Nearly 29,000 men are expected to die of the prostate cancer in 2003, more than those felled by any other neoplasm except lung cancer,1
and evidence increasingly suggests that early treatment can decrease cancer-specific mortality. A recent trial randomizing patients with clinically-detected prostate tumors to RP or WW found that RP yielded a 6.6% reduction in disease-specific mortality; a comparable reduction in overall survival was not statistically significant, although the study was underpowered with respect to this secondary outcome.8
Non-randomized cohort trials of RP, EBRT, and brachytherapy have consistently demonstrated excellent long-term disease-free survival rates for low-risk patients.5–7
Although these studies have offered evidence of the success of local therapy in select groups of patients, other recent papers in both the urologic and general medical literature have paid increasing attention to the question of overdiagnosis in prostate cancer. There exists general agreement that some proportion of patients diagnosed with prostate cancer would not suffer significant adverse impact to the length or quality of their lives were the cancer never detected. Estimates of the overdiagnosis rate vary dramatically depending on such factors as the definition of overdiagnosis used, variation in rates and patterns of cancer screening, the average lead time between screening and clinical presentation, and secular trends in cancer incidence.4,18,19
, Perhaps the best estimate to date was recently reported by Etzioni et al, who calculated overdiagnosis rates of 15% among white men and 37% among black men.4
However, what should be considered in these discussions is that overdiagnosis is a problem primarily to the extent that it leads to the over-treatment of patients with tumors unlikely to reduce their life expectancy or quality of life. A major challenge in prostate cancer research, therefore, remains distinguishing those at mortal risk from a curable cancer from those harboring more indolent tumors. While biomedical research continues to advance toward the goal of better tissue-, serum-, and urine-based prognostic markers, algorithms based on the clinical variables measured in standard practice have steadily progressed in sophistication and currently are the primary means of risk stratification.
Compared with higher risk groups, there exists relatively good agreement among various classification schemes regarding the definition of low-risk patients. Using the D’Amico classification we have employed in this study, a low-risk patient should expect 5-year disease-free survival rates after surgery better than 85%.13
Likewise, under the Kattan nomogram,20
these patients would have 5-year recurrence-free survival rates of 81–96%. Within the low-risk group, stage T1c carries a better prognosis than does T2a disease; likewise, lower PSA and Gleason score within the low-risk ranges predict better long-term recurrence free survival.13,20
A previous study from CaPSURE demonstrated that the proportion of patients diagnosed with low-risk disease has risen dramatically in the PSA era.21
In the present analysis, we found that even within this group, both stage and PSA at diagnosis have fallen significantly. While Gleason scores have risen, this has been shown to be at least in part an artifact of changes over time in pathologists’ grading methods.22
The sharp fall in T1a and T1b tumors, from over 10% to 2% of low-risk cases, is of tangential interest: this trend is likely attributable to a combination of the high prevalence of PSA screening among benign prostatic hypertrophy patients23
and to the contemporary decline in surgical management of this condition, thus reducing the incidence of prostate cancers incidentally identified in transurethral resection prostate specimens.
The American Urological Association’s clinical practice guidelines for prostate cancer suggest that localized prostate cancer should be managed with one of three local treatment options—RP, EBRT, or brachytherapy—or with observation.24
Although the guidelines were published in 1995, these remain the modalities whose use is best supported by the medical literature. While they have been and remain the strategies most commonly employed for the management of low-risk disease, we have identified dramatic shifts over time in the proportional frequency with which they are employed. Utilizations rates for RP, EBRT, and observation have all fallen significantly, with the greatest absolute drop (12.2%) in RP use, and large proportional declines in EBRT (57.7%) and observation (42.8%) use. There have been concomitant sevenfold and four-fold increases in the rates of brachytherapy and PADT use.
In our analysis, 18.1% of the low-risk patients overall received androgen ablation, either as monotherapy or as neoadjuvant therapy prior to definitive local treatment. In the AUA practice guidelines,24
PADT is considered to be an experimental approach in the setting of localized disease. Indeed, eight years after the guidelines’ publication, while androgen deprivation remains the mainstay of therapy for recurrent and metastatic prostate cancer, few studies have formally evaluated its use as monotherapy for localized disease. Three extant analyses reported favorable rates of PSA control, but all were non-randomized cohort studies of selected patients medically unfit for or otherwise averse to standard local treatment.25–27
To date no trials have compared PADT to observation or to local treatment strategies in terms of oncologic or quality of life outcomes.
A large study has found significant benefit for immediate versus deferred treatment of locally advanced or metastatic prostate cancer.28
Good evidence moreover supports the use of NADT in association with EBRT in high risk disease,29,30
and investigators have recently reported favorable experience using NADT with RP for locally advanced disease.31
Other recent studies in patients with more favorable risk factors, in contrast, have demonstrated that NADT prior to RP does not improve outcomes.32,33
The benefit for NADT prior to EBRT, likewise, appears to be restricted to patients with higher risk tumors. In the case of brachytherapy, NADT is used to shrink large prostate glands prior to implantation. This approach does result in effective cytoreduction, but does not change clinical outcomes.34
Moreover, NADT increases treatment costs,35
and in association with any primary local treatment exerts an additive impact on HRQOL.9
A recent critical review of the appropriate role for hormonal therapy in prostate cancer found no indication for its use in low-risk, localized disease.36
Plausible reasons for the increased use of PADT and NADT in low-risk prostate cancer include physician financial incentives, specific patient requests for this form of treatment, and a decrease in patients’ and/or physicians’ psychological willingness to manage any form of cancer conservatively. The true explanation is most likely multifactorial, but is not answerable with the data collected in CaPSURE. Population-based data from the Prostate Cancer Outcomes Study indicated that among prostate cancer patients in all risk groups diagnosed between 1994 and 1995, 8.4% of men ≥ 75 elected RP, 25.6% opted for EBRT, 27.4% chose PADT, and 38.6% pursued WW.16
A recently published Markov model decision analysis found no benefit in terms of either life expectancy or quality-adjusted life expectancy gains for aggressive therapy (RP or EBRT vs WW) among patients ≥ 75 with Gleason scores up to 7, although those with Gleason score 8–10 tumors experienced a clear benefit with either RP or EBRT.17
Patients in our dataset 75 and older remain unlikely to undergo RP; brachytherapy and PADT now account for 61% of their primary treatment selections, and are less clearly associated with age than is RP.
Overall, 39.4% of these older patients received either PADT or NADT, 49.6% of those diagnosed between 1999 and 2001—more than in the overall cohort. Even in the absence of androgen deprivation, elderly men face a higher risk of anemia37
and osteoporotic fractures38
than younger men. Testosterone suppression, which in older men can be prolonged even after the discontinuation of therapy,39
can exacerbate these problems. Although there is evidence that many older men with higher-risk tumors may in fact be under
patients in this age group are also those for whom competing causes of mortality are most relevant—cause-specific mortality is inversely proportional to age17,41,42
—and for whom overdiagnosis and over-treatment of low
-risk prostate cancer are of greatest concern. Pursuit of WW among this group, however, has fallen by half in the PSA era, with fewer than one-quarter of low-risk patients over 75 electing initial observation.
We found no significant associations between ethnicity and treatment patterns; however, patients of higher socioeconomic status and those with fee-for-service insurance were significantly more likely to undergo surgery, while those with lower income and education levels and no insurance were more likely to receive PADT. These associations, along with the geographic regional variation we observed, raise the concern that non-clinical factors may be influencing treatment selection.
CaPSURE tracks utilization patterns in actual community practice, free of the constraints typically imposed by clinical trial protocols. Moreover, all data since 1995 have been collected prospectively, irrespective of any specific research objectives. The practice sites in the database project have not been chosen at random, and therefore cannot be assumed to represent a statistically valid sample of the United States patient population. Nevertheless, they do represent a broad range of geographic locales, and a mix of academic and community practices.
We elected to exclude patients treated primarily with cryotherapy. These constitute a small fraction (<2%) of the contemporary low-risk patients in CaPSURE. A recent poll by the American Urological Association found likewise that between 1997 and 2001 the percentage of American urologists offering cryotherapy remained constant at 2% (during the same period, by comparison, the percentage of urologists offering brachytherapy increased from 16 to 51%).43
Moreover, over two-thirds of the CaPSURE cryotherapy patients were treated at a single practice site. We therefore felt that including cryotherapy in this study would increase the complexity of the analysis unnecessarily without contributing significantly to our understanding of national treatment trends.
CaPSURE data are submitted only by patients and urologists; therefore any treatments by other practitioners which are not reported by patients either to their urologists or in their questionnaires may be missed. Quality assurance mechanisms, including chart review of all hospital admissions, help to minimize this problem. An enrollment bias may persist which could artificially lower the proportion of observation patients: patients who are diagnosed with prostate cancer but who elect not to undergo treatment may simply follow their PSA with their primary care provider, or not at all. If diagnosed by a CaPSURE urologist and enrolled in the database, however, patients should have completed at least one treatment questionnaire, even if they were not followed in more extended follow-up. Despite these caveats, we believe our data provide the best available description of national practice patterns.
As a result of patient education and screening protocols, low-risk features characterize a growing proportion of newly-diagnosed prostate cancers, and are increasingly likely to be associated with clinical stage T1c, Gleason score 5–6, and serum PSA 4–10 ng/ml. A growing number of patients with low-risk features are choosing brachytherapy, PADT, and NADT, and fewer than previously are receiving RP or EBRT or pursuing observation. Age and socioeconomic status are associated with treatment selection; we also found significant geographic variability. These data highlight the concern that a significant and growing number of low-risk prostate cancer patients are being possibly over-treated. We hope that future clinical trials and updated practice guidelines will clarify optimal, evidence-based treatment for these low-risk patients.