key: cord-0045094-ytmjjxa2 authors: Nikas, Christine V.; Smith, Angela B. title: Goldilocks and the BCG: Bacillus Calmette-Guérin Dose Reduction in the Age of Shortage date: 2020-06-09 journal: Eur Urol DOI: 10.1016/j.eururo.2020.05.021 sha: 8f564e8a92ec77f1a4db0cb4745b4d3905898f75 doc_id: 45094 cord_uid: ytmjjxa2 nan In the field of oncology, striking the perfect balance between undertreatment and overtreatment of cancer is a perpetual challenge faced by physician-scientists. Balance in treatment must be tempered by research that challenges efficacy, toxicity and other relevant outcomes. Perhaps no better example in surgical oncology is the transition from the Halstead radical mastectomy to modified radical mastectomy, sparing countless women from a disfiguring surgery with little oncologic benefit [1] . Within our own field of urology, similar evolutions have occurred in the way in which we treat genitourinary malignancies. Radical nephrectomy has largely been replaced by nephronsparing surgery and active surveillance for small renal masses [2] . Likewise, radical prostatectomy and radiation have been replaced by active surveillance for low-risk prostate cancer [3] . While these examples highlight important changes in surgical treatment, changes in medical treatments can be equally important. Finding that "Goldilocks" balance between too much and not enough medication is critical. Optimal dosing and treatment schedules for chemotherapeutic agents must preserve efficacy, minimize toxicity, and avoid wasting existing supply. In the realm of non-muscleinvasive bladder cancer (NMIBC), bacillus Calmette-Guérin (BCG) toxicity and global shortages have led urologic oncologists to confront this challenge head-on [4] . Never has it been more important to determine that "just right" dose to achieve equivalent oncologic outcomes with a lesser amount of drug (and ideally less toxicity). Until recently, the induction BCG dose and schedule had changed very little since first introduced more than 40 yr ago by Morales and colleagues [5] . Over the years, subsequent studies expounded on the therapeutic effect of further maintenance instillations of BCG, but clear evidencebased guidelines on the optimal dosage and duration were lacking. The optimal dosage was then evaluated in the EORTC 30962 trial, which aimed to determine whether a one-third dose could achieve similar efficacy as full-dose BCG [6] . The goal of the EORTC 30962 trial was to minimize the adverse effects of BCG by reducing the BCG dose, and identified no significant differences in progression or survival for patients treated with a one-third dose compared to full-dose BCG. Not long after publication of the EORTC 30962 results, a global shortage of BCG had a widespread impact on bladder cancer, leading to increased recurrence rates and higher costs of care for patients with intermediate-and high-risk NMIBC [4] . In this issue of European Urology, Grimm and colleagues [7] further question BCG dosage and duration through the innovative NIMBUS trial design. The goal of the NIMBUS trial was to determine whether a reduced number of standard-dose BCG instillations is noninferior to the standard number and dose in patients with high-grade NMIBC. NIMBUS represents the logical continuation of the EORTC trial, attempting to further question the dosage and duration of BCG we deliver to patients rather than relying on historical precedence. The proposed treatment schedule reduced the total number of BCG doses from 15 to nine, whereby patients would receive induction BCG at weeks 1, 2, and 6, followed by 2 wk of maintenance at months 3, 6, and 12. The trial was a multicenter, noninferiority study that included 51 sites in five countries. Patients were stratified by center, Ta versus T1 disease, presence versus absence of carcinoma in situ (CIS), strain of BCG, and single versus multiple tumors. The study was halted before completion, as early results revealed that the reduced frequency schedule was inferior to the standard schedule based on the primary endpoint of time to recurrence. The NIMBUS trial provides us with a salient example of the value of a "negative" study. Arguably, these results provide similar albeit different value to that from the EORTC trial, enabling us to cut back on treatment, but not so much that it negatively impacts outcomes. Drawing again from our Goldilocks metaphor, the EORTC trial demonstrated that full-dose BCG may be "too hot", but NIMBUS suggests that reducing the number of weeks for induction may be "too cold". For now, a BCG induction schedule of 6 sequential weeks with a one-third dose with a standard maintenance schedule is "just right", but future studies will continue to improve optimization of the appropriate timing and duration of BCG instillation. We are now facing massive global shortages due to the COVID-19 epidemic for items ranging from toilet paper to life-saving ventilators. Physicians everywhere are learning new ways to treat our patients in an unprecedented time, questioning our current practices to optimize care for our patients with limited resources. Likewise, understanding the optimal treatment schedule for our patients with NMIBC in a way that maximizes efficacy while minimizing toxicity and waste will remain a critical objective, and the NIMBUS trial adds valuable information in this noble quest. Conflicts of interest: Angela B. Smith is an advisor for Urogen, Photocure, Fergene, and Merck. Christine V. Nikas has nothing to disclose. Evolution of radical mastectomy for breast cancer Evolving trends for selected treatments of T1a renal cell carcinoma Active surveillance for prostate cancer: a systematic review of the literature Connaught strain for bladder cancer patients Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediate-and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance Treatment of high-grade non-muscle-invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: results of the European Association of Urology Research Foundation randomised phase III clinical trial "NIMBUS Acknowledgments: Angela B. Smith is supported by a PCORI grant and a BCAN grant.