Sequential intravesical gemcitabine and mitomycin C chemotherapy regimen in patients with non-muscle invasive bladder cancer

ObjectivesCurrently, there are few options other than cystectomy for the management of BCG refractory non-muscle invasive bladder cancer. We report our experience with intravesical combination chemotherapy using gemcitabine and MMC in such patients.Materials and methodsWe identified all patients with non-muscle invasive bladder cancer who were BCG refractory or intolerant and had been treated with intravesical gemcitabine and MMC at our institution. Patients were treated with a combination of intravesical gemcitabine (1000 mg in 50 ml sterile water) followed sequentially by intravesical MMC (40 mg in 20 ml sterile water) every week for 6 weeks (induction). Induction therapy was followed by a maintenance regimen using the same dose of gemcitabine and MMC once a month for 12 months. Data regarding patient demographics and disease information such as previous intravesical therapy, previous cystoscopy, cytology results, time to recurrence, and side effect profile were collected.ResultsA total of 10 patients (6 male and 4 female) aged 48 to 85 years (median 67 years) underwent treatment with a median follow-up of 26.5 months (4–34 months). Six patients were recurrence free and have maintained their response at a median of 14 months (4–34 months). Four patients had biopsy proven recurrence. Median time to recurrence was 6 months (range 4–13 months). The therapy was well tolerated in all patients. There were no major complications. Two patients experienced irritative lower urinary tract symptoms, which did not require cessation of therapy and one experienced a maculopapillary rash that improved with benadryl.ConclusionsIn patients with recurrent BCG refractory bladder cancer, intravesical combination chemotherapy with gemcitabine and MMC appears to be well tolerated and yields a response in a good proportion number of patients.     

Long-term efficacy of hyperthermic intravesical chemotherapy for BCG-unresponsive non-muscle invasive bladder cancer

BackgroundThe recommended treatment for patients with Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) is radical cystectomy (RC). However, many patients refuse, or are unfit for RC. Therefore, alternative bladder-sparing treatment modalities are needed for BCG-unresponsive NMIBC. In this study we sought to assess the long-term efficacy of hyperthermic intravesical chemotherapy (HIVEC) as alternative to radical cystectomy in BCG-unresponsive non-muscle invasive bladder cancer patients.Methods and materialsRetrospectively collected data from 56 patients with BCG-unresponsive NMIBC who received ≥5 HIVEC instillations between October 2014 and March 2020 was analyzed. All patients met the BCG-unresponsive criteria according to the current EAU guideline on NMIBC 2020. Patients were followed-up with cystoscopy and/or bladder biopsies, urine cytology and annually CT-urography. The Primary outcome was the high grade (HG) recurrence-free survival (RFS), defined as the time from the first HIVEC instillation until histologically confirmed intravesical recurrence or last follow-up. The Kaplan Meier method was used to estimate survival outcomes. Secondary outcomes were: complete response rate (CR), adverse events (AE), assessed by the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) and tumor progression to muscle invasive disease or distant metastases.ResultsThe median follow-up was 32.2 months (IQR 13.7–44.8). The 1- and 2-year HG-RFS was 53% (SE:6.8) and 35% (SE:6.9), respectively. The CR for patients with CIS was 70% (21/30) at 6 months. Overall, 80% of the population developed an AE, only 1 was classified as CTCAE ≥3. Limitation of this study was the small sample size.ConclusionHIVEC resulted in a 2-year HG-RFS of 35% for BCG-unresponsive NMIBC patients without severe side-effects and therefore HIVEC seems to be an alternative treatment option for patients who refuse or are unfit for RC.     

经尿道电切联合丝裂霉素膀胱内灌注治疗非肌层浸润性膀胱癌

目的 探讨经尿道电切术(transurethral reseetion of bladder tumor,TURBT)及术后使用丝裂霉素C(mitomycin C,MMC)膀胱内灌注治疗非肌层浸润性膀胱癌的临床疗效. 方法 本组46例非肌层浸润性膀胱癌均采用TURBT,术后使用MMC膀胱内灌注治疗. 结果 所有病例均一次完整切除.随访2年,37例非肌层浸润性膀胱癌无复发,7例分别于1年内复发,2例2年内复发.复发病例均再行TURBT并继续MMC膀胱内灌注. 结论 TURBT治疗非肌层浸润性膀胱癌具有手术简单、损伤小、出血少、恢复快和疗效好等优点.MMC膀胱内灌注能明显减少非肌层浸润性膀胱癌的复发.     

The effects and effectiveness of electromotive drug administration and chemohyperthermia for treating non-muscle invasive bladder cancer

Introduction

Preliminary studies show that device assisted intravesical therapies appear more effective than passive diffusion intravesical therapy for the treatment of non-muscle invasive bladder cancer (NMIBC) in specific settings, and phase III studies are now being conducted. Consequently, we have undertaken a non-systematic review with the objective of describing the scientific basis and mechanisms of action of electromotive drug administration (EMDA) and chemohyperthermia (CHT).

Methods

PubMed, ClinicalTrials.gov and the Cochrane Library were searched to source evidence for this non-systematic review. Randomised controlled trials, systematic reviews and meta-analyses were evaluated. Publications regarding the scientific basis and mechanisms of action of EMDA and CHT were identified, as well as clinical studies to date.

Results

EMDA takes advantage of three phenomena: iontophoresis, electro-osmosis and electroporation. It has been found to reduce recurrence rates in NMIBC patients and has been proposed as an addition or alternative to bacillus Calmette–Guérin (BCG) therapy in the treatment of high risk NMIBC. CHT improves the efficacy of mitomycin C by three mechanisms: tumour cell cytotoxicity, altered tumour blood flow and localised immune responses. Fewer studies have been conducted with CHT than with EMDA but they have demonstrated utility for increasing disease-free survival, especially in patients who have previously failed BCG therapy.

Conclusions

It is anticipated that EMDA and CHT will play important roles in the management of NMIBC in the future. Techniques of delivery should be standardised, and there is a need for more randomised controlled trials to evaluate the benefits of the treatments alongside quality of life and cost-effectiveness.     

Long-term outcomes of intravesical therapy for non-muscle invasive bladder cancer

Objectives  

The purpose of the current review was to evaluate the long-term outcomes of intravesical therapy for non-muscle invasive bladder cancer.     

The value of perioperative mitomycin C instillation in improving subsequent bacillus calmette-guerin instillation efficacy in intermediate and high-risk patients with non-muscle invasive bladder cancer: a prospective randomized study

Purpose: We evaluated the efficacy of perioperative mitomycin C (MMC) instillation to improve subsequent bacillus Calmette-Guérin (BCG) instillation efficacy in intermediate and high risk patients with non-muscle invasive bladder cancer (NMIBC). Materials and Methods: From November 2004 to May 2006, 51 patients with intermediate or high risk NMIBC were enrolled in this prospective randomized trial. In group A, patients were treated with perioperative MMC (40 mg MMC in 40 mL saline was administered within 6 hours of surgery) followed by delayed (at least 15 days from surgery) BCG instillations (once a week for 6 weeks, 5 x 108 colony-forming units in 50 mL saline). Patients in group B were treated with delayed BCG instillations alone. The primary end points were recurrence-free interval and recurrence rate. Results: There were 25 and 26 patients in groups A and B, respectively. Median follow-up was 41.3 months (range 8 to 64) in group A and 40.9 months (range 6 to 68) in group B. Recurrence rate was 36 % (9 of 25) and 19.3 % (5 of 26) in group A and B, respectively (p = 0.052). Median time to the first recurrence was 8 months in group A and 7 months in group B (p = 0.12). Conclusions: The present study showed no statistically significant difference in terms of recurrence rate and median time to first recurrence between intermediate or high-risk patients with NMIBC who were treated with early single dose instillation of MMC plus delayed BCG and those who were treated with only BCG.     

4'-epidoxorubicin versus mitomycin C intravesical chemoprophylaxis of superficial bladder cancer.

The authors report the preliminary data concerning a phase III study comparing the chemoprophylactic effects of mitomycin C and epirubicin in Ta-T1 primary and recurrent superficial bladder tumors. 60 patients were treated, 32 with epirubicin and 28 with mitomycin C, with a medium follow-up of 17.7 and 16.2 months, respectively. There were no systemic side effects. The remission rate was 62.5% in the epirubicin group and 64.2% in the mitomycin C group. Both drugs were equally useful in the chemoprophylaxis of superficial bladder cancer.     

Immediate administration of intravesical mitomycin C after tumour resection for superficial bladder cancer

OBJECTIVE: To assess the feasibility and safety of administering intravesical mitomycin C in theatre immediately after transurethral resection of bladder tumour (TURBT). PATIENTS AND METHODS: A protocol was developed to allow the safe administration of mitomycin C in theatre immediately after TURBT. Over a 32-month period all patients not excluded by the protocol were given mitomycin C in theatre after TURBT, and any adverse events reported. RESULTS: In all, 177 instillations were carried out; there were two minor patient-related complications, and no staff-related adverse events. CONCLUSION: The immediate administration of mitomycin C in theatre after TURBT is feasible and safe for patients and staff. It provides the earliest and surest prophylaxis against tumour cell re-implantation at TURBT.     

Distal ureteral stenosis after early adjuvant intravesical mitomycin C application for superficial bladder cancer

We report a case of distal ureteral stenosis after transurethral resection of a small bladder tumor near the left ureteral orifice and early postoperative mitomycin C instillation for prevention of recurrence. The patient developed late recurrent stenosis of the ureteral orifice with histologic evidence of localized, severe benign inflammatory reaction. The recurrent stenosis was successfully managed by transurethral resection of the scar tissue and ureteric stenting. Although ureteral stenosis does occur after transurethral resection, the severity and time course of the stenosis in this case suggest an influence of the intravesical chemoprophylaxis used.     

Immune phenotype of peripheral blood mononuclear cells in patients with high-risk non-muscle invasive bladder cancer

Purpose

To explore the immune phenotype of peripheral blood mononuclear cells (PBMC) in patients with high-risk non-muscle invasive bladder cancer (NMIBC).

Methods

We prospectively collected blood samples from patients with high-risk NMIBC treated at our institution. PBMC were analyzed by flow cytometry to determine the frequency of T cells and NK cells and the expression of immunoregulatory molecules (Tim-3, TIGIT and PD-1). PBMC from healthy donors (HD) were included for comparison, and associations with response to BCG were investigated.

Results

A total of 38 patients were included, 19 BCG responders and 19 BCG refractory. Compared to 16 PBMC from HD, the frequency of total NK cells was significantly higher in patients with NMIBC [15.2% (IQR: 11.4, 22.2) vs. 5.72% (IQR: 4.84, 9.79); p?=?0.05], whereas the frequency of T cells was not statistically different. Both Tim-3 and TIGIT expressions were significantly higher in NMIBC compared to HD, particularly in NK cells [13.8% (11.0; 22.4) vs. 5.56% (4.20; 10.2) and 34.9% (18.9; 53.5) vs. 1.82% (0.63; 5.16), respectively; p?<?0.001]. Overall, the expression of PD-1 in all cell types was low in both NMIBC patients and HD. The immune phenotype was not significantly different before and after initiation of BCG. However, the proportion of CD8⁺ T cells before BCG was significantly higher in responders.

Conclusion

The immune phenotype of PBMC from patients with high-risk NMIBC was significantly different from HD, regardless of the presence of disease or the initiation of BCG. Peripheral CD8⁺ T cells could play a role in response to BCG.

     

Bladder wall calcification after intravesical mitomycin C treatment of superficial bladder cancer

Calcification of the bladder wall associated with intravesical mitomycin C for the treatment of superficial bladder cancer is a rare complication. We report on a patient with this complication and discuss the literature.     

T1G3 high-risk NMIBC (non-muscle invasive bladder cancer): conservative treatment versus immediate cystectomy

Background  

The management of stage T1 poorly differentiated G3 bladder cancer invading the lamina propria continues to be debated. These tumours are associated with a high risk of recurrence and progression; concomitant carcinoma in situ and/or multifocality are negative prognostic factors. Choosing between a preserving approach such as trans-urethral resection of the bladder (TURB) followed by maintenance bacillus Calmette-Guerin (BCG) and an invasive approach like cystectomy is critical.     

Practical applications of intravesical chemotherapy and immunotherapy in high-risk patients with superficial bladder cancer

The following steps are practical in the treatment of intermediate-to-high risk patients with superficial bladder cancer: Resect all visible tumor at the time of first TUR of bladder tumor. Strongly consider re-resection, especially for high-risk, large, multifocal, stage T1 tumors. Apply one dose of cytotoxic chemotherapy perioperatively within 6 hours of TUR (ideally immediately). Once histopathology is available, consider intravesical induction chemotherapy for intermediate-risk patients and BCG for intermediate- or high-risk patients and those having failed prior chemotherapy. At least 1 year of maintenance therapy should be planned for all intermediate-to-high risk BCG-treated patients. Chemotherapy maintenance may be useful if perioperative chemotherapy was omitted. For patients failing standard therapy, a thorough discussion of the risks (including progression and metastasis) and expected benefits should take place before the initiation of salvage therapy. The radical cystectomy option should be openly entertained. Consider BCG plus interferon or gemcitabine-based salvage programs if appropriate. Explore clinical trial options. Contact urologic cancer experts for guidance and advice.     

Thermo-chemotherapy and electromotive drug administration of mitomycin C in superficial bladder cancer eradication. a pilot study on marker lesion

OBJECTIVE: To assess the feasibility and safety of two novel methods for intravesical chemotherapy administration in patients suffering from superficial bladder carcinomas. To draw preliminary considerations concerning the ablative effect on marker lesion using novel approaches compared to standard intravesical chemotherapy. METHODS: Eighty patients suffering from single, recurrent, low-stage, low-grade superficial bladder tumor entered a prospective nonrandomized study. Thirty-six of them were treated by means of mitomycin C instillation as a standard procedure. In 29 patients mitomycin C solution was administered in combination with local microwave-induced hyperthermia and in 15 patients the mitomycin C solution was administered according to the electromotive drug procedure. The treatment was scheduled as a short term neo-adjuvant regimen prior to transurethral resection. Feasibility and safety of the different procedures were evaluated on an outpatients basis. The local toxicity induced by different approaches was defined and compared using a subjective questionnaire. RESULTS: Both intravesical chemotherapy administered in combination with hyperthermia and according to the electromotive drug technique appeared to be feasible and safe. Local toxicity induced by thermo-chemotherapy was more severe than that registered for electromotive drug technique and standard intravesical chemotherapy. Local toxicity was always short and self healing without early or delayed major complications. A higher complete response rate on marker lesion was observed after thermo-chemotherapy compared to other administration methods. CONCLUSION: The intravesical administration of mitomycin C can be safely performed in the form of both thermo-chemotherapy and electromotive drug approach with an increased ablative success rate on small superficial tumor involving only minimal local side effects.     

Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study

PURPOSE: In laboratory studies electromotive mitomycin C (MMC) demonstrated markedly increased transport rates compared with passive transport. We performed a prospective study in patients with high risk superficial bladder cancer to assess the efficacy of intravesical electromotive vs passive MMC using bacillus Calmette-Guerin (BCG) as a comparative treatment. MATERIALS AND METHODS: Following transurethral resection and multiple biopsies 108 patients with multifocal Tis, including 98 with T1 tumors, were randomized into 3 equal groups of 36 each who underwent 40 mg electromotive MMC instillation with 20 mA electric current for 30 minutes, 40 mg passive MMC with a dwell time of 60 minutes or 81 mg BCG with a dwell time of 120 minutes. Patients were scheduled for an initial 6 weekly treatments, a further 6 weekly treatments for nonresponders and a followup 10 monthly treatments for responders. Primary end points were the complete response rate at 3 and 6 months. MMC pharmacokinetics were assessed. RESULTS: The complete response for electromotive vs passive MMC at 3 and 6 months was 53% versus 28% (p = 0.036) and 58% versus 31% (p = 0.012). For BCG the responses were 56% and 64%. Median time to recurrence was 35 vs 19.5 months (p = 0.013) and for BCG it was 26 months. Peak plasma MMC was significantly higher following electromotive MMC than after MMC (43 vs 8 ng/ml), consistent with bladder content absorption. CONCLUSIONS: Intravesical electromotive administration increases bladder uptake of MMC, resulting in an improved response rate in cases of high risk superficial bladder cancer.     

经尿道等离子电切联合吡柔比星膀胱灌注治疗高龄高危非肌层浸润性膀胱癌

目的 探讨经尿道膀胱癌等离子电切术(PKRBT)联合吡柔比星(THP)治疗高龄高危非肌层浸润性膀胱癌的效果.方法 对2008年9月至2012年2月本院17例高龄高危非肌层浸润性膀胱癌患者行经尿道膀胱肿瘤电切联合吡柔比星膀胱灌注治疗的综合措施进行分析.结果 全部患者治疗的短期效果好,能改善患者的生活质量,延长患者的生命.结论 经PKRBT联合THP膀胱灌注治疗对高龄高危非肌层浸润性膀胱癌有较好的治疗效果,有望降低瘤荷,可作为高龄高危非肌层浸润性膀胱癌的较好的治疗方法.