Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer – Review of the literature

Nelius, Thomas; Rinard, Katherine; Filleur, Stéphanie

doi:10.1016/j.ctrv.2010.12.006

Cited by 35 publications

(23 citation statements)

References 62 publications

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“…As previously highlighted, no patients discontinued therapy due to major toxicities and lymphopenia was the only grade 3 or 4 AEs reported. This finding is consistent with other previous studies showing good tolerability of metronomic CTX [14].…”

Section: Discussionsupporting

confidence: 95%

“…Although the exact mechanisms in which metronomic chemotherapy inhibits tumor growth is not completely elucidated, increasing evidence suggest that, besides antiangiogenic mechanism [10], this type of regimen may help to restore anticancer immune response, through decreasing the number of regulatory T cells (Treg) blocking its suppressive functions [11,12]. In this context, the classical bifunctional alkylating agent cyclophosphamide (CTX) given orally in metronomic regimens has been most frequently used in metastatic castration-resistant prostate cancer (mCRPC) and breast cancer [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Metronomic oral cyclophosphamide plus prednisone in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer

et al. 2014

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We evaluated the efficacy and safety of metronomic oral cyclophosphamide (CTX) and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients. We analyzed retrospectively patients with mCRPC previously treated with docetaxel, and who received metronomic CTX (from 50 mg PO daily to 150 mg PO, 14 days/7 days off) and prednisone 10 mg PO daily between September 2009 and April 2014 were analyzed. The primary endpoint was prostate-specific antigen (PSA) decrease ≥50 %. Secondary analysis included PSA decrease ≥30 %, time-to-treatment failure (TTF) and toxicity. Demographics and baseline characteristics were summarized using descriptive statistics. PSA response and adverse events were reported as relative rates. Kaplan-Meier estimates were calculated and plotted for time-to-event endpoints. Forty patients were evaluated. The median age was 69 years old (52-86), 12 (30.0 %) patients presented a Karnofsky performance status (KPS) of <80 %, and 34 (85 %) presented with bone with or without nodal metastases. Median pre-treatment PSA was 192 ng/dL (7-2696 ng/dL). All patients were previously exposed to docetaxel, including 33 (82.5 %) with docetaxel-refractory disease. PSA response rate was achieved in eight (20.0 %) out of 40 patients. Additionally, PSA declines of ≥30 % occurred in 14 (35.0 %) patients. The median TTF was 3 months (95 % confidence interval 2.5-3.5). The treatment was well tolerated. Grade 3/4 lymphopenia was reported in 11 (27.5 %) patients and was the only grade 3-4 toxicity reported. Metronomic oral CTX showed activity and safety in docetaxel-pretreated mCRPC patients. This regimen deserves further investigation in this setting.

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Section: Discussionsupporting

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Metronomic oral cyclophosphamide plus prednisone in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer

et al. 2014

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“…24, 25 Cyclophosphamide (CTX) is a nitrogen mustard alkylating agent that is used to treat various types of cancer. 26 High doses of CTX have been associated with cytotoxicity and immunosuppression. 26 In contrast, low-dose oral CTX demonstrated anti-angiogenic, 27, 28, 29, 30, 31 anti-vasculogenic 32 and increased anti-tumor immunity properties.…”

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confidence: 99%

Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer

et al. 2014

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There is currently no cure for advanced castration-refractory prostate cancer (CRPC) despite the recent approval of several new therapeutic agents. We report here the anti-tumor effect of the angio-inhibitory pigment epithelium-derived factor (PEDF) in the metastatic LNCaP-derivative CRPC CL1 model and explore PEDF anti-neoplasic efficacy in combination with low-dose chemotherapy. Androgen-sensitive LNCaP and CRPC PC3 cell lines were examined as comparison. Using a retroviral expression system, we showed that PEDF limited the proliferation of all prostatic cell lines tested; an effect attributed to interleukin 8 (IL8)-CXCR1/IL8RA inhibition. PEDF also reduced the number and size of 3D tumor spheroids in vitro, but only induced cell differentiation in CRPC spheroids. Similarly, PEDF inhibited the migration of CRPC cells suggesting both anti-proliferative and anti-migratory functions. In vivo, PEDF decreased by 85% and 65% the growth of subcutaneous (s.c.) PC3 and CL1 tumors, respectively. In the CL1 orthotopic model, tumor intake with lethal metastases was found in all animals; nevertheless, PEDF prolonged the median survival of tumor-bearing mice (95% confidence interval: 53±0.001 to 57±1 days). Accordingly, PEDF delayed the emergence of skeletal-related event in intra-tibial xenografts. Next, we evaluated low-dose docetaxel (DTX; 5, 1, 0.5 mg/kg) or cyclophosphamide (CTX; 10–20 mg/kg) on established s.c. PC3 tumors that conditionally express PEDF anti-tumoral epitope/NT3. Although NT3–DTX-5 mg/kg combination was inefficient, NT3–DTX-1 mg/kg and -0.5 mg/kg inhibited by 95% and 87.8%, respectively, tumor growth compared with control and induced tumor stasis. Both NT3–CTX combinations were advantageous. Inversely, PEDF–DTX-5 mg/kg and PEDF–CTX-10 mg/kg delayed the most CL1 tumor growth (15, 11 and 5 days for PEDF–DTX-5 mg/kg, PEDF–CTX-10 mg/kg and single treatments, respectively) with elevated apoptosis and serum thrombospondin-1 as possible mechanism and marker, respectively. As well, both PEDF–CTX-10 mg/kg and PEDF–DTX-5 mg/kg prolonged significantly the survival of tumor-bearing mice compared with single treatments. Metastases were reduced in PEDF–DTX-5 mg/kg compared with other treatments, suggesting that PEDF–DTX delayed metastases formation. Our results advocate that PEDF/low-dose chemotherapy may represent a new therapeutic alternative for CRPC.

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“…A literature review [8] confirmed the positive impact of this treatment. Furthermore, other studies analyzed the possibility of associating cyclophosphamide with other drugs, as celecoxib [9].…”

Section: Discussionmentioning

confidence: 68%

Exceptional response after metronomic chemotherapy and palliative radiotherapy in castration-resistant prostate cancer: A case report

Morganti¹,

Macchia²,

Frakulli³

et al. 2017

EJMCR

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Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer – Review of the literature

Cited by 35 publications

References 62 publications

Metronomic oral cyclophosphamide plus prednisone in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer

Metronomic oral cyclophosphamide plus prednisone in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer

Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer

Exceptional response after metronomic chemotherapy and palliative radiotherapy in castration-resistant prostate cancer: A case report

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