Dr. Rahul Aggarwal
Question: How do you treat patients with neuroendocrine prostate cancer presenting with systemic disease?
Answer: Neuroendocrine prostate cancer (NEPC) is a lethal disease subset with median overall survival of less than 1 year from time of detection.1 The choice of systemic therapy depends on the clinical context (de novo vs. treatment emergent) and pathologic findings (small cell vs. focal neuroendocrine differentiation). Patients presenting with de novo pure small cell carcinoma arising from the prostate gland, a rare entity observed in approximately 1% of all prostate cancer cases, should be treated with a platinum plus etoposide combination similar to the treatment for small cell lung cancer. In contrast, patients with metastatic high-grade carcinoma with evidence of focal neuroendocrine differentiation on prostate biopsy (e.g., positive chromogranin staining by immunohistochemistry) without small cell morphology should be treated with primary androgen deprivation therapy (ADT) plus the addition of six cycles of concurrent docetaxel for those with high-volume metastatic disease.2
More commonly than de novo disease, NEPC is a treatment-emergent phenomenon arising among patients with metastatic castration-resistant prostate cancer (mCRPC) following the application of ADT. Treatment-emergent NEPC (t-NEPC) may involve 30% to 40% of patients with mCRPC, including 10% to 15% with pure small cell histologic differentiation and a larger proportion (about 25%) with an intermediate phenotype between adenocarcinoma and small cell.1 Despite the relatively high prevalence of t-NEPC, detection is a challenge. Serum neuroendocrine markers, including chromogranin and neuron-specific enolase, have limited sensitivity. An aggregate of clinical factors (e.g., visceral metastases, elevated serum markers, lytic-predominant bone metastases, and disease burden out of proportion to serum prostate-specific antigen [PSA]), as used in a prior phase II study, are likely to enrich for detection of t-NEPC at the expense of lower specificity.3 Circulating tumor cell analysis has recently been shown to enable detection and characterization of t-NEPC but remains a research tool.4 Metastatic tumor biopsy remains the gold standard for t-NEPC detection, despite limitations such as tumor heterogeneity. Consideration of tumor biopsy is particularly important in cases in which pure small cell histology is suspected.
In cases in which mCRPC biopsies reveal pure small cell differentiation, cytotoxic chemotherapy is preferred over androgen pathway inhibitors, such as abiraterone or enzalutamide. In cases of biopsy-proven small cell carcinoma with concomitant persistent androgen receptor (AR) expression/activity (e.g., high serum PSA and AR/PSA immunohistochemical expression),5 carboplatin plus docetaxel is a reasonable option for patients who are deemed fit. In cases with minimal evidence of dependence on AR signaling (e.g., very low serum PSA, AR-null expression on biopsy, and primary resistance to ADT), platinum/etoposide doublet may be the preferred front-line chemotherapeutic option. For patients with metastatic castration-resistant tumor biopsies that reveal high-grade adenocarcinoma with focal neuroendocrine differentiation, or for those with intermediate phenotypic features without frank small cell morphology, standardly applied clinical factors per National Comprehensive Cancer Network and other treatment guidelines can be used to guide the choice of therapy.6 This may include both cytotoxic chemotherapy and/or androgen signaling inhibitors, among others. A taxane plus carboplatin doublet may be considered in this situation in patients who are deemed fit, but clinical trials are lacking to prove superiority of this approach over taxane monotherapy. Given the relatively poor outcomes and aggressive clinical course, as novel therapeutic targets are identified t-NEPC, participation in prospective clinical trials is strongly encouraged.