Intravesical Instillation Chemotherapy Research Articles

Feasibility of early intravesical instillation chemotherapy after transurethral resection of the bladder: A prospective evaluation in a consecutive series of 210 cases

Early instillation chemotherapy (less than 6 h after tumour resection) is an accepted adjuvant treatment after transurethral resection of non-muscle-invasive papillary bladder tumours. Because most studies have reported on selected patients fulfilling specific eligibility criteria, this study investigated the feasibility of this therapy in a non-selected, consecutive series of patients who had undergone transurethral surgery to the bladder at a single institution. All transurethral resections of the bladder were prospectively evaluated. In patients with assumed non-muscle-invasive papillary bladder cancer, resection was followed by early instillation of 50mg epirubicin. Practical problems, staging and cystoscopic follow-up were systematically registered and evaluated. From October 2002 to February 2005, 210 transurethral resections (including 31 diagnostic biopsies) were performed in 163 patients (median age at resection 73.8 years). The following pathological T-stages were found: pT0 27.6%, pTa 39.0%, pT1 8.6%, > or =pT2 19.0% and pTis 5.7%. Patients received early instillation chemotherapy in 110 cases, which was generally well tolerated, but was prevented in four patients by intense bleeding or perforation. The treatment decision was correct in 82.8% and positively correlated with the experience of the treating urologist. Cumulative incidence rates of first postoperative tumour recurrence in the pTa group at 6, 12 and 24 months were 6.7, 24.5 and 52.0%, respectively. Early instillation chemotherapy with epirubicin after transurethral resection of bladder tumours is generally feasible and usually has no major side-effects, but evaluation of intraoperative T-stage can be a problem and depends on experience.

Bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location

To better define the predictors of bladder tumour development in patients operated for upper urinary tract urothelial cancer (UT-UC). Surgical specimens from 191 consecutive patients with no history of bladder cancer and operated for UT-UC were chosen for analysis. Bladder tumour development was assessed in relation to UT-UC location, tumour multiplicity, stage and grade, margin status, mode of operation, age and gender. Overall, 51 of 191 (27%) patients developed subsequent bladder tumours, including 25 of 123 (20%) with pelvic, 19 of 47 (40%) with ureteric and seven of 21 (33%) with multifocal tumours (P = 0.04 for all subgroups; P = 0.01 for pelvic vs ureteric). There was no influence of the other variables. The median (mean, range) time to recurrence was 12 (18, 3-64) months. In a multivariate analysis, ureteric tumour location was an independent predictor (P = 0.02; risk ratio, RR, 2.0, 95% confidence interval, CI, 1.1-3.7). After excluding 68 patients with systemic disease progression, bladder tumour development was noted in 39 of 123 (32%), including 18 of 76 (24%) with pelvic, 16 of 34 (47%) with ureteric and five of 13 with multifocal tumours (P = 0.06 for all subgroups; P = 0.02 for pelvic vs ureteric). In a multivariate analysis, ureteric location (P = 0.03; RR 2.1, 95% CI 1.1-4.2) and high tumour grade (P = 0.04; RR 2.2, 95% CI 1.03-4.7) were independent predictors of subsequent bladder tumour development. The risk of developing a bladder tumour after surgery for UT-UC is significantly related to ureteric tumour location and high tumour grade. Clinical trials to evaluate a possible reduction of bladder cancer risk by intraoperative ureteric ligation and/or peri-operative topical intravesical chemotherapy instillation are justified.

Bladder cancer

This article will review the diagnosis and management of bladder cancer at each stage, from superficial to metastatic disease with an emphasis on recent developments over the last year. Bacille Calmette-Guerin is the most effective therapy for carcinoma in situ. All patients who receive intravesical therapy with bacille Calmette-Guerin should be considered for ongoing maintenance therapy. The management of muscle invasive disease in the United States centers on radical cystectomy with bilateral pelvic lymphadenectomy. Areas of research include the optimal role for bladder preservation therapy, a growing experience in centers with laparoscopy, the effect of urinary diversion on quality of life, and the optimal standard for pelvic lymphadenectomy at surgery. The role of combination chemotherapy for advanced bladder cancer continues to evolve. Many questions remain unanswered including the relative value of neoadjuvant versus adjuvant chemotherapy for locally advanced disease and optimal chemotherapy regimen. The detection of bladder cancer continues to rely on direct visualization with cystoscopy. Efforts are underway to improve the utility of urinary markers and cystoscopy through fluorescence endoscopy. The management of superficial bladder cancer is based on transurethral resection of the tumor with perioperative intravesical instillation of chemotherapy strongly suggested for most patients. Risk stratifying patients with high-risk superficial bladder cancer remain a challenge and area of future research.

A SINGLE IMMEDIATE POSTOPERATIVE INSTILLATION OF CHEMOTHERAPY DECREASES THE RISK OF RECURRENCE IN PATIENTS WITH STAGE Ta T1 BLADDER CANCER: A META-ANALYSIS OF PUBLISHED RESULTS OF RANDOMIZED CLINICAL TRIALS

We determined if 1 immediate instillation of chemotherapy after transurethral resection (TUR) decreases the risk of recurrence in patients with stage Ta T1 single and multiple bladder cancer overall and separately. A meta-analysis was performed of the published results of randomized clinical trials comparing TUR alone to TUR plus 1 immediate instillation of chemotherapy. Our study included 7 randomized trials with recurrence information on 1476 patients. Based on a median followup of 3.4 years and a maximum of 14.5 years, 267 of 728 patients (36.7%) receiving 1 postoperative instillation of epirubicin, mitomycin C, thiotepa or (2'R)-4'-O-tetrahydropyranyl-doxorubicin (pirarubicin) had recurrence compared to 362 of 748 patients (48.4%) with TUR alone, a decrease of 39% in the odds of recurrence with chemotherapy (OR 0.61, p <0.0001). Patients with a single tumor (OR 0.61) and those with multiple tumors (OR 0.44) benefited. However, after 1 instillation 65.2% of patients with multiple tumors had recurrence compared to 35.8% of patients with single tumors, showing that 1 instillation alone is insufficient treatment for patients with multiple tumors. One immediate intravesical instillation of chemotherapy significantly decreases the risk of recurrence after TUR in patients with stage Ta T1 single and multiple bladder cancer. It is the treatment of choice in patients with a single, low risk papillary tumor and is recommended as the initial treatment after TUR in patients with higher risk tumors.

A randomized controlled trial of short-term vs. long-term prophylactic intravesical instillation chemotherapy for recurrence after transurethral resection of Ta/T1 transitional cell carcinoma of the bladder: Koga H, Kuroiwa K, Yamaguchi A, Osada Y, Tsuneyoshi M, Naito S, Department of Urology, Graduate School of Medicine, Kyushu University, Japan

A randomized controlled trial of short-term vs. long-term prophylactic intravesical instillation chemotherapy for recurrence after transurethral resection of Ta/T1 transitional cell carcinoma of the bladder: Koga H, Kuroiwa K, Yamaguchi A, Osada Y, Tsuneyoshi M, Naito S, Department of Urology, Graduate School of Medicine, Kyushu University, Japan

A Randomized Controlled Trial of Short-Term Versus Long-Term Prophylactic Intravesical Instillation Chemotherapy for Recurrence After Transurethral Resection of Ta/T1 Transitional Cell Carcinoma of the Bladder

In a prospective randomized controlled study, we investigated the optimal schedule for intravesical instillation of epirubicin for maximizing its effect on prophylaxis and disease progression after transurethral resection of newly diagnosed Ta/T1 bladder cancer. The patients were instilled with epirubicin (30 mg/30 ml in normal saline) within 24 hours after transurethral resection and then randomized into 2 groups after a definite histopathological diagnosis of Ta/T1 bladder cancer. One group of 77 patients received 19 intravesical instillations of epirubicin in the year after transurethral resection (group 1). The second group of 73 patients received 9 intravesical instillations of epirubicin during the 3 months after transurethral resection (group 2). Nonrecurrence rates and toxicity were compared. In the followup period, 10 group 1 patients (13.0%) and 23 group 2 patients (31.5%) had recurrent disease. The 3-year nonrecurrence rate was 85.2% in group 1, whereas it was 63.9% in group 2. The nonrecurrence rate of group 1 was significantly higher than that of group 2 throughout the observation period (p = 0.005). The incidence and severity of toxicity were not significantly different between the 2 groups. Our study indicates that long-term instillation of epirubicin is more effective than short-term instillation in preventing recurrence after transurethral resection of Ta/T1 bladder cancer.

Treatment of patients with superficial bladder cancer by intravesical instillation of anticancer drugs plus oral chemotherapy following TUR-Bt: A randomized controlled trial

We conducted a randomized controlled trial to compare local recurrence rate after transurethral resection of superficial bladder cancer treated by either intravesical instillation of an anticancer drug alone (method A) and the intravesical instillation plus oral chemotherapy (doxifluridine, 5'-DFUR, an intermediate metabolite of capecitabine) (method B). Results between groups showed no difference in recurrence-free survival curves in 196 patients subjected to primary analysis. However, patients subjected to secondary analysis (method B, over 3 months administration of 5'-DFUR) showed a significantly better prognosis than method A (p=0.0244, Wilcoxon). Regarding correlation between thymidine phosphorylase (TP, an enzyme to convert 5'-DFUR to 5-fluorouracil) level and prognosis, method A patients showed poorer prognosis in higher TP level cases than in lower TP levels. However, there was no significant difference in prognosis between those with higher and lower TP levels. In method B patients, there was no difference in prognosis between those with higher and lower TP levels. Method A patients tended to show a slightly better prognosis than those with lower TP levels, while method B patients tended to have a slightly better prognosis with higher TP levels, but no significant difference was observed. These findings suggested 5'-DFUR showed a mild efficacy in patients with higher TP levels and that patients with higher TP levels resulted in poorer prognosis.

An alternative procedure for the instillation of intravesical chemotherapy

An alternative procedure for the instillation of intravesical chemotherapy

Results of transurethral resection plus adjuvant intravesical chemotherapy for superficial bladder cancer.

We analyzed the results of conservative therapy for superficial bladder cancer to determine the risk factors for recurrence and progression. Between May 1984 and February 1997, 111 patients with primary superficial bladder cancer were treated by a transurethral resection with or without intravesical instillation of chemotherapy, or for patients with concomitant carcinoma in situ (CIS), bacillus Calmette-Guérin. We examined the relationship between tumor stage, grade, incidence of concomitant CIS and recurrence-free survival according to pathologic findings and the drugs instilled. The incidence of concomitant CIS in pT1, grade 3 tumors was significantly higher than that in pTa, grade 1 tumors (42% vs. 3%, P= 0.006). The 5-year recurrence-free survival rate of all patients was 73%. There was no significant difference in recurrence-free survival and pathologic stage, tumor grade, presence of concomitant CIS, or drugs used for instillation. However, the recurrence-free survival in patients with > or = 5 tumors was significantly lower than in patients with less than 5 tumors. Of the 111 patients, only 3 patients demonstrated disease progression and underwent a radical cystectomy, while 1 patient with a pT1b, grade 3 tumor developed a tumor in the ureter. No patient died of bladder cancer. Our results indicate that the prognosis of superficial bladder cancer patients with a high-stage, high-grade (pT1, grade 3) tumor is favorable when treated by a transurethral resection and intravesical instillation. Bacillus Calmette-Guérin therapy is useful to prevent the recurrence of tumors with concomitant CIS.

Application of clinical trials to the care of patients with bladder cancer.

Patients with bladder cancer are fortunate because much of the treatment they receive is based on the findings of randomized clinical trials that ensure a sound, scientific basis for the treatment decisions they will agree with their urologist. Patients with Ta or T1 transitional cell carcinoma will be distressed to learn their diagnosis but will be comforted to know that they are most unlikely to die of the disease. They will be well advised to have at least one instillation of intravesical chemotherapy and if they are confirmed to have a good-prognosis tumour, they will probably need only annual follow-up cystoscopies. Other patients will have to accept the inconvenience of more frequent cystoscopies. Should they develop multiple superficial recurrences, more intensive intravesical chemotherapy or BCG is effective. This should probably be repeated at 6-monthly intervals for up to 3 years, although the optimum duration of treatment and the best treatment regimens require further clarification. Patients with muscle invasive bladder cancer do not have a good prognosis and, unfortunately, the addition of systemic chemotherapy does not offer any clear survival advantage at the present time. New, more effective forms of treatment are awaited. The confidence with which bladder cancer patients can be treated is based on the results of collaborative, multicentre trials that have been conducted over the past two decades. The important lesson to be learned, by physician and patient alike, is that randomized clinical trials are worthwhile because the results influence clinical practice and assure best possible care.

Intravesical instillation chemotherapy of adriamycin with or without verapamil for the treatment of superficial bladder cancer: the final results of a collaborative randomized trial

A collaborative randomized clinical trial on the intravesical administration of Adriamycin (ADM) with or without verapamil (VR), a calcium-channel blocker, as chemotherapy of superficial bladder cancer (Ta, T1) was carried out at two universities, Okayama and Kagoshima, and their affiliated hospitals. Arm A consisted of ADM given at 50 mg/50 ml saline, and arm B consisted of ADM given at 50 mg/40 ml saline plus five ampules (25 mg/10 ml saline) of injectable VR. The drugs were instilled into the bladder for 3 consecutive days, and three such courses were given with a 4-day interval between each course for a total of nine instillations. A total of 96 patients (48 in arm A and 48 in arm B) were entered into this study. The two treatment groups showed no significant difference in background factors. Of the 40 evaluated arm-A patients, 24 (60.0%) showed a response (CR + PR), whereas 19 (48.7%) of the 39 patients in arm B responded. The difference between these response rates was not statistically significant. As for adverse reactions to the intravesical chemotherapy, local inflammatory symptoms were observed in half of the patients, although no systemic reaction was observed. No significant difference was found between arm A and arm B, except for urinary turbidity. In conclusion, at the dose employed in the present clinical trial, there was no clear enhancement of the effect of ADM combined with VR in patients with superficial bladder cancer. Further clinical studies are required to determine the optimal doses of ADM and VR for their combination in intravesical chemotherapy.

Intravesical therapy with adriamycin plus verapamil in patients with superficial bladder cancer: a pilot study.

Nineteen patients with histologically proven superficial bladder cancer (Ta, T1) were treated with intravesical instillation of 30 mg of adriamycin (ADM) dissolved in 24 ml physiological saline plus 15 mg of verapamil (VR) (6 ml) every day for 10 days. In spite of the short period of treatment, 6 of the 18 evaluable patients (33.3%) showed complete response (CR) and a further 5 (27.8%) showed partial response (PR). Five of the 6 patients with CR were recurrent cases who had previously received prophylactic intravesical instillation chemotherapy including ADM. Irritative urinary symptoms were observed in 11 of the 19 patients (57.9%). However, these symptoms were mild in the majority of patients and the treatment was completed without interruption in all but 1 patient. There was no significant absorption of ADM and VR into the systemic circulation. No clinical evidence of systemic toxicity was observed. These results suggest that combination of ADM and VR has a possibility to be a useful prophylactic intravesical instillation chemotherapy after endoscopic resection of not only primary but also recurrent chemoresistant bladder cancers.

異型度3膀胱癌患者の予後

The pathological features and clinical outcome of grade 3 transitional cell carcinoma of the bladder, excluding CIS, encountered between 1972 and 1988 were studied to clarify the clinical characteristics of the disease. The subjects of this study were 108 patients consisting of 76 males and 32 females aged 33-87 years, with a mean age of 66 years. The survival rate according to each factor was calculated by Kaplan-Meier method, and the survival curves were compared by generalized Wilcoxon test. Grade 3 bladder cancer was often papillary, sessile and about 3 cm in diameter and showed a tendency of multiple occurrence. Histopathologically, it was often in high stages of pT2 or above and frequently with vascular invasion. Total cystectomy is not considered to be an absolute necessity for pT1, G3 bladder cancer patient, because, in our experience, it did not improve the prognosis. However, bladder-preserving operation requires strict postoperative follow-ups. After this operation, the 5-year survival rate was higher in the no-recurrence group than in the recurrence group, and the out come tended to be better in the group that had undergone intravesical instillation chemotherapy for prevention of recurrence than in the group without this therapy. Ample intravesical instillation chemotherapy after bladder-preserving operation seems to improve the postoperative course of bladder cancer patients. Total cystectomy may be unavoidable in patients with pT2 or above, and no effect of postoperative adjuvant chemotherapy was noted in our series. The establishment of multidisciplinary approaches is considered to be needed for improvement of the prognosis of high stage bladder cancer.

Intravesical chemotherapy with 4'-epi-Adriamycin in patients with superficial bladder tumors.

We evaluated the effects of 4'-epi-Adriamycin (EPI), a derivative of Adriamycin (ADR), in intravesical instillation chemotherapy. The patients received two courses of three daily instillations of 50-80 mg EPI dissolved in 30 ml physiological saline on 3 consecutive days, with an interval of 4 days between courses. Full evaluation was possible in 33 of 35 patients with superficial bladder tumors treated with EPI. Complete response was observed in 4 cases and partial response in 14 cases, giving a response rate of 55%. Side effects such as pollakiuria and pain on micturition occurred in 9 cases. EPI appears to be an effective agent for intravesical instillation chemotherapy in patients with superficial bladder tumors.

Should continuous bladder irrigation be recommended when single instillation of intravesical chemotherapy cannot be used after transurethral resection in low-risk non-muscle invasive bladder cancer?

Reducing the recurrence rate in patients with low-risk non-muscle invasive bladder cancer patients is a critical concern in the urologic community. The gold standard treatment is single instillation (SI) of intravesical chemotherapy after transurethral resection of bladder tumor (TURBT), but unfortunately, it is underused. Continuous bladder irrigation (CBI) after TURBT is an alternative strategy to SI for the prevention of bladder tumor implantation and recurrence. The aim of this review was to present the evidence that supports CBI after TURBT when SI is not possible.