Paul Russo

Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study

BACKGROUND Chronic kidney disease is a graded and independent risk factor for substantial comorbidity and death. We aimed to examine new onset of chronic kidney disease in patients with small, renal cortical tumours undergoing radical or partial nephrectomy. METHODS We did a retrospective cohort study of 662 patients with a normal concentration of serum creatinine and two healthy kidneys undergoing elective partial or radical nephrectomy for a solitary, renal cortical tumour (</=4 cm) between 1989 and 2005 at a referral cancer centre. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification in Diet and Renal Disease Study equation. Separate analysis was undertaken, with chronic kidney disease defined as GFR lower than 60 mL/min per 1.73 m(2) and GFR lower than 45 mL/min per 1.73 m(2). FINDINGS 171 (26%) patients had pre-existing chronic kidney disease before surgery. After surgery, the 3-year probability of freedom from new onset of GFR lower than 60 mL/min per 1.73 m(2) was 80% (95% CI 73-85) after partial nephrectomy and 35% (28-43; p<0.0001) after radical nephrectomy; corresponding values for GFRs lower than 45 mL/min per 1.73 m(2) were 95% (91-98) and 64% (56-70; p<0.0001), respectively. Multivariable analysis showed that radical nephrectomy remained an independent risk factor for patients developing new onset of GFR lower than 60 mL/min per 1.73 m(2) (hazard ratio 3.82 [95% CI 2.75-5.32]) and 45 mL/min per 1.73 m(2) (11.8 [6.24-22.4]; both p<0.0001). INTERPRETATION Because the baseline kidney function of patients with renal cortical tumours is lower than previously thought, accurate assessment of kidney function is essential before surgery. Radical nephrectomy is a significant risk factor for the development of chronic kidney disease and might no longer be regarded as the gold standard treatment for small, renal cortical tumours.

Interferon-Alfa as a Comparative Treatment for Clinical Trials of New Therapies Against Advanced Renal Cell Carcinoma

PURPOSE To define outcome data and prognostic criteria for patients with metastatic renal cell carcinoma (RCC) treated with interferon-alfa as initial systemic therapy. The data can be applied to design and interpretation of clinical trials of new agents and treatment programs against this refractory malignancy. PATIENTS AND METHODS Four hundred sixty-three patients with advanced RCC administered interferon-alpha as first-line systemic therapy on six prospective clinical trials were the subjects of this retrospective analysis. Three risk categories for predicting survival were identified on the basis of five pretreatment clinical features by a stratified Cox proportional hazards model. RESULTS The median overall survival time was 13 months. The median time to progression was 4.7 months. Five variables were used as risk factors for short survival: low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and time from initial RCC diagnosis to start of interferon-alpha therapy of less than one year. Each patient was assigned to one of three risk groups: those with zero risk factors (favorable risk), those with one or two (intermediate risk), and those with three or more (poor risk). The median time to death of patients deemed favorable risk was 30 months. Median survival time in the intermediate-risk group was 14 months. In contrast, the poor-risk group had a median survival time of 5 months. CONCLUSION Progression-free and overall survival with interferon-alpha treatment can be compared with new therapies in phase II and III clinical investigations. The prognostic model is suitable for risk stratification of phase III trials using interferon-alpha as the comparative treatment arm.

Prognostic Factors for Survival in Previously Treated Patients With Metastatic Renal Cell Carcinoma

PURPOSE To describe survival in previously treated patients with metastatic renal cell carcinoma (RCC) who are candidates for clinical trials of new agents as second-line therapy. PATIENTS AND METHODS The relationship between pretreatment clinical features and survival was studied in 251 patients with advanced RCC treated during 29 consecutive clinical trials between 1975 and 2002. Clinical features were first examined in univariate analyses, and then a stepwise modeling approach based on Cox regression was used to form a multivariate model. RESULTS Median survival for the 251 patients was 10.2 months and differed according to year of treatment, with patients treated after 1990 showing longer survival. In this group, the median overall survival time was 12.7 months. Because the purpose of this analysis was to establish prognostic factors for present-day clinical trial design, prognostic factor analysis was performed on these patients. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status, low hemoglobin level, and high corrected serum calcium. These were used as risk factors to categorize patients into three different groups. The median time to death in patients with zero risk factors was 22 months. The median survival in patients with one of these prognostic factors was 11.9 months. Patients with two or three risk factors had a median survival of 5.4 months. CONCLUSION Treatment with novel agents during a clinical trial is indicated for patients with metastatic RCC after progression to cytokine treatment. Three prognostic factors for predicting survival were used to categorize patients into risk groups. These risk categories can be used in clinical trial design and interpretation.

A POSTOPERATIVE PROGNOSTIC NOMOGRAM FOR RENAL CELL CARCINOMA

PURPOSE Few published studies have combined prognostic factors to predict the likelihood of recurrence after surgery for renal cell carcinoma. We developed a nomogram for this purpose. MATERIALS AND METHODS With Cox proportional hazards regression analysis, we modeled pathological data and disease followup for 601 patients with renal cell carcinoma who were treated with nephrectomy. Predictor variables were patient symptoms, including incidental, local or systemic, histology, including chromophobe, papillary or conventional, tumor size, and pathological stage. Treatment failure was recorded when there was either clinical evidence of disease recurrence or death from disease. Validation was performed with a statistical (bootstrapping) technique. RESULTS Disease recurrence was noted in 66 of the 601 patients, and those in whom treatment was successful had a median and maximum followup of 40 and 123 months, respectively. The 5-year probability of freedom from failure for the patient cohort was 86% (95% confidence interval 82 to 89). With statistical validation, predictions by the nomogram appeared accurate and discriminating with an area under the receiver operating characteristic curve, that is a comparison of the predicted probability with the actual outcome of 0.74. CONCLUSIONS A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among patients with newly diagnosed renal cell carcinoma. The nomogram may be useful for patient counseling, clinical trial design and patient followup planning.

Partial nephrectomy versus radical nephrectomy in patients with small renal tumors--is there a difference in mortality and cardiovascular outcomes?

PURPOSE Compared with partial nephrectomy, radical nephrectomy increases the risk of chronic kidney disease, which is a significant risk factor for cardiovascular events and death. Given equivalent oncological efficacy in patients with small renal tumors, radical nephrectomy may result in overtreatment. We analyzed a population based cohort of patients to determine whether radical nephrectomy is associated with an increase in cardiovascular events and mortality compared with partial nephrectomy. MATERIALS AND METHODS Using Surveillance, Epidemiology and End Results cancer registry data linked with Medicare claims we identified 2,991 patients older than 66 years who were treated with radical or partial nephrectomy for renal tumors 4 cm or less between 1995 and 2002. The primary end points of cardiovascular events and overall survival were assessed using Kaplan-Meier survival estimation, Cox proportional hazards regression and negative binomial regression. RESULTS A total of 2,547 patients (81%) underwent radical nephrectomy and 556 (19%) underwent partial nephrectomy. During a median followup of 4 years 609 patients experienced a cardiovascular event and 892 died. When adjusting for preoperative demographic and comorbid variables, radical nephrectomy was associated with an increased risk of overall mortality (HR 1.38, p <0.01) and a 1.4 times greater number of cardiovascular events after surgery (p <0.05). However, radical nephrectomy was not significantly associated with time to first cardiovascular event (HR 1.21, p = 0.10) or with cardiovascular death (HR 0.95, p = 0.84). CONCLUSIONS Radical nephrectomy, which is currently the most common treatment for small renal tumors, may be associated with significant, adverse treatment effects compared with partial nephrectomy. Partial nephrectomy should be considered in most patients with small renal tumors.

Surgical management of renal tumors 4 cm. or less in a contemporary cohort.

PURPOSE We evaluated a patient cohort with renal tumors 4 cm. or less treated with partial or radical nephrectomy. We compared patient and tumor characteristics, and survival in these 2 groups. MATERIALS AND METHODS We retrospectively analyzed the records of 670 patients with a median age of 63 years treated surgically for renal cell carcinoma between July 31, 1989 and July 31, 1997. Renal tumors 4.0 cm. or less were noted in 252 patients (38%) who underwent a total of 262 procedures, including 183 radical (70%) and 79 partial (30%) nephrectomies. Ten patients required 2 operations each because of bilateral renal cell carcinoma. Median followup was 40 months. We compared clinicopathological parameters in the partial and radical nephrectomy groups using chi-square or Wilcoxon analysis as appropriate. Survival analysis was determined by the log rank test and Cox regression model. RESULTS The partial and radical nephrectomy groups were comparable with respect to gender ratio, tumor presentation, histological classification, pathological stage and complication rate. Median tumor size was 2.5 and 3.0 cm. in the partial and radical nephrectomy groups, respectively (p = 0.0001). Resection was incomplete in 1 patient (1.3%) in the partial and none in the radical nephrectomy group. There was no local recurrence after either procedure, and no significant difference in disease specific, disease-free and overall survival (p = 0.98, 0.23 and 0.20, respectively). CONCLUSIONS Patients with a small renal tumor have similar perioperative morbidity, pathological stage and outcome regardless of treatment with partial or radical nephrectomy. Therefore, partial nephrectomy remains a safe alternative for tumors of this size.

SYSTEMIC THERAPY FOR RENAL CELL CARCINOMA

PURPOSE We review the status of systemic therapy for patients with advanced renal cell carcinoma. MATERIALS AND METHODS A literature search was performed on MEDLINE and CANCERLIT to identify results of systemic therapy for patients with renal cell carcinoma published from January 1990 through December 1998. Treatment results of chemotherapy agents, immunotherapy, combination programs and adjuvant therapy were reviewed. RESULTS No chemotherapy agent has produced response rates that justify its use as a single agent. Interferon-alpha and interleukin (IL)-2 demonstrated low response rates ranging from 10% to 20%. The results of 2 randomized trials suggest that treatment with interferon-alpha compared to vinblastine or medroxyprogesterone achieves a small improvement in survival. Response rates in patients treated with low dose IL-2 are similar to those achieved with a high dose bolus schedule but whether the responses are as durable is being addressed in an ongoing randomized trial. A randomized trial of interferon-alpha plus IL-2 compared to monotherapy with either agent showed increased toxicity but no improvement in survival. In 3 randomized trials no survival benefit was associated with adjuvant interferon-alpha therapy following complete resection of locally advanced renal cell carcinoma. CONCLUSIONS Despite extensive evaluation of many different treatment modalities, metastatic renal cell carcinoma remains highly resistant to systemic therapy. A few patients exhibit complete or partial responses to interferon and/or IL-2 but most do not respond, and there are few long-term survivors. Preclinical research, and clinical evaluation of new agents and treatment programs to identify improved antitumor activity against metastases remain the highest priorities in this refractory disease.

Natural history of chronic renal insufficiency after partial and radical nephrectomy

OBJECTIVES To compare the incidence of newly developed chronic renal insufficiency after partial nephrectomy (PN) and radical nephrectomy (RN). Elective PN for renal tumors is intended to preserve renal function; however, studies of transplant donors suggest normal renal function is also maintained after unilateral nephrectomy. METHODS We retrospectively compared all patients undergoing PN or RN for renal tumors 4 cm or less in the presence of a normal contralateral kidney from 1989 to 2000. Creatinine failure was defined as a serum creatinine value greater than 2.0 mg/dL. Risk factors for renal insufficiency, including diabetes, hypertension, American Society of Anesthesiologists score, age, preoperative creatinine, and history of smoking tobacco, were compared between the two groups. We compared the two groups using the chi-square and Mann-Whitney U tests and the creatinine failure rates using the Kaplan-Meier method. RESULTS One hundred seventy-three patients met the criteria for analysis after RN and 117 did so after PN (median follow-up 25 months). The 5-year freedom from recurrence rate was 96.4% and 98.6% for PN and RN, respectively (P >0.05). The mean preoperative serum creatinine was 1.0 mg/dL (range 0.4 to 1.4) and 0.98 (range 0.6 to 1.5) for RN and PN, respectively (P = 0.4, not significant). The incidence of risk factors for renal insufficiency did not differ between the two groups. The mean postoperative serum creatinine in the RN and PN groups was 1.5 mg/dL (range 0.8 to 3.8) and 1.0 mg/dL (range 0.5 to 1.9), respectively (P <0.001). The chance of creatinine failure over time was significantly greater in the RN group (P = 0.008). CONCLUSIONS When controlled for preoperative risk factors for renal insufficiency, patients undergoing RN are at a greater risk of chronic renal insufficiency than a similar cohort of patients undergoing PN.

Resection of metastatic renal cell carcinoma.

PURPOSE Resection of solitary metastases from renal cell carcinoma (RCC) is associated with a 5-year survival rate of 35% to 50%. Selection criteria are not well defined. PATIENTS AND METHODS We retrospectively analyzed our experience with 278 patients with recurrent RCC from 1980 to 1993. RESULTS One hundred forty-one of 278 patients underwent a curative metastectomy for their first recurrence (44% 5-year overall survival [OS] rate), 70 patients underwent noncurative surgery (14% 5-year OS rate), and 67 patients were treated nonsurgically (11% 5-year OS rate). Favorable features for survival were a disease-free interval (DFI) greater than 12 months versus 12 months or less (55% v 9% 5-year OS rate; P < .0001), solitary versus multiple sites of metastases (54% v 29% 5-year OS rate; P < .001), and age younger than 60 years (49% v 35% 5-year OS rate; P < .05). Among 94 patients with a solitary metastasis, lung (n = 50; 54% 5-year OS rate) was more favorable than brain (n = 11; 18% 5-year OS rate; P < .05). Survival rates after curative resection of second and third metastases were not different compared with initial metastectomy (46% and 44%, respectively, v 43% 5-year OS rates; P = nonsignificant). Favorable predictors of survival by multivariate analysis included a single site of first recurrence, curative resection of first metastasis, a long DFI, a solitary site of first metastasis, and a metachronous presentation with recurrence. CONCLUSION Selected patients with recurrent RCC who can undergo a curative resection of their disease have a good opportunity for long-term survival, particularly those with a single site of recurrence and/or a long DFI.

Treatment Outcome and Survival Associated With Metastatic Renal Cell Carcinoma of Non–Clear-Cell Histology

PURPOSE To define outcome data for patients with metastatic renal cell carcinoma (RCC) with histology other than clear-cell type, including collecting duct (or medullary carcinoma), papillary, chromophobe, and unclassified histologies. PATIENTS AND METHODS Sixty-four patients with metastatic non-clear-cell RCC histology were the subjects of this retrospective review. Included in the analysis were 22 (8%) of 286 patients from a clinical trials database, 19 of 1,166 patients from a surgery database, and 23 of 357 patients from a pathology database. RESULTS The prevalent histology was collecting duct, present in 26 (41%) patients. The number of patients with chromophobe and papillary histologies was 12 (19%) and 18 (28%), respectively. Eight (12%) of the patients had tumors that could not be classified for specific tumor histology. Among the 43 patients treated with 86 systemic therapies, including 37 cytokine therapies, two patients (5%) were observed to have a partial response. The median overall survival time was 9.4 months (95% confidence interval, 8 to 14 months). The survival was longer for patients with chromophobe tumors compared with collecting duct or papillary histology, and this group included four patients with survival of greater than 3 years. CONCLUSION RCC consists of a heterogeneous group of tumors including clear-cell, papillary, chromophobe, collecting duct, and unclassified cell types. Non-clear-cell histologies constitute less than 10% of patients in general populations of patients with advanced RCC treated on clinical trials. Metastatic non-clear-cell RCC is characterized by a resistance to systemic therapy and poor survival, with the survival for patients with chromophobe tumors longer than that for patients with metastatic collecting duct or papillary RCC. Treatment with novel agents on clinical trials is warranted.