Altering the Natural History of Oligometastatic Prostate Cancer With Local Therapies: Reality Versus Illusion

Authors

Phuoc T. Tran

Emmanuel S. Antonarakis

Doi

10.1200/JOP.2016.018846

PMID: 28045614 · DOI: 10.1200/JOP.2016.018846 · Journal: Journal of Oncology Practice (2017)

TL;DR

A commentary by Tran and Antonarakis accompanying the Clement and Sweeney review on hormone-sensitive oligometastatic prostate cancer. The authors frame the oligometastatic state — clinically operationalized as up to five radiographically visible metastatic lesions — as an intermediate position on the cancer-progression spectrum where local, metastasis-directed therapies (e.g., stereotactic ablative radiotherapy) may alter natural history and potentially cure men who would otherwise progress to widely metastatic, castration-resistant disease. They highlight four outstanding questions (definition, prevalence, biology, and whether polymetastatic disease can be converted to an oligometastatic/curable state) and point to self-seeding biology of circulating tumor cells as a mechanistic rationale for ablating all macroscopic metastases. No new cohort or primary data are presented. (PMID:28045614)

Cohort & data

Key findings

  • Working clinical definition. Until a biologic (and likely genomic) definition exists, the authors endorse a clinical definition of oligometastatic prostate cancer based on up to five radiographically visible metastatic lesions, anchored in conventional imaging to preserve compatibility with existing clinical data. (PMID:28045614)
  • Prevalence is uncertain but meaningful. Synchronous / de novo oligometastatic PRAD comprises “likely… several thousands” of men per year in the United States; metachronous / oligorecurrent disease after failed primary therapy may be far more common and possibly the majority of men who eventually progress to metastatic disease, but is understudied. (PMID:28045614)
  • Cross-tumor precedent from NSCLC. Randomized clinical-trial evidence in NSCLC (Gomez et al., Lancet Oncol 2016) showed that local consolidative therapy prolongs progression-free survival in patients with three or fewer metastases after first-line systemic therapy. Preclinical work (Uppal et al., Oncotarget 2015) attributes a distinct oligometastatic NSCLC biology to 14q32-encoded microRNA–mediated attenuation of pro-metastatic epithelial-plasticity programs including epithelial-mesenchymal transition. (PMID:28045614)
  • Self-seeding rationale. The authors argue that older unidirectional models of metastasis have been supplanted by preclinical data in breast, colon, and melanoma models showing multidirectional seeding of circulating tumor cells — “self-seeding” — and that genomic lineage tracing of metastases in rapid-autopsy series of metastatic castration-resistant prostate cancer (citing Gundem et al., Nature 520:353-357, 2015) is consistent with macroscopic metastases acting as “communal sanctuaries” composed of cells from many other metastatic sites. If true in the hormone-sensitive oligometastatic state, ablating all macroscopic lesions could eliminate these sanctuaries and alter natural history. (PMID:28045614)
  • Conversion hypothesis. The authors raise the provocative possibility of converting an incurable polymetastatic biology to a curable oligometastatic biology through metastasis-directed therapies, to be tested in prospective trials and through initiatives such as the Movember Global Action Plan 6 (GAP6). (PMID:28045614)

Genes & alterations

  • No specific gene-level alterations are reported. The authors note that genetic and transcriptomic profiling of hormone-sensitive localized (citing Boutros et al., Nat Genet 47:736-745, 2015) and metastatic castration-resistant prostate cancer (citing Robinson et al., Cell 161:1215-1228, 2015) has been well described, but a complementary hormone-sensitive oligometastatic data set “is still unavailable.” (PMID:28045614)

Clinical implications

  • Standard of care endorsement. The authors explicitly agree with Clement and Sweeney that the current standard of care for men with hormone-sensitive oligometastatic PRAD remains systemic therapy (androgen deprivation therapy); any additional local therapies should “ideally be implemented in the setting of a clinical trial.” (PMID:28045614)
  • Imaging and stage migration. Clinical definitions must proceed in parallel with validation of newer advanced-imaging modalities so that future definitions of actionable oligometastatic disease reflect both biology and diagnostics. (PMID:28045614)
  • Biomarker opportunity. Biology of the oligometastatic state may yield biomarkers such as blood-based microRNA signatures to direct care, though none are validated here. (PMID:28045614)

Limitations & open questions

  • No primary data. This is a commentary; all empirical claims are derived from cited literature. (PMID:28045614)
  • Definition not biologically grounded. The five-lesion clinical threshold is a pragmatic placeholder pending a biologic / genomic definition of oligometastasis. (PMID:28045614)
  • Metachronous / oligorecurrent prevalence understudied. Most prevalence estimates come from a limited number of retrospective series (cited refs 8–11: Soloway 1988, Singh 2004, Schweizer 2013, Sridharan 2016); the authors call for “additional studies to examine this potentially large prevalence in a more robust fashion.” (PMID:28045614)
  • Self-seeding evidence is indirect for hormone-sensitive disease. Direct preclinical and lineage-tracing data supporting self-seeding come from breast / colon / melanoma models and from metastatic castration-resistant (not hormone-sensitive) PRAD autopsy series; whether the same biology holds earlier in the disease course is unresolved. (PMID:28045614)
  • Whether polymetastatic → oligometastatic conversion is achievable. Posed explicitly as an open question awaiting prospective trials and GAP6-style collaborative efforts. (PMID:28045614)

Citations from this paper used in the wiki

  • “a clinical diagnosis based on up to five radiographically visible metastatic lesions is a reasonable definition.” (p. 22)
  • “synchronous or de novo oligometastatic prostate cancer comprises an even smaller subset of these men, likely numbered in the several thousands in the United States.” (p. 22)
  • “macroscopic metastases represent communal sanctuaries that are composed of prostate cancer cells from many other metastatic sites throughout the body.” (p. 23, paraphrasing Gundem et al. 2015)
  • “the standard of care for these men is still systemic therapy in the form of androgen deprivation and that any additional local therapies should ideally be implemented in the setting of a clinical trial.” (p. 23)
  • “can we convert a polymetastatic incurable biology into an oligometastatic presumably curable biology in a man with prostate cancer?” (p. 23)

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