High fat mass associates with occurrence of targeted therapy-induced left ventricular ejection fraction reduction in patients with renal cell carcinoma.

BACKGROUND & AIMS: Recent research suggests that variations of skeletal muscle (SM) and fat predict the severity of chemotherapy-induced toxicities in patients with renal cell carcinoma (RCC). Cardio-toxicity has not been evaluated in this context. METHODS: In this study we considered 47 RCC patients who participated in randomized clinical trials of sorafenib or sunitinib (i.e., targeted therapy). To capture cardio-toxicity, multi gated acquisition (MUGA) scan-defined left ventricular ejection fraction (LVEF) tests (at least 3 tests over 1 year of treatment) were abstracted. Computed tomography (CT) cross-sectional images were analyzed before start of targeted therapy and at 1 year to define SM and fat at baseline and changes over time concurrent with MUGA-defined LVEF measurement. RESULTS: MUGA-defined cardio-toxicity (usually fall in LVEF >10% to an absolute LVEF<55%) occurred in 8/47 (17%) patients over 1 year of targeted therapy (all were male). Percentage of patients with high fat mass (baseline CT-defined total adipose tissue/indexed by height2 greater than the gender-specific median value) was higher among patients with cardio-toxicity versus patients without cardio-toxicity [7 (87.5%) versus 16 (41.0%); p = 0.02]. The percentage of SM loss in patients with cardio-toxicity was higher than the patients without cardio-toxicity [median of loss (%) -7 versus 0 respectively; p = 0.04]. CONCLUSION: Cardio-toxicity in RCC patients might be associated with high fat mass. This finding is distinct from prior observations that low body weight and sarcopenia associated with non-cardiac toxicities of targeted therapies. Concurrence of SM loss over time and development of cardio-toxicity is reported for the first time.

Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer.

PURPOSE: To compare the efficacy and safety of docetaxel plus high-dose calcitriol (DN-101) to docetaxel plus prednisone in an open-label phase III trial. PATIENTS AND METHODS: Nine hundred fifty-three men with metastatic castration-resistant prostate cancer (CRPC) were randomly assigned to Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere (ASCENT; 45 µg DN-101, 36 mg/m(2) docetaxel, and 24 mg dexamethasone weekly for 3 of every 4 weeks) or control (5 mg prednisone twice daily with 75 mg/m(2) docetaxel and 24 mg dexamethasone every 3 weeks) arms. The primary end point was overall survival (OS), assessed by the Kaplan-Meier method. RESULTS: At an interim analysis, more deaths were noted in the ASCENT arm, and the trial was halted. The median-follow-up for patients alive at last assessment was 11.7 months. Median OS was 17.8 months (95% CI, 16.0 to 19.5) in the ASCENT arm and 20.2 months (95% CI, 18.8 to 23.0) in the control arm (log-rank P = .002). Survival remained inferior after adjusting for baseline variables (hazard ratio, 1.33; P = .019). The two arms were similar in rates of total and serious adverse events. The most frequent adverse events were GI (reported in 75% of patients), and blood and lymphatic disorders (48%). Docetaxel toxicity leading to dose modification was more frequent in the ASCENT (31%) than in the control arm (15%). CONCLUSION: ASCENT treatment was associated with shorter survival than the control. This difference might be due to either weekly docetaxel dosing, which, in a prior study, showed a trend toward inferior survival compared with an every-3-weeks regimen, or DN-101 therapy.

Association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma: results from a placebo-controlled study.

PURPOSE Effects of specific antineoplastic therapies on progression of cancer-associated wasting remain uncharacterized. We selected a targeted therapy, sorafenib, because of its reported association with weight loss. PATIENTS AND METHODS Patients with metastatic renal cell cancer (RCC) who were resistant to standard therapy (N = 80) received sorafenib 400 mg twice daily or placebo in a randomized, double-blinded clinical trial. Computed tomography image analysis, which has high precision and specificity for evaluation of specific muscles and adipose tissues, was used to define change in total skeletal muscle and adipose tissue. Results At inclusion, 51% of patients were overweight or obese (ie, body mass index [BMI] > 25 kg/m(2)). Only 5% were underweight. Advanced muscle wasting (ie, sarcopenia) was present in 72% of patients with BMI less than 25 and in 34% of those with a BMI greater than 25. Patients received placebo for an average of 6 months and received sorafenib for 1 year. Patients in the placebo group had stable body weight during 6 months (0.8 kg +/- 0.7 kg), with no significant alteration of muscle or fat. Patients who received sorafenib lost 2.1 kg +/- 0.6 kg (P < .01) in 6 months and lost 4.2 kg +/- 0.7 kg (P < .01) by 1 year. Sorafenib-treated patients lost skeletal muscle progressively at 6 months (decrease of 4.9%; P < .01) and 12 months (decrease of 8.0%; P < .01). CONCLUSION Sarcopenia is prevalent in patients with metastatic RCC and is an occult condition in patients with normal or high BMI. Muscle loss is specifically exacerbated by sorafenib, consistent with the evidence for a role of kinases in regulating muscle mass. Muscle loss is a sorafenib adverse effect that may relate to asthenia, fatigue, and physical disability.

Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.

PURPOSE: There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy. METHODS: Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS. RESULTS: The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73. CONCLUSION: This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.

C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial.

BACKGROUND: Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen-independent prostate cancer (AIPC) who are initiating docetaxel-based chemotherapy. METHODS: Baseline plasma samples were stored (-80 degrees C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo-controlled trial comparing weekly docetaxel plus high-dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate-specific antigen (PSA) decline. RESULTS: C-reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20-1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52-5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60-0.92 [P = .007]). CONCLUSIONS.: Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel-based therapy.

Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel.

BACKGROUND: Survival in patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer (AIPC) is improved with 10 to 12 cycles of docetaxel-containing chemotherapy but further management is undefined. In the current study, the authors examined retreatment with the same regimen after a treatment holiday. METHODS: Patients treated with docetaxel at a dose of 36 mg/m(2) plus either high-dose calcitriol (DN-101; 45 mug) or placebo administered weekly for 3 of every 4 weeks could suspend treatment if their serum prostate-specific antigen (PSA) level was reduced >or=50% and reached a level or=50% and was >or=2 ng/mL or when there was other evidence of disease progression. The study was not powered to compare treatment holiday outcomes between the 2 arms. RESULTS: A total of 250 patients were randomized 1:1. Overall, 18% of patients (20% in the high-dose calcitriol group and 16% in the placebo group) entered the intermittent chemotherapy arm. The median duration of the first chemotherapy holiday was 18 weeks (range, 4%70 weeks). On resumption of treatment after the first holiday, 45.5% of evaluable patients responded with a >or=50% reduction in serum PSA from their postholiday baseline, 45.5% met the criteria for stable PSA for at least 12 weeks, and 9.1% of patients developed disease progression. CONCLUSIONS: To the authors' knowledge, the current study is the first report of intermittent chemotherapy in patients with AIPC who were prospectively tested in a large multi-institutional trial. This strategy results in a clinically significant duration of chemotherapy holidays and can be offered to a minority of patients. At the time of retreatment, the majority of patients again respond to treatment or their PSA levels stabilized. Additional studies of intermittent chemotherapy are needed to better characterize the optimal patient population and the optimal approach.

Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators.

PURPOSE: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel. PATIENTS AND METHODS: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. RESULTS: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%). CONCLUSION: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

High dose calcitriol may reduce thrombosis in cancer patients.

The incidence of venous and arterial thrombosis in a placebo-controlled randomised trial of DN-101 (high dose calcitriol) with docetaxel versus docetaxel was compared. Of the 13 thrombotic events observed in the 250 patients enroled in this study, two occurred in DN-101 and 11 in placebo-treated patients (P = 0.01). This difference remained significant after adjustment for baseline history of thrombosis, atrial fibrillation and use of anti-thrombotic agents. In vitro and vitamin D receptor (VDR) knockout mouse studies predict that nanomolar concentrations of calcitriol may act as an antithrombotic agent. We report the first clinical observation that supports this hypothesis in humans.