Cardiovascular comorbidity and treatment regret in men with recurrent prostate cancer
Paul L. Nguyen, Department of Radiation Oncology, Dana-Farber/Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. e-mail: pnguyen@LROC.harvard.edu
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
Treatment regret can have an adverse impact on a patient's overall outlook and has been associated with a poorer global quality of life. Understanding predictors of regret can help clinicians better counsel patients about their treatments so that later regret can be avoided. In previous studies, regret has been associated with lesser educational attainment, non-White race, greater post-treatment declines in sexual function and systemic symptoms.
The present study found that, among men with recurrent prostate cancer, those with cardiovascular comorbidity were >50% more likely to regret their treatment choice than men without cardiovascular comorbidity. This study highlights the growing importance of considering comorbidity when counselling patients about prostate cancer treatment options, and provides a rationale for men with cardiovascular comorbidity to give additional consideration to active surveillance for their newly diagnosed prostate cancer.
- • To determine whether cardiovascular comorbidity is associated with increased treatment regret among men with recurrent prostate cancer.
- • The study cohort comprised 795 men in the Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma (COMPARE) registry who experienced biochemical recurrence at a median (interquartile range) of 5.5 (2.8–9.1) years after prostatectomy (n= 410), external beam radiation therapy (n= 237), brachytherapy (n= 124) or primary androgen deprivation therapy (n= 24).
- • Multivariable logistic regression analysis was used to determine whether cardiovascular comorbidity was associated with treatment regret.
- • Cardiovascular comorbidity, which included myocardial infarction, congestive heart failure, angina, diabetes, stroke or circulation problems, was defined using a validated two-question screening process after adjusting for sociodemographic and treatment factors and post-treatment bladder and bowel toxicity.
- • Of 795 men, 14.8% reported regret.
- • Men with cardiovascular comorbidity were more likely to experience post-therapy bowel toxicity (P= 0.022).
- • In the adjusted multivariable model, the factors associated with increased treatment regret were: cardiovascular comorbidity (adjusted odds ratio [AOR]= 1.52 [95% CI:1.00–2.31], P= 0.048); younger age (AOR: 0.97 [95% CI 0.94–0.99] per year increase in age, P= 0.019); and bowel toxicity after treatment (AOR 1.58 [95% CI 1.03–2.43], P= 0.038).
- • Among men with recurrent prostate cancer, those with cardiovascular comorbidity were >50% more likely to experience treatment regret than men without cardiovascular comorbidity.
- • These data provide a rationale for men with cardiovascular comorbidity to give additional consideration to active surveillance for their newly diagnosed prostate cancer.
androgen deprivation therapy
adjusted odds ratio
Men with prostate cancer often have to choose between a wide range of treatment options, including various radiation techniques, surgical approaches, androgen deprivation therapy (ADT) or active surveillance. Each approach has potential risks and benefits, and after completing a treatment, some men may come to regret their decision and wish that they had chosen a different option or chosen not to be treated at all.
Treatment regret can have an adverse impact on a patient's overall outlook and has been associated with a poorer global quality of life [1,2]. Understanding predictors of regret can help clinicians better counsel patients about their treatments so that later regret can be avoided. In previous studies, regret has been associated with lesser educational attainment , non-White race , greater post-treatment declines in sexual function  and systemic symptoms .
In recent years, comorbidity has become an increasingly important factor in whether treatment is recommended and what type of treatment is recommended [4–7]. Patients with high comorbidity and low life expectancy may be advised to seek less aggressive therapy or to participate in active surveillance initiatives [7–10]. To our knowledge, no previous study has examined whether comorbidities also significantly impact post-treatment regret. We analysed a large prospective registry of men with recurrent prostate cancer to determine whether the presence of cardiovascular comorbidity was associated with post-treatment regret.
Between February 2004 and August 2006, 1120 men with biochemical recurrence after primary therapy for localized prostate cancer were enrolled at 150 geographically diverse sites throughout the USA on the Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma (COMPARE) prospective registry study . Men of any age presenting with a higher PSA level after treatment of their primary non-metastatic prostate adenocarcinoma were eligible, with the higher PSA level defined as follows: (i) an increase of ≥0.2 ng/mL on repeated testing after radical prostatectomy, or (ii) two increases above nadir, with a PSA value at least 50% higher than nadir and a minimum PSA value at least 0.2 ng/mL above the post-radiation therapy nadir (a steering committee recommended modification of the Phoenix definition). Patients who received adjuvant or neoadjuvant ADT for ≤3 years were eligible but must have ceased ADT for >4 months before enrolment. Exclusion criteria were: known hypersensitivity to LHRH agonists; hypopituitarism, previous orchiectomy or any chronic and/or acute disease that could interfere with study evaluations; and ongoing management of prostate cancer after initial definitive therapy, including ADT of >4 months. Patients who received ADT, salvage radiation, salvage surgery, or salvage cryotherapy beginning ≤4 months before the time of study enrolment were eligible. Of this group, 795 had complete information about demographic characteristics, comorbidity level and regret status and these patients formed the study cohort.
No specific treatments were mandated as part of this study. At the baseline (enrolment) visit, data obtained from each patient or from their medical records included prostate cancer history, comorbidities, current physical examination parameters and pertinent laboratory data, and patient-reported common complaints. Each patient also completed a questionnaire including questions on demographics, and the impact on quality of life during the previous 4 weeks of his urinary function, sexual function, bowel function, and other medical problems. Patients gave informed consent and the data were made anonymous. Each participating site submitted registry documents to the central or local Institutional Review Board and obtained written approval before conducting any registry-related procedures. Investigators obtained informed consent from patients and provided them with a Health Insurance Portability and Accountability Act statement before enrolment.
DEFINITION OF REGRET, CARDIOVASCULAR COMORBIDITY AND FUNCTIONAL PROBLEMS
Regret was assessed based on a validated two-question questionnaire. Patients were considered to have treatment regret if they either answered ‘definitely false’ or ‘mostly false’ to the question ‘If I had known everything I could have known, I would still have chosen the same treatment approach for prostate cancer’, or if they answered ‘mostly true’ or ‘definitely true’ to the question ‘During the past 4 weeks, I felt I would be better off if I had chosen a different treatment approach for prostate cancer.’[1,2] Cardiovascular comorbidity was measured at the time of study entry (i.e. at the time of prostate cancer recurrence). Cardiovascular comorbidity was defined based on having any of the following physician-reported comorbidities at the time of the questionnaire: myocardial infarction, congestive heart failure, angina, diabetes, stroke, or circulation problems. For each of sexual, bowel and urinary domains, patients were asked ‘Overall, how big a problem has your function been for you during the last 4 weeks?’, with the five possible answers being ‘No problem’, ‘very small problem’, ‘small problem’, ‘moderate problem’, ‘very big problem’. As more than half of the patients tended to answer ‘No problem’, we dichotomized functional issues for the purpose of modelling as ‘No problem’ vs any problem.
A Mantel–Haenszel chi-squared metric was used to compare the distribution of men by the presence of cardiovascular comorbidity and bowel, urinary and sexual complications after therapy. Multivariable logistic regression was used to determine whether cardiovascular comorbidity was associated with an increased risk of treatment regret, after adjusting for the potential prognostic factors of age (continuous), urinary, sexual or bowel dysfunction after treatment (categorical with ‘no problem’ as baseline), treatment type (categorical, with primary ADT or external beam radiation therapy as baseline), Black race, whether or not a patient is living with someone, and whether or not he has completed a high school education. Adjusted odds ratios (AORs) and 95% CIs were reported for each covariate and a P value of <0.05 was considered to indicate statistical significance. SAS version 9.2 (SAS Institute, Cary, NC) was used for all calculations.
BASELINE CLINICAL CHARACTERISTICS ASSOCIATED WITH CARDIOVASCULAR COMORBIDITY AT THE TIME OF BIOCHEMICAL RECURRENCE
The patient baseline characteristics at the time of study entry are shown in Table 1. The median (interquartile range) time from initial therapy to the administration of the questionnaires was 5.5 (2.8–9.1) years. A total of 243 patients (30.6%) were classified as having cardiovascular comorbidity. Patients with cardiovascular comorbidity were slightly older (median age 67.6 vs 66.7 years, P= 0.05) and were less likely to have undergone surgery as primary therapy than patients without cardiovascular comorbidity (45.7% vs 54.2%, P= 0.027).
Table 1. Baseline patient characteristics (N= 795)
|Initial Gleason score|| || |
|Initial clinical AJCC tumour category|
|Initial PSA in ng/mL|| || |
|Age|| || |
|Comorbidity|| || |
| Other non-cardiac||343||43.1|
| No comorbidity||209||26.3|
|Initial treatment|| || |
| External beam radiation therapy||237||29.8|
| ADT alone||24||3.0|
|Race|| || |
|Not completed high school||89||11.2|
Men with cardiovascular comorbidity were significantly more likely to report bowel problems after therapy (P= 0.013): 35.8% of those without cardiovascular comorbidity reported bowel problems, while 44.4% of men with cardiovascular comorbidity reported bowel problems after primary therapy. Similarly, while 39.1% without cardiovascular comorbidity reported urinary problems, 45.7% of those with cardiovascular comorbidity reported urinary problems after treatment, although the difference was not quite significant (P= 0.08). There was no significant difference observed in patient-reported sexual problems among those with and without cardiovascular comorbidity (P= 0.69).
CLINICAL FACTORS ASSOCIATED WITH TREATMENT REGRET
Of 795 men, 118 (14.8%) reported regret. As shown in Table 2, on univariable analysis, the factors associated with treatment regret were cardiovascular comorbidity (odds ratio [OR] 1.56, [95% CI: 1.04–2.34], P= 0.032), younger age at diagnosis (OR = 0.97 [95% CI: 0.95–0.998] per year increase in age, P= 0.037), Black race (OR 1.73 [95% CI: 1.05–2.86], P= 0.032), and increased post-treatment bowel problems (OR 1.58 [95% CI: 1.07–2.35], P= 0.022). There was a trend toward an association between treatment regret and more sexual problems after treatment (OR 1.44 (95% CI: 0.97–2.14, P= 0.071).
Table 2. Logistic regression analysis of factors associated with treatment regret
|Cardiovascular comorbidity*||1.56 (1.04–2.34)||0.032||1.52 (1.00–2.31)||0.048|
|Age at diagnosis, years||0.97 (0.95–0.998)||0.037||0.97 (0.94–0.99)||0.019|
|Black race||1.73 (1.05–2.86)||0.032||1.58 (0.93–2.71)||0.092|
|Prostatectomy†||0.90 (0.58–1.38)||0.640||0.80 (0.49–1.31)||0.377|
|Brachytherapy†||0.91 (0.50–1.65)||0.761||0.91 (0.49–1.69)||0.774|
|Lives with a partner||1.31 (0.76–2.24)||0.328||1.28 (0.73–2.23)||0.388|
|Did not complete high school||1.19 (0.66–2.15)||0.572||1.26 (0.67–2.36)||0.468|
|Bowel problems after treatment||1.58 (1.07–2.35)||0.022||1.58 (1.03–2.43)||0.038|
|Sexual problems after treatment||1.44 (0.97–2.14)||0.071||1.15 (0.75–1.78)||0.520|
|Urinary problems after treatment||1.30 (0.88–1.93)||0.191||1.14 (0.74–1.75)||0.548|
On multivariable analysis (Table 2), the factors associated with increased treatment regret were cardiovascular comorbidity (adjusted odds ratio [AOR]= 1.52 [95% CI:1.00–2.31], P= 0.048); younger age (AOR: 0.97 [95% CI: 0.94–0.99] per year increase in age; P= 0.019); and bowel toxicity after treatment (AOR 1.58 [95% CI: 1.03–2.43], P= 0.038).
The majority of men diagnosed with localized prostate cancer have multiple treatment options, each with its own set of potential risks and benefits. While many patients are grateful for the opportunity to select their treatment, some may subsequently regret their treatment selection if outcomes after therapy do not meet their expectations. In the present study of 795 men with recurrent prostate cancer, we found that 15% of men regretted their treatment choice and on multivariable analysis we found that men with cardiovascular comorbidity and men who were diagnosed at a younger age were significantly more likely to regret their choice of treatment after adjustment for sociodemographic factors and the patient-reported impact of complications after treatment.
Men with cardiovascular comorbidity were more likely to report problems with bowel function after therapy (P= 0.013) and there was a trend towards increased problems with urinary (P= 0.08) function. This finding may reflect the observed association between vascular disease and increased toxicity after radiation therapy [12,13] from poorer wound healing, or may reflect an increased risk of postoperative complications in men with cardiovascular comorbidity. Recently, Gore et al. also found that patients with higher baseline comorbidity had more urinary bother after treatment. Interestingly, however, the greater number of problems after treatment could not entirely explain the higher risk of treatment regret for men with cardiovascular comorbidity in the present study, because cardiovascular comorbidity remained associated with regret even after adjustment for bowel, urinary and sexual problems after therapy. A possible reason for greater regret in patients with cardiovascular comorbidity is that patients who are already facing bodily ailments for other reasons may be less able to cope with any additional toxicities of treatment. In addition, patients with cardiovascular comorbidity may have a limited life expectancy, and therefore may regret having received treatment at all for a disease that has a mean time horizon of ≈13 years from the time of biochemical recurrence until cancer-specific death now that salvage ADT is given at the time of developing distant metastases .
The clinical implication of the present study is that it provides another rationale for patients with cardiovascular comorbidities to consider active surveillance, because the potential benefit to prostate cancer radiation or surgical therapy is relatively small for men with a short life expectancy owing to comorbidities, and the potential for regret is significantly higher . Accordingly, the updated National Comprehensive Cancer Network Practice Guidelines currently take comorbidity into account, as they recommend active surveillance as the best option for men with very low-risk prostate cancer and a life expectancy of <20 years . In addition, the present study suggests that patients with cardiovascular comorbidity should be alerted to their potential for an increased risk of post-treatment toxicity, as this may help to mitigate treatment regret if their cancer recurs.
The present study also found an association between younger age and regret, and this may reflect a feeling among younger patients in whom the cancer recurred that they had chosen the wrong treatment, and potentially missed their chance of cure. For younger patients, a prostate cancer recurrence may represent a major threat to longevity, and so the consequences of recurrence can be grave. Younger patients should, therefore, be given ample opportunity to carefully weigh their treatment options beforehand so that they feel fully informed and as less likely to regret their choice if cancer recurs. The finding of greater regret in men with greater bowel toxicity reinforces the notion that continued attention must be paid to ways of minimizing the toxicity of treatment.
A major strength of the present study is that we used a validated instrument for detecting and defining treatment regret that has also been used in previous publications. The 15% rate of regret in the present study is similar to the 16% rate observed by Hu et al. in a series of treated patients, in not all of whom the cancer recurred. It was also similar to the 19% reported by Schroeck et al. after radical prostatectomy. Davis et al. have reported that patients in whom cancer recurs are more likely to regret their treatment than those in whom it did not recur, and so we had expected our patients to have a greater risk of regret compared with the Hu et al. and Schroeck et al. cohorts. Clark et al. had initially reported that 23% of men who developed metastatic disease regretted their treatment choice, and it is understandable that patients with metastases would regret their choices more often than those who had not developed metastases or who had biochemical recurrence.
The present study is unique in that it focuses on patients who have developed mainly biochemical recurrence, and it is interesting to note that despite having biochemical recurrence, only 15% regretted their initial treatment choice. Experiencing a biochemical recurrence can be psychologically distressing to patients, and the problem may be compounded when patients must deal with regret about their choices. Hu et al. have found regret to be associated with a poorer global quality of life, and so it is important to take all possible measures to educate patients up front at the time of the treatment choices to minimize the potential for regret.
One limitation of the present study is that we were not able to determine whether men with cardiovascular comorbidity simply regretted choosing the particular treatment they did, or whether they more globally regretted being treated for their prostate cancer at all.
In addition, the comorbidity data we have was acquired at the time of recurrence rather than at the time of treatment (which was a median of 5.5 years earlier), and so it is possible that not all of a patient's cardiovascular comorbidities were present at the time of diagnosis. It is reasonable to assume, however, that patients with cardiovascular comorbidities at recurrence were more likely than the rest of the study cohort to have had cardiovascular comorbidities at the time of treatment. Finally, the present study included only patients who experienced recurrence, and the factors that drive regret for men who have experienced recurrence may or may not be exactly the same as the factors that drive regret for men who have not experienced recurrence.
In summary, the present study found that among men with recurrent prostate cancer, those with cardiovascular comorbidity were >50% more likely to regret their treatment choice than men without cardiovascular comorbidity. The present study highlights the growing importance of considering comorbidity when counselling patients about prostate cancer treatment options, and provides a rationale for men with cardiovascular comorbidities to give additional consideration to active surveillance for their newly diagnosed prostate cancer.
This research was supported in part by a grant from Sanofi-Aventis, David and Cynthia Chapin, and an anonymous grant from a family foundation.
CONFLICT OF INTEREST
Karen Stein was formerly employed by Sanofi and is currently employed by Novartis.