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Cáncer de Vejiga no músculo infiltrante: lo que el oncólogo debe saber en 2020

Javier Puente, MD, PhD Director of the Institute of Oncology

Associate Professor of Medicine, Complutense University of Madrid, Spain Medical Oncology Department, GU Cancer Unit

Hospital Clínico San Carlos, Madrid, Spain

Employment: SERMAS

Consultant or Advisory Role: Astellas, Janssen, MSD, Bayer, Pfizer, Eisai, Ipsen, Sanofi, Roche, BMS, Merck

Stock Ownership: None

Research Funding: Astellas

Speaking: Astellas, Pfizer, Roche, BMS, Janssen, Astra Zeneca, Ipsen, MSD, Sanofi, Merck

Grant support: Roche

Other (Travels/Accommodation): MSD, Roche, Ipsen

Disclosure Information

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Bladder Cancer: a big health problem

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Different scenarios in bladder cancer

Non–muscle-invasive UC

70% of newly diagnosed cases

Stages 0a–1

Ta: noninvasive papillary carcinoma

Tis: carcinoma in situ

T1: tumour invades lamina propria

mUC

5% of newly diagnosed cases

Stages 3a and 4

T4b: tumour invades the pelvic wall, abdominal wall

N1–3: pelvic lymph-node involvement

M1: distant metastasis 40-50%

progress

Muscle-invasive UC

25% of newly diagnosed cases

Stages 2 and 3

T2: tumour invades muscle

T3: tumour invades perivesical fat

T4a: tumour invades contiguous organs

(prostate, uterus, vagina) 15–20%

progress

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Pathological Classification of NMIBC

Smith AB, et al. BJU Int 2018

VARIANTS UROTHELIAL CARCINOMA

1. urothelial carcinoma (more than 90% of all cases)

2. urothelial carcinomas with partial squamous and/or glandular or trophoblastic differentiation

3. micropapillary urothelial carcinoma*

4. nested variant (including large nested variant) and microcystic urothelial carcinoma

5.plasmocytoid*, giant cell, signet ring, diffuse, undifferentiated

6.lymphoepithelioma-like

7.some urothelial carcinomas with other rare differentiation

8.small-cell carcinomas

9. sarcomatoid* urothelial carcinoma.

LVI is associated with an increased risk of pathological upstaging and worseprognosis

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Pathological Classification of NMIBC PATHOLOGICAL CLASSIFICATION

Smith AB, Jaeger B, Pinheiro LC, et al. Impact of bladder cancer on health-related quality of life. BJU Int. 2018;121(4):549-557. doi:10.1111/bju.14047

The 2009 TNM classification approved by the UnionInternational Contre le Cancer (UICC) was updated in 2017 (8th Edn.), but with no changes in relation to bladder tumours

PATHOLOGICAL CLASSIFICATION

Smith AB, Jaeger B, Pinheiro LC, et al. Impact of bladder cancer on health-related quality of life. BJU Int. 2018;121(4):549-557. doi:10.1111/bju.14047

The 2009 TNM classification approved by the UnionInternational Contre le Cancer (UICC) was updated in 2017 (8th Edn.), but with no changes in relation to bladder tumours

Smith AB, et al. BJU Int 2018

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T1 subclassification of NMIBC

Smith AB, et al. BJU Int 2018

T1 SUBCLASSIFICATION

1. The depth and extent of invasion into the lamina propria (T1 substaging) has been demonstrated to be of prognostic value in retrospective cohort studies

2. Its use is recommended by the most recent2016 World Health Organization (WHO) classification

3. The optimal system to substage T1 remains to be defined

T1m

T1e

T1 SUBCLASSIFICATION

• T1a: invasion above the muscularis mucosae vascular plexus (MM-VP)

• T1b: in the MM-VP

• T1c: beyond the MM-VP

Most studies found substage to be an important prognostic factor .

However, the T1 substage has not been adopted in clinical guidelines or classification systems for stage

The main reason has been lack of consensus among pathologists regarding the identification of the MM-VP at the invasion front of the tumor

• T1m: a single focus of lamina propria invasion ≦ 0.5 mm

• T1e: specimens showing a >0.5-mm lamina propria invasion or multiple microinvasiveareas.

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Pathological Classification of NMIBC

Soukup V, et al. Eur Urol 2017

PATHOLOGICAL CLASSIFICATION

Soukup, V., et al. Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review. Eur Urol, 2017. 72: 801.

A systematic review and meta-analysis did not show that the 2004/2016 classification outperforms the 1973 classification in prediction of recurrence and progression

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Risk stratification NMIBC RISK STRATIFY PATIENTS AUA/EAU/NICE

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BCG is the standard of care for HighRisk-NMIBC

- Current guidelines recommend the USE OF INTRAVESICAL BCG in some intermediate and high-risk NMIBC to reduce the risk of recurrence and progression.

EAU, AUA guidelines 2020; Herr et al,. J Urol 1979

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BCG is the standard of care: Current problems

- Although there is a high rate of complete response (70%) to initial therapy, most patients do not maintain response:

- 30% recurrence within 1 year - 40% progress to MIBC - 20-30% progress to metastatic disease

- Global demand for BCG is up to 2 million doses per year but…

- BCG shortage: Only few companies produce BCG for oncotherpay and export it worldwide, closures of BCG plants in 2012 and 2014, reduction of production in 2015, withdrawal of a large BCG manufacturer in 2017…

- Tumor heterogeneity

Hemdan T, et al. J Urol 2014 ; Herr et al,. J Urol 2015; Anastasiadis A, et al. Ther Adv Urol 2012

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Tumor heterogeneity in NMIBC

Pietzak et al. Eur Urol 2017

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Risk stratification NMIBC

MOLECULAR SUBTYPES (THE FUTURE)

MOLECULAR SUBTYPES (THE FUTURE)

Hedegaard J, et al. Cancer Cell 2017

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How to treat bladder cancer patients in the BCG shortage era?

- Optimise the use of BCG - Selecting BCG responders (ARID1A mutations, etc) - Reducing BCG dose (One-third dose vs full dose was not inferior DFS & OS) - Shorten the lengh of the BCG course? - Reduce the number of instillations per maintenance cycle

- Radical Cistectomy (depth of invasion, LVI, CIS, >3 cm..) - Intravesical chemotherapy (Mytomicin C, Volrubicin, Gemcitabine, Docetaxel) - Thermochemotherapy - Oncolityc adenoviruses (CG0070.AD-INF) - Photodynamic therapy (5-aminolevulinic acid, hexaminolevulinic acid) - Checkpoints inhbitors

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Pembrolizumab in NMIBC (Keynote-057)

Balar A, et al. ASCO 2020 (abstract 5041)

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Atezolizumab for BCG unresponsive NMIBC

Black P, et al. ASCO 2020 (abstract 5022)

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Be careful with the population included…

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Phase III Clinical Trials on going in NMIBC

Study Population Estimated N Treatment

POTOMAC BCG naive 975 Durvalumab + BCG vs BCG

ALBAN BCG naive 641 Atezolizumab + BCG vs BCG

CREST BCG naive 999 Sasanlimab + BCG vs BCG

KEYNOTE-676 Persistent or recurrent after BCG induction

550 Pembrolizumab + BCG vs BCG

CheckMate 7G8 Persistent or recurrent after BCG >24 months (not unresponsive)

700 Nivolumab + BCG vs BCG

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Gracias

Javier Puente, MD, PhD Director of the Institute of Oncology

Associate Professor of Medicine Medical Oncology Department

GU Cancer Unit Hospital Clínico San Carlos, Madrid, Spain Complutense University of Madrid, Spain