TREATMENT OF LATE RELAPSE

1
TREATMENT OF LATE RELAPSE

• Aude Fléchon
• Centre Léon Bérard
• 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, 1997841-47)
• included patients with prior early relapses
• (Baniel et al, J Clin Oncol, 1995 5 1170-1176
  Gerl et al annals Oncol, 1997841-47 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 200219520-525)
• 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 200219520-525)
• included extragonadal GCT
• (Gerl et al annals Oncol, 1997841-47,
  Oldenburg et al Brit J Cancer, 200694 820-827)
• excluded extragonadal GCT
• (Dieckmann et al ,J Urol, 2005 173 824-825,
  Shahidi etal, Cancer 200219520-525)
• 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 200321
  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 200321
  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

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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 lt 5

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Pathology of late relapse in non seminoma
patientsMichael et al, Am J Sur Path,
200024(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, 200314873-80)
• 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, 200314873-80)
• 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, 200410 2368-78)

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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 200321
  113-22)
• Cisplatin based chemotherapy and surgery of
  residual disease
• cisplatin-based
  chemotherapy

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Treatment of marker-only late relapse (Gerl et
al annals Oncol, 1997841-47)

• 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

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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
  131170-76)
• 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

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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

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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.