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

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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, King’s College London, †Guy’s and St Thomas’ NHS Foundation Trust and King’s College London’s 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.

Read more articles of the week

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

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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: 932–42

 

2 Crawley D, Garmo H, Rudman S et al. Association between type 2 diabetes, curative treatment and survival in men with intermediate and high risk localized prostate cancer. BJU Int 2018; 121: 209–16

 

3 Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med 2007; 167: 1145–51

 

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: 24–30

 

5 Margel D, Urbach DR, Lipscombe LL et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol 2013; 31: 3069–75

 

6 Werny DM, Saraiya M, Gregg EW. Prostate-specific antigen values in diabetic and nondiabetic US men, 2001–2002. Am J Epidemiol 2006; 164: 978–83

 

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

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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.

View more videos

What’s the Diagnosis?

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pq-apr-2

This diabetic man had a perineal abscess drained. He made a good recovery but 2 days later crepitus was noted in the scrotum.

No such quiz/survey/poll

Article of the Week: Better fit than fat when it comes to radical cystectomy for bladder cancer

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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.

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

Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy

Thomas F. Chromecki1,2*, Eugene K. Cha1*, Harun Fajkovic1,3, Michael Rink1,4, Behfar Ehdaie1, Robert S. Svatek5, Pierre I. Karakiewicz6, Yair Lotan7, Derya Tilki8, Patrick J. Bastian8, Siamak Daneshmand9,Wassim Kassouf10, Matthieu Durand1, Giacomo Novara11, Hans-Martin Fritsche12, Maximilian Burger12, Jonathan I. Izawa13, Antonin Brisuda14, Marek Babjuk14, Karl Pummer2 and Shahrokh F. Shariat1

1Weill Medical College of Cornell University, New York, NY, USA, 2Medical University Graz, Graz, Austria, 3Landeskrankenhaus St Poelten, St Poelten, Austria, 4University Medical Centre Hamburg-Eppendorf, Hamburg, Germany, 5University of Texas Health Science Center San Antonio, San Antonio, TX, USA, 6University of Montréal, Montréal, QC, Canada, 7University of Texas Southwestern Medical Center, Dallas, TX, USA, 8Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Munich, Germany, 9University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 10McGill University Health Centre, Montréal, QC, Canada, 11University of Padua, Padua, Italy, 12Caritas St Josef Medical Centre, University of Regensburg, Regensburg, Germany, 13University of Western Ontario, London, ON, Canada, and 14Hospital Motol, 2nd Faculty of Medicine, Charles University, Praha, Czech Republic
*These authors contributed equally.

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OBJECTIVE

• To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi-institutional series.

PATIENTS AND METHODS

• Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded.

• Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer-specific mortality and overall mortality.

• BMI was analysed as a continuous and categorical variable (<25 vs 25–29 vs 30 kg/m2).

RESULTS

• Median BMI was 28.8 kg/m2 (interquartile range 7.9); 25.3% had a BMI <25 kg/m2, 32.5% had a BMI between 25 and 29.9 kg/m2, and 42.2% had a BMI 30 kg/m2.

• Patients with a higher BMI were older (P < 0.001), had higher tumour grade (P < 0.001), and were more likely to have positive soft tissue surgical margins (P = 0.006) compared with patients with lower BMI.

• In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI >30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.46–1.91, P < 0.001), cancer-specific mortality (HR 1.43, 95% CI 1.24–1.66, P < 0.001), and overall mortality (HR 1.81, CI 1.60–2.05, P < 0.001). The main limitation is the retrospective design of the study.

CONCLUSIONS

• Obesity is associated with worse cancer-specific outcomes in patients treated with RC for UCB.

• Focusing on patient-modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB.

 

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Editorial: Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy

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Michael R. Abern, Stephen J. Freedland and Brant A. Inman

Division of Urologic Surgery, Duke University Medical Center, Durham, NC, USA

Obesity is a worldwide epidemic: it is estimated over 300 million adults are obese and over 1 billion are overweight. As obesity is a risk factor for cancers and is modifiable, the authors of this report retrospectively analyse the association between body mass index (BMI) and outcomes in a large multinational cohort of bladder cancer patients that underwent radical cystectomy. They found that obese patients were older and more likely to have high-grade tumours. Furthermore, obese patients received inferior lymphadenectomies, had more positive margins, and were less likely to receive adjuvant chemotherapy. The end result is an association between obesity and bladder cancer recurrence, and both cancer-specific and overall mortality.

Although these data suggest that obesity is associated with poor radical cystectomy outcomes, this contrasts with evidence showing no link between obesity and bladder cancer mortality in population-based trials such as the Cancer Prevention Study II, which prospectively followed over 900 000 participants. Why the discrepancy? One possible explanation is the presence of confounding factors and one possible confounder is the presence of type 2 diabetes. In population-based studies that considered both BMI and diabetes, people with diabetes were noted to have an increased risk of developing bladder cancer independent of BMI, whereas the converse was not true. Additionally, diabetes has been associated with recurrence and progression of non-muscle invasive bladder cancer whereas obesity has not. The impact of diabetes was not adequately addressed in the current study.

Other limitations also probably affect the results. In the current study, overweight patients (BMI 25–30) had significantly better cancer-specific survival (hazard ratio 0.80, P = 0.01) than those of ‘normal’ weight (BMI < 25). However, a threshold BMI ≥ 30 has been shown to have poor sensitivity for obesity in elderly populations, with over 25% of patients with BMI under 30 qualifying as obese based on body fat. This may result in an overstatement of the effect of obesity. Conversely, the inclusion of underweight patients (BMI < 18.5) in the ‘normal’ group may underestimate the effect between obesity and outcome, as cachexia may be associated with poor outcomes. Another factor mentioned by the authors is the inferior lymphadenectomies performed in obese patients, which introduces a detection bias for lymph node positivity, the strongest predictor after advanced stage for all of their tested outcomes on multivariate analysis (hazard ratio 2.01–2.33, P < 0.001).

Although the true effect of obesity may be hard to quantify with these data, all would agree that maintaining a non-obese bodyweight will help many disease states with little apparent harm. Patients undergoing neoadjuvant chemotherapy before radical cystectomy have a 3-month window to lose weight and exercise more. This could improve surgical outcomes, and possibly tolerance of chemotherapy. Furthermore, if we can prove that obesity leads to increased bladder cancer recurrence or progression, a window of opportunity may exist when a low-risk tumour is diagnosed. Otherwise, we are left with the eighteenth century wisdom of Benjamin Franklin: ‘An ounce of prevention is worth a pound of cure.’

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