Efficacy of intravesical gemcitabine instillation compared with intravesical Bacillus Calmette-Guérin instillation for non-muscle invasive bladder cancer

Article information

Kosin Med J. 2024;39(4):254-258

Publication date (electronic) : 2024 December 11

doi : https://doi.org/10.7180/kmj.24.143

Dong Ha Kim, Taek Sang Kim, Su Hwan Kang, Seong Bin Kim

Department of Urology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea

Corresponding Author: Taek Sang Kim, MD, PhD Department of Urology, Kosin University Gospel Hospital, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea Tel: +82-51-990-5077 Fax: +82-51-990-3994 E-mail: threeb74@naver.com

Received 2024 September 24; Revised 2024 October 14; Accepted 2024 October 18.

Abstract

Introduction

Non-muscle invasive bladder cancer (NMIBC) accounts for about 70% to 75% of all bladder cancers [1]. Its recurrence rate within 1 year is about 50% [2]. If appropriate treatment is not received for NMIBC, the cancer may progress and invade the muscle layer or metastasize. Therefore, effective treatment for NMIBC is very important in the overall treatment strategy for bladder cancer.

Currently, one of the most commonly used methods for treating NMIBC is intravesical Bacillus Calmette-Guérin (BCG) instillation. BCG, a type of live attenuated vaccine, can induce an immune response that plays a role in inhibiting the growth of cancer cells [2]. Although the efficacy of BCG instillation has been proven in many studies [3,4], a significant number of patients experience side effects from BCG treatment, with some not responding to the treatment [4].

Recently, as global supply of BCG has become insufficient, many medical institutions are seeking alternative treatments. The shortage of BCG supply is due to various factors such as production issues, increased demand, and supply chain limitations [5]. In this context, gemcitabine is being considered as an alternative [6]. Gemcitabine is an anticancer agent that can inhibit the repair of DNA in cancer cells and suppresses the growth of cancer cells [7]. As an alternative to BCG intravesical instillation, intravesical gemcitabine instillation is being considered for treating NMIBC. It is known to have fewer side effects and higher tolerance in patients than BCG instillation [8]. However, direct comparative studies on the efficacy of these two treatments are limited. Therefore, the purpose of this retrospective study was to compare patients with NMIBC who received BCG intravesical instillation and those who received gemcitabine intravesical instillation. Recurrence rates of the two treatments were evaluated. Their long-term utility was also explored.

Methods

This retrospective study targeted a cohort of 78 patients who received complete resection of visible tumors in the bladder via transurethral resection of bladder tumors from January 2022 to September 2023. These patients were diagnosed with NMIBC. They received intravesical BCG or gemcitabine instillation therapy. Among them, 42 patients received intravesical gemcitabine to reduce bladder recurrence and 36 patients received intravesical BCG. The BCG therapy involved weekly intravesical BCG instillations for 6 weeks, while the gemcitabine therapy involved weekly intravesical gemcitabine instillations for 6 weeks. The maintenance therapy for BCG was administered every 6 months for 3 consecutive weeks for up to 2 years. For gemcitabine, maintenance therapy was administered once a month for up to 1 year as a general principle. Clinical data of patients were collected retrospectively through electronic medical records. Collected data items included demographic information (age, sex), tumor characteristics (number, size, grade), recurrence after treatment, and bladder storage time after instillation (BST). These collected data were analyzed using statistical software SPSS version 28 (IBM Corp.). Recurrence rates and recurrence-free survival (RFS) time between the two groups were compared and analyzed. Recurrence rates and RFS were compared using Kaplan-Meier survival analysis. Differences between groups were evaluated using the log-rank test. Adverse event rates were compared using the chi-square test. Statistical significance was set at p<0.05.

Results

Among a total of 78 patients, 42 were in the gemcitabine instillation group and 36 were in the BCG instillation group. The mean age of all patients was 72.6 years (range, 53–93 years). It was 73.1 years for the gemcitabine group and 71.9 years for the BCG group. The median follow-up period for all patients was 20.0 months (range, 9–29 months). It was 19.5 months for the gemcitabine group and 20.0 months for the BCG group. Eleven patients in the gemcitabine group (26.2%) and three patients in the BCG group (8.3%) had tumors larger than 2 cm, showing a significant (p=0.040) difference between the two groups. For BST, three patients in the gemcitabine group (7.1%) and 31 patients in the BCG group (86.1%) had a storage time of more than 2 hours, showing a significant difference between the two groups (p<0.001). Other characteristics showed no significant differences between the two groups (Table 1). During the follow-up period, 36 patients (46.2%) experienced bladder recurrence, including 22 (22/42, 52.4%) patients in the gemcitabine group and 11 (14/36, 38.9%) patients in the BCG group. The mean RFS (mRFS) was 15.92 months in the gemcitabine group and 19.84 months in the BCG group. The difference in mRFS between the two groups was not statistically significant (p=0.397) (Fig 1). Three patients in the gemcitabine group (3/42, 7.1%) and 31 patients in the BCG group (31/36, 86.1%) had a BST of more than 2 hours, indicating more severe bladder irritation symptoms in the gemcitabine group. In the gemcitabine group, no patients (0/42) reported any adverse effects during or after treatment. In contrast, in the BCG group, three patients (3/36, 8.3%) experienced adverse effects, including lower urinary tract symptoms (LUTS) such as increased urinary frequency and a urinary urgency. Despite these side effects, no patients discontinued treatment. The difference in adverse event rates between the gemcitabine and BCG groups was not statistically significant (p=0.056).

Table 1.

Baseline characteristics

Fig. 1.

Gemcitabine versus BCG: recurrence-free survival. Kaplan-Meier curve compares recurrence-free survival between gemcitabine and BCG groups. No significant difference was observed (p=0.397). BCG, Bacillus Calmette-Guerin.

Discussion

Several studies have investigated the efficacy of intravesical instillation therapies such as gemcitabine and docetaxel in BCG failure cases of NMIBC. Skinner et al. [9] have reported a 1-year recurrence rate of 72% and an mRFS of 6.1 months after intravesical gemcitabine was administered to BCG failure patients. Di Lorenzo et al. [10] have also reported a recurrence rate of 52.5% and an mRFS of 3.9 months when intravesical gemcitabine was administered to BCG intractable patients. Although studies on first-line intravesical instillation therapies are limited, Bendary et al. [11] have reported no significant difference in recurrence rate between first-line gemcitabine and BCG groups (p=0.66), showing similar results to our study. Various agents such as docetaxel, mitomycin C, and adriamycin have been suggested as potential alternatives to BCG [12-14], although BCG has been traditionally preferred due to its effectiveness, especially in high-grade tumors and carcinoma in situ. Recently, due to BCG shortage, there is an increasing need to use alternative agents as first-line or BCG substitutes [5]. However, studies comparing these alternatives to BCG are insufficient. Although the present study was a retrospective study, we could see that the efficacy of gemcitabine intravesical instillation therapy was comparable to that of BCG intravesical instillation therapy in NMIBC patients as a first-line treatment (gemcitabine instillation mRFS, 15.92 months; BCG instillation mRFS, 19.84 months; p=0.397) (Fig. 1).

Among individuals known to be at risk of bladder cancer recurrence [15,16], there was no difference in tumor multiplicity, tumor grade, or tumor T stage (Ta, T1), although there was a difference in tumor size between the two groups (Table 1). However, there was no significant difference in mRFS between the two groups (Fig. 1). Larger-scale research is needed to confirm these findings. In the study by Cambier et al. [15], the sample size was large at 762 individuals, which might explain such different results compared to the present study. While the efficacy of gemcitabine and BCG instillations was similar in terms of RFS, the adverse event profiles differed between the two groups. Notably, no patients in the gemcitabine group reported any adverse effects, whereas 8.3% of patients in the BCG group experienced mild LUTS, including increased urinary frequency and urinary urgency. Although the difference in adverse event rates between the two groups was not statistically significant (p=0.056), this trend suggests that BCG treatment may be associated with more frequent adverse effects. Clinically, these results underscore the importance of monitoring tolerability, as even mild adverse effects can influence patient comfort and treatment adherence. In this study, patients were allowed to refrain from urination for up to 2 hours after BCG and gemcitabine instillation. Most patients in the BCG group were able to hold for 2 hours after drug administration. However, in the gemcitabine group, only 7.1% of patients could hold for more than 2 hours and only 47.5% could hold for more than 1 hour. The actual toxicity was higher and more severe in the BCG group [11,17]. The gemcitabine group had less toxicity and shorter BST. This indicates that to increase effectiveness, research on appropriate BST, gemcitabine administration methods, administration concentration, and oral LUTS medication are needed. Research on the treatment sequence after failure of 1st line gemcitabine intravesical instillation is also necessary. In conclusion, this study compared efficacies of gemcitabine and BCG intravesical instillation methods in NMIBC patients through retrospective analysis. Both treatment methods showed similar RFS. Considering the issue of BCG supply shortage, gemcitabine could be a viable alternative. However, further research on methods to maintain drug retention in the bladder for a sufficient period after instillation is needed to enhance its effectiveness.

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