We conducted and subsequently published the findings from a multi-institutional, randomized study that examined the efficacy of LCT on PFS in oligometastatic non–small cell-lung cancer (NSCLC) in 2016. 4 The trial was closed early after it demonstrated an observed 8-month benefit in PFS for patients who received LCT relative to patients who received maintenance therapy or observation (MT/O); the median PFS was 11.9 months in the LCT arm (90% CI, 5.72 to 20.90 months) versus 3.9 months in the MT/O arm (log-rank P = .005). The aims of this paper were to present final PFS data for these patients and to report OS outcomes, with supplementary analyses used to generate hypotheses about the biologic basis for the effects of LCT on these patients. The exploratory analyses also allowed us to assess differences in OS outcomes after early (initial) versus late (after progression) LCT.

Oligometastatic cancer continues to be defined biologically, 1 , 2 and the roles of radiation therapy and surgery have evolved substantially during the past decade. In patients with these cancers, it is technically feasible to use definitive radiation therapy or surgical therapy to control all known sites of disease, termed local consolidative therapy (LCT). The notion that LCT could improve progression-free survival (PFS) has been suggested from retrospective and single-arm prospective studies and, more recently, from five prospective randomized studies (two in lung cancer, 3 , 4 one in prostate cancer, 5 one in colorectal cancer, 6 and one in multiple histology 7 ). Other ongoing trials are addressing this issue, but to date no randomized clinical trials have demonstrated an overall survival (OS) benefit from LCT in patients with lung cancer.

Next, we analyzed the association of OS with major clinical variables of interest on which random assignment was balanced: (1) number of metastases (0 to 1 v 2 to 3), (2) response to first-line chemotherapy (stable disease v partial response), (3) CNS metastases (no v yes), (4) nodal status (N0/N1 v N2/N3), and (5) EGFR / EML4ALK status (none v EGFR / EML4ALK ). Finally, we fit a multivariable model that included treatment arm and the above clinical variables that were most strongly correlated with OS, and we incorporated one variable for every 10 events (eg, deaths) in the trial to reduce the chance of overfitting data.

Late LCT was defined as definitive LCT to all radiographically visible disease sites at the time of progression. Two additional exploratory analyses were done to assess OS after progression, using progression date as the index date and stratified by randomly assigned arm and receipt of late LCT. Notably, in both of these exploratory analyses, the three patients in the MT/O arm who crossed over to receive LCT before progression were excluded. We excluded these patients because, given that crossover and LCT receipt occurred before progression, they did not adhere to either arm and did not receive either early (after front-line therapy) or late (at the time of progression) LCT per our definitions.

The trial used a one-sided 10% type I error and had 90% power to detect an improvement in PFS from 4 months in the standard of care MT/O arm (chosen on the basis of prior studies of maintenance therapy 9 - 13 ) to 7 months in the experimental LCT arm, which corresponded to a hazard ratio (HR) of 0.57 or a 75% improvement in median PFS. In view of these assumptions, the design was powered for 94 patients to be randomly assigned in 37.6 months with an additional 9 months of follow-up. PFS, the appearance of new lesions, and OS were compared between the LCT and MT/O arms with log-rank tests and an intent-to-treat analysis. The log-rank test was used to compare survival distributions between treatment arms. 14

The primary outcome, PFS, was defined from the time of random assignment to the time of disease progression or death, whichever occurred first. To evaluate this end point, radiographic evaluations were conducted at follow-up intervals of every 8 ± 2 weeks, regardless of the treatment arm. To avoid introduction of a delay in follow-up imaging for patients in the LCT arm, the protocol was intentionally designed to index all imaging to the date of enrollment and to not deviate from this calendar during local therapy. Secondary outcomes were OS, safety and tolerability (ie, toxicity), and time to new lesion progression. OS was defined from the time of random assignment to death or, for alive patients, the date of last contact. Time to new lesion progression from the time of random assignment was compared between treatment groups using log-rank tests. Findings for quality of life were insufficient to report.

In lieu of stratification, the random assignment was balanced dynamically on five prognostic covariables related to PFS, 8 namely number of metastatic disease sites (0–1 v 2 to 3); response to first-line systemic therapy (stable disease v partial response); CNS metastases (yes v no); (d) intrathoracic nodal status (N0/N1 v N2/N3), and EGFR / ALK mutation (yes v no). The choice of LCT (surgery v radiation) was made by a multidisciplinary treatment team. 4 Although patients with a complete response were not eligible for random assignment, those with a complete response in the metastatic sites and a persistent primary tumor could remain in the study and were considered to have zero metastatic sites. Patients in the MT/O arm were allowed to cross over at the time of progression and receive LCT.

Although the details of the study design and statistical methods have been previously published, 4 this is a brief summary: Three institutions contributed patients to this study (MD Anderson Cancer Center, Houston, TX; London Health Sciences Center, London, Ontario; and The University of Colorado, Aurora, CO), and all three sites approved the study. Eligible patients (1) had pathologically confirmed NSCLC, (2) had stage IV disease according to the seventh edition of the American Joint Committee on Cancer staging system, (3) had three or fewer metastases, not including the primary tumor, (4) had an Eastern Cooperative Oncology Group performance status of 2 or less, (5) were age 18 years or older, and (6) received standard front-line systemic therapy. This standard therapy was defined as (1) at least four cycles of platinum doublet chemotherapy, (2) erlotinib or another approved first-line epidermal growth factor receptor tyrosine kinase inhibitor for at least 3 months for tumors with known EGFR mutations, or (3) crizotinib for at least 3 months for tumors with an anaplastic lymphoma kinase rearrangement.

When the effect of other major clinical variables was assessed, OS was associated with two to three metastases (HR, 1.65; P = .208), partial response to first-line chemotherapy (HR, 1.35; P = .452), N2/N3 disease (HR, 1.33; P = .443), and CNS metastases (HR, 1.01; P = .979). However, none of these associations were statistically significant. Conversely, EGFR / EML4ALK status was correlated with a reduced risk of death (HR, 0.12; P = .041). Because of the small size of the EGFR / EML4ALK patient cohort (n = 8), additional exploratory assessments with EGFR / EML4ALK status were not considered. However, to better assess the effect of the treatment arm in the presence of potentially prognostic features, a multivariable model was fitted with the two clinical covariables that demonstrated the strongest association with OS: number of metastases and EGFR / EML4ALK alterations. In this model, the LCT arm remained associated with improved OS (HR, 0.46; 95% CI, 0.21 to 0.99; P = .048; Table 2 ). Finally, with regard to toxicity, no patient experienced any severe (grade ≥ 3) toxicity event aside from those reported previously. 4

Of the 39 patients who experienced progression, 15 (41%; n = 6 in the LCT group and n = 9 in the MT/O group) received LCT at the time of progression. Reasons for not undergoing LCT at the time of progression in the MT/O arm were polymetastatic progression (n = 7), poor performance status (n = 3), and refusal of radiation therapy (n = 1). Calculated from the time of progression, patients who received LCT at progression had a median OS time that was not reached (95% CI, 11.5 months to not reached) versus 16.4 months without late LCT (95% CI, 8.7 to 40.9 months; P = .119; Fig 3 ). In a multivariable Cox model analysis that assessed OS and incorporated both initial treatment assignment (LCT v MT/O) and late LCT (yes v no), both initial (HR, 0.30; 95% CI, 0.12 to 0.75) and late (HR, 0.44; 95% CI, 0.18 to 1.06; P = .064) treatment with LCT correlated with improved OS.

Salvage therapies for all patients included additional systemic therapy, LCT to all progressing sites of disease, and combinations thereof (Appendix Table A2 , online only) on or off a clinical trial. The median survival-after-progression time for all patients was 13.6 months (95% CI, 8.4 to 37.6 months). χ 2 tests revealed no difference in the proportions of patients who received late LCT in the LCT versus MT/O group ( P = .39). However, patients in the LCT group survived longer after progression relative to patients in the MT/O group (37.6 months [95% CI, 9.0 months to not reached] v 9.4 months [95% CI, 5.9 to 19.6 months]; P = .034; Fig 2 ).

Twenty-nine of the original 49 patients died by the time of this analysis: 11 of 25 died in the LCT group, and 18 of 24 died in the MT/O group. The median OS time for all patients was 37.7 months (95% CI, 16.6 to 41.2 months). OS time was significantly longer in the LCT group (median, 41.2 months; 95% CI, 18.9 months to not reached) than in the MT/O group (median, 17.0 months; 95% CI, 10.1 to 39.8 months; P = .017; Fig 1B ).

As noted in our initial publication, the trial was closed early after a planned annual Data Safety Monitoring Board analysis revealed that, according to the data at that time, there was a 99.46% probability of superiority of the LCT arm if the current trend continued. Of the 74 patients enrolled on the trial at the time of closure, 49 (66%) were randomly assigned and included in this analysis. Patient characteristics have been previously published and are listed in Table 1 . Treatment regimens also have been previously published and are listed in Appendix Table A1 (online only). Note that the LCT regimens could include surgery, radiation, or a combination of the two. Concurrent chemoradiation also was allowed for the primary tumor and regional lymph nodes. The median follow-up time for censored patient data at the date the patient was last known to be alive was 38.8 months (range, 28.3 to 61.4 months). Thirty-nine patients were identified as having progression (19 of 25 in the LCT group and 20 of the 24 in the MT/O group), and three patients in the MT/O arm had their data censored, because they received upfront LCT before disease progression. The median PFS time for all patients was 8.3 months (95% CI, 5.2 to 14.2 months). The previously noted PFS benefit from LCT was maintained; the median PFS was 14.2 months in the LCT group (95% CI, 7.4 to 23.1 months) versus 4.4 months in the MT/O group (95% CI, 2.2 to 8.3 months; P = .022; Fig 1A ). The median time to appearance of new lesions was 14.2 months in the LCT group (95% CI, 5.7 to 24.3 months) versus 6.0 months in the MT/O group (95% CI, 4.4 to 8.3 months; P = 0.11).

DISCUSSION Section: Choose Top of page Abstract INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION << REFERENCES

Our previously published findings, to our knowledge, represent the first multicenter, randomized trial of LCT for selected oligometastatic NSCLC (three or fewer metastatic lesions, no progression after front-line systemic therapy) to demonstrate that aggressive consolidation therapy led to a PFS benefit. These updated PFS and OS findings provide evidence that the PFS benefit was durable and that patients who received LCT immediately after front-line systemic therapy had better OS than did patients who received MT/O. Two features of these new results are particularly notable: (1) the median OS time in the LCT group, 41.2 months, was markedly longer than previously reported for metastatic NSCLC, particularly in the preimmunotherapy era; and (2) an OS benefit in the group originally assigned to receive LCT was observed despite allowance for patients to cross over from the MT/O arm to the LCT arm at the time of progression.

To explore possible reasons for these findings, we assessed the effects of salvage therapy after progression in both treatment groups. Two findings emerged from these analyses: (1) survival after progression was substantially longer in the LCT group; and (2) patients who received late LCT at the time of progression exhibited long OS (median OS not reached), although only 41% of patients who experienced progression received this treatment. Put another way, early LCT is better than no LCT, but late LCT at progression, if feasible, may improve OS to an extent that partly compensates for this difference. These results also imply that a primary risk of reserving LCT until progression (late LCT) is that definitive treatment to all sites of disease can be achieved in only a subset of patients.

Several potential mechanisms may explain the benefit from LCT in terms of OS and survival after progression. First, initial systemic therapy that leads to stable or responsive disease leaves behind treatment-resistant malignant cells that are less likely to be eliminated by subsequent maintenance therapy and could serve as a source for subsequent metastatic spread, even in the absence of radiographic progression. In that case, LCT would reduce the burden of treatment-resistant cells. Thus, in this scenario, delaying LCT to the time of radiographic progression would be less effective than early LCT, because it would not address distant micrometastatic disease that developed during maintenance therapy.15,16 Second, LCT may potentiate the effects of systemic therapy; for example, consolidative radiotherapy could render residual disease more sensitive to subsequent maintenance therapy. A third possibility is that residual tumor after initial systemic therapy promotes the growth of distant micrometastatic disease, for example, via immunosuppressive or proangiogenic effects, as observed in preclinical models.17 In that case, by reducing the residual tumor burden, LCT would also slow the growth of distant micrometastatic disease. Notably, these mechanisms are not mutually exclusive, and more than one could contribute to the benefits of LCT.

The OS time observed after initial LCT in this study was impressive, even in the context of other studies of consolidative therapy and before the inclusion of immunotherapy in standard treatment of NSCLC. For example, a propensity score-matched analysis of patients treated with comprehensive LCT for oligometastatic NSCLC demonstrated an OS time of 27.1 months for patients given LCT.18 In a recent single-arm, prospective study of 29 patients given consolidative radiation therapy for oligometastatic NSCLC after three to six cycles of platinum-based chemotherapy, the median OS time was 28.4 months (95% CI, 14.5 to 45.8 months).19 The eight patients in this study who had EGFR or ALK mutations exhibited long survival times (median PFS, 23.1 months, and median OS, not reached). These survival times are similar to, or longer than, recent reports of consolidative LCT for NSCLC with EGFR activating mutations. One such study recently found that OS time after LCT to all sites was 40.9 months relative to 30.8 months without any ablative therapy.20 However, given the small number of patients in this category, the utility of LCT for NSCLC with epidermal growth factor receptor or anaplastic lymphoma kinase tyrosine kinase inhibitors merits additional investigation; we are currently enrolling patients to a randomized, phase II study of osimertinib with or without LCT for stage IV NSCLC to address this issue (ClinicalTrials.gov identifier: NCT03410043).

These results are subject to several limitations. First, and most notably, as discussed previously,4 early closure of the trial because of efficacy resulted in the random assignment of only 49 patients, which substantially limits subgroup analyses. We attempted to account for imbalances in patient characteristics through our approach of balanced random assignment, which considered major prognostic factors (number of disease sites, response to first-line systemic therapy, presence of CNS metastases, intrathoracic nodal status, and presence of EGFR or ALK mutation). However, we intend the subset analyses of this study to be provocative and supplementary rather than paradigm shifting. Second, the front-line and maintenance systemic therapies used were somewhat heterogeneous, although all were considered standard-of-care regimens in the United States at the time of the study. Conceivably, then, the effect of LCT could differ depending on the systemic therapy used, a possibility that would be difficult to detect given the modest size of some of the subgroups. Finally, because our trial opened in 2012, it did not include immunotherapy, which has revolutionized the treatment of both locally advanced and metastatic NSCLC during the past 5 years. Thus, the use of LCT needs additional assessment in this context.

In summary, this multicenter, phase II, randomized study showed that LCT improves both PFS and OS among patients with oligometastatic NSCLC that does not progress after front-line systemic therapy. Patients originally assigned to LCT had prolonged OS times (median OS, 41.2 months) and durable survival after progression (37.6 months). These results build on our prior report by demonstrating that benefits of LCT extend beyond delay of initial progression. Overall, this study provides randomized OS data in support of the integration of LCT for patients with oligometastatic disease. However, although these data are compelling, given the limitations expressed in this Discussion, we emphasize that future studies should be supported to definitively assess the role of LCT in larger populations (eg, phase III trials such as NRG-LU002) and in the context of novel systemic therapies. Furthermore, at this time, given the restrictions of the subset analyses performed in this study, we would support an oligometastatic definition that is consistent with the inclusion criteria of this trial and with the vast majority of patients enrolled in Stereotactic Ablative Radiation Therapy for the Comprehensive Treatment of Oligometastatic Tumors (SABR-COMET)7 and the UT Southwestern3 randomized, phase II studies: zero to three metastases and unconstrained by molecular profile/mutational status. Note that, although these two trials allowed enrollment of patients with up to five metastases, most patients enrolled had three or fewer metastases. Our proposed definition will likely continue to evolve as the benefit of aggressive treatment is better elucidated in specific patient subgroups and through both clinical and correlative investigations.