Novel Metastatic Strategies Gain Traction

Ralph R. Weichselbaum, MD

Emboldened by strong evidence from a mounting number of positive trials, investigators are growing confident that localized therapy in oligometastatic disease across cancers may soon lead to a new staging system and become standard of care (SOC). The tasks ahead are to learn more about why some patients respond better than others and to improve patient selection.

Oligometastatic cancer is a transitional disease that, while not yet systemic, may have spread to 1 or more sites in the body beyond the primary site (Figure 1¹). It is increasingly addressed with surgery, if needed, at the primary site, followed by resection and/or ablation at the metastatic sites. Multiple phase III trials are underway to clarify the value of these interventions.

Although much excitement has developed for localized treatment in patients with oligometastatic cancer, it wasn’t always this way. In 1995, the paper that coined the term “oligometastatic cancer” to hypothesize a potentially curable middle state between purely localized (secondary) and fully metastatic disease evoked little support.² The idea that many metastatic cancers should be locally treated is still controversial, but a growing number of studies support this once very unorthodox notion (Figure 2³).

The first phase II trial to report results found that adding local treatment to systemic therapy nearly tripled progression-free survival (PFS) in patients with non—small cell lung cancer (NSCLC).^4,5 Several more randomized phase II trials have found that localized treatment delays both progression and death (and may produce some cures) in patients whose disease appears to meet the somewhat hazy definition of oligometastatic cancer. The most recent trial to report, which enrolled 99 patients with various primary tumor sites, found that SOC plus stereotactic ablative radiotherapy (SABR) led to an absolute improvement in overall survival (OS) of 13 months.⁶

Figure 1. Inefficient Metastatic Process Provides A Window For Localized Curative Therapy¹

Figure 2. Goals of Localized Therapy Oligometastatic Disease³

At least 9 phase III trials designed to test the efficacy of local treatment—either surgery or stereotactic radiotherapy or both—on oligometastatic cancers that originated in the breast, lung, or prostate are currently enrolling.⁷

A Spectrum of Disease

“The prevailing view in 1995 was that cancer is fully metastatic as soon it spreads beyond the primary tumor and that local treatment is not useful,” said Ralph R. Weichselbaum, MD, of the Ludwig Center for Metastasis Research at the University of Chicago, who cowrote that initial paper with Samuel Hellman, MD, a 2016 Giants of Cancer Care^® award winner and former dean of the Division of Biological Sciences and the Pritzker School of Medicine at the University of Chicago. “We argued that what was called metastatic cancer actually encompasses a spectrum of disease that varies in the pace of its growth and extent of its spread and that relatively slow-paced cancers with relatively few metastases could be classified as oligometastatic. The implication of this concept is that such cancers might be combated or cured with local treatment (Table⁸). The paper ran as an editorial because reviewers rejected it, and I had colleagues come up to me after it ran to tell me that they didn’t like it, which is really unusual.”

Over the next 10 years, investigators published just 12 papers that even mentioned oligometastatic cancer,9 but Weichselbaum and Hellman, along with several colleagues at the University of Chicago and a few researchers elsewhere, kept returning to the idea. The papers they produced—which included the first phase I trial as well as molecular and animal experiments to define the basis of oligometastasis—eventually got others interested.

The spread of noninvasive SABR devices, also known as stereotactic body radiation therapy devices, also spurred interest by making local therapy feasible for many metastases that were ill-suited to surgical removal.

The trickle of research grew first into a stream and then into a flood. Investigators published 366 papers that mentioned oligometastatic cancer between 2006 and 2015 and more than twice that number since 2016.¹⁰

“The concept moved very quickly from relative obscurity to clinical trials, and I went from worrying that research was advancing too slowly to worrying that it was advancing too quickly,” said Weichselbaum, who estimates that, about 90,000 Americans have oligometastatic breast (14,000), lung (50,000), prostate (10,000), or colorectal cancer (14,000), which, if confirmed, has the potential to make oligometastatic disease much more important that previously thought.

“I wasn’t sure we had learned enough about separating oligometastatic disease from more aggressive cancers to figure out which patients would be most likely to benefit from local treatment, and I worried that a potentially effective idea for curing significant numbers of patients would be falsely discredited because it was tested on the wrong patients. I breathed a big sigh of relief when the positive results started coming in.”

Table. Oligometastatic Tumors Form a Distinct Class With Unique Potential⁸

The first data from a randomized, controlled trial arrived in 2016, when investigators reported preliminary results in 49 patients who underwent standard first-line systemic therapy for non—small cell lung cancer and emerged from that treatment with ≤3 metastatic lesions and an ECOG performance status score of 2 or less. Those patients were randomized to either local consolidative therapy (radiotherapy or surgery on all lesions) plus standard maintenance/observation or standard maintenance/ observation alone. After a median follow-up of 12.39 months, median PFS was 11.9 months (90% CI, 5.7-20.9) in the local consolidative therapy (LCT) group and 3.9 months (95% CI, 2.3-6.6) in the control group. Adverse events (AEs) were similar between groups, with no grade 4 AEs or deaths due to treatment.^4,5

Positive Early Results

The initial intent of the study was to enroll 94 patients,¹¹ but those preliminary results were good enough to end the phase II trial immediately and allow crossover. The investigators did keep following those 49 patients, however, and recently reported long-term results that were just as promising as those first numbers. With an updated median follow-up of 38.8 months (range, 28.3-61.4), median PFS was 14.2 months (95% CI, 7.4-23.1) with LCT plus maintenance/observation and 4.4 months (95% CI, 2.2-8.3) with maintenance/observation alone (P = .022). The more recent analysis also found an OS benefit of 2 years: LCT median of 41.2 months (95% CI, 18.9 months-not reached) versus a maintenance/observation-only median of 17.0 months (95% CI, 10.1-39.8).⁵

A smaller phase II trial—this one in patients with oligometastatic NSCLC (in this case defined as ≤5 metastases), no targetable EGFR or ALK mutations, and stable disease after induction chemotherapy—was also stopped after interim analysis found significantly better PFS in patients who underwent SABR before maintenance therapy. Median PFS was 9.7 months among the 14 patients who received SABR plus maintenance and 3.5 months for the 15 patients who received maintenance alone.¹²

Localized treatment has also shown promise in patients with other types of oligometastatic cancers.

Investigators in the Netherlands randomized 62 men with asymptomatic oligorecurrent prostate cancer to either observation or surgery/SABR on detected lesions. The primary endpoint was androgen deprivation therapy (ADT)—free survival. ADT was started at symptomatic progression, progression to more than 3 metastases, or local progression of known metastases. After a median follow-up of 3 years (interquartile range, 2.3-3.75 years), the median ADT-free survival was 21 months (80% CI, 14-29) for the local therapy group and 13 months (80% CI, 12-17) for the surveillance group (HR for progression, 0.60; 80% CI, 0.40-0.90).¹³

Another phase II trial focused on patients with liver cancer. Investigators in several European countries randomized 119 patients with ≤10 unresectable colorectal liver metastases to systemic treatment alone or systemic treatment plus radiofrequency ablation. After a median follow up of 9.7 years, 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm had died. Median OS was 45.6 months (95% CI , 30.3-67.8) in the combined modality arm versus 40.5 months (95% CI , 27.5-47.7) in the systemic treatment arm. There was a statistically significant difference in OS in favor of the combined modality arm (HR, 0.58; 95% CI, 0.38-0.88; P = .01).¹⁴

The phase II SABR-COMET study enrolled 99 patients with different cancers whose disease had returned in up to 5 places after primary treatment. Investigators randomized those patients 2:1 between palliative SOC treatments and SOC plus SABR for all metastatic lesions. Median PFS was 12.0 months (95% CI, 6.9-30.0 ) in the radiation arm compared with 6.0 months (95% CI, 3.4-7.1) for control patients (P = .001). Median OS was 41 months (95% CI, 26 months-upper limit not reached) for SABR patients and 28 months (95% CI, 19-33) in the SOC arm. The P value for the OS benefit was .09, satisfying the primary endpoint. Significant AEs (grade 2 or higher), including 3 treatment-related deaths, occurred in 30% of radiation therapy patients and 9% of patients who received palliative care. SABR treatment was not associated with significant changes in quality of life.¹⁵

A number of women in the SABR-COMET study had breast cancer, although to date no randomized trial results exclusively for patients with breast cancer have been published. The first such trial that is expected to report data is a phase II/III that is designed to treat 128 women in its initial phase.¹⁶

Retrospective Studies Support Findings

“In addition to those relatively few randomized, controlled trials that have reported data, a fair number of single-arm studies analyze retrospective data, and they also tend to suggest that removing or ablating metastases can significantly improve outcomes for patients with oligometastatic cancer,” said Michael T. Milano, MD, PhD, a professor of radiation oncology at the University of Rochester School of Medicine and Dentistry in New York.

Milano has co-authored several of those retrospective data analyses, and he was the lead author of what appears to be the largest single-arm prospective study of local therapy in patients with oligometastatic breast cancer. Milano and his colleagues provided hypofractionated stereotactic radiation therapy in varying doses to 48 patients with breast cancer with up to 5 metastases. The study’s main goal was to find factors that predicted response to local treatment. It found several, the most significant of which was the difference between the 12 women with bone-only metastases (BO) and the remaining 36 women. The 5-year and 10-year OS rates were 83% and 75%, respectively, for patients with BO versus 31% and 17%, respectively, for all other patients (P = .002).¹⁷

“We’re still in the early stages of determining which patients truly have the type of oligometastatic cancer that is most likely to benefit from local treatment,” Milano said. “Everyone who works in this space has seen some patients who don’t appear to benefit and others who seem to be cured, and now we have to figure out whether the radiotherapy really is helping the patients who do well and, if so, which patients are the ones who will benefit.”

Some experts believe that trial results to date, although not definitive, have been good enough to justify the routine use of SABR for oligometastatic cancer in regular clinical practice. Radiation oncologist David Palma, MD, PhD, a clinical scientist at the Ontario Institute for Cancer Research and the leader of the SABR-COMET study, has said that, when SABR is carefully delivered by an experienced team, the benefits now appear to outweigh the risks. Palma said that every physician should at least consider SABR as a treatment option or even the SOC for patients with oligometastatic cancer.¹⁸

Other experts believe it’s too early for most clinical practices to begin offering aggressive local therapy to all of their patients with oligometastatic cancers. “With the information that’s being unveiled from numerous ongoing studies, treatment guidelines may soon change, but they haven’t changed yet,” said Mara Antonoff, MD, an assistant professor of thoracic and cardiovascular surgery at The University of Texas MD Anderson Cancer Center in Houston.

“Centers of excellence that have experience with these trials may be ready to offer aggressive local therapy for oligometastatic disease as an option for select groups of nontrial patients after multidisciplinary review. However, this is an area of ongoing investigation,” noted Antonoff. “We need to prove that these treatment strategies are consistently safe, as well as to determine which patients they will benefit the most, before they are practiced widely.”

A large number of ongoing trials will provide more evidence about which oligometastatic cancers, if any, benefit from particular types of local treatment. A search of ClinicalTrials.gov for trials that mention oligometastatic cancer and are either “recruiting” or “active, not recruiting” returns more than 100 results.¹⁹ A search for phase III trials in patients with oligometastatic cancer returns 15 results.²⁰

Radiotherapy With Immunotherapy

Among the most intriguing of the many trials underway are several that combine local radio-therapy with immune checkpoint inhibitors (ICIs) rather than chemotherapy. Preclinical studies indicate that the damage that radiotherapy does to tumor cells can make immunologically “cold” tumors into “hot” tumors that the immune system can recognize and attack.²¹ Therefore, it is possible that the combination of radiotherapy and ICIs would produce a synergistic effect, most notably by increasing the percentage of patients who responded to ICI treatment.

The randomized, controlled phase II trials published to date have included some patients who used ICIs as systemic therapy, but not enough to establish whether there is synergy. Some promising data, however, emerged from a nonrandomized, noncontrolled trial of local ablative therapy and pembrolizumab (Keytruda) in 45 patients with oligometastatic NSCLC, defined for this study as ≤4 metastatic sites. Median PFS from the time of localized treatment was 19.1 months (95% CI, 9.4-28.7), which was significantly greater than the historical median of 6.6 months (P = .005). Overall mean survival at 12 months was 90.9% and 77.5% at 24 months.²²

The phase III Lonestar Trial could provide definitive answers about the potential synergy between radiotherapy and ICIs. It is the follow-up to that first phase II trial that published preliminary results for the 46 patients with oligometastatic NSCLC in 2016. Investigators will randomize 270 patients who take nivolumab (Opdivo) and ipilimumab (Yervoy) for metastatic NSCLC to either maintenance alone or maintenance plus LCT for all metastases. The estimated study completion date is late 2022.²³

“If the phase III trials produce positive results, they will obviously change standards of care, but that’s still just the first step,” said Weichselbaum. “The next challenge will be to look at what will presumably be heterogeneous trial results and figure out why some people responded to local treatment better than others and then use that information, along with our steadily increasing understanding of cancer biology, to build a clinical and molecular staging system for metastatic cancers.”

References

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