Recurrence of Primary Superficial Bladder Cancer Treated with Prophylactic Intravesical Tokyo 172 Bacillus Calmette-Guerin: A Long-Term Follow-up

Background Long-term results after transurethral resection (TUR) and prophylactic intravesical Tokyo 172 bacillus Calmette-Guerin (BCG) therapy for primary superficial bladder cancer were analyzed by multivariate analysis, and factors affecting the recurrence of bladder tumors after this therapy were examined.
Methods One-hundred and forty-one consecutive patients with primary superficial bladder cancer who consulted the Department of Urology at Wakayama Medical College and affiliated hospitals between May 1985 and May 1990 were studied. Tokyo strain BCG was given intravesically (80 mg in 40mL saline) weekly for 6 weeks.
Results The 5-year cumulative recurrence-free rate by the Kaplan-Meier method was 0.702 in 141 patients with primary superficial bladder cancer. The 5-year recurrence-free function using the proportional hazard model was 0.743. Using the Cox proportional hazard model, variables that significantly contributed to recurrence after intravesical BCG included female sex, tumor size less than 1 cm in diameter, and T1 tumor stage. Patient age, tumor type, multiplicity, tumor grade, and concomitant carcinoma in situ did not contribute to recurrence.
Conclusion Long-term results showed that prophylactic intravesical Tokyo strain BCG after TUR for primary superficial bladder cancer is also effective in preventing the recurrence of bladder cancer, and the biologic behavior of superficial bladder cancer other than stage T1 tumor may be altered after intravesical BCG.     

The Effect of Lubricants on Viability of Bacillus Calmette-Guerin for Intravesical Immunotherapy Against Bladder Carcinoma

Purpose

The viability of bacillus Calmette-Guerin (BCG) is crucial for induction of a local immune response and for effective therapy of recurrent superficial bladder carcinoma. During intravesical instillation of BCG lubricants are administered to assist catheterization, which contain bacteriostatic components that may interfere with the viability of mycobacteria. To verify this assumption, 5 commercially available lubricants were analyzed with regard to inhibition of viable BCG growth.

Materials and Methods

Five different lubricants and their components were co-incubated with Connaught strain BCG and the resultant growth of BCG was assessed. To prove the significant passage of lubricants into the bladder, fluid was recovered from the bladder after catheterization, analyzed with regard to the bacteriostatic effect and compared to normal urine of different acidity.

Results

Significant impairment of BCG viability, dependent on dosage and time of co-incubation, was noted with all lubricants analyzed. Several components, namely lidocaine hydrochloride, glyceryl stearate, propyl-4-hydroxy-benzoate and chlorhexidine digluconate, were identified as responsible for this inhibition. Fluid recovered from the bladder after lubricant assisted catheterization also showed an inhibitory effect, indicating significant mixture of the instillate with lubricants.

Conclusions

Generous use of lubricants to assist catheterization during intravesical BCG therapy will result in a clinically significant decrease in the number of intravesically instilled viable mycobacteria. For this reason, during intravesical immunotherapy with BCG only small amounts of lubricants should be used for urethral catheterization, and use of catheters not requiring lubricants should be considered.     

密集膀胱灌注对抑制非肌层浸润性膀胱肿瘤术后复发的随机对照研究

目的：观察短期密集疗程膀胱腔内蒽环类药物灌注化疗对抑制非肌层浸润性膀胱肿瘤（nonmuscle invasive bladder cancer,NMIBC）经尿道电切术（TUR）后复发的效果。方法：我院自2006年1月～2008年12月对221例NMIBC患者行TUR术,经随机分为两组,密集疗程组术后执行表柔比星（epirubicin,EPI）40mg／40ml每周1次,连续8次的腔内灌注方案;常规化疗组则在连续8次的密集灌注化疗后续行40mg／40ml每月1次,连续10次的灌注方案。记录患者每3个月1次膀胱镜检查情况至术后24个月或肿瘤复发。结果：共有141例获得完整资料。24个月随访期中;45例（31．9％）肿瘤复发。其中常规化疗组22例（30．1％）,密集化疗组23例（33．2Vo）（p-0．64）。复发时间常规化疗组为（8．73±5．23）个月,密集化疗组为（8．74±4．42）个月（P=0．38）。15例（10．6％）复发肿瘤进展,其中常规化疗组7例（9．6％）,密集疗程组8例（11．8％）（P=0．675）。对141例患者的肿瘤大小,单发多发,初发复发,肿瘤病理类型,以及临床分期方面进行分层研究,密集疗程组与常规化疗组的无肿瘤复发率差异均无统计学意义。结论：TUR术后短期密集葸环类药物膀胱腔内灌注化疗可以获得与常规灌注化疗方案相同的降低NMIBC复发的效果。     

Clinicopathological Evaluation of Repeated Courses of Intravesical Bacillus Calmette-Guerin Instillation for Preventing Recurrence of Initially Resistant Superficial Bladder Cancer

Purpose

The efficacy of repeated courses of intravesical bacillus Calmette-Guerin (BCG) for superficial bladder cancer was assessed with particular attention to initially resistant cases.

Materials and Methods

A total of 75 patients with stages Ta to T1b superficial transitional cell bladder carcinoma received 6 weekly instillations of 80 mg. Tokyo strain BCG in 40 ml. saline followed by 6 instillations at monthly intervals. If tumors recurred, another course of treatment was given with surgery.

Results

Of 17 patients (22.7 percent) with recurrent tumor at followup periods of up to 84 months 12 received an additional course of BCG instillations according to the same protocol after transurethral resection of bladder tumors, and 10 (83.3 percent) showed no further recurrence with or without additional surgery and BCG therapy after a median followup of 42.9 months. Thus, the overall success rate with this approach was 90.7 percent (68 of 75 patients). Comparison of patients with and without recurrence revealed a significant difference in number of tumors before therapy (p less than 0.05), and a pronounced tendency (p = 0.00507) for recurrence after prior systemic chemotherapy or intravesical instillation.

Conclusions

The results suggest that up to 3 courses of repeated intravesical instillation of BCG are effective even for cases that initially did not respond, and that best results may be achieved if no other prior chemotherapy has been attempted.     

Intravesical Epirubicin Versus Doxorubicin for Superficial Bladder Tumors (Stages pTa and pT1): a Randomized Prospective Study

Purpose

We performed a prospective, randomized, controlled study to compare intravesical epirubicin and doxorubicin as adjuvant therapy after endoscopic resection of superficial bladder tumor.

Materials and Methods

We randomly allocated 253 eligible patients to 4 study arms. Seven to 14 days after transurethral bladder tumor resection instillation of the intravesical agent was instituted, including 50 and 80 mg. epirubicin in study arms 1 and 2, respectively, and 50 mg. doxorubicin in arm 3. Control arm 4 included patients who underwent transurethral bladder tumor resection alone. Instillation was repeated weekly for 8 weeks and monthly thereafter to complete 1 year of treatment. All patients were followed every 3 months by cystourethroscopy, urine cytology and deoxyribonucleic acid flow cytometry for 12 to 48 months (mean 30.1).

Results

Rates of recurrence were significantly lower in the chemotherapy groups than in controls (p <0.001) and in the epirubicin groups than in the doxorubicin group (p = 0.02). In arms 1 to 4 recurrence rates were 25, 17.6, 36.7 and 65.6%, respectively. Recurrence rates per 100 patient months were 0.83, 0.60, 1.18 and 2.73, respectively, which were significant statistically, and lower after chemotherapy in general and epirubicin in particular (p <0.05). Mean interval to first recurrence was 16, 15.4, 18.9 and 6.3 months, respectively, with a significant difference between the chemotherapy and control groups (p <0.05). Progression to muscle invasive disease occurred in 7 (10.9%), 3 (4.4%), 6 (10%) and 5 patients (8.2%), respectively, in arms 1 to 4 (p >0.05). We studied the relationships among different risk factors, and patterns of recurrence and progression. For pT1 tumors recurrence rates in arms 1 to 4 were 26.3, 17.8, 39.3 and 70.9%, respectively, which were significantly lower in the chemotherapy group than in controls (p <0.001) and in the epirubicin groups than in the doxorubicin group (p = 0.01). Toxic and untoward side effects developed in 10 (15.6%), 16 (23.5%) and 25 (41.7%) patients in chemotherapy arms 1 to 3, respectively, with a marginal insignificant difference between low and high dose epirubicin (p = 0.3), and significantly lower toxicity rates in arms 1 and 2 than in 3 (p = 0.002). A contracted bladder developed in 2.1% of all patients who received chemotherapy.

Conclusions

This study demonstrates that epirubicin has better efficacy and lower toxicity than doxorubicin when used as an intravesical agent.     

Localization of IL-1, IL-2, IL-4, IL-8 and TNF in Superficial Bladder Tumors Treated with Intravesical Bacillus Calmette-Guerin

Purpose

Cytokines have been detected in the urine during the first hours after intravesical Bacillus Calmette Guerin (BCG) treatment against superficial bladder cancer. To investigate the long-lasting mucosal inflammatory response, we analyzed intracellular cytokines by immunohistochemistry in biopsies taken 2 weeks after BCG treatment.

Materials and Methods

Tumor biopsies were obtained from 8 patients with noninvasive, papillary transitional cell carcinoma (TCC), and intracellular cytokines were visualized by immunohistochemistry using cytokine-specific monoclonal antibodies.

Results

Interleukin (IL)-1 beta sup + or tumor necrosis factor (TNF)-alpha sup + cells were abundant in tumor and stroma. Interleukin-1 alpha, IL-2, IL-4, IL-8 and TNF-beta were variably expressed, while IL-10 sup + and interferon (IFN)-gamma sup + cells were not detected. Among the few patients studied (5 responders and 3 nonresponders to BCG treatment) no single cytokine or cytokine profile was associated with clinical response to BCG therapy.

Conclusion

We conclude that the in situ cytokine response after BCG treatment is highly complex, since cytokine profiles differed among the 8 patients investigated and between tumor and surrounding tumor-free mucosa. Further studies, investigating larger number of patients, is required to clarify whether cytokine profiles correlate with the clinical response to BCG.     

The Effect of Intravesical Mitomycin C on Recurrence of Newly Diagnosed Superficial Bladder Cancer: A Further Report with 7 Years of Followup

Purpose

We determined the role, if any, of 1 and 5 instillations of intravesical mitomycin C in the treatment of newly diagnosed superficial bladder cancer.

Materials and Methods

A multicenter randomized clinical trial was done involving 502 patients with newly diagnosed superficial bladder cancer. After complete transurethral resection patients were randomized into 1 of 3 treatment arms: no further treatment, 1 instillation of mitomycin C at resection and 1 instillation at resection and at 3-month intervals for 1 year (total 5 instillations). The dose of mitomycin C used was 40 mg./40 ml. water. End points were interval to first superficial recurrence, recurrence rate (defined as the number of positive cystoscopies per year) and progression-free interval rate (progression defined as the development of muscle invasive or metastatic disease, or death from bladder cancer).

Results

After a median followup of 7 years 1 and 5 instillations of mitomycin C resulted in decreased recurrence rates and increased recurrence-free interval. The benefit of mitomycin C was observed in patients at low, medium and high risk for subsequent recurrence. There was suggestive but not conclusive evidence that 5 instillations of mitomycin C offered a slight advantage over 1 instillation.

Conclusions

Our analysis confirms the positive benefit of mitomycin C to decrease the number of subsequent recurrences and increase the recurrence-free interval.     

Apparent Failure of Current Intravesical Chemotherapy Prophylaxis to Influence the Long-Term Course of Superficial Transitional Cell Carcinoma of the Bladder

During the 4 decades since the first introduction of intravesical chemotherapy, 3,899 patients were enrolled in 22 randomized prospective controlled studies. Of these 22 studies 13 reported a statistically significant benefit of intravesical chemotherapy. With varying followup, the reported decrease in the incidence of patients with tumor recurrence averaged only 14 percent (range -3 to +43 percent). Unfortunately, long-term (5-year) studies show no decrease in the incidence of recurrent tumor. Maintenance chemotherapy has failed to improve these results and data suggest that a single early postoperative instillation may, in fact, be most effective. Among 10 studies that include progression data none showed decreased tumor progression, and overall among 2,011 randomized patients progression occurred in 7.5 percent of those receiving intravesical chemotherapy and 6.9 percent of those treated by surgery alone. Since intravesical chemotherapy has been demonstrated in animal models to be carcinogenic, these data raise the concern that intravesical chemotherapy might possibly be carcinogenic in humans. In the absence of demonstrated long-term benefit we question the advisability of routine prophylactic intravesical chemotherapy.     

Immunohistochemical Study of Tumor-Infiltrating Lymphocytes Before and After Intravesical Bacillus Calmette-Guérin Treatment for Superficial Bladder Cancer

¹Department of Urology, Juntendo University School of Medicine, Tokyo Japan
Background This study investigated changes in the phenotypic characteristics of tumor-infiltrating lymphocytes during intravesical bacillus Calmette-Guérin (BCC) treatment using an immunohistochemical technique.
Methods A total of 16 patients with superficial bladder cancer underwent intravesical BCG treatment for therapeutic purposes. Tissue specimens were obtained from these patients before and after BCG treatment by cold cup biopsies.
Results The numbers of CD3⁺ cells, CD4⁺ cells, CD8⁺ cells, and CD19⁺ cells significantly increased after treatment compared with numbers before treatment (P <0.01). Although γ/δT cells were not observed before treatment, they appeared after treatment in 6 patients- In all these patients, the tumors disappeared or their size was reduced by more than 50%, and none of the tumors recurred. The induction of CD25⁺ cells after treatment was seen in 11 of the 16 patients.
Conclusions γ/δT cells may play an important role in the immune response of the host to the tumor in intravesical BCG treatment (although this correlation was statistically insignificant).     

吡柔比星术后即刻膀胱灌注联合常规灌注预防表浅性膀胱癌术后复发的对照研究

目的：比较吡柔比星两种膀胱内灌注方法预防表浅性膀胱癌术后复发的有效性及安全性。方法：将52例经尿道膀胱癌电切术后表浅性膀胱癌患者随机分为两组。每次吡柔比星灌注剂量30mg,治疗组术后24h内膀胱灌注1次,此后每周灌注1次,连续8周,再改为每月灌注1次,至术后1年。对照组术后2周开始灌注,此后每周灌注1次,连续8周,再改为每月灌注1次,至术后1年。结果：全部病例均获随访,时间为12～24个月,平均随访16．3个月。其中治疗组随访期内2例复发,复发率8％;对照组随访期内4例复发,复发率14％,两组复发率比较差异有统计学意义（P〈0．05）,不良反应主要为尿路刺激症状。结论：本研究显示,吡柔比星膀胱灌注预防表浅性膀胱癌术后复发的疗效满意,用药方便,患者耐受性好;术后即刻膀胱灌注联合常规灌注较常规灌注可以降低肿瘤复发率,值得推荐。     

A Prospective Randomized Study Comparing Patients with Morbid Obesity Submitted to Sleeve Gastrectomy With or Without Omentectomy

Background

Increased visceral adipose tissue is a risk factor for the metabolic complications associated with obesity and promotes a low-grade chronic inflammatory process. Resection of the great omentum in patients submitted to a bariatric procedure has been proposed for the amelioration of metabolic alterations and the maximization of weight loss. The aim of the present study was to investigate the impact of omentectomy performed in patients with morbid obesity undergoing sleeve gastrectomy (SG) on metabolic profile, adipokine secretion, inflammatory status, and weight loss.

Methods

Thirty-one obese patients were randomized into two groups: SG alone or with omentectomy. Adiponectin, omentin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), blood lipids, fasting glucose, insulin, and insulin resistance were measured before surgery and at 7 days, and 1, 3 and 12 months after surgery.

Results

During the 1-year follow-up, body mass index (BMI) decreased markedly and comparably in both groups (p?<?0.001). Insulin, IL-6, and hs-CRP levels decreased significantly compared to baseline (p?<?0.05) in both groups with no significant difference between groups. Adiponectin and high-density lipoprotein cholesterol levels were significantly and similarly increased compared to baseline (p?<?0.001) in both groups. Omentin levels increased significantly (p?<?0.05) in the control group and decreased in the omentectomy group 1 year postoperatively. There was no significant change in TNF-α levels in either group.

Conclusions

The theoretical advantages of omentectomy in regard to weight loss and obesity-related abnormalities are not confirmed in this prospective study. Furthermore, omentectomy does not induce important changes in the inflammatory status in patients undergoing SG.