Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer

Abstract

Purpose Clinical features characteristic of small-cell prostate carcinoma (SCPC), (““anaplastic””) often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined “anaplastic” clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low PSA levels relative to tumor burden or short response to androgen deprivation therapy. Experimental Design A 120-patient phase II trial of frontline carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity. Results Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after 4 cycles of CD and EP, respectively. Median overall survival (OS) was 16 months (95% CI, 13.6-19.0 months). Of the 7 “anaplastic” criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase (LDH) strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy. Conclusion Our findings support the hypothesis that patients with “anaplastic” prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with CRPC and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.

Dynamic Regulation of Rad51 by E2F1 and p53 in Prostate Cancer Cells upon Drug-Induced DNA Damage under Hypoxia

“…Thus, prostate cancer cells with mutant p53 not only can evade apoptosis but likely will have more effective homologous recombination repair due to lack of suppression of RAD51 transcription by wild-type p53. Although none of the DNA-damaging chemotherapy agents has been approved for the treatment of prostate cancer, a platinum-based chemotherapy regimen demonstrated a 16-month median overall survival in a phase 2 study of 120 patients who met the predefined criteria of anaplastic prostate cancers (Aparicio et al, 2013). Anaplastic prostate cancer shares several features of small-cell prostate cancer and is likely enriched with cell cycle checkpoint alterations, based on its rapid proliferation.…”

Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study

“…2,3 In a subset of patients, therapeutic resistance to AR-targeting therapy is accompanied by the emergence of a histologic subtype that morphologically resembles de novo small-cell prostate cancer, a highly aggressive histologic variant present in , 1% of untreated prostate cancers at the time of diagnosis. 4 It is not clear if the treatment-emergent variant, variously labeled neuroendocrine prostate cancer and aggressive variant, 5,6 is the same disease entity as de novo small-cell prostate cancer. We have termed this histology treatment-emergent smallcell neuroendocrine prostate cancer or t-SCNC.…”

Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

“…2). Evolving or secondary neuroendocrine transformation is increasingly recognized in advanced PC [20,21] and may represent one form of EP similar to what has recently been described in lung cancer [22]. It is well documented from autopsy and pathology studies of human PC that many histological phenotypes emerge during hormonal therapy for PC, including squamous differentiation, neuroendocrine differentiation, and a general loss of markers of prostate differentiation [6,23], as shown in Fig.…”