Oligometastases: history and future vision of breast cancer

History of cancer theory

Patients with any metastatic or recurrent cancers were considered incurable and were not expected to survive for a long-term. Samuel Hellman proposed a new theory in 1994 at the Karnofsky Memorial Lecture (1). This theory was termed the spectrum theory. Until this theory was proposed, the systemic disease theory was accepted worldwide which indicated that all patients with cancer had potential metastases even if they did not have metastatic or recurrent cancer. Before the systemic disease theory was proposed by Bernard Fisher in 1980, cancer was considered to follow the Halsted theory, which was proposed by William Stewart Halsted in 1894. The Halsted theory suggested that if left untreated, cancer consecutively spreads through regional lymph nodes and then by hematogenous dissemination to the other organs in the body.

For a long time, there have been many investigations and discussions on where the systemic disease theory or spectrum theory is more accurate. Nowadays, the spectrum theory is well accepted among leading cancer professionals. The premise of the spectrum theory lies between the Halsted and systemic disease theories. According to his hypothesis, cancer is a spectrum of diseases than ranges from being a local disease to one metastasizes.

Indeed, some cancers are both local and systemic, which can be described as a “spectrum”. Hellman suggested these differences raise the “tumor burden” in this hypothesis. Because, breast cancer tends to remain a local disease, as far as it is a small tumor. More recently, the concepts of oligometastases (2), oligo-recurrence (3-5), and sync-oligometastases (4) have been reported.

History of the concepts of oligometastases, oligo-recurrence and sync-oligometastases

In 1995, Hellman and Weichselbaum proposed the concept of “oligometastases” (1). This concept was based on the spectrum theory and expands beyond small breast cancer. In an editorial published in the Journal of Clinical Oncology, they suggested that some patients with cancer having metastases could have long-term survival. This was the first description of oligometastases and related concepts. Around the same time, Niibe trained as a medical intern at the National Institute of Radiological Sciences Hospital in Japan. He observed the disappearance of para-aortic lymph node metastases with uterine cervical cancer patient, following treatment with external radiation therapy (6). Furthermore, he reviewed the medical charts of patients the same stage of the disease and who were previously treated with external radiation therapy alone or combined with systemic chemotherapy and found that they had long-term survival or were even cured. This experience gave him highly interest of cancer patients with metastases or recurrences, and he began investigating oligometastases: however, at that time, he was not aware of this concept because there was no internet or PubMed when he trained as a medial intern. After his experience, he wrote the original articles about par-aortic lymph node metastases or recurrences in patients with uterine cervical cancer (7-9), and in 2006, he finally proposed the concept of “oligo-recurrence”. The differences between oligometastases and oligo-recurrence were previously described in detail with figures (3,4)). Briefly described here, Niibe et al. defined the concept of oligo-recurrence as the state in which patients had a controlled primary cancerous lesion and 1–5 metastatic or recurrent cancerous lesions, and all active cancerous lesions could be treated with local therapies, such as surgery, radiation therapy, radiofrequency ablation, and others with or without systemic therapy. In 2012, Niibe and Chang defined sync-oligometastases as the state in which patients with cancer have active primary cancerous lesions and 1–5 metastatic or recurrent cancerous lesions, and all active cancerous lesions require local treatment, with or without systemic therapy. This classification had very important implications in the oligometastases field because the prognosis of these patients was different. Patients with oligo-recurrence have significantly superior outcomes to those with sync-oligometastatic patients (5,6,10,11). These studies included a nationwide survey of 1,378 oligometastases patients published in 2020 (5). Nowadays, oligometastases is a generous technical term including oligo-recurrence, sync-oligometastases, oligoprogression and others.

The important caution was reported here. The concept of “metachronous Oligometastases” was proposed firstly by Niibe and Chang (4).

Future visions of breast cancer

In 2019, one of the biggest news concerning of oligometastases, COMET-SABR randomized phase 2 reported the final outcomes (12,13). These outcomes suggested that the median overall survival of the control group (palliation therapy) was 28 months, which was significantly inferior to the 41-month overall survival of patient in the SABR group (hazard ratio: 0.57, 95% confidence interval: 0.30–1.10, P=0.090) (12). The finding of this study phase 2 randomized trial was significant as they applied a two-sided α of 0.20 and a power of 80%. Of the patients in this randomized phase 2 trial, 18% had breast cancer. However, the inclusion criteria of this randomized phase 2 study were limited to oligo-recurrence. The appropriate description of this study’s technical terms of oligometastases should be revised to oligo-recurrence when citing appropriate articles (3,4,14-17). This means that our proposed concept of oligo-recurrence and retrospective studies of oligo-recurrence are relevant to this randomized phase 2 trial (5,14,15). Thus, we re-emphasize here that the appropriate technical terms use of oligo-recurrence should be the standardized according to scientific society rules (15,16).

A prospective study for oligo-recurrence from breast cancer was reported in 2019 (18). This prospective study indicated that patient with 1–3 bone-only oligo-recurrences achieved both a long-term local progression-free survival (LPFS) and distant progression-free survival (DPFS). The LPFS was 100% at 2 years. The 1- and 2-year DPFS were 80% (95% CI: 62–100%) and 65% (95% CI: 45–95%), respectively. Many retrospective studies suggested that bone-only oligo-recurrences achieved longer survival rates compared with visceral oligo-recurrence (19-22). Although retrospective study, Miyata et al. showed that 90% of patients with oligo-recurrence in lymph node, soft tissue, visceral organ and bone had an objective response to salvage mainly conventional radiotherapy and the 3-year local control rate was 93% in Japan (22). Further stereotactic body radiotherapy (SBRT) for oligo-recurrence in regional lymph node from breast cancer without past irradiation history must be performed more proactively. Because, Jingu et al., Yamashita et al. and Niibe et al. reported excellent results of esophageal or uterine cervical cancer lymph node oligo-recurrence treated by radiation therapy (23-25) and many radiation oncologists also experienced excellent results of breast lymph node oligo-recurrence. Moreover, SBRT are expected better outcomes of conventional radiation therapy with local control, survival and toxicities (5,26).

Further studies exploring the new age of metastatic breast cancer and even other cancers should include phase 3 clinical trials. To better understand, the detailed mechanisms of oligometastases, oligo-recurrence and sync-oligometastases, including the abscopal effect should also be required (27-29). In this view point of breast cancer oligometastases, there is ongoing research in this field: the NRG-BR002 is a randomized phase II/III trial assessing the role of SBRT or surgical ablation for oligometastatic breast cancer patients (30). The authors expect clinical trials should require focus on the appropriate combinations of local therapy and systemic therapy, including immunoradiotherapy and others.

Acknowledgments

The authors thank Hitomi Kataoka, MD, PhD, Susumu Kanazawa MD, PhD, for significant supports and thank for all research collaborators of the related studies.

Funding: This work was supported by JSPS KAKENHIGrant Number JP17K10494.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Tadahiko Shien and Kaori Terata) for the series “Loco-regional therapy for metastatic breast cancer” published in Translational Cancer Research. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-325). The series “Loco-regional therapy for metastatic breast cancer” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Hellman S. Karnofsky Memorial Lecture. Natural history of small breast cancers. J Clin Oncol 1994;12:2229-34. [Crossref] [PubMed]
2. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8-10. [Crossref] [PubMed]
3. Niibe Y, Hayakawa K. Oligometastases and oligo-recurrence: the new era of cancer therapy. Jpn J Clin Oncol 2010;40:107-11. [Crossref] [PubMed]
4. Niibe Y, Chang JY. Novel insights of oligometastases and oligo-recurrence and review of literatures. Pulm Med 2012:2012:261096.
5. Niibe Y, Yamamoto T, Onishi H, et al. Pulmonary oligometastases treated by stereotactic body radiation therapy: a nationwide survey of 1,378 patients. Anticancer Res 2020;40:393-9. [Crossref] [PubMed]
6. Niibe Y, Yamashita H, Sekiguchi K, et al. Stereotactic body radiotherapy results for pulmonary oligometastases: a two-institutional collaborative investigation. Anticancer Res 2015;35:4903-8. [PubMed]
7. Niibe Y, Nakano T, Ohno T, et al. Prognostic significance of c-erbB-2/HER2 expression in advanced uterine cervical carcinoma with para-aortic lymph node metastasis treated with radiation therapy. Int J Gynecol Cancer 2003;13:849-55. [Crossref] [PubMed]
8. Niibe Y, Kazumoto T, Toita T, et al. Frequency and characteristics of isolated para-aortic lymph node recurrence in patients with uterine cervical carcinoma in Japan: A multi-institutional study. Gynecol Oncol 2006;103:435-8. [Crossref] [PubMed]
9. Niibe Y, Oguchi M, Kazumoto T, et al. Multi-institutional study of radiation therapy for isolated para-aortic lymhnode recurrence in uterine cervical carcinoma: 84 subjects of a population more than 5,000. Int J Radiat Oncol Biol Phys 2006;66:1366-9. [Crossref] [PubMed]
10. Yamashita H, Niibe Y, Jingu K, et al. Lung stereotactic radiotherapy for oligometastases: comparison of oligo-recurrence and sync-oligometastases. Jpn J Clin Oncol 2016;46:687-91. [Crossref] [PubMed]
11. Niibe Y, Nishimura T, Shirato H, et al. Oligo-recurrence predicts favorable prognosis of brain-only oligometastases in patients with non-small cell lung cancer treated with stereotactic radiosurgery or stereotactic radiotherapy: a multi-institutional study of 61 subjects. BMC Cancer 2016;16:659. [Crossref] [PubMed]
12. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomized, phase 2, open-label trial. Lancet 2019;393:2051-8. [Crossref] [PubMed]
13. Olson R, Senan S, Harrow S, et al. Quality of life outcomes after stereotactic ablative radiation therapy (SABR) versus standard of care treatments in the oligometastatic setting: a secondary analysis of the SABR-COMET randomized trial. Int J Radiat Oncol Biol Phys 2019;105:943-7. [Crossref] [PubMed]
14. Office of Sciences and Technology Policy. Executive Office of the President; Federal Policy on Research Misconduct; Preamble for Research Misconduct Policy. Accessed July 6, 2017. Available online: https://ori.hhs.gov/
15. CITI Program. Program homepage. Accessed July 6, 2017. Available online: https://about.citiprogram.org/en/homepage/
16. Niibe Y, Jingu K, Onishi H. Long-term outcome of surgery or stereotactic radiotherapy for lung oligo-recurrence. J Thorac Oncol 2017;12:e191. [Crossref] [PubMed]
17. Niibe Y, Jingu K, Onishi H. Oligo-recurrence and Sync-oligometastases. J Thorac Oncol 2018;13:e59-e60. [Crossref] [PubMed]
18. David S, Tan J, Savas P, et al. Stereotactic ablative body radiotherapy (SABR) for bone only oligometastatic breast cancer: a prospective clinical trial. Breast 2020;49:55-62. [Crossref] [PubMed]
19. Coleman RE, Smith P, Rubens RD. Clinical course and prognostic factors following bone recurrences from breast cancer. Br J Cancer 1998;77:336-40. [Crossref] [PubMed]
20. Lee CG, McCormick B, Mazumdar M, et al. Infiltrating breast carcinoma in patients age 30 years and younger: long term outcome for life, relapse, and second primary tumors. Int J Radiat Oncol Biol Phys 1992;23:969-75. [Crossref] [PubMed]
21. Vogel CL, Azevedo S, Hilsenbeck S, et al. Survival after first recurrence of breast cancer. The Miami experience. Cancer 1992;70:129-35. [Crossref] [PubMed]
22. Miyata M, Ohguri T, Yahara K, et al. Salvage radiotherapy for second oligo-recurrence in patients with breast cancer. J Radiat Res 2018;59:58-66. [Crossref] [PubMed]
23. Jingu K, Niibe Y, Yamashita H, et al. Re-irradiation for oligo-recurrence from esophageal cancer with radiotherapy history: a multi-institutional study. Radiat Oncol 2017;12:146. [Crossref] [PubMed]
24. Yamashita H, Jingu K, Niibe Y, et al. Definitive salvage radiation therapy and chemoradiation therapy for lymph node oligo-recurrence of esophageal cancer: a Japanese multi-institutional study of 237 patients. Radiat Oncol 2017;12:38. [Crossref] [PubMed]
25. Niibe Y, Uno T, Oguchi M, et al. Multi-institutional study of radiation therapy Isolated para-aortic lymph node recurrence in uterine cervical carcinoma; 84 subjects of population of more than 5,000. Int J Radiat Oncol Biol Phys 2006;66:1366-9. [Crossref] [PubMed]
26. Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small cell lung cancer: can SBRT be comparable to surgery? Int J Radiat Oncol Biol Phys 2011;81:1352-8. [Crossref] [PubMed]
27. Takaya M, Niibe Y, Tsunoda S, et al. Abscopal effect of radiation on toruliform para-aortic lymph node metastases of advanced uterine cervical carcinoma--a case report. Anticancer Res 2007;27:499-503. [PubMed]
28. Okuma K, Yamashita H, Niibe Y, et al. Abscopal effect of radiation on lung metastases of hepatocellular carcinoma: a case report. J Med Case Rep 2011;5:111. [Crossref] [PubMed]
29. Postow MA, Sallahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect I a patient with melanoma. N Engl J Med 2012;366:925-31. [Crossref] [PubMed]
30. Available online: https://www.nrgoncology.org/Clinical-Trials/Protocol/nrg-br002?filter=nrg-br002. Assessed by December 29, 2019.