Skip to main content

Main menu

  • Home
  • Our journals
    • Clinical Medicine
    • Future Healthcare Journal
  • Subject collections
  • About the RCP
  • Contact us

Clinical Medicine Journal

  • ClinMed Home
  • Content
    • Current
    • Ahead of print
    • Archive
  • Author guidance
    • Instructions for authors
    • Submit online
  • About ClinMed
    • Scope
    • Editorial board
    • Policies
    • Information for reviewers
    • Advertising

User menu

  • Log in

Search

  • Advanced search
RCP Journals
Home
  • Log in
  • Home
  • Our journals
    • Clinical Medicine
    • Future Healthcare Journal
  • Subject collections
  • About the RCP
  • Contact us
Advanced

Clinical Medicine Journal

clinmedicine Logo
  • ClinMed Home
  • Content
    • Current
    • Ahead of print
    • Archive
  • Author guidance
    • Instructions for authors
    • Submit online
  • About ClinMed
    • Scope
    • Editorial board
    • Policies
    • Information for reviewers
    • Advertising

The oligometastatic paradigm and the role of radiotherapy

Killian Nugent and James Good
Download PDF
DOI: https://doi.org/10.7861/clinmed.2022-0559
Clin Med January 2023
Killian Nugent
AGenesiscare UK and Oxford University Hospital, Oxford, UK
Roles: clinical oncology research fellow
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: killian.nugent@ouh.nhs.uk
James Good
BGenesiscare UK
Roles: consultant clinical oncologist
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
Loading

ABSTRACT

Most cancer-related deaths are due to metastatic disease. There is now an emerging evidence base suggesting that a subgroup of metastatic patients benefit significantly from local resection (surgery) or ablation (stereotactic ablative body radiation, SABR) of their metastatic sites. These patients are in what has been termed the ‘oligometastatic state’, a transitional window between local and disseminated disease where locally ablative, metastasis-directed therapy prolongs progression-free survival, improves overall survival and sometimes achieves cure. Appropriately selecting those who fit this oligometastatic phenotype, while integrating advances in ablative technologies such as SABR with modern systemic treatments, is an evolving challenge for oncologists.

  • oligometastatic
  • oligoprogression
  • metastasectomy
  • SABR
  • RFA

Key points

  • Cancer rates globally are estimated to increase by 47% in 2040, with most cancer-related deaths resulting from metastasis.

  • Oligometastatic disease can be defined as a patient with a limited burden of metastatic disease.

  • Metastases-directed locally ablative treatment in cancer patients with oligometastatic disease can improve cancer clinical outcomes. Advances in SABR radiotherapy technology (immobilisation and organ motion tracking, image guidance and adaptive planning) have allowed ablative treatments to be given to metastatic sites not previously safe to do so.

  • Predictive factors for patients who may benefit from SABR include the size, site and number of metastases, the length of interval between progression, primary tumour histology, number of lines of previous systemic treatment and performance status.

  • The oligometastatic phenotype will evolve with further retrospective data analysis, prospective randomized clinical trials, advances in diagnostic radiology, new biomarkers and further study exploring the optimisation of SABR with systemic and immune-oncology treatments.

Introduction

Globally, cancer rates expected to increase by 47% by 2040.1 In the UK each year there are 140,000 new metastatic cases diagnosed.2 Most cancer deaths (up to 90%) result from the metabolic and immunological sequalae of metastatic disease.3 The focus of treatment in the metastatic setting has conventionally been palliative systemic therapy aimed at prolonging survival, with low-dose radiotherapy used for palliation of symptoms only.

There is now a growing evidence base defining a subgroup of metastatic patients in a transitional state between localised and widespread disease, known as the ‘oligometastatic state’. Patients with a limited burden of metastatic disease can achieve a significant improvement in long-term outcome (progression-free survival, overall survival), and in some cases cure, with metastasis-directed surgical resection or more recently stereotactic ablative radiotherapy (SABR).4 SABR treatment, the result of advances in radiotherapy technology over the years, can now deliver very high doses of radiation to metastatic sites while sparing normal tissue. In selected patients SABR can also be used as a strategy to delay burdensome systemic treatment with time to/time off chemotherapy or hormone treatment being considered a valuable endpoint for patients quality of life.5,6 These interventions have been coupled with improvements in diagnostic imaging, with gains seen in the sensitivity of detecting early metastatic cancer, PSMA PET in prostate cancer being a prominent example.7 Appropriately identifying oligometastatic patients and integrating SABR with their systemic treatments is an ongoing challenge for oncologists.

Defining oligometastatic disease

There is no consensus on the definition of oligometastatic cancer, but no more than five radiologically visible metastases is considered a reasonable benchmark.8 A more qualitative approach to categorising oligometastatic disease, factoring in tumour type, timing of progression/recurrence, systemic treatment options and expected outcome of treatment, is seen in recently published guidelines.9 Oligometastatic disease can be further subcategorised based on disease chronicity: synchronous, in which oligometastatic disease presents at the time of initial diagnosis; metachronous, in which oligometastatic recurrence presents after treatment of the initial primary site; and oligoprogressive, where disease progresses at a few metastatic sites while other sites are stable (Box 1).

View this table:
  • View inline
  • View popup
Box 1.

Common terms associated with the oligometastatic disease state and its treatment

The biological basis of the oligometastatic state is thought to be due to the existence of different cell phenotypes within a tumour's population. Genomic studies have demonstrated that metastatic tumour is composed of differing subclones of cells and that there is intra-tumour heterogeneity between different metastatic sites.10 Certain subclones may be resistant to chemotherapy or acquire resistance after treatment due to selective pressure.11 These aggressive subclones may be responsible for the further disease progression and, in turn, be the source of further metastatic dissemination. Because metastases can arise not just from the primary tumour but also from existing metastases, targeting and ablating the resistant subclones present in oligometastatic disease may halt or delay further progression.

Selecting metastatic patients to undergo SABR treatment

Several tumour- and patient-specific factors are considered when deciding on which patients may benefit from ablative treatment:

  • The number of metastases: Generally, having fewer than five metastases has been considered an important factor in predicting that a patient is in the oligometastatic state.9

  • What organ is involved: Patients with lung and nodal metastases have longer overall survival (OS) compared to liver and brain metastases.12

  • The size of individual metastases: Large cohort studies have demonstrated that metastases under 3 cm are associated with improved OS,13 with a lung metastasis size >2 cm having been shown to predict a short time to disseminated disease.14

  • Progression-free survival length: Short intervals between disease progression infer poor prognostic outcomes.15

  • The number of previous systemic treatment lines: Patients who received three or more lines of chemotherapy before SABR have a worse progression-free survival outcome.16

  • The primary tumour histology: There is a strong correlation with both prostate and breast primary cancer and improved survival with SABR.17

  • The patient's performance status (PS): Patients with better PS have an increased OS benefit with SABR.18 Most PS assessments include parameters of age, cognition, mobility, comorbidities and sarcopenia, with formal scoring assessments available.19

Metastasis-directed ablative treatment

SABR is highly focused radiation treatment that delivers a high dose to the tumour while limiting the dose to surrounding organs. Multiple technological advances have led to the development of this innovative treatment. These include linear accelerators (LINACs) that can deliver radiation with multiple small-field photon beams of various shapes and intensities at different angles to precisely target the tumour. Advances in patient immobilisation, body motion tracking and image guidance have facilitated safe ablative radiation approaches; Table 1 sets out SABR doses recommended by the SABR UK Consortium.

View this table:
  • View inline
  • View popup
Table 1.

Typical prescriptions for oligometastatic sites recommended by the SABR UK Consortium.27 The dose prescribed depends on a number of factors including therapeutic goal, tumour location, histopathological subtype, and radiation dose to adjacent organs at risk

MRI-guided stereotactic adaptive radiotherapy (SMART) has the potential to further expand the ablative prowess of SABR. By providing enhanced soft tissue definition through MRI, the radiation treatment plan delivered to the patient can be changed to account for temporal changes in anatomical organ and tumour position (eg internal organ motion, tumour shrinkage, etc). These adapted plans can now be delivered on LINACs that can track in real time the position of the target and normal tissue, only delivering radiation when the target is within a certain treatment boundary. This increased accuracy allows for the investigation of whether larger radiation doses delivered in shorter treatment courses can achieve higher rates of local control. For example, the Emerald trial is a currently recruiting phase I non-randomised study in patients with localised pancreatic cancer. The trial will be looking at the safety of dose-escalated SABR to the pancreas with 50Gy in five fractions, 39Gy in three fractions and 25Gy in a single fraction.20

Overall, post-SABR local control of 80% at 2–3 years can be expected.21 A landmark phase II randomised trial (SABR COMET) has shown a significant survival benefit in oligometastatic patients, across a range of primary tumour types, who have undergone SABR. The 5-year OS rate was 42% compared to 18% in oligometastatic patients in the SABR versus non-SABR treatment arms respectively, with no detrimental impact on quality of life after SABR treatment (Fig 1).4 Furthermore, in selected patients SABR can also be used as a strategy to delay burdensome systemic treatment with time to/time off chemotherapy/hormone treatment being considered a valuable endpoint for patients quality of life.5,6 One study, for example, demonstrated a median 8-month extra androgen-deprivation free survival in metastatic prostate patients treated with metastasis directed SABR as an initial substitute to commencing systemic treatment.

Fig 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig 1.

Kaplan-Meier plots for a) overall survival and b) progression-free survival seen in the SABR COMET Trial.4

Non-SABR metastasis-directed treatment such as surgical metastasectomy and interventional-radiology-led procedures, eg radiofrequency ablation (RFA), microwave ablation (MWA) and irreversible electroporation (IRE), are valuable alternative therapeutic options in oligometastatic patients. One large surgical series, exploring outcomes after lung metastasectomy, demonstrated an OS rate of 36% at 5 years and 26% at 10 years.22 This series included a broad range of primary tumour histology sites including epithelial tumours, sarcomas, germ cell tumours and metastatic melanomas.22 Resection of brain metastasis can improve OS and local control in selected patients.23 Neurosurgical resection is often accompanied by adjuvant stereotactic radiation to the surgical cavity, which improves local control.24 Interventional radiologists also have an important role in the management of oligometastatic disease. Various directly ablative procedures are available, the most frequently used being percutaneous RFA, a technique of tissue ablation that is used to treat lung, liver, and kidney metastases.25 It involves placing a needle-type electrode that uses heat generated by radio waves to destroy tissue directly into the tumour site. The CLOCC trial explored its use in unresectable CRC liver metastasis and showed an OS benefit (median 45.6 months) compared to systemic treatment alone (median 40.5 months).26 There is currently no randomised evidence comparing SABR to RFA treatment in the oligometastatic setting.

Fig 2 shows a case example of a complete response to treatment in a patient undergoing SABR for a solitary liver metastasis following breast cancer.

Fig 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig 2.

Case example oligometastatic SABR. (a) A 53-year-old woman with a background history of triple-negative local breast cancer presents, 2 years after her initial diagnosis, with a solitary biopsy-proven liver metastasis (arrow). (b) She undergoes 45 Gy in 3 fractions SABR to this oligometastatic site. (c) A 6-month post treatment MRI shows a complete response to treatment (arrow).

Future developments and conclusion

The definition, treatment, and subcategorisation of the oligometastatic phenotype will evolve as the following developments occur:

  • Further randomised clinical trials are completed. The SABR COMET 10 trial, for example, is investigating clinical outcomes in patients with 4–10 metastatic lesions treated with SABR, asking the question whether there is benefit with SABR in patients with more than three metastatic lesions. Other clinical trials will explore the combination and optimisation of SABR with immunotherapies.

  • Imaging modalities become more sensitive. It may become possible to detect and locally ablate what is currently occult disease, as shown in the development of PSMA PET CT prostate cancer.

  • Novel biomarkers emerge, for example blood circulating tumour DNA (ct DNA), that might identify patients who are more likely to benefit from local ablative therapies.

Appropriately selecting those who fit the oligometastatic phenotype, while integrating advances in ablative radiotherapy technologies with modern systemic treatments, will continue to be an increasingly important paradigm in improving survival in the metastatic stage.

  • © Royal College of Physicians 2023. All rights reserved.

References

  1. ↵
    1. Sung H
    , Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49.
    OpenUrlCrossRefPubMed
  2. ↵
    1. NHS England
    . Stereotactic ablative radiotherapy (SABR) for patients with metachronous extracranial oligometastatic cancer (all ages). www.england.nhs.uk/publication/stereotactic-ablative-radiotherapy-sabr-for-patients-with-metachronous-extracranial-oligometastatic-cancer-all-ages/. Accessed December 12, 2022.
  3. ↵
    1. Dillekås H
    , Rogers MS, Straume O. Are 90% of deaths from cancer caused by metastases? Cancer Med 2019;8:5574–6.
    OpenUrl
  4. ↵
    1. Palma DA
    , Olson R, Harrow S, 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 2020;38:2830–8.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Siva S
    , Louie AV. Substituting SABR for systemic therapy in oligometastatic renal cell carcinoma — buying time or time to change? Nat Rev Urol 2022;19:197–8.
    OpenUrl
  6. ↵
    1. Ost P
    , Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter Phase II trial. J Clin Oncol 2018;36:446–53.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Tsechelidis I
    , Vrachimis A. PSMA PET in imaging prostate cancer. Front Oncol 2022;12:831429.
    OpenUrl
  8. ↵
    1. Dingemans A-MC
    , Hendriks LEL, Berghmans T, et al. Definition of synchronous oligometastatic non-small cell lung cancer – a consensus report. J Thorac Oncol 2019;14:2109–19.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Lievens Y
    , Guckenberger M, Gomez D, et al. Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document. Radiother Oncol 2020;148:157–66.
    OpenUrlPubMed
  10. ↵
    1. Gerlinger M
    , Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883–92.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Savas P
    , Teo ZL, Lefevre C, et al. The subclonal architecture of metastatic breast cancer: results from a prospective community-based rapid autopsy program ‘CASCADE.’ PLoS Med 2016;13:e1002204.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Franceschini D
    , De Rose F, Franzese C, et al. Predictive factors for response and survival in a cohort of oligometastatic patients treated with stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2019;104:111–21.
    OpenUrl
  13. ↵
    1. Sharma A
    , Duijm M, Oomen-de Hoop E, et al. Survival and prognostic factors of pulmonary oligometastases treated with stereotactic body radiotherapy. Acta Oncol 2019;58:74–80.
    OpenUrl
  14. ↵
    1. Nicosia L
    , Franceschini D, Perrone-Congedi F, et al. A multicenter LArge retrospectIve daTabase on the personalization of stereotactic ABlative radiotherapy use in lung metastases from colon-rectal cancer: The LaIT-SABR study. Radiother Oncol 2022;166:92–9.
    OpenUrl
  15. ↵
    1. Chen H
    , Poon I, Atenafu EG, et al. Development of a prognostic model for overall survival in patients with extracranial oligometastatic disease treated with stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2021;114:892–901.
    OpenUrl
  16. ↵
    1. Klement RJ
    , Guckenberger M, Alheid H, et al. Stereotactic body radiotherapy for oligo-metastatic liver disease - Influence of pre-treatment chemotherapy and histology on local tumor control. Radiother Oncol 2017;123:227–33.
    OpenUrl
  17. ↵
    1. Franzese C
    , Di Brina L, D'Agostino G, et al. Predictive factors for survival outcomes of oligometastatic prostate cancer patients treated with metastases-directed therapy: a recursive partitioning-based analysis. J Cancer Res Clin Oncol 2019;145:2469–79.
    OpenUrl
  18. ↵
    1. Yamamoto T
    , Niibe Y, Aoki M, et al. Analyses of the local control of pulmonary Oligometastases after stereotactic body radiotherapy and the impact of local control on survival. BMC Cancer 2020;20:997.
    OpenUrl
  19. ↵
    1. West H
    , Jin JO. Performance status in patients with cancer. JAMA Oncol 2015;1:998.
    OpenUrl
  20. ↵
    1. University of Oxford Medical Sciences Division
    . Evaluation of hypofractionated adaptive radiotherapy using the MR Linac in localised pancreatic cancer. www.oncology.ox.ac.uk/clinical-trials/oncology-clinical-trials-office-octo/current-trials/emerald-pancreas (Accessed 24 November 2022).
  21. ↵
    1. Royal College of Radiology
    . Radiotherapy dose fractionation. Third edition. RCR, 2019. www.rcr.ac.uk/publication/radiotherapy-dose-fractionation-third-edition.
  22. ↵
    1. Pastorino U
    , Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37–49.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Patchell RA
    , Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494–500.
    OpenUrlCrossRefPubMed
  24. ↵
    1. El Shafie RA
    , Dresel T, Weber D, et al. Stereotactic cavity irradiation or whole-brain radiotherapy following brain metastases resection – outcome, prognostic factors, and recurrence patterns. Front Oncol 2020;10:693.
    OpenUrl
  25. ↵
    1. Winkelmann MT
    , Clasen S, Pereira PL, Hoffmann R. Local treatment of oligometastatic disease: current role. Br J Radiol 2019;92: 20180835.
    OpenUrl
  26. ↵
    1. Ruers T
    , Van Coevorden F, Punt CJA, et al. Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial. J Natl Cancer Inst 2017;109:djx015.
    OpenUrlCrossRefPubMed
  27. ↵
    1. SABR UK Consortium
    . Stereotactic Ablative Body Radiation Therapy (SABR): a resource. www.sabr.org.uk/wp-content/uploads/2019/04/SABRconsortium-guidelines-2019-v6.1.0.pdf [Accessed 30 January 2023].
Back to top
Previous articleNext article

Article Tools

Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
The oligometastatic paradigm and the role of radiotherapy
Killian Nugent, James Good
Clinical Medicine Jan 2023, 23 (1) 61-64; DOI: 10.7861/clinmed.2022-0559

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
The oligometastatic paradigm and the role of radiotherapy
Killian Nugent, James Good
Clinical Medicine Jan 2023, 23 (1) 61-64; DOI: 10.7861/clinmed.2022-0559
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • ABSTRACT
    • Key points
    • Introduction
    • Defining oligometastatic disease
    • Selecting metastatic patients to undergo SABR treatment
    • Metastasis-directed ablative treatment
    • Future developments and conclusion
    • References
  • Figures & Data
  • Info & Metrics

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • Next-generation sequencing and molecular therapy
  • Essentials of cardio-oncology
Show more CME clinical oncology

Similar Articles

FAQs

  • Difficulty logging in.

There is currently no login required to access the journals. Please go to the home page and simply click on the edition that you wish to read. If you are still unable to access the content you require, please let us know through the 'Contact us' page.

  • Can't find the CME questionnaire.

The read-only self-assessment questionnaire (SAQ) can be found after the CME section in each edition of Clinical Medicine. RCP members and fellows (using their login details for the main RCP website) are able to access the full SAQ with answers and are awarded 2 CPD points upon successful (8/10) completion from:  https://cme.rcplondon.ac.uk

Navigate this Journal

  • Journal Home
  • Current Issue
  • Ahead of Print
  • Archive

Related Links

  • ClinMed - Home
  • FHJ - Home
clinmedicine Footer Logo
  • Home
  • Journals
  • Contact us
  • Advertise
HighWire Press, Inc.

Follow Us:

  • Follow HighWire Origins on Twitter
  • Visit HighWire Origins on Facebook

Copyright © 2021 by the Royal College of Physicians