This study provides further evidence that AS can be offered as an option in a highly select group of patients with low risk prostate cancer. To assess predictors of subsequent progression we used 2 definitions of progression, that is including and excluding a PSA increase of greater than 10 ng/ml. Results were more favorable when the PSA definition was excluded with a 5-year probability of 76% vs 60% to still meet the criteria when using PSA as a criterion. This difference occurred since most cases that failed due to increased PSA had no other evidence of progression. PSA at diagnosis was an independent predictor of progression only when a PSA increase was deemed to be progression. When biopsy criteria were used as the end point, baseline PSA did not distinguish patients at higher risk for failure.
Although it was suggested that PSA changes (PSA velocity or PSA doubling time) should be used to trigger therapy in patients on AS,11
little evidence supports such an approach. In many studies PSA changes were used to define progression, creating an artifactual relationship between predictor and outcome. For example, Klotz et al treated 450 men with prostate cancer expectantly with a median followup of 6.8 years.12
The absolute treatment rate was 30% with PSA doubling time less than 3 years the most common trigger for treatment. Serum PSA testing at baseline was investigated to characterize its potential to predict disease progression.6,8–10
Highly variable results coupled with arbitrary cutoffs limit its use in clinical practice.2,11
Results in studies analyzing PSA changes before radical treatment were also used to justify using PSA dynamics in AS cohorts.13
However, evidence to support the hypothesis that PSA dynamics have additional prognostic value over a single PSA level is lacking.14,15
While following a cohort from the Scandinavian radical prostatectomy trial, Fall et al concluded that the PSA rate of change had low accuracy to classify the disease as destined to progress, casting doubt on the accuracy of early PSA characteristics as a decision tool for therapeutic intervention in patients at low risk on AS.16
Ross et al also found that PSA velocity after diagnosis is an unreliable predictor of progression in patients on AS.17
Baseline PSA proved to be an independent predictor for AS failure only when we included PSA as a criterion for progression. This finding highlights a problem when analyzing PSA as a predictor of treatment in AS series. Usually PSA is an entry criterion as well as a trigger to define failure, creating a self-fulfilling prophecy. For example, if high PSA triggers treatment, higher PSA at entry onto AS means that this patient is more likely to meet the definition of PSA failure while on AS. Cancer was up-graded on subsequent biopsy in only 5 of the 34 men in whom failure was defined only by PSA greater than 10 ng/ml. Thus, we believe that until more accurate predictors of tumor biology become available, PSA criteria alone should not be used to define progression. Rather, PSA changes should prompt repeat biopsy. Also, stable or even decreasing PSA should not provide a false sense of security. Men on AS should undergo routine re-biopsy regardless of any PSA trends.
A critical factor for the success of an AS program is the use of appropriate entry criteria (patient selection).18
While a number of prognostic models have been developed to help identify men who are appropriate candidates for AS, their accuracy is limited and has not been validated.19,20
Most patients in whom AS fails experience failure in the initial observation period, usually within 2 years.12,21
In this short period it is unlikely that cancer actually increases substantially in grade or volume and failure more likely results from sampling error on initial biopsy.22
Berglund et al confirmed the limitations of a single biopsy by analyzing a cohort of 104 patients from our institution who met full inclusion criteria for AS based on initial biopsy but underwent confirmatory prostate biopsy within 3 months of diagnosis.5
Larger, higher grade cancer was found on confirmatory biopsy in 27% of the patients, who were then excluded from AS. Our policy has been to recommend repeat confirmatory biopsy, usually within 6 months, in all men eligible for AS to decrease the risk of substantially underestimating cancer size and grade. A multi-institutional cohort of patients on AS with the same inclusion and progression criteria as in the current study confirmed that the absolute proportion of patients treated was 16% compared with the 25% to 30% treatment rate reported in other series.12,23–25
The low progression rate by biopsy criteria in our series underscores the importance of repeat, confirmatory biopsy before recommending AS.
Absent tumor on confirmatory biopsy identifies a patient group that is unlikely to progress during the first 5 to 10 years of AS. Previous studies showed similar results.4,21,26
Despite a higher risk of progression during followup almost half of the patients with cancer in the confirmatory biopsy remain progression free at 5 years. Thus, treatment is not mandatory if cancer is seen on the confirmatory biopsy. Biopsy results should be used to counsel patients about therapy and judge the intensity of followup if the patient elects AS.
Our study has several limitations. Results are based on modest followup, which is related to the higher number of patients who elected AS in recent years. Long-term AS results are lacking and patients should be appropriately counseled regarding this limitation. Our study includes a long period, which led to variations in followup intensity, diagnostic biopsy strategies and the frequency of surveillance biopsy. Lastly, the only definitive evidence for progression of AS is metastasis or death from prostate cancer that could have been prevented by immediate treatment. To our knowledge there is no evidence that our progression criteria are appropriate surrogates for metastasis or death from prostate cancer. However, until better selection criteria are defined our bias is to be conservative, including routine confirmatory biopsy, when identifying appropriate AS candidates.