Original Study
Metronomic Oral Cyclophosphamide Chemotherapy Possibly Contributes to Stabilization of Disease in Patients With Metastatic Castration-Resistant Prostate Cancer: A Prospective Analysis of Consecutive Cases

https://doi.org/10.1016/j.clgc.2014.02.007Get rights and content

Abstract

Introduction/Background

Castration-resistant prostate cancer remains a therapeutic challenge, even after establishing the survival benefits of docetaxel chemotherapy. Metronomic chemotherapy stabilizes various cancers through antiangiogenic and immunomodulatory effects. We evaluate the activity of metronomic oral cyclophosphamide chemotherapy in metastatic CRPC patients, and assess predictive factors for clinical outcomes.

Patients and Methods

Twenty-four patients with metastatic CRPC received an oral cyclophosphamide and dexamethasone regimen. Of those, 11 patients (45.8%) had been exposed and resistant to previous docetaxel chemotherapy. Six patients had refused to receive docetaxel chemotherapy, and 7 patients could not receive the therapy because of deteriorated performance status. All patients had already shown resistance to continuous dexamethasone therapy. Demographic and clinical data were collected prospectively.

Results

A total of 16 patients (66.7%) experienced a reduction in PSA levels, and PSA decrease ≥ 50% was observed in 8 patients (33.3%). The median PSA progression-free and overall survival were 5.0 months and 19.0 months, respectively. The favorable PSA decrease had no associations with the progression-free and overall survival, but 7 patients (29.2%) in whom response had exceeded 8 months achieved long overall survival of 28 months in median. None of the patients discontinued therapy because of the presence of toxicities.

Conclusion

Metronomic cyclophosphamide is an active and well tolerated chemotherapy and can be an option for metastatic CRPC patients. The benefit of this regimen could not always be evaluated according to a favorable PSA decrease; thus, we must identify the predictive factors of response other than known clinical factors.

Introduction

The current standard treatment for castration-resistant prostate cancer (CRPC) is chemotherapy based on docetaxel, which has a confirmed survival benefit of approximately 2 months in randomized controlled clinical trials.1, 2 However, more than half of the patients experience Grade ≥ 3 toxicities,2 and the docetaxel-based regimen is contraindicated in elderly patients with comorbidities or patients with deteriorated performance status. Recent understanding of the progression mechanism of CRPC in which persistent ligand activation of the androgen receptor (AR) remains in substantial proportion has led to the development of novel agents targeting AR signaling, such as abiraterone acetate and enzalutamide. These new agents showed additional survival advantage when used after docetaxel chemotherapy,3, 4 and have been used in clinical settings in Western countries, but have not been approved in our country. Despite these new targeted agents making paradigm changes and becoming a second-line or new standard treatment in the post-docetaxel era,5 CRPC still remains a therapeutic challenge.

Metronomic chemotherapy is low daily dosing of chemotherapy without a break period. The oldest alkylating agent, cyclophosphamide, can be administered on a metronomic schedule and has been demonstrated to involve antiangiogenic and immunomodulatory effects in various tumor types.6 In human prostate cancer, there are several retrospective studies that achieved respectable prostate-specific antigen (PSA) response with minimal toxicity; reports of these studies have suggested metronomic oral cyclophosphamide as a possible alternative therapeutic method in patients with metastatic CRPC.7, 8, 9, 10, 11 In this study, we evaluated the efficacy and toxicity of a metronomic oral chemotherapy with low-dose cyclophosphamide and dexamethasone in metastatic CRPC patients who acquired resistance to continuous dexamethasone therapy, and assessed predictive factors for clinical outcomes, and briefly reviewed the recent literature published in the docetaxel era to discuss the current and future position of this oldest chemotherapy agent.

Section snippets

Patients Enrolled in the Study

Twenty-four patients with metastatic CRPC received oral metronomic chemotherapy at Dokkyo Medical University Hospital and St Luke's International Hospital between September 2009 and December 2013. The criteria for enrollment of this study were CRPC patients who developed resistance to docetaxel chemotherapy, or who did not receive docetaxel chemotherapy because of refusal or comorbidities; an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤ 3; a life expectancy of

Clinical Response

A total of 16 of 24 patients (66.7%) experienced a reduction in PSA levels. Figure 1 shows the percentage of change in PSA from baseline to 12 weeks and the maximum decline in PSA at any point after the metronomic therapy. At the maximal change, a PSA decrease of ≥ 50% was observed in 8 patients (33.3%), and 6 patients showed a PSA decrease of ≥ 80% (25%). There was no significant association between PSA response and the previous exposure to docetaxel chemotherapy (P = .674) or response

Discussion

Even after establishing the survival benefits of taxan-based chemotherapy and new agents targeting AR signaling, there is no curative method for metastatic CRPC, and it still remains a therapeutic challenge.1, 2, 3, 4, 5 Metronomic chemotherapy with cyclophosphamide stabilizes various types of cancer through antiangiogenic and immunomodulatory effects,6, 14, 15 but this treatment is not widely recognized as an alternative for CRPC. On the basis of respectable PSA response in the previous

Conclusion

The metronomic oral cyclophosphamide and dexamethasone is an active and well tolerated chemotherapy for metastatic CRPC patients, and can be an option in patients in whom docetaxel chemotherapy has failed or are unfit for docetaxel chemotherapy, and possibly after current AR-targeted therapies. This option is also valuable for physicians and patients in countries where abiraterone or enzalutamide is not available as another relatively nontoxic treatment. Metronomic oral cyclophosphamide

Disclosure

The authors have stated that they have no conflicts of interest.

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