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Michael Friedlander

MANAGEMENT OF OVARIAN GERM CELL AND STROMAL TUMOURS- An update. Michael Friedlander . Ovarian Germ Cell Tumours. 1-2% of all ovarian malignancies Usually in adolescents but 42% of 614 patients were over 30! 60-70% STAGE 1 at diagnosis No randomized trials in OGCT

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Michael Friedlander

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  1. MANAGEMENT OF OVARIAN GERM CELL AND STROMAL TUMOURS- An update Michael Friedlander

  2. Ovarian Germ Cell Tumours • 1-2% of all ovarian malignancies • Usually in adolescents but 42% of 614 patients were over 30! • 60-70% STAGE 1 at diagnosis • No randomized trials in OGCT • Guided by results of large body of data from randomized trials in testis cancer

  3. Ovarian Germ Cell Tumours • Dysgerminoma • Endodermal sinus tumour • Embryonal Carcinoma • Choriocarcinoma • Teratoma-Mature/Immature Immature – low grade/high grade

  4. Surgical Principles • Suspect diagnosis • Pre-operative markers • Conservative- fertility preserving surgery • Staging-controversial- careful inspection of peritoneum, omentum, contralateral ovary and nodes with washings and biopsies of suspicious areas adequate • Unilateral oophorectomy with debulking if advanced stage

  5. Management Principles • Monitoring tumour markers b hcg AFP LDH t ½ b HCG 24- 48 hrs AFP 5-7 days • Switch to salvage therapy if markers not falling adequately or rising during treatment • Radiological re-staging following therapy • Resection of residual masses particularly if teratoma elements in primary

  6. IGCCCG Prognostic classificationTestis cancer

  7. Staging System-POG • Stage 1-limited to ovary. Washings –ve. Markers fall within T ½ • Stage 2-microscopic residual/positive nodes<2cm.-ve washings • Stage 3->2cm nodes;gross residual,contiguous visceral involvement;+ve washings • Stage 4-distant metastases

  8. Malignant Germ Cell Tumors in Children and Adolescents-POG StudyJ Paed.Surg 39;424:2004 Stage No. 6yr EFS% 6yr S% • 41 95 95.1 • 16 87.5 93.8 • 58 96.6 97.3 • 16 86.7 93.3 BEP B 15mg/m2 D1 E 100mg/m2 1-5 P 20/m2 1-5 4 cycles at 3 weekly intervals

  9. Management of Dysgerminomas • Most patients Stage 1a- surveillance appropriate. • 15% will relapse and salvaged with chemotherapy • Rare-therefore not clear if BEP X 3 is essential-in advanced or recurrent disease • GOG STUDY- 39 patients with stage 1b-3 completely resected-treated with Carboplatin 400mg/m2 and etoposide 120mg/m2 x3 every 4 weeks x 3 No recurrences

  10. Management of Good Prognosis Subset • BEP x 3 • If Bleomycin contraindicated or dropped- EP X 4 • 5 day BEP less toxic and optimal regimen B 30 U d1,8,15 E 100mg/m2 1-5 Cisplatin 20mg/m21-5

  11. Australian Germ Cell StudyLancet 357;739;2001 Indiana BEP vs. 4 Cycles Cisplatin 100mg/m2 day1 Etoposide 120mg/m2 d1-3 Bleomycin 30 u q21 166 randomized Trial stopped as 1 vs. 9 deaths from cancer in the 2 regimens 5 day BEP-Indiana superior regimen

  12. Toxicity of BEP • Pulmonary toxicity 3%; decreased DLCO 20% • AML 0.2- 1% • Neuropathy 20% • Raynauds 20% • Tinnitus 24% • High tone hearing loss 70% • Gonadal dysfunction 16 -30% • Cardiovascular disease/Hypertension

  13. How important is Bleomycin • Bleomycin should only be omitted if contra-indications when 4 cycles of EP can be used • Inconsistent findings from trials of 4 EP vs 3 BEP

  14. Management of Intermediate to Poor Risk Subgroup • BEP X 4- represents standard of care • Multiple studies using various combinations and permutations do not appear superior • VeIP appropriate if compromised lung function • High dose therapy not demonstrated to be superior first line treatment

  15. Accelerated BEPIntermediate-high risk- new Australian study Administer every 14 days with pegylated GCF support day 6 Cisplatin 20 mg/m2 day1-5 Etoposide 100mg/m2 d1-5 Bleomycin 30 u weekly x 12

  16. Role of Second Look Surgery • Not necessary in patients with completely resected disease at primary surgery • Resection of residual masses-particularly if teratomatous elements in primary tumour • Resection of residual masses in non-dysgerminoma – 50% necrosis;35% mature teratoma; 15% residual cancer

  17. Second look surgery Matthew et al J Postgrad Med 2006 • 68 patients with germ cell tumors • 35 residual mass post chemo • 29 laparotomy 3 patients had viable tumor, 7 immature teratoma, 3 mature teratoma and 16 necrosis or fibrosis no cases of viable tumour if dysgerminoma, embryonal carcinoma /absence of teratoma in primary

  18. Salvage therapy TIPJournal of Clinical Oncology 18; 2000: 2413-2418 • Treatment consisted of four cycles of TIP given 21 days apart. • Paclitaxel 250/m2 by 24-hour infusion on day 1, followedby an ifosfamide 1.2 g/m2 infusion given over 4 hours, and cisplatin20 mg/m2 on days 2 through 6. • 80% of 30achieved a favorable response. • 22 (73%) of the favorable responses remaindurable at a median follow-up duration of 33 months

  19. Survival for patients with relapsed testicular GCTs treated with TIP therapy (n = 30; 25 alive) Motzer, R. J. et al. J Clin Oncol; 18:2413-2418 2000

  20. Stem Cell Transplant ? European Bone Marrow Transplant Group- Randomized 280 relapsed patients to VIP/VeIP X4 vs VIP/VeIP X3 followed by High Dose Chemo and stem cell support No advantage to High dose and stem cell support 53% 3 year survival in both arms

  21. Stem Cell Transplant • Results of 2 randomized trials EORTC and an intergroup study do not support role in first line therapy for high risk disease • Still contentious for salvage therapy

  22. Ovarian Germ Cell TumorsCan stage 1 be managed with close surveillance? • Surveillance successful in male germ cell tumours- 20-30% relapse but salvaged 2 cycles of BEP in “high risk” • What about ovarian germ cell tumours

  23. Surveillance for Stage 1 tumors

  24. Surveillance programCharing Cross /Mount Vernon Pre-op markers and scans 3 months post surgery CT Chest/abd-pelvis If clear- 2nd look laparoscopy if inadequate staging/immature teratoma

  25. Surveillance Markers HCG AFP LDH CA125 1st year every 2 weeks x 6 m and then monthly x 6 2nd year monthly 3rd year every 3/12 4th year every 4/12 Subsequent years 6/12

  26. Surveillance Clinical exam 1st year monthly 2nd year every 2 months 3rd year every 3 months 4th year every 4 months 5-10 every 6 months

  27. Imaging • Chest X ray alternate visits • Abdo-pelvic US every 3rd visit for first 2 years followed by annual abdo-pelvic ultrasound subsequent years

  28. Surveillance in stage 1 • Relapses occur within 1 year in almost all cases • Salvage high • Advantages- reduced toxicty leukemia 0.9% hypertension 15% neuropathy 15%

  29. Conclusions • Paradigm of a curable malignancy • Can not be complacent- still needs expert treatment rather than “recipe –based’’ • Good evidence base for treatment • Focus on reduction of toxicity in low risk and improving outcomes in intermediate to poor risk • Surveillance has not been standard of care in ovarian germ cell tumors but should be considered for 1A

  30. Sex cord stromal tumours

  31. Sex Cord Stromal Tumors • 5-8% of ovarian malignancies • Derive from sex cords and ovarian stroma • Granulosa Cell;Sertoli Leydig • Adult granulosa cell tumors are the most common of the group

  32. Granulosa Cell Tumors(GCT) • Median Age 54 • 2-5% of ovarian cancers • 5% juvenile-prepubertal age group • Usually unilateral • 70% secrete estrogen- concurrent endometrial cancer in 5-10% • Increased risk of breast cancer • Most stage 1 at diagnosis • Late recurrences 10-30 years post diagnosis can occur

  33. GCT-Survival by Stage

  34. GCT- Natural History • Indolent • Late relapses in up to 30% Stage 1 –but data not robust • 90% 5 year survival • Recurrences can occur many decades later 10 year survival after recurrence-56% Median Survival after recurrence 2 yrs

  35. GCT –Prognostic Factors • Stage • Poorly differentiated or sarcomatoid variant-worse prognosis • Mitotic count 4/10HPF 100% @ 5yrs 5-9 –80% 5yr survival >10-no long term survivors • Ploidy- better prognosis in diploid tumors • Residual disease post surgery

  36. Management • Unilateral oophorectomy in children or women of reproductive age group • Bilateral tumours uncommon • TAHBSO in post menopausal women • No evidence to support adjuvant radiation • No evidence that adjuvant chemotherapy prevents recurrence-but no studies !

  37. Recurrent Disease management • Median time to relapse 4-6 years • Repeat debulking surgery should be considered in all patients • Localised recurrence-consider radiation • Hormonal therapy • Chemotherapy

  38. Compilation of Results of Chemotherapy

  39. Chemotherapy of GCTHomesley et al Gynecol Oncol 1999;72:131 • GOG study- 55 women with Stage 2-4 or recurrent GCT- BEP • RR 40% CR 24% • 14/38 women had negative second look surgery • 50% of patients with recurrent disease progression free at 3 years • 69% of patients with advanced tumors progression free at 3 years • Significant toxicity with 2 bleomycin related deaths

  40. Taxanes in Sex Cord Stromal TumoursMD Anderson Experience-JCO 22;3517;2004 • Non-randomized • 44 patients-both adjuvant and recurrent • Taxane +/- platinum • 42% response rate in measurable disease • Median PFS 20 months in recurrent disease • Less toxic than BEP in this older population

  41. Hormone ReceptorsHardy et al Gyn Oncol 2005 ER + 32% PR + 100%

  42. Hormonal Therapy

  43. Conclusions • Good prognosis for most • Rare –no strong evidence base for treatment decisions • Adjuvant therapy controversial-? In high risk • Surveillance-long term

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