1. 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

2. 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?

3. 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?

4. Case presentation (3)
CT scan a/p negative for lymphadenopathy; CXR negative
Pt. present for opinion about further therapy.
What is your recommendation now??

5. 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)

6. Not all Testis Cancers are the same
Non-Seminoma
Any serum marker
Path could be mixed
Observation of RPLND

7. Pathological Features & Relapse:
Non-Seminoma
% Embryonal component
Lymphovascular invasion
Paratesticular involvement
Seminoma
Tumor size (> 4cm)
Retetestis invasion

8. Early Testis Cancer Staging
Stage I
Stage IIa
Miscroscopic
LNs < 2cm
Stage IIb
LNs 2-5cm
Stage IIc (LNs > 5cm) = Advanced disease

9. Treatment Options for Stage I NSGCT
Observation/surveillance
30% risk of occult RPL metastases
RPLND
Cisplatin-based chemotherapy

10. Clinical trials of adjuvant chemotherapy in ‘high-risk’ clinical stage I NSGCT (1)
Author / year # of pts Treatment Relapse (median f/u)
Oliver, BEP x 2 5% (1 pt) at months; 1 relapse at m w/ chemo response, then relapse/death
Abratt, BEP x 2 0% at 31 months
Cullen, BEP x % (2 pts) at years; 1 PD/death; w/o GCT on retrosp review

11. 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 pts) at 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, BEP x 2 (39pts.) 3.3% (2 pts) at PVB x 2 (20 pts.) months; 1 mature teratoma resected at 22m; 1 stage II seminoma at 7.5yrs.

12. 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

13. Treatment Options for Stage I Seminoma
Observation/surveillance
15% risk of occult disease
Radiotherapy
Chemotherapy with Carboplatin (only scenario where this agent is accepted in testis cancer)

14. 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

15. Stage I Seminomas: Outcomes in published reports
Management
Number 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%

16. EORTC/MRC Randomized Controlled Trial: Single Dose of Carboplatin vs
EORTC/MRC Randomized Controlled Trial: Single Dose of Carboplatin vs. Radiation
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% ( )
94.8% (92.5 – 96.4)
Arm
3-yr Relapse Rate RT
4.1% (2.9 – 5.6)
Carbo (1 cycle)
5.2% (3.6 – 7.5)
RT Oliver, Lancet, 2005;366:293

17. EORTC/MRC Trial: 1 cycle Carboplatin v
EORTC/MRC Trial: 1 cycle Carboplatin v. Radiation: Relapse-Free Survival
RT Oliver, Lancet, 2005;366:293

18. Carboplatin: one or two cycles?
RT Oliver, Lancet, 2005;366:293

19. Toxicity from Single Agent Carboplatin
400 mg/m2 x 2 cycles
AUC = 7 x 2 cycles

20. Disability and toxicity during treatment: Radiation vs. Carboplatin RCT
More missed work
More moderate to severe lethargy
More dyspepsia
Carboplatin
More thrombocytopenia
RT Oliver, Lancet, 2005;366:293

21. New Primary Cancers: EORTC/MRC RCT
Radiotherapy
Carboplatin
Germ-Cell Tumors 10 2
Other 4 3
TOTAL 14 5
RT Oliver, Lancet, 2005;366:293

22. What’s wrong with radiation. . Burden of treatment 
What’s wrong with radiation?  Burden of treatment  Secondary Cancers  Cardiovascular Dz  Deaths from digestive diseases

23. 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

24. 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

25. 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

26. 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 following carboplatin.
The latest relapse after 2 cycles carbo was at 28 months

27. 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%

28. 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.

29. 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

30. 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

31. 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

32. 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)

33. 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%

34. 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%

35. 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%

36. 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
Nonpulmonary visceral metastases, AND
10% of seminomas, 5-year PFS 67%, 5-year OS 72%

37. 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= )
Myalgias (p= )
Williams SD, et al. NEJM 316, 1987

38. 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 ??

39. Are 4 cycles of PEB better than 3 ??
Institution n Regimen Response Relapses Toxicities
PEB x % Relapse
SECSG v %
PEB x % NED
74.9% v 73% (p= 0.41) year PFS
PEB x 4 2-year OS (90.4% v 89.4%)
EORTC v (97% v 97.1%) HR 0.93
PEB x HR (80%CI )
(80%CI )
Adapted from Einhorn LH, et al. JCO 7:
de Wit R, et al. JCO 19:

40. Administration Schedule: Is it 5 days better than 3 days ?
PEB x 3 for 3 days
(CDDP 50mg/m2 D1-2, VP mg/m2 D1-3
Bleomycin 30mg D1, D8, D15 for 3 cycles)
PEB x 3 for 5 days
(CDDP 20mg/m2 D1-5, VP mg/m2 D1-5 R A N D O M I Z T
n = 812
PEB x 3 + PE x 1 for 3 days
(CDDP 50mg/m2 D1-2, VP mg/m2 D1-3
Bleomycin 30mg D1, D8, D15 for 3 cycles)
PEB x 3 + PE x 1 for 5 days
de Wit R, et al. JCO 19:

41. Administration Schedule: Is it 5 days better than 3 days ?
3days (n = 333) 5 days (n = 329)
_____________________ _______________________
Variable No % No % p
Complete Response % % 0.718
(Chemo + Surgery)
2 year PFS % %
HR 1.05 (80% CI )
96.4% %
2 year OS
HR 0.80 (80% CI )
Adapted from de Wit R, et al. JCO 19:

42. What is the Role of Bleomycin ?
ECOG (Loehrer PJ, et al. JCO 13: , 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: ,1997)
Randomized 395 pts to PEB x 4 v PE x 4 (European regimen)
Complete Response 95% v 87% (p= )
TTP (p= 0.136) and Overall Survival (p= 0.262)
Neurotoxicity and Pulmonary Toxicity greater with PEB
(p< 0.001)

43. Carboplatin instead of CDDP ?
MSKCC (Bajorin DF, et al. JCO 11: , 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: , 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)

44. Goal is to Increase Efficacy
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

45. 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%)
Suboptimal outcome of poor-risk patients - 5-year PFS 41% and 5-year OS 48%
*Motzer et al. J Clin Oncol 1997;15:

46. Intergroup Study of Poor-risk GCT
BEP X4
Cisplatin 20 mg/m2 daily x 5 days
Etoposide 100 mg/m2 daily x 5 days
Bleomycin 30 mg days 1, 8, and 15
G-CSF days 5 mcg/kg days 7-16 excluding
bleomycin days
Eligibility/Stratification
Modified IGCCCG*
- Poor vs. Intermediate
Center (CALGB-MSKCC-SWOG and ECOG)
Randomization (N=218)
BEP X2 – HDCT (CEC) X2
Carboplatin 600 mg/m2 daily x 3 days
Etoposide 600 mg/m2 daily x 3 days
Cyclophosphamide 50 mg/kg x 3 days
Autologous stem cells day 5
Growth factor support
Target accrual was 218 pts to detect an improvement of 20% in CR at 1 year
with an alpha=0.05 and 80% power
*Motzer et al. J Clin Oncol 1997;15:
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.

47. 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 52
Completion of C1-2 BEP 99
100
Completion of C3-4 BEP or HD-CEC 88 77
Suboptimal outcome of poor-risk patients - 5-year PFS 41% and 5-year OS 48%
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.

48. Event-Free Survival and Overall Survival
Suboptimal outcome of poor-risk patients - 5-year PFS 41% and 5-year OS 48%
p=0.40
p=0.94
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.

49. Long-Term Outcomes According to Initial Marker Decline Status
Event-Free Survival
Overall Survival
p=0.03
p=.02
Suboptimal outcome of poor-risk patients - 5-year PFS 41% and 5-year OS 48%
1-yr Durable CR 63% vs 45%
2-yr survival 83% vs 68%
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.

50. Marker Decline Status and Event-free Survival
Unsatisfactory Marker Decline
Satisfactory Marker Decline
P=.50
P=.03
Suboptimal outcome of poor-risk patients - 5-year PFS 41% and 5-year OS 48%
1-yr durable CR 58% vs 66%
1-yr durable CR 61% vs 34%
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.

51. Marker Decline Status and Overall Survival
Unsatisfactory Marker Decline
Satisfactory Marker Decline
P=.34
P=.10
Suboptimal outcome of poor-risk patients - 5-year PFS 41% and 5-year OS 48%
2-yr survival 78% vs 85%
2-yr survival 78% vs 55%
Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.

52. 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

53. 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

54. Viable Cells After Chemotherapy for NSGCT International Study Group
- 238 pts with viable malignant cells in their resected specimen
- 5 year PFS and OS = 64% and 73%
Multivariate Analysis of Survival
PFS OS
Unfavorable Prognostic Factors
Risk Ratio
95 % CI P
95% CI
Incomplete surgery
2.75
1.51 – 4.98
<.001
3.82
1.94 – 7.52
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
3.22
1.32 – 7.82
.01
Prognostic Index
5 – Year PFS
5 – Year OS
Risk Group
No of Adverse Factors
Patients (%) %
95% CI
Favorable 22 90
100
Intermediate 1 40 76
65 – 87 83
Poor
>= 2 38 41 51
Adapted from Fizazi K, et al. JCO 19, 2001

55. 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

56. 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)