Several dozen studies focused on oligometastatic disease (OMD) were presented across four major oncology meetings of 2025, underscoring that what was once a speculative concept is now a cornerstone of oncology discourse. According to experts, the definition of OMD has also evolved.

One of these studies, the SABR-5 clinical trial, was presented at the 2025 Annual Meeting of the American Society for Radiation Oncology (ASTRO). Long-term data from this study support the use of stereotactic ablative radiotherapy for patients with OMD. In the updated analysis of this phase 2 nonrandomized trial, median overall survival reached 64.6 months and median progression-free survival was 14.6 months, underscoring that carefully selected patients with low-volume disease may benefit from local therapy.

The study also highlights a more fundamental question driving much of the current research: Why do some patients respond to local therapy while others do not? The answer is central to a rapidly evolving paradigm that is shifting the definition of OMD beyond simple lesion count.

Viewed alongside additional OMD-focused studies presented at this year’s major oncology meetings, the results reinforce a growing consensus among experts: OMD is not simply a matter of counting lesions; it reflects a distinct clinical state that can respond meaningfully to metastasis-directed therapy when identified early.

“We’ve been looking at oligometastatic disease as a snapshot in time instead of a movie,” Puneeth Iyengar, MD, PhD, told Medscape Medical News in an interview. Iyengar is the director of the Metastatic Program in the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center in New York City. “Now we’re starting to understand its trajectory.”

Until a seminal 1995 editorial by Samuel Hellman, MD, and Ralph R. Weichselbaum, MD, proposed that some metastases may remain biologically limited, the prevailing view held that cancer should be treated as a systemic disease, one requiring system-wide therapies such as chemotherapy rather than local measures like surgery or radiation.

Their paper proposed a new intermediate state, oligometastasis, in which some tumors have only limited metastatic potential. In this model, metastatic capability develops along a spectrum rather than all at once, meaning not every cancer is widely disseminated from the start of progression. For patients in this intermediate state, they argued, aggressive local control of all visible disease could still meaningfully affect survival.

“Oligo means few, but it’s not really about the number — it’s about biology,” surgical oncologist Kiran Turaga, MD, told Medscape Medical News, in an interview. Turaga is the division chief of Surgical Oncology at Yale Cancer Center in New Haven, Connecticut.

That shift from counting lesions to asking why they behave differently sets up the central question of the field today.

Does an Oligometastatic State Exist?

Current thinking now is OMD is not as a simple “snapshot” between localized and widespread metastasis but is part of a biological spectrum. Multiple lines of evidence built over the past three decades support the idea that some tumors have genuinely limited metastatic potential. The concept was first articulated by Hellman and Weichselbaum and subsequently refined through molecular and clinical research, such as an analysis by Guckenberger and colleaguesthat outlined the biological spectrum underlying oligometastatic behavior.

That spectrum-based model raises a key question: Does a truly durable oligometastatic state exist?

“What Hellman and Weichselbaum were really implying was whether or not there was a durable oligometastatic state — not just a simple transition from localized or locally advanced disease to metastatic disease — but some intermediate state that persisted,” said Iyengar.

Another key concept is that whether OMD remains limited depends on both tumor and host biology — clonal diversity, immune interactions, and the broader systemic environment. Evidence for this comes from genomic evolution studies, including the 2010 analysis by Shinichi Yachida and Siân Jones, which showed that metastatic subclones arise only after specific late genetic divergences within the tumor — meaning metastatic capability is not present in all clones, but emerges through defined evolutionary steps.

Biology is not operating in isolation though. “It’s not just about tumor-intrinsic biology, which will decide metastatic distributions and organ tropism. It’s about how our ‘host biology’ interacts with the tumor biology. A combination of those factors will be required for us to truly understand when and in what scenarios we need to offer systemic vs local therapy,” said Iyengar.

That distinction between a static snapshot and an evolving system is reflected in genomic-evolution studies, such as the TRACERx project, which demonstrated that metastatic capability evolves over time through ongoing subclonal diversification, supporting the modern view of oligometastasis as a dynamic biological process rather than a fixed intermediate state.

Several groups are now using large genomic and clinical datasets to map patterns of metastatic spread. A group at the University of Chicago is examining metastatic trajectories in longitudinal clinical datasets. Researchers at MD Anderson are working to integrate molecular residual disease dynamics into models of progression. And multi-institutional efforts such as the Moffitt Cancer Center-led ORIEN consortium are linking patterns of metastatic spread with underlying genomic and clinical characteristics.

“Only by studying metastatic disease as a function of time and therapy will we know which patients have aggressive disease and which may benefit from consolidation,” said Iyengar.

How Are the Biology and Behavior of OMD Characterized?

How well experts can characterize the biology and behavior of OMD now depends on advanced imaging and biomarker tools, such as newer types of PET imaging and circulating-tumor DNA (ctDNA) detection. For example, next-generation PET tracers such as prostate-specific membrane antigen (PSMA) PET — validated in trials like the ProPSMA study by Michael S. Hofman and colleagues — can reveal small-volume metastatic disease with far greater sensitivity. Likewise, ctDNA assays validated in studies such as a 2016 analysis by Jeanne Tie, MD, and colleagues have demonstrated the ability to detect minimal residual disease and track tumor dynamics.

“Circulating tumor DNA is the next frontier. If a patient has ctDNA positivity, even with no evidence of disease on scans, we know that’s a harbinger of bad things to come,” Michael Serzan, MD, said in an interview with Medscape Medical News. Serzan is a bladder cancer specialist at the Dana Farber Cancer Center in Boston. Large prospective studies such as DYNAMIC by Tie and colleagues and the GALAXY cohort of CIRCULATE-Japan by Nakamura and colleagues, both show that ctDNA positivity strongly predicts recurrence even when scans are negative.

Turaga added, “PET scans are becoming interesting where they pick up oligometastatic disease, and new tracers like FAPI-PET (fibroblast activation protein inhibitor PET) identify cancers with even higher sensitivity than FDG (fluorodeoxyglucose). Circulating tumor DNA will be important to stratify patients by volume.”

In a 2019 study published in the Journal of Nuclear Medicine by Frederik L. Geisel and colleagues, FAPI-PET demonstrated substantially higher lesion conspicuity than FDG-PET in solid tumors; PSMA-PET outperformed conventional imaging for detecting small metastases in the proPSMA trial.

Together, these advances are shifting OMD from a numbers game to a biologically defined state, where trajectory, clonal architecture, and host response matter more than how many lesions appear on a scan. Foundational molecular work from Weichselbaum’s group provided early evidence that limited metastatic potential reflects true biological differences. The 2011 Lussier PLoS ONE study identified distinct microRNA expression patterns in oligometastatic vs polymetastatic disease. Subsequent genomic and evolutionary analyses, including the TRACERx lung cancer cohort by Jamal-Hanjani and colleagues, which demonstrated that patterns of clonal diversification predict metastatic behavior — further support the concept that disease trajectory, not lesion count, drives outcomes. These biological clues matter most when the disease begins to move.

Why Is Progression of OMD Unpredictable?

Not all oligometastatic tumors are the same with some staying quiet for years, while others progress very quickly. The challenge is to identify truly indolent tumors from those likely to progress quickly. Evidence from Sean P. Pitroda and colleagues’ 2018 study in Nature Communications, which analyzed genomic and clinical patterns in patients with lung and colorectal cancer with limited metastases, showed that patients with OMD fall into distinct biological subsets — some with long-term stability and others with rapid progression.

“We want to see limited progression or limited development of widespread metastasis as long as the patients are on a relatively successful systemic therapy,” Iyengar said. “The direction the field is heading is to predict which patients are going to met out widely vs those that will not, and then use local therapy only for the latter.”

“We know that some oligometastatic tumors are biologically quiet. They smolder for years,” said Iyengar. “Others look limited but are already primed to disseminate.” The field’s next leap, he added, will come from learning to tell the difference early enough to act.

One reason progression is so unpredictable is that OMD is not a single biological entity. Tumors are genetically heterogeneous, consisting of multiple subclones with distinct mutations and behaviors. Work from the TRACERx program demonstrated that clonal diversity strongly influences metastatic spread. In addition, Pitroda and colleagues showed that patients with OMD fall into biologically distinct subsets driven by different clonal architectures. Some are indolent, others highly aggressive. Because a few visible lesions can arise from very different clonal populations, simply counting metastases (≤ 3 or 5) is not sufficient to guide treatment decisions in OMD.

“There’s polyclonality in cancer,” said Turaga. “When we measure DNA levels in the blood, not every metastasis sheds widespread ctDNA. Some are very quiet or very low. Those are the patients that lend themselves well to oligometastatic therapies.”

Multiregion sequencing studies have shown that metastases often arise from distinct cancer cell clones with very different biological behaviors, including variable patterns of ctDNA shedding, by Gerlinger and colleagues.

Tumor factors such as clonality aren’t the only drivers of progression. The immune milieu surrounding the tumor plays an equally important role. A tumor with an immune-rich signature exists within the body’s active immune surveillance: Dense populations of T cells and other immune mediators help keep residual disease in check. Classic immune-oncology analyses — such as Galon and colleagues’ Science 2006 work — demonstrated that tumors with heavy T-cell infiltration progress more slowly and are associated with better outcomes, reinforcing the role of host immunity in OMD behavior.

Those with “immune-rich signatures…are the types of patients where oligometastatic interventions generally have better long-term outcomes,” said Turaga.

For example, Tom Donnem and colleagues reported that patients with stronger immune activity around their tumors had significantly better long-term outcomes. Paul C. Tumeh and colleagues showed a similar pattern in melanoma, where tumors with active immune engagement tended to have more durable disease control.

In these patients, the immune system provides an added layer of containment, restraining micrometastases that might otherwise seed new growth. Conversely, tumors in an immune-poor environment grow largely unopposed. They may appear limited on scans, but biologically they carry far greater potential for progression because the immune presence is weak.

Together, the internal diversity of the tumor and the external immune milieu of the “host” determine whether OMD stays stable or evolves into widespread metastasis. The field is now trying to identify the signatures that predict more progressive OMD.

This relationship between immune activity and metastatic behavior has been documented across solid tumors. For example, Wolf Herman Fridman and colleagues showed that immune-infiltrated tumors experience greater containment, whereas immune-poor environments are associated with more rapid progression. Mikhail Binnewies and colleagues reported similar patterns, noting that immune-poor settings allow micrometastases to expand unchecked.

Iyengar’s team is working on that, using radiomics and ctDNA signatures to forecast trajectory. “We’re using genetics, laboratory data, radiomics, and liquid biopsy programs to determine which components can predict the trajectory of metastatic disease,” he said.

Why Is Multidisciplinary Input Crucial for Caring for Patients With OMD?

The biological complexity of OMD, coupled with research spanning a broad range of diagnostic tools, means that all hands are needed on deck to manage and treat these patients.

“It really has to be a conversation. We can’t have radiation oncologists doing their thing and medical oncologists doing theirs. The best outcomes happen when everyone sits together and decides which lesions to target, when to pause systemic therapy, and when to escalate,” said Iyengar.

Turaga added, “For some patients, removing all visible disease may make sense. For others, biology is telling you that even though you can remove everything, you probably shouldn’t. That’s where multidisciplinary input is crucial — to stop you from doing something that looks curative but isn’t.”

For example, in colorectal cancer, a patient may have a single resectable liver metastasis. Surgery is technically feasible, but the biology may be aggressive based on rapid recurrence, rising tumor markers, or poor response to systemic therapy. In a case like this, a multidisciplinary team may recommend systemic therapy alone rather than a curative-intent resection.

Serzan echoed the need for collaboration across disciplines.

“We’re learning that if you’re not talking across specialties, you’ll either overtreat or undertreat. You need the radiologist to tell you if the pattern of spread fits OMD, the pathologist to explain the immune signatures, and the medical oncologist to decide whether the systemic therapy is still working.”