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Effects of a combined exercise plus diet program on cardiorespiratory fitness of breast cancer patients.
Okumatsu, K, Tsujimoto, T, Wakaba, K, Seki, A, Kotake, R, Yamauchi, T, Hirayama, S, Kobayashi, H, Yamauchi, H, Tanaka, K
Breast cancer (Tokyo, Japan). 2019;(1):65-71
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Abstract
BACKGROUND Decreases in cardiorespiratory fitness among breast cancer patients have often been reported in previous studies, affecting patients' health and survival. Peak oxygen uptake ([Formula: see text]) is the gold standard for assessing cardiorespiratory fitness and is inversely correlated with cardiovascular disease among women with breast cancer. Some previous studies have reported that aerobic exercise and proper diet positively influence [Formula: see text]. However, almost all studies have been conducted in the Western countries, and few studies are investigating on Asian women who have lower BMI compared with Western ones. PURPOSE Investigating the effects of a combined exercise and diet program among Japanese cancer patients undergoing therapy on [Formula: see text]. METHODS Thirty-two Japanese women with breast cancer undergoing endocrine therapy (age; 50 ± 6 years, body weight; 59 ± 10 kg) were voluntarily assigned to either intervention group (n = 21) or control group (n = 11). The intervention group completed a 12-week combined exercise plus diet program, consisting of weekly aerobic exercise and maintaining a nutritionally well-balanced 1200 kcal/day diet. The control group was instructed to continue with their usual activities. Anthropometric indices and [Formula: see text] were measured at baseline and after the 12-week program. RESULTS All 21 women completed the 12-week program. The [Formula: see text] significantly increased from 26.7 to 30.4 mL/kg/min (1.57-1.62 L/min) in the intervention group, while it remained unchanged (26.9-26.9 mL/kg/min) in the control group. Mean reduction of body mass index was - 2.1 in the intervention group (P < .001) and + 0.1 in the control group. CONCLUSIONS Our combined exercise plus diet program may contribute to improvement in cardiorespiratory fitness and body weight compared with control group.
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Impact of resistance training on body composition and metabolic syndrome variables during androgen deprivation therapy for prostate cancer: a pilot randomized controlled trial.
Dawson, JK, Dorff, TB, Todd Schroeder, E, Lane, CJ, Gross, ME, Dieli-Conwright, CM
BMC cancer. 2018;(1):368
Abstract
BACKGROUND Prostate cancer patients on androgen deprivation therapy (ADT) experience adverse effects such as lean mass loss, known as sarcopenia, fat gain, and changes in cardiometabolic factors that increase risk of metabolic syndrome (MetS). Resistance training can increase lean mass, reduce body fat, and improve physical function and quality of life, but no exercise interventions in prostate cancer patients on ADT have concomitantly improved body composition and MetS. This pilot trial investigated 12 weeks of resistance training on body composition and MetS changes in prostate cancer patients on ADT. An exploratory aim examined if a combined approach of training and protein supplementation would elicit greater changes in body composition. METHODS Prostate cancer patients on ADT were randomized to resistance training and protein supplementation (TRAINPRO), resistance training (TRAIN), protein supplementation (PRO), or control stretching (STRETCH). Exercise groups (EXE = TRAINPRO, TRAIN) performed supervised exercise 3 days per week for 12 weeks, while non-exercise groups (NoEXE = PRO, STRETCH) performed a home-based stretching program. TRAINPRO and PRO received 50 g⋅day- 1 of whey protein. The primary outcome was change in lean mass assessed through dual energy x-ray absorptiometry. Secondary outcomes examined changes in sarcopenia, assessed through appendicular skeletal mass (ASM) index (kg/m2), body fat %, strength, physical function, quality of life, MetS score and the MetS components of waist circumference, blood pressure, glucose, high-density lipoprotein-cholesterol, and triglyceride levels. RESULTS A total of 37 participants were randomized; 32 participated in the intervention (EXE n = 13; NoEXE n = 19). At baseline, 43.8% of participants were sarcopenic and 40.6% met the criteria for MetS. Post-intervention, EXE significantly improved lean mass (d = 0.9), sarcopenia prevalence (d = 0.8), body fat % (d = 1.1), strength (d = 0.8-3.0), and prostate cancer-specific quality of life (d = 0.9) compared to NoEXE (p < 0.05). No significant differences were observed between groups for physical function or MetS-related variables except waist circumference (d = 0.8). CONCLUSIONS A 12-week resistance training intervention effectively improved sarcopenia, body fat %, strength and quality of life in hypogonadal prostate cancer patients, but did not change MetS or physical function. PRO did not offer additional benefit in improving body composition. TRIAL REGISTRATION ClinicalTrials.gov: NCT01909440 . Registered 24 July 2013.
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Testicular vs adrenal sources of hydroxy-androgens in prostate cancer.
Zang, T, Taplin, ME, Tamae, D, Xie, W, Mesaros, C, Zhang, Z, Bubley, G, Montgomery, B, Balk, SP, Mostaghel, EA, et al
Endocrine-related cancer. 2017;(8):393-404
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Abstract
Neoadjuvant androgen deprivation therapy (NADT) is one strategy for the treatment of early-stage prostate cancer; however, the long-term outcomes of NADT with radical prostatectomy including biochemical failure-free survival are not promising. One proposed mechanism is incomplete androgen ablation. In this study, we aimed to evaluate the efficiency of serum hydroxy-androgen suppression in patients with localized high-risk prostate cancer under NADT (leuprolide acetate plus abiraterone acetate and prednisone) and interrogate the primary sources of circulating hydroxy-androgens using our recently described stable isotope dilution liquid chromatography mass spectrometric method. For the first time, three androgen diols including 5-androstene-3β,17β-diol (5-adiol), 5α-androstane-3α,17β-diol (3α-adiol), 5α-androstane-3β,17β-diol (3β-adiol), the glucuronide or sulfate conjugate of 5-adiol and 3α-adiol were measured and observed to be dramatically reduced after NADT. By comparing patients that took leuprolide acetate alone vs leuprolide acetate plus abiraterone acetate and prednisone, we were able to distinguish the primary sources of these androgens and their conjugates as being of either testicular or adrenal in origin. We find that testosterone, 5α-dihydrotestosterone (DHT), 3α-adiol and 3β-adiol were predominately of testicular origin. By contrast, dehydroepiandrosterone (DHEA), epi-androsterone (epi-AST) and their conjugates, 5-adiol sulfate and glucuronide were predominately of adrenal origin. Our findings also show that NADT failed to completely suppress DHEA-sulfate levels and that two unappreciated sources of intratumoral androgens that were not suppressed by leuprolide acetate alone were 5-adiol-sulfate and epi-AST-sulfate of adrenal origin.
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Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer.
Yi, JH, Do, IG, Jang, J, Kim, ST, Kim, KM, Park, SH, Park, JO, Park, YS, Lim, HY, Kang, WK, et al
Scientific reports. 2014;:7592
Abstract
To investigate the prognostic role of the estrogen receptor (ER) in gastric cancer (GC) patients, tumor tissues from 932 patients with advanced GC were assessed for ER expression using immunohistochemistry, and their clinicopathologic features were evaluated. Forty patients (4.3%) had ER expression and they were more frequently associated with diffuse type gastric cancer and shorter disease free survival. Furthermore, we carried out in vitro analysis to evaluate the effect of ER modulation on the proliferation of GC cell lines. Estradiol enhanced proliferation of ER positive GC cells while it did not show any effect on ER negative GC cells. When ER was inhibited by fulvestrant and ER siRNA, estradiol-induced proliferation of ER positive GC cell was suppressed. Paclitaxel showed synergistic anti-proliferative impacts with fulvestrant. Suppressing ER by fulvestrant, paclitaxel and ER siRNA showed increased expression of E-cadherin, which is a crucial factor in diffuse-type carcinogenesis.
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Impact of adding the multikinase inhibitor sorafenib to endocrine therapy in metastatic estrogen receptor-positive breast cancer.
Massarweh, S, Moss, J, Wang, C, Romond, E, Slone, S, Weiss, H, Karabakhtsian, RG, Napier, D, Black, EP
Future oncology (London, England). 2014;(15):2435-48
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BACKGROUND Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. MATERIALS & METHODS A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. RESULTS Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. CONCLUSION The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.
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Responder analysis of the effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer.
Egerdie, RB, Saad, F, Smith, MR, Tammela, TL, Heracek, J, Sieber, P, Ke, C, Leder, B, Dansey, R, Goessl, C
Prostate cancer and prostatic diseases. 2012;(3):308-12
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BACKGROUND Denosumab, a fully human monoclonal antibody against RANK ligand, increased bone mineral density (BMD) and reduced fracture risk vs placebo in a phase 3 trial in men with prostate cancer on androgen deprivation therapy (ADT). The present analysis of this study evaluated BMD changes after 36 months in responder subgroups and in individual patients for three key skeletal sites (lumbar spine (LS), femoral neck (FN) and total hip (TH)) and the distal radius. METHODS Men with nonmetastatic prostate cancer receiving ADT were treated with subcutaneous denosumab 60 mg (n=734) or placebo (n=734) every 6 months for up to 36 months in a phase 3, randomized, double-blind study. Patients were instructed to take supplemental calcium and vitamin D. For this BMD responder analysis, the primary outcome measure was the percentage change in BMD from baseline to month 36 at the LS, FN and TH as measured by dual-energy X-ray absorptiometry. BMD at the distal 1/3 radius at 36 months was measured in a substudy of 309 patients. RESULTS At 36 months, significantly more patients in the denosumab arm had increases of >3% BMD from baseline at each site studied compared with placebo (LS, 78 vs 17%; FN, 48 vs 13%; TH, 48 vs 6%; distal 1/3 radius, 40 vs 7% (P<0.0001 for all)). BMD loss at the LS, FN and TH occurred in 1% of denosumab-treated patients vs 42% of placebo patients, and BMD gain at all three sites occurred in 69% of denosumab patients vs 8% of placebo patients. Lower baseline BMD was associated with higher-magnitude BMD responses to denosumab at the LS, FN and TH. CONCLUSIONS In men with prostate cancer receiving ADT, significantly higher BMD response rates were observed with denosumab vs placebo. Patients with lower baseline T-scores benefited the most from denosumab treatment.
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Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.
Giobbie-Hurder, A, Price, KN, Gelber, RD, , , ,
Clinical trials (London, England). 2009;(3):272-87
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BACKGROUND Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.
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Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole.
Viale, G, Giobbie-Hurder, A, Regan, MM, Coates, AS, Mastropasqua, MG, Dell'Orto, P, Maiorano, E, MacGrogan, G, Braye, SG, Ohlschlegel, C, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;(34):5569-75
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PURPOSE To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. PATIENTS AND METHODS Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. RESULTS Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). CONCLUSION Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.
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A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer.
Chi, KN, Ellard, SL, Hotte, SJ, Czaykowski, P, Moore, M, Ruether, JD, Schell, AJ, Taylor, S, Hansen, C, Gauthier, I, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2008;(4):746-51
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BACKGROUND The purpose of this trial was to evaluate the antitumor activity of sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, in patients with castration-resistant prostate cancer. PATIENTS AND METHODS This was a multicenter, two-stage, phase II study. Sorafenib 400 mg was administered orally twice daily continuously. Primary end point was prostate-specific antigen (PSA) 'response' defined as a > or =50% decrease for > or =4 weeks. RESULTS In all, 28 patients were enrolled. Eastern Cooperative Oncology Group performance status was zero or one in 19 and 9 patients. Two patients had no metastases, and 26 had bone and/or lymph node disease. A median of two cycles (range 1-8) was delivered. Adverse events were typical for sorafenib. The PSA response rate was 3.6% [95% confidence interval (CI) 0.1% to 18.3%] with response occurring in one patient (baseline = 10 000 and nadir = 1643 microg/l). No measurable disease responses occurred in eight patients. Time to PSA progression was 2.3 months (95% CI 1.8-6.4). Of 16 patients who discontinued sorafenib and then did not receive any immediate therapy, 10 had postdiscontinuation PSA declines of 7%-52%. CONCLUSIONS Sorafenib has limited activity using current PSA criteria. The declines in PSA observed on treatment discontinuation indicate an effect on PSA production/secretion. Further study may be warranted but needs to consider the limitations of PSA as an indicator of progression and response.
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A phase II study investigating the re-induction of endocrine sensitivity following chemotherapy in androgen-independent prostate cancer.
Shamash, J, Davies, A, Ansell, W, Mcfaul, S, Wilson, P, Oliver, T, Powles, T
British journal of cancer. 2008;(1):22-4
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When chemotherapy is used in androgen-independent prostate cancer (AIPC), androgen deprivation is continued despite its failure. In this study, we investigated whether it was possible to re-induce hormone sensitivity in previously castrate patients by stopping endocrine therapy during chemotherapy. A phase II prospective study investigated the effects of reintroduction of endocrine therapy after oral chemotherapy in 56 patients with AIPC, which was given without concurrent androgen deprivation. After chemotherapy, patients were given maximum androgen blockade until failure when treatment was switched to diethylstilbestrol and dexamethasone. Patients had already received these endocrine treatments in the same sequence before chemotherapy. All patients were castrate at the start of chemotherapy. Forty-three subsequently restarted endocrine therapy after the completion of chemotherapy. The median overall survival for these 43 patients from the time of restarting endocrine therapy was 7.7 months (95% confidence interval (CI): 3.7-10.9 months). Sixteen (37%) patients had a 50% PSA response to treatment, which was associated with improved overall survival (14.0 months vs 3.7 months P=0.003). Eight out of 12 patients who did not respond to diethylstilbestrol before chemotherapy did so post chemotherapy. Re-induction of hormone sensitivity can occur after chemotherapy in AIPC.