Tag Archive for: non-muscle-invasive bladder cancer

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Editorial: Is 42 days the ‘magic number’ for repeat TURBT?

Gökçe et al. [1] have evaluated a group of 242 patients from 10 centres with high-risk non-muscle-invasive bladder cancer (NMIBC) who underwent repeat resection and subsequent follow-up treatment, including induction and maintenance BCG for at least 1 year. They included patients who had repeat transurethral resection (TUR) within 90 days and excluded anyone who was upstaged to T2 or who did not complete 1 year of maintenance BCG. They divided patients into two groups according to time to second TUR, Group A (14–42 days) and Group B (43–90 days). The groups were similar in terms of patient age and gender, tumour multifocality, presence of carcinoma in situ (CIS), and stage and grade. The only factors on multivariable analysis that were statistically significant predictors of recurrence were grade, associated CIS, and time to second TUR. Only grade and time to second TUR were significant predictors of progression.

Figures 1 and 2 in the paper show an enormous difference in both recurrence-free survival and progression-free survival according to time to second TUR. For both outcomes, 42 days seemed to be the ‘magic number’, since re-TUR after 42 days was associated with much worse outcome. Patients who had repeat TUR at >42 days had nearly double the rate of both recurrence and progression than those who had repeat TUR within 6 weeks.

This is quite a dramatic result, and it is hard to imagine biologically how such an effect could be explained. Second TUR has two primary objectives, to identify occult muscle-invasive disease, and to remove tumour that was inadvertently left behind at the first resection. Both of these goals have been shown to be important and to result in better outcomes compared with no repeat TUR [2]. However, in this study [1], patients who had repeat TUR at >6 weeks after the initial resection had a progression rate similar to those in prior studies who had no second TUR at all [2]. What could be occurring that would cause a delay of just a few weeks in second TUR to double the risk of subsequent progression of disease?

This is a retrospective study without centralised pathology review, and no information is available about the reasons that patients had repeat TUR at an earlier or later interval, nor about the pathological findings at the repeat TUR. One must be wary that there is significant selection bias involved. There is a hint of this in the fact that the rate of residual tumour at repeat TUR in the two groups is very different (35% vs 53%). Perhaps the later group also had a higher rate of residual invasive components on the repeat resection? Herr et al. [3] have shown that residual T1 disease on repeat TUR is highly predictive of subsequent progression. Or alternatively, perhaps it is the delay in administration of BCG that really results in the worse outcome? Patients with a longer delay to repeat TUR by definition also have at least an equivalent delay in starting BCG.

Although high-risk NMIBC can certainly be aggressive, it seems highly unlikely that a week or two-one way or another in terms of treatment would make such a huge difference in the outcome. However, this is a provocative study that remains to be validated. It will be useful to see if other groups with similar patient populations can duplicate these findings. For the time being, as a routine practice it makes sense to repeat the TUR sooner rather than later whenever possible.

Eila C. Skinner

 

Thomas A. Stamey Research Professor of Urology, Chair, Department of Urology, Stanford University, Stanford, CA, USA

 

References

Video: Significance of time interval between first and second TUR on recurrence and progression rates in BCG-treated NMIBC

Significance of time interval between first and second transurethral resection on recurrence and progression rates in patients with high risk non muscle invasive bladder cancer treated with maintenance intravesical Bacillus Calmette-Guerin

 

Sumer Baltacı, Murat Bozlu*, Asıf Yıldırım, Mehmet Ilker Gokce, İlker TinayGuven Aslan§, Cavit Can, Levent Turkeri,Ugur Kuyumcuoglu** and Aydın Mungan††

 

Department of Urology, Ankara University School of Medicine, Ankara , *Department of Urology, University of Mersin School of Medicine, Mersin,Department of Urology, Istanbul Medeniyet University School of Medicine, ‡Department of Urology, Marmara University School of Medicine, Istanbul§Department of Urology, Dokuz Eylul University School of Medicine Inciralti, IzmirDepartment of Urology, Medical Faculty, Eskisehir Osmangazi University, Eskisehir**Department of Urology, Trakya University School of Medicine, Edirneand ††Department of Urology, Bulent Ecevit University School of Medicine, Zonguldak, Turkey

 

OBJECTIVES

To evaluate the effect of the interval between the initial and second transurethral resection (TUR) on the outcome of patients with high-risk non-muscle-invasive bladder cancer (NMIBC) treated with maintenance intravesical Bacillus Calmette-Guérin (BCG) therapy.

PATIENTS AND METHODS

We reviewed the data of patients from 10 centres treated for high-risk NMIBC between 2005 and 2012. Patients without a diagnosis of muscle-invasive cancer on second TUR performed ≤90 days after a complete first TUR, and received at least 1 year of maintenance BCG were included in this study. The interval between first and second TUR in addition to other parameters were recorded. Multivariate logistic regression analysis was used to identify predictors of recurrence and progression.

RESULTS

In all, 242 patients were included. The mean (sd, range) follow-up was 29.4 (22.2, 12–96) months. The 3-year recurrence- and progression-free survival rates of patients who underwent second TUR between 14 and 42 days and 43–90 days were 73.6% vs 46.2% (P < 0.001) and 89.1% vs 79.1% (P = 0.006), respectively. On multivariate analysis, the interval to second TUR was found to be a predictor of both recurrence [odds ratio (OR) 3.598, 95% confidence interval (CI) 1.885–8.137; P = 0.001] and progression (OR 2.144, 95% CI 1.447–5.137; P = 0.003).

CONCLUSIONS

The interval between first and second TUR should be ≤42 days in order to attain lower recurrence and progression rates. To our knowledge, this is the first study demonstrating the effect of the interval between first and second TUR on patient outcomes.

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BCG – An all or nothing treatment for NMIBC?

November 2014 ushered in the third year of the international urology journal club (@iurojc) and also marked the 2500th follower of @iurojc.

This month’s article was published in European Urology (@Uroweb) on October 10, 2014, Sequential Combination of Mitomycin C Plus Bacillus Calmette-Guerin (BCG) Is More Effective but More Toxic Than BCG Alone in Patients with Non-Muscle-Invasive Bladder Cancer in Intermediate- and High-risk Patients: Final Outcome of CUETO 93009, a Randomized Prospective Trial.

 

The discussion was once again well attended by many of the Urology twitter gurus and leaders in the field of intravesical chemotherapy for non-muscle-invasive bladder cancer (NMIBC) (@davisbj, @JimCatto, @DrHWoo, @jimmontie, @uretericbud, @shomik_s, @UroDocAsh, etc).

Given the recent worldwide shortage of BCG, this article proved timely for discussion @iurojc. The authors from Spain conducted a prospective, randomized trial including 407 patients with intermediate- to high-risk NMIBC – 211 patients were allocated to receive mitomycin-C (MMC) and BCG, and 196 patients to receive BCG-alone. At 5 years, the disease free interval significantly improved with sequential MMC and BCG compared to BCG alone (HR 0.57, 95%CI 0.39-0.83, p=0.003), and reduced the relapse rate from 33.9% to 20.6%. However, sequential treatment lead to increased toxicity even after lowering the MMC dose to 10mg (p<0.001). The authors concluded that due to higher toxicity, sequential MMC and BCG therapy should only be given to patients with high likelihood of tumor recurrence (ie. recurrent T1 tumors).

The discussion started with the point being made that BCG strain may influence outcomes, with reference made to the @Uroweb article discussing the outcomes of NMIBC and BCG strain.

Subsequently, we were reminded that patients with recurrent T1 tumors are at high risk for disease progression and mortality, and that appropriately fit patients should be offered aggressive treatment (radical cystectomy).

@uretericbud also made the point that we aggressively treat T1 prostate and T1 kidney cancer, which have low cancer specific mortality, however cystectomy is the last resort for T1 bladder cancer (mortality >30%).

The reality of the worldwide BCG shortage was also highlighted during the discussion, ultimately affecting other ongoing MMC and BCG trials.

This month’s discussion concluded with a conversation regarding treatment options during the BCG shortage.  The conclusion among the discussants was for MMC during the induction phase of treatment.

Overall, the consensus was that although the results of MMC and BCG in sequence are encouraging, appropriately fit patients may still benefit from radical cystectomy for recurrent T1 disease. With the worldwide shortage of BCG, perhaps this decision will be easier to make. Happy #movember everyone.

The winner of the Best Tweet prize is Vincent Misrai who will receive a complimentary registration to the USANZ Annual Scientific Meeting to be held in Adelaide, Australia in March 2015.

Thank you to the Urological Society of Australia and New Zealand (USANZ) for providing this generous prize.  Thanks also to European Urology for enabling this paper to be open access for the November #urojc.

Zach Klaassen is a Resident in the Department of Surgery, Section of Urology Georgia Regents University – Medical College of Georgia Augusta, USA. @zklaassen_md
 

Article of the week: What does metformin use have to do with NMIBC outcomes?

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 of Dr. Rieken discussing his paper.

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

Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer

Malte Rieken1,3, Evanguelos Xylinas1,4, Luis Kluth1,5, Joseph J. Crivelli1, James Chrystal1, Talia Faison1, Yair Lotan6, Pierre I. Karakiewicz7, Harun Fajkovic10, Marek Babjuk8, Alexandra Kautzky-Willer10, Alexander Bachmann3, Douglas S. Scherr1 and Shahrokh F. Shariat1,2,10

1Department of Urology, 2Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA, 3Department of Urology, University Hospital Basel, Basel, Switzerland, 4Department of Urology Cochin Hospital, APHP, Paris Descartes University, Paris, France, 5Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 6Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 7Department of Urology, University of Montreal, Montreal, QC, Canada, 8Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic, 9Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, and 10Department of Urology, Medical University of Vienna, Vienna, Austria

Read the full article
OBJECTIVE

• To assess the association between diabetes mellitus (DM) and metformin use with prognosis and outcomes of non-muscle-invasive bladder cancer (NMIBC)

PATIENTS AND METHODS

• We retrospectively evaluated 1117 patients with NMIBC treated at four institutions between 1996 and 2007.

• Cox regression models were used to analyse the association of DM and metformin use with disease recurrence, disease progression, cancer-specific mortality and any-cause mortality.

RESULTS

• Of the 1117 patients, 125 (11.1%) had DM and 43 (3.8%) used metformin.

• Within a median (interquartile range) follow-up of 64 (22–106) months, 469 (42.0%) patients experienced disease recurrence, 103 (9.2%) experienced disease progression, 50 (4.5%) died from bladder cancer and 249 (22.3%) died from other causes.

• In multivariable Cox regression analyses, patients with DM who did not take metformin had a greater risk of disease recurrence (hazard ratio [HR]: 1.45, 95% confidence interval [CI] 1.09–1.94, P = 0.01) and progression (HR: 2.38, 95% CI 1.40-4.06, P = 0.001) but not any-cause mortality than patients without DM.

• DM with metformin use was independently associated with a lower risk of disease recurrence (HR: 0.50, 95% CI 0.27–0.94, P = 0.03).

CONCLUSION

• Patients with DM and NMIBC who do not take metformin seem to be at an increased risk of disease recurrence and progression; metformin use seems to exert a protective effect with regard to disease recurrence.

• The mechanisms behind the impact of DM on patients with NMIBC and the potential protective effect of metformin need further elucidation.

 

Read Previous Articles of the Week

 

Editorial: Diabetes mellitus and non-muscle-invasive bladder cancer: not just a coincidence?

Urologists are familiar with the plethora of comorbidities affecting patients with bladder cancer. Many are smoking-related, such as respiratory disease, ischaemic heart disease and peripheral vascular disease. Other conditions are associated with an ageing, increasingly obese population. Rieken et al. [1], present intriguing observations suggesting an association between diabetes mellitus (DM), its treatment and the prognosis of non-muscle-invasive bladder cancer (NMIBC). In a retrospective, multicentre cohort study of 1117 patients diagnosed with NMIBC, the authors conclude that patients taking metformin have better recurrence-free survival compared with patients with diabetes who did not take metformin. The Kaplan–Meier curves even hint at improved outcomes for patients taking metformin compared with the population without diabetes, although the difference did not reach statistical significance. Only 125 patients (out of 1117) had DM, of whom 43 were prescribed metformin. Outcome measures were recurrence and progression, with comparison of cancer-specific mortality not possible because of the low frequency of events. The study population was treated between 1996 and 2007, so re-resection was not routine, and rates of postoperative intravesical chemotherapy and adjuvant chemotherapy/immunotherapy were low. Treatment for some patients was therefore suboptimal by current standards, and there may have been differences between the multinational institutions.

The association between type 2 diabetes and the incidence of several cancer types (e.g. breast, colorectal and pancreatic) is well documented. The biological mechanisms responsible are unclear [2], and a causal relationship is debated. Postulated mechanisms include the effects of hyperinsulinaemia, hyperglycaemia and signalling pathways involving the IGF receptors. The protective effect of metformin is similarly unclear, although the authors cite studies indicating anti-proliferative properties.

A number of large cohort studies have endeavoured to show there is a higher risk of cancers in populations with diabetes. The challenge for such studies is the relatively low incident rate of bladder cancer in the population (17.1 per 100 000) [3]. Additionally, studies using general practice databases encounter problems obtaining data relating to bladder cancer characteristics. The increased detection of bladder cancer in the population with diabetes is a potential confounder, as monitoring using urine analysis is more likely.

Rieken et al. [1], in taking the opposite approach by identifying their cohorts on the basis of confirmed diagnosis of NMIBC, present accurate data regarding cancer characteristics but accept there is a potential for lack of accuracy in the recording of DM and treatment using chart review. We are not able to draw any conclusions regarding the severity of DM, its complications or compliance with prescribed medication. Future studies would be strengthened by incorporating tests such as HbA1c concentration as a marker for glycaemic control. Additionally, they do not specify the type of diabetes, although the reader can speculate that patients treated with metformin had type 2 DM. It is important to recognize that the pattern of cancer risk appears to be different for type 1 diabetes [4].

Whilst detailed discussion of the management of DM is outside the remit of a urological study, there are some important factors to be considered. Metformin is frequently recommended as a first-line agent in the management of type 2 DM [5]. It follows, therefore, that patients treated with metformin may be different from those requiring second- or third-line drugs and drug combinations; thus the cohort treated with metformin may be younger, exhibit better glycaemic control, and have improved renal function compared with those treated with other drugs and exogenous insulin. An important consideration is that rather than a protective effect being exerted by metformin, it may be that other hypoglycaemic agents have an adverse effect on NMIBC outcomes. Pioglitazone has recently been associated with an increased incidence of urothelial cancer when taken for >2 years, although effects on prognosis are not established [6]. Were the patients with diabetes not taking metformin in fact treated with hypoglycaemic agents implicated in the aetiology of bladder cancer? When considering the plausibility of biological mechanisms, the time-lag between exposure to carcinogen and the development of bladder cancer is pertinent. There is a prolonged time-lag between exposure to cigarette smoking and the development of bladder cancer, so are we ready to accept that drug exposure for a short time-scale is protective or causative? Finally, we must consider the clinical relevance of these findings. As metformin is the current first-line therapy, it may be contraindicated in those not prescribed it and conversion may not be possible.

Notwithstanding the above caveats, when treating patients with NMIBC we are often embarking on a lifelong process of treatment and surveillance. We are obliged as doctors to consider the implications of common comorbidities in order to tailor treatment. In much the same way that we now consider metabolic syndrome when evaluating erectile dysfunction, in the future we may need to consider NMIBC and DM together, and work collaboratively with other healthcare professionals to optimize the management of both conditions.

Joanne Cresswell
Department of Urology, James Cook University Hospital, Middlesbrough, UK

Read the full article

References

  1. Rieken M, Xylinas E, Kluth L et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU Int 2013; 112: 1105–1112
  2. Johnson JA, Carstensen B, Witte D et al. Diabetes and cancer (1). Evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologica 2012; 55: 1607–1618
  3. Cancer Research UK. Bladder cancer, average number of new cases per year and age-specific incidence rates, 2006–2008. Cancer Research UK, 2012
  4. Zendehdel K, Nyren O, Ostenson CG, Adami HO, Ekbom A, Ye W. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst 2003; 95: 1797–1800
  5. NICE. NICE Clinical Guideline, 66, 2008
  6. Azoulay L, Yin H, Filion K et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344: e3645

Video: Metformin for diabetics with NMIBC

Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer

Malte Rieken1,3, Evanguelos Xylinas1,4, Luis Kluth1,5, Joseph J. Crivelli1, James Chrystal1, Talia Faison1, Yair Lotan6, Pierre I. Karakiewicz7, Harun Fajkovic10, Marek Babjuk8, Alexandra Kautzky-Willer10, Alexander Bachmann3, Douglas S. Scherr1 and Shahrokh F. Shariat1,2,10

1Department of Urology, 2Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA, 3Department of Urology, University Hospital Basel, Basel, Switzerland, 4Department of Urology Cochin Hospital, APHP, Paris Descartes University, Paris, France, 5Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 6Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 7Department of Urology, University of Montreal, Montreal, QC, Canada, 8Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic, 9Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, and 10Department of Urology, Medical University of Vienna, Vienna, Austria

Read the full article
OBJECTIVE

• To assess the association between diabetes mellitus (DM) and metformin use with prognosis and outcomes of non-muscle-invasive bladder cancer (NMIBC)

PATIENTS AND METHODS

• We retrospectively evaluated 1117 patients with NMIBC treated at four institutions between 1996 and 2007.

• Cox regression models were used to analyse the association of DM and metformin use with disease recurrence, disease progression, cancer-specific mortality and any-cause mortality.

RESULTS

• Of the 1117 patients, 125 (11.1%) had DM and 43 (3.8%) used metformin.

• Within a median (interquartile range) follow-up of 64 (22–106) months, 469 (42.0%) patients experienced disease recurrence, 103 (9.2%) experienced disease progression, 50 (4.5%) died from bladder cancer and 249 (22.3%) died from other causes.

• In multivariable Cox regression analyses, patients with DM who did not take metformin had a greater risk of disease recurrence (hazard ratio [HR]: 1.45, 95% confidence interval [CI] 1.09–1.94, P = 0.01) and progression (HR: 2.38, 95% CI 1.40-4.06, P = 0.001) but not any-cause mortality than patients without DM.

• DM with metformin use was independently associated with a lower risk of disease recurrence (HR: 0.50, 95% CI 0.27–0.94, P = 0.03).

CONCLUSION

• Patients with DM and NMIBC who do not take metformin seem to be at an increased risk of disease recurrence and progression; metformin use seems to exert a protective effect with regard to disease recurrence.

• The mechanisms behind the impact of DM on patients with NMIBC and the potential protective effect of metformin need further elucidation.

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