Local Therapies Show Promise for Metastatic Lung Cancer

H. Jack West, MD


February 14, 2023

"Don't close the barn door after the horse is gone," the old proverb goes. In other words, there's no sense in trying to prevent something when it's already too late.

In many ways and for many years, this saying has applied to providing local therapies to treat cancers that have metastasized to distant sites. I learned this lesson early on from my mentors and have relayed it to countless patients with advanced cancer over the past several decades.

But a growing body of evidence, alongside promising new therapies, highlights more and more exceptions to this long-held belief. Over my career, I have increasingly learned about the nuances of metastatic disease, specifically that metastasis represents a broad spectrum of indolent to extremely aggressive cancers.

This concept was outlined decades ago for oligometastatic disease and has since been studied in greater depth, and is even being applied in practice. Local therapy for colorectal cancer with limited liver-only metastases is now established as a path to potentially excellent long-term survival. And prospective randomized trials of local therapies for oligometastatic lung cancer or prostate cancer have also demonstrated improvements in clinical outcomes that should lead us to strongly consider integrating local therapy for appropriately selected patients.

In addition, early retrospective studies have provided a proof of principle that patients with solitary brain or adrenal metastases from non–small cell lung cancer (NSCLC) can do exceptionally well and even remain disease-free for many years after definitive local therapy to the primary tumor and oligometastatic disease. For example, a recent press release on the LUNAR trial reported an improvement in overall survival with tumor-treating fields (TTFs), a local therapy, compared with docetaxel as second-line therapy for patients with advanced NSCLC.

That said, the selection process for who receives local therapy remains subjective. In practice, I see patients who fall well outside of conventional oligometastatic parameters but who are directed to local therapy, commonly when systemic therapy is considered futile or prohibitively toxic.

At the same time, however, I also see many patients who would be appropriate candidates for local therapy for oligometastatic disease for whom this strategy is not pursued, perhaps because some oncologists remain dubious about the value of local therapy in this setting. And although we await the full data from the LUNAR trial, I would expect TTFs to face challenges in broad adoption because it is a novel platform with cumbersome practical application, particularly outside of larger centers.

But beyond the potential for TTFs to change management of previously treated advanced NSCLC, I think the findings are more significant because they represent a step, perhaps even a quantum leap, in the role that local therapy could play in improving survival in a broad, unselected population with advanced disease. That is a far more meaningful prospect than conferring benefits in well-selected patients with a narrow subtype of lung cancer. It will be important to determine whether certain subgroups from the LUNAR trial are driving this overall survival benefit.

Local therapy may even have value in the advanced cancer setting beyond oligometastatic disease. That potential is being explored in the SABR-COMET-10 trial, which randomly assigned 159 patients with four to 10 metastatic lesions from various cancers to stereotactic ablative body radiation with standard systemic therapy or the latter alone. With overall survival as the primary endpoint, this study could further revise our understanding of the use of local therapy for treating patients whose cancer biology does not fit the definition of oligometastatic disease.

Does this evolving landscape mean that we were wrong to minimize the role of local therapy?

I don't think so. The risk/benefit of local therapy today is predicated on two key factors that were absent a few decades ago. First, local therapies like stereotactic ablative body radiation, minimally invasive surgery, and TTFs now offer disease control with far less attendant toxicity than conventional external beam radiation therapy or open surgery. Second, newer systemic therapies that include targeted therapies and immunotherapy confer remarkably greater disease control for far more patients than does conventional chemotherapy alone.

It is this combination of local therapy's excellent therapeutic index applied against a background of far better systemic disease control that makes the interplay of local and systemic treatments a newly relevant, open question.

We have yet to see the details of several pivotal trials, but I feel that we should be prepared to question some of the historic dogma in our field to achieve better outcomes not just for selected, narrow subgroups but for a broader population with different types of metastatic cancer.

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