Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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

References

  1. Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559–1564 (2011).

    CAS  PubMed  Article  Google Scholar 

  2. Hellman, S. & Weichselbaum, R. R. Oligometastases. J. Clin. Oncol. 13, 8–10 (1995).

    CAS  PubMed  Article  Google Scholar 

  3. Weichselbaum, R. R. & Hellman, S. Oligometastases revisited. Nat. Rev. Clin. Oncol. 8, 378–382 (2011).

    CAS  PubMed  Article  Google Scholar 

  4. Palma, D. A. et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet 393, 2051–2058 (2019).

    PubMed  Article  Google Scholar 

  5. Ost, P. et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J. Clin. Oncol. 36, 446–453 (2018).

    CAS  PubMed  Article  Google Scholar 

  6. Phillips, R. et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 6, 650–659 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  7. Ruers, T. et al. Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC intergroup phase II study (EORTC 40004). Ann. Oncol. 23, 2619–2626 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Gomez, D. R. et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 17, 1672–1682 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Gomez, D. R. et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J. Clin. Onol. 37, 1558–1565 (2019).

    CAS  Article  Google Scholar 

  10. Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).

    CAS  PubMed  Article  Google Scholar 

  11. Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).

    CAS  PubMed  Article  Google Scholar 

  12. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).

    CAS  PubMed  Article  Google Scholar 

  14. Soria, J.-C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).

    CAS  PubMed  Article  Google Scholar 

  15. Ramalingam, S. S. et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N. Engl. J. Med. 382, 41–50 (2020).

    CAS  PubMed  Article  Google Scholar 

  16. James, N. D. et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N. Engl. J. Med. 377, 338–351 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Davis, I. D. et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N. Engl. J. Med. 381, 121–131 (2019).

    CAS  PubMed  Article  Google Scholar 

  18. Finn, R. S. et al. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 375, 1925–1936 (2016).

    CAS  PubMed  Article  Google Scholar 

  19. Goetz, M. P. et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 35, 3638–3646 (2017).

    CAS  PubMed  Article  Google Scholar 

  20. Guckenberger, M. et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol. 21, e18–e28 (2020).

    PubMed  Article  Google Scholar 

  21. Lievens, Y. et al. Defining oligometastatic disease from a radiation oncology perspective: an ESTRO-ASTRO consensus document. Radiother. Oncol. 148, 157–166 (2020).

    PubMed  Article  Google Scholar 

  22. Nordlinger, B. et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer 77, 1254–1262 (1996).

    CAS  PubMed  Article  Google Scholar 

  23. Iwatsuki, S. et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J. Am. Coll. Surg. 189, 291–299 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Fong, Y., Fortner, J., Sun, R. L., Brennan, M. F. & Blumgart, L. H. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann. Surg. 230, 309–318; discussion 318–321 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Tanvetyanon, T. et al. Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small-cell lung cancer: a systematic review and pooled analysis. J. Clin. Oncol. 26, 1142–1147 (2008).

    PubMed  Article  Google Scholar 

  26. Choong, P. F. M., Pritchard, D. J., Rock, M. G., Sim, F. H. & Frassica, F. J. Survival after pulmonary metastasectomy in soft tissue sarcoma: prognostic factors in 214 patients. Acta Orthop. Scand. 66, 561–568 (1995).

    CAS  PubMed  Article  Google Scholar 

  27. van Geel, A. N. et al. Surgical treatment of lung metastases: the European Organization for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer 77, 675–682 (1996).

    PubMed  Article  Google Scholar 

  28. Chudgar, N. P. et al. Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma. J. Thorac. Cardiovasc. Surg. 154, 319–330.e1 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  29. Wagner, J. S., Adson, M. A., Van Heerden, J. A., Adson, M. H. & Ilstrup, D. M. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann. Surg. 199, 502–508 (1984).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Pogrebniak, H. W., Roth, J. A., Steinberg, S. M., Rosenberg, S. A. & Pass, H. I. Reoperative pulmonary resection in patients with metastatic soft tissue sarcoma. Ann. Thorac. Surg. 52, 197–203 (1991).

    CAS  PubMed  Article  Google Scholar 

  31. Treasure, T., Moller, H., Fiorentino, F. & Utley, M. Editorial comment: forty years on: pulmonary metastasectomy for sarcoma. Eur. J. Cardiothorac. Surg. 43, 799–800 (2013).

    PubMed  Article  Google Scholar 

  32. Treasure, T. et al. Pulmonary metastasectomy versus continued active monitoring in colorectal cancer (PulMiCC): a multicentre randomised clinical trial. Trials 20, 718 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Salama, J. K. et al. Stereotactic body radiotherapy for multisite extracranial oligometastases: final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease. Cancer 118, 2962–2970 (2012).

    PubMed  Article  Google Scholar 

  34. Nuyttens, J. J. et al. Stereotactic body radiation therapy for oligometastases to the lung: a phase 2 study. Int. J. Radiat. Oncol. Biol. Phys. 91, 337–343 (2015).

    PubMed  Article  Google Scholar 

  35. Rusthoven, K. E. et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J. Clin. Oncol. 27, 1572–1578 (2009).

    PubMed  Article  Google Scholar 

  36. Rusthoven, K. E. et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J. Clin. Oncol. 27, 1579–1584 (2009).

    PubMed  Article  Google Scholar 

  37. Wang, X. S. et al. Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1–2 trial. Lancet Oncol. 13, 395–402 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  38. Milano, M. T., Zhang, H., Metcalfe, S. K., Muhs, A. G. & Okunieff, P. Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy. Breast Cancer Res. Treat. 115, 601–608 (2009).

    PubMed  Article  Google Scholar 

  39. David, S. et al. Stereotactic ablative body radiotherapy (SABR) for bone only oligometastatic breast cancer: a prospective clinical trial. Breast 49, 55–62 (2020).

    PubMed  Article  Google Scholar 

  40. Palma, D. A. et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J. Clin. Oncol. 38, 2830–2838 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  41. Harrow, S. et al. Stereotactic radiation for the comprehensive treatment of oligometastases (SABR-COMET)–extended long-term outcomes. Int. J. Radiat. Oncol. Biol. Phys. https://doi.org/10.1016/j.ijrobp.2022.05.004 (2022).

    Article  PubMed  Google Scholar 

  42. Ost, P. et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): five-year results of a randomized phase II trial [abstract]. J. Clin. Oncol. 38 (Suppl. 6), 10 (2020).

    Article  Google Scholar 

  43. Tang, C. et al. Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: a single-arm, single-centre, feasibility, phase 2 trial. Lancet Oncol. 22, 1732–1739 (2021).

    PubMed  Article  Google Scholar 

  44. Ruers, T. et al. Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial. J. Natl Cancer Inst. 109, djx015 (2017).

    PubMed Central  Google Scholar 

  45. Iyengar, P. et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 4, e173501 (2018).

    PubMed  Article  Google Scholar 

  46. Wang, X.-S. et al. Randomized trial of first-line tyrosine kinase inhibitor with or without radiotherapy for synchronous oligometastatic EGFR-mutated NSCLC. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/djac015 (2022).

    Article  PubMed  Google Scholar 

  47. Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017).

    CAS  PubMed  Article  Google Scholar 

  48. Parker, C. C. et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 392, 2353–2366 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  49. You, R. et al. Efficacy and safety of locoregional radiotherapy with chemotherapy vs chemotherapy alone in de novo metastatic nasopharyngeal carcinoma: a multicenter phase 3 randomized clinical trial. JAMA Oncol. 6, 1345–1352 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  50. Soran, A. et al. Randomized trial comparing resection of primary tumor with no surgery in stage IV breast cancer at presentation: protocol MF07-01. Ann. Surg. Oncol. 25, 3141–3149 (2018).

    PubMed  Article  Google Scholar 

  51. Khan, S. A. et al. Early local therapy for the primary site in de novo stage IV breast cancer: results of a randomized clinical trial (EA2108). J. Clin. Oncol. 40, 978–987 (2022).

    CAS  PubMed  Article  Google Scholar 

  52. Shah, S. et al. Clinical and molecular features of innate and acquired resistance to anti-PD-1/PD-L1 therapy in lung cancer. Oncotarget 9, 4375–4384 (2018).

    PubMed  Article  Google Scholar 

  53. Wang, D. Y. et al. Clinical features of acquired resistance to anti-PD-1 therapy in advanced melanoma. Cancer Immunol. Res. 5, 357–362 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Mahmood, U. et al. Retrospective review of outcomes following radiotherapy for oligoprogressive disease on immune checkpoint blockade. Int. J. Radiat. Oncol. Biol. Phys. https://doi.org/10.1016/j.ijrobp.2022.05.008 (2022).

    Article  PubMed  Google Scholar 

  55. Chicas-Sett, R. et al. Combination of stereotactic ablative radiotherapy with anti-PD-1 in oligoprogressive non-small-cell lung cancer and melanoma: results of a prospective multicenter observational study. Int. J. Radiat. Oncol. Biol. Phys. https://doi.org/10.1016/j.ijrobp.2022.05.013 (2022).

    Article  PubMed  Google Scholar 

  56. Weiss, J. et al. Phase II study of stereotactic radiosurgery for the treatment of patients with oligoprogression on erlotinib. Cancer Treat. Res. Commun. 19, 100126 (2019).

    PubMed  Article  Google Scholar 

  57. Iyengar, P. et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J. Clin. Oncol. 32, 3824–3830 (2014).

    PubMed  Article  Google Scholar 

  58. Cheung, P. et al. Stereotactic radiotherapy for oligoprogression in metastatic renal cell cancer patients receiving tyrosine kinase inhibitor therapy: a phase 2 prospective multicenter study. Eur. Urol. 80, 693–700 (2021).

    CAS  PubMed  Article  Google Scholar 

  59. Tsai, C. J. et al. Consolidative use of radiotherapy to block (CURB) oligoprogression–interim analysis of the first randomized study of stereotactic body radiotherapy in patients with oligoprogressive metastatic cancers of the lung and breast. Int. J. Radiat. Oncol. Biol. Phys. 111, 1325–1326 (2021).

    Article  Google Scholar 

  60. [No authors listed] Highly focused radiation may curb oligoprogression. Cancer Discov. 12, 8–9 (2022).

    Article  Google Scholar 

  61. Foster, C. C., Pitroda, S. P. & Weichselbaum, R. R. Beyond palliation: the rationale for metastasis-directed therapy for metastatic non-small cell lung cancer. J. Thorac. Oncol. 14, 1510–1512 (2019).

    PubMed  Article  Google Scholar 

  62. Reuben, A. et al. Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma. NPJ Genom. Med. 2, 10 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Chalkidou, A. et al. Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study. Lancet Oncol. 22, 98–106 (2021).

    PubMed  Article  Google Scholar 

  65. Olson, R. A. et al. Population based phase II trial of stereotactic ablative radiotherapy (SABR) for up to 5 oligometastases: preliminary results of the SABR-5 trial [abstract]. Int. J. Radiat. Oncol. Biol. Phys. 111 (Suppl. 3), S4 (2021).

    Article  Google Scholar 

  66. Chmura, S. et al. Evaluation of safety of stereotactic body radiotherapy for the treatment of patients with multiple metastases: findings from the NRG-BR001 phase 1 trial. JAMA Oncol. 7, 845–852 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  67. Al-Hallaq, H. A. et al. Rationale of technical requirements for NRG-BR001: the first NCI-sponsored trial of SBRT for the treatment of multiple metastases. Pract. Radiat. Oncol. 6, e291–e298 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  68. Olson, R. et al. Stereotactic ablative radiotherapy for the comprehensive treatment of 1–3 oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial. BMC Cancer 20, 380 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Palma, D. A. et al. Stereotactic ablative radiotherapy for the comprehensive treatment of 4–10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial. BMC Cancer 19, 816 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. Ashworth, A. B. et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin. Lung Cancer 15, 346–355 (2014).

    PubMed  Article  Google Scholar 

  71. Newman, S. et al. Long-term survival with 18-fluorodeoxyglucose positron emission tomography-directed therapy in non-small cell lung cancer with synchronous solitary brain metastasis. Clin. Oncol. 33, 163–171 (2021).

    CAS  Article  Google Scholar 

  72. Pastorino, U. et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J. Thorac. Cardiovasc. Surg. 113, 37–49 (1997).

    CAS  PubMed  Article  Google Scholar 

  73. Tanadini-Lang, S. et al. Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastatic lung disease. Radiother. Oncol. 123, 182–188 (2017).

    CAS  PubMed  Article  Google Scholar 

  74. Lussier, Y. A. et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS ONE 7, e50141 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Rueda, O. M. et al. Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups. Nature 567, 399–404 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Pitroda, S. P. et al. Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis. Nat. Commun. 9, 1793 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. Iacobuzio-Donahue, C. A. et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J. Clin. Oncol. 27, 1806–1813 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Deek, M. P. et al. The mutational landscape of metastatic castration-sensitive prostate cancer: the spectrum theory revisited. Eur. Urol. 80, 632–640 (2021).

    CAS  PubMed  Article  Google Scholar 

  79. Sutera, P. et al. Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics. Prostate Cancer Prostatic Dis. https://doi.org/10.1038/s41391-021-00484-4 (2022).

    Article  PubMed  Google Scholar 

  80. Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell 173, 581–594.e12 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Oshima, G. et al. DNA methylation controls metastasis-suppressive 14q32-encoded miRNAs. Cancer Res. 79, 650–662 (2019).

    CAS  PubMed  Article  Google Scholar 

  82. Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).

    CAS  PubMed  Google Scholar 

  83. Fidler, I. J. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat. Rev. Cancer 3, 453–458 (2003).

    CAS  PubMed  Article  Google Scholar 

  84. de Groot, A. E., Roy, S., Brown, J. S., Pienta, K. J. & Amend, S. R. Revisiting seed and soil: examining the primary tumor and cancer cell foraging in metastasis. Mol. Cancer Res. 15, 361–370 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. Van den Eynde, M. et al. The link between the multiverse of immune microenvironments in metastases and the survival of colorectal cancer patients. Cancer Cell 34, 1012–1026.e3 (2018).

    PubMed  Article  CAS  Google Scholar 

  86. Siva, S. et al. Single-fraction vs multifraction stereotactic ablative body radiotherapy for pulmonary oligometastases (SAFRON II): the Trans Tasman Radiation Oncology Group 13.01 phase 2 randomized clinical trial. JAMA Oncol. 7, 1476–1485 (2021).

    PubMed  Article  Google Scholar 

  87. Arina, A. et al. Tumor-reprogrammed resident T cells resist radiation to control tumors. Nat. Commun. 10, 3959 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. Hou, Y. et al. Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity. Sci. Transl. Med. 13, eabb0130 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Yang, K. et al. Suppression of local type I interferon by gut microbiota-derived butyrate impairs antitumor effects of ionizing radiation. J. Exp. Med. 218, e20201915 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Jani, A. B. et al. 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial. Lancet 397, 1895–1904 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Siva, S. et al. Stereotactic abative body radiotherapy (SABR) for oligometastatic prostate cancer: a prospective clinical trial. Eur. Urol. 74, 455–462 (2018).

    PubMed  Article  Google Scholar 

  92. Glicksman, R. M. et al. Curative-intent metastasis-directed therapies for molecularly-defined oligorecurrent prostate cancer: a prospective phase II trial testing the oligometastasis hypothesis. Eur. Urol. 80, 374–382 (2021).

    CAS  PubMed  Article  Google Scholar 

  93. Loupakis, F. et al. Detection of molecular residual disease using personalized circulating tumor DNA assay in patients with colorectal cancer undergoing resection of metastases. JCO Precis. Oncol. https://doi.org/10.1200/PO.21.00101 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Xia, L. et al. Perioperative ctDNA-based molecular residual disease detection for non-small cell lung cancer: a prospective multicenter cohort study (LUNGCA-1). Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-21-3044 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Dhiman, A. et al. Phase II prospective, open-label randomized controlled trial comparing standard of care chemotherapy with and without sequential cytoreductive interventions for patients with oligometastatic foregut adenocarcinoma and undetectable circulating tumor deoxyribose nucleic acid (ctDNA) levels. Ann. Surg. Oncol. https://doi.org/10.1245/s10434-021-11249-7 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Hopkins, A. M., Kichenadasse, G., McKinnon, R. A., Rowland, A. & Sorich, M. J. Baseline tumor size and survival outcomes in lung cancer patients treated with immune checkpoint inhibitors. Semin. Oncol. 46, 380–384 (2019).

    CAS  PubMed  Article  Google Scholar 

  97. Joseph, R. W. et al. Baseline tumor size is an independent prognostic factor for overall survival in patients with melanoma treated with pembrolizumab. Clin. Cancer Res. 24, 4960–4967 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Castello, A., Rossi, S., Mazziotti, E., Toschi, L. & Lopci, E. Hyperprogressive disease in patients with non–small cell lung cancer treated with checkpoint inhibitors: the role of 18F-FDG PET/CT. J. Nucl. Med. 61, 821–826 (2020).

    CAS  PubMed  Article  Google Scholar 

  99. Chardin, D. et al. Baseline metabolic tumor volume as a strong predictive and prognostic biomarker in patients with non-small cell lung cancer treated with PD1 inhibitors: a prospective study. J. Immunother. Cancer 8, e000645 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  100. Nabet, B. Y. et al. Noninvasive early identification of therapeutic benefit from immune checkpoint inhibition. Cell 183, 363–376.e13 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Marsavela, G. et al. Circulating tumor DNA predicts outcome from first-, but not second-line treatment and identifies melanoma patients who may benefit from combination immunotherapy. Clin. Cancer Res. 26, 5926–5933 (2020).

    CAS  PubMed  Article  Google Scholar 

  102. Dall’Olio, F. G. et al. Tumour burden and efficacy of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 19, 75–90 (2022).

    PubMed  Article  CAS  Google Scholar 

  103. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

    CAS  PubMed  Article  Google Scholar 

  105. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y.-X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017).

    CAS  PubMed  Article  Google Scholar 

  106. Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  107. Formenti, S. C. et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 24, 1845–1851 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Bauml, J. M. et al. Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial. JAMA Oncol. 5, 1283–1290 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  109. Siva, S. et al. Stereotactic radiotherapy and short-course pembrolizumab for oligometastatic renal cell carcinoma–the RAPPORT trial. Eur. Urol. 81, 364–372 (2022).

    CAS  PubMed  Article  Google Scholar 

  110. Bestvina, C. M. et al. A phase 1 trial of concurrent or sequential ipilimumab, nivolumab, and stereotactic body radiotherapy in patients with stage IV NSCLC study. J. Thorac. Oncol. 17, 130–140 (2022).

    CAS  PubMed  Article  Google Scholar 

  111. Luke, J. J. et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J. Clin. Oncol. 36, 1611–1618 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Luke, J. J. et al. Improved survival associated with local tumor response following multisite radiotherapy and pembrolizumab: secondary analysis of a phase I trial. Clin. Cancer Res. 26, 6437–6444 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Foster, C. C. et al. Phase I study of stereotactic body radiotherapy plus nivolumab and urelumab or cabiralizumab in advanced solid tumors. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-21-0810 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).

    CAS  PubMed  Article  Google Scholar 

  115. Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. McBride, S. et al. Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma. J. Clin. Oncol. 39, 30–37 (2021).

    CAS  PubMed  Article  Google Scholar 

  117. Masini, C. et al. Nivolumab in combination with stereotactic body radiotherapy in pretreated patients with metastatic renal cell carcinoma. Results of the phase II NIVES study. Eur. Urol. https://doi.org/10.1016/j.eururo.2021.09.016 (2021).

    Article  PubMed  Google Scholar 

  118. Mahmood, U. et al. A randomized phase 2 study of pembrolizumab with or without radiation in patients with recurrent or metastatic adenoid cystic carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 109, 134–144 (2021).

    PubMed  Article  Google Scholar 

  119. Welsh, J. et al. Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial. J. Immunother. Cancer 8, e001001 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  120. Theelen, W. S. M. E. et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol. 5, 1276–1282 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  121. Theelen, W. S. M. E. et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir. Med. 9, 467–475 (2021).

    CAS  PubMed  Article  Google Scholar 

  122. Tian, S. et al. Lung stereotactic body radiation therapy and concurrent immunotherapy: a multicenter safety and toxicity analysis. Int. J. Radiat. Oncol. Biol. Phys. 108, 304–313 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. Tchelebi, L. T. et al. Radiotherapy and receptor tyrosine kinase inhibition for solid cancers (ROCKIT): a meta-analysis of 13 studies. JNCI Cancer Spectr. 5, pkab050 (2021).

    PubMed Central  Article  Google Scholar 

  124. Jia, W. et al. An especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib. Radiother. Oncol. 152, 96–100 (2020).

    CAS  PubMed  Article  Google Scholar 

  125. Corkum, M. T., Fakir, H., Palma, D. A., Nguyen, T. & Bauman, G. S. Can polymetastatic disease be ARRESTed using SABR? A dosimetric feasibility study to inform development of a phase 1 trial. Adv. Radiat. Oncol. 6, 100734 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  126. Guckenberger, M. et al. Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy. Radiother. Oncol. 118, 485–491 (2016).

    PubMed  Article  Google Scholar 

  127. Young, E. R., Diakos, E., Khalid-Raja, M. & Mehanna, H. Resection of subsequent pulmonary metastases from treated head and neck squamous cell carcinoma: systematic review and meta-analysis. Clin. Otolaryngol. 40, 208–218 (2015).

    CAS  PubMed  Article  Google Scholar 

  128. Al-Batran, S.-E. et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 trial. JAMA Oncol. 3, 1237–1244 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  129. Tachezy, M. et al. Synchronous resections of hepatic oligometastatic pancreatic cancer: disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery 160, 136–144 (2016).

    PubMed  Article  Google Scholar 

  130. Kuo, S.-W. et al. Prognostic factors for pulmonary metastasectomy in hepatocellular carcinoma. Ann. Surg. Oncol. 14, 992–997 (2007).

    PubMed  Article  Google Scholar 

  131. Franzese, C. et al. Stereotactic body radiotherapy in the management of oligometastatic and recurrent biliary tract cancer: single-institution analysis of outcome and toxicity. J. Cancer Res. Clin. Oncol. 146, 2289–2297 (2020).

    PubMed  Article  Google Scholar 

  132. Scorsetti, M. et al. Final results of a phase II trial for stereotactic body radiation therapy for patients with inoperable liver metastases from colorectal cancer. J. Cancer Res. Clin. Oncol. 141, 543–553 (2015).

    CAS  PubMed  Article  Google Scholar 

  133. Kavolius, J. P. et al. Resection of metastatic renal cell carcinoma. J. Clin. Oncol. 16, 2261–2266 (1998).

    CAS  PubMed  Article  Google Scholar 

  134. Patel, V. et al. Survival after metastasectomy for metastatic urothelial carcinoma: a systematic review and meta-analysis. Bladder Cancer 3, 121–132 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  135. Otto, T., Krege, S., Suhr, J. & Rübben, H. Impact of surgical resection of bladder cancer metastases refractory to systemic therapy on performance score: a phase II trial. Urology 57, 55–59 (2001).

    CAS  PubMed  Article  Google Scholar 

  136. Anraku, M. et al. Pulmonary metastases from uterine malignancies: results of surgical resection in 133 patients. J. Thorac. Cardiovasc. Surg. 127, 1107–1112 (2004).

    PubMed  Article  Google Scholar 

  137. Lazzari, R. et al. Stereotactic body radiation therapy for oligometastatic ovarian cancer: a step toward a drug holiday. Int. J. Radiat. Oncol. Biol. Phys. 101, 650–660 (2018).

    PubMed  Article  Google Scholar 

  138. Trovo, M. et al. Radical radiation therapy for oligometastatic breast cancer: results of a prospective phase II trial. Radiother. Oncol. 126, 177–180 (2018).

    PubMed  Article  Google Scholar 

  139. Sosman, J. A. et al. A phase 2 trial of complete resection for stage IV melanoma: results of Southwest Oncology Group clinical trial S9430. Cancer 117, 4740-06 (2011).

    PubMed  Article  Google Scholar 

  140. Howard, J. H. et al. Metastasectomy for distant metastatic melanoma: analysis of data from the first multicenter selective lymphadenectomy trial (MSLT-I). Ann. Surg. Oncol. 19, 2547–2555 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

Authors

Contributions

All authors made substantial contributions to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Ralph R. Weichselbaum.

Ethics declarations

Competing interests

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.

Peer review

Reviewer information

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-022-00655-9

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer