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The oligometastatic spectrum in the era of improved detection and modern systemic therapy

Abstract

Metastases remain the leading cause of cancer-related mortality. The oligometastasis hypothesis postulates that a spectrum of metastatic spread exists and that some patients with a limited burden of metastases can be cured with ablative therapy. Over the past decade, substantial advances in systemic therapies have resulted in considerable improvements in the outcomes of patients with metastatic cancers, warranting re-examination of the oligometastatic paradigm and the role of local ablative therapies within the context of the improved therapeutic responses, shifting patterns of disease recurrence and possible synergy with systemic treatments. Herein, we reframe the oligometastatic phenotype as a dynamic state for which locally ablative, metastasis-directed therapy improves clinical outcomes, including by prolonging survival and increasing cure rates. Important risk factors defining the metastatic spectrum are highlighted that inform both staging and therapy. Finally, we synthesize the literature on combining local therapies with modern systemic treatments, identifying general themes to optimally integrate ablative therapies in this context.

Key points

  • Metastases remain the leading cause of cancer-associated mortality; however, the oligometastasis hypothesis postulates the existence of a spectrum of metastatic spread.

  • In the context of modern systemic therapies and improved cancer detection, the oligometastatic phenotype is framed as a dynamic state within which local ablative therapies improve clinical outcome, including prolonging survival and achieving cure.

  • The definition of the oligometastatic state should be expanded beyond the number or size of metastases, and incorporate clinical risk factors, tumour biology, host biology and novel biomarkers that intersect to define the metastatic spectrum.

  • Blood-based biomarkers (such as circulating tumour DNA) might help select patients across the metastatic spectrum for systemic therapy and/or local therapy.

  • As imaging modalities are improved and become more sensitive, it will become increasingly possible to detect and locally ablate all oligometastases (including those previously undetectable with less-sensitive imaging techniques), potentially facilitating the de-escalation of systemic therapy.

  • In patients who are unable to be cured with ablative metastasis-directed therapies, cytoreduction might still improve the efficacy of systemic therapies via several mechanisms, such as elimination of subclones poised to confer resistance; thus, the integration of local therapies with evolving systemic treatments could result in long-term survival.

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Fig. 1: The oligometastatic state across primary cancer types.

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Acknowledgements

The work of the authors is supported by the Virginia and D. K. Ludwig Fund for Cancer Research and the Foglia Family Foundation.

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Correspondence to Ralph R. Weichselbaum.

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S.P.P and R.R.W. are co-inventors on a patent entitled “Methods and kits for diagnosis and triage of patients with colorectal liver metastases” and on a provisional patent entitled “Molecular subtyping of colorectal liver metastases to personalize treatment approaches”. A.J. has served in a consulting role for Isoray. S.J.C. has participated on advisory boards for AstraZeneca and Genentech, receives research support from AstraZeneca, Bristol Myers Squibb, EMD Serono and Merck, and his spouse is employed as the medical director of Astellas Pharma. R.R.W. has stock and other ownership interests in Aqualung Therapeutics, Boost Therapeutics, Coordination Pharmaceuticals, Immvira LLC, Magi Therapeutics, Oncosenescence and Reflexion Pharmaceuticals; has served in a consulting or advisory role for Aettis, Aqualung Therapeutics, AstraZeneca, Coordination Pharmaceuticals, Genus, Highlight Therapeutics, Merck Serono, Nano Proteagen, NKMax America and Shuttle Pharmaceuticals; has received research grants from Regeneron and Varian; and has received compensation including travel, accommodation or expense reimbursement from AstraZeneca, Boehringer Ingelheim and Merck Serono.

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Nature Reviews Clinical Oncology thanks A. Louie, who co-reviewed with R.J.M. Correa; M. Guckenberger; S. Siva; and other, anonymous, reviewer(s), for their contribution to the peer review of this work.

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Katipally, R.R., Pitroda, S.P., Juloori, A. et al. The oligometastatic spectrum in the era of improved detection and modern systemic therapy. Nat Rev Clin Oncol 19, 585–599 (2022). https://doi.org/10.1038/s41571-022-00655-9

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