Gary D. Steinberg

EFFICACY AND SAFETY OF VALRUBICIN FOR THE TREATMENT OF BACILLUS CALMETTE-GUERIN REFRACTORY CARCINOMA IN SITU OF THE BLADDER

Purpose: We assess the efficacy and safety of intravesical valrubicin for the treatment of carcinoma in situ in patients with failure or recurrence after bacillus Calmette-Guerin (BCG) and who othe...

Multicenter, Randomized, Phase III Trial of CD8+ Tumor-Infiltrating Lymphocytes in Combination With Recombinant Interleukin-2 in Metastatic Renal Cell Carcinoma

PURPOSE To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients. PATIENTS AND METHODS Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs. RESULTS Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board. CONCLUSION Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.

Phase III Study of Molecularly Targeted Adjuvant Therapy in Locally Advanced Urothelial Cancer of the Bladder Based on p53 Status

INTRODUCTION Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) adjuvant chemotherapy. PATIENTS AND METHODS Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10% nuclear reactivity on centrally performed immunohistochemistry for p53 were offered random assignment to three cycles of adjuvant MVAC versus observation; p53-negative patients were observed. By using a log-rank test with one-sided α = .05 and β = .10, 190 p53-positive patients were planned to be randomly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30. RESULTS A total of 521 patients were registered, 499 underwent p53 assessment, 272 (55%) were positive, and 114 (42%) were randomly assigned. Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis. Overall 5-year probability of recurring was 0.20 (95% CI, 0.16 to 0.24) with no difference on the basis of p53 status. Only 67% of patients randomly assigned to MVAC received all three cycles with 12 patients receiving no treatment. There was no difference in recurrence in the randomly assigned patients (hazard ratio, 0.78; 95% CI, 0.29 to 2.08; P = .62). CONCLUSION Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed, but the high patient refusal rate, lower than expected event rate, and failures to receive assigned therapy severely compromised study power.

Management of Stage D1 Adenocarcinoma of the Prostate: The Johns Hopkins Experience 1974 to 1987

There is no consensus on the proper management of men with stage D1 adenocarcinoma of the prostate. Although cure is unlikely, many men survive for long intervals apparently free of metastatic disease. Thus, effective palliation of the local lesion with low morbidity is desirable. From 1974 to 1987, 120 consecutive men with stage D1 prostate cancer were treated with 3 primary modes of therapy (mean followup 48 months): 1) expectant therapy (35), 2) external beam radiotherapy (21) and 3) radical prostatectomy (64). These patients were statistically homogeneous as determined by Gleason grade but not by extent of metastatic disease. The over-all 5 and 10-year projected actuarial survival rates for the radical prostatectomy patients were 97 and 62%, respectively, and the apparent clinical survival free of disease at 5 years and 80 months, respectively, was 83 and 68%. The direct disease-specific 10-year survival free of disease was 46%. However, only 3 of 27 patients followed for 3 years or longer had undetectable levels of prostate specific antigen. Using a Cox univariate proportional hazards model several factors appeared to have significant prognostic value including volume of lymph node metastases (macroscopic greater than 2 mm.), percentage of positive lymph nodes sampled and frozen section diagnosis. Gleason grade, clinical stage and the number of positive nodes did not have significant prognostic value. Local recurrence requiring an operation was noted in 8 of 35 patients (23%) treated expectantly, 5 of 21 (24%) treated with radiotherapy and 2 of 64 (3%) treated with radical prostatectomy. Significant gastrointestinal or genitourinary complications occurred in 33% of the men treated with radiotherapy and 1.5% of those undergoing radical prostatectomy. Since the introduction of nerve-sparing radical prostatectomy in 1982, potency resumed in 55% of the 33 patients who were potent preoperatively and have been followed 1 year or longer. These data suggest that in properly selected patients radical prostatectomy, although not curative, can provide excellent palliation of the local lesion with acceptable morbidity and that symptomatic local recurrence of prostatic cancer achieved with radiation therapy is identical to the results in men who were managed expectantly.

Immunohistochemical distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma.

Primary adenocarcinoma of the urinary bladder sometimes causes a diagnostic dilemma because it can be indistinguishable morphologically from adenocarcinoma of colorectal origin secondarily involving the bladder by metastasis or direct extension. It is much less well studied than conventional urothelial carcinoma and colorectal adenocarcinoma because of its rarity. The current study was specifically designed to investigate whether an important mechanism involved in the pathogenesis of colorectal adenocarcinoma, &bgr;-catenin dysregulation, was also important for the development of primary bladder adenocarcinoma and whether these two morphologically similar tumors could be distinguished immunohistochemically. Formalin-fixed, paraffin-embedded tissues from 17 primary adenocarcinomas of the urinary bladder, 16 colorectal adenocarcinomas involving the bladder, and 10 conventional urothelial (transitional) carcinomas were included in this study. Thirteen of the primary bladder adenocarcinomas were moderately to well differentiated (enteric type) and morphologically indistinguishable from colorectal cancers. The remaining four primary tumors were poorly differentiated (two cases) or of clear cell type (two cases). Immunohistochemical studies using a panel of monoclonal antibodies demonstrated positive nuclear staining for &bgr;-catenin expression in 13 of the 16 (81%) colorectal adenocarcinomas secondarily involving the bladder but in none of the primary adenocarcinomas or the urothelial carcinomas. Instead, positive membranous (and some cytoplasmic) staining was present in all primary bladder tumors with the exception of two poorly differentiated adenocarcinomas where no &bgr;-catenin staining was detected. All secondary colorectal adenocarcinomas stained negatively for CK7 and thrombomodulin (TM), whereas positivity for CK20 was observed in 15 (94%) cases. All urothelial carcinomas stained positively for CK7 and TM, and four of them also for CK20. Primary adenocarcinomas of the bladder showed mixed staining patterns for CK7, CK20, and TM with a positive rate of 65%, 53%, and 59%, respectively. These data indicate that dysregulation of &bgr;-catenin, an important aberration seen in colorectal carcinogenesis, does not appear to play a role in the pathogenesis of the bladder adenocarcinoma. In addition, our data demonstrate that a panel of immunostains, including CK7, CK20, TM, and &bgr;-catenin, is of diagnostic value in differentiating primary bladder adenocarcinoma from secondary adenocarcinoma of colorectal origin.

Robotic Radical Prostatectomy in Overweight and Obese Patients: Oncological and Validated-Functional Outcomes

OBJECTIVES To determine the impact of body mass index (BMI) on perioperative functional and oncological outcomes in patients undergoing robotic laparoscopic radical prostatectomy (RLRP) when stratified by BMI. METHODS Data were collected prospectively for 945 consecutive patients undergoing RLRP. Patients were evaluated with the UCLA-PCI-SF36v2 validated-quality-of-life questionnaire preoperatively and postoperatively to 24 months. Patients were stratified by BMI as normal weight (BMI < 25 kg/m(2)), overweight (BMI = 25 to < 30 kg/m(2)) and obese (BMI > or = 30 kg/m(2)) for outcomes analysis. RESULTS Preoperatively, obese men had a significantly greater percentage of medical comorbidities (P < .01) as well as a baseline erectile dysfunction (lower mean baseline Sexual Health Inventory for Men score [P = .01] and UCLA-PCI-SF36v2 sexual function domain scores [P = .01]). Mean operative time was significantly longer in obese patients when compared with normal and overweight men (234 minutes vs 217 minutes vs 214 minutes; P = .0003). Although overall complication rates were comparable between groups, a greater incidence of case abortion caused by pneumoperitoneal pressure with excessive airway pressures was noted in obese men. Urinary continence and potency outcomes were significantly lower for obese men at both 12 and 24 months (all P < .05). CONCLUSIONS In this series, obese men experienced a longer operative time, particularly during the initial robotic experience. As such, surgeons early in their RLRP learning curve should proceed cautiously with surgery in these technically more difficult patients or reserve such cases until the learning curve has been surmounted. These details, including inferior urinary and sexual outcomes, should be discussed with obese patients during preoperative counseling.

Alvimopan Accelerates Gastrointestinal Recovery After Radical Cystectomy: A Multicenter Randomized Placebo-Controlled Trial

BACKGROUND Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). OBJECTIVE To assess the efficacy of alvimopan to accelerate GI recovery after RC. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. INTERVENTION Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. RESULTS AND LIMITATIONS Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. CONCLUSIONS Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. PATIENT SUMMARY This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT00708201.

Local Recurrence and Survival Following Nerve-Sparing Radical Cystoprostatectomy

From March 1982 through July 1988, 76 men underwent nerve-sparing radical cystoprostatectomy for carcinoma of the bladder at our hospital. Of the 76 patients 2 (2.6%) had positive surgical margins (dome of the bladder and left ureter) and neither had positive margins at the site of nerve-sparing modifications. Of 3 patients (3.9%) who had local recurrence none had positive surgical margins. The 5-year actuarial local recurrence rate is 7.5%. Thirteen of 76 patients (17%) died of transitional cell carcinoma and 7 (9%) died of other causes, while 53 (70%) are alive without evidence of disease with a mean followup of 38.4 months. The 5-year actuarial survival rates are 64% over-all, 68% without disease and 78% disease-specific. Of the 42 evaluable men who underwent cystoprostatectomy alone 27 (64%) are potent, compared to 2 of the 12 men (17%) who also underwent urethrectomy. We conclude that the nerve-sparing modifications do not compromise cancer control, that local recurrence and survival rates are at least comparable to those achieved with standard radical cystoprostatectomy, and that it is possible to preserve potency in most men undergoing this procedure.

Prostatic duct adenocarcinoma. Findings at radical prostatectomy.

Previous studies of prostatic duct adenocarcinoma have reported a poor prognosis, but they included few patients treated by radical prostatectomy. The authors studied 15 cases treated with radical prostatectomy to define more completely their pathologic features and determine the clinical outcome in these surgically treated patients. The study included morphometry and DNA image analysis using the CAS‐200 system. The most common presentation was urinary outlet obstruction (n = 9), and most patients were clinical Stage B with palpable prostatic lesions (n = 12). Compared with acinar cancers of similar clinical stage, duct cancers were large (tumor volume, 8.4 ± 10.0 cc) and occupied a large portion of the gland (23 ± 21%). Duct cancers were in an advanced final pathologic stage with 93% having capsular penetration, 47% positive margins, 40% seminal vesicle invasion, and 27% positive pelvic lymph nodes. The DNA analysis on cells disaggregated from paraffin revealed that 54% of cases were diploid, 15% tetraploid, 8% aneuploid, and 23% tetraploid/aneuploid. On clinical follow‐up, eight patients had no evidence of tumor at intervals ranging from 1 to 28 months, and seven patients (47%) had persistent tumor at intervals of 3 to 18 months. This study demonstrates that duct cancers are in an advanced pathologic stage by the time of presentation and have a much higher short‐term failure rate after radical prostatectomy compared with acinar cancers.

Prognostic factors in men with stage D1 prostate cancer: identification of patients less likely to have prolonged survival after radical prostatectomy.

The role of radical prostatectomy in the management of stage D1 disease is controversial. Although cure is unlikely, some men survive for long intervals apparently free of metastatic disease. For this reason, effective palliation of the local lesion is desirable in men who will live long enough to benefit. In an effort to identify factors that correlated with interval to progression to distant metastases, we studied 113 men with stage D1 disease who underwent radical prostatectomy between 1974 and 1991. Progression of disease to distant metastases did not independently correlate with the size of the nodal metastases, number of positive lymph nodes or bilaterality of lymph node metastases. Only high Gleason score (8 to 10) on the preoperative biopsy correlated with rapid progression to distant metastases (p < or = 0.00001) in a multivariate analysis. If the Gleason score was less than 8, the likelihood of distant metastases was only 18% and 41% at 5 and 10 years, respectively, whereas 85% of men with a Gleason score of 8 to 10 had distant metastases by 5 years. For urologists who believe that radical prostatectomy is useful in providing local control in men with positive lymph nodes, frozen section analysis of lymph nodes is probably not necessary in men who are candidates for radical prostatectomy and have preoperative Gleason scores of less than 8. Conversely, in patients with a Gleason score of 8 to 10 on needle biopsy, careful analysis of lymph nodes is necessary to avoid radical prostatectomy in those who will derive little benefit.