Non–small cell lung cancer with very limited extent of metastatic spread commonly is termed, oligometastatic disease ( OMD ), and typically described as no more than 3 to 5 lesions. Definitive local therapy potentially leads to significant improvement in progression-free survival and overall survival. OMD may occur de novo prior to initiation of systemic therapy or as an induced state after initiation of systemic therapy. Although prospective data are limited to small trials, they have consistently supported local therapy as an appropriate consideration if not a clear standard of care for well-selected patients. Several trials in OMD are ongoing.
A subset of patients with metastatic non–small cell lung cancer (NSCLC) has very limited spread, known as oligometastatic disease (OMD), that may be amenable to local therapy that may confer significant clinical benefit. Definitions of the number of lesions vary but are most commonly up to 3 to 5 lesions.
Local therapies may provide clinical benefit for patients with de novo OMD as well as oligoresidual disease or oligoprogression after a good response to systemic therapy for advanced NSCLC.
Limited prospective data are available, but the small studies of oligoresidual disease are consistent in demonstrating a marked improvement in progression-free survival and some evidence of improved overall survival.
As systemic therapies for advanced NSCLC improve response rates, more patients may become candidates for local therapies for oligopersistent disease and oligoprogression. Important trials are ongoing.
In the absence of more definitive prospective data, local therapies may be considered an appropriate option, but not a clear standard of care, in well-selected patients.
Introduction: defining the concept and the setting of oligometastatic disease
For multiple reasons, the setting of oligometastatic disease (OMD) in advanced non–small cell lung cancer (NSCLC) as well as other cancers currently is among the more controversial in clinical oncology. The first element in considering whether there should be a distinct management approach for patients with advanced NSCLC that demonstrates a pattern of OMD is to define this state. Although there is no uniformly accepted precise definition of OMD, the concept is that metastatic disease is not an absolute, binary process in which a cancer is either nonmetastatic and potentially curable or metastatic and categorically incurable. Instead, Hellman and Weichselbaum introduced the pivotal concept that the behavior of metastatic disease represents a spectrum in which patients first demonstrate metastatic spread limited to 1 or few sites before disease spreads more diffusely. Moreover, cancer biology is quite variable, with some cancers progressing rapidly, whereas others follow an indolent pattern that may track over years to decades, and this pattern is associated with different expression patterns of microRNA. These concepts can be integrated into the hypothesis that emerged that OMD, dominated by 1 or a few metastatic lesions for an extended interval, may be amenable to unique efficacy and even potentially cure with aggressive local therapy. This challenges the simpler historical model that metastatic disease, once established and regardless of the degree of metastatic spread, is a systemic process for which local therapy is not indicated aside from unusual cases, in which palliation or local control are the goals of this intervention.
The concept of OMD in NSCLC includes several subtypes and variants ( Fig. 1 ). Patients may present with de novo OMD at the time of the initial work-up of NSCLC (synchronous OMD) or limited relapse after previous treatment with curative intent (metachronous OMD), the latter associated with a particularly prolonged natural history relative to broad populations of patients with advanced NSCLC. Identification of very isolated metastatic spread may be more likely to be identified with routine incorporation of sensitive imaging studies like positron emission tomography (PET) and brain magnetic resonance imaging (MRI) at diagnosis and routine surveillance imaging. Beyond these settings that are the product only of the tumor biology, new targeted therapies that commonly include targeted therapies, immunotherapy, and potentially chemotherapy increasingly lead to what may be interpreted as induced OMD. Specifically, I commonly see patients develop limited oligoprogression in 1 or a few sites of disease after an excellent response over an extended period, most commonly while on targeted therapy, immunotherapy, or chemoimmunotherapy. This setting also typically is viewed through the same lens of potential utility of local therapy, as described later.
In addition, dramatic responses to more effective systemic therapies may yield oligopersistent (or oligoresidual) disease, with just 1 or a few sites of visible disease on imaging that may be amenable to definitive local therapy.
Another controversy in the study of OMD centers around defining a threshold for defining OMD in terms of the number of lesions and sites involved. Unfortunately, the few trials in this space have not adopted any shared definition and have employed their own eligibility criteria from study to study, both in terms of number of lesions and of organs/anatomic areas involved. Some investigators reasonably may argue that although the biological concept of OMD may apply as a unique setting when the definition is applied judiciously, such as to 1 to 2 sites of metastatic spread, the biological behavior is more systemic when considering patients with 3 or even 5 or more lesions, potentially in several organs, as some studies have done. A recent review of published studies on OMD in NSCLC found no consensus in the definition used but noted that the most common adopted definition was of no more than 5 lesions. The European Organisation for Research and Treatment of Cancer Lung Cancer Group developed a consensus definition of no more than 5 lesions in a maximum of 3 organs. Although a developing consensus definition is an important step, it should be recognized that this proposed definition is based on judgment and bias of the participants rather than data on actual clinical outcomes from trials of OMD in NSCLC to clarify whether an evidence-based threshold can be identified to demonstrate that patients with, for example, up to 3 sites of disease fare far better with local therapy than those with 4 or more. As described later, a clear majority of patients enrolled on to trials of definitive local therapy for OMD have had no more than 2 sites of disease even when eligibility is far more liberal.
A common thread running through the expanding field of OMD in NSCLC, as well as in other cancer types, is that the available clinical data are limited and heterogeneous in eligibility and treatment approach, but they also demonstrate a strong magnitude of benefit that has been highly consistent across trials. Such trials have rarely had power or follow-up sufficient to indicate an improvement in overall survival (OS), which remains the leading arbiter for many clinicians in revising clinical management standards. The field of OMD in NSCLC forces reliance on judgment about how to weigh the value of limited but convergent data for a relatively narrow population, a judgment further challenged by heterogenous inclusion/exclusion criteria, trial designs, and endpoints.
A historical perspective on oligometastatic disease
Although trials specifically focusing on patients with OMD have been developed only in the past several years, there is a long history of recognition that prolonged survival, in the range of 20% to 25%, even well beyond 5 years may be demonstrated in patients with a solitary brain metastasis who undergo a craniotomy or stereotactic radiosurgery as well as in patients with a solitary adrenal metastasis who underwent adrenalectomy. These retrospective case series were predominantly in patients with NSCLC. Such cases sometimes were characterized as having a “precocious metastasis” that represents an isolated process rather than being representative of broader metastatic spread, thereby being amenable to cure by local therapies.
A more recent meta-analysis of individual patient data included 757 patients with NSCLC who presented with 1 to 5 metastases. These metastatic lesions may have been demonstrated synchronously or metachronously. Among these patients, 62% underwent surgery to metastatic lesions, whereas 38% received radiation to metastatic sites. The OS for this large cohort was 29%, demonstrating a result far exceeding the anticipated long-term clinical outcome for a broader population with metastatic NSCLC.
Such results illustrate that patients with NSCLC and OMD may demonstrate a prolonged OS after receiving local therapies to all identified metastatic foci; these retrospective results leave open the question of whether these more favorable outcomes are due to local therapies or whether the more favorable biology of OMD that made these patients compelling candidates for local therapies may have been the more critical determinant of their encouraging long-term OS.
One argument that local therapy shapes the overall trajectory of even metastatic cancer is the finding that the radiation dose in the setting of OMD is correlated with OS. In a study of prognostic factors associated with OS in patients with oligometastatic NSCLC, a radiation dose to metastatic foci beyond the median of 63 Gy was associated with a significantly longer OS than radiation treatment to a dose below the median. Other studies also have observed superior OS among recipients of a higher radiation dose, even in patients with metastatic disease, indicating that more effective local therapy has an influence on global cancer outcome measurements.
Local therapy for oligoprogression
As described previously, oligoprogression is the clinical scenario in which a patient with advanced NSCLC demonstrates a good response to systemic therapy (most commonly targeted therapy or immunotherapy) and then develops 1 or a few areas of limited progression against a background, more broadly, of overall good disease control. There has been scant research on this scenario, but what little has been reported supports the conclusion that local therapy to 1 or a few sites of progression in patients who have demonstrated a good response to a targeted therapy is safe, feasible, and associated with favorable clinical outcomes. Yu and colleagues, from Memorial Sloan Kettering Cancer Center, reported on a retrospective series of 18 patients with an activating epidermal growth factor receptor (EGFR) mutation who had responded well on EGFR inhibitor therapy and then received definitive local therapy for oligoprogression; this group was able to continue on the same EGFR tyrosine kinase inhibitor (TKI) therapy without subsequent progression on for a median of 10 months and a median of 22 months before enough progression developed to warrant a change in systemic therapy. Weickhardt and colleagues, from the University of Colorado, published a similar experience in patients with EGFR mutation–positive (N = 10) or anaplastic lymphoma kinase (ALK) -positive NSCLC (N = 15), with a median of 6.2 months before demonstrating subsequent progression.
The brain has been identified as a site of progression particularly appropriate for local therapy, because several therapies in prior years, such as earlier-generation EGFR and ALK TKIs, had relatively poor penetration in the central nervous system (CNS) and accordingly limited CNS activity. In this setting, intracranial progression may be interpreted as a failure in pharmacodynamics more than broad acquired resistance to the systemic therapy, for which addition of local therapy to addition CNS progression, without switching systemic therapy approach, has been accepted as a valuable solution. In the study by Weickhardt and colleagues, those with intracranial disease as the first site of progression demonstrated a median PFS after local therapy of 10.2 months.
Despite scant evidence, all of which is retrospective, this practice of local therapy for oligoprogression has become widely adopted with little controversy. This presumably is because so many clinical oncologists have routinely observed the pattern of prolonged subsequent disease control after local therapy for oligoprogression in practice. This same strategy of local definitive therapy for oligoprogression also is an accepted practice for patients on immunotherapy, despite that this represents an extrapolation of data from patients treated with targeted therapies. Current guidelines from the National Comprehensive Cancer Network (NCCN) support this approach for patients with oligoprogression, regardless of the specific systemic therapy a patient is receiving at the time when limited progression is identified. The rationale for and convergent clinical experience supporting definitive local therapy for oligoprogression is likely so widely accepted that clinicians and patients would not consider a prospective trial in this setting to be a valuable exercise, nor would they have equipoise about randomizing patients to have this intervention omitted for appropriate candidates.
Prospective data supporting local ablative therapy for oligopersistent disease
The concept of pursuing definitive local therapy, such as surgical resection, radiation, or a combination of these, has gained traction over the past several years based on the results of several randomized trials that have demonstrated benefits that have been highly favorable despite the small size of these trials. In contrast with the earlier retrospective research on OMD in NSCLC that was previously defined primarily if not exclusively by tumor biology, independent of treatment effect, several prospective trials of definitive local therapy in recent years all have focused on a broader concept of OMD that includes induced OMD, representing the interaction of increasingly effective systemic therapy with the native biology of the cancer. By incorporating a lead-in time of several months of systemic therapy and then pursuing definitive local therapy in a subset with very limited metastatic disease after first-line treatment, this study design enriches for a population of patients who have demonstrated a favorable clinical trajectory over the preceding months, without progression, in whom addition of definitive local therapy potentially may work in conjunction with systemic therapy to alter the overall trajectory of cancer progression over time.
A study by Gomez and colleagues enrolled patients with oligometastatic NSCLC from 3 centers, starting with 74 patients with 3 or fewer metastatic sites who were receiving or had recently completed 3 months of systemic therapy, which could be either targeted therapy for those with an activating EGFR mutation or ALK rearrangement, or a standard platinum-based chemotherapy doublet for those without a driver mutation. From this group, 49 had no progression and were inclined to pursue randomization to either maintenance therapy or observation, as clinically indicated, which was at the discretion of the enrolling investigator, or the same maintenance therapy or observation in combination with definitive local therapy to all sites of residual disease. The specific modality of definitive local therapy also was individualized to the patient, in some cases a combination of surgery to some sites and radiation to others and in other cases a combination of radiation with concurrent systemic therapy was administered.
The trial terminated earlier than planned based on the decision of the data safety monitoring committee (DSMC), which performed an annual analysis and determined that the difference in the primary endpoint of progression-free survival (PFS) was too substantial to continue enrollment and randomization according to the trial. The median PFS for all randomized patients was 11.9 months for the patients who received definitive local therapy with maintenance therapy or observation compared with 3.9 months for those who received maintenance systemic therapy or observation alone (hazard ratio [HR] 0.35; P = .0054). Along with the highly significant improvement in PFS, this trial demonstrated a statistically significant improvement in time to new metastases in patients who received definitive local therapy along with maintenance therapy vs observation (median 11.9 months vs 5.7 months, respectively; P = .0497), whereas OS compared with maintenance or observation alone results were too immature at the time of the initial publication to be reported.
Despite the low numbers in the trial due to the early termination of the trial and the potential for patients assigned to maintenance therapy or observation alone to cross over to definitive local therapy on progression, a subsequent update of the trial results revealed that definitive local therapy was associated with a significant improvement in OS (median 41.2 vs 18.9 months, respectively; P = .017).
Subsequently reported randomized trials also have supported the role of definitive local therapy for patients with oligometastatic NSCLC, although these studies are all limited by their small size. Iyengar and colleagues randomized nonprogressing patients with EGFR and ALK wild-type NSCLC and a more liberal definition of oligometastatic NSCLC, with up to 5 sites of metastatic disease along with the primary tumor, to maintenance systemic therapy or with stereotactic ablative body radiotherapy (SABR) after completion of 4 to 6 cycles of first-line platinum-based chemotherapy. Similar to the trial by Gomez and colleagues, this study was closed early to accrual by the DSMC, with just 29 patients randomized, due to the significant benefit observed in the consolidation SBRT vs maintenance systemic therapy alone arms (median PFS 9.7 months vs 3.5 months, respectively; P = .01). This trial demonstrated no in-field failures and fewer overall recurrences with SABR consolidation after first-line chemotherapy.
The SABR-COMET trial enrolled 99 patients with OMD, defined as 1 to 5 metastatic lesions, from any of several primary cancer types, including 18 with lung cancer. This trial randomized participants 2 to 1 to either SABR to all metastatic sites along with standard-of-care systemic therapy or a control group of standard-of-care therapy alone, respectively. This relatively small trial did not divide outcomes by primary cancer. The trial demonstrated a significant improvement in PFS in the SABR plus standard-of-care arm (HR 0.47; P = .0012), although this endpoint is compromised by the fact that SABR renders it impossible to assess for progression in the sites most likely to demonstrate progression. In light of the limited size of the trial, it is not surprising that the favorable difference in OS, although encouraging, was not statistically significant (HR 0.57; P = .09).
Finally, Peng and colleagues reported on the potential benefit of SBRT to oligopersistent disease after initial treatment with EGFR TKI therapy in Chinese patients with an activating EGFR mutation. This randomized trial found that PFS was significantly greater in recipients of SBRT along with EGFR TKI vs ongoing EGFR TKI therapy alone (17.4 months vs 8.9 months, respectively; log rank P = .042).
Taken together, the data from these small studies provide converging evidence of a significant improvement in PFS, although interpretation of PFS is limited by the fact that the local consolidation therapy itself compromises the interpretability of this endpoint, as discussed later.
A subset of these studies also provides limited support for definitive local therapy, also conferring an improvement in OS, albeit with small patient numbers, even when looking at the collective data.
Interaction of immunotherapy with radiation for oligometastatic disease
Another potential interaction of systemic therapy with local therapy for patients with OMD is the potential synergy of immunotherapy with radiation. The phenomenon of the abscopal effect, in which tumor shrinkage outside of the radiated field is demonstrated and presumably mediated by an immune-stimulatory systemic effect induced by radiation, provides a compelling rationale for combining radiation to 1 or more lesions with immunotherapy, such as the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab that has now become a standard of care in treatment of advanced NSCLC, alone , or in combination with chemotherapy. , Preclinical studies have demonstrated the potential for immunotherapy to increase release of tumor antigens, antigen presentation, and T-cell infiltration in radiated cancers. Recent phase II trials have explored the promise of administering SBRT to 1 or more foci of disease to promote an initial immune response that then can be potentiated by longitudinal pembrolizumab.
The PEMBRO-RT trial from the Netherlands enrolled chemotherapy-pretreated but immunotherapy-naïve patients and was not focused on the subset with OMD but assessed the potential interaction of SBRT with pembrolizumab by comparing pembrolizumab monotherapy alone to the same immunotherapy preceded by SBRT to a single lesion, leaving the remaining unirradiated lesions assessable for response to pembrolizumab monotherapy. The primary endpoint of objective response rate (ORR) was 12 weeks from the time of randomization; a total of 76 patients were randomized. Although the study failed to demonstrate a statistically significant difference in ORR, the marked difference in ORR favoring the arm that received initial SBRT along with pembrolizumab vs pembrolizumab alone (36% vs 18%, respectively) suggested that the trial may have been woefully underpowered to detect a potentially real effect. The difference in ORR was limited to those patients with tumor programmed death-ligand 1 (PD-L1) expression of 0% (22% with SBRT followed by pembrolizumab compared with 4% for recipients of pembrolizumab alone). Overall, these findings are provocative but insufficient to suggest a change in practice.
A single-arm phase 2 trial also exploring the potential beneficial interaction of SBRT with pembrolizumab was conducted at University of Pennsylvania and focused exclusively on patients with OMD as defined by up to 4 metastatic sites. This study administered definitive local therapy to all sites of disease in 51 patients, most with 1 or 2 (93%) lesions, and more than two-thirds (69%) having metachronous metastatic disease, who received pembrolizumab starting 4 weeks to 12 weeks after definitive local therapy. Patients received a wide range of local therapies, including surgery to the primary tumor and/or metastasis, stereotactic radiosurgery, chemotherapy, chemoradiation, standard external beam radiation, and radiofrequency ablation, in varying combinations. The median PFS was 19.1 months from the initiation of definitive local therapy. Although this PFS was noted to far exceed historical controls of 6.6 months, these are different populations, because the trial population would be expected to have a PFS that should exceed historical controls based on the metachronous pattern of metastatic disease in most of the patients, which would be expected to have a far more favorable natural history than the benchmark population with a lower proportion of metachronous OMD. In addition, for the reasons discussed previously, PFS interpretation also is affected by the elimination of all visible disease in the sites most likely to demonstrate progression. Nevertheless, the results suggest the potential for increased efficacy and prolonged nonprogression in patients with advanced NSCLC and OMD who receive immunotherapy after eradication of all sites of disease through local therapy. A definitive test would require randomization of patients with OMD and likely favorable natural history compared with broader advanced NSCLC populations, to pembrolizumab monotherapy alone or preceded by local therapy to all sites of disease, with OS as the primary endpoint.
The NRG LU-002 trial is randomizing patients with advanced NSCLC and OMD with up to 3 extracranial metastatic disease sites after initial systemic therapy to subsequent chemotherapy with or without SBRT to all sites of disease. This trial is anticipated to provide insight about the interaction of radiation and immunotherapy, because immunotherapy alone or in combination with chemotherapy as the initial systemic therapy has emerged as a leading first-line treatment approach.
Tolerability and safety concerns
Alongside the potential efficacy benefits of definitive local therapy in the setting of oligometastatic NSCLC, it is important to weigh the risks of treatment. Trials that have definitive local therapy often have not proscribed a specific management approach, so that the most influential trials, such as those reported by Gomez and colleagues , and SABR-COMET, allowed any combination of radiation (including potential external beam or stereotactic radiation), chemoradiation, or surgery.
In Gomez and colleagues’ trial, , local therapy was not associated with unexpected or prohibitive toxicity, with 5 of 25 patients (20%) assigned to local ablation therapy experiencing a grade 3 event, all of limited duration. The SABR-COMET trial, however, reported that the rate of grade 2 or higher adverse events was 29% (19 of 66 patients) in the SABR arm compared with just 9% (3 of 33 patients) in the control group; more concerning was the fact that 3 patients assigned to the SABR arm experienced grade 5 (fatal) adverse events, specifically from radiation pneumonitis (N = 1), pulmonary abscess (N = 1), and subdural hemorrhage after surgery to repair a SABR-related perforated gastric ulcer (N = 1).
The variability in definitive local therapy administered and locations treated preclude the ability to define projected risk or anticipated toxicity of definitive local therapy; it can at least be concluded that the risk incurred by definitive local therapy is not negligible and potentially is serious and even life-threatening. This should lead to focusing on this aspect of clinical outcomes in ongoing and future clinical trials.
Current recommendations with limited data in de novo oligometastatic disease or oligopersistent non–small cell lung cancer
Overall, the data from the available studies converge in demonstrating consistent improvement in PFS along with suggestion of a potential improvement in OS with the addition of local consolidation therapy in combination with optimally effective systemic therapy for selected patients with OMD. These trials typically have been limited by small numbers of patients, which has in many cases been a by-product of early termination of these trials by a DSMC reviewing preliminary data and from considering it unethical to continue randomization of patients to these studies. These trials vary in the definition of what number of metastatic sites constitutes OMD.
Ironically, these trials are now widely believed too small to guide treatment recommendations, requiring larger randomized studies to clarify the potential survival benefit of definitive local therapy in this setting more definitively. Such studies are ongoing and described later.
In the meantime, clinicians are left to decide whether the highly consistent but limited amount of data from the completed trials is sufficient to recommend local therapy for selected patients. The current version of the NCCN guidelines specifically recommends consideration of local consolidation therapy for patients with OMD, although no definition is provided for what should be considered a threshold number of lesions to be treated with local therapy:
Definitive local therapy to isolated or limited metastatic sites (oligometastases) (including but limited to brain, lung, and adrenal gland) achieves prolonged survival in a small proportion of well-selected patients with good PS who have also received radical therapy to the intrathoracic disease. Definitive RT to oligometastases, particularly SABR, is an appropriate option in such cases if it can be delivered safely to the involved sites. ,
This recommendation for consideration of definitive local therapy was initiated in the form of a campaign by patients to have the NCCN guidelines include language to support this strategy.
Defining optimal patients for definitive local therapy
Given the importance of clarifying the extent of metastatic disease before pursuing local therapy, brain MRI and metabolic (PET) imaging as well as body CT imaging should be performed in order to make staging as comprehensive as possible. Once completed, the definition of what constitutes OMD remains unclear and varies from 1 trial to another.
It is interesting and arguably telling that a majority of patients enrolled on OMD trials have fewer than 3 sites of disease to treat with definitive local therapy, even in trials that permit more lesions. For instance, in the trial by Gomez and colleagues, , two-thirds of randomized patients (32 of 49%, 65%) had 0 to 1 site of residual disease after first-line systemic therapy (0 sites representing residual primary tumor only, without other metastatic sites), although the trial allowed up to 3 sites. Similarly, 74 of 99 patients (75%) enrolled to the SABR-COMET trial, which allowed up to 5 sites of metastatic disease, had just 2 or fewer metastatic foci. In the trial of pembrolizumab after definitive local therapy by Bauml and colleagues, 42 of 45 patients (93%) had 2 or fewer sites of metastatic disease, despite the trial eligibility specifying up to 4 sites of disease.
This consistent finding clearly illustrates that OMD rarely is observed as more than 2 sites of disease, that physicians enrolling on these trials demonstrate strong selection bias for directing patients with only few lesions to definitive local therapy, or both. For all of the debate about whether patients with 4 or more lesions can be defined as having OMD, the fact that nearly all of the still limited data available for local therapies for oligometastatic NSCLC is in those patients with 2 of fewer sites of disease indicates that OMD is being operationally defined more narrowly. Caution should be used in applying the results of local therapy for OMD obtained thus far to patients with more than 3 sites of disease, given the almost negligible representation of these patients on the studies reported to date.
At the same time, it is telling that these same trials have taken many years to enroll modest numbers of patients, despite most being conducted over several high-volume centers. Patients who are appropriate candidates for definitive local therapy to treat oligometastatic NSCLC are highly selected and infrequent in real-world practice.
Endpoint selection and the goals of treatment
Another challenge that has limited adoption of definitive local therapy in the setting of OMD is the controversy around which endpoints are most valid and clinically meaningful. As discussed previously, the endpoint of PFS is compromised if not completely undermined when all existing disease, representing the sites most likely to demonstrate subsequent progression, is resected or ablated. Time to new sites of metastatic disease, such as reported by Gomez and colleagues, , represents a poorly studied and unvalidated endpoint, but it is at least one that arguably serves as a more relevant surrogate for the systemic trajectory of advanced cancer.
OS is the central goal in management of advanced cancer, although it would be incorrect to resist the potential value of definitive local therapy for OMD in NSCLC on skepticism that this strategy will feasibly lead to a cure for patients. Although cure is certainly an elusive goal that may represent an ideal outcome in such patients, any clinically significant improvement in OS, perhaps in the range of several months, is consistent with the long-standing definition of a valuable treatment approach for patients with advanced cancer. Systemic therapies historically have been hailed as clinically meaningful advances for delivering an improvement in median OS of several months, without being held to a standard of providing a curative intervention. The fact that these local therapies typically are so well tolerated, particularly compared with sometimes challenging systemic therapies, further supports the concept that definitive local therapies may offer a compelling clinical benefit, even if cure is understood to be an unlikely outcome.
Assessing the evidence and prioritizing ongoing trials
Another important question for local definitive therapy for oligometastatic NSCLC centers on the extent of data required to conclude that this strategy is appropriate for off-protocol administration. Many clinicians await results of larger randomized trials before considering definitive local therapy in this setting. At the same time, several of the smaller trials providing results thus far have been terminated early by their DSMC based on their review of the data that appeared so dramatically beneficial that they felt it unethical to continue to randomize eligible patients to not receive local therapy. This unfortunately has led to the current situation of having trials with only dozens of patients, even when viewed in aggregate.
There are several clinical trials ongoing that continue to examine the potential benefit of definitive local therapy for patients with oligometastatic NSCLC. The NRG LU-002 trial is evaluating local therapy after first-line therapy and provides a new opportunity to study the potentially beneficial combination of immunotherapy with radiation. Other trials are evaluating definitive local therapy in the setting of an oligopersistent disease after initial treatment with targeted therapies against an established driver mutation. In Europe, the UK-based SARON trial will enroll patients with 1 to 3 metastases amenable to SBRT who receive 2 cycles of first-line platinum-based chemotherapy without progression to additional chemotherapy and maintenance therapy as per standard practice or the same systemic therapy with conventional radiation or SABR to the primary tumor and SABR/stereotactic radiosurgery to metastatic foci ; this trial is seeking to identify a significant improvement in OS as the primary endpoint. These randomized trials hold the promise of delivering further insights in this challenging setting; they also presume equipoise in having patients pursue local therapy or not.
Treating oncologists have varying thresholds for directing selected patients with oligometastatic NSCLC to off-protocol treatment, based on the limited but consistent data available thus far and the liberal language of the NCCN guidelines. Based on the actual rates of enrollment for patients in these trials, OMD in NSCLC may be interpreted as a relatively rare setting for which it is appropriate to act on highly convergent results, even in the face of limited numbers of patients. For other clinicians, who may have more stringent expectations about the magnitude of data required to guide treatment recommendations, current and future trials on OMD that can generate more data will be more appealing options. In an emerging era of patient-centered care and shared decision making, the perspective of the individual patient, ideally well informed of anticipated benefits and potential risks, also is a variable that will loom large in these decisions.
Management of lung cancer as well as several other tumor types increasingly is refining perception of metastatic disease as more nuanced than either being present or absent. Instead, the biology and clinical behavior of metastatic cancer can be understood better as a continuum that can range from very limited systemic spread of the cancer that is dominated by local progression of existing disease over a prolonged period to a pattern of diffusely metastatic spread of disease that is diffusely distributed throughout the body and tends to progress readily. For patients on the end of the spectrum with the most limited disease spread, typically described in dedicated studies as no more than 3 to 5 lesions, definitive local therapy may alter the systemic trajectory of the disease and potentially lead to a significant improvement in not only PFS but also OS. This state of OMD may exist de novo as an uncommon presentation of disease or with limited relapse after initial curative therapy, may occur as limited progression in 1 or a few sites after a prolonged response, or may develop as an induced state of OMD after initial systemic therapy that may have eradicated the majority of the previously identified disease.
Retrospective analyses have revealed that a subgroup of patients with OMD can demonstrate far more prolonged PFS and OS after definitive local therapy to existing sites of disease than would be expected for a broad patient population. The unusual natural history of OMD and selection bias of these studies, however, make it impossible to interpret whether the favorable clinical outcomes in these series are due to the intervention or to the qualification of these patients to receive the intervention. Over the past few years, several small prospective trials have been conducted in patients with OMD that support a highly beneficial effect from local definitive therapy compared with ongoing systemic therapy or observation alone, but they are underpowered to provide more than provocative support for the concept.
In this setting, some patients and physicians have been inclined to modify current clinical guidelines to include consideration of definitive local therapy for patients with OMD, and this has led to some changes that offer at least modest support for this strategy in appropriately selected patients. Oncologists readily recommend local therapy for oligoprogression after a good systemic response, given the highly convergent favorable results in a setting in which prospective clinical trial data are infeasible.
Cancer care increasingly is splintered from a large monolithic population to much narrower populations for which prospective randomized trials cannot be expected and are widely perceived as unnecessary when the treatment effects are substantial. Viewed through this lens, it is arguably appropriate to apply clinical judgment and recommend definitive local therapy for well-selected patients. Given the slow pace of enrollment to the studies with results available, it may interpreted that the population of patients with OMD represents such a small population that they may be interpreted as analogous to a narrow molecularly defined population, such that larger randomized trial data may never be feasible or at least elusive and slow to arrive.
At the same time, several pivotal trials are ongoing and are designed to test the utility of definitive local therapy for a larger population that includes those with oligopersistent disease after targeted therapy, immunotherapy, chemotherapy, or some combination of these. As seen in more dramatic and prolonged responses to systemic therapies, trials are poised to identify far more patients who will be strong candidates for combinations of local and systemic therapies. If there is equipoise to complete these new trials that are ongoing and in development, not only can a treatment approach for patients with OMD be mapped that is optimized by being multidisciplinary but also valuable novel insights will be gained about the biology of cancer that can redefine the interplay of local and systemic therapies, even for patients with stage IV NSCLC.
The author has nothing to disclose.