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Original Research |

Observation Versus Initial Treatment for Men With Localized, Low-Risk Prostate Cancer: A Cost-Effectiveness Analysis

Julia H. Hayes, MD; Daniel A. Ollendorf, MPH; Steven D. Pearson, MD, MSc; Michael J. Barry, MD; Philip W. Kantoff, MD; Pablo A. Lee, BS; and Pamela M. McMahon, PhD
[+] Article and Author Information

From Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Institute for Clinical and Economic Review, Institute for Technology Assessment, and Massachusetts General Hospital, Boston, Massachusetts.

Acknowledgment: The authors thank Cancer Intervention and Surveillance Modeling Network investigators for helpful discussions.

Grant Support: By grant R25 CA92203-08 (National Cancer Institute at the National Institutes of Health), grant W81XWH-09-1-0512 (U.S. Department of Defense), a Young Investigators Award to Dr. Hayes (Prostate Cancer Foundation), and funding to the Institute for Clinical and Economic Review from the Blue Shield of California Foundation.

Potential Conflicts of Interest: Dr. Hayes: Grants (money to institution): U.S. Department of Defense, Prostate Cancer Foundation; Royalties: UpToDate. Dr. Ollendorf: Grants (money to institution): Blue Shield of California Foundation. Dr. Pearson: Consultancy: National Institutes of Health, Yale University; Employment: Massachusetts General Hospital; Grants/grants pending (money to institution): Agency for Healthcare Research and Quality. Dr. Barry: Board membership: Informed Medical Decisions Foundation; Employment: Informed Medical Decisions Foundation; Royalties (money to institution): Health Dialog. Dr. McMahon: Grants (money to institution): Blue Shield of California Foundation, Harvard Community Health Plan. All other authors have no disclosures. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0857.

Reproducible Research Statement: Study protocol: Not available. Statistical code: Available to approved individuals after discussion with Dr. Hayes (e-mail, Julia_Hayes@dfci.harvard.edu). Data set: Available from Dr. Hayes (e-mail, Julia_Hayes@dfci.harvard.edu).

Requests for Single Reprints: Julia H. Hayes, MD, Dana-Farber Cancer Institute, Dana 1230, 450 Brookline Avenue, Boston, MA 02115; e-mail, Julia_Hayes@dfci.harvard.edu.

Current Author Addresses: Drs. Hayes and Kantoff: Dana-Farber Cancer Institute, Dana 1230, 450 Brookline Avenue, Boston, MA 02115.

Drs. Ollendorf and Pearson: Institute for Clinical and Economic Review, 101 Merrimac Street, 10th Floor, Boston, MA 02114.

Dr. Barry: General Medicine Division, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114.

Mr. Lee and Dr. McMahon: Institute for Technology Assessment, 101 Merrimac Street, 10th Floor, Boston, MA 02114.

Author Contributions: Conception and design: J.H. Hayes, D.A. Ollendorf, M.J. Barry, P.W. Kantoff, P.M. McMahon.

Analysis and interpretation of the data: J.H. Hayes, D.A. Ollendorf, S.D. Pearson, M.J. Barry, P.W. Kantoff, P.M. McMahon.

Drafting of the article: J.H. Hayes, D.A. Ollendorf.

Critical revision of the article for important intellectual content: J.H. Hayes, D.A. Ollendorf, S.D. Pearson, M.J. Barry, P.M. McMahon.

Final approval of the article: J.H. Hayes, D.A. Ollendorf, S.D. Pearson, M.J. Barry, P.W. Kantoff, P.M. McMahon.

Provision of study materials or patients: D.A. Ollendorf.

Statistical expertise: J.H. Hayes, D.A. Ollendorf, P.M. McMahon.

Obtaining of funding: J.H. Hayes.

Collection and assembly of data: J.H. Hayes, D.A. Ollendorf, P.A. Lee, P.M. McMahon.


Ann Intern Med. 2013;158(12):853-860. doi:10.7326/0003-4819-158-12-201306180-00002
Text Size: A A A

Chinese translation

Background: Observation is underutilized among men with localized, low-risk prostate cancer.

Objective: To assess the costs and benefits of observation versus initial treatment.

Design: Decision analysis simulating treatment or observation.

Data Sources: Medicare schedules, published literature.

Target Population: Men aged 65 and 75 years who had newly diagnosed low-risk prostate cancer (prostate-specific antigen level <10 µg/L, stage ≤T2a, Gleason score ≤3 + 3).

Time Horizon: Lifetime.

Perspective: Societal.

Intervention: Treatment (brachytherapy, intensity-modulated radiation therapy, or radical prostatectomy) or observation (active surveillance [AS] or watchful waiting [WW]).

Outcome Measures: Quality-adjusted life expectancy and costs.

Results of Base-Case Analysis: Observation was more effective and less costly than initial treatment. Compared with AS, WW provided 2 additional months of quality-adjusted life expectancy (9.02 vs. 8.85 years) at a savings of $15 374 ($24 520 vs. $39 894) in men aged 65 years and 2 additional months (6.14 vs. 5.98 years) at a savings of $11 746 ($18 302 vs. $30 048) in men aged 75 years. Brachytherapy was the most effective and least expensive initial treatment.

Results of Sensitivity Analysis: Treatment became more effective than observation when it led to more dramatic reductions in prostate cancer death (hazard ratio, 0.47 vs. WW and 0.64 vs. AS). Active surveillance became as effective as WW in men aged 65 years when the probability of progressing to treatment on AS decreased below 63% or when the quality of life with AS versus WW was 4% higher in men aged 65 years or 1% higher in men aged 75 years. Watchful waiting remained least expensive in all analyses.

Limitation: Results depend on outcomes reported in the published literature, which is limited.

Conclusion: Among these men, observation is more effective and costs less than initial treatment, and WW is most effective and least expensive under a wide range of clinical scenarios.

Primary Funding Source: National Cancer Institute, U.S. Department of Defense, Prostate Cancer Foundation, and Institute for Clinical and Economic Review.

Figures

Grahic Jump Location
Appendix Figure 1.

Formula used to approximate a and b on the basis of mean and SD for β-distribution function for probabilistic sensitivity analysis (from TreeAge Pro).

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.

Probabilistic sensitivity analysis of costs (in U.S. dollars) and effectiveness (QALE, in years) for men aged 65 years.

Ellipses represent 95% CIs for each strategy. AS = active surveillance; BT = brachytherapy; IMRT = intensity-modulated radiation therapy; QALE = quality-adjusted life expectancy; RP = radical prostatectomy; WW = watchful waiting.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.

Probabilistic sensitivity analysis of costs (in U.S. dollars) and effectiveness (QALE, in years) for men aged 75 years.

Ellipses represent 95% CIs for each strategy. AS = active surveillance; BT = brachytherapy; IMRT = intensity-modulated radiation therapy; QALE = quality-adjusted life expectancy; RP = radical prostatectomy; WW = watchful waiting.

Grahic Jump Location

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Comments

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Unstable HR estimate used in cost-effectiveness model
Posted on June 28, 2013
Paul Pinsky
National Cancer Institute
Conflict of Interest: None Declared
Hayes et al in their report on a cost-effectiveness analysis of treatment versus observation for low risk prostate cancer conclude that watchful waiting (WW) is both less costly and more effective, in terms of quality adjusted life expectancy, than the standard treatments of surgery or radiation. Their base case results depend heavily on a hazard ratio (HR) for prostate cancer specific mortality of 1.48 for treatment versus WW, an HR taken from that observed in the low risk sub-group in the PIVOT trial. However, the 95% confidence intervals on this HR were extremely wide, 0.42-5.24, a result of the fact that there were only 10 prostate cancer deaths in PIVOT in this sub-group (6 in treatment versus 4 in WW). The fact that such a pivotal parameter in the model was derived from such an unstable estimate should make readers very cautious in interpreting the model findings. Further, the point estimate used, besides being unstable, lacks credulity. As stated by the authors, it is already controversial that men with low risk prostate cancer, who comprise up to 70% of men with clinically localized disease and who have less than a 6% risk of prostate cancer specific death through 15 years, are being routinely treated with radiation or surgery, given the fact that these treatments are known to cause major quality of life harms (impotence and incontinence) and utilize substantial health care resources. However, if it were widely accepted that such treatments also were associated with a 50% increase in the risk of dying from prostate cancer (or from treatment for prostate cancer) as compared to observation only, then this situation would move well past controversial – it would be one of the greatest medical scandals in the U.S. in recent decades. Solid evidence for such an increased risk is clearly not in yet.
Author's Response
Posted on July 26, 2013
Julia H. Hayes, MD, Michael J. Barry, MD, Pamela M. McMahon, PhD
Harvard
Conflict of Interest: None Declared

We appreciate the concerns articulated by Dr. Pinsky regarding the hazard ratio for prostate cancer specific death for treatment vs. watchful waiting used in the base case of our study1.  We chose to use the results from the low-risk subset of men in PIVOT, despite the small number of deaths in both arms, in the absence of other randomized controlled data comparing watchful waiting to treatment in the PSA era2.  The dearth of long-term data directing therapeutic choices in this context is one reason to perform decision analysis, which allows assumptions to be made and then varied over a wide range to determine their effect on results.  We chose the best available data for our base case, but then varied this hazard ratio over a wide range (HR 0.42, the lower limit of the 95% confidence interval reported in PIVOT, to 2.96, twice the base case hazard ratio) and performed threshold analyses to determine at what HR of prostate cancer-specific death treatment would be favored over watchful waiting in terms of QALE (HR 0.47 in 65 year old men).  Watchful waiting remained the least expensive strategy over the entire range tested (Appendix Table 2).  Probabilistic sensitivity analysis was also performed to assess the effect of varying all key parameters over a wide range simultaneously, including the hazard ratio of prostate cancer-specific death, and our conclusions did not change. 

We recognize the suboptimal nature of the hazard ratio of prostate cancer-specific death for men with low-risk prostate cancer provided by PIVOT.  However, we used the best available data and then demonstrated in multiple analyses that our results were impervious to changes in this estimate over a wide range.  We hope that with time, better data will be available to us to use in future models.

Hayes JH, Barry MJ, McMahon PM

 

1.         Hayes JH, Ollendorf DA, Pearson SD, et al. Observation versus initial treatment for men with localized, low-risk prostate cancer: a cost-effectiveness analysis. Ann Intern Med. Jun 18 2013;158(12):853-860.

2.         Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. The New England journal of medicine. Jul 19 2012;367(3):203-213.

 

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