Arie S. Belldegrun

THE CHANGING NATURAL HISTORY OF RENAL CELL CARCINOMA

PURPOSE Our understanding of the natural history of renal cell carcinoma, the role of nephrectomy, the benefits of immunotherapy and the possibilities of new technologies are evolving and being integrated with advances in classification and staging. We reviewed the relevant literature to clarify these pertinent questions and provide a current review of the changes in the epidemiology, treatment and prognosis of patients with renal cell carcinoma. MATERIALS AND METHODS We comprehensively reviewed the peer reviewed literature on the current management of and results of treatment for renal cell carcinoma. RESULTS The incidence of and mortality from renal cell carcinoma have continuously increased during the last 50 years. Despite this increase in the number of new patients and consequently the number of deaths yearly the percent of those surviving for 5 years has notably improved. Factors related to improved survival include advances in renal imaging, earlier diagnosis, improved staging, better understanding of prognostic indicators, refinement in surgical technique and the introduction of immunotherapy approaches for advanced disease. CONCLUSIONS Currently patients with localized and metastatic renal cell carcinoma have had improvements in outlook and the therapeutic options available have expanded.

Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease

Surveillance after surgery for RCC is important because approximately 50% of these patients will develop a disease recurrence, two thirds of who will recur within the first year. Although the prognosis is generally poor in these patients, some may respond favorably to immunotherapy. The small subset of patients who develop solitary metastases has the greatest chance to achieve long-term survival. Aggressive surgical resection is an integral part of this success. Proposed surveillance protocols using a stage-based approach or an integrated approach combining stage with other important prognostic factors attempt to provide a rational approach to identifying treatable recurrences while minimizing unnecessary examinations and patient anxiety. However, strict adherence to follow-up guidelines may not be appropriate for all patients. Factors including patient comorbidities and patient willingness to pursue aggressive management in the event of recurrence may alter the follow-up for each individual.

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.

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.

Phase II Study of Pomegranate Juice for Men with Rising Prostate-Specific Antigen following Surgery or Radiation for Prostate Cancer

Purpose: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy. Experimental Design: A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA >0.2 and <5 ng/mL and Gleason score ≤7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels. Results: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption. Conclusions: We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.

Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy.

The mammalian target of rapamycin (mTOR) pathway is up‐regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).

Efficacy of Nephron-Sparing Surgery for Renal Cell Carcinoma: Analysis Based on the New 1997 Tumor-Node-Metastasis Staging System

PURPOSE To analyze the experience with nephron-sparing surgery as a treatment modality for renal cell carcinoma (RCC). PATIENTS AND METHODS Between 1980 and 1997, 146 patients underwent partial nephrectomy at the University of California-Los Angeles Medical Center. A matched group of 125 patients who underwent radical nephrectomy at the same institution between 1986 and 1997 were selected for comparison. Patients were monitored for an average period of 57 months. Patients were staged according to both the 1997 and 1987 tumor-node-metastasis (TNM) staging criteria. Survival data were calculated in terms of both staging criteria. RESULTS When comparing cancer-specific survival rates for patients with T1 lesions under both the 1987 and 1997 TNM staging criteria, no statistically significant difference in survival was noted (P =.53), although most of the tumors in our series measured < or = 4 cm. Patients with T2 lesions (1997 TNM) demonstrated a significant decrease in survival (66%) when compared with patients with T1 lesions (100%; P <.001). No statistically significant difference in survival for patients with T1 RCC treated with either radical or partial nephrectomy was noted (P =.219). Survival rates of partial and radical nephrectomies for patients with unilateral T1 RCC and a normal contralateral kidney also were not significantly different (P =.53). In contrast, for patients with lesions greater than T1, survival rates were significantly higher with radical versus partial nephrectomy (P =.001). CONCLUSION Partial nephrectomy has become an effective method of treating T1 RCC lesions as categorized by both the 1987 and the revised 1997 TNM staging criteria. Selected patients with localized unilateral RCC lesions less than 7 cm (ideally, < 4 cm) and a normal contralateral kidney will benefit from partial nephrectomy.

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.

Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.

PURPOSE To evaluate ability of the University of California Los Angeles Integrated Staging System (UISS) to stratify patients with localized and metastatic renal cell carcinoma (RCC) into risk groups in an international multicenter study. PATIENTS AND METHODS 4,202 patients from eight international academic centers were classified according to the UISS, which combines TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status. Distribution of the UISS categories was assessed in the overall population and in each center. RESULTS The UISS stratified both localized and metastatic RCC into three different risk groups (P <.001). For localized RCC, the 5-year survival rates were 92%, 67%, and 44% for low-, intermediate-, and high-risk groups, respectively. A trend toward a higher risk of death was observed in all centers for increasing UISS risk category. For metastatic RCC, the 3-year survival rates were 37%, 23%, and 12% for low-, intermediate-, and high-risk groups, respectively; in 6 of 8 centers, a trend toward a higher risk of death was observed for increasing UISS risk category. A greater variability in survival rates among centers was observed for high-risk patients. CONCLUSION This study defines the general applicability of the UISS for predicting survival in patients with RCC. The UISS is an accurate predictor of survival for patients with localized RCC applicable to external databases. Although the UISS may be useful for patients with metastatic RCC, it may be less accurate in this subset of patients due to the heterogeneity of patients and treatments.

Using protein expressions to predict survival in clear cell renal carcinoma.

Purpose: An accurate system for predicting survival for patients with solid tumors will allow for better patient selection for both established and novel therapies. We propose a staging system for clear cell variants of renal cell carcinoma (RCC) that includes molecular predictors and standard clinical predictors such as tumor-node-metastasis (TNM) stage, histological grade, and performance status (PS). Experimental Design: A custom tissue array was constructed using clear cell RCC from 318 patients, representing all stages of localized and metastatic RCC, and immunohistochemically stained for molecular markers Ki67, p53, gelsolin, CA9, CA12, PTEN, EpCAM, and vimentin. We present a strategy for evaluating individual candidate markers for prognostic information and integrating informative markers into a multivariate prognostic system. Results: The overall median follow-up and the median follow-up for surviving patients were 28 and 55 months, respectively. A prognostic model based primarily on molecular markers included metastasis status, p53, CA9, gelsolin, and vimentin as predictors and had high discriminatory power: its statistically validated concordance index (C-index) was found to be 0.75. A prognostic model based on a combination of clinical and molecular predictors included metastasis status, T stage, Eastern Cooperative Oncology Group PS, p53, CA9, and vimentin as predictors and had a C-index of 0.79, which was significantly higher (P < 0.05) than that of prognostic models based on grade alone (C = 0.65), TNM stage alone (C = 0.73), or the University of California Los Angeles integrated staging system (C = 0.76). Conclusions: Protein expressions obtained using widely available technology can complement standard clinical predictors such as TNM stage, histological grade, and PS.