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. 2020 Nov 17;2(4):553-563.
doi: 10.1016/j.jaccao.2020.08.011. eCollection 2020 Nov.

Reduced Cardiorespiratory Fitness and Increased Cardiovascular Mortality After Prolonged Androgen Deprivation Therapy for Prostate Cancer

Jingyi Gong  1 , David Payne  1 , Jesse Caron  1 , Camden P Bay  2 , Bradley A McGregor  3 , Jon Hainer  4 , Ann H Partridge  5 , Tomas G Neilan  6 , Marcelo Di Carli  4 , Anju Nohria  1   5 , John D Groarke  1   5
Affiliations

Reduced Cardiorespiratory Fitness and Increased Cardiovascular Mortality After Prolonged Androgen Deprivation Therapy for Prostate Cancer

Jingyi Gong et al. JACC CardioOncol. .

Abstract

Background: Prolonged androgen deprivation therapy (ADT) is favored over short-term use in patients with localized high-risk prostate cancer (PC).

Objectives: This study sought to compare cardiorespiratory fitness (CRF) and cardiovascular (CV) mortality among patients with PC with and without ADT exposure and to explore how duration of ADT exposure influences CRF and CV mortality.

Methods: Retrospective cohort study of patients referred for exercise treadmill testing (ETT) after a PC diagnosis. PC risk classification was based on Gleason score (GS): high risk if GS ≥8; intermediate risk if GS = 7; and low risk if GS <7. CRF was categorized by metabolic equivalents (METs): METs >8 defined as good CRF and METs ≤8 as reduced CRF. ADT exposure was categorized as short term (≤6 months) versus prolonged (>6 months).

Results: A total of 616 patients underwent an ETT a median of 4.8 years (interquartile range: 2.0, 7.9 years) after PC diagnosis. Of those, 150 patients (24.3%) received ADT prior to the ETT; 99 with short-term and 51 with prolonged exposure. 504 patients (81.8%) had ≥2 CV risk factors. Prolonged ADT was associated with reduced CRF (odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.31 to 5.61; p = 0.007) and increased CV mortality (hazard ratio [HR]: 3.87; 95% CI: 1.16 to 12.96; p = 0.028) in adjusted analyses. Although the association between short-term ADT exposure and reduced CRF was of borderline significance (OR: 1.71; 95% CI: 1.00 to 2.94; p = 0.052), there was no association with CV mortality (HR: 1.60; 95% CI: 0.51 to 5.01; p = 0.420) in adjusted Cox regression models.

Conclusions: Among patients with PC and high baseline CV risk, prolonged ADT exposure was associated with reduced CRF and increased CV mortality.

Keywords: ADT, androgen deprivation therapy; BMI, body mass index; CI, confidence interval; CRF, cardiorespiratory fitness; CV, cardiovascular; ETT, exercise treadmill test; HR, hazard ratio; IQR, interquartile range; MET, metabolic equivalent; OR, odds ratio; PC, prostate cancer; androgen deprivation therapy; cardio-oncology; cardiorespiratory fitness; cardiovascular mortality; cardiovascular risk; prostate cancer.

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Conflict of interest statement

This work was supported by the Goodman Master Clinician Award from Brigham and Women’s Hospital (to Dr. Groarke) and by the Gelb Master Clinician Award and the Catherine Fitch Fund form Brigham and Women’s Hospital (to Dr. Nohria). Dr. McGregor has served as a consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, and Genentech; and has received research support paid to his institution from Bristol Myers Squibb. Dr. Neilan was supported in part through a gift from A. Curt Greer, Pamela Greer, and Kohlberg Foundation, National Institutes of Health/National Heart, Lung, and Blood Institute (grants 1R01HL130539-01A1, 1R01HL137562-01A1, K24HL113128-06), and National Institutes of Health/Harvard Center for AIDS Research (grant P30 AI060354). Dr. Nohria has served as a consultant for Takeda Oncology and Triple Gene Therapy; and has received research support from Amgen, Inc. Dr. Groarke has received research support from Amgen, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Consort Diagram Consort diagram outlining steps used to identify the final study cohort. Patients were excluded if prostate cancer diagnosis occurred after exercise treadmill test (ETT), if data on prostate cancer treatment/vital status were missing, or if exposure to androgen deprivation therapy (ADT) occurred only after ETT.
Figure 2
Figure 2
Frequency of Reduced CRF in ADT-Exposed Versus ADT-Naive Patients With PC Frequency of reduced cardiorespiratory fitness (CRF), defined as failure to achieve >8 metabolic equivalents during exercise treadmill testing, was compared in androgen deprivation therapy (ADT)-exposed versus ADT-naive patients with prostate cancer (PC) using chi-square test. Reduced CRF was more frequent among patients with ADT exposure than among those with no ADT exposure (48.7% vs. 32.6%, p < 0.001).
Figure 3
Figure 3
Cumulative Incidence of CV Mortality by ADT Exposure Status Cumulative incidence for cardiovascular (CV) mortality for patients with prostate cancer and no androgen deprivation therapy (ADT) exposure (green), ADT exposure of ≤6 months (blue), and ADT exposure of >6 months (red) were compared using Gray test of equality. Incidence was similar for patients with no ADT exposure and those with ≤6 months’ exposure (p = 0.077). Incidence was significantly higher among patients with >6 months’ exposure compared with among ADT-naive patients with prostate cancer (p = 0.029).
Central Illustration
Central Illustration
Potential Mechanisms Underlying Association of Prolonged ADT Exposure With Reduced CRF and Increased CV Mortality Association of prolonged androgen deprivation therapy (ADT) exposure with reduced cardiorespiratory fitness (CRF) and increased cardiovascular (CV) mortality are presented together with some proposed mechanisms. Baseline CV risk modifies these associations. Reduced CRF may also in part mediate increased risk of CV mortality. ADT exposure may not only directly influence CRF and CV mortality but may also modify the association between CRF and CV mortality. An exercise intervention concurrent with ADT may mitigate against reduced CRF, and whether this could offset some of the increased risk of CV mortality warrants investigation.
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