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© 2003 American Society for Clinical Oncology Temporarily Deferred Therapy (watchful waiting) for Men Younger Than 70 Years and With Low-Risk Localized Prostate Cancer in the Prostate-Specific Antigen Era
From the Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences; Department of Urology, National Naval Medical Center, Bethesda; Department of Urology, Malcolm Grow Air Force Medical Center, Andrews Air Force Base, MD; Urology Service, Department of Surgery, Walter Reed Army Medical Center; Urology Service, Department of Surgery, Eisenhower Army Medical Center, Washington, DC; Department of Urology, San Diego Naval Medical Center, San Diego, CA; Urology Service, Department of Surgery, Madigan Army Medical Center, Tacoma, WA; Urology Service, Department of Surgery, Brooke Army Medical Center; Department of Urology, Wilford Hall Air Force Medical Center, Lackland Air Force Base, San Antonio, TX; and Department of Urology, Portsmouth Naval Medical Center, Portsmouth, VA. Address reprint requests to Judd Moul, MD, Center for Prostate Disease Research, 1530 E Jefferson St, Rockville, MD 20852; e-mail: jmoul{at}cpdr.org or Timothy Donahue, MD, Department of Urology, National Naval Medical Center, Bethesda, MD 20889; e-mail: tfdonahue{at}bethesda.med.navy.mil.
Purpose: Watchful waiting (WW) is an acceptable strategy for managing prostate cancer (PC) in older men. Prostate-specific antigen (PSA) testing has resulted in a stage migration, with diagnoses made in younger men. An analysis of the Department of Defense Center for Prostate Disease Research Database was undertaken to document younger men with low- or intermediate-grade PC who initially chose WW.
Patients and Methods: We identified men choosing WW who were diagnosed between January 1991 and January 2002, were 70 years or younger, had a Gleason score Results: Three hundred thirteen men were identified. Median follow-up time was 3.8 years. Median age was65.4 years (range, 41 to 70 years). Ninety-eight patients remained on WW; 215 proceeded to treatment. A total of 57.3% and 73.2% chose treatment within the first 2 and 4 years, respectively. Median PSA doubling time (DT) was 2.5 years for those who underwent therapy; those remaining on WW had a median DT of 25.8 years. The type of secondary treatment was associated with the number of patient’s comorbidities (P = .012). Conclusion: Younger patients who choose WW seemed more likely to receive secondary treatment than older patients. PSA DTs often predict the use of secondary treatment. The number of comorbidities a patient has influences the type of secondary therapy chosen. The WW strategy may better be termed temporarily deferred therapy.
PROSTATE CANCER (PC) is the most common solid tumor in men in the United States and is the second-leading cause of cancer death.1 Since the introduction of the prostate-specific antigen (PSA) screening test in the late 1980s and an increase in public awareness of the disease in the early 1990s, there has been a marked stage and age migration; the preponderance of PC is now a clinically localized disease in younger men.2–4 More than two-thirds of men now have localized disease at initial diagnosis. The optimal management of clinically localized PC remains controversial. Traditional treatment options for younger men diagnosed with clinically localized PC have focused on definitive therapy, such as radical prostatectomy or radiation therapy.5–7 Watchful waiting (WW), also known as deferred therapy, has been used as a management strategy primarily in older men. Both prospective and retrospective studies indicate that patients with localized PC who choose WW may have no loss in life expectancy.8–11 However, there are inadequate data describing WW in young men with low-grade, low-stage PC. It may be safe to monitor some men expectantly without immediate treatment and the risks associated with definitive therapy.
It is estimated that as many as one-third of patients diagnosed with PC will have low-volume disease (less than 0.5 mL) with no poorly differentiated elements (Gleason score 6 or less). Work done by Epstein et al12 has helped to identify criteria predictive of small-volume cancers in men with nonpalpable tumors. In that study, if PSA density was less than 0.15 ng/mL and no adverse pathologic findings were present at the time of prostate biopsy, 79% of men had cancers that were small volume (0.5 mL or less), organ confined, and not of high grade. Epstein et al12 defined the favorable criteria on needle biopsy as Gleason score The goal of this cohort study was to identify and describe younger men diagnosed with PC with lower-risk features during the PSA era and who chose WW as their initial treatment strategy, and to identify the factors associated with the decision to proceed to definitive therapy.
The clinical information and follow-up in this study have been collected as part of the Department of Defense Center for Prostate Disease Research (CPDR) Tri-Service Multicenter Prostate Disease Research Database as described previously by Sun et al.13 In brief, standardized data collection forms for prostate biopsy, registration, staging, WW, surgery, radiation treatment, hormone treatment, cryotherapy, follow-up, and necropsy have been developed and were used. Data were collected and entered by physicians and data managers and maintained in a relational database using Microsoft Access (Microsoft Corp, Redmond, WA) software as the front end and Oracle software (Oracle, Redwood Shores, CA) as the back end. The CPDR Database has been approved by the Uniformed Services University Research Administration institutional review board (IRB), as well as the IRBs of all participating military hospitals. The original protocol in use from 1991 to 1998 did not require each patient to sign a formal informed consent document. However, between 1998 and 1999, the IRBs of all sites required patients to provide informed consent to participate. All data entered before 1998 to 1999 (exact dates vary by institution) without gaining patients’ informed consent were allowed to be maintained. The data query for this study was performed in August 2002. At this time, the overall database contained 345,954 clinical records (eg, transrectal ultrasound, biopsy, staging, WW, follow-up) on 15,063 patients. Of these, 2,074 patients (13.8%) had selected WW as their initial treatment between January 1, 1991, and December 31, 2001, with complete information on progression of the disease. We identified patients who chose WW as their primary treatment strategy and who were believed to be the most suitable candidates for deferred therapy, adapting the criteria developed by Epstein et al.12 The goal of these selection criteria was to identify patients who were believed to have low-grade, low-stage disease at the time of diagnosis and who were considered to be potential candidates for definitive therapy. These patients had the option of pursuing any type of therapy for their PC and were not hindered in our equal-access military healthcare system because of cost or insurance considerations. Patients older than 70 years or with advanced disease were excluded from analysis to minimize the influence of age and aggressiveness of disease on the decision to pursue WW.
Inclusion criteria for this analysis were the date of diagnosis between January 1991 and January 2002, age
The data fields analyzed included the patient’s age at diagnosis, ethnicity or race, clinical stage at diagnosis, diagnosed PSA level, biopsy Gleason score, number of positive biopsy cores, family history of PC in a first- or second-degree relative, and prior treatment (if any) for symptomatic benign prostate hyperplasia (BPH). Vascular disease risk factors and concurrent comorbidities at diagnosis were analyzed as independent and collective risk factors for progression to secondary treatment. In addition, histologic grading on repeat biopsies, PSA doubling times (DTs), and the type of secondary definitive treatment were also analyzed. PSA DTs were calculated using the assumption that PSA changes with time in an exponential manner once PC has been diagnosed.14–16 All patients with at least two PSA levels in the database were used to calculate DTs in a regression analysis to determine the slope of the exponential curve. PSA DTs were calculated for 241 patients, with a median of three PSA entries used (range, two to 28 entries). More than 90% of the 241 patients had at least three PSA entries.
Clinical characteristics of patients who remained on the WW protocol were compared with those of patients who underwent secondary treatment, using
Three hundred thirteen patients met the selective inclusion criteria of this analysis. The mean and median follow-up times were 4.2 and 3.8 years, respectively (range, 0.5 to 10.5 years). Sixty-six percent of the patients were diagnosed before 1997. The median age at diagnosis was 65.4 years (range, 41 to 70 years). Two-thirds of the patients were non-Hispanic white, nearly one fourth were black, and the remaining 9% were Asian (including Filipino) or Hispanic. Two-thirds of patients had nonpalpable disease at the time of diagnosis. The median PSA at diagnosis was 5.1 ng/mL, with a range of 0.5 to 20 ng/mL. Eighty-seven percent of men had a PSA level less than 10 ng/mL at diagnosis, with 20.4% having an initial PSA level less than 4 ng/mL. As an inclusion criterion, no patient had a Gleason score greater than 6, and no patient had Gleason pattern 4 in any biopsy core. The median Gleason score was 5. Nearly two thirds of patients (63.6%) had only one positive biopsy core at diagnosis. During the period of analysis, there were 23 deaths in the entire cohort of patients. Two of these deaths were related to PC, four were related to comorbid illness, and 17 were as a result of other or unknown causes. Three patients developed metastatic disease. Family history of PC in a first- or second-degree relative was positive in 19.5% of patients. Nearly one-fifth (18.2%) of patients were undergoing active therapy for BPH at the time of diagnosis. Vascular disease risk factors (ie, smoking history, hypertension, and hyperlipidemia) were positive in 51.1%, 45%, and 16.9% of men, respectively. The prevalences of comorbidities were as follows: coronary artery disease, 18.8%; cerebral vascular accident, 5.1%; renal insufficiency, 3.8%; chronic obstructive pulmonary disease, 8.6%; diabetes mellitus, 8.6%; systemic disease, 1.6%; and concurrent malignancy, 16.9%. Repeat prostate biopsy was performed in 77 (24.6%) of the patients electing to pursue WW. The decision to perform a repeat prostate biopsy was made by the urologist caring for the patient, and its timing was scheduled according to the surgeon’s preference. Only 24% of repeat biopsies identified an upgrade in Gleason score from the initial score; 61% remained unchanged, and 14% experienced a decrease in the Gleason score. PSA DTs were calculated and stratified as follows: less than 2 years, 22%; 2 to 5 years, 17.6%; 5 to 10 years, 10.2%; 10 to 20 years, 3.2%; 20 to 50 years, 3.5%; and greater than 50 years, 20.4%.
Table 2
Table 5  lists the type of treatment elected by the 215 patients who moved on to secondary treatment. The median time to definitive treatment was 9.6 months. Table 6 compares the number of comorbidities at the time of diagnosis with the choice of secondary treatment chosen by these patients. Patients with fewer comorbidities were more likely to select radical prostatectomy or brachytherapy; those with two or more comorbidities were more likely to undergo external-beam radiation therapy (P = .012).
Figure 1 is a KM graph demonstrating the likelihood a patient will remain free from treatment with time. After 2 years, 57% of men had proceeded to secondary therapy, and at 4 years, this portion approached 74%. If a patient remained on WW after 4 years, there was little probability of moving to definitive therapy. Figures 2 and 3 are representative KM curves stratified by DT and the patient’s clinical stage. Patients with the fastest PSA DTs ( 2 years and 2 to 5 years) and those with palpable disease (cT2a and cT2b/c) more often elected to abandon WW in pursuit of definitive treatment.
WW has been proposed as a reasonable treatment strategy of localized PC in patients with less than 10 years of life expectancy.8 In both prospective and retrospective studies, there is indication that patients with localized PC who choose WW may have no loss in life expectancy and that it may be reasonable to defer therapy initially.8–11 Albertsen et al11 found in a retrospective analysis of the Connecticut tumor registry that men age 65 to 75 years with conservatively treated low-grade PC can expect to incur no loss of life expectancy. In comparison, men with higher-grade tumors (Gleason scores 5 to 10) experienced a progressively increasing loss of life. Their cohort of men was observed in the era before PSA testing, and a substantial number of men were older than 70 years at the time of diagnosis. There are no data available for WW in those men who would be considered excellent candidates for definitive therapy but who opted to pursue a strategy of deferred therapy. We analyzed the CPDR database to identify a selective cohort of younger men with low-grade, early-stage PC diagnosed during the PSA era who, in general, have a greater than 10-year life expectancy and who elected to pursue WW as their primary treatment. Despite having quite favorable disease characteristics, the vast majority of these men opted to proceed with definitive therapy within 4 years of their diagnosis of PC. The key message is that PSA use has changed the traditional concept of WW from lifelong deferred definitive therapy to temporarily deferred therapy for the majority of men who initially select it.
Koppie et al17 used the CaPSURE database (University of California, San Francisco, CA) to evaluate both advanced and localized PC patients who chose WW and determined that men who chose WW were more likely to be older than 75 years, have lower serum PSA levels, have organ-confined disease, and have a total Gleason score of We have also tried to evaluate the epidemiology and effectiveness of deferred therapy as a primary treatment strategy in younger men. By choosing WW, these men elected to pursue an initially conservative strategy for managing their PC and thereby avoided the possible side effects associated with surgery or radiation therapy. Despite selecting men with tumor characteristics that would appear favorable for WW, we found that 53% of these younger men abandoned this strategy within 2 years. However, if a patient continued the WW strategy longer than 4 years, there was little likelihood of his progressing to secondary therapy. This is the first study to show that WW in contemporary younger men is temporarily deferred local therapy dictated primarily by PSA level. As with other investigators,14,15,18,19 we found that PSA DT is the most significant factor associated with secondary treatment. Nam et al20 suggested that a rapidly increasing PSA level occurs in as many as 31% of patients who choose WW. We found similar results: 22% of the patients in our analysis had a PSA DT of less than 2 years, and an additional 17.6% of patients had DTs between 2 and 5 years. The patients with the fastest PSA DTs were found to have an 81% chance of abandoning WW to undergo definitive treatment. This may reflect an initial underestimation of the patient’s tumor burden or the presence of occult higher-grade cancer, suggesting the patient may not have been a suitable candidate for WW. Although we found, by univariate analysis, that age was a factor in the choice to pursue secondary treatment, when we analyzed the patients’ ages using both the log-rank and the Cox analyses, we found it was not a predictor of secondary treatment for this cohort. In these younger men, PSA level, not age, drives the decision for secondary therapy. Similar to Koppie et al,17 we found clinical stage was a highly significant factor for predicting which patients will undergo secondary treatment. Those with palpable disease (cT2b or cT2c) were most likely to abandon WW as their primary treatment strategy. This may reflect a greater burden of tumor than was initially estimated at the time of diagnosis. However, in contrast to Koppie et al,17 the initial PSA level at diagnosis was not a predictor of secondary treatment. A likely explanation of the difference between our results and those of Koppie et al17 is that we included only those patients whose initial PSA was less than 20 ng/mL; no exclusionary PSA criteria were used in the review by Koppie et al. For patients in our review, the initial PSA level at the time of diagnosis was not a predictor of progression to secondary therapy. Epstein et al21 demonstrated that men undergoing WW who underwent repeat biopsies showed little evidence of worsening PC grade over the short term. Epstein et al implied that tumor differentiation is not expected to worsen during a 1.5- to 2-year period after initial biopsy. In their study, all 77 men had either an increase or stability in their Gleason score. In our review, 77 patients received repeat biopsies and the decision to undertake the biopsy was made by the attending urologist and patient. Sixty-one percent of patients had the same Gleason score, and 24% had an increase in their Gleason score on repeat needle biopsy. If a higher proportion of the cohort had undergone repeat biopsy, this factor may have been more predictive of secondary treatment. However, the fact that only one fourth of men had a repeat biopsy emphasizes the powerful clinical use of PSA change in this setting. Bratt et al22 reported on hereditary PC and found there was no relationship between the clinical characteristics of patients with positive family history, compared with those with sporadic PC. Our analysis found similar results, in that a positive family history did not statistically influence the decision to progress to secondary therapy. The database does not include reasons patients initially chose WW, but much is known about their initial comorbidities and vascular disease risk factors. It has been documented that comorbidities often influence the initial decision to choose WW.9,11 Our study tried to determine how comorbidities affect decisions in secondary treatment. It is conceivable that if a patient has multiple comorbidities, both the surgeon and patient would be less likely to opt initially for aggressive therapy, and that these comorbidities could influence the decision to proceed to secondary treatment. Our results, however, suggest there is no relationship between a patient’s comorbidities and the ability to remain free from secondary treatment. However, we identified that the number of comorbid illnesses did statistically influence the choice of secondary therapy. Those patients with no comorbidities were most likely to pursue radical prostatectomy or brachytherapy; those with two or more comorbidities chose external-beam radiation therapy. This study provides a better understanding of patients younger than 70 years who have clinically localized PC. There are many factors that influence both a patient’s and a surgeon’s decisions to choose WW, as well as many factors that influence the decision to receive secondary treatment. Our review of carefully selected younger men with low-grade, low-stage PC found these men unlikely to pursue this strategy as a long-term treatment. Instead of WW, this approach may better be termed temporarily deferred therapy. The initial PSA level, age, race or ethnicity, family history, and number or type of comorbidities did not predict the progression to secondary treatment. The most predictive factors for a patient’s abandoning WW and progressing to definitive therapy were the PSA DT and the initial clinical stage. Those patients with faster DTs (< 5 years) and palpable tumor burden (T2b or T2c) were statistically most likely to move to secondary treatment. The fact that as many as 73.2% of patients discontinued WW at the 4-year point suggests the necessity of redefining the criteria used for the WW option. Alternatively, this percentage may indicate that PSA level and other factors generate unwarranted concern that needs to be managed more effectively. The next analysis to be performed in this review is a comparison of the outcomes of the 215 patients who started on a course of WW and moved to definitive therapy with the outcomes of the men who elected immediate, definitive treatment. This study is underway and should provide insight into whether temporarily deferred therapy or WW is a reasonable management strategy for young men during the PSA era. Despite the encouraging data regarding WW in this clinical setting, caution is in order. The lack of uniformity in the manner of informing patients about the WW option and standardized procedures to manage the implications of changes in PSA level, and other factors, may, over time, create confounding issues. These would be minimized by a prospective study.
The authors indicated no potential conflicts of interest.
Supported by US Army Medical Research and Materiel Command grant PCRP-DAMD17-02-1-0066, funded by the US Department of Defense. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Departments of the Army, Navy, or Air Force or the Department of Defense.
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8. Chodak G, Thisted R, Glenn G, et al: Results of conservative management of clinically localized prostate cancer. N Engl J Med 330:242–248, 1994 9. Steinberg G, Bales G, Brendler C: An analysis of watchful waiting for clinically localized prostate cancer. J Urol 159:1431–1436, 1998[CrossRef][Medline] 10. Johansson JE, Holmberg L, Johansson S, et al: Fifteen-year survival in prostate cancer: A prospective, population study in Sweden. JAMA 277:467–472, 1997[Abstract] 11. Albertson P, Fryback D, Storer B, et al: Long-term survival among men with conservatively treated localized prostate cancer. JAMA 274:626–632, 1995[Abstract] 12. Epstein J, Walsh PC, Carmichael M, et al: Pathologic and clinical findings to predict tumor extent of non-palpable (stage TIc) prostate cancer. JAMA 271:368–374, 1994[Abstract] 13. Sun L, Gancarczyk K, Paquette EL, et al: Introduction to Department of Defense Center for Prostate Disease Research Multicenter National Prostate Cancer Database, and analysis of changes in the PSA-era. Urol Oncol 6:203–210, 2001[CrossRef]
14. Carter H, Morrell C, Pearson J, et al: Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease. Cancer Res 52:3323–3328, 1992 15. McLaren D, McKenzie M, Duncan G, et al: Watchful waiting or watchful progression? Prostate specific doubling times and clinical behavior in patients with early untreated prostate carcinoma. Cancer 82:342–348, 1998[CrossRef][Medline] 16. Egawa S, Matsumoto K, Suyama K, et al: Observations of prostate specific antigen doubling time in Japanese patients with nonmetastatic prostate carcinoma. Cancer 86:463–469, 1999[CrossRef][Medline] 17. Koppie T, Grossfeld G, Miller D, et al: Patterns of treatment of patients with prostate cancer initially managed with surveillance: Results from the CaPSURE database. J Urol 164:81–88, 2000[CrossRef][Medline] 18. Zietman A, Thakral H, Wilson L, et al: Conservative management of prostate cancer in the prostate specific antigen ERA: The incidence and time course of subsequent therapy. J Urol 166:1702–1706, 2001[CrossRef][Medline] 19. Choo R, Klotz L, Danjoux C, et al: Feasibility study: Watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol 167:1664–1669, 2002[CrossRef][Medline] 20. Nam R, Klotz L, Jewett M, et al: Prostate specific antigen velocity as a measure of the natural history of prostate cancer: Defining a "rapid riser" subset. B J Urol 81:100–104, 1998 21. Epstein J, Walsh P, Carter H: Dedifferentiation of prostate cancer grade with time in men followed expectantly for stage TIc disease. J Urol 166:1688–1691, 2001[CrossRef][Medline] 22. Bratt O, Damber J, Emanuelsson M, et al: Hereditary prostate cancer: Clinical characteristics and survival. J Urol 167:2423–2426, 2002[CrossRef][Medline] Submitted April 11, 2003; accepted August 11, 2003. Related Correspondence
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 and Fisher’s exact test. These factors were further tested using a log-rank method. In addition, a multivariate Cox proportional hazards regression model was used to assess the predictors of secondary treatment in the total WW cohort. Of the patients who proceeded to definitive treatment, a 
