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Article of the week: PCa-specific mortality increased in older men with low-risk disease

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by prominent members of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Aizer discussing his paper.

If you only have time to read one article this week, it should be this one

Initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer

Ayal A. Aizer*, Ming-Hui Chen, Jona Hattangadi* and Anthony V. D’Amico

*Harvard Radiation Oncology Program, Boston, MA, Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA, and, Department of Statistics, University of Connecticut, Storrs, CT, USA

OBJECTIVE

• To evaluate whether older age in men with low-risk prostate cancer increases the risk of prostate cancer-specific mortality (PCSM) when non-curative approaches are selected as initial management.

PATIENTS AND METHODS

• The study cohort consisted of 27 969 men, with a median age of 67 years, with prostate-specific antigen (PSA)-detected, low-risk prostate cancer (clinical category T1c, Gleason score ≤6, and PSA ≤10) identified by the Surveillance, Epidemiology and End Results programme between 2004 and 2007.

• Fine and Gray’s competing risk regression analysis was used to evaluate whether management with non-curative vs curative therapy was associated with an increased risk of PCSM after adjusting for PSA level, age at diagnosis and year of diagnosis.

RESULTS

• After a median follow-up of 2.75 years, 1121 men died, 60 (5.4%) from prostate cancer.

• Both older age (adjusted hazard ratio [AHR] 1.05; 95% confidence interval (CI) 1.02–1.08; P < 0.001) and non-curative treatment (AHR 3.34; 95% CI 1.97–5.67; P < 0.001) were significantly associated with an increased risk of PCSM.

• Men > the median age experienced increased estimates of PCSM when treated with non-curative as opposed to curative intent (P< 0.001); this finding was not seen in men ≤ the median age (P = 0.17).

CONCLUSION

• Pending prospective validation, our study suggests that non-curative approaches for older men with ‘low-risk’ prostate cancer result in an increased risk of PCSM, suggesting the need for alternative approaches to exclude occult, high grade prostate cancer in these men.

 

Read Previous Articles of the Week

 

Editorial: The age old question: who benefits from prostate cancer treatment?

Widespread PSA-based screening has dramatically altered the profile of newly diagnosed prostate cancer in many countries. Although screening effectively decreases the rates of metastatic disease and prostate cancer death [1], the increasing proportion of low-risk disease necessitates a critical assessment of the need for aggressive therapy.

Active surveillance and watchful waiting are potential alternatives to delay or avoid the need for treatment in carefully selected patients. The key issue is determining which patients are appropriate for conservative management. Although these approaches are often targeted toward elderly men, such men are more likely to be diagnosed with high-risk disease. A recent study by Scosyrev et al. [2] raised concern about excess prostate cancer mortality attributable to under-treatment in the elderly.

Overall, there is very little Level 1 evidence to guide prostate cancer treatment selection. One such trial, the Swedish Prostate Cancer Group 4 (SPCG-4), showed that radical prostatectomy significantly improved survival compared with watchful waiting [3]; however, that study examined a primarily clinically detected population from the 1990s. Subsequently, the Prostate Cancer Intervention versus Observation Trial (PIVOT) randomized US male veterans diagnosed with prostate cancer from 1994 to 2002 to radical prostatectomy vs observation [4]. At 10 years, they reported no significant difference in overall survival between the two arms in the intent-to-treat analysis (hazard ratio 0.88; 95% CI 0.71–1.08, P = 0.22). However, that study was smaller than anticipated owing to difficulty with recruitment and there was a high rate of crossovers between the intervention and observation arms. Per-protocol analysis was not reported for PIVOT and the prostate cancer landscape has continued to change in the past decade, raising unanswered questions over what the results would be if we compared contemporary men who were actually treated to those who were not.

This is the knowledge gap addressed by Aizer et al. [5] who used Surveillance, Epidemiology and End Results (SEER) data for 27 969 US men diagnosed with low-risk prostate cancer from 2004 to 2007. Overall, 67.1% of these men received radical prostatectomy or radiation therapy, while >30% underwent active surveillance or watchful waiting. Using competing risks regression, they showed that both age and non-curative treatment were associated with a significantly higher short-term prostate cancer-specific mortality. These results should be interpreted with caution, however, since they comprise observational data with great potential for confounding. Interestingly, at a short median follow-up of only 2.75 years, 5.4% of these men with presumed low-risk disease died from prostate cancer. Recently, there has been debate over whether Gleason 6 disease should really be considered a cancer [6], but these data highlight the limitations of current clinical staging, such that even presumed low-risk disease may be understaged. The authors suggest that use of a more extended biopsy scheme before active surveillance might reduce the risk of early progression due to undersampling. MRI represents another potential non-invasive treatment method to improve clinical staging and patient selection for active surveillance in the future [7].

Stacy Loeb
Department of Urology, New York University, New York, NY, USA

References

  1. Schroder FH, Hugosson J, Roobol MJ et al. Prostate-cancer mortality at 11 years of follow-upN Engl J Med 2012; 366: 981–990
  2. Scosyrev E, Messing EM, Mohile S et al. Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortalityCancer 2012; 118: 3062–3070
  3. Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancerN Engl J Med 2011; 364: 1708–1717
  4. Wilt TJ, Brawer MK, Jones KM et al. Radical prostatectomy versus observation for localized prostate cancerN Engl J Med 2012;367: 203–212
  5. Aizer AA, Chen MH, Hattangadi J, D’Amico AV. Initial management of prostate-specific-antigen-detected, low-risk prostate cancer and the risk of death from prostate cancerBJU Int 2014; 113: 43–50
  6. Carter HB, Partin AW, Walsh PC et al. Gleason score 6 adenocarcinoma: should it be labeled as cancer? J Clin Oncol 2012; 30:4294–4296
  7. Vargas HA, Akin O, Afaq A et al. Magnetic Resonance Imaging for Predicting Prostate Biopsy Findings in Patients Considered for Active Surveillance of Clinically Low Risk Prostate CancerJ Urol 2012; 188: 1732–1738

 

Video: PCa in older men, is it really low-grade disease?

 

Initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer

Ayal A. Aizer*, Ming-Hui Chen, Jona Hattangadi* and Anthony V. D’Amico

*Harvard Radiation Oncology Program, Boston, MA, Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA, and, Department of Statistics, University of Connecticut, Storrs, CT, USA

OBJECTIVE

• To evaluate whether older age in men with low-risk prostate cancer increases the risk of prostate cancer-specific mortality (PCSM) when non-curative approaches are selected as initial management.

PATIENTS AND METHODS

• The study cohort consisted of 27 969 men, with a median age of 67 years, with prostate-specific antigen (PSA)-detected, low-risk prostate cancer (clinical category T1c, Gleason score ≤6, and PSA ≤10) identified by the Surveillance, Epidemiology and End Results programme between 2004 and 2007.

• Fine and Gray’s competing risk regression analysis was used to evaluate whether management with non-curative vs curative therapy was associated with an increased risk of PCSM after adjusting for PSA level, age at diagnosis and year of diagnosis.

RESULTS

• After a median follow-up of 2.75 years, 1121 men died, 60 (5.4%) from prostate cancer.

• Both older age (adjusted hazard ratio [AHR] 1.05; 95% confidence interval (CI) 1.02–1.08; P < 0.001) and non-curative treatment (AHR 3.34; 95% CI 1.97–5.67; P < 0.001) were significantly associated with an increased risk of PCSM.

• Men > the median age experienced increased estimates of PCSM when treated with non-curative as opposed to curative intent (P< 0.001); this finding was not seen in men ≤ the median age (P = 0.17).

CONCLUSION

• Pending prospective validation, our study suggests that non-curative approaches for older men with ‘low-risk’ prostate cancer result in an increased risk of PCSM, suggesting the need for alternative approaches to exclude occult, high grade prostate cancer in these men.

 

Article of the week: Prostate cancer treatments: How much do you want to spend?

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Matthew Cooperberg discussing his paper.

If you only have time to read one article this week, it should be this one.

Primary treatments for clinically localised prostate cancer: a comprehensive lifetime cost-utility analysis

Matthew R. Cooperberg, Naren R. Ramakrishna, Steven B. Duff*, Kathleen E. Hughes, Sara Sadownik, Joseph A. Smith§ and Ashutosh K. Tewari

Departments of Urology and Epidemiology and Biostatistics, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, *Veritas Health Economics Consulting, Inc., Carlsbad, CA, Department of Radiation Oncology, MD Anderson Cancer Center, Orlando, FL, Avalere Health LLC, Washington, DC, §Department of Urologic Surgery, Vanderbilt University, Nashville, TN, and Department of Urology, Cornell University, New York, NY, USA

Read the full article
OBJECTIVE

• To characterise the costs and outcomes associated with radical prostatectomy (open, laparoscopic, or robot-assisted) and radiation therapy (RT: dose-escalated three-dimensional conformal RT, intensity-modulated RT, brachytherapy, or combination), using a comprehensive, lifetime decision analytical model.

PATIENTS AND METHODS

• A Markov model was constructed to follow hypothetical men with low-, intermediate-, and high-risk prostate cancer over their lifetimes after primary treatment; probabilities of outcomes were based on an exhaustive literature search yielding 232 unique publications.

• In each Markov cycle, patients could have remission, recurrence, salvage treatment, metastasis, death from prostate cancer, and death from other causes.

• Utilities for each health state were determined, and disutilities were applied for complications and toxicities of treatment.

• Costs were determined from the USA payer perspective, with incorporation of patient costs in a sensitivity analysis.

RESULTS

• Differences across treatments in quality-adjusted life years across methods were modest, ranging from 10.3 to 11.3 for low-risk patients, 9.6–10.5 for intermediate-risk patients and 7.8–9.3 for high-risk patients.

• There were no statistically significant differences among surgical methods, which tended to be more effective than RT methods, with the exception of combined external beam + brachytherapy for high-risk disease.

• RT methods were consistently more expensive than surgical methods; costs ranged from $19 901 (robot-assisted prostatectomy for low-risk disease) to $50 276 (combined RT for high-risk disease).

• These findings were robust to an extensive set of sensitivity analyses.

CONCLUSIONS

• Our analysis found small differences in outcomes and substantial differences in payer and patient costs across treatment alternatives.

• These findings may inform future policy discussions about strategies to improve efficiency of treatment selection for localised prostate cancer.

 

Read Previous Articles of the Week

Editorial: Valuing interventions for localised prostate cancer

Robert Pickard and Luke Vale

Governments of all nations struggle to work out how best to use the limited resources available for health care. One key area of uncertainty is long term conditions with multiple therapeutic options including no active treatment, where relative merits of different treatments are unclear and there is associated unexplained variation in use of often expensive interventions such as surgery. The management of localised prostate cancer typifies this situation. The problem is how to decide the relative worth of options especially as this judgement might differ between patients, clinicians, providers and funders. The best way is to perform well designed randomised trials between competing interventions with sufficient follow-up to identify any differences. For localised prostate cancer the ProTect trial is due to report in 2014. In the meantime, health care agencies commission Health Technology Assessments (HTA) to comparatively value interventions usually on the basis of the monetary cost of the added benefit they give in terms of better outcomes. This is commonly measured as the extra cost of each additional quality-adjusted life year (QALY) they give. The well laid out paper by Cooperberg et al. certainly adds to previous similar work  that is available on relevant health agency websites (HTA 2003CADTH 2011HTA 2011HTA 2012), but was interestingly funded by an industrial stakeholder, Intuitive Surgical. Given its perspective focusing predominantly on Medicare tariffs, it is perhaps most relevant to the US Government who pays these rates, but careful reading by all will at the very least give a flavour of the use of predictive statistical and economic modelling of the possible benefits to patients, and costs to funders of the treatments advised by clinicians.

It is important to highlight that the methods of meta-analysis of the existing literature used by Cooperberg et al. are unclear – this makes it hard to critique whether the best data have been used in the model. Furthermore, the data analyses are unusual. A more typical presentation would have been to explore the likelihood that each treatment would be considered cost-effective. The method used does not really illustrate whether the conclusion should be that there are no differences between treatments or whether there is insufficient evidence to determine whether there are differences. Furthermore, although baseline characteristics of patients included in the meta-analysis are not given it is likely that some would differ between men undergoing surgery or radiotherapy leading to bias in outcome. The linear Markov model used is also perhaps an inadequate reflection of reality since it does not appear to calculate QALYs for repeated transit through further cancer treatment/remission/recurrence states and between incontinent/continent and sexual dysfunction/no sexual dysfunction states which men would value specifically and independently. In terms of costs the have included costs of patient recovery time. Arguably recovery should be captured within the QALY measure and to include it again under costs might be an element of double counting. In addition they showed that the results were sensitive to certain assumptions that may be questioned such as the four year shorter time to metastasis after biochemical recurrence for radiotherapy.

Cooperberg et al. have certainly provided a useful example of how different treatments supervised by clinicians may be valued by those that pay the bills. A parting thought is if only clinicians of differing specialties could collaborate on large definitive RCTs we would not need to rely on predictive models based on imperfect data.

 

Robert Pickard is a Professor of Urology at the Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. email: [email protected]

Luke Vale is Health Foundation Chair in Health Economics at the Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK. email: [email protected]

Read the full article

Video: Dr Cooperberg’s article commentary on prostate cancer treatment

Primary treatments for clinically localised prostate cancer: a comprehensive lifetime cost-utility analysis

Matthew R. Cooperberg, Naren R. Ramakrishna, Steven B. Duff*, Kathleen E. Hughes, Sara Sadownik, Joseph A. Smith§ and Ashutosh K. Tewari

Departments of Urology and Epidemiology and Biostatistics, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, *Veritas Health Economics Consulting, Inc., Carlsbad, CA, Department of Radiation Oncology, MD Anderson Cancer Center, Orlando, FL, Avalere Health LLC, Washington, DC, §Department of Urologic Surgery, Vanderbilt University, Nashville, TN, and Department of Urology, Cornell University, New York, NY, USA

Read the full article
OBJECTIVE

• To characterise the costs and outcomes associated with radical prostatectomy (open, laparoscopic, or robot-assisted) and radiation therapy (RT: dose-escalated three-dimensional conformal RT, intensity-modulated RT, brachytherapy, or combination), using a comprehensive, lifetime decision analytical model.

PATIENTS AND METHODS

• A Markov model was constructed to follow hypothetical men with low-, intermediate-, and high-risk prostate cancer over their lifetimes after primary treatment; probabilities of outcomes were based on an exhaustive literature search yielding 232 unique publications.

• In each Markov cycle, patients could have remission, recurrence, salvage treatment, metastasis, death from prostate cancer, and death from other causes.

• Utilities for each health state were determined, and disutilities were applied for complications and toxicities of treatment.

• Costs were determined from the USA payer perspective, with incorporation of patient costs in a sensitivity analysis.

RESULTS

• Differences across treatments in quality-adjusted life years across methods were modest, ranging from 10.3 to 11.3 for low-risk patients, 9.6–10.5 for intermediate-risk patients and 7.8–9.3 for high-risk patients.

• There were no statistically significant differences among surgical methods, which tended to be more effective than RT methods, with the exception of combined external beam + brachytherapy for high-risk disease.

• RT methods were consistently more expensive than surgical methods; costs ranged from $19 901 (robot-assisted prostatectomy for low-risk disease) to $50 276 (combined RT for high-risk disease).

• These findings were robust to an extensive set of sensitivity analyses.

CONCLUSIONS

• Our analysis found small differences in outcomes and substantial differences in payer and patient costs across treatment alternatives.

• These findings may inform future policy discussions about strategies to improve efficiency of treatment selection for localised prostate cancer.

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