Oligometastatic Lung Cancer: How Should It Be Managed?

Cancer has historically been divided between localized and metastatic disease. The underlying principle, derived from the Halsted theory of cancer progression, is that once cancer has spread to other sites, it is a systemic disease. Heroic efforts to remove or ablate all evidence of visible cancer thus would expose patients to toxicity without a chance for benefit.

Joshua M. Bauml, MD

Cancer has historically been divided between localized and metastatic disease. The underlying principle, derived from the Halsted theory of cancer progression, is that once cancer has spread to other sites, it is a systemic disease. Heroic efforts to remove or ablate all evidence of visible cancer thus would expose patients to toxicity without a chance for benefit.

We now know that cancer is not quite so simple. In colorectal cancer, for instance, patients with metastases only to the liver can be cured up to 20% of the time with hepatic resection. Although there is potentially some unique biology surrounding the lymphatic drainage of colorectal cancer, multiple series have shown that oligometastatic disease occurs in a wide range of tumor types. It is important to clarify some terms, however, because many of these retrospective series conflate different clinical situations. These terms do not have widely accepted definitions, but for the purposes of this article, I think we need a shared vocabulary.

Defining Oligometastatic Disease

I would defineoligometastatic diseaseas cancer that has spread to a limited number of sites. The specific number is unknown; trials have used cutoffs of 2 to 10, but it is unclear if there is a true numeric cutoff to define this. Regardless of the cutoff, oligometastases can occur at the same time as the initial diagnosis (eg, a lung tumor with local lymphatic involvement and a simultaneous solitary brain metastasis); as a condition termedsynchronous oligometastases; or after the initial diagnosis (eg, a lung tumor that is resected and a solitary brain metastasis develops 6 months later), a condition termedmetachronous oligometastases. Central to the definition of oligometastatic disease here is that the oligometastatic phenotype is not dependent on any specific prior therapy; rather, it seems to be a function of the underlying cancer biology.

With systemic cancer therapies more effective than ever before, we are beginning to see 2 other conditions that are similar to, but not quite the same as, oligometastatic disease. In what I calloligo-residual disease, a patient with widely metastatic cancer receives treatment and nearly all their disease has a complete response.

Another condition, termedoligo-progressive disease, is frequently seen among patients receiving targeted therapy for lung cancer. In this condition, a patient initially has an excellent response to systemic therapy but later develops focal progression in a few lesions with continued control elsewhere. Oligo-residual and oligo-progressive disease seem to be different biologically from oligometastatic disease described above, in which the cancer cells initially show the ability to cause diffuse metastases.

Experience in Clinical Trials

In recent years, multiple studies have evaluated the role of locally ablative therapy in non—small cell lung cancer (NSCLC). In a study by Daniel R. Gomez, MD, and colleagues, patients with oligometastatic NSCLC initially received systemic therapy; in the absence of progression, patients with up to 3 metastatic sites of disease were randomized to locally ablative therapy with continued systemic therapy or systemic therapy alone.1,2 The authors found that adding locally ablative therapy was associated with an improvement in progression-free survival (PFS; 14.2 vs 4.4 months;P= .022) and overall survival (OS; 41.2 vs 17 months;P= .017).2 It is important to note that this was an oligo-residual cohort. In addition, because the randomization happened after systemic therapy, this is a heavily preselected population for patients who are likely to respond to systemic therapies. Finally, on subgroup analyses, the only subgroup of patients who had an OS benefit included those patients with 0 to 1 metastatic lesion. There seems to be confusion about what type of locally ablative therapy was done to patients with 0 lesions, and it is also unclear how widely we could apply these data to patients with more metastatic lesions.

In a study by David A. Palma, MD, and colleagues, patients with oligometastatic cancers (up to 5 metastatic foci, not just lung cancer) underwent definitive treatment to their primary cancer and were then randomized to standard-of-care palliative therapy with or without stereotactic radiotherapy.3

It is important to note that this was designed as a “screening” phase II study. The investigators wanted to randomize patients to get a sense of clinical efficacy, but they did not have adequate power to definitively say if the stereotactic radiotherapy was better. As a result, they set the prespecified cutoff of statistical significance at a 2-sided α of 0.2, whereinP<.2 designates a positive trial. Using this definition, the use of stereotactic radiation was associated with an improvement in PFS (12 vs 6 months;P= .0012) and OS (41 vs 28 months;P= .09). It is critical to remember that because this was a screening study, these “statistically significant” improvements are not definitive and must be confirmed in a randomized phase III trial. Luckily, Palma is already leading such a trial.

Another limitation of this study was a clear imbalance in terms of tumor types between the arms, with a much larger percentage of prostate cancer in the experimental arm. Finally, the authors did not record or control for types of systemic therapy used.

Based on these trials and others, many in the oncology community have been using locally ablative therapy for certain patients with oligometastatic disease. As access to minimally invasive surgery and stereotactic radiation improves, this becomes an increasingly appealing option.

Our group recently completed a trial that assessed the impact of adding immunotherapy to locally ablative therapy in oligometastatic lung cancer.4 Patients with oligometastatic lung cancer (defined as less than or equal to 4 metastatic foci) were given locally ablative therapy and then received 6 months of pembrolizumab (Keytruda). If they experienced no progression or unacceptable toxicity, patients were allowed to receive an additional 6 months of the PD-1 inhibitor.

We found that this treatment approach was associated with excellent outcomes, with a PFS of 19.1 months from the start of locally ablative therapy. This was statistically greater than our historical reference of 6.6 months (P= .005), and the addition of pembrolizumab was not associated with any new safety signals beyond what has been seen with pembrolizumab in other trials.

Looking Toward Future Treatment of Oligometastatic Disease

So where should we go from here? Multiple randomized controlled trials are ongoing to definitively evaluate the role of locally ablative therapy in lung cancer. In the United States, the largest study is NRG-LU002 (NCT03137771), being run through the cooperative group infrastructure led by Puneeth Iyengar, MD, PhD, and providers should be actively encouraged to enroll patients to this important trial.

In this and other trials, it remains critical that clinicians do a better job of defining who benefits from locally ablative therapy. Our current practice of simply counting metastatic foci is a crude estimate of underlying biology and unlikely to reflect the true clinical picture. Preliminary efforts by Ralph R. Weichselbaum, MD, and others have identified microRNA signatures that may predict the oligometastatic phenotype. Such efforts should be applied to patient samples from ongoing trials to validate this and other biomarkers.

In terms of the role of immunotherapy in this setting, if the intriguing findings of our study are confirmed in a randomized controlled trial, we may be able to improve outcomes further for patients with oligometastatic lung cancer. I am hopeful that ongoing efforts to identify biomarkers for immunotherapy in general—specifically, biomarkers of response to immunotherapy after chemoradiotherapy, as in the PACIFIC study5—may help direct us to the patients most likely to benefit from the combination of locally ablative therapy and immunotherapy in lung cancer.

In conclusion, oligometastatic disease is an emerging and important field. With careful patient selection, I am hopeful that we may be able to widen the group of patients with lung cancer that we can try to cure.

References

  1. Gomez DR, Tang C, Zhang J, et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligo-metastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study.J Clin Oncol. 2019;37(18):1558-1565. doi: 10.1200/JCO.19.00201.
  2. Gomez DR, Blumenschien GR, 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, ran- domised, controlled, phase 2 study.Lancet Oncol. 2016;17(12): 1672-1682. doi: 10.1016/S1470-2045(16)30532-0.
  3. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.Lancet. 2019;393(10185):2051-2058. doi: 10.1016/S0140-6736(18)32487-5.
  4. 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(9):1283-1290. doi: 10.1001/jamaoncol.2019.1449.
  5. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med. 2017;377(20):1919-1929. doi: 10.1056/ NEJMoa1709937.