1. Treatment of Testicular Germ-cell tumors: The state of art in 2012
Prof. Josep Ramon Germà i Lluch
Institut Català d’Oncologia
Braga abril 2012

2. State of art: Stage I seminoma and no seminoma. Seminoma stage IIa,b.
Metastatic disease.
PET in residual masses.
Prognosis and treatment of relapses.
Global results of GG
State of art:

3. Germ-Cell testicular tumors New strategy with less toxicity
Surveillance post-orchiectomy avoids both staging RLND and prophylactic Radioth. in GCTT, achieving the same cure rate.
This policy prevents patients from unnecessary surgery, infertility and second tumors.
1993

5. Risk adapted policy in Stage I SEMINOMA The first two GG studies
STUDY nº Follow-up relapses EFS
94-99 (Ann Oncol 2003)
- Surveillance 143 (70%) m 23 (16.1%) %
- CBDCA 60 (30%) “ (3.3%) %
99-03 (J Clin Oncol 2005)
- Surveillance (32%) m (4.2%) %
CBDCA (68%) “ (2.4%) %

6. Risk-Adapted Treatment in Clinical Stage I TesticularSeminoma:
The Third Spanish Germ Cell Cancer Group Study
Jorge Aparicio, Pablo Maroto, Xavier García del Muro, Josep Guma`, Alfonso Sa´nchez-Mun˜oz, Mireia Margelí,
Montserrat Dome´nech, Roma´ Bastu´s, Antonio Ferna´ndez, Marta Lo´pez-Brea, Josefa Terrassa, Andre´s Meana,
Purificacio´n Martínez del Prado, Javier Sastre, Juan J. Satru´stegui, Regina Girone´s, Lidia Robert,
and Jose´ R. Germa
J Clin Oncol 29: © 2011
Risk factors: Both size>4 cm and rete testis invasion

7. Actuarial disease-free survival for the entire study population according to
treatment allocation: adjuvant carboplatin (upper curve, n 74) versus surveillance
(lower curve, n 153).
Actuarial disease-free survival for 153 patients undergoing active surveillance
according to the presence of each risk criteria (P .067, log-rank test with
2 df).

8. Risk adapted policy in Stage I SEMINOMA
The Three GG studies
Study nº f-up relapses EFS
94-99 (Ann Oncol 2003)
- Surveillance 143 (70%) m 23 (16.1%) %
- CBDCA 60 (30%) “ (3.3%) %
99-03 (J Clin Oncol 2005)
- Surveillance 96 (32%) m (4.2%) %
- CBDCA (68%) “ (2.4%) %
04-08 (J Clin Oncol 2011)
- Surveillance 153 (67%) m (8.5%) %
- CBDCA (33%) “ (1.4%) %
TOTAL (6.4%) 99.4% OS
(46% CBDCA)

9. Relapse rate by risk factors and treatment allocation
in three series of stage I seminoma patients
Study No risk criteri Tumor size > 4 cm Rete testis invasion Both
Warde 2002 Surveillance Surveillance Surveillance Surveillance
n= % 17.0% 14.4% 31.5%
SGCCG 2005 Surveillance Carboplatin Carboplatin Carboplatin
n= % 0.8% 9.1% 6.0%
SGCCG 2010 Surveillance Surveillance Surveillance Carboplatin
n= % 13.6% 20.0% 1.4%

10. Proposal Standard: Risk-adapted policy
Stage I clinical seminoma
Low Risk
Tumor size<4 and non-rete testis inv.
High Risk
Tumor size>4 and rete testis inv. No
surveillance
Adjuvant
treatment:
1-2 CBDCA
(AUC:7)
Standard
Adjuvant
treatment:
1-2 CBDCA
(AUC:7)
No-
Chemo or
Surveil.
Radio
therapy
Standard
Surveillance
No surveil.
No chemo
Radio
therapy
No-chemo
Surveillance

11. Ann.Oncol 2005
seguimiento VS BEP (1-2 ciclos)

12. 382 patients. Follow-up 4,6 y. Vascular Invasion 42% Relapse rate:
JCO,2008
382 patients.
Follow-up ,6 y.
Vascular Invasion 42%
Relapse rate:
Adjuvant Chemo 1,16 %
LNRT ,5%

13. Proposal New Standard: Risk-adapted policy
Risk-factor -
Surveillance
Stage I clinical
Non-seminoma
Adjuvant treatment:
2 BEP
Risk-factor +
Risk-factors: Vascular invasion

14. Patients lost for follow-up
Quality of Surveillance for Stage I Testis Cancer in the Community
Hua-yin Yu, Rodger A. Madison, Claude M. Setodji, and Christopher S. Saigal
J Clin Oncol 27: © 2009
Risk-Adapted Treatment in Clinical Stage I TesticularSeminoma:
The Third Spanish Germ Cell Cancer Group Study
Jorge Aparicio, Pablo Maroto, Xavier García del Muro, Josep Guma`, Alfonso Sa´nchez-Mun˜oz, Mireia Margelí,
Montserrat Dome´nech, Roma´ Bastu´s, Antonio Ferna´ndez, Marta Lo´pez-Brea, Josefa Terrassa, Andre´s Meana,
Purificacio´n Martínez del Prado, Javier Sastre, Juan J. Satru´stegui, Regina Girone´s, Lidia Robert,
and Jose´ R. Germa
J Clin Oncol 29: © 2011
policy
Nº cases
Nº lost (%)
surveillance
153
7 (4,5)
Carboplatin 73
4 (5,5)

15. J Clin Oncol 26:5416-5421. © 2008 Relapses NED 0 17 6 52 3
0 17
6 52 3
Chemotherapy As an Alternative to Radiotherapy in the
Treatment of Stage IIA and IIB Testicular Seminoma: A
Spanish Germ Cell Cancer Group Study
Xavier Garcia-del-Muro, Pablo Maroto, Josep Guma`, Javier Sastre, Marta Lo´pez Brea, Jose´ A. Arranz,
Nuria Lainez, Diego Soto de Prado, Jorge Aparicio, Jose´ M. Piulats, Xavier Pe´rez, and Josep R. Germa´-Lluch
J Clin Oncol 26: © 2008

16. IIa (RT) 29 3 2 10% IIb (Chemo) 73 - 0% IIa,b 102 3%
Management of Seminomatous Testicular Cancer:A Binational Prospective Population-Based Study From the Swedish NorwegianTesticular Cancer Study Group
Torgrim Tandstad, Rune Smaaland, Arne Solberg, Roy M. Bremnes, Carl W. Langberg, Anna Laurell, Ulrika K. Stierner, Olof Ståhl, Eva K. Cavallin-Ståhl, Olbjørn H. Klepp, Olav Dahl, andGabriella Cohn-Cedermark
J Clin Oncol 29: © 2011
Stages
Nº cases
Relapses
RT field %
IIa
(RT) 29 3 2
10%
IIb
(Chemo) 73 - 0%
IIa,b
102 3%

17. Emission Tomography Study Group
[18F]Fluorodeoxyglucose Positron Emission Tomography in Nonseminomatous Germ Cell Tumors After Chemotherapy: The German Multicenter Positron
Emission Tomography Study Group
Karin Oechsle, Michael Hartmann, Winfried Brenner, Stephan Venz, Lothar Weissbach, Christiane Franzius,
Sabine Kliesch, Stephan Mueller, Susanne Krege, Ruediger Heicappell, Roland Bares, Carsten Bokemeyer,
Maike de Wit
J Clin Oncol 26: © 2008
In contrast to prior studies, this prospective trial, which is the only with histologic confirmation in all patients, demonstrated that FDG-PET is unable to give a clear additional clinical benefit to the standard diagnostic procedures, CT and STM, in the prediction of tumor viability in residual masses

18. 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) for postchemotherapy
seminoma residual lesions: a retrospective validation of the SEMPET trial
M. Bachner, Y. Loriot, M. Gross-Goupil P. A. Zucali, A. Horwich4 J.-R. Germa-Lluch, C. Kollmannsberger, F. Stoiber, A. Flechon, K. Oechsle9, S. Gillessen10, J. Oldenburg, G. Cohn-Cedermark G. Daugaard1 F. Morelli, A. Sella, S. Harland, M. Kerst, J. Gampe, C. Dittrich, K. Fizazi & M. De Santis*
Annals of Oncology 23: 59–64, 2012

19. BEP 3 ciclos 4 ciclos CDDP 20 mg/m2 d1-5 VP16 100 mg/m2 d1-5
Bleom. 30 mg DT d1,8,15

20. Randomized Phase III Study Comparing Paclitaxel–Bleomycin, Etoposide, and Cisplatin (BEP) to Standard BEP in Intermediate-Prognosis Germ-Cell Cancer: Intergroup Study EORTC J Clin Oncol 30: © 2012
Ronald de Wit, Iwona Skoneczna, Gedske Daugaard, Maria De Santis, August Garin, Nina Aass, Alfred J. Witjes, Peter Albers, Jeffery D. White, Jose´ R. Germa-Lluch, Sandrine Marreaud, and Laurence Collette
P<.153
P<.738
P<.250
P<.031
The primary analysis of the trial could not demonstrate statistical superiority of T-BEP for PFS. When ineligible patients were excluded, the analysis of all eligible patients demonstrated a 12% superior 3-year PFS with T-BEP, which was statistically significant.

21. Salvage Second Line Chemotherapy
> 80% NSGCT of testes are curables with first line chemotherapy
Second line chemotherapy with Ifosfamide (VeIP, VIP) achieves aproximatelly 25% of long-term complete remisions.*
Among the new introduced drugs, Paclitaxel appears to have an important activity: RR 26% in refractory patients. **
* Loeher PJ. Ann Intern Med 1988
** Motzer RJ. J Clin Oncol 1994

22. TIP as second line chemotherapy
in relapsed NSGC
46 patients with relapse after Complete Remison with first line conventional chemotherapy (mediastínal and refractory cases excluded)
Tto: Paclitaxel 250 mg/m2 en 24 h, day1
Ifosfamida 1500 mg/m2/día x 5 days + Mesna
Cisplatin 25 mg/m2/día x 5 días
x 4 cycles. Surgery of ressidual masses postQT (3 pts)
Toxicity: Febril Neutropenia 22 pts, Neurotoxicity G3: 4 pts,
Nefrotoxicity G4: 3 pts. 1 tóxic death
Long-term CR (Follow-up med 69 m): 29/46 (63%)
2 years DFS: 65% (95% CI, 51% a 79%)
* Kondagunta GV. J Clin Oncol 2005

23. High dose chemotherapy integrated as initial therapy in poor prognosis metastatic non seminomatous germ cell tumours: The ICO experience

24. PVeBV x “ cycles + 1 PEC+ TAMOVs
PVeBV x “ cycles + 1 PEC+ TAMO
Eur.Urol, 2007

25. 4 BEP vs BEP+ 2 courses of HDCT
JCO 25: 247, 2007

26. Chemotherapy with 2 cycles of HD-EP?
This series is not conclusive.
N=184
Chemotherapy with 2 cycles of HD-EP?

27. Salvage: summary of the largest trials
Referenc
Protocol
Nb pts CR
NED
benefit
IU( )
CE x 2 65
42 (65%)
40 (62%)
IU( )
135 ?
94 (70%)
MSKCC
TICE 29 17 13
Randomised trials.
IT94
Standard
136
42%
47% No
HD CEC
138
43%
GTCSG
3 HD CE
111
48%
1HDCEC
105
45%
46%

28. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with
poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974) Annals of Oncology 22: 1054–1061, 2011
G. Daugaard*, I. Skoneczna, N. Aass, R. De Wit, M. De Santis, H. Dumez, S. Marreaud,
L. Collette, J. R. Germa-Lluch, C. Bokemeyer & H. J. Schmoll
222 patients planned
p>< .057
p>< .362
This study could not demonstrate that high-dose chemotherapy given as part of first-line therapy
improves outcome in patients with poor-prognosis GCC.

29. The International Prognostic Factors Study Group
Prognostic Factors in Patients With Metastatic Germ CellTumors Who Experienced Treatment Failure WithCisplatin-Based First-Line Chemotherapy
The International Prognostic Factors Study Group
J Clin Oncol 28: © 2010

32. Thomas Powles, Christian Kollmannsberger, and Jo¨rg Beyer
Conventional-Dose Versus High-Dose Chemotherapy As First Salvage Treatment in Male Patients With Metastatic Germ Cell Tumors: Evidence From a Large International Database
Anja Lorch, Caroline Bascoul-Mollevi, Andrew Kramar, Lawrence Einhorn, Andrea Necchi,Christophe Massard, Ugo De Giorgi, Aude Fle´chon, Kim Margolin, Jean-Pierre Lotz, Jose Ramon Germa-Lluch,
Thomas Powles, Christian Kollmannsberger, and Jo¨rg Beyer
J Clin Oncol 29: © 2011

34. This retrospective analysis suggests a benefit from HDCT given as intensification of first salvage treatment in male patients with GCTs and emphasizes the need for another prospective randomized trial comparing CDCT to HDCT in this patient population.

35. New drugs in the treatment of refractory NSGCT
Drugs and combos RR Referencia
GEMCITABINA Bokemeyer JCO-99
OXALIPLATINO GTCSG JCO-02
TEMOZOLOMIDA 10 GG ASCO-04
IRINOTECAN 0 GTCSG BrJC-02
TRASTUZUMAB 1 caso GTCSG Ann O-99
IMATINIB 0 GG
Paclitaxel + Gemcitabina 21 ECOG JCO-02
Oxaliplatino + Gemcitabina 46 GTCSG JCO-04
Irinotecan + Cisplatino 45 Miki Cancer02
Irinotecan + Oxaliplatino 40 Pectasides IND-04

36. Patients characteristics by stages and IGCCG Prognosis Classification (GG experience)
Good
Intermediate
Poor

37. Overall survival (%) at 5 and 10 years by histology, stage and IGCCG prognosis classification
GG experience N=4.928
(All stages)
(All stages)
TOTAL

38. Non-seminomatous metastatic patients treated by GGOS GP
95,3% IP
83,9% PP
64,6%
1014 cases