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Options in High-Risk Nonmuscle Invasive Bladder Cancer During the Shortage of Bacillus Calmette-Guérin Jeongwan Yoo 1, Yeon Joo Kim 2, Bum Sik Tae 1, Jae Young Park 1 1 Department of Urology, Korea

the urinary tract and is the seventh most common cancer among men worldwide and 17th among women.

1 Korean J Urol Oncol 2020;18(2): Review Article Bacillus Calmette-Guérin 부족시고위험비근침윤성방광암의치료대안 1 고려대학교의과대학고려대학교안산병원비뇨의학과, 2 대구파티마병원비뇨의학과 유정완 1 ㆍ김연주 2 ㆍ태범식 1 ㆍ박재영 1 Therapeutic Options in High-Risk Nonmuscle Invasive Bladder Cancer During the Shortage of Bacillus Calmette-Guérin Jeongwan Yoo 1, Yeon Joo Kim 2, Bum Sik Tae 1, Jae Young Park 1 1 Department of Urology, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Korea 2 Department of Urology, Daegu Fatima Hospital, Daegu, Korea Bladder cancer is the second most common malignant tumor of the urinary tract and is the seventh most common cancer among men worldwide and 17th among women. Seventy to eighty percent of bladder cancers are nonmuscle invasive bladder cancer (NMIBC) at the first diagnosis, and about 20% 25% of patients progress to invasive bladder cancer. According to the EORTC (European Organisation for Research and Treatment of Cancer) risk classification study, patients with high-risk NMIBC (T1, high grade/g3, carcinoma in situ) have a 5-year recur risk of up to 80% and a 50% chance of advance. Treatment options for high-risk NMIBC recommend Bacillus Calmette-Guérin (BCG) intrabladder infusion therapy after transurethral resection of bladder tumor, and intrathecal bladder chemotherapy such as mitomycin C or epirubicin, or early radical bladder resection may also be considered in recurrent high-risk patients. Among them, BCG intrathecal bladder infusion therapy has been demonstrated to reduce progression to mycoinvasive disease and has been used as a primary treatment for high risk NMIBC patients. BCG intrathecal infusion therapy reported that less than 10% 20% of patients in the responding group developed myoinvasive disease, while 66% of the patients in the poor response group developed myoinvasive disease. However, because BCG is made from Mycobacterium bovis, mass production is difficult due to a number of factors, such as the strength, quality, purity, and potency of BCG vaccines that pharmaceutical companies need to control. Most of all, BCG vaccines are prone to bacterial contamination due to long incubation periods and expensive specialized equipment. These factors eventually led to the closure of the Sanofi Institute for BCG vaccines in 2012, which continues the difficulties Merck has faced due to the lack of BCG supplies. Because BCG is a generic drug, the 2003 Medicare Modernization Act limited costs by up to 6% above the Medicare average selling price. Therefore, in 2016, Sanofi did not find any party to continue BCG s manufacturing technology and acquire the company, as a result, it announced that it will stop production in the United States, Canada, the United Kingdom, and France. In this article, we will discuss how to treat high-risk NMIBC patients under these BCG deficiencies, along with some of the treatment options that can be implemented in cases of drug shortage. (Korean J Urol Oncol 2020;18:73-77) Key Words: BCG vaccine ㆍ Urinary bladder neoplasms ㆍ Intravesical administration Received November 11, 2019, Revised December 31, 2019, Accepted January 2, 2020 Corresponding Author: Jae Young Park Department of Urology, Korea University Ansan Hospital, Korea University College of Medicine, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea jaeyoungpark@korea.ac.kr, Tel: , Fax: , ORCID: ㆍ This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2017R1A2B ). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited C Copyright The Korean Urological Oncology Society and The Korean Prostate Society. All Rights Reserved. 73

2 74 대한비뇨기종양학술지 : 제 18 권제 2 호 2020 서 론 BCG 의용량및투여기간을조정하는방법 방광암은비뇨기계종양중두번째로흔하게발생하는악성종양이며전세계의암중남성에게는 7번째로, 여성에게는 17번째로흔한발병률을보이고있다. 1 방광암의 70% 80% 는첫진단시비근침윤성방광암 (nonmuscle invasive bladder cancer, NMIBC) 이며약 20% 25% 의환자들이근침윤성방광암으로진행한다. 2 European Organisation for Research and Treatment of Cancer (EORTC) risk classification 연구에따르면고위험 NMIBC (T1, high grade/g3, carcinoma in situ) 환자는 5년재발위험이최대 80%, 병기진행의확률은최대 50% 까지이르는것으로보고되고있다. 3 고위험 NMIBC에대한치료옵션에는경요도적방광종양절제술 (transurethral resection of bladder tumor, TURBT) 후 Bacillus Calmette-Guérin (BCG) 방광내주입요법이권장되며, mitomycin C 또는 epirubicin 등의방광내항암제주입요법, 또는재발성고위험환자군에서는조기근치적방광절제술도고려할수있다. 4 그중 BCG 방광내주입요법은근침윤성질환으로의진행을감소시키는것으로입증되었으며, 고위험 NMIBC 환자들에게 1차치료제로사용되어졌다. BCG 방광내주입요법은반응이좋은그룹의경우 10% 20% 미만의환자들이근침윤성질환으로발전되는반면에, 반응이좋지않은그룹의경우 66% 환자들이근침윤성질환으로발전되는것으로보고된바있다. 5 하지만 BCG는 Mycobacterium bovis에서만들기때문에제약회사가제어해야할 BCG 백신의강도, 품질, 순도및효능등의여러가지요소들로인해대량생산이어렵다. 무엇보다도 BCG 백신은인큐베이션기간이길고전문장비가비싸세균오염이발생되기쉽다. 6 이러한요소들은결국 2012년 BCG 백신 Sanofi 연구소의폐쇄로이어졌으며, 이로인한 BCG 공급의부족으로 Merck 회사가겪은어려움이지금까지이어오고있다. BCG는제네릭의약품이므로 2003년 Medicare Modernization Act는메디케어평균판매가격보다최대 6% 까지비용을제한하였다. 따라서 2016년에 Sanofi는 BCG의제조기술지속및회사를인수할당사자를찾지못했으며, 이에인해미국, 캐나다, 영국및프랑스에서의생산을중단한다고발표하였다. 7 이원고에서는이러한 BCG 부족현상하에서어떻게고위험 NMIBC 환자들을치료할것인지와함께약물부족시시행할수있는치료대안들이어떠한것들이있는지정리하고자한다. 이전메타분석에따른결과및 Level 1 evidence에따라 TURBT를단독으로시행하는것에비해방광내주입요법을시행하는것이 NMIBC 환자들의재발을줄이는것으로알려져있다. 특히 BCG ( 유지요법포함 ) 를다른치료법 (TURBT 단독, TURBT 및기타면역요법 ) 과비교하는 24 개의무작위대조군연구에서 4,800명이상의대상자에대한 EORTC-GUCG 분석결과, 방광내 BCG 주입유지요법은 NMIBC의진행확률을 27% 로낮추는것으로나타났다. 8 특히고위험도 NMIBC 연구에서 BCG를주입하는것이방광내 mitomycin C 단독, 방광내 epirubicin 단독또는 epirubicin과 interferon의병용주입요법에비해재발률에있어서우월하다고밝혀졌다. 9,10 따라서재발위험이높은 NMIBC 환자에서 1년이상 BCG 유지요법을시행하는것이재발방지를위한다른화학요법보다효과적임을시사하였다. 아직까지 BCG 유지요법에대한정확한스케줄은정해져있지는않지만, BCG induction 시행후 3, 6, 12 개월에매주 3회 BCG 방광내주입을시행하는스케줄이 BCG 유지요법에대한임상시험에서흔하게사용되는방법이라고할수있다. 4,11 하지만최근 BCG가제한적으로공급되고있으므로, 줄어들고있는예비품의적절한분배가필요하다. 이미치료중인환자의경우방광의상피내암 (carcinoma in situ, CIS) 이없는환자에서 1년후에 BCG 유지치료를중단하는것을고려할수있다. 또한 CIS가있는환자의경우에는유지요법을용량을 1/3로줄이고 3년까지 BCG 유지요법을시행하는것을고려할수있다. 초고위험도환자에서재발위험이더높을수있지만이러한용량조절은종양의무진행생존율에서는큰차이가없는것으로알려졌다. 12 이에대해 National Comprehensive Cancer Network (NCCN) 패널에서는 BCG 공급이부족할때에는 1/3 혹은 1/2 용량으로 BCG Induction 하는것을고려할수있으며, BCG 유지요법도 1/3 혹은 1/2 용량으로시행할수있다고하였다. 13 MITOMYCIN C Mitomycin C (MMC) 의방광내주입유지요법은중간및고위험 NMIBC에서재발위험을감소시키는것으로나타났지만 BCG만큼효과적이지는않는것으로알려져있다. 방광내 MMC 요법과 BCG 요법의비교임상시험은환자군들이동일하지않다는점과각기다른방광내약물주

3 유정완외 :BCG 부족시고위험비근침윤성방광암의치료대안 75 입스케줄로인해서그우열여부를정확히파악하기가힘들다는한계점이있다. 그중대표적인연구중하나로서 Rintala는재발성 Ta/T1G1 3 방광암또는 CIS 환자 109명을대상으로 4주동안 BCG를매주주입후 2달에 1번씩 1년까지주입하는일정을사용한무작위대조군연구에서 2 년추적결과 97% 의완전관해율을보였다고보고한바있다. 동일한일정을사용한 MMC 유지요법은완전관해율이 70% 였다 명의고위험 NMIBC 환자들을대상으로한 SWOG (Southwest Oncology Group) 연구에서는무재발생존율이 BCG 그룹에게유의하게높았으나, 무진행생존율에서는양군간에큰차이가없었다. 15 Malmström 등 16 의다른연구에서는다발성또는재발성 Ta/T1G1 2 또는 CIS 또는 T1G3 환자 126명을 BCG 유지군또는 MMC 유지군으로무작위배정하였다. 이연구에서는 5년간무재발생존율이 BCG 군은 47%, MMC군 34% 로두군간유의한차이를보였으나, 무진행생존율에서는차이가없었다. 이러한 9개의무작위대조군연구를대상으로총 2,800여명의 NMIBC 환자들을메타분석하였을때 BCG 유지요법은 MMC 유지요법에비해 32% 의재발위험도를낮추는것으로나타났으나, BCG 유지요법을시행하지않는경우에는 MMC 유지군에비해재발위험도가 28% 높은것으로나타났다. 하지만전반적생존율, 무진행생존율, 암특이생존율에는차이가없었다. 4 이는결국 BCG 유지요법이 MMC에비해우월한효과를보이지만, MMC 유지요법또한고위험 NMIBC 환자들에게재발을막는효과가있음을나타낸다. 이러한이유로 MMC의 induction에이은유지요법은 BCG가부족한시기에고위험군 NMIBC 환자들에게 BCG 방광내주입요법의대안이될수있다. GEMCITABINE Gemcitabine 방광내주입요법의효능에대한코크란리뷰는 700명이넘는환자를대상으로한 6건의임상시험을대상을분석하였으나, 환자들의 heterogenicity로인해직접적인비교는불가능하였다. 17 CIS가없는 Ta T1 환자들을대상으로하였을때, gemcitabine은 BCG에비해비슷한 30% 와 25% 의재발률을보였으며, 전반적인무진행생존율은비슷하였다. 다른고위험환자들을대상으로분석하였을때에는 gemcitabine은 53.1% 로 28.1% 의 BCG에비해재발률이높은것으로나타났으며, 재발기간또한 25.5개월대 39.4개월로유의하게짧았다. 마지막으로 BCG 초기치료에실패한고위험군환자들을대상으로분석하였을때에는 52.5% 대 87.5% 로낮은재발률을보였으며 3.9개월대 3.1 개월의재발기간을보였다. BCG와비교하였을때 gemcitabine은 중등도환자들에게는비슷한재발률을보였으나, 고위험환자들에게는효과가적었으며, BCG 불응성환자들에게는좋은효과를보였다. 이에 NCCN 가이드라인에서는 BCG 공급이부족할시 gemcitabine 방광내주입요법을고려할수있다고권고한바있다. 한국에서는최근건강보험심사평가원이 NMIBC 환자들에게 gemcitabine 방광내주입요법에대한허가초과항암요법사용을승인하였다. 2018년도 7월에개정된허가초과항암요법의사용기준에따라한기관에서승인을받은경우, 타기관에서는다학제적위원회를거쳐건강보험심사평가원에신청한후부터항암제사용이환자부담 100% 로가능하다. Gemcitabine 방광내주입요법은 2019년도 5월 15일부터사용이가능하게되었으며기관내다학제위원회승인결정을받은후기인정요법서식과가이드라인및근거자료를건강보험심사평가원에제출하여신고한후사용할수있다. OTHER INTRAVESICAL CHEMOTHERAPIES NMIBC에서재발을막기위한여러가지약제를대상으로하는임상시험들이이루어지고있다. 이중대표적인약제들은 epirubicin, docetaxel, interferon alpha, thiotepa, Immune checkpoint inhibitor 등이있다. Chou 등 18 이시행한메타분석에서는 TURBT 단독요법에비해 BCG, MMC, doxorubicin, epirubicin은방광암재발위험을 20% 44% 감소시키는것으로나타났다. 하지만타약제및 BCG 등은암특이생존율을낮추지는못했다. 먼저 epirubicin은 BCG 와비교한무작위대조군연구에서 BCG가 T1 및 CIS 모두에서방광암재발의위험을낮추지만진행의위험도를낮추지는못하였다. 19,20 또한 doxorubicin과 pirarubicin과같은안트라사이클린계열약제또한주로단기추적관찰에서질병재발을줄이기위해사용될수있음을보고하였다. 이중에서는 epirubicin이 doxorubicin과의비교연구에서방광암재발의위험도를낮추었으나방광암진행의위험도를낮추지는못하였다. 21 또한, Alkylating agent인 thiotepa의방광주입요법은 TURBT만시행하는것에비해방광암의재발과진행의위험도를낮추지못하였다. 하지만메타분석은각약제에대한 regimen이통일되지않았다는점과더불어질병군의 heterogenicity로인해유의한결과를도출하지못하다고분석하였다. 22,23 이와더불어, 최근에 immune checkpoint inhibitor인 PD-1 과 PL-L1의보조적치료로서의유용성에대한연구가진행되고있으나, 아직효용가능한결과는도출되지않았다. 24,25 여전히 BCG 방광내주입요법은질병재발의위험을낮추는데에있어서여러다른항암제

4 76 대한비뇨기종양학술지 : 제 18 권제 2 호 2020 주입요법보다효과가있는것으로나타났지만, 최적의보조치료가아직명확하지않기때문에질병재발의위험성을낮추기위한보조치료법으로서 BCG 공급부족기간에고려해볼수있는방법으로생각한다. 있는규제개혁업체에대한정책적, 재정적지원, 약품의적정수가보장이속히시행되어야할것으로생각한다. 이해관계 (Conflict of Interest) EARLY RADICAL CYSTECTOMY 고위험 NMIBC는 TURBT와 BCG 방광내주입요법으로적절한치료를받았음에도불구하고약 20% 에서근침윤성방광암으로발전한다. 조기근치적방광절제술 (early radical cystectomy) 은좋은종양학적성적을보이고있으나모든고위험환자가근치적방광절제술을받는다면 50% 의환자들이과잉치료를받게된다는연구결과가있다. 26 여러무작위대조군연구를바탕으로한메타분석에따르면 BCG는다른화학요법제제와비교하여단기및장기치료실패및질병진행위험을감소시킨다고알려져있다. 9 하지만 BCG가없는경우즉각적인근치적방광절제술이환자들에게는가장효과적인옵션중하나이다. 만일열등한효능을가진다른방광주입요법을사용한다면환자의질병진행위험도가증가할것이다. 또한이러한환자들은첫 TURBT 시 T2 환자와비교하여 oncologic outcome이더나쁜것으로판명되었다. 27 하지만근치적방광절제술은환자의삶의질에상당한영향을주기때문에그시행여부를결정하기가쉽지는않다. 그럼에도불구하고 BCG가부족할때는근치적방광절제술을고려해야하며, BCG가부족하지않은경우에서도 lymphovascular invasion, variant pathology 등의질병진행의위험이높은환자는근치적방광절제술을고려해야한다. NCCN 패널들은이같은 evidence들을바탕으로 BCG 부족시고위험 NMIBC의경우에는조기근치적방광절제술을고려할것을권유하고있다. 결론경제적인, 산업적인, 법규적인이유들로인해전세계적으로 BCG 공급부족사태가발생하였다. 고위험 NMIBC의치료에서 TURBT 후 BCG 방광내주입요법을시행하는것이필수적인데, BCG 공급이부족한상황에서이를극복할수있는방법으로는 (1) BCG의용량을 1/3 1/2으로줄이고유지요법의기간도 1년으로줄이는방법, (2) 방광내 mitomycin C 주입, (3) 방광내 gemcitabine 주입, (4) 그외다른약제의방광내주입, (5) 조기근치적방광절제술등이가능할것이다. 하지만, 여러고위험 NMIBC의연구에서 BCG 방광내주입요법의효과가가장우수한것으로보고되고있는만큼, 현재의 BCG 공급부족을해결할수 저자들은이논문과관련하여이해관계의충돌이없음을명시합니다. REFERENCES 1. Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 2013;63: Chavan S, Bray F, Lortet-Tieulent J, Goodman M, Jemal A. International variations in bladder cancer incidence and mortality. Eur Urol 2014;66: Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49: 466-5; discussion Malmström PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer. Eur Urol 2009;56: Solsona E, Iborra I, Dumont R, Rubio-Briones J, Casanova J, Almenar S. The 3-month clinical response to intravesical therapy as a predictive factor for progression in patients with high risk superficial bladder cancer. J Urol 2000;164: Baylor NW. The regulatory evaluation of vaccines for human use. In: Thomas S, editor. Vaccine design: methods and protocols. Volume 2: vaccines for veterinary diseases. New York: Springer New York; p Messing EM. The BCG Shortage. Bladder Cancer 2017;3: Järvinen R, Kaasinen E, Sankila A, Rintala E; FinnBladder Group. Long-term efficacy of maintenance bacillus Calmette-Guérin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol 2009;56: Sylvester RJ, van der MEIJDEN AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clin-

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R