TREATMENT OF LATE RELAPSE

1. TREATMENT OF LATE RELAPSE Aude Fl�chon Centre L�on B�rard Lyon, France ESMO Symposium Munich 15-16 May 2008

2. Definition: Recurrence of disease more than 2 years after completion of first line treatment

3. BUT (I) Definition of late relapse is widely variable. Some series restricted to testicular relapsing patients with viable GCT other than teratoma after CR to initial chemotherapy (Ronnen et al J Clin Oncol 2005; 23(28): 6999-7004) included patients with PRm- after initial treatment (Gerl et al Ann Oncol, 1997;8:41-47) included patients with prior early relapses (Baniel et al, J Clin Oncol, 1995; 5: 1170-1176 ; Gerl et al annals Oncol, 1997;8:41-47 ; George et al,,J Clin Oncol, 2003; 21: 113-122)

4. BUT (II) included seminoma pts with clinical stage I (Dieckmann et al ,J Urol, 2005; 173: 824-825; Oldenburg et al Brit J Cancer, 2006; 94: 820-827, shahidi et al, Cancer 2002;19:520-525) included non seminoma pts with clinical stage I (Baniel et al, J Clin Oncol, 1995, George et al,J Clin Oncol, 2003; 21: 113-122, Oldenburg et al Brit J Cancer, 2006; 94: 820-827, Shahidi et al, Cancer 2002;19:520-525) included extragonadal GCT (Gerl et al annals Oncol, 1997;8:41-47, Oldenburg et al Brit J Cancer, 2006;94: 820-827) excluded extragonadal GCT (Dieckmann et al ,J Urol, 2005; 173: 824-825, Shahidi etal, Cancer 2002;19:520-525) Definition must be clarified

5. Incidence Rate of late relapse: 2-4% Incidence is rare:� 3.1 per 1000 person-years of follow-up in non seminoma (Ronnen et al J Clin Oncol; 2005; 23(28): 6999-7004) 1.4 per 1000 person-years of follow-up in seminoma (Oldenburg J Clin Oncol, 2006, 24: 5003-11) Time interval to relapse: 2-32 years Median time to relapse: 7-10 years (Ronnen et al J Clin Oncol; 2005; 23(28): 6999-7004; George et al J Clin Oncol 2003;21: 113-22)

6. Detection of late relapse Symptoms : 60-72% of cases 28%-40% of cases elevated serum tumor markers AFP : 49% hCG: 24% Radiographic abnormalities (Ronnen et al J Clin Oncol; 2005; 23(28): 6999-7004. George et al J Clin Oncol 2003;21: 113-22) FDG PET scan (De santis, 2004 World J Urol) Negative for teratoma Risk of negative exam in case of slow progression disease Might be useful for patients with normal CT scan and increased level serum tumor marker

7. Major sites of late relapse(Oldenburg J Clin Oncol, 2006, 24: 5003-11) Retroperitoneal lymph nodes and retrocrural involvement : 52% Lung : 15% Mediastinum : 11% Neck and supraclavicular lymph nodes : 7% Pelvis : 4% Other :< 5%

8. Pathology of late relapse in non seminoma patientsMichael et al, Am J Sur Path, 2000;24(2): 257-273 Active GCT disease : 60% Yolk sac: 58% Glandular Clear cell hepatoid Other GCT: 20% Embryonal Carcinoma : 72% Choriocarcinoma 18% GCT + teratoma 13% GCT + transformed teratoma 9% Growing Teratoma: 22% Transformed teratoma: 18% Sarcoma: 37% Carcinoma: 63% (adenocarcinoma, small cell�) 60% of the patients have a teratoma component

9. Molecular and cytogenetic analysis of late relapse Over-expression of KIT (Madani et al, Ann Oncol, 2003;14:873-80) Positive EGFR staining : in the majority of late relapse (more often yolk sac tumors) in half of the patients with malignant transformation of teratoma. (Madani et al, Ann Oncol, 2003;14:873-80) Microarray technology with gene expression profiling : over expression of a small nuclear ribonucleoprotein 70kD polypeptide gene in late relapse yolk sac tumor not in early relapse (Sugimura et al Clin Cancer Res, 2004;10: 2368-78)

10. Treatment of late relapsein naive cisplatin-chemotherapy patients Stage I seminoma (surveillance) Cisplatin-based chemotherapy, RTE, surgery (warde et el J Urol 1997, 157: 1705-9) Stage I Seminoma (adjuvant RTE, carboplatin) Stage IIA seminoma (RTE) Stage I Non seminoma (RPLND or surveillance) (Baniel et al, J Clin Oncol, 1995) Stage II nonseminoma RPLND without adjuvant chemotherapy (George et al J Clin Oncol 2003;21: 113-22) Cisplatin based chemotherapy and surgery of residual disease cisplatin-based chemotherapy

11. Treatment of marker-only late relapse (Gerl et al annals Oncol, 1997;8:41-47) FDG PET scan to identify the site of evolution in a minority of patients Detection by CT scan in the majority of patients Withhold any treatment until the site of evolution is demonstrated and manageable by surgical excision Surgery

12. Treatment of late relapse in advanced disease patients Growing teratoma and transformed teratoma: surgery Viable GCT disease Chemotherapy (Baniel et al, J Clin Oncol 1995; 13:1170-76) Unresectable disease Multiple localization Chemo VeIP alone 26% CR Durable response with chemotherapy alone 3% NED Chemo + surgery : 38% NED Which chemotherapy ? (Ronnen et al J Clin Oncol; 2005; 23(28): 6999-7004) VeIP ? TIP: 7 CR and 8 NED / 14 patients Surgery when feasible (George et al,,J Clin Oncol, 2003; 21: 113-122) Surgery only 46% NED No chemotherapy if the resection is complete and serum tumor markers have normalized after surgery

13. CONCLUSION Late relapse is rare More frequent in advanced non seminoma Importance of post-chemotherapy exeresis of residual disease: Risk of growing teratoma Risk of transformed teratoma More often yolk sac tumor Resistant to chemotherapy except for chemo-naive patients Importance of salvage surgery Management in reference center Long term follow-up

14. The best definition of late relapse Initial diagnosis of advanced seminomatous or non seminomatous GCT. Recurrence of disease more than 2 years after initial treatment (cisplatin-based chemotherapy +/- surgery). No clinical evidence of second primary tumor at late relapse (either contolateral testis tumor or extragonadal tumor). Recurrence of GCT established by biopsy, serum tumor marker elevation or progression of previously stable residual masses.