in a phase II study of 64 patients with 1–4 oligometastases from NSCLC, all participants underwent locally ablative therapy (resection and/or radiotherapy), with many receiving systemic chemotherapy, followed by a course of pembrolizumab. The median PFS (19.1 months) and 2-year OS (91%) were markedly better than those of the historic controls (183). These encouraging results suggest ICIs may have their greatest clinical impact in combinatorial regimens, and further support for systematic investigation of the combination of ICIs and radiotherapy is urgently required.

Consensus 4.2: Different dose-fractionation regimens can have diverse immunologic effects in the modulation of the tumor microenvironment and could impact the treatment efficacy of combined therapy

An increasing body of eloquent preclinical work indicates different dose-fractionation regimens can have diverse immunologic effects in the tumor microenvironment. On the one hand, radiation exposure to single fraction doses of just 1–3 Gy can have destructive effects on lymphocytes (184), and radiation dose per fraction and fraction number are among the factors correlating with radiation-induced lymphopenia (185). There is emerging evidence indicating radiation-induced lymphopenia is linked with poorer outcomes in patients with NSCLC (186,187), and the absolute lymphocyte count is a predictive factor of the response rate to ICI treatment (188,189). On the other hand, radiotherapy can be immune-activating through enhanced antigen presentation (190), and different radiation doses in a single fraction or short-course fraction regimen may induce diverse immunogenic effects. For example, Reits et al. reported that in irradiated tumor cells, radiation induced a dose-dependent increase in MHC-1 (191), which is essential for T-cell-mediated tumor cell killing. In addition, Vanpouille-Box et al. demonstrated high doses above 12–18 Gy may attenuate radiation-driven anti-tumor immunity through inducing Trex1 exonuclease expression and degrading cytosolic DNA (192). Thus, moderately fractionated doses (e.g., 8–12 Gy) below the dose threshold for Trex1 induction may be optimal for IFN-stimulatory DNA accumulation, cGAS/STING pathway activation, and induction of anti-tumor T cell responses.

Additionally, substantial work over the past decades has expanded understanding of the great difference in the immune response after irradiation with varying fractionation schedules. In a mouse model of ovalbumin (OVA)-expressing B16–F0 tumors, researchers observed enhanced antigen presentation and T-cell priming in draining lymph nodes after single (1×15 Gy) or fractionated (5×3 Gy) doses of localized radiation. Notably, compared with a 5×3 Gy fractionated schedule, 1×15 Gy irradiation led to greater numbers of host immune cells infiltrating the irradiated tumors (193). In another murine study by Schaue et al., antitumor responses were evaluated in mice bearing B16-OVA melanoma treated with up to 15 Gy radiation in various sized fractions (194), and found single-dose radiation of 7.5 and 10 Gy were successful in stimulating an effective antitumor immune response, but not 5 Gy. Compared with other fractionation schedules (5×3, 3×5, 1×15 Gy), two fractions of 7.5 Gy gave the maximal tumor control and antitumor immunity while maintaining low regulatory T cell (Treg) numbers. The diverse immunologic effects of varying dose-fractionation regimens on the tumor environment were further highlighted in a preclinical study showing the use of 30 Gy single-dose irradiation transformed the immunosuppressive tumor environment by decreasing the infiltration of myeloid-derived suppressor cells, while the addition of 10×3 Gy to the single dose of 30 Gy resulted in significantly increased infiltration of myeloid-derived suppressor cells (195). Overall, these findings suggest different dose-fractionation regimens of radiation can have diverse immunologic effects in the modulation of the tumor microenvironment and could significantly impact treatment efficacy when combined with ICIs.

Increasingly, studies suggest hypo-fractionated radiation, especially SBRT, may induce more potent antitumor immunity than conventionally fractionated radiotherapy. Using SBRT allows a high-dose per fraction to be delivered to the tumor with an exceedingly high level of conformality and limited exposure of adjacent critical structures. Thus, SBRT has the potential to better preserve lymphocyte function and induce more potent antitumor immunity compared with conventional fractionation regimens. Indeed, an increasing body of preclinical work suggests hypo-fractionated radiation may be more immunogenic than standard fractionation (196-198). Lan et al. reported that compared with conventional daily low-dose fractionated radiotherapy, hypo-fractionated schemes reduced vascular endothelial growth factor expression and inhibited recruitment of myeloid-derived suppressor cells into tumors (199). Grapin et al. investigated the effect of different fractionation schemes (3×8, 18×2, 1×16.4 Gy) on the immune response in an in vivo murine model (198). They found each fractionation protocol induced different lymphoid and myeloid responses with standard fractionation inducing a predominantly myeloid response and hypo-fractionated radiation inducing an intense and predominantly lymphoid response which may be more favorable for anti-tumor adaptive immunity.

While these studies explored the immunologic effects of hypo-fractionated radiation, the potential synergy of hypo-fractionated radiation in combination with ICIs has also been reported. In a mouse model, researchers demonstrated 3×8 Gy was the most effective scheme compared with other fractionation protocols (18×2, 1×16.4 Gy) when combined with anti-PD-L1 therapy (198). Dewan et al. explored the effects of different SBRT fractionation schemes (1×20, 3×8, 5×6 Gy) combined with anti-CTLA-4 antibody on tumor growth in a murine model of TSA mouse breast carcinoma (197), and found the combination treatment led to enhanced or complete primary tumor regressions compared with the use of an anti-CTLA-4 antibody alone. Intriguingly, researchers noted substantial growth inhibition of the tumor outside the radiation field (abscopal effect) when an anti-CTLA-4 antibody was added to the fractionated radiotherapy but not the single-dose regimen. There have also been several case reports describing the abscopal effect in patients with metastatic NSCLC treated with the combination of ICIs and SBRT (200). Furthermore, the results from a pooled analysis of the PEMBRO-RT trial and the MDACC trial showed a striking improvement in abscopal response rate for patients treated with pembrolizumab plus SBRT at either 50 Gy in four fractions or 24 Gy in three fractions, compared with those treated with pembrolizumab plus IMRT at 45 Gy in 15 fractions or pembrolizumab alone (27).

Collectively, the current body of preclinical and clinical data suggests hypo-fractionated radiation, especially SBRT, may induce more potent antitumor immunity than conventionally fractionated radiotherapy. The optimal dose-fractionation regimen remains a controversial quandary, with a growing body of preclinical evidence favoring 3×8 Gy, and several ongoing clinical trials (NCT04081688, NCT03801902, NCT03589547, NCT03237377) are investigating the efficacy of the combination of ICIs and non-conventional fractionation regimens.

Limitations

Although the current consensus was reached by an international multidisciplinary team centering around radiotherapy-based treatment for metastatic NSCLC, limitations are inevitable since phase III clinical studies were not available in every clinical scenario discussed and considerable heterogeneity existed in terms of methodology and patient characteristics among the studies providing the crucial supporting evidence.

Furthermore, besides oligo-metastasis, CNS metastasis, and synergic effects between radiotherapy and immunotherapy, the current consensus also included palliative radiotherapy, with the main purpose of presenting a comprehensive view of the clinical utilities of radiotherapy in the management of metastatic NSCLC.

Questions to be further discussed and considered

(I) To maximize the synergy between ICIs and radiotherapy, should all sites of disease be targeted by radiotherapy? If not, which is the optimal site of metastases to be targeted by radiation (lung vs. liver vs. lymph node vs. bone vs. others)?

Arturo Navarro-Martin: In my opinion, it depends on which kind of patient we are referring to. In an oligometastatic patient, we can treat all metastatic locations to increase the local control. However, in the poly-metastatic setting, I think we must choose the most immunogenic dose and the most immunogenic location to increase the PFS. Given the choice of which location will be the most immunogenic, some authors (201) suggest this will be lung metastases, as liver metastases are less immunogenic. In addition, Chicas-Sett et al. (202) suggest irradiation should be performed over visceral lesions instead of bone and lymph nodes. Therefore, in my opinion, lung lesions should be targeted first.

Dirk De Ruysscher: We do not know what the optimal sites for irradiation are in the context of synergy of radiotherapy and immune therapy. Theoretically, irradiating all sites with a detectable tumor would lower the tumor burden to an extent that immune therapy may be more efficient. On the other hand, too large a volume of the body, including the bone marrow, and/or the circulating pool of lymphocytes and stem cells may then receive a significant radiation dose, which may cause lymphopenia and immune suppression. This is topic of ongoing research (203).

Ben G. L. Vanneste: In my opinion, not all sites should be targeted by radiotherapy, as the goal is to obtain a systemic effect with LT in combination with the ICI. Although the optimal effect for choice of site is not known, and is part of investigations, it should be a site where no/the lowest side-effects are expected, taking into account the surrounding organs to avoid stereotactic ablative radiotherapy (SABR) with overlap of the intestines, and avoiding the use of large fields on bone marrow.

J. Isabelle Choi: This is very much an area of active investigation. Oncologically, all sites should be targeted to maximize local tumor control, but it may be possible that intentionally not targeting one or more sites can increase immunogenicity and lead to better outcomes. More research is needed in this field, but for now, the more common approach would be to target all sites in a patient with oligometastatic NSCLC. If intentionally not targeting one or more sites, it is likely the primary tumor should most optimally be targeted, as this may be more likely to induce an immune response compared with a bone metastasis or liver metastasis. This is because it is often larger and potentially harder to control with an abscopal response, and is likely to have the highest ability to itself metastasize to additional sites.

Jacek Jassem: There is no simple answer to this question, this is highly dependent on the clinical situation and should be individualized.

Joe Y. Chang: Based on translational and clinical data, comprehensive targets coverage with radiotherapy should be considered if it is safe to do so. While tolerance and other clinical data must be considered, lung and liver, and not weight bearing bone, are optimal sites for ablative radiotherapy.

Lucyna Kepka: We have no evidence from randomized trials on the number of metastases to be treated with the addition of radiotherapy for oligometastases in cases where ICIs are used. Many trials on this issue are ongoing, and most are dedicated to the local treatment of oligometastatic disease (OMD) include all sites of the disease into the radiation field (or surgery). However, the definition of OMD varies between trials, with some including a primary in the count and others not so, which is similar for BMs. Some also include baseline metastases, and some, residual metastases (so-called “induced oligometastases”). For these reasons, it is certainly conceivable in some clinical instances for patients outside of clinical trials to receive radiation to only some metastases, whilst others might only be observed during treatment with ICIs (+/− chemotherapy). A rationale for including only some portions of the disease into a radiation volume in cases of combined immunotherapy is that too large a radiation field may lead to the depletion of lymphocytes, which reduces the immunomodulatory effect of the drugs. Additionally, in treating only a minority of lesions, theoretically it is still possible to cause a systemic anti-tumor effect via the so-called abscopal effect, described elsewhere in the article. Obviously, it is common practice to treat only progressive sites of the disease (“oligo-progression”). For baseline oligometastases, a priority for radiation is given to BMs, which are commonly managed before or at the beginning of ICI use, when the extracranial metastases are left to the action of the systemic treatment only. In addition, large volume of oligometastases +/− primary may be a reason not to perform radiotherapy. Symptomatic bone metastases are often a priority of treatment, and lung oligometastases +/− primary are sometimes not treated with radiation if the patient has concomitant lung disorders such as interstitial lung disease or a very low respiratory reserve. Concluding, we may formulate such a consensus on the radiation volume in OMD of patients treated with ICIs outside of clinical trials. If a decision on the use of radiotherapy in patients with OMD treated with ICIs is made, all accessible sites of the disease should be targeted, providing the risk of the use of radiotherapy related to the volume and location of the disease does not surpass the potential benefit of treatment. If it is not the case that all sites of the disease are targeted with radiotherapy, the choice of site should be individualized, taking into account the symptoms and characteristics of the disease.

Lukas Kӓsmann: The irradiated site may play a pivotal role in inducing ICD and durable antitumor immunity by radiotherapy (204). We recommend targeting all active sites of disease if safe radiation treatment constraints for organs at risk (OAR) can be achieved. However, we assume SBRT of bone and brain lesions may have a less synergistic effect on the establishment of an antitumor immune response compared with SBRT of the pathological lymph nodes and pulmonary lesions, including primary tumor and metastases (204-206). This could be explained by an attenuated antitumor response in the bone and intracranial compartment due to the insufficient recruitment of certain immune cell subsets from peripheral blood (207).

Michael T. Milano: When feasible, all sites should be treated. In my opinion we do not know which sites are best treated.

Paul Van Houtte: If we are looking for a synergy with ICI, all sites of metastatic disease should not be irradiated except in the presence of OMD. The site I would prefer will depend on the toxicity profile, and the lung is a good candidate because of its location and immunologic profile.

Rafal Suwinski: In my opinion, to maximize synergy between ICIs and radiotherapy, it is not necessary to treat all sites of disease. In our institutional practice, if multiple lesions exist, we select for radiotherapy the two lesions with the largest volumes. The aim of this is to release as many antigen targets as possible, while minimizing the toxicity of therapy. If multiple lesions of similar volume exist in diverse organs, we select those in organs with higher radiation tolerance doses (e.g., better lung than liver, better bone than kidney, etc.). There is weak evidence for this, the best of which comes from experience with melanoma (208-210).

Alberto Traverso: According to recent results, even if many studies come from pre-clinical models, there seems to be benefit in irradiating all site of disease for patients with >two lesions. Nevertheless, it is important to maintain consideration of the heterogeneity found within different metastatic lesions. The immune response elicited will only be efficacious for lesions sharing the same antigenic profile and sites secreting appropriate chemokines to traffic effector T-cells from the peripheral circulation.

Hiroshi Doi: I would suggest bone > liver > lung for treatment sites in terms of the synergy between ICIs and radiotherapy because it is necessary to minimize toxicities due to radiotherapy. Lymph nodes might also be avoided because of the effect on the immune reaction.

Yang-Gun Suh: I have not observed an abscopal effect in patients with NSCLC, and suspect it is very rare. Therefore, I am of the view radiation should be delivered to all active disease sites (if before the use of ICI, then for all sites, and if during the use of ICI, then for all active sites including progressing or persistent lesions).

Georges Noёl: Notably, the efficacy of the combination of ICI and radiotherapy should be studied according to at least four prisms; the efficacy in terms of local control, the impact on OS, the tolerance of combination, and the immunologic reaction of this combination.

Importantly, because of difficulties of recruitment, publications are more often retrospective or prospective trials with oligometastases in several locations without specific analysis.

Finally, the delivery of ICI and irradiation is an important issue as there appears to be variation in the focus of studies to date. Since some studies have analyzed their concurrent or non-concurrent use (145), while others have investigate drug use before, after, or currently with irradiation (26,211).

Combining ICI and stereotactic irradiation (SRS) for brain metastasis, Chen et al. reported for SRS alone, SRS plus nonconcurrent ICI, and SRS plus concurrent ICI, and found a median OS of 12.9 months, 14.5 months, and 24.7 months, respectively (145).

Theelen et al. reported a phase two trial in 76 patients receiving SRS alone (40 pts) or SRS followed with pembrolizumab (36 pts). The main irradiated locations in the experimental arm were the lung or nodes, in 24 patients. In the control arm, 21 of 40 patients (53%) showed progressive disease as best ORR compared with 14 partial responses of 36 (39%) as best ORR in the experimental group. In the overall population, significant improvement (64% vs. 40%; P=0.04) was observed in the 12-week disease control rate in favor of the experimental arm. Hence, an increase of medians of survival were 7.6 and 15.9 months, respectively, but OS was not significantly different between both groups (26).

In their series of 68 patients with 151 metastases in different location and from several primitive tumors treated with SRS and at least one pembrolizumab cycle, Luke et al. showed the mean percent change in tumor diameter was −21.7% for irradiated metastases versus −1.7% for nonirradiated metastases (P=0.0008). However, the authors did not report a difference in response according to the kind of metastases (212). In a recent review focusing on immunotherapy stereotactic irradiation and liver metastases in NSCLC, Corrao et al. failed to retrieve publications (213). However, a list of arguments led them to propose an association of ICI and SRS. On one hand, the activity of radiotherapy on vessels, the liver immune-reaction to irradiation, and the efficiency of irradiation on liver metastasis, and on the other hand, the vessel activity of bevacizumab and the activity of Checkmate 017/057 trials (214). While the specific results of nodes irradiation with ICI are rarely reported, two notable case reports presented results of the abscopal effect after the irradiation of nodes, one with the response of an unirradiated node and the other with unirradiated bone metastases (215,216).

SRS is efficient in adrenal metastasis (217-219). Arcidiacono et al. showed results were better for metachronous-oligoprogressive patients, with a 2-year LR-FS rate of 100% compared with 53% for synchronous and 45% for metachronous-oligorecurrent patients. However, metachronous-oligoprogressive patients received target therapy and/or immunotherapy. The reasons for these differences of results could be conditioned by the time of appearance of the metastases as well as the combined treatment (217).

Toxicity is relatively low in series with SBRT. A retrospective review of patients treated with palliative irradiation and ICI retrieved a 4% grade three or higher immune-related side-event rate, and the authors showed toxicity was not related to the anatomic location of irradiation (220). Although in the series by Luke et al., toxicity was generally low, when it appeared, it was often in the irradiated region. Hence, it difficult to discriminate toxicity from combination therapy and this from radiation alone (212). Bang et al. did not show any correlation between time of irradiation accord and time of checkpoint blockade, before, during, or after, or in the 14 days after the beginning of checkpoint blockade. Analysis according to dose or EQD2 showed no correlation with complications (220).

Independently of the antitumoral activity of ICI and radiation independently, their combination could lead to induced-ICD, not only at the irradiated site but also in non-irradiated locations; a reaction known as the abscopal effect. Käsmann et al. suggested the need to irradiate sites other than the brain and bone to stimulate this induced-ICD (204), because bone and the CNS are insufficiently efficient to recruit certain immune cell subsets from peripheral blood (207). By assessing the aggregation of the sum of response of non-irradiated lesions but receiving ICI also, another lesion was irradiated, Luke et al. concluded the response rate was consistent with preclinical models of the abscopal response (212). For the authors, a microenvironment characterizing the liver may help tumors escape from anti-tumor immune surveillance during immunotherapy (221,222).

In conclusion, literature cannot easily separate the different location of oligometastases and their response to stereotactic irradiation, alone or combined with ICI. Response rates with SRS are always high whatever the location of metastasis and are higher with ICI. This response of combined treatment likely increases OS, but the roles of ICI alone or the abscopal effect when combined with irradiation is impossible to discriminate. Finally, and notably, combined treatment is safe and well tolerated, and if side-effects appear, the causality of radiation therapy, ICI, or both is difficult to differentiate.

Natsuo Tomita: This is a difficult task. I think that for patients with between one and five oligometastatic tumors, all sites of disease should be targeted by stereotactic radiotherapy regardless of the regime of systemic therapy. However, if doses to the lung have a high risk of radiation pneumonitis, stereotactic radiotherapy for all sites is inadvisable. When patients with more than six oligometastatic tumors receive ICIs, stereotactic radiotherapy for one or two sites of disease may be reasonable in view of abscopal effects.

The optimal site of metastases targeted by radiation depends on doses to normal tissues. If patients can be treated with an acceptable range of doses to normal tissues, all sites may be optimal for targets of stereotactic radiotherapy.

Roman O. Kowalchuk: This is certainly a challenging topic, and clinical practice varies. In our practice, if the patient presents with limited (oligometastatic) disease, we may treat in a consolidative manner to all sites of disease. If a patient presents with many sites of disease, another common practice at our institution would be to treat only the dominant lesion and/or any lesions threatening nearby organs or causing worsening of symptoms were the lesions to progress.

Terence T. Sio: This has been well addressed in the manuscript as well (see my comments). In RTOG 0937, for small-cell lung cancer, up to four extracranial sites were consolidated, and it did not seem to significantly improve clinical outcomes (older systemic therapy era). For NSCLC and the use of ICI’s, clearly, there is no randomized and level one data to guide us on this topic. As a result, I do not believe all sites of disease should be targeted by radiotherapy. For a patient with good PS and systemic treatment options left for future consideration, I think it is reasonable to treat up to three subsites that are oligoprogressive, and that is regardless of anatomic location, although the lung should be controlled as first consideration if possible, which is extrapolated from Slotman’s ESCLC trial for thoracic RT. However, there are certainly practice variation on this topic, at least among the American providers.

(II) For patients with oligo-metastatic disease, what is the optimal duration of systemic therapy after ablative radiotherapy covering all the metastatic lesions? (Should systemic therapy be used until disease progression or stopped at some time point?)

Arturo Navarro-Martin: This is also a good question. The problem of administering systemic therapy until progression or adverse event is that we may be treating patients who really do not need it, so we are espousing them of suffering unnecessary adverse events. However, we do not know the real benefit of this. In my opinion, after SBRT in all locations, if we do not know what systemic therapy is doing, it is better to hold off until disease progression.

Dirk De Ruysscher: The role is of maintenance immunotherapy after induction (chemo)-immunotherapy and radical LT is presently unknown. Systemic therapy remains the standard of care in polymetastatic disease to address as many as possible distant metastases that may be below detection thresholds. New trials are awaited to answer the questions of if and how long immune therapy should continue and the role of biomarkers such as circulating tumor (ct)DNA for patient selection.

Ben G. L. Vanneste: Systemic therapy could be continued until disease progression or unacceptable toxicity occurs, although a discontinuation after several years [1–2] of treatment may be a reasonable alternative to decrease the continuous risk of toxicity and the high costs of sustained therapy. While Waterhouse et al. revealed in a randomized trial that continuing nivolumab beyond 1 year improves outcomes (223), more research is needed to confirm this.

J. Isabelle Choi: While some providers administer four–six cycles of systemic therapy following LT for OMD, especially when delivering cytotoxic chemotherapy, in the era of immunotherapy I favor continuing immunotherapy until progression or patient intolerance to optimize PFS and OS.

Jacek Jassem: It depends on the type of systemic therapy. Chemotherapy is rarely used for more than six cycles, whereas targeted therapies and immunotherapy are frequently continued until progression or serious side effects occur.

Joe Y. Chang: Current data support continuing immunotherapy, targeted therapy, or maintenance chemotherapy until progression or issues of tolerance.

Lucyna Kepka: Obviously, it is of crucial importance to have an effective systemic treatment for micro-metastatic disease in cases of local treatment of OMD. However, I am a radiation oncologist, and not a medical oncologist. There are many controversies and new data on the duration and types of maintenance systemic therapy. This is a topic that is not in my professional area of interest.

Lukas Kӓsmann: Based on growing evidence, we recommend at least eight cycles of pembrolizumab (200 mg every 21 days) until disease progression with possible extension up to 16 cycles if the ICI treatment is well tolerated (183). Another phase II trial from Theelen et al. recommended a maximum duration of pembrolizumab treatment of 24 months (26).

Michael T. Milano: Again, I do not think we have an answer to this. For NSCLC, chemotherapy is usually given for four–six cycles and immunotherapy for up to 2 years. So even for widespread disease, it is stopped at some point. I think it makes sense to do so for oligometastases as well.

Paul Van Houtte: It may depend on the systemic treatment TKI, chemotherapy, or PD-L1 inhibitor. For chemotherapy, the duration is often limited by the toxicity, while TKI or PD-L1 inhibitors may be delivered until progression or toxicity.

Rafal Suwinski: In my opinion, for NSCLC, systemic therapy after radiotherapy for oligometastatic lesions should be used until disease progression. There is some evidence immunotherapy beyond progression may also be beneficial, but this is highly controversial, mainly due to financial concerns.

Alberto Traverso: Systemic therapy should be used until disease progression.

Hiroshi Doi: I suggest systemic therapy might be used until disease progression.

Yang-Gun Suh: In the case of ICIs or targeted agents, these drugs can be administered until loss of clinical benefit such as experiencing toxicities or disease progression.

Georges Noёl: The issue of the duration of systemic therapy could be considered globally equivalent for adjuvant therapy in localized or advanced disease requiring adjuvant therapy and oligometastases. The Pacific trial demonstrated the advantage of continuing targeted treatment 12 months after chemoradiation. The durvalumab added in the experimental arm led to an increase of OS (HR =0.68; 95% CI: 0.53 to 0.87; P=0.0025) with a median not reached versus 28.7 months, and an improvement of PFS (HR =0.52; 95% CI: 0.42 to 0.65; P<0.0001) with a median of 16.8 versus 5.6 months, respectively (224).

Continuation of systemic therapy is controversial and depends on several factors. It may be argued that its delivery could limit undetectable micrometastases to progress, keeping patients controlled. However, reverse arguments can be used. Postponement of systemic therapy can allow patients to maintain their quality of life and commence treatment only if new metastases appear and may avoid unnecessary treatment, although there is a risk of diminishing the activity of subsequent systemic therapy because of a larger burden of disease should it re-appear. Some authors propose postponing adjuvant hormonotherapy in prostate cancer (225) although in renal cell cancer systemic therapy and SRS seem additive (226).

In a retrospective series of brain metastasis from several primitive tumors, Guénolé et al. showed SRT delivered concurrently with systemic therapy and mainly immunotherapy seemed to be associated with improved local control, freedom for distant BMs, and OS, as well as with a higher rate of radionecrosis (227).

In a phase two trial, Iyengar et al. proposed stereotactic irradiation plus erlotinib in patients with limited progressive metastatic NSCLC and when progression of the disease was observed through at least one prior chemotherapy regimen (228). All metastases up to five were irradiated, and the main locations were the lung and mediastinum. No patients presented brain metastasis, and only three metastases of 47 progressed. Evolution of the disease was mainly new metastasis, and with a 6-month PFS at 69%, the authors considered the treatment worthy of further investigation. The median PFS at 14.7 months and OS at 24 months were considered longer than those observed in historical series (228). Collen et al. presented the results of a phase II trial studying chemotherapy and SBRT in 26 patients with oligometastatic NSCLC cancer, in which six patients presented with brain metastasis. Synchronous metastatic disease was diagnosed in 73% of the patients, and all metastases and the primitive tumor were irradiated, with a median PFS and OS of 11.2 and 23 months, respectively (68). Iyengar et al. led a two-arm randomized phase two trial comparing stereotactic radiation therapy plus maintenance chemotherapy with maintenance chemotherapy alone in the setting of limited metastatic NSCLC (11). The trial was stopped before the completion of accrual because intermediate analysis showed improvement of OS in the arm combining stereotactic radiation therapy plus maintenance chemotherapy, with a median OS of 9.7 vs. 3.5 months (P=0.01), respectively (11). Finally, a recent phase two randomized study included 49 patients with limited metastatic NSCLC, with or without targetable mutation positive disease. Patients were randomly assigned to LT with or without maintenance chemotherapy or observation versus maintenance chemotherapy or observation alone. Patients in the local consolidative therapy group had a longer median PFS at 11.93 months compared to 3.9 months for those not receiving local treatment. Furthermore, the 1-year PFS was 48% and 20%, respectively. The authors concluded that performing local aggressive treatment for all locations of oligometastatic NSCLC with or without maintenance therapy improved PFS compared to maintenance alone (80). The COMET randomized phase II trial included 99 patients with OMD to receive either standard-of-care (SOC) or SOC plus SABR. Eighteen patents had a primitive NSCLC. Overall, the 5-year and median OS rates were 17.7% and 28 months versus 42.3% 50 months, respectively (P=0.006) (229).

In conclusion, for patients with synchronous oligometastases, SBRT can be delivered in all metastases, and the primitive tumor can be treated with normofractionated RT or SBRT according to its size. Concurrent chemotherapy, ICI, or targeted treatment can be used, and maintenance treatment can be used for 12 months. For metachronous BMs alone accessible to an SRS, exclusive radiation treatment is acceptable. If other metastases are present, concomitant and maintenance systemic treatment is recommended. For oligoprogressive lesions, the same chemotherapy/ICI/targeted treatment can be continued, and progressive lesions irradiated.

Natsuo Tomita: I think the optimal duration of systemic therapy after ablative radiotherapy covering all metastatic lesions depends on various factors such as efficacy, adverse effect, and cost of systemic therapy, patient status, and tumor burden at the times of recurrence. When patients receive molecularly targeted drugs or ICI after ablative radiotherapy, at least 2 years may be necessary if disease progression is not observed.

Roman O. Kowalchuk: This will depend on the underlying tumor characteristics, disease extent at presentation, duration of time to recurrence or development of metastatic disease, how well tolerated the systemic therapy regimen is, the patient’s PS, and other factors.

Terence T. Sio: I follow the Gomez phase II (MDACC) and the UTSW (Iyengar) studies, which were also well discussed in this manuscript (11,12). The criteria per Gomez would be “no progression at 3 or more months after front-line systemic therapy”. We do not routinely continue systemic therapy after giving ablative radiotherapy, which is consistent with how the two trials above were completed. Patients should be given a chance for remission (in some cases, it is very durable), and consider more treatment again at the earliest sign of clinical or radiographic progression.

(III) What is the optimal timing of ablative radiotherapy for patients with synchronic oligo-metastatic disease? (Should radiotherapy be performed concurrently with systemic therapy from the beginning, or should it be preferred as consolidation therapy after tumor response to systemic therapy?)

Arturo Navarro-Martin: This is a relevant question. The Gomez trial (80) and Iyengar (228), indicate SBRT or radiotherapy after induction chemotherapy it is a good strategy to select good responders for treatment. However, this is a question for active research.

Dirk De Ruysscher: The optimal timing of local treatments has not been investigated in randomized studies. The latter have given typically 3 months of systemic treatment in responders followed by radical LT. While none of the randomized trials included immune therapy, non-randomized studies suggest giving LT first may be an option in selected patients. However, this approach cannot be put forward as standard care in view of the paucity of data and unclear patient selection criteria for benefit (69,230).

Ben G. L. Vanneste: Radiotherapy could preferentially be performed concurrently with immunotherapy to obtain the maximum synergistic effect, including the possible upregulation of PD-L1 expression and adapting tumor micro-environment. However, this is mostly based on preclinical and small clinical research, and not on randomized clinical studies, which are needed to confirm this hypothesis (28,231).

J. Isabelle Choi: This is also an area of active investigation. The literature is conflicting on the most optimal timing. It also appears different ICIs are more optimally delivered in different sequences relative to radiation therapy. As radiation has been shown to increase PD-L1 expression, administering it early in the treatment course is likely the preferred approach, especially when performed with stereotactic body radiation therapy that is less immunosuppressive than conventionally fractionated radiation therapy and can even be immunostimulatory. However, that does not necessarily mean at the initiation of therapy, and I favor initial induction with immunotherapy followed shortly thereafter (i.e., 2–4 cycles) by stereotactic body radiation therapy in an attempt to maximize synergy between the modalities.

Jacek Jassem: There is no firm clinical data supporting either option. Intuitively, I would prefer the latter, as radiotherapy makes sense in patients responding to systemic therapies. In this scenario, treatment volume is much smaller than the initial dose.

Joe Y. Chang: Based on published data, consolidative radiotherapy after about 3 months of systemic treatment should be considered. More data is needed for concurrent systemic treatment with radiotherapy in oligo-metastases.

Lucyna Kepka: There is no evidence for the timing of radiotherapy from randomized studies. Currently, we have only one ongoing randomized trial (OITROLOC, NCT 02076477) trying to answer the question of the timing of ablative radiotherapy for patients with synchronic OMD. All patients received systemic treatment, but they are randomized to radiotherapy (to the primary and metastatic sites) given up-front or after completion of chemotherapy.

Among three fully published randomized trials, one which included patients with EGFR-mutated adenocarcinoma with synchronous, treatment-naïve oligometastases (≤five metastases excluding BMs), demonstrated a significant improvement of outcome with the use of up-front radiotherapy with TKIs versus TKIs only (70), and two demonstrated benefit from the use of local treatment (radiotherapy or surgery) after a course of systemic disease vs. systemic treatment only (11,12).

In the setting of immunotherapy, administering up-front ablative radiotherapy and following it with “pseudo-adjuvant” ICIs has a solid theoretical background. As described elsewhere in this article, radiation has a synergistic effect with the action of ICIs by releasing tumor antigens and proinflammatory cytokines, leading to activation of the immune system which is a target for ICIs. Apart from this local effect, radiation may also cause a systemic anti-tumor response (abscopal effect) by activation of the immune system. In the phase two trial, 51 oligometastatic patients received up-front ablative radiotherapy to all disease sites followed by pembrolizumab for eight cycles, with provision to continue to 16 cycles in the absence of progressive disease or untoward toxic effects. The median PFS from the start of radiotherapy was 19.1 months, significantly greater than the historical median of 6.6 months, P=0.005, and the median PFS from the start of pembrolizumab was 18.7 months. Giving pembrolizumab after radiotherapy was safe and did not reduce quality of life (183).

On the other hand, in two pivotal randomized trials that demonstrated a benefit of local treatment, patients with NSCLC without driver mutation in one and only with a small percentage of oncogene-addicted tumors in another were included after a course of systemic therapy regardless of the number of metastases at the beginning of treatment (11,12). Thus, patients with “induced” not “genuine” OMD were treated. This may be a selection test of tumors with less aggressive biological behavior, i.e., patients with a response to therapy may receive a greater benefit from ablative therapy. Patients who progress quickly with systemic therapy or their PS quickly deteriorates during such treatment probably have an inherently more aggressive tumor, and local treatment in the absence of amenable to alleviation by radiation symptoms cannot bring any benefit. Obviously, in the scenario of the symptomatic burden that may be decreased by radiation, any form of radiotherapy should be used before systemic treatment.

Thus, we may formulate a consensus on the timing of ablative radiotherapy for OMD treated outside clinical trials. In patients treated with chemotherapy, we have more data that radiotherapy should be used after a course of systemic treatment that may select patients with a less aggressive disease course and reduce radiation volume. However, some pre-clinical and clinical data incite the use of radiotherapy before the start or at the beginning of therapy with ICIs. In EGFR mutated tumors, the use of up-front radiotherapy combined with TKIs is supported by results from a randomized trial. Before gathering evidence from ongoing prospective trials, the sequence of treatment should be individualized for each patient, taking into account the molecular characteristics of the tumor, type of systemic treatment planned, the volume of the disease, PS, and symptoms of the disease.

Lukas Kӓsmann: In the case of synchronous oligo-metastatic disease, following Bauml et al. and Theelen et al. (26,183), we recommend performing radiation treatment at all active sites before the start of pembrolizumab therapy However, the number of treatment fractions and overall radiation treatment time must be considered because a prolonged radiation treatment regimen results in a significant risk of severe lymphocytopenia (205). Despite a controversial discussion with growing evidence based on preclinical data favoring 3×8 Gy, several ongoing clinical trials (NCT04081688, NCT03801902, NCT03589547, NCT03237377) are investigating the synergistic mechanisms of the combination of ICIs and altered fractionation regimens.

Paul Van Houtte: If we are looking to a possible enhancement of the PD-L1 effect, then radiotherapy should be given at the beginning of treatment to one or two sites. When chemotherapy is used, I would prefer to delay radiotherapy and use it as a consolidative approach.

Rafal Suwinski: In my opinion, ablative radiotherapy for patients with synchronic oligo-metastatic disease should be performed concurrently with systemic therapy from the very beginning, although symptomatic BMs requiring steroid therapy might be an exception (232).

Alberto Traverso: The decision should be based on identification of the prognostic factors of patients that will respond to systemic therapy. An example of a work in progress is: https://www.thegreenjournal.com/article/S0167-8140(22)00023-8/fulltext

Hiroshi Doi: I would suggest radiotherapy should be preferred as consolidation therapy after tumor response to systemic therapy.

Yang-Gun Suh: To avoid unnecessary treatment, physicians in our institution prefer consolidation or salvage treatment for local progression.

Georges Noёl: This question is very important, and two points are of concern; the size of the lesion and whether the lesion is symptomatic. Symptomatic lesions should be treated at the beginning of treatment to avoid worsening and because radiation, mainly SRS, and other local treatments can control symptoms quickly. A recent PRISMA analysis concluded SRS led to a symptom improvement of 55%, and these results compared favorably to trials of targeted or immunotherapy for BMs (233). Concerning painful metastasis, ablative radiotherapy is efficient but compared to conventional irradiation, comparisons have yielded contradictory results (234,235). In adrenal metastasis, Zhao et al. reported a 100% alleviation of symptoms after SBRT when patients received systemic treatment after SBRT (219). To our knowledge, comparison of the timing of SBRT in a symptom decreasing goal has not been addressed in trials, and only expert conclusions can propose SRS at the beginning of combined treatment.

The second point is the size of the lesion. The risk is that growth of the lesion during systemic therapy does not allow efficient SRS because of the reached size or because of the proximity to critical organs. Recently, Cao et al. showed the total volumetric burden of metastases at initial oligometastatic presentation to SBRT is strongly and independently prognostic for the risk of distant and widespread progression, with each twofold increase in total PTV conferring a 40.6% increased risk of distant progression (236). The same constatation was observed for survival, with twofold PTV change increasing the risk of death by 60.7% during the first 6 months and by 34% thereafter (236).

Another issue is the volume to irradiate at time of partial response, as this optimal volume (i.e., initial volume or volume at time of the best response) is unknown. Furthermore, limits of the volume can be blurred after the response to systemic treatment complicating delineation of the volume.

In conclusion, there is no definitive response to the question. Pragmatic management is proposed, leading to irradiation volume as soon as possible if the patient is symptomatic, if the volume could be non-sustainable for irradiation if it would grow. For the other cases, beginning the irradiation early will not increase any risk.

Natsuo Tomita: I think the optimal timing of ablative radiotherapy for patients with synchronic oligo-metastatic disease depends on various factors such as the range and organ of radiotherapy field, and the predicted effect of systemic therapy. I think the concurrent use of radiotherapy and systemic therapy may carry a risk of adverse effects. Either ablative radiotherapy → systemic therapy or neoadjuvant short-term systemic therapy → ablative radiotherapy → long-term systemic therapy may be feasible.

Roman O. Kowalchuk: This depends on whether or not the systemic therapy is also a radiosensitizer. Radiotherapy to metastatic sites can often be performed in a single fraction at our institution. In such cases, it is often given upfront.

Terence T. Sio: Pursuant to the answer to Question (II) above, I would typically wait to give radiotherapy based consolidation therapy after the patient has demonstrated a tumoral response to systemic therapy, including cases with synchronic presentation here, rather than metachronous. This is also a biologically sound approach, as it is more likely patients will benefit from radiotherapy if they can demonstrate they will not progress with more distant metastatic diseases while on best systemic therapies including ICI’s.

Acknowledgments

We thank Yue Zhou (Fudan University Shanghai Cancer Center) and Tiantian Guo (Fudan University Shanghai Cancer Center) for data collecting and manuscript drafting. Finally, we thank Jinming Yu (Shandong Cancer Hospital Affiliated to Shandong University), Lvhua Wang (Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College) and Ping Wang (Tianjin Medical University Cancer Institute and Hospital) for their guidance and kindly support in this project. The authors also appreciate the academic support from the AME Lung Cancer Collaborative Group.

Funding: The study was supported by the Science and Technology Commission of Shanghai Municipality (Nos. 20Y11913500 and 19411965900) and the Hospital Development Center of Shanghai (No. SHDC2020CR4010).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-644/coif). DDR’s institution received grants from BMS, AstraZeneca, Philips Health, and Beigene. JIC received speaker honoraria from Varian Medical Systems. JYC received research grant from BMS and consulting fees from Legion Healthcare Partners. Lukas Käsmann received honoraria from AMGEN. MTM received a speaker fee from Astra Zeneca and royalties from Wolters Kluwer. HD received research grant from Japan Society for the Promotion of Science and lecture fee from AstraZeneca. TTS provides strategic and scientific recommendations as a member of the Advisory Board and speaker for Novocure, Inc., which is not in any way associated with the content presented in this manuscript. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Gridelli C, Rossi A, Carbone DP, et al. Non-small-cell lung cancer. Nat Rev Dis Primers 2015;1:15009. [Crossref] [PubMed]
3. Reck M, Rabe KF. Precision Diagnosis and Treatment for Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:849-61. [Crossref] [PubMed]
4. Blumenthaler AN, Antonoff MB. Classifying Oligometastatic Non-Small Cell Lung Cancer. Cancers (Basel) 2021;13:4822. [Crossref] [PubMed]
5. Lievens Y, Guckenberger M, Gomez D, et al. Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document. Radiother Oncol 2020;148:157-66. [Crossref] [PubMed]
6. Guckenberger M, Lievens Y, Bouma AB, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol 2020;21:e18-28. [Crossref] [PubMed]
7. Amini A, Verma V, Simone CB 2nd, et al. American Radium Society Appropriate Use Criteria for Radiation Therapy in Oligometastatic or Oligoprogressive Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2022;112:361-75. [Crossref] [PubMed]
8. Buglione M, Jereczek-Fossa BA, Bonù ML, et al. Radiosurgery and fractionated stereotactic radiotherapy in oligometastatic/oligoprogressive non-small cell lung cancer patients: Results of a multi-institutional series of 198 patients treated with "curative" intent. Lung Cancer 2020;141:1-8. [Crossref] [PubMed]
9. Agolli L, Valeriani M, Nicosia L, et al. Stereotactic Ablative Body Radiotherapy (SABR) in Pulmonary Oligometastatic/Oligorecurrent Non-small Cell Lung Cancer Patients: A New Therapeutic Approach. Anticancer Res 2015;35:6239-45. [PubMed]
10. Niibe Y, Nishimura T, Inoue T, et al. Oligo-recurrence predicts favorable prognosis of brain-only oligometastases in patients with non-small cell lung cancer treated with stereotactic radiosurgery or stereotactic radiotherapy: a multi-institutional study of 61 subjects. BMC Cancer 2016;16:659. [Crossref] [PubMed]
11. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2018;4:e173501. [Crossref] [PubMed]
12. Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol 2019;37:1558-65. [Crossref] [PubMed]
13. Rim CH, Shin IS, Park S, et al. Benefits of local consolidative treatment in oligometastases of solid cancers: a stepwise-hierarchical pooled analysis and systematic review. NPJ Precis Oncol 2021;5:2. [Crossref] [PubMed]
14. Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012;77:556-60. [Crossref] [PubMed]
15. Schuler M, Wu YL, Hirsh V, et al. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol 2016;11:380-90. [Crossref] [PubMed]
16. Tsuchiya-Kawano Y, Shiraishi Y, Kiyomi F, et al. Phase II Study of Nivolumab Plus Ipilimumab with Platinum-Based Chemotherapy for Treatment-Naïve Advanced Non-Small Cell Lung Cancer with Untreated Brain Metastases: NIke Trial (LOGiK2004). Cancer Manag Res 2021;13:8489-93. [Crossref] [PubMed]
17. Du W, Sirbu C, Lucas BD Jr, et al. A Retrospective Study of Brain Metastases From Solid Malignancies: The Effect of Immune Checkpoint Inhibitors. Front Oncol 2021;11:667847. [Crossref] [PubMed]
18. Chinnaiyan P, Huang S, Vallabhaneni G, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 2005;65:3328-35. [Crossref] [PubMed]
19. Aspeslagh S, Postel-Vinay S, Rusakiewicz S, et al. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer 2016;52:50-66. [Crossref] [PubMed]
20. Kaczanowska S, Joseph AM, Davila E. TLR agonists: our best frenemy in cancer immunotherapy. J Leukoc Biol 2013;93:847-63. [Crossref] [PubMed]
21. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-92. [Crossref] [PubMed]
22. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-51. [Crossref] [PubMed]
23. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-30. [Crossref] [PubMed]
24. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004;58:862-70. [Crossref] [PubMed]
25. Shi W, Siemann DW. Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment. Anticancer Res 2006;26:3445-53. [PubMed]
26. Theelen WSME, Peulen HMU, Lalezari F, et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol 2019;5:1276-82. [Crossref] [PubMed]
27. Theelen WSME, Chen D, Verma V, et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir Med 2021;9:467-75. [Crossref] [PubMed]
28. Vanneste BGL, Van Limbergen EJ, Reynders K, et al. An overview of the published and running randomized phase 3 clinical results of radiotherapy in combination with immunotherapy. Transl Lung Cancer Res 2021;10:2048-58. [Crossref] [PubMed]
29. Mac Manus MP, Matthews JP, Wada M, et al. Unexpected long-term survival after low-dose palliative radiotherapy for non-small cell lung cancer. Cancer 2006;106:1110-6. [Crossref] [PubMed]
30. Halfdanarson TR, Hogan WJ, Madsen BE. Emergencies in Hematology and Oncology. Mayo Clin Proc 2017;92:609-41. [Crossref] [PubMed]
31. Cervantes A, Chirivella I. Oncological emergencies. Ann Oncol 2004;15:iv299-306. [Crossref] [PubMed]
32. Kepka L, Olszyna-Serementa M. Palliative thoracic radiotherapy for lung cancer. Expert Rev Anticancer Ther 2010;10:559-69. [Crossref] [PubMed]
33. Silva GT, Bergmann A, Thuler LC. Incidence, associated factors, and survival in metastatic spinal cord compression secondary to lung cancer. Spine J 2015;15:1263-9. [Crossref] [PubMed]
34. Hirshberg B, Biran I, Glazer M, et al. Hemoptysis: etiology, evaluation, and outcome in a tertiary referral hospital. Chest 1997;112:440-4. [Crossref] [PubMed]
35. Daneshvar C, Falconer WE, Ahmed M, et al. Prevalence and outcome of central airway obstruction in patients with lung cancer. BMJ Open Respir Res 2019;6:e000429. [Crossref] [PubMed]
36. Stevens R, Macbeth F, Toy E, et al. Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer. Cochrane Database Syst Rev 2015;1:CD002143. [PubMed]
37. Moeller B, Balagamwala EH, Chen A, et al. Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline. Pract Radiat Oncol 2018;8:245-50. [Crossref] [PubMed]
38. Rodrigues G, Videtic GM, Sur R, et al. Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiat Oncol 2011;1:60-71. [Crossref] [PubMed]
39. Bezjak A, Dixon P, Brundage M, et al. Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 2002;54:719-28. [Crossref] [PubMed]
40. Sundstrøm S, Bremnes R, Brunsvig P, et al. Immediate or delayed radiotherapy in advanced non-small cell lung cancer (NSCLC)? Data from a prospective randomised study. Radiother Oncol 2005;75:141-8. [Crossref] [PubMed]
41. Metcalfe SK, Milano MT, Bylund K, et al. Split-course palliative radiotherapy for advanced non-small cell lung cancer. J Thorac Oncol 2010;5:185-90. [Crossref] [PubMed]
42. Topkan E, Yildirim BA, Guler OC, et al. Safety and palliative efficacy of single-dose 8-Gy reirradiation for painful local failure in patients with stage IV non-small cell lung cancer previously treated with radical chemoradiation therapy. Int J Radiat Oncol Biol Phys 2015;91:774-80. [Crossref] [PubMed]
43. Kowalchuk RO, Mullikin TC, Kim DK, et al. Cost-Effectiveness of Treatment Strategies for Spinal Metastases. Pract Radiat Oncol 2022;12:236-44. [Crossref] [PubMed]
44. Rowell NP, Gleeson FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus. Cochrane Database Syst Rev 2001;CD001316. [PubMed]
45. Bhattacharya IS, Hoskin PJ. Stereotactic body radiotherapy for spinal and bone metastases. Clin Oncol (R Coll Radiol) 2015;27:298-306. [Crossref] [PubMed]
46. Choi HS, Jeong BK, Jeong H, et al. Role of radiotherapy in the management of malignant airway obstruction. Thorac Cancer 2020;11:2163-9. [Crossref] [PubMed]
47. Fraser I, Lefresne S, Regan J, et al. Palliative thoracic radiotherapy near the end of life in lung cancer: A population-based analysis. Lung Cancer 2019;135:97-103. [Crossref] [PubMed]
48. Cho YJ, Cho YM, Kim SH, et al. Clinical analysis of patients with skeletal metastasis of lung cancer. BMC Cancer 2019;19:303. [Crossref] [PubMed]
49. Lupattelli M, Maranzano E, Bellavita R, et al. Short-course palliative radiotherapy in non-small-cell lung cancer: results of a prospective study. Am J Clin Oncol 2000;23:89-93. [Crossref] [PubMed]
50. Rastogi M, Revannasiddaiah S, Gupta MK, et al. When Palliative Treatment Achieves More Than Palliation: Instances of Long-term Survival after Palliative Radiotherapy. Indian J Palliat Care 2012;18:117-21. [Crossref] [PubMed]
51. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8-10. [Crossref] [PubMed]
52. Yang L, Wang S, Zhou Y, et al. Evaluation of the 7th and 8th editions of the AJCC/UICC TNM staging systems for lung cancer in a large North American cohort. Oncotarget 2017;8:66784-95.
53. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989;8:98-101. [PubMed]
54. Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell 2006;127:679-95. [Crossref] [PubMed]
55. Li Y, Tang ZY, Ye SL, et al. Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol 2001;7:630-6. [Crossref] [PubMed]
56. Shindo-Okada N, Takeuchi K, Nagamachi Y. Establishment of cell lines with high- and low-metastatic potential from PC-14 human lung adenocarcinoma. Jpn J Cancer Res 2001;92:174-83. [Crossref] [PubMed]
57. Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015;520:353-7. [Crossref] [PubMed]
58. Dingemans AC, Hendriks LEL, Berghmans T, et al. Definition of Synchronous Oligometastatic Non-Small Cell Lung Cancer-A Consensus Report. J Thorac Oncol 2019;14:2109-19. [Crossref] [PubMed]
59. Mazzola R, Jereczek-Fossa BA, Antognoni P, et al. OLIGO-AIRO: a national survey on the role of radiation oncologist in the management of OLIGO-metastatic patients on the behalf of AIRO. Med Oncol 2021;38:48. [Crossref] [PubMed]
60. Kowalchuk RO, Johnson-Tesch BA, Marion JT, et al. Development and Assessment of a Predictive Score for Vertebral Compression Fracture After Stereotactic Body Radiation Therapy for Spinal Metastases. JAMA Oncol 2022;8:412-9. [Crossref] [PubMed]
61. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:1807-14. [Crossref] [PubMed]
62. Grootjans W, de Geus-Oei LF, Troost EG, et al. PET in the management of locally advanced and metastatic NSCLC. Nat Rev Clin Oncol 2015;12:395-407. [Crossref] [PubMed]
63. Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med 2003;348:2500-7. [Crossref] [PubMed]
64. Decoster L, Schallier D, Everaert H, et al. Complete metabolic tumour response, assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET), after induction chemotherapy predicts a favourable outcome in patients with locally advanced non-small cell lung cancer (NSCLC). Lung Cancer 2008;62:55-61. [Crossref] [PubMed]
65. Levy A, Hendriks LEL, Berghmans T, et al. EORTC Lung Cancer Group survey on the definition of NSCLC synchronous oligometastatic disease. Eur J Cancer 2019;122:109-14. [Crossref] [PubMed]
66. Lieverse RIY, Van Limbergen EJ, Oberije CJG, et al. Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial. BMC Cancer 2020;20:557. [Crossref] [PubMed]
67. Chan OSH, Lam KC, Li JYC, et al. ATOM: A phase II study to assess efficacy of preemptive local ablative therapy to residual oligometastases of NSCLC after EGFR TKI. Lung Cancer 2020;142:41-6. [Crossref] [PubMed]
68. Collen C, Christian N, Schallier D, et al. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients. Ann Oncol 2014;25:1954-9. [Crossref] [PubMed]
69. Arrieta O, Barrón F, Maldonado F, et al. Radical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: A phase II study. Lung Cancer 2019;130:67-75. [Crossref] [PubMed]
70. Blake-Cerda M, Lozano-Ruíz F, Maldonado-Magos F, et al. Consolidative stereotactic ablative radiotherapy (SABR) to intrapulmonary lesions is associated with prolonged progression-free survival and overall survival in oligometastatic NSCLC patients: A prospective phase 2 study. Lung Cancer 2021;152:119-26. [Crossref] [PubMed]
71. Xu D, Yu F, Guo T, et al. Clinical value of PET/CT in identifying patients with oligometastatic/oligoprogressive disease among first-line tyrosine kinase inhibitor-treated advanced EGFR-mutant non-small cell lung cancer: Implications from survival comparisons. Br J Radiol 2022;95:20220035. [Crossref] [PubMed]
72. Giaj-Levra N, Giaj-Levra M, Durieux V, et al. Defining Synchronous Oligometastatic Non-Small Cell Lung Cancer: A Systematic Review. J Thorac Oncol 2019;14:2053-61. [Crossref] [PubMed]
73. Rossi G, Bauckneht M, Genova C, et al. Comparison Between 18F-FDG PET-Based and CT-Based Criteria in Non-Small Cell Lung Cancer Patients Treated with Nivolumab. J Nucl Med 2020;61:990-8. [Crossref] [PubMed]
74. Parikh RB, Cronin AM, Kozono DE, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014;89:880-7. [Crossref] [PubMed]
75. Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol 2009;27:1579-84. [Crossref] [PubMed]
76. Milano MT, Katz AW, Zhang H, et al. Oligometastases treated with stereotactic body radiotherapy: long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys 2012;83:878-86. [Crossref] [PubMed]
77. Petrelli F, Ghidini A, Cabiddu M, et al. Addition of radiotherapy to the primary tumour in oligometastatic NSCLC: A systematic review and meta-analysis. Lung Cancer 2018;126:194-200. [Crossref] [PubMed]
78. Borghetti P, Bonù ML, Giubbolini R, et al. Concomitant radiotherapy and TKI in metastatic EGFR- or ALK-mutated non-small cell lung cancer: a multicentric analysis on behalf of AIRO lung cancer study group. Radiol Med 2019;124:662-70. [Crossref] [PubMed]
79. Conibear J, Chia B, Ngai Y, et al. Study protocol for the SARON trial: a multicentre, randomised controlled phase III trial comparing the addition of stereotactic ablative radiotherapy and radical radiotherapy with standard chemotherapy alone for oligometastatic non-small cell lung cancer. BMJ Open 2018;8:e020690. [Crossref] [PubMed]
80. Gomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:1672-82. [Crossref] [PubMed]
81. Wang XS, Bai YF, Verma V, et al. Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated NSCLC. J Natl Cancer Inst 2022;djac015. [Crossref] [PubMed]
82. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786-92. [Crossref] [PubMed]
83. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. [Crossref] [PubMed]
84. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42. [Crossref] [PubMed]
85. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213-22. [Crossref] [PubMed]
86. Horn L, Whisenant JG, Wakelee H, et al. Monitoring Therapeutic Response and Resistance: Analysis of Circulating Tumor DNA in Patients With ALK+ Lung Cancer. J Thorac Oncol 2019;14:1901-11. [Crossref] [PubMed]
87. Stinchcombe TE, Doebele RC, Wang X, et al. Preliminary Clinical and Molecular Analysis Results From a Single-Arm Phase 2 Trial of Brigatinib in Patients With Disease Progression After Next-Generation ALK Tyrosine Kinase Inhibitors in Advanced ALK+ NSCLC. J Thorac Oncol 2021;16:156-61. [Crossref] [PubMed]
88. Rusthoven KE, Hammerman SF, Kavanagh BD, et al. Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol 2009;48:578-83. [Crossref] [PubMed]
89. Simon R, Norton L. The Norton-Simon hypothesis: designing more effective and less toxic chemotherapeutic regimens. Nat Clin Pract Oncol 2006;3:406-7. [Crossref] [PubMed]
90. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-92. [Crossref] [PubMed]
91. Al-Halabi H, Sayegh K, Digamurthy SR, et al. Pattern of Failure Analysis in Metastatic EGFR-Mutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy. J Thorac Oncol 2015;10:1601-7. [Crossref] [PubMed]
92. Guo T, Ni J, Yang X, et al. Pattern of Recurrence Analysis in Metastatic EGFR-Mutant NSCLC Treated with Osimertinib: Implications for Consolidative Stereotactic Body Radiation Therapy. Int J Radiat Oncol Biol Phys 2020;107:62-71. [Crossref] [PubMed]
93. Hu F, Xu J, Zhang B, et al. Efficacy of Local Consolidative Therapy for Oligometastatic Lung Adenocarcinoma Patients Harboring Epidermal Growth Factor Receptor Mutations. Clin Lung Cancer 2019;20:e81-90. [Crossref] [PubMed]
94. Song YQ, Wang N, Qiao Y, et al. Treatment patterns and survival after 18F-fluorodeoxyglucose positron emission tomography/computed tomography-guided local consolidation therapy for oligometastatic non-small cell lung cancer: a two-center propensity score-matched analysis. J Cancer Res Clin Oncol 2020;146:1021-31. [Crossref] [PubMed]
95. Togashi Y, Masago K, Fukudo M, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol 2010;5:950-5. [Crossref] [PubMed]
96. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17. [Crossref] [PubMed]
97. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26. [Crossref] [PubMed]
98. Schoenfeld AJ, Hellmann MD. Acquired Resistance to Immune Checkpoint Inhibitors. Cancer Cell 2020;37:443-55. [Crossref] [PubMed]
99. Rheinheimer S, Heussel CP, Mayer P, et al. Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors. Cancers (Basel) 2020;12:1046. [Crossref] [PubMed]
100. Heo JY, Yoo SH, Suh KJ, et al. Clinical pattern of failure after a durable response to immune check inhibitors in non-small cell lung cancer patients. Sci Rep 2021;11:2514. [Crossref] [PubMed]
101. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:346-51. [Crossref] [PubMed]
102. Yoshida T, Yoh K, Niho S, et al. RECIST progression patterns during EGFR tyrosine kinase inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation. Lung Cancer 2015;90:477-83. [Crossref] [PubMed]
103. Schmid S, Klingbiel D, Aeppli S, et al. Patterns of progression on osimertinib in EGFR T790M positive NSCLC: A Swiss cohort study. Lung Cancer 2019;130:149-55. [Crossref] [PubMed]
104. Lee YJ, Choi HJ, Kim SK, et al. Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer. Cancer 2010;116:1336-43. [Crossref] [PubMed]
105. Castellanos EH, Horn L. Re-Evaluating Progression in an Era of Progress: A Review of First- and Second-Line Treatment Options in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer. Oncologist 2016;21:755-61. [Crossref] [PubMed]
106. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012;18:1472-82. [Crossref] [PubMed]
107. Jiang T, Chu Q, Wang H, et al. EGFR-TKIs plus local therapy demonstrated survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC patients with oligometastatic or oligoprogressive liver metastases. Int J Cancer 2019;144:2605-12. [Crossref] [PubMed]
108. Gettinger SN, Wurtz A, Goldberg SB, et al. Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non-Small Cell Lung Cancer. J Thorac Oncol 2018;13:831-9. [Crossref] [PubMed]
109. Xu Y, Li H, Fan Y. Progression Patterns, Treatment, and Prognosis Beyond Resistance of Responders to Immunotherapy in Advanced Non-Small Cell Lung Cancer. Front Oncol 2021;11:642883. [Crossref] [PubMed]
110. Park C, Papiez L, Zhang S, et al. Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol Phys 2008;70:847-52. [Crossref] [PubMed]
111. Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell 2005;8:89-91. [Crossref] [PubMed]
112. Salama JK, Milano MT. Radical irradiation of extracranial oligometastases. J Clin Oncol 2014;32:2902-12. [Crossref] [PubMed]
113. Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol 2009;27:1572-8. [Crossref] [PubMed]
114. Garg AK, Shiu AS, Yang J, et al. Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer 2012;118:5069-77. [Crossref] [PubMed]
115. Bezjak A, Paulus R, Gaspar LE, et al. Safety and Efficacy of a Five-Fraction Stereotactic Body Radiotherapy Schedule for Centrally Located Non-Small-Cell Lung Cancer: NRG Oncology/RTOG 0813 Trial. J Clin Oncol 2019;37:1316-25. [Crossref] [PubMed]
116. Modh A, Rimner A, Williams E, et al. Local control and toxicity in a large cohort of central lung tumors treated with stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2014;90:1168-76. [Crossref] [PubMed]
117. Ost P, Reynders D, Decaestecker K, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol 2018;36:446-53. [Crossref] [PubMed]
118. Mujoomdar A, Austin JH, Malhotra R, et al. Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph node metastases. Radiology 2007;242:882-8. [Crossref] [PubMed]
119. Ni J, Li G, Yang X, et al. Optimal timing and clinical value of radiotherapy in advanced ALK-rearranged non-small cell lung cancer with or without baseline brain metastases: implications from pattern of failure analyses. Radiat Oncol 2019;14:44. [Crossref] [PubMed]
120. Singh R, Lehrer EJ, Ko S, et al. Brain metastases from non-small cell lung cancer with EGFR or ALK mutations: A systematic review and meta-analysis of multidisciplinary approaches. Radiother Oncol 2020;144:165-79. [Crossref] [PubMed]
121. Yu X, Sheng J, Pan G, et al. Real-world utilization of EGFR TKIs and prognostic factors for survival in EGFR-mutated non-small cell lung cancer patients with brain metastases. Int J Cancer 2021;149:1121-8. [Crossref] [PubMed]
122. Zhu Q, Sun Y, Cui Y, et al. Clinical outcome of tyrosine kinase inhibitors alone or combined with radiotherapy for brain metastases from epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC). Oncotarget 2017;8:13304-11. [Crossref] [PubMed]
123. Robin TP, Camidge DR, Stuhr K, et al. Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non-Small Cell Lung Cancer. J Thorac Oncol 2018;13:715-20. [Crossref] [PubMed]
124. Doherty MK, Korpanty GJ, Tomasini P, et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer. Radiother Oncol 2017;123:195-202. [Crossref] [PubMed]
125. Yomo S, Serizawa T, Yamamoto M, et al. The impact of EGFR-TKI use on clinical outcomes of lung adenocarcinoma patients with brain metastases after Gamma Knife radiosurgery: a propensity score-matched analysis based on extended JLGK0901 dataset (JLGK0901-EGFR-TKI). J Neurooncol 2019;145:151-7. [Crossref] [PubMed]
126. Kim HJ, Kim WS, Kwon DH, et al. Effects of an Epithelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Add-on in Stereotactic Radiosurgery for Brain Metastases Originating from Non-Small-Cell Lung Cancer. J Korean Neurosurg Soc 2015;58:205-10. [Crossref] [PubMed]
127. Zhao B, Wang Y, Wang Y, et al. Efficacy and safety of therapies for EGFR-mutant non-small cell lung cancer with brain metastasis: an evidence-based Bayesian network pooled study of multivariable survival analyses. Aging (Albany NY) 2020;12:14244-70. [Crossref] [PubMed]
128. Zhuang H, Tao L, Wang X, et al. Tyrosine Kinase Inhibitor Resistance Increased the Risk of Cerebral Radiation Necrosis After Stereotactic Radiosurgery in Brain Metastases of Non-small-Cell Lung Cancer: A Multi-Institutional Retrospective Case-Control Study. Front Oncol 2020;10:12. [Crossref] [PubMed]
129. Magnuson WJ, Lester-Coll NH, Wu AJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol 2017;35:1070-7. [Crossref] [PubMed]
130. Lee JH, Chen HY, Hsu FM, et al. Cranial Irradiation for Patients with Epidermal Growth Factor Receptor (EGFR) Mutant Lung Cancer Who Have Brain Metastases in the Era of a New Generation of EGFR Inhibitors. Oncologist 2019;24:e1417-25. [Crossref] [PubMed]
131. Miyawaki E, Kenmotsu H, Mori K, et al. Optimal Sequence of Local and EGFR-TKI Therapy for EGFR-Mutant Non-Small Cell Lung Cancer With Brain Metastases Stratified by Number of Brain Metastases. Int J Radiat Oncol Biol Phys 2019;104:604-13. [Crossref] [PubMed]
132. Wu YL, Ahn MJ, Garassino MC, et al. CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3). J Clin Oncol 2018;36:2702-9. [Crossref] [PubMed]
133. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 2018;19:1654-67. [Crossref] [PubMed]
134. Lin JJ, Jiang GY, Joshipura N, et al. Efficacy of Alectinib in Patients with ALK-Positive NSCLC and Symptomatic or Large CNS Metastases. J Thorac Oncol 2019;14:683-90. [Crossref] [PubMed]
135. Gadgeel S, Shaw AT, Barlesi F, et al. Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC. Br J Cancer 2018;118:38-42. [Crossref] [PubMed]
136. Nishio M, Nakagawa K, Mitsudomi T, et al. Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer 2018;121:37-40. [Crossref] [PubMed]
137. Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol 2018;29:2214-22. [Crossref] [PubMed]
138. Park S, Lee MH, Seong M, et al. A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol 2020;31:1397-404. [Crossref] [PubMed]
139. Li C, Nie W, Guo J, et al. Osimertinib alone as second-line treatment for brain metastases (BM) control may be more limited than for non-BM in advanced NSCLC patients with an acquired EGFR T790M mutation. Respir Res 2021;22:145. [Crossref] [PubMed]
140. Yu F, Ni J, Zeng W, et al. Clinical Value of Upfront Cranial Radiation Therapy in Osimertinib-Treated Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer With Brain Metastases. Int J Radiat Oncol Biol Phys 2021;111:804-15. [Crossref] [PubMed]
141. Lau SCM, Poletes C, Le LW, et al. Durability of CNS disease control in NSCLC patients with brain metastases treated with immune checkpoint inhibitors plus cranial radiotherapy. Lung Cancer 2021;156:76-81. [Crossref] [PubMed]
142. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 2017;18:895-903. [Crossref] [PubMed]
143. Shepard MJ, Xu Z, Donahue J, et al. Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study. J Neurosurg 2019; Epub ahead of print. [Crossref] [PubMed]
144. Singh C, Qian JM, Yu JB, et al. Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non-small cell lung cancer with brain metastases. J Neurosurg 2019;132:512-7. [Crossref] [PubMed]
145. Chen L, Douglass J, Kleinberg L, et al. Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma. Int J Radiat Oncol Biol Phys 2018;100:916-25. [Crossref] [PubMed]
146. Scoccianti S, Olmetto E, Pinzi V, et al. Immunotherapy in association with stereotactic radiotherapy for non-small cell lung cancer brain metastases: results from a multicentric retrospective study on behalf of AIRO. Neuro Oncol 2021;23:1750-64. [Crossref] [PubMed]
147. Lehrer EJ, Peterson J, Brown PD, et al. Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: An international meta-analysis of individual patient data. Radiother Oncol 2019;130:104-12. [Crossref] [PubMed]
148. Qian JM, Martin AM, Martin K, et al. Response rate and local recurrence after concurrent immune checkpoint therapy and radiotherapy for non-small cell lung cancer and melanoma brain metastases. Cancer 2020;126:5274-82. [Crossref] [PubMed]
149. Ahmed KA, Kim S, Arrington J, et al. Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases. J Neurooncol 2017;133:331-8. [Crossref] [PubMed]
150. Schapira E, Hubbeling H, Yeap BY, et al. Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1 Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With Brain Metastases. Int J Radiat Oncol Biol Phys 2018;101:624-9. [Crossref] [PubMed]
151. Hubbeling HG, Schapira EF, Horick NK, et al. Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer. J Thorac Oncol 2018;13:550-8. [Crossref] [PubMed]
152. Alomari AK, Cohen J, Vortmeyer AO, et al. Possible Interaction of Anti-PD-1 Therapy with the Effects of Radiosurgery on Brain Metastases. Cancer Immunol Res 2016;4:481-7. [Crossref] [PubMed]
153. Kluger HM, Chiang V, Mahajan A, et al. Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. J Clin Oncol 2019;37:52-60. [Crossref] [PubMed]
154. Colaco RJ, Martin P, Kluger HM, et al. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg 2016;125:17-23. [Crossref] [PubMed]
155. Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 2016;316:401-9. [Crossref] [PubMed]
156. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10:1037-44. [Crossref] [PubMed]
157. Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 2012;2:210-25. [Crossref] [PubMed]
158. Chao ST, De Salles A, Hayashi M, et al. Stereotactic Radiosurgery in the Management of Limited (1-4) Brain Metasteses: Systematic Review and International Stereotactic Radiosurgery Society Practice Guideline. Neurosurgery 2018;83:345-53. [Crossref] [PubMed]
159. Milano MT, Chiang VLS, Soltys SG, et al. Executive summary from American Radium Society's appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases. Neuro Oncol 2020;22:1728-41. [Crossref] [PubMed]
160. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15:387-95. [Crossref] [PubMed]
161. Hughes RT, Masters AH, McTyre ER, et al. Initial SRS for Patients With 5 to 15 Brain Metastases: Results of a Multi-Institutional Experience. Int J Radiat Oncol Biol Phys 2019;104:1091-8. [Crossref] [PubMed]
162. Joshi RS, Hirshman BR, Ali MA, et al. Prognostic Importance of Cumulative Intracranial Tumor Volume in Patients with Gastrointestinal Brain Metastasis Treated with Stereotactic Radiosurgery. World Neurosurg 2019;121:e747-54. [Crossref] [PubMed]
163. Hirshman BR, Wilson B, Ali MA, et al. Superior Prognostic Value of Cumulative Intracranial Tumor Volume Relative to Largest Intracranial Tumor Volume for Stereotactic Radiosurgery-Treated Brain Metastasis Patients. Neurosurgery 2018;82:473-80. [Crossref] [PubMed]
164. Morris PG, Reiner AS, Szenberg OR, et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol 2012;7:382-5. [Crossref] [PubMed]
165. Lee SJ, Lee JI, Nam DH, et al. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol 2013;8:185-91. [Crossref] [PubMed]
166. Li YS, Jiang BY, Yang JJ, et al. Leptomeningeal Metastases in Patients with NSCLC with EGFR Mutations. J Thorac Oncol 2016;11:1962-9. [Crossref] [PubMed]
167. Schiopu SR, Habl G, Haefner M, et al. Helical tomotherapy in patients with leptomeningeal metastases. Cancer Manag Res 2018;11:401-9. [Crossref] [PubMed]
168. Wolf A, Donahue B, Silverman JS, et al. Stereotactic radiosurgery for focal leptomeningeal disease in patients with brain metastases. J Neurooncol 2017;134:139-43. [Crossref] [PubMed]
169. Lekovic G, Drazin D, Mak AC, et al. Cyberknife Radiosurgery and Concurrent Intrathecal Chemotherapy for Leptomeningeal Metastases: Case Report of Prolonged Survival of a HER-2+ Breast Cancer Patient Status-Post Craniospinal Irradiation. Cureus 2016;8:e453. [Crossref] [PubMed]
170. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65. [Crossref] [PubMed]
171. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2019;381:2020-31. [Crossref] [PubMed]
172. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
173. Golden EB, Pellicciotta I, Demaria S, et al. The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol 2012;2:88. [Crossref] [PubMed]
174. Weichselbaum RR, Liang H, Deng L, et al. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 2017;14:365-79. [Crossref] [PubMed]
175. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007;13:1050-9. [Crossref] [PubMed]
176. Hallahan DE, Virudachalam S, Sherman ML, et al. Tumor necrosis factor gene expression is mediated by protein kinase C following activation by ionizing radiation. Cancer Res 1991;51:4565-9. [PubMed]
177. Abuodeh Y, Venkat P, Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer 2016;40:25-37. [Crossref] [PubMed]
178. Wennerberg E, Lhuillier C, Vanpouille-Box C, et al. Barriers to Radiation-Induced In Situ Tumor Vaccination. Front Immunol 2017;8:229. [Crossref] [PubMed]
179. Gong X, Li X, Jiang T, et al. Combined Radiotherapy and Anti-PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non-Small Cell Lung Cancer. J Thorac Oncol 2017;12:1085-97. [Crossref] [PubMed]
180. Samuel E, Lie G, Balasubramanian A, et al. Impact of Radiotherapy on the Efficacy and Toxicity of anti-PD-1 Inhibitors in Metastatic NSCLC. Clin Lung Cancer 2021;22:e425-30. [Crossref] [PubMed]
181. Ni J, Zhou Y, Wu L, et al. Sintilimab, stereotactic body radiotherapy and granulocyte-macrophage colony stimulating factor as second-line therapy for advanced non-small cell lung cancer: safety run-in results of a multicenter, single-arm, phase II trial. Radiat Oncol 2021;16:177. [Crossref] [PubMed]
182. Welsh J, Menon H, Chen D, et al. Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial. J Immunother Cancer 2020;8:e001001. [Crossref] [PubMed]
183. Bauml JM, Mick R, Ciunci C, et al. Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer: A Phase 2 Trial. JAMA Oncol 2019;5:1283-90. [Crossref] [PubMed]
184. Kaur P, Asea A. Radiation-induced effects and the immune system in cancer. Front Oncol 2012;2:191. [Crossref] [PubMed]
185. Ellsworth SG. Field size effects on the risk and severity of treatment-induced lymphopenia in patients undergoing radiation therapy for solid tumors. Adv Radiat Oncol 2018;3:512-9. [Crossref] [PubMed]
186. Tang C, Liao Z, Gomez D, et al. Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol Biol Phys 2014;89:1084-91. [Crossref] [PubMed]
187. Campian JL, Ye X, Brock M, et al. Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Cancer Invest 2013;31:183-8. [Crossref] [PubMed]
188. Karantanos T, Karanika S, Seth B, et al. The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study. Clin Transl Oncol 2019;21:206-12. [Crossref] [PubMed]
189. Diehl A, Yarchoan M, Hopkins A, et al. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget 2017;8:114268-80. [Crossref] [PubMed]
190. Ostrand-Rosenberg S, Horn LA, Ciavattone NG. Radiotherapy Both Promotes and Inhibits Myeloid-Derived Suppressor Cell Function: Novel Strategies for Preventing the Tumor-Protective Effects of Radiotherapy. Front Oncol 2019;9:215. [Crossref] [PubMed]
191. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 2006;203:1259-71. [Crossref] [PubMed]
192. Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 2017;8:15618. [Crossref] [PubMed]
193. Lugade AA, Moran JP, Gerber SA, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol 2005;174:7516-23. [Crossref] [PubMed]
194. Schaue D, Ratikan JA, Iwamoto KS, et al. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys 2012;83:1306-10. [Crossref] [PubMed]
195. Filatenkov A, Baker J, Mueller AM, et al. Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions. Clin Cancer Res 2015;21:3727-39. [Crossref] [PubMed]
196. Morisada M, Clavijo PE, Moore E, et al. PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation. Oncoimmunology 2017;7:e1395996. [Crossref] [PubMed]
197. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009;15:5379-88. [Crossref] [PubMed]
198. Grapin M, Richard C, Limagne E, et al. Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination. J Immunother Cancer 2019;7:160. [Crossref] [PubMed]
199. Lan J, Li R, Yin LM, et al. Targeting Myeloid-derived Suppressor Cells and Programmed Death Ligand 1 Confers Therapeutic Advantage of Ablative Hypofractionated Radiation Therapy Compared With Conventional Fractionated Radiation Therapy. Int J Radiat Oncol Biol Phys 2018;101:74-87. [Crossref] [PubMed]
200. Garelli E, Rittmeyer A, Putora PM, et al. Abscopal effect in lung cancer: three case reports and a concise review. Immunotherapy 2019;11:1445-61. [Crossref] [PubMed]
201. García-Mulero S, Alonso MH, Pardo J, et al. Lung metastases share common immune features regardless of primary tumor origin. J Immunother Cancer 2020;8:e000491. [Crossref] [PubMed]
202. Chicas-Sett R, Zafra-Martin J, Morales-Orue I, et al. Immunoradiotherapy as An Effective Therapeutic Strategy in Lung Cancer: From Palliative Care to Curative Intent. Cancers (Basel) 2020;12:2178. [Crossref] [PubMed]
203. Pointer KB, Pitroda SP, Weichselbaum RR. Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer 2022;8:9-20. [Crossref] [PubMed]
204. Käsmann L, Eze C, Manapov F. Stereotactic Body Radiation Therapy (SBRT) Combined with Immune Check-Point Inhibition (ICI) in Advanced Lung Cancer: Which Metastatic Site Should Be Irradiated to Induce Immunogenic Cell Death? Int J Radiat Oncol Biol Phys 2020;108:225-6. [Crossref] [PubMed]
205. Manapov F, Eze C, Taugner J, et al. Combination of pembrolizumab with radiotherapy can change treatment paradigm in metastatic "non-driver" non-small-cell lung cancer: Assembling a path. Clin Respir J 2021;15:1139-44. [Crossref] [PubMed]
206. Manapov F, Käsmann L, Roengvoraphoj O, et al. Multimodal "synergistic" treatment based on tumour immunological contexture for advanced non-driver non-small cell lung cancer: A myth or reality? Eur J Cancer Care (Engl) 2020;29:e13291. [Crossref] [PubMed]
207. McGee HM, Daly ME, Azghadi S, et al. Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site. Int J Radiat Oncol Biol Phys 2018;101:1259-70. [Crossref] [PubMed]
208. D'Andrea MA, Reddy GK. Systemic Antitumor Effects and Abscopal Responses in Melanoma Patients Receiving Radiation Therapy. Oncology 2020;98:202-15. [Crossref] [PubMed]
209. D’Andrea MA, Reddy GK. The systemic immunostimulatory effects of radiation therapy producing overall tumor control through the abscopal effect. J Radiat Oncol 2019;8:143-56. [Crossref]
210. Ko EC, Formenti SC. Radiotherapy and checkpoint inhibitors: a winning new combination? Ther Adv Med Oncol 2018;10:1758835918768240. [Crossref] [PubMed]
211. Antoni D, Burckel H, Noel G. Combining Radiation Therapy with ALK Inhibitors in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer (NSCLC): A Clinical and Preclinical Overview. Cancers (Basel) 2021;13:2394. [Crossref] [PubMed]
212. Luke JJ, Lemons JM, Karrison TG, et al. Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. J Clin Oncol 2018;36:1611-8. [Crossref] [PubMed]
213. Corrao G, Marvaso G, Ferrara R, et al. Stereotatic radiotherapy in metastatic non-small cell lung cancer: Combining immunotherapy and radiotherapy with a focus on liver metastases. Lung Cancer 2020;142:70-9. [Crossref] [PubMed]
214. Vokes EE, Ready N, Felip E, et al. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol 2018;29:959-65. [Crossref] [PubMed]
215. Britschgi C, Riesterer O, Burger IA, et al. Report of an abscopal effect induced by stereotactic body radiotherapy and nivolumab in a patient with metastatic non-small cell lung cancer. Radiat Oncol 2018;13:102. [Crossref] [PubMed]
216. Vilinovszki O, Andratschke N, Huellner M, et al. True abscopal effect in a patient with metastatic non-small cell lung cancer. Radiat Oncol 2021;16:194. [Crossref] [PubMed]
217. Arcidiacono F, Aristei C, Marchionni A, et al. Stereotactic body radiotherapy for adrenal oligometastasis in lung cancer patients. Br J Radiol 2020;93:20200645. [Crossref] [PubMed]
218. Voglhuber T, Kessel KA, Oechsner M, et al. Single-institutional outcome-analysis of low-dose stereotactic body radiation therapy (SBRT) of adrenal gland metastases. BMC Cancer 2020;20:536. [Crossref] [PubMed]
219. Zhao X, Zhu X, Fei J, et al. Short-term outcomes and clinical efficacy of stereotactic body radiation therapy (SBRT) in treatment of adrenal gland metastases from lung cancer. Radiat Oncol 2018;13:205. [Crossref] [PubMed]
220. Bang A, Wilhite TJ, Pike LRG, et al. Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. Int J Radiat Oncol Biol Phys 2017;98:344-51. [Crossref] [PubMed]
221. Tagliamonte M, Petrizzo A, Tornesello ML, et al. Combinatorial immunotherapy strategies for hepatocellular carcinoma. Curr Opin Immunol 2016;39:103-13. [Crossref] [PubMed]
222. Buonaguro L, Petrizzo A, Tagliamonte M, et al. Challenges in cancer vaccine development for hepatocellular carcinoma. J Hepatol 2013;59:897-903. [Crossref] [PubMed]
223. Waterhouse DM, Garon EB, Chandler J, et al. Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: CheckMate 153. J Clin Oncol 2020;38:3863-73. [Crossref] [PubMed]
224. Faivre-Finn C, Vicente D, Kurata T, et al. Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC-an Update From the PACIFIC Trial. J Thorac Oncol 2021;16:860-7. [Crossref] [PubMed]
225. Decaestecker K, De Meerleer G, Ameye F, et al. Surveillance or metastasis-directed Therapy for OligoMetastatic Prostate cancer recurrence (STOMP): study protocol for a randomized phase II trial. BMC Cancer 2014;14:671. [Crossref] [PubMed]
226. Zhang Y, Schoenhals J, Christie A, et al. Stereotactic Ablative Radiation Therapy (SAbR) Used to Defer Systemic Therapy in Oligometastatic Renal Cell Cancer. Int J Radiat Oncol Biol Phys 2019;105:367-75. [Crossref] [PubMed]
227. Guénolé M, Lucia F, Bourbonne V, et al. Impact of concomitant systemic treatments on toxicity and intracerebral response after stereotactic radiotherapy for brain metastases. BMC Cancer 2020;20:991. [Crossref] [PubMed]
228. Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J Clin Oncol 2014;32:3824-30. [Crossref] [PubMed]
229. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol 2020;38:2830-8. [Crossref] [PubMed]
230. Lim SH, Lee JY, Lee MY, et al. A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer. Ann Oncol 2015;26:762-8. [Crossref] [PubMed]
231. Vanneste BGL, Van Limbergen EJ, Dubois L, et al. Immunotherapy as sensitizer for local radiotherapy. Oncoimmunology 2020;9:1832760. [Crossref] [PubMed]
232. Suwinski R. Combination of immunotherapy and radiotherapy in the treatment of brain metastases from non-small cell lung cancer. J Thorac Dis 2021;13:3315-22. [Crossref] [PubMed]
233. Chen WC, Baal UH, Baal JD, et al. Efficacy and Safety of Stereotactic Radiosurgery for Brainstem Metastases: A Systematic Review and Meta-analysis. JAMA Oncol 2021;7:1033-40. [Crossref] [PubMed]
234. Pielkenrood BJ, van der Velden JM, van der Linden YM, et al. Pain Response After Stereotactic Body Radiation Therapy Versus Conventional Radiation Therapy in Patients With Bone Metastases-A Phase 2 Randomized Controlled Trial Within a Prospective Cohort. Int J Radiat Oncol Biol Phys 2021;110:358-67. [Crossref] [PubMed]
235. Sahgal A, Myrehaug SD, Siva S, et al. Stereotactic body radiotherapy versus conventional external beam radiotherapy in patients with painful spinal metastases: an open-label, multicentre, randomised, controlled, phase 2/3 trial. Lancet Oncol 2021;22:1023-33. [Crossref] [PubMed]
236. Cao Y, Chen H, Sahgal A, et al. Volumetric burden of metastatic lesions drives outcomes in patients with extracranial oligometastatic disease. Cancer Med 2021;10:8091-9. [Crossref] [PubMed]

(English Language Editor: B. Draper)