Artículos

Chronic Kidney Disease and Kidney Cancer Surgery: New Perspectives

Huang W, Donin N, Levey A and Campbell S
Journal of Urology Vol. 203, 475-485, March 2020
DOI: 10.1097/JU.0000000000000326

Abstract

Purpose

We sought to provide a contemporary understanding of chronic kidney disease and its relevance to kidney cancer surgery. Another purpose was to resolve points of discrepancy regarding the survival benefits of partial vs radical nephrectomy by critically evaluating the results of prospective and retrospective studies in the urological literature.

Materials and Methods

We performed a comprehensive literature search for relevant articles listed in MEDLINE® from 2002 to 2018 using the key words radical nephrectomy, partial nephrectomy, glomerular filtration rate, kidney function and chronic kidney disease. We also assessed select review articles and society guidelines about chronic kidney disease pertinent to urology and nephrology.

Results

Complete evaluation of the potential consequences of chronic kidney disease involves assessment of the cause, the glomerular filtration rate level and the degree of albuminuria. Chronic kidney disease is commonly defined in the urological literature solely as a glomerular filtration rate less than 60 ml/minute/1.73 m 2. This ignores the significance of the cause of chronic kidney disease, and the presence and degree of albuminuria. Although this glomerular filtration rate is relevant for preoperative assessment of patients who undergo surgery of kidney tumors, recent studies suggest that a glomerular filtration rate less than 45 ml/minute/1.73 m 2 represents a more discerning postoperative prognostic threshold. Reported survival benefits of partial over radical nephrectomy in retrospective studies were likely influenced by selection bias. The lack of survival benefit in the partial nephrectomy cohort in the only randomized trial of partial vs radical nephrectomy was consistent with data demonstrating that patients in each study arm were at relatively low risk for mortality due to chronic kidney disease when accounting for the chronic kidney disease etiology and the postoperative glomerular filtration rate.

Conclusion

The prognostic risk of chronic kidney disease in patients with kidney cancer is increased when the preoperative glomerular filtration rate is less than 60 ml/minute/1.73 m 2 or the postoperative rate is less than 45 ml/minute/1.73 m 2. Additional factors, including nonsurgical causes of chronic kidney disease and the degree of albuminuria, can also dramatically alter the consequences of chronic kidney disease after kidney cancer surgery. Urologists must have a comprehensive knowledge of chronic kidney disease to assess the risks and benefits of partial vs radical nephrectomy when managing tumors with increased complexity and/or oncologic aggressiveness.

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Long-term Risk of Recurrence in Surgically Treated Renal Cell Carcinoma: A Post Hoc Analysis of the Eastern Cooperative Oncology Group—American College of Radiology Imaging Network E2805 Trial Cohort

Jamil, Marcus L. et al.
European Urology, Volume 77, Issue 2, 277 – 281
DOI: 10.1016/j.eururo.2019.10.028

Abstract

Currently, surveillance guidelines following surgical resection of clinically localized renal cell carcinoma (RCC) are clear within the first 5 yr; however, these lack the same degree of objectivity following this cutoff. We sought to investigate the long-term risk of recurrence in surgically treated RCC in order to determine the utility of long-term surveillance. A post hoc analysis of patients within the Eastern Cooperative Oncology Group—American College of Radiology Imaging Network (ECOG-ACRIN) E2805 trial cohort was performed. The 36-mo cumulative incidence of recurrence was assessed at set intervals following surgery, in order to dynamically assess recurrence through the use of a conditional survival model. Of the 1943 patients included in the original cohort, 730 developed recurrence. The 36-mo cumulative incidences of recurrence were found to be 31%, 26%, 19%, 16%, 19%, and 20% for patients at 0, 12, 24, 36, 48, and 60 mo from surgery, respectively. At 0 mo from surgery, age, pathological T3/4 stage (hazard ratio [HR] = 1.56), pathological N1/2 stage (HR = 2.38), and Fuhrman grades 3 and 4 (HR = 1.36 and HR = 2.41, respectively) were independent predictors of recurrence; however, this was not seen at 60 mo following surgery. These findings support that surveillance imaging should be performed beyond 5 yr following surgical resection of intermediate- to high-risk RCC.

Patient summary

Follow-up for surgically resected localized renal cell carcinoma should be performed beyond 5 yr, for the rates of recurrence remain significant beyond this 5 yr endpoint.

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Comparable efficacy and safety between second-line and later-line nivolumab therapy for metastatic renal cell carcinoma

Ishihara, H., Takagi, T., Kondo, T. et al.
Int J Clin Oncol 25, 705–712 (2020).
DOI: 10.1007/s10147-019-01605-9

Abstract

Background

The aim of this study was to compare the efficacy and safety of nivolumab as second-line and later-line (third-line or thereafter) therapy in metastatic renal cell carcinoma (mRCC).

Methods

Sixty-seven patients who received nivolumab after the failure of at least one molecular-targeted therapy were evaluated. The patients were divided into two groups based on the line of nivolumab: second-line and later-line groups. Efficacy was assessed using progression-free survival and overall survival (OS) after nivolumab initiation, and objective response rate. Safety was assessed using the incidence of immune-related adverse events. These outcomes were compared between the second-line and later-line groups.

Results

Forty-two patients (62.7%) received nivolumab as second-line therapy. There was no significant difference in the progression-free survival (median: 5.06 vs. 6.28 months, p = 0.691) or objective response rate (35.7% vs. 32.0%, p = 0.757) between the second-line and later-line groups. The OS tended to be longer in the second-line group (not reached vs. 26.0 months, p = 0.118), and the rate of patients who received subsequent therapy after nivolumab failure was significantly higher in the second-line group (90.9% vs. 55.0%, p = 0.0025). There was no difference in the incidences of immune-related adverse events between the second-line and later-line groups (any grade: 54.8% vs. 48.0%, p = 0.592; grade ≥ 3: 19.1% vs. 20.0%, p = 0.924).

Conclusion

The efficacy of nivolumab did not deteriorate and the tolerability was also maintained even in later-line therapy. However, a tendency of longer OS and a higher chance of subsequent therapy after nivolumab failure were observed with nivolumab as second-line therapy.

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Long-Term Survival after Percutaneous Radiofrequency Ablation of Pathologically Proven Renal Cell Carcinoma in 100 Patients

Marshall, Harry R. et al.
Journal of Vascular and Interventional Radiology, Volume 31, Issue 1, 15 – 24
DOI: 10.1016/j.jvir.2019.09.011

Abstract

Purpose

To determine the long-term survival of patients treated with percutaneous radiofrequency (RF) ablation for pathologically proven renal cell carcinoma (RCC).

Materials and Methods

In this single-center retrospective study, 100 patients with 125 RCCs (100 clear-cell, 19 papillary, and 6 chromophobe) 0.8–8 cm in size treated with RF ablation were evaluated at a single large tertiary-care center between 2004 and 2015. Technical success, primary and secondary technique efficacy, and pre- and postprocedural estimated glomerular filtration rate (eGFR) at 3–6 months and 2–3 years were recorded. Overall survival, cancer-specific survival, and local tumor progression–free survival were calculated by Kaplan–Meier survival curves. Complications were classified per the Clavien–Dindo system. Statistical testing was done via χ2tests for proportions and paired t test for changes in eGFR. Statistical significance was set at α = 0.05.

Results

Overall technical success rate was 100%, and primary and secondary technique efficacy rates were 90% and 100%, respectively. Median follow-up was 62.8 months, ranging from 1 to 120 months. The 10-year overall, cancer-specific, and local progression–free survival rates were 32%, 86%, and 92%, respectively. The number of ablation probes used was predictive of residual unablated tumor (P < .001). There were no significant changes in preprocedure vs 2–3-years postprocedure eGFR (65.2 vs 62.1 mL/min/1.73 m2; P = .443). There was a 9% overall incidence of complications, the majority of which were grade I.

Conclusion

Image-guided percutaneous RF ablation of RCCs is effective at achieving local control and preventing cancer-specific death within 10 years from initial treatment.

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Perioperative Detection of Circulating Tumor Cells in Radical or Partial Nephrectomy for Renal Cell Carcinoma

Haga, N., Onagi, A., Koguchi, T. et al.
Ann Surg Oncol 27, 1272–1281 (2020)
DOI: 10.1245/s10434-019-08127-8

Abstract

Background

The current study was conducted to clarify the frequency of systemic circulating tumor cells (CTCs) appearing after surgery for renal cell carcinoma and to evaluate the differences in postoperative CTCs between different surgical procedures.

Methods

This prospective, cohort study included 60 consecutive patients who underwent laparoscopic radical nephrectomy (RN) (n = 22), laparoscopic partial nephrectomy (PN) (n = 19), open RN (n = 8), or open PN (n = 11). In this study CTCs were measured by the FISHMAN-R system, and CTCs drawn from a peripheral artery were collected just before and immediately after surgery. The number of pre- and postoperative CTCs and the perioperative changes in CTCs were measured for each surgical method.

Results

Six patients were excluded from the current analyses. Preoperative CTCs did not differ significantly by surgical approach (laparoscopic RN: 3.4 ± 4.2; laparoscopic PN: 3.4 ± 4.1; open RN: 7.7 ± 6.8; open PN: 6.0 ± 7.6; P = 0.19). Open RN resulted in a significantly greater number of postoperative CTCs (laparoscopic RN: 4.8 ± 3.7; laparoscopic PN: 7.9 ± 9.1; open RN: 22.5 ± 26.3; open PN: 6.4 ± 6.3; P < 0.001) and perioperative changes in CTCs (laparoscopic RN: 1.3 ± 5.3; laparoscopic PN: 4.5 ± 9.6; open RN: 14.7 ± 25.0; open PN: 0.4 ± 6.3; P < 0.001). No significant differences in these were observed among the three groups except in the open RN group. In the multivariate analysis, the surgical approach was significantly correlated with the number of postoperative CTCs (P = 0.016) and the perioperative change in CTCs (P = 0.01).

Conclusion

This proof-of-concept study indicated that after surgery, more cancer cells can be expelled into the bloodstream, especially after open RN. Sufficient and careful follow-up assessment for the emergence of distant metastases is needed for patients undergoing open RN.

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Non-contrast imaging characteristics of papillary renal cell carcinoma: implications for diagnosisand subtyping

Badri AV, Waingankar N, Edwards K, et al.
Can J Urol. 2019 Oct;26(5):9916-9921.

Abstract

Introduction

Current radiographic guidelines suggest unenhanced renal lesions < 20 Hounsfield Units (HU) are overwhelmingly benign, requiring no further evaluation. We evaluate our experience with papillary renal cell carcinoma (pRCC) presenting with low pre-contrast attenuation and the relationship of attenuation with histologic pRCC subtype.

Materials and Methods

We reviewed our institutional kidney cancer database for patients with pT1 or pT2 pRCC between 2003-2017. Tumors were categorized by papillary subtype by expert uropathologists. Preoperative CT images were analyzed at six regional tumor locations. Low, presumably benign, unenhanced median attenuation was defined as ≤ 20 HU. We calculated the frequency of pRCC with low attenuation and assessed the relationship between attenuation and pRCC subtype using logistic regression.

Results

Sixty-one patients with evaluable imaging were included. Median tumor size was 6 cm (1.7 cm-15.3 cm) with 39% (n = 24) type-1 and 61% (n = 37) type-2. Half of all pRCC tumors (n = 30) exhibited very low pre-contrast attenuation (< 20 HU), risking misdiagnosis as benign using current guidelines. Of these, 80% (n = 24) were type-2 with significant biological potential. Overall, type-2 tumors demonstrated a lower pre-contrast attenuation than type-1 (median HU: 19.8 (1.5-42.3) versus 29.6 HU (10-45.8), p < 0.01; max HU: 25.3 versus 36.5 HU, p < 0.01). After adjustment, lower pre-contrast HU was an independent predictor of pRCC subtype associated with a 5.5-fold increase of being type-2 (OR = 5.47, p < 0.01).

Conclusion

pRCCs may exhibit very low attenuation on pre-contrast CT. This appears more common among the more aggressive type-2 subtype. These data suggest that low attenuation (< 20 HU) alone on non-contrast CT imaging is insufficient as a single parameter to rule out malignancy.

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First-line Immuno-Oncology Combination Therapies in Metastatic Renal-cell Carcinoma: Resultsfrom the International Metastatic Renal-cell Carcinoma Database Consortium

Dudani S, Graham J, Wells JC, et al.
Eur Urol. 2019 Dec;76(6):861-867.
DOI: 10.1016/j.eururo.2019.07.048. Epub 2019 Aug 22.

Abstract

Background

In metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) inhibitor combinations. Comparative data between these strategies are limited.

Objective

To compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies.

Design, setting, and participants

Using the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo.

Intervention

All patients received first-line IO combination therapies.

Outcome measurements and statistical analysis

First- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors.

Results and limitations

In total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval [CI] -8% to 22%, p =  0.4), TTF was 14.3 versus 10.2 mo (p =  0.2), TNT was 19.7 versus 17.9 mo (p =  0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46-1.12, p =  0.14), 0.65 (95% CI 0.38-1.11, p =  0.11), and 1.74 (95% CI 0.82-3.68, p =  0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3-57%, p =  0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p =  0.4; n = 55). Limitations include the study’s retrospective design and sample size.

Conclusions

There were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially.

Patient summar

There were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinomareceiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.

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Predicting Renal Cancer Recurrence: Defining Limitations of Existing Prognostic Models With Prospective Trial-Based Validation

Correa AF, Jegede O, Haas NB, et al.
J Clin Oncol. 2019 Aug 10;37(23):2062-2071.
DOI: 10.1200/JCO.19.00107.

Abstract

Purpose

To validate currently used recurrence prediction models for renal cell carcinoma (RCC) by using prospective data from the ASSURE (ECOG-ACRIN E2805; Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) adjuvant trial.

Patients and methods

Eight RCC recurrence models (University of California at Los Angeles Integrated Staging System [UISS]; Stage, Size, Grade, and Necrosis [SSIGN]; Leibovich; Kattan; Memorial Sloan Kettering Cancer Center [MSKCC]; Yaycioglu; Karakiewicz; and Cindolo) were selected on the basis of their use in clinical practice and clinical trial designs. These models along with the TNM staging system were validated using 1,647 patients with resected localized high-grade or locally advanced disease (≥ pT1b grade 3 and 4/pTanyN1Mo) from the ASSURE cohort. The predictive performance of the model was quantified by assessing its discriminatory and calibration abilities.

Results

Prospective validation of predictive and prognostic models for localized RCC showed a substantial decrease in each of the predictive abilities of the model compared with their original and externally validated discriminatory estimates. Among the models, the SSIGN score performed best (0.688; 95% CI, 0.686 to 0.689), and the UISS model performed worst (0.556; 95% CI, 0.555 to 0.557). Compared with the 2002 TNM staging system (C-index, 0.60), most models only marginally outperformed standard staging. Importantly, all models, including TNM, demonstrated statistically significant variability in their predictive ability over time and were most useful within the first 2 years after diagnosis.

Conclusions

In RCC, as in many other solid malignancies, clinicians rely on retrospective prediction tools to guide patient care and clinical trial selection and largely overestimate their predictive abilities. We used prospective collected adjuvant trial data to validate existing RCC prediction models and demonstrate a sharp decrease in the predictive ability of all models compared with their previous retrospective validations. Accordingly, we recommend prospective validation of any predictive model before implementing it into clinical practice and clinical trial design.

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Management of Renal Masses and Localized Renal Cancer: Systematic Review and Meta-Analysis

Pierorazio PM, Johnson MH, Patel HD, et al.
J Urol. 2016 Oct;196(4):989-99.
DOI: 10.1016/j.juro.2016.04.081.

Abstract

Purpose

Several options exist for management of clinically localized renal masses suspicious for cancer, including active surveillance, thermal ablation and radical or partial nephrectomy. We summarize evidence on effectiveness and comparative effectiveness of these treatment approaches for patients with a renal mass suspicious for localized renal cell carcinoma.

Materials and methods

We searched MEDLINE®, Embase® and the Cochrane Central Register of Controlled Trials from January 1, 1997 through May 1, 2015. Paired investigators independently screened articles to identify controlled studies of management options or cohort studies of active surveillance, abstracted data sequentially and assessed risk of bias independently. Strength of evidence was graded by comparisons.

Results

The search identified 107 studies (majority T1, no active surveillance or thermal ablation stratified outcomes of T2 tumors). Cancer specific survival was excellent among all management strategies (median 5-year survival 95%). Local recurrence-free survival was inferior for thermal ablation with 1 treatment but reached equivalence to other modalities after multiple treatments. Overall survival rates were similar among management strategies and varied with age and comorbidity. End-stage renal disease rates were low for all strategies (0.4% to 2.8%). Radical nephrectomy was associated with the largest decrease in estimated glomerular filtration rate and highest incidence of chronic kidney disease. Thermal ablation offered the most favorable perioperative outcomes. Partial nephrectomy showed the highest rates of urological complications but overall rates of minor/major complications were similar among interventions. Strength of evidence was moderate, low and insufficient for 11, 22 and 30 domains, respectively.

Conclusions

Comparative studies demonstrated similar cancer specific survival across management strategies, with some differences in renal functional outcomes, perioperative outcomes and postoperative harms that should be considered when choosing a management strategy.

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A Pilot Study of Radiation Therapy in Combination With Pembrolizumab in Patients With Metastatic Renal Cell Cancer

Lin J, Song AJ, Hoffman-Censits J, et al.
Am J Clin Oncol. 2020 Feb;43(2):82-86.
DOI: 10.1097/COC.0000000000000636.

Abstract

Objectives

There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors.

Materials and methods

mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry.

Results

Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92).

Conclusion

Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.

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