SUPERFICIAL BLADDER CANCER: THE ROLE OF INTERFERON-alpha

No AccessJournal of UrologyClinical Urology: Review Article1 Jun 1998SUPERFICIAL BLADDER CANCER: THE ROLE OF INTERFERON-alphais corrected bySUPERFICIAL BLADDER CANCER ARIE S. BELLDEGRUN, JOHN R. FRANKLIN, MICHAEL A. O'DONNELL, LEONARD G. GOMELLA, ERIC KLEIN, RUDOLPH NERI, UNYIME O. NSEYO, TIMOTHY L. RATLIFF, and RICHARD D. WILLIAMS ARIE S. BELLDEGRUNARIE S. BELLDEGRUN , JOHN R. FRANKLINJOHN R. FRANKLIN , MICHAEL A. O'DONNELLMICHAEL A. O'DONNELL , LEONARD G. GOMELLALEONARD G. GOMELLA , ERIC KLEINERIC KLEIN , RUDOLPH NERIRUDOLPH NERI , UNYIME O. NSEYOUNYIME O. NSEYO , TIMOTHY L. RATLIFFTIMOTHY L. RATLIFF , and RICHARD D. WILLIAMSRICHARD D. WILLIAMS View All Author Informationhttps://doi.org/10.1016/S0022-5347(01)63160-4AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We evaluate the clinical experience with recombinant interferon-alpha in superficial transitional cell carcinoma and discuss the most rational use of recombinant interferon-alpha in the context of current treatment options. Materials and Methods: The available data were reviewed and discussed at a consensus conference in August 1996. The conclusions and recommendations are those of the authors based on the consensus reached at that meeting. Results: While bacillus Calmette-Guerin (BCG) is recognized as the most efficacious intravesical agent in the prophylaxis and treatment of superficial transitional cell carcinoma, it is associated with significant toxicities and a 20 to 40% relapse rate. Interferons, particularly recombinant interferon-alpha, have demonstrated efficacy against primary and recurrent papillary transitional cell carcinoma and carcinoma in situ with minimal toxicity, although the response and relapse rates are inferior to BCG. Intravesical recombinant interferon-alpha therapy has also produced responses in patients who failed to respond or were refractory to BCG or chemotherapy. Conclusions: The clinical experience suggests that recombinant interferon-alpha has an important role in the treatment of superficial transitional cell carcinoma, particularly as second line therapy following failure of BCG or chemotherapy, and it may have synergistic effects when combined with chemotherapy or BCG. We propose a prospective randomized study comparing the efficacy of recombinant interferon-alpha, BCG and BCG plus recombinant interferon-alpha as maintenance following complete response to primary BCG therapy. The proposed study would also investigate the efficacy of BCG plus recombinant interferon-alpha as second line therapy following BCG failure. This study will be important to determine the most effective strategy to integrate recombinant interferon-alpha into current treatment options for superficial bladder cancer. References 1 : Cancer statistics, 1997. CA1997; 47: 5. Google Scholar 2 : Pathology and staging of bladder cancer. Sem. Oncol.1996; 23: 546. Medline, Google Scholar 3 : Urothelial tumors of the urinary tract. In: Campbell's Urology. Edited by . Philadelphia: W. B. Saunders Co.1992: 1094. chapt. 28. Google Scholar 4 : Intravesical bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J. Clin. Oncol.1995; 13: 1404. Crossref, Medline, Google Scholar 5 : Therapy of superficial bladder cancer. Sem. Oncol.1996; 23: 598. Medline, Google Scholar 6 : BCG in perspective: advances in the treatment of superficial bladder cancer. Eur. Urol. suppl.1995; 27: 2. Crossref, Google Scholar 7 : Experience with intravesical bacillus Calmette-Guerin therapy of superficial bladder tumors. Urology1985; 25: 119. Crossref, Medline, Google Scholar 8 : Long-term effect of intravesical bacillus Calmette-Guerin on flat carcinoma in situ of the bladder. J. Urol.1986; 135: 265. Link, Google Scholar 9 : Bacillus Calmette-Guerin immunotherapy for bladder cancer. J. Urol.1985; 134: 40. Link, Google Scholar 10 : Complications of bacillus Calmette-Guerin immunotherapy. Urol. Clin. N. Amer.1992; 19: 565. Crossref, Medline, Google Scholar 11 : Intravesical bacillus Calmette-Guerin immunoprophylaxis of superficial bladder cancer: results of a controlled prospective trial with modified treatment schedule. J. Urol.1993; 149: 744. Link, Google Scholar 12 : A low dose bacillus Calmette-Guerin regimen in superficial bladder cancer therapy: is it effective?. J. Urol.1991; 146: 32. Link, Google Scholar 13 : Natural history and treatment of low and high risk superficial bladder tumors. J. Urol.1988; 139: 283. Link, Google Scholar 14 : Induction of urinary interleukin-1 (IL-1), IL-2, IL-6, and tumour necrosis factor during intravesical immunotherapy with bacillus Calmette-Guerin in superficial bladder cancer. Cancer Immunol. Immunother.1992; 34: 306. Crossref, Medline, Google Scholar 15 : Bacillus Calmette-Guerin plus interleukin-2 and/or granulocyte/macrophage-colony-stimulating factor enhances immunocompetent cell production of interferon-gamma, which inhibits B16F10 melanoma cell growth in vitro. Cancer Immunol. Immunother.1996; 42: 280. Crossref, Medline, Google Scholar 16 : The immunomodulatory effects of urine from patients with superficial bladder cancer receiving intravesical evans BCG therapy. Cancer Immunol. Immunother.1993; 36: 25. Crossref, Medline, Google Scholar 17 : Evaluation of local immune response after intravesical bacille Calmette-Guerin treatment for superficial bladder cancer. Brit. J. Urol.1996; 78: 709. Crossref, Medline, Google Scholar 18 : Long-term results of intravesical therapy for superficial bladder cancer. Urol. Clin. N. Amer.1992; 19: 573. Crossref, Medline, Google Scholar 19 : Current status of intravesical therapy for bladder cancer. In: Urology Annual. Edited by . New York: W. W. Norton and Co.1994: 113. vol. 8. Google Scholar 20 : Experience with bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J. Urol.1982; 128: 27. Link, Google Scholar 21 : BCG (RIVM) versus mitomycin intravesical therapy in superficial bladder cancer. First results of randomized prospective trial. Urology, suppl.1988; 31: 20. Medline, Google Scholar 22 : Immunotherapy (BCG) versus chemotherapy (MMC) in intravesical treatment of superficial urinary bladder cancer. In: Immunotherapy of Urological Tumours. Edited by . Edinburgh: Churchill Livingstone1990: 13. chapt. 2. Google Scholar 23 : A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. New Engl. J. Med.1991; 325: 1205. Crossref, Medline, Google Scholar 24 : SWOG 8795: A randomized comparison of bacillus Calmette-Guerin and mitomycin C prophylaxis in stage Ta and T1 transitional cell carcinoma of the bladder. J. Urol., part 21993; 149: 282A. abstract 275. Google Scholar 25 : Advances in the treatment of superficial bladder cancer: optimizing BCG immunotherapy. Introduction. Eur. Urol., suppl.1995; 27: 1. Crossref, Google Scholar 26 : Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J. Urol.1990; 143: 502. Link, Google Scholar 27 : A comparison of treatment methods for the prophylaxis of recurrent superficial bladder tumors. J. Urol.1983; 129: 33. Link, Google Scholar 28 : Prospective randomized study of adjuvant therapy after complete resection of superficial bladder cancer: mitomycin C vs BCG Connaught vs TUR alone. In: Immunotherapy of Urological Tumours. Edited by . Edinburgh: Churchill Livingstone1990: 27. chapt. 3. Google Scholar 29 : A randomised prospective study comparing intravesical instillations of mitomycin-C, BCG-Tice, and BCG-RIVM in pTa-pT1 tumours and primary carcinoma in situ of the urinary bladder. Dutch South-East Cooperative Urological Group. Eur. J. Cancer1993; 29A: 1672. Crossref, Medline, Google Scholar 30 : The interferons. Mechanisms of action and clinical applications. J.A.M.A.1991; 266: 1375. Crossref, Medline, Google Scholar 31 : 5-halo-6-phenyl pyrimidinones: new molecules with cancer therapeutic potential and interferon-inducing capacity are strong inducers of murine natural killer cells. J. Immunol.1983; 130: 965. Crossref, Medline, Google Scholar 32 : Stimulation of natural killer cells in two random-bred strains of athymic rats by interferon-inducing pyrimidinone. J. Immunol.1984; 132: 2566. Crossref, Medline, Google Scholar 33 : Antiviral and other bioactivities of pyrimidinones. Pharmacol. Ther.1985; 30: 67. Crossref, Medline, Google Scholar 34 : Mechanisms of immunostimulation by pyrimidinones. In: Immunopharmacology of Infectious Diseases: Vaccine Adjuvants and Modulators of Non-Specific Resistance. Edited by . New York: Alan R. Liss, Inc.1987: 279. Google Scholar 35 : Interferons-alpha, beta, gamma: basic principles and preclinical studies. In: Biologic Therapy of Cancer. Edited by . Philadelphia: J. B. Lippincott Co.1991: 247. chapt. 14. Google Scholar 36 : Antiproliferative activities of interferons against human bladder carcinoma cell lines in vitro. J. Urol.1984; 132: 800. Link, Google Scholar 37 : In vitro antiproliferative effect of interferon alpha in solid tumors: a potential predictive test. Neoplasma1993; 40: 293. Medline, Google Scholar 38 : Determination of interferon-alpha receptors in urothelial cancer and in normal urothelium. J. Urol.1997; 157: 79. Link, Google Scholar 39 : The effects of recombinant human interferon-gamma on a panel of human bladder cancer cell lines. J. Urol.1991; 145: 1078. Link, Google Scholar 40 : An investigation of factors influencing the in vitro induction of LAK activity against a variety of human bladder cancer cell lines. J. Urol.1992; 147: 207. Link, Google Scholar 41 : Interferon-alpha can alter the lytic susceptibility of murine bladder transitional cell carcinoma (MBT-2) by their original poor specific cytotoxic tumor infiltrating lymphocytes. J. Urol.1992; 147: 523. Link, Google Scholar 42 : Immunomodulatory effect of interferon-alpha 2b on natural killer cells and T lymphocytes from patients with transitional cell carcinoma of the bladder. Anticancer Drugs, suppl.1992; 3: 5. Crossref, Medline, Google Scholar 43 : Intracavitary prophylactic treatment with interferon alpha 2b of patients with superficial bladder cancer is associated with a systemic T-cell activation. Brit. J. Cancer1994; 70: 1247. Crossref, Medline, Google Scholar 44 : Use of intracavitary interferon-alpha-2b in the prophylactic treatment of patients with superficial bladder cancer. Cancer1995; 75: 2720. Crossref, Medline, Google Scholar 45 : Clinical studies on cell-mediated immunity in patients with urinary bladder carcinoma: blastogenic response, interleukin-2 production and interferon-gamma production of lymphocytes. Brit. J. Urol.1990; 65: 333. Crossref, Medline, Google Scholar 46 : Interferon therapy in neoplastic disease. Acta Med. Scand.1978; 204: 471. Crossref, Medline, Google Scholar 47 : Can recombinant human alpha-2 interferon prevent recurrence of high-grade superficial bladder tumors? Cancer Detect. Prev.1987; 10: 405. Google Scholar 48 : Immunotherapeutic alternatives in superficial bladder cancer. Interferon, interleukin-2, and keyhole-limpet hemocyanin. Urol. Clin. N. Amer.1992; 19: 581. Crossref, Medline, Google Scholar 49 : Systemic IFN-alpha treatment of multiple bladder papilloma grade I or II patients: pilot study. J. Interferon Res.1982; 2: 339. Crossref, Medline, Google Scholar 50 : Application of human leucocyte interferon in patients with urinary bladder papillomatosis, breast cancer, and melanoma. Lancet1981; 1: 1022. Medline, Google Scholar 51 : Intralesional alpha interferon therapy in papillary superficial transitional cell carcinoma of the bladder. A pilot study. Brit. J. Urol.1993; 71: 422. Crossref, Medline, Google Scholar 52 : Alpha lymphoblastoid interferon for non-invasive bladder cancer. Brit. J. Cancer1986; 53: 432. Google Scholar 53 : Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group Study. J. Clin. Oncol.1988; 6: 476. Crossref, Medline, Google Scholar 54 : A randomized controlled study of intravesical alpha-2b-interferon in carcinoma in situ of the bladder. J. Urol.1990; 144: 658. Link, Google Scholar 55 : Oral bropirimine immunotherapy of carcinoma in situ of the bladder: results of a phase II trial. Urology1996; 48: 21. Crossref, Medline, Google Scholar 56 : Intravesical treatment of bladder cancer with recombinant human interferon-beta. Intravesical GKT-beta Chemotherapy Research Group. Cancer Immunol. Immunother.1989; 30: 81. Crossref, Medline, Google Scholar 57 : Gamma-interferon in the therapeutic and prophylactic management of superficial bladder cancer. J. Urol., part 21987; 137: 276A. abstract 691. Abstract, Google Scholar 58 : Intravesical interferon alfa-2b administration in the treatment of superficial bladder tumors. Eur. Urol.1990; 18: 201. Crossref, Medline, Google Scholar 59 : Results at 43 months' follow-up of a double-blind, randomized, prospective clinical trial using intravesical interferon alpha-2b in the prophylaxis of stage pT1 transitional cell carcinoma of the bladder. Urology1997; 49: 187. Crossref, Medline, Google Scholar 60 : Interferon alfa 2a in superficial bladder cancer prophylaxis: toleration and long-term follow-up. A phase I-II study. Anticancer Res.1991; 11: 2167. Medline, Google Scholar 61 : Prophylaxis of superficial bladder cancer with mitomycin or interferon alfa-2b: results of a multicentric Italian study. J. Clin. Oncol.1994; 12: 7. Crossref, Medline, Google Scholar 62 : How effective is topical alpha-2b interferon in preventing recurrence of superficial bladder cancer?. Brit. J. Urol.1991; 68: 495. Crossref, Medline, Google Scholar 63 : BCG vs interferon A for prevention of recurrence of superficial bladder cancer. A prospective randomized study. Urologe1994; 33: 133. Google Scholar 64 Donovan, M. G., Grainger, R. and Hegarty, J. H.: A prospective, randomized study of intravesical BCG and interferon in superficial bladder cancer. Presented at the 4th European Conference on Clinical Oncology and Cancer Nursing, 1987. Google Scholar 65 : Intravesical (IV) IFN compared to BCG therapy in "high risk" superficial bladder cancer-results of a prospective multicentric randomized study. J. Urol., part 21997; 157: 213. abstract 832. Google Scholar 66 : Pilot study of intravesical alfa-2b interferon for treatment of bladder carcinoma in situ following BCG failure. J. Urol., part 21996; 155: 494A. abstract 735. Google Scholar 67 : Interferons modify in vitro proliferation of human bladder transitional cell carcinoma in the presence of doxorubicin and mitomycin C. J. Urol.1996; 156: 1492. Link, Google Scholar 68 : Cytostatic effect of different strains of bacillus Calmette-Guerin on human bladder cancer cells in vitro alone and in combination with mitomycin C and interferon-alpha. Urol. Res.1992; 20: 215. Crossref, Medline, Google Scholar 69 : Antiproliferative effects of bacillus Calmette-Guerin and interferon alpha 2b on human bladder cancer cells in vitro. Cancer Immunol. Immunother.1995; 41: 309. Crossref, Medline, Google Scholar 70 : Immunotherapy of murine transitional cell carcinoma of the bladder using alpha and gamma interferon in combination with other forms of immunotherapy. J. Urol.1992; 147: 212. Link, Google Scholar 71 : Combination immunotherapy of murine transitional cell cancer using BCG and an interferon-inducing pyrimidinone. J. Urol.1989; 142: 1376. Link, Google Scholar 72 : A comparison of the local immune response to intravesical alpha-interferon and bacillus Calmette-Guerin (BCG) in patients with superficial bladder cancer. J. Urol.1994; 151: part 2: 473A. abstract 983. Google Scholar 73 : Experimental and clinical evidence of enhancement of BCG efficacy by adding interferon-alpha. J. Urol., part 21997; 157: 383. abstract 1502. Google Scholar 74 : Bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. New prospects for an old warhorse. Surg. Oncol. Clin. N. Amer.1995; 4: 189. Crossref, Medline, Google Scholar 75 : Murine bladder carcinoma cells present antigen to BCG-specific CD4+ T-cells. Cancer Res.1992; 52: 4286. Medline, Google Scholar 76 : Interferon-alpha 2b instillation prophylaxis in superficial bladder cancer-a prospective, controlled three-armed trial. Project Group Bochum-interferon and superficial bladder cancer. Anticancer Drugs, suppl.1992; 3: 33. Crossref, Medline, Google Scholar 77 : Chemoimmunotherapy for prophylaxis of recurrence in superficial bladder cancer: interferon-alpha 2b versus interferon-alpha 2b with epirubicin. Anticancer Drugs, suppl.1992; 3: 25. Crossref, Medline, Google Scholar 78 : Current views on intravesical treatment and chemoprophylaxis of superficial bladder cancer. The present role of epirubicin and doxorubicin. J. Chemother.1993; 5: 207. Crossref, Medline, Google Scholar 79 : Results of conservative treatment (transurethral resection plus adjuvant intravesical chemotherapy) in patients with primary T1, G3 transitional cell carcinoma of the bladder. Urology1996; 47: 647. Crossref, Medline, Google Scholar 80 : Bacillus Calmette-Guerin plus intravesical interferon alpha-2b in patients with superficial bladder cancer. Urology1996; 48: 957. Crossref, Medline, Google Scholar 81 : BCG vs. BCG plus recombinant alpha-interferon 2b in superficial tumors of the bladder. Arch. Ital. Urol. Androl.1995; 67: 257. Medline, Google Scholar 82 : Pharmacological biocompatibility between intravesical preparations of BCG and interferon-alfa 2b. J. Urol.1997; 158: 2311. Link, Google Scholar 83 : Fludarabine-present status and future developments in chronic lymphocytic leukemia and lymphoma. Ann. Oncol. suppl.1994; 5: 79. Crossref, Medline, Google Scholar 84 : Phase 1 trial of oral bropirimine in superficial bladder cancer. J. Urol.1992; 147: 31. Link, Google Scholar From the Division of Urologic Oncology, UCLA School of Medicine, Los Angeles, California, Department of Urology, Montefiore Medical Center and Jack D. Weiler Hospital of the Albert Einstein College of Medicine, Bronx, New York, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, Thomas Jefferson University, Philadelphia, Pennsylvania, Section of Urologic Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio, Schering-Plough Research Institute, Kenilworth, New Jersey, and Departments of Urology, West Virginia University, Morgantown, West Virginia, and The University of Iowa Hospital, Iowa City, Iowa© 1998 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited by Epperla N, Hanel W and Talpaz M (2022) Cytokines, Interferons, and Hematopoietic Growth Factors Holland‐Frei Cancer Medicine, 10.1002/9781119000822.hfcm064.pub2, (1-21) Hugar L, Gilbert S, Sexton W, Kamat A and Li R (2020) Immunotherapy in Bacillus Calmette–Guerin (BCG) unresponsive nonmuscle invasive bladder cancerCurrent Opinion in Urology, 10.1097/MOU.0000000000000846, VOL. 31, NO. 2, (160-169), Online publication date: 1-Mar-2021. Goonewardene S, Persad R, Motiwala H and Albala D (2020) Systematic Review Results on BCG Refractory Disease Management Management of Non-Muscle Invasive Bladder Cancer, 10.1007/978-3-030-28646-0_47, (235-249), . Peyton C, Chipollini J, Azizi M, Kamat A, Gilbert S and Spiess P (2018) Updates on the use of intravesical therapies for non-muscle invasive bladder cancer: how, when and whatWorld Journal of Urology, 10.1007/s00345-018-2591-1, VOL. 37, NO. 10, (2017-2029), Online publication date: 1-Oct-2019. Duplisea J, Mokkapati S, Plote D, Schluns K, McConkey D, Yla-Herttuala S, Parker N and Dinney C (2018) The development of interferon-based gene therapy for BCG unresponsive bladder cancer: from bench to bedsideWorld Journal of Urology, 10.1007/s00345-018-2553-7, VOL. 37, NO. 10, (2041-2049), Online publication date: 1-Oct-2019. Gupta M, Kates M and Bivalacqua T (2019) Immunotherapy in nonmuscle invasive bladder cancer: current and emerging treatmentsCurrent Opinion in Oncology, 10.1097/CCO.0000000000000533, VOL. 31, NO. 3, (183-187), Online publication date: 1-May-2019. Lopez-Beltran A, Montironi R, Raspollini M, Cheng L and Netto G (2018) Iatrogenic pathology of the urinary bladderSeminars in Diagnostic Pathology, 10.1053/j.semdp.2018.03.001, VOL. 35, NO. 4, (218-227), Online publication date: 1-Jul-2018. (2018) Immunotherapy Bladder Cancer, 10.1016/B978-0-12-809939-1.00020-5, (277-325), . Shore N, Boorjian S, Canter D, Ogan K, Karsh L, Downs T, Gomella L, Kamat A, Lotan Y, Svatek R, Bivalacqua T, Grubb R, Krupski T, Lerner S, Woods M, Inman B, Milowsky M, Boyd A, Treasure F, Gregory G, Sawutz D, Yla-Herttuala S, Parker N and Dinney C (2017) Intravesical rAd–IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin–Refractory or Relapsed Non–Muscle-Invasive Bladder Cancer: A Phase II Randomized StudyJournal of Clinical Oncology, 10.1200/JCO.2017.72.3064, VOL. 35, NO. 30, (3410-3416), Online publication date: 20-Oct-2017. Ekmekcioglu S and Grimm E (2017) Cytokines, Interferons, and Hematopoietic Growth Factors Holland-Frei Cancer Medicine, 10.1002/9781119000822.hfcm064, (1-17) Lopez-Beltran A, Paner G, Montironi R, Raspollini M and Cheng L (2016) Iatrogenic changes in the urinary tractHistopathology, 10.1111/his.13090, VOL. 70, NO. 1, (10-25), Online publication date: 1-Jan-2017. Campbell M, Siefker-Radtke A and Gao J (2016) The State of Immune Checkpoint Inhibition in Urothelial CarcinomaThe Cancer Journal, 10.1097/PPO.0000000000000175, VOL. 22, NO. 2, (96-100), Online publication date: 1-Mar-2016. Geavlete P, Georgescu D, Mulţescu R, Drăguţescu M, Jecu M and Geavlete B (2016) Endoscopic Treatment of Bladder Tumors Endoscopic Diagnosis and Treatment in Urinary Bladder Pathology, 10.1016/B978-0-12-802439-3.00004-9, (83-203), . Patel S, Cohen A, Weiner A and Steinberg G (2015) Intravesical therapy for bladder cancerExpert Opinion on Pharmacotherapy, 10.1517/14656566.2015.1024656, VOL. 16, NO. 6, (889-901), Online publication date: 13-Apr-2015. Kamat A, Flaig T, Grossman H, Konety B, Lamm D, O'Donnell M, Uchio E, Efstathiou J and Taylor J (2015) Consensus statement on best practice management regarding the use of intravesical immunotherapy with BCG for bladder cancerNature Reviews Urology, 10.1038/nrurol.2015.58, VOL. 12, NO. 4, (225-235), Online publication date: 1-Apr-2015. Yu Q, Zhang J, Zhang G and Gan Z (2014) Synthesis and Functions of Well-defined Polymer-drug Conjugates as Efficient Nanocarriers for Intravesical Chemotherapy of Bladder Cancer a Macromolecular Bioscience, 10.1002/mabi.201400416, VOL. 15, NO. 4, (509-520), Online publication date: 1-Apr-2015. Downs T, Lee D and Scherr D (2015) Management of BCG Recurrent Bladder Cancer Management of Bladder Cancer, 10.1007/978-1-4939-1881-2_20, (245-263), . Ahn J and McKiernan J (2015) Intravesical Therapy Management of Bladder Cancer, 10.1007/978-1-4939-1881-2_18, (223-238), . Pagano M, Badalato G and McKiernan J (2014) Optimal Treatment of Non-Muscle Invasive Urothelial Carcinoma Including Perioperative Management RevisitedCurrent Urology Reports, 10.1007/s11934-014-0450-1, VOL. 15, NO. 11, Online publication date: 1-Nov-2014. Liu X, Dowell A, Patel P, Viney R, Foster M, Porfiri E, James N and Bryan R (2014) Cytokines as effectors and predictors of responses in the treatment of bladder cancer by bacillus Calmette–GuérinFuture Oncology, 10.2217/fon.14.79, VOL. 10, NO. 8, (1443-1456), Online publication date: 1-Jun-2014. Dinney C, Fisher M, Navai N, O'Donnell M, Cutler D, Abraham A, Young S, Hutchins B, Caceres M, Kishnani N, Sode G, Cullen C, Zhang G, Grossman H, Kamat A, Gonzales M, Kincaid M, Ainslie N, Maneval D, Wszolek M and Benedict W (2013) Phase I Trial of Intravesical Recombinant Adenovirus Mediated Interferon-α2b Formulated in Syn3 for Bacillus Calmette-Guérin Failures in Nonmuscle Invasive Bladder CancerJournal of Urology, VOL. 190, NO. 3, (850-856), Online publication date: 1-Sep-2013. (2012) Treatment Effects Bladder Pathology, 10.1002/9781118275436.ch24, (507-523) Ding G, Yu Y, Shen Z, Zhou X, Chen S, Liao G and Zhang Y (2012) Antitumor effects of human interferon-alpha 2b secreted by recombinant bacillus Calmette-Guérin vaccine on bladder cancer cellsJournal of Zhejiang University SCIENCE B, 10.1631/jzus.B1100366, VOL. 13, NO. 5, (335-341), Online publication date: 1-May-2012. Jones J and Larchian W (2012) Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS) Campbell-Walsh Urology, 10.1016/B978-1-4160-6911-9.00081-5, (2335-2354.e8), . Jackson R, Al-Ahmadie H, Reuter V and Lee C (2012) Non-Muscle-Invasive Low- and High-Grade Neoplasia The Urinary Tract, 10.1007/978-1-4614-5320-8_6, (113-141), . Zhang Z, Xu X, Zhang X, Chen X, Chen Q, Dong L, Hu Z, Li J and Gao J (2011) The therapeutic potential of SA-sCD40L in the orthotopic model of superficial bladder cancerActa Oncologica, 10.3109/0284186X.2010.549838, VOL. 50, NO. 7, (1111-1118), Online publication date: 1-Oct-2011. Rosevear H, Lightfoot A, Birusingh K, Maymí J, Nepple K and O'Donnell M (2011) Factors Affecting Response to Bacillus Calmette-Guérin Plus Interferon for Urothelial Carcinoma in SituJournal of Urology, VOL. 186, NO. 3, (817-823), Online publication date: 1-Sep-2011. Adiyat K, Katkoori D and Soloway M (2011) Intravesical Chemotherapy Bladder Tumors:, 10.1007/978-1-60761-928-4_13, (253-270), . Rosevear H, Lightfoot A, Nepple K and O'Donnell M (2010) Safety and Efficacy of Intravesical Bacillus Calmette-Guérin Plus Interferon α-2b Therapy for Nonmuscle Invasive Bladder Cancer in Patients With Prosthetic DevicesJournal of Urology, VOL. 184, NO. 5, (1920-1924), Online publication date: 1-Nov-2010.Nepple K, Lightfoot A, Rosevear H, O'Donnell M and Lamm D (2010) Bacillus Calmette-Guérin With or Without Interferon α-2b and Megadose Versus Recommended Daily Allowance Vitamins During Induction and Maintenance Intravesical Treatment of Nonmuscle Invasive Bladder CancerJournal of Urology, VOL. 184, NO. 5, (1915-1919), Online publication date: 1-Nov-2010. Sexton W, Wiegand L, Correa J, Politis C, Dickinson S and Kang L (2010) Bladder Cancer: A Review of Non-Muscle Invasive DiseaseCancer Control, 10.1177/107327481001700406, VOL. 17, NO. 4, (256-268), Online publication date: 1-Oct-2010. Kresowik T and Griffith T (2010) Bacillus Calmette–Guerin (BCG) for Urothelial Carcinoma of the Bladder Emerging Cancer Therapy, 10.1002/9780470626528.ch3, (49-70), Online publication date: 16-Jul-2010. Agarwal A, Agrawal U, Verma S, Mohanty N and Saxena S (2010) Serum Th1 and Th2 cytokine balance in patients of superficial transitional cell carcinoma of bladder pre- and post-intravesical combination immunotherapyImmunopharmacology and Immunotoxicology, 10.3109/08923970903300151, VOL. 32,