Steven C. Campbell

Renal cell carcinoma

Considerable progress has been made in the treatment of patients with renal cell carcinoma, with innovative surgical and systemic strategies revolutionising the management of this disease. In localised disease, partial nephrectomy for small tumours and radical nephrectomy for large tumours continue to be the gold-standard treatments, with emphasis on approaches that have reduced invasiveness and preserve renal function. Additionally, cytoreductive nephrectomy is often indicated before the start of systemic treatment in patients with metastatic disease as part of integrated management strategy. The effectiveness of immunotherapy, although previously widely used for treatment of metastatic renal cell carcinoma, is still controversial, and is mainly reserved for patients with good prognostic factors. Development of treatments that have specific targets in relevant biological pathways has been the main advance in treatment. Targeted drugs, including inhibitors of the vascular endothelial growth factor and mammalian target of rapamycin pathways, have shown robust effectiveness and offer new therapeutic options for the patients with metastatic disease.

The Epidemiology of Renal Cell Carcinoma

CONTEXT Kidney cancer is among the 10 most frequently occurring cancers in Western communities. Globally, about 270 000 cases of kidney cancer are diagnosed yearly and 116 000 people die from the disease. Approximately 90% of all kidney cancers are renal cell carcinomas (RCC). OBJECTIVE The causes of RCC are not completely known. We have reviewed known aetiologic factors. EVIDENCE ACQUISITION The data provided in the current review are based on a thorough review of available original and review articles on RCC epidemiology with a systemic literature search using Medline. EVIDENCE SYNTHESIS Smoking, overweight and obesity, and germline mutations in specific genes are established risk factors for RCC. Hypertension and advanced kidney disease, which makes dialysis necessary, also increase RCC risk. Specific dietary habits and occupational exposure to specific carcinogens are suspected risk factors, but results in the literature are inconclusive. Alcohol consumption seems to have a protective effect for reasons yet unknown. Hardly any information is available for some factors that may have a high a priori role in the causation of RCC, such as salt consumption. CONCLUSIONS Large collaborative studies with uniform data collection seem to be necessary to elucidate a complete list of established risk factors of RCC. This is necessary to make successful prevention possible for a disease that is diagnosed frequently in a stage where curative treatment is not possible anymore.

Every Minute Counts When the Renal Hilum Is Clamped During Partial Nephrectomy

BACKGROUND The safe duration of warm ischemia during partial nephrectomy remains controversial. OBJECTIVE Our aim was to evaluate the short- and long-term renal effects of warm ischemia in patients with a solitary kidney. DESIGN, SETTING, AND PARTICIPANTS Using the Cleveland Clinic and Mayo Clinic databases, we identified 362 patients with a solitary kidney who underwent open (n=319) or laparoscopic (n=43) partial nephrectomy using warm ischemia with hilar clamping. MEASUREMENTS Associations of warm ischemia time with renal function were evaluated using logistic or Cox regression models first as a continuous variable and then in 5-min increments. RESULTS AND LIMITATIONS Median tumor size was 3.4 cm (range: 0.7-18.0 cm), and median ischemia time was 21 min (range: 4-55 min). Postoperative acute renal failure (ARF) occurred in 70 patients (19%) including 58 (16%) who had a glomerular filtration rate (GFR) <15 ml/min per 1.73 m(2) within 30 d of surgery. Among the 226 patients with a preoperative GFR >or=30 ml/min per 1.73 m(2) and followed >or=30 d, 38 (17%) developed new-onset stage IV chronic kidney disease during follow-up. As a continuous variable, longer warm ischemia time was associated with ARF (odds ratio: 1.05 for each 1-min increase; p<0.001) and a GFR<15 (odds ratio: 1.06; p<0.001) in the postoperative period, and it was associated with new-onset stage IV chronic kidney disease (hazard ratio: 1.06; p<0.001) during follow-up. Similar results were obtained adjusting for preoperative GFR, tumor size, and type of partial nephrectomy in a multivariable analysis. Evaluating warm ischemia in 5-min increments, a cut point of 25 min provided the best distinction between patients with and without all three of the previously mentioned end points. Limitations include the retrospective nature of the study. CONCLUSIONS Longer warm ischemia time is associated with short- and long-term renal consequences. These results suggest that every minute counts when the renal hilum is clamped.

Nephrectomy Induced Chronic Renal Insufficiency is Associated With Increased Risk of Cardiovascular Death and Death From Any Cause in Patients With Localized cT1b Renal Masses

PURPOSE Radical nephrectomy has traditionally been preferred to partial nephrectomy in patients with localized renal cell cancer because of its simplicity and established cancer control. Recent data suggest that these patients have significant competing risks of death, some of which may be increased by chronic renal insufficiency. Therefore, we compared overall survival, cancer specific survival and cardiac specific survival in patients undergoing partial or radical nephrectomy for cT1b tumors. MATERIALS AND METHODS From 1999 to 2006, 1,004 patients with renal masses between 4 and 7 cm underwent extirpative surgery, partial nephrectomy (524) or radical nephrectomy (480). We generated a propensity model based on preoperative patient characteristics, and then modeled survival with the additional variables of pathological stage and new baseline renal function. RESULTS On multivariate analysis cancer specific survival was equivalent for patients treated with partial nephrectomy or radical nephrectomy. Those patients undergoing radical nephrectomy lost significantly more renal function than those undergoing partial nephrectomy. The average excess loss of renal function observed with radical nephrectomy was associated with a 25% (95% CI 3-73) increased risk of cardiac death and 17% (95% CI 12-27) increased risk of death from any cause on multivariate analysis. CONCLUSIONS Partial nephrectomy offers cancer specific survival equivalent to that of radical nephrectomy and is technically feasible in at least 50% of patients with cT1b tumors. Preservation of renal function was significantly better in patients treated with partial nephrectomy. Postoperative renal insufficiency was a significant independent predictor of overall and cardiovascular specific survival, and efforts should be made to limit the renal function loss associated with surgery for localized renal masses.

10-Year Oncologic Outcomes After Laparoscopic and Open Partial Nephrectomy

PURPOSE Open partial nephrectomy has proven long-term oncologic efficacy. Laparoscopic partial nephrectomy outcomes at 5 to 7 years of followup appear comparable to those of the open approach. We present the 10-year outcomes of patients who underwent laparoscopic or open partial nephrectomy for a single clinical stage cT1 7 cm or less renal cortical tumor. MATERIALS AND METHODS Of 1,541 patients treated with partial nephrectomy for a single cT1 tumor between 1999 and 2007 with a minimum 5-year followup, an actual followup of 10 years or greater was available in 45 and 254 after laparoscopic and open partial nephrectomy, respectively. RESULTS Median followup after laparoscopic and open surgery was 6.6 and 7.8 years, respectively. At 10 years the overall survival rate was 77.2%. The metastasis-free survival rate was 95.2% and 90.0% after partial nephrectomy for clinical T1a and T1b renal cell carcinoma, respectively (p <0.0001). Baseline differences between patients treated with laparoscopic and open partial nephrectomy accounted for most observed differences between the cohorts. The median glomerular filtration rate decrease was 16.9% after the laparoscopic approach and 14.1% after the open approach (p = 0.5). On multivariable analysis predictors of all cause mortality included advancing age (HR 1.52/10 years, p <0.0001), comorbidity (HR 1.33/1 U, p <0.0001), absolute indication (HR 2.25, p = 0.003) and predicted recurrence-free survival (HR 1.58/10% increased risk, p = 0.004) but not laparoscopic vs open operative approach (p = 0.13). Similarly, predictors of metastasis included absolute indication (HR 4.35, p <0.0001) and predicted recurrence-free survival (HR 2.67, p <0.0001) but not operative approach (p = 0.42). CONCLUSIONS The 10-year outcomes of laparoscopic nephrectomy and open partial nephrectomy are excellent in carefully selected patients with limited risk of recurrence for cT1 renal cortical tumors. Overall survival at 10 years is mediated by patient factors such as age, comorbidity and operative indication, and by cancer factors such as predicted recurrence-free survival but not by the choice of operative technique, which depends on surgeon preference and experience.

Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function

PURPOSE Factors that determine renal function after partial nephrectomy are not well-defined, including the impact of cold vs warm ischemia, and the relative importance of modifiable and nonmodifiable factors. We studied these determinants in a large cohort of patients with a solitary functioning kidney undergoing partial nephrectomy. MATERIALS AND METHODS From 1980 to 2009, 660 partial nephrectomies were performed at 4 centers for tumor in a solitary functioning kidney under cold (300) or warm (360) ischemia. Data were collected in institutional review board approved registries and followup averaged 4.5 years. Preoperative and postoperative glomerular filtration rates were estimated via the Chronic Kidney Disease-Epidemiology Study equation. RESULTS At 3 months after partial nephrectomy median glomerular filtration rate decreased by equivalent amounts with cold or warm ischemia (21% vs 22%, respectively, p = 0.7), although median cold ischemic times were much longer (45 vs 22 minutes respectively, p <0.001). On multivariable analyses increasing age, larger tumor size, lower preoperative glomerular filtration rate and longer ischemia time were associated with decreased postoperative glomerular filtration rate (p <0.05). When percentage of parenchyma spared was incorporated into the analysis, this factor and preoperative glomerular filtration rate proved to be the primary determinants of ultimate renal function, and duration of ischemia lost statistical significance. CONCLUSIONS This nonrandomized, comparative study suggests that within the relatively strict parameters of conventional practice, ie predominantly short ischemic intervals and liberal use of hypothermia, ischemia time was not an independent predictor of ultimate renal function after partial nephrectomy. Long-term renal function after partial nephrectomy is determined primarily by the quantity and quality of renal parenchyma preserved, although type and duration of ischemia remain the most important modifiable factors, and warrant further study.

Complications of nephron sparing surgery for renal tumors

The technical results of 259 nephron sparing operations for renal cell carcinoma or renal oncocytoma were reviewed. Local or renal related complications occurred after 78 procedures (30.1%). The incidence of complications was less for operations performed after 1988 (22% versus 37%, p = 0.009) and for incidentally detected versus suspected tumors (p = 0.009). The most common complications were urinary fistula formation (45 operations) and acute renal failure (33). Significant predisposing factors for urinary fistula formation included central tumor location (p = 0.001), tumor size greater than 4 cm. (p = 0.001), the need for major reconstruction of the collecting system (p = 0.001) and ex vivo surgery (p = 0.001). Only 1 urinary fistula required open operative repair, while the remainder resolved either spontaneously (30) or with endoscopic management (14). Significant predisposing factors for acute renal failure included a solitary kidney (p = 0.001), tumor size greater than 7 cm. (p = 0.008), greater than 50% parenchymal excision (p = 0.001), greater than 60 minutes of ischemia time (p = 0.035) and ex vivo surgery (p = 0.001). Acute renal failure resolved in 28 patients, of whom 9 required temporary dialysis, while 5 required permanent dialysis. Overall, 8 complications (3.1%) required repeat open surgery for treatment while all other complications resolved with noninterventive or endourological management. Surgical complications contributed to an adverse clinical outcome in only 7 patients (2.9%). Nephron sparing surgery can be performed safely with preservation of renal function in most patients with renal tumors.

RENAL CRYOSURGERY: EXPERIMENTAL EVALUATION OF TREATMENT PARAMETERS

OBJECTIVES Cryosurgery represents a minimally invasive alternative for the management of small or equivocal lesions of the kidney. We evaluated the relationship between ultrasonographic appearance and intrarenal temperatures and the effect of renal artery occlusion on the efficacy of the freezing process in a canine model. METHODS Ten animals were treated with intraparenchymal cryoablative therapy with (n = 5) or without (n = 5) renal artery occlusion using a rapid freeze technique. Intrarenal temperatures were measured 1.0 cm away from the cryoprobe at various times during the freezing process. The distance from the cryoprobe to the ice ball as monitored by ultrasonography was also determined. The contralateral kidney was removed to facilitate studies of renal function and all animals were killed on day 28 for autopsy and histopathologic examination. RESULTS A target temperature of less than -20 degrees C was achieved 3.1 mm behind the ice ball in all animals tested. The ice ball stabilized at a radius of 16 mm with prolonged treatment, suggesting that multiple probes will be required to treat renal lesions greater than 2.5 cm in diameter. Renal artery occlusion did not significantly alter the freezing process and provided no practical advantage. Renal function remained stable (final serum creatinine level 1.5 mg/dL or less) in all but 1 animal in which an obstructive stricture of the ureteropelvic junction developed. Effective tissue ablation was confirmed at the treatment site in all instances. CONCLUSIONS Renal cryoablative therapy is a nephron-sparing modality that can be delivered in a safe, efficacious, and reproducible manner. The treatment parameters defined in this study should allow for intelligent patient selection and rational administration of renal cryotherapy.

Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904.

BACKGROUND In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) was associated with reduced overall survival compared with radical nephrectomy (RN) over a median follow-up of 9.3 yr (hazard ratio: 1.50; 95% confidence interval [CI], 1.03-2.16). OBJECTIVE To examine the impact of NSS relative to RN on kidney function in EORTC 30904. DESIGN, SETTING, AND PARTICIPANTS This phase 3 international randomized trial was conducted in patients with a small (≤5 cm) renal mass and normal contralateral kidney who were enrolled from March 1992 to January 2003. INTERVENTION Patients were randomized to RN (n=273) or NSS (n=268). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Follow-up estimated glomerular filtration rates (eGFR; milliliters per minute per 1.73 m(2)) were recorded for 259 subjects in the RN arm and 255 subjects in the NSS arm. Percentages of subjects developing at least moderate renal dysfunction (eGFR <60), advanced kidney disease (eGFR <30), or kidney failure (eGFR <15) were calculated for each treatment arm based on the lowest recorded follow-up eGFR (intent-to-treat analysis). RESULTS AND LIMITATIONS With a median follow-up of 6.7 yr, eGFR <60 was reached by 85.7% with RN and 64.7% with NSS, with a difference of 21.0% (95% CI, 13.8-28.3); eGFR <30 was reached by 10.0% with RN and 6.3% with NSS, with a difference of 3.7% (95% CI, -1.0 to 8.5); and eGFR <15 was reached by 1.5% with RN and 1.6% with NSS, with a difference of -0.1% (95% CI, -2.2 to 2.1). Lack of longer follow-up for eGFR is a limitation of these analyses. CONCLUSIONS Compared with RN, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR <60), although with available follow-up the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR <15) was nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population. REGISTRATION EORTC trial 30904; ClinicalTrials.gov identifier NCT00002473.

Patterns of Tumor Recurrence and Guidelines for Followup After Nephron Sparing Surgery for Sporadic Renal Cell Carcinoma

PURPOSE We delineated patterns of tumor recurrence and developed guidelines for followup after nephron sparing surgery for sporadic renal cell carcinoma. MATERIALS AND METHODS Before December 1994, 327 patients underwent nephron sparing surgery for sporadic localized renal cell carcinoma at our clinic. Mean postoperative followup was 55.6 months. The course and outcome for patients with postoperative recurrent renal cell carcinoma were reviewed in detail. RESULTS Renal cell carcinoma recurred after nephron sparing surgery in 38 patients (11.6%), including 13 (4.0%) who had local tumor recurrence with (7) or without (6) metastatic disease and 25 (7.6%) who had metastatic disease without local tumor recurrence. Recurrent renal cell carcinoma was detected by associated symptoms in 25 patients and by a followup chest x-ray or abdominal computerized tomography (CT) in 13. The respective incidences of postoperative local tumor recurrence and metastatic disease according to initial pathological tumor stage were 0 and 4.4% for stage T1, 2.0 and 5.3% for stage T2, 8.2 and 11.5% for stage T3a, and 10.6 and 14.9% for stage T3b disease. The peak postoperative intervals until local tumor recurrence were 6 to 24 months (7 of 10 patients with stage T3 renal cell carcinoma) and longer than 48 months (all 3 with stage T2 disease). Patients with isolated local tumor recurrence had better survival compared to those with local tumor recurrence and metastatic disease or metastases only. CONCLUSIONS Followup for recurrent malignancy after nephron sparing surgery for renal cell carcinoma can be tailored according to the initial pathological tumor stage. All patients should be evaluated yearly with a medical history, physical examination and select laboratory studies. Patients with stage T1 renal cell carcinoma require no additional monitoring, while those with stage T2 disease should also undergo a yearly chest x-ray and abdominal CT every 2 years. The same recommendations are offered for patients with stage T3 renal cell carcinoma except that abdominal CT should be done every 6 months for the first 2 years postoperatively.