Katherine Rinard

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

PURPOSE Castration-refractory prostate cancer remains a therapeutic challenge even after introduction of docetaxel as first-line treatment. Castration-refractory prostate cancer cannot be cured by any available therapeutic option, and chemotherapy still needs to be considered palliative. The survival benefit is modest, and treating physicians are searching for alternative treatment options. Despite new drugs currently under investigation, some conventional and well known chemotherapeutic drugs are experiencing a renaissance. The development of anti-angiogenic approaches in cancer treatment has led to the development of metronomic dosing of conventional chemotherapeutic drugs including cyclophosphamide. The intention of this review is to evaluate the efficacy and toxicity of oral/metronomic cyclophosphamide in the treatment of patients with castration-refractory prostate cancer. MATERIALS AND METHODS A comprehensive literature search was performed in different databases using various key words. Relevant articles and references between 1962 and 2010 were reviewed and analyzed for data regarding the association between oral cyclophosphamide treatment and prostate cancer. RESULTS Oral cyclophosphamide is active in the treatment for castration-refractory prostate cancer even in patients treated with previous chemotherapy including docetaxel. It yields symptomatic and objective remissions. The side effects are usually grade 1-2 and easy to manage. Grade three to four side effects are less common. CONCLUSIONS Oral cyclophosphamide treatment for patients with castration-refractory prostate cancer deserves more attention and validation, and warrants further testing of various treatment combinations. Given the fact that castration-refractory prostate cancer includes an extremely heterogeneous group of patients with variability of tumor growth rates, the combination of cyclophosphamide with other active agents such as angiogenesis inhibitors and immunomodulatory compounds need to be explored.

Effect of PEDF on survival and the in vivo antitumor activities of low-dose chemotherapy in castration-refractory prostate cancer.

237 Background: The development of metronomic/low dose of conventional chemotherapeutic drugs have recently showed great promise in the treatment of castration-refractory prostate cancer (CPRC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which is down-regulated in prostate cancer. We have previously demonstrated that the over-expression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validated PEDF anti-tumor properties in the highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF may enhance the cytotoxicity effects of low dose docetaxel (Doc) and cyclophosphamide (CTX) chemotherapies in vivo. METHODS Human PC3 and CL1 cell lines were genetically modified to stably express the fluorescent DsRed Express protein with PEDF. Resulting cells were characterized in vitro for PEDF expression by western blot and, for proliferation by growth curves and clone formation in matrigel. PEDF anti-tumor effects were assessed on established s.c. xenografts in mice treated with Doc (5mg/kg ip every 4 dy, 1mg/kg ip daily for 10 days, 0.5mg/kg every other day), CTX (10-20mg/kg in the drinking water) or placebo. Survival studies were performed by injecting CL1 cells with 50nM hrPEDF or carrier control into the left lobe of the dorsal prostate of anesthetized mice. RESULTS We showed that PEDF inhibits the proliferation and induces the differentiation of all CPRC cells tested in vitro. Similarly, PEDF expression decreases by 85% and 70% the development of s.c. PC3 and CL1 tumors, respectively. In the survival study, we found that all control animals die within 61 days after surgery while 50% of PEDF-pretreated animals were still alive. Most importantly, we demonstrated that PEDF enhances the cytotoxicity effects of low dose chemotherapy on established tumors (best Doc dose: 1mg/kg for PC3 and 5mg/kg for CL1; best CTX dose: 10mg/kg for PC3 and CL1). CONCLUSIONS These data reinforce the significance of PEDF as a potential new target for the treatment of advanced prostate cancer. It also emphasizes PEDF as a promising new agent to enhance the anti-tumor efficacy of low dose Doc and CTX chemotherapies.

A relationship between female genital piercings and genital mutilation

Sir, Kelly and Foster offer up an astounding discussion of the Female Genital Mutilation (FGM) Act in England and Wales, and we certainly laud the efforts of this Act to ‘protect girls and women from the medical dangers and societal pressures that produce FGM’. The authors’ realistic debate (Case 3) about any relationship between FGM and females with genital piercings (FGP) was good, especially their conclusion that ‘few, if any of the significant ethical or medical objections to female genital cosmetic surgery (FGCS), apply to FGP’. We believe that our published research supports Kelly and Foster’s beliefs, even for FGM, from evidence obtained in three different cross-sectional studies performed over the past 10 years that included more than 800 national and international FGPs. These studies document the motivations for genital piercing as ‘helped improve and express myself sexually’ and ‘helped me feel unique’, rather than being mutilating actions of self-harm or body alteration. Men more frequently obtained genital piercing in the early years of modern body piercing, but now there are more FGPs. Interestingly, over half the FGPs report abuse, and a third describe forced sexual activity against their will, with many illustrating how their genital piercing ‘helped them to take control of (or reclaim) their body after these violations’. Infibulations for abstinence on women (locked labial rings) and men (passing a fastening device along the foreskin) remain rare. Of women wearing general body piercings, 1–3% choose genital sites, are older (‡30 years of age), and exhibit more deliberate decision making; they demonstrate effective genital piercing care and suffer few complications. A recent genital piercing review found numerous uncited, but published, assumptions about genital piercing complications, yet only 17 actual peer-reviewed cases over 35 years were found. Certainly we favour regulations to reduce medical risks, such as infectious disease transmission: there should be a requirement for the specific education of genital piercing piercers, and compliance issues regarding piercing jewellery and equipment should also be monitored. From our perspective, the only commonalities between FGP and the FGM Act seem to be the terms ‘females’ and ‘genitals’. Our evidence reported by consenting adult FGPs is not the same as the permanent mutilating outcome of FGM to young girls or women, nor does it encompass the permanent surgical alternation of FGCS. Not only are there striking intentional differences for FGM but also immediate and major complications, including specific psychological concerns, as well as urinary incontinence, dysmenorrhoea, dyspareunia, infertility, haematocolpos, haematometra, vesicovaginal and rectovaginal fistulas, and increased female/neonatal mortality. In contrast, when genital piercing wearers no longer value their piercings as a ‘meaningful part of their lives that enhances sexual satisfaction and self-expression’, they have the control/ability to remove the genital piercing swiftly, and without anyone’s permission or assistance, with little or no residual scarring. j