Randomised clinical trial: preventive treatment with topical rectal beclomethasone dipropionate reduces post-radiation risk of bleeding in patients irradiated for prostate cancer

Aliment Pharmacol Ther 2011; 34: 628–637

Summary

Background Radiotherapy is an established treatment modality for prostate cancer; however, up to a third of patients develops a radiation‐induced proctopathy. Aim To assess the effect of topical beclomethasone dipropionate (BDP) in the prevention of radiation‐induced proctopathy in patients undergoing radiotherapy for prostate cancer through a double‐blind, placebo‐controlled, randomised trial. Methods Patients were randomised either to BDP or to placebo (PL). Patients received daily a 3 mg BDP enema or identical‐looking PL during radiotherapy and, subsequently, two 3 mg BDP suppositories or PL for 4 more weeks. Clinical and endoscopic evaluations before, 3 and 12 months after the end of radiotherapy were assessed with the RTOG/EORTC toxicity scales, the modified Simple Clinical Colitis Activity Index (SCCAI), the modified Inflammatory Bowel disease Quality of Life Index (IBDQ) and the Vienna Rectoscopy Score (VRS). Results From June 2007 to October 2008, 120 patients were randomised to the BDP (n = 60) and PL (n = 60) arms and were followed up for 12 months. The overall assessment of rectal side effects did not show significant differences between the two groups of treatment. However, when only rectal bleeding was considered, a significantly reduced risk was observed in patients on BDP (OR 0.38; 95% CI 0.17–0.86; P = 0.02; NNT = 5). Patients on BDP had also significantly lower VRS scores (P = 0.028) and significantly higher IBDQ scores (P = 0.034). Conclusions Preventive treatment with topical rectal BDP during radiotherapy for prostate cancer significantly reduces the risk of rectal bleeding and radiation‐induced mucosal changes and improves patient’s quality of life, but does not influence other radiation‐induced symptoms.     

Radiosensitization of prostate cancer by soy isoflavones

A trend in investigating the use of several nutritional compounds for cancer chemoprevention has revealed that phytochemicals demonstrated anti-cancer properties by inhibiting signal transduction pathways essential for cancer cell proliferation, tumor growth, invasion and metastasis. Emerging evidence suggests that the anti-proliferative and anti-oxidant effects of some of these dietary agents could be utilized to both potentiate the response of cancer cells to radiotherapy and reduce radiation-induced toxicity to normal surrounding tissues. Using pre-clinical orthotopic models of prostate cancer, studies on the combination of soy isoflavones with tumor irradiation demonstrate a synergistic anti-cancer effect between these two modalities and emphasize the potential and safety of dietary factors to improve conventional radiotherapy for a better control of tumor growth and metastasis. The goal of this review is to focus on the role of soy isoflavones as potent radiosensitizers for prostate cancer and other malignancies. We will discuss molecular pathways regulated by soy isoflavones that inhibit survival pathways activated by radiation and ultimately drive the cells to cell death both in vitro and in vivo in pre-clinical models.     

Genetics of prostate cancer risk

For decades, physicians and researchers have recognized that family history is a significant risk factor for prostate cancer. The identification of the genes responsible for inherited risk, however, proved difficult. With the sequencing of the human genome and the completion of the initial phases of the International HapMap Project, the tools are available to scan the entire genome and find genetic markers for disease. Since 2006, more than 30 inherited variants strongly associated with prostate cancer have been reported. As the inherited component of the disease is revealed, efforts are ongoing to translate genetic findings into the clinic.     

Carotenoids and prostate cancer risk

Chemoprevention is presumably one of most effective means to combat prostate cancer (PCa). Patients usually require more than a decade to develop a clinically significant Pca, therefore, an ideal target for chemoprevention. This review will focus on recent findings of a group of naturally occurring chemicals, carotenoids, for potential use in reducing PCa risk.     

Randomised clinical trial: a 'nudge' strategy to modify endoscopic sedation practice

Aliment Pharmacol Ther 2011; 34: 229–234

Summary

Background In behavioural economics, a ‘nudge’ describes configuration of a choice to encourage a certain action without taking away freedom of choice. Aim To determine the impact of a ‘nudge’ strategy – prefilling either 3 mL or 5 mL syringes with midazolam – on endoscopic sedation practice. Methods Consecutive patients undergoing sedation for EGD or colonoscopy were enrolled. On alternate weeks, midazolam was prefilled in either 3 mL or 5 mL syringes. Preprocedure sedation was administered by the endoscopist to achieve moderate conscious sedation; dosages were at the discretion of the endoscopist. Meperidine was not prefilled. Results Overall, 120 patients received sedation for EGD [59 (5 mL), 61 (3 mL)] and 86 patients were sedated for colonoscopy [38 (5 mL), 48 (3 mL)]. For EGDs, average midazolam dose was significantly higher in the 5‐mL group (5.2 mg) vs. 3‐mL group (3.3 mg), (P < 0.0001); for colonoscopies, average midazolam dose was also significantly higher in the 5‐mL group (5.1 mg) vs. 3‐mL group (3.3 mg), (P < 0.0001). There was no significant difference in mean meperidine dose (42.1 mg vs. 42.8 mg, P = 0.9) administered to both colonoscopy groups. No adverse sedation‐related events occurred; no patient required reversal of sedation. Conclusions These findings demonstrate that ‘nudge’ strategies may hold promise in modifying endoscopic sedation practice. Further research is required to explore the utility of ‘nudges’ in impacting other aspects of endoscopic practice.     

Phase II trial of GM-CSF in advanced prostate cancer

Objectives. Prostate-specific antigen onlydisease progression following definitivetherapy is significant therapeutic dilemma. The benefit of hormonal therapy remainsunproven and is associated with significanttoxicity, more pronounced with chronic use. Biochemical progression following hormonaltherapy has no standard treatment. Newapproaches to the management of this subsetof patients are needed. A previous studyin advanced prostate cancer demonstratedbiologic activity of granulocytemacrophage-colony stimulating factor. Thepurpose of this study was to evaluate theactivity of granulocyte macrophage-colonystimulating factor in a less heavilypretreated population. Materials and methods. Sixteenpatients with advanced prostate cancer, 7hormonally naïve, and 9 androgenindependent, were treated with granulocytemacrophage-colony stimulating factoradministered subcutaneously at 250 gthree times a week for up to 6 months. Prostate-specific antigen measurements wereobtained every 2 weeks. Results. No patient achieved anobjective response. Six patientsdemonstrated a 10–15% decline in theirbaseline prostate-specific antigen whichwas maintained during the entire treatmentperiod. Five of these 6 patientsdemonstrated a rise in theirprostate-specific antigen following studycompletion. Therapy was well tolerated,with only 1 grade 3 event which was nottreatment-related. Conclusions. Granulocytemacrophage-colony stimulating factordemonstrates modest biologic evidence ofactivity in prostate cancer as manifestedby prostate-specific antigen response. Further investigation of the mechanism ofactivity and additional clinical evaluationof this agent seems warranted.     

异黄酮对前列腺癌细胞及PTEN基因的影响

目的 通过大豆异黄酮抑制前列腺癌PC-3和LNCaP细胞生长和相关基因表达的影响，探讨大豆异黄酮类抑制前列腺癌的机制。方法 对染料木黄酮和大豆甙元作用后的雄激素非依赖型前列腺癌(PC-3)、雄激素依赖型前列腺癌LNCaP细胞的存活率、细胞毒作用、细胞周期和PTEN基因的mRNA表达等进行了研究。结果 染料木黄酮和大豆甙元对PC-3、LNCaP细胞抑制效应具有时间和剂量依赖性，具有诱导凋亡和引起坏死效应；染料木黄酮能诱导PC-3和LNCaP细胞的(PTEN)表达，而大豆甙元只能诱导LNCaP细胞PTEN表达。结论 PTEN基因表达的变化可能在染料木黄酮和大豆甙元抑制PC-3和LNCaP细胞中具有重要的意义。染料木黄酮和大豆甙元抑制PC-3和LNCaP细胞可能存在多种作用途径。     

A phase II trial of irinotecan in hormone-refractory prostate cancer

Irinotecan is a DNA topoisomerase I inhibitor that has a wide spectrum of activity against human tumors in both preclinical and clinical studies. To evaluate the efficacy of irinotecan in hormone-refractory prostate cancer, we conducted a phase II study in 15 men with metastatic, PSA-progressive disease after primary androgen deprivation. Irinotecan was administered at a dose of 125 mg/m² weekly for four weeks followed by a two-week rest period; cycles were repeated every six weeks. Response was assessed by evaluation of serial changes in the serum PSA. None of fifteen patients had a decline in PSA of greater than 50%; eight patients had stable disease as a best response. None of three patients with measurable disease had a partial or complete response. Toxicity was primarily hematologic and gastrointestinal, with 40% of patients requiring dose modification due to granulocytopenia and 20% requiring intravenous fluid supplementation after development of diarrhea. There were no treatment-related deaths. We conclude that irinotecan in the dose and schedule used in this trial does not have significant activity against hormone-refractory prostate cancer.     

Phase II trial of pyrazine diazohydroxide in androgen-independent prostate cancer

No effective therapy has been demonstrated for hormone refractory prostate cancer (HRPC). Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent with a broad range of activity in preclinical studies and a moderate toxicity profile in Phase I trials. We undertook a Phase II study of PZDH in HRPC utilizing decline in PSA as the primary end point. Fifteen patients were enrolled, median age of 70 (55–86), median pretherapy PSA 206 ng/ml (range 42–10,000). Four patients were African American. Sites of disease: bone only 7, soft tissue only 2, both 6. All were evaluable for toxicity and response. PZDH was administered at 250 mg/m2 IV every three weeks. The median number of cycles administered was two (range 1–6). Toxicity was mild, with only one patient manifesting serious (grade 3–4) toxicity. Unfortunately, activity was minimal with only a single patient demonstrating a >75% decline in PSA. As this patient's PSA began to rise almost immediately the response was considered transient and not felt to justify pursuing a second stage of the trial. Supporting this conclusion was the disappointing median survival of 220 days. In summary, we conclude that PZDH, while well tolerated at this dose and schedule has only minimal activity in HRPC.