Ather, M Hammad

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eCommons@AKU Section of Urology Department of Surgery 2-1-2022 What after BCG fails in non-muscle invasive bladder cancer? M Hammad Ather Aga Khan University, hammad.ather@aku.edu Follow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_surg_urol  Part of the Critical Care Commons, Oncology Commons, Radiation Medicine Commons, Surgery Commons, Urology Commons, and the Women's Health Commons Recommended Citation Ather, M. (2022). What after BCG fails in non-muscle invasive bladder cancer?. Journal of the College of Physicians and Surgeons Pakistan, 32(2), 139-140. Available at: https://ecommons.aku.edu/pakistan_fhs_mc_surg_urol/179 EDITORIALJournal  of  the College of  Physicians and Surgeons Pakistan 2022,  Vol.  32(02):  139-140 139What after BCG Fails in Non-muscle Invasive BladderCancer?Mohammad Hammad AtherDepartment of Surgery, The Aga Khan University Hospital, Karachi, PakistanThe journey from the pioneering work of Albert Calmette andCamille Guerrin in the discovery of BCG vaccine for tubercu-losis to development of BCG in the management of carcinomain  situ  and  high  grade  non-muscle  invasive  (NMI)  bladdercancer is over 100 years old.1,2 The story is not only exhilaratingbut  also  full  of  exciting  endeavours  from Coleys  toxin  andZbars’ rule to the development of immune checkpoint inhibi-tors.  The concept  and development  of  BCG as  an immunebooster in the defence against infectious diseases to a potentanti-cancer drug, owes to the “magic bullet” concept of PaulEhrlich.3BCG has become one of the most potent immunotherapeuticagents in the management of high-risk bladder cancer. It is thetreatment of choice for Ta/T1 high-grade (HG) cancer, Ta lowgrade (>3cm) as well as for carcinoma in situ (CIS). It is the stan-dard of care for these types of NMI urothelial carcinoma (UC) asa first occurrence and for recurrent BCG naïve cancers. It is alsotreatment of choice in cases of recurrent cancer with prior BCGtreatment, not yet a case for radical cystectomy.4 Two majorconcerns in NMI urothelial cancer are recurrence and progres-sion of the disease. BCG is highly efficacious in the preventionof  both  complications.  In  five  meta-analyses,  it  has  beenshown  that  BCG  is  superior  to  transurethral  resection  ofbladder  tumor  (TURBT)  /  TURBT  +  chemotherapy  for  theprevention  of  recurrence.5  Two  high  quality  meta-analyseshave provided level 1a evidence in support of BCG in signifi-cantly lowering the progression rate.6 BCG is most effectivewhen administered in 5-6 cycles of induction with follow-up ofmaintenance treatment upto three years. The maintenancetreatment is 3-weekly instillations at 3, 6, 12, 18, 24, 30 and 36months.BCG, however, is not an infallible remedy. It is not only associ-ated with significant side effects, but there is also significantproportion of patients who fail BCG therapy. The terminologyto describe BCG failure is standardised.Correspondence  to:  Dr.  Mohammad  Hammad  Ather,Department  of  Surgery,  The  Aga  Khan  UniversityHospital,  Stadium  Road,  Karachi,  PakistanE-mail:  hammad.ather@aku.edu.....................................................Received: July 09, 2021;  Revised: September 12, 2021;Accepted:  September  22,  2021DOI:  https://doi.org/10.29271/jcpsp.2022.02.139BCG  refractory  tumors  are  high-grade  or  CIS  NMI  cancerpresenting at 3-month or following re-induction or one-cycle ofmaintenance and/or if a high-grade tumor appears during main-tenance.  BCG  unresponsive  includes  T1Ta/HG  recurrencewithin six months of completion of adequate BCG exposure or ifa  patient  develops  CIS  within  12  months  of  completion  ofadequate BCG exposure. BCG relapsing is a high-grade recur-rence after complete response on completion of maintenancetherapy. BCG intolerance is the term used for discontinuation oftherapy mandated by significant side effects.7BCG  refractory/unresponsive  cancers  are  considered  as  anaggressive variant with significant potential for metastases.8 Thestandard of care in these patients is radical cystectomy (RC).RC is not only oncologically safe, but it also provides bettercancer-free survival than any other bladder sparing modality.It may, at times, be an over treatment; albeit in a small propor-tion of cases. There is overwhelming evidence that delay inperforming  cystectomy  for  BCG  refractory  cancer  canadversely affect the survival.Many  bladder-sparing  regimens  are  available  for  patientsunwilling or unfit for cystectomy. These include cytotoxic treat-ment with newer cytotoxic agents, chemotherapy combina-tions, new drug delivery systems, device instillations, vaccine,recombinant proteins, photodynamic therapy, oncolytic aden-ovirus, gene therapy (nadofaragenefirodenovac), and immunecheckpoint inhibitors. The last two are of particular interest;and have received recent FDA approval. However, they shouldbe considered experimental until wider clinical experience isreported.Cancers  express  various  proteins  that  make  them  appearforeign. This results in T cell mediated immune response. Inorder to avoid this cascade, tumors often express programmedeath ligand (PD L1). This adaptive tumor response turns theimmune system off. In order to reactivate the immune system,PD and PDL1 need to be blocked. In a recent phase II  trial,pembrolizumab  efficacy  was  assessed  in  a  study  calledKeynote  057.  Patients  with  high-grade  papillary  UC  weredivided into two groups, i.e. with or without concomitant CIS.Complete response of UC with CIS was the primary end-point;whereas, CR of any disease, duration of response and safetyand tolerability were the secondary end-points. The CR was justover 40%, mean duration of response was 16.2 months.9In another interesting phase III  study, a novel drug deliveryMohammad Hammad AtherJournal  of  the College of  Physicians and Surgeons Pakistan 2022,  Vol.  32(02):  139-140140system,  nadofaragenefiradenovac,  for  human  IFNα2b  gene,was studied. In a non-replicating adenovirus, gene of interest isinserted, the virus infects the cell and releases DNA that hassignificant anti-tumor activity. The anti-tumor activity is anti-proliferative, TRAIL (tumor necrosis factor apoptosis inducingligand) mediated cytotoxicity and anti-angiogenic activity. Theinvestigators concluded that intravesical nadofaragenefiraden-ovec was efficacious. Risk assessment indicates a favourablebenefit: risk ratio, in patients with BCG-unresponsive NMI UC.10The current European Association of Urology (EAU) guidelinesindicate that standard of care for patients with BCG unrespon-sive disease is radical cystectomy (strong recommendation);whereas, evidence-favouring bladder preserving technique isweak. Close monitoring and early recognition of BCG unrespon-siveness is important, as this shows aggressive cancer withsignificant potential for metastases.REFERENCESCalmette A. Preventive vaccination against tuberculosis with1.BCG. Proc R Soc Med 1931; 24(11): 1481-90.Morales  A,  Eidinger  D,  Bruce  AW.  Intracavitary  bacillus2.calmette-guerin  in  the  treatment  of  superficial  bladdertumors.  J  Urol  1976;  116(2):180-3.  doi:  10.1016/s0022-5347(17)58737-6.Ehrlich, P. Die Wertbemessungddes diphterieheilserums and3.derentheoretischgrundlagen. KlinJahrb 1897; 6:299-326.Witjes JA, Bruins HM, Cathomas R, Compérat EM, Cowan NC,4.Gakis G, et al. European association of urology guidelines onmuscle-invasive and metastatic bladder cancer: Summary ofthe  2020  guidelines.  Eur  Urol  2021;  79(1):82-104.  doi:10.1016/j.eururo.2020.03.055.Malmstrom, PU, Sylvester RJ, Crawford DE, Friedrich M, Krege5.S, Rintala E, et al. An individual patient data meta-analysis ofthe  long-term outcome of  randomised  studies  comparingintravesicalmitomycin C versus bacillus Calmette-Guerin fornonmuscle-invasive bladder cancer. Eur Urol  2009; 56(2):247-56. doi: 10.1016/j.eururo.2009.04.038.Sylvester  RJ,  van der  Meijden APM,  LammDL.  Intravesical6.bacillus Calmette-guerin reduces the risk of progression inpatients  with  superficial  bladder  cancer:  A  meta-analysis  ofthe  published  results  of  randomised  clinical  trials.  J  Urol2002;  168(5):1964-70.  doi:  10.1097/01.ju.0000034450.80198.1c.Kamat AM, Sylvester RJ, Böhle A, Palou J, Lamm DL, Brausi M,7.Soloway  M,  et  al.   Definitions,  end  points,  and  clinical  trialdesigns  for  non-muscle-invasive  bladder  cancer:Recommendations  from  the  international  bladder  cancergroup.  J  ClinOncol  2016;  34(16):1935-44.  doi:  10.1200/JCO.2015.64.4070.Klaassen Z, Kamat AM, Kassouf W, Gontero P, Villavicencio8.H, Bellmunt J, et al. Treatment strategy for newly diagnosedT1 high-grade bladder  urothelial  carcinoma:  New insightsand  updated  recommendations.  Eur  Urol  2018;  74(5):597-608. doi: 10.1016/j.eururo.2018.06.024.Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL,9.Roumiguié  M,  et  al.  Pembrolizumabmonotherapy  for  thetreatment of  high-risk non-muscle-invasive bladder cancerunresponsive to BCG (KEYNOTE-057): An open-label, single-arm,  multicentre,  phase  2  study.  Lancet  Oncol  2021;22(7):919-30. doi: 10.1016/S1470-2045(21)00147-9.Boorjian  SA,  Alemozaffar  M,  Konety  BR,  Shore  ND,  Gomella10.LG,  Kamat  AM,  et  al.  Intravesicalnadofaragenefiradenovecgene  therapy  for  BCG-unresponsive  non-muscle-invasivebladder cancer: A single-arm, open-label, repeat-dose clinicaltrial.  Lancet  Oncol  2021;  22(1):107-117.  doi:  10.1016/S1470-2045(20)30540-4.••••••••••

What after BCG fails in non-muscle invasive bladder cancer?

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What after BCG fails in non-muscle invasive bladder cancer?

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