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Slide 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
Slide 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?
Slide 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?
Slide 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??
Slide 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)
Slide 6-

Not all Testis Cancers are the same Non-Seminoma Any serum marker Path could be mixed Observation of RPLND
Slide 7-

Non-Seminoma % Embryonal component Lymphovascular invasion Paratesticular involvement Seminoma Tumor size (> 4cm) Retetestis invasion Pathological Features & Relapse:
Slide 8-

Stage I Stage IIa Miscroscopic LNs < 2cm Stage IIb LNs 2-5cm Stage IIc (LNs > 5cm) = Advanced disease Early Testis Cancer Staging
Slide 9-

Observation/surveillance 30% risk of occult RPL metastases RPLND Cisplatin-based chemotherapy Treatment Options for Stage I NSGCT
Slide 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
Slide 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-> 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.
Slide 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
Slide 13-

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
Slide 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
Slide 15-

Stage I Seminomas: Outcomes in published reports
Slide 16-

EORTC/MRC Randomized Controlled Trial: Single Dose of Carboplatin vs. Radiation RT Oliver, Lancet, 2005;366:293
Slide 17-

EORTC/MRC Trial: 1 cycle Carboplatin v. Radiation: Relapse-Free Survival RT Oliver, Lancet, 2005;366:293
Slide 18-

Carboplatin: one or two cycles? RT Oliver, Lancet, 2005;366:293
Slide 19-

Toxicity from Single Agent Carboplatin
Slide 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, 2005;366:293
Slide 21-

Radiotherapy Carboplatin Other TOTAL Germ-Cell Tumors 10 2 4 3 14 5 New Primary Cancers: EORTC/MRC RCT RT Oliver, Lancet, 2005;366:293
Slide 22-

What’s wrong with radiation?  Burden of treatment  Secondary Cancers  Cardiovascular Dz  Deaths from digestive diseases
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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%
Slide 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.
Slide 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
Slide 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
Slide 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
Slide 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)
Slide 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%
Slide 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%
Slide 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%
Slide 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%
Slide 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= 0.0008) Myalgias (p= 0.00002) Williams SD, et al. NEJM 316, 1987
Slide 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 ??
Slide 39-

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)
Slide 40-

Administration Schedule: Is it 5 days better than 3 days ? R A N D O M I Z A T I O N 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) 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) n = 812 de Wit R, et al. JCO 19:1629-1640. 2001
Slide 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 19:1629-1640. 2001
Slide 42-

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)
Slide 43-

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)
Slide 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
Slide 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%) *Motzer et al. J Clin Oncol 1997;15:2546-2552.
Slide 46-

Eligibility/Stratification Modified IGCCCG* - Poor vs. Intermediate Center (CALGB-MSKCC-SWOG and ECOG) Randomization (N=218) 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 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 BEP X2 – HDCT (CEC) X2 BEP X4 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;15:2546-2552. Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006. Intergroup Study of Poor-risk GCT
Slide 47-

Outcome: Response Rate Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.
Slide 48-

Event-Free Survival and Overall Survival Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006. p=0.40 p=0.94 Overall Survival Event-Free Survival
Slide 49-

Long-Term Outcomes According to Initial Marker Decline Status Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006. Overall Survival Event-Free Survival p=.02 p=0.03 1-yr Durable CR 63% vs 45% 2-yr survival 83% vs 68%
Slide 50-

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 1-yr durable CR 58% vs 66% 1-yr durable CR 61% vs 34%
Slide 51-

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% P=.34 P=.10
Slide 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
Slide 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
Slide 54-

Viable Cells After Chemotherapy for NSGCT International Study Group 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%
Slide 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 VIP-TIP
Slide 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)