Original StudyMetronomic Oral Cyclophosphamide Chemotherapy Possibly Contributes to Stabilization of Disease in Patients With Metastatic Castration-Resistant Prostate Cancer: A Prospective Analysis of Consecutive Cases
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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2021, Critical Reviews in Oncology/HematologyMetronomic Oral Cyclophosphamide in 2 Heavily Pretreated Patients With Metastatic Castration-resistant Prostate Cancer With Homologous Recombination Deficiency (HRD): A Case Report
2019, Clinical Genitourinary CancerCitation Excerpt :Cyclophosphamide, one of the oldest DNA inter-strand crosslinking agents like platinum,7 may confer better sensitivity to HRD-associated mutations.8 In previous studies, administration of oral cyclophosphamide has resulted in modest response in docetaxel-pretreated patients with mCRPC through its antiangiogenic and immunomodulatory effects.9-11 Here, we report 2 novel cases of heavily pretreated patients with mCRPC with HRD-associated mutations, being treated with metronomic oral cyclophosphamide, who demonstrated a prostate-specific antigen (PSA) response defined as a ≥ 50% decline from baseline, confirmed by a second evaluation at least 3 weeks later.12