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Japanese Journal of Clinical Oncology 33:1-5 (2003)
© 2003 Foundation for Promotion of Cancer Research
Watchful Waiting as a Treatment Option for Localized Prostate Cancer in the PSA Era
Department of Urology, Faculty of Medicine, Kagawa Medical University, Kita-gun, Kagawa, Japan
ABSTRACT
The incidence rate of early-stage prostate cancer has dramatically increased since the introduction of the widespread use of PSA testing in developed countries, including Japan. With the downward stage migration there has been much interest in the concept of watchful waiting not only for elderly patients with a life expectancy of less than 10 years but also in younger patients with good social and sexual activity. The results of a recent randomized comparison between radical prostatectomy and watchful waiting for localized disease indicated comparable overall survival but superiority of surgery in disease-specific survival. The predictive value of clinico-pathological parameters including biopsy features and serum PSA seems insufficient to predict tumor growth potential. Our ongoing prospective study is aimed at clarifying whether PSA doubling time assessment for 6 months in patients with favorable biopsy features can be a good indicator for further watchful waiting or immediate aggressive treatment without any survival disadvantage.
INTRODUCTION
Prostate cancer has recently received considerable attention because its incidence rates and mortality rates in developed countries have significantly increased (1). Evidence suggests that the major cause of the dramatic increase in prostate cancer incidence is the widespread use of serum PSA screening and systematic prostate sampling under transrectal ultrasound guidance. Despite the apparent success of the screening efforts, a clear decrease in cancer-related mortality remains to be definitely demonstrated even in the USA (2,3). Rather, some authors have voiced concern that early-stage localized prostate cancers detected in the current PSA era include a non-negligible percentage of insignificant or indolent tumors that previously existed as latent or incidental cancers (4,5).
Watchful waiting, also termed active surveillance or expectant management, implies no therapy until the patient becomes symptomatic resulting from complications of local or systemic disease. Historically, watchful waiting has been widely accepted in Scandinavian countries, whereas it has been less frequently accepted as a treatment option in North America and other countries, including Japan. Today, however, watchful waiting is gradually being highlighted because the obvious downward stage shift has affected our concept of the natural history of untreated localized prostate cancer.
This review mainly surveys the biological properties of early-stage prostate cancer detected in this PSA era and the possibilities and limitations of watchful waiting compared with other treatment options for this particular subset of disease. Lastly, our longitudinal observational study on watchful waiting for early-stage prostate cancer that is now under way in Japan together with other prospective studies in Europe and the USA is introduced.
PROSTATE CANCER INCIDENCE AND MORTALITY TRENDS
Between the mid-1980s and 1992, a dramatic increase was observed in prostate cancer incidence in the USA owing to the widespread use of PSA screening (6). The overall age-adjusted incidence rate increased from 86 to 179 per 100 000 per year between 1986 and 1992. The incidence of prostate cancer for both white and black men peaked between 1992 and 1993. Thereafter, the incidence declined for several years to the level seen in the era before 1988 when the PSA campaign started.
The incidence rate in Japan is still lower than those in Western countries, but the number of newly diagnosed cases in Japan has dramatically increased since the mid-1990s. There is no doubt that the widespread use of PSA in Japan is a major cause of the increase in the incidence rate of prostate cancer (7). Nevertheless, the ‘true’ incidence of prostate cancer in Japanese men is considered to be increasing, probably owing to changes in dietary habits and other intrinsic and extrinsic factors. Yatani and co-workers (8,9) compared the frequency of latent prostate carcinoma in Japanese men between two eras (1965–79 and 1982–86). They found that Japanese men showed an ~1.5–2 times increase in the frequency of latent prostate cancer from 1965–79 to 1982–86 in each decade of age group.
The age-adjusted mortality rate of Japanese men dying from prostate cancer increased from 0.5 in 1950 to 8.2 in 1997, correlating with the increasing incidence rate (10). It should be noted, however, that only a fairly small fraction of patients with prostate cancer die from the disease. Generally, prostate cancer tends to affect older men and to progress relatively slowly. Since co-morbidity increases with advancing age, competing causes of death are important contributors to death rates among prostate cancers. In the USA, despite the large number of men diagnosed with prostate cancer, it is estimated that only about 20% will succumb to the disease, with an average reduction in life expectancy in these men of about 9 years (11,12).
POSSIBILITY OF OVER-DIAGNOSIS
In the USA, the widespread early detection program for prostate cancer consisting of PSA checking and systematic prostate sampling has brought about an obvious downward stage migration (2,13). The majority of cancers detected by PSA testing were classified as stage T1c (non-palpable and non-visible) tumor. This downward stage migration has resulted in improved biochemical recurrence-free survival (PSA failure-free survival) following radical prostatectomy (13). In Japan, community-based PSA screening has become popular since the late-1990s. Stage shift and improved clinical outcome are therefore also expected to occur in Japan as has been seen in the USA. In addition to the widespread use of PSA testing, the recent trend to sample a larger number of cores at systematic biopsy (from six to as many as 13 cores or more) may result in an increased ability to detect smaller foci of tumors (14).
Based on these circumstances, several authors are concerned that the rate of detecting insignificant or indolent tumors will also increase with these early detection efforts. The extent of over-diagnosis due to PSA testing, however, remains unclear. Etzioni et al. (4) compared the model-projected incidence with the observed incidence derived from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry data and estimated over-diagnosis rates to be 29% for whites and 44% for blacks among men with prostate cancer detected by PSA screening. McGregor et al. (5), however, considered that this estimation might be in some sense conservative. When they used mortality as an endpoint, the over-diagnosis rate was raised to 84%.
DEFERRED TREATMENT IN SCANDINAVIAN COUNTRIES
Historically, watchful waiting and delayed hormone therapy have been preferred in Scandinavian countries, which has resulted in an accumulation of knowledge about the natural history of untreated localized prostate cancer detected prior to the PSA era (15–17). More recent meta-analysis of six non-randomized expectant management studies revealed that the 10-year disease-specific survival rates were 87, 87 and 34% for grades I, II and III localized prostate cancer, respectively, and the metastasis-free survival rate for grades I, II and III was 81, 58 and 26%, respectively (18). Major criticisms against these observational studies were related to the preponderance of older patients (mean age: 71 years) in the series and methodological problems such as the lacking of a central review of pathology. Moreover, 42% were diagnosed by needle aspiration biopsy instead of needle core biopsy, which might have resulted in a high false-positive rate. Nevertheless, these observational studies have clearly demonstrated that for patients with well-differentiated prostate cancers, time to progression may be particularly prolonged because of slow tumor doubling times, although the behavior of moderately differentiated cancers remains to be investigated.
WATCHFUL WAITING FOR MEN WITH AN EXPECTED LIFETIME OF LESS THAN 10 YEARS
Nowadays, watchful waiting is considered a reasonable choice of strategy in men with early-stage prostate cancer and a life expectancy of <10 years (19), because the lead time resulting from PSA testing can be estimated as at least 5 years and even a patient who manifests metastatic disease can thereafter be controlled with hormonal therapy for several years. Estimation of life expectancy is therefore very important in choosing the initial treatment strategy. Life expectancy is usually predicted by age and co-morbidity. In the USA, watchful waiting is considered to be most suitable for patients older than 70 years. The age criterion, however, varies from race to race. According to the life tables for 2001, otherwise healthy Japanese men aged 76 years are expected to have a life expectancy of 10 years.
WATCHFUL WAITING FOR SEXUALLY AND SOCIALLY ACTIVE MEN WITH SUFFICIENT LIFE EXPECTANCY
Many urologists consider that watchful waiting is not suitable for patients with a life expectancy >10 years (particularly those younger than 65 years). It is generally conceded that a degree of over-treatment for these patients has to be tolerated, although some of them might have tumors of low bioactivity. Albertsen et al. (20), however, studied 767 men with localized prostate cancer aged 55–74 years at diagnosis and made nomograms to demonstrate that men with Gleason scores of 5 and 6 would face a 4–7 and 6–11% chance, respectively, of dying from prostate cancer 15 years after starting watchful waiting. Major criticisms against these predictions are that they are based on the patients diagnosed and treated before the routine use of PSA. Judging from the downward stage migration currently observed, the outcomes for contemporary patients, however, are likely to be better rather than worse from the viewpoint of lead-time bias resulting from PSA testing.
If tumor volume and tumor growth velocity could be accurately predicted with clinical and pathological parameters, a certain percentage of younger patients with good sexual and social activity would choose and enjoy watchful waiting for a durable time without suffering morbidities such as erectile dysfunction and urine incontinence associated with curable treatment. Many attempts have been made to predict clinical significance of the tumor with pathological features of biopsy specimens and PSA-related parameters prior to deciding the treatment strategy (21–25). Whittemore et al. (26) combined the data on prostate cancer volume at autopsy with incidence data from the Surveillance, Epidemiology and End Results reporting system of the National Cancer Institute. Their analysis strongly suggests that initial tumor volume is a major determinant of biological activity. Tumor volume can be predicted to some extent from pathological features. Investigators at the Urology and Pathology Department of Johns Hopkins University analyzed a large number of radical prostatectomy specimens and reported that needle biopsy findings including positive core number, percentage involvement of cancer in the core and Gleason score together with PSA density (PSA level divided by prostate weight) could be a good predictor of small tumors (<0.5 cm3) with a positive predictive value of 75% (27).
PREDICTION OF TUMOR GROWTH VELOCITY
Clinico-pathological parameters including biopsy features and serum markers at diagnosis can predict tumor volume to some extent. Another and maybe much more important parameter that prompts immediate aggressive treatment, however, is growth velocity of the tumor. Growth velocity is hardly predictable only with clinical and pathological parameters obtained at diagnosis. Up to now, changes in PSA levels with time have been the sole available surrogate to predict tumor growth velocity because serum PSA has been shown to be proportional to the volume of prostate cancer (28). Consecutive frozen serum samples from the Baltimore Longitudinal Study of Aging, which began in 1958, clearly demonstrated PSA changes with time in men who later manifested prostate cancer clinically (the disease was diagnosed in most individuals before the use of PSA and transrectal ultrasound) (29). Serum PSA in all the cancer patients showed an early linear phase followed by an exponential phase of increase. The exponential phase of PSA elevation began 7–9 years before the tumors were detected clinically (29). The Stanford University group observed serial PSA changes in 43 untreated patients (28 were organ confined and 15 were non-organ confined or metastatic) and estimated the doubling time of PSA (30). The data showed that 79% of all patients had a doubling time of more than 2 years, including 14% of patients who showed stable PSA levels (30). Gerber et al. (31) retrospectively analyzed PSA changes in 49 prostate cancer patients managed by watchful waiting. They found a significant variability of PSA doubling time, from 15.1 to 994.5 months (median: 55.7 months). We studied 131 Japanese patients with localized prostate cancer who were managed expectantly at the time on July 1, 1997, in eight institutions. They were then prospectively followed up and the PSA doubling time was calculated. There was a significant difference in the distribution of PSA doubling time between locally advanced (T2b or T3) disease and early-stage (T1c or T2a) disease groups and the PSA doubling time varied substantially in the latter group (32). These data suggest that the PSA doubling time offers a dynamic view of tumor behavior, although there is only limited evidence for its validity in the watchful waiting population.
PSA DOUBLING TIME CALCULATION PRIOR TO DETERMINING TREATMENT OPTION
Several investigators have started to validate an initial strategy involving serial measurement of PSA for a durable period prior to any definitive treatment to assess the growth potential of the tumor. A group of 113 untreated patients who were referred to the British Columbia Cancer Agency were placed in a prospective watchful waiting program to calculate the PSA doubling time (33). It was found that the PSA doubling time was a more powerful indicator of disease activity than standard histopathological criteria. We have started a non-randomized prospective observational study of watchful waiting for patients with T1c prostate cancer with favorable biopsy features, supported by the Ministry of Health, Labor and Welfare of Japan. In this multi-institutional study, we recommend watchful waiting for 6 months as an initial strategy for patients who fulfil the inclusion criteria shown in Table 1. After 6 months, we calculate the PSA doubling time based on four serial points (every 2 months) of PSA. If the patient shows a PSA doubling time of <2 years, we recommend aggressive treatment. For the rest of the patients, who show longer PSA doubling times, watchful waiting is recommended with PSA checking every 3 months and assessment of PSA doubling time every 6 months. The primary and secondary endpoints of this study are shown in Table 2. A pilot study with a similar protocol enrolled 63 patients during the period between 2000 and 2001 and 50 of them chose watchful waiting as an initial strategy. The distribution of the first 6 months of PSA doubling time for the patients under surveillance is shown in Fig. 1. Following the pilot study, the main study started on January 4, 2002, and will finish enrolling patients on December 26, 2003. These studies should clarify whether such a durable period of surveillance and PSA doubling time calculation are safely conducted without any prognostic disadvantage for early-stage prostate cancer patients.
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RANDOMIZED COMPARATIVE STUDIES; WATCHFUL WAITING VERSUS SURGERY
A number of prospective trials are currently enrolling patients in an attempt to determine the impact of treatment on the prognosis of prostate cancer detected in the current PSA testing era. Perhaps the most notable is the Prostatectomy Intervention Versus Observation Trial (PIVOT) of the Veterans Administration and the National Cancer Institute in the USA (34). In the PIVOT trial, 1000 men will undergo either radical prostatectomy or watchful waiting. Several simultaneous studies are also in progress in Europe. Recently, Holmberg et al. (35) at Uppsala University, Sweden, assessed the outcomes for 695 men with early-stage prostate cancer who were randomized to undergo radical prostatectomy or a watchful waiting strategy. During the study period (median observation: 6.2 years) the number of men who died was not significantly different between the two groups. However, the percentage of men who died from prostate cancer was significantly higher in the watchful waiting group. In addition, men in the watchful waiting group were 37% more likely to develop distant metastasis. A longer period is needed to clarify whether the absolute benefit of radical prostatectomy is less than our expectation or whether there is a benefit to overall survival of surgery.
QUALITY OF LIFE IN WATCHFUL WAITING PATIENTS
Watchful waiting can have its own effect on health-related quality of life (HR-QOL), which patients need to consider when they choose a treatment strategy. Uncertainty regarding disease course and the possibility of regret may cause psychological distress for patients (36). Jonler et al. (37) studied 52 consecutive patients who initially chose watchful waiting for localized prostate cancer. Thirty-five of them reported at least some problems from their cancer or deferred treatment when progression occurred, although 96% would choose watchful waiting as their primary therapy if they faced the decision again. Steineck et al. (38) at the Karolinska Institute prospectively compared QOL between radical prostatectomy and watchful waiting. Erectile dysfunction was reported by 80% of men in the surgery group compared with 45% of men in the watchful waiting group, and 49% of surgical patients reported urinary leakage compared with 21% in the watchful waiting group. Bowel function, rates of anxiety and depression and general well-being were similar in the two groups. These studies indicate that watchful waiting has an effect on QOL, but the effect is certainly different from that of aggressive treatment.
CONCLUSION
With earlier stage migration of prostate cancer since the introduction of PSA testing, candidates for watchful waiting are apparently increasing although the selection criteria for patients for whom watchful waiting should be recommended has not been well established. We should bear in mind, however, that each individual places different priorities on survival versus quality of life. Sufficient information about each treatment modality should therefore be provided at the time of clinical decision making.
Acknowledgments
The author thanks Drs Tadao Kakizoe, Haruhiko Fukuda and Ken-ichi Tobisu and Ms Yuko Saito of the National Cancer Center and Drs Osamu Ogawa, Toshiyuki Kamoto and Hidefumi Kinoshita of Kyoto University Graduate School of Medicine for advice and support. This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan (11-10).
FOOTNOTES
+ For reprints and all correspondence: Yoshiyuki Kakehi, Department of Urology, Faculty of Medicine, Kagawa Medical University, 1750–1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761–0793, Japan. E-mail: kakehi@kms.ac.jp 
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Received October 17, 2002; accepted October 22, 2002
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