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Cardiovascular risks and toxicity - The Achilles heel of androgen deprivation therapy in prostate cancer patients.

ABSTRACT: Androgen deprivation therapy (ADT) is the primary systemic therapy for treating locally advanced or metastatic prostate cancer (PCa). Despite its positive effect on PCa patient survival, ADT causes various adverse effects, including increased cardiovascular risk factors and cardiotoxicity. Lifespans extension, early use of ADT, and second-line treatment with next-generation androgen receptor pathway inhibitors would further extend the duration of ADT and possibly increase the risk of ADT-induced cardiotoxicity. Meanwhile, information on the molecular mechanisms underlying ADT-induced cardiotoxicity and measures to prevent it is limited, mainly due to the lack of specifically designed preclinical studies and clinical trials. This review article compiles up-to-date evidence obtained from observational studies and clinical trials, in order to gain new insights for deciphering the association between ADT use and cardiotoxicity. In addition, potential cardioprotective strategies involving GnRH receptors and second messenger cGMP are discussed.

SUBMITTER: Muniyan S

PROVIDER: S-EPMC7473503 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Cardiovascular risks and toxicity - The Achilles heel of androgen deprivation therapy in prostate cancer patients.

Muniyan Sakthivel S Xi Lei L Datta Kaustubh K Das Anindita A Teply Benjamin A BA Batra Surinder K SK Kukreja Rakesh C RC

Biochimica et biophysica acta. Reviews on cancer 20200611 1

Androgen deprivation therapy (ADT) is the primary systemic therapy for treating locally advanced or metastatic prostate cancer (PCa). Despite its positive effect on PCa patient survival, ADT causes various adverse effects, including increased cardiovascular risk factors and cardiotoxicity. Lifespans extension, early use of ADT, and second-line treatment with next-generation androgen receptor pathway inhibitors would further extend the duration of ADT and possibly increase the risk of ADT-induced ...[more]

PMID: 32535158

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Project description:BackgroundAndrogen deprivation therapy (ADT) worsens glycaemic control and cardiovascular outcomes. The prognostic value of visit-to-visit HbA1c variability (VVHV) has been unexplored in prostate cancer (PCa) patients receiving ADT.ObjectiveTo explore the effect of ADT on VVHV and the cardiovascular prognostic value of VVHV.Design setting and participantsPCa patients receiving ADT in Hong Kong between January 1, 1993 and March 31, 2021 were included in this retrospective cohort study. Those with fewer than three HbA1c results available within 3 yr after ADT initiation, <6 mo of ADT, missing baseline HbA1c, prior diagnosis of any component of major adverse cardiovascular events (MACEs), and MACEs occurring within 3 yr were excluded. Patients were followed up until September 31, 2021.Outcome measurements and statistical analysisThe outcome was MACEs (composite of heart failure, myocardial infarction, stroke, and cardiovascular mortality). VVHV was calculated from HbA1c levels within 3 yr after and, separately where available, before ADT initiation using coefficient of variation (CV; standard deviation [SD] divided by mean) and average real variability (ARV; average difference between consecutive measurements).Results and limitationsAltogether, 1065 patients were analysed (median age 74.4 yr old [interquartile range 68.3-79.5 yr]). In 709 patients with VVHV available before and after ADT initiation, VVHV increased after ADT initiation (p < 0.001), with 473 (66.2%) and 474 (66.9%) having increased CV and ARV, respectively. Over a median follow-up of 4.3 yr (2.8-6.7 yr), higher VVHV was associated with a higher risk of MACEs (adjusted hazard ratio [per SD] for CV 1.21 [95% confidence interval: 1.02, 1.43], p = 0.029; ARV 1.25 [1.06, 1.48], p = 0.008). Limitations included residual confounding and selection bias.ConclusionsIn PCa patients receiving ADT, VVHV increased after ADT initiation. Higher VVHV was associated with an increased risk of MACEs.Patient summaryIn prostate cancer patients receiving androgen deprivation therapy (ADT), glycaemic control is less stable after initiating ADT, which was associated with an increased cardiovascular risk.

Project description:PurposeExcess fat mass (FM) contributes to poor prostate cancer (PCa) prognosis and comorbidity. However, FM gain is a common side effect of androgen deprivation therapy (ADT). We examined the efficacy of a 12-wk weight loss intervention to reduce FM and maintain lean mass (LM) in ADT-treated obese PCa patients.MethodsFourteen ADT-treated obese PCa patients (72 ± 9 yr, 39.7% ± 5.4% body fat) were recruited for a self-controlled prospective study, with 11 completing the 6-wk control period, followed by a 12-wk intervention comprising 300 min·wk-1 of exercise including supervised resistance training and home-based aerobic exercise, and dietitian consultations advising a daily energy deficit (2100-4200 kJ) and protein supplementation. Body composition was assessed by dual x-ray absorptiometry. Secondary outcomes included muscle strength (one-repetition maximum), cardiorespiratory fitness (maximal oxygen consumption), and blood biomarkers.ResultsThere were no significant changes during the control period. Patients attended 89% of supervised exercise sessions and 100% of dietitian consultations. No changes in physical activity or energy intake were observed. During the intervention, patients experienced significant reductions in weight (-2.8 ± 3.2 kg, P = 0.016), FM (-2.8 ± 2.6 kg, P < 0.001), and trunk FM (-1.8 ± 1.4 kg, P < 0.001), with LM preserved (-0.05 ± 1.6 kg, P = 0.805). Muscle strength (4.6%-24.7%, P < 0.010) and maximal oxygen consumption (3.5 ± 4.7 mL·min-1·kg-1, P = 0.041) significantly improved. Leptin significantly decreased (-2.2 (-2.7 to 0.5) ng·mL-1, P = 0.016) with no other changes in blood biomarkers such as testosterone and lipids (P = 0.051-0.765); however, C-reactive protein (rs = -0.670, P = 0.024) and triglycerides (r = -0.667, P = 0.025) were associated with individual changes in LM.ConclusionsThis study shows preliminary efficacy for an exercise and nutrition weight loss intervention to reduce FM, maintain LM, and improve muscle strength and cardiorespiratory fitness in ADT-treated obese PCa patients. The change in body composition may affect blood biomarkers associated with obesity and PCa progression; however, further research is required.

Project description:BackgroundThe association between patient demographics and CV events after ADT using real-world data was evaluated. In addition to encompassing >30 times more patients than all previous MACE studies, this is the first study, to the best of our knowledge, to include a comprehensive listing of many demographic factors from one large, recent US dataset over a long period of time.Materials and methodsThe retrospective analysis of data in the Decision Resources Group (now Clarivate) Real World Evidence repository, representing >300M US patients from 1991 to 2020 across all US regions, was performed. Patients with PCa receiving ≥1 ADT injection were included. MACE risk after ADT initiation was evaluated for demographic and potential PCa-related risk factors. Kaplan-Meier survival curves were constructed, and Cox regression was used to evaluate the association between MACE risk and demographic/PCa-related risk factors.ResultsOverall, MACE risk was slightly lower in the first year after ADT initiation (3.9%) vs. years 2-4 (∼5.2%). In a multivariate Cox model, MACE risk after ADT initiation was significantly higher for older vs. younger patients (adjusted HR per increasing year = 1.08, 95% CI: 1.07-1.09), men with a history of MACE vs. without (HR = 2.22, 95% CI: 1.72-2.88), men with very low BMI vs. normal or high BMI (HR for decreasing BMI per kg/m2 = 1.02, 95% CI: 1.01-1.03), White vs. Black patients (HR = 1.30, 95% CI: 1.08-1.55), and patients who did not use statins vs. those who did (HR = 1.13, 95% CI: 1.00-1.27). Of the PCa-related risk factors, MACE risk after ADT initiation was significantly higher for oncology vs. urology treatment setting (HR = 2.47, 95% CI: 2.12-2.88), patients with baseline metastasis vs. those without (HR = 2.30, 95% CI: 1.72-3.07), and patients treated with antagonists vs. agonists (HR = 1.62, 95% CI: 1.25-2.10).ConclusionsDemographic factors are important contributors to increased MACE risk for men with PCa on ADT. Clinicians should monitor risk factors and modify if possible.

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Cardiovascular risks and toxicity - The Achilles heel of androgen deprivation therapy in prostate cancer patients.

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Cardiovascular risks and toxicity - The Achilles heel of androgen deprivation therapy in prostate cancer patients.

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