Myths and Mysteries Surrounding Adjuvant Therapy for NMIBC Ashish - PowerPoint PPT Presentation

Myths and Mysteries Surrounding Adjuvant Therapy for NMIBC Ashish M. Kamat, MD, MBBS, FACS Professor of Urologic Oncology Wayne B. Duddlesten Professor of Cancer Research President, International Bladder Cancer Group

NMIBC is a heterogeneous group of tumors Risk categories are not uniform

Lancet, June 2016

Lancet, June 2016

European Association of Urology v

American Urological Association

Common Definition • Low Risk § Solitary, primary, TaLG < 3 cm • High Risk § Any T1 or any high grade (Ta, T1), including CIS § Progression main concern • Intermediate Risk § Everything else (i.e. recurrent/multiple TaLG) § Recurrence main concern Adopted from IBCG, Brausi M et al. 2011

Adjuvant Therapy

Intermediate Risk Tumors

Intermediate Risk Tumors (Low Grade) Kamat et al, J Urol, 2014

High Risk Tumors

BCG is the ORIGINAL ~ 1.2 Million Doses of BCG used globally for Bladder Cancer

Myth #1 BCG does not reduce progression rates (only reduces recurrences)

Intravesical BCG Progression Progression Progression Progression Progression Progression Progression Progression Progression Progression Progression Progression Progression Progression Pr Progression Progression All All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance All Studies With Maintenance Analysis of Progression in 20 Controlled Trials Study Publ Year Events / Patients Statistics OR & CI |1-OR| Author and Group No BCG BCG (O-E) Var. (BCG : No BCG) % ± SD 1991 Pagano (Padova) 11 / 63 3 / 70 -4.4 3.1 1987 Badalament (MSKCC) 6 / 46 6 / 47 -0.1 2.6 2000 Lamm (SW8507) 102 / 192 87 / 192 -7.5 24.1 2001 Palou 2 / 61 3 / 65 0.4 1.2 1996 Rintala (Finnbl 2) 3 / 90 3 / 92 0 1.5 1995 Rintala (Finnbl 2) 4 / 40 2 / 28 -0.5 1.3 1995 Lamm (SW8795) 24 / 186 15 / 191 -4.8 8.8 1999 Malmstrom (Sw-N) 22 / 125 15 / 125 -3.5 7.9 2001 Nogueira (CUETO) 8 / 127 10 / 247 -1.9 3.9 1991 Rintala (Finnbl 1) 2 / 58 3 / 51 0.7 1.2 2001 de Reijke (EORTC) 18 / 84 10 / 84 -4 5.9 2001 vd Meijden (EORTC) 19 / 279 24 / 558 -4.7 9.1 1982 Brosman (UCLA) 0 / 22 0 / 27 0 0 1990 Martinez-Pineiro 4 / 109 1 / 67 -0.9 1.2 1999 Witjes (Eur Bropir) 2 / 25 1 / 28 -0.6 0.7 1997 Jimenez-Cruz 7 / 61 6 / 61 -0.5 2.9 1994 Kalbe 2 / 35 0 / 32 -1 0.5 1991 Kalbe 2 / 17 0 / 21 -1.1 0.5 1993 Melekos (Patras) 7 / 99 2 / 62 -1.5 2 1988 Ibrahiem (Egypt) 12 / 30 5 /17 -1.1 2.6 27% ±9 reduction Total 257 / 1749 196 /2065 -36.8 80.9 (14.7 %) (9.5 %) 0.0 0.5 1.0 1.5 2.0 Test for heterogeneity BCG No BCG c 2 =9.73, df=18: p=0.9 better better Sylvester, 2002 Treatment effect: p=0.00004

BCG reduces progression only when maintenance is used Meta analysis of 24 RCT of BCG with 4,863 pts Sylvester RJ: J Urol. 2002, 168:1964-70

Myth #2 Optimal maintenance schedule unknown (induction alone is enough)

BCG Maintenance: Not Created Equal Only SWOG protocol shows clear benefit Kamat & Porten, Eur Urol, 2014

BCG Maintenance: Not Created Equal Only SWOG protocol shows clear benefit Kamat & Porten, Eur Urol, 2014

BCG Maintenance: Not Created Equal Only SWOG protocol shows clear benefit Kamat & Porten, Eur Urol, 2014

BCG Maintenance: Not Created Equal Only SWOG protocol shows clear benefit Kamat & Porten, Eur Urol, 2014

Optimal BCG Urinary IL-2 Assay Induction Re-induction De Reijke, 1999

Why timing is important Adapted from Lamm, JU 2000

Why timing is important 3 month eval Adapted from Lamm, JU 2000

Why timing is important Adapted from Lamm, JU 2000

Why timing is important 6 month eval Adapted from Lamm, JU 2000

Why timing is important 6 month eval 64% of ‘failures’ salvaged with 3 weeks of BCG Adapted from Lamm, JU 2000

Key Fact Duration appears to be more crucial than dose

EORTC30962 – FD vs LD, 1 yr vs 3 yr Four groups (5 year Disease Free Rates) 3 year @ full dose: 64.2% 3 year @ 1/3 rd dose: 62.6% 1 year @ full dose: 58.8% 1 year @ 1/3 rd dose: 54.5% FD @ 3 yrs was superior to LD @ 1 yr was (p = 0.01) Oddens et al, Eur Urol, 2013

Myth #3 BCG is only indicated for high grade disease

EORTC 30911 3 Week Maintenance BCG vs Epirubicin Rec reduced with BCG Mets reduced with BCG Maintenance (p<0.0001) Maintenance (p=0.046) Overall survival (& DSS) Improved with BCG Maint. 837 randomized pts without CIS (P=0.023) followed for 9.2 yrs. 497 intermediate risk (LOW GRADE) - as good/better benefit vs high risk Sylvester RJ: Eur Urol. 12: 2009

Myth #4 Most patient cannot tolerate full course of BCG

BCG is well tolerated EORTC 30962 — Comparison of full dose vs 1/3 rd dose BCG for 1 year vs 3 years — 1355 patients; median follow-up of 7.1 yrs, — < 10% patients discontinued due to toxicity International IPD Survey — 971 patients — only 5.2% discontinued BCG maintenance due to toxicity. Oddens J et al, Eur Urol, 2012; Witjes et al, BJUI, 2012

— Minimize fluid intake before — No rotisserie-style turning instillation — Statins/aspirin therapy okay — Start with empty bladder — Antispasmodicsfor local — Inspect voided urine for visible symptoms hematuria — Antipyretics for influenza-like — (routine urinalysis/dipstick not symptoms necessary) — Give 1 dose of quinolone 6 — Catheterize atraumatically hours after BCG — Minimize lubricant (to avoid — Suspected BCGosis/BCG sepsis BCG clumping) needs prompt workup and — Avoid lidocaine (acidity aggressive therapy degrades BCG)

Myth #5 BCG is not effective in older patients

BCG fails older patients? — Kanematsu et al – higher recurrence and reduced PPD in patients >80 yr with BCG [HinyokikaKiyo 1998] — Joudi et al – non-randomized study, 22% lower DSS in patients >80 yr with BCG + interferon [J Urol 1996] — Other smaller reports : claimed lower efficacy of intravesical immunotherapy in elderly patients — No control group for comparison. Kamat & Lamm, Eur Urol, 2014

EORTC 30911 – Sub Analysis Patients >70 yr had a shorter time to progression (p=0.028), OS (p<0.001), and NMIBC-specific survival (p=0.049) but similar time to recurrence compared with younger patients. Oddens et al, Eur Urol, 2014

EORTC 30911 – Sub Analysis BCG was still more effective than epirubicinfor all four end points considered; including in patients >70 yr Oddens et al, Eur Urol, 2014

Myths and Mysteries Surrounding Adjuvant Therapy for NMIBC Ashish M. Kamat, MD, MBBS, FACS Professor of Urologic Oncology Wayne B. Duddlesten Professor of Cancer Research President, International Bladder Cancer Group

Thank You Ashish M. Kamat, MD, MBBS, FACS akamat@mdanderson.org @UroDocAsh