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Efficacy of Three BCG Strains (Connaught, TICE and RIVM) with or Without Secondary Resection (Re-TUR) for Intermediate/high-Risk Non-Muscle-Invasive Bladder Cancers: Results from a Retrospective Single-Institution Cohort Analysis - Beyond the Abstract

Since its introduction by Albert Calmette and Camille Guérin at the Pasteur Institute in Paris in 1921, the original BCG vaccine was distributed worldwide for many clinical uses, including immunotherapy against various types of cancer.1,2 After the first clinical experiences on human subjects by Morales et al in 1976.3 who showed that intravesical BCG was associated with a lower recurrence rate, the subsequent adoption of this method and the individual laboratory production that followed led the development of the various BCG strains available today. As demonstrated in genetic-determination studies on the different BCG mutations from the last 40-50 years, the genomic deletions and insertions which characterized several groups of BCG sub-strains may have led to further attenuation of potential efficacy.4 Consequently, the global distribution of different strains used to treat BCa might have led to potential imbalances in survival outcomes worldwide, potentially playing an important role in daily practice, especially in the era of BCG shortages.


Several other trials comparing different available BCG strains have been performed over the years,5 but heterogeneity both in study design and the implementation of induction therapy alone led to mixed results in determining whether a specific strain was superior over the others. In the present study, we compared a large historical cohort of patients who had been treated, as per institution protocol, with three of the most representative BCG strains worldwide. To our knowledge, this represents the first series with adequate follow-up allowing direct comparison of survival outcomes in these three different cohorts. A second strength of the present analysis is that patients were consistently treated with a standardized maintenance protocol. Another novel aspect of our study is the determination of the relative importance of secondary resection on survival outcomes and the effect of re-resection in combination with one specific strain. After having corroborated the importance of performing a routine secondary resection in intermediate/high-risk NMIBCs, the following clinical question urologists all around the world might ask themselves is whether the choice of the adoption of one strain over the other could influence their patients' survival outcomes. This seems indeed of particular relevance within the current context of BCG supply shortages.

In our series, we highlighted the recurrence-free survival benefit of both TICE and RIVM compared to Connaught when administered with a maintenance protocol. Then, we explored the clinical implication of the two most widely utilized American (TICE) and European (RIVM) strains. Of note, when stratifying our data for re-staging procedures we found in TICE a “winner” regarding RFS while differently a trend towards potential benefit of RIVM for progression-free survival endpoints. With all the precautions deriving from a retrospective study design, these seem relevant points to further explore in prospective, randomized, and hopefully multicentric matched pair trials. Future NMIBCs trials modeling the contribution of patient individualized risk stratification (e.g., liquid biopsy,6-8 functional imaging,9,10 pathologic sub-staging,11 etc.) in combination with personalized treatment therapeutic choices (±re-TUR, BCG strain, etc) will provide new horizons on optimizing oncologic efficacy and safety.

Written by: Francesco Del Giudice, MD,1,2 Benjamin I. Chung MD,2 Alessandro Sciarra, MD, PhD,1 Eila C. Skinner, MD2 and Ettore De Berardinis, MD1

  1. Department of Maternal-Infant and Urological Sciences, “Sapienza” Rome University, Policlinico Umberto I Hospital, Rome, Italy.
  2. Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.

References:

  1. Mathé G, Amiel JL, Schwarzenberg L, et al. Active immunotherapy for acute lymphoblastic leukaemia. Lancet. 1969;1(7597):697-699.
  2. Morton D, Eilber FR, Malmgren RA, Wood WC. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery. 1970;68(1):158-164.
  3. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976; 116(2): 180-183.
  4. Gan C, Mostafid H, Khan MS, Lewis DJ. BCG immunotherapy for bladder cancer--the effects of substrain differences Nat Rev Urol. 2013; 10(10): 580-588.
  5. Huang Z, Liu H, Wang Y, Zhang C, Xu T. Determining optimal maintenance schedules for adjuvant intravesical bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis. Curr Med Res Opin. 2017; 33(8): 1379-1387.
  6. Nicolazzo C, Busetto GM, Del Giudice F, Sperduti I, Giannarelli D, Gradilone A, Gazzaniga P, de Berardinis E, Raimondi C. The long-term prognostic value of survivin expressing circulating tumor cells in patients with high-risk non-muscle invasive bladder cancer (NMIBC). J Cancer Res Clin Oncol. 2017 Oct;143(10):1971-1976.
  7. Ferro M, Di Lorenzo G, Vartolomei MD, Bruzzese D, Cantiello F, Lucarelli G, Musi G, Di Stasi S, Hurle R, Guazzoni G, Busetto GM, Gabriele A, Del Giudice F, Damiano R, Perri F, Perdona S, Verze P, Borghesi M, Schiavina R, Almeida GL, Bove P, Lima E, Autorino R, Crisan N, Farhan ARA, Battaglia M, Russo GI, Ieluzzi V, Morgia G, De Placido P, Terracciano D, Cimmino A, Scafuri L, Mirone V, De Cobelli O, Shariat S, Sonpavde G, Buonerba C. Absolute basophil count is associated with time to recurrence in patients with high-grade T1 bladder cancer receiving bacillus Calmette-Guérin after transurethral resection of the bladder tumor. World J Urol. 2020 Jan;38(1):143-150.
  8. Nicolazzo C, Busetto GM, Gradilone A, Sperduti I, Del Giudice F, Loreni F, Cortesi E, de Berardinis E, Gazzaniga P, Raimondi C. Circulating Tumor Cells Identify Patients with Super-High-Risk Non-Muscle-Invasive Bladder Cancer: Updated Outcome Analysis of a Prospective Single-Center Trial. Oncologist. 2019 May;24(5):612-616.
  9. Del Giudice F, Leonardo C, Simone G, Pecoraro M, De Berardinis E, Cipollari S, Flammia S, Bicchetti M, Busetto GM, Chung BI, Gallucci M, Catalano C, Panebianco V. Preoperative detection of Vesical Imaging-Reporting and Data System (VI-RADS) score 5 reliably identifies extravesical extension of urothelial carcinoma of the urinary bladder and predicts significant delayed time to cystectomy: time to reconsider the need for primary deep transurethral resection of bladder tumour in cases of locally advanced disease? BJU Int. 2020 Nov;126(5):610-619.
  10. Woo S, Panebianco V, Narumi Y, Del Giudice F, Muglia VF, Takeuchi M, Ghafoor S, Bochner BH, Goh AC, Hricak H, Catto JWF, Vargas HA. Diagnostic Performance of Vesical Imaging Reporting and Data System for the Prediction of Muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis. Eur Urol Oncol. 2020 Jun;3(3):306-315.
  11. de Jong FC, Hoedemaeker RF, Kvikstad V, Mensink JTM, de Jong JJ, Boevé ER, van der Schoot DKE, Zwarthoff EC, Boormans JL, Zuiverloon TCM. T1 Substaging of Nonmuscle Invasive Bladder Cancer is Associated with bacillus Calmette-Guérin Failure and Improves Patient Stratification at Diagnosis. J Urol. 2021 Mar;205(3):701-708.

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