Sc Urologia Italian Germ-cell cancer Study Group

1. Mediterranean School of Oncology Highlights in the Management of Urogenital Cancer Rome, May 9-10, 2008 Controversies in treatment and surveillance of clinical stage I seminoma and nonseminoma testis cancer Nicola Nicolai, Milan Sc Urologia Italian Germ-cell cancer Study Group

2. Background • Germ-cell tumors (GCTs) are rare, 1% only of solid tumors • Age of onset (20-40 yrs old) is critical • Highly curable neoplasms: almost 90% of patients are cured

3. Low-stage GCTs • There is no Consensus concerning low-stages (stage and therapy) • In contrast with what we have reached in advanced disease (IGCCCG, 1997)

4. Low-stage GCTs (2) • Prognosis is not the main issue of low-stage disease • In fact, the global outcome is extraordinarily favorable as nearly 98-99% of low-stages patients are cured • QoL is the main issue • QoL depends on: early and late toxicity of treatment and critical age of patients

5. Non-seminoma stage I Staging and Therapy

6. Clinical stage I NS: common landmarks • Definition  No evidence of disease beyond the testis (normal t/2 markers decay following orchiectomy, normal imaging, as recent as possible) • Cure-rate: 98-99% • 50 - 70% of NS are diagnosed at this stage: treatment at this stage is crucial for the best global outcome (cure & morbidity) in most patients • Risk factors: vascular invasion (VI), %ECa, others

7. Medical Research Council Model (the only validated predictive model) • Risk factors: venous invasion, lymphatic invasion, no YST, presence of ECa • ≥ 3 factors  high risk: 20% of patients, 50% of them bearing occult metastases • < 3 factors low risk: 80% of patients, 20% of them bearing occult metastases

8. European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Metting of the European Germ Cell Cancer Consensus Group (EGCCCG). Eur Urol 2008;53:497 • Algorithm after orchiectomy for stage I NS • Low-risk (no VI)  standard: surveillance  alternative: 2 PEB RPLND • High-risk (VI)  standard: 2 PEB  alternative: surveillance RPLND

10. 2587 pts

11. VI OR 5.2

12. Availability of Vascular Invasion information (Nicolai et Al, J Urol 2004) No. VI (%) Absent 131 (41) Present 72 (22) Not available 119 (37)

13. Reliability of VI information: Local (L) Vs Central Pathology (P) (Sesterhenn et Al, J Clin Oncol, 1992) ~40% ~30%

14. Reliability of VI information: Local (L) Vs Central Pathology (P) Fondazione INT, AUA Proc 2008) ~23% ~15% ~56%

15. Vascular Invasion (as it is!) • Many reports (nearly 50%) do not contain this information • There is a discrepancy of about 20% between first diagnosis and central review • If this information is not reported and possibly reviewed, up to 70% of patients are randomly or wrongly treated in respect of the main prognostic factor!

16. Decision Making by issues • Ease of use of therapy (single shot therapy) • Complexity of administration • Simplification of follow-up • Late relapses • Early and late toxicities

17. Decision Making by issues • Ease of use of therapy (single shot therapy) • Complexity of administration • Simplification of follow-up • Late relapses • Early and late toxicities

18. Ease of use of therapy Adj ChT ≥ RPLND ≥ surv?

19. 14% 0% 7% 0% 29% 88% 0% 79% 12% 4% 0% 71% 40% 23% 14% 8% 14% 0% 4% 4% 0% 0% DISTRIBUTION OF NODAL METASTASIS IN NSGTCJ.P.Donohue J.Urol., 1982 Right tumor Left tumor

20. Sympathetic retroperitoneal chain

21. Full bilateral (infra-hilar) nerve sparing RPLND

22. Modified bilateral RPLND for right tumor

23. Modified bilateral RPLND for left tumor

25. Post-chemotherapy (PC) RPLND and ejaculation • Coogan et Al (Indiana Univ) J Urol, 156:1656, 1996 • preservation of normal ejaculation in 76.5% of 81 patients undergoing nerve sparing PC RPLND

26. Complexity Adj ChT > Surv > >RPLND?

27. Decision Making by issues • Ease of use of therapy (single shot therapy) • Complexity of administration • Simplification of follow-up • Late relapses • Early and late toxicities

28. Follow-up: NS • No consensus exists • Schedules tend to be less intensive in case of active treatment • Follow-up schedule is the treatment when active surveillance is chosen • Different schedules may give different results

29. Sites of relapses following active surveillance (from Stephenson & Sheinfeld Curr Treat Options Oncol, 2005)

30. Results of surveillance studies (Segal Uro Oncol: Seminars and Original Invest 2006 68–74)

31. Active surveillance Vs RPLND: INT experience

32. RPLND: therapeutic role 31/44 pN+  M0: 70.5% Nicolai et Al, J Urol, 2004

33. Adjuvant Chemo in CS I NS (from Stephenson & Sheinfeld Curr Treat Options Oncol, 2005)

34. Teratoma in RP lymph-nodes following primary RPLND (from Carver & Sheinfeld Nat Clin Practice Urol, 2005)

35. One Course of adjuvant PEB Vs RPLND in patients with stage I NSGCTT: results of the German Prospective Multicentric Trial (Albers et Al, ASCO proc 2006) • 1996-2005: 382 pts  ® 1 PEB Vs RPLND • PS II at RPLND  2 PEB • 346 valuable: 172 RPLND, 174 PEB • Median F-U: 47 mos (93% with 1 yr of minimum f-u) • 13 (8%) relapses among RPLNDs* (3 in RP, 3 markers elevation, 2 inguino-scrotal relapses) • 2 (1%) relapses among PEBs (1 MT in RP, 1 markers elevation) * 15 recurrences in updated series presented at 2008 EAU conference (Milan, March 2008)

36. Late Relapses (LR) (Geldart et Al, Brit J Urol 98, 2006) • 1980-2004: 742 NSGCT of the testis • 405 Metastatic disease • 329 CRs (101 or 31% needed surgery too) • 18 early relapses • 20 LR, median time 108 (26–217) mos (≈ 9 years) • 15 surgery alone 14 NED at 44 (9-184) mos • 5 chemotherapy  1 NED

37. Follow-up Ad ChT = RPLND >> surv?

38. Late relapses RPLND >> Adj ChT > Surv?

39. Decision Making by issues • Ease of use of therapy (single shot therapy) • Complexity of administration • Simplification of follow-up • Late relapses • Early and late toxicities

40. primary RPLND morbidity 1 unpublished 2 Donohue et Al J Urol, 1993 3 Heidenreich et Al J Urol, 2003

41. CardioVascular Events (CVE) • Huddart et Al, J Clin Oncol 2003 • 68/992 (6.9%) CVE among pts treated for GCTC (1982-92) after a median follow-up of 10.2 yrs

42. Cardiovascular events (Huddart et Al, JCO, 2003)

43. Second cancers • Travis et Al, J Nat Cancer Inst 97:1354, 2005 • 14 tumor registries northam/eur 1943-01 • 40576 pts with testis ca &1 yr of min survival • 2285 second solid cancers • RR 2.0 following RT • RR 1.8 following ChT • RR 2.9 following both RT & ChT • RR tends to decrease for non-seminomas which were treated since1975

44. Second cancers Travis et Al, J Nat Cancer Inst 97:1354, 2005

45. Toxicity RPLND > Surv ≥ Adj ChT?

46. Ease of use of therapy (single shot therapy) Complexity of administration Simplification of follow-up Late relapses Early and late toxicities Cht ≥ RPLND ≥ Surv Cht > Surv >> RPLND Cht = RPLND >> Surv RPLND >> Cht > Surv RPLND >> Surv ≥ Cht Decision analysis by issues Clinician-oriented Decision Patient-oriented Decision

47. Laparoscopic retroperitoneal lymph-node dissection Lap-RPLND

48. Lap-RPLND in testis cancer • Possible applications • As staging and therapeutic procedure (primary or post-ChT) • Advantages • Less invasive than open RPLND • Criticisms • Is it curative? In case of nodal metastasis at staging, adjuvant chemo is required (more chemotherapy) • Is it cost-effective?

49. Risk adpted RPLND (open Vs Lap)

50. Risk factors for pN+ (Nicolai et Al, J Urol 2004) • # pts: 322 • Considered factors: V+ %ECa > 90% • Risk assignement: high  ≥ 1 factor low  no factor • Risk Categories : “low-risk” for pN+ (<14%) “high risk” for pN+ (35%)