Oligometastases: history of a hypothesis.

The term oligometastases represents a clinical state of metastatic disease that is limited in the number of metastatic sites and extent of disease, and amenable to metastasis-directed surgical or ablative therapy. While metastasis-directed approaches are used for palliation, the primary goal of such treatment for patients with oligometastases is to prolong survival and the duration of cancer control. Metastasis-directed therapy, for patients with limited number of metastatic sites, has been practiced for decades, dating back to the era before chemotherapy was widely used. Systemic therapy has become the accepted standard of care for metastatic disease. And while not curative for most solid cancers, systemic therapy can delay cancer progression, prolong life, and maintain or improve quality of life, albeit often at the expense of toxicities which can adversely impact quality of life. From the 1960s to 1980s, prominent physicians questioned whether metastasis-directed resection or radiotherapy could potentially be curative treatment approaches. In 1995, Drs. Hellman and Weichselbaum wrote an editorial that coined the term "oligometastases" and refined the hypothesis of metastasis-directed surgical and radiotherapeutic treatments as potentially curative for select patients. Their article was the first to explicitly describe the clinical state of metastases existing along a spectrum, with a spectrum of behaviors (ranging from indolent disease confined to limited sites to widespread disease) and, therefore, a spectrum of potential treatments. In the ensuing decades, there were rapid technologic advancements in radiotherapy, including stereotactic body radiation therapy (SBRT), which facilitated delivery of ablative doses of radiation to precisely and accurately targeted tumors. SBRT has been considered an optimal non-surgical approach to treat oligometastases, allowing for definitive-dose delivery and for targeting accuracy that minimizes normal tissue radiation exposure. In the early 2000s, many institutions began publishing prospective studies demonstrating favorable outcomes in patients with oligometastases treated with SBRT. Not answered in these single-arm studies was whether patients generally fared better than expected due to selection of patients with relatively indolent disease, or from metastasis-directed treatment. There is also a potential for immortal time bias with non-randomized comparisons. However, recent randomized phase II studies have suggested that SBRT for oligometastases is associated with improved survival outcomes. Phase III studies, many specific for certain cancers (i.e., breast, prostate or lung cancers) are accruing. Future work will be needed to identify which patients are most apt to benefit from metastasis-directed therapy; in addition to clinical factors, host and/or tumor genomics may prove to be prognostic. Metastasis-directed therapy may become more important with improvements in systemic therapy in controlling micrometastatic disease. Incorporating immunotherapy with SBRT may also be a promising approach, with SBRT perhaps augmenting the immune response. As personalized medicine evolves, patients with oligometastases will be better served. The history of oligometastases will continue to unfold.