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Article of the Week: Association between T2DM, curative treatment and survival in localized PCa

Every Week, the Editor-in-Chief selects an 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 discussing the paper.

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

Association between type 2 diabetes, curative treatment and survival in men with intermediate- and high-risk localized prostate cancer

Danielle Crawley*, Hans Garmo*, Sarah Rudman, Par Stattin§, Bjorn Zethelius**, Lars Holmberg*, Jan Adolfsson†† and Mieke Van Hemelrijck*

 

*Division of Cancer Studies, Cancer Epidemiology Group, Kings College London, Guys and St Thomas NHS Foundation Trust and Kings College Londons Comprehensive Biomedical Research Centre, London, UK, Department of Surgical Sciences, Uppsala University, Uppsala, §Department of Surgical and Peri-operative Sciences, Urology and Andrology, Umea University, Umea, Department of Public Health and Geriatric, Uppsala University, **Medical Products Agency, Uppsala, and ††Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

 

Abstract

Objective

To investigate whether curative prostate cancer (PCa) treatment was received less often by men with both PCa and Type 2 diabetes mellitus (T2DM) as little is known about the influence of T2DM diagnosis on the receipt of such treatment in men with localized PCa.

Subjects and Methods

The Prostate Cancer database Sweden (PCBaSe) was used to obtain data on men with T2DM and PCa (n = 2210) for comparison with data on men with PCa only (n = 23 071). All men had intermediate- (T1–2, Gleason score 7 and/or prostate-specific antigen [PSA] 10–20 ng/mL) or high-risk (T3 and/or Gleason score 8–10 and/or PSA 20–50 ng/mL) localized PCa diagnosed between 1 January 2006 and 31 December 2014. Multivariate logistic regression was used to calculate the odds ratios (ORs) for receipt of curative treatment in men with and without T2DM. Overall survival, for up to 8 years of follow-up, was calculated both for men with T2DM only and for men with T2DM and PCa.

Results

Men with T2DM were less likely to receive curative treatment for PCa than men without T2DM (OR 0.78, 95% confidence interval 0.69–0.87). The 8-year overall survival rates were 79% and 33% for men with T2DM and high-risk PCa who did and did not receive curative treatment, respectively.

Conclusions

Men with T2DM were less likely to receive curative treatment for localized intermediate- and high-risk PCa. Men with T2DM and high-risk PCa who received curative treatment had substantially higher survival times than those who did not. Some of the survival differences represent a selection bias, whereby the healthiest patients received curative treatment. Clinicians should interpret this data carefully and ensure that individual patients with T2DM and PCa are not under- nor overtreated.

Editorial: Selecting patients for PCa treatment: the role of comorbidity

The risk of dying from prostate cancer is strongly influenced by competing causes related to age and comorbidity. In the past, indiscriminate screening and treatment of prostate cancer in men with limited life expectancy have been heavily criticized. In the SPCG-4 study, Bill-Axelson et al. [1] showed that patient age significantly modified the likelihood of benefit from radical prostatectomy: while patients aged <65 years at the time of treatment saw significantly decreased risk of overall mortality, prostate cancer mortality, and metastases, those aged >65 years did not have a significant improvement in survival, despite significantly decreased risk of metastases [1]. Significant progress has since been made with regard to treatment, in offering surveillance to men unlikely to die from their prostate cancer, either because of indolent disease or competing risks.

In this issue of BJUI, Crawley et al. [2] describe the association between type 2 diabetes and receipt of curative treatment for patients newly diagnosed with intermediate- and high-risk prostate cancer. Using the Prostate Cancer database Sweden (PCBaSE), the authors convincingly show us that patients who received oral therapies or insulin for type 2 diabetes were significantly less likely to undergo curative treatment after a prostate cancer diagnosis compared with men without diabetes. They also demonstrated a gradient of effect, as men treated with insulin (with presumably more severe diabetes) were even less likely to receive curative therapies than those treated with oral agents (odds ratios 0.62 and 0.91, respectively, both compared with men without diabetes). This could have been better assessed with more objective measures of disease severity including micro- and macrovascular complications or glycated haemoglobin levels. Interestingly, the authors found that men with diabetes had more aggressive disease, with higher Gleason scores, a greater proportion of biopsy cores involved with cancer, and higher PSA levels. We therefore must consider the question, is withholding curative therapy from these patients undertreatment or appropriate?

Mortality rates for men with diabetes are significantly higher than for those without. Among men aged ≥50 years, life expectancy is 7.5 years (95% CI: 5.5–9.5) shorter for those with diabetes [3]. The effect of diabetes on mortality is mediated through cardiovascular disease, the leading cause of mortality among men diagnosed with prostate cancer [4]. Thus, competing risks of mortality, rather than prostate cancer mortality, are likely to be the limiters of these patients’ life expectancy.

Interestingly, the authors found that men with diabetes who received pharmacotherapy for dyslipidaemia or cardiovascular disease had a similar likelihood of receiving treatment as men treated for diabetes alone [2].

The authors then assessed whether receipt of curative treatment was associated with overall survival among patients with diabetes. The authors conclude that curative treatment was associated with improved overall survival among these men [2], with differences in both prostate cancer and non-prostate cancer mortality. We should be sceptical of these findings, however, because of significant selection bias and confounding as the authors present only unadjusted results. The greater comorbidity and more aggressive cancers among men with diabetes in this cohort may explain a large portion of the differences in non-prostate cancer mortality and prostate cancer-mortality, respectively, separate from the effect of local treatment. This is supported by the authors’ observation that men with type 2 diabetes treated with curative intent had better overall survival than men with type 2 diabetes without prostate cancer [2]. In fact, non-prostate cancer causes contributed to the majority of deaths in these men with intermediate- and high-risk cancer, regardless of receipt of curative treatment. Lastly, with respect to survival, it should be noted that previous analyses have demonstrated a protective effect of metformin on overall and prostate cancer mortality among men with diabetes [5].

What are we to take from this paper? First, men with diabetes appear to present with more aggressive disease at the time of diagnosis. This may relate to decreased prostate cancer screening, lower PSA levels among screened men leading to a decreased index of suspicion [6], or a lower likelihood of biopsy at a given PSA level. Further, we believe that this paper shows that Swedish urologists are understandably providing curative prostate cancer treatment to men with the potential to benefit from these interventions, while sparing men with significant medical comorbidity the side effects of such therapies which are unlikely to benefit them. Caution should be applied in using these data to reflexively justify more aggressive screening and treatment in all men with diabetes. Individualized decision-making should be made on a case-by-case basis based on the best estimates of risks of prostate cancer and non-prostate cancer mortality.

Christopher J.D. Wallis,*† Raj Satkunasivam,*† and Bimal Bhindi
*Division of Urology, Department of Surgery, University of Toronto, Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada and Department of Urology, Mayo Clinic, Rochester, MN, USA

 

 

References

 

1 Bill-Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in early prostate cancer. New Engl J Med 2014; 6: 93242

 

 

3 Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder WAssociations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med 2007; 167: 114551

 

4 Ketchandji M, Kuo YF, Shahinian VB, Goodwin JS. Cause of death in older men after the diagnosis of prostate cancer. J Am Geriatr Soc 2009;57: 2430

 

5 Margel D, Urbach DR, Lipscombe LL et al. Metformin use and all-cause and prostate cancer-specic mortality among men with diabetes. J Clin Oncol 2013; 31: 306975

 

6 Werny DM, Saraiya M, Gregg EW. Prostate-specic antigen values in diabetic and nondiabetic US men, 20012002. Am J Epidemiol 2006; 164: 97883

 

Video: Association between T2DM, curative treatment and survival in localized PCa

Association between type 2 diabetes, curative treatment and survival in men with intermediate- and high-risk localized prostate cancer

Abstract

Objective

To investigate whether curative prostate cancer (PCa) treatment was received less often by men with both PCa and Type 2 diabetes mellitus (T2DM) as little is known about the influence of T2DM diagnosis on the receipt of such treatment in men with localized PCa.

Subjects and Methods

The Prostate Cancer database Sweden (PCBaSe) was used to obtain data on men with T2DM and PCa (n = 2210) for comparison with data on men with PCa only (n = 23 071). All men had intermediate- (T1–2, Gleason score 7 and/or prostate-specific antigen [PSA] 10–20 ng/mL) or high-risk (T3 and/or Gleason score 8–10 and/or PSA 20–50 ng/mL) localized PCa diagnosed between 1 January 2006 and 31 December 2014. Multivariate logistic regression was used to calculate the odds ratios (ORs) for receipt of curative treatment in men with and without T2DM. Overall survival, for up to 8 years of follow-up, was calculated both for men with T2DM only and for men with T2DM and PCa.

Results

Men with T2DM were less likely to receive curative treatment for PCa than men without T2DM (OR 0.78, 95% confidence interval 0.69–0.87). The 8-year overall survival rates were 79% and 33% for men with T2DM and high-risk PCa who did and did not receive curative treatment, respectively.

Conclusions

Men with T2DM were less likely to receive curative treatment for localized intermediate- and high-risk PCa. Men with T2DM and high-risk PCa who received curative treatment had substantially higher survival times than those who did not. Some of the survival differences represent a selection bias, whereby the healthiest patients received curative treatment. Clinicians should interpret this data carefully and ensure that individual patients with T2DM and PCa are not under- nor overtreated.

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