COMMENTARY

Local Consolidation Therapy for Oligometastatic NSCLC: Can the Horse Be Led Back Into the Barn?

H. Jack West, MD

Disclosures

April 11, 2017

One of the historical truisms of management of non–small cell lung cancer (NSCLC) is that local therapy has no value in metastatic disease except to treat local complications such as brain lesions, hemoptysis, a compressed airway from bulky chest disease, or painful bone metastases. By suggesting that "the horse is out of the barn," I'm noting that metastatic spread represents the systemic dissemination of micrometastatic disease that obviates any value from directing treatment against selected visible lesions on scans.

However, a series of selected patients with solitary brain or adrenal "precocious" metastases has revealed that a significant minority of these patients, approximately 25%, can demonstrate prolonged disease-free survival for many years after receiving definitive local therapy to the primary tumor and an isolated metastasis.[1] This proof of principle in highly selected patients raises the question of whether the concept of metastatic disease is not a binary distinction but a spectrum in which local therapy may provide significant value for a wider range of patients with advanced NSCLC than previously recognized.

At the same time, more refined radiation techniques such as stereotactic ablative body radiation therapy (SBRT) and minimally invasive surgeries have reduced the morbidity of local therapies. Combining the lower risk and theoretical benefits with the inherent appeal to patients and physicians of treating visible disease, as well as the market-driven incentives to pursue feasible if unproven interventions, this confluence of factors explains why clinical practice of local therapies for metastatic NSCLC greatly outpaces the evidence to support it.

 
Use of local therapies for metastatic NSCLC greatly outpaces the evidence to support it.
 

In this setting, a recent publication by Gomez and colleagues[2] uses greater rigor to move the field forward. This phase 2 study enrolled 49 patients with advanced "oligometastatic" NSCLC with three or fewer sites of residual visible disease after at least four cycles of standard chemotherapy or, for patients with an EGFR mutation or ALK rearrangement, 3 or more months of targeted therapy with an EGFR or ALK inhibitor, respectively, without progression. Subjects were then randomly assigned to ongoing maintenance therapy or observation per the discretion of the treating physician, with or without local consolidation therapy (LCT) to areas of residual disease. LCT could consist of surgery and/or radiation, potentially combined with chemotherapy.

The primary endpoint of the study was progression-free survival (PFS), which was significantly superior in patients randomly assigned to LCT (median 11.9 vs. 3.9 months for those receiving vs not receiving LCT, respectively; hazard ratio, 0.35; log-rank P=.0054), a difference great enough to have led to the early termination of the trial by the data and safety monitoring board. In addition, an analysis of time to new site of metastatic disease was significantly longer in recipients of LCT compared with those who received maintenance systemic therapy or observation only (median 11.9 vs. 5.7 months, P=.0497). Overall survival was too immature to be reported.

There were no significant differences in side effects between the two arms and no grade 4 or higher toxicity with LCT.

These results are clearly provocative, but should they change practice? I would argue that they should not for the vast majority of patients. First, it is critical to note that the primary endpoint of PFS is an extremely poor choice for this type of study because the proscribed intervention of LCT undermines this endpoint. Because the most common areas of progression in patients with advanced NSCLC are pre-existing sites of disease, patients who received LCT have had these areas resected or ablated and are no longer eligible to demonstrate progression at these sites. This effectively invalidates the endpoint of PFS.

In contrast, the significant difference in time to development of new metastatic sites may be interpreted as a reflection of the trajectory of the systemic process and, we may surmise, serve as a better proxy for overall survival. This finding of a markedly longer time to sites of new metastatic disease suggests that LCT, by eliminating all macroscopic evidence of residual disease, may "set the clock back" and effectively prolong the timeline of the evolving systemic cancer process—at least in patients with a very limited disease burden and one or very few sites of residual disease.

The other critical aspect of interpreting these results is the highly selected patient population. The total number of patients randomly assigned was only 49 from three large cancer centers over 3 years, representing a very small minority of patients with metastatic NSCLC who received treatment at these centers in that time. This underscores the strong potential for selection bias, or at least an inability to extrapolate the results of this small study to a much broader population.

Though enthusiastic proponents of local therapy for oligometastatic disease note that "more than half of advanced NSCLC patients have metastatic deposits amenable to SBRT after first line therapy,"[3] it is critical to make the distinction between what we can and what we should do.

 
It is critical to make the distinction between what we can and what we should do.
 

We cannot presume that the biology of disease in highly selected patients with a low tumor burden and minimal residual disease will apply to patients with more than three areas of visible disease or any areas of disease progression. Such patients have "polymetastatic" disease, not oligometastatic disease, and should not be recommended for local therapies merely due to a blind, reflexive, and potentially marketing-driven perspective that more treatment is inherently better. Treating more than a few areas of disease in patients with advanced NSCLC may treat our compulsion to improve the scan but be no more valuable to patients than using Adobe Photoshop® to erase visible lesions.

Fortunately, in the wake of the completed trial by Gomez and colleagues, which provided necessary rigor and defined limits on the patient population and interventions, larger randomized trials are underway, with others in development, to test the value of LCT more thoroughly. In the absence of corroborating results from these trials, my perspective is that it is very appropriate to consider LCT for highly selected patients with very limited residual disease but not to consider it a standard approach. These early results have major implications in suggesting that local therapies may slow the trajectory of the systemic disease process and even prolong survival in some patients, but we await further research to clarify whether these findings can be corroborated in larger trials as well as clarify which patients truly benefit from this strategy.

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