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US Clinical Practice Patterns of Intravesical Chemotherapy for BCG-Unresponsive and BCG-Exposed Non-muscle Invasive Bladder Cancer - Beyond the Abstract

In the US urologic community, there is a dearth of data regarding the treatment regimens currently used for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). According to our survey, the most commonly used treatment for NMIBC cases who failed BCG is intravesical single-agent chemotherapy (more than 50% of respondents), with gemcitabine or mitomycin C accounting for over 70% of these chemotherapy regimens. This practice pattern was consistent, independent of BCG exposure and whether therapy was for carcinoma in situ (CIS) tumors or papillary-only tumors.1


In 1998, Valrubicin was the first FDA-approved, intravesical chemotherapy drug for BCG-refractory CIS. In 2020, pembrolizumab received FDA approval for the same indication. Nadofaragene firadenovec, a non-replicating adenovirus that produces human interferon alpha-2b, was also FDA approved for BCG-unresponsive CIS in December 2022 but awaits widespread distribution. Interestingly, none of these agents achieved top status in our survey.2,3,4

The BCG shortage has further complicated the management of NMIBC cases, especially in the BCG-naïve setting. This has resulted in fewer than one-third of patients receiving adequate BCG treatment during the first induction and even fewer patients who receive a second induction or extended maintenance therapy.5,6,7 In response to that shortage, various intravesical chemotherapy agents such as gemcitabine (Gem), epirubicin, docetaxel (Doce), valrubicin, or sequential gemcitabine/docetaxel (Gem/Doce) or gemcitabine/mitomycin (Gem/MMC) have been utilized for induction and maintenance regimens.5 Unfortunately, there are no clear guidelines on how and when to select one treatment over another because of the absence of well-controlled comparative trials. One particular unaddressed consideration is how these agents perform on recurrent NMIBC in the BCG-exposed population and whether efficacy differs by tumor type, Ta vs. T1 vs. CIS.

In BCG failure, treatment decisions are even more challenging. Urological societies still recommend radical cystectomy as the best therapy. Still, patients are less willing to undergo this major operation due to comorbidities and acceptance to remove their bladder if no muscle invasiveness is detected in pathology. This was reflected in real-world results where the rate of radical cystectomy was substantially greater in the pre-shortage era, contradicting the assumption that this rate would increase in response to the BCG shortage.8, 9

There are several novel agents in the pipeline for BCG failure disease, such as atezolizumab, N-803, Tar-200, enfortumab vedotin, and others. Their usage may already be limited before FDA approval because of their high cost, unfamiliarity, and potential systemic toxicity. Device-assisted chemothermotherapy has been used in several centers, but it is not yet approved in the US.10 With these obstacles to novel treatment, intravesical Gem, MMC, and sequential Gem/Doce and Gem/MMC have emerged as the practical options available to urologists outside of major medical centers, either as rescue therapies or even upfront treatments for NMIBC.10

While direct comparative trials between these agents are very limited (Gem outperformed MMC by about 15% in one study of BCG-exposed patients with papillary only disease), a recent analysis of single arm studies to determine the average 2-year recurrence-free rate (2yr RFR) provides some insight into the relative efficacy of each agent under specific circumstances.10 Gem provides a ~40% 2yr RFR for BCG-naïve (mostly high-risk papillary) cases but this rate decreases to ~30% for patients with BCG failure and only ~20% for BCG failure with CIS. MMC has similar efficacy but has been less widely studied.11 Sequential Gem/Doce, by contrast, had better efficacy with a 2yr RFR of ~80% among BCG naïve patients (high-risk mixed papillary and CIS), ~60% in BCG failure papillary disease (whether high-risk or intermediate-risk), and ~45% for BCG-failure CIS.10,12,13 Gem/Doce has been shown to be equally efficacious as conventional BCG treatment for intermediate-risk disease.14,15 The combination of intravesical Gem/MMC has only been studied in the BCG-failure setting but appears to be similar in efficacy to Gem/Doce.10


The urologist has a pivotal role in the management of NMIBC. While phase 3 comparative trials are still lacking, treatment should be chosen based on relative agent effectiveness, tumor types to be treated, BCG exposure state, and previous therapy. Logistic constraints and personal beliefs should never be a justification for using a less effective drug, as the implications of ineffective second-line therapy are significant.

Written by: Mohamad Abou Chakra, MD,1 Neal D. Shore, MD, FACS,2 Michael A. O'Donnell, MD1


  1. Department of Urology, University of Iowa, Iowa City, Iowa, US.
  2. Carolina Urologic Research Center, Myrtle Beach, SC, US.
References:

  1. Abou Chakra M, Shore ND, Dillon R, O'Donnell MA. US Clinical Practice Patterns of Intravesical Chemotherapy for Bacillus Calmette-Guérin-Unresponsive and Bacillus Calmette-Guérin-Exposed Nonmuscle-Invasive Bladder Cancer [published online ahead of print, 2023 Oct 30]. Urol Pract. 2023;101097UPJ0000000000000481.
  2. Chehroudi AC, Black PC. Emerging intravesical therapies for the management of bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer: Charting a path forward. Can Urol Assoc J. 2020;14(6):204-213.
  3. Pfail JL, Katims AB, Alerasool P, Sfakianos JP. Immunotherapy in non-muscle-invasive bladder cancer: current status and future directions. World J Urol. 2021;39(5):1319-1329.
  4. U.S. Food & Drug Administration. FDA approves first gene therapy for the treatment of high-risk, non-muscle-invasive bladder cancer [media release]. 16 Dec 2022.
  5. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196(4):1021-1029.
  6. Williams SB, Howard LE, Foster ML, et al. Estimated Costs and Long-term Outcomes of Patients With High-Risk Non-Muscle-Invasive Bladder Cancer Treated With Bacillus Calmette-Guérin in the Veterans Affairs Health System. JAMA Netw Open. 2021;4(3):e213800.
  7. Kumar N, Balaji H parthasarathy, Emond B, et al. Real-world treatment patterns among patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical Bacillus Calmette-Guerin (BCG). Journal of Clinical Oncology 2022; 40: 404–404.
  8. Joudi FN, Smith BJ, O'Donnell MA, Konety BR. Contemporary management of superficial bladder cancer in the United States: a pattern of care analysis. Urology. 2003;62(6):1083-8.
  9. Tully KH, Cole AP, Krimphove MJ, et al. Contemporary Treatment Patterns for Non-muscle-invasive Bladder Cancer: Has the Use of Radical Cystectomy Changed in the BCG Shortage Era?. Urology. 2021;147:199-204.
  10. Nazmifar M, Williams C, Naser-Tavakolian A, et al. Clinical and Preclinical Therapies for Bladder Cancer Following Bacillus Calmette-Guérin Failure. J Urol. 2023;209(1):32-48.
  11. Abou Chakra M, Packiam VT, O'Donnell MA. Real-world efficacy of adjuvant single-agent intravesical gemcitabine for non-muscle invasive bladder cancer [published online ahead of print, 2023 Oct 16]. Expert Opin Pharmacother. 2023;1-11.
  12. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer. J Urol. 2020;203(5):902-909.
  13. McElree IM, Steinberg RL, Mott SL, et al. Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non-Muscle-Invasive Bladder Cancer. JAMA Netw Open. 2023;6(2):e230849.
  14. Tan WS, McElree IM, Davaro F, et al. Sequential Intravesical Gemcitabine and Docetaxel is an Alternative to Bacillus Calmette-Guérin for the Treatment of Intermediate-risk Non-muscle-invasive Bladder Cancer [published online ahead of print, 2023 Jul 18]. Eur Urol Oncol. 2023;S2588-9311(23)00143-8.
  15. McElree IM, Orzel J, Stubbee R, et al. Sequential intravesical gemcitabine and docetaxel for treatment-naïve and previously treated intermediate-risk nonmuscle invasive bladder cancer [published online ahead of print, 2023 Jul 11]. Urol Oncol. 2023;S1078-1439(23)00228-4.
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