ABSTRACT
Background
Androgen‐deprivation therapy (ADT) remains a cornerstone in treatment for patients with advanced prostate cancer. ADT is associated with several adverse effects, including osteoporosis, metabolic syndrome, and cardiovascular events, leading to guidelines recommending routine testing to monitor for these toxicities. There is a lack of data assessing adherence to these recommendations.
Methods
The authors conducted a retrospective cohort study using administrative data from Ontario, Canada between 2008 and 2021. They identified all older men (aged 65 years and older) who received ADT for prostate cancer using comprehensive provincial health databases. The primary outcomes were the use of testing for lipids, dysglycemia (glucose), bone health serum, and bone density between 6 weeks before and 1 year after the initiation of ADT.
Results
In total, 29,097 patients were examined, of whom 52.8% were prescribed ADT by urologists, 37.9% were prescribed ADT by radiation oncologists, 2.8% were prescribed ADT by medical oncologists, and 2.4% were prescribed ADT by other physicians. Adherence to guidelines was low: only 21.3% of patients received a bone density scan, 41.2% underwent bone health–related serum tests, 51.3% completed a lipid profile, and 65.9% underwent dysglycemia testing within 1 year of diagnosis. Overall, only 11.9% of patients received all of the recommended investigations. Adherence to testing did not appear to improve over time (2008–2021) or with guideline publication. Patient (age) and physician (specialty) factors had important associations with adherence to testing.
Conclusions
Most patients receiving ADT for prostate cancer do not receive recommended testing to monitor for treatment‐related toxicity. Further study is required to address barriers to therapeutic monitoring of men on ADT and to reduce treatment‐associated adverse events.
Keywords: androgen‐deprivation therapy; bone mineral density; dysglycemia; dyslipidemia, hypogonadism; prostate cancer
Short abstract
Androgen‐deprivation therapy (ADT) remains a cornerstone in treatment for patients with advanced prostate cancer and is associated with several adverse effects. Population‐based assessment revealed that only 11.9% of patients on ADT received all of the recommended testing to screen for adverse effects associated with ADT.
INTRODUCTION
Androgen‐deprivation therapy (ADT) remains a mainstay in the management of patients with locally advanced and metastatic prostate cancer. Patients on ADT are increasingly exposed to a longer duration of prostate cancer therapy, which can lead to long‐term toxicity and morbidity and can increase other‐cause mortality. Side effects of ADT include dyslipidemia, increased plasma glucose levels, and decreased bone mineral density. 1 , 2 , 3 , 4 , 5 These metabolic changes observed in men on ADT increase the risk of cardiovascular disease, fractures related to osteoporosis, and neurocognitive disease. 6 , 7 , 8 , 9 These effects are concerning, especially in older patients who are at increased baseline risk of these conditions.
To reduce the complications of ADT, the American, Canadian, and European Urologic Associations have developed monitoring guidelines specifying that all patients on ADT should undergo routine measurement of plasma glucose levels, lipid profiles, calcium/vitamin D levels, and bone mineral density measurement at the initiation of therapy and at regular intervals thereafter (every 6–12 months for laboratory investigations, every 1–3 years for bone mineral density; see Table S1). 10 , 11 , 12 However, adherence to such guidelines in a real‐world setting is unclear.
We sought to examine the trends and predictors of adherence to ADT monitoring recommendations using a large, retrospective cohort of patients with locally advanced and metastatic prostate cancer from population‐based administrative databases in Ontario, Canada.
MATERIALS AND METHODS
Study design
We conducted an observational, retrospective cohort study using administrative data sources in Ontario, Canada (the Institute for Clinical Evaluative Sciences) between April 2008 and June 2021 (Figure 1). We identified all male patients receiving ADT for prostate cancer in Ontario. Exclusion criteria included patients without provincial health coverage, those younger than 65 years (the database does not include drug prescription data for those younger than 65 because they do not qualify for drug insurance), those without prostate‐specific antigen (PSA) measurements after diagnosis (this was used as a surrogate for undergoing blood work at a laboratory reporting to the Ontario Laboratories Information System), or those who were missing data for key exposures (treating physician specialty). All residents of Ontario with Canadian citizenship, indigenous status, refugee status, permanent resident status, or on a valid work permit and working for an Ontario employer >6 months are eligible for provincial health coverage under the Ontario Health Insurance Plan (OHIP). OHIP is required to receive any publicly funded health services. All prostate cancer‐related care, as well as general medical, health, and laboratory care (physician consultation, surgery, radiation therapy, hospital care, outpatient care, PSA testing, dysglycemia testing, bone health serum, and density testing) is covered under OHIP. It is estimated that greater than 95% of Ontario residents have OHIP overage. All OHIP insurance claims were evaluated for our study.
FIGURE 1.
Cohort selection. ADT indicates androgen‐deprivation therapy; OLIS, Ontario Laboratories Information System.
Outcomes
The primary outcomes of interest were the use of bone density testing (dual x‐ray absorptiometry scan [DEXA]), bone health serum testing (serum calcium and 25‐hydrovitamin D), lipid testing (triglyceride, total cholesterol, low‐density and high‐density lipoprotein cholesterol), and dysglycemia testing (HgbA1c, fasting plasma glucose, or oral glucose tolerance test) between 6 weeks before and 1 year after the initiation of ADT. Sensitivity analyses were completed by conducting the same analyses for the period between 6 weeks before and 6 months after the initiation of ADT (see Tables 2S–S4).
Exposure
We assessed the specialty of the physician prescribing ADT by using the ICES Physician Database.
Covariates
Patient‐level demographic data included age at initial ADT prescription, socioeconomic status, rurality, and medical comorbidities (both Charlson score and specific diagnoses of relevance; see Supporting Materials). We also captured preindex health use to account for differences in health‐seeking behaviors. Disease‐specific data included prostate cancer stage and grade, serum PSA, type and duration of ADT used, and prior local prostate cancer therapy (surgery or radiation).
Statistical analysis
Baseline characteristics were determined at the date of prostate cancer diagnosis and were stratified by the specialty of the prescribing physician at first ADT prescription. Categorical variables were summarized with counts and percentages. Continuous variables were summarized as the median and range or the mean and standard deviation, as appropriate.
Tests that included the incidence of a dysglycemia test, a lipids profile test, a serum bone health test, and a DEXA bone scan were defined in a period from 6 weeks before the first ADT prescription (index date) to either 6 months (sensitivity analysis) or 1 year (primary analysis) after the index date (see Supporting Materials). For each of the primary outcomes individually and for an aggregate measure of the receipt of all recommended testing, a hierarchical, log‐binomial model was defined at the patient and physician levels to assess the association between prescribing physician specialty and receipt of primary outcome testing.
RESULTS
Patient demographics and disease and treatment characteristics
We included 29,097 patients aged 65 years and older who were newly initiating ADT (Table 1). The median age at the time of ADT initiation was 75 years (interquartile range [IQR], 71–81 years). Most patients resided in urban neighborhoods and had at least one visit with a general practitioner before the index date. In terms of disease characteristics, 45.1% of patients had American Joint Committee on Cancer (AJCC) stage II disease, 14.9% had AJCC stage III disease, and 23.2% had AJCC stage IV disease at the time of diagnosis. The median PSA at the time of ADT initiation was 16 ng/mL (IQR, 9–46 ng/mL). Of these patients 52.8% were prescribed ADT by urologists, 37.9% were prescribed ADT by radiation oncologists, 2.8% were prescribed ADT by medical oncologists, and 2.4% were prescribed ADT by other physicians, including primary care physicians (PCPs) and other internists. Most patients received pharmacologic ADT, and only 164 (0.6%) underwent bilateral orchiectomy. The most prescribed formulation was a luteinizing hormone‐releasing hormone (LHRH) agonist plus an anti‐androgen (67.4%), followed by a LHRH agonist alone (9.3%), and a LHRH antagonist alone (6.2%). A small proportion of patients received both an LHRH agonist and an LHRH antagonist at different points throughout their treatment course (4.8%).
TABLE 1.
Baseline characteristics for the total cohort by the specialty of the physician prescribing androgen‐deprivation therapy.
| No. (%) | |||||||
|---|---|---|---|---|---|---|---|
| Variable | Value | Total, N = 29,097 | GP, N = 1221 | Urologist, N = 15,372 | Radiation oncologist, N = 11,016 | Medical oncologist, N = 801 | Other, N = 686 |
| Age at index date, years | Mean ± SD | 76.18 ± 6.68 | 79.98 ± 7.65 | 77.49 ± 6.87 | 73.73 ± 5.30 | 78.39 ± 7.46 | 76.97 ± 7.02 |
| Median [IQR] | 75 [71–81] | 80 [74–86] | 77 [72–83] | 73 [70–77] | 78 [72–84] | 76 [71–82] | |
| Neighborhood income quintile | Missing | 74 (0.3) | ≤5 | 41 (0.3) | 26 (0.2) | ≤5 | ≤5 |
| 1 | 5189 (17.8) | 255 (20.9) | 2879 (18.7) | 1758 (16.0) | 170 (21.2) | 127 (18.5) | |
| 2 | 5857 (20.1) | 280 (22.9) | 3173 (20.6) | 2084 (18.9) | 183 (22.8) | 137 (20.0) | |
| 3 | 5877 (20.2) | 236 (19.3) | 3101 (20.2) | 2234 (20.3) | 150 (18.7) | 155 (22.6) | |
| 4 | 5804 (19.9) | 226 (18.5) | 2970 (19.3) | 2307 (20.9) | 158 (19.7) | 143 (20.8) | |
| 5 | 6296 (21.6) | 220 (18.0) | 3208 (20.9) | 2607 (23.7) | 138 (17.2) | 123 (17.9) | |
| Rurality | Urban | 24,486 (84.2) | 985 (80.7) | 12,853 (83.6) | 9339 (84.8) | 712 (88.9) | 596 (86.9) |
| Rural | 4581 (15.7) | 236 (19.3) | 2501 (16.3) | 1666 (15.1) | 88 (11.0) | 90 (13.1) | |
| Charlson score | Missing | 23,067 (79.3) | 792 (64.9) | 11,954 (77.8) | 9236 (83.8) | 564 (70.4) | 520 (75.8) |
| 0 | 3027 (10.4) | 177 (14.5) | 1702 (11.1) | 959 (8.7) | 103 (12.9) | 86 (12.5) | |
| 1 | 1342 (4.6) | 105 (8.6) | 771 (5.0) | 387 (3.5) | 47 (5.9) | 32 (4.7) | |
| 2 | 944 (3.2) | 74 (6.1) | 546 (3.6) | 259 (2.4) | 40 (5.0) | 25 (3.6) | |
| ≥3 | 717 (2.5) | 73 (6.0) | 399 (2.6) | 175 (1.6) | 47 (5.9) | 23 (3.4) | |
| No. of visits with a GP in the year before diagnosis | Mean ± SD | 8.67 ± 8.18 | 13.67 ± 14.91 | 9.03 ± 8.05 | 7.44 ± 6.75 | 10.35 ± 9.39 | 9.51 ± 9.21 |
| Median [IQR] | 7 [4–11] | 10 [6–16] | 7 [4–12] | 6 [3–9] | 8 [4–13] | 7 [4–12] | |
| No. of visits with a GP in the year after diagnosis | None | 614 (2.1) | 18 (1.5) | 321 (2.1) | 246 (2.2) | 18 (2.2) | 11 (1.6) |
| 1–5 | 11,333 (38.9) | 275 (22.5) | 5651 (36.8) | 4909 (44.6) | 244 (30.5) | 254 (37.0) | |
| 6–10 | 9374 (32.2) | 345 (28.3) | 4924 (32.0) | 3647 (33.1) | 252 (31.5) | 206 (30.0) | |
| ≥11 | 7776 (26.7) | 583 (47.7) | 4476 (29.1) | 2214 (20.1) | 287 (35.8) | 215 (31.3) | |
| Long‐term care resident | 251 (0.9) | 157 (12.9) | 69 (0.4) | 13 (0.1) | ≤5 | 7–11 | |
| Gleason score | Missing | 14,972 (51.5) | 798 (65.4) | 8093 (52.6) | 5037 (45.7) | 627 (78.3) | 416 (60.6) |
| ≤6 | 1260 (4.3) | 31 (2.5) | 580 (3.8) | 608 (5.5) | 13 (1.6) | 28 (4.1) | |
| 7 | 5212 (17.9) | 131 (10.7) | 2256 (14.7) | 2686 (24.4) | 44 (5.5) | 95 (13.8) | |
| 8–10 | 7653 (26.3) | 261 (21.4) | 4443 (28.9) | 2685 (24.4) | 117 (14.6) | 147 (21.4) | |
| Stage | 3808 (13.1) | 299 (24.5) | 2503 (16.3) | 740 (6.7) | 170 (21.2) | 96 (14.0) | |
| I | 1068 (3.7) | 21 (1.7) | 493 (3.2) | 511 (4.6) | 14 (1.7) | 29 (4.2) | |
| II | 13,114 (45.1) | 355 (29.1) | 5843 (38.0) | 6576 (59.7) | 93 (11.6) | 247 (36.0) | |
| III | 4348 (14.9) | 74 (6.1) | 1937 (12.6) | 2237 (20.3) | 32 (4.0) | 68 (9.9) | |
| IV | 6759 (23.2) | 472 (38.7) | 4596 (29.9) | 952 (8.6) | 492 (61.4) | 246 (35.9) | |
| Prostate‐specific antigen, μg/mL | Median [IQR] | 16 [9–46] | 47 [12–267] | 23 [10–81] | 11 [7–20] | 131 [24–589] | 22 [9–120] |
| Systemic treatment characteristics | Orchiectomy | 164 (0.6) | 15 (1.2) | 114 (0.7) | ≤5 | ≤5 | 28 (4.1) |
| LHRH agonist alone | 2694 (9.3) | 153 (12.5) | 1999 (13.0) | 387 (3.5) | 87 (10.9) | 68 (9.9) | |
| LHRH antagonist alone | 1806 (6.2) | 74 (6.1) | 1350 (8.8) | 225 (2.0) | 112 (14.0) | 44 (6.4) | |
| LHRH agonist + anti‐androgen | 19,610 (67.4) | 726 (59.5) | 9668 (62.9) | 8272 (75.1) | 485 (60.5) | 458 (66.8) | |
| LHRH agonist/antagonist + docetaxel | 548 (1.9) | 22 (1.8) | 390 (2.5) | 64 (0.6) | 59 (7.4) | 13 (1.9) | |
| LHRH agonist/antagonist + prednisone | 843 (2.9) | 37 (3.0) | 599 (3.9) | 92 (0.8) | 89 (11.1) | 26 (3.8) | |
| Radical prostatectomy | 2168 (7.5) | 18 (1.5) | 1029 (6.7) | 1065 (9.7) | 17 (2.1) | 39 (5.7) | |
| Radiotherapy | 9961 (34.2) | 152 (12.4) | 3151 (20.5) | 6434 (58.4) | 66 (8.2) | 158 (23.0) | |
| Hospitalization for any reason | 3741 (12.9) | 308 (25.2) | 2161 (14.1) | 988 (9.0) | 158 (19.7) | 126 (18.4) | |
| Myocardial infarction | 586 (2.0) | 40 (3.3) | 325 (2.1) | 184 (1.7) | 19 (2.4) | 18 (2.6) | |
| ED/hospitalization for arrhythmia | 424 (1.5) | 32 (2.6) | 209 (1.4) | 142 (1.3) | 24 (3.0) | 17 (2.5) | |
| Cerebrovascular accident | 351 (1.2) | 32 (2.6) | 211 (1.4) | 83 (0.8) | 18 (2.2) | 7 (1.0) | |
| Congestive heart failure | 2787 (9.6) | 204 (16.7) | 1715 (11.2) | 684 (6.2) | 102 (12.7) | 82 (12.0) | |
| COPD | 6432 (22.1) | 353 (28.9) | 3553 (23.1) | 2182 (19.8) | 191 (23.8) | 153 (22.3) | |
| Dementia | 1918 (6.6) | 245 (20.1) | 1104 (7.2) | 446 (4.0) | 75 (9.4) | 48 (7.0) | |
| Hypertension | 20,770 (71.4) | 919 (75.3) | 11,239 (73.1) | 7541 (68.5) | 574 (71.7) | 496 (72.3) | |
| Liver disease | 1958 (6.7) | 247 (20.2) | 1124 (7.3) | 458 (4.2) | 81 (10.1) | 48 (7.0) | |
| Diabetes | 8832 (30.4) | 445 (36.4) | 4730 (30.8) | 3177 (28.8) | 280 (35.0) | 200 (29.2) | |
| Renal disease | 2177 (7.5) | 147 (12.0) | 1268 (8.2) | 609 (5.5) | 92 (11.5) | 61 (8.9) | |
Abbreviations: COPD, chronic obstructive pulmonary disease; ED, emergency department; IQR, interquartile range; LHRH, luteinizing hormone‐releasing hormone; SD, standard deviation.
Overall trends in adherence to therapeutic monitoring
Within the first year of ADT initiation, 21.3% of patients received a bone density scan, 41.2% underwent bone health–related serum tests, 51.3% completed a lipid profile, and 65.9% underwent dysglycemia testing (Table 2). Overall, 11.9% of patients received all of the recommended investigations. Disease stage at diagnosis (stage IV vs. I) was associated with a decreased likelihood of lipid testing (relative risk [RR], 0.81; 95% CI, 0.68–0.99; p = .04) and an increased likelihood of bone health serum testing (RR, 1.46; 95% CI, 0.68–0.99; p = .0004). In contrast, disease stage was not associated with the likelihood of dysglycemia testing or DEXA bone testing. Likely reflecting initial treatment intent, we observed that patients who ultimately received longer durations of ADT were more likely to receive these monitoring tests within the first year of initiating ADT (Tables 3 and 4). The frequency of testing was relatively stable over the past decade (2008–2019); however, it decreased in the last 2 years of data capture (2020–2021; Table 5). Sensitivity analyses revealed that the results were generally consistent when adherence to testing was examined over a shorter time period of 6 months (see Tables S2–S4).
TABLE 2.
Frequency of test outcomes among individuals who remained alive 1 year after ADT prescription by specialty of the physician prescribing androgen‐deprivation therapy.
| No. (%) | ||||||
|---|---|---|---|---|---|---|
| Test | Total, N = 26,381 | GP, N = 844 | Urologist, N = 13,715 | Radiation oncologist, N = 10,708 | Medical oncologist, N = 549 | Other, N = 565 |
| Bone health within 1 year a | 10,879 (41.2) | 383 (45.4) | 5654 (41.2) | 4382 (40.9) | 242 (44.1) | 218 (38.6) |
| DEXA scan within 1 year | 5608 (21.3) | 127 (15.0) | 2611 (19.0) | 2687 (25.1) | 72 (13.1) | 111 (19.6) |
| Lipid profile within 1 year | 13,541 (51.3) | 377 (44.7) | 6892 (50.3) | 5804 (54.2) | 211 (38.4) | 257 (45.5) |
| Dysglycemia tests within a year | 17,377 (65.9) | 560 (66.4) | 9119 (66.5) | 7007 (65.4) | 329 (59.9) | 362 (64.1) |
| All tests received within 1 year | 3144 (11.9) | 71 (8.4) | 1431 (10.4) | 1560 (14.6) | 32 (5.8) | 50 (8.8) |
Abbreviations: DEXA scan, dual x‐ray absorptiometry scan; GP, general practitioner.
Test outcomes are defined from 6 weeks before to 1 year after the date of first ADT prescription.
TABLE 3.
Log‐binomial model of receipt of primary outcome tests from 6 weeks before to 1 year after androgen‐deprivation therapy (ADT) prescription among men with prostate cancer in Ontario who remained alive within 1 year after ADT prescription.
| Dysglycemia | Lipids | Bone health serum tests | DEXA bone scan | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Parameter | Category | RR (95% CI) | p | RR (95% CI) | p | RR (95% CI) | p | RR (95% CI) | p |
| Prescribing physician specialty | GP vs. urologist | 0.9505 (0.7988–1.1311) | .5676 | 0.8055 (0.6801–0.9541) | .0123 | 1.1766 (0.9292–1.4898) | .1769 | 0.8404 (0.5568–1.2684) | .4078 |
| Medical oncology vs. urologist | 0.8056 (0.6569–0.988) | .0379 | 0.677 (0.555–0.8258) | .0001 | 0.963 (0.7559–1.2269) | .7603 | 0.6504 (0.4481–0.944) | .0236 | |
| Other vs. urologist | 0.8829 (0.7186–1.0847) | .2357 | 0.801 (0.6554–0.979) | .0302 | 0.9784 (0.7415–1.2909) | .8772 | 1.0613 (0.7058–1.5957) | .7751 | |
| Radiation oncology vs. urologist | 1.0099 (0.9149–1.1147) | .8451 | 1.0633 (0.9663–1.1699) | .2084 | 1.2039 (0.9806–1.4782) | .0763 | 1.4314 (1.0358–1.978) | .0298 | |
| Physician years of practice | 1.004 (0.9998–1.0081) | .0597 | 1.002 (0.9986–1.0054) | .2452 | 0.9898 (0.9824–0.9973) | .0075 | 0.984 (0.9714–0.9968) | .0146 | |
| ADT duration, months | 13–36 vs. <12 | 1.3275 (1.2344–1.4275) | < .0001 | 1.254 (1.1702–1.3438) | < .0001 | 1.7124 (1.5343–1.9111) | < .0001 | 2.3358 (1.9629–2.7794) | < .0001 |
| >36 vs. <12 | 1.3739 (1.2528–1.5067) | < .0001 | 1.3877 (1.2752–1.5102) | < .0001 | 1.7985 (1.5867–2.0386) | < .0001 | 2.6056 (2.1467–3.1626) | < .0001 | |
| Prostate‐specific antigen, μg/mL | 10–20 vs. <10 | 0.8664 (0.7977–0.941) | .0007 | 0.8092 (0.7514–0.8715) | < .0001 | 0.9932 (0.9189–1.0734) | .8626 | 1.0102 (0.9171–1.1127) | .8374 |
| >20 vs. <10 | 0.7388 (0.6809–0.8017) | < .0001 | 0.6976 (0.6457–0.7537) | < .0001 | 1.0149 (0.9296–1.108) | .7415 | 0.9511 (0.8471–1.0678) | .3955 | |
| Patient age, years | 76–85 vs. 66–75 | 1.0405 (0.9834–1.1008) | .1679 | 0.9216 (0.8696–0.9767) | .0059 | 1.0531 (0.9847–1.1261) | .1309 | 0.9578 (0.8763–1.047) | .3428 |
| 86–95 vs. 66–75 | 0.9935 (0.8954–1.1024) | .9029 | 0.6678 (0.601–0.7421) | < .0001 | 1.0223 (0.9136–1.1441) | .7004 | 0.6911 (0.5842–0.8176) | < .0001 | |
| ≥96 vs. 66–75 | 0.5285 (0.2518–1.1093) | .0919 | 0.2743 (0.1136–0.6624) | .004 | 0.3844 (0.1709–0.8645) | .0208 | 0.6474 (0.2304–1.8192) | .4095 | |
| No. of GP visits in year before index | 1.0298 (1.0245–1.0352) | < .0001 | 1.0181 (1.0139–1.0224) | < .0001 | 1.0084 (1.0043–1.0126) | < .0001 | 0.9981 (0.9928–1.0034) | .4837 | |
| Rurality | Rural vs. urban | 0.4477 (0.1371–1.4621) | .1832 | 1.1134 (0.422–2.938) | .8281 | 0.5815 (0.197–1.7164) | .3262 | 0.7912 (0.195–3.2096) | .743 |
| Income quintile | 1 vs. 5 | 0.9571 (0.8709–1.0517) | .3617 | 0.9376 (0.8637–1.0178) | .1237 | 0.8562 (0.7833–0.9358) | .0006 | 0.8227 (0.7356–0.9202) | .0006 |
| 2 vs. 5 | 0.9599 (0.8865–1.0394) | .3136 | 1.013 (0.9375–1.0945) | .7438 | 0.9058 (0.832–0.9861) | .0224 | 0.8745 (0.7798–0.9806) | .0217 | |
| 3 vs. 5 | 1.0291 (0.9502–1.1146) | .4806 | 1.024 (0.952–1.1013) | .524 | 0.931 (0.86–1.0079) | .0776 | 0.8566 (0.773–0.9492) | .0031 | |
| 4 vs. 5 | 1.0536 (0.9729–1.141) | .1991 | 0.9952 (0.9192–1.0774) | .9046 | 0.9511 (0.879–1.0291) | .2127 | 0.9114 (0.8253–1.0065) | .0669 | |
| Gleason score | ≤6 vs. 7 | 0.9964 (0.9184–1.0809) | .9305 | 0.9844 (0.9118–1.0627) | .6866 | 1.1715 (1.0672–1.2861) | .0009 | 1.2167 (1.0868–1.3622) | .0007 |
| 8–10 vs. 7 | 1.114 (0.9349–1.3274) | .2273 | 1.2147 (1.0348–1.4258) | .0174 | 1.0476 (0.8602–1.2759) | .6438 | 1.1265 (0.8846–1.4345) | .334 | |
| Myocardial infarction | 1.0968 (0.8913–1.3496) | .3827 | 1.1303 (0.9411–1.3575) | .1901 | 1.0827 (0.8906–1.3163) | .4253 | 1.0262 (0.8185–1.2866) | .8229 | |
| Cerebrovascular accident | 0.9434 (0.7032–1.2655) | .6973 | 1 (0.7763–1.288) | .9998 | 1.0748 (0.8071–1.4311) | .6217 | 1.0393 (0.7492–1.4418) | .8173 | |
| Hospitalization in year before diagnosis | 0.6599 (0.5814–0.7491) | < .0001 | 0.6686 (0.5887–0.7592) | < .0001 | 0.932 (0.8293–1.0475) | .2376 | 0.9473 (0.8133–1.1034) | .4865 | |
| Long‐term care residence | 1.7497 (1.1198–2.7337) | .014 | 1.1128 (0.7722–1.6036) | .5664 | 1.2654 (0.8694–1.8419) | .219 | 0.6409 (0.3544–1.1593) | .1412 | |
| AJCC stage | II vs. I | 0.9623 (0.792–1.1694) | .6994 | 0.9919 (0.8288–1.187) | .9289 | 0.9945 (0.8282–1.1941) | .9526 | 1.1821 (0.9077–1.5395) | .2145 |
| III vs. I | 0.892 (0.7263–1.0956) | .2759 | 0.9105 (0.7476–1.1087) | .3507 | 1.0554 (0.8614–1.2932) | .6026 | 1.3114 (0.9977–1.7237) | .052 | |
| IV vs. I | 0.9143 (0.7452–1.1216) | .3901 | 0.8176 (0.6763–0.9885) | .0376 | 1.4557 (1.1824–1.7921) | .0004 | 1.2467 (0.9178–1.6935) | .1581 | |
| Systemic treatment | 1.1197 (1.0249–1.2232) | .0122 | 1.0523 (0.967–1.1452) | .2374 | 1.2048 (1.0825–1.341) | .0006 | 1.1814 (1.0117–1.3796) | .0351 | |
| Prostate treatment | Both vs. none | 0.9016 (0.7355–1.1051) | .3183 | 1.2522 (1.0398–1.5081) | .0177 | 0.9379 (0.7714–1.1404) | .5206 | 1.2414 (0.9824–1.5686) | .07 |
| Prostatectomy vs. none | 1.1219 (0.9711–1.2961) | .1183 | 1.3201 (1.161–1.501) | < .0001 | 0.8631 (0.7544–0.9874) | .032 | 1.097 (0.9208–1.3069) | .2999 | |
| Radiotherapy vs. none | 1.042 (0.9722–1.1167) | .2447 | 1.1151 (1.0397–1.1959) | .0023 | 1.0157 (0.9328–1.106) | .7197 | 1.2907 (1.1452–1.4547) | < .0001 | |
| Charlson score | 1 vs. 0 | 1.316 (1.1228–1.5425) | .0007 | 1.2292 (1.0648–1.4191) | .0049 | 0.956 (0.8191–1.1157) | .5679 | 0.9143 (0.7519–1.1116) | .3686 |
| 2 vs. 0 | 1.4371 (1.1851–1.7427) | .0002 | 1.3371 (1.1144–1.6043) | .0018 | 1.1387 (0.9554–1.3572) | .147 | 0.78 (0.622–0.9781) | .0314 | |
| ≥3 vs. 0 | 1.7803 (1.3985–2.2663) | < .0001 | 1.5277 (1.2431–1.8775) | < .0001 | 1.0897 (0.8918–1.3315) | .4009 | 0.8634 (0.6556–1.1371) | .2958 | |
| Missing vs. 0 | 1.102 (0.9805–1.2386) | .1033 | 1.0647 (0.9529–1.1895) | .2681 | 1.005 (0.8965–1.1266) | .9316 | 1.0063 (0.88–1.1507) | .9273 | |
| Year of first ADT prescription | 0.9794 (0.9688–0.9902) | .0002 | 0.9782 (0.9691–0.9874) | < .0001 | 1.0128 (0.9975–1.0284) | .1018 | 0.9821 (0.9609–1.0039) | .1066 | |
Abbreviations: ADT, androgen‐deprivation therapy; AJCC, American Joint Committee on Cancer; CI, confidence interval; DEXA, dual x‐ray absorptiometry scan; GP, general practitioner; RR, relative risk.
TABLE 4.
Frequency of test outcomes among individuals who remained alive 1 year after androgen‐deprivation therapy prescription by therapy duration.
| No. (%) | |||||
|---|---|---|---|---|---|
| Variable | ≤12 months of ADT, N = 6709 | 13–36 months of ADT, N = 11,594 | >36 months of ADT, N = 8078 | Total, N = 26,381 | p |
| Bone health within 1 year a | 2010 (30.0) | 5218 (45.0) | 3651 (45.2) | 10,879 (41.2) | < .001 |
| DEXA scan within 1 year | 826 (12.3) | 2761 (23.8) | 2021 (25.0) | 5608 (21.3) | < .001 |
| Lipid profile within 1 year | 3114 (46.4) | 6025 (52.0) | 4402 (54.5) | 13,541 (51.3) | < .001 |
| Dysglycemia testing within 1 year | 3950 (58.9) | 7846 (67.7) | 5581 (69.1) | 17,377 (65.9) | < .001 |
| All tests received within 1 year | 441 (6.6) | 1526 (13.2) | 1177 (14.6) | 3144 (11.9) | < .001 |
Abbreviations: ADT, androgen‐deprivation therapy; DEXA, dual x‐ray absorptiometry scan.
Test outcomes are defined from 6 weeks before to 1 year after the date of first ADT prescription.
TABLE 5.
Tests received within 1 year of first androgen‐deprivation therapy (ADT) prescription based on the year of first ADT prescription.
| No. (%) | ||||
|---|---|---|---|---|
| ADT year | Dysglycemia | Lipid profile | Bone health serum tests | DEXA scan |
| 2008–2010 | 2697 (67.73) | 2048 (51.43) | 1603 (40.26) | 860 (21.6) |
| 2011–2013 | 3633 (65.38) | 2755 (49.58) | 2119 (38.13) | 1122 (20.19) |
| 2014–2016 | 4468 (67.29) | 3439 (51.79) | 2872 (43.25) | 1468 (22.11) |
| 2017–2019 | 5697 (66.58) | 4387 (51.27) | 3720 (43.48) | 1760 (20.57) |
| 2020–2021 | 2233 (51.19) | 1540 (35.3) | 1524 (34.94) | 601 (13.78) |
| Cochran–Armitage trend test | p < .0001 | p < .0001 | p = 0.4176 | p < .0001 |
Abbreviation: DEXA, dual x‐ray absorptiometry scan.
Physician/provider factors
The administration of tests varied according to the specialty of the prescribing provider after correction for covariates (Table 2). ADT prescription by a medical oncologist, compared with a urologist, was associated with a lower likelihood of testing for dysglycemia (RR, 0.81; 95% CI, 0.66–0.99; p = .04), testing for lipids (RR, 0.68; 95% CI, 0.56–0.83; p = .0001), and DEXA scanning (RR, 0.65; 95% CI, 0.45–0.94; p = .02). ADT prescription by a radiation oncologist, compared with a urologist, was associated with greater likelihood of DEXA scanning (RR, 1.43; 95% CI, 1.04–1.98; p = .03) but did not differ in testing for dysglycemia, lipids, or bone health serum. Increasing physician years of practice were associated with a lower likelihood of serum bone health serum tests (RR, 0.99 per 1 additional year of experience; 95% CI, 0.98–0.99; p = .01) and DEXA scanning (RR, 0.98; 95% CI, 0.97–0.99; p = .01). Finally, a more recent year of first ADT prescription was associated with a lower likelihood of testing for dysglycemia (RR, 0.98; 95% CI, 0.97–0.99; p = .0002) and lipids (RR, 0.98; 95% CI, 0.97–0.99; p ≤ .0001; Table 3).
Patient/disease factors
Adherence to testing was analyzed according to patient and disease factors (Table 3). Increasing patient age was associated with a significantly lower rate of testing for lipids (RR, 0.27; 95% CI, 0.11–0.66; p = .004), bone health serum tests (RR, 0.38; 95% CI, 0.17–0.86; p = .02), and DEXA scanning (RR, 0.69; 95% CI, 0.58–0.82; p < .0001). A greater number of GP visits in the year before ADT initiation (consistent with greater health care engagement) was associated with higher rates of testing for dysglycemia (RR, 1.03; 95% CI, 1.02–1.04; p < 0.0001), lipids (RR, 1.02; 95% CI, 1.01–1.02; p < .0001), and bone health serum (RR, 1.01; 95% CI, 1.004–1.013; p < .0001). Patient comorbidities influenced testing for dysglycemia and lipids only. A greater Charlson score was associated with a higher likelihood of testing for dysglycemia (RR, 1.78; 95% CI, 1.40–2.23; p < .0001) and lipids (RR, 1.53; 95% CI, 1.23–1.88; p < .0001); whereas hospitalization in the year before diagnosis was associated with a lower likelihood of testing for dysglycemia (RR, 0.66; 95% CI, 0.58–0.75; p < .0001) and lipids (RR, 0.67; 95% CI, 0.58–0.76; p < .0001). Lower neighborhood income quintile and patient residence in a rural setting did not appear to negatively affect the rates of testing.
Greater serum PSA was also associated with a lower rate of testing for dysglycemia (RR, 0.74; 95% CI, 0.68–0.80; p < .0001) and lipids (RR, 0.70; 95% CI, 0.65–0.75; p < .0001). Increasing disease stage was associated with a lower likelihood of lipid testing (RR, 0.82; 95% CI, 0.68–0.98; p = .04) but a greater likelihood of bone health serum testing only (RR, 1.46; 95% CI, 1.18–1.79; p = .0004). Disease stage did not influence the incidence of dysglycemia or DEXA testing. Finally, patients who had received prior local treatment (surgery, radiation, or both) were more likely to receive lipid testing (RR, 1.25; 95% CI, 1.04–1.51; p = .02) but not the other tests assessed.
DISCUSSION
In a large, population‐based sample of older men initiating ADT, we observed that adherence to guideline‐recommended testing of metabolic, cardiac, and bone health was poor. Our study revealed that, within 1 year of the index date, only 21.3% of patients received a bone density scan, 41.2% underwent bone health‐related serum tests, 51.3% completed a lipid profile, and 65.9% underwent dysglycemia testing. Overall, only 11.9% of patients received all of the recommended investigations.
As therapies for men with advanced prostate cancer continue to evolve, men are increasingly exposed to a greater duration of ADT and other androgen receptor axis–targeted agents. Among patients with prostate cancer, the second leading cause of death (after prostate cancer) was related to cardiovascular disease. 13 Appropriate testing and subsequent management of metabolic, cardiac, and bone health abnormalities may improve oncologic outcomes, including overall survival. 14 , 15 To our knowledge, our study is the first to evaluate the real‐world use of recommended testing to monitor and mitigate these treatment‐related toxicities.
In a previous survey of ADT prescribers in Canada, although they were still much below guideline‐based targets, physicians reported rates of metabolic, cardiovascular, and bone health testing that were substantially higher than in our study, which leveraged objective data to examine actual practice. 16 The differences between these studies may reflect a sampling bias of the survey, a select set of particularly engaged physicians who adhere closer to guidelines than the general community, or social desirability bias in which physicians report the answer they know to be correct, regardless of their actual behavior. Our study presents real‐world data demonstrating that only a minority of patients undergo the recommended complete testing within 1 year of ADT initiation. Although we observed that some physician/provider factors influenced the likelihood of testing, testing remained poor across all providers and settings. Although rates of testing were relatively stable from 2008 to 2019, there was an observed decrease in testing more recently (2020–2021), which may be attributed to a decrease in access to care during the coronavirus pandemic.
Although ADT is most often prescribed by specialists (urology, radiation oncology, medical oncology), patients are often evaluated more frequently by their primary care providers, who often deliver more generalized/holistic care with lower barriers to access. Our study revealed that an increasing number of visits to primary care in the year before ADT prescription was associated with greater rates of testing for dysglycemia, lipids, and bone health serum tests. Although adherence to testing was poor across the board, it should be noted that it was especially poor for bone density evaluation with DEXA scanning (21.3%) and bone health–related serum tests (41.2%); tests that are often not routinely done in the general population. In contrast, the adherence to testing for lipids (51.3%) and dysglycemia (65.9%) was greater, likely because of the existence of nonurologic indications for testing in our patient population. By nature of their training, PCPs may be more comfortable testing for, diagnosing, and subsequently managing lipid, dysglycemia, and bone health abnormalities. This suggests that primary care providers may play an important role in improving the delivery of care to patients on ADT, and engagement of PCPs through communication and education should be a priority. We advocate that PCPs should be informed when patients are started on ADT and that there may be adverse events associated with treatment. Different models of PCP engagement in cancer survivorship care have been described, including intervention‐focused primary care and the development of oncogeneralists (PCPs with additional training in survivorship care). 17 , 18 Further study and advocacy are required to address barriers to the integration of PCPs into the survivorship pathway, which include gaps in knowledge/skills, inconsistent exchange of information between oncologists and PCPs, and financial/administrative barriers.
On a broader systems level, we believe that quality‐improvement initiatives are required to characterize and reduce barriers involved with testing (knowledge gaps, costs, access to laboratories) and to incentivize care providers. Financial incentivization by linking funding with compliance to testing and the subsequent management of metabolic, cardiac, and bone health of patients on ADT is one possible strategy that may further enhance the quality of prostate cancer survivorship care. 19
Increasing patient age was associated with lower rates of testing. This trend is concerning because the elderly are at a particularly increased risk of major adverse cardiac events, falls, and fragility fractures. Efforts must be made to improve testing in this population, understanding that major adverse cardiac events and fractures in these patients can lead to permanent impairment or death.
One notable trend was that increasing physician years of practice were inversely related to the rate of testing for bone health and density parameters. This is in keeping with prior studies in other medical disciplines demonstrating that more experienced physicians often practice in patterns that are not in keeping with guidelines. 16 We believe that this gap can be addressed through continued medical education.
Our study has limitations. First, because the Ontario Drug Benefit program only covers patients older than 65 years, we were unable to examine patients younger than 65, which limits the generalizability of our results. However, the population studied represents greater than 60% of patients who have prostate cancer in Ontario and a population with a greater risk of ADT‐induced toxicity. Furthermore, because our study captures only insured persons, our findings may be an overestimate of testing adherence. Second, the intent of the care provider when ordering the tests is unknown. There are several other nonurologic indications for dysglycemia, lipid, and bone health testing; therefore, our findings should not be interpreted as intentional testing and likely represent an overestimate of intentional, guideline‐concordant testing. Finally, despite our efforts to identify major prescriber and patient factors that may influence outcomes, unmeasured confounders for may exist because of the retrospective nature of this study.
Despite these limitations, our findings provide evidence that a significant gap exists between guideline recommendations, physician‐reported adherence, and real‐world administration of lipid, glucose, and bone health tests in men on ADT. Although physician/provider and patient/disease factors may influence the likelihood of testing, overall adherence across all providers remains low. Physician education, PCP engagement, and systems quality‐improvement initiatives are required to improve the care of men on ADT and reduce the morbidity associated with treatment. Future studies evaluating the efficacy of such educational quality‐improvement interventions are needed.
AUTHOR CONTRIBUTIONS
Ahmad Mousa: Conceptualization, data curation, writing–original draft, writing–review and editing, project administration, methodology, visualization, and software. David‐Dan Nguyen: Conceptualization and writing–review and editing. Aly‐Khan Lalani: Writing–review and editing. Raj Satkunasivam: Writing–review and editing. Khatereh Aminoltejari: Writing–review and editing. Amanda Hird: Writing–review and editing. Soumyajit Roy: Writing–review and editing. Scott C. Morgan: Writing–review and editing. Shawn Malone: Writing–review and editing. Andrea Kokorovic: Writing–review and editing. Luke T. Lavallée: Writing–review and editing. Melissa Huynh: Writing–review and editing. Bobby Shayegan: Writing–review and editing. Di Maria Jiang: Writing–review and editing. Geofrey Gotto: Writing–review and editing. Rodney H. Breau: Writing–review and editing. Girish S. Kulkarni: Writing–review and editing. Alexandre Zlotta: Writing–review and editing. Christopher J. D. Wallis: Writing–review and editing, conceptualization, methodology, data curation, investigation, validation, formal analysis, supervision, funding acquisition, and resources.
CONFLICT OF INTEREST STATEMENT
Aly‐Khan Lalani reports research grants from Bristol Myers Squibb, BioCanRx, Novartis, Roche, Ipsen, and EMD Serono; and speaker's honoraria from AbbVie, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, EMD Serona, Ipsen, Janssen, McKesson Corporation, Merck, Novartis, Pfizer, Roche, and TerSera Therapeutics outside the submitted work. Soumkyajit Roy reports research grants from the Prostate Cancer Foundation and the Swim Across America Foundation and speaker's honoraria from Varian Medical Systems outside the submitted work. Scott C. Morgan reports institutional research funding from Knight Therapeutics Inc. and personal/consulting fees from Astellas, Bayer, Janssen, and TerSera Therapeutics outside the submitted work. Shawn Malone reports personal/consulting fees from Bayer and Janssen Biotech outside the submitted work. Andrea Kokorovic reports personal/consulting fees from Astellas Pharma Canada, AstraZeneca, Bayer, CG Oncology, EMD Serono, Ferring Pharmaceuticals Ltd., Janssen Pharmaceuticals, Johnson & Johnson, Knight Therapeutics Inc., Pfizer Canada Inc., TerSera Therapeutics, and Tolmar Pharmaceuticals Inc.; and travel support from Janssen Pharmaceuticals and TerSera Therapeutics outside the submitted work. Luke T. Lavallée reports personal/consulting fees from AbbVie, Astellas Pharma Canada, Ferring, Janssen Biotech, Sumimoto Dainippon Pharma Oncology, and Tolmar Pharmaceuticals Inc.; and support for other professional activities from TerSera Therapeutics outside the submitted work. Melissa Huynh reports support for professional activities from Astellas Pharma Canada and Knight Therapeutics Inc. outside the submitted work. Di Maria Jiang reports research grants from Astellas, TerSera Therapeutics, Amgen Canada, and Bayer; personal/consulting fees from Seagen, Bayer, EMD Serona, Pfizer Canada Inc., McKesson Corporation, AstraZeneca Canada, Merck, Janssen Biotech, and Novartis Advanced Accelerator Applications; speaker's honoraria from Seagen, Bayer, Janssen Biotech, EMD Serono, Amgen Canada, AstraZeneca, Astellas, and Novartis Advanced Accelerator Applications/Medunik; service on a data safety monitoring/advisory board at Seagen, Bayer, EMD Serono, Pfizer, McKesson Corporation, AstraZeneca, Merck, Janssen, and Novartis Advanced Accelerator Applications; and support for other professional activities from Knight Therapeutics Inc. outside the submitted work. Geoffrey Gotto reports personal/consulting fees from Astellas Pharma Canada, AstraZeneca Canada, Bayer, Bristol Myers Squibb Canada, EMD Serono, Ferring Inc., Janssen Pharmaceuticals, Merck, and Tolmar Pharmaceuticals Inc.; travel support from Janssen Pharmaceuticals; and expert witness fees from Janssen Pharmaceuticals outside the submitted work. Girish S. Kulkarni reports personal/consulting fees from AbbVie, Astellas Pharma Canada, AstraZeneca, Bristol Myers Squibb Canada, CG Oncology. EMD Serono, enGene, F. Hoffman‐La Roche, Ferring Pharmaceuticals Ltd., Johnson & Johnson Health Care Systems Inc., Knight Pharmaceuticals, Merck Sharp & Dohme, Novartis, Pfizer Canada Inc., Photocure Inc., TerSera Therapeutics, Tolmar Pharmaceuticals Inc., and Verity Pharmaceuticals Inc. outside the submitted work. Christopher J. D. Wallis reports research funding from Knight Therapeutics Inc., Tolmar Pharmaceuticals Inc., and Bayer; grants/contracts from AbbVie; personal/consulting fees from Janssen Global Services LLC, Nanostics Inc., Precision Point Specialty LLC, and Sesen Bio; and honoraria/travel support from AbbVie, Astellas, AstraZeneca Canada, Bayer, EMD Serono, Haymarket Media, the Healing and Cancer Foundation, Knight Therapeutics, Merck, Science & Medicine Canada, Sesen Bio, TerSera Canada, and Tolmar Pharmaceuticals Canada outside the submitted work. The remaining authors disclosed no conflicts of interest.
Supporting information
Supplementary Material
Supplementary Material
ACKNOWLEDGMENTS
This study was supported by investigator‐initiated research grants from Tolmar Pharmaceutiques Canada and Knight Therapeutics.
Mousa A, Nguyen D‐D, Lalani A‐K, et al. Metabolic, cardiac, and bone health testing in patients with prostate cancer on androgen‐deprivation therapy: A population‐based assessment of adherence to therapeutic monitoring guidelines. Cancer. 2025;e35606. doi: 10.1002/cncr.35606
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the Institute for Clinical Evaluative Sciences. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors with the permission from the Institute for Clinical Evaluative Sciences.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material
Supplementary Material
Data Availability Statement
The data that support the findings of this study are available from the Institute for Clinical Evaluative Sciences. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors with the permission from the Institute for Clinical Evaluative Sciences.