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Video: Survival after RP for clinically localised prostate cancer

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Survival after radical prostatectomy for clinically localised prostate cancer: a population-based study

Martin Andreas Røder1, Klaus Brasso1, Ib Jarle Christensen2, Jørgen Johansen3, Niels Christian Langkilde4, Helle Hvarness1, Steen Carlsson5, Henrik Jakobsen6, Michael Borre7 and Peter Iversen1

1Copenhagen Prostate Cancer Center and Department of Urology, 2The Finsen Laboratory, Copenhagen Biotech Research and Innovation Centre (BRIC), Rigshospitalet Copenhagen University Hospital, Faculty of Health and Medical Sciences, Copenhagen, 3Department of Urology, Regional Hospital West Jutland, Holstebro, 4Department of Urology, Aalborg University Hospital, Faculty of Medicine, Aalborg, 5Department of Urology, Odense University Hospital, Faculty of Health Sciences, Odense, 6Department of Urology, Herlev Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, Herlev and 7Department of Urology, Skejby, Aarhus University Hospital, Department of Clinical Medicine, Aarhus, Denmark

 

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OBJECTIVES

• To describe survival and cause of death in a nationwide cohort of Danish patients with prostate cancer undergoing radical prostatectomy (RP).

• To describe risk factors associated with prostate cancer mortality.

PATIENTS AND METHODS

• Observational study of 6489 men with localised prostate cancer treated with RP at six different hospitals in Denmark between 1995 and 2011.

• Survival was described using Kaplan–Meier estimates. Causes of death were obtained from the national registry and cross-checked with patient files.

• Cumulative incidence of death, any cause and prostate cancer-specific, was described using Nelson–Aalen estimates.

• Risk for prostate cancer death was analysed in a Cox multivariate regression model using the covariates: age, cT-category, PSA level and biopsy Gleason score.

RESULTS

• The median follow-up was 4 years. During follow-up, 328 patients died, 109 (33.2%) from prostate cancer and 219 (66.8%) from other causes. Six patients (0.09%) died ≤30 days of RP.

• In multivariate analysis, cT-category was a predictor of prostate cancer death (P < 0.001). Compared with T1 disease, both cT2c (hazard ratio [HR] 2.2) and cT3 (HR 7.2) significantly increased the risk of prostate cancer death. For every doubling of PSA level the risk of prostate cancer death was increased by 34.8% (P < 0.001). Biopsy Gleason score 4 + 3 and ≥8 were associated with an increased risk of prostate cancer death compared with biopsy Gleason score ≤ 6 of 2.3 and 2.7 (P = 0.003), respectively.

• The cumulative hazard of all-cause and prostate cancer-specific mortality after 10 years was 15.4% (95% confidence interval [CI] 13.2–17.7) and 6.6% (95% CI 4.9–8.2) respectively.

CONCLUSIONS

• We present the first survival analysis of a complete, nationwide cohort of men undergoing RP for localised prostate cancer.

• The main limitation of the study was the relatively short follow-up.

• Interestingly, our national results are comparable to high-volume, single institution, single surgeon series.

 

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Article of the week: SEER shows no benefit from LND in RCC

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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 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 Maxine Sun discussing her paper.

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

Extent of lymphadenectomy does not improve the survival of patients with renal cell carcinoma and nodal metastases: biases associated with the handling of missing data

Maxine Sun*, Quoc-Dien Trinh*‡, Marco Bianchi*, Jens Hansen*††, Firas Abdollah, Zhe Tian*, Shahrokh F. Shariat§, Francesco Montorsi, Paul Perrotte† and Pierre I. Karakiewicz*†

*Cancer Prognostics and Health Outcomes Unit, †Department of Urology, University of Montreal Health Center, Montreal, Canada, ‡Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, §Department of Urology,Weill Medical College of Cornell University, New York, NY, USA, Department of Urology, Vita-Salute San Raffaele University, Milan, Italy, and ††Martini Clinic, Prostate Cancer Center Hamburg-Eppendorf, Hamburg, Germany

Maxine Sun and Quoc-Dien Trinh contributed equally to this study.

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OBJECTIVE

• Previous studies showed no survival benefit with respect to performing lymph node dissection (LND) at nephrectomy, whereas a recent population-based analysis suggested otherwise, although the latter relied on imputation. To reconcile the findings of that study by critically evaluating the handling of missing data.

PATIENTS AND METHODS

• Study participants comprised patients diagnosed with non-metastatic renal cell carcinoma (RCC) of all stages who underwent LND at nephrectomy (n = 10 596).

• Multivariable Cox regression models were performed to predict cancer-specific mortality (CSM), where the primary variable of interest was the extent of LND.

• To examine differences in approaches with respect to handling missing data, separate analyses were performed: (i) imputed population; (ii) exclusion of patients with missing data; and (iii) inclusion of patients with missing data as a sub-category.

RESULTS

• Overall, 2916 (28%) patients had missing tumour grade.

• In multivariable analyses, our findings showed that increasing the extent of LND was associated with a significant protective effect on CSM in patients with pN1 after imputation (hazard ratio [HR], 0.82; P = 0.04).

• By contrast, the extent of LND was no longer significantly associated with a lower risk of CSM after excluding patients with a missing tumour grade (HR, 0.83; P = 0.1) or when including patients with missing tumour grade as a sub-category (HR, 0.82; P = 0.05).

CONCLUSIONS

• The findings of the present study failed to corroborate the association of a survival benefit with increasing extent of LND at nephrectomy.

• The different methodologies employed to account for missing data may introduce important biases.

• Such considerations are non-negligible with respect to the interpretation of results for investigators who rely on administrative cohorts.

 

Read Previous Articles of the Week

 

Editorial: Does performing LND at nephrectomy give a survival benefit or not?

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We read with interest the article by Sun et al. [1] in this issue of the BJU International. We were pleased to see another research group interested in this important aspect of the management of patients with lymph-node-positive non-metastatic RCC. The question of the benefits of lymphadenectomy in such patients could not be answered by the European Organization for Research and Treatment of Cancer randomized trial [2], as only 4% of clinically node-negative patients had micrometastatic disease.

Given some of the complexities involved in the analysis of Surveillance, Epidemiology and End Results data and the particular statistical analysis we used in showing a benefit to increasing nodal yield in patients with positive nodes [3], we were reassured that Sun et al. were able to validate our findings when replicating our data extraction and analysis. They performed two additional analyses and the four results are shown in Table 1.

 

While Sun et al. concluded that multiple imputation introduces bias into the findings, inspection of the estimates of the impact of lymph node dissection (the hazard ratio) appear identical. If bias is a deviation of an estimate from the truth [4], we would argue that Sun et al. found no evidence of bias introduced by the multiple imputation method. This is not to say that all four analyses are free from potential bias – the reported hazard ratios may in fact still be biased results – but that there is no more bias in the multiple imputation model than in the others. In addition, we were somewhat surprised to see the use of a missing indicator approach proposed as less likely than multiple imputation to introduce bias as studies have shown the opposite [5].

Furthermore, the CIs show that the benefit to extent of lymphadenectomy may be as great as a 34% reduction in cancer-related death, with exclusion of all but a 5% increase in death associated with the procedure. CIs provide extremely valuable information, particularly in the setting of marginally significant or nonsignificant P values. Sun et al. could have strengthened their paper on statistical considerations by discussing this further. In fact, we would argue that their additional analyses lend further support to the potential benefit of the extent of lymphadenectomy.

The most notable difference across the analyses is a drift in the P value. We would argue that this mirrors the loss in power associated with the censoring of almost 3000 patients (28%) with missing grades. In addition, grade does not appear to be missing at random, as patients with missing tumour grades were associated with larger tumours, higher local stage, increased probability of nodal involvement and increased risk of kidney cancer death. The censoring of such patients may in and of itself introduce bias, although again the hazard ratios do not seem to reflect this. The devaluation of the P value continues to be an active area of biostatistical research, although in general journals have not foregone its inclusion in favour of an entirely Bayesian approach [6]. We believe that, in this case, Sun et al. have taken a far too traditional approach to interpretation of small differences in P values, particularly in the setting of changing sample sizes.

We agree with Sun et al. that consideration of another randomized trial focused on patients at high risk of nodal involvement or with clinically apparent nodes on CT is warranted based upon our combined results.

Jared M. Whitson and Maxwell Meng
Department of Urology, Kaiser Permanente South Sacramento Medical Center, Sacramento, CA, USA

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References

  1. Sun M, Trinh Q-D, Bianchi M et al. Extent of lymphadenectomy does not improve survival of patients with renal cell carcinoma and nodal metastases: biases associated with handling of missing data. BJU Int 2014; 113: 36–42
  2. Blom JH, van Poppel H, Marechal JM et al. Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol 2009; 55: 28–34
  3. Whitson JM, Harris CR, Reese AC, Meng MV. Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol 2011; 185: 1615–1620
  4. Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet 2002; 359: 248–252
  5. Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 1995; 142: 1255–1264
  6. Goodman SN. Toward evidence-based medical statistics. 2: the Bayes factor. Ann Intern Med 1999; 130: 1005–1013
 

Video: Survival for RCC and nodal metastases

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Extent of lymphadenectomy does not improve the survival of patients with renal cell carcinoma and nodal metastases: biases associated with the handling of missing data

Maxine Sun*, Quoc-Dien Trinh*‡, Marco Bianchi*, Jens Hansen*††, Firas Abdollah, Zhe Tian*, Shahrokh F. Shariat§, Francesco Montorsi, Paul Perrotte† and Pierre I. Karakiewicz*†

*Cancer Prognostics and Health Outcomes Unit, †Department of Urology, University of Montreal Health Center, Montreal, Canada, ‡Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, §Department of Urology,Weill Medical College of Cornell University, New York, NY, USA, Department of Urology, Vita-Salute San Raffaele University, Milan, Italy, and ††Martini Clinic, Prostate Cancer Center Hamburg-Eppendorf, Hamburg, Germany

Maxine Sun and Quoc-Dien Trinh contributed equally to this study.

Read the full article
OBJECTIVE

• Previous studies showed no survival benefit with respect to performing lymph node dissection (LND) at nephrectomy, whereas a recent population-based analysis suggested otherwise, although the latter relied on imputation. To reconcile the findings of that study by critically evaluating the handling of missing data.

PATIENTS AND METHODS

• Study participants comprised patients diagnosed with non-metastatic renal cell carcinoma (RCC) of all stages who underwent LND at nephrectomy (n = 10 596).

• Multivariable Cox regression models were performed to predict cancer-specific mortality (CSM), where the primary variable of interest was the extent of LND.

• To examine differences in approaches with respect to handling missing data, separate analyses were performed: (i) imputed population; (ii) exclusion of patients with missing data; and (iii) inclusion of patients with missing data as a sub-category.

RESULTS

• Overall, 2916 (28%) patients had missing tumour grade.

• In multivariable analyses, our findings showed that increasing the extent of LND was associated with a significant protective effect on CSM in patients with pN1 after imputation (hazard ratio [HR], 0.82; P = 0.04).

• By contrast, the extent of LND was no longer significantly associated with a lower risk of CSM after excluding patients with a missing tumour grade (HR, 0.83; P = 0.1) or when including patients with missing tumour grade as a sub-category (HR, 0.82; P = 0.05).

CONCLUSIONS

• The findings of the present study failed to corroborate the association of a survival benefit with increasing extent of LND at nephrectomy.

• The different methodologies employed to account for missing data may introduce important biases.

• Such considerations are non-negligible with respect to the interpretation of results for investigators who rely on administrative cohorts.

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

/3 Comments/by

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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