Background
Cancer is the second leading cause of death in the United States, chiefly from an inability to control metastatic disease. Systemic therapy alone is not curative for patients with most metastatic solid tumors [
1]. The metastatic capacity of cancers behaves along a spectrum of disease progression, such that some tumors have spread widely before clinical detectability and others rarely if ever metastasize. The presence of an oligometastatic state, at which point metastases are limited in number and location, was originally proposed by Hellman and Weichselbaum, who suggested that these patients would benefit from effective local therapy in addition to systemic therapy [
1].
The treatment of metastases depends on multiple factors including 1) the location of the primary tumor, 2) the size, number and location of metastases, 3) the availability and effectiveness of therapies (e.g. surgery, radiation, and chemotherapy), and 4) the patient’s functional status. Conventional moderate dose radiation for metastatic disease is given primarily for palliation, but recent advances in radiation delivery now make it possible to image and treat precisely within any anatomic region of the body [
2,
3]. As a result, highly accurate radiation at tumorocidal doses can be delivered in 1 to 5 outpatient treatments [
4‐
8].
Stereotactic radiation therapy entails highly conformal and precisely targeted radiation delivered in a very dose intensive fashion. In the brain, this approach (termed stereotactic radiosurgery or SRS) has been shown to be a highly effective treatment for brain metastases [
9]. Data suggests that select small extracranial tumors (either primary or metastatic tumors) may be effectively controlled using a similar approach known as stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR). Local control in excess of 75% has been reported for metastatic tumors of the spine, lung and liver, which is significantly higher than standard conventional moderate dose radiation [
5,
7,
8,
10‐
23]. Toxicity has been minimal in multiple U.S., European, and Japanese trials of SABR to the lung, liver, spine, pelvis and abdomen despite the use of very high biological equivalent doses for patients with both organ-confined and metastatic cancer.
The natural history of hormone sensitive oligometastatic prostate cancer is under studied. However, much is known regarding the preceding state of biochemically recurrent prostate cancer that has failed primary treatment. The management of this heterogeneous group of men with a rising PSA often involves relatively long periods of observation until metastases develop at which time the initiation of androgen deprivation therapy (ADT) is typically recommended. Although not entirely appropriate for all men with biochemical failure, data would suggest stalling initiation of ADT is not likely overtly detrimental to overall survival [
24]. In the modern era with conventional imaging, oligometastatic hormone sensitive prostate cancer likely comprises a large number of men, possibly the majority of men following failed primary therapy [
25‐
28]. Assuming these men are at a potentially curable state before castration-resistance develops, we need additional treatment strategies to re-examine this large cohort of men.
Based on this emerging evidence, we propose a phase II study of SABR in patients with oligometastatic hormone sensitive prostate cancer. This study is designed to determine if we can improve the outcome of prostate cancer in these men and also to advance the basic understanding of the oligometastatic state as it pertains to signaling dynamics, cell biology, and immunologic responses. Clinically, we anticipate that SABR in the oligometastatic setting will safely forestall disease progression, thereby lengthening the time before initiation of hormonal therapy and protecting patients from the known deleterious side effects of this conventional systemic approach and thus improve quality of life [
24].
As we continue to refine the standard approaches to treatment of oligometastatic cancer within and beyond the prostate, principle questions remain unanswered which may greatly enhance our collective ability to improve patient outcomes. Chief among these are how best to identify patients in the oligometastatic state, and what aspects of this state differentiate it fundamentally from patients with organ-confined or polymetastatic disease. To address the former, PET/CT imaging utilizing the investigational prostate specific membrane antigen (PMSA) targeted radiotracer,
18F-DCFPyL, will be compared to conventional bone scan and CT imaging to assess the utility of this imaging test in identifying oligometastases before SABR and monitoring disease response following SABR [
29‐
31]. Alterations in the biology of the oligometastatic state induced by SABR will be investigated using leading-edge correlatives, including: analysis of circulating tumor cells (CTCs; Epic Sciences, San Diego, CA), deep sequencing of circulating tumor DNA (ctDNA) using Cancer Personalized Profiling by deep sequencing (CAPP-Seq) to non-invasively assess tumor burden, and ImmunoSEQ profiling of T-cell repertoires to elucidate the immunological response to SABR (Adaptive Technologies, Seattle, WA). Finally, use of the Color Genomics platform (Burlingame, CA), a hereditary cancer assay assessing pathogenic mutations in 30 cancer predisposition genes that account for >90% of the germline mutations known to occur in men with castrate resistant metastatic prostate cancer (mCRPC), will inform efforts to advance a more personalized medicine approach to tailor screening and therapies to these men [
32,
33].
Discussion
The standard treatment options for metastatic hormone sensitive prostate cancer have remained unchanged for many years involving principally hormonal therapy. However, hormonal therapy can have troublesome side effects and any effort to delay the start of hormonal therapy would be an advantage to the patient. Radiation treatment was historically not given at high enough doses to metastases to provide durable local control. SABR is highly targeted radiation, delivered in a dose-intensive fashion in 1 to 5 fractions, which has been shown to be very effective on bone and soft tissue metastases. This phase II randomized study will compare SABR to observation with respect to progression of disease, freedom from hormonal therapy, and other relevant clinical endpoints. Simultaneously, a unique perspective on the impact of SABR on the biology of the oligometastatic state will be obtained through correlation of clinical response with measures of tumor burden, hematologic dynamics of metastasis, and immunologic response. Finally, the pursuit of patient-centered, personalized approaches to treatment will be furthered through investigation of targeted imaging and genomic susceptibility characterization.
Acknowledgements
We would like to thank the following team members for their contribution to the success of this on-going trial: Helen Kim, Terry Caldwell, Christina Rodriguez, Shirl Dipasquale, Ashley Bruns, Jo Hurtt, Ruth Chamberlain, Barbara Squiller and Julie Ambrozak. The granting bodies had no role in the design or execution of the study; data collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript.