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Understanding Testicular Cancer: A MUST for the Medical Oncologist

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.

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Understanding Testicular Cancer: A MUST for the Medical Oncologist

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

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

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

  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-> 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. 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

  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

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

  17. 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. 400 mg/m2 x 2 cycles AUC = 7 x 2 cycles 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, 2005;366:293

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

  22. 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 • 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 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

  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 (80%CI 0.71-1.24) (80%CI 0.61-1.73) Adapted from Einhorn LH, et al. JCO 7:387-391.1989. de Wit R, et al. JCO 19:1629-1640. 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 19:1629-1640. 2001

  41. Administration Schedule: Is it 5 days better than 3 days ? 3days (n = 333) 5 days (n = 329) _____________________ _______________________ VariableNo. %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

  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)andOverall 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 11:598-606, 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 vCEB 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. 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%) *Motzer et al. J Clin Oncol 1997;15:2546-2552.

  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 (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;15:2546-2552. Adapted from Bajorin DF, et al. Abstract 4510, ASCO 2006.

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

  48. Event-Free Survival and Overall Survival Overall Survival Event-Free Survival 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 Overall Survival Event-Free Survival p=0.03 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.

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