Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer provide multidisciplinary recommendations for the clinical management of patients with prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Abiraterone acetate is a first-in-class hormonal agent that represents a new standard of care for patients with metastatic castration-recurrent prostate cancer who have previously received docetaxel (category 1 recommendation). Abiraterone acetate also received category 2B recommendations in the prechemotherapy setting for asymptomatic patients or symptomatic patients who are not candidates for docetaxel. The NCCN Prostate Cancer Panel also added new indications for existing agents, including the option of sipuleucel-T as second-line therapy. In addition, brachytherapy in combination with external beam radiation therapy with or without androgen deprivation therapy is now an alternative for patients with high-risk localized tumors or locally advanced disease.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Outcome of hand assisted laparoscopic bilateral native nephrectomy in transplant recipients.

PURPOSE: We explored the safety and reproducibility of hand assisted laparoscopic bilateral native nephrectomy. We also present our improvements to the surgical technique. MATERIALS AND METHODS: We retrospectively reviewed the charts of 36 patients who underwent hand assisted laparoscopic bilateral nephrectomy at our institution between 2003 and 2010. In all cases the 2 kidneys were removed transperitoneally via a hand assisted laparoscopic technique. RESULTS: Mean operative time was 222 minutes. Pathological kidney size was 20 to 34 cm. Mean hospital stay was 3 days (range 1 to 13). Average estimated blood loss was 175 cc (range 50 to 200). No patient required intraoperative blood transfusion. There were no intraoperative complications and no conversions to open surgery. Postoperatively complications developed in 8 patients (22%), including temporary adrenal insufficiency and pulmonary embolism in 1 each, and myocardial infarction, superficial wound infection and loss of arteriovenous fistula function in 2 each. According to the Clavien-Dindo classification complications were grades 1, 2, 3 and 4a in 2, 3, 1 and 2 patients, respectively. A total of 18 patients with kidney transplants continued to have normal graft function after surgery. CONCLUSIONS: Simultaneous hand assisted bilateral nephrectomies are safe and reproducible. The complication rate is low and postoperative hospital stay is short compared to those in published open surgery series. Graft function was preserved in patients who underwent renal transplantation before native kidney removal.

Association between lymph node density and disease specific survival in patients with penile cancer.

PURPOSE: We assessed the value of lymph node density for predicting disease specific survival after lymphadenectomy for penile cancer. MATERIALS AND METHODS: Data were collected retrospectively in 75 and prospectively in 88 consecutive patients with squamous cell carcinoma of the penis treated at M. D. Anderson Cancer Center between 1979 and 2007. We identified 45 patients with penile cancer and nodal metastasis who underwent lymphadenectomy with curative intent. Lymph node density was analyzed as a categorical variable by grouping patients into 2 or 3 categories based on equal percents. We explored the prognostic value of lymph node density for predicting disease specific survival in this cohort. RESULTS: Median followup was 23.7 months in all patients. By the time of analysis 22 patients had died, including 18 (82%) of penile cancer and 4 (18%) of other causes. Median lymph node density in patients alive or dead of other causes was 3.4% (IQR 2.9-5.9) compared to 43.3% (IQR 15.6-80) in those dead of disease (p <0.001). Median lymph node density in all patients was 6.7%. Estimated 5-year disease specific survival in patients with lymph node density 6.7% or less was significantly better than that in patients with lymph node density greater than 6.7% (91.2%, 95% CI 53.9-98.8 vs 23.3%, 95% CI 7.0-45.1, p <0.001). In models comparing lymph node density to known prognostic features lymph node density remained statistically significant, while the other factors were no longer statistically associated with disease specific survival. CONCLUSIONS: Lymph node density proved to be a significantly better prognosticator of disease specific survival than the current TNM nodal staging system in patients with penile cancer and nodal involvement. Further independent validation is required to determine the clinical usefulness of lymph node density in this patient population.

Salvage therapy for prostate cancer recurrence after radiation therapy.

Radiotherapy has been successful in treating localized prostate cancer; however, a subset of patients will experience disease recurrence. Determination of the recurrence location must be made using pretreatment and posttreatment clinical variables, imaging, and postradiotherapy biopsy. Patients presumed to have local-only recurrence, optimal clinical risk factors, and an extended life expectancy may be considered for salvage local treatment. Current options include salvage surgery, cryoablation, and brachytherapy. Although they are associated with higher morbidity than primary therapy, salvage treatments can be effective and can still provide patients with a good oncologic and functional outcome. As these modalities continue to improve and patient selection is optimized, better results will evolve.

Ureteroscopic treatment of renal calculi.

Although ureteroscopic treatment of renal calculi is safe and effective. it is relatively inefficient compared with ESWL and PCNL. It should be considered primary therapy for patients with lower pole stones who have adverse ESWL characteristics and patients who are not suitable candidates for PCNL. There are also numerous clinical situations, as outlined previously, where the ureteroscopic approach is favored over other treatment modalities.

Can urinary PCA3 supplement PSA in the early detection of prostate cancer?

PURPOSE: Given the limited sensitivity and specificity of prostate-specific antigen (PSA), its widespread use as a screening tool has raised concerns for the overdiagnosis of low-risk and the underdiagnosis of high-grade prostate cancer. To improve early-detection biopsy decisions, the National Cancer Institute conducted a prospective validation trial to assess the diagnostic performance of the prostate cancer antigen 3 (PCA3) urinary assay for the detection of prostate cancer among men screened with PSA. PATIENTS AND METHODS: In all, 859 men (mean age, 62 years) from 11 centers scheduled for a diagnostic prostate biopsy between December 2009 and June 2011 were enrolled. The primary outcomes were to assess whether PCA3 could improve the positive predictive value (PPV) for an initial biopsy (at a score > 60) and the negative predictive value (NPV) for a repeat biopsy (at a score < 20). RESULTS: For the detection of any cancer, PPV was 80% (95% CI, 72% to 86%) in the initial biopsy group, and NPV was 88% (95% CI, 81% to 93%) in the repeat biopsy group. The addition of PCA3 to individual risk estimation models (which included age, race/ethnicity, prior biopsy, PSA, and digital rectal examination) improved the stratification of cancer and of high-grade cancer. CONCLUSION: These data independently support the role of PCA3 in reducing the burden of prostate biopsies among men undergoing a repeat prostate biopsy. For biopsy-naive patients, a high PCA3 score (> 60) significantly increases the probability that an initial prostate biopsy will identify cancer.

Multi-institutional analysis of robotic radical cystectomy for bladder cancer: perioperative outcomes and complications in 227 patients.

PURPOSE: Recently, some surgeons have begun to describe single-institution case series with less invasive surgical approaches to bladder cancer such as laparoscopic or robotic-assisted techniques. We report on a multi-institutional, multi-surgeon experience with robotic radical cystectomy with regard to operative and pathologic outcomes and complications to evaluate the feasibility and reproducibility of this technique in a large cohort of patients. SUBJECTS AND METHODS: Two hundred twenty-seven patients (178 males and 49 females) underwent a robotic cystectomy and urinary diversion at one of four institutions. Operative outcomes, pathological results, and complications of this combined case series are herein reported. RESULTS: Mean age of this cohort was 67.1 years (range, 33-86 years) with a mean American Society of Anesthesiologists score of 2.7 (range, 2-4). One hundred sixty-eight patients (74%) underwent ileal conduit diversion, 58 (26%) underwent orthotopic ileal neobladder, and 1 patient (<1%) had no diversion (end-stage renal disease). The urinary diversion was performed extracorporeally in 97% cases, with 7 patients (3%) undergoing an intracorporeal diversion. Mean operating room time of all patients was 5.5 hours, and mean surgical blood loss was 256 mL. On surgical pathology, 120 (53%) patients had pT2 or less disease, 35 (15%) had pT3/T4 disease, and 46 (20%) had N+ disease. The mean number of lymph nodes removed was 18 (range, 3-52). There was a positive surgical margin in 5 cases--all with pT3-4 disease. Mean time to discharge was 5.5 days (median, 5 days), with 70% of patients discharged on postoperative day 5 or sooner. Sixty-eight patients (30%) experienced complications, with 7% having Clavien grade 3 or higher. On multivariate analysis, decreased age and increased American Society of Anesthesiologists score were predictors of higher Clavien complication score, with younger patients more likely to undergo neoadjuvant chemotherapy prior to surgery. CONCLUSION: A multi-institutional experience with robotic radical cystectomy appears to demonstrate acceptable operative and pathologic outcomes, thus helping to validate the previously reported single-institution case series. Ultimately, oncologic follow-up of these patients will remain as the most important measure of therapeutic success.

A phase 2 cancer chemoprevention biomarker trial of isoflavone G-2535 (genistein) in presurgical bladder cancer patients.

The soy compound genistein has been observed preclinically to inhibit bladder cancer growth with one potential mechanism being the inhibition of epidermal growth factor receptor phosphorylation (p-EGFR). A phase 2 randomized, placebo-controlled trial investigated whether daily, oral genistein (300 or 600 mg/d as the purified soy extract G-2535) for 14 to 21 days before surgery alters molecular pathways in bladder epithelial tissue in 59 subjects diagnosed with urothelial bladder cancer (median age, 71 years). G-2535 treatment was well tolerated; observed toxicities were primarily mild to moderate gastrointestinal or metabolic and usually not attributed to study drug. Genistein was detected in plasma and urine of subjects receiving G-2535 at concentrations greater than placebo subjects' but were not dose-dependent. Reduction in bladder cancer tissue p-EGFR staining between the placebo arm and the combined genistein arms was significant at the protocol-specified significance level of 0.10 (P = 0.07). This difference was most prominent when comparing the 300-mg group with placebo (P = 0.015), but there was no significant reduction in p-EGFR staining between the 600-mg group and placebo. No difference in normal bladder epithelium p-EGFR staining was observed between treatment groups. No significant differences in tumor tissue staining between treatment groups were observed for COX-2, Ki-67, activated caspase-3, Akt, p-Akt, mitogen-activated protein kinase (MAPK), or p-MAPK. No significant differences in urinary survivin or BLCA-4 levels between treatment groups were observed. Genistein displayed a possible bimodal effect (more effective at the lower dose) on bladder cancer tissue EGFR phosphorylation that should be evaluated further, possibly in combination with other agents.

Aberrant activation of androgen receptor in a new neuropeptide-autocrine model of androgen-insensitive prostate cancer.

Treatment of advanced prostate cancer with androgen deprivation therapy inevitably renders the tumors castration-resistant and incurable. Under these conditions, neuroendocrine differentiation of prostate cancer (CaP) cells is often detected and neuropeptides released by these cells may facilitate the development of androgen independence. Exemplified by gastrin-releasing peptide (GRP), these neuropeptides transmit their signals through G protein-coupled receptors, which are often overexpressed in prostate cancer, and aberrantly activate androgen receptor (AR) in the absence of androgen. We developed an autocrine neuropeptide model by overexpressing GRP in LNCaP cells and the resultant cell line, LNCaP-GRP, exhibited androgen-independent growth with enhanced motility in vitro. When orthotopically implanted in castrated nude mice, LNCaP-GRP produced aggressive tumors, which express GRP, prostate-specific antigen, and nuclear-localized AR. Chromatin immunoprecipitation studies of LNCaP-GRP clones suggest that GRP activates and recruits AR to the cognate promoter in the absence of androgen. A Src family kinase (SFK) inhibitor, AZD0530, inhibits androgen-independent growth and migration of the GRP-expressing cell lines, and blocks the nuclear translocation of AR, indicating the involvement of SFK in the aberrant activation of AR and demonstrating the potential use of SFK inhibitor in the treatment of castration-resistant CaP. In vivo studies have shown that AZD0530 profoundly inhibits tumor metastasis in severe combined immunodeficient mice implanted with GRP-autocrine LNCaP cells. This xenograft model shows autocrine, neuropeptide- and Src kinase-mediated progression of androgen-independent CaP postcastration, and is potentially useful for testing novel therapeutic agents.

Comparing lymphadenectomy during radical nephroureterectomy: open versus laparoscopic.

OBJECTIVES: Laparoscopic nephroureterectomy (LNU) is an accepted treatment for tumors of the ureter and renal pelvis, although the ability to perform a regional lymphadenectomy has been criticized. We compared the quality of lymphadenectomy with LNU with that involving open nephroureterectomy (ONU) to determine whether oncologic principles are maintained. METHODS: We searched our institutional database for patients who had undergone ONU from 1990 to 2005. These were compared with a series of patients from January 2003 to April 2007 who underwent LNU. From each patient's medical records, we assessed the number of lymph nodes removed, the number of positive nodes removed, and the density of positive nodes. The differences between groups were analyzed using the Wilcoxon rank sum statistical test. RESULTS: We identified 106 patients who underwent ONU with lymphadenectomy and 28 who underwent LNU with lymphadenectomy. The median number of nodes removed, median number of positive nodes, and median density of positive nodes were, respectively, 3, 0, and 0 for the ONU group; and 6, 0, and 0, for the LNU group. There was a statistically significant difference between groups with respect to the number of nodes removed (P = 0.01) but not with respect to the number of positive nodes removed (P = 0.61) or the lymph node density (P = 0.42). CONCLUSIONS: Offsetting the benefits of laparoscopy could be a flawed oncologic technique. We have demonstrated that lymphadenectomy, which is a potentially important component of nephroureterectomy, can be performed as well during LNU as it is with ONU when a dedicated effort is made.

Laparoscopic radical nephroureterectomy for transitional cell carcinoma: where are we in 2007?

PURPOSE OF REVIEW: Nephroureterectomy has undergone critical changes during the past 15 years with the advent of the laparoscopic approach. New data supporting laparoscopic nephroureterectomy (LNU) continue to emerge as new techniques are developed and current approaches refined. The purpose of this study was to investigate the findings within LNU from the past 2 years as an evolving although proven modality for treatment of upper-tract transitional cell carcinoma (TCC). RECENT FINDINGS: Intermediate outcomes continue to be published equating the oncologic efficacy and perioperative parameters (i.e. blood loss and pain medication requirements) of LNU to those of open nephroureterectomy, allaying previous arguments against the minimally invasive approach. Newer approaches to the nephrectomy segment of LNU have been described, including robot assistance in retroperitoneoscopic cases and hand-assisted laparoscopic nephrectomy without the use of a hand-port. Data supporting specific approaches to the distal ureter have been published, including implementing robotics and flexible cystoscopy. SUMMARY: Findings over the past 2 years show both the continued progress of LNU and the need for further evolution to optimize patient morbidity and oncologic outcomes. As laparoscopic training is integrated into urologic residency programs, standardizing the variables within LNU will be paramount.

Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma.

PURPOSE: Combination chemotherapy for advanced penile cancer can produce partial response rates of up to 64%. Complete responses are rare, suggesting a need for adjunct therapies to facilitate cure. We evaluated patients with metastases who underwent surgical consolidation after responding to chemotherapy. MATERIALS AND METHODS: We reviewed the records of 59 patients with advanced penile carcinoma treated from 1985 to 2000 and identified 10 treated with surgical consolidation after demonstrating a stable, partial or complete response to chemotherapy. Presenting tumor burden included pelvic and inguinal metastases. Surgical outcomes and survival were assessed. RESULTS: After chemotherapy 4 patients had a complete response, 1 had a partial response and 5 had stable disease. Three major perioperative complications, including postoperative bleeding, an episode of acute renal failure and deep venous thrombosis in 1 patient each, and 4 minor complications, including skin breakdowns in 3 and wound seroma in 1, occurred. Three cases were rendered pN0. All 3 patients received ifosfamide, paclitaxel and cisplatin chemotherapy. Seven patients had 3 or fewer metastatic lymph nodes following surgery, of whom 4 showed no disease and 3 died. All 3 patients with greater than 3 metastatic lymph nodes died. For all patients the 5-year actuarial survival rate was 40% with a median survival of 26 months. Patients with 3 or fewer and greater than 3 positive nodes had a median survival of 48 and 23 months, respectively (p = 0.116). CONCLUSIONS: Select patients with metastatic penile cancer that shows disease stabilization or a response to chemotherapy should be considered for surgical consolidation to extend survival.

Ability of clinical grade to predict final pathologic stage in upper urinary tract transitional cell carcinoma: implications for therapy.

OBJECTIVES: To evaluate whether the clinical grade predicts the final pathologic stage in upper urinary tract transitional cell carcinoma. METHODS: We retrospectively reviewed the records of 184 consecutive patients undergoing nephroureterectomy for upper urinary tract transitional cell carcinoma at our institution from 1986 to 2004. Their clinical, surgical, and pathologic data were reviewed to determine the positive and negative predictive values of the clinical biopsy grade with respect to the final pathologic disease stage. RESULTS: Of the 184 patients, 119 (64.7%) had information available regarding the clinical grade of disease from the preoperative endoscopic biopsy. The distribution was grade 1 in 2 (1.6%), grade 2 in 46 (38.7%), and grade 3 in 71 (59.7%) patients. Of the 71 patients with grade 3 disease, 47 had Stage pT2 disease or higher (66% positive predictive value). Of the 48 patients with less than grade 3 disease, 35 had less than pT2 disease (72% negative predictive value). Of the 71 patients with grade 3 disease, 30 had pT3 disease or greater (42% positive predictive value), and of the 48 patients with less than grade 3 disease, 44 had less than pT3 disease (92% negative predictive value). CONCLUSIONS: The histologic grade obtained from the diagnostic biopsy for upper urinary tract transitional cell carcinoma can be used to predict the pathologic disease stage. This information can be used to counsel patients before surgery and to identify patients for whom neoadjuvant chemotherapy would be most beneficial.

Chemoprevention for bladder cancer.

PURPOSE: Bladder cancer is the most expensive cancer to treat and follow in the United States due to often extended courses of treatment coupled with the necessity for frequent surveillance examinations. Because direct exposure to carcinogens is implicated in bladder cancer development and many potentially protective compounds are concentrated in urine, bladder cancer is a logical target for chemoprevention. MATERIALS AND METHODS: We performed a MEDLINE search of the English language literature to identify reports of chemoprevention of bladder cancer. Study outcomes were evaluated and mechanisms of action were identified when possible. In cases of multiple reports of the same compound critical comparisons were performed. RESULTS: For most putative chemopreventive agents against bladder cancer the results of different studies are conflicting. Megadose vitamins, certain vitamin A analogues and pyridoxines have been associated with promising findings. For vitamins C and E and selenium, studies showing benefit are balanced by studies showing no benefit. Other compounds, such as soy, green tea and isothiocyanates, have been suggested by some studies to be protective and by others to be tumor promoting. CONCLUSIONS: For most bladder cancer chemopreventive agents studied to date results regarding efficacy vary, precluding the possibility of universal support by health care providers for this specific role. Megadose multivitamin supplements have demonstrated the ability to prevent bladder cancer recurrences in a single smaller study. Some analogues of vitamins A, B6, C and E have been shown to be beneficial in other disease processes, suggesting that these compounds may be advocated with the caveat that they do not have a specific protective role in bladder cancer. Data from randomized, prospective trials show a benefit in bladder cancer only after eliminating early or initial recurrences, suggesting the need for long-term administration of a chosen agent. Additional prospective trials with long-term followup, likely involving multiple institutions, are required before definitive recommendations can be made about chemoprevention for bladder cancer. In 2006 no oral agent can be recommended and to our knowledge the best chemopreventive strategy remains to be determined.

Histological changes in prostate biopsies after salvage cryotherapy: effect of chronology and the method of biopsy.

OBJECTIVES: To examine changes in prostate biopsies at different intervals after salvage cryotherapy and the effect of biopsy type (transrectal ultrasonography-guided vs transurethral resection, TUR), as the sequence and extent of histological changes occurring in the prostate after salvage cryotherapy for local failure of prostate cancer treatment are unknown. PATIENTS AND METHODS: In all, 158 prostate biopsies from 150 patients were examined histologically after salvage cryotherapy for prostate cancer after radiotherapy had failed. Specimens were grouped by time from cryotherapy and biopsy technique. RESULTS: Biopsies showed hyalinization, necrosis, inflammation and residual cancer. Hyalinization became predominant over time, most notably in biopsies with no residual cancer. Core biopsies showed more hyalinization and regenerating glands, while TUR biopsies showed more necrosis and inflammation. CONCLUSIONS: Tissue cryo-injury and reactive changes last for >1 year; more extensive cryo-injury suggests more effective cancer ablation. A long-term follow-up is necessary, as prostate cancer might remain indolent for >1 year.

Upper urinary tract tumors with nontransitional histology: a single-center experience.

OBJECTIVES: To review our experience with patients with upper urinary tract tumors of nonurothelial origin. Upper urinary tract tumors of nonurothelial origin are uncommon entities. To our knowledge, no series of patients with these neoplasms has been published in the past decade. METHODS: We reviewed the records at the University of Texas M. D. Anderson Cancer Center from 1990 to 2004 to identify patients with primary nonurothelial tumors of the upper urinary tract. We reviewed the patient records to collect data on tumor subtype, treatment, recurrence, and survival. RESULTS: Sixteen patients (1.9% of our database of patients with upper urinary tract tumors) were identified; 12 had squamous cell carcinoma, 2 had adenocarcinoma, 1 had sarcomatoid carcinoma, and 1 had small cell carcinoma. The tumors were located in the renal pelvis in 10 and the ureter in 6. Of the 16 patients, 15 had been treated with nephrectomy or nephrouterectomy and 1 with chemotherapy and radiotherapy. Fifteen of the tumors were pathologic Stage T3 or worse. Ten patients received adjuvant chemotherapy. Of the 16 patients, 9 died (1 of unknown causes), 4 were alive without disease, 2 were alive with disease, and 1 was alive at last follow-up with the disease status unknown. The median follow-up was 30.1 months, the median overall survival time was 11.3 months, and 1-year survival rate was 46%. The median recurrence-free survival time and 1-year recurrence-free survival rate were 5.8 months and 38%, respectively. CONCLUSIONS: Primary nonurothelial carcinomas of the renal pelvis and ureter are rare. Our analysis suggests a poor prognosis for most patients with these pathologic types, probably resulting from the advanced stage at diagnosis and poor responses to systemic therapy.

Therapy of multidrug resistant human prostate tumors in the prostate of nude mice by simultaneous targeting of the epidermal growth factor receptor and vascular endothelial growth factor receptor on tumor-associated endothelial cells.

BACKGROUND: Inhibiting epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) activation with AEE788 can decrease prostate cancer (CaP) growth/progression. We determined whether tumor cells or tumor-associated endothelial cells were the primary target by treating multidrug-resistant (MDR) CaP growing in the prostate of nude mice. METHODS: MDR human CaP cells with 30-fold increased taxane-resistance were implanted into nude mouse prostates. After 2 weeks, mice were randomized to control, paclitaxel, AEE788, and AEE788/paclitaxel for 10 weeks. Mice were necropsied and tumors stained. RESULTS: AEE788 or AEE788 plus paclitaxel significantly reduced tumor incidence and tumor weight, and eradicated lymph node metastasis. Inhibiting VEGF-R and EGF-R phosphorylation induced apoptosis of tumor-associated endothelial cells causing a second apoptotic wave of surrounding tumor cells. CONCLUSION: Inhibiting VEGF-R and EGF-R activation on tumor-associated endothelial cells with AEE788 combined with paclitaxel can bypass CaP cell resistance and prevent lymph node metastasis.

Nephroureterectomy for treating upper urinary tract transitional cell carcinoma: Time to change the treatment paradigm?

OBJECTIVE: To evaluate factors associated with disease recurrence and survival in patients undergoing nephroureterectomy for upper urinary tract transitional cell carcinoma (UUT-TCC) in one centre over an 18-year period. PATIENTS AND METHODS: The records of patients who had a nephroureterectomy for UUT-TCC at our institution from 1986 to 2004 were reviewed for clinical, pathological and treatment period data. Cox's proportional hazards regression model was used to test the statistical significance of several potential prognostic factors for recurrence and survival. RESULTS The median overall duration of follow-up was 2.5 years for 184 patients. Significant prognosticators for disease-specific survival (DSS) by univariate analysis were tumour stage (P < 0.01), tumour grade (P < 0.01), node-positive disease (P < 0.01), multifocality (P = 0.03), previous cystectomy (P < 0.01) and synchronous bilateral UUT-TCC (P = 0.02). On multivariate analysis, only tumour stage (P = 0.03) and grade (P = 0.01) correlated with DSS. The median recurrence-free survival duration was 2.4 years. In 44 patients, the disease recurred outside the bladder; 15 (8.2%) had local recurrence, 20 (10.9%) distant metastasis, and nine (4.9%) both local and distant recurrence. Bladder tumours occurred in 40 (26.1%) patients with no previous cystectomy. The evaluation of treatment outcome during three periods of the study showed no significant effect on DSS. CONCLUSION: Tumour stage and grade correlated with DSS in this cohort, with no improvement in outcome over the 18-year period assessed. Patients with high-stage and high-grade disease continue to fare poorly, suggesting a need for changing the treatment protocol. Judiciously applying a multimodal approach to the management of high-risk patients by incorporating neoadjuvant chemotherapy and surgical resection might provide, for the first time, the opportunity to improve patient outcome.