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Understanding Testicular Cancer: A MUST for the Medical Oncologist. Jorge A. Garcia, MD., FACP. Associate Professor Medicine Director, Advanced Prostate Cancer Program Cleveland Clinic Taussig Cancer Institute Glickman Urological & Kidney Institute. Medellin, Colombia November 2012. - PowerPoint PPT Presentation
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Understanding Testicular Cancer:A MUST for the Medical Oncologist
Jorge A. Garcia, MD., FACP.
Associate Professor Medicine
Director, Advanced Prostate Cancer Program
Cleveland Clinic Taussig Cancer Institute
Glickman Urological & Kidney Institute
Medellin, Colombia November 2012
Case presentation (1)
• 23 y.o. man presented with right testicular swelling x 3 months; u/s revealed heterogenous mass; serum tumor markers: B-HCG nl, LDH nl, AFP 13.2.
• What do you do now?
Case presentation (2)
• Pt. taken immediately to right radical inguinal orchiectomy
• Path = non-seminomatous GCT with 20% embryonal, no LV invasion, confined to testicle (T1)
• Serum tumor markers post-surgery nl with appropriate AFP decline.
• What is the next step in his management?
Case presentation (3)
• CT scan a/p negative for lymphadenopathy; CXR negative
• Pt. present for opinion about further therapy.
• What is your recommendation now??
Not all Testis Cancers are the same
• Early Seminoma–No AFP–Spurious elevations of HCG–Path must have 100% + seminoma cells–Radiotherapy or chemotherapy (recently)
Not all Testis Cancers are the same
• Non-Seminoma–Any serum marker–Path could be mixed–Observation of RPLND
• Non-Seminoma–% Embryonal component
–Lymphovascular invasion
–Paratesticular involvement
• Seminoma–Tumor size (> 4cm)
–Retetestis invasion
Pathological Features & Relapse:
• Stage I
• Stage IIa– Miscroscopic
– LNs < 2cm
• Stage IIb– LNs 2-5cm
• Stage IIc (LNs > 5cm) = Advanced disease
Early Testis Cancer Staging
• Observation/surveillance–30% risk of occult RPL metastases
• RPLND
• Cisplatin-based chemotherapy
Treatment Options for Stage I NSGCT
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
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 months
PVB 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.
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
--------------------------------------------------------------------------------------
• 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
• 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
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
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%
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;366:293
EORTC/MRC Trial: 1 cycle Carboplatin v. Radiation: Relapse-Free Survival
RT Oliver, Lancet, 2005;366:293
Carboplatin: one or two cycles?
RT Oliver, Lancet, 2005;366:293
Toxicity from Single Agent Carboplatin
AUC = 7 x 2 cycles
400 mg/m2 x 2 cycles
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;366:293
Radiotherapy Carboplatin
Other
TOTAL
Germ-CellTumors
10 2
4 3
14 5
New Primary Cancers: EORTC/MRC RCT
RT Oliver, Lancet, 2005;366:293
What’s wrong with radiation? Burden of treatment Secondary Cancers Cardiovascular Dz Deaths from digestive
diseases
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
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
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
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 havebeen reported following RT but NOT followingcarboplatin.
The latest relapse after 2 cycles carbo was at 28 months
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%
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.
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
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
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
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)
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%
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%
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%
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%
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
Clinical Trials for Good-Risk Advanced Germ Cell Tumors
Goal is to decrease toxicity
• Are 4 cycles of PEB better than 3 ??
• Administration over 5 days vs. 3 days ??
• Bleomycin or not ??
• Carboplatin vs. Cisplatin ??
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% Relapse
SECSG 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)
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
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
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)
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)
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
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.
Eligibility/Stratification
• Modified IGCCCG*
- Poor vs. Intermediate
• Center (CALGB-MSKCC-SWOG and ECOG)
Ran
do
miz
atio
n (
N=
218)
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
Outcome: Response Rate
BEP (%)(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.
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
-FR
EE
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
RT
ION
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
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
S at 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
-FR
EE
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%
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
B E P alone (62 P ts , 23 Failures )
B E P + HD T (33 P ts , 15 Failures )
PR
OP
OR
TIO
N E
VE
NT
-FR
EE
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
B E P alone (29 P ts , 20 Failures )
B E P + HD T (38 P ts , 17 Failures )
PR
OP
OR
TIO
N E
VE
NT
-FR
EE
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%
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%
B E P alone (31 P ts , 18 Alive)
B E 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
B E P alone (63 P ts , 53 Alive)
B E P + 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
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
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
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 P
Incomplete 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% CI
Favorable 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%
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
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)