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UPDATE IN TESTICULAR CANCER

J. L. Passos Coelho

Hospital da Luz

Hospital Beatriz Ângelo

Multidisciplinary Genitourinary Oncology CourseLisboa, Oct 14th 2017

UPDATE IN TESTICULAR CANCER

Purpose today:

Review recent data on old paradigms

Multidisciplinary Genitourinary Oncology CourseLisboa, Oct 14th 2017

De Angelis R. et al. Lancet Oncology 2013,

“Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5—a population-based

study”

European mean age-standardised

5-year relative survival

SEER Data – Testicular Cancer: Stage and Survival

Fig 1. (A) Overall survival and (B) disease-free survival over time, stratified by International Germ Cell

Cancer Collaborative Group risk group. Hashes represent censored patients. FAV, favorable-risk group;

INT, intermediate-risk group; POOR, poor-risk group.

Published in: Jenny J. Ko; Brandon Bernard; Ben Tran; Haocheng Li; Tehmina Asif; Igor Stukalin; Margaret Lee; Daphne Day; Nimira Alimohamed; Christopher J. Sweeney; Philippe L.

Bedard; Daniel Y.C. Heng; JCO 2016, 34, 714-720. DOI: 10.1200/JCO.2015.64.7909

Copyright © 2016 American Society of Clinical Oncology

Conditional Survival Metastatic Testicular GCT: 5 centers (Canada, USA, Australia) 1990-2012 (N=942)

Published in: Jenny J. Ko; Brandon Bernard; Ben Tran; Haocheng Li; Tehmina Asif; Igor Stukalin; Margaret Lee; Daphne Day; Nimira Alimohamed; Christopher J. Sweeney; Philippe L.

Bedard; Daniel Y.C. Heng; JCO 2016, 34, 714-720. DOI: 10.1200/JCO.2015.64.7909

Copyright © 2016 American Society of Clinical Oncology

Conditional Survival in Metastatic Testicular GCT: 5 centers (Canada, USA, Australia) 1990-2012 (N=942)

2y Conditional OS At baseline At 2 years

Overall Population 92% (IC: 91-94%) 98% (IC: 97-99%)

(IGCCCG)Favorable

97 % 99 %

Intermediate 94 % 99 %

Poor 71 % 93 %

SEMINOMA: estádio I

Risco Recidiva pos-orquidectomia: ~20% (até aos 5 anos – 95%)

Factores Prognóstico:

T>4cm e invasão rete testis (não consensual)

Opções Terapêuticas após Orquidectomia

• Radioterapia Retroperitoneal

(recidivas ~4%; recidiva RP rara; neoplasia secundária pos-RT

• Observação sem Tratamento

(recidiva ~20%; predomínio GG RP; necessidade f/u longo

• Carboplatina Adjuvante (AUC7 c/ Cl EDTA) x 1 (x2?)

(eficácia semelhante à RT adjuvante? Recidiva RP (predomínio)

SEMINOMA - estádio Iestudos randomizados

• MRC: RT (para-aórtica/dogleg, 20/30Gy) vs carboplatina (AUC 7) x 1(N=1.477; f/u median 6,5 anos, 79% > 5 anos)

RT CarbopRFS5y 96% 95%Morte por seminoma 1 0TCG contralateral 15 (1.2%) 2 (0.2%) (p=0.03)

Oliver et al. JCO 2011, 29:957

SEMINOMA - estádio Irisk adapted treatment

2nd Spanish GCCG Study (n=314; f/u 34 meses, mínimo 12 meses)

s/ factores risco (1/3) Observação

T>4cm e/ou invasão rete testis (2/3) carboplatina (AUC7) x 2

Observação Carbo x 2

Recidivas 6% 3%

DFS 5y 93% 96%

12/13 recidivas no RP; salvage EP (12), BEP (1); último f/u – só 1 c/ doença

Aparicio et al. JCO 2005;23:8717

SEMINOMA – CS Irisk adapted treatment

3rd Spanish GCCG Study (2004/8, n=227; median f/u 34 mo, >2yr – 74%)

0 /1 risk factors (2/3) surveillance

Both risk factors (1/3) carboplatin (AUC7) x 2

T>4cm rete testis invasion neither both

% 19% 11% 37% 33%

Relapses 6/44 (15%) 5/25 (20%) 4/84 (5%) 1/74 (1.4%)

(15/16 recidivas no RP)

Surveillance Carbo x 2

Relapse 9.8% 1.4%

DFS 3y 88% 98%

OS 3y 100% 100%

Aparicio et al. JCO 2011, 29:4677

SEMINOMA – CS Ipopulation based registry

SWENOTECA V (2000/2006); N=1.384; F/U: median 5.2 yr

OPTIONS Surveillance RT (25.2Gy) Carbo x 1Number 512 481 188RFS 5yr (%) 86 99 98OS 5yr (%) 99.8 100 100

CS 1 on Surveillance: all relapses in RP (94% as single site)median time to relapse 1.4yr (31% after 2yr; 3% after 5 yr)

CS2A - RT N=29 / Relapses - 3CS2A/2B - (B)EP N=73 / Relapses - 0

Tandstad et al. JCO 2011, 29: 719

Stage I Seminoma: treatment algorithm

• Tumor < 4cm or NO rete testis invasionSurveillance

• Tumor > 4cm AND (OR??) rete testis invasion Carboplatin (AUC7) x 1 (x2?)

Surveillance ??

Relapse following Carboplatin for Stage I Testicular Seminoma: 17y UK experience

N=517, all consecutive pts South Central England 7/1996–10/2013Carboplatin AUC7 (EDTA Cl) x 1

If relapse:“stage IIA” – dog leg RT “IIB-III good progn” – BEP x 3“III intermediate progn” – BEP x 4

med time to relapse: 23 mo(3 of 21, beyond 3 years)19/21 – RP only20/21 – good progn IGCCCGNo GCT deaths

CTGCT: 20 (3.9%), 3 synchronousMed time to: 8.8y9 seminoma, 8 NSGCT

Chau et al. Ann Oncol 2015

Relapse following Carboplatin for Stage I Testicular Seminoma: 17y UK experience

Chau et al. Ann Oncol 2015

Prognostic factors:• T>4cm 5y-RFS5.9% (vs 3.3% for T<4cm)p=0.04• rete testis invasion p=0.8• both factorsp=0.07

Stage I NSGCT: algorithm

• NO lymphovascular invasion

(stage IA - pT1N0M0S0)

Orchidectomy surveillance (chemo if relapse)

• WITH lymphovascular invasion

(stage IB - pT2-4N0M0S0)

Orchidectomy Adjuvant BEP x 1? (2?)

TCG estádio II/III: Tratamento

Estádio Seminoma Não

Seminoma

II

(low tumor burden

subgroups)

IIA / IIB(GG < 5cm)

RT ou QT

IIC - QT

QT

(RPLND QT se

GG c/ <3cm e

marcadores Nl)

III QT QT

Fig 2

Clinical Oncology 2016 28, 513-521DOI: (10.1016/j.clon.2016.02.008)

Copyright © 2016 The Royal College of Radiologists Terms and Conditions

Stage II Testicular Seminoma: Patterns of Care and Survival by Treatment Strategy

S.M. Glaser, J.A. Vargo, G.K. Balasubramani, S. Beriwal

Clinical Oncology28; 8: 513-521 (August 2016)

DOI: 10.1016/j.clon.2016.02.008

US National Cancer Data Base 1998-2012Stage II Seminoma (N=2.437)median f/u 5.5y

IIA 960 - RT (78%), QT (22%) (OS, p=0.03)IIB 812 - RT (54%), QT (46%) (OS, p=NS)IIC 665 - RT 4%, QT 96%

Estádio II/III: Grupos prognóstico do IGCCCG

Grupo Seminoma Não-Seminoma

Bom Restantes (90%)

PFS5y: 82%

FP<1.000 S1 (56%)

hCG<5.000 PFS5y: 89%

LDH<1.5x Nl

Intermédio metástases viscerais

extrapulmonares (10%)

PFS5y: 67%

1.000<FP<5.000 S2 (28%)

5.000<hCG<50.000

1.5x <LDH<10x Nl PFS5y: 75%

Mau ______ mets viscerais extrapulm. (16%)

FP>5.000 S3

hCG>50.000 PFS5y: 41%

LDH>10x Nl

Primário do mediastino

IGCCCG. JCO 1997;15:594

Estádio II/III: Bom Prognóstico (II)

• BEP x 3 melhor que EP x 3Indiana minimal & moderate extent disseminated diseaseFFS 86% vs 69% (p=0.01)OS 95% vs 86% (p=0.01)

Loehrer et al. JCO 1995;13:470

• BEP x 3 = EP x 4 (Good Risk IGR: NSGCT primário do testículo ou RP, valores FP/hCG)EFS4y 91% vs 86% (p=0.2)OS4y 96% vs 92% (p=0.1)

Culine et al Annals Oncol 2007;18:917

• E500P100 x 4 melhor que E500C500 x 4 (Good Risk MSKCC)RC mantidas: 87% vs 76%EP: superior EFS e RFS

Bajorin et al JCO 1993;11:598

Figure 1

The Journal of Urology 2015 193, 507-512DOI: (10.1016/j.juro.2014.09.090)

Copyright © 2015 American Urological Association Education and Research, Inc. Terms and Conditions

The Impact of Bleomycin on

Retroperitoneal Histology at Post-Chemotherapy Retroperitoneal Lymph

Node Dissection of Good Risk Germ Cell Tumors

K. Clint Cary, Jose A. Pedrosa, Hristos Z. Kaimakliotis, Timothy A. Masterson, Lawrence H.

Einhorn, Richard S. Foster

The Journal of UrologyVolume 193, Issue 2, Pages 507-512 (February

2015) DOI: 10.1016/j.juro.2014.09.090

Indiana Univ. 1985-2011IGCCCG Good Risk

Metastatic Testicular GCTQT → RPLND

Figure 2 The Journal of Urology 2015 193, 507-512DOI: (10.1016/j.juro.2014.09.090)

Copyright © 2015 American Urological Association Education and Research, Inc. Terms and Conditions

Indiana Univ. 1985-2011 IGCCCG Good Risk Metastatic Testicular GCT QT →RPLND

Estádio II/III: Mau Prognóstico

• BEP100 = BEP200 Nichols et al. JCO 1991;9:1163

• BEP = VIP Hinton et al. Cancer 2003;97:1869

• BEP = T-BEP de Wit et al. JCO 2012;30:792

Better in IGCCCG intermediate prognosis ?

• BEP x 4 = BEP x 2 + HD CarbopEC/TMO x 2

IGCCCG intermediate & poor prognosis

N = 165 BEP BEP/TMO

CR 1y 48% 52%

OS 2y 72% 71%

Motzer et al. JCO 2007;25:247

Salvage HDC in female pts w/ relapsed/refractory GCT: a retrospective analysis of EBMT

De Giorgi et al. Ann Oncol 2017

60 pts multi-institutional cohort between 1985-2013Primary: ovary 38, mediastinum 11, other non-ovarian 11HDC as 2nd to 6th line of RxMediastinal primary – median OS of 7.4mo

What about Routine Contralateral Testicular Biopsy?

• 3.5-5% of pts w/ testicular GCT develop a contralateral GCT• TIN (testicular intraepithelial neoplasia, or CIS) can be

detected in ~5% of contralateral testicular biopsies• TIN progress to GCT in 50-70% of pts within 5-7 years• Testicular low dose RT (16Gy) can prevent progression from

TIN to GCT but compromises testicular funtion

Thus, Routine Contralateral Testicular Biopsy is controversial

Screening for CIS of contralateral testicle population-based study in Denmark (1984-2007)

Kier et al. Ann Oncol 2015

Western Denmark 1984 -1988

Screening for CIS of contralateral testicle population-based study in Denmark

Kier et al. Ann Oncol 2015

Screening for CIS of contralateral testicle population-based study in Denmark

Kier et al. Ann Oncol 2015

Tandstad et al. Acta Oncologica 2015;54:493

Contralateral testicular GCT in stage I NSGCT in SWENOTECA III and VI protocols

2%

2%

N= 988 Med f/u: 8.3y(Surv. 494; adjuv Qt 494)Contralateral BxSurv – 25%Adjuv Qt – 32%

1 - “synchronous”1 - 3y after RT

Tandstad et al. Acta Oncologica 2015;54:493

Bilateral testicular GCT in pts w/ stage I NSGCT: two SWENOTECA protocols

N=11 N=13

Has Cancer Immunotherapy reached GCT?

Fankhauser et al. Br J Cancer 2015

Frequent PD-L1 expression in Testicular GCT

Univ Zurich, 1990-2003

329 primary testicular GCT

FFPE specimens

Prognostic value of PD-1 and PD-L1in testicular GCT

• Diagnostic biopsy specimens: testes 131; extragonadal 9 (abdominal 7; mediastinal 2)• NSGCT - 70, Seminoma - 31, Mixed GCT - 39• No PD-1 stainingPD-L1 staining: 89% of NSGCT; 76% of Seminomas (highest in choriocarcinoma; lowest in seminoma)• PD-L1 staining associated w/ ≥3 meatastatic sites, non-pulmonary visceral mets, >tumor markers

Cierna Z. et al. Ann Oncol 2015

Zschabitz et al. Eur J Cancer 2017

Fig 2. Beta-human chorionic gonadotropin (β-HCG) trend, with arrows indicating treatment with pembrolizumab.

Published in: Marilyn Huang; Andre Pinto; Rosa Patricia Castillo; Brian M. Slomovitz; JCO 2017, 35, 3172-3174.

DOI: 10.1200/JCO.2017.74.4052

Copyright © 2017 American Society of Clinical Oncology

Case Report: Pembrolizumab for Metastatic Choriocarcinoma progressing after EP, EMA-CO and EMA-EP

Phase II trial Pembrolizumab for Incurable Platinum-Refractory GCT

Adra et al. ASCO 2017 / Indiana U. & U Penn

Phase II trial Pembrolizumab for Incurable Platinum-Refractory GCT

Adra et al. ASCO 2017 / Indiana U. & U Penn

CLINICAL TRIAL PROTOCOL

Phase II multi-institutional proof of concept single-arm

trial of Nivolumab in the treatment of patients with

platinum-recurrent or platinum-refractory metastatic

germ cell tumors

Type: Interventional, Phase II

EudraCT Number 2017-003336-37

Investigators: Francisco Paralta Branco, Margarida Brito,

Joaquina Mauricio, Gabriela Sousa & JL Passos Coelho,

CLINICAL TRIAL PROTOCOL