Download - Terapia sistémica en cáncer de testículo
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Systemic therapy in testicular cancer
Mauricio Lema Medina MD
Clínica de Oncología Astorga, Clínica SOMA, Medellín
Simposio ACHO GU, Septiembre 23-24 de 2016, Bogotá
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Mauricio Lema <[email protected]>[email protected]
Today at 7:36 AM
Hola Jorge, espero que estés bien. Te escribo para pedirte permiso para usar tu conferencia de cáncer de testículo de 2012 que diste en Medellín, que creo es la mejor conferencia que he escuchado sobre GCTs. Tengo que hablar del tema, y voy a tomarla como base.
Te agradezco que me autorices su uso (con crédito, por supuesto).
Un abrazo,
Mauricio Lema Medina MD
Garcia, M.D. Jorge A <[email protected]>ToMauricio Lema
Today at 8:30 AM
Claro Mauricio
Si necesitas algunas otras slides me avisas
Un abrazo
Jorge
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Case 1
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Not all Testis Cancers are the same
Seminoma- No AFP- Spurious elevations of HCG- Path must have 100% + seminoma cells- Radiotherapy or chemotherapy (recently)
Courtesy of Jorge A. García
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Not all Testis Cancers are the same
Non-Seminoma- Any serum marker- Path could be mixed- Observation of RPLND
Courtesy of Jorge A. García
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Non-Seminoma- % Embryonal component- Lymphovascular invasion- Paratesticular involvement
Seminoma- Tumor size (> 4cm)- Retetestis invasion
Pathological Features & Relapse
Courtesy of Jorge A. García
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Stage I Stage IIa
- Microscopic- LNs < 2cm
Stage IIb- LNs 2-5cm
Stage IIc (LNs > 5cm) = Advanced disease
Early Testis Cancer Staging
Courtesy of Jorge A. García
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Observation/surveillance- 15% risk of occult disease
Radiotherapy
Chemotherapy with Carboplatin (only scenario where this agent is accepted in testis cancer)
Treatment Options for Stage I Seminoma
Courtesy of Jorge A. García
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The Argument for Carboplatin for Stage I Seminoma Carboplatin is the most effective way to prevent relapse
Carboplatin is associated with minimal acute toxicity
Radiation therapy is associated with unacceptable late toxicity
The risk of late complications from single agent carboplatin is hypothetical whereas the risk of late complications from radiation therapy is well documented
Carboplatin appears to reduce the risk of second primary germ cell tumors
Courtesy of Jorge A. García
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Stage I Seminomas: Outcomes in published reports
ManagementNumber of Patients Relapse
Median Time To Relapse(range) 5-year DSS
Surveillance 1032 18.4% 99.6%
Carboplatin(2 cycles) 660 2.0%
9 – 15 mo(4 – 28)
100%
Radiation 4630 3.8%13 – 26 mo
(1 – 102)99.7%
Courtesy of Jorge A. García
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EORTC/MRC Randomized Controlled Trial: Single Dose of Carboplatin vs. Radiation
Arm 3-yr Relapse Rate
RT 4.1% (2.9 – 5.6)
Carbo (1 cycle) 5.2% (3.6 – 7.5)
Arm N Relapses 2 year RFS
3 year RFS
Seminoma Deaths
RT 904 36 96.7%(95.3 – 97.7)
95.9%(94.4 – 97.1)
1
Carbo(1 cycle)
573 29 97.7% (96.0-98.6)
94.8%(92.5 – 96.4)
0
RT Oliver, Lancet, 2005;366:293Courtesy of Jorge A. García
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EORTC/MRC Trial: 1 cycle Carboplatin v. Radiation: Relapse-Free Survival
RT Oliver, Lancet, 2005;366:293Courtesy of Jorge A. García
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Carboplatin: one or two cycles?
RT Oliver, Lancet, 2005;366:293Courtesy of Jorge A. García
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Toxicity from Single Agent Carboplatin
AUC = 7 x 2 cycles
400 mg/m2 x 2 cycles
Courtesy of Jorge A. García
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Disability and toxicity during treatment: Radiation vs. Carboplatin RCT
Radiation- More missed work- More moderate to severe
lethargy- More dyspepsia
Carboplatin- More thrombocytopenia
RT Oliver, Lancet, 2005;366:293Courtesy of Jorge A. García
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Radiotherapy Carboplatin
Other
TOTAL
Germ-CellTumors 10 2
4 3
14 5
New Primary Cancers: EORTC/MRC RCT
RT Oliver, Lancet, 2005;366:293Courtesy of Jorge A. García
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Sperm count in Swedish clinical stage I testicular cancer patients following modern adjuvant treatment.
Weibring K, Proc ASCO 2016, 4542
182 pts Stage I GCT
Surveillance: 28 ptsSingle-dose carboplatin: 22 ptsBEP x1: 62 ptsRT: 70 ptsSperm Count over time
Courtesy of Jorge A. García
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What’s wrong with radiation? Burden of treatment Secondary Cancers Cardiovascular Dz Deaths from digestive
diseases
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Do the math 100 men with stage I seminoma
- 80-82 cured with orchiectomy
- 18-20 destined to relapse on surveillance
- 3-5 relapse after radiation
- 13-17 relapses prevented by radiation
- 6-13 cancers result from radiation
Courtesy of Jorge A. García
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False Arguments Against Carboplatin
Claim: Relapses after radiation are above the diaphragm so surveillance CT scans are not needed
Fact: In the RT vs. Carbo trial, 41% of relapses in the RT arm were below the diaphragm
In the two large RCTs of radiation for seminoma, two thirds of relapses presented with disease below the diaphragm
Courtesy of Jorge A. García
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False Arguments Against Carboplatin
Claim: Relapses after radiation are above the diaphragm so surveillance CT scans are not needed
Fact: In the RT vs. Carbo trial, 41% of relapses in the RT arm were below the diaphragm
In the two large RCTs of radiation for seminoma, two thirds of relapses presented with disease below the diaphragm
Claim: Late relapses are a risk after carboplatin Fact: Relapses more than five years after treatment have
been reported following RT but NOT followingcarboplatin.
The latest relapse after 2 cycles carbo was at 28 months
Courtesy of Jorge A. García
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False Arguments Against Carboplatin
Claim: Carboplatin isn’t good enough for GCTs – cisplatin is needed
Fact: Disease specific survival is between 99.9% and 100%.Two cycles of carboplatin results in a relapse rate of 2%
Courtesy of Jorge A. García
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False Arguments Against Carboplatin
Claim: Carboplatin isn’t good enough for GCTs – cisplatin is needed
Fact: Disease specific survival is between 99.9% and 100%.Two cycles of carboplatin results in a relapse rate of 2%
Claim: Carboplatin causes secondary malignancies. Fact: Carboplatin has been associated with secondary
leukemias in women treated for ovarian cancer but not at the doses used for seminoma.
Courtesy of Jorge A. García
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False Arguments Against Carboplatin
Claim: Carboplatin isn’t good enough for GCTs – cisplatin is needed
Fact: Disease specific survival is between 99.9% and 100%.Two cycles of carboplatin results in a relapse rate of 2%
Claim: Carboplatin causes secondary malignancies. Fact: Carboplatin has been associated with secondary
leukemiasin women treated for ovarian cancer but not at the doses used for seminoma.
Claim: Modern radiation is safe Fact: We have no long-term follow-up data on modern radiation
Courtesy of Jorge A. García
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Summary: Radiation Therapy
Radiation therapy has been proven to result in substantial late morbidity and mortality
The long-term safety of current radiation therapy which uses lower doses and smaller fields remains unproven
The switch to lower doses and small radiation fields has resulted in more infra-diaphragmatic relapses after radiation
Courtesy of Jorge A. García
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Summary: Carboplatin
Single-Agent Carboplatin is very well tolerated
Two cycles of single-agent carboplatin has resulted in the lowest published relapse rates for stage I seminoma
One cycle of carboplatin results in equivalent relapse rates to radiation therapy
With over 1200 patients treated with carboplatin in published reports, only one unsalvageable relapse has been reported
Whether or not single-agent carboplatin causes any significant late morbidity or mortality remains unknown
Courtesy of Jorge A. García
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Stage II Seminoma
RT CTBEP x3EP x4
NCCN Guidelines Version 2.2016
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Metastatic Low-Risk Seminoma
Carboplatin AUC 10
PET-CT day 17-22
CMR No CMR
Carboplatin AUC 10 x3* (total) Carboplatin AUC 10 x4* (total)
*Cycles when plt>75, and rising
CarPET: Carboplatin AUC 10 in metastatic seminoma – early PET scanning can reduce the amount of treatment whilst maintaining outcome – A Phase
II Trial
Shamash J, Proc ASCO 2016, Abstract 4545
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Metastatic Low-Risk Seminoma
Carboplatin AUC 10
PET-CT day 17-22
CMR No CMR
Carboplatin AUC 10 x3* (total) Carboplatin AUC 10 x4* (total)
*Cycles when plt>75, and rising
CarPET: Carboplatin AUC 10 in metastatic seminoma – early PET scanning can reduce the amount of treatment whilst maintaining outcome – A Phase
II Trial
n=48
n=21 n=26
Median follow-up of 25.8 mo: OS 100%
PFS: 97.1%Shamash J, Proc ASCO 2016, Abstract 4545
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Observation/surveillance- 30% risk of occult RPL metastases
RPLND
Cisplatin-based chemotherapy- BEP x1-2
Treatment Options for Stage I NSGCT
Courtesy of Jorge A. García
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Clinical trials of adjuvant chemotherapy in ‘high-risk’ clinical stage I NSGCT (1)
Author / year # of pts. Treatment Relapse (median f/u)
Oliver, 1992 22 BEP x 2 5% (1 pt) at 43 months; 1 relapse at 6m w/ chemo response, then relapse/death
Abratt, 1994 20 BEP x 2 0% at 31 months
Cullen, 1996 114 BEP x 2 1.7% (2 pts) at 4 years; 1 PD/death; 1 w/o GCT on retrosp. review
Courtesy of Jorge A. García
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Clinical Trials of adjuvant chemotherapy in ‘high-risk’ clinical stage I NSGC T (2)
Author / year # of pts. Treatment Relapse (median f/u)
Pont ‘96 29 BEP x 2 6.9% (2 pts) at 79 months - 1 mature teratoma s/p sg-> NED; 1 embryonal w/chemo response, then relapse/death
Chevreau ‘97 38 BEP x 2 (33 pts.) 0% at 36 monthsPVB x 2 (5 pts.)
Studer, 2000 59 BEP x 2 (39pts.) 3.3% (2 pts) at 93 PVB x 2 (20 pts.) months; 1 mature teratoma resected at 22m; 1 stage II seminoma at 7.5yrs.
Courtesy of Jorge A. García
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Acute and Long-term AEs in Adjuvant Chemo Trials
Hematologic: G3 leukopenia (3.5%, 18%, 24%); no other significant toxicity
GI: G3 emesis (27%, 13%); G2 Alopecia and G1Tinitus
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Fertility: no change in pre- vs. post-sperm density/motility in two studies; 2 others with 1-2 pts. with azoospermia (not different than controls in one study)
Lung function: no change in PFTs in 2 studies
Audiometry: high-tone hearing loss (12%, 5%)
No 11q23 (etoposide-induced) AML reported
Courtesy of Jorge A. García
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Case 2: 23 year-old patient undergoing BEP cycle #2 for early-stage GCT
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Advanced Germ Cell Tumors
Defined as Stage IIC or higher- Any pT/Tx N3 (>5cm) M0
Overall CR’s 70-80% Poor outcome 20-30%Identification by risk groups
- International Germ Cell Cancer Collaborative Group (IGCCCG)
Courtesy of Jorge A. García
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International Germ Cell Cancer Collaborative Group (IGCCCG)
I – triple C – entre Gs
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Risk Assessment of Advanced Disease (IGCCCG) NSGCT - Good Prognosis
Testis or RP primary, AND No nonpulmonary visceral metastases, AND Good Markers including all the following:
- AFP < 1,000 ng/ml- HCG < 5,000 IU/L (1,000 ng/ml)- LDH < 1.5 x upper limit of normal
56% of nonseminomas 5-year PFS 89% 5-year OS 92%
Courtesy of Jorge A. García
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Risk Assessment of Advanced Disease (IGCCCG) NSGCT - Intermediate Prognosis
Testis or RP primary, AND No nonpulmonary visceral metastases, And Intermediate Markers including any the following:
- AFP >= 1,000 ng/ml and <= 10,000 ng/ml- HCG >= 5,000 IU/L and <= 50,000 IU/L- LDH >= 1.5 x Nl and <= 10 x Nl
28% of nonseminomas 5-year PFS 75% 5-year OS 80%
Courtesy of Jorge A. García
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Risk Assessment of Advanced Disease (IGCCCG) NSGCT - Poor Prognosis
Mediastinal primary, OR Nonpulmonary visceral metastases, OR Poor Markers including any the following:
- AFP >= 10,000 ng/ml- HCG >= 50,000 IU/L (10,000 ng/ml)- LDH >= 10 x upper limit of normal
16% of nonseminomas 5-year PFS 41% 5-year OS 48%
Courtesy of Jorge A. García
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Risk Assessment of Advanced Disease (IGCCCG) Seminoma
Good Prognosis Any primary site, AND No nonpulmonary visceral metastases, AND Normal Markers
- 90% of seminomas, 5-year PFS 82%, 5-year OS 86%
Intermediate Prognosis Any primary site, AND Nonpulmonary visceral metastases, AND Normal Markers
- 10% of seminomas, 5-year PFS 67%, 5-year OS 72%
Courtesy of Jorge A. García
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Outcomes by IGCCCG risk categories in GCTs
Page 59
Clinical scenario 5-yr PFS 5-yr OSSeminoma Good-Prognosis 82% 86%Seminoma Intermediate-Prognosis 67% 72%Non-Seminoma Good-Prognosis 89% 92%Non-Seminoma Intermediate-Prognosis 75% 80%Non-Seminoma Poor-Prognosis 41% 48%
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Treatment for Good-Risk Advanced Germ Cell Tumors
Cisplatin, Etoposide and Bleomycin (PEB) x 4- Standard of Therapy since the late 80’s
PVB x 4 v PEB x 4 (E = Etoposide or VP-16)- Randomized Phase III study of 244 patients- CR 74% v 83% with or without surgery (P not significant)- High-Tumor Volume (n=157) - CR 61% v 77% (P < 0.05)
- 5-year OS greater with PEB (P < 0.048)
- Less toxicities with PEB- Paresthesias (p= 0.02)- Abdominal Cramps (p= 0.0008)- Myalgias (p= 0.00002)
Williams SD, et al. NEJM 316, 1987
Courtesy of Jorge A. García
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Clinical Trials for Good-Risk Advanced Germ Cell Tumors
Goal is to decrease toxicityAre 4 cycles of PEB better than 3 ??Administration over 5 days vs. 3 days ??Bleomycin or not ??Carboplatin vs. Cisplatin ??
Courtesy of Jorge A. García
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Are 4 cycles of PEB better than 3 ??
Adapted from Einhorn LH, et al. JCO 7:387-391.1989. de Wit R, et al. JCO 19:1629-1640. 2001.
Institution n Regimen Response Relapses Toxicities
PEB x 4 6% RelapseSECSG 184 v 98%
PEB x 3 92% NED
74.9% v 73% (p= 0.41) 2-year PFS PEB x 4 2-year OS (90.4% v 89.4%)
EORTC 812 v (97% v 97.1%) HR 0.93 PEB x 3 HR 1.02 (80%CI 0.71-1.24)
(80%CI 0.61-1.73)
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Administration Schedule: Is it 5 days better than 3 days ?
RANDOMIZATION
PEB x 3 for 3 days(CDDP 50mg/m2 D1-2, VP-16 165mg/m2 D1-3Bleomycin 30mg D1, D8, D15 for 3 cycles)
PEB x 3 for 5 days(CDDP 20mg/m2 D1-5, VP-16 100mg/m2 D1-5 Bleomycin 30mg D1, D8, D15 for 3 cycles)
PEB x 3 + PE x 1 for 3 days(CDDP 50mg/m2 D1-2, VP-16 165mg/m2 D1-3Bleomycin 30mg D1, D8, D15 for 3 cycles)
PEB x 3 + PE x 1 for 5 days(CDDP 50mg/m2 D1-2, VP-16 165mg/m2 D1-3Bleomycin 30mg D1, D8, D15 for 3 cycles)
n = 812
de Wit R, et al. JCO 19:1629-1640. 2001
Courtesy of Jorge A. García
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Administration Schedule: Is it 5 days better than 3 days ?
3days (n = 333) 5 days (n = 329) _____________________ _______________________
Variable No. % No. % p
Complete Response 247 74.1% 240 72.9% 0.718(Chemo + Surgery)
2 year PFS 89.7% 88.8%
HR 1.05 (80% CI 0.78-1.41)
96.4% 97.5% 2 year OS
HR 0.80 (80% CI 0.4-1.42)
Adapted from de Wit R, et al. JCO 19:1629-1640. 2001
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What is the Role of Bleomycin ?
ECOG (Loehrer PJ, et al. JCO 13:470-476, 1995)- Randomized 178 pts to PEB x 3 v PE x 3 (American regimen)
- Complete Response 94% v 88% (p= not significant)- Greater Treatment Failures in PE arm (post-chemo masses and relapses
from CR) (p= 0.004)- Overall Survival 95% v 86% (p= 0.01)
EORTC (de Wit R, et al. JCO 15:1837-1843,1997) - Randomized 395 pts to PEB x 4 v PE x 4 (European regimen)
- Complete Response 95% v 87% (p= 0.0075)- TTP (p= 0.136) and Overall Survival (p= 0.262)- Neurotoxicity and Pulmonary Toxicity greater with PEB (p< 0.001)
Courtesy of Jorge A. García
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Carboplatin instead of CDDP ?
MSKCC (Bajorin DF, et al. JCO 11:598-606, 1993)- Multicenter Phase III - Randomized 270 pts to EP x 4 v EC x 4
- Complete Response 90% v 88% (p= 0.32)- Event-Free Survival inferior for EC arm (p= 0.02)- Relapse-Free Survival inferior for EC arm (p= 0.005) - No difference in Overall Survival (p= 0.52)
MRC/EORTC (Horwich A, et al. JCO 15:1844-1852, 1997)- Multicenter Phase III - Randomized 598 pts to PEB x 4 v CEB x 4
- Complete Response 94.4% v 87.3% (p= 0.009)- 1-year failure-free rates 91% (95% CI, 88%-94%) and 77% (95% CI, 72%-82%) p < 0.001- Overall Survival 97% v 90% (p= 0.003)
Courtesy of Jorge A. García
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IGCCCG Good-Risk GCT
EPx4 BEPx3
NCCN Guidelines Version 2.2016
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Case 3
Page 68
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Clinical Trials for Intermediate and Poor-Risk Advanced Germ Cell Tumors
Goal is to Increase Efficacy Exploiting agents used in the salvage setting Evaluation of the role of dose escalation Alternating non-cross resistant Chemotherapy Evaluation of HDC-PSCT as in the salvage setting
Courtesy of Jorge A. García
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Poor Risk – Advanced NSGCT’s
Suboptimal outcome of poor-risk patients - 5-year PFS 41% and 5-year OS 48%
Goal is to increase efficacy- Alternating non-cross-resistant chemotherapy- Dose escalation- Exploiting agents used in the salvage setting including
HDCT-ASCT
Single Institutional Trials (MSKCC)*- VAB-6 and VAB-6 + EP (CR’s = 45% and 46%)- VAB-6 + HDCT(EC)-ASCT (CR = 56%)- VIP X4 vs.VIPX2 > HDCT (EC)-ASCT (CR = 53%)
*Motzer et al. J Clin Oncol 1997;15:2546-2552.Courtesy of Jorge A. García
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Eligibility/Stratification
• Modified IGCCCG* - Poor vs. Intermediate
• Center (CALGB-MSKCC-SWOG and ECOG)
Ran
dom
izat
ion
(N=2
18)
Cisplatin 20 mg/m2 daily x 5 days Etoposide 100 mg/m2 daily x 5 daysBleomycin 30 mg days 1, 8, and 15G-CSF days 5 mcg/kg days 7-16 excluding bleomycin days
Carboplatin 600 mg/m2 daily x 3 days Etoposide 600 mg/m2 daily x 3 daysCyclophosphamide 50 mg/kg x 3 daysAutologous stem cells day 5Growth factor support
BEP X2 – HDCT (CEC) X2
BEP X4
Target accrual was 218 pts to detect an improvement of 20% in CR at 1 yearwith an alpha=0.05 and 80% power
*Motzer et al. J Clin Oncol 1997;15:2546-2552.Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
Intergroup Study of Poor-risk GCT
Courtesy of Jorge A. García
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Outcome: Response RateBEP (%)(n=111)
BEP + HD (%)(n=108)
Complete response (CR) 55 56
CR to chemotherapy 46 48
CR to chemotherapy + Surgery 9 8
Incomplete response 44 43
PR – negative markers 5 10
1-year durable CR rate 48 52
Completion of C1-2 BEP 99 100
Completion of C3-4 BEP or HD-CEC 88 77
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
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Event-Free Survival and Overall Survival
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
B E P alone (110 P ts , 60 Failures )
B E P + HD T (107 P ts , 55 Failures )
PR
OP
OR
TIO
N E
VE
NT-
FRE
E
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
p=0.40
B E P alone (111 P ts , 77 Alive)
B E P + HD T (108 P ts , 73 Alive)P
RO
PO
RTI
ON
SU
RV
IVIN
G
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
p=0.94
Overall SurvivalEvent-Free Survival
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Long-Term Outcomes According to Initial Marker Decline Status
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
S at D ec line (96 P ts , 78 Alive)
Uns at D ec line (69 P ts , 46 Alive)PR
OP
OR
TIO
N S
UR
VIV
ING
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
Sat D ec line (95 P ts , 38 Failures )
Uns at D ec line (67 P ts , 37 Failures )
PR
OP
OR
TIO
N E
VE
NT-
FRE
E
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
Overall SurvivalEvent-Free Survival
p=.02p=0.03
1-yr Durable CR 63% vs 45% 2-yr survival 83% vs 68%
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Marker Decline Status and Event-free Survival
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
Satisfactory Marker Decline
Unsatisfactory Marker Decline
P=.50 P=.03
BE P alone (62 P ts , 23 Failures )
BE P + HD T (33 P ts , 15 Failures )
PR
OP
OR
TIO
N E
VE
NT-
FRE
E
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
BE P alone (29 P ts , 20 Failures )
BE P + HD T (38 P ts , 17 Failures )
PR
OP
OR
TIO
N E
VE
NT-
FRE
E
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
1-yr durable CR 58% vs 66% 1-yr durable CR 61% vs 34%
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Marker Decline Status and Overall Survival
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
Satisfactory Marker Decline Unsatisfactory Marker Decline
2-yr survival 78% vs 85% 2-yr survival 78% vs 55%
BE P alone (31 P ts , 18 Alive)
BE P + HD T (38 P ts , 28 Alive)PR
OP
OR
TIO
N S
UR
VIV
ING
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
BEP alone (63 P ts , 53 Alive)
BEP + HD T (33 P ts , 25 Alive)PR
OP
OR
TIO
N S
UR
VIV
ING
0 .0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MO NTHS0 12 24 36 48 60 72 84 96 108 120
P=.34 P=.10
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell tumors
Fizazi K, Proc ASCO 2016, Abstract 4504
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
High-Risk (or Modified Intermediate-Risk GCT_ LDH greater 3x ULN)
Paclitaxel 120 mg/m2, d1, d2Ifosfamide/MESNA 1200 mg/m2, d1-d5Cisplatin 20 mg/m2, d1-d5
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
High-Risk (or Modified Intermediate-Risk GCT_ LDH greater 3x ULN)
Paclitaxel 120 mg/m2, d1, d2Ifosfamide/MESNA 1200 mg/m2, d1-d5Cisplatin 20 mg/m2, d1-d5
MESNA 120 mg/m2 30 minutes Ifosfamide, d1-d5Dexamethasone 20 mg in the night before and morning of PaclitaxelAnti H1/H2 before Paclitaxel5-HT3 antagonist dailyAprepitant on d4-d6Dexamethasone 12 mg/d on d3-d7Pegfilgrastim 6 mg on d6 or d7Levofloxacin 500 mg/d on d7-d13
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
High-Risk (or Modified Intermediate-Risk GCT_ LDH greater 3x ULN)
Paclitaxel 120 mg/m2, d1, d2Ifosfamide/MESNA 1200 mg/m2, d1-d5Cisplatin 20 mg/m2, d1-d5
MESNA 120 mg/m2 30 minutes Ifosfamide, d1-d5Dexamethasone 20 mg in the night before and morning of PaclitaxelAnti H1/H2 before Paclitaxel5-HT3 antagonist dailyAprepitant on d4-d6Dexamethasone 12 mg/d on d3-d7Pegfilgrastim 6 mg on d6 or d7Levofloxacin 500 mg/d on d7-d13
If ANC less than 1000 or Plat less than 90,000/uL on d1, CT was delayed 1 week
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Paclitaxel, Ifosfamide, and
Cisplatin Efficacy for First-Line Treatment
of Patients With Intermediate- or
Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
High-Risk (or Modified Intermediate-Risk GCT_ LDH greater 3x ULN)
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
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Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With
Intermediate- or Poor-Risk Germ-Cell Tumors
Feldman DR, JCO, 2016
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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High-dose Chemotherapy and Autologous Peripheral-Blood Stem Cell Transplant for Relapsed Metastatic
Germ-Cell Tumors: The Indiana University Experience.
Adra N, Proc ASCO 2016, Abstract 4505
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Case 4
Page 135Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Bosl G, Warde P, Heidenreich A, ASCO 2016: Testicular Cancer – a Multidisciplinary Case Based Discussion
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Risk Assessment of Residual Masses after Chemotherapy for Seminoma
Observed in 60-85% 20-25% with (+) masses have residual malignancy 42% of residual mass > 3cm will have viable malignant cells and
should undergo surgery Masses < 3cm can be observed PET has been shown to be a predictor for malignancy:
(De Santis M, et al. JCO 19, 2001) Predicting: 96% of masses < 3cm / 100% of masses > 3cm
Courtesy of Jorge A. García
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Risk Assessment of Residual Masses after Chemotherapy for NSGCT
Observed in 30-40% 15% with (+) masses have viable malignant cells Histology is a predicting factor for survival:
- Carcinoma 15% with CR 60-70%- Teratoma 35% with CR 85%- Necrosis/Fibrosis 50% with CR 85-90%
Role of Surgery Role of Chemotherapy post-surgery
Courtesy of Jorge A. García
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Viable Cells After Chemotherapy for NSGCT International Study Group
Multivariate Analysis of SurvivalPFS OS
Unfavorable Prognostic Factors Risk Ratio 95 % CI P Risk Ratio 95% CI PIncomplete surgery 2.75 1.51 – 4.98 <.001 3.82 1.94 – 7.52 <.001
Viable malignant cells > = 10 2.25 1.28 – 3.94 .005 3.31 1.62 – 6.78 .001
Poor or intermediate IGCCC 2.58 1.34 – 4.97 .005 3.22 1.32 – 7.82 .01
Prognostic Index5 – Year PFS 5 – Year OS
Risk GroupNo of Adverse
FactorsPatients
(%) % 95% CI % 95% CIFavorable 0 22 90 79 - 100 100
Intermediate 1 40 76 65 – 87 83 73 - 93
Poor >= 2 38 41 28 - 54 51 37 - 65
Adapted from Fizazi K, et al. JCO 19, 2001
- 238 pts with viable malignant cells in their resected specimen- 5 year PFS and OS = 64% and 73%
Courtesy of Jorge A. García
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Summary of Management for Advanced Germ Cell Tumors
Stratification by IGCCCG Good-risk
- PEB x 3 (if Pulmonary toxicity) >PE x 4
Intermediate-risk - PEB x 4 v Clinical Trial - VIP-TIP
Poor-risk - PEB x 4 v Clinical trial - VIP-TIP
Courtesy of Jorge A. García
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Summary of Management for Advanced Germ Cell Tumors
Salvage Therapy - VIP - TIP - HDCT/PSCT
Post-chemotherapy residual masses- Observation if <3cm (seminoma)- Resection if >3cm (seminoma)- Resection in NSGCT vs. Salvage chemotherapy (poor-risk)
Courtesy of Jorge A. García