Improved prognostication of renal cell carcinoma using an integrated staging system.

PURPOSE: To integrate stage, grade, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) into a clinically useful tool capable of stratifying the survival of renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: The medical records of 661 patients undergoing nephrectomy at University of California Los Angeles between 1989 and 1999 were evaluated. Median age was 61 years, male-to-female ratio was 2.2:1, and median follow-up was 37 months. Survival time was the primary end point assessed. Sixty-four possible combinations of stage, grade, and ECOG PS were analyzed and collapsed into distinct groups. The internal validity of the categorized was challenged by a univariate analysis and a multivariate analysis testing for the accountability of each UCLA Integrated Staging System (UISS) category against independent variables shown to have impact on survival. RESULTS: Combining and stratifying 1997 tumor-node-metastasis stage, Fuhrman's grade and ECOG PS resulted in five survival stratification groups designated UISS, and numbered I to V. The projected 2- and 5-year survival for the UISS groups are as follows for the groups: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; and V, 9% and 0%, respectively. UISS accounted for the significant variables in the variate analysis. CONCLUSION: A novel system for staging and predicting survival for RCC integrating clinical variables is offered. UISS is simple to use and is superior to stage alone in differentiating patients' survival. Our data suggests that UISS is an important prognostic tool for counseling patients with various stages of kidney cancer. Further prospective large-scale validation with external data is awaited.

Blood loss and the need for transfusion in patients who undergo partial or radical nephrectomy for renal cell carcinoma.

PURPOSE: We assessed blood loss and subsequent transfusion associated with nephrectomy performed for suspected renal cell carcinoma to establish guidelines for preoperative autologous blood donation and identify a subgroup of patients that may benefit from erythropoietin administration. MATERIALS AND METHODS: We retrospectively reviewed the charts of 211 patients who underwent partial (73%) or radical (23%) nephrectomy for presumed renal cell carcinoma at our institution between 1990 and 1999. Patients were divided into groups 1-44.5% treated with radical nephrectomy for localized disease, 2-21.3% radical nephrectomy for metastatic lesions invading the renal vasculature or inferior vena cava, 3-8% radical nephrectomy for metastatic disease with locally extensive lesions and 4-26.5% partial nephrectomy for localized lesions. Patient charts were evaluated for preoperative and postoperative hematocrit, estimated blood loss, transfusions received, surgical complications and underlying disease. RESULTS: Median estimated blood loss was 200, 400, 250 and 555 cc in groups 1 to 4, respectively. However, patients in groups 2 and 3 had a substantially greater range of blood loss than those in groups 1 and 4, respectively. The incidence of those with a blood loss of greater than 1 l. was 7%, 36%, 24% and 11% in groups 1, to 4, respectively. The incidence of those requiring transfusion was significantly lower in group 1 than in groups 2 to 4 (18% versus 44%, 24% and 30%, respectively, p <0.009). Mean transfusion requirement plus or minus standard deviation was significantly greater in groups 2 and 3 than in 1 and 4 (2.3 +/- 1.08, 5.5 +/- 4.4, 11.3 +/- 9.6 and 2.3 +/- 1.7 units, respectively, p <0.05). No significant difference was noted in the change in hematocrit as a result of surgery in the 4 groups (p >0.05). Similarly underlying disease and operative complications did not have a significant effect on blood loss or transfusion (p >0. 05). CONCLUSIONS: Radical or partial nephrectomy for localized renal cell carcinoma leads to consistent and well tolerated operative blood loss that rarely results in the need for substantial transfusion. In contrast, nephrectomy for advanced disease may cause a risk of greater blood loss and subsequent need for the transfusion of multiple units of blood. While preoperative autologous blood donation may have limited value in this regard due to the high cost and number of units needed, preoperative erythropoietin administration may be a viable option. Prospective randomized studies are currently planned.

Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria.

PURPOSE: We determine independent prognostic indicators for renal cell carcinoma using the revised 1997 TNM staging criteria. MATERIALS AND METHODS: The records of 643 consecutive patients undergoing partial or radical nephrectomy at our institution between 1987 and 1998 were reviewed. Preoperative evaluation of functional status using the Eastern Cooperative Oncology Group (ECOG) criteria was performed in all cases. Renal cell carcinoma grade and stage were evaluated using the 1997 American Joint Committee on Cancer grading and TNM staging criteria, respectively. Patients were followed for a mean plus or minus standard deviation of 47+/-40 months (median 87). Kaplan-Meier survival curves were used to determine 5-year cancer specific survival for all patient groups. Univariate analysis using log rank sum tests was performed to evaluate the prognostic significance of overall TNM stage, tumor stage, disease grade and ECOG status. Multivariate analysis was performed to determine which factors had an independent impact on survival of patients with renal cell carcinoma. RESULTS: The 5-year cancer specific survival rate was 91%, 74%, 67% and 32% for TNM stages I, II, III and IV lesions, respectively (p<0.001). Analysis demonstrated a survival rate of 83% for stage T1, 57% for stage T2, 42% for stage T3 and 28% for stage T4 disease (p<0.001), and 89% for grade 1, 65% for grade 2, and 46% for grades 3 and 4 (p<0.001). Multivariate analysis revealed that overall TNM stage and grade of disease were the most important prognostic indicators for renal cell carcinoma (p<0.001). ECOG classification was a less significant predictor (p = 0.031) and tumor stage was not shown to have any independent impact on patient survival (p = 0.138). CONCLUSIONS: Better survival rates of patients with localized and advanced renal cell carcinoma can be demonstrated with recent advances in diagnosis and treatment. The revised 1997 TNM criteria manifest an appropriate adjustment in staging renal cell carcinoma based on these improvements, with overall stage correlating with cancer specific survival. In contrast, while effectively predicting survival, tumor stage did not demonstrate an independent impact on renal cell carcinoma prognosis under multivariate analysis. Instead, other factors, such as ECOG status and more importantly grade of disease, appeared to affect survival significantly as independent elements. Based on our recent experience with patients treated for renal cell carcinoma in the era of enhanced technology and improved survival, tumor grade and molecular markers may serve as useful adjuncts to TNM staging in guiding treatment and predicting survival outcomes.

Expanding the indications for surgery and adjuvant interleukin-2-based immunotherapy in patients with advanced renal cell carcinoma.

PURPOSE: To determine the role of surgery and adjuvant interleukin (IL)-2-based immunotherapy in the treatment of patients with advanced metastatic renal cell carcinoma PATIENTS AND METHODS: The survival of 354 consecutive patients with metastatic renal cell carcinoma treated with IL-2-based immunotherapy through the UCLA Medical Center Kidney Cancer Program was analyzed There were five groups of patients. Patients who initially presented with metastatic disease received either (1) IL-2 therapy with primary tumor in place; (2) nephrectomy followed by IL-2 therapy, or (3) nephrectomy followed by immunotherapy with IL-2 plus tumor-infiltrating lymphocytes. Patients who underwent nephrectomy for localized disease were divided into two groups: (4) those who developed metastatic disease > or = 6 months after nephrectomy and then received IL-2 therapy; and (5) those who developed metastatic disease < 6 months after nephrectomy and then received IL-2 therapy. Kaplan-Meier survival curves were generated for all patient groups. RESULTS: Among patients who received IL-2-based immunotherapy with their primary tumor in place (group 1; n = 36), 1- and 2-year survival rates were 29% and 4%, respectively, compared with 1- and 2-year survival rates of 67% and 44%, respectively, for all similar patients who underwent nephrectomy prior to IL-2 therapy (n = 235). Among patients initially presenting with metastatic disease who underwent nephrectomy followed by IL-2 therapy without tumor-infiltrating lymphocytes (group 2; n = 69), the 1- and 2-year survival rates were 53% and 25%, respectively. The best survival was observed in patients treated with nephrectomy followed by IL-2 plus tumor-infiltrating lymphocyte therapy (group 3; n = 102), which yielded 1- and 2-year survival rates of 73% and 55%, respectively. Among patients initially undergoing nephrectomy for localized disease, patients receiving IL-2-based therapy for subsequent metastasis > or = 6 months following nephrectomy (group 4; n = 128) had 1- and 2-year survival rates of 64% and 40%, respectively, compared with 45% and 15%, respectively, for patients developing metastasis < 6 months after nephrectomy (group 5; n = 19). CONCLUSION: The role of surgery prior to IL-2-based immunotherapy remains controversial Our data demonstrate that aggressive surgery is safe, causing minimal morbidity despite extensive tumor involvement, and significantly improves survival outcomes in patients with metastatic renal cell carcinoma when carried out in conjunction with an IL2-based immunotherapy regimen.

Renal cell carcinoma: prognostic significance of incidentally detected tumors.

PURPOSE: We determined the prognostic significance of incidentally discovered renal cell carcinoma in the era of increased incidental detection. MATERIALS AND METHODS: We reviewed the records of 633 consecutive patients who underwent radical or partial nephrectomy for renal cell carcinoma at our institution between 1987 and 1998. Patients were divided into those who were asymptomatic and tumor was diagnosed incidentally and those diagnosed after presenting with any of the classic symptoms of renal cell carcinoma or subsequent metastasis. All renal cell carcinoma lesions were assigned a stage and grade according to 1997 TNM criteria. All patients were followed postoperatively to assess survival rates, and monitor recurrence and metastasis. RESULTS: Of the 633 patients 95 (15%) were treated for incidentally discovered renal cell carcinoma and 538 (85%) presented with symptoms secondary to renal cell carcinoma at diagnosis. Patient age and sex distribution were similar in the 2 groups. Stage I lesions were observed in 62.1% of patients with incidental renal cell carcinoma and in 23% with symptomatic renal cell carcinoma. In contrast, stage IV lesions were present in 27.4% of patients with incidental versus 54% with symptomatic renal cell carcinoma. Thus, incidental lesions were of significantly lower stage than those causing symptoms (p <0.001). Similarly 15.8% of incidental but 42.4% of symptomatic lesions were grade 3 or 4 (p = 0.006). Patients were followed postoperatively for a mean of 47 months plus or minus 40 months. The 5-year cancer specific survival rate was significantly higher for incidental than for symptomatic tumors (85.3% versus 62.5%). Likewise, the local and distal recurrence rates were higher for symptomatic lesions. When adjusted for stage, no difference in survival was noted in the 2 groups for stages I to III disease and a minimally significant difference was noted for stage IV cancer. Multivariate analysis of stage and grade attributed the survival difference in stage IV disease to the significantly higher grade of symptomatic lesions. CONCLUSIONS: At presentation incidental tumors are of significantly lower stage and grade than tumors producing symptoms. Subsequently these clinically and histologically less aggressive lesions lead to better patient survival and decreased recurrence. Thus, the detection of renal cell carcinoma before symptom onset enables treatment of less aggressive tumors and provides a better prognosis for patients. Given these data efforts should be directed toward the development of a screening protocol to detect these lesions early, so that they may be prevented from progressing to the point when symptoms are apparent and prognosis becomes worse. In addition, the significant correlation of tumor grade with survival in our study further demonstrates the prognostic value of tumor grade and molecular markers for the future evaluation and treatment of renal cell carcinoma.

Is adrenalectomy a necessary component of radical nephrectomy? UCLA experience with 511 radical nephrectomies.

PURPOSE: We determine the incidence and characteristics of adrenal involvement in localized and advanced renal cell carcinoma, and evaluate the role of adrenalectomy as part of radical nephrectomy. MATERIALS AND METHODS: The records of 511 patients undergoing radical nephrectomy with ipsilateral adrenalectomy for renal cell carcinoma at our medical center between 1986 and 1998 were reviewed. Mean patient age was 63.2 years (range 38 to 85), and 78% of the subjects were males and 22% were females. Patients were divided into subgroups of 164 with localized (stage T1-2 tumor, group 1) and 347 with advanced (stage T3-4N01M01, group 2) renal cell carcinoma. Staging of tumors was performed according to the 1997 TNM guidelines. A retrospective review of preoperative computerized tomography (CT) of the abdomen was performed. Radiographic findings were subsequently compared to postoperative histopathological findings to assess the predictive value of tumor characteristics and imaging in determining adrenal metastasis. RESULTS: Of the 511 patients 29 (5.7%) had adrenal involvement. Average size of the adrenal tumor was 3.86 cm. (standard deviation 1.89). Tumor stage correlated with probability of adrenal spread, with T4, T3 and T1-2 tumors accounting for 40%, 7.8% and 0.6% of cases, respectively. Upper pole intrarenal renal cell carcinoma most likely to spread was local extension to the adrenal glands, representing 58.6% of adrenal involvement. In contrast, multifocal, lower pole and mid region renal cell carcinoma tumors metastasized hematogenously, representing 32%, 7% and 4% of adrenal metastasis, respectively. The relationship between intrarenal tumor size (mean 8.9 cm., range 3 to 17) and adrenal involvement (independent of stage) was not statistically significant. Renal vein thrombus involvement was demonstrated in 8 of 12 cases (67%) with left and 2 of 9 (22%) with right adrenal involvement. Preoperative CT demonstrated 99.6% specificity, 99.4% negative predictive value, 89.6% sensitivity and 92.8% positive predictive value for adrenal involvement by renal cell carcinoma. CONCLUSIONS: With a low incidence of 0.6%, adrenal involvement is not likely in patients with localized, early stage renal cell carcinoma and adrenalectomy is unnecessary, particularly when CT is negative. In contrast, the 8.1% incidence of adrenal involvement with advanced renal cell carcinoma supports the need for adrenalectomy. Careful review of preoperative imaging is required to determine the need for adrenalectomy in patients at increased risk with high stage lesions, renal vein thrombus and upper pole or multifocal intrarenal tumors. With a negative predictive value of 99.4%, negative CT should decrease the need for adrenalectomy. In contrast, positive findings are less reliable given the relatively lower positive predictive value of this imaging modality. Although such positive findings may raise suspicion of adrenal involvement, they may not necessarily indicate adrenalectomy given the low incidence, unless renal cell carcinoma with risk factors, such as high stage, upper pole location, multifocality and renal vein thrombus, is present.

Current Status of Partial Nephrectomy in the Management of Kidney Cancer.

BACKGROUND: The technique of partial nephrectomy for managing renal cancers is well recognized, but guidelines regarding indications for its use are not generally accepted. METHODS: The authors review the indications for partial nephrectomy in various clinical situations, and they include their own experience to clarify the utility of the technique. RESULTS: Intraoperative renal ultrasound and helical computed tomography can assist the surgeon in technical decisions. Partial nephrectomy is considered when nephrectomy would render the patient anephric and dependent on dialysis. CONCLUSIONS: The technical and operative advances in partial nephrectomy make the approach increasingly attractive for patients with kidney cancer in a variety of clinical circumstances.

Nephron-sparing surgery for renal cell carcinoma.

Nephron-sparing surgery has become an established surgical treatment for patients with renal cell carcinoma (RCC), particularly in situations in which preservation of renal parenchyma is critical. However, due to the fear of local renal fossa recurrence with nephron-sparing surgery, radical nephrectomy has historically been the treatment of choice for patients with unilateral RCC and a normal contralateral kidney. Recently, increased incidence of low-stage, localized, solitary RCC has led to renewed interest in partial nephrectomy. With excellent disease-specific survival and recurrence rates comparable to that achieved with radical nephrectomy, nephron-sparing surgery can be confidently utilized in treating patients with stage T1 RCC lesions (<7 cm) and a normal contralateral kidney. The utility of nephron-sparing surgery in the context of adjunctive systemic immunotherapy remains to be explored.

Benefits of early surgical repair in fixed subaortic stenosis.

OBJECTIVES: We sought to determine whether early resection can improve outcome in fixed subaortic stenosis. BACKGROUND: The diagnosis of subaortic stenosis (SAS) is often made before significant gradients occur. Whereas resection is the accepted treatment, it remains uncertain whether surgical intervention at this early stage can reduce the incidence of recurrence or influence the progression of aortic valve damage. METHODS: Follow-up was available for 75 of 83 consecutive patients operated on for fixed SAS; the average duration of follow-up was 6.7 years. The lesion was discrete in 68 patients (91%) and of a tunnel type in 7, with associated ventricular septal defect in 28 (37%). All underwent transaortic resection. RESULTS: There were no deaths. There were 18 recurrences of SAS in 15 patients (20%). Thirteen patients (17%) underwent 17 reoperations for recurrence or aortic valve disease. The cumulative hazard of recurrence was 8.9%, 16.1% and 29.4% +/- 2.3% (mean +/- SEM), and the hazard of events, including recurrence and reoperation, was 9.2%, 18.4% and 35.1% +/- 3.5% at 2, 5 and 10 years, respectively. Residual end-operative left ventricular outflow tract (LVOT) gradients (> 10 mm Hg, n = 8) and tunnel lesions were univariate predictors of recurrence (p = 0.0006 and p = 0.003, respectively). Multivariate predictors included higher preoperative LVOT gradient (p < 10(-4)) and younger patient age (p = 0.002). Only two recurrences (0.87 per 100 patient-years of follow-up) were noted in patients with a preoperative peak LVOT gradient < or = 40 mm Hg (n = 40), whereas higher gradients (n = 35) were associated with a greater than sevenfold recurrence rate (6.45 events per 100 patient-years, p = 0.002). The aortic valve required concomitant repair in 17 cases in the high gradient group (48.6%) but in only 8 in the low gradient group (20%, p = 0.018). Despite relief of the obstruction, progressive aortic regurgitation was noted at follow-up after 14 procedures in the high gradient group (40%) but after only 5 procedures in the low gradient group (12.5%, p = 0.014). CONCLUSIONS: The data suggest that surgical resection of fixed subaortic stenosis before the development of a significant (> 40 mm Hg) outflow tract gradient may prevent recurrence, reoperation and secondary progressive aortic valve disease.

Controlled periadventitial administration of verapamil inhibits neointimal smooth muscle cell proliferation and ameliorates vasomotor abnormalities in experimental vein bypass grafts.

OBJECTIVE: Inhibition of early myointimal proliferation may improve longterm patency of vein grafts, but the clinical use of many experimental drugs is limited by systemic toxicity. To determine whether this goal can be achieved by low-dose targeted drug administration, we constructed a polymeric system delivering verapamil and evaluated the effects on local and downstream vein graft morphology, neointimal smooth muscle cell proliferation, and vasomotor function. METHODS: Ethylene-vinyl acetate polymeric delivery systems were constructed, containing 2% verapamil by weight. These are flexible, biocompatible, and nonbiodegradable matrices, delivering the drug at a rate of 10 micrograms/day. The autologous external jugular vein was used to create a carotid artery bypass graft in hypercholesterolemic (n = 22) rabbits. Verapamil-containing matrices (n = 12) or plain polymers (control, n = 10) were wrapped around the proximal third of the veins after reperfusion. Graft vasomotor function was evaluated and was also compared with function of an additional group of normocholesterolemic vein grafts (n = 8). RESULTS: Twenty-eight days after grafting, intimal index (intima/media thickness ratio) was 31% lower, neointima/original lumen surface ratio was 26% lower, and residual luminal area was 71% greater (4.00 +/- 1.2 mm2 versus 2.34 +/- 0.9 mm2, all p < 0.01) under verapamil matrices compared with control grafts. Neointimal smooth muscle cell content was reduced from 45.4% to 28.2%, and net neointimal smooth muscle cell thickness was reduced by 47% (30 microns vs 15.8 microns, both p < 0.01). Verapamil-treated segments distal to the matrices also showed significantly lower neointimal smooth muscle cell density and increased lumen size. Sensitivity to serotoin and vasomotor responses to serotonin, norepinephrine, and sodium nitroprusside in distal segments were significantly lower in verapamil-treated grafts than in controls. CONCLUSIONS: Periadventitial controlled administration of verapamil below 1% of the systemic dose effectively inhibits myointimal hyperplasia in vein grafts. Local polymeric drug delivery may be readily applicable to coronary revascularization operations.

Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts: method and efficacy of adenovirus-mediated transduction.

OBJECTIVE: Allograft-targeted immunosuppressive gene therapy may inhibit recipient immune activation and provide an alternative to systemic immunosuppression. We studied the optimal technique and efficacy of intracoronary gene transfer of viral interleukin-10 and human transforming growth factor-beta 1 in a rabbit model of heterotopic heart transplantation. METHODS: Replication-defective adenoviral vectors were constructed, expressing viral interleukin-10 (AdSvIL10) or transforming growth factor-beta 1 (AdCMVTGF-beta 1). Intracoronary delivery of vectors was accomplished ex vivo by either bolus injection or slow infusion. The allografts were implanted heterotopically in recipient rabbits and collected 4 days after the operation. Vector dose was 4 x 10(9) to 6 x 10(10) pfu/gm of donor heart. Transfer was confirmed by DNA amplification for both genes. Gene product expression in tissue was quantified by immunoassay and visualized by immunohistochemical staining. RESULTS: Allograft viral uptake was only 9.9% +/- 2.4% with bolus injection, but increased to 80.5% +/- 6.8% at 1 ml/min infusion rate (p = 5 x 10(-14)). Uptake ratio was not affected by vector quantity or slower infusion rates. Transforming growth factor-beta 1 was consistently detected in allografts infected with AdCMVTGF-beta 1, but not with control adenovirus or AdSvIL10. Expression was proportional to infused vector quantity and reached 10 ng/gm of allograft at infused 10(10) pfu/gm. Transforming growth factor-beta 1 was also detected in recipient's serum at less than 1 ng/ml. Viral interleukin-10 was detected in minor amounts only (< 1 ng/gm) in allografts infected with AdvIL10 up to 5 x 10(10) pfu/gm. Nevertheless, it was detected in recipient serum at concentrations up to 0.4 ng/ml. CONCLUSIONS: Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts during cold preservation is feasible. Slow infusion is superior to bolus injection. In vivo effects on allograft rejection remain to be determined.