Urologic Oncology: Seminars and Original Investigations
Original articleIntravesicle gemcitabine in management of BCG refractory superficial TCC of urinary bladder—our experience
Introduction
Incidence of transitional cell carcinoma (TCC) of urinary bladder is increasing worldwide with a projected rise of 28% by 2010 for both sexes (according to the WHO). This malignancy is particularly significant for the social system of industrialized countries. After initial therapy by transurethral resection of bladder tumor (TURBT), 75% to 80% will recur within 1 year and 20% to 25% will progress to muscle invasiveness if no adjuvant therapy is considered.
Intravesical instillation of bacillus Calmette-Guérin (BCG) is superior intravesical adjuvant therapeutic agent in reducing tumor recurrences and delaying disease progression time in mostly intermediate risk (Ta/T1-Gr.I-II, multifocal, size >3 cm) and rarely in high risk (T1G3, CIS) group as per European guidelines [1], [2].
Although BCG is currently considered the most effective agent in reducing recurrence rate and disease progression rate in superficial bladder cancer (SBC), its real efficacy remains controversial. A 2-year follow up with BCG showed 40% recurrence rate [3]. Peyromaure et al. [4] reported a 42% and 28% recurrence and progression rate, respectively, in the follow-up of 57 patients for 53 months with BCG therapy. Recent studies have shown BCG is effective in only two-thirds of SBC while one-third will be nonresponders [5]. Those SBC and CIS that fail to respond to initial BCG therapy are defined as BCG failures or nonresponders [6]. Post-BCG therapy recurrences show poor prognosis, and for these patients radical cystectomy remains the only treatment option. The side effect profile of 120 mg BCG represent another limiting factor for its use intravesically.
Chemotherapeutic agents such as mitomycin-C and doxorubicin, in spite of the low probability of systemic side effects, can give rise to severe chemical cystitis [7]. Recent studies have shown good result with intravesical electro motive MMC instillation.
Again following conventional intravesical chemotherapy, the short term recurrence rate of intermediate risk SBC cannot be reduced by more than 15% to 20% and long term risk of recurrence by 6% according to Lamn [8]. Hence, there is a need for a new intravesical agent for treatment SBC intermediate and high risk groups who do not respond to initial BCG therapy.
Systemic chemotherapy with gemcitabine and cisplatin for locally advanced muscle invasive bladder cancer has shown promising result [9], [10], with low side effects and good tolerance, as an alternative treatment option to conventional radical cystectomy.
Gemcitabine, a deoxycytidine analogue, has broad spectrum antitumor activity and as a nonvesicant drug, has very little local toxicity; hence high concentration in bladder could be achieved without drug induced cystitis; it penetrates bladder mucosa better, unlike mitomycin-C, because of its lower molecular weight of 299 Da, and preferentially produces cytotoxicity in bladder cancer cells while sparing nontransferred bladder mucosa and submucosal cells. Its rapid transformation to an inactive metabolite helps prevent systemic toxicity.
On the basis of the high relative advantage for regional therapy with gemcitabine and proven efficacy on systemically administration against the invasive cancer bladder, we undertook the following study with an aim to determine the efficacy, safety, and tolerability of fixed dose intravesical gemcitabine (2,000 mg) weekly for 6 weeks for 2 h duration in only those patients with superficial bladder cancer who had experienced failure to previous intravesical therapy with BCG.
Section snippets
Study design
This was a prospective, single arm, nonrandomized study conducted between January 2004 and December 2006.
Patients with superficial TCC of urinary bladder (Ta, T1, all grades) who had earlier indications for BCG therapy, i.e., multiple tumors, size more than 3 cm, and of younger age group but had shown repeated recurrence on follow-up were recruited in our study. This is a continuous, on-going study. Other eligibility criteria included in this study are age more than 18 years, good performance
Results
All 35 patients had initially intravesical therapy with BCG after TURBT, since they were fulfilling the inclusion criteria for adjuvant therapy with BCG, i.e., Ta/T1 stage, multiple tumors, and size more than 3 cm. On periodic follow-up, they showed repeated multiple recurrences; hence they were designated as BCG refractory, which made them eligible to receive intravesical gemcitabine. Histology grade of these 35 patients before therapy is shown in Table 1.
At the end of 18 months follow-up 21
Discussion
Pharmacokinetic data from different phase studies clearly demonstrate that systemic absorption of intravesical gemcitabine is minimal and transient and this is unlikely to produce clinically significant adverse events.
In vitro cytotoxic effects of gemcitabine in intravesical therapy showed selective cytotoxicity to human and rodent TCC cell line with relative sparing of fibroblast suggesting its effectiveness in SBC [11]. Another In vitro study comparing gemcitabine, epirubicin, mitomycin-C,
Conclusion
Intravesical gemcitabine seems to have fulfilled all the requirements of an alternative agent in managing BCG failure patients with superficial bladder cancer in whom bladder can be salvaged, but warrants further investigation in respect to its antitumor activity with marker lesion concept, its tolerability, and long term efficacy.
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Systematic Review of the Therapeutic Efficacy of Bladder-preserving Treatments for Non–muscle-invasive Bladder Cancer Following Intravesical Bacillus Calmette-Guérin[Formula presented]
2020, European UrologyCitation Excerpt :Of these, six SAs consisting of 281 patients with CIS-containing recurrences (two SAs i/ves gemcitabine ± PO everolimus, two SAs i/ves valrubicin, one SA i/ves oportuzumab monatox, and one SA i/ves photodynamic therapy) demonstrated median (range) CRRs of 44% (36–58%, n = 5) at 3 mo, 26% (18–44%, n = 5) at 6 mo, and 17% (9–31%, n = 6) at 12 mo [18,26,38,39,43,47]. Another five SAs evaluated cytotoxic agents in 193 patients with papillary recurrences (one SA i/ves mitomycin and four SA i/ves gemcitabine), yielding median (range) RFRs of 100% (100%, n = 1) at 3 mo, 81% (67–95%, n = 2) at 6 mo, and 61% (44–78%, n = 2) at 12 mo [7,19,22,25]. Fourteen SAs evaluated cytotoxic agents in 419 patients with CIS and/or papillary recurrences (five SAs i/ves gemcitabine, three SA i/ves thermochemotherapy, one SA i/ves oportuzumab monatox, one SA i/ves photodynamic therapy, one SA i/ves docetaxel, two SAs i/ves paclitaxel, and one SA PO dovitinib), yielding median (range) DFRs of 51% (28–99%, n = 10) at 3 mo, 66% (8–73%, n = 4) at 6 mo, and 41% (8–88%, n = 8) at 12 mo.
Intravesical and alternative bladder-preservation therapies in the management of non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guérin
2016, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :In total, 11 (37% of the entire cohort) patients ultimately required cystectomy. Other phase II trials have demonstrated variable efficacy at 1 year (22%–100%) [36–38], but variations in the administration schedule, dosing, and prior BCG exposure have made comparison of these studies difficult. In 2013, Skinner et al. reported on the results of a phase III trial in which 47 patients with 2 previous BCG failures received 2 g of intravesical gemcitabine weekly for 6 weeks of induction, followed by monthly maintenance for 1 year.
Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer
2014, Urologic Oncology: Seminars and Original InvestigationsMulti-institutional analysis of sequential intravesical gemcitabine and mitomycin C chemotherapy for non-muscle invasive bladder cancer
2014, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Currently, gemcitabine is being evaluated as an intravesical treatment option in patients who have previously failed BCG therapy. Three initial studies evaluating the use of intravesical gemcitabine in the treatment of BCG refractory NMIBC have had widely variable results [17–19]. RFS rates these studies were 10% at 12 months [18], 60% at 18 months [17], and 75% at 12 months [19].
Phase II study of biweekly gemcitabine as first line therapy in CIS of the bladder: What does an aborted trial tell us?
2013, Urologic Oncology: Seminars and Original InvestigationsPerioperative Chemotherapy. When to Use It, What to Use, and Why.
2013, Urologic Clinics of North AmericaCitation Excerpt :The reduction in the recurrence rate was significantly higher, whereas toxicity, particularly chemical cystitis, was lower than in the group treated with a 4-week course of MMC. Mohanty and colleagues80 reported a 60% (21 of 35 patients) tumor-free rate after 18 months in a similar cohort of patients with Ta or T1 BCG-refractory bladder cancer. Several more observational studies have evaluated the efficacy and tolerability of gemcitabine as an alternative intravesical treatment in patients who are BCG refractory or BCG intolerant.