Breaking Down the Safety of BCG in Patients With NMIBC

Bacille Calmette–Guerin (BCG) therapy is associated with a high frequency of symptoms and side effects (SSEs) among patients with non-muscle invasive bladder cancer (NMIBC), according to research published in Cancers. However, when used in sequential combination with chemotherapy, fewer SSEs were reported.

Furthermore, a lower frequency of SSEs were noted when BCG induction was given with maintenance compared with the induction stage. Regarding toxicity, the study authors concluded that low-dose BCG is less toxic than full-dose BCG through a comparison of SSEs.

“The principal findings of this study indicate that BCG induction alone was more toxic than BCG induction with maintenance, that BCG in combination with intravesical chemotherapy was less toxic than BCG monotherapy, that full-dose BCG was more toxic than low-dose BCG, and finally, BCG induction with maintenance was more toxic than chemotherapy with induction and maintenance,” first study author Dr. John Lahoud, of the Department of Urology, Westmead Hospital, in Sydney, Australia, and co-authors wrote in the journal.

NMIBC comprises approximately 75% of new bladder cancer cases and has high recurrence rates. Currently, BCG as the first-line option for intermediate- and high-risk NMIBC is currently recommended by The American Urological Association and European Association of Urology. Despite its efficacy, BCG has high toxicity, leading to treatment discontinuation in 8% of patients.

Furthermore, global shortages of the treatment have increased interest in alternatives like mitomycin C and gemcitabine. Progression on BCG therapy, defined as high-grade recurrence within six months, often requires radical cystectomy, though alternatives exist for ineligible patients. Adjuvant therapies cause significant side effects, impacting adherence and patient-reported outcomes. In order to learn more, investigators conducted this study to systematically assess BCG-related side effects and compare symptom frequency among treatments.

How Did Investigators Evaluate These Outcomes?

Investigators included patients over 18 years of age with any grade of NMIBC from any setting from studies which were primary research of prospective quantitative design, such as randomized controlled trials, a cohort study or comparative study. The studies’ primary or secondary outcomes assessed must have been symptoms, side effects and/or toxicities through direct patient reports and had sufficient data on patient reported outcomes.

If the study or sample included patients with stage T2 or greater MIBC, if symptoms were assessed by a healthcare provider or proxy, limited to pediatric populations, a study was a retrospective review of medical records, qualitative or a conference abstract or the study population included re-treatment cases, then they were not eligible for evaluation.

Researchers chose studies to include in their evaluation from various information sources by searching for terms like NMIBC, treatment symptoms and side effects. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) process was followed.

Going Into Detail With the Data

In total, out of the 2,126 records retrieved, 34 met the eligibility criteria and 7,070 patients were evaluable. Out of these 34 studies, 21 were randomized prospective trials while 13 were prospective cohort studies. In Europe 16 studies were conducted, and in Asia, Africa, the Middle East and North America, these numbers were 11, three, two, and two, respectively.

In the 1,311 patients who received only BCG induction for six to eight weeks (with 30 patients receiving 12 weeks), treatment toxicity was reported post-instillation and at follow-up. Contrarily, 3,251 patients underwent BCG induction with maintenance. Symptoms were more frequent in the induction-only group, including lower urinary tract symptoms (33.3% versus 29.2%), bladder pain (44% versus 30.2%), hematuria (24.3% versus 14.2%), fever (19.2% versus 12.1%), cystitis (32% versus 16.3%), severe bladder complications (0.7% versus 0%), prostatitis/epididymitis (0.8% versus 0.2%) and BCG sepsis (0.3% versus 0.1%). However, serious side effects requiring treatment cessation were less common in the induction-only group (3.1% versus 5.4%).

Among 4,499 patients who received BCG, 2,981 received a full dose, while 1,518 received a low dose. Side effects were more frequent in the full-dose group, including irritative lower urinary tract symptoms (36.6% versus 23.5%), bladder pain (40.4% versus 17.6%), hematuria (29% versus 15.5%), fever (17.4% versus 6.8%), fatigue/malaise (12.3% versus 8%), prostatitis/epididymitis (0.7% versus 0.1%) and serious side effects requiring treatment cessation (10.2% versus 4.5%).

In the 2,040 patients receiving induction therapy, 1,311 underwent BCG monotherapy, while 729 received BCG sequentially with chemotherapy. Patients who received BCG monotherapy experienced higher rates of irritative lower urinary tract symptoms (33.3% versus 22.4%), bladder pain (44% versus 7.4%), hematuria (24.3% versus 10.2%), and fever (19.2% versus 6.6%). In contrast, cystitis (21.3% versus 16.3%) and severe local bladder complications (0% versus 1.7%) were less frequent with BCG plus chemotherapy. Treatment cessation rates were similar between groups (3.2% versus 3.1%).

Finally, among the 5,702 patients receiving induction with maintenance therapy, 3,251 underwent BCG, while 2,451 received intravesical chemotherapy. BCG was associated with higher toxicity, including irritative lower urinary tract symptoms (29.2% versus 10%), bladder pain (30.2% versus 14.1%), hematuria (14.2% versus 12.4%), cystitis (32% versus 18.8%) and fever (12.1% versus 0.2%). Severe local bladder complications were slightly more common with chemotherapy (1.1% versus 0.7%), though not statistically significant. Additionally, the study authors noted that treatment cessation rates due to side effects were similar (5.4% versus 5.2%).

"Future studies should assess PROs in addition to oncological outcomes associated with treatment for NMIBC," the study authors concluded.

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Reference

“Symptoms and Side Effects of Bacille Calmette–Guerin Therapy for Non-Muscle Invasive Bladder Cancer as Reported by Patients: A Systematic Review” by Dr. John Lahoud, et al., Cancers.