Systemic treatment of advanced testicular cancer Karim Fizazi, MD, PhD Institut Gustave Roussy, France
Metastatic GCT: Prognosis (IGCCC) Good prognosis Intermediate prognosis Poor prognosis J Clin Oncol 1997, 15: 594-603
Stage II seminoma <ul><li>Stage IIa: </li></ul><ul><ul><li>Consider repeating CT scan (or PET): false+? </li></ul></ul><ul...
Séminome testiculaire stade IIA/B: Résultats de la radiothérapie <ul><li>Classen, JCO, 21: 1101-1106, 2003 </li></ul>Etude...
Chemotherapy for metastatic seminoma <ul><li>IGCCCG classification : </li></ul><ul><ul><li>Good Pc : No extra-pul visceral...
GETUG S99 study <ul><li>Prospective multicenter study (n=132) </li></ul><ul><li>Chemotherapy regimen based on prognosis as...
Séminomes métastatiques Bon pronostic Pronostic intermédiaire Pas de M+ visc extra-P LDH < 2N si supra-diaph M+ viscérales...
Progression-free survival: 3-year PFS:  91%  (84-95) 5-year PFS:  85%  (76-91) Overall survival: 3-year OS:  96%  (91-99) ...
Survival according to prognosis Progression-free survival (3-year): Good prognosis group:  93%  (85-97) Intermediate progn...
Séminomes avancés: Masses résiduelles post-chimiothérapie <ul><li>Réponses tardives: Ne pas se précipiter! </li></ul><ul><...
TEP for residual masses after chemotherapy for metastatic seminoma <ul><li>n=51 pts </li></ul><ul><li>Specificity: 100%, S...
Vers une décroissance thérapeutique? <ul><li>Radiothérapie:  </li></ul><ul><ul><li>RR=2 pour seconds cancers </li></ul></u...
Proposition étude française Séminome stade II (A-C?) 2 cycles d’EP Pet-scan Si - 1 cycle carbo Si + 2 cycles EP
Treatment for metastatic  non-seminomatous germ-cell tumors (NSGCT)
Principles of treatment for metastatic NSGCT <ul><li>Assess patient for prognosis by IGCCC </li></ul><ul><li>Chemotherapy:...
The BEP regimen <ul><li>3 drugs: </li></ul><ul><ul><li>Bleomycin 30 U/week </li></ul></ul><ul><ul><li>Etoposide 100 mg/m2/...
Good  prognosis metastatic NSGCT <ul><li>Definition: </li></ul><ul><ul><li>Primary tumor site: Testis/RP </li></ul></ul><u...
Good prognosis metastatic NSGCT <ul><li>3 BEP  established as standard treatment: no difference with 4 BEP (Einhorn 1989) ...
Logrank p=0.06 n= 251 Good-risk NSGCT Event-Free Survival GETUG T93 trial:  3 BEP vs 4 EP Culine et al., Ann Oncol 2007 0,...
GETUG T93 trial:  3 BEP vs 4 EP Logrank p=0.14 BEP: 5 deaths EP: 12 deaths Median follow-up = 51 months Culine et al., Ann...
Poor  prognosis metastatic NSGCT <ul><li>Definition: any of: </li></ul><ul><ul><li>Primary tumor site: Mediastinal </li></...
A standard established in 1987… <ul><li>Phase III trial:  4 BEP  vs 4 PVB (n=261) </li></ul><ul><li>BEP > PVB: </li></ul><...
4 BEP are not 5, 6, or 7… <ul><li>Giving additional cycles: </li></ul><ul><ul><li>Did not demonstrate any improvement in o...
Giving > 4 BEP makes your patient at a 2% risk of meeting this: <ul><li>2% risk of secondary acute leukemia if etoposide >...
Time to treatment failure Overall survival Phase III intergroup US trial  Intermediate/poor risk pts n= 219 2 BEP + 2 HDCT...
Poor prognosis NSGCT: Randomized trials  Courtesy of S. Culine   Chemotherapy   Number of patients    Favorable  response ...
Poor prognosis NSGCT:  where do we stand? <ul><li>No progress demonstrated by randomized trials in the last 20 years  </li...
Management of pts at high risk of ARDS: « Very high risk NSGCT » Massard, Ann Oncol 2010 <ul><li>Extensive lung mets </li>...
Overall survival according to  tumor marker decline at day 21 or day 42 TM assessed at Day 21 Fizazi, J Clin Oncol 2004, 2...
GETUG 13 trial <ul><li>- France + MD Anderson + Slovakia </li></ul><ul><li>- 1st patient 01/2004 </li></ul><ul><li>n= 260 ...
GETUG 13:  dose-dense regimen BEP x 1 Taxol-BEP + Oxaliplatin  (d10) + G-CSF / 3 weeks x 2 cycles Cisplatin, Ifosfamide, b...
Is the number of treated cases important for outcome? <ul><li>n= 380 patients from the EORTC/MRC phase III trial testing B...
Kaplan-Meier estimate of failure-free survival according to total accrual of patients by the treating institution in trial...
Kaplan-Meier estimate of overall survival according to the total accrual of patients by the treating institution in trial ...
Salvage chemotherapy Stage I Survival 99% Metastatic stages (IGCCCG) <ul><li>Good pronosis </li></ul><ul><li>Intermediate ...
Salvage treatment for patients failing first-line chemotherapy <ul><li>4 cycles of a 3-drug regimen: </li></ul><ul><li>Con...
Prognostic classification: metastatic GCT + failure to first-line cisplatin-based chemotherapy J Clin Oncol 2010, 28: 4906...
HD chemotherapy for 2 nd  line:  IT94 phase III trial n= 280 1994-2001
IT94: Overall survival Pico et al., Ann Oncol 2005, 16: 1152-1159 Conclusion: No demonstrated benefit for single HD chemot...
Single vs Sequential  HD chemotherapy for salvage Lorch A et al., J Clin Oncol 2007, 25: 2778-84 n= 230 pts 1 VIP + 3 HD C...
Conclusion: Metastatic GCT <ul><li>Highly-curable cancers </li></ul><ul><li>Cure achieved if: </li></ul><ul><ul><li>Strict...
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ECCLU 2011 - K. Fizazi - Testicular cancer - Treatment of advanced testicular cancer

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  • Kaplan-Meier estimate of failure-free survival according to total accrual of patients by the treating institution in trial 30895/TE13. O = number of events; N = number of patients in each group. Two-sided P = .018 in stratified analysis; hazard ratio of institutions that entered fewer than five patients versus institutions that entered five patients or more = 1.56 (95% confidence interval = 1.09-2.27). The 1-year failure-free survival rate was 43% (95% confidence interval = 29%-56%) in the institutions that entered fewer than five patients and 59% (95% confidence interval = 54%-65%) in those that entered five patients or more. At 2 years, the failure-free survival rates were 38% (95% confidence interval = 25%-51%) and 55% (95% confidence interval = 50%-61%) in the two groups of institutions, respectively.
  • Kaplan-Meier estimate of overall survival according to the total accrual of patients by the treating institution in trial 30895/TE13. O = number of deaths; N = number of patients in each group. Two-sided P = .010 in stratified analysis; hazard ratio of institutions that entered fewer than five patients versus institutions that entered five patients or more = 1.85 (95% confidence interval = 1.16-3.03). The 1-year survival rate was 70% (95% CI = 57%-82%) in the group that entered fewer than five patients and 82% (95% confidence interval = 78%-87%) in the group with at least five patients. The 2-year survival rates were 62% (95% confidence interval = 48%-75%) and 77% (95% confidence interval = 72%-81%) in the two groups of institutions, respectively.
  • ECCLU 2011 - K. Fizazi - Testicular cancer - Treatment of advanced testicular cancer

    1. 1. Systemic treatment of advanced testicular cancer Karim Fizazi, MD, PhD Institut Gustave Roussy, France
    2. 2. Metastatic GCT: Prognosis (IGCCC) Good prognosis Intermediate prognosis Poor prognosis J Clin Oncol 1997, 15: 594-603
    3. 3. Stage II seminoma <ul><li>Stage IIa: </li></ul><ul><ul><li>Consider repeating CT scan (or PET): false+? </li></ul></ul><ul><ul><li>Radiotherapy Iliac + para-aortic field </li></ul></ul><ul><ul><li>35 Gy </li></ul></ul><ul><li>Stage IIb: </li></ul><ul><ul><li>RXT or CT (debated) </li></ul></ul><ul><ul><li>CT if > 3 cm? </li></ul></ul><ul><li>Stage IIc: </li></ul><ul><ul><li>Chemotherapy (high relapse rate with RXT) </li></ul></ul><ul><ul><li>4 EP (or 3 BEP) </li></ul></ul>
    4. 4. Séminome testiculaire stade IIA/B: Résultats de la radiothérapie <ul><li>Classen, JCO, 21: 1101-1106, 2003 </li></ul>Etude prospective; suivi: 6 ans No. pts: 87; IIA: 66; IIB: 21 4 rechutes: médiastin ± métas: 3; iliaque controlatéral: 1 Taux de rechute: IIA: 4.7% IIB: 11.1% Ces 4 rechutes ont été rattrapées par chimiothérapie Disease-specific survival: 100%
    5. 5. Chemotherapy for metastatic seminoma <ul><li>IGCCCG classification : </li></ul><ul><ul><li>Good Pc : No extra-pul visceral mets OS: 86% </li></ul></ul><ul><ul><li>Intermediate Pc : Ex-pul visceral mets OS: 72% </li></ul></ul><ul><li>Standard regimen: 4 cycles of EP (/3 weeks): </li></ul><ul><ul><li>CDDP 20 mg/m 2 /d x 5d </li></ul></ul><ul><ul><li>Etoposide 100 mg/m 2 /d x 5d </li></ul></ul><ul><li>Option: 3 cycles of BEP </li></ul><ul><li>No phase III trial </li></ul><ul><li>More chemotherapy if intermediate prognosis? </li></ul>
    6. 6. GETUG S99 study <ul><li>Prospective multicenter study (n=132) </li></ul><ul><li>Chemotherapy regimen based on prognosis assessment: </li></ul><ul><ul><li>Good prognosis seminoma: 4 EP </li></ul></ul><ul><ul><li>Intermediate prognosis seminoma: 4 VIP (+ G-CSF) </li></ul></ul>
    7. 7. Séminomes métastatiques Bon pronostic Pronostic intermédiaire Pas de M+ visc extra-P LDH < 2N si supra-diaph M+ viscérales extra-P ou LDH > 2N si supra-diaph 4 EP 4 VIP + G-CSF IGCCCG MRC
    8. 8. Progression-free survival: 3-year PFS: 91% (84-95) 5-year PFS: 85% (76-91) Overall survival: 3-year OS: 96% (91-99) 5-year OS: 92 % (83-96) <ul><li>Causes of death (n=9/132): </li></ul><ul><li>Seminoma: 2 (1.5%) </li></ul><ul><li>Toxicity: 1 (0.8%) </li></ul><ul><li>Toxicity of salvage chemotherapy: 1 (0.8%) </li></ul><ul><li>Other: 5 (4%) </li></ul>GETUG S99 study in metastatic seminoma
    9. 9. Survival according to prognosis Progression-free survival (3-year): Good prognosis group: 93% (85-97) Intermediate prognosis group: 83% (63-93) Overall survival (3-year): Good prognosis group: 99% (92-100) Intermediate prognosis group: 87% (67-95) Fizazi K et al., ASCO 2009
    10. 10. Séminomes avancés: Masses résiduelles post-chimiothérapie <ul><li>Réponses tardives: Ne pas se précipiter! </li></ul><ul><li>Irradiation systématique: Inutile (Duchesne EJC 1997) </li></ul><ul><li>Classiquement (Puc, JCO 1996) : </li></ul><ul><ul><li>T< 3cm: surveillance </li></ul></ul><ul><ul><li>T> 3 cm: exérèse (séminome viable: 25%) </li></ul></ul><ul><li>Pet scan? </li></ul>
    11. 11. TEP for residual masses after chemotherapy for metastatic seminoma <ul><li>n=51 pts </li></ul><ul><li>Specificity: 100%, Sensitivity: 80% </li></ul><ul><li>n VP VN FN FP </li></ul><ul><li>Si T> 3 cm 19 7 12 0 0 </li></ul><ul><li>Si T< 3 cm 37 1 34 2 0 </li></ul><ul><li>False result = 2/51 (4%) </li></ul>De Santis, J Clin Oncol 2004, 22: 1034-1039
    12. 12. Vers une décroissance thérapeutique? <ul><li>Radiothérapie: </li></ul><ul><ul><li>RR=2 pour seconds cancers </li></ul></ul><ul><ul><li>Insuffisante si > stade IIB </li></ul></ul><ul><li>4 EP: </li></ul><ul><ul><li>Guérit 99% des patients (S99) </li></ul></ul><ul><ul><li>Trop long, trop d’effets secondaires pour guérison >96% ? </li></ul></ul>
    13. 13. Proposition étude française Séminome stade II (A-C?) 2 cycles d’EP Pet-scan Si - 1 cycle carbo Si + 2 cycles EP
    14. 14. Treatment for metastatic non-seminomatous germ-cell tumors (NSGCT)
    15. 15. Principles of treatment for metastatic NSGCT <ul><li>Assess patient for prognosis by IGCCC </li></ul><ul><li>Chemotherapy: </li></ul><ul><ul><li>Good prognosis: 3 cycles of BEP </li></ul></ul><ul><ul><li>Intermediate prognosis: 4 cycles of BEP </li></ul></ul><ul><ul><li>Poor prognosis: 4 cycles of BEP </li></ul></ul><ul><li>After chemotherapy: resection of residual masses </li></ul>
    16. 16. The BEP regimen <ul><li>3 drugs: </li></ul><ul><ul><li>Bleomycin 30 U/week </li></ul></ul><ul><ul><li>Etoposide 100 mg/m2/d x 5d </li></ul></ul><ul><ul><li>Cisplatin 20 mg/m2/d x 5d </li></ul></ul><ul><li>1 cycle every 3 weeks +++ </li></ul><ul><li>Main side effects: </li></ul><ul><ul><li>Alopecia, nausea, neutropenia </li></ul></ul><ul><ul><li>Peripheral neuropathy, ototoxicity, Raynaud </li></ul></ul><ul><ul><li>Moderate fertility impairment </li></ul></ul>
    17. 17. Good prognosis metastatic NSGCT <ul><li>Definition: </li></ul><ul><ul><li>Primary tumor site: Testis/RP </li></ul></ul><ul><ul><li>Extra-pulmonary visceral mets: No </li></ul></ul><ul><ul><li>Tumor marker before chemo: </li></ul></ul><ul><ul><ul><li>hCG: < 5000 </li></ul></ul></ul><ul><ul><ul><li>AFP < 1000 </li></ul></ul></ul><ul><ul><ul><li>LDH < 1.5 x norm </li></ul></ul></ul><ul><li>60% of metastatic NSGCT </li></ul><ul><li>Cure rate >95% </li></ul>J Clin Oncol 1997, 15: 594-603
    18. 18. Good prognosis metastatic NSGCT <ul><li>3 BEP established as standard treatment: no difference with 4 BEP (Einhorn 1989) </li></ul><ul><li>Cisplatin>Carboplatin (relapse): </li></ul><ul><ul><li>Phase III EP vs EC (Bosl 1994) </li></ul></ul><ul><ul><li>Phase III BEP vc BEC (Bokemeyer 1996) </li></ul></ul><ul><li>Role of bleomycin debated </li></ul><ul><ul><li>Most specialists would support bleomycin use </li></ul></ul><ul><ul><li>Also recommended in the European consensus </li></ul></ul>
    19. 19. Logrank p=0.06 n= 251 Good-risk NSGCT Event-Free Survival GETUG T93 trial: 3 BEP vs 4 EP Culine et al., Ann Oncol 2007 0,5 0,6 0,7 0,8 0,9 1,0 0 2 4 6 8 YEARS PROBABILITY 4EP; 84% at 4 years 3BEP; 90% at 4 years
    20. 20. GETUG T93 trial: 3 BEP vs 4 EP Logrank p=0.14 BEP: 5 deaths EP: 12 deaths Median follow-up = 51 months Culine et al., Ann Oncol 2007 Overall Survival
    21. 21. Poor prognosis metastatic NSGCT <ul><li>Definition: any of: </li></ul><ul><ul><li>Primary tumor site: Mediastinal </li></ul></ul><ul><ul><li>Extra-pulmonary visceral mets: Yes </li></ul></ul><ul><ul><li>Tumor marker before chemo: </li></ul></ul><ul><ul><ul><li>hCG: > 50 000 </li></ul></ul></ul><ul><ul><ul><li>AFP > 10 000 </li></ul></ul></ul><ul><ul><ul><li>LDH > 10 x norm </li></ul></ul></ul><ul><li>15% of metastatic NSGCT </li></ul><ul><li>Cure rate: 50% </li></ul>J Clin Oncol 1997, 15: 594-603
    22. 22. A standard established in 1987… <ul><li>Phase III trial: 4 BEP vs 4 PVB (n=261) </li></ul><ul><li>BEP > PVB: </li></ul><ul><ul><li>Poor prognosis NSGCT: DFS: 77% vs 61% (p<0.05) and OS (p<0.05) </li></ul></ul><ul><ul><li>Better tolerance (neurotoxicity) </li></ul></ul>4 BEP= standard
    23. 23. 4 BEP are not 5, 6, or 7… <ul><li>Giving additional cycles: </li></ul><ul><ul><li>Did not demonstrate any improvement in outcome </li></ul></ul><ul><ul><li>Increases the risk of: </li></ul></ul><ul><ul><ul><li>severe paresthesia, </li></ul></ul></ul><ul><ul><ul><li>auditive toxicity, </li></ul></ul></ul><ul><ul><ul><li>neutropenic fever, </li></ul></ul></ul><ul><ul><ul><li>and fertility troubles </li></ul></ul></ul>
    24. 24. Giving > 4 BEP makes your patient at a 2% risk of meeting this: <ul><li>2% risk of secondary acute leukemia if etoposide > 2 g/m 2 </li></ul><ul><li>80% mortality… </li></ul><ul><li>… a rate similar to that after a cobra bite. </li></ul>Kollmansberger, J Clin Oncol 1998, 16: 3386-91
    25. 25. Time to treatment failure Overall survival Phase III intergroup US trial Intermediate/poor risk pts n= 219 2 BEP + 2 HDCT (CBDCA, VP16, CPM) Motzer, J Clin Oncol 2007; 25: 247-256 4 BEP R
    26. 26. Poor prognosis NSGCT: Randomized trials Courtesy of S. Culine   Chemotherapy   Number of patients   Favorable response rates (%)     Conclusion   Reference BEP x 4 v BEP 200 x 4 78   81 73   68 Double dose cisplatin not superior and more toxic   Nichols 1991 BEP x 4 v BEP/PVB x 4 125   125 76   72 Alternating regimen not superior and more toxic   de Wit 1995 BEP x 4/EP x 2 v BOP/VIP-B 190   190 57   54 Dose dense alternating regimen not superior and more toxic   Kaye 1998 BEP x 4 v VIP x 4 148   151 60   63 Substitution of ifosfamide for bleomycin not superior and more toxic   Nichols 1998 P 200 VBE x ¾ v P 200 VBE x 2 + P 200 EC 58   57 75   67 High dose chemotherapy not superior and more toxic   Droz 2007 BEP x 4 v BEP x 3 + CaEC 111   108 55   56 High dose chemotherapy not superior and more toxic   Motzer 2007 BEP x 4 v CISCA/VB 96   94 61   54 Alternating regimen not superior and more toxic   Culine 2008
    27. 27. Poor prognosis NSGCT: where do we stand? <ul><li>No progress demonstrated by randomized trials in the last 20 years </li></ul><ul><li>However, general improvement observed (from  45% to  60% survival): </li></ul><ul><ul><li>Patient education (lower tumor burden)? </li></ul></ul><ul><ul><li>Referral to well-trained centers (Collette JNCI 1999)? </li></ul></ul><ul><ul><li>Improvement in the management of chemotherapy side effects? </li></ul></ul><ul><ul><li>Improvement in surgery? </li></ul></ul><ul><ul><li>Others? </li></ul></ul>
    28. 28. Management of pts at high risk of ARDS: « Very high risk NSGCT » Massard, Ann Oncol 2010 <ul><li>Extensive lung mets </li></ul><ul><li>Dyspnea or pO2<80 </li></ul>8/25 4/10 ( 40% ) 4/15 ( 27% ) Long-term survivor 12/25 2/10 10/15 Death from ARDS 16/25 3/10 ( 30% ) 13/15 ( 87% ) ARDS Total 1997-2006 1980-1997
    29. 29. Overall survival according to tumor marker decline at day 21 or day 42 TM assessed at Day 21 Fizazi, J Clin Oncol 2004, 22: 3868-76 Motzer, J Clin Oncol 2007; 25: 247-256 TM assessed at Day 42
    30. 30. GETUG 13 trial <ul><li>- France + MD Anderson + Slovakia </li></ul><ul><li>- 1st patient 01/2004 </li></ul><ul><li>n= 260 planned </li></ul><ul><li>Hypothesis: 20% improvement in PFS in the unfavorable decline group </li></ul>
    31. 31. GETUG 13: dose-dense regimen BEP x 1 Taxol-BEP + Oxaliplatin (d10) + G-CSF / 3 weeks x 2 cycles Cisplatin, Ifosfamide, bleomycine + G-CSF / 3 weeks x 2 cycles
    32. 32. Is the number of treated cases important for outcome? <ul><li>n= 380 patients from the EORTC/MRC phase III trial testing BEP vs BOP-VIP </li></ul><ul><li>65% had a poor-prognosis according to IGCCCG </li></ul><ul><li>49 European institutions: </li></ul><ul><ul><li>26 treated <5 patients </li></ul></ul><ul><li>Cox analysis for PFS and OS </li></ul>Collette L et al. J Natl Cancer Inst 1999;91:839-846
    33. 33. Kaplan-Meier estimate of failure-free survival according to total accrual of patients by the treating institution in trial 30895/TE13. Collette L et al. JNCI J Natl Cancer Inst 1999;91:839-846 Oxford University Press Failure-Free Survival
    34. 34. Kaplan-Meier estimate of overall survival according to the total accrual of patients by the treating institution in trial 30895/TE13. Collette L et al. JNCI J Natl Cancer Inst 1999;91:839-846 Oxford University Press Overall survival
    35. 35. Salvage chemotherapy Stage I Survival 99% Metastatic stages (IGCCCG) <ul><li>Good pronosis </li></ul><ul><li>Intermediate prognosis </li></ul><ul><li>Poor pronosis </li></ul>Salvage setting post-first-line CT 95% 80% 50% 25%
    36. 36. Salvage treatment for patients failing first-line chemotherapy <ul><li>4 cycles of a 3-drug regimen: </li></ul><ul><li>Containing cisplatin and ifosfamide </li></ul><ul><li>Third drug: </li></ul><ul><ul><li>Vinblastine (VeIP) </li></ul></ul><ul><ul><li>Etoposide (VIP) </li></ul></ul><ul><ul><li>Paclitaxel (TIP) </li></ul></ul><ul><ul><li>Gemcitabine? (GIP) </li></ul></ul><ul><li>G-CSF required </li></ul><ul><li>+ surgery for residual masses </li></ul><ul><li>Cure achieved in ~ 25% </li></ul><ul><li>Evidence based on large phase II experiences </li></ul>
    37. 37. Prognostic classification: metastatic GCT + failure to first-line cisplatin-based chemotherapy J Clin Oncol 2010, 28: 4906-11 <ul><li>Prognostic factors: </li></ul><ul><li>Histology: NS vs Seminoma </li></ul><ul><li>Tumor site: Testis/Extra/Med </li></ul><ul><li>Visceral metastases </li></ul><ul><li>Previous response </li></ul><ul><li>Progression-free interval (3m) </li></ul><ul><li>hCG (1000) </li></ul><ul><li>AFP (1000) </li></ul><ul><li>Prognostic score </li></ul>PFS n= 1984 pts
    38. 38. HD chemotherapy for 2 nd line: IT94 phase III trial n= 280 1994-2001
    39. 39. IT94: Overall survival Pico et al., Ann Oncol 2005, 16: 1152-1159 Conclusion: No demonstrated benefit for single HD chemotherapy
    40. 40. Single vs Sequential HD chemotherapy for salvage Lorch A et al., J Clin Oncol 2007, 25: 2778-84 n= 230 pts 1 VIP + 3 HD CE 3 VIP + 1 HD CEC R Accrual stopped for tox (B) No difference in outcome Sequential CT better tolerated OS PFS EFS
    41. 41. Conclusion: Metastatic GCT <ul><li>Highly-curable cancers </li></ul><ul><li>Cure achieved if: </li></ul><ul><ul><li>Strict use of chemotherapy regimens </li></ul></ul><ul><ul><li>Patients treated in expert centers </li></ul></ul><ul><ul><li>Surgical resection of residuals </li></ul></ul><ul><li>Long-term toxicity to be prevented: </li></ul><ul><ul><li>No « extra »-treatment </li></ul></ul><ul><ul><li>Long-term follow-up </li></ul></ul>

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