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The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer
European Journal of Cancer, Volume 51, Issue 14, September 2015, Pages 1970 - 1977
New hormonal agents are available for treating metastatic castration-resistant prostate cancer (mCRPC). We aim to define the incidence and relative risk (RR) of cardiovascular events in mCRPC patients treated with these agents.
Prospective studies were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods.
We included six articles in this meta-analysis covering a total of 6735 patients who were used to evaluate cardiac toxicity. The use of new hormonal agents was associated with an increased risk of all grades of such toxicity (RR = 1.32, 95% CI, 1.08–1.60; p = 0.006) compared to a placebo, even if the absolute difference in terms of incidence was small at 14.8% versus 11.5%, respectively. No increased risk of grade 3–4 events (RR = 1.35, 95% CI, 0.90–2.03; p = 0.15) was observed.
A total of 7830 patients were used to evaluate hypertension, and it was found that the use of new hormonal agents compared to a placebo was associated with an increased risk of all-grades (RR = 1.84, 95% CI, 1.37–2.46; p < 0.001) and grade 3–4 events (RR = 1.77, 95% CI, 1.13–2.77; p = 0.01). The absolute incidence was 12.5% versus 7.5% for all-grades and 3.7% versus 2.4% for grade 3–4.
This analysis revealed a significant increase in the incidence and RR of cardiovascular toxicity in mCRPC treated with new hormonal agents as opposed to a placebo, even though the occurrence of all- and grade 3–4 events rose only 14% and 4%, respectively. Follow-ups for the onset of treatment-related cardiovascular events should therefore be considered in these patients.
Keywords: CRPC, Abiraterone acetate, Enzalutamide, Prostate cancer, Orteronel, Cardiac toxicity, Arterial hypertension, Safety.
Prostate cancer is the most frequently diagnosed cancer in men, with 220,800 new cases and 27,540 deaths estimated to occur in 2015 in the US  . Androgen deprivation therapy (ADT) is a cornerstone for treating locally advanced and metastatic disease, with the intent being to shrink the size of any tumours, limit their growth and relieve pain and other symptoms. Most commonly, ADT is provided using medical castration with gonadotropin-releasing hormone (GnRH) agonists or antagonists. This treatment is characterised by a spectrum of adverse effects, including: reductions in bone mineral density; metabolic changes such as weight gain, the loss of muscle mass and increased insulin resistance; the loss of libido; sexual dysfunction; hot flashes; reduced testicle size; anaemia and fatigue  . Several observational studies have also suggested an increased risk of diabetes and cardiovascular events, although most published research reports that ADT is not linked to greater cardiovascular mortality  . Smith and colleagues investigated the mechanisms through which ADT has been suspected to heighten cardiovascular risk, and these include an increased fat mass, low-density lipoprotein and total cholesterol levels, triglycerides and insulin resistance , , and .
Despite the fact that prostate cancer is considered to be responsive to ADT, after a period of time ranging from months to years, tumours inevitably progress and become ‘castration-resistant prostate cancer’ (CRPC). In recent years, there has been a growing interest in research regarding metastatic CRPC (mCRPC), because of the availability of new molecules in the form of chemotherapy (e.g. docetaxel and cabazitaxel) or new hormonal agents. These have been able to inhibit the extra-gonadic production of testosterone by: inhibiting the enzymatic activity of steroid 17alpha-monooxygenase, which is a member of the cytochrome p450 family that catalyses the 17alpha-hydroxylation of the steroid intermediates involved in testosterone synthesis (e.g. abiraterone acetate and orteronel); or the direct inhibition of androgen receptor activity (e.g. enzalutamide)  . Abiraterone and enzalutamide are currently the standard treatments for mCRPC with asymptomatic or mildly symptomatic docetaxel-naive disease. They are also one of the options for patients who were previously treated with docetaxel. Generally, new hormonal agents are characterised by a favourable toxicity profile with respect to fluid retention, oedema, hypokalaemia and transaminase increases for abiraterone, and fatigue and hot flashes for enzalutamide. Cardiovascular toxicity, including hypertension, cardiac events and atrial fibrillation, has been reported for both drugs, although this has not been extensively investigated.
In this analysis, we aim to define the incidence and relative risk (RR) of cardiovascular events in patients treated with new hormonal therapies for mCRPC.
2. Materials and methods
2.1. Definition of the outcome
The objective of this analysis was to assess the incidence and RR of cardiovascular events in patients treated with new hormonal agents for mCRPC. The cardiovascular events considered included both arterial hypertension and cardiovascular toxicity. The latter was defined as the onset of any adverse cardiac event like ischaemic heart disease, myocardial infarction (MI), supraventricular tachyarrhythmias, ventricular tachyarrhythmias, cardiac failure and possible arrhythmia-related tests, signs and symptoms.
For each trial, the new hormonal agent ± prednisone was considered to be the experimental arm and a placebo ± prednisone the control. Both all-grades (grades 1–4) and high-grade (grades 3–4) events were considered to be the main outcomes, and the analysis was conducted in order to identify a significant difference between the two treatment arms. A sub-group analysis was performed to highlight any differences between the classes of treatment used, i.e. CYP-17 inhibitors versus new AR inhibitors, and pre- and post-docetaxel settings in terms of the incidence and RR of cardiovascular toxicity.
2.2. Selection of the studies
We reviewed MEDLINE/PubMed, the Cochrane Library, and ASCO University Meeting abstracts for citations up to 31 December, 2014. The search criteria were limited to articles published in the English language and phase III or phase II RCTs in mCRPC patients. The MeSH terms used for the search of PubMed and the Cochrane Library were ‘abiraterone’ or ‘enzalutamide’ or ‘orteronel or TAK700’. For the search in the ASCO University abstracts, we used the name of the drugs and the terms ‘phase II’ or ‘phase III’. The summaries for the product characteristics were searched for at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm . If more than one publication was found for the same trial, the most recent, complete and updated version was included in the final analysis.
Study quality was assessed using the Jadad 5-item scale, taking into account randomisation, double blinding and withdrawals. The final score ranged from 0 to 5  . The protocol for this systematic review was registered on the PROSPERO International prospective register of systematic reviews (CRD42014008920), and is available in full on the website at http://www.york.ac.uk/inst/crd/ .
2.3. Data extraction
Two authors (R.I. and E.V.) independently conducted the data extraction according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement  , and a consensus approach was used to resolve any discrepancies. The data obtained for each trial included the first author’s name, year of publication, trial phase, number of evaluable patients, number of arms, drugs used in the experimental and control arms, dosage, median follow-up, median treatment duration and number of patients with any cardiac event or hypertension.
2.4. Statistical method
The calculation of incidence was performed from the data available in each study. The proportion of patients who suffered cardiovascular events and the derived 95% confidence intervals (CIs) were calculated for each study. We also calculated the RR and CIs of events in patients assigned to treatment with new hormonal agents compared to the controls in the same study. To calculate the 95% CIs, the variance of a log-transformed study-specific RR was derived using the delta method  .
Statistical heterogeneity between the trials included in the meta-analysis was assessed using Cochrane’s Q statistic, and inconsistency was quantified with an I2 statistic (100% × [Q-df)/Q])  . The assumption of homogeneity was considered to be invalid for p values less than 0.1. Summary incidence and RRs were calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. When there was no substantial heterogeneity, the pooled estimate that was calculated based on the fixed-effects model was reported using the inverse variance method. When substantial heterogeneity was observed, the pooled estimate that was calculated based on the random-effects model was reported using the DerSimonian et al. method  , which considers both within- and between-study variations  . An indirect comparison between the groups was performed using a chi-square test. A two-tailed p-value of less than 0.05 was considered to be statistically significant. All the data were collated using Microsoft Office Excel 2007. The statistical analyses were performed using the RevMan software for meta-analysis (v. 5.2.3)  .
3.1. Search results
The electronic search revealed 189 citations. After screening, 180 records were immediately eliminated because they did not match the initial requirements. Thereafter, nine full-text articles were assessed and three were eliminated for the reasons reported in Fig. 1 . At the end of the review process, six articles were included in the qualitative and quantitative syntheses , , , , , and . Of these six, they all contained data for the analysis of hypertension, but only five had adequate data for the assessment of cardiotoxicity. Four studies compared CYP-17 inhibitors (i.e. abiraterone and orteronel) plus prednisone over a placebo plus prednisone, while the remaining two compared the new AR inhibitor enzalutamide over a placebo. Three studies were performed in mCRPC docetaxel-naive and three in docetaxel-pretreated patients. In all the studies, the castrate level of testosterone was required for patient inclusion. The characteristics of the studies are shown in Table 1 .
|Trial||Year||Previous docetaxel||Required ADT||Experimental arm||Control arm||Median Treatment Duration (mos) Exp./Ctr.||Median Follow-up (mos)||CTCAE version||Jadad’ Score|
|N° Pts||Therapy||N° Pts||Therapy|
|COU-AA-301 ||2012||Yes||Yes||791||Abiraterone + P||394||Placebo + P||8.0/4.0||12.8||3||5|
|COU-AA-302 ||2013||no||yes||542||Abiraterone + P||540||Placebo + P||15.0/9.0||22.0||3||5|
|ELM-PC5 ||2014||Yes||Yes||732||Orteronel + P||363||Placebo + P||6.2/5.0||10.7||4||5|
|ELM-PC4 ||2014||No||Yes||784||Orteronel + P||770||Placebo + P||10.1/8.9||NA||4||5|
Legend: ADT = androgen deprivation therapy; CTCAE = common terminology criteria for adverse events; Ctr. = control group; Exp. = experimental group; mos = months; N° = number; NA = not available; P = prednisone; pts = patients.
3.2. Cardiac toxicity
Five studies were included in this analysis, covering a total of 6735 patients. Among them, 3788 were treated in the experimental arms with CYP-17 inhibitors (55.9%) or enzalutamide (44.1%), while 2947 received a placebo ± prednisone in the control arms.
In the overall cohort, the incidence of any grade cardiac events was 14.8%, while in the control arms it was 11.5%. Treatment with new hormonal agents increased the risk of any grade toxicity by 32% (random effect, RR = 1.32, 95% CI, 1.08–1.60; p = 0.006). There was significant heterogeneity (Chi2 = 9.01, p = 0.06; I2 = 56%) ( Fig. 2 A and Supplementary Table 1 ).
The incidence of high-grade cardiac events was 4.5% in the experimental arms and 3.5% in the control arms. Treatment with new hormonal agents did not significantly increase the risk of high-grade toxicity (random effect, RR = 1.35, 95% CI, 0.90–2.03; p = 0.15) and significant heterogeneity was found (Chi2 = 9.6, p = 0.05; I2 = 58%) ( Fig. 2 B and Supplementary Table 1 ).
The incidence of all- and high-grade cardiac toxicity by class of treatment is reported in Table 2 . Significant differences were found between the CYP-17 inhibitors and enzalutamide for both the all-grade and high-grade groups (p < 0.001).
|Type of Toxicity||Toxicity grade||CYP-17 inhibitors||Enzalutamide|
|Exp. arm (%)||Ctr. Arm (%)||RR (95%CI); p-value||Heterogeneity||Exp. arm (%)||Ctr. Arm (%)||RR (95%CI); p-value||Heterogeneity|
|Cardiac||All||20.0||14.2||1.47 (1.27–1.70); p < 0.001||Chi2 = 2.61, p = 0.27; I2 = 23%||8.2||7.7||1.06 (0.67–1.65); p = 0.8||Chi2 = 2.9, p = 0.09; I2 = 65%|
|High||6.7||4.6||1.55 (1.18–2.05); p = 0.002||Chi2 = 4.0, p = 0.13; I2 = 50%||1.9||2.1||0.81 (0.28–2.33); p = 0.7||Chi2 = 3.3, p = 0.07; I2 = 70%|
|Hypertension||All||14.0||9.8||1.53 (1.30–1.80); p < 0.001||Chi2 = 4.1, p = 0.26; I2 = 26%||10.1||3.7||2.97 (2.16–4.07); p < 0.001||Chi2 = 0.8, p = 0.37; I2 = 0%|
|High||3.1||2.6||1.36 (0.97–1.92); p = 0.08||Chi2 = 3.9, p = 0.27; I2 = 24%||4.5||1.9||2.67 (1.71–4.19); p < 0.001||Chi2 = 1.0, p = 0.31; I2 = 2%|
Legend: Exp. = experimental; Ctr. = control; RR = risk ratio; CI = confidence interval; Chi2 = chi square test; I2 = inconsistency.
The incidence of all-grade toxicity in the experimental arms in the pre- and post-docetaxel settings was 17.6% and 11.0%, respectively (p < 0.001), while it was 12.2% and 9.6%, respectively, in the control arms. Consequently, the incidence of grade 3–4 toxicity in the experimental arms in the pre- and post-docetaxel settings was 5.6% and 3.0%, respectively (p < 0.001), while it was 4.0% and 2.1%, respectively, in the control arms.
Six studies were included in this analysis covering a total of 7830 mCRPC patients. Among them, 4520 were treated in the experimental arms with CYP-17 inhibitors (76.6%) or enzalutamide (23.4%), while 3310 received a placebo ± prednisone in the control arms.
In the overall cohort, the incidence of all-grade hypertension was 12.5% in the experimental arms and 7.5% in the control arms. Treatment with new hormonal agents increased the RR for all-grade toxicity by 84% (random effect, RR = 1.84, 95% CI, 1.37–2.46; p < 0.001). There was significant heterogeneity (Chi2 = 18.6, p = 0.002; I2 = 73%) ( Fig. 3 A and Supplementary Table 1 ).
The incidence of high-grade hypertension was 3.7% in the patients treated in the experimental arms and 2.4% in the control groups. Treatment with new hormonal agents increased the risk of high-grade toxicity (random effect, RR = 1.77, 95% CI, 1.13–2.77; p = 0.01). Significant heterogeneity was found (Chi2 = 11.0, p = 0.05; I2 = 55%) ( Fig. 3 B and Supplementary Table 1 ).
The incidence of all- and high-grade cardiac toxicity by type of molecule is reported in Table 2 . A significant difference was found between the CYP-17 inhibitors and enzalutamide for the all-grade (p < 0.001), and for the high-grade (p = 0.014), groups.
The incidence of all-grade hypertension in the experimental arms in the pre- and post-docetaxel settings was 15.7% and 9.6%, respectively (p < 0.001), and 8.6% and 5.5%, respectively, in the control arms. Accordingly, the incidence of grade 3–4 toxicity in the experimental arms in the pre- and post-docetaxel settings was 5.2% and 2.2%, respectively (p < 0.001), and 3.1% and 1.0%, respectively, in the control arms.
3.4. Quality of the studies
All the studies were randomised, double blind clinical trials. Those with CYP-17 inhibitors used prednisone to alleviate adverse events related to the mechanism of action, and also used it in the control arms. Meanwhile, its use in the enzalutamide trials was permitted, but not required. All the trials had Jadad scores of five, confirming the good quality of those included in the analysis ( Table 1 ).
The correlation between anti-androgen therapies and cardiovascular toxicity is a disputed topic in prostate cancer. Several retrospective analyses have investigated this relationship, with differing results. Keating and colleagues studied more than 73,000 patients with localised prostate cancer from the Surveillance Epidemiology and End Results (SEER) database. They found an increased risk of coronary heart disease, MI and sudden cardiac death, with an adjusted HR of 1.11 (95% CI, 1.01–1.21; p = 0.03), 1.16 (95% CI, 1.10–1.21; p < 0.001) and 1.16 (95% CI, 1.05–1.27; p = 0.004), respectively  . Another analysis used the prospective clinical Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database and reported a significantly increased RR of death of 2.6 because of cardiovascular disease among patients who underwent a radical prostatectomy, but not in the patients treated with radiation therapy  . Moreover, in a pooled analysis with data from three randomised controlled trials of short-term adjuvant ADT in men undergoing radiation, a significantly shorter time to fatal MI was identified, but the risk seemed to be confined to men over the age of 65  .
In contrast, a retrospective cohort study based on administrative data from Ontario, Canada among 19,079 matched pairs of ADT users and non-users age 66 or older did not report a significantly increased risk of MI and sudden cardiac death.  Moreover, three large phase III trials (i.e. RTOG 85-31, RTOG 86-10 and RTOG 92-02) with an enrolled population ranging from 456 to 1554 men and a follow-up of 8–10 years did not find a significantly increased risk of cardiovascular mortality in ADT users , , and .
Furthermore, a large analysis performed by Punnen and colleagues analysed the risk of cardiovascular mortality among four separate treatment groups: primary ADT, local therapy only, local treatment plus ADT and no active treatment. They reported a significantly increased risk in the primary ADT group compared with the group receiving local therapy alone, but not in men treated with local treatment plus ADT, suggesting that the treatment of the primary disease did not affect cardiovascular mortality  .
Given that the greatest killer of older men with non-high-risk prostate cancer is still cardiovascular disease  , previous analyses have mainly focused on non-metastatic and non-CRPC patients. The effects of long-term exposure to ADT, as is usually expected in CRPC patients, and the addition of new hormonal therapies have never been extensively investigated.
The current analysis found that new hormonal therapies might increase cardiovascular toxicity in patients treated for mCRPC. The risk of all-grade cardiac toxicity significantly increased with the use of these therapies, even if the incidence was only 14.8%, while non-significant differences were found for high-grade toxicity. When a sub-group analysis was performed, the incidence and RR for both all-grade and high-grade adverse cardiac events were higher in patients treated with CYP-17 inhibitors compared to a placebo, while no significant increases were found in enzalutamide studies.
Regarding the incidence of hypertension, we found that such new hormonal therapies significantly increased the risk for both all- and high-grade hypertension, but this was more evident in patients treated with enzalutamide. These data may be of interest, because reports of them as two classes of drugs that both act on the androgen axis and were both used in the same groups of patients may have different levels of cardiovascular toxicity, with CYP-17 inhibitors mainly generating cardiac events, while enzalutamide primarily leads to peripheral toxicity.
The evaluation of cardiovascular toxicity in this analysis must also account for several factors. First, all the patients had castrate levels of testosterone due to the use of GnRH agonists or antagonists over several years and the continuation of this treatment during the administration of new hormonal therapies. Unfortunately, our analysis was unable to explore whether this combination has an additive or multiplicative effect on toxicity. Moreover, it is unclear whether the use of steroids, particularly in patients treated with CYP-17 inhibitors, might exacerbate cardiovascular toxicity.
Several other factors may also have affected our results. First, the findings were based on trial results and not individual patient data. Moreover, when they were sub-analysed, they were affected by the number of studies included and based on indirect comparisons. Second, different versions of the Common Terminology Criteria for Adverse Events (CTCAE) were used in different trials, while the definition of cardiac toxicity in our analysis encompassed several diseases, such as ischaemic heart disease, MI, supraventricular tachyarrhythmia, ventricular tachyarrhythmia, cardiac failure and other possible arrhythmia-related conditions. Third, some variables, such as a patient’s medical history, age, number of cycles, type and length of therapies received in previous years, and other possible factors that may be predictive of cardiovascular toxicity, could not be included in the analysis. After treatment, the patients enrolled in clinical trials generally had adequate organ function, and those with chronic or concomitant disease were excluded. Moreover, patients with clinically significant cardiovascular disease, including MI within 6 months, uncontrolled angina within 3 months, congestive heart failure that is at a New York Heart Association (NYHA) class three or four level, or a history of clinically significant ventricular arrhythmias, bradycardia or uncontrolled hypertension, were generally excluded. As a result of these criteria, the incidence of cardiovascular events is expected to be higher in the unselected population.
Despite these limitations, our analysis reported a significant increase in cardiac events and hypertension in mCRPC patients treated with new hormonal therapies. Even if high-grade events are not as frequent, they may nevertheless affect patient survival and quality of life, especially in those who received new hormonal therapies prior to docetaxel because of an expected median survival greater than 2.5 years. Finally, we suggest investigating patients for existing risk factors in order to optimise those who are modifiable, and carefully following them up for the onset of new treatment-related cardiovascular events.
Conflict of interest statement
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a Medical Oncology Division of Urogenital and Head & Neck Tumours, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
b Department of Radiology, Oncology and Human Pathology, “Sapienza” University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
c Division of Urology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
⁎ Corresponding author at: Medical Oncology Division of Urogenital and Head & Neck Tumours, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Fax: +39 (0)294379234.
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