Surena F. Matin

Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration

The literature on upper tract urothelial carcinoma (UTUC) has been limited to small, single center studies. A large series of patients treated with radical nephroureterectomy for UTUC were studied, and variables associated with poor prognosis were identified.

RENAL OUTCOME 25 YEARS AFTER DONOR NEPHRECTOMY

PURPOSE The extended outcome after kidney donation has been a particular concern ever since the recognition of hyperfiltration injury. Few published reports have examined donor renal outcome after 20 years or greater. Kidney transplantation has been performed at the Cleveland Clinic Foundation since 1963, at which there is extensive experience with live donor transplantation. We assess the impact of donor nephrectomy on renal function, urinary protein excretion and development of hypertension postoperatively to examine whether renal deterioration occurs with followup after 20 years or greater. MATERIALS AND METHODS From 1963 to 1975, 180 live donor nephrectomies were performed at the Cleveland Clinic. We attempted to contact all patients to request participation in our study. Those 70 patients who agreed to participate in the study were mailed a package containing a 24-hour urine container (for assessment of creatinine, and total protein and albumin), a vial for blood collection (for assessment of serum creatinine) and a medical questionnaire. All specimens were returned to and processed by the Cleveland Clinic medical laboratories. Blood pressure was taken and recorded by a local physician. A 24-hour creatinine clearance and the Cockcroft-Gault formula were used to estimate renal function, and values were compared with an age adjusted glomerular filtration rate for a solitary kidney. RESULTS Mean patient followup was 25 years. The 24-hour urinary creatinine clearance decreased to 72% of the value before donation. For the entire study cohort serum creatinine and systolic blood pressure after donation were significantly increased compared with values before, although still in the normal range. The overall incidence of hypertension was comparable to that expected in the age matched general population. There was no gender or age difference (younger or older than 50 years) for 24-hour urinary creatinine clearance, or change in serum creatinine before or after donation. Urinary protein and albumin excretion after donation was significantly higher in males compared with females. There were 13 (19%) subjects who had a 24-hour urinary protein excretion that was greater than 0.15 gm./24 hours, 5 (7%) of whom had greater than 0.8. No gender difference was noted in blood pressure, and there were no significant changes in diastolic pressure based on gender or age. CONCLUSIONS Overall, renal function is well preserved with a mean followup of 25 years after donor nephrectomy. Males had significantly higher protein and albumin excretion than females but no other clinically significant differences in renal function, blood pressure or proteinuria were noted between them or at age of donation. Proteinuria increases with marginal significance but appears to be of no clinical consequence in most patients. Patients with mild or borderline proteinuria before donation may represent a subgroup at particular risk for the development of significant proteinuria 20 years or greater after donation. The overall incidence of proteinuria in our study is in the range of previously reported values after donor nephrectomy.

Prognostic Factors in Upper Urinary Tract Urothelial Carcinomas: A Comprehensive Review of the Current Literature

CONTEXT The heterogeneity of upper tract urothelial carcinoma (UTUC) biology and prognosis, as well as the presence of different treatment options, makes the clinical decision-making process extremely challenging. OBJECTIVE Provide an overview of the currently available prognostic factors for UTUC, focusing on clinical and pathologic characteristics, as well as on molecular markers. EVIDENCE ACQUISITION A systematic literature search was conducted using the PubMed, Scopus, and Embase databases to identify original articles, review articles, and editorials regarding prognostic factors in patients with UTUC. Keywords included urothelial carcinoma, renal pelvis, ureter, upper urinary tract urothelial carcinoma, upper urinary tract transitional cell carcinoma, prognosis, prognostic factors, markers, and survival. Articles published between 2000 and 2011 were reviewed and selected with the consensus of all the authors. EVIDENCE SYNTHESIS Prognostic factors can be divided into four different categories: preoperative/clinical factors, intraoperative/surgical factors, postoperative/pathologic factors, and molecular markers. Because of the rarity of the disease, only a small amount of level 1 evidence information from prospective randomized trials is available. Conversely, several single-institutional and multi-institutional studies have been published providing level 3 evidence information on various prognostic factors. Tumor stage and grade represent the best-established predictors of prognosis in patients with UTUC, but controversies still exist regarding the prognostic impact of tumor location and tumor necrosis. Several promising biomarkers have also been evaluated, but further studies evaluating their prognostic role are still needed. Finally, few prognostic models have been developed to provide clinicians with accurate estimates of the outcome of interest. CONCLUSIONS In the past few years, several prognostic factors have been identified to help clinicians dealing with patients with UTUC in the decision-making process. However, well-designed multi-institutional studies are still needed to provide stronger evidence and to promote the use of these prognostic factors in clinical practice.

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial

BACKGROUND Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.

Training, credentialing, proctoring and medicolegal risks of robotic urological surgery: recommendations of the society of urologic robotic surgeons.

PURPOSE With the exponential growth of robotic urological surgery, particularly with robot assisted radical prostatectomy, guidelines for safe initiation of this technology are a necessity. Currently no standardized credentialing system exists to our knowledge to evaluate surgeon competency and safety with robotic urological surgery performance. Although proctoring is a modality by which such competency can be evaluated, other training tools and guidelines are needed to ensure that the requisite knowledge and technical skills to perform this procedure have been acquired. We evaluated the current status of proctoring and credentialing in other surgical specialties to discuss and recommend its application and implementation specifically for robot assisted radical prostatectomy. MATERIALS AND METHODS We reviewed the literature on safety and medicolegal implications of proctoring and the safe introduction of surgical procedures to develop recommendations for robot assisted radical prostatectomy proctoring and credentialing. RESULTS Proctoring is an essential mechanism for robot assisted radical prostatectomy institutional credentialing and should be a prerequisite for granting unrestricted privileges on the robot. This should be differentiated from preceptoring, wherein the expert is directly involved in hands-on training. Advanced technology has opened new avenues for long-distance observation through teleproctoring. Although the medicolegal implications of an active surgical intervention by a proctor are not clearly defined, the role as an observer should grant immunity from malpractice liability. CONCLUSIONS The implementation of guidelines and proctoring recommendations is necessary to protect surgeons, proctors, institutions and, above all, the patients who are associated with the institutional introduction of a robot assisted radical prostatectomy program. With no current guidelines we anticipate this article will serve as a catalyst of interorganizational discussion to initiate regulatory oversight of surgeon certification and proctorship.

Surgical Morbidity Associated With Administration of Targeted Molecular Therapies Before Cytoreductive Nephrectomy or Resection of Locally Recurrent Renal Cell Carcinoma

PURPOSE Targeted molecular therapies such as bevacizumab, sunitinib and sorafenib before surgical resection hold promise as rational treatment paradigms for patients with metastatic or locally recurrent renal cell carcinoma. To analyze the safety of this approach we evaluated surgical parameters and perioperative complications in patients treated with targeted molecular therapies before cytoreductive nephrectomy or resection of retroperitoneal renal cell carcinoma recurrence, and compared them to a matched patient cohort who underwent up-front surgical resection. MATERIALS AND METHODS We evaluated surgical parameters and perioperative complications in 44 patients treated with targeted molecular therapies before cytoreductive nephrectomy or resection of local renal cell carcinoma recurrence, and in a matched cohort of 58 patients who underwent up-front surgery. RESULTS Cohorts of patients treated with preoperative targeted molecular therapy and initial surgical resection were matched in terms of clinical characteristics, burden of metastatic disease and number of adverse prognostic factors. A total of 39 complications occurred in 17 (39%) patients treated with preoperative targeted molecular therapy and in 16 (28%) who underwent up-front resection (p = 0.287). There were no statistically significant differences in surgical parameters, incidence of perioperative mortality, re-exploration, readmission, thromboembolic, cardiovascular, pulmonary, gastrointestinal, infectious or incision related complications between patients treated with preoperative targeted molecular therapy and those who underwent up-front surgery. Duration, type and interval from targeted molecular therapy to surgical intervention were not associated with the risk of perioperative morbidity. CONCLUSIONS Preoperative administration of targeted molecular therapies is safe, and does not increase surgical morbidity or perioperative complications in patients treated with cytoreductive nephrectomy or resection of recurrent retroperitoneal renal cell carcinoma.

Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high‐risk upper tract transitional cell carcinoma

The authors evaluated the incidence of pathologic downstaging and complete remission (CR) in patients with high‐grade ureteral and renal pelvic transitional cell carcinoma (TCC) (upper tract TCC) who received neoadjuvant chemotherapy followed by surgery.

Outcome of Laparoscopic Radical and Open Partial Nephrectomy for the Sporadic 4 cm. or Less Renal Tumor With a Normal Contralateral Kidney

PURPOSE Nephron sparing surgery provides effective therapy in patients with a solitary sporadic renal tumor 4 cm. or less and a normal contralateral kidney. Laparoscopic radical nephrectomy has been applied as a newer alternative therapy in these patients. These 2 contemporary approaches represent divergent treatment alternatives at centers where laparoscopic nephron sparing surgery is not offered. We compared the short-term and long-term impact of these 2 treatment modalities in patients with a sporadic localized solitary renal tumor 4 cm. or less and a normal opposite kidney. MATERIALS AND METHODS A retrospective review of a contemporary series of patients (1996 to 2001) who underwent open nephron sparing surgery and met study inclusion criteria was performed and compared with a similar cohort (1997 to 2001) that underwent laparoscopic radical nephrectomy. Only patients with a single renal tumor of 4 cm. or less, normal serum creatinine less than 1.5 mg./dl. and a normal contralateral kidney were included in analysis. The 2 groups were compared in regard to demographic, clinical and pathological variables using parametric and nonparametric tests. Linear regression analysis was done to compare the percent change in serum creatinine, while adjusting for demographic and clinical variables, and followup. RESULTS A total of 35 patients who underwent laparoscopic radical nephrectomy and 82 who underwent open nephron sparing surgery met study inclusion criteria. Mean patient age in the laparoscopic group was significantly greater (67.3 versus 56.2 years, p <0.001), mean American Society of Anesthesiologists class score was higher (p = 0.04) and mean tumor size was greater (3.1 versus 2.6 cm., p = 0.003) than in the nephron sparing group. The laparoscopic group had significantly decreased mean blood loss (100 versus 200 ml., p <0.001), hospital stay (1 versus 5 days, p <0.001), narcotic use (16.5 versus 224 mg., p <0.001) and operative time (184.4 versus 216.2 minutes, p <0.007) compared with the nephron sparing group. Patients who underwent nephron sparing surgery experienced less postoperative deterioration in renal function, as measured by the percent increase in serum creatinine postoperatively (0% versus 25%, p <0.001). The results of regression analyses at 4 and 6 months of followup indicated that open nephron sparing surgery is associated with significantly lower serum creatinine than laparoscopic radical nephrectomy after adjusting for demographic and clinical variables, and followup. CONCLUSIONS Open nephron sparing surgery and laparoscopic radical nephrectomy are relatively recent and significant developments for treating patients with renal cell carcinoma and they represent accepted standards of care in those with a small renal mass and normal contralateral kidney. In patients presenting with a sporadic solitary renal tumor of 4 cm. or less and a normal contralateral kidney the significant short-term and intermediate term benefits of the laparoscopic approach must be weighed against the long-term advantage of better renal function associated with open nephron sparing surgery. The distinct advantages of these 2 approaches may ultimately be realized with the standardization of laparoscopic partial nephrectomy.

Laparoscopic Radical Nephrectomy For Cancer With Level I Renal Vein Involvement

PURPOSE Venous involvement develops in 5% to 10% of patients with renal cell carcinoma and is generally considered a relative contraindication to laparoscopic radical nephrectomy. To our knowledge we report the initial clinical series of laparoscopic radical nephrectomy for renal cell carcinoma associated with level I renal vein thrombus. MATERIALS AND METHODS At our 2 institutions 8 patients each underwent laparoscopic radical nephrectomy for level I microscopic renal vein thrombus (group 1) and level I gross thrombus (group 2). In all 8 group 2 patients the level I thrombus was preoperatively diagnosed by computerized tomography. Mean renal tumor size in groups 1 and 2 was 7.8 and 12.4 cm., respectively. After controlling the renal artery the renal vein was secured by firing an endoscopic gastrointestinal anastomosis stapler on its collapsed, uninvolved proximal part adjacent to the vena cava. Intraoperative, postoperative and pathological parameters were assessed in the 2 groups. RESULTS In group 1 laparoscopic radical nephrectomy was technically successful in all 8 patients. Mean operative time was 3.1 hours, mean estimated blood loss was 382 cc and mean hospital stay was 1.9 days. In 1 patient each a soft tissue and a vascular margin was positive for cancer. At a mean follow up of 19.5 months (range 2 to 36) metastatic disease occurred in 3 cases (38%). In group 2 laparoscopic radical nephrectomy was technically successful in 7 cases with open conversion in 1. Mean operative time was 3.3 hours, mean estimated blood loss was 354 cc and mean hospital stay was 2.3 days. Surgical soft tissue and the renal vein vascular margin of the transected vein were negative for cancer in all 8 cases. At a mean followup of 9.4 months (range 5 to 16) pulmonary metastasis developed in 1 patient (13%). CONCLUSIONS Although it is an advanced procedure, laparoscopic radical nephrectomy in patients with level I renal vein thrombus is feasible, safe and follows established oncological principles.

Urothelial carcinoma of the bladder and the upper tract: disparate twins.

PURPOSE Urothelial carcinoma of the bladder is the 4th most common malignancy in men and the 8th most common cause of male cancer death in the United States. Conversely, upper tract urothelial carcinoma accounts for only 5% to 10% of all urothelial carcinoma. Due to the relative preponderance of urothelial carcinoma of the bladder, much of the clinical decision making regarding upper tract urothelial carcinoma is extrapolated from evidence that is based on urothelial carcinoma of the bladder cohorts. In fact, only 1 major urological organization has treatment guidelines specific for upper tract urothelial carcinoma. While significant similarities exist between these 2 diseases, ignoring the important differences may be preventing us from optimizing therapy in patients with upper tract urothelial carcinoma. Therefore, we explored these dissimilarities, including the differential importance of gender, anatomy, staging, intracavitary therapy, surgical lymphadenectomy and perioperative systemic chemotherapy on the behavior of urothelial carcinoma of the bladder and upper tract urothelial carcinoma. MATERIALS AND METHODS A nonsystematic literature search using the MEDLINE/PubMed® database was conducted to identify original articles, review articles and editorials. Searches were limited to the English language and studies in humans and in adults, and used the key words urothelial carcinoma, upper tract urothelial carcinoma or transitional cell carcinoma combined with several different sets of key words to identify appropriate publications for each section of the manuscript. The key words, broken down by section, were 1) epidemiology, sex, gender; 2) location, tumor location; 3) staging, stage; 4) intracavitary, intravesical, topical therapy; 5) lymphadenectomy, lymph node, lymph node dissection and 6) adjuvant, neoadjuvant, chemotherapy. RESULTS Women who present with urothelial carcinoma of the bladder do so with less favorable tumor characteristics and have worse survival than men. However, gender does not appear to be associated with survival outcomes in upper tract urothelial carcinoma. The prognostic effect that urothelial carcinoma tumor location has on outcomes prediction is a matter of debate, and the influence of tumor location may reflect our technical ability to accurately stage and treat the disease more than the actual tumor biology. Moreover, technical limitations of upper tract urothelial carcinoma sampling compared to transurethral resection for urothelial carcinoma of the bladder are the most important source of staging differences between the 2 diseases. Intravesical chemotherapy and immunotherapy are essential components of standard of care for most nonmuscle invasive bladder cancer, while adjuvant intracavitary therapy for patients with upper tract urothelial carcinoma treated endoscopically or percutaneously has been sparsely used and without any clear guidelines. The widespread adoption of the use of intracavitary therapy in the upper tract will likely not only require additional data to support its efficacy, but will also require a less cumbersome means of administration. Lymphadenectomy at the time of radical cystectomy is widely accepted while lymphadenectomy at the time of radical nephroureterectomy is performed largely at the discretion of the surgeon. Among other reasons, this may be due in part to the variable lymphatic drainage along the course of the ureter compared to the relatively confined lymphatic landing sites for the bladder. Level I evidence has demonstrated a clear survival benefit for systemic chemotherapy before radical surgery or radiation in patients with clinical T2-4N0M0 urothelial carcinoma of the bladder. Such data are not available in the population with upper tract urothelial carcinoma. However, the use of neoadjuvant chemotherapy may be even more important in upper tract urothelial carcinoma than in urothelial carcinoma of the bladder because of the obligatory kidney function loss that occurs at radical nephroureterectomy. CONCLUSIONS While urothelial carcinoma of the bladder and upper tract urothelial carcinoma share many characteristics, they represent 2 distinct diseases. There are practical, anatomical, biological and molecular differences that warrant consideration when risk stratifying and treating patients with these disparate twin diseases. To overcome the challenges that impede progress toward evidence-based medicine in upper tract urothelial carcinoma, we believe that focused collaborative efforts will best augment our understanding of this rare disease and ultimately improve the care we deliver to our patients.