Topographic distribution of first landing sites of lymphatic metastases from patients with renal cancer.

INTRODUCTION AND OBJECTIVE: Adjuvant studies with checkpoint inhibitors have attracted new interest in accurate pathological lymph node (LN) staging in renal cell carcinoma. Sentinel lymph node (SN) studies in cN0 patients revealed the pattern of lymphatic radiotracer drainage from renal tumors. The aim of this study was to describe the location of single- or oligometastatic LN and analyze if the topography of these first landing sites matches the drainage pattern observed in SN studies of renal tumors. MATERIALS AND METHODS: We collected data from 8 referral centers from 1990 to 2018 of all patients with pT1-4 cN0 or cN1 M0 renal cell carcinoma with pathologically confirmed single- or oligometastases in locoregional LN. The location of LN metastases, number, size of metastatic LN, and survival were analyzed using descriptive statistics with SPSS version 22 (IBM, Chicago, IL). RESULTS: From 3,794 patients with histologically confirmed pN1, a total of 76 patients (2%) with single- or oligometastatic pN1 were identified, of whom 24 (31.6%) and 52 (68.4%) were cN0 and cN1, respectively. On the left side, LN metastases were predominantly located in the para-aortal (48.0%; 95% confidence interval [CI] 29.22-63.12%) and hilar (31.42%; 95% CI 17.4-49.4%) area. On the right side, metastases located in retrocaval (26.82%; 95% CI 14.7-43.2%), hilar (26.82%; 95% CI 14.7-43.2%), interaortocaval (26.82%; 95% CI 14.7-43.2%), and paracaval (17.07%; 95% CI 7.6-32.6%) LNs. These landing sites exactly matched the lymphatic drainage pattern of intratumorally injected radiotracer reported in SN studies for both sides. CONCLUSIONS: Single- or oligometastatic LNs in renal cancer are mainly located in the hilar, retro-, para, and interaortocaval region on the right side and para-aortal region on the left side. These first landing sites match the drainage pattern reported in SN trials.

Deferred Cytoreductive Nephrectomy Following Presurgical Vascular Endothelial Growth Factor Receptor-targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A Pooled Analysis of Prospective Trial Data.

BACKGROUND: Cancer du Rein Métastatique Nephrectomie et Antiangiogéniques (CARMENA) concluded that sunitinib alone is not inferior to cytoreductive nephrectomy (CN) followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. It remains uncertain whether deferred CN is beneficial in this setting. OBJECTIVE: The aim of this study was to compare outcome in patients treated with presurgical VEGFR-TKI followed by CN (deferred CN) with that in patients receiving CN followed by VEGFR-TKI (upfront CN). DESIGN, SETTING, AND PARTICIPANTS: Pooled data from prospective trials in which a strategy of deferred CN in the absence of disease progression was investigated were compared with a retrospective dataset of upfront CN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) in the Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate-risk group. RESULTS AND LIMITATIONS: Patients were treated between 2006 and 2016. In the MSKCC intermediate-risk group, 144 patients with a strategy of deferred CN after systemic therapy were compared with 131 patients treated with upfront CN. OS in the deferred cohort was 33.0 mo (95% confidence interval [CI] 25.0-51.0) compared with 22.8 mo (95% CI 17.9-30.6) after upfront CN (hazard ratio 0.72 [95% CI 0.52-0.996], p = 0.047). This study is limited by retrospective comparison of data, subgroup analysis, and a lack of intention-to-treat data for the upfront CN cohort. CONCLUSIONS: In MSKCC intermediate-risk patients, a strategy of deferred CN in the absence of progression yields OS, which compares favourably with upfront CN and published trial data from CARMENA. This warrants a formal individual patient data analysis of CARMENA, SURTIME, and single-arm prospective studies to define the role and timing of deferred CN in intermediate-risk patients. PATIENT SUMMARY: In this study, we report outcomes in patients with metastatic renal cell cancer treated with targeted therapy followed by nephrectomy, which compared favourably with nephrectomy followed by targeted therapy and results from published studies.

Surgical Safety of Cytoreductive Nephrectomy Following Sunitinib: Results from the Multicentre, Randomised Controlled Trial of Immediate Versus Deferred Nephrectomy (SURTIME).

The European Organisation for Research and Treatment of Cancer SURTIME trial explored timing of sunitinib, a tyrosine kinase inhibitor (TKI), and cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. Previous retrospective studies suggest increased surgery-related adverse events (AEs) after presurgical TKI. We report surgical safety from a randomised comparison of CN before or after sunitinib. In-hospital mortality, 30-d readmission rate, and intraoperative and 30-d postoperative AEs according to Common Terminology Criteria for Adverse Events version 4 and Clavien-Dindo (CD) were analysed. Patients were randomised 1:1 to immediate CN followed by sunitinib versus sunitinib followed by deferred CN 24h after the last dose of sunitinib. None of the tumours in the deferred arm became unresectable, and only two patients had a sunitinib-related delay of CN of >2wk. AEs related to surgery (all grades) in the immediate and deferred arms occurred in 52% and 53% after CN, respectively, although the number of intraoperative surgery-related AEs was higher in the immediate arm. Postoperative AEs (CD ≥3), 30-d readmission, and in-hospital mortality rates were 6.5%, 13%, and 4.3% in the immediate arm and 2.5%, 7.5%, and 2.5% in the deferred arm, respectively. There were no differences in surgery time, blood loss, and hospital stay. PATIENT SUMMARY: Patients with metastatic kidney cancer do not have more surgical complications irrespective of whether they are treated with systemic therapy before or after surgery.

Outcome of sentinel lymph node biopsy in patients with clinically non-metastatic renal cell carcinoma.

OBJECTIVE: To investigate the rate of occult SN metastases, oncological outcome, and association of recurrence with the pattern of lymphatic tumour drainage in RCC. MATERIALS AND METHODS: A pooled RCC sub-group analysis was conducted of secondary endpoints from a published feasibility and a phase II prospective single-arm SN study to investigate oncological outcome. Patients with cT1-3 (<10 cm) cN0M0 RCC of any sub-type were enrolled. After intratumoural injection of Tc99m nanocolloid, pre-operative imaging of SNs with SPECT/CT was followed by (partial) nephrectomy with SN and regional lymph node dissection using a γ-probe. The patients were followed with a risk-adapted surveillance programme. Endpoints of the studies were analysed using Cox proportional hazard models. RESULTS: Sixty-six RCC patients were included. Two patients (3%, 95% CI =0.5-11%) had occult SN metastases and remained free of disease at 57 and 72 months. Ten patients (15%, 95% CI =7-26%) developed recurrences, and four (6%, 95% CI =2.3-14.5%) had died of disease at a median follow-up of 57 months (IQR =18-72 months). Occurrence of distant metachronous metastases were associated with tumour size (HR =1.39, p = 0.02), pT stage (HR =6.83, p < 0.01 for comparison T1 vs T3/4), Grade 3/4 (HR =8.38, p = 0.05 for comparison 1/2 vs 3/4) and interaortocaval sentinel lymph node location (HR =10.52, p = 0.03 for comparison yes vs no). CONCLUSIONS: The rate of occult metastatic SN is low, but long disease-free survival (DFS) was observed in two patients with occult SN metastases. We hypothesize an interaortocaval lymphatic route in thoracic recurrences. Evaluation of the prognostic and therapeutic role of sentinel lymph node biopsy (SLNB) requires a clinical trial in high-risk RCC.

An analysis of SPECT/CT non-visualization of sentinel lymph nodes in renal tumors.

BACKGROUND: Sentinel lymph node biopsy (SLNB) after intratumoral injection of 99mTc labeled nanocolloid and imaging with scintigraphy and SPECT/CT in renal tumors is feasible. However, sentinel lymph node (SN) non-detection rate with scintigraphy and SPECT/CT is high. The aim of the study was to determine factors affecting non-visualization (NV) of SN imaging in renal tumors. Seventy-eight patients with cT1-3 renal tumors received intratumoral injection of 225 MBq 99mTc-labeled nanocolloid 1 day before (partial) nephrectomy. Radiotracer injection was followed by anterioposterior and lateral scintigraphy in combination with SPECT/CT 20 min and 2-4 h after. Surgical treatment of the tumor with sentinel lymph node biopsy by aid of γ-probe and-camera was performed the next day. Scintigraphy and SPECT/CT images were evaluated and patient, tumor, and procedure characteristics were collected for 73 eligible patients used in uni- and multivariable analysis of a potential association with NV. RESULTS: A total of 80 (mean 1.1, IQR 0-2, max 6) sentinel lymph nodes in 46 patients were detected with scintigraphy and SPECT/CT. Preoperative visualization rate and intraoperative detection rate was 63% [95% CI 50-73%] and 61% [95% CI 49-72%], respectively. In uni- and multivariable analysis, the only factor associated with non-visualization was age, showing higher odds of non-visualization with higher age. CONCLUSION: Our study demonstrated that non-visualization of SNs in renal tumors is relatively high and is associated with patient age. Furthermore, kidneys and also its tumors are highly vascularized which may cause a wash-out effect that could be identified with decreased kidney-liver ratios. However, in our data, the effect was statistically inconclusive. Further studies are needed to improve visualization and standardize the procedure of SLNB in renal tumors. The percentage of NV limits the use of SLNB for research and clinical purposes in renal cancer.

External validation of a predictive model of survival after cytoreductive nephrectomy for metastatic renal cell carcinoma.

INTRODUCTION: Recent trials have emphasized the importance of a precise patient selection for cytoreductive nephrectomy (CN). In 2013, a nomogram was developed for pre- and postoperative prediction of the probability of death (PoD) after CN in patients with metastatic renal cell carcinoma. To date, the single-institutional nomogram which included mostly patients from the cytokine era has not been externally validated. Our objective is to validate the predictive model in contemporary patients in the targeted therapy era. METHODS: Multi-institutional European and North American data from patients who underwent CN between 2006 and 2013 were used for external validation. Variables evaluated included preoperative serum albumin and lactate dehydrogenase levels, intraoperative blood transfusions (yes/no) and postoperative pathologic stage (primary tumour and nodes). In addition, patient characteristics and MSKCC risk factors were collected. Using the original calibration indices and quantiles of the distribution of predictions, Kaplan-Meier estimates and calibration plots of observed versus predicted PoD were calculated. For the preoperative model a decision curve analysis (DCA) was performed. RESULTS: Of 1108 patients [median OS of 27 months (95% CI 24.6-29.4)], 536 and 469 patients had full data for the validation of the pre- and postoperative models, respectively. The AUC for the pre- and postoperative model was 0.68 (95% CI 0.62-0.74) and 0.73 (95% CI 0.68-0.78), respectively. In the DCA the preoperative model performs well within threshold survival probabilities of 20-50%. Most important limitation was the retrospective collection of this external validation dataset. CONCLUSIONS: In this external validation, the pre- and postoperative nomograms predicting PoD following CN were well calibrated. Although performance of the preoperative nomogram was lower than in the internal validation, it retains the ability to predict early death after CN.

Lymphatic Drainage from Renal Tumors In Vivo: A Prospective Sentinel Node Study Using SPECT/CT Imaging.

PURPOSE: Lymphatic drainage from renal tumors is unpredictable. In vivo drainage studies of primary lymphatic landing sites may reveal the variability and dynamics of lymphatic connections. The purpose of this study was to investigate the lymphatic drainage pattern of renal tumors in vivo with single photon emission/computerized tomography after intratumor radiotracer injection. MATERIALS AND METHODS: We performed a phase II, prospective, single arm study to investigate the distribution of sentinel nodes from renal tumors on single photon emission/computerized tomography. Patients with cT1-3 (less than 10 cm) cN0M0 renal tumors of any subtype were enrolled in analysis. After intratumor ultrasound guided injection of 0.4 ml 99mTc-nanocolloid we performed preoperative imaging of sentinel nodes with lymphoscintigraphy and single photon emission/computerized tomography. Sentinel and locoregional nonsentinel nodes were resected with a γ probe combined with a mobile γ camera. The primary study end point was the location of sentinel nodes outside the locoregional retroperitoneal templates on single photon emission/computerized tomography. Using a Simon minimax 2-stage design to detect a 25% extralocoregional retroperitoneal template location of sentinel nodes on imaging at α = 0.05 and 80% power at least 40 patients with sentinel node imaging on single photon emission/computerized tomography were needed. RESULTS: Of the 68 patients 40 underwent preoperative single photon emission/computerized tomography of sentinel nodes and were included in primary end point analysis. Lymphatic drainage outside the locoregional retroperitoneal templates was observed in 14 patients (35%). Eight patients (20%) had supradiaphragmatic sentinel nodes. CONCLUSIONS: Sentinel nodes from renal tumors were mainly located in the respective locoregional retroperitoneal templates. Simultaneous sentinel nodes were located outside the suggested lymph node dissection templates, including supradiaphragmatic sentinel nodes in more than a third of the patients.

Observation After Cytoreductive Nephrectomy in Patients With Synchronous Not Completely Resected Metastases of Renal Cell Carcinoma.

OBJECTIVE: To determine the time-to-targeted therapy (TTT) in patients with not completely resected low-volume oligometastatic disease who were observed following debulking cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC). METHODS: Patients with synchronous mRCC with not completely resected low-volume metastases and in whom observation after CN was a multidisciplinary tumor board recommendation were identified from an approved institutional database. Patient data, International Metastatic Renal Cell Cancer Database Consortium (IMDC) risk, Fuhrman grade, site, and number of sites, time-to-progression (TTP), TTT, and overall survival (OS) were retrospectively analyzed. RESULTS: From 251 synchronous mRCC patients treated since 2006, 40 (15.9 %) were identified who underwent CN with observation as a result of low-volume multiple metastasis considered not completely resectable (19 single site and 21 with ≥2 sites). IMDC risk was favorable in 7, intermediate in 24, and poor in 9 patients. Median TTP was 6 (range 2-30) months and TTT was 16 (range 2-43) months. In 11 patients targeted therapy was further deferred by observation beyond Response Evaluation Criteria in Solid Tumors progression and in 10 patients by additional local therapy of the most rapidly progressing lesion. Median OS was 30 (range 2-71) months. CONCLUSION: In patients with synchronous mRCC and not completely resected low-volume metastasis, the TTT following CN was substantial. Local therapy to control the most rapidly progressing lesion or observation beyond progression was an additional means to defer systemic therapy.

The current management of renal cell carcinoma.

INTRODUCTION: Although the broad use of ultrasound and computed tomography (CT) has led to an early diagnosis of the disease, renal cell carcinoma (RCC) remains one of the most lethal urological cancers. The present review is based on the latest data published on RCC management. EVIDENCE ACQUISITION: A literature search was carried out searching recent publications from PubMed, MEDLINE, Embase up to December 2016 as well as European Association of Urology (EAU) and European Society of Medical Oncology (ESMO) guidelines. EVIDENCE SYNTHESIS: A narrative synthesis based on recent publications was undertaken. Current evidence regarding treatment strategies and guidelines is based on prospective randomized controlled trials and retrospective studies although the level of evidence for surgical management is generally lower than for systemic therapy. CONCLUSIONS: This narrative review depicts a summary of the evidence base for treatment of RCC. Management of RCC is a rapidly evolving and changing field. As a consequence guidelines need regular updating and patients may benefit from centralization of care and multidisciplinary approach.

Comparison of pre-treatment MSKCC and IMDC prognostic risk models in patients with synchronous metastatic renal cell carcinoma treated in the era of targeted therapy.

PURPOSE: To compare prognostic performance of MSKCC and IMDC risk models in patients with synchronous mRCC. METHODS: Retrospective analysis of pre-therapeutic MSKCC and IMDC prognostic factors and outcomes in patients with synchronous mRCC treated at a single institute in the targeted therapy era was performed. Cytoreductive nephrectomy (CN) was performed in patients with WHO performance 0-1 and limited metastasis. RESULTS: Of 190 patients, only 2 had favourable risk. Overall, 141 patients received targeted therapy and 97 underwent CN. By MSKCC score, 143 (76.1 %) patients were intermediate risk (median OS 16 months) but only 97 (51.9 %) by IMDC (median OS 23 months). Conversely, 46 of the MSKCC intermediate-risk patients (31.2 %) were IMDC poor risk. Only poor risk by MSKCC and ≥4 IMDC factors had similar poor outcome (median OS 5 months and OS 2 years of 4.1 % and 10.4 %, respectively). Following CN, baseline elevated platelets and neutrophils decreased to normal in 61.5 and 75 %, respectively. This suggests that the primary tumour may influence baseline counts resulting in more IMDC poor risk. In both models, CN status was associated with better OS. CONCLUSION: Patients with synchronous mRCC and poor risk by MSKCC or ≥4 IMDC factors have a short survival expectancy, and CN may not be the primary objective in this population. Conversely, with either MSKCC or IMDC intermediate risk the probability to survive 2 years is 38.6-45.7 %, which suggests that a subgroup of patients live long enough to derive a potential benefit of CN.

Baseline tumor volume in assessing prognosis of patients with intermediate-risk synchronous metastatic renal cell carcinoma.

OBJECTIVE: To analyze if prediction of survival for patients with synchronous metastatic renal cell cancer (mRCC) could be further refined by baseline volume of the primary tumor, the metastases, or the remaining volume after surgery; this study was performed because survival expectancies of patients with intermediate-risk mRCC vary substantially. MATERIAL AND METHODS: The predictive value of the different volumes on overall survival (OS) was analyzed retrospectively in patients with intermediate Memorial Sloan-Kettering Cancer Center (MSKCC) risk profile and ≤3 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) factors, who received sunitinib in our institute. Tumor volumes were calculated on segmented computed tomography using in-house developed software. A multivariate analysis was performed including number of metastatic sites and baseline tumor burden (TB). RESULTS: A total of 68 patients were included. Median OS for patients without cytoreductive nephrectomy (CN) was 6 months (95% CI: 3.0-8.9mo) vs. 31 months (95% CI: 23.1-38.8mo) for those with CN, respectively. More second-line treatment was given after CN (49% vs. 17%, P = 0.125). There was no correlation between tumor volume and TB measured by Response Evaluation Criteria in Solid Tumors. Of all included clinical and volumetric parameters, remaining volume after CN, CN status and 2 vs. 3 IMDC factors were significantly correlated with OS. In the Cox regression analysis, CN was the only remaining significant parameter (P = 0.003). CONCLUSIONS: None of the baseline volumetric parameters is an independent prognostic factor in patients with intermediate MSKCC risk mRCC with≤3 IMDC factors receiving sunitinib. Only CN status correlated significantly with prognosis. None of the baseline volumes nor TB by Response Evaluation Criteria in Solid Tumors was associated with CN status, suggesting that extent of disease had no significant influence on the decision to perform surgery.

Patients with penile cancer and the risk of (pre)malignant cervical lesions in female partners: a retrospective cohort analysis.

OBJECTIVE: To determine if female partners of patients with penile cancer have more cervical lesions and neoplasia than would be expected from population-based data. PATIENTS AND METHODS: We included all consecutive patients with primary penile carcinoma in the period 2004-2010. Results of Dutch cervical cancer screening were used to consider (pre)malignant cervical lesions in female partners of patients with penile cancer. RESULTS: In all, 206 women were included. Gynaecological information was available in 195 women: Papanicolaou test (PAP) smears were normal were in 129 partners, 10 smears were abnormal (5.1%, 95% confidence interval 2.5-9.2). PAP2 was found in five, PAP3a in two, PAP3b in two women and PAP4 in one woman. Colposcopy in two women with PAP3b showed cervical intraepithelial neoplasia grade 3 in both. This prevalence was not different from baseline results in the general Dutch population. CONCLUSION: Female partners of patients with penile cancer did not show more premalignant cervical lesions than in the general population.

Probability of downsizing primary tumors of renal cell carcinoma by targeted therapies is related to size at presentation.

OBJECTIVE: To evaluate the probability of downsizing primary renal tumors by targeted therapy in correlation to size. METHODS: A literature search was conducted and our own data were pooled with data of retrospective series and prospective trials in which patients were treated with tyrosine kinase inhibitors (TKIs) and in which tumor sizes before and after treatment were reported. Included were 89 primary clear cell renal tumors, including 34 from our institutes. The longest diameter of the primary tumors before and after treatment was obtained. Primary tumor size at presentation was divided in 4 categories: <5 cm (n=10), 5 to 7 cm (n=21), 7 to 10 cm (n=31), and >10 cm (n=27). Pearson correlation and t test were used for statistical analysis. RESULTS: The TKI was sorafenib in 21 tumors and sunitinib in the remaining 68. Smaller tumor size was related to more effective downsizing (P=0.01). Median downsizing was 32% (-46% to 11%) in the first group (<5 cm) and 11% (-55% to 16%) in the second group (5-7 cm); however, 8 of 21 (38%) in this group reduced to a range of 2.3 to 4.7 cm in which ablative techniques are feasible and nephron-sparing surgery may benefit from the reduced size. Median downsizing was 18% (-39% to 2%) in tumors of 7 to 10 cm and 10% (-31% to 0%) in those>10 cm. CONCLUSION: The smaller the primary tumor, the greater the likelihood and the more effective the downsizing. A potential benefit of neoadjuvant treatment to downsize the primary tumor for ablative techniques or nephron-sparing surgery may exist, particularly in tumors sized 5 to 7 cm.