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Importance听 Although intermittent androgen-deprivation therapy (ADT) has not been associated with better overall survival in prostate cancer (PC), it has the potential for lower adverse effects. To our knowledge, the incidence of long-term adverse health events has not been reported.

Objective听 To examine long-term late events in elderly patients randomized to intermittent or continuous ADT to determine whether late cardiovascular and endocrine events would be lower in patients treated with intermittent ADT.

Design, Setting, and Participants听 This was a secondary analysis of a multicenter clinical trial using linkage between patient data from S9346, a randomized SWOG trial of intermittent vs continuous ADT in men with metastatic PC, and corresponding Medicare claims.

Exposure听 Intermittent or continuous ADT.

Main Outcomes and Measures听 The main outcome was to identify long-term adverse health events by treatment arm. Patients were classified as having an adverse health event if they had any hospital claim鈥攐r at least 2 physician or outpatient claims at least 30 days apart鈥攆or any of the following diagnoses: ischemic and thrombotic events, endocrine events, sexual dysfunction, dementia, and depression. To incorporate time from beginning of observation through evidence of an event, we determined the cumulative incidence of each event. Competing risks Cox regression was used, adjusting for covariates.

Results听 In total, 1134 eligible US-based male patients with metastatic PC were randomized to continuous vs intermittent ADT in the S9346 trial. A total of 636 of trial participants (56%) had at least 1 year of continuous Medicare parts A and B coverage and no health maintenance organization participation. The median age was 71.3 years. The most common long-term events were hypercholesterolemia (31%) and osteoporosis (19%). The 10-year cumulative incidence of ischemic and thrombotic events differed by arm; 24% for continuous and 33%for intermittent ADT (hazard ratio, 0.69; 笔鈥�=鈥�.02). There were no statistically significant differences by arm in any other adverse health events.

Conclusions and Relevance听 Contrary to our hypothesis that intermittent ADT would reduce long-term health-related events compared with continuous ADT, we found that older men assigned to intermittent ADT had no apparent reduction in bone, endocrine, or cognitive events and an increased incidence of ischemic and thrombotic events.

Trial Registration听 clinicaltrials.gov Identifier:

The methodology to compare experimental with standard therapies through large, randomized clinical trials in a network of large cooperative oncology groups has been refined and improved over decades. The result has been notable improvements in patient survival, and a dramatic increase in the number of cancer survivors in the United States, especially survivors of breast and prostate cancer (PC).¹ Such trials routinely capture detailed patient information on prognostic factors for eligibility, detailed treatment information, short-term acute toxic effects and adverse effect information, cancer recurrence dates, and dates of death. However, the ascertainment of long-term adverse health events following treatment is often a challenge. Ascertainment of adverse health events require the evaluation of large numbers of patients for many years following primary treatment and is typically prohibitively expensive. In addition, some events may not be anticipated or recognized and therefore not attributed to the intervention.

Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists or bilateral orchiectomy, is the mainstay of treatment of metastatic PC, and its use has been increasing steadily over time.² Although ADT improves outcomes in patients with PC, it is associated with an array of adverse effects, including sexual dysfunction, bone demineralization, cardiovascular disease, metabolic complications, cognitive changes, and diminished quality of life.³ To study these outcomes, investigators have used large administrative databases, such as the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database, that contain clinical, demographic, and medical claims data. With regard to skeletal complications, the incidence of vertebral fractures increases by 40% in men on ADT, with longer duration associated with increased risk.⁴ Incident diabetes mellitus (DM) is likely an adverse effect of ADT, with 2 reports showing risks of new-onset DM ranging from 36% to 49%.^5,6 Increased cardiovascular mortality has also been reported. In a recent study, GnRH agonist use was associated with increased risk of coronary heart disease (adjusted hazard ratio [HR], 1.16; P鈥�<鈥�.001), myocardial infarction (adjusted HR, 1.11; P鈥�=鈥�.03), and sudden cardiac death (adjusted HR, 1.16; P鈥�=鈥�.004).⁵ In addition, an increased risk of acute kidney injury has recently been reported with ADT.^7,8 These observational studies are often limited owing to selection bias and lack of detailed information on treatments and prognostic factors.

Efforts to minimize toxic effects have focused on the use of intermittent ADT in which the GnRH agonist is started and stopped cyclically to allow androgen levels to return to normal, reducing the hypogonadal period, and potentially reducing adverse effects. In general, patients can experience improvements in quality of life, sexual function, anemia, weight gain, hot flashes, and psychological well-being while not taking ADT; symptoms generally return when ADT is restarted.⁹ In 2013, results of 2 randomized clinical trials intensified the controversy with regard to these 2 therapies. In patients with metastatic PC, SWOG 9346 randomized 1535 individuals to continuous or intermittent ADT; while there was a short-term benefit for intermittent therapy in terms of impotence and mental health, intermittent ADT was inferior in terms of survival.¹⁰ In nonmetastatic cancer, a randomized clinical trial found the 2 treatments to be equivalent for cancer control but that intermittent ADT had improved endocrine symptoms. Long-term outcomes were not reported.¹¹

To overcome some of the challenges of selection and treatment indication bias from observational studies, we have linked the clinical records for patients with PC in SWOG trials to their Medicare administrative claims. Given that older patients are more likely to experience long-term complications from ADT, we examined long-term late adverse events in elderly patients randomized to intermittent or continuous ADT. Our hypothesis was that late cardiovascular and endocrine events would be lower in patients receiving intermittent ADT.

Box Section Ref ID

We studied patients from SWOG study S9346, a randomized clinical trial of intermittent vs continuous ADT; the study design was previously described.¹⁰ In brief, men with newly diagnosed, metastatic, hormone-sensitive PC were initially registered if they had a performance status of 0 to 2 and a prostate-specific antigen (PSA) level of at least 5 ng/mL. After 7 months of induction GnRH and an antiandrogen, patients whose PSA level fell to 4 ng/mL or less were randomized to continuous vs intermittent ADT. Patients randomized to the intermittent group discontinued ADT and then resumed once the PSA level increased, and discontinued again if, after 7 months, the PSA level fell again to 4 ng/mL or less. Patients were excluded if they had active medical illness that precluded protocol treatment.

Prospective clinical trial data were obtained according to protocol specifications and included demographic factors (age [<65 years vs 鈮�65 years]), race (black vs white vs other), and data on prognostic factors used in stratification performance status (based on a Zubrod score of 0-1 vs 2), extent of disease (minimal vs extensive), and type of prior hormone therapy (neoadjuvant vs finasteride vs neither).¹⁰ Patients on the trial were followed for 10 years after initial registration or until death, whichever came first.

To identify long-term adverse health events following treatment, we established a linkage between the SWOG clinical records and Medicare claims data. To establish the link, Medicare claims must have matched the SWOG clinical record according to social security number, sex, and date of birth. To be included, patients must have had at least 1 year of continuous Medicare Parts A and B coverage to ensure a sufficient minimum amount of coverage to identify potential adverse health events. While enrolled in Medicare, patients must not have had health maintenance organization (HMO) coverage for 1 continuous year because HMO providers do not submit data to the Centers for Medicare and Medicaid Services. To increase the amount of available follow-up claims information, we included patients with at least 1 year of Medicare claims at any time in the follow-up period; thus, patients may not have been 65 years or older at randomization but instead could have aged into the Medicare claims cohort. Identification of late adverse effects of treatment relied on physician supplier Part B (ie, carrier), hospital outpatient, and hospital inpatient Medicare claims records. Long-term events were determined using Healthcare Common Procedure Coding System and International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. We established the set of codes used to identify adverse events prior to the analysis; codes were chosen based on the literature and clinical relevance. The date of death was based on the SWOG clinical record when available and on Medicare records when SWOG data were not available. Although S9346 was an international clinical trial because the study relies on a linkage to Medicare claims data, we analyzed only US-based patients. Approval to conduct this research was obtained from the institutional review board of Cancer Research and Biostatistics (Seattle, Washington).

Patients were classified as having an adverse health event if they had any hospital claim (Current Procedural Terminology codes)鈥攐r at least 2 physician or outpatient claims at least 30 days apart鈥攆or any of the following diagnoses: ischemic and thrombotic events (acute myocardial infarction, ischemic heart disease, thrombosis); endocrine events (DM, DM with sequelae, hypercholesterolemia, obesity, osteoporosis, fractures, any bone event); sexual dysfunction, dementia, and depression; and acute kidney injury (eTable 1 in the Supplement).^7,12,13 Superficial thrombosis was removed owing to a small number of events. A history of a specific event was defined as any claim within 12 months before study registration. For the analysis of a given adverse event, patients with evidence that the event occurred within 1 year prior to study randomization (ie, preexisting comorbid conditions) were excluded.¹⁴ This was done to emphasize the incidence of new events.

To incorporate time from beginning of observation until evidence of an event, and to account for potential competing risks of death, we analyzed the cumulative incidence from randomization. Data were left truncated given that there may have been a gap between randomization and the initiation of Medicare claims coverage, especially for patients younger than 65 years at randomization. For each event, multivariable competing risk regression analysis was conducted, based on Cox regression (procedure proc phreg; SAS statistical software, version 9.4), to examine time-to-event adjusting for covariates and incorporating left-truncated and right-censored data.^15,16 The subdistribution HRs, 95% CIs, and P values were generated for each event. In each model, the adverse health event was considered the event of interest and deaths were analyzed as a competing risk; otherwise, patients were censored at their date of last contact if no death was observed. Model covariates included demographic and stratification factors as previously specified. To examine event rates alone by arm (rather than time to event), multivariable logistic regression models were used, adjusting for the same demographic and stratifications as covariates.

A total of 1134 eligible patients from the United States were randomized to continuous or intermittent ADT on S9346. We linked 748 of these patients to Medicare claims, of which 636 (56% of total US-based patients) had at least 1 year of continuous Medicare parts A and B coverage and no HMO participation. This cohort comprised the evaluable patient set for this analysis.

Patient characteristics by intervention assignment are shown in Table 1. No notable imbalances by arm were observed by age, ethnicity, weight, performance status, extent of disease, or prior hormonal therapy. Most patients had a body mass index, calculated as weight in kilograms divided by height in meters squared, higher than 25 (76%), took no prior hormonal therapy (86%), and had a performance status of 0 to 1 (98%). Patients in this subset had a similar profile to the parent study population. At baseline, there was a small difference in the proportion of patients with DM with sequelae (4% on the continuous arm vs 1% on the intermittent arm; P鈥�=鈥�.02). Baseline event rates were otherwise similar between the treatment groups for all other events examined.

We examined whether survival patterns in the subset of patients with Medicare claims could have influenced ascertainment of adverse health events by arm. The HR of death for intermittent to continuous therapy was 1.14 (95% CI, 0.94-1.38; P鈥�=鈥�.18) in those with Medicare claims and 1.09 (95% CI, 0.93-1.27; P鈥�=鈥�.31) in those without Medicare claims. There was no evidence that these survival patterns by arm differed by Medicare claims group (interaction P鈥�=鈥�.79).

The adverse health events following ADT observed through Medicare claims are shown in Table 2. Overall, the most common events were endocrine (41% of events), especially hypercholesterolemia (31%). Bone-related events were also common with 19% of men diagnosed as having osteoporosis and 14% having a fracture. Ischemic and thrombotic events were also common (27% of events) with 10% having a claim for ischemic heart disease.

The 10-year cumulative incidence of any ischemic or thrombotic event was 24% for continuous ADT and 33% for intermittent ADT (HR, 0.69; P鈥�=鈥�.02). The 10-year cumulative incidence of ischemic heart disease alone was 7% for continuous ADT and 12% for intermittent ADT (HR, 0.55; P鈥�=鈥�.05). There were no statistically significant differences by arm in the cumulative incidence of any other events (Table 2). Dementia was observed in 8% of patients receiving continuous ADT and 4% of those receiving intermittent ADT (HR, 1.98; P鈥�=鈥�.07), however these results should be interpreted with caution given the low number of reported events. Plots of the predicted cumulative incidence functions for the common adverse health events are shown in the Figure.

To rule out the impact of postprogression interventions on patterns of adverse health events, we examined the average impact of randomized treatment on the cumulative incidence of adverse events prior to progression. The median time to progression among patients who progressed was 2.2 years. To avoid selection bias, we truncated follow-up at this time point for all patients. The results were consistent with those of the primary results (Table 3), suggesting that observed differences by arm were consistent throughout follow-up.

One concern about the primary analysis by randomized assignment is that patients in the intermittent ADT arm may not have received any additional therapy. As a sensitivity analysis, we excluded the 12% of intermittent ADT arm patients with no evidence of receipt of any antiandrogen deprivation consolidation therapy. No substantive differences compared with the primary analysis results were evident (see eTable 2 in the Supplement); however, the increased incidence of dementia in the continuous ADT arm was now significant (HR, 2.51; P鈥�=鈥�.03). To assess whether potential differences by arm in the duration of ADT influenced the results, we included a time-dependent covariate in the multivariable Cox regression models indicating whether the event occurred within 6 months of the completion of ADT. The regression model results by arm were similar (data not shown). Also, in the intermittent ADT arm, there was no difference in the mean percentage of time receiving therapy between those with and without ischemic or thrombotic events (47% vs 47%; P鈥�=鈥�.86). Finally, for severe thrombosis, fracture, and acute kidney injury, there was no substantial differences in the results when only procedure codes, rather than the combination of diagnosis and procedure codes, were used to identify events (data not shown).

Using a novel linkage between elderly patients enrolled in SWOG S9346 and Medicare claims, we have shown that known complications from ADT were common in men on both treatment arms. Despite a belief that intermittent androgen deprivation would reduce complications from ADT, we found no difference between arms for the endocrine, psychiatric, sexual, or neurologic adverse events. In addition, we found an increased cumulative incidence of ischemic and thrombotic events in patients receiving intermittent ADT.

Prior, population-based observational studies have shown an increased risk of cardiovascular disease among men with PC treated with ADT. In a study¹⁷ of patients treated in the Veterans Healthcare Administration, ADT was associated with an increased risk of coronary heart disease (adjusted HR, 1.19), myocardial infarction (adjusted HR, 1.28), and sudden cardiac death (adjusted HR, 1.35). Similar results have been seen with SEER-Medicare.⁵ We found a higher cumulative incidence of these events among men receiving intermittent ADT compared with those receiving continuous ADT. This result was unexpected. In 2 prior trials^18,19 comparing intermittent ADT with continuous ADT, patients in the continuous ADT arm had a higher risk of cardiovascular mortality. Of interest, however, results from a phase 2 study²⁰ found patients treated with intermittent ADT to have an increased incidence of myocardial infarction during their off-treatment period (4.6%) compared with during their on-treatment period (2.8%), but these differences were not statistically significant and patients were evaluated only until disease progression. The biologic reasons for an increase in ischemic events in elderly patients treated with intermittent ADT are unclear, but changes in the coagulation cascade have been reported with lowering of testosterone during ADT as well as with increasing estrogen (after stopping ADT).²¹ The risk of vascular events is highest initially, before coagulation cascade homeostasis is reached.^21,22 In addition, a large study²³ from the Swedish national health registry reported that the risk of incident cardiovascular disease was highest in the first 6 months after initiation of ADT in men with PC, particularly in those with a history of cardiovascular disease. While patients in our study had a high rate of baseline DM and hypercholesterolemia, there was no difference in claims between the treatment groups.

Compared with patients not receiving ADT, the incidence of vertebral fractures increases by 40% in men prescribed ADT, with longer duration associated with increased risk.⁴ In our study, bone events (osteoporosis or fracture) were common in both the intermittent and continuous ADT arms but were not different between arms. The cumulative incidence of these events was slightly higher than in a previous report²⁴ with shorter follow-up. The rates of skeletal events may be an underestimate of actual rates because all patients were randomized after receiving 7 months of ADT. It is also possible that events were misclassified as PC progression. A prior study²⁵ has shown that the largest decline in bone mineral density occurs during the first ADT on-treatment period with substantial heterogeneity in subsequent cycles. It is also possible that there were inaccuracies in the submission of the claims. Finally, it was not known which patients were receiving bisphosphonate therapy, which may have affected the fracture rate.

It is assumed that the main advantage of intermittent ADT seems to be a reduction in short-term symptoms while a patient is receiving ADT and reduced ADT cost. In a recent systematic review²⁶ of trials comparing intermittent with continuous ADT, 6 of the 9 trials evaluated quality of life and treatment-related adverse effects. In some of the trials, patients prescribed intermittent ADT had improved sexual function, physical activity, and general well-being, but these results often did not persist over time, and there was significant superiority of overall quality of life only for men receiving intermittent ADT in 1 study. In the results from the primary study¹⁰ there were no differences in grade 3 or 4 treatment-related adverse events between the intermittent (30.4%) and continuous (32.7%) ADT groups, and no difference in cardiovascular events. It is possible that differences in severity may have resulted in the submission of claims for events that were not captured by event reporting; however, we would expect that bias to be similar by arm given the random assignment of treatments. It is also possible that not all toxic effects are captured in clinical trials, especially if the event was unknown to the primary investigative team. This difference may increase as a patient is further out from randomization and study monitoring becomes less frequent.

We acknowledge several limitations of our study and of the Medicare database in general. Although we required participants to have 2 claims to reduce misclassification bias, a process routinely performed in studies using administrative claims, it is still possible that not all patients with Medicare claims had the complication we assigned.^27-29 It is also possible that the patients who experienced toxic effects did not have claims associated with it. Medicare lacks data on the severity of the toxic effects; therefore, it is possible that these complications were mild and not life-threatening and therefore not known to research staff reporting adverse events. Alternatively, because mild complications are sometimes not captured with billing data, our findings may have underestimated some complications in these older men. However, we would anticipate that this misclassification bias would not differ between randomly assigned treatments. We did not adjust for multiple comparisons; thus, more marginal results may be more likely due to chance. Any positive findings should be confirmed in other studies. It is also possible that our results are not generalizable to younger patients in whom complication rates may be lower; however, PC is more common in elderly men. Finally, all of the patients were enrolled in a randomized clinical trial, and therefore these results may not be generalizable to all patients who did not meet eligibility criteria for S9346. Most patients had a performance status of 0 or 1.

This study has several unique strengths. Unlike previous observational studies of late toxic effects, our study benefited from random assignment between the arms, reducing the potential for unmeasured confounders to influence the treatment decisions as well as the outcomes. In addition, the extent of disease and prior therapy were known for all participants. Also, evaluation of intermittent ADT with observational data would be complex because PSA results and the reason for the treatment gap would not be captured in billing claims. Finally, we used methodology in defining outcome events similar to those of many prior investigators using claims data.

We did not find that patients randomly assigned to intermittent ADT had consistently fewer long-term adverse health events compared with those assigned to continuous ADT. In fact, unexpectedly, we observed that elderly men assigned to intermittent ADT had an increased incidence of ischemic and thrombotic events. If these finding are confirmed, given the failure of the parent study to prove its noninferiority end point, clinicians should be cautious about using intermittent ADT therapy in older men with metastatic PC given our inability to demonstrate a reduction in long-term adverse health events, the primary rationale for intermittent ADT.

Corresponding Author: Dawn L. Hershman, MD, MS, Columbia University Medical Center, 161 Fort Washington Ave, 10-1068, New York, NY 10032 (dlh23@columbia.edu).

Accepted for Publication: September 22, 2015.

Published Online: December 23, 2015. doi:10.1001/jamaoncol.2015.4655.

Author Contributions: Dr Hershman (principal investigator) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hershman, Unger, Ramsey, Tangen, Barlow, Thompson, Hussain.

Acquisition, analysis, or interpretation of data: Hershman, Unger, Wright, Ramsey, Till, Tangen, Barlow, Blanke, Hussain.

Drafting of the manuscript: Hershman, Unger, Wright, Ramsey, Tangen, Hussain.

Critical revision of the manuscript for important intellectual content: Hershman, Unger, Till, Barlow, Blanke, Thompson, Hussain.

Statistical analysis: Unger, Wright, Till, Barlow.

Obtained funding: Hershman, Unger, Ramsey.

Administrative, technical, or material support: Unger, Blanke, Thompson, Hussain.

Study supervision: Hershman, Ramsey, Tangen, Thompson, Hussain.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Hershman and Dr Wright are recipients of grants from the National Cancer Institute (NCI R01CA134964 and NCI R01CA169121-01A1, respectively), and Division of Cancer Prevention, NCORP Research Base grant 1UG1CA189974-01.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.