Tag Archive for: extent

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

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.

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?

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

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 metastasesJ Urol 2011; 185: 1615–1620
  4. Grimes DA, Schulz KF. Bias and causal associations in observational researchLancet 2002; 359: 248–252
  5. Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analysesAm J Epidemiol 1995; 142: 1255–1264
  6. Goodman SN. Toward evidence-based medical statistics. 2: the Bayes factorAnn Intern Med 1999; 130: 1005–1013
 

Video: Survival for RCC and nodal metastases

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.

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.

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