Prophylaxis of recurrence of superficial bladder tumor by intravesical chemotherapy

During the past 10 years, we have experienced 110 bladder tumor cases. Among them, 70 patients were diagnosed superficial bladder tumor. Of these 70 cases, 30 were treated with intravesical adriamycin (ADR) and peplomycin (PEP), 13 with ADR only and one case with PEP and remaining 26 with TUR and hydrostatic pressure technique. We studied the efficacy of combination intravesical chemotherapy with ADR and PEP and other treatments in the prevention of recurrence in the superficial bladder tumor cases. The recurrence rate during 3 years of each group, was 25% in the group treated with ADR and PEP, 35% with ADR and 55% in remaining group. 3 years recurrence rate in the group treated with ADR and PEP was significantly low than that in the group tread with TUR and hydrostatic pressure technique alone (Wilcoxon test). Side effects was pollakisuria, pain after micturition and others. Anaphylactic shock appeared in one case. From these results we concluded that intravesical chemotherapy with combined agents is more effective than that with a single one or no treatment after TUR.     

Prophylactic effect of UFT on the recurrence of bladder cancer

To evaluate the effect of UFT, a mixture of ftorafur and uracil in a ratio of 1:4, in preventing postoperative recurrence of bladder cancer, we performed a randomized controlled study with a non-medication group as control. UFT was given orally 400 mg a day for 6 months. Of 111 patients, 56 were given UFT and 55 were followed up without any medication. The non-recurrence rate in the group treated with UFT was 62.8% after 1 year and 36.3% after 2 years of follow up, and that of the control group was 45.7% and 39.5%, respectively. The rate of non-recurrence in the UFT group was significantly higher (p less than 0.05) than that of the control group during the period of follow up for 2 years. The incidence of side effects was 6.8% in UFT patients. These results indicate the clinical usefulness of prophylactic administration of UFT for bladder cancer patients.     

Prophylactic effect of pirarubicin (THP) on postoperative recurrence of superficial bladder cancer in terms of intravesical retention time]

In order to determine the modality of prophylactic intravesical instillation of pirarubicin (THP = tetrahydropyranyladriamycin) following transurethral resection (TUR) of superficial bladder cancer, a prospective randomized study was performed. A total of 79 patients were randomized into "2-hour instillation" (A), "5-min instillation" (B) and "control" (C) groups. Prophylactic efficacy and side effects were analyzed in each group. In groups A and B, 20 mg of THP was first dissolved in 10 ml of distilled water, adjusted to 40 ml with saline and was administered intravesically once a week for 10 weeks, starting from 1 week after TUR. The recurrence-free rate was calculated in 65 evaluable patients. The one-year recurrence-free rate was 70.2% in group A, 62.8% in group B and 52.1% in group C. The one-year recurrence-free rate was significantly higher in group A than in group C. Adverse effects were observed in 21.4% of the patients in group A and 40.7% in group B. There was no significant difference in the occurrence rate of side effects between these two groups. Taking the prophylactic efficacy and side effects into consideration, "2-hour instillation" seemed to be better than "5-min instillation".     

The effect of intravesical chemotherapy on superficial urinary bladder cancer

The effect of intravesical chemotherapy on superficial urinary bladder cancer was analysed. Fifty-nine patients with low-staged, low-grade bladder cancer were treated with intravesical instillation of three anticancer drugs (adriamycin, carbazilquinone and bleomycin). Complete response (CR) was observed in 15 out of 42 patients and partial response (PR) in 9 patients. Overall, a better response rate was observed with adriamycin and carbazilquinone than with bleomycin. Papillary tumors responded well to these intravesical chemotherapies compared to the non-papillary tumors . Intravesical recurrence of tumors was evaluated in 68 patients who received intravesical instillation of these three drugs after TUR of tumors. The actuarial recurrence rate of 68 patients was 11, 22 and 34% within 1, 2 and 3 years, respectively. These rates were significantly lower than that of TUR therapy alone. No serious side effect was seen in these patients. From these results, it is noted that intravesical chemotherapy is a useful approach for controlling superficial urinary bladder cancer.     

Study of combination chemotherapy with cytosine arabinoside in the intravesical treatment of superficial bladder tumors

The effect of instillation therapy using CA alone or in combination with MMC, NCS or CQ was examined in 111 patients (92 males and 19 females, aged 32-87 years old with an average age of 66 years) with multiple superficial bladder tumors. The response rate of 29 patients given CA 400 mg alone was 48.3%, that of 25 patients given combination therapy of CA 200 mg and MMC 20 mg was 84.0%, that of 28 patients given combination therapy of CA 200 mg and NCS 4,000 U was 71.4%, that of 22 patients given combination therapy of CA 200 mg and NCS 6,000 U was 95.5% and that of 7 patients given combination therapy of CA 200 mg and CQ 10 mg was 100%. The response rates of the patients given any of the combination therapies were higher than that of the patients given CA alone. But because MMC, NCS and CQ were not administered singly, combination therapy cannot be concluded to be superior to single therapy. There was little difference between the response rate of primary cases and that of follow up cases. The side effects were all symptoms of local irritation, and were not indicative of systemic damage. Side effects were seen in 3.4%, 71.4%, 40.0% and 3.6% of the patients given CA alone, CA + CQ combination therapy, CA + MMC combination therapy and CA + NCS (4,000) therapy, respectively, combination therapy of CA and CQ producing the highest percentage of side effects.     

Prophylactic intravesical instillation therapy in patients with superficial bladder cancer--results of a randomized prospective study]

A randomized prospective study was conducted for the purpose of investigating the efficacy of intravesical chemoprophylaxis of superficial bladder cancers. Eligible patients were randomized into three groups: 1) adriamycin (ADM) group; intravesical instillation with 50 mg of ADM dissolved in 100 ml physiological saline, 2) mitomycin C (MMC) group; intravesical instillation with 30 mg of MMC dissolved in 100 ml of physiological saline, 3) control group; transurethral resection or transurethral coagulation only. The characteristic features of our protocol consisted of frequent (six times) instillations of the drugs within two weeks after transurethral resection, followed by instillations on two consecutive days at four-week intervals for two years. Furthermore, large quantities (100 ml) of instillation fluid containing relatively low concentrations of the drugs (500 micrograms/ml for ADM or 300 micrograms/ml for MMC) were employed. One hundred and forty-four patients have been submitted to the study; 110 patients were fully evaluable for recurrence and 34 patients were eliminated as non-evaluable patients. The cumulative five-year non-recurrence rates of the patients with multiple tumors were 32% in the MMC group, 25% in the ADM group and 7% in the control group. The cumulative non-recurrence rates of the ADM and MMC groups were significantly higher than that of the control group. It is considered that this instillation therapy with ADM and MMC is useful for preventing the recurrence of superficial bladder cancers.     

羟基喜树碱膀胱灌注化疗联合体外热电场热疗预防浅表性膀胱癌复发的临床研究

目的探讨羟基喜树碱(HCPT)膀胱内灌注化疗联合体外热电场热疗预防浅表性膀胱癌复发的疗效及安全性。方法 83例原发性或复发性浅表性膀胱移形上皮细胞癌患者,均行经尿道膀胱肿瘤电切术(TURBT),术后随机分配到疗法1组及疗法2组,疗法1组为羟基喜树碱膀胱内灌注化疗联合体外热场热疗(42例),疗法2组为单独应用羟基喜树碱膀胱内灌注化疗(41例)。本研究的有效性评估终点是无复发生存率及复发概率的估计评价(应用Kaplan-Meier分析及Log-rank检验)。最小随访时间为24个月。安全评价包括主观和客观的副作用和并症发。结果在随机分配的83例患者中,76例坚持完成研究并进行有效的统计分析。其中疗法1组39例6例复发(15.4%),疗法2组37例,14例复发(37.8%)。两种治疗法经Log-rank检验显示其无复发生存率有显著性差异(P=0.017),疗法2组的复发率高于疗法1组(P=0.03)。结论羟基喜树碱膀胱内灌注化疗联合体外热电场热疗效果明显优于单独应用羟基喜树碱膀胱内灌注化疗,患者耐受性良好,安全可行。     

New agents in intravesical chemotherapy of superficial bladder cancer

Although intravesical chemotherapy has been used in the management of superficial bladder cancer for some decades, until recently there has been little or no progress in the search for new agents. However, in the past few years there have been developments of investigational drugs that may play a future role in this indication. This review highlights the mode of action, indications, dose and administration, efficacy, safety and significance of new chemotherapeutic agents such as intravesical valrubicin, gemcitabine, suramin, gamma-linolenic acid, eflornithine (DFMO), tipifarnib (R115777), fenritinide and celecoxib. Although the initial results achieved with these agents in clinical development seem encouraging, long-term data on the prevention of recurrence, disease progression and survival have yet to be obtained.     

Experimental and clinical study of intravesical BCG therapy. The role in the prevention of recurrence of superficial bladder tumor]

The effects of Tokyo strain bacillus Calmette-Guerin (BCG), which is available in Japan for treatment, were studied in an experimental murine bladder tumor (MBT-2) model prior to clinical study for treatment of superficial bladder tumor. The results were as follows: Tokyo-strain BCG is more effective on the local injection around the tumor than on systemic administration. BCG therapy is more effective at earlier time of small tumor burden. BCG also has a prophylactic effect against the tumor growth. Clinical trial of intravesical instillation of BCG was performed on patients with superficial bladder tumor for prophylaxis of tumor recurrence after transurethral resection of the tumor. In patients of 145 primary cases, the tumor recurrence rate after BCG therapy was estimated, comparing with that of historical control in our department. The historical control groups are consisted of 50 patients who were treated by some intravesical chemotherapy after TUR and 38 patients, who were treated by TUR alone. The tumor recurrence rate in BCG group was significantly lower than that in both control groups. No relationship between PPD responsiveness and the tumor recurrence rate could be detected. On the other hand, in the patients of 36 recurrent cases, evaluation was performed by the tumor recurrence rate comparing with those during the two years prior to BCG therapy. The results demonstrated a statistically significant decrease in recurrent tumor following BCG therapy. Although most of the adverse effects in this study such as bladder irritability, flu-like syndrome and macroscopic hematuria were minimal and tolerable. There were no significant side effects or serious complications attributable to BCG therapy in this series. These results indicate that intravesical Tokyo strain BCG instillation provide prophylactic effects against recurrence of superficial bladder cancer.     

表柔比星与吉西他滨膀胱灌注化疗对浅表性膀胱尿路上皮癌术后复发及安全性的影响

目的比较表柔比星与吉西他滨膀胱灌注化疗对浅表性膀胱尿路上皮癌术后复发及安全性的影响。方法遴选本院2014年3月至2017年3月收治并接受TURBT治疗的300例浅表性膀胱尿路上皮癌患者作为研究对象,根据术后灌注化疗药物选择随机分为表柔比星组和吉西他滨组各150例,并对患者进行为期2年的随访,观察两组患者术后化疗复发情况及化疗期间不良反应。结果表柔比星组患者术后6、12、24个月的复发例数分别为3、10、14例,总复发率为18.0%;吉西他滨组患者术后6、12、24个月的复发例数分别为3、8、13例,总复发率为16.0%,两组患者总复发率比较差异无统计学意义(χ^2=0.617,P=0.362)。表柔比星组总不良反应发生率为49.33%(53/150),吉西他滨组总不良反应发生率为26.67%(40/150),两组总不良反应发生率比较,差异有统计学意义(χ^2=5.52,P=0.023)。结论表柔比星与吉西他滨膀胱灌注化疗对预防浅表性膀胱尿路上皮癌术后复发的效果相当,但吉西他滨膀胱灌注产生的不良反应少,患者耐受性较好,值得临床推广。     

四氢吡喃基阿霉素膀胱内灌注预防表浅膀胱肿瘤

目的：观察四氢吡喃基阿霉素(THP)膀胱内灌注在预防表浅膀胱肿瘤的疗效。方法：将80膀胱肿瘤患分实验组和对照组进行研究，完成为期3年的随访观察。结果：实验组较对照组的1、2、3年无瘤生存率均有显性提高。结论：THP是一种新型的、有效的、安全性好的膀胱内灌注药，对预防膀胱肿瘤的发生有良好的作用。     

Clinical results of prophylactic intravesical chemotherapy on superficial bladder cancer using the dye exclusion assay]

A chemosensitivity test was carried out on superficial bladder cancer using the dye exclusion assay for the purpose of screening chemosensitive drugs for prophylactic intravesical chemotherapy. Bladder cancer cells of each patients were incubated, in vitro, in the presence of adriamycin, (2"R)-4'-0-tetrahydropyranyladriamycin, mitomycin C, pepleomycin and 4'-epi-adriamycin (500 micrograms/ml) at 5%, CO2, 37 degrees C for 2 hours. The cytotoxic effect of the drugs was evaluated by the ratio of stained cells by trypan-blue. The most effective drug was instilled postoperatively into the bladder 3 times for the first week, and every 2 weeks during the following 14 weeks. In 18 patients followed more than 4 months the prophylactic effect was evaluated. Fifteen of the 18 patients completed the protocol, but the remaining 3 patients failed to complete to the instillation because of severe irritability of the bladder. Tumor recurrence was demonstrated in two patients. Non-recurrence rates of tumors at 12 and 24 months were 93.8% and 82.0%, respectively. These results suggested that this rapid and handy assay was useful for the purpose of screening chemosensitive drugs for the intravesical chemotherapy.     

介入治疗联合膀胱灌注预防膀胱癌术后复发的临床价值

目的　探讨介入治疗联合膀胱灌注丝裂霉素C(MMC)预防浅表性膀胱癌术后复发的临床价值。　方法　 2 8例浅表性膀胱癌患者局部手术后随机分为二组 ,每组 14例。分别采用介入治疗加膀胱灌注MMC和MMC单纯膀胱灌注治疗。　结果　 2 8例随访 12～ 2 6个月 ,平均 2 1个月。介入加灌注组肿瘤复发 1例 ,单纯MMC灌注组肿瘤复发 4例 ,两组肿瘤复发率差异有显著性意义 (P <0 .0 5 )。　结论　介入治疗联合膀胱灌注MMC预防浅表性膀胱癌术后复发疗效较好 ,副反应少 ,临床应用安全可靠     

Prophylactic effect of etretinate on the recurrence of superficial bladder tumors--results of a randomized control study

The recurrence preventing effect of Etretinate on 174 superficial bladder tumors was examined by a randomized study using the envelope method. After transurethral resection of the bladder tumor, the tumor-free patients were divided into two groups, one administered one 10 mg capsule of Etretinate once a day, and the other group untreated (control group). As a rule, the patients were examined for recurrence every 3 months. There were 9 drop outs (9.6%) in the Etretinate group, and 8 (10%) in the control group. Therefore, 85 subjects in the Etretinate group and 72 patients in the control group were analyzed for statistics. The recurrence rate during the observation period of over 2 years was 38% in the control group and 18% in the Etretinate group, the number of relapsing cases in the latter group tending to be decreased (P less than 0.1). The cumulative recurrence inhibition rate for cases observed over one year tested by the Kaplan Meier method tended to be higher in the Etretinate group compared to the control group (P less than 0.1). Etretinate administration had a high recurrence inhibitory effect (P less than 0.05) in the cases of relapse, multiple tumors, and tumors less than 1 cm. Side effects of Etretinate administration were seen in 21 cases (22.3%). The major symptoms were dry lips, cheilitis, stomatitis, dermal desquamation, etc., and drug use was discontinued in 7 cases (7.4%). The symptoms all disappeared after drug administration was discontinued.     

Sequential intravesical chemotherapy with mitomycin C and adriamycin for superficial bladder tumor (preliminary report)

Intravesical chemotherapy with sequential instillation of mitomycin C and adriamycin was carried out on 19 patients with superficial bladder cancer (Ta, T1 and Tis). Twenty milligram of mitomycin C on day 1 and 40 mg of adriamycin on day 2 were instilled into the bladder, this treatment being repeated weekly for 5 consecutive weeks if there were no serious side effects. The following results were obtained. Of 16 evaluable patients, 10 patients (63%) achieved complete response and 2 patients achieved partial response, 4 patients showing no response. In patients with high grade tumor, especially with carcinoma in situ, a high CR rate (6/7 or 86%) was achieved. Chemical cystitis occurred in 10 out of 19 (53%) patients. In 5 of the 6 patients who suffered from severe cystitis symptoms, treatment was discontinued. However, the symptoms resolved within 4 weeks in all patients.     

膀胱灌注黏膜黏附化疗药物HPC-MMC预防肿瘤复发的疗效观察(附46例报告)

目的探讨黏膜黏附化疗药物HPC—MMC预防肿瘤复发的效果。方法对46例表浅膀胱癌患者于TURBt术后随机分两组行膀胱灌注化疗,黏膜黏附化疗药物组20例,以20mg／20ml％HPC—MMC膀胱灌注;MMC组26例,以20mg／20ml MMC膀胱灌注。疗程1年。HPCMMC组总灌注次数少于MMC组4次。随访6～36个月。结果HPC-MMC组未发现出血性膀胱炎,无明显尿路刺激症状。平均随访27．4个月,7例复发,1年复发率为16．7％,3年总复发率38．9％。MMC组平均随访26．8个月,9例复发,1年复发率为22,7％．3年总复发率40．9％。结论黏膜黏附化疗药物HPC-MMC膀胱灌注防止肿瘤复发优于单用MMC,同时可降低副作用,减轻患者痛苦及经济负担。     

ATP—TCA技术指导浅表性膀胱癌术后灌注化疗的临床应用

目的：探讨生物荧光体外肿瘤药敏检测技术（ATP—TCA）在浅表性膀胱癌肿瘤细胞药敏试验中的应用,探讨该技术在指导膀胱癌个体化治疗上的应用价值。方法：对40例浅表性膀胱癌标本进行肿瘤细胞分离,原代培养,应用ATP—TCA技术检测肿瘤标本对五种常用化疗药物的敏感率和耐药率。试验组术后选用最敏感的化疗药物对患者常规行膀胱灌注化疗,对照组选择丝裂霉素进行术后常规化疗。术后随访2年,评价两组膀胱癌复发情况。结果：40例标本中,吡柔比星（THP）、羟基喜树碱（HCPT）、丝裂霉素（MMC）、表柔比星（EPI）、吉西他滨（GEM）的敏感率分别为75．0％、10．0％、5．0％、37．5％、10．0％,肿瘤细胞对五种化疗药物的敏感率和耐药率差异有统计学意义（P〈0．01）。膀胱肿瘤对化疗药物的敏感性存在个体差异。术后随访2年,药敏组膀胱癌复发率为17．5％（7／40）,对照组膀胱癌复发率为37．5％（15／40）。两组肿瘤复发率差异有统计学意义（P〈0．05）。结论：应用ATP—TCA技术检测出的药敏结果能够反映个体对化疗药物的敏感性,可以作为选择灌注化疗用药的理论基础,指导临床用药进行个体化治疗。同时,应用ATP—TCA技术指导临床膀胱癌术后灌注化疗,可显著降低浅表性膀胱癌患者术后复发率,提高临床疗效。