Intravesicle gemcitabine in management of BCG refractory superficial TCC of urinary bladder—our experience

Abstract

Introduction

The incidence of bladder malignancy is increasing worldwide and the projected rise is 28% by 2010 for both sexes (according to the WHO). Though intravesical adjuvant therapy with bacillus Calmette-Guérin (BCG) is superior to any other immunotherapeutic/chemotherapeutic agent in reducing tumor recurrences and disease progression, its real efficacy remains controversial as one-third of the patients will soon develop BCG failure. Hence, there is a need for an alternative intravesical agent for treatment of BCG failure. Our aim is to study the efficacy, tolerability, and safety of intravesical gemcitabine in managing BCG refractory superficial bladder malignancy.

Material and Methods

Thirty-five BCG failure patients, 26 males and 9 females between 20 and 72 years of age were instilled 2000 mg of gemcitabine in 50 ml of normal saline intravesically 2 weeks post-tumor resection, for 6 consecutive weeks. Mean follow-up for 18 months with cystoscopy was done.

Result

Twenty-one patients (60%) showed no recurrences, 11 patients (31.4%) had superficial recurrences, while 3 patients (8.75%) progressed to muscle invasiveness. Average time to first recurrence was 12 months and to disease progression was 16 months. Adverse event was low and mild. Therapy was well tolerated.

Conclusion

Gemcitabine fulfills all requirements as an alternative agent in treating BCG failure patients with low adverse events, well tolerated, and highly effective in reducing tumor recurrences.

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.