ELPIDA ARGENZIANO was 40 years old when she was initially diagnosed with stage II hormone receptor-positive breast cancer in 2015. She had a double mastectomy, but before she could start chemotherapy and radiation, a scan revealed a single metastatic tumor in one of her pelvic bones.
Argenziano’s oncologist told her that the cancer was now incurable but treatable. “He said, ‘Unfortunately, you have stage IV breast cancer. It is metastatic,’” says Argenziano, who lives in Garden City, New York, with her husband and three children, now 16, 11 and 8 years old.
When Argenziano got a second opinion, though, the oncologist used a new term. “What you have is a very unique case. You are oligometastatic,” Argenziano recalls her saying. Unlike metastatic cancer that has spread widely, the oncologist explained, oligometastatic cancer has spread to only a few sites in the body.
“It’s generally been thought for decades that if somebody had metastases, they were generally considered incurable,” says David Palma, a radiation oncologist at London Health Sciences Centre in Ontario. “The treatment would be focused on slowing down the cancer with things like chemotherapy or gentle doses of radiation. … But over the past 10 or 20 years, there’s been a change in thinking where people have suggested that maybe if someone only has one, two or three metastases, then they could be treated aggressively.”
For patients with only a few metastases, researchers are investigating whether local treatments aimed at eliminating the metastases, such as surgery or radiation, could improve quality of life, lengthen life or even cure cancers.
Seeing Metastasis as a Spectrum
Radiation oncologists Samuel Hellman and Ralph Weichselbaum of the University of Chicago coined the term oligometastases in a 1995 editorial published in the Journal of Clinical Oncology. “I think the general perception of the public and a lot of my colleagues as well is that metastases are always widely spread, that they’re everywhere,” says Weichselbaum, who is still a physician-scientist at the University of Chicago. “What Sam Hellman and I postulated was that it’s really a spectrum of disease.”
The researchers argued that cancer must undergo genetic changes to spread through the body. When someone presents with many metastases in different areas, the cancer has shown itself to be very good at spreading, and it is likely to be present in many other places as well. Attempting to eliminate the cancer by treating visible metastases would probably be futile. Unlike widely spreading cancer, however, oligometastatic cancer might spread less efficiently or to only a few types of tissues. Treating these isolated tumors using surgery or radiation could be curative, the researchers proposed.
Some studies consider disease to be oligometastatic if it has spread to three or fewer locations. Others have a cutoff of four or five metastases, and one ongoing trial allows participants who have up to 10 metastases. “It’s a moving target,” says radiation oncologist C. Jillian Tsai, director of metastatic disease radiation oncology research at Memorial Sloan Kettering Cancer Center in New York City. “I don’t think there is an absolute number, and we need to study the tumor biology to better define it.”
Surgery and radiation are the most common treatment approaches for oligometastatic disease. A newer form of radiation therapy called stereotactic ablative body radiation therapy (SABR), also known as stereotactic body radiation therapy (SBRT), allows doctors to deliver a high dose of radiation to a targeted location. This can allow treatment to happen over a shorter period with less damage to surrounding tissues. Improvements in imaging have also made it possible to more accurately identify which patients have oligometastatic disease and where these metastases are. “If you think about how much our phones have changed over the past 20 years … our radiation machines have improved even more so,” Palma says. “For example, we can see a tumor as it changes position when a patient is breathing.”
Doctors hope that some patients who are treated aggressively for oligometastatic cancer might be cured, or at least live longer with their cancer, says Phuoc Tran, a radiation oncologist focusing on genitourinary cancers at Johns Hopkins Medicine in Baltimore. He says prolonged survival “obviously is one big-ticket item that all patients would like.” In other cases, aggressive local treatment could allow a patient to delay needing a systemic therapy with undesirable side effects. “I don’t think it should be undersold that you can improve patients’ quality of life,” Tran says. Treating oligometastatic disease aggressively could also lead to improved symptom control, adds Tsai, citing a study published in the June 2019 JAMA Oncology which showed that SABR was more likely to reduce pain from bone metastases than the conventional radiation typically used to improve symptoms.
Putting Treatments to the Test
Over the years, doctors have released studies on outcomes for patients who received local therapies for oligometastases at various institutions. But University of Chicago radiation oncologist Steven Chmura points out that people with oligometastatic cancer are already likely to live longer than the average stage IV patient. “It is very easy to then do a single-arm intervention, think you’re doing some good, and you lose sight of the fact that people are going to do well no matter what you do,” he says. To definitively determine whether local treatments for oligometastatic cancer work, Chmura says, large randomized controlled trials are necessary.
In the past few years, relatively small randomized trials of treatments for oligometastatic cancer have shown promising results. Perhaps most prominently, the SABR-COMET trial enrolled 99 patients with a variety of cancer types to test whether the addition of SABR to standard treatment could extend life for patients with five or fewer metastases. These patients had been treated for an early-stage cancer and then learned it had spread. According to updated results published in the Sept. 1, 2020, Journal of Clinical Oncology, 42.3% of people who were randomly assigned to receive SABR and standard care were still alive after five years, compared to 17.7% of people who received just standard care.
Generally, participants who received SABR did not have worse quality of life than those who were assigned to standard care, despite their additional treatment. Three patients died of complications that appeared to be related to SABR. This underlines that SABR must be done carefully by experienced doctors and technicians, notes Palma, who led the trial.
Despite the trial’s largely positive results, SABR-COMET wasn’t large enough to provide a definitive answer on whether SABR is effective at treating oligometastases, says Palma. Phase II studies like SABR-COMET provide preliminary information on the efficacy of a treatment in a particular group of patients. If phase II trial results are promising, researchers can move the treatment into a phase III trial, which is necessary to confirm in a larger group of people whether a treatment is helpful. Researchers are currently running the phase III SABR-COMET-3 and SABR-COMET-10 trials, which will test adding SABR to standard care in 297 people with up to three metastases and 159 people with four to 10 metastases, respectively. “We’re looking to prove definitively that we can improve survival,” Palma says.
In Search of a Study
Although Argenziano’s second oncologist explained the concept of oligometastasis to her, she only offered her standard care, which was hormone therapy. “I always felt like, why aren’t we doing more?” Argenziano says.
Via Google searches, Argenziano learned about a clinical trial at the University of Texas MD Anderson Cancer Center in Houston. In January 2016, she traveled to Texas for an appointment with an oncologist leading a trial that used aggressive radiation therapy or surgery to treat breast cancer that had only spread to the bones and at most to three sites.
At MD Anderson, Argenziano learned the cancer had also spread to two vertebrae. She could still qualify for the trial, but she would first need to receive chemotherapy back in New York. By the time Argenziano completed her chemotherapy, however, the trial had stopped enrolling patients due to failure to sign up enough participants. Despite that, the oncologist who had been leading the trial agreed to treat her with a protocol similar to the one used in the trial.
Argenziano flew weekly from New York to Texas for a combination of SABR and intensity-modulated radiation therapy—a form of radiation used near sensitive structures in the body—over nine weeks during the summer of 2016. “Of all the treatments, it wasn’t as bad as I thought it would be,” she says. “It’s not like chemo, where you’re throwing up and nauseous and just exhausted.
“You are tired. I think the hardest part is laying in the [radiation bed] alone with your thoughts,” she says, adding that it was difficult to be away from her home and family.
While the breast cancer clinical trial Argenziano tried to join never began recruiting again, other trials are shedding light on whether local treatments will be effective for specific types of oligometastatic cancer. The SABR-COMET-3 and SABR-COMET-10 trials are enrolling patients with various solid tumors, but they will separate out results to report efficacy for the four most common cancer types: breast, lung, colorectal and prostate.
These large clinical trials are testing treatments for oligometastatic cancer in North America.
Cancer type: non-small cell lung cancer with three or fewer metastases
Treatment: stereotactic ablative body radiation therapy (SABR)
Location: mainly U.S. and Canada
Cancer type: breast cancer with four or fewer metastases, where the primary tumor has been controlled
Treatment: SABR and/or surgery
Location: mainly U.S. and Canada
Cancer type: gastric or esophageal cancer with three or fewer metastases
Treatment: radiation therapy
SABR-COMET-3 and SABR-COMET-10
Cancer type: any solid cancer with three or fewer metastases or four to 10 metastases, where the primary tumor has been controlled
Location: Canada, Europe and Australia
Separating out results by cancer type is important because the definition of oligometastatic disease—or whether treating oligometastases will be helpful at all—likely varies by cancer type, according to Nataliya Uboha, a medical oncologist specializing in gastrointestinal cancers at the University of Wisconsin Carbone Cancer Center in Madison. On the one hand, she explains, it is standard to treat some colorectal cancer that has only metastasized to the liver with surgery or other aggressive local therapy. Pancreatic cancer, by contrast, is usually widely metastatic at diagnosis, and even if a patient presented with only limited metastases to the liver, oncologists would be unlikely to pursue aggressive local treatment.
It’s less certain whether treating oligometastatic stomach cancer or esophageal cancer will lengthen life, Uboha says. That’s why she is leading a large phase III trial testing radiation therapy plus standard care versus standard care alone in patients with up to three metastases who have stable disease after initial systemic therapy.
Tran of Johns Hopkins says prostate cancer will be a cancer type where doctors will see the greatest improvements from treating oligometastases, at least early on. Prostate cancer grows relatively slowly, and patients can be monitored for signs of cancer using PSA blood testing. A radioactive tracer used in a new form of imaging called PSMA PET was approved by the Food and Drug Administration in December 2020, and this technique will make it possible to more accurately detect prostate cancer metastases, he adds. Two randomized phase II studies—one Tran ran in the U.S. and one run by researchers in Belgium—have already shown that aggressively treating hormone-sensitive prostate cancer that has recurred with up to three metastases can increase the amount of time patients live without their cancer progressing or needing hormone therapy, respectively.
Non-small cell lung cancer (NSCLC) is another cancer type where randomized phase II trials have had positive results. Studies have shown that patients with oligometastatic disease who received treatments to eliminate their metastases, as well as their primary tumor if still present, lived longer without their cancer growing than those who got only standard care. A phase II/III trial testing SABR alongside standard care in NSCLC patients with three or fewer metastases following initial systemic treatment will provide more definitive answers, says radiation oncologist Puneeth Iyengar of UT Southwestern Medical Center in Dallas, who is running the trial. “That’s the study we hope will answer the question one way or the other whether adding radiation to current standard-of-care systemic therapy will help non-small cell lung cancer patients with oligometastatic disease live longer,” he says.
For people with breast cancer, data on treating oligometastatic disease are more limited. Chmura is testing in a combined phase II/III trial whether SABR or surgery combined with standard care can lengthen progression-free survival and overall survival for breast cancer patients with four or fewer metastases.
Researchers are studying the role of local therapies like radiation in treating patients who are receiving targeted therapies or immunotherapies.
With the advent of targeted therapies and immunotherapies, doctors and researchers are questioning whether local treatments, such as surgery and high-dose radiation, could bolster treatment response, particularly in patients with non-small cell lung cancer (NSCLC).
Immune checkpoint inhibitors have helped increase lifespans for NSCLC patients, says radiation oncologist Puneeth Iyengar of UT Southwestern Medical Center in Dallas. One challenge is determining whether radiation will work synergistically with these new treatments for patients with oligometastatic NSCLC. “We are hoping that the [local therapy] will be able to enhance the immunotherapy effects to a higher level and in a broader percentage of patients,” Iyengar says. Alternatively, it is possible that as immunotherapy increases patient survival, it will dilute the benefits of adding local therapies such as radiation.
Iyengar hopes to answer this question as part of a trial he is running in NSCLC patients with three or fewer metastases. The trial will compare standard care plus SABR to standard care alone, and the trial allows Keytruda (pembrolizumab), an immune checkpoint inhibitor, as a standard therapy.
Researchers are asking similar questions about targeted therapies, which have extended life for people with NSCLC who have certain tumor mutations. One area of research is whether patients who have only a few metastases following initial treatment with targeted therapy can benefit from aggressive radiation or surgery to their metastases and original tumor. A small number of patients in this situation were included in a phase II randomized trial of treatment for oligometastatic NSCLC. This trial showed a longer time without progression and longer survival for those patients who got aggressive local therapy, explains radiation oncologist C. Jillian Tsai, director of metastatic disease radiation oncology research at Memorial Sloan Kettering Cancer Center in New York City. Nonrandomized data also support the strategy. However, there haven’t been any published randomized phase III trials focusing specifically on this group of patients.
Tsai is investigating whether a different subset of patients can benefit from aggressive local therapies. These patients may have started out with widely metastatic disease or oligometastatic disease, only to find their cancers stay stable or recede while taking immunotherapy, targeted therapy or chemotherapy. If these patients develop progression in only a few lesions at any point during their treatment course, they are considered to have oligoprogressive disease. Tsai is leading a trial studying the use of SABR to treat up to five progressing metastases in patients with oligoprogressive NSCLC or breast cancer.
“It’s a totally different population than oligometastases,” says David Palma, a radiation oncologist at London Health Sciences Centre in Ontario, speaking of the contrast between oligometastatic disease and oligoprogressive disease. Rather than potentially trying to cure disease, as can be the goal in people with oligometastases, doctors treating oligoprogression are trying to help patients remain on a drug that is working for a longer period of time, Palma says.
While research is ongoing, patients continue to need to make decisions about their cancer treatment. Tiffany Fagnani of Mechanicsburg, Pennsylvania, was 36 when she was diagnosed with stage IV NSCLC in 2017. Fagnani received radiation and surgery to treat a metastasis to her brain that was causing acute symptoms, as well as the targeted therapy Tarceva (erlotinib) to treat her EGFR-positive cancer. After her cancer progressed in 2018, Fagnani switched to another targeted therapy, Tagrisso (osimertinib). Since then, the only remaining cancer visible on scans has been her original lung tumor. In July 2020, Fagnani received SABR to the remaining tumor in her lung. She has experienced some inflammation in her lungs related to radiation therapy, and the inflammation makes it difficult to tell if her cancer was fully eliminated, but scans in early January 2021 indicated at least stable disease.
Fagnani continues to take Tagrisso and says she is just trying to stay a step ahead of her cancer. She says she didn’t expect to ever be able to get treatment to eliminate her original tumor. During her five days of SABR, she remembers watching other patients ring a bell as they finished their radiation treatments. “Every time somebody rang the bell, I would just get chills and tears in my eyes, and I got to ring the bell then at the end too,” she says.
The Waiting Game
One hurdle in the way of getting more data on oligometastatic cancer, says Chmura, is that some people are reluctant to enroll in a trial where they might be randomized to standard care only, especially when many oncologists are willing to treat oligometastatic disease with surgery or radiation outside of trials. Chmura and his colleagues conducted an international survey, published in 2017, in which 61% of around 1,000 radiation oncologists said they used SABR to treat patients with three or fewer metastases.
“A lot of people have the bias that this [treatment] has to work,” Chmura says. “Trust me: It doesn’t have to work.” Chmura says that patients with oligometastatic disease can consider joining a clinical trial, but he cautions against getting aggressive local treatments for oligometastases outside of research studies.
But Palma points out that trials aren’t available for every patient. Even once current phase III trials are complete, there will still be patients who don’t have clinical trial data specific to their situation or cancer type to guide them. “On balance, if there’s no trial available, I feel the vast majority of evidence supports the fact that stereotactic radiation [SABR] in that setting can provide benefit,” says Palma, referring to his support for sometimes treating oligometastases aggressively outside of trials. Iyengar also emphasizes the importance of trials but says he will treat patients outside of trials if there is no study available, although this can require some effort to get approval from health insurance companies.
For Argenziano, oligometastatic cancer has thus far come with the good prognosis she hoped for. She has had no evidence of disease since her radiation treatment in 2016. She is still taking hormone therapy and says she lives in a “bizarre world” of both feeling lucky while also knowing her cancer could return.
Still, Argenziano feels good about her choice to get radiation for her metastases. “It could have been the radiation, it could have been the chemo, it could have been the additional hormonal treatments that I’m on now, it could be luck, because there’s so much of this disease that is just luck,” she says of possible reasons for her positive outcome. “But from my standpoint, I will never regret what I did, because I feel like I’ve done the most to actually try and beat this disease.”
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