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

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

Oct 15, 2022 358 likes •812 views

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

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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

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NMIBC is a heterogeneous group of tumors

Risk categories are not uniform

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Lancet, June 2016

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Lancet, June 2016

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European Association of Urology

v

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American Urological Association

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Common Definition

Adopted from IBCG, Brausi M et al. 2011

  • 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

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Adjuvant Therapy

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Intermediate Risk Tumors

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Kamat et al, J Urol, 2014

Intermediate Risk Tumors (Low Grade)

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High Risk Tumors

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~ 1.2 Million Doses of BCG used globally for Bladder Cancer

BCG is the ORIGINAL

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Myth #1

BCG does not reduce progression rates (only reduces recurrences)

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Study Publ Year Author and Group Events / Patients No BCG BCG Statistics (O-E) Var. OR & CI : (BCG No BCG) |1-OR| % ± SD

Progression

All Studies With Maintenance

1991 Pagano (Padova) 11 / 63 3 / 70

  • 4.4

3.1

Progression

All Studies With Maintenance

1987 Badalament (MSKCC) 6 / 46 6 / 47

  • 0.1

2.6

Progression

All Studies With Maintenance

2000 Lamm (SW8507) 102 / 192 87 / 192

  • 7.5

24.1

Progression

All Studies With Maintenance

2001 Palou 2 / 61 3 / 65 0.4 1.2

Progression

All Studies With Maintenance

1996 Rintala (Finnbl 2) 3 / 90 3 / 92 1.5

Progression

All Studies With Maintenance

1995 Rintala (Finnbl 2) 4 / 40 2 / 28

  • 0.5

1.3

Progression

All Studies With Maintenance

1995 Lamm (SW8795) 24 / 186 15 / 191

  • 4.8

8.8

Progression

All Studies With Maintenance

1999 Malmstrom (Sw-N) 22 / 125 15 / 125

  • 3.5

7.9

Progression

All Studies With Maintenance

2001 Nogueira (CUETO) 8 / 127 10 / 247

  • 1.9

3.9

Progression

All Studies With Maintenance

1991 Rintala (Finnbl 1) 2 / 58 3 / 51 0.7 1.2

Progression

All Studies With Maintenance

2001 de Reijke (EORTC) 18 / 84 10 / 84

  • 4

5.9

Progression

All Studies With Maintenance

2001 vd Meijden (EORTC) 19 / 279 24 / 558

  • 4.7

9.1

Progression

All Studies With Maintenance

1982 Brosman (UCLA) / 22 / 27

Progression

All Studies With Maintenance

1990 Martinez-Pineiro 4 / 109 1 / 67

  • 0.9

1.2

Progression

All Studies With Maintenance

1999 Witjes (Eur Bropir) 2 / 25 1 / 28

  • 0.6

0.7

Progression

All Studies With Maintenance

1997 Jimenez-Cruz 7 / 61 6 / 61

  • 0.5

2.9

All Studies With Maintenance

1994 Kalbe 2 / 35 / 32

  • 1

0.5

Pr

All Studies With Maintenance

1991 Kalbe 2 / 17 / 21

  • 1.1

0.5

All

1993 Melekos (Patras) 7 / 99 2 / 62

  • 1.5

2 1988 Ibrahiem (Egypt) 12 / 30 5 /17

  • 1.1

2.6 Total 257 / 1749 196 /2065

  • 36.8

80.9 (14.7 %) (9.5 %)

27% ±9 reduction

0.0 0.5 1.0 1.5 2.0

BCG No BCG

Test for heterogeneity

better better

c

2=9.73, df=18: p=0.9

Treatment effect: p=0.00004

Intravesical BCG

Analysis of Progression in 20 Controlled Trials

Sylvester, 2002

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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

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Myth #2

Optimal maintenance schedule unknown (induction alone is enough)

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BCG Maintenance: Not Created Equal

Only SWOG protocol shows clear benefit

Kamat & Porten, Eur Urol, 2014

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BCG Maintenance: Not Created Equal

Only SWOG protocol shows clear benefit

Kamat & Porten, Eur Urol, 2014

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BCG Maintenance: Not Created Equal

Only SWOG protocol shows clear benefit

Kamat & Porten, Eur Urol, 2014

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BCG Maintenance: Not Created Equal

Only SWOG protocol shows clear benefit

Kamat & Porten, Eur Urol, 2014

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Optimal BCG

Urinary IL-2 Assay

Induction Re-induction

De Reijke, 1999

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Why timing is important

Adapted from Lamm, JU 2000

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Why timing is important

Adapted from Lamm, JU 2000

3 month eval

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Why timing is important

Adapted from Lamm, JU 2000

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Why timing is important

Adapted from Lamm, JU 2000

6 month eval

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Why timing is important

Adapted from Lamm, JU 2000

64% of ‘failures’ salvaged with 3 weeks of BCG

6 month eval

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Key Fact

Duration appears to be more crucial than dose

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EORTC30962 – FD vs LD, 1 yr vs 3 yr

Oddens et al, Eur Urol, 2013

Four groups (5 year Disease Free Rates) 3 year @ full dose: 64.2% 3 year @ 1/3rd dose: 62.6% 1 year @ full dose: 58.8% 1 year @ 1/3rd dose: 54.5% FD @ 3 yrs was superior to LD @ 1 yr was (p = 0.01)

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Myth #3

BCG is only indicated for high grade disease

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EORTC 30911 3 Week Maintenance BCG vs Epirubicin

Rec reduced with BCG Maintenance (p<0.0001) Mets reduced with BCG Maintenance (p=0.046) Overall survival (& DSS) Improved with BCG Maint. (P=0.023)

837 randomized pts without CIS followed for 9.2 yrs. 497 intermediate risk (LOW GRADE)

  • as good/better benefit vs high risk

Sylvester RJ: Eur Urol. 12: 2009

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Myth #4

Most patient cannot tolerate full course

  • f BCG
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BCG is well tolerated

EORTC 30962

— Comparison of full dose vs 1/3rd 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

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— Minimize fluid intake before

instillation

— Start with empty bladder — Inspect voided urine for visible

hematuria

— (routine urinalysis/dipstick not

necessary)

— Catheterize atraumatically — Minimize lubricant (to avoid

BCG clumping)

— Avoid lidocaine (acidity

degrades BCG)

— No rotisserie-style turning — Statins/aspirin therapy okay — Antispasmodicsfor local

symptoms

— Antipyretics for influenza-like

symptoms

— Give 1 dose of quinolone 6

hours after BCG

— Suspected BCGosis/BCG sepsis

needs prompt workup and aggressive therapy

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Myth #5

BCG is not effective in older patients

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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

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EORTC 30911 – Sub Analysis

Oddens et al, Eur Urol, 2014

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.

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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

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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

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Ashish M. Kamat, MD, MBBS, FACS

akamat@mdanderson.org

Thank You

@UroDocAsh