Despite the widespread use of PADT in localized (T1-T2) prostate cancer,3, 4
there is little information regarding the clinical outcomes associated with this practice. Our study was designed to evaluate the association between PADT and prostate cancer-specific and overall survival in men who did not initially receive definitive therapy (eg., surgery or radiation) for localized prostate cancer.
Utilizing instrumental variable analysis as one of the best available means of controlling for both measured and unmeasured confounding variables, we found no overall survival benefit for elderly men with localized prostate cancer receiving PADT. Results obtained with a traditional Cox model that adjusts only for measured confounding factors differed from those with the instrumental variable approach. These observations suggest that there is significant unaccounted residual bias associated with traditional analytical methods in this setting and that the instrumental variable approach may be particularly advantageous. In addition, one potential advantage of this study over clinical trials is that it includes “real-world” patients that would often be excluded from clinical trials even though these patients would receive the treatment in practice.
An interesting outcome of our study was the observation that cancer-specific survival, but not overall survival, appeared worse for men with lower risk cancer treated with PADT. This observation had also been previously documented in a randomized study of PADT in men with T0-T4 disease.36
The authors suggested several possible explanations for this finding, including competing causes of death, misclassification, and statistical variation.36
Another possibility could be that suppression of moderately- or well-differentiated cells not destined to harm a patient’s overall survival may allow for the establishment or overgrowth of more rapidly growing malignant clones (as seen in preclinical models)37–39
that increase the probability of death due to prostate cancer instead of a competing cause of death. As is evident from , the likelihood of death from competing causes normally exceeds the risk of death from prostate cancer in this population; this balance may be altered if PADT preferentially allows for the establishment or overgrowth of a more malignant fraction of a tumor.
Our study had some limitations. The study was limited to men aged ≥66 years and the results could differ for younger men. The SEER-Medicare database does not capture information on antiandrogen use. Therefore, patients utilizing antiandrogens only might be misclassified into the conservative management cohort and, because a previous study40
suggested that antiandrogens may result in adverse outcomes in these patients, it is possible that the conservative management group performed unusually poorly. However, previous data from another large database (CaPSURE)41
showed that the use of antiandrogens as sole treatment for localized prostate cancer is relatively uncommon (~2%) and it is unlikely that this small subset could alter the outcomes of the conservative management group overall.
Just like the success of a randomized study is dependent on factors such as the attainment of a sufficient sample size to balance both measured and unmeasured characteristics in different treatment groups, the use of IVA to balance treatment group characteristics (eg., PSA, family history, diet, body mass, etc.) depends on finding a suitable, partly random, varying factor (instrumental variable) that can be used to balance treatment groups. Our instrumental variable (high- and low-PADT use HSAs) had excellent properties. However, as in randomized studies, it is possible that some unmeasured factors may have been somewhat imbalanced between groups. Nonetheless, sensitivity analyses, using various geographic-based instruments and removing patients with other cancers or comorbidity scores >0, yielded similar results and suggested that the analyses were robust. However, it is still possible that the use of an instrumental variable approach in this setting does not adequately control for unknown confounding variables and therefore, if possible, a randomized trial should be considered.
There are very few data comparing PADT with conservative management, or any other established treatment option (eg., surgery or radiation), in men with localized (T1-T2, NO, M0) prostate cancer even though the popularity of PADT has grown the most in this population, increasing 2-3-fold in recent years.3
Published studies have generally not provided data specific for localized (T1-T2) disease and have had limited sample sizes.42, 43
The largest published study describing PADT use among T1-T2 patients was descriptive, non-comparative, and had limited follow-up.41
The randomized Early Prostate Cancer (EPC) trial44
had a large subset of patients with T1-T2 disease, but a non-traditional form of PADT (ie., bicalutamide) was employed. Results from this trial revealed a trend toward decreased overall survival in patients treated with PADT.40
The Veterans Administration Co-operative Urological Research Group (VACURG) study45
also utilized a non-conventional form of PADT (diethylstilbestrol). Results were inconsistent, with benefit in T2 disease but harm in T1 disease. In a related randomized study (European Organization for Research and Treatment of Cancer (EORTC) Trial 30891) that included patients with both localized, and advanced disease (eg., T0-4, N0-2),36
a modest overall survival benefit was found in favor of PADT but further analyses suggested that this benefit was associated with a group of patients with high-risk disease.46
Studies by the Medical Research Council (MRC),47
the EORTC 30846,10
and the Swiss Group for Clinical Cancer Research 48
focused on patients with more advanced disease. In general, though the designs, therapies and settings vary significantly from our study, the findings of these previous studies are inferentially consistent with our documentation of a lack of overall benefit, and some suggestion of potential benefit in high-risk or advanced disease subgroups.
In summary, our analyses suggest that PADT is not associated with improved survival among the majority of elderly men with T1-T2 prostate cancer. The significant side effects and costs associated with PADT, along with our finding of a lack of overall survival benefit, suggest that healthcare providers and their patients should very carefully consider the rationale for initiating PADT in their elderly patients with T1-T2 prostate cancer.