Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study

Abstract

Purpose: Nontaxane-based chemotherapeutic options in castrate-resistant prostate cancer (CRPC) are limited despite the long natural history of the disease. We carried out a phase 1 dose-escalation study of the alkylating agent melphalan with autologous stem cell transplantation, comparing rapid changes in circulating tumor cells (CTC) and prostate-specific antigen (PSA) as a measure of response.Experimental Design: Cohorts of individuals with advanced CRPC received high-dose intravenous melphalan, and autologous blood was returned to patients during treatment. The efficacy endpoints were the PSA reduction rate, CTC response, survival parameters, toxicity and whether reinduction of endocrine sensitivity occurred.Results: Twenty-four patients were recruited. Dose escalation was feasible with the highest dose cohort being reached. Of 23 individuals evaluable for response, 16 had a PSA response of more than 30%; of 11 patients with soft tissue disease, 4 achieved a partial response and 7 had stable disease. Patients with CTC counts that decreased to less than 5 within 2 weeks from the start of therapy had a longer overall survival (30.6 months vs. 15.3 months, P ¼ 0.03) Treatment was associated with myelosuppression and frequent hospitalizations. In 20 patients after the study, hormone therapy was reintroduced when PSA increased again; response rates were high.Conclusions: Autologous transplantation following high-dose alkylating agent chemotherapy induces responses but proved toxic, although dose escalation proved possible. The possibility of using CTCs to identify responders at two weeks may be used to justify such an intensive approach. Many individuals went on to further respond to both docetaxel and hormonal therapy.

Reduced Dissemination of Circulating Tumor Cells With No-Touch Isolation Surgical Technique in Patients With Pancreatic Cancer

“…24 However, the CellSearch system has been shown to be the most reliable tool in clinical trials using CTCs as a prognostic marker. [25][26][27][28][29][30] Limitations to this method and the functional significance of detected CTCs are further discussed in the eAppendix in the Supplement.…”

Circulating Tumor Cells in Prostate Cancer Diagnosis and Monitoring: An Appraisal of Clinical Potential

“…Subjects with conversion experienced a higher response rate and a longer median time on study; the reported results strongly suggest the prognostic role of CTC assessment. Shamash and colleagues [79] evaluated the clinical benefit of high doses of the alkylating agent melphalan in CRPC patients and found that patients who experienced a CTC count drop below 5/7.5 ml had a significantly longer OS (30.6 vs. 15.3 months; p = 0.03); very interestingly, the CTC conversion happened within 2 weeks from the beginning of the therapy and faster than a concomitant PSA decline, suggesting that CTC evaluation could be helpful to promptly target such a toxic approach only to CTC-responding patients. Most recently, Goldkorn et al [80] prospectively analyzed the prognostic value of CTC enumeration in 212 evaluable CRPC patients receiving first-line docetaxel-based therapy within a large phase III clinical trial (SWOG S0421).…”

Circulating Tumor Cells: A Window to Understand Cancer Metastasis, Monitor and Fight Against Cancers

“…Meanwhile, in a study of patients with CRPC, post-treatment CTC numbers were a stronger prognostic factor for survival than a 50% decline in PSA (receiver operating characteristic area under the curve: 0.87 vs 0.62), and the authors suggested that CTC numbers measured at 4 or 8 weeks can even discriminate between favorable or unfavorable outcomes with therapy [60]. Decrease of number of CTCs after chemotherapy for CRPC patients was also observed correlated with better survival in a Phase I study [96]. In metastatic colorectal cancer patients, a conversion of baseline unfavorable CTC number to a favorable one at 3-5 weeks after treatment was reported to be correlated with significant longer survival compared to those without this change [77].…”