A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial.

OBJECTIVE: To examine the antitumor activity of zoledronic acid (ZA) combined with androgen deprivation therapy (ADT) for men with treatment-naive prostate cancer and bone metastasis. METHODS: We enrolled 227 men with treatment-naive prostate cancer and bone metastasis. Participants were randomly assigned (1:1 ratio) to receive combined androgen blockade alone (CAB group) or ZA with combined androgen blockade (CZ group). Time to treatment failure (TTTF), time to the first skeletal-related event (TTfSRE), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. Median follow-up duration was 41.5 months. RESULTS: Median TTTFs were 12.4 and 9.7 months for the CZ and CAB groups, respectively (HR 0.75; 95 % CI 0.57-1.00; p = 0.051). For men with baseline prostate-specific antigen levels <200 ng/mL, median TTTFs were 23.7 and 9.8 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.35-0.93; p = 0.023). Median TTfSREs were 64.7 and 45.9 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.38-0.88; p = 0.009). OS was similar between the groups. CONCLUSIONS: This study failed to demonstrate that combined use of ZA and ADT significantly prolonged TTTF in men with treatment-naive prostate cancer and bone metastasis. However, it generates a new hypothesis that the combined therapy could delay the development of castration resistance in a subgroup of patients with low baseline prostate-specific antigen values <200 ng/mL. The treatment also significantly prolonged TTfSRE but did not affect OS.

Predictive factors of rectal toxicity after permanent iodine-125 seed implantation: Prospective cohort study in 2339 patients.

PURPOSE: To evaluate the incidence and the associated factors of rectal toxicity in patients with prostate cancer undergoing permanent seed implantation (PI) with or without external beam radiation therapy (EBRT) in a nationwide prospective cohort study in Japan (J-POPS) during the first 2 years. METHODS AND MATERIALS: A total of 2,339 subjects were available for the analyses. Rectal toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: The 3-year cumulative incidence for grade ≥2 rectal toxicity was 2.88%, 1.76%, and 6.53% in all subjects, PI group and EBRT combination therapy group, respectively. On multivariate analysis, among all subjects, grade ≥2 rectal toxicity was associated with rectal volumes receiving 100% of the prescribed dose (R100; p < 0.0001) and EBRT combination therapy (p = 0.0066). R100 in the PI group (p = 0.0254), and R100 (p = 0.0011) and interactive planning (p = 0.0267) in the EBRT combination therapy group were also associated with grade ≥2 toxicity. The 3-year cumulative incidence of grade ≥2 rectal toxicity was 3.80% and 1.37% for R100 ≥ 1 mL and R100 < 1 mL, respectively, in the PI group (p = 0.0068), and 14.09% and 5.52% for R100 ≥ 1 mL and R100 < 1 mL, respectively, in the EBRT combination therapy group (p = 0.0070). CONCLUSIONS: Rectal toxicity was relatively rare in this study compared with previous reports. For Japanese prostate cancer patients, R100 < 1 mL in both PI and EBRT combination therapy groups and interactive planning in EBRT combination therapy group may be effective in decreasing the incidence of rectal toxicity.

Urinary and Rectal Toxicity Profiles After Permanent Iodine-125 Implant Brachytherapy in Japanese Men: Nationwide J-POPS Multi-institutional Prospective Cohort Study.

PURPOSE: To assess, in a nationwide multi-institutional cohort study begun in 2005 and in which 6927 subjects were enrolled by 2010, the urinary and rectal toxicity profiles of subjects who enrolled during the first 2 years, and evaluate the toxicity profiles for permanent seed implantation (PI) and a combination therapy with PI and external beam radiation therapy (EBRT). METHODS AND MATERIALS: Baseline data for 2339 subjects out of 2354 patients were available for the analyses. Toxicities were evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events, and the International Prostate Symptom Scores were recorded prospectively until 36 months after radiation therapy. RESULTS: Grade 2+ acute urinary toxicities developed in 7.36% (172 of 2337) and grade 2+ acute rectal toxicities developed in 1.03% (24 of 2336) of the patients. Grade 2+ late urinary and rectal toxicities developed in 5.75% (133 of 2312) and 1.86% (43 of 2312) of the patients, respectively. A higher incidence of grade 2+ acute urinary toxicity occurred in the PI group than in the EBRT group (8.49% vs 3.66%; P<.01). Acute rectal toxicity outcomes were similar between the treatment groups. The 3-year cumulative incidence rates for grade 2+ late urinary toxicities were 6.04% versus 4.82% for the PI and the EBRT groups, respectively, with no significant differences between the treatment groups. The 3-year cumulative incidence rates for grade 2+ late rectal toxicities were 0.90% versus 5.01% (P<.01) for the PI and the EBRT groups, respectively. The mean of the postimplant International Prostate Symptom Score peaked at 3 months, but it decreased to a range that was within 2 points of the baseline score, which was observed in 1625 subjects (69.47%) at the 1-year follow-up assessment. CONCLUSIONS: The acute urinary toxicities observed were acceptable given the frequency and retention, and the late rectal toxicities were more favorable than those of other studies.

Nationwide Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS).

BACKGROUND: To evaluate the safety and efficacy of brachytherapy with permanent iodine-125 seed implantation (PI) for prostate cancer. The nationwide Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS) has continued since July 2005. This manuscript presents the rationale, J-POPS study design, and the characteristics of initial participants enrolled in this study from July 2005 to June 2007. METHODS: All participants were treated with PI in accordance with the American Brachytherapy Society recommendations. The primary outcome measure was biochemical progression-free survival. Progression-free survival, overall survival, cause-specific survival, longitudinal changes in health-related quality of life, disease-specific quality of life, the International Prostate Symptom Score, and the incidence of adverse events were also investigated as secondary outcome measurements. RESULTS: Overall, 6,927 patients were enrolled by the end of 2010, that is approximately 40 % of all cases treated around the country. During the first 2 years, 2,354 participants were enrolled and 2,339 were actually treated with PI. The age range of participants was 45 to 89 years (median 69 years) and their risk classifications were 1,037 (44.3 %) at low risk, 1,126 (48.1 %) at intermediate risk, and 134 (5.7 %) at high risk, in addition to 16 participants whose classification was unknown. Of all patients, 76.6 % were treated with PI without external beam radiation therapy and 49.3 % received neoadjuvant hormone therapy. CONCLUSIONS: The J-POPS, a nationwide prospective cohort study that enrolled approximately 40 % of all PI cases in Japan, will provide highly reliable evidence, including outcomes and quality of life, after long-term follow-up.

Effect of therapy with insulin glargine (lantus) on glycemic control in toddlers, children, and adolescents with diabetes.

To determine the effect of insulin glargine on glycemic control in pediatric type 1 and 2 diabetes, a retrospective repeated-measure analysis of variance was performed of hemoglobin A1C (HbA1C), frequency of hypoglycemia and hyperglycemia, mean blood glucose, body mass index (BMI), and daily weight-adjusted insulin dosage before and after institution of glargine therapy in 72 children and adolescents with diabetes. At glargine start, age range was 1.2-19.6 years, mean age was 12.5 +/- 4.6 years, BMI was 22.48 +/- 6.3 kg/m(2), and mean HbA1C was 9.7 +/- 1.9%. Mean duration of diabetes was 3.58 years, and mean baseline insulin dose was 0.93 U/kg/day. Gender breakdown was 60% female, and the majority (83%) had type 1 diabetes. Average HbA1C decreased from 9.5% pre-glargine to 8.6% post-glargine (p < 0.001). HbA1C decrease was significant in both types of diabetes without a concomitant increase in frequency of hypoglycemia, BMI, or weight-adjusted insulin dose. Hypoglycemia decreased significantly in type 1 diabetes. Thus, glargine therapy may decrease HbA1C and frequency of hypoglycemia in toddlers, children, and adolescents with diabetes, without an increase in BMI or insulin requirements.