Men aged 65 years at diagnosis followed up with active surveillance received an additional 6.0 months of QALE compared with treatment with brachytherapy, the most effective initial treatment, in the base-case results. This analysis demonstrates that when a broad spectrum of possible disease-and quality of life–related outcomes associated with active surveillance and treatment is taken into account, active surveillance is a reasonable approach to consider in 65-year-old men with clinically localized, low-risk prostate cancer.
However, in the United States, active surveillance is used infrequently for management of prostate cancer. Although 16% to 40% of men newly diagnosed as having prostate cancer meet criteria for active surveillance, less than 10% of eligible men elect this approach.40,41
Barriers to its use have included concerns about long-term disease outcomes, the perception that most men will ultimately undergo treatment, and concerns about the quality of life of men who elect active surveillance.42,43
The long-term outcomes of men who undergo active surveillance are poorly characterized. Prospective studies of active surveillance have differing eligibility criteria and triggers for treatment, complicating the interpretation of results9–11,13,39
). The relative merits of one set of eligibility criteria and treatment triggers over another for capturing clinically significant disease and minimizing overtreatment have not been established. Recently, Klotz et al9
published results on the cohort with the longest median follow-up to date, 6.8 years. Thirty percent of the cohort progressed to definitive treatment; outcomes were favorable after short follow-up, with 97.2% 10-year prostate cancer–specific survival and 78.6% overall survival.
Given the uncertainty surrounding long-term outcomes with active surveillance, we analyzed the effect on the results of varying the estimates of prostate cancer–specific death and progressive disease during active surveillance. In the base case, we assumed that the relative risk of prostate cancer–specific death after initial treatment compared with active surveillance was 0.83, half that of radical prostatectomy compared with watchful waiting as reported in a randomized controlled trial.24
In that trial, men were not screen-detected and in general had higher-risk disease than patients typically followed up with active surveillance, who are offered potentially curative treatment. The relative risk of prostate cancer–specific death was 0.65 (95% confidence interval, 0.45–0.94) for treatment vs watchful waiting in men of all ages; in men older than 65 years, the relative risk was 0.87 (95% confidence interval, 0.51–1.49) and was not significant. We chose 0.83 as the base case assumption of relative risk to approximate a conservative but reasonable risk of prostate cancer–specific death in the absence of a randomized controlled trial comparing treatment to active surveillance. We then performed sensitivity analyses to assess the point at which the QALE advantage of active surveillance could be overcome by a higher risk of prostate cancer–specific death. For active surveillance and initial treatment to be associated with equal QALE, the relative risk of prostate cancer–specific death after initial treatment vs active surveillance would have to be 0.6. Even if choosing active surveillance places men at a substantially higher risk of dying of prostate cancer or the risk of progressive disease on active surveillance is doubled, active surveillance is associated with higher QALE.
Few studies of quality of life in men undergoing active surveillance have been performed, and even fewer have measured utilities for active surveillance health states. However, anxiety in men who have chosen active surveillance or watchful waiting has not been shown to be higher than in men who elect initial treatment.44–47
In this analysis, active surveillance was favored over initial treatment for low-risk disease in men aged 65 years at diagnosis, but this result was highly dependent on the utility individuals place on living under active surveillance compared with having been treated.48
In the base case, the utility for living under active surveillance was 0.83; having been treated without adverse effects of therapy but at risk of recurrence carried a utility of 0.80, 2 values taken from the same population.36
If these values are varied, the results of the model change significantly. If the utility for active surveillance is raised above 0.94, active surveillance is favored no matter the utility assigned to the posttreatment health state. If the utility for the posttreatment health state is 0.80 (the base-case value), the utility for active surveillance must be greater than 0.77 for active surveillance to be favored. To place this utility in context, a utility of 0.77 is assigned to living with both impotence and urinary difficulty (). However, there is no posttreatment utility at which initial treatment is favored independent of the utility for living under active surveillance. demonstrates the importance of utilities in the model results but also reflects the central role of patient preference in the decision-making process.
These findings challenge the perception that active surveillance is a reasonable approach only if the risk of prostate cancer–specific death is equal to that seen with initial treatment. We found that as the utility for living under active surveillance increases, the minimal risk of prostate cancer–specific death associated with active surveillance necessary for initial treatment to be favored increases as well (). This analysis simulates the decision-making process experienced by patients and physicians, who must weigh disease-specific and psychological risks of active surveillance.
Probabilistic sensitivity analysis indicates the degree to which uncertainty surrounding each variable affects the results as a whole. The uncertainty surrounding the probabilities and utilities used in the model reflects the gaps in the published literature from which we generated the model inputs. We have been conservative in modeling, assuming a high degree of uncertainty in the distribution parameters and no correlation between events, thereby exaggerating the uncertainty in the results. The overlapping confidence intervals seen in this analysis are therefore not unexpected. However, the ranking of strategies and the magnitude of benefit of active surveillance compared with other strategies mirror the base-case results. The contribution of the probabilistic sensitivity analysis, and of this analysis as a whole, lies in the finding that despite substantial uncertainty surrounding this clinical question, active surveillance appears to be a reasonable alternative to initial treatment.
To our knowledge, this is the first decision analysis comparing active surveillance with initial treatment for low-risk prostate cancer. Previous decision analyses have compared watchful waiting with initial treatment.18,48–52
The most recent decision analysis48
used probabilities derived from Bill-Axelson et al53
for the watchful waiting cohort and found that, in contrast to our study, initial treatment was associated with a benefit in QALE for men with low- and medium-risk disease aged 70 years when average, patient-derived preferences were used. However, as in our study, individual patient preferences were critical in determining the optimal treatment for patients with low-risk disease.
This decision analysis modeled outcomes only for 65-year-old men; therefore, interpretation of these results must be limited to this population. Most studies performed to date in younger men have demonstrated disease-specific outcomes equivalent to older men.54–58
However, given the uncertainty surrounding long-term outcomes in men followed up with active surveillance, presenting results including younger men would have required extensive sensitivity analysis and discussion surrounding this issue. In addition, this model does not incorporate comorbidities common in older men. Including analyses of younger or older men would have limited the ability to consider the importance of utilities in the outcomes in healthy 65-year-old men, the focus of this analysis.
Additional limitations of this study reflect those in the literature on which model inputs were based. The results of randomized studies comparing active surveillance with initial treatment are expected to emerge over the next few years. A more comprehensive catalog of prostate cancer health states is needed, as is an assessment of the disutility associated with uncertainty among men who choose not to be actively treated.37
In addition, the use of adjuvant and salvage radiation therapy after radical prostatectomy was not modeled. In this low-risk population, the use of subsequent radiation therapy is relatively rare, and given the magnitude of QALE benefit of active surveillance compared with radical prostatectomy, it is unlikely that including a small survival benefit from subsequent radiation would substantively alter these conclusions.59–62
The quality-of-life advantage associated with active surveillance is robust in this model of treatment alternatives for men with clinically localized, low-risk prostate cancer. This benefit reflects the deferred and substantially lower incidence of adverse effects of treatment experienced by men under active surveillance. Active surveillance is associated with significant improvements in QALE even in analyses in which the probability of dying of prostate cancer or of developing progressive disease during active surveillance is increased. However, the finding that the optimal strategy is sensitive to utility weights is evidence that the decision whether to pursue active surveillance must be individualized. Models that incorporate individual patient utilities should be developed to assist patients and their caregivers to estimate the risks and potential benefits of active surveillance before making this decision.