Watchful Waiting Versus Active Surveillance with Selective Delayed Definitive Therapy

Traditionally, watchful waiting has meant that no active treatment is begun until a patient develops evidence of symptomatic disease progression, at which time androgen deprivation therapy is initiated. The goal of this approach is to limit morbidity from either the disease or the therapy, not to administer potentially curative treatment (Table 101–3). The assumption is that definitive local therapy provides little or no benefit to the majority of men diagnosed with prostate cancer.

Table 101–3 Contrasts between Active Surveillance and Watchful Waiting

An alternative and more widely practiced strategy is to delay curative local therapy until the natural history and threat posed by the cancer can be more accurately characterized. Active surveillance (AS) with selective delayed definitive therapy attempts to distinguish clinically insignificant cancers from life-threatening cancers while they are still localized and potentially curable. This approach weighs the threat posed by the cancer within the patient’s remaining lifespan and the risks of definitive, local therapy, continually reassessing the risk-benefit ratio at each evaluation. The assumption is that the risk posed by a given cancer can be assessed with some degree of certainty. The goal is to avoid overtreating the majority of patients while administering curative therapy when needed in selected cases (Table 101–3). The risks are the delayed therapy may be less effective or would need to be more intensive, with greater morbidity, to be as effective as immediate treatment.

Watchful Waiting

Many clinicians recommend watchful waiting for the treatment of prostate cancer in elderly men with competing comorbidities. Several investigators have attempted to document the long-term risk of metastatic disease and death for men whose clinically localized prostate cancer was treated conservatively (Adolfsson et al, 1994; Chodak et al, 1994; Albertsen et al, 1995, 1998, 2005; Johansson et al, 1997, 2004; Cuzick et al, 2006). The impact of this slow-growing cancer depends on the life expectancy (age and comorbidities) of the patient and the clinical features (Gleason score, PSA) of the cancer (Table 101–4). Those patients expected to live less than 5 years may develop local symptoms, but few patients will develop metastases or die of the disease.

Table 101–4 Life Expectancy of Men (All Races) in the United States by Age in 5-Year Increments

The risk of metastases or death from clinical stage T1 to T2 cancer managed conservatively was estimated in a meta-analysis of six watchful waiting series (Chodak et al, 1994). The risk of metastasis at 10 years was 19% for well-differentiated cancers, 42% for moderately differentiated cancers, and 74% for poorly differentiated cancers. Furthermore, if the primary tumor was not controlled, the risk for development of metastases persisted, even accelerated, after 10 years. These findings were confirmed by Johansson and colleagues (2004), who reported their long-term results among men with early-stage prostate cancer (T1-T2, NX, M0) or watchful waiting. They observed a consecutive sample of 223 men for a mean period of 21 years. Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 to 20 years revealed a substantial decrease in cumulative progression-free survival (from 45% at 15 years to 36% at 20 years), survival without metastases (from 77% to 51%), and prostate cancer-specific survival (from 79% to 54%) (Fig. 101–1). The authors concluded that although most prostate cancers diagnosed at an early clinical stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term and early local treatment should be considered for men with a life expectancy exceeding 15 years.

Figure 101–1 Cause-specific survival of men with prostate cancer managed conservatively, by stage of disease and tumor grade at diagnosis. Disease stages were T0 localized, T0 diffuse, and T1-T2. Grades were as follows: grade 1, highly differentiated; grade 2, moderately differentiated; and grade 3, poorly differentiated.

(From Johansson JE, Andren O, Andersson SO, et al. Natural history of early, localized prostate cancer. JAMA 2004;291:2713–9.)

The impact on mortality was further documented in a large, population-based study (Albertsen et al, 1998, 2005). The probability of death from prostate cancer within 20 years of diagnosis depended on the Gleason sum of the cancer and the age of the patient at diagnosis. Patients with a well-differentiated cancer (Gleason sum 2 to 4) had a low probability of death from cancer within 20 years (6 deaths per 1000 person-years; 95% confidence interval [CI], 2-11); higher-grade cancers took a substantial toll even among older men (Gleason score of 8 to 10, 121 deaths per 1000 person years; 95% CI, 90-156). In contrast to Johannsen, the Albertson cohort did not experience acceleration in the rate of metastases or death from cancer between 15 and 20 years.

Kattan and colleagues (2008) reviewed United Kingdom cancer registry data to determine predictors of long-term outcomes for men with clinically localized prostate cancer managed without curative intent in the PSA era. The study included men who at the time of diagnosis were aged 30 to 75 years (inclusive), had a baseline serum PSA level of less than 100 ng/mL, had no evidence of metastatic disease, were not treated with curative intent, and were alive for at least 6 months after diagnosis of their disease. Diagnosis was by transurethral resection of the prostate in 1358 (56%) and needle biopsy in 1088 (44%). Most men were managed without initial treatment, while 30% were treated with hormone therapy within 6 months of diagnosis. In a competing risk analysis, 30% of the patients died of prostate cancer and 30% of other causes within 12 years. This was the first long-term watchful waiting study to include PSA at diagnosis and Gleason grade (reviewed centrally). Figure 101–2 shows the 10-year probability of death from prostate cancer and death from any cause by PSA and Gleason score at diagnosis (Cuzick et al, 2006). However, among men who did not die of another cause in this cohort, the probability of metastases, death from prostate cancer, or additional therapy within 12 years was 90%. These results suggest that localized prostate cancer detected clinically, in an unscreened population, results in a high rate of progression or secondary treatment within 12 years when managed with watchful waiting. In these watchful waiting cohorts, age, Gleason grade, and PSA were able to identify men at increased risk for the development of metastatic disease and death from prostate cancer. Nevertheless, not all men with “adverse” features do poorly, nor do all men with favorable features do well. Additional clinical and pathologic parameters are necessary to predict outcomes more accurately and to place expectant management of some patients on a sound basis.

Figure 101–2 Proportion of patients dead from prostate cancer (orange), dead from other causes (blue), at different follow-up times up to 10 years, according to baseline PSA and Gleason score, separately for patients aged 70 years or younger at diagnosis and patients aged older than 70 years at diagnosis.

(From Cuzick J, Fisher G, Kattan MW, et al. Long-term outcome among men with conservatively treated localized prostate cancer. Br J Cancer 2006;95(9):1186–94.)

Watchful Waiting Versus Treatment

Perhaps the most compelling evidence that selected patients with prostate cancer benefit from active treatment compared with watchful waiting comes from the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), which randomized 695 men with clinically localized prostate cancer to either radical prostatectomy or watchful waiting, with systemic treatment deferred until the development of symptomatic progression (Bill-Axelson et al, 2005, 2008). During a median of 10.8 years of follow-up, 47 of the 347 men (13.5%) who were randomly assigned to surgery died of prostate cancer, as did 68 of the 348 men (19.5%) assigned to watchful waiting (Fig. 101–3). At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% CI, 0.2 to 11.1), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03), and 19.3% in the surgery group and 26% in the watchful waiting group had distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). This elegant study, which was carried out in a population not screened for prostate cancer with PSA, documents the overall benefit of radical prostatectomy for patients whose cancer is detected clinically. Because the estimated lead time for PSA screen–detected cancers is 6 to 8 years compared with clinically detected prostate cancers, the relevance of the Scandinavian study to the cancers detected by screening is uncertain.

Figure 101–3 Scandinavian randomized trial comparing radical prostatectomy and watchful waiting for localized prostate cancer (PC) detected clinically in the absence of prostate-specific antigen screening. Surgical excision altered the natural history of prostate cancer, reducing cumulative incidence of A, overall mortality, B, prostate cancer death, C, metastases, D, local progression, E, hormonal treatment, and F, other palliative treatment.

(From Bill-Axelson A, Holmberg L, Filen F, et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst 2008;100(16):1144–54.)

Although the development of metastatic disease and death from prostate cancer are important adverse outcomes, local cancer progression and the need for treatment also have significant impact on quality of life (Fig. 101–3). For example, the Scandinavian Prostate Cancer Group reported that fewer men in the radical prostatectomy group than in the watchful waiting group developed local recurrence or disease progression (Steineck et al, 2002; Bill-Axelson et al, 2008). At 12 years, the cumulative incidence of local recurrence and/or progression was 21.7% in the surgery group and 45.6% in the watchful waiting group (difference = 23.9, 95% CI = 16.8 to 30.9). A total of 132 men in the radical prostatectomy group versus 205 in the watchful waiting group started hormonal therapy. The difference in cumulative incidence of hormonal therapy at 12 years was 19.3% (95% CI = 11.7 to 26.9), with a lower probability of starting hormonal therapy in the radical prostatectomy group. All other palliative treatments (including radiation, treatment with cytotoxic drugs, and laminectomy) were also less common in the radical prostatectomy group. The difference in the cumulative incidence of palliative treatment at 12 years was 5.2% (95% CI = 0.1 to 10.3). Erectile dysfunction and incontinence were higher in men treated with radical prostatectomy, whereas men on watchful waiting experienced significantly more obstructive voiding complaints and bowel problems, resulting in similar levels of treatment-related distress (Table 101–5).

Table 101–5 Comparison of Urinary Quality of Life (Function) between Radical Prostatectomy and Watchful Waiting in Patients from the Scandinavian Prostate Cancer Group

Active Surveillance

Widespread use of PSA screening, combined with low thresholds for recommending prostate biopsy and more aggressive biopsy techniques (12 core, saturation), have resulted in a profound shift toward detection of prostate cancer earlier (Draisma et al, 2009). Furthermore, large randomized trials of PSA screening have shown a limited impact on cancer specific mortality (Andriole et al, 2009; Schroder et al, 2009). These studies suggest that a proportion, estimated in one study as 23% to 42% (Draisma et al, 2009), of prostate cancers are being detected by PSA screening that would never have been detected in the subjects’ lifetime. These cancers are considered by some to be “overdetected,” and this concept has led to wider acceptance of AS for low-risk prostate cancers.

AS refers to a systematic program of periodic monitoring of men diagnosed with a prostate cancer judged to pose little immediate threat to life or health. Such patients are offered AS as an alternative to immediate radical therapy. They return frequently for examination and PSA testing and periodically for prostate biopsy. Active intervention is delayed until there is clear evidence of progression of the cancer, although some patients become anxious and choose definitive therapy in the absence of progression. Although AS is now more widely accepted for very early, low-risk prostate cancer, the appropriate criteria for inclusion in an AS program and the definition of progression of the cancer are controversial, and the results of interim intervention and the long-term outcomes remain uncertain.

Identifying Men with “Low-Risk” Prostate Cancer

Many physicians and patients consider AS for selected low-risk prostate cancers. The difficulty is in defining “low risk.” Initial clinical staging, when limited to digital rectal examination, PSA, and diagnostic biopsy results, has limited potential for accurately characterizing localized prostate cancers, although systematic needle biopsies, serial PSA determinations, and modern imaging are promising tools for more accurately assessing the size, grade, and extent of the cancer.

Systematic Biopsy Results

In an attempt to identify patients who have low-risk cancer, Epstein and colleagues (1994) examined preoperative clinical and pathologic features in 157 men with clinical stage T1c prostate cancer (who later underwent radical prostatectomy) to find features that could predict “insignificant” cancer (pathologically organ-confined, < 0.2 mL, Gleason sum ≤ 6). Their model for predicting an insignificant cancer included no Gleason grade 4 or 5 in the biopsy specimen and either:

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