Alendronate decreases the fracture risk in patients with prostate cancer on androgen‐deprivation therapy and with severe osteopenia or osteoporosis

OBJECTIVE

To evaluate changes in bone mass and fracture risk in patients with prostate cancer on androgen‐deprivation therapy (ADT) and with a basal T‐score of >?2.0, who were treated with an oral bisphosphonate, as such patients treated with ADT are at increased risk of bone loss and bone fracture.

PATIENTS AND METHODS

We selected 61 patients with prostate cancer treated with ADT; 31 were treated with oral alendronate 70 mg once‐weekly and a control group of 30 were not. At baseline and 12 months we measured bone mineral density (BMD) of the lumbar spine, femoral neck and total hip by dual‐energy X‐ray absorptiometry. All patients had severe osteopenia or osteoporosis at baseline. The risk of femoral neck fracture was calculated at baseline and 12 months (Z‐score 2.7).

RESULTS

Patients treated with alendronate had a significant increase in BMD at the lumbar spine and femoral neck after 1 year of follow‐up, with mean (sd ) values of 1.06 (0.26) vs 1.01 (0.21) g/cm² at baseline (P < 0.001), and 0.75 (0.07) vs 0.73 (0.07) g/cm² (P = 0.03), respectively, while the control group had a significant loss of BMD at the total hip of 0.79 (0.14) vs 0.81 (0.13) g/cm² (P = 0.03). BMD was significantly improved at the three locations in patients treated with alendronate compared with the control group, with differences at the lumbar spine, femoral neck and total hip of 0.05 (0.07) vs 0.01 (0.10) (P = 0.001), 0.01 (0.04) vs ?0.002 (0.03) (P = 0.04) and 0.01 (0.04) vs ?0.01 (0.02) g/cm², respectively (P = 0.001). Patients treated with alendronate had a significant decrease in the fracture risk at the femoral neck, by ?0.54 (1.29) (P = 0.04) after 1 year of follow‐up.

CONCLUSIONS

Treatment with once‐weekly 70 mg alendronate significantly improved the BMD at the lumbar spine and femoral neck in patients with prostate cancer with severe osteopenia or osteoporosis and on ADT, and significantly decreased the risk of femoral neck fracture.     

Risk of cardiovascular thrombotic events after surgical castration versus gonadotropin-releasing hormone agonists in Chinese men with prostate cancer

We investigated the cardiovascular thrombotic risk after surgical castration (SC) versus gonadotropin-releasing hormone agonists (GnRHa) in Chinese men with prostate cancer. All Chinese prostate cancer patients who were treated with SC or GnRHa from year 2000 to 2009 were reviewed and compared. The primary outcome was any new-onset of cardiovascular thrombotic events after SC or GnRHa, which was defined as any event of acute myocardial infarction or ischemic stroke. The risk of new-onset cardiovascular thrombotic event was compared between the SC group and the GnRHa group using Kaplan–Meier method. Multivariate Cox regression analysis was performed to adjust for other potential confounding factors. A total of 684 Chinese patients was included in our study, including 387 patients in the SC group and 297 patients in the GnRHa group. The mean age in the SC group (75.3 ± 7.5 years) was significantly higher than the GnRHa group (71.8 ± 8.3 years) (P < 0.001). There was increased risk of new cardiovascular thrombotic events in the SC group when compared to the GnRHa group upon Kaplan–Meier analysis (P = 0.014). Upon multivariate Cox regression analysis, age (hazard ratio [HR] 1.072, 95% confidence interval [CI] 1.04–1.11, P< 0.001), hyperlipidemia (HR 2.455, 95% CI 1.53–3.93, P< 0.001), and SC (HR 1.648, 95% CI 1.05–2.59, P = 0.031) were significant risk factors of cardiovascular thrombotic events. In conclusion, SC was associated with increased risk of cardiovascular thrombotic events when compared to GnRHa. This is an important aspect to consider while deciding on the method of androgen deprivation therapy, especially in elderly men with known history of hyperlipidemia.     

Association of age and response to androgen‐deprivation therapy with or without radiotherapy for prostate cancer: data from CaPSURE

Study Type – Therapy (prospective cohort)
Level of Evidence 2b

OBJECTIVE

To assess whether the response to primary androgen‐deprivation therapy (PADT) and radiotherapy (RT) plus adjuvant ADT would be muted in older men, as their tumours might already be relatively androgen insensitive, because serum testosterone levels decline with increasing age.

PATIENTS AND METHODS

Using the Cancer of the Prostate Strategic Urologic Research Endeavor database, we conducted an observational study evaluating two groups of men treated for prostate cancer from 1995 to 2006. One group of 1748 men was treated with PADT and the second group of 612 men was treated with RT (external beam RT or brachytherapy) with neoadjuvant and/or adjuvant ADT. We tested whether age was a predictor of disease progression in the PADT group and prostate‐specific antigen (PSA) recurrence in the RT + ADT group (Phoenix definition). Secondary outcomes were all cause (ACM) and prostate cancer‐specific mortality (PCSM).

RESULTS

In both univariate and multivariate analysis stratifying by clinical risk group, age (<65, 65–69, 70–74, and ≥75 years) was not associated with the risk of secondary treatment or PSA recurrence for the PADT and the RT + ADT groups, respectively. Age category had no relationship to increased ACM or PCSM for the RT + ADT group. However, for the PADT group the oldest category (>75 years) had an increased hazard ratio (2.26, 95% confidence interval 1.04–4.88; P = 0.02) for ACM, but a decreased ratio for PCSM (0.29, 0.21–0.42; P < 0.01).

CONCLUSION

If we assume that age is a valid proxy measure for free available testosterone levels, then these levels do not seem to affect the likelihood of response to ADT, either used alone or combined with RT.     

Increased risk of a herpes zoster attack in patients receiving androgen deprivation therapy for prostate cancer

This study aimed to examine the association of herpes zoster (HZ) with androgen deprivation therapy (ADT) use among patients with prostate cancer (PC), using a population‐based data set. The study sample for this study was retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We selected 877 patients with PC who had received ADT as the study group, while 849 patients with PC who had not received ADT served as the comparison group. Each study patient was individually tracked for a 3‐year period to discriminate those who subsequently received a diagnosis of HZ. Of the total 1,726 sampled patients, the incidence rate of HZ per 100 person‐years was 1.80 (95% CI: 1.41–2.25) during the 3‐year follow‐up period. In particular, incidence rates of HZ per 100 person‐years were 2.36 (95% CI: 1.75–3.13) and 1.24 (95% CI: 0.81–1.81), respectively, for patients with PC who had and those who had not received ADT. Furthermore, Cox proportional hazard regressions showed that the adjusted hazard ratio for an HZ attack during the 3‐year follow‐up period for patients with PC who had received ADT was 1.88 (95% CI: 1.13–3.11) than those who had not received ADT. We concluded that patients with PC who had received ADT had an increased risk of HZ.     

Carbon‐ion radiation therapy for prostate cancer

In 1994, carbon‐ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy‐Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phase I/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon‐ion radiotherapy for both early‐ and advance‐stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon‐ion radiotherapy, a phase II study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5 weeks) obtained from the phase I/II studies, and was successfully completed in October 2003. The data from 175 patients in the phase II study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon‐ion radiotherapy for prostate cancer was approved as “Highly Advanced Medical Technology” from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon‐ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon‐ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described.     

Use of androgen deprivation therapy for metastatic prostate cancer in older men

OBJECTIVE

To assess factors associated with early or delayed androgen deprivation therapy (ADT) among men diagnosed with metastatic prostate cancer, and to assess the relationship between ADT and overall survival, as there is uncertainty about the ideal timing for initiating ADT in men with metastatic prostate cancer.

PATIENTS AND METHODS

We studied a population‐based cohort of American men aged ≥66 years diagnosed with metastatic prostate cancer during 1992–2002 and followed to 2003. We assessed the receipt of ADT early (≤4 months from diagnosis), delayed (>4 months), or not at all, using multinomial logistic regression to identify factors associated with treatment, and Cox proportional‐hazard models to assess whether treatment was associated with survival.

RESULTS

Overall, 69.5% of men received early ADT and 7.3% delayed. Adjusted rates of early ADT were lower for black than white men (58.3% vs 71.0%), and of delayed ADT were higher for black than white men (12.7% vs 6.2%). Receipt of ADT was associated with improved survival (adjusted hazard ratio 0.69, 95% confidence interval 0.66–0.73). The benefit of early treatment did not differ from delayed treatment (P = 0.58).

CONCLUSIONS

A large minority of men with metastatic prostate cancer, particularly black men, receive delayed or no ADT. Early or delayed ADT was associated with similarly prolonged survival. After controlling for patient and tumour characteristics, survival did not differ by race, and receipt of ADT did not contribute to racial differences in survival.     

Management of decreased bone mineral density in men starting androgen‐deprivation therapy for prostate cancer

OBJECTIVE

To determine whether clinicians discuss bone‐specific side‐effects with patients on androgen‐deprivation therapy (ADT) for prostate cancer, or prescribe lifestyle and pharmacological interventions for low bone mineral density (BMD), as decreased BMD is a common side‐effect of ADT, leading to increased risk of fracture.

PATIENTS AND METHODS

Sixty‐six men (mean age 70.6 years) with non‐metastatic prostate cancer and starting continuous ADT were enrolled in a prospective longitudinal study. BMD was determined by dual X‐ray absorptiometry (DXA) at baseline. Patients were interviewed to obtain their medical histories, and charts were reviewed to determine whether clinicians documented potential bone side‐effects in clinic notes, and made lifestyle and/or medication recommendations. Both were done at the start of ADT, and 3 and 6 months later. Patients were classified based on DXA T‐score as having normal BMD, as osteopenic, or osteoporotic.

RESULTS

At baseline, 53% of patients had osteopenia and 5% had osteoporosis. Within 6 months of starting ADT, general side‐effects and bone‐specific side‐effects of ADT were documented as being discussed with 26% and 15%, respectively. Clinicians recommended lifestyle interventions to 11% of patients. Pharmacological interventions (calcium, vitamin D, and/or bisphosphonates) were recommended to 18% of all patients within 6 months of starting ADT, and to 26% and 67% of osteopenic and osteoporotic patients, respectively.

CONCLUSIONS

A minority of patients is being informed of bone‐specific side‐effects of ADT. Lifestyle and drug interventions to prevent declines in BMD were recommended uncommonly. Practices around bone health for men starting ADT are suboptimal.     

Use of androgen deprivation therapy in prostate cancer: indications and prevalence

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer. This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.     

Prognostic significance of genetic polymorphisms in disease progression and survival in prostate cancer after androgen deprivation therapy

It is believed that androgens and their receptors regulate normal prostate growth and mediate prostate cancer development. Androgen deprivation therapy is the most commonly used treatment for advanced prostate cancer. Although the therapy is initially effective, progression of the disease to castration-resistant prostate cancer is almost inevitable, leading to treatment failure. Despite the existence of current clinical parameters, new biomarkers are urgently needed to improve the prognosis. Some molecules and DNA-based genetic biomarkers are under investigation as potential prognostic factors. The advancement in molecular cytogenetic research, such as genome-wide association for single-nucleotide polymorphisms, has made possible the detection of genetic mutations. In this study, a literature search from August 1985 to April 2013 was performed through the PubMed database using the keywords “genetic polymorphisms”, “prostate cancer” and “androgen deprivation therapy”. The results revealed that several genome-wide association studies (such as rs16901979, rs7931342, HSD17B4, rs6162 in the CYP17A1, rs4243229 and rs7201637 in the HSD17B2, rs1062577 in the ESR1, SLCO1B3, SLCO2B1, rs2939244 in the ARRDC3, rs9508016 in the FLT1, rs6504145 in the SKAP1, rs7830611 in the FBXO32, rs9508016 in the FLT1, rs12529 in the AKR1C3, rs16934641 in the BNC2, rs3763763 in the TACC2, rs2051778 in the ALPK1, and rs3763763 in the TACC2, AR, ESR1, and ESR2) and single-nucleotide polymorphisms in important pathways (such as androgen signal, biosynthesis, metabolism, androgen receptor binding site, response element, androgen receptor CAG repeat polymorphism length, and estrogen receptor-binding sites) involved in prostate cancer occurrence and mechanism could serve as candidate biomarkers for the early detection of castration-resistant prostate cancer after androgen deprivation therapy. Additional investigations are required to decipher precisely the gene combinations and personalize the management of prostate cancer.     

A natural history of weight change in men with prostate cancer on androgen‐deprivation therapy (ADT): results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Study Type – Harm (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Prior studies have shown that men undergoing ADT tend to gain weight, with a net increase in fat mass and decrease in bone density and lean body mass. We sought to characterize the natural history of weight gain on ADT by studying patients over a three‐year interval, finding that most weight gain occurs within the first year of initiating therapy. Furthermore, we confirm these prior findings in a more racially heterogeneous population of men, an important finding given the different outcomes of prostate cancer in black and white men.

OBJECTIVES

• ? To better understand the natural history of weight change with androgen‐deprivation therapy (ADT), we investigated the effect of ADT on body weight among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.
• ? Men undergoing ADT lose lean muscle but gain fat mass, contributing to an overall gain in weight.

PATIENTS AND METHODS

• ? We identified 132 men in SEARCH who received ADT after radical prostatectomy.
• ? ‘Weight change’ was defined as the difference in weight before starting ADT (6 months before ADT) and the on‐ADT weight (between 6 and 18 months after starting ADT).
• ? In a subanalysis, baseline characteristics of weight‐gainers and ‐losers were analysed using univariate and multivariate analysis to test association with weight change.

RESULTS

• ? In all, 92 men (70%) gained weight, and 40 (30%) either lost or maintained a stable weight.
• ? On average, weight on ADT was 2.2 kg higher than the weight before ADT, with the mean change for weight‐gainers and ‐losers being +4.2 kg and ?2.4 kg, respectively.
• ? This compared with no significant weight change in the year before starting ADT (paired t‐test, change ?0.7 kg, P= 0.19) or in the second year on ADT (paired t‐test, change ?0.5 kg, P= 0.46) for 84 men in whom these additional weight values were recorded.
• ? There was no significant association between any of the features examined and weight change on univariate and multivariate analysis.

CONCLUSION

• ? In this longitudinal study, ADT was accompanied by significant weight gain (+2.2 kg). This change occurred primarily in the first year of therapy, with men neither losing nor gaining additional weight thereafter.

     

Effect of androgen deprivation therapy on bone mineral density in prostate cancer patients

Aim: To evaluate the effect of androgen deprivation therapy (ADT) on bone mineral density (BMD) in prostate cancer patients. Methods: Forty-nine prostate cancer patients with their BMD determined were divided into two groups: the non-treated group included 21 patients before the commencement of ADT and the treated group, 28 patients, who had received ADT for more than 1 year. BMD was measured by dual energy X-ray absorptiometry (DEXA) in the lumbar spine (L2-4) and femoral neck. Results: Thirteen (62 %) non-treated and 23 (82 %) treated patients fulfilled the BMD criteria for osteopenia or osteoporosis. Z scores for age-matched control in lumbar spine and femoral neck were -0.9 ± 0.7 and -0.6 ± 0.5, respectively, in the treated group, and -1.8 ± 1.1 and-1.6 ± 1.0 , respectively, in the non-treated group, the differences between the two groups were highly significant (P<0.01). Conclusion: Prostate cancer patients who received ADT for more than 1 year had a significantly lower BMD in the lumbar spine a