Debby H. Chao

Risk Group Assessment and Clinical Outcome Algorithm to Predict the Natural History of Patients With Surgically Resected Renal Cell Carcinoma

PURPOSE To create a comprehensive algorithm that can predict postoperative renal cell carcinoma (RCC) patient outcomes and response to therapy. PATIENTS AND METHODS A prospective cohort study was performed with outcome assessment on the basis of chart review of 814 patients who underwent nephrectomy between 1989 and 2000. At diagnosis, M1 or N1/N2M0 metastatic disease (M) was present in 346 patients (43%), whereas 468 patients had no metastatic disease (NM) (N0M0). On the basis of UCLA Integrated Staging System category and the presence of metastases, patients were divided into low-risk (LR), intermediate-risk (IR), and high-risk (HR) groups. Decision boxes integrating tumor-node-metastasis staging, tumor grade, and performance status were compiled for determining a patients risk group. RESULTS NM-LR patients had 91% disease-specific survival at 5 years, lower recurrence rate, and better disease-free survival compared with NM-IR and HR patients. Disease progressed in 50% of NM-HR patients. Disease-specific survival of NM-HR patients who received immunotherapy (IMT) for recurrent disease was similar to that of M-LR patients treated with cytoreductive nephrectomy and adjuvant IMT. Time from recurrence to death for NM-HR patients was inferior to that for M-LR patients. After IMT, approximately 25% of M-LR and 12% of M-IR patients had long-term progression-free survival. M-HR patients did poorly despite IMT. CONCLUSION Stratifying RCC patients into high-, intermediate-, and low-risk subgroups provides a clinically useful system for predicting outcome and provides a unique tool for risk assignment and outcome analysis. Subclassifying RCC into well-defined risk groups should allow better patient counseling and identification of both NM-HR subgroups that need adjuvant treatment and nonresponders who need alternative therapies.

REEVALUATION OF THE 1997 TNM CLASSIFICATION FOR RENAL CELL CARCINOMA: T1 AND T2 CUTOFF POINT AT 4.5 RATHER THAN 7 CM. BETTER CORRELATES WITH CLINICAL OUTCOME

PURPOSE We analyzed the effects of the change in TNM classification from the 1987 to the 1997 version and suggest a modified tumor size cutoff point between T stages 1 and 2 for renal cell carcinoma. MATERIALS AND METHODS We evaluated a database containing the records of 661 patients who underwent nephrectomy between 1989 and 1999. The effect of the change in TNM classification on the distribution of patients between stages, the rates of M+ and N+ disease, and the local and distant recurrence rates were outlined for 280 patients with T stages 1 and 2 disease. The Cox model was used to identify the optimal cutoff point between T1 and T2 disease, and the resulting effect of adopting this cutoff was outlined. RESULTS A total of 174 and 128 cases were down staged from 1987 version stage T2 to 1997 version stage T1 and from 1987 TNM stage II to 1997 TNM stage I, respectively. Survival was not significantly different in patients with 1997 TNM stages I and II disease due to a lack of survival difference during the first 2 years of followup. Stage shift also caused an increase in average tumor size, the proportion of patients with high grade cancer, and M+ and N+ disease at diagnosis in 1997 stages T1 and T2 as well as an increase in the proportion of 1997 stage T2N0M0 cases at diagnosis with systemic failure. Analysis of 11 potential cutoff points between 1 and 10 cm. revealed that 4.5 cm. was most predictive of patients survival (hazards ratio 4.99, p = 0.0001). Using this cutoff resulted in improved discriminatory power of the TNM classification and a moderating effect on the distribution of patients, average tumor size, high grade disease, M+ and N+ disease at diagnosis, and systemic failure between T(14.5) and T(24.5) compared with 1997 T1 and T2. CONCLUSIONS Our data imply that the current cutoff point of 7 cm. between stages T1 and T2 tumors is too high. Lowering the cutoff to 4.5 cm. resulted in better discriminatory power of the TNM classification in our dataset. This observation should be further validated by external data.

COLLECTING DUCT RENAL CELL CARCINOMA: CLINICAL STUDY OF A RARE TUMOR

PURPOSE Collecting duct carcinoma is a rare type of renal cell carcinoma that affects younger patients, and is associated with aggressive regional and distant spread. The clinical and pathological features of 6 patients with collecting duct carcinoma treated at a single institution are described. MATERIALS AND METHODS There were 6 patients with collecting duct carcinoma included in the University of California School of Medicine, Los Angeles, Kidney Cancer Database. Demographic, clinical, pathological and survival data were gathered. RESULTS Average patient age plus or minus standard deviation was 56 +/- 11 years, and 5 of 6 had TNM stage IV disease. The average survival of these patients was 11.5 months (range 7 to 17). There was 1 patient who had TNM stage I disease and survived without evidence of disease at 5 years. Transient response to chemotherapy was seen in 1 patient. CONCLUSIONS Collecting duct carcinoma is associated with poor prognosis. For the majority of patients surgical treatment will not result in a cure. Previously recommended chemotherapy and/or immunotherapy appears to have a limited role in treatment of this disease, and early detection may be the best method for prolonging patient survival.

Mathematical Model to Predict Individual Survival for Patients With Renal Cell Carcinoma

PURPOSE To develop a multivariate model and mathematical formula capable of calculating personalized survival for renal cell carcinoma (RCC) patients with clinically available variables. PATIENTS AND METHODS A total of 477 patients out of 661 undergoing nephrectomy at the University of California Los Angeles between 1989 and 1999 were eligible for evaluation and formed the analyzed cohort for this retrospective study. Time to death was the primary end point assessed. Univariate analysis for 14 to 20 variables was conducted, followed by a multivariate Cox analysis. The variables that provided independent information as to the time of death for metastatic and nonmetastatic patients were coded and incorporated into a function based on the Nadas equation principle. RESULTS For nonmetastatic patients, the significant variables in the multivariate analysis were Fuhrmans grade and Eastern Cooperative Oncology Group performance status. For the metastatic patients, Fuhrmans grade, 1997 classification T stage, number of symptoms, nodal involvement, and immunotherapy were independent predictors for survival. These variables, based on the Cox multivariate regression model, were implanted into an exponential Nadas equation. The expected survival predicted by use of the Nadas equations faithfully describes the actual survival based on Kaplan-Meier curves. CONCLUSION We have developed mathematical equations for estimating survival after radical nephrectomy for RCC. The resulting formulas are capable of better tailoring survival estimates for a specific patient and are based on widely accepted clinical prognostic variables. On validation with external data, this type of representation can be used as a tool for the determination of personalized prognosis and may be useful for patient education and counseling.

A pilot trial of tumor lysate-loaded dendritic cells for the treatment of metastatic renal cell carcinoma.

Cultured tumor lysate-loaded dendritic cells (TuLy-DC) have been demonstrated in vitro to stimulate potent immune modulations and generate significant antitumor response. We report the results of a pilot trial of TuLy-DC vaccine for patients with metastatic renal cell carcinoma (mRCC). Fourteen mRCC patients underwent nephrectomy to obtain autologous TuLy prepared by subjecting tumor cells to 3 freeze/thaw cycles. Dendritic cells were generated from peripheral blood CD14+ precursors cultured in the presence of GM-CSF, IL-4, and 10% autologous serum. Patients received one vaccination of TuLy alone as an immunologic control, followed by 3 weekly vaccinations of DC-TuLy injected intradermally in the midaxillary region. Peripheral blood lymphocytes were collected before and after weekly vaccines and were assessed for changes in phenotype, cytotoxicity, and cytokine profile. The TuLy-DC vaccine was successfully prepared and administered to 12 patients, whereas 2 patients did not receive vaccine treatment due to declines in postoperative performance status. The vaccines were well tolerated, with only grade 1 toxicities noted. One patient had a partial response to treatment that did not correspond to any significant change in immunologic profile. This pilot trial demonstrated both the safety and feasibility of reliably preparing a DC-based vaccine for mRCC patients. Our data suggest that autologous TuLy-DC vaccines generate only limited clinical response. Further clinical studies are needed to identify the most potent treatment regimen that can consistently mediate an antitumor immune response in vivo.

Unclassified Renal Cell Carcinoma: Clinical Features and Prognostic Impact of a New Histological Subtype

PURPOSE We characterized the histopathological features and clinical behavior of unclassified renal cell carcinoma and compared the prognostic outcome in patients with unclassified and conventional (clear cell) renal cell carcinoma. MATERIALS AND METHODS A total of 31 patients with unclassified renal cell carcinoma are included in the kidney cancer database at our institution. Another 317 matched patients with clear cell carcinoma were used for comparing demographic, clinical, pathological and survival data. RESULTS The incidence of unclassified renal cell carcinoma was 2.9%. At initial diagnosis 29 patients (94%) with unclassified and 264 (83%) with clear cell renal cell carcinoma had metastatic disease (p = 0.143). Compared with the clear cell variety unclassified disease was associated with larger tumors (p = 0.005), increased risk of adrenal gland involvement (25% of cases, p = 0.0001), direct invasion to adjacent organs (42%, p = 0.00001), bone (52%, p = 0.022), regional (52%, p = 0.0042) and nonregional lymph node (41%, p = 0.03) metastases. Nephrectomy was less likely to be attempted or completed in unclassified renal cell carcinoma cases (61%, p = 0.00007). Unclassified histology was a significant indicator for poor prognosis on multivariate analysis (p <0.0001). Median survival in patients with unclassified renal cell carcinoma was 4.3 months. Nephrectomy alone did not confer any survival advantage in these cases (p = 0.1086), while immunotherapy did (p = 0.008). The combination of nephrectomy and immunotherapy yielded improved survival over immunotherapy alone (p = 0.0356) but patients with unclassified renal cell carcinoma were significantly less likely than those with clear cell disease to be eligible for immunotherapy regimens (p = 0.05). CONCLUSIONS Unclassified renal cell carcinoma is associated with distinct and highly aggressive biological behavior, and poor clinical outcome. Whenever feasible, immunotherapy with nephrectomy is warranted.

Renal Cell Carcinoma With Tumor Thrombus: Is Cytoreductive Nephrectomy For Advanced Disease Associated With An Increased Complication Rate?

PURPOSE We examined whether cytoreductive nephrectomy in patients with venous tumor thrombus and metastatic disease is associated with more complications than in those with thrombus without metastatic disease. MATERIALS AND METHODS Between 1989 and 2000, 74 patients with renal vein extension, 87 with inferior vena caval extension and 491 without tumor thrombus underwent nephrectomy at our institution. Metastatic and nonmetastatic renal vein extension in 51 and 23 cases, inferior vena caval extension in 54 and 33, and nontumor thrombus in 171 and 320, respectively, were compared for symptoms at presentation, surgical data, mortality and complications. RESULTS For nonmetastatic and metastatic inferior vena caval extension presenting symptoms, hospital stay, surgical time and the number of patients undergoing thoraco-abdominal incision, lymph node dissection, venacavotomy alone for thrombus and adrenal sparing surgery were similar. Five patients with thrombus died intraoperatively or postoperatively, including 3.1% with and 0.8% without thrombus (p = 0.03), while 3 had metastatic (2.3%) and 2 (2.6%) had nonmetastatic disease. The rate of postoperative complications was higher in thrombus cases overall but there was no difference in nonmetastatic and metastatic disease with thrombus. On multivariate analysis inferior vena caval thrombus (odds ratio 10.5), adjacent organ resection due to locally advanced tumor (odds ratio 6), partial nephrectomy (odds ratio 3.8), regional lymph node involvement (odds ratio 1.7) and lower preoperative hemoglobin (odds ratio 1.6) were independent variables predicting bleeding requiring transfusion. Inferior vena caval thrombus (odds ratio 1.7) and adjacent organ resection (odds ratio 2) were also associated with nonhemorrhagic complications. Systemic metastasis was not an independent risk factor in either analysis. CONCLUSIONS To our knowledge there are no published data comparing surgical complications in patients with metastatic and nonmetastatic renal cell carcinoma who have gross tumor thrombus. Cytoreductive surgery in patients with thrombus and metastasis is not associated with an increase in the extent of surgery, morbidity or mortality compared with their counterparts with nonmetastatic disease.

Sarcomatoid renal cell carcinoma

Abstract All histological subtypes of renal cell carcinoma (RCC) are capable of undergoing sarcomatous transformations that result in tumors with distinctive appearances and aggressive biologic behavior. The history of sarcomatoid renal cell carcinoma (SRCC) is traced from the time when it was thought to be a true sarcoma to the present when its epithelial origin is fully appreciated. The distinctive macroscopic and microscopic features as well as various diagnostic methods are reviewed. A description of the complex genetic aberrations associated with various types of RCC are summarized. It is apparent that the chromosomal changes known at this time are common to both SRCC and classic RCC while the unique alterations that lead to the sarcomatoid transformation remain unknown. The mode of presentation, the clinical behavior, and the prognostic factors common to SRCC are also reviewed. Finally, the various modalities that have been examined for the treatment of SRCC are detailed to evaluate for patient response and overall improvement in survival. A comparison of the treatment methods suggest that high-dose recombinant interleukin-2 may hold the greatest promise in improving the dismal prognosis associated with this disease.