Kenneth Steven

RADICAL CYSTECTOMY: EXTENDING THE LIMITS OF PELVIC LYMPH NODE DISSECTION IMPROVES SURVIVAL FOR PATIENTS WITH BLADDER CANCER CONFINED TO THE BLADDER WALL

PURPOSE We assess the influence of the limits of pelvic lymph node dissection on survival following radical cystectomy for bladder cancer. MATERIALS AND METHODS From January 1990 to September 1997, 194 patients underwent radical cystectomy without prior treatment. Between March 1993 and September 1997, 126 consecutive patients underwent radical cystectomy with extended pelvic lymph node dissection beginning at the bifurcation of the aorta, including the common and external iliac vessels, presacral nodes and obturator fossa. Between January 1990 and March 1993, 68 consecutive patients underwent radical cystectomy, with limited pelvic lymph node dissection beginning at the bifurcation of the common iliac vessels, including the external iliac vessels and obturator fossa. The cystectomy procedure remained unchanged throughout this period and 1 surgeon performed all procedures. RESULTS A total of 117 patients had tumors confined to the bladder wall (stage pT3a or less) and 77 had tumors penetrating beyond the bladder into perivesical fat or adjacent structures (stage pT3b or greater). The prevalence of patients with tumors penetrating the bladder was higher in the extended dissection group (42.9 versus 33.8% limited dissection). The incidence of lymphatic involvement was 26.2% and slightly higher in the extended than the limited dissection group. There was a modest improvement in the 5-year recurrence-free survival for the extended dissection group (62 versus 56% limited dissection, p = 0.33), and a substantial improvement for the subgroups with tumors confined to the bladder wall (tumor stage pT3a or less) (85 versus 64%, p <0.02) and without lymph node metastasis (stage pT3a or less, pN0) (90 versus 71%, p <0.02). Accordingly, extended pelvic lymph node dissection reduced the 5-year probabilities for pelvic and distant metastasis (2 versus 7% limited dissection, p = 0.17 and 10 versus 21%, p = 0.15, respectively) for patients with tumors confined to the bladder wall (stage pT3a or less). Survival was similar for patients with pT3b or greater tumor. CONCLUSIONS This retrospective analysis suggests that extending the limits of pelvic lymph node dissection from the bifurcation of the common iliac vessels to the bifurcation of the aorta improves the recurrence-free survival rate for patients undergoing radical cystectomy for bladder cancer confined to the bladder wall (stage pT3a or less).

THE ORTHOTOPIC KOCK ILEAL NEOBLADDER: FUNCTIONAL RESULTS, URODYNAMIC FEATURES, COMPLICATIONS AND SURVIVAL IN 166 MEN

PURPOSE We report our experience with 166 patients who underwent radical cystectomy and orthotopic bladder substitution with the ileal Kock neobladder between February 1990 and January 1999. MATERIALS AND METHODS We classified complications as early (3 months or less postoperatively) and late. Continence was assessed by patient interview, the need to use protective devices and provocative incontinence testing. Neobladder function was evaluated by uroflowmetry, post-void residual urine volume measurement and enterocystometry, and renal function was assessed by 51creatinine ethylenediaminetetraacetic acid clearance. RESULTS There were no perioperative deaths. However, 52 early complications developed in 39 patients (23.5%) and 73 late complications in 62 (37.4%). The rate of early and late complications associated with the urinary tract was 11.5% and 23.5% with abdominal reoperation rates of 1.8% and 2.4%, respectively, due to these complications. At 3 and 5 years the risk of stone formation on the metallic staples was 18% and 34%, and the risk of B12 deficiency was 30% and 33%, respectively. One patient (0.6%) underwent reoperation for ureteral anastomotic stricture. Anterior urethral stricture in 5 cases (3%) was caused by recurrence in 1 and urethral anastomotic stricture in 1 also resulted from recurrent disease. Daytime continence was reported by 97% and 100% of our patients at 1 and 5 years, respectively. Provocative incontinence testing confirmed this level of daytime continence. Overall 75% of patients reported nighttime continence at 1 year and 94% at 5 years. The need for a nighttime protective device decreased with time. At 1 versus 3 years 39.8% versus 45.9% of patients used no protection, 29.7% versus 39.2% used a sanitary pad and 30.5% versus 14.9% used a condom device. Enterocystometric capacity and subtracted maximum reservoir pressure remained remarkably uniform at 456 versus 411 ml. and 47 versus 50 cm. water 6 months and 5 years postoperatively, respectively. Nevertheless, median post-void residual urine volume increased from 20 ml. at 6 months to 40 ml. at 5 years with an increased prevalence of patients requiring intermittent catheterization due to post-void residual urine greater than 100 ml. from 16% at 6 months to 44% at 5 years. 51Creatinine ethylenediaminetetraacetic acid clearance remained unchanged. There was a substantial 5-year survival advantage for the subpopulation with stage pT3a or less, pN0 tumors (94% versus 51%, p <0.001). CONCLUSIONS Radical cystectomy and orthotopic bladder substitution with the Kock ileal neobladder may be performed with an acceptable complication rate and good functional results. The probability of survival was considerably higher for patients with tumor confined to the bladder. Consequently we believe that early aggressive treatment should be considered in those with invasive disease, and reconstruction with orthotopic bladder substitution may encourage patients to accept radical surgery.

Distressful Symptoms and Well-being After Radical Cystectomy and Orthotopic Bladder Substitution Compared With a Matched Control Population

Purpose: We compared subjective quality of life, well-being, urinary tract symptoms and distress in patients after radical cystectomy and orthotopic urinary reconstruction with those in a matched control population.Materials and Methods: Included in this study were 101 consecutive recurrence-free patients who underwent radical cystectomy and orthotopic bladder substitution with an ileal urethral Kock neobladder at Herlev Hospital with a minimum followup of 1 year. A frequency matched control group comprising 147 individuals was selected from the same geographical region. Information was collected by an anonymous postal questionnaire and analyzed externally in Sweden.Results: The prevalence of low or moderate psychological well-being (32% versus 36%) and subjective quality of life (30% versus 38%), and high or moderate anxiety (23% versus 18%) and depression (26% versus 37%) was similar in patients with an orthotopic neobladder and population controls. Patients with a neobladder felt as attractive as the c...

Failure of Combined Supratrigonal Cystectomy and Mainz Ileocecocystoplasty in Intractable Interstitial Cystitis: is Histology and Mast Cell Count a Reliable Predictor for the Outcome of Surgery?

Eight women with severe intractable interstitial cystitis were treated with supratrigonal cystectomy and Mainz ileocecocystoplasty. The preoperative evaluation consisted of symptom analysis, cystometry, cystoscopy and bladder pathological findings. Seven patients had increased mast cell density. Median followup was 10 months. The symptoms resolved in 2 patients but recurred in 6 shortly after the operation. Voiding could not be established in 4 patients. Self-catheterization was difficult and painful. Ultimately, cystectomy and urinary diversion were performed in 5 patients and is scheduled in 1. The 2 cured patients had a small contracted bladder preoperatively while they were under anesthesia, while all 6 failed cases had a large bladder capacity. Postoperative biopsies from the trigone showed no difference in the amount of fibrosis, the degree of degenerative changes in the muscle and mast cell density between the 2 cured patients and the 6 who failed to improve. The mast cell density and the histological status of the trigone cannot be used as predictors of the outcome of supratrigonal cystectomy. The role of the mast cells in interstitial cystitis is reviewed. Combination of supratrigonal cystectomy and a Mainz augmentation cystoplasty cannot be recommended in patients with intractable interstitial cystitis and a large bladder capacity.

Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events.

The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically screened FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC, ARF, DBC1, INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4, SFRP5 and WIF1 in a prospective series of tumor biopsies (N = 105) and urine samples (N = 113) from 118 bladder tumor patients. We also analyzed urine samples from 33 patients with noncancerous urinary lesions. A total of 95 oncogenic mutations and 189 hypermethylation events were detected in the 105 tumor biopsies. The total panel of markers provided a sensitivity of 93%, whereas mutation and methylation markers alone provided sensitivities of 72% and 70%, respectively. In urine samples, the sensitivity was 70% for all markers, 50% for mutation markers and 52% for methylation markers. FGFR3 mutations occurred more frequently in tumors with no methylation events than in tumors with one or more methylation events (78% vs. 33%; p < 0.0001). FGFR3 mutation in combination with three methylation markers (APC, RASSF1A and SFRP2) provided a sensitivity of 90% in tumors and 62% in urine with 100% specificity. These results suggest an inverse correlation between FGFR3 mutations and hypermethylation events, which may be used to improve noninvasive, DNA‐based detection of bladder cancer.

Predicting Recurrence and Progression of Noninvasive Papillary Bladder Cancer at Initial Presentation Based on Quantitative Gene Expression Profiles

BACKGROUND Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based on specific tumor biology, are yet to be identified. OBJECTIVE To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of patients with Ta G2/3 bladder tumors at initial presentation with three distinct clinical outcomes: absence of recurrence (n=16), recurrence without progression (n=16), and progression to carcinoma in situ or invasive disease (n=16). MEASUREMENTS Expressions of 24 genes that feature in relevant pathways that are deregulated in bladder cancer were quantified by real-time polymerase chain reaction on tumor biopsies from the patients at initial presentation. RESULTS AND LIMITATIONS CCND3 (p=0.003) and HRAS (p=0.01) were predictive for recurrence by univariate analysis. In a multivariable model based on CCND3 expression, sensitivity and specificity for recurrence were 97% and 63%, respectively. HRAS (p<0.001), E2F1 (p=0.017), BIRC5/Survivin (p=0.038), and VEGFR2 (p=0.047) were predictive for progression by univariate analysis. Multivariable analysis based on HRAS, VEGFR2, and VEGF identified progression with 81% sensitivity and 94% specificity. Since this is a small retrospective study using medium-throughput profiling, larger confirmatory studies are needed. CONCLUSIONS Gene expression profiling across relevant cancer pathways appears to be a promising approach for Ta bladder tumor outcome prediction at initial diagnosis. These results could help differentiate between patients who need aggressive versus expectant management.

Neoadjuvant Chemotherapy with Cisplatin and Methotrexate in Patients with Muscle-Invasive Bladder Tumours

This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of the bladder. In the first trial, local treatment consisted of cystectomy (DAVECA 8901) and in the other trial the treatment was radiotherapy (DAVECA 8902); 153 eligible patients were randomized. The majority of the patients (89%) completed the protocol. The overall time to progression for all 153 patients was 12.9 months. Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy. The actuarial 5-year overall survival rate for all 153 patients was 29%, and 29% for both treatment groups. Multivariate analyses showed that T-stage, tumour size and serum creatinine were independent prognostic factors for survival. The cystectomy trial included 33 patients. Median survival was 78.9 months, 82.5 months with chemotherapy and 45.8 months without chemotherapy (p=0.76). The radiotherapy trial included 120 patients. The median survival was 17.6 months. Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy. The 5-year survival rate was 19% in the group receiving chemotherapy and 24% in the groups not receiving chemotherapy (p=0.98). Late toxicity grade 3 or 4 of the bladder was recorded in 25% of the patients (actuarial rate). Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 randomized patients with invasive bladder cancer.

Long-Term Efficacy of Intravesical Bacillus Calmette-Guerin for Carcinoma in Situ: Relationship of Progression to Histological Response and p53 Nuclear Accumulation

PURPOSE We assessed the influence of the histological response to intravesical bacillus Calmette-Guerin (BCG) and the prevalence of p53 nuclear accumulation on the clinical behavior of patients with carcinoma in situ. MATERIALS AND METHODS Of 60 patients with Bergquist grade 3 carcinoma in situ 13 had primary and 47 had secondary carcinoma in situ. Patients received 6 weekly instillations and nonresponders received an additional 6 instillations at 2-week intervals. No maintenance was administered. Median followup was 48 months. The p53 nuclear accumulation was detected by immunohistochemical analysis with antibody PAb 1801. RESULTS The complete histological response rate to BCG therapy was 64%, which decreased to 52% at 4 years. BCG was more effective for treatment of primary than secondary carcinoma in situ (complete response rate 85 versus 57%, respectively). The 45% progression rate was related to the initial histological response occurring in 26% of patients with a complete versus 77% with a partial and no response. Consequently, the progression rate was only 8% for primary versus 57% for secondary carcinoma in situ. Of the patients receiving only 1 course of BCG 40% had progression compared to 62% of those who received 2 courses. Patients in whom both courses failed had a progression rate of 89%. Intravesical BCG converted the p53 nuclear immunoreactivity from positive to negative in 73% of the 26 patients expressing reactivity before treatment, of whom 68% also had a complete response. The progression rate was related to the prevalence of p53 nuclear reactivity after but not before treatment (90% of patients with versus 37% without p53 nuclear accumulation had progression). All 3 complete responders with p53 nuclear reactivity after BCG had progression, which suggests that molecular genetic change may precede histological change. Complete responders without p53 nuclear accumulation after BCG treatment experienced the lowest progression rate (21%). CONCLUSIONS Our results suggest that patients with a persistent complete histological response and without p53 nuclear accumulation after BCG treatment can be followed conservatively. Cystectomy should be considered in all other patients.

Case Reports: Implantation Metastasis After Laparoscopic Biopsy of Bladder Cancer

We report a case of tumor implantation in the abdominal wall following laparoscopic biopsy of a transitional cell tumor. Tumor seeding is a known risk in patients with transitional cell carcinoma and we recommend that laparoscopic biopsy of urothelial tumors be avoided.

Relative importance of sources of symptom-induced distress in urinary bladder cancer survivors

OBJECTIVE The influence of specific symptoms on emotions and social activities in the individual patient varies. Little is known about this variation in urinary bladder cancer survivors (in other words, about the relative importance of sources of symptom-induced distress). METHODS We attempted to enroll 404 surgical patients treated with cystectomy and a conduit or reservoir in four Swedish towns (Stockholm, Orebro, Jönköping, Linköping), 101 surgical patients treated with cystectomy and orthotopic neobladder at the Herlev Hospital in Copenhagen, Denmark, and 71 patients treated with radical radiotherapy for bladder cancer, as well as 581 men and women controls in Stockholm and Copenhagen. An anonymous postal questionnaire was used to collect the information. RESULTS A total of 503 out of 576 (87%) treated patients and 422 out of 581 (73%) controls participated but 59 patients were excluded. The primary source of self-assessed distress among cystectomised patients was compromised sexual function; reduced intercourse frequency caused great distress in 19% of the conduit patients, 20% of the reservoir patients and 19% of the bladder substitute patients. The primary source of self-assessed distress in patients treated with radical radiotherapy was symptoms from the bowel; 17% reported great distress due to diarrhoea, 16% due to abdominal pain, 14% due to defecation urgency and 14% due to faecal leakage. The highest proportion of subjects being distressed was 93% (substantial: 43%, moderate: 29% and little: 21%) for treated upper or lower urinary retention (indwelling catheter or nephrostomy). CONCLUSION The distress caused by a specific symptom varies considerably and the prevalence of symptoms causing great distress differs between treatments in bladder cancer survivors. It is possible that patient care and clinical research can be made more effective by focusing on important sources of symptom-induced distress.