Clinical Investigation
Oligometastasis: Past, Present, Future

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In this review, we discuss the oligometastatic state, with a focus on its current and future relevance within the field of radiation therapy. We first outline the scope of the problem and the evolving understanding of metastatic disease existing along a spectrum. We then transition to a discussion of the clinical data that led to the formulation of the oligometastatic hypothesis, delving in some detail into the clinical factors associated with improved outcomes in the setting of local therapy—whether surgical or radiotherapeutic. In particular, we highlight the marked limitations of using clinical criteria alone to determine the absence or presence of true extracranial oligometastatic disease. After this, we briefly discuss the radiation therapy literature that has recently demonstrated benefits in cancer-specific outcomes with ablative treatment of oligometastatic disease. We emphasize data in the setting of non-small cell lung cancer and prostate cancer and briefly discuss the importance of our enhanced ability to detect occult metastatic disease with improved imaging technologies. After noting that resulted and ongoing prospective trials of ablative radiation therapy use the most rudimentary of oligometastatic classifiers—number of metastases—as their inclusion criteria, we transition to our core argument: a growing body of preclinical and translational work aims to refine the definition of oligometastatic disease using molecular features. We address genomic, epigenetic, and immunologic features that have, across histology, demonstrated an improved ability to prognosticate when combined with classic clinical correlates of oligometastatic disease. We also discuss studies that suggest particular molecular targets which, when manipulated for therapeutic purposes, have the potential to revert the polymetastatic phenotype to the oligometastatic one. We conclude with what we believe are the repercussions of this work for radiation therapy trials and clinical practice, and the importance of enriching and supporting these inquiries for the future of our field.

Introduction

Cancer is the second leading cause of death both in the United States and globally, responsible for approximately 600,000 and 9.6 million deaths, respectively, in the most recent year for which data have been reported.1,2 Ninety percent of this mortality is driven by metastatic disease, a number that has changed little in more than 50 years.3 In spite of efforts to decrease incidence of a large subset of malignant disease through primary prevention efforts4, 5, 6 and increase early detection of a smaller subset through cancer screening,7, 8, 9, 10 the suboptimal uptake of these interventions11,12 combined with an aging population ensures the continued escalation of this problem for the foreseeable future.

In this context, the oncologic community is in the midst of a paradigm shift in the classification and treatment of metastatic disease. The advent of immune checkpoint blockade and targeted molecular therapies has resulted in recent, meaningful overall survival (OS) benefits and likely cures in a minority of patients with metastases from certain tumor types.13, 14, 15, 16 At the same time, there has been a movement away from the classical teaching concerning the absolute fatality of any degree of distant metastatic disease toward a more nuanced understanding of clinical metastasis existing along a spectrum.17,18 This oligometastatic hypothesis—an intermediate state between locoregionally confined disease and diffuse metastatic disease—was first proposed by Hellman and Weichselbaum in 1995.19 This idea has gained significant traction over the intervening decades, has recently been incorporated into the American Joint Committee on Cancer 8th edition staging system for non-small cell lung cancer (NSCLC), and underpins numerous recently published phase II and ongoing phase III studies of localized treatment beyond palliation in the metastatic setting.20

At present, a growing wealth of preclinical, translational, and clinical data are strengthening the oligometastatic framework and, intriguingly, suggesting ways in which it might interact with the genetic, epigenetic, and immunologic features of metastatic malignancy. In this review, we first outline the clinical factors that led to the formulation of the oligometastatic hypothesis and predict improved oncologic outcomes in the setting of locally ablative therapies for extracranial disease. We then elaborate on emerging molecular and immune features that further refine our ability to place patients along the metastatic spectrum. We delve into the diagnostic and therapeutic promise of such classification and raise the possibility of altering the virulence of patients’ metastatic states before concluding with a discussion of the current limitations and proposed future directions for the field.

Section snippets

The Clinical Oligometastatic State

The first evidence of an oligometastatic state emerged in the surgical literature. Several large series have demonstrated prolonged disease-free survival and OS in patient subsets after resection of hepatic metastases from colorectal primaries or pulmonary metastases from a variety of primary tumor types.21, 22, 23, 24, 25, 26, 27, 28, 29, 30 The most salient updated results come from work by Rees and colleagues,30 Fong and colleagues,26 Pastorino and colleagues,28 and Casiraghi and colleagues.

Local Ablation for Oligometastatic Disease

The first reported clinical trial of SBRT for oligometastatic disease was a phase I dose escalation study investigating the safety of ablative therapy in patients with ≤5 sites of extracranial metastases.32 The study enrolled 61 patients with 113 metastases and demonstrated safety and a potential efficacy signal. Since that time, there have been several reported prospective phase II studies investigating the benefit of SBRT when added to standard therapy, in addition to a large number of

The metastatic cascade

Metastasis is not a random, passive process. Since Paget41 first postulated the “seed and soil” hypothesis, much has been learned about the various steps in the metastatic cascade. These steps include loss of cellular adhesion, increased motility and invasiveness of the primary tumor, entry into and survival in the circulation, and adhesion to the blood vessel wall followed by extravasation and colonization of new organs.42 The process has been shown to be reliant on specific genetic or

Future Directions

Despite entering its third decade, the study of oligometastatic disease has only just begun. As molecular analysis refines patient selection and provides the opportunity for therapeutic intervention, prospective trials using clinical parameters originally drawn from the surgical literature are already delivering striking improvements in cancer-specific outcomes. Enrollment in ongoing phase III trials is essential. Multidisciplinary collaboration investigating everything from improved radiologic

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    We would like to acknowledge the Ludwig Cancer Research Foundation and the Foglia Family Foundation for their funding support.

    Disclosures: R.R.W. is a consultant and/or adviser for Aettis, AstraZeneca, Genus, ImmunoVir, Merck Serono, Nano Proteagen, Reflexion Pharmaceuticals, RiMO and Shuttle Pharmaceuticals, has been a guest speaker sponsored by Boehringer Ingelheim and has equity or intellectual property rights with Boost Therapeutics, Oncosenescence, Reflexion Pharmaceuticals, RiMO, and Immunovir. S.P. has a patent "Methods and Kits for Diagnosis and Triage of Patients with Colorectal Liver Metastases" pending. S.G. has no conflicts of interest.

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