Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial

PURPOSE: The indication for topic chemotherapy or immunotherapy for well differentiated, noninvasive superficial bladder cancer remains controversial. Side effects of these treatments promoted use of unconventional therapies with cytokines, immunomodulators and mistletoe extracts. However, there are no controlled clinical data available on the efficacy of these extracts for bladder cancer. We evaluate the influence of subcutaneously applicated mistletoe lectin on bladder tumor recurrence after transurethral resection. MATERIALS AND METHODS: The study consists of 45 patients with pTa G1-2 bladder cancer treated with transurethral resection during a 3-year period. Median patient age was 65 years and 33 patients were male. The study cohort was randomly divided into a treatment group receiving adjuvant therapy with mistletoe lectin and a control group receiving no additional treatment. Patients in the treatment group received mistletoe lectin according to schedule 2 weeks after transurethral resection. Clinical followup was assessed 3, 6, 9, 12 and 18 months after the initial resection, and included uretherocystoscopy. RESULTS: Both study arms comprised similar patients with regard to total number of previous tumors (mean 2.6 versus 2.9), number of primary lesions (14 versus 12) and number of recurrent tumors (8 versus 11). After followup of 18 months the recurrence-free interval in both study arms was similar (p = 0.76) and the total number of recurrences comparable (p = 0.48). CONCLUSIONS: Subcutaneous use of mistletoe lectin as adjuvant treatment after transurethral resection does not seem to affect the time to first recurrence, total number of recurrences or recurrence-free outcome.     

Can topical chemoprevention modify the rate of recurrence and progression of superficial bladder cancer?

Several studies indicate that intravesical chemotherapy is an effective treatment for superficial bladder tumors. We have carried out a retrospective study of 321 patients with superficial bladder cancer who where treated between 1972 and 1982 at our Institute. In 63 of the 321 patients, adriamycin 50 mg or mitomycin C 20 mg was administered topically. In an average follow-up of 20.2 months the overall recurrence rate was 54.2%. In the control group the mean times to recurrence were 21 months for Ta tumors and 17.4 months for T1 tumors, while those in the topically treated patients were 14 and 8 months for the mitomycin and 17 and 6 months for the adriamycin group. The only factor that influenced the recurrence rate was the depth of infiltration of the lamina propria. Our data indicate that topical chemotherapy has no effect in patients with superficial cancer of the bladder.     

Short-term versus long-term chemoprevention of recurrence with Epodyl following transurethral resection of superficial urinary bladder cancer

This investigation compares the short and long-term administration of intravesical Epodyl (etoglucid), following transurethral bladder tumor resection. This chemoprophylactic agent was used specifically in the treatment of bladder tumors that displayed different associated tumor risk factors: solitary versus multiple tumors, grade(s) I-III, primary versus recurrent tumors, and the presence of associated dysplasia. Within this study, 114 patients with carcinoma of the bladder underwent primary transurethral resection (TUR), followed in 10 days by short-term intravesical therapy (STIT) or long-term intravesical therapy (LTIT). Short-term intravesical therapy was administered to 56 patients. The therapy consisted of a 1% solution of Epodyl, which was given once per week for 6 weeks. Long-term intravesical therapy was given to 58 patients. This consisted of the short-term intravesical therapy protocol, followed by an additional dose once a month during an observation period of 2 years. The follow-up in both groups was for a minimum of 2 years. When the total number of recurrences in patients receiving (STIT) or (LTIT) was compared, no marked differences were noted (39% vs 38%). However, there was a difference when the individual tumor risk features were compared, e.g. for solitary tumors, the recurrence rate was 67% within the (STIT) group and 43% within the (LTIT). These results demonstrate that the decision of whether superficial bladder carcinomas are to be treated with short- or long-term Epodyl should be based on tumor-associated risk factors. Furthermore, if multiple tumor risk factors are present, maximal therapy is require; in the absence of risk factors TUR alone may be sufficient.     

Immunotherapy in bladder cancer with keyhole-limpet hemocyanin: a randomized study

A randomized, controlled study was begun in 1982 on the effect of keyhole-limpet hemocyanin and mitomycin C in the prevention of recurrent superficial bladder cancer (stages pTa to pT1, grades 0 to 3) in 44 patients. All tumors were resected and all patients were presumed to be free of tumor at initiation of the prophylactic instillations. Before the bladder instillation program was begun all patients in the keyhole-limpet hemocyanin group Ia were immunized with 1 mg. keyhole-limpet hemocyanin intracutaneously and then monthly bladder instillations of 10 mg. were given. The control group Ib received 20 mg. mitomycin C monthly. Of the 21 patients in the keyhole-limpet hemocyanin group Ia (mean followup 20.7 months) 3 (14.2 per cent) had recurrences, compared to 9 of 23 (39.1 per cent) in the mitomycin C group Ib (mean followup 18.3 months). The over-all preventive effect was significantly better (p less than 0.05, chi-square) in keyhole-limpet hemocyanin-treated patients than in those given mitomycin C. In 1984 a new single drug study (group II) was started with keyhole-limpet hemocyanin alone, administered as in group Ia. Of 81 patients in group II (nonrandomized, mean followup 22.8 months) 17 (20.9 per cent) had recurrences. Of the patients given keyhole-limpet hemocyanin 20 of 21 (95.2 per cent) in group Ia and 70 of 81 (86.4 per cent) in group II had complete and partial prevention (downgrading), compared to 16 of 23 (69.5 per cent) in group Ib. Our study was established to analyze the effect of a new method of immunotherapy; no adverse local or systemic side effects were noted.     

A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non-muscle-invasive bladder cancer recurrence

Background

Narrow band imaging (NBI) is an optical enhancement technology that filters white light into two bandwidths of illumination centered on 415 nm (blue) and 540 nm (green). NBI cystoscopy can increase bladder cancer (BCa) visualization and detection at the time of transurethral resection (TUR). NBI may therefore reduce subsequent relapse following TUR.

Objective

Assess the impact of NBI modality on 1-yr non–muscle-invasive BCa (NMIBC) recurrence risk.

Design, setting, and participants

Consecutive patients with overt or suspected BCa were included in a prospective study powered to test a 10% difference in 1-yr recurrence risk in favor of cases submitted to NBI TUR. Excluding patients with muscle-invasive BCa, negative pathologic examination, or without follow-up, the study population was composed of 148 subjects randomized from August 2009 to September 2010 to NBI TUR (76 cases) or white light (WL) TUR (72 cases).

Intervention

TUR was performed in NBI or standard WL modality.

Measurements

The 1-yr recurrence risks in NBI or WL TUR groups were compared using odds ratio (OR) point and interval estimates derived from logistic regression modeling.

Results and limitations

The 1-yr recurrence-risk was 25 of 76 patients (32.9%) in the NBI and 37 of 72 patients (51.4%) in the WL group (OR = 0.62; p = 0.0141). Simple and multiple logistic regression analyses provided similar OR points and interval estimates.

Conclusions

TUR performed in the NBI modality reduces the recurrence risk of NMIBC by at least 10% at 1 yr.     

Intravesical prevention of recurrence of superficial urinary bladder cancer with BCG and KLH. A prospective randomized study

In a prospective randomized trial intravesical prophylaxis for recurrence of superficial bladder cancer with BCG versus KLH was performed in 42 patients, 38 of whom were then evaluable. After a mean observation period of 20 +/- 7 months (8-32 months) 41.2% (7/17) of the patients in the KLH and 14.3% (3/21) of the patients in the BCG group developed recurrent bladder tumours. The recurrence rate according to EORTC was 1.95 in the KLH group versus 0.76 in the BCG group. Among the BCG treated patients, 60% (15/25) had cystitis and 28% (7/25) fever, whereas only 1 of 19 (5.3%) patients treated with KLH had cystitis. BCG is a highly effective prophylactic against recurrence of superficial bladder cancer. Intravesical instillation therapy with KLH has only a slight prophylactic effect if treatment is started 6 weeks postoperatively.     

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.     

Hexaminolevulinate-guided transurethral resection of non-muscle-invasive bladder cancer does not reduce the recurrence rates after a 2-year follow-up: a prospective randomized trial

Purpose

To assess the impact of hexaminolevulinate (HAL) on the long-term recurrence rate of NMIBC.

Methods

A total of 130 patients with bladder tumour were randomized into two groups. The patients in one group had a HAL instillation before surgery, and they first had a white-light and after that a blue-light cystoscopy (BL group) and resection. The second group had only white-light cystoscopy (WL group) and resection. They have been followed up with cystoscopy every 3 months for a period of up to 40 months.

Results

The recurrence-free period was not significantly different between the two groups (BL and WL groups) (long-rank test p = 0.202). The use of HAL helped detect four flat lesions and 28 papillary lesions with cancer that would have been missed under WL only, on 16 out of the 54 patients (29.6 % CI 95 % 11.1–33.3). The use of HAL changed the proposed postoperative treatment and follow-up for one out of the five patients.

Conclusions

Although the use of HAL cystoscopy identified at least one cancer lesion more than WL cystoscopy on one out of the three patients, the recurrence-free period was not significantly different.     

预防膀胱肿瘤术后复发的临床研究

目的 探讨不同方法预防膀胱肿瘤术后复发的效果,降低膀胱肿瘤复发率。方法对１９８２～１９９７年间采用膀胱灌注ＢＣＧ、丝裂霉素Ｃ（ＭＭＣ）、噻替呱、口服中药猪苓煎剂、后装腔内放疗５ 不同方法预防膀胱肿瘤复发,评价其效果。结果 随访２～１５年,其复发率分别为ＢＣＧ组３５．１％,猪苓３４．９％,ＭＭＣ组４１．７％,噻替呱组５２．６％,空白对照组６４．７％。后装放疗组处理高危性膀胱癌２５例,随访１２～４２个     

Randomized prospective phase III trial of difluoromethylornithine vs placebo in preventing recurrence of completely resected low risk superficial bladder cancer

PURPOSE: Ornithine decarboxylase catalyzes the rate limiting step in polyamine synthesis and its activity can be inhibited by difluoromethylornithine, which has been shown in preclinical studies, to prevent bladder cancer. MATERIALS AND METHODS: To assess the ability of difluoromethylornithine to prevent recurrence of low risk superficial bladder cancer, 454 patients with newly diagnosed (283) or occasionally recurrent (171), stage Ta (425) or T1 (29), grade 1 (263) or grade 2 (191), completely resected urothelial cancer were randomized to receive 1 gm difluoromethylornithine daily or placebo for 1 year. Patients were followed with cystoscopy every 3 months for 2 years and then semiannually for 2 years or until first recurrence. Index and recurrent tumors underwent central pathology review. RESULTS: No serious drug related toxicities were seen in either arm. Two patients died of bladder cancer at 2 and 4 years after randomization, both in the difluoromethylornithine arm. At 42 months followup, 103 patients in the difluoromethylornithine arm (46%) and 97 in the placebo arm (43%) (p = 0.30) experienced at least 1 tumor recurrence. Over 73% of recurrences occurred within 1 year in each arm. Each arm had similar responses for each stratification factor. During the 42 months of followup, 10 (4.4%) difluoromethylornithine and 9 (3.9%) placebo treated patients had progression to TIS or grade 3 disease, and 2 (0.9%) in the difluoromethylornithine arm and none in the placebo arm developed stage T2+ cancers. CONCLUSIONS: A year of difluoromethylornithine did not prevent recurrence of completely resected low risk superficial bladder cancer, when started shortly after surgery.     

膀胱癌患者癌症复发恐惧水平及影响因素的纵向研究

目的 调查膀胱癌患者癌症复发恐惧水平在疾病确诊后的动态变化,并分析其影响因素。方法 分别于膀胱癌确诊时、确诊后1个月、确诊后3个月、确诊后6个月采用一般资料调查表、恐惧疾病进展简化量表、社会支持量表、简易应对方式量表对213例膀胱癌患者进行调查。结果 4个时间点膀胱癌患者癌症复发恐惧得分分别为(28.92±6.69)分、(28.18±6.11)分、(27.15±5.84)分、(25.44±6.43)分;年龄、家庭人均月收入、肿瘤TNM分期、肿瘤复发、社会支持、应对方式为癌症复发恐惧的影响因素(均P<0.05)。结论 膀胱癌患者普遍存在癌症复发恐惧,确诊时至确诊后6个月癌症复发恐惧水平呈下降趋势。应早期识别与干预,以降低患者癌症复发恐惧水平。     

A randomized controlled study to compare bladder instillation therapy of anticancer agents and combination therapy with OK-432 injection in prevention of post-TUR recurrence of bladder cancer

To evaluate the effects of bladder instillation chemotherapy of anticancer agents with OK-432 intradermal injection (group A) in preventing postoperative recurrence of bladder carcinoma, a randomized controlled study with intravesical instillation chemotherapy of anticancer agents (group B) as the reference standard was performed. As the anticancer agents, pepleomycin (PEP) was usually used at a concentration of 30 mg/30 ml physiological saline. OK-432 injection dose was gradually increased from 0.5 KE to 5.0 KE and maintenance dose was decided by local skin reactions. There were no differences in the patient's background factors between group A (22 cases) and group B (17 cases). The no-recurrence rate of bladder carcinoma was similar in the two groups, but the no-recurrence rate for the virgin tumor or the stage T0 cases was higher in group B. On the other hand, the values for the recurrent cases or the stage T1,2 cases was higher in group A. The SU-PS skin reaction as an immunological response was significantly higher in group A. There were no severe side effects derived from anticancer bladder instillation or OK-432 injection.     

浅表性膀胱癌保留膀胱术后预后影响因素分析

目的 探讨浅表性膀胱肿瘤术后预后的各种影响因素.方法 回顾性分析186例浅表性膀胱肿瘤患者保留膀胱手术治疗的资料,研究肿瘤临床病理特征及治疗措施对手术预后的影响.结果本组病例中,复发65例,初诊时为多发、大于3 cm、病理为G2级以上的高危肿瘤复发率分别要高于单发、小于3 cm、病理为C1级的中低危肿瘤;对于保留膀胱的...     

Interval report of a phase I-II study utilizing multiple modalities in the treatment of invasive bladder cancer. A bladder-sparing trial

Clinicians at the Massachusetts General Hospital have used two cycles of methotrexate, cisplatin, and vinblastine (MCV) before radiotherapy and cisplatin in 53 patients with muscle-invasive bladder cancer. Eleven patients did not complete the protocol, but overall, the toxicity was not formidable. Of the total patients accessioned, 34 are alive. Of the 34 patients in the series who completed the full treatment protocol, the estimated survival rate at 54 months is 77%. This interim analysis suggests that the treatment is achieving at least limited success in saving lives and bladders.     

Influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized, double-blind, controlled trial

The influence of the instillation of thiotepa or doxorubicin hydrochloride into the bladder at the end of transurethral surgical treatment on the recurrence of bladder cancer was evaluated. We studied in a randomized, double-blind, controlled fashion 89 patients with transitional cell epithelioma (carcinoma in situ or papillary carcinoma) whose tumors were considered to have been completely removed. Of these patients 28 (the control group) received a placebo (sterile water), 30 received thiotepa and 31 received doxorubicin. By 3 to 4 months postoperatively 71 per cent of the control group, and 30 and 32 per cent, respectively, of the patients treated with thiotepa and doxorubicin had recurrences (p less than 0.01). Additional treatment during the followup interval was ineffective in all groups. Patients studied also were classified according to grade, histological findings, multiplicity of tumors and history of bladder tumor. Treatment was most effective in reducing recurrence in patients with low grade, papillary or multiple tumors and in patients with a history of bladder cancer. No effect was observed in patients with single tumors and only modest effects were found in those with high grade tumors, carcinoma in situ or new tumors. The results support the concept that recurrences may arise from tumor cell implantation at the time of transurethral management of bladder tumors and may be reduced effectively by concomitant intravesical chemotherapy.