Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome

BACKGROUND: In men with prostate cancer, gonadotropin-releasing hormone (GnRH) agonists increase fat mass, decrease insulin sensitivity, and increase triglycerides, features that are shared with metabolic syndrome. To the authors' knowledge, however, less is known regarding the effects of GnRH agonists on other attributes of the metabolic syndrome. METHODS: In an open-label prospective study, 26 men with recurrent or locally advanced prostate cancer were treated with leuprolide for 12 months. Outcomes included changes in blood pressure, body composition, lipids, adipocytokines, and C-reactive protein. RESULTS: The mean weight, body mass index, and waist circumference increased significantly from baseline to Month 12 (P < .001 for each comparison). Fat mass increased by 11.2% +/- 1.5% (P < .001) and the percentage lean body mass decreased by 3.6% +/- 0.5% (P < .001). The total abdominal fat area increased by 16.5% +/- 2.6% (P < .001), with the accumulation of subcutaneous fat accounting for 94% of the observed increase. The waist-to-hip ratio and blood pressure did not change significantly. Serum high-density lipoprotein (HDL) cholesterol concentrations increased significantly (P = .002). Serum adiponectin levels increased by 36.4 +/- 5.9% from baseline to Month 3 and remained significantly elevated through Month 12 (P < .001). Resistin and C-reactive protein levels did not change significantly. CONCLUSIONS: The term metabolic syndrome does not appear to adequately describe the effects of GnRH agonists in men with prostate cancer. In contrast to the metabolic syndrome, GnRH agonists increase subcutaneous fat mass, HDL cholesterol, and adiponectin, and do not alter the waist-to-hip ratio, blood pressure, or C-reactive protein level.     

Changes in bone mineral density and body composition during initial and long-term gonadotropin-releasing hormone agonist treatment for prostate carcinoma

BACKGROUND: Initial treatment with a gonadotropin-releasing hormone (GnRH) agonist increases fat mass, decreases lean body mass, and decreases bone mineral density (BMD) in men with prostate carcinoma. To the authors' knowledge, little is known regarding either the long-term effects of treatment or predictors of treatment-related changes in BMD and body composition. METHODS: The authors analyzed prospective 12-month data from 65 men during initial and long-term GnRH agonist treatment for prostate carcinoma. Relationships between baseline characteristics (age, treatment duration, body mass index, and baseline values for outcome of interest) and changes in lean mass, fat mass, and BMD were assessed using univariate and multivariate regression models. RESULTS: Mean BMD of total hip decreased by 1.9 +/- 2.7%, lean body mass decreased by 2.0 +/- 3.3%, and fat mass increased by 6.6 +/- 9.4% at 12 months (P < 0.001 for each comparison). Twenty-three men (35%) had received treatment with a GnRH agonist before study entry, and the mean (+/- standard deviation) duration of previous treatment was 35 +/- 41 months. Longer duration of previous GnRH agonist treatment was found to independently predict less fat accumulation and less loss of lean body mass in multivariate models. In contrast, the duration of GnRH agonist treatment did not significantly predict changes in BMD. Other covariates did not appear to predict changes in body composition or BMD consistently. CONCLUSIONS: The results of the current study showed that fat mass increased and lean body mass decreased mostly during initial GnRH agonist therapy whereas BMD decreased steadily during initial and long-term treatment.     

Abarelix for injectable suspension: first-in-class gonadotropin-releasing hormone antagonist for prostate cancer

Abarelix, a gonadotropin-releasing hormone antagonist, with its indication for advanced symptomatic prostate cancer, represents the newest category of hormonal therapy introduced in the past 15 years. Results from Phase II and III clinical trials demonstrate the advantages of abarelix over commonly used luteinizing hormone-releasing hormone (LHRH) agonist therapy: abarelix does not cause a surge in serum testosterone that can precipitate a flare phenomenon or worsening of disease, particularly dangerous for patients with metastatic, symptomatic disease, and produces medical castration more quickly. Abarelix was also demonstrated to promptly and substantially reduce follicle-stimulating hormone levels to lower than LHRH agonist. Study results demonstrate effective anticancer responses during extended exposure to abarelix: improvements in pain score and/or analgesic use, improvements in urinary symptoms (including urinary catheter removal) and complete avoidance of bilateral orchiectomy for patients undergoing at least 12 weeks of treatment. In Phase III clinical trials, abarelix demonstrated a similar overall safety profile when compared with LHRH agonist monotherapy, and a superior safety profile when compared with LHRH agonist plus antiandrogen combination therapy. Abarelix patients experienced a greater incidence of immediate-onset systemic allergic reactions as compared with control arms.     

Reversal of gonadotropin-releasing hormone agonist induced reductions in mammographic densities on stopping treatment.

Previously, we described the reduction in mammographic densities that occurred in premenopausal women after 12 months on a hormonal regimen designed to be chemopreventive for breast (and ovarian) cancer consisting of a gonadotropin-releasing hormone agonist (GnRHA) plus low-dose add-back estrogen-progestin. We sought to determine whether the density reduction persisted with continuation of the regimen for 24 months, and, if so, whether the densities would return to baseline after the regimen was discontinued. Twenty-one women, 27-40 years of age, with a 5-fold greater than normal risk of breast cancer, were randomly assigned in a 2:1 ratio to the treatment group (14 women) and to a control group (7 women). The percentage of mammographic densities, calculated as the proportion of the breast area on the mammogram containing densities, were assessed blindly using a computer-based threshold method at baseline, after 12 and 24 months of treatment, and at between 6 and 12 months after treatment was stopped. The previously described percentage of mammographic density reductions of 9.7% (P = 0.012) after 12 months of treatment were increased slightly to 11.4% (P = 0.010) after 24 months of treatment, but the additional change was not statistically significant. Ten of 11 treated women assessed at 24 months had reduced percentages of mammographic densities compared with baseline. Six to 12 months after completion of treatment, the mean percentage of mammographic density in the treated group was no different from that at baseline (mean decline of 2.0%; P = 0.73). The women in the control group had no statistically significant changes in densities over the period of the study. Reductions in mammographic densities engendered by the GnRHA plus a low-dose add-back estrogen-progestin regimen persist as long as the women receive treatment. The densities return to baseline when the women resume normal menstrual cycles. These results confirm that mammographic densities are influenced by ovarian function. Improved efficacy of mammographic screening is to be expected as long as a woman continues on such a regimen. Whether such a regimen is chemopreventive for breast cancer remains to be established, but the recent report on a randomized trial of use of GnRHA alone in premenopausal breast cancer cases showing a marked reduction in incidence of contralateral disease provides strong support for the hypothesis.     

Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma

BACKGROUND: The role of androgen deprivation therapy in prostate carcinoma is controversial in earlier stages of disease. The authors examined the time trends and patterns of use for androgen deprivation in the form of gonadotropin-releasing hormone (GnRH) agonists or orchiectomy, in population-based tumor registries. METHODS: Data were obtained from the linked Surveillance, Epidemiology and End Results-Medicare database. A total of 100,274 men with prostate carcinoma diagnosed from 1991 through 1999 were selected. The main outcome was the proportion of men who received >/= 1 dose of a GnRH agonist in the first 6 months of diagnosis. This was plotted by year and stratified for age, grade, stage as well as primary versus adjuvant usage. Multiple logistic regression was used to examine predictors of GnRH agonist use in the subset of patients with localized cancer. RESULTS: There was a consistent increase in GnRH agonist use by year for all ages, stages, and grades. Even in men >/= 80 years with localized stage and low to moderate grade tumors, primary GnRH agonist use increased over the study period, from 3.7% in 1991 to 30.9% in 1999 (P < 0.001). The multivariable analysis showed that significant variability in GnRH agonist use existed among SEER geographic regions. CONCLUSIONS: The use of GnRH agonists for prostate carcinoma increased dramatically during the 1990s. This increase occurred across all stages and histologic grades of prostate carcinoma, and was greatest in patients >/= 80 years.     

Prediction of ovarian function recovery in young breast cancer patients after protection with gonadotropin-releasing hormone agonist during chemotherapy

Purpose

While the role of natural killer (NK) cells in breast cancer therapy has been investigated, little information is known about NK cell function and presence in nonmalignant and premalignant breast tissue. Here, we investigate and quantify NK cell marker CD56 and activating ligand MICA in breast tissue with benign breast disease.

Methods

Serial tissue sections from 88 subjects, 44 with benign breast disease (BBD) who remained cancer-free, and 44 with BBD who later developed cancer, were stained with H&E, anti-MICA, and anti-CD56. Up to ten representative lobules were identified on each section. Using digital image analysis, MICA and CD56 densities were determined for each lobule, reported as percent of pixels in the lobule that registered as stained by each antibody. Analyses were performed on a per-subject and per-lobule basis.

Results

Per-subject multivariate analyses showed associations of CD56 and MICA with age: CD56 was increased in older subjects (p = 0.03), while MICA was increased in younger subjects (p = 0.005). Per-lobule analyses showed that CD56 and MICA levels were both decreased in lobules with fibrocystic change, with median levels of CD56 and MICA staining, respectively, at 0.31 and 7.0% in fibrocystic lobules compared to 0.76 and 12.2% in lobules without fibrocystic change (p < 0.001 for each). Among fibrocystic lobules, proliferative/atypical lobules showed significantly lower expression compared to nonproliferative lobules for MICA (p = 0.02) but not for CD56 (p = 0.80).

Conclusion

Levels of CD56+ NK cells and activating ligand MICA were decreased in breast lobules with fibrocystic change, and MICA levels showed a significant stepwise decrease with increasing histopathologic abnormality. MICA levels were also significantly decreased in older subjects, who generally have higher risk of developing cancer. These findings advance a model in which MICA promotes cytotoxic activity in CD56+ NK cells to protect against tumorigenesis in breast lobules, and suggest further research is warranted.

     

Remission of postmenopausal breast cancer during treatment with the luteinising hormone releasing hormone agonist ICI 118630

Ten previously untreated postmenopausal women with metastatic breast cancer, none of whom had received prior systemic therapy, were treated with the luteinising hormone releasing hormone (LHRH) analogue D-Ser(But)6, Azgly10-LHRH (ICI 118630). Two obtained an objective partial remission, one in bone metastases and one in lung metastases. One patient proved unassessable. Amongst the seven failures, incomplete pituitary gonadotrophin suppression over the relatively short treatment period with the daily injections was noted. The seven patients failing ICI 118630 received tamoxifen and two with high tumour oestrogen receptor values responded. LHRH analogues may provide a novel endocrine therapy for postmenopausal breast cancer although more data are needed. In this study, the monthly depot injection proved superior to daily injections with regard to gonadotrophin suppression, although it is not clear that this provides the mechanism of action.     

Obesity and prostate cancer mortality

It has long been known that obesity modestly increases the risk of prostate cancer mortality. Only recently, however, have studies examined whether this association is due to an increased risk of aggressive disease and/or worse outcomes following initial diagnosis and treatment. This distinction is important, because if obesity increases the risk of metastasis and death following treatment, weight loss could be an effective adjunct treatment. We now have good evidence that obesity increases the risk of aggressive prostate cancer, but reduces the risk of low-grade, nonaggressive cancer. In addition, several studies have found that obesity increases the risk of biochemical recurrence following prostatectomy; however, the few studies that have examined more definitive end points, metastases and death, have been less consistent. Furthermore, there are no studies that have examined whether weight loss after diagnosis favorably affects prostate cancer outcome. While accepting the current limitations in our knowledge base, it is our opinion that it is appropriate for physicians to counsel their patients to lose weight following prostate cancer diagnosis and motivate this change in behavior by emphasising the likely benefit of improving long-term outcome.     

Circulating sex steroids and sex hormone binding globulin in pancreatic adenocarcinoma

Circulating total testosterone is reported to be low in pancreatic adenocarcinoma but the free, more biologically important fractions of sex-steroid hormones remain unstudied. This study further elucidates the influence of pancreatic cancer on circulating sex steroids. Serum testosterone, 5 alpha-dihydrotestosterone, oestradiol and androst-4-ene-3, 17-dione and the free fractions of these hormones were determined in 46 patients. Control groups comprised healthy people (40) and patients with tumours of other primary sites (45). Both total (p less than 0.001) and free (p less than 0.001) androgen fractions were markedly decreased, free testosterone by about 17-fold, and free dihydrotestosterone by about 35-fold; sex hormone binding globulin levels were elevated (p less than 0.001) in all male cancer patients. Total oestradiol was elevated 2-fold in pancreatic cancer (p less than 0.01) compared with controls or other primary malignancy patients.     

Predictive initial parameters for response of stage D prostate cancer to treatment with the luteinizing hormone-releasing hormone agonist goserelin

One hundred eighteen patients with stage D (D1 or D2) prostate cancer with a mean age of 69 years were treated with monthly goserelin (Zoladex; ICI 118, 630; ICI Americas Inc, Wilmington, DE, property of Imperial Chemical Industries PLC) injections and the data were analyzed for predictive parameters for best response and time to treatment failure (National Prostatic Cancer Project [NPCP] and Eastern Cooperative Oncology Group [ECOG] criteria). For best response in a univariate analysis, the performance status (PS 0-1 v 2-3) (P = .01), hematocrit (P = .04), and pain (P = .04) were significant. For time to treatment failure by univariate analysis, ECOG performance status (0-1 v 2-3) was most predictive (P less than .0001), followed by pain at entry (P = .0002), initial testosterone (T) level (greater than 250 ng/dL) (P = .0005), age less than 69 years (P = .02), alkaline phosphatase (less than 115 IU/L) (P = .03), hemoglobin (less than 14 g/dL) (P = .03), whereas normal acid phosphatase (less than 3 IU/mL) (P = .29) was not predictive. In multivariate analysis for time to treatment failure, only the ECOG performance status was of significance (P = .01). Estimated median time to treatment failure for PS of 0-1 was 88 weeks and for PS of 2-3 was 31 weeks.     

激素抵抗性前列腺癌的治疗进展

多西他赛联合泼尼松的3周治疗方案是激素抵抗性前列腺癌的首选一线化疗方案.近年来许多临床研究着重于研究抗肿瘤血管生成联合多西他赛为基础的治疗方案能否进一步提高疗效、新一代抗雄激素治疗以及多西他赛化疗失败后的解救治疗.对于激素抵抗性前列腺癌,阿比特龙可为首选,Enzalutamide可作为多西他赛耐受后的另一内分泌治疗选择,而化疗联合靶向药物仍然无法挑战多西他赛联合泼尼松的一线治疗地位.     

激素抵抗性前列腺癌的治疗进展

激素抵抗性前列腺癌的治疗是目前前列腺癌治疗中的重点与难点。虽然各种治疗方法层出不穷，从化疗到放疗，从生物治疗到同位素治疗，但真正能延长生存的治疗方法并不多。多西他赛联合强的松方案已经成为治疗前列腺癌的一线化疗方案，可有效延长患者生存期。唑来膦酸能明显减少骨相关事件的发生率，已被广泛应用于前列腺癌骨转移的治疗。而生物靶向治疗在前列腺癌中的研究正热，已有许多初步有效的研究报道，进一步确切的疗效评估有待大样本研究证实。     

Combined hypofractionated radiation and hormone therapy for the treatment of intermediate-risk prostate cancer

PURPOSE: Because of the low alpha/beta value of prostate cancer, a therapeutic gain may be possible with a hypofractionated radiation scheme, and this gain may be further increased with the adjunct of hormone therapy. A Phase II study was undertaken to study the toxicity of such a treatment. METHODS AND MATERIALS: Forty-two patients with intermediate-risk prostate cancer were recruited for this study. Neoadjuvant and concomitant hormone therapy consisted of one injection of leuprolide acetate (4-month preparation) and 1 month of oral nonsteroidal, anti-androgen medication starting on the day of the injection. Radiation treatment was started 8 weeks after the injection and patients received 57 Gy in 19 fractions. RESULTS: Median follow-up was 46 months. The treatment was well tolerated and no interruptions occurred. The majority (59%) had Grade 0 or 1 acute genitourinary (GU) toxicity, whereas 36% had Grade 2 and 5% had Grade 3 acute GU toxicity. Only Grade 1 or 2 gastrointestinal toxicity was seen. All chronic toxicity was of Grade 1 or 2 except for 3 patients (8%) with Grade 3 toxicity. Sixty-eight percent (68%) of patients had no long-term side effects from the treatment. At time of analysis, 79% showed no sign of treatment failure. CONCLUSIONS: Hypofractionated radiation with neoadjuvant and concomitant hormone therapy is well tolerated with no significant short- or long-term morbidity. Control for this risk group is good, and comparative Phase III studies should be undertaken to determine whether this treatment is superior to new evolving treatments.     

Luteinizing hormone-releasing hormone (LRH) agonist in the treatment of breast cancer, osteosarcoma and prostate carcinoma--analysis of 12 patients

This paper first reports the results of 12 patients with sex hormone-dependent neoplasms, including 9 women with breast cancer, 2 men with osteosarcoma and 1 man with prostate carcinoma, treated by LRH agonist, (D-Ala6, des-Gly-NH2(10))-LRH-ethylamide (LRH-A) 100-200 micrograms, IM, QD. After 15-30 days of administration, the concentrations of plasma mean estradiol, progesterone, testosterone, serum luteinizing hormone and follicle-stimulating hormone were lowered significantly in the peripheral blood of all patients, associating with improvement of the patients' general condition and reduction of the tumors and/or metastatic foci. No serious side effects were observed except vaginal irregular bleeding in isolated patients. Three patients died and the others were alive in follow-up of 4-30 months. The results suggest that LRH-A be useful in the treatment of the sex hormone-dependent tumors and worth further study.     

子宫肌瘤剔除术后复发的影响因素及促性腺激素释放素激动剂的预防效果

目的探讨子宫肌瘤剔除术后患者复发的影响因素,并分析促性腺激素释放素激动剂(GnRH-a)的预防效果。方法选取2015年1月至2016年1月间空军军医大学第一附属医院收治的接受子宫肌瘤剔除术的211例患者,对患者进行随访,按照复发情况分为复发组和对照组,对两组患者临床资料进行子宫肌瘤复发的单因素分析和多因素Logistic回归分析。结果对211例患者随访3年后发现,63例患者复发,复发率为29. 9%。根据单因素分析的结果,在年龄、肿瘤直径、肌瘤数量和术后GnRH-a治疗方面,组间比较,差异均有统计学意义(均P <0. 05)。多因素Logistic回归分析结果显示,年龄低、肌瘤直径小、肌瘤数量多发和术后未进行GnRH-a治疗是导致子宫肌瘤剔除术后患者复发的危险因素,组间比较,差异均有统计学意义(均P <0. 05)。结论年龄、直径、肌瘤数量多发以及术后未进行GnRH-a治疗是导致子宫肌瘤剔除术后患者复发的危险因素,针对子宫肌瘤剔除术患者,术后给予GnRH-a治疗能够有效控制肌瘤复发,预防效果好,值得临床推广。     

Targeted cancer therapy with gonadotropin-releasing hormone chimeric proteins

Tumor-associated antigens (TAAs) have been identified mainly to determine cancer prognosis. In the past few years, TAAs have been used in the development of treatment modalities such as tumor vaccination. This review describes an additional application of TAAs: as a target for specific antitumor treatment. Since TAAs are overexpressed on the tumor cell surface, they can be targeted to deliver drugs directly to cancer cells. One such delivery system exploits chimeric proteins. Chimeric proteins are a class of targeted molecules designed to recognize and specifically destroy cells that overexpress specific receptors. These molecules, designed and constructed by gene fusion techniques, comprise both cell-targeting and cell-killing moieties. The authors’ laboratory has developed a number of chimeric proteins using gonadotropin-releasing hormone (GnRH) as the targeting moiety. These chimeras recognize a GnRH binding site that is expressed on adenocarcinoma cells. GnRH was fused to a large number of killing moieties, including bacterial and human proapoptotic proteins. All GnRH-based chimeric proteins selectively killed adenocarcinoma cells both in vitro and in vivo. Utilizing chimeric proteins for targeted therapy represents a new and exciting therapeutic modality for the treatment of cancer in humans.     

Targeted cancer therapy with gonadotropin-releasing hormone chimeric proteins

Tumor-associated antigens (TAAs) have been identified mainly to determine cancer prognosis. In the past few years, TAAs have been used in the development of treatment modalities such as tumor vaccination. This review describes an additional application of TAAs: as a target for specific antitumor treatment. Since TAAs are overexpressed on the tumor cell surface, they can be targeted to deliver drugs directly to cancer cells. One such delivery system exploits chimeric proteins. Chimeric proteins are a class of targeted molecules designed to recognize and specifically destroy cells that overexpress specific receptors. These molecules, designed and constructed by gene fusion techniques, comprise both cell-targeting and cell-killing moieties. The authors' laboratory has developed a number of chimeric proteins using gonadotropin-releasing hormone (GnRH) as the targeting moiety. These chimeras recognize a GnRH binding site that is expressed on adenocarcinoma cells. GnRH was fused to a large number of killing moieties, including bacterial and human proapoptotic proteins. All GnRH-based chimeric proteins selectively killed adenocarcinoma cells both in vitro and in vivo. Utilizing chimeric proteins for targeted therapy represents a new and exciting therapeutic modality for the treatment of cancer in humans.