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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