International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationOligometastasis: Past, Present, Future
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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Oligometastases
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Patterns of metastatic spread and tumor burden in unselected cancer patients using PET imaging: Implications for the oligometastatic spectrum theory
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2024, Clinical Lung CancerThe oligometastatic setting in HNSCC: A critical review by the Rete Oncologica Piemonte e Valle d′Aosta multidisciplinary team
2023, Critical Reviews in Oncology/HematologyThe Role of Stereotactic Body Radiation Therapy in the Management of Liver Metastases
2023, Seminars in Radiation OncologyMoving Away From Counting the Numbers: Leveraging a Sensible Clinical Trial Design for Oligometastatic Disease and Beyond
2022, International Journal of Radiation Oncology Biology PhysicsLocal Treatment of the Primary Tumor for Patients With Metastatic Cancer (PRIME-TX): A Meta-Analysis
2022, International Journal of Radiation Oncology Biology PhysicsCitation Excerpt :Traditionally, patients not requiring primary tumor treatment for symptoms or prevention of oncologic morbidities are treated with palliative systemic therapy, as there is a questionable benefit for local control in the setting of metastases, and many still think local control is akin to “closing the barn door after the horse has bolted.”5 Others believe in aggressive ablation of all sites because of the enhanced ability to detect occult metastatic disease with improved imaging technologies and acceptable toxicities with complete ablation.6-8 While some trials have demonstrated an OS benefit with local treatment,1-3,9,10 many others have shown no benefit.11-18
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.