Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.

Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674.

A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer.

BACKGROUND: The primary objective of this study was to compare the effects of pomegranate juice on PSA doubling times (PSADT) in subjects with rising PSA levels after primary therapy for prostate cancer. METHODS: Double-blind, placebo-controlled multi-institutional study, evaluated the effects of pomegranate liquid extract on serum PSA levels. The primary end point of this study was change in serum PSADT. Additional secondary and exploratory objectives were to evaluate the safety of pomegranate juice and to determine the interaction of manganese superoxide dismutase (MnSOD) AA genotype and pomegranate treatment on PSADT. RESULTS: One-hundred eighty-three eligible subjects were randomly assigned to the active and placebo groups with a ratio of 2:1 (extract N=102; placebo N=64; juice N=17). The majority of adverse events were of moderate or mild grade. Median PSADT increased from 11.1 months at baseline to 15.6 months in the placebo group (P<0.001) compared with an increase from 12.9 months at baseline to 14.5 months in the extract group (P=0.13) and an increase from 12.7 at baseline to 20.3 in the juice group (P=0.004). However, none of these changes were statistically significant between the three groups (P>0.05). Placebo AA patients experienced a 1.8 month change in median PSADT from 10.9 months at baseline to 12.7 months (P=0.22), while extract patients experienced a 12 month change in median PSADT from 13.6 at baseline to 25.6 months (P=0.03). CONCLUSIONS: Compared with placebo, pomegranate extract did not significantly prolong PSADT in prostate cancer patients with rising PSA after primary therapy. A significant prolongation in PSADT was observed in both the treatment and placebo arms. Men with the MnSOD AA genotype may represent a group that is more sensitive to the antiproliferative effects of pomegranate on PSADT; however, this finding requires prospective hypothesis testing and validation.

Pomegranate Extracts in the Management of Men's Urologic Health: Scientific Rationale and Preclinical and Clinical Data.

Multiple strands of research provide growing evidence that diet, nutrition, and life style play a role in the development and the course of urological diseases. Numerous micronutrients and polyphenols found in soy, green tea, and many fruits and vegetables have been described to impact diseases including erectile dysfunction, benign prostatic hyperplasia, and prostate cancer. However, oftentimes these reports lack both a scientific rationale and supportive evidence base. The efficacy of pomegranate, on the other hand, in the modulation of central biological processes like inflammation, hypoxia, and oxidative stress that are important in the pathogenesis of urological maladies has been robustly demonstrated in preclinical in vitro and in vivo studies. Moreover, clinical trials have further supported its use in the treatment of several diseases, in particular in the management of prostate cancer. Herein, we critically review the scientific knowledge about the current role and future prospects for the use of pomegranate extracts in the therapy of erectile dysfunction, benign prostatic hyperplasia, and prostate cancer.

[How radical nephrectomy compares to partial nephrectomy for the treatment of pT1a papillary renal cell carcinomas?]. / Comment se comparent néphrectomies partielles et élargies pour le traitement des carcinomes papillaires pT1aN0M0? Etude comparative rétrospective de 277 cas.

PURPOSE: Our objective was to compare oncologic results of nephron sparing surgery (NSS) versus radical nephrectomy (RN) in T1aN0-x M0 papillary renal cell carcinoma (PRCC). PATIENTS AND METHODS: We retrospectively reviewed 277 patients treated for a pT1aN0M0 PRCC selected from an academic database from 12 centres. We compared the clinico-pathological features by using Chi-square and Student statistical analyses. Survivals analyses using Kaplan-Meier and Log-rank models were performed. RESULTS: The two groups were composed by 186 patients treated by NSS and 91 by RN. The TNM stage was fixed and the two groups were, in terms of age and Fuhrman grade, comparable. Median age at diagnosis was 59 years (27-85). Median tumor size was 2.7 cm (0.4-4). The average follow-up was 49 months (1-246). Very few events arose in both groups: two local recurrences were observed in the NSS group (1.07%), three patients died of cancer in the NSS treated group (1.6%) and five in the RN treated group (5.5%). The five and 10 cancer-specific survival rate were comparable in the two groups (98% vs. 100% and 98% vs. 97%). The specific survival curves were perfectly similar for both groups (log rank test, p=0.25). CONCLUSION: NSS is equivalent to RN as far as oncologic control of pT1aN0M0 PRCC is concerned.

Combined cytoreductive laser therapy and immunotherapy for palliation of metastatic renal cell carcinoma to the head and neck.

Interleukin-2 (IL-2) remains the mainstay of treatment for metastatic renal cell carcinoma (RCC), but minimally invasive surgical techniques have provided new options for the combined treatment of RCC. Two patients with metastatic RCC to the head and neck treated by combined laser-induced thermal therapy and IL-2 were described in this case report. Both patients had an extended survival compared to the historical survival of 10 months for metastatic RCC but eventually succumbed to progressive disease. The authors' initial experience with metastatic RCC suggests that laser thermoablation and immunotherapy in selected patients with metastatic RCC is warranted as a palliative treatment, but a larger study with long-term follow-up is necessary to determine the effectiveness of this approach.

Prostate cryoablation using direct transperineal placement of ultrathin probes through a 17-gauge brachytherapy template-technique and preliminary results.

OBJECTIVES: To describe a new surgical approach to third-generation cryoablation of the prostate and present our preliminary results. METHODS: The technique is detailed and demonstrated in a Web-based video- clip tutorial. Ninety-two men underwent prostate cryoablation (71 primary ablations, 19 salvage procedures, and 2 repeated cryoablations), using direct transperineal placement of ultrathin probes through a 17-gauge brachytherapy template. RESULTS: No fistulous or major complications were observed. Eight patients (8.3%) had minor complications. In 36 patients, the follow-up period was long enough to permit nadir prostate-specific antigen (PSA) evaluation. In 31 (86%), the nadir PSA was 0.5 ng/mL or less. In 5 patients, the nadir PSA was greater than 0.5 ng/mL. The workup revealed systemic failure in 3 patients and inadequate eradication of the prostate gland in 2 patients. In 18 (86%) of 21 androgen-ablation-naive patients, the nadir PSA was 0.5 ng/mL or less. Nine (43%) had an undetectable nadir PSA and 3 had a nadir PSA of greater than 0.5 ng/mL. CONCLUSIONS: A modified, less-invasive approach to cryoablation of the prostate is presented. The preliminary results do not show an increased rate of complications compared with other published series. The clinical outcome data are preliminary. Longer follow-up data are required to draw conclusions concerning efficacy.

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.

Society of Urologic Oncology Biotechnology Forum: new approaches and targets for advanced prostate cancer.

PURPOSE: We provide an overview of advances in molecular based therapeutic strategies for prostate cancer and summarize the studies presented at the Society of Urologic Oncology Biotechnology Forum in 2000. MATERIALS AND METHODS: Three promising new treatment strategies are presented, and a critique of the advantages and limitations of each is offered by a leading expert in the field. RESULTS: Treatment results and the current state of dendritic cell based immunotherapy, monoclonal antibody therapy and anti-apoptotic treatment approaches are presented. CONCLUSIONS: Currently patients with advanced prostate carcinoma have expanded therapeutic options available in the form of molecular based phases II and III clinical trials.

Gene and immune therapy for renal cell carcinoma.

Conventional therapy for metastatic renal cell carcinoma is associated with a poor response rate and few patients are long-term survivors. The occurrence of spontaneous regression and the prolonged latency period between primary tumor removal and the appearance of metastases in some patients suggest the existence of important host immune responses to autologous tumor cells. With the advent of molecular gene transfer techniques and increased knowledge of the basic pathways of immune activation, the field of cancer immunotherapy has finally begun to develop novel and effective approaches for harnessing the immune system as a therapeutic agent. Current immunotherapy and gene therapy strategies, including methods of cytokine delivery and tumor-cell-based vaccines, are presented.

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.

Management of penile toilet seat injury--report of two cases.

Blunt trauma to the penis is an uncommon injury in young children. We present two cases of blunt penile trauma secondary to mechanical compression from a toilet seat.

Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology.

Twenty-four patients with locally advanced prostate cancer (CaP) were enrolled in a phase I clinical trial using gene-based immunotherapy. A functional DNA-lipid complex encoding the interleukin 2 (IL-2) gene (Leuvectin; Vical, San Diego, CA) was administered intraprostatically into the hypoecogenic tumor lesion, using transrectal ultrasound guidance. Two groups of patients having locally advanced tumors were enrolled to receive a treatment regimen composed of two serial intraprostatic injections of the IL-2 gene agent administered 1 week apart. The first groups of patients included radical prostatectomy candidates who subsequently underwent surgery after the completion of the treatment regimen. The second group consisted of patients who had failed a prior therapy. Prostate specimens of the treated areas were attained after treatment and compared with the transrectal biopsies performed at baseline to assess for any responses. IL-2 gene therapy was well tolerated, with no grade 3 or 4 toxic reactions occurring. The most commonly reported symptoms were mild hematuria, transient rectal bleeding, and perineal discomfort that are likely attributable to the injection itself. During the entire course of treatment, there were no significant changes in American Urologic Association (AUA) symptom scores, in hematologic disturbances, electrolyte imbalances, or hepatic functions. Evidence of systemic immune activation was observed after IL-2 gene therapy, based on an increase in the intensity of T cell infiltration seen on immunohistochemical analysis of tissue samples from the injected tumor sites, and based on increased proliferation rates of peripheral blood lymphocytes that were cocultured with patient serum collected after treatment. Furthermore, transient decreases in serum prostate-specific antigen (PSA) (responders) were seen in 16 of 24 patients (67%) on day 1. Fourteen of the patients persisted in this decrease to day 8 (58%). In eight patients the PSA level rose (nonresponders). More patients (9 to 10) in the group that failed prior therapy responded to the IL-2 gene injections (chi-square test, p = 0.04), and 6 of the 9 also had lower than baseline PSA levels at week 10 after treatment. To the best of our knowledge, this is the first clinical study of its kind aimed at exploring the role of IL-2-based gene therapy in CaP patients. This phase I trial demonstrated the safety of intraprostatic Leuvectin injection, with transient PSA-based responses seen after therapy.

Laparoscopic radical nephrectomy.

Most of the open renal procedures have been duplicated or approximated by laparoscopy. Past concerns about increased operative time, cost, resection completeness, and port site metastases are being overruled or put into perspective as experience with laparoscopic radical nephrectomy (LRN) is gained: necessary skills can be acquired, operative times are approaching those for open procedure, and a 14% difference in cost is counterbalanced by reduced postoperative expenditures. Moreover, LRN is acknowledged by its quality-of-life advantages-reduced morbidity and improved cosmetic outcome. Disease-free rate with LRN at last follow-up is 100% for TNM stage I and 89% +/- 6.6 for stage II (1997 classification). Complications are acceptable with an 8% to 35% incidence of minor complications and a 3% to 19% incidence of severe complications. Conversion to an open procedure occurs in 0% to 10% of cases. The procedure's limitations and the appropriate criteria for patient selection are evident. The learning process is believed to last for approximately 20 procedures and patient selection is based on both clinical criteria and one's insight on his location on the learning curve. Therefore, LRN is becoming the treatment of choice for most TNM stages I and II renal tumors. Moreover, recent data advocating pre-immunotherapy nephrectomy in metastatic patients may permit laparoscopic nephrectomy to further benefit selected metastatic patients by potentially shortening the time interval from nephrectomy to immunotherapy and improving immune responsiveness.

Biology of renal cell carcinoma: changing concepts in classification and staging.

Advances in our understanding of the pathogenesis, behavior, and importance of prognostic factors for renal cell carcinoma (RCC) have paved the way for increased sophistication in its classification and staging. In the past, lack of consistent classification and terminology for RCC histology and staging has complicated comparability of clinical studies looking at patient prognosis and response to treatment. In this review, the results of international consensus efforts to achieve uniform classification systems for RCC are outlined and some future directions are considered.

New biologicals for prostate cancer prevention: Genes, vaccines, and immune-based interventions.

For at least 100 years, immunologists have proposed activating the immune system to specifically target and eradicate autologous tumor cells. The idea that tumor cells can be recognized as foreign to the host's immune system is an essential concept of tumor immunology that was first postulated by Paul Ehrlich at the turn of the century. Anecdotal reports of spontaneous tumor regression have been presumed to be immunologically mediated. With the advent of molecular gene transfer techniques and increased knowledge of the regulation of the immune response, effective methods for harnessing the immune system as a therapeutic agent are finally being realized. Current results of clinical immune/gene therapy protocols will be reviewed with consideration towards the concept of cancer prevention.

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.

Immunotherapy of prostate cancer.

The realization that prostate cancer is an immunogenic tumor, in conjunction with the discovery of novel methods for priming the immune system to generate an antitumor response, has resulted in several new approaches for prostate cancer immunotherapy. Based on these various approaches, several human clinical trials have begun using immune-based therapies for prostate cancer. These approaches can be divided into cytokine-based therapies, tumor-associated antigen-based therapies, tumor vaccines, and dendritic cell-based therapies. This review summarizes the latest findings from each of these approaches and gives results from the few completed human clinical trials.

Dendritic cell-based immunotherapy of renal cell carcinoma.

Although mostly resistant to cytotoxic therapy, renal cell carcinoma has been a testing ground for immunotherapy. The approval of interleukin-2 for the treatment of renal cell carcinoma was a landmark "proof of principle" which showed that agents working solely via the immune system can cause durable cancer remission. Dendritic cells are central to immune-mediated surveillance and destruction of abnormal cells. They possess all the components required to educate immune effector cells that can then mediate tumor destruction. In vitro strategies to expand and load dendritic cells with antigens have now led to human vaccine trials in renal cell carcinoma and other malignancies.