In the present study, we demonstrated that intensive intravesical instillation of low-dose pirarubicin (THP) for six times was safer than Bacillus Calmette-Guérin (BCG) in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). In addition, no significant difference was observed in terms of oncological outcomes, including intravesical and upper urinary tract (UUT) recurrences, progression to muscle-invasive bladder cancer (MIBC), and metastasis, cancer-specific mortality, and overall mortality between patients treated with intensive intravesical instillation of low-dose THP and BCG.
Several guidelines strongly recommend intravesical instillation of BCG, including induction and subsequent maintenance therapy, after transurethral resection of bladder tumor (TURBT) in patients with high-risk NMIBC.1-3 However, it causes a significantly higher occurrence of adverse events (AEs) than chemotherapy,4 and severe systemic AEs that occur in <5% of patients can be life-threatening.5,6
Repeat intravesical instillation of chemotherapy is recommended to patients with intermediate-risk NMIBC because of its oncological benefits.1,2,7 Regarding high-risk NMIBC, several studies have reported that the efficacy of long-term repeat intravesical instillation of mitomycin C (MMC) is similar to that of BCG without maintenance therapy.8-10 However, patients present with an increased occurrence of AEs and require long-term hospital visits (for six months to three years) for MMC therapy.8
THP, which is one of the most widely used intravesical chemotherapeutic agents in Japan,11 has the low permeability from the bladder wall to the systemic circulation, contributing to a low systemic AE rate.11,12 However, little is known about the safety and efficacy of repeat intravesical instillation in patients with NMIBC. We speculated that the efficacy of intensive intravesical instillation of THP for six times within 10 days after TURBT might be similar to that of BCG therapy. In addition, low-dose (20 mg) THP with 30 mg of normal dose might reduce the occurrence of AEs caused by repeat instillation.
Therefore, we evaluated the safety and efficacy of intensive intravesical instillation of low-dose THP for six times versus BCG induction therapy after TURBT in patients with primary high-risk NMIBC.
In the present study, 370 patients with primary high-risk NMIBC who were treated with either intensive intravesical instillation of low-dose THP for six times (THP group) or BCG induction therapy (BCG group) after TURBT from November 1993 to April 2019 at four Hospitals were retrospectively evaluated. The patients in the THP group received 20 mg of THP with 30 mg of normal dose in 50 mL of normal saline intravesically within two hours after TURBT. Subsequently, the patients received an additional 20 mg of THP for five times every other day within 10 days. The solution was kept in the bladder for one hour. Intravesical instillation of BCG was not performed in the THP group. The incidence of AEs associated with intravesical instillation and oncological outcomes were compared between the two groups.
The median age and median follow-up period after TURBT was 72 years and 45 months, respectively. Of the 370 patients with primary high-risk NMIBC, 180 (49%) and 190 (51%) were classified into the BCG and THP groups, respectively. The treatment completion rate in the BCG group was significantly lower than that in the THP group (P = 0.032). The incidence of AEs (all grade) in the BCG group was significantly higher than that in the THP group (58% vs 11%, P < 0.001). Similarly, the incidence of AEs (all grade) in the BCG group was significantly higher than that in the THP group in patients aged 75 years or older (56% vs 12%, P < 0.001).
In the background-adjusted multivariate analyses with the inverse probability of treatment weighting model, no significant differences were observed between the BCG and THP groups on intravesical recurrence-free survival (RFS), UUT RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival.
To the best of our knowledge, this is the first study that has evaluated the safety and efficacy of intensive intravesical instillation of low-dose THP for six times versus BCG in patients with primary high-risk NMIBC. Results showed that intensive intravesical instillation of low-dose THP for six times was safer than BCG. In addition, no significant differences were observed in terms of oncological outcomes between the two groups.
Several guidelines strongly recommend intravesical instillation of BCG, including induction and subsequent maintenance therapy after TURBT in patients with high-risk NMIBC.1-3 However, intravesical instillation of BCG is not widely used in general clinical practice.13 Recently, Balakrishnan et al. reported that of 47,694 patients with high-risk NMIBC, only 24% received intravesical instillation of BCG after TURBT.14 They speculated that patients’ factors, such as age, comorbidities, and difficulty in complying with treatment schedules contributed to nonadherence to the guidelines.14 In addition, a high incidence of AEs may influence the outcomes.4,6,11 By contrast, intensive intravesical instillation of low-dose THP for six times resulted in a lower incidence of AEs compared with BCG in the present study, and patients could complete the treatment schedule within 10 days after TURBT. Therefore, if clinicians assess that patients cannot withstand BCG therapy, intensive intravesical instillation of low-dose THP for six times may be one of the treatment options in patients with high-risk NMIBC.
Although the present study has several limitations, intensive intravesical instillation of low-dose THP for six times may be one of the treatment options in view of safety and efficacy after TURBT in patients with primary high-risk NMIBC. A prospective randomized study is needed to validate the results.
Written by: Naoki Fujita, MD, and Shingo Hatakeyama, MD, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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