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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2141-2149 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.062 The Changing Face of Low-Risk Prostate Cancer: Trends in Clinical Presentation and Primary ManagementFrom the Department of Urology, Program in Urologic Oncology, Urologic Outcomes Research Group, University of California San Francisco Mt Zion Comprehensive Cancer Center, San Francisco, CA; TAP Pharmaceutical Products Inc, Lake Forest, IL. Address reprint requests to Peter R. Carroll, MD, University of California San Francisco Mt Zion Cancer Center, 1600 Divisadero St, 3rd floor, San Francisco, CA 94115-1711; e-mail: pcarroll{at}urol.ucsf.edu
PURPOSE: Early intervention for prostate cancer is associated with excellent long-term survival, but many affected men, especially those with low-risk disease characteristics, might not experience adverse impact to survival or quality of life were treatment deferred. We sought to characterize temporal trends in clinical presentation and primary disease management among patients with low-risk prostate cancer.
METHODS: Data were abstracted from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a disease registry of 8,685 men with various stages of prostate cancer. Included were 2,078 men who were diagnosed between 1989 and 2001 and had a serum prostate specific antigen RESULTS: The proportion of patients with low-risk tumor characteristics rose from 29.8% in 1989 to 1992, to 45.3% in 1999 to 2001 (P < .0001). There have been sharp increases in the use of brachytherapy and androgen deprivation monotherapy, from 3.1% and 3.1%, to 12.0% and 21.7%, respectively. Utilization rates for prostatectomy, external-beam radiotherapy, and observation have fallen accordingly, from 63.8%, 16.1%, and 13.8%, to 51.6%, 6.8%, and 7.9% (P < .0001 for all except prostatectomy [P = .0019]). Age and socioeconomic status were significantly associated with treatment selection, but overall, the treatment trends were echoed on subgroup analysis of patients 75 years or older. CONCLUSION: Low-risk features characterize a growing proportion of prostate cancer patients, and there have been significant shifts in the management of low-risk disease. Overtreatment may be a growing problem, especially among older patients.
With an estimated incidence in 2003 of 220,900, prostate cancer is the most common malignancy in the United States.1 The rising prevalence of prostate specific antigen (PSA)–based screening for this tumor has facilitated great strides in its early diagnosis and treatment. However, the natural history of cases diagnosed early, by PSA screening or otherwise, may be prolonged; as a result, only 25% to 33% of men diagnosed with prostate cancer actually die of the disease.2,3 Recent reports have drawn attention to this problem of overdiagnosis, arguing that a significant fraction of tumors detected by screening might not have adversely affected patients' life span or quality of life if they were to remain undetected.4 While local therapy yields excellent long-term survival rates among patients with clinically localized disease,5-7 and has been recently been shown to reduce prostate cancer metastases and cause-specific mortality,8 all available active treatments exert a significant impact on patient health-related quality of life.9 In an effort to avoid such treatment-related morbidity, several recent studies have highlighted the feasibility of active surveillance as a viable initial treatment alternative in carefully selected patients with low-risk disease characteristics.10,11 More than ever, therefore, it is crucial that prostate cancer treatment decisions be informed by estimates of the likelihood of future disease progression, morbidity, and mortality.
Many instruments have been developed in the last decade to predict prostate tumors' clinical behavior; the best validated of these are based on the serum PSA at diagnosis, the Gleason score of the diagnostic biopsy, and the clinical T stage. There appears to exist good consensus especially on those clinical characteristics defining low-risk cancers: serum PSA at diagnosis Patients with low-risk tumors enjoy the greatest likelihood of prolonged disease-free survival following definitive local treatment; however, they are also the most likely to remain free of progression on active surveillance protocols. To our knowledge, however, contemporary practice patterns in terms of treatments for these patients have not been well described at the national level. Therefore, we identified a cohort of patients with low-risk tumors from a large, community-based database of men with prostate cancer, and analyzed temporal trends in their presentation and management.
Description of the Disease Registry CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) is a longitudinal, observational database of men with biopsy-proven prostate adenocarcinoma, recruited from more than 30 academic- and community-based urology practices across the United States. All newly diagnosed prostate cancer patients are recruited consecutively by participating urologists, who report complete clinical data and follow-up information on diagnostic tests and treatments. Informed consent is obtained from each patient under local institutional review board supervision. Patients are treated according to their physicians' usual practices, and are observed until time of death or withdrawal from the study. Completeness and accuracy of the data are assured by periodic random sample chart review.14,15
Study Population
Analysis: Predictors of Low-Risk Stratification
Analysis: Temporal Trends in Risk Factors at Diagnosis and Primary Treatment Selection
In the analysis, 1,990 (37.2%) of 5,343 men met the criteria for low-risk disease: 29.8% of those diagnosed in 1989 through 1992, 32.6% in 1993 through 1995, 32.7% in 1996 through 1998, and 45.3% in 1999 through 2001 (P < .0001 for trend). Table 1 compares the sociodemographic characteristics of low-risk and non-low-risk patients in the data set. Compared with those in higher risk strata, low-risk patients are significantly younger, and have higher incomes and more education. They are less likely to be covered by Medicare, more likely to be white, and slightly more likely to be seen in a community setting. In multivariable analysis, year of diagnosis, age, ethnicity, and geographic region were significant predictors of low-risk diagnosis. Patients diagnosed during all periods after 1992 are more likely to be diagnosed with low-risk tumors than those in 1989 to 1992. The likelihood of a low-risk diagnosis decreases steadily with advancing age, and is less likely among African Americans than among whites. Patients in the Southern United States are also more likely than those in the West to be diagnosed at low-risk. The time trend toward increasing low-risk diagnoses in the more recent years of the analysis was seen in all ethnic groups and geographic regions studied.
Figure 1 illustrates the shifts over time in the clinical characteristics of low-risk tumors. In terms of clinical stage (Fig 1A), screen-detected T1c cancers now represent nearly two-thirds of incident low-risk cases, whereas unilaterally palpable T2a tumors have fallen from nearly three-quarters to 36% of cases. T1a and T1b tumors, diagnosed incidentally on pathological analysis of resected benign prostatic hypertrophy tissue, have fallen to a total of only 2% of tumors. Figure 1B demonstrates a shift toward higher Gleason scores within the low-risk group; the proportion of low-risk tumors graded 5 to 6 has risen from 59.5% to 96.1% throughout the study period. As shown in Figure 1C, the proportion of low-risk tumors associated with a serum PSA less than 4 ng/mL has fallen from 25.5% to 17.2%. Although this is a statistically significant trend during the entire study period, there has been little change in the PSA distribution since 1993.
The distribution of primary treatment modality selected by patients with low-risk tumors is presented in Figure 2. The most striking trends are the four- and seven-fold increases in the use of PADT and brachytherapy, from 3.1% and 3.1%, respectively, in 1989 to 1992, to 12.0% and 21.7% in 1999 to 2001. EBRT and observation utilization have each fallen by roughly half, from 16.1% to 6.8% and from 13.8% to 7.9%, respectively. These trends are all statistically significant (P < .0001 for each). The use of RP has also fallen, from 63.8% to 51.6% (P = .0019), but this trend has been less pronounced, and rates have been relatively stable since 1993. Use of NADT in conjunction with local treatment increased steadily, with 3.9%, 6.5%, 8.8%, and 10.7% of treated low-risk patients in each year group, respectively, receiving neoadjuvant therapy (P = .0001 for trend). Across the time periods, 4.1% of RP patients, 26.3% of brachytherapy patients, and 25.1% of EBRT patients received NADT. Overall, 18.1% of the low-risk patients in our analysis received primary or neoadjuvant androgen ablation.
We analyzed sociodemographic factors associated with differing treatment patterns among low-risk patients (Table 2). Among patients younger than 60 years, the vast majority (86.3%) received RP; with advancing age, the proportion dropped precipitously, with only 18.5% of those aged 70 to 79 years, and no patients 80 years or older undergoing RP. EBRT use, including both EBRT and brachytherapy, increased with age up to the 70 to 79 years group, among whom a total of 39.4% received EBRT. Compared with RP, however, the associations between other local treatments and age are less pronounced. PADT and observation use both increased sharply with advancing age, accounting for 36.4% and 38.6% of patients older than 80 years, respectively.
Although African American patients were notably less likely than other patients to receive brachytherapy, ethnicity was not significantly associated with treatment selection. Socioeconomic status, by contrast, as reflected by income and education, was strongly associated with treatment. Patients with annual incomes over $50,000 were nearly twice as likely as those earning less than $10,000 to undergo RP; those with higher education were also more likely than those with less education to receive surgery. Likelihoods of receiving brachytherapy or PADT were both inversely associated with income. Low-risk patients with high incomes were also less likely to pursue observation; there was no clear association with income and EBRT use. Similar trends, though less consistent, are also evident with respect to education. Insurance type was also associated with treatment selection, with fee-for-service patients most likely, and uninsured patients least likely, to receive RP. Veterans Administration patients were most likely to opt for WW or brachytherapy. Medicare patients were the most evenly distributed among the various alternatives, whereas patients participating in managed-care plans appeared intermediate to fee-for-service and Medicare patients. Patients in the East and Midwest United States were more likely than those in the West and South to receive surgery, and less likely to receive PADT or pursue observation. There were no significant associations with practice type.
Finally, we performed a subgroup analysis of treatment patterns for the 250 patients in the database who were aged
Nearly 29,000 men are expected to die as a result of prostate cancer in 2003, a higher number than any other neoplasm except lung cancer,1 and evidence increasingly suggests that early treatment can decrease cancer-specific mortality. A recent trial randomly assigning 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, though the study was underpowered with respect to this secondary outcome.8 Nonrandomized 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 articles 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 overtreatment 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. Under the D'Amico classification used in this study, a low-risk patient should expect 5-year disease-free survival rates better than 85% after surgery.13 Likewise, under the Kattan nomogram,20 these patients would have 5-year recurrence-free survival rates of 81% to 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 more than 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 hyperplasia 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 seven-fold 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 before definitive local treatment. In the American Urological Association practice guidelines,24 PADT is considered to be an experimental approach in the setting of localized disease. Indeed, 8 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 nonrandomized 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 before RP does not improve outcomes.32,33 The benefit for NADT before EBRT, likewise, seems to be restricted to patients with higher-risk tumors. In the case of brachytherapy, NADT is used to shrink large prostate glands before 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 health-related quality of life.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 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 undertreated,40 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 overtreatment 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 older than 75 years 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 nonclinical 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 urologists in the United States 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, more than 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 to 6, and serum PSA 4 to 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 possibly being overtreated. We hope that future clinical trials and updated practice guidelines will clarify optimal, evidence-based treatment for these low-risk patients.
The authors indicated no potential conflicts of interest.
Cancer of the Prostate Strategic Urologic Research Endeavor is supported by TAP Pharmaceutical Products Inc (Lake Forest, IL). This research was additionally funded by National Institutes of Health/National Cancer Institute, University of California, San Francisco SPORE Special Program of Research Excellence p50 c89520. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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34. Potters L, Torre T, Ashley R, et al: Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 18:1187-1192, 2000 35. Penson DF, Schonfeld WH, Flanders SC, et al: Relationship of first-year costs of treating localized prostate cancer to initial choice of therapy and stage at diagnosis: Results from the CaPSURE database. Urology 57:499-503, 2001[CrossRef][Medline] 36. Chodak GW, Keane T, Klotz L: Critical evaluation of hormonal therapy for carcinoma of the prostate. Urology 60:201-208, 2002[CrossRef][Medline] 37. Nilsson-Ehle H, Jagenburg R, Landahl S, et al: Blood haemoglobin declines in the elderly: Implications for reference intervals from age 70 to 88. Eur J Haematol 65:297-305, 2000[CrossRef][Medline] 38. Roy DK, O'Neill TW, Finn JD, et al: Determinants of incident vertebral fracture in men and women: Results from the European Prospective Osteoporosis Study (EPOS). Osteoporos Int 14:19-26, 2003[CrossRef][Medline] 39. Kurek R, Renneberg H, Lubben G, et al: Intermittent complete androgen blockade in PSA relapse after radical prostatectomy and incidental prostate cancer. Eur Urol 35:27-31, 1999 (suppl 1) 40. Alibhai SMH, Krahn MD, Cohen MM, et al: Is there age bias in the treatment of localized prostate carcinoma? Cancer 100:71-81, 2003 41. Hugosson J, Aus G, Bergdahl C, et al: Prostate cancer mortality in patients surviving more than 10 years after diagnosis. J Urol 154:2115-2117, 1995[CrossRef][Medline] 42. Brasso K, Friis S, Juel K, et al: Mortality of patients with clinically localized prostate cancer treated with observation for 10 years or longer: A population based registry study. J Urol 161:524-528, 1999[CrossRef][Medline] 43. O'Leary MP, Baum NH, Blizzard R, et al: 2001 American Urological Association Gallup Survey: Changes in physician practice patterns, satisfaction with urology, and treatment of prostate cancer and erectile dysfunction. J Urol 168:649-652, 2002[CrossRef][Medline] Submitted October 8, 2003; accepted January 2, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 ng/mL, Gleason sum 
2 test for categorical variables and the Mantel-Haenszel 
75 years elected RP, 25.6% opted for EBRT, 27.4% chose PADT, and 38.6% pursued WW.
