Understanding Testicular Cancer: A MUST for the Medical Oncologist

1
Understanding Testicular CancerA 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 (gt 4cm)
• Retetestis invasion

8
Early Testis Cancer Staging

• Stage I
• Stage IIa
• Miscroscopic
• LNs lt 2cm
• Stage IIb
• LNs 2-5cm
• Stage IIc (LNs gt 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, 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

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 6.9 (2 pts) at 79
  months - 1 mature teratoma s/p sg-gt
  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.

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. 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 (96.0-98.6) 94.8(92.5 96.4) 0
Arm 3-yr Relapse Rate
RT 4.1 (2.9 5.6)
Carbo (1 cycle) 5.2 (3.6 7.5)
RT Oliver, Lancet, 2005366293
17
EORTC/MRC Trial 1 cycle Carboplatin v.
Radiation Relapse-Free Survival
RT Oliver, Lancet, 2005366293
18
Carboplatin one or two cycles?
RT Oliver, Lancet, 2005366293
19
Toxicity from Single Agent Carboplatin
20
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, 2005366293
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New Primary Cancers EORTC/MRC RCT
Radiotherapy
Carboplatin
10
Germ-CellTumors
2
Other
4
3
14
TOTAL
5
RT Oliver, Lancet, 2005366293
22
Whats 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 isnt 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 isnt 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 isnt 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 (gt5cm) M0
• Overall CRs 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 lt 1,000 ng/ml
• HCG lt 5,000 IU/L (1,000 ng/ml)
• LDH lt 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 gt 1,000 ng/ml and lt 10,000 ng/ml
• HCG gt 5,000 IU/L and lt 50,000 IU/L
• LDH gt 1.5 x Nl and lt 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 gt 10,000 ng/ml
• HCG gt 50,000 IU/L (10,000 ng/ml)
• LDH gt 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
• Any primary site, AND
• Nonpulmonary visceral metastases, AND
• Normal Markers
• 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 80s
• 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 (n157) - CR 61 v 77 (P lt
  0.05)
• 5-year OS greater with PEB (P lt 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

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 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
  (80CI 0.71-1.24)
• (80CI 0.61-1.73)

Adapted from Einhorn LH, et al. JCO
7387-391.1989. de Wit R, et al. JCO
191629-1640. 2001.
40
Administration Schedule Is it 5 days better
than 3 days ?

PEB x 3 for 3 days (CDDP 50mg/m2 D1-2, VP-16
165mg/m2 D1-3 Bleomycin 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)
R A N D O M I Z A T I O N
n 812
PEB x 3 PE x 1 for 3 days (CDDP 50mg/m2 D1-2,
VP-16 165mg/m2 D1-3 Bleomycin 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 D1-3 Bleomycin 30mg
D1, D8, D15 for 3 cycles)
de Wit R, et al. JCO 191629-1640. 2001
41
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 191629-1640.
2001
42
What is the Role of Bleomycin ?

• ECOG (Loehrer PJ, et al. JCO 13470-476, 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 151837-1843,1997)
• 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
• (plt 0.001)

43
Carboplatin instead of CDDP ?

• MSKCC (Bajorin DF, et al. JCO 11598-606, 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 151844-1852,
  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 lt 0.001
• Overall Survival 97 v 90 (p 0.003)

44
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 NSGCTs

• 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 (CRs 45 and 46)
• VAB-6 HDCT(EC)-ASCT (CR 56)
• VIP X4 vs.VIPX2 gt HDCT (EC)-ASCT (CR 53)

Motzer et al. J Clin Oncol 1997152546-2552.
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 (N218)
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
alpha0.05 and 80 power
Motzer et al. J Clin Oncol 1997152546-2552. Ad
apted from Bajorin DF, et al. Abstract 4510, ASCO
2006.
47
Outcome Response Rate
BEP () (n111) BEP HD () (n108)
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.
48
Event-Free Survival and Overall Survival
Overall Survival
Event-Free Survival
p0.40
p0.94
Adapted from Bajorin DF, et al. Abstract 4510,
ASCO 2006.
49
Long-Term Outcomes According to Initial Marker
Decline Status
Overall Survival
Event-Free Survival
p0.03
p.02
2-yr survival 83 vs 68
1-yr Durable CR 63 vs 45
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.03
P.50
1-yr durable CR 61 vs 34
1-yr durable CR 58 vs 66
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
2-yr survival 78 vs 55
2-yr survival 78 vs 85
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 gt 3cm will have viable
  malignant cells and should undergo surgery
• Masses lt 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 lt 3cm / 100 of
  masses gt 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 Multivariate Analysis of Survival Multivariate Analysis of Survival Multivariate Analysis of Survival Multivariate Analysis of Survival Multivariate Analysis of Survival Multivariate Analysis of Survival
PFS PFS PFS OS OS OS
Unfavorable Prognostic Factors Risk Ratio 95 CI P Risk Ratio 95 CI P
Incomplete surgery 2.75 1.51 4.98 lt.001 3.82 1.94 7.52 lt.001
Viable malignant cells gt 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 Index Prognostic Index Prognostic Index Prognostic Index Prognostic Index Prognostic Index Prognostic Index
5 Year PFS 5 Year PFS 5 Year OS 5 Year OS
Risk Group No of Adverse Factors Patients () 95 CI 95 CI
Favorable 0 22 90 79 - 100 100
Intermediate 1 40 76 65 87 83 73 - 93
Poor gt 2 38 41 28 - 54 51 37 - 65
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) gtPE x 4
• Intermediate-risk
• PEB x 4 v Clinical Trial
• VIP-TIP
• Poor-risk
• PEB x 4 v Clinical trial
• VIP-TIP

56
Summary of Management for Advanced Germ Cell
Tumors

• Salvage Therapy
• VIP - TIP - HDCT/PSCT
• Post-chemotherapy residual masses
• Observation if lt3cm (seminoma)
• Resection if gt3cm (seminoma)
• Resection in NSGCT vs. Salvage chemotherapy
  (poor-risk)