Understanding Testicular Cancer: A MUST for the Medical Oncologist Jorge A. Garcia, MD., FACP. Associate Professor Medicine Director, Advanced Prostate

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?


• 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?


• 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


Carboplatin: one or two cycles?


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


Radiotherapy Carboplatin

Other

TOTAL

Germ-CellTumors

10 2

4 3

14 5

New Primary Cancers: EORTC/MRC RCT


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


• 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


• 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%



• 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.



• 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


• 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


• 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


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


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


Satisfactory Marker Decline

Unsatisfactory Marker Decline

P=.50 P=.03



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



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


Satisfactory Marker Decline

Unsatisfactory Marker Decline

2-yr survival 78% vs 85% 2-yr survival 78% vs 55%


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 + 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)

Documents

Understanding Testicular Cancer: A MUST for the Medical Oncologist Jorge A. Garcia, MD., FACP. Associate Professor Medicine Director, Advanced Prostate