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Do Older Men Benefit From Curative Therapy of Localized Prostate Cancer?

Shabbir M.H. Alibhai, Gary Naglie, Robert Nam, John Trachtenberg, Murray D. Krahn

From the Division of General Internal Medicine & Clinical Epidemiology, University Health Network; Geriatric Program, Toronto Rehabilitation Institute; and Departments of Medicine, Health Policy, Management and Evaluation, and Surgery, University of Toronto, Toronto, Canada.

Address reprint requests to S.M.H. Alibhai, MD, University Health Network, Room ENG-233, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4; e-mail: shabbir.alibhai{at}uhn.on.ca.

	ABSTRACT

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Purpose: Prior decision-analytic models are based on outdated or suboptimal efficacy, patient preference, and comorbidity data. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) associated with available treatments for localized prostate cancer in men aged 65 years, adjusting for Gleason score, patient preferences, and comorbidity.

Methods: We evaluated three treatments, using a decision-analytic Markov model: radical prostatectomy (RP), external beam radiotherapy (EBRT), and watchful waiting (WW). Rates of treatment complications and pretreatment incontinence and impotence were derived from published studies. We estimated treatment efficacy using three data sources: cancer registry cohort data, pooled case series, and modern radiotherapy studies. Utilities were obtained from 141 prostate cancer patients and from published studies.

Results: For men with well-differentiated tumors and few comorbidities, potentially curative therapy (RP or EBRT) prolonged LE up to age 75 years but did not improve QALE at any age. For moderately differentiated cancers, potentially curative therapy resulted in LE and QALE gains up to age 75 years. For poorly differentiated disease, potentially curative therapy resulted in LE and QALE gains up to age 80 years. Benefits of potentially curative therapy were restricted to men with no worse than mild comorbidity. When cohort and pooled case series data were used, RP was preferred over EBRT in all groups but was comparable to modern radiotherapy.

Conclusion: Potentially curative therapy results in significantly improved LE and QALE for older men with few comorbidities and moderately or poorly differentiated localized prostate cancer. Age should not be a barrier to treatment in this group.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
TREATMENT DECISION making in localized prostate cancer is complex. With a recent notable exception,¹ there are no randomized clinical trials that have demonstrated a survival advantage of potentially curative therapy (radical prostatectomy [RP] or radiotherapy) over watchful waiting (WW). Expert guidelines were developed prior to the aforementioned trial to identify patients most likely to benefit from treatment.^2,3 Key factors to consider are tumor grade,^4,5 prostate-specific antigen level,^6,7 and the patient’s remaining life expectancy,^8–10 which declines with increasing age and comorbid illnesses.^11,12 Some researchers have attempted to simplify treatment decisions by using nomograms incorporating tumor variables.^13,14

The role of age in decision making is particularly problematic. Published data suggest that otherwise healthy older men with higher-grade cancers may not be receiving potentially life-prolonging treatment, as a result of the perception that they are unlikely to benefit from these therapies.⁸ Rates of RP use decline sharply in patients older than 70 years.^15–18 Men younger than 60 years who have clinically localized disease are 25 times more likely to receive RP than men age 70 years or older.¹⁷ A similar but less dramatic pattern is seen in radiotherapy.^15–18 In contrast, decreased rates of potentially curative therapy do not seem to be influenced by tumor grade or comorbidity,^15,17 indicating that a patient’s chronological age alone may be inappropriately influencing treatment decisions.¹⁹

In an effort to identify which patients should be offered potentially curative treatment, two decision analyses have been published.^20,21 Both models demonstrated no gain in quality-adjusted life expectancy (QALE) with RP as compared to WW for patients older than 70 years, regardless of tumor grade.^20,21

Several features of these models have been criticized.^10,22 First, the studies used to estimate treatment efficacy may be outdated and were subject to selection bias. The former may be particularly true for radiotherapy with which improvements in radiation-delivery techniques have led to significant improvements in biochemical outcomes.^23–26 Second, pretreatment potency and continence status were not consistently considered. This may be particularly important for older men, who may be less concerned by long-term treatment-related toxicities because of pre-existing impotence and incontinence. Finally, the utilities used in the models were not obtained from men with prostate cancer, which may have led to unrealistically harsh valuations of treatment-related complications. Thus, published models may not adequately inform current clinical decision making.

The recently published randomized trial of RP versus WW demonstrated a statistically significant and clinically important improvement in disease-specific mortality in the RP arm after a median of 6.2 years of follow-up.¹ Although RP seems to be superior to WW, this study leaves several important questions unanswered: Does surgery lead to improved overall survival compared with WW? What is the role of radiotherapy? What is the optimal treatment of patients with Gleason stage 8 to 10 tumors, all of whom were excluded from the Scandinavian trial? How should age, comorbidity, and patient preferences influence treatment choice?

We have constructed a decision model that integrates patient-specific data (age and comorbidity), tumor-specific data (grade), and patient-preference data, and that addresses the limitations of previous analyses to identify which older patients may benefit from potentially curative therapy of localized prostate cancer.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Model Design
We developed a Markov state transition model to compare life expectancy (LE) and QALE associated with treatment of localized prostate cancer (Fig 1). The model simulates the natural history of hypothetical cohorts of men with newly diagnosed cancer of varying grades.²⁷ Three treatment strategies were considered: RP, external-beam radiotherapy (EBRT), and, WW. Three grades of disease were considered: well-differentiated (grade 1, Gleason score 2 to 4²⁸), moderately-differentiated (grade 2, Gleason score 5 to 7), and poorly differentiated (grade 3, Gleason score 8 to 10) prostate cancer.

View larger version (21K): [in this window] [in a new window]   Fig 1. Key healthcare states and transitions in Markov model, radical prostatectomy branch. After undergoing treatment, patients entered one of eight post-treatment healthcare states. In each cycle, patients could remain stable, die as a result of other causes, or develop hormone-responsive metastases. Patients with metastases could either remain stable, die as a result of other causes, or die as a result of advanced prostate cancer.

Each year, patients could remain in their current health state; could develop age-associated incontinence, impotence, or both; or could develop metastatic disease. We assumed that patients who develop metastatic disease are administered hormonal therapy.²⁹ In each subsequent year, their disease might remain stable or become hormone-resistant (resulting in death from prostate cancer). Within each year, patients might also die as a result of other causes. Actuarial life-tables for men were used to estimate the age-specific annual risk of dying from other causes.³⁰

Data Sources
We performed a computerized search using the MEDLINE database from January 1966 to November 2000. Combinations of the following medical subject headings and text words or phrases were employed: prostatic neoplasms, follow-up studies, treatment outcome, prostatectomy, radiotherapy, and watchful waiting. Citations were restricted to the English language. We also cross-referenced prostatic neoplasms with the text word "utilities" and the headings "decision making" or "quality-adjusted life years" in order to identify all published studies in which utilities for prostate cancer outcomes were measured. Reference lists from identified studies, published meta-analyses, decision analyses, selected review articles, book chapters, and our own files were also examined. Content experts in urology, radiation oncology, incontinence, and impotence were contacted to ensure that no important studies were overlooked.

Treatment Efficacy
We chose to examine disease-specific survival as our primary efficacy outcome because this outcome is clinically important to patients and clinicians. Moreover, it avoids the pitfalls associated with intermediate end points, such as biochemical relapse (ie, increasing prostate-specific antigen level), which do not always have a consistent relationship with outcomes such as survival or development of metastases.^31,32

We used three sets of data to estimate treatment efficacy. In our baseline analysis, we used grade-stratified, 10-year, disease-specific survival data from the only large, population-based data set (n = 59,876) of prostate cancer patients stratified by grade and treatment.³³ We used the annual probability of dying from progressive metastatic prostate cancer reported in a systematic overview of randomized trials of androgen blockade in metastatic prostate cancer (Table 1).³⁴ We imputed the probability of developing metastatic disease using disease-specific survival rates and the mortality risk associated with metastatic disease. We chose to impute rates of developing metastases rather than directly obtain them from the literature because of systematic differences in clinical, biochemical, and radiographic follow-up of patients in published studies. We then assumed that once patients developed metastatic disease, the annual probability of dying from prostate cancer was independent of initial treatment.

Finally, we had initially planned to include in our analyses only those studies that reported grade-stratified disease-specific mortality. However, major changes have taken place in the delivery of radiotherapy during the last decade.²³ Newer therapeutic modalities, such as escalated-dose, conformal and intensity-modulated radiotherapy, have led to impressive results in intermediate outcomes such as biochemical relapse.^25,67,68 To date, however, few published studies have reported disease-specific survival. To estimate the impact of newer radiotherapeutic techniques on outcomes, we identified studies that reported grade-stratified biochemical relapse rates after conformal radiotherapy.^24,67,69,70 We obtained grade-stratified progression rates after biochemical relapse from a study of patients treated with radiotherapy and observed from biochemical relapse to death.⁷¹ We then derived progression rates from biochemical relapse to metastatic disease, on the basis of our previously employed method, assuming the same progression rate from metastatic disease to death as described. These data were substituted into our model and compared with results from RP, WW, and EBRT.

Treatment Complications
The probability of age-stratified 30-day mortality after RP was obtained from a large cohort study of Medicare patients.³⁷ For 30-day mortality data after EBRT, we used unstratified case series mortality data.^41,42 To examine long-term treatment-related complications, we included all studies that featured patient-reported complication rates at least 1 year after treatment. Studies that did not include pretreatment incontinence and impotence rates were excluded to avoid labeling a pre-existing condition as a treatment side effect. For incontinence, we calculated the proportion of patients with incontinence that reported severe (equivalent to at least grade 3 Radiation Therapy Oncology Group toxicity⁵³) and nonsevere incontinence directly from studies that provided this information. For impotence, studies were excluded if age-stratified rates were not reported. Severe bowel injury was defined as equivalent to at least grade 3 toxicity. Pooled rates were obtained for each complication, weighted by the inverse of the study estimate’s variance.

We estimated the age-stratified prevalence of incontinence and impotence before treatment, as well as the distribution of incontinence severity (severe v nonsevere) from a recently published prospective treatment study of 1,291 men with prostate cancer.³⁹ For men older than age 80 years, incontinence and impotence rates were obtained from large, population-based studies.^58,59 Annual incidence rates of incontinence and impotence were derived from the studies used for prevalence data.^39,58,59

Utilities
Utilities for long-term complications were primarily derived from Krahn et al.⁷² For each complication (incontinence, impotence, and bowel injury), a disutility rating was obtained by finding the difference in mean self-reported utility rating between patients in the highest and lowest quintiles of symptom severity on the Prostate Cancer Index⁷³ (Table 1). The disutility of nonsevere incontinence was obtained from couples attending a general medicine clinic.⁶¹ Utilities related to metastatic disease were obtained from Bennett et al.⁶³ Plausible ranges for sensitivity analyses were obtained from other published studies^21,52–79 (Table 1).

Utilities for acute treatment-related morbidity and disability for RP and EBRT were modeled as a single value for a period of 13 weeks for RP and 8 weeks for EBRT (Table 1). The duration of symptoms and associated utility were estimated on the basis of published descriptions of typical treatment-related morbidity experienced by patients immediately after treatment.^80,81 We did not explicitly assign a disutility to WW but examined this assumption in sensitivity analyses.

Comorbidity Adjustment
In our model, we assumed that comorbidity modifies short-term and long-term outcomes as well as quality of life. To model the influence of comorbidity on annual mortality rates, we obtained hazard rates from the only published study that stratified mortality rates for prostate cancer by comorbidity.⁸² The study used the Index of Coexistent Disease (ICED)⁸³ to stratify patients into four levels of comorbidity (0 = no disease or asymptomatic disease, 3 = severely disabling or life-threatening disease). The ICED rates both severity of illness (across 11 organ systems) and functional limitations.⁸³ The hazard ratio for each comorbidity level, relative to no comorbidity, was then multiplied by the age-stratified annual probability of dying from other diseases.³⁰

We also adjusted the risk of 30-day mortality after RP for comorbidity. Descriptions of health states representing different ICED levels were used to assign scores using a commonly employed perioperative risk index.⁸⁴ This allowed us to obtain an odds ratio of the increased risk of mortality caused by comorbidity, which was used to adjust the age-stratified 30-day mortality risk after RP.

A utility rating for each level of comorbidity was derived by determining a severity of angina rating corresponding to each ICED level. We chose angina as a proxy for cardiovascular disease, the most common cause of morbidity and mortality in an older cohort.^85,86 Utility ratings for each ICED level were then obtained from two studies of patients with varying severities of angina.^65,66 The resultant utility was multiplied by other utilities for each hypothetical patient in each branch of the model.

Sensitivity Analyses
To examine the stability of the results of our model to variation in the base-case estimates, we performed extensive sensitivity analyses on all variables in our model. We chose age 75 years for our base-case, given that most patients 75 years or older do not receive potentially curative therapy.¹⁵ For probabilities related to treatment efficacy, upper and lower bounds of the 95% confidence interval (CI) of published 10-year disease-specific survival were used (Table 1). For long-term complication probabilities, the plausible range was obtained from published estimates (Table 1). A similar strategy was used for utilities (Table 1).

Discounting
We examined differences in LE and QALE until death or age 100 years with no discounting.

	RESULTS

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Our analyses incorporated information on age, comorbidity, and tumor grade using three complementary treatment-efficacy data sources. To provide results that are most clinically relevant, we have organized our results for men who have no comorbidity by histologic grade. To maximize the transparency of our findings for clinicians, our results are also summarized for different age and tumor-grade combinations in a look-up table (Fig 2). The influence of comorbidity on treatment choice is discussed separately.

View larger version (71K): [in this window] [in a new window]   Fig 2. Look-up table identifying patients who will gain in quality-adjusted life expectancy from potentially curative therapy, stratified by age and tumor grade. The figure illustrates gains from potentially curative therapy (higher of radical prostatectomy or modern radiotherapy), radical prostatectomy, and modern radiotherapy compared to watchful waiting. Gains are stratified into three levels of benefit, which are stratified by tumor grade. Units are in quality-adjusted life years.

Grade 3 (Gleason score 8 to 10) Disease
For otherwise healthy men with grade 3 tumors, potentially curative therapy (RP or EBRT) results in improved LE and QALE compared with WW up to the age of 85 years, regardless of treatment efficacy data. Relatively large gains in both LE and QALE (ie, greater than 1 year⁸⁷) are seen in men who undergo potentially curative therapy up to age 75 years, when compared with WW (LE gains for RP and EBRT compared to WW of 1.40 years and 0.40 years, respectively, for a 75-year-old man). Although surgery generally results in greater gains than EBRT in LE and QALE when cohort or case-series data are used, results are comparable when modern radiotherapy data are examined (LE at age 75 of 7.86 and 7.78 years for RP and modern radiotherapy, respectively).

Impact of Comorbidity
In general, overall LE and QALE decreased as comorbidity increased across all tumor grades (results for QALE are shown in Table 3). For patients with low-grade disease, potentially curative therapy did not result in clinically significant QALE gains as compared with WW for patients aged 65 years or older, regardless of comorbidity. For grade 2 tumors, RP (but not EBRT) resulted in higher QALE than WW for patients with mild or moderate comorbidity up to age 75 and 65 years, respectively. For high-grade disease, potentially curative therapy resulted in higher QALE than WW for men even with moderate comorbidity up to age 75 years (QALE for a 75-year-old man with moderate comorbidity of 3.57, 3.42, and 3.39 years for RP, EBRT, and WW, respectively).

External Validation
Our model’s results were compared to the 5- and 8-year disease-specific mortality from the randomized trial by Holmberg et al.¹ Our model predicted a 3.3% and 6.4% 5- and 8-year disease-specific mortality for the RP arm, respectively, compared to 2.6% (95% confidence interval [CI], 0.7% to 4.6%) and 7.1% (95% CI, 3.3% to 11.0%) in the trial. For WW, our model predicted a 6.8% and 14.8% 5- and 8-year disease-specific mortality, respectively; the corresponding figures from the trial were 4.6% (95% CI, 2.1% to 7.2%) and 13.6% (95% CI, 7.9% to 19.7%). Thus, our model’s predictions were similar to those observed in the trial.

Sensitivity Analyses
For a 75-year-old man with grade 1 cancer, the preference for potentially curative therapy versus WW changes depending on the value of three variables (Table 4). The most influential variable was the utility associated with WW. WW was preferred in the baseline analysis, but if the utility of WW was less than 0.99, RP became the preferred strategy. EBRT was preferred to WW if the utility of WW was less than 0.96. Other key variables included the disease-specific survival associated with WW and the utility of impotence. For grade 2 tumors, the preferred treatment option was influenced only by the utility of impotence. For grade 3 cancers, potentially curative therapy was preferred over WW across the plausible range of all probabilities and utilities for a 75-year-old man.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

For patients with low-grade (Gleason score 2 to 4) disease, the survival advantages of potentially curative therapy are modest. In this group of patients, the tumor is slow growing, treatment complications are important, and the risk of dying from competing causes exceeds the risk of cancer death. Moreover, benefits from potentially curative therapy are restricted to men with no comorbidity and are conditional on patients’ preferences for outcomes of treatment. In particular, an individual patient’s level of discomfort associated with leaving his disease untreated significantly influences the preferred treatment.⁹⁰

For patients with moderate-grade (Gleason score 5 to 7) tumors, there is significant uncertainty. The choice of optimal treatment is highly dependent on which outcome studies one accepts. If one believes in long-term outcomes reported in population-based cohort studies or biochemical outcomes with modern radiotherapy, potentially curative therapy is beneficial up to age 75 years for men with either no or mild comorbidity. If one accepts results from highly selected individuals at specialized tertiary care institutions, the benefits of treating anyone age 65 years or older with either surgery or radiotherapy are marginal, regardless of overall health. A key patient preference that may influence treatment is the patient’s values regarding preservation of sexual function.

For patients with high-grade (Gleason score 8 to 10) lesions, the results are most clear. Otherwise healthy men up to age 80 years would experience significant benefits in terms of both survival and quality-adjusted survival with potentially curative therapy. Increasing comorbidity leads to decreased benefits, such that potentially curative therapy is no longer superior to WW for 75-year-old men with moderate comorbidity or 80-year-old men with even mild comorbidity. Although surgery seems to show somewhat greater benefit than radiotherapy, variation in preferences among individual patients, along with innovations in radiotherapeutic techniques in some centers, may make either option the preferred choice. Our results are robust for every variable examined in our model, and argue strongly for wider consideration of potentially curative therapy for older men with high-grade disease. We believe our finding with respect to treatment of high-grade disease represents the single insight of greatest clinical value provided by our decision model.

Our results point to the need to avoid making treatment decisions simply on the basis of age. Large gains in quality-adjusted survival result from potentially curative therapy for high-grade tumors in 75-year-old men—larger, in fact, than from treating 65-year-old men with low-grade disease. Our findings indicate that age thresholds are set too low for men with high-grade and, to a lesser extent, moderate-grade disease. Our results also point out the importance of determining patient preferences with respect to prolonging life versus preserving quality of life⁹¹ because this has a significant influence on optimal treatment in situations in which survival gains are large but quality-adjusted survival benefits may be smaller. For example, a 75-year-old otherwise healthy man with a localized Gleason score 6 tumor may opt for potentially curative therapy if he values maximizing his remaining years of life, but may opt for conservative management if he strongly values maintaining continence and potency.

Our findings are in contrast to those of previous decision models. Our analysis is the first to indicate that potentially curative therapy results in improved health outcomes for patients older than age 70 years, especially for men with high-grade disease. Several significant differences between our model and previous models^20,21 likely account for the discrepant findings. First, previous studies used efficacy data from individual institutions or pooled case series and assumed that radiotherapy was equally efficacious as surgery. We examined the efficacy of treatment using three discrete, complementary data sources (cohort studies, pooled case series, and modern radiotherapy data) to reduce uncertainty attributable to study selection. Second, previous studies obtained rates of progression from metastatic disease from selected studies with variable follow-up and surveillance criteria, whereas we used data from a systematic overview of 27 randomized trials of hormonal therapy in advanced disease.³⁴ Third, we obtained treatment-related complication rates from studies in centers where nerve-sparing surgical procedures⁹² were regularly used, and we adjusted for pretreatment potency and continence status. Finally, most of the utilities for various health states used in our model were elicited from a relatively large cohort of men with prostate cancer, and are more representative of men with prostate cancer than those used in previous studies. Quantitatively, better disease-specific survival with potentially curative therapy and higher utility ratings for treatment-related complications accounted for much of the differences between our results and those of Fleming et al²⁰ and Kattan et al,²¹ respectively.

The greatest limitation to our analyses is the lack of efficacy data from randomized trials. The recently published Scandinavian trial¹ addresses neither the role of radiotherapy nor the treatment of Gleason score 8 to 10 tumors. Although another large randomized trial is underway, results will not be available for several years, and will only address the question of surgery versus WW.⁹³

Despite using multiple data sources in our study, observational data are more prone to bias than are randomized clinical trials. It is nonetheless reassuring that use of multiple data sources generally yielded qualitatively similar results that were comparable to those of Holmberg et al.¹ In addition, although results for intermediate outcomes, such as biochemical relapse, in studies using modern radiotherapeutic techniques seem promising, long-term survival data have yet to be published.^25,67,94 Thus, our results using modern radiotherapy must be viewed with caution in the absence of mature outcome data. The current quality of evidence also does not allow us to determine which of the two potentially curative modalities (surgery or radiotherapy) is superior. Because of limited long-term disease-specific survival data from published studies, we were also unable to separate Gleason-score 7 from Gleason score 5 and 6 tumors, which limits our ability to provide recommendations about the optimal management of these more aggressive tumors.^95–98

What is most clear from our results is that potentially curative therapy should be seriously considered in reasonably healthy men up to age 80 years who have high-grade disease. More generally, clinicians need to consider age, comorbidity, and patient preferences in addition to tumor grade when considering treatment options for older men with localized prostate cancer.

	ACKNOWLEDGMENTS

 
We thank Drs. Padraig Warde and Mack Roach III for their helpful comments on previous versions of the manuscript.

	NOTES

 
Supported in part by the Department of Medicine, University of Toronto; the Queen Elizabeth Hospital Research Foundation, Toronto; and the Toronto Rehabilitation Institute (S.M.H.A.), by the Mary Trimmer Chair in Geriatric Medicine Research at the University of Toronto (G.N.), and by an Investigator Award (M.D.K.) from the Canadian Institutes for Health Research.

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Submitted September 4, 2002; accepted June 9, 2003.

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