Severely contracted bladder following intravesical mitomycin C therapy

Most superficial bladder tumors are best treated by transurethral resection. However, because of their multifocal origin and high rate of recurrence they often present challenging therapeutic problems. Intravesical chemotherapy often is used in such cases in the treatment and prevention of recurrent transitional cell carcinoma of the bladder. Recently, mitomycin C intravesical chemotherapy was shown to be effective in the treatment of superficial bladder tumors. No systemic toxicities were described but bladder irritation and drug-related palmar desquamation were noted. We report a case of a severely contracted bladder requiring urinary diversion following intravesical chemotherapy with mitomycin C. A possible relationship of this complication to the mitomycin C treatment is suggested.     

Treatment of superficial papillary transitional cell carcinoma of the ureter by vesicoureteral reflux of mitomycin C

We report 2 cases of recurrent superficial papillary transitional cell carcinoma of the bladder with right vesicoureteral reflux in which superficial papillary transitional cell carcinoma developed in the distal ureter with reflux. Both patients received intravesical mitomycin C that was delivered by the vesicoureteral reflux to the tumor sites. Diagnosis and management were facilitated through the use of ureteroscopy, which allowed for accurate pathological staging and surveillance. No systemic toxicity or change in renal function was noted in either patient and both have remained free of recurrent tumor for more than 2 years.     

Analysis of factors predicting intravesical recurrence of superficial transitional cell carcinoma of the bladder without concomitant carcinoma in situ

BACKGROUND: The objective of this study was to investigate risk factors for intravesical recurrence in patients with superficial bladder cancer without concomitant carcinoma in situ (CIS). METHODS: In this series, we analyzed data from patients with newly diagnosed superficial Ta or T1 transitional cell carcinoma (TCC) of the bladder without concomitant CIS who underwent complete transurethral resection (TUR) without any adjuvant intravesical instillation therapies. Multivariate analysis was used to determine significant risk factors affecting intravesical recurrence after TUR. Differences in clinicopathological features between primary and recurrent tumors were also characterized. RESULTS: Among 341 patients undergoing TUR of Ta or T1 bladder cancer, 187 diagnosed as having concomitant CIS and/or treated with adjuvant intravesical therapy were excluded, and the remaining 154 were evaluated. Intravesical recurrence was detected in 64 of the 154 patients, showing a 5-year recurrence-free survival rate of 58.3%. Among several factors examined, only tumor size was significantly associated with intravesical recurrence. Multivariate analysis identified tumor size as an independent predictor for intravesical recurrence irrespective of other parameters including age, gender, multiplicity, growth pattern, grade and stage. Recurrent tumors were significantly smaller and of a lower grade and lower stage than primary tumors, despite the absence of differences in growth pattern and the multiplicity between them. CONCLUSIONS: These findings suggest that primary tumor size could be used as a potential risk factor for predicting intravesical recurrence following TUR of superficial TCC of the bladder without concomitant CIS, and that the pathological characteristics of recurrent tumors are more favorable than those of primary tumors.     

Prophylactic intravesical instillation of mitomycin C and cytosine arabinoside for prevention of recurrent bladder tumors following surgery for upper urinary tract tumors: A prospective randomized study

BACKGROUND: A recurrence of bladder tumors following surgery for transitional cell carcinoma of the upper urinary tract is not rarely observed. A prospective randomized study was conducted to examine the significance of prophylactic intravesical instillation of mitomycin C (MMC) and cytosine arabinoside (Ara-C) to prevent recurrent bladder tumors after surgery for superficial transitional cell carcinoma of the upper urinary tract. METHODS: The patients were randomized into an instillation group, who received postoperative intravesical instillation of MMC (20 mg) and Ara-C (200 mg) 28 times over a period of 2 years, and a non-instillation group. The non-recurrence rate was then compared between the groups. RESULTS: Of the 27 patients registered, 25 patients (13 with instillation and 12 without instillation) were able to be evaluated, with a median follow-up period of 45 months. The non-recurrence rate of bladder tumors in the instillation group was higher than that in the non-instillation group. Although the difference was not statistically significant, the P-value (P = 0.079) demonstrated a strong trend. When any possible bias was allowed for a multivariate analysis, the difference was almost significant (P = 0.0567). No patients withdrew from this study due to any side-effects. CONCLUSION: The postoperative instillation of MMC and Ara-C may be a useful approach for reducing the recurrence of bladder tumors after surgery for upper urinary tract tumors.     

Topical mitomycin C therapy for carcinoma in situ of the bladder: a followup

We studied 15 patients with histologically proved multifocal carcinoma in situ of the bladder who were in remission at a mean followup of 21 months after induction intravesical chemotherapy with mitomycin C. These patients have been followed for a further 28 months, for a total mean duration of 49 months. Of the 15 patients 4 suffered new areas of carcinoma in situ, including 3 who subsequently required cystectomy (2 after unsuccessful intravesical bacillus Calmette-Guerin therapy and 1 with a simultaneous invasive tumor). One patient underwent transurethral resection of the prostate for carcinoma in situ of the prostatic urethra, which subsequently was shown to be limited to mucosa and not involving the deeper ducts nor the stroma. Of the remaining 11 patients 1 died of unrelated disease and 2 suffered recurrent papillary transitional cell carcinoma treated successfully with a combination of intravesical bacillus Calmette-Guerin therapy and resection. The other 8 patients have remained free of tumor. None of the 15 patients had metastatic cancer. We believe that these results support the durability of response after induction mitomycin C therapy. We stress the necessity for prolonged close followup to detect recurrent tumor and to avoid metastatic disease.     

Immunohistochemical localization of metallothionein in transitional cell carcinoma of the bladder

Metallothionein is a metal binding protein thiol found in high concentrations in the liver and kidney. Recent evidence has linked overexpression of cellular metallothionein with tumor cell resistance to chemotherapeutic drugs, such as alkylating agents and cis-diamminedichloroplatinum (II) (cisplatin). We studied the metallothionein content of 9 human transitional cell carcinomas of the bladder with immunohistochemical methods. All tumors stained positive for metallothionein and the staining was localized almost exclusively to the cytoplasm. Uroepithelium displaying dysplastic changes or carcinoma in situ demonstrated the greatest intensity of staining, while staining in the invasive portions of the tumor was weak and variable. These findings were of interest, since combination chemotherapy of invasive transitional cell carcinoma of the bladder often is ineffective against carcinoma in situ. Normal uroepithelium stained strongly in all 3 patients who experienced disease progression and death, and in only 1 of the 5 who are currently without evidence of disease.     

TUR and adjuvant intravesical chemotherapy in T1G3 bladder tumors: recurrence, progression and survival in 137 selected patients followed up to 20 years

OBJECTIVES: To evaluate a highly selected population of patients affected by T1G3 bladder transitional cell carcinoma (TCCB) treated by transurethral resection (TUR) and adjuvant intravesical chemotherapy. MATERIALS AND METHODS: Between January 1976 and April 1999, 137 patients with T1G3 TCCB were treated by TUR plus intravesical chemotherapy. Particularly, a sequential combination of mitomycin C (MMC) and epirubicin (EPI) was adopted in 91 patients (66.4%). The main exclusion criteria were concomitant or previous Tis, previous T1G3 TCCB, tumor size greater than 3 centimeters and number of tumors more than 3. TUR was repeated if a superficial tumor recurred. Patients went off study if Tis, recurrent T1G3 or invasive tumor were detected during treatment or thereafter. Adjuvant therapy, recurrence and progression were considered in multivariate analysis regarding recurrence, progression and survival respectively. RESULTS: Observation period was up to 240 months with a minimum of 2 years in 112 patients (82%). Seventy patients (51%) recurred. The recurring tumor was again a T1G3 in 22 (16%) patients. Thirteen patients (9.5%) progressed. The 5-year progression-free survival rate was 90%. Median progression-free survival was 149 months. Twenty-two patients (16%) died, 9 (6.6%) of whom due to bladder cancer. Median overall survival was 155 months. The 3- and 5-year disease-free overall survival rates were 89% and 80% respectively. Ten cystectomies (7.3%) were performed. In conclusion, 123 patients (90%) maintained their intact bladder with a mean disease-free overall survival of 104 months. The sequential combination of MMC and EPI adjuvant therapy resulted more effective to be than single drug chemotherapy on recurrence rate (p=0.0021) but had no impact upon progression (p=0.127) and specific survival (p=0.163). Progression (p<0.001) after conservative treatment was the main prognostic factor for survival. CONCLUSION: A conservative approach is an appropriate therapeutic option for the initial management of selected T1G3 bladder tumors.     

The effect of antisense Bcl-2 oligonucleotides on Bcl-2 protein expression and apoptosis in human bladder transitional cell carcinoma

PURPOSE: Bcl-2 is an important determinant of transitional cell carcinoma of the bladder recurrence and progression as well as a factor in patient response to chemotherapy or radiotherapy. We determined Bcl-2 down-regulation after antisense oligonucleotide therapy and synergism with mitomycin C in transitional cell carcinoma of the bladder. MATERIALS AND METHODS: Bcl-2 protein was quantified using flow cytometry and immunohistochemistry in 4 bladder cancer cell lines, in bladder washings from 6 patients with carcinoma in situ and in 16 patient tumor samples. The synergistic effects of antisense oligonucleotides G3139 and 2009, and mitomycin C were investigated in 4 cell lines, while 2009 down-regulation was examined in 20 tumor explants in an ex vivo model. RESULTS: Bcl-2 protein expression was found in all 4 cell lines and in 5 of the 6 cell populations derived from patients with carcinoma in situ. Of the 16 tumors 7 were classified positive by frozen section immunohistochemistry and quantitative flow cytometry. G3139 and 2009 down-regulated Bcl-2 protein expression in all 4 cell lines and 2009 down-regulated Bcl-2 protein expression in half of the Bcl-2 positive tumor specimens. There was only evidence in 1 cell line, T24/83, that Bcl-2 protein expression down-regulation enhanced mitomycin C induced apoptotic cell death. CONCLUSIONS: Bcl-2 was expressed in a significant proportion of bladder tumors and in carcinoma in situ. Therefore, antisense oligonucleotides represent a viable strategy for Bcl-2 protein down-regulation. However, it may not always translate into an increased level of mitomycin C induced apoptosis in transitional cell carcinoma of the bladder.     

Intravesical instillation of doxorubicin hydrochloride and its incorporation into bladder tumors

We studied single dose intravesical doxorubicin instillation (50 mg. dissolved in 30 ml. saline) in 29 patients with bladder tumor and 2 with dysplasia of the bladder. The results demonstrated that 1) the levels of doxorubicin hydrochloride in extracts of tumors were significantly higher than those of histologically normal bladder tissues in all regions examined except the dome, 2) the incorporation concentration of the drug into the smallest tumor was 3-fold greater than that of larger tumors, 3) tissue concentration of the drug in histologically normal bladder tissues was 2.4-fold greater in patients with recurrent than with primary bladder tumors, and 4) a high concentration of the agent was noted in unifocal, multifocal and primary tumors classified as papillary noninvasive or invasive transitional cell carcinoma. These findings indicate that intravesical installation of doxorubicin hydrochloride can be incorporated to a high degree by relatively small papillary noninvasive or invasive transitional cell carcinoma located in almost all regions except the bladder dome.     

组织培养药敏测试法在表浅膀胱肿瘤化疗药敏测试中的应用价值

目的：探讨Hoffman式组织培养药敏测试法在表浅膀胱癌腔内化疗药敏测试中的应用价值。方法：对31例表浅膀胱癌分别进行Hoffman式组织培养，对丝裂霉素C(MMC)进行改良MTT法药敏测试，检测MMC在浓度为1g/L、作用时间为2h情况下对表浅膀胱癌的生长抑制率。采用MMC 40mg加生理盐水40m1对表浅膀胱癌进行术后标准腔内化疗，并随访20个月。结果：18例培养成功，15例进入药敏测试，其中9例对MMC敏感，6例不敏感。术后腔内化疗随访结果显示敏感者有2例复发，不敏感者有5例复发；单因素Kaplan—Meier生存分析显示敏感者无复发生存率明显高于不敏感者。与临床实际疗效比较，该药敏测试法的特异性为75．0％，敏感性为85．7％，准确率达80．0％。结论：组织培养药敏测试法不仅可以检测表浅膀胱癌对化疗药物的敏感性，还能预测利用敏感药物进行腔内化疗的预后。     

细胞周期蛋白D1在膀胱移行细胞癌中表达的意义

目的　探讨细胞周期蛋白Ｄ１（ｃｙｃｌｉｎ Ｄ１） 与膀胱移行细胞癌（ＴＣＣ） 生物学行为的关系。　方法　应用免疫组化法检测７１ 例膀胱ＴＣＣ 组织中ｃｙｃｌｉｎ Ｄ１ 的表达。　结果　３９ 例（５４ ．９％ ）ＴＣＣ 中ｃｙｃｌｉｎ Ｄ１ 呈阳性表达,其中Ｇ１ １１ 例（６８－８ ％ ）、Ｇ２ ２３ 例（６０－５ ％ ）、Ｇ３ ５ 例（２９－４ ％ ） 。３２ 例为胞核阳性,７ 例为胞浆阳性,其中Ｇ２ ３ 例,Ｇ３ ４ 例。６０ 例初发者阳性３５ 例（５８－３ ％ ） ,１１ 例再发者阳性４ 例（３６－４％ ） 。　结论　膀胱ＴＣＣ 是ｃｙｃｌｉｎ Ｄ１ 高表达的肿瘤类型之一,ｃｙｃｌｉｎ Ｄ１ 的过表达是膀胱癌发生过程中的早期事件,其与肿瘤病理分级显著相关,再发性ＴＣＣ 中表达有减少趋势,胞浆阳性代表着更高的恶性潜能     

Tumor angiogenesis and recurrence in stage I non-small cell lung cancer.

BACKGROUND: Tumor angiogenesis appears to relate to recurrence after an operation as a route for distant metastasis. We assessed the association of vascular endothelial growth factor (VEGF) expression and intratumoral microvessel density (MD) with recurrence in primary lung cancer. METHODS: Samples were randomly obtained from 104 stage I lung cancer patients who underwent curative operations (43 recurrent, 61 nonrecurrent patients). Microvessels were highlighted by staining endothelial cells for factor VIII and VEGF antigen was detected using a polyclonal antibody. RESULTS: VEGF antigen was detected in large amounts in both recurrent (100%) and nonrecurrent tumors (73.8%). The percentages of patients with the strongest VEGF stain (more than 50% of staining area in tumor cells) were 46.5% in tumors with recurrence and 11.5% in tumors without recurrence. The mean MD in recurrent and nonrecurrent tumors were 18.2+/-10.5 and 8.5+/-5.0, respectively, resulting in a significantly greater value in tumors with recurrence (p<0.0001). Although there were no significant differences in mean MD according to pathological types, in adenocarcinoma and adenosquamous carcinoma, the mean value in the recurrent group was significantly greater than that in the nonrecurrent one. CONCLUSIONS: An evaluation of VEGF expression and MD in tumors may contribute to the estimation of the risk of recurrence of non-small cell lung cancer in early stages.     

Intravesical interferon alfa-2b administration in the treatment of superficial bladder tumors

This study was undertaken to assess the value of intravesical interferon alfa-2b treatment in preventing the recurrences of superficial transitional cell carcinoma of the bladder. A total of 30 patients aged from 33 to 78 entered the protocol. The intravesical instillations were performed once a week for 8 weeks. A solution of 10 x 10(6) IU interferon alfa-2b in 30 ml of normal saline was used. Follow-up ranged from 12 to 28 months. Of the 30 patients, 19 (63.33%) were tumor free at the end of follow-up. Of the remaining 11 patients, 7 presented with recurrent superficial tumors and 4 with invasive bladder tumors. No side effects were noted.     

Value of bladder wash cytology in the follow-up of patients with bladder carcinoma receiving intravesical chemoprophylaxis with mitomycin C.

511 bladder wash cytologic findings in 121 patients receiving intravesical chemoprophylaxis with mitomycin C after transurethral resection of stage pTa to stage pT2 bladder carcinoma were retrospectively analyzed. In 42 recurrent tumors, sensitivity of detection by cytology amounted to 67% in GIII tumors, 56% in GII tumors, and 20% in GI tumors. 16% of G0 tumors were cytologically positive. 33% of a total of 30 endoscopically detected recurrent GI-GIII tumors yielded negative results at bladder wash cytology, the findings were suspicious in 27%, while only 40% of all recurrences had a positive bladder wash cytology. Positive cytologic findings combined with normal endoscopic results were obtained in 24 patients. 15 of these (62%) developed recurrences after a mean interval of 15 months (3-60 months) during or after metaphylaxis. When suspicious findings were included, 20 of 30 carcinomas were detected, while 7 of 12 G0 tumors were overgraded. Bladder wash cytology has its merits for early detection of recurrences, since almost two thirds of the patients with positive cytologic findings and negative endoscopy developed a recurrent tumor at a later date. Whether or not positive cytology combined with negative endoscopic results should lead to therapeutic consequences remains to be discussed.     

Intravesical mitomycin C instillation as a prophylactic treatment of superficial bladder tumor

A study was performed to determine the prophylactic efficacy of intravesical mitomycin C instillation in 43 patients with recurrent (more than 3), multiple (more than 3) or large (more than 3 cm.) superficial bladder tumors (stage Ta or T1). Of the patients 21 were treated with 8 weekly intravesical instillations of 40 mg. mitomycin C after transurethral resection and 22 were followed conventionally. The recurrence rate was 42.9 per cent in the mitomycin C group and 40.9 per cent in the controls during the first 3 months, and it was 81.0 and 77.3 per cent, respectively during 24 months. Recurrences per 100 patient-months were 8.7 and 8.9, respectively. Two patients in the mitomycin C group and 4 controls had recurrent tumors with progression in stage. We conclude tentatively from these observations that intravesical mitomycin C instillation is not effective in the prophylaxis of tumor recurrence in patients at high risk. This finding is contrary to other reports indicating a marked decrease in recurrence with mitomycin C.     

Topical mitomycin C therapy for carcinoma of the bladder

We studied 19 consecutive patients with biopsy proved carcinoma in situ of the bladder who had received 8 weekly doses of 30 mg. intravesical mitomycin C. Followup with cystoendoscopy, biopsy and cytology studies every 3 months ranged from 6 to 48 months, with an average of 21 months. A complete initial response was achieved in 15 patients, 11 of whom have remained free of tumor with no further therapy. The 4 patients who failed to respond to initial therapy subsequently were free of tumor after further intravesical mitomycin C (2), excision (1) or doxorubicin (1). Three patients died of unrelated diseases. Only 1 patient has had metastatic transitional cell carcinoma. No patient had undergone cystectomy or radiotherapy. These data indicate that mitomycin C achieves a high initial response in patients with carcinoma in situ of the bladder and maintains this control in many patients for months or years.     

Prophylactic intravesical chemotherapy in bladder tumors after surgery of upper tract urothelial carcinoma

Sixteen patients with upper tract urothelial carcinoma underwent intravesical chemotherapy usually at 2 week intervals in the first year and at 4 week intervals in the second year after nephrouretectomy. For bladder instillation 10 mg mitomycin C in 20 ml saline was used on 7 patients, 5 mg carboquone and 100 mg cytosine arabinoside in 40 ml saline on 5 patients and 30 mg adriamycin in 40 ml saline on 4 patients. Two (12.5%) of the 16 patients developed bladder tumors within 2 years after surgery, but 11 (42.3%) of the 26 patients with upper tract urothelial carcinoma who did not receive intravesical chemotherapy suffered from bladder tumor within 2 years after surgery. Prophylactic intravesical chemotherapy reduced significantly (p less than 0.1) the incidence of bladder tumor after the surgery of renal pelvic and ureteral tumors.     

Intravesical bacillus Calmette-Guerin therapy for stage T1 grade 3 transitional cell carcinoma of the bladder: recurrence,progression and survival in a study of 57 patients

PURPOSE: Stage T1 grade 3 transitional cell carcinoma of the bladder is associated with a high risk of tumor recurrence and progression. We report our experience with stage T1 grade 3 bladder tumors treated with bacillus Calmette-Guerin (BCG) therapy in the last 10 years. MATERIALS AND METHODS: We analyzed the outcome in 57 consecutive patients treated with intravesical BCG for stage T1 grade 3 bladder cancer between 1991 and 2001. After initial transurethral resection all patients received a 6-week course of BCG therapy consisting of 1 instillation weekly. All patients underwent systematic biopsies at the end of the first BCG course. Patients with negative biopsies received maintenance BCG therapy, consisting of intravesical instillations each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months after the first course. Patients with residual tumor received a second course of 6 weekly instillations. Time to tumor recurrence and progression, and the rate of patient survival were retrospectively analyzed. RESULTS: Median followup was 53 months (range 9 to 110). Minimum followup was 2 years in 36 cases (63.2%) and 5 years in 28 (49.1%). After the first BCG course 50 patients (87.7%) had no residual disease, while 7 (12.3%) had residual tumor. The recurrence and progression rates were 42.1% and 22.8%, respectively. The rate of delayed cystectomy was 14%. The rate of disease specific survival was 87.7%. CONCLUSIONS: Our study confirms that BCG therapy is effective conservative treatment for patients with stage T1 grade 3 bladder tumors.     

LOCAL MICROWAVE HYPERTHERMIA AND INTRAVESICAL CHEMOTHERAPY AS BLADDER SPARING TREATMENT FOR SELECT MULTIFOCAL AND UNRESECTABLE SUPERFICIAL BLADDER TUMORS

Purpose

The role of a combined regimen of local hyperthermia and topical chemotherapy in patients with multifocal and recurrent superficial bladder tumors not curable by transurethral resection was evaluated in a neodjuvant organ sparing clinical study.

Materials and Methods

A total of 19 patients with multifocal, superficial grades 1 to 3 bladder tumors that recurred after intravesical chemoprophylaxis or immunoprophylaxis underwent local combined administration of microwave induced hyperthermia and intravesical chemotherapy as a debulking approach. Due to extensive superficial involvement of the bladder walls complete transurethral resection of all tumors seemed technically unfeasible in all cases and radical cystectomy was considered the treatment of choice. Endovesical hyperthermia at 42.5 to 46C was delivered using the SB-TS 101 system,* based on a microwave transurethral applicator that irradiates the bladder filled with a circulating solution of mitomycin C. Patients underwent 8 weekly 1-hour sessions on an outpatient basis without anesthesia. When possible, after treatment patients underwent transurethral resection of residual tumors and all suspicious areas.*Boston Scientific Corp., Natick, Massachusetts.

Results

After treatment transurethral resection appeared to be feasible and curative in 16 patients (84%). Histological study revealed complete and partial responses in 9 (47%) and 7 (37%) cases, respectively. Due to extensive residual tumors radical cystectomy was performed in 3 patients (16%). At a median 33-month followup 8 superficial transitional tumor recurrences were documented and easily eradicated by transurethral resection or laser therapy in patients in whom the bladder had been saved.

Conclusions

Microwave induced hyperthermia combined with intravesical mitomycin C seems to be a feasible, safe and elective approach for conservative treatment of multifocal and recurrent superficial bladder tumors when other treatment strategies have failed.