Tag Archive for: Article of the Week

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Editorial: Perioperative aspirin: To give or not to give?

As the population ages and life expectancy increases, one may safely assume that more men will be diagnosed with diseases of the elderly such as prostate cancer. In the USA, it is estimated that the number of older adults (≥65 years old) will double between 2010 and 2030, contributing to a 45% increase in cancer incidence [1]. Also, it is likely that these older patients will present with multiple comorbidities, commonly described as ‘multimorbidity’ in the contemporary medical literature, including chronic cardiac and pulmonary conditions requiring multidisciplinary medical management.

Hence, the present study by Leyh-Bannurah et al. [2] examining the peri-operative use of aspirin in patients undergoing radical prostatectomy (RP) is a timely and important contribution, and may very well influence our clinical decision-making regarding the perioperative management of the anti-coagulated patient. Their results show that perioperative continuation of aspirin made no difference in peri and postoperative outcomes following RP. Previous studies have assessed the effect of aspirin continuation in patients undergoing minimally invasive RP, but the present study is the first to evaluate the effect of aspirin continuation in patients undergoing minimally invasive and open RP at a high-volume tertiary centre. Studies from other surgical specialties evaluating the role of anti-platelet therapy and its timing before surgery have shown conflicting results. The study by Park et al. [3], looking at discontinuation of aspirin for ≥7 days vs <7 days before surgery in patients undergoing lumbar spinal fusion, found that aspirin discontinued only 3–7 days before surgery significantly increased the risk of intraoperative bleeding. Alghamdi et al. [4] found similar results in patients undergoing coronary artery bypass grafting. In contrast, the study by Wolf et al. [5] showed that continuation of aspirin up to the day of the surgery did not increase the risk of bleeding, transfusion or other adverse outcomes in patients undergoing pancreatectomy. Similarly, Khudairy et al. [6] assessed the use of clopidogrel and its discontinuation time in hip fracture repair, and found that whether it was stopped ≥1 week or <1 week before surgery did not make any difference to the risk of bleeding or peri-operative complications. Nonetheless, the evidence provided by the present study by Leyh-Bannurah et al. is important, as the risk of bleeding seems to be procedure-specific, depending on the nature and source of potential bleeding (primarily arterial vs primarily venous). The lack of information, however, regarding cardiovascular morbidities in their patient population is an important limitation of their study; as such factors may influence perioperative decision-making, including the threshold for transfusion.

Akshay Sood and Quoc-Dien Trinh*
VUI Center for Outcomes Research, Analytics and Evaluation, Henry Ford Health System, Detroit, MI, and *Division of Urologic Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

References

  1. Lamb A. Fast Facts: prostate cancer, seventh edition. BJU Int 2012; 110: E157
  2. Park JH, Ahn Y, Choi BS et al. Antithrombotic effects of aspirin on 1- or 2-level lumbar spinal fusion surgery: a comparison between 2 groups discontinuing aspirin use before and after 7 days prior to surgery. Spine 2013; 38: 1561–1565
  3. Alghamdi AA, Moussa F, Fremes SE. Does the use of preoperative aspirin increase the risk of bleeding in patients undergoing coronary artery bypass grafting surgery? Systematic review and meta-analysis. J Cardiac Surg 2007; 22: 247–256
  4. Wolf AM, Pucci MJ, Gabale SD et al. Safety of perioperative aspirin therapy in pancreatic operations. Surgery 2014; 155: 39–46
  5. Al Khudairy A, Al-Hadeedi O, Sayana MK, Galvin R, Quinlan JF. Withholding clopidogrel for 3 to 6 versus 7 days or more before surgery in hip fracture patients. J Orthop Surg 2013; 21: 146–150

Video: Effect of peri-operative aspirin medication in open or robot-assisted RP

Open and robot-assisted radical retropubic prostatectomy in men receiving ongoing low-dose aspirin medication: revisiting an old paradigm?

Sami-Ramzi Leyh-Bannurah, Jens Hansen, Hendrik Isbarn, Thomas Steuber, Pierre Tennstedt, Uwe Michl, Thorsten Schlomm*, Alexander Haese, Hans Heinzer, Hartwig Huland, Markus Graefen and Lars Budäus

Martini Clinic, Prostate Cancer Center at University Hospital Hamburg-Eppendorf, and *Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

OBJECTIVE

• To assess blood loss, transfusion rates and 90-day complication rates in patients receiving ongoing 100 mg/day aspirin medication and undergoing open radical prostatectomy (RP) or robot-assisted RP (RARP).

PATIENTS AND METHODS

• Between February 2010 and August 2011, 2061 open RPs and 400 RARPs were performed. All patients received low-molecular-weight heparin for thrombembolism prophylaxis. Aspirin intake during surgery was recorded in 137 patients (5.5%).

• Descriptive statistics and multivariable analyses after propensity-score matching for balancing potential differences in patients with and without aspirin medication were used to assess the risk of blood loss above the median in patients undergoing open RP or RARP.

RESULTS

• The median blood loss in the open RP cohort with and without aspirin medication was 750 and 700 mL, respectively, and in the RARP cohort it was 200 and 150 mL, respectively. Within the same cohorts, transfusions were administered in 21 and 8% and 0 and 1% of patients, respectively.

• The 90-day complication rates in patients with ongoing aspirin medication were 5.8, 4.4, 7.3 and 0% for Clavien grades I, II, III and IV complications, respectively.

• In multivariable analyses and after propensity-score matching, prostate volume (odds ratio 1.03; 95% CI 1.02–1.04; P < 0.01) but not ongoing aspirin medication achieved independent predictor status for the risk of blood loss above the median.

CONCLUSIONS

• Major surgery such as open RP and RARP can be safely performed in patients with ongoing aspirin medication without greater blood loss.

• Higher 90-day complication rates were not detected in such patients.

• Differences in transfusion rates between the groups receiving and not receiving ongoing aspirin medication may be explained by a higher proportion of patients with coronary artery disease in the group receiving ongoing aspirin mediciation. This comorbidity may result in a higher peri-operative threshold for allogenic blood transfusion.

Article of the week: Guideline of guidelines: prostate cancer screening

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The introduction 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.

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

Guideline of guidelines: prostate cancer screening

Stacy Loeb
Department of Urology and Population Health, New York University, New York, NY, USA

INTRODUCTION

Prostate cancer screening is one of the most controversial topics in urology [1]. On one hand, there is randomised data showing that PSA screening results in earlier stages at diagnosis, improved oncological outcomes after treatment, and lower prostate cancer mortality rates. However, the downsides include unnecessary biopsies due to false-positive PSA tests, over-diagnosis of some insignificant cancers, and potential side-effects from prostate biopsy and/or prostate cancer treatment. The ongoing controversy is highlighted by the divergent recommendations on screening from multiple professional organisations. The purpose of this article is to summarise the recent guidelines on prostate cancer screening from 2012 to present.

Article of the Month: Neutrophil–lymphocyte ratio helps predict survival in patients with upper tract urothelial carcinoma

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 from Georg Hutterer discussing his paper.

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

Validation of pretreatment neutrophil–lymphocyte ratio as a prognostic factor in a European cohort of patients with upper tract urothelial carcinoma

Orietta Dalpiaz, Georg C. Ehrlich, Sebastian Mannweiler*, Jessica M. Martín Hernández, Armin Gerger, Tatjana Stojakovic, Karl Pummer, Richard Zigeuner, Martin Pichler and Georg C. Hutterer

Department of Urology, *Institute of Pathology, Division of Oncology, Department of Internal Medicine, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

OBJECTIVE

• To investigate the potential prognostic significance of the neutrophil–lymphocyte ratio (NLR) in a large European cohort of patients with upper urinary tract urothelial cell carcinoma (UUT-UCC).

PATIENTS AND METHODS

• We retrospectively evaluated data from 202 consecutive patients with non-metastatic upper urinary tract urothelial cell carcinoma (UUT-UCC), who underwent surgery between 1990 and 2012 at a single tertiary academic centre.

• Patients’ cancer-specific survival (CSS) and overall survival (OS) were assessed using the Kaplan–Meier method.

• To evaluate the independent prognostic significance of the NLR, multivariate proportional Cox regression models were applied for both endpoints.

RESULTS

• A higher NLR was significantly associated with shorter CSS (P = 0.002, log-rank test), as well as with shorter OS (P < 0.001, log-rank test).

• Multivariate analysis identified a high NLR as an independent prognostic factor for patients’ CSS (hazard ratio 2.72, 95% CI 1.25–5.93, P = 0.012), and OS (hazard ratio 2.48, 95% CI 1.31–4.70, P = 0.005).

CONCLUSIONS

• In the present cohort, patients with a high preoperative NLR had higher cancer-specific and overall mortality after radical surgery for UUT-UCC, compared with those with a low preoperative NLR.

• This easily identifiable laboratory measure should be considered as an additional prognostic factor in UUT-UCC in future.

Editorial: Neutrophil-to-lymphocyte ratio as a prognostic factor in upper tract urothelial cancer

The immune system response is critical to cancer development, treatment and progression. Dalpiaz et al. [1]. show that patients with a higher neutrophil-to-lymphocyte ratio (NLR) have a higher cancer-specific and overall mortality when undergoing radical nephroureterectomy for upper tract urothelial cell cancer (UTUC). The study is the first and largest one to evaluate the impact of preoperative NLR on UTUC and proposes its incorporation into our risk assessment tools as an independent predictor of survival.

Pathological prognostic factors such as tumour stage and grade have established importance in UTUC [2]. Additionally, lymphovascular invasion and tumour necrosis have been shown to be independent predictors of survival [3]. Preoperative markers have the advantage of prospective planning and counselling for treatment. The NLR has been studied in various cancers, including renal and gastric, and was recently incorporated into a risk stratification scheme for radical cystectomy patients as an independent prognostic factor for survival [4].

Dalpiaz et al. retrospectively reviewed 202 patients with UTUC who underwent radical nephroureterectomy. A threshold NLR value of 2.7 was used to discriminate between patients. NLR was significantly associated with lymphovascular invasion, but not with age, gender, tumour site, vascular invasion, tumour grade, pathological T-stage, tumour site, tumour location or presence of tumour necrosis. The mean follow-up was 45 months. The median survival was 44.5 months in the low-NLR group and 27 months in the high-NLR group. Multivariate analysis showed that T-stage and NLR were predictors of cancer-specific survival. High NLR and muscle invasion were shown to be independent predictors of overall survival.

Although interesting, these results should be interpreted cautiously as it is very difficult to control all confounders in a retrospective study. The authors did try to address aspects of the inflammatory response by incorporating Eastern Cooperative Oncology Group Performance Status and Charlson Comorbidity Index into their analysis. They found no statistically significant association between NLR and Eastern Cooperative Oncology Group Performance Status or Charlson Comorbidity Index. When adjusting for these variables, the relationships between NLR and cancer-specific survival and between NLR and overall survival were maintained. Although helpful in supporting the conclusions, using the Eastern Cooperative Oncology Group Performance Status and Charlson Comorbidity Index as markers of the inflammatory response should be approached carefully, as many other factors, such as hydronephrosis, tumour invasion, and pre-procedure treatments, which were not evaluated could have a more significant effect on the NLR than general measures of chronic conditions.

The threshold value of the NLR (2.7) was obtained by testing all possible thresholds and choosing a value based on its ability to predict survival and mathematical convenience. Thus the threshold value is self-serving to the conclusion. The statistical analysis suffers due to the dichotomous discrimination as opposed to further divisions like quartiles, but nonetheless shows the value of NLR as an important predictor, the threshold value of which might differ from cohort to cohort.

The present study shows that NLR as an important predictor of survival in UTUC. NLR is easy to perform, relatively inexpensive and is probably already available as part of the standard evaluation of patients with UTUC. It is therefore easy to assess. How should it change our practices? For example, should we be considering neoadjuvant chemotherapy, lymph node dissections or earlier radical surgery in patients with high NLR? The present study develops the hypothesis that can serve as the basis of future validation in a larger cohort or in a prospective fashion.

Moben Mirza
Department of Urology, University of Kansas, Kansas City, KS, USA

References
  1. Rouprêt M, Hupertan V, Seisen T et al.; French National Database on Upper Tract Tumors; Upper Tract Urothelial Carcinoma Collaboration. Prediction of cancer specific survival after radical nephroureterectomy for upper tract urothelial carcinoma: development of an optimized postoperative nomogram using decision curve analysis. J Urol 2013; 189: 1662–1669
  2. Zigeuner R, Shariat SF, Margulis V et al. Tumour necrosis is an indicator of aggressive biology in patients with urothelial carcinoma of the upper urinary tract. Eur Urol 2010; 57: 575
  3. Gondo T, Nakashima J, Ohno Y et al. Prognostic value of neutrophil-to-lymphocyte ratio and establishment of novel preoperative risk stratification model in bladder cancer patients treated with radical cystectomy. Urology 2012; 79: 1085

 

Video: Prognostic value of neutrophil–lymphocyte ratio in patients with UTUC

Validation of pretreatment neutrophil–lymphocyte ratio as a prognostic factor in a European cohort of patients with upper tract urothelial carcinoma

Orietta Dalpiaz, Georg C. Ehrlich, Sebastian Mannweiler*, Jessica M. Martín Hernández, Armin Gerger, Tatjana Stojakovic, Karl Pummer, Richard Zigeuner, Martin Pichler and Georg C. Hutterer

Department of Urology, *Institute of Pathology, Division of Oncology, Department of Internal Medicine, and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

OBJECTIVE

• To investigate the potential prognostic significance of the neutrophil–lymphocyte ratio (NLR) in a large European cohort of patients with upper urinary tract urothelial cell carcinoma (UUT-UCC).

PATIENTS AND METHODS

• We retrospectively evaluated data from 202 consecutive patients with non-metastatic upper urinary tract urothelial cell carcinoma (UUT-UCC), who underwent surgery between 1990 and 2012 at a single tertiary academic centre.

• Patients’ cancer-specific survival (CSS) and overall survival (OS) were assessed using the Kaplan–Meier method.

• To evaluate the independent prognostic significance of the NLR, multivariate proportional Cox regression models were applied for both endpoints.

RESULTS

• A higher NLR was significantly associated with shorter CSS (P = 0.002, log-rank test), as well as with shorter OS (P < 0.001, log-rank test).

• Multivariate analysis identified a high NLR as an independent prognostic factor for patients’ CSS (hazard ratio 2.72, 95% CI 1.25–5.93, P = 0.012), and OS (hazard ratio 2.48, 95% CI 1.31–4.70, P = 0.005).

CONCLUSIONS

• In the present cohort, patients with a high preoperative NLR had higher cancer-specific and overall mortality after radical surgery for UUT-UCC, compared with those with a low preoperative NLR.

• This easily identifiable laboratory measure should be considered as an additional prognostic factor in UUT-UCC in future.

Article of the week: Free testosterone levels in PCa reclassification

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.

Low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillance

Ignacio F. San Francisco, Pablo A. Rojas, William C. DeWolf* and Abraham Morgentaler*

Departamento de Urología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile and *Division of Urological Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

OBJECTIVE

To determine whether total testosterone and free testosterone levels predict disease reclassification in a cohort of men with prostate cancer (PCa) on active surveillance (AS).

PATIENTS AND METHODS

Total testosterone and free testosterone concentrations were determined at the time the men began the AS protocol. Statistical analysis was performed using Student’s t-test and a chi-squared test to compare groups. Odds ratios (ORs) with 95% confidence intervals (CIs) were obtained using univariate logistic regression. Receiver–operator characteristic curves were generated to determine the investigated testosterone thresholds. Kaplan–Meier curves were used to estimate time to disease reclassification. A Cox proportional hazard regression model was used for multivariate analysis.

RESULTS

A total of 154 men were included in the AS cohort, of whom 54 (35%) progressed to active treatment. Men who had disease reclassification had significantly lower free testosterone levels than those who were not reclassified (0.75 vs 1.02 ng/dL, P = 0.03). Men with free testosterone levels <0.45 ng/dL had a higher rate of disease reclassification than patients with free testosterone levels ≥0.45 (P = 0.032). Free testosterone levels <0.45 ng/dL were associated with a several-fold increase in the risk of disease reclassification (OR 4.3, 95% CI 1.25–14.73). Multivariate analysis showed that free testosterone and family history of PCa were independent predictors of disease reclassification.

CONCLUSIONS

Free testosterone levels were lower in men with PCa who had reclassification during AS. Men with moderately severe reductions in free testosterone level are at increased risk of disease reclassification.

Editorial: The importance of knowing testosterone levels in patients with prostate cancer

The paper by San Francisco et al. [1] in this issue of BJUI, reviews 154 patients with prostate cancer who were included in an active surveillance cohort. In all, 54 (35%) progressed to active treatment. Men who had disease reclassification had significantly lower free testosterone than those who were not reclassified. They concluded that on multivariate analysis, free testosterone and a family history of prostate cancer were independent predictors of disease reclassification. The authors acknowledge that this was a retrospective study of small size and the data was missing in some of the men, sex hormone-binding globulin (SHBG), luteinizing hormone and oestradiol were not measured. Nevertheless, this review adds to the increasing evidence that it is important to measure testosterone levels in men with prostate cancer.

Previous studies have indicated that a low testosterone level before treatment for prostate cancer is an independent predictor of a more aggressive high-grade cancer [2]. In addition to this, there appears to be an increased likelihood of extraprostatic disease at the time of diagnosis [3] and an unfavourable response to treatment [4].

Garcia-Cruz et al. [5] in 2012 reported that low testosterone bioavailability is related to a positive prostate cancer diagnosis in patients submitted for prostate biopsy. In a further study, he showed that low testosterone levels were related to poor prognosis factors in men with prostate cancer prior to treatment. Testosterone was inversely related to prostate cancer bilaterally and percentage of tumour in the biopsy. Higher testosterone levels were found in patients allocated to the low-risk progression group. In the multivariate analysis, older age and lower testosterone levels were related to a higher D’Amico risk of progression [5]. The researchers went on to show that higher SHBG and lower bioavailable testosterone are related to prostate cancer detection on biopsy. The study was a prospective analysis of 279 patients referred for prostate biopsy. Low bioavailable testosterone and high SHBG levels were related to a 4.9- and 3.2-fold increased risk of detection of prostate cancer on prostate biopsy taken due to an abnormal PSA result or an abnormal DRE [6].

Free testosterone accounts for about 1–2% of total testosterone and hence most circulating testosterone is bound to SHBG and as such, is inactive. Yamamoto et al. [7] had previously shown that men with a low free testosterone (<1.5 ng/dL) had an increased risk of a high Gleason score (>8) compared with men with higher free testosterone (8% vs 2%; P = 0.04). Additionally, a free testosterone level of <1.5 ng/dL was associated with increased risk of biochemical recurrence of tumour.

Morgentaler et al. [8] have been turning conventional wisdom upside down. They report on 13 symptomatic testosterone deficient men who also had untreated prostate cancer. The men received testosterone therapy while undergoing active surveillance for a median of 2.5 years. None of the men had aggressive or advanced prostate cancer and they were rigorously followed up. Despite effective treatment, neither the PSA level nor prostate volume showed any change. Follow-up biopsies were taken in all of the men at yearly intervals and none developed cancer progression.

It is intriguing to think that the decline in testosterone with age and comorbidities may contribute to tumorigenesis in the prostate. Clearly this study needs to be replicated with much larger numbers. But it seems reasonable to suggest that we ought to know about the hormonal environment existing in our patients with prostate cancer. This will of course, raise the even more controversial area of what to do about men with symptomatic hypogonadism with treated and untreated prostate cancer. There is limited data available on this issue.

Before considering testosterone therapy, the first step should be intensive lifestyle intervention; this is not only known to improve cancer survival, but raises total and free testosterone. Weight loss inhibits aromatase, and other complex cytokines, this reduces the suppression of the pituitary gonadal axis and conversion of testosterone to oestrogen, raising testosterone levels.

Michael Kirby*,†
*The Prostate Centre, London, and Institute of Diabetes for Older People (IDOP), Beds & Herts Postgraduate Medical School, Puckeridge Bury Campus, Luton, UK

References

  1. San Francisco I, Rojas P, Dewolf W, Morgentaler A. Low free testosterone predicts disease reclassification in men with prostate cancer undergoing active surveillance. BJU Int 2014; 114: 229–235
  2. Massengill JC, Sun L, Moul JW et al. Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol 2003; 169: 1670–1675
  3. Chen SS, Chen KK, Lin AT, Chang YH, Wu HH, Chang LS. The correlation between pretreatment serum hormone levels and treatment outcome for patients with prostatic cancer and bony metastasis. BJU Int 2002; 89: 710–713
  4. Ribeiro M, Ruff P, Falkson G. Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer. Am J Clin Oncol 1997; 20: 605–608
  5. Garcia-Cruz E, Piqueras M, Huguet J et al. Low testosterone levels are related to poor prognosis factors in men with prostate cancer prior to treatment. BJU Int 2012; 110: E541–546
  6. Garcia-Cruz E, Carrión Puig A, Garcia-Larrosa A et al. Higher sex hormone-binding globulin and lower bioavailable testosterone. Scand J Urol 2013; 47: 282–289
  7. Yamamoto S, Yonese J, Kawakame S et al. Preoperative serum testosterone level as an independent predictor of treatment failure following radical prostatectomy. Eur Urol 2007; 52: 696–701
  8. Morgentaler A, Liphultz LI, Bennett R, Sweeney M, Avila D Jr, Khera M. Testosterone therapy in men with untreated prostate cancer. J Urol 2011; 185: 1256–1260

Article of the week: Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity

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 Angela Smith and David Johnson discussing their paper.

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

Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity

David C. Johnson*, Matthew E. Nielsen*†‡, Jonathan Matthews*, Michael E. Woods*, Eric M. Wallen*, Raj S. Pruthi*, Matthew I. Milowsky*†§ and Angela B. Smith*

*Department of Urology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Cancer Outcomes Research Group, Multidisciplinary Genitourinary Oncology, Department of Epidemiology, Gillings School of Global Public Health, and §Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

OBJECTIVE

To determine whether neoadjuvant chemotherapy (NAC) is a predictor of postoperative complications, length of stay (LOS), or operating time after radical cystectomy (RC) for bladder cancer.

PATIENTS AND METHODS

A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was performed to identify patients receiving NAC before RC from 2005 to 2011. Bivariable and multivariable analyses were used to determine whether NAC was associated with 30-day perioperative outcomes, e.g. complications, LOS, and operating time.

RESULTS

Of the 878 patients who underwent RC for bladder cancer in our study, 78 (8.9%) received NAC. Excluding those patients who were ineligible for NAC due to renal insufficiency, 78/642 (12.1%) received NAC. In all, 457 of the 878 patients (52.1%) undergoing RC had at least one complication ≤30 days of RC, including 43 of 78 patients (55.1%) who received NAC and 414 of 800 patients (51.8%) who did not (P = 0.58). On multivariable logistic regression, NAC was not a predictor of complications (P = 0.87), re-operation (P = 0.16), wound infection (P = 0.32), or wound dehiscence (P = 0.32). Using multiple linear regression, NAC was not a predictor of increased operating time (P = 0.24), and patients undergoing NAC had a decreased LOS (P = 0.02).

CONCLUSIONS

Our study is the first large multi-institutional analysis specifically comparing complications after RC with and without NAC. Using a nationally validated, prospectively maintained database specifically designed to measure perioperative outcomes, we found no increase in perioperative complications or surgical morbidity with NAC. Considering these findings and the well-established overall survival benefit over surgery alone, efforts are needed to improve the uptake of NAC.

Editorial: Unveiling the surgical risk associated with neoadjuvant chemotherapy in bladder cancer

In this issue of BJU International, Johnson et al. [1] examine the association between neoadjuvant chemotherapy (NAC) for bladder cancer and 30-day morbidity related to radical cystectomy (RC). Level 1 evidence supports use of cisplatin-based NAC for bladder cancer; a meta-analysis of 11 randomised trials including 3005 patients who received NAC found a 5% absolute increase in 5-year overall survival and a 9% absolute increase in 5-year disease-free survival compared with RC alone [2]. Despite this, recent studies have reported underutilisation of NAC at ≈20% [3], with several reasons proposed for this ‘non-compliance’ to guidelines. A 2013 National Cancer Data Base (NCDB) analysis found that increasing age, lower patient income, and treatment at a non-academic institution (P < 0.01) negatively influenced the receipt of NAC, while higher clinical stage and fewer comorbid conditions were associated with higher likelihood of receiving NAC (P < 0.01) [3].

Another relevant concern is that NAC may increase perioperative complications for RC given the toxicities associated with chemotherapy, advanced age and often high rates of renal and cardiac comorbidities among potential candidates [4]. Credit should be given to Millikan et al. [5] for first negating this fear in 2001 with a randomised trial comparing NAC vs adjuvant chemotherapy in patients with bladder cancer; this study did not find any increase in perioperative morbidity.

The present analysis by Johnson et al. [1] further debunks this misconception in contemporary practice (2005–2011), drawing on the American College of Surgeons National Surgical Quality Improvement Program (NSQIP), which prospectively collects a sample of risk-adjusted validated surgical patient data from >450 participating USA hospitals. The authors show that NAC was not an independent predictor of complications, reoperation, wound infection or dehiscence. The robustness of these findings is reinforced by the shorter adjusted length of stay among patients receiving NAC. Given that scant data exists on this topic, the authors contribute a valuable paper that substantially adds to the literature.

Despite its strengths, the study should be interpreted in light of notable limitations that the authors acknowledge. Many crucial variables are not tracked by the NSQIP and therefore cannot be accounted for, including type of chemotherapy regimen, delay between chemotherapy and surgery, surgical technique (open, laparoscopic, robotic), surgical quality (margins, extent of lymphadenectomy), clinical/pathological stage of bladder cancer, and hospital/surgeon volume. Besides, because RC is a morbid procedure with a mean length of stay of 11 days, 30-day complication rates do not capture its true morbidity as well as 90-day rates. In particular, several common complications, such as postoperative ileus or small bowel obstruction, tend to occur later during the postoperative recovery period. As such, chances are that the event rate is biased downward by the short-term duration of data capture by the NSQIP. This study also cannot fully examine the association of NAC with certain subtypes of complications, including gastrointestinal or bleeding complications, especially when other investigators examining robotic RC have reported a conflicting increase in perioperative complications associated with NAC [6] driven by a 27% rate of gastrointestinal complications, which are not tracked by the NSQIP. Of note, unadjusted rates of transfusion and bleeding events were both higher in the NAC group in the present study.

One of the relevant and heartening observations of the report is the gradual increase in the use of NAC over the study period from 4% of eligible patients to 11%, close to the NCDB estimates of 7.6% in 2006 to 20.9% in 2010 (P < 0.01) [3]. Interestingly, there was an increased probability of any complication in the most recent time period (odds ratio 0.47 for 2005–2009 relative to 2010–2011 in the primary multivariate model, P < 0.001). A plausible explanation is that as physicians have heeded the message to increase usage of NAC, treatment has expanded into a wider population with more comorbidities and therefore a greater propensity for complications. It would have been of interest to address this point by restricting the analyses to the most recent data to see if NAC does indeed predict perioperative complications in the most recent period from 2010 to 2011.

Finally, given the lack of detail available in the NSQIP, other relevant questions could not be addressed. Among them it would be relevant to know if complication rates vary between standard MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) and newer chemotherapy regimens such as dose dense MVAC (DD-MVAC) or gemcitabine plus cisplatin (GC). Similarly, the role of the delay or the elapsed time between chemotherapy and surgery on complications might be helpful in future trial planning.

Additional work still needs to be done to identify prognostic factors for both perioperative complications and long-term outcomes after NAC, so that this valuable therapy can be appropriately provided to the correct patients. Indeed, given the lack of randomised controlled trial data investigating less toxic regimens than MVAC, perhaps NAC is underused because clinicians and patients are underserved by the available data. The authors should be commended for their efforts in deconstructing possible barriers to increased uptake of NAC, a therapy known to confer survival benefits for our patients with bladder cancer.

Joaquim Bellmunt,* Jeffrey J.Leow and William Martin-Doyle§
*Bladder Cancer Center, Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA; University Hospital Del Mar-IMIM, Barcelona, Spain; Brigham and Women’s Hospital, Division of Urology and Center for Surgery and Public Health, Boston, MA, USA; §University of Massachusetts Medical School, Worcester, MA, USA

References

  1. Johnson DC, Nielsen ME, Matthews J et al. Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity. BJU Int 2014; 114: 221–228
  2. Bellmunt J, Orsola A, Wiegel T et al. Bladder cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO Guidelines Working Group. Ann Oncol 2011; 22 (Suppl. 6): 45–49
  3. Zaid HB, Patel SG, Stimson CJ et al. Trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: results from the National Cancer Database. Urology 2014; 83: 75–80
  4. Meeks JJ, Bellmunt J, Bochner BH et al. A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 2012; 62: 523–533
  5. Millikan R, Dinney C, Swanson D et al. Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 2001; 19: 4005–4013
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