Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Epithelial Ovarian Cancer

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Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Epithelial Ovarian Cancer

  1. 1. Epithelial Ovarian Cancer Clinical Presentation, Diagnosis, Staging (1) Treatment (2) Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium ESO student course, Ioannina, 2011
  2. 2. Antwerp University Hospital
  3. 3. Epithelial Ovarian Cancer Epidemiology <ul><li>Second most common gynecologic malignancy in Western Europe and US </li></ul><ul><li>An estimated 21.550 new cases of ovarian cancer are expected in the US in 2009 </li></ul><ul><ul><li>During 2001-2005, ovarian cancer incidence declined at a rate of 2.4% per year </li></ul></ul><ul><li>An estimated 14.600 deaths were expected in 2009. Death rates have been stable since 1998 </li></ul><ul><ul><li>Silent killer </li></ul></ul><ul><li>70% of patients present with advanced disease </li></ul>
  4. 4. Epithelial Ovarian Cancer Epidemiology <ul><li>The crude incidence of ovarian cancer in the European Union is 18/100.000 women per year, the mortality is 12/100.000 women per year </li></ul><ul><li>The median age at diagnosis is 63 years. The incidence increases with age and peaks in the 8th decade. Between the age of 70-74 years the age-specific incidence is 57/100.000 women per year </li></ul><ul><li>* ESMO minimum Clinical Recommendations </li></ul><ul><li>Ann Oncol 19 (suppl 2): ii14-ii16, 2008 </li></ul>
  5. 5. Ovarian Cancer Risk Factors <ul><li>Increase </li></ul><ul><li>Age </li></ul><ul><li>Family history </li></ul><ul><li>Infertility / low parity </li></ul><ul><li>Personal cancer history </li></ul><ul><li>Estrogen alone* </li></ul><ul><li>Heavier body weight </li></ul><ul><li>Inherited mutations in </li></ul><ul><li>BRCA1 or BRCA2 genes </li></ul><ul><li>Decrease </li></ul><ul><li>OCPs (long-term use) </li></ul><ul><li>Pregnancy </li></ul><ul><li>Tubal ligation / hysterectomy </li></ul><ul><li>Breast feeding </li></ul><ul><li>Prophylactic oophorectomy </li></ul>* As postmenopausal hormone therapy
  6. 6. Ovarian Cancer Pathology (1) <ul><li>Epithelial tumors </li></ul><ul><li>Sex cord stromal tumors </li></ul><ul><li>Germ cell tumors </li></ul><ul><li>Metastatic tumors </li></ul>
  7. 7. Ovarian Cancer Pathology (2) <ul><li>Common “Epithelial” Tumors </li></ul><ul><li>Serous a) benign </li></ul><ul><li>Mucinous b) borderline </li></ul><ul><li>Endometrioid c) malignant </li></ul><ul><li>Clear cell (mesonephroid) </li></ul><ul><li>Transitional cell </li></ul><ul><li>Squamous </li></ul><ul><li>Modified WHO classification of Ovarian Epithelial Tumors </li></ul>
  8. 8. Two Types of Ovarian Cancer <ul><li>Type 1 – Low grade – Early stage – Slow growing </li></ul><ul><ul><li>Resistant to platinum-based therapy </li></ul></ul><ul><ul><li>Ras/Raf and PTEN mutations </li></ul></ul><ul><ul><li>IGFR expression </li></ul></ul><ul><ul><li>Wild-type p53 </li></ul></ul><ul><li>Type 2 – High grade – Advanced stage – Agressive </li></ul><ul><ul><li>Responsive to platinum-based therapy </li></ul></ul><ul><ul><li>p53 mutations </li></ul></ul><ul><ul><li>BRCA1/2 mutations </li></ul></ul><ul><ul><li>Activation of the PI3K pathway </li></ul></ul><ul><li>Bast Jr RC, Valencia meeting, March 4, 2011 </li></ul>
  9. 9. Ovarian Cancer Clinical Presentation Early disease: no specific signs / symptoms nausea, indigestion, lower abominal disconfort, abnormal vaginal bleeding Advanced disease: GI symptoms – constipation Urinary symptoms – frequency Abdominal symptoms – pain, distension
  10. 10. Distended abdomen: ovarian mass
  11. 11. Ovarian Cancer Paraneoplastic syndromes <ul><li>Neurologic </li></ul><ul><ul><li>Peripheral neuropathies </li></ul></ul><ul><ul><li>Organic dementia </li></ul></ul><ul><ul><li>Cerebellar ataxia </li></ul></ul><ul><ul><li>Amyotrophic lateral sclerosis </li></ul></ul><ul><li>Thrombophlebitis </li></ul><ul><li>Hypercalcemia </li></ul>
  12. 12. Ovarian Cancer Diagnostic modalities <ul><li>Rectovaginal pelvic exam </li></ul><ul><li>TVS and/or CT scan or MRI </li></ul><ul><li>CA-125 </li></ul><ul><li>If diagnosis uncertain  laparoscopy </li></ul><ul><li>Surgical exploration </li></ul>
  13. 13. Ovarian Cancer Surgical exploration <ul><li>Diagnostic </li></ul><ul><li>Vertical incision </li></ul><ul><li>Peritoneal fluid  cytology (or saline irrigation) </li></ul><ul><li>Scrupulous inspection - right diaphragm </li></ul><ul><li>- liver, serosa, parenchyma </li></ul><ul><li>Biopsies of contralateral ovary, retroperitoneal LN and suspicious changes on the peritoneum, omentum </li></ul><ul><li>Therapeutic </li></ul><ul><li>Early disease – TAH + BSO, omentectomy, LND </li></ul><ul><li>Advanced disease – debulking surgery </li></ul>
  14. 14. FIGO Staging (2008) Ovarian Cancer IA Confirmed to one ovary, no ascites, intact capsule IB Confirmed to both ovaries (same criteria as IA) IC IA or IB + tumor surface/capsule rupture/pos. cells IIA Extension to the uterus or tubes IIB Extension to other pelvic tissues IIC IIA or IIB + tumor surface/capsule rupture/pos. cells III One or both ovaries + extension outside pelvis or limited to true pelvis + extension to small bowel or omentum IIIA LN Θ , extension only microscopically IIIB LN Θ , extension not exceeding 2 cm in diameter IIIC LN + (RP/inguinal) and/or extension >2 cm in diameter IV One or both ovaries + DM (or parenchymal liver mets)
  15. 15. Treatment Options in Ovarian Cancer <ul><li>Surgery* </li></ul><ul><li>Chemotherapy* </li></ul><ul><li>Occasionally radiation therapy </li></ul><ul><li>* Depends upon stage and other clinicopathological prognostic factors </li></ul>
  16. 16. Diagnosis in Epithelial Ovarian Cancer The crux <ul><li>Early-stage disease </li></ul><ul><li>28.1% of all obviously malignant cases* </li></ul><ul><li>Advanced-stage disease </li></ul><ul><li>71.9% of all obviously malignant cases* </li></ul><ul><li>*Int J Gynaecol Oncol, 2003 (FIGO report) </li></ul>
  17. 17. Five-year Survival in Ovarian Cancer 30 years of experience Vol. Year Cases Ia IV Overall (n) % 16 1963-68 4588 66.7 5.0 27.3 19 1976-78 6724 72.3 4.5 29.8 21 1982-86 10912 82.3 8.0 35.0 23 1990-92 7059 83.5 11.1 41.6 25 1996-98 4116 89.3 13.4 46.4 26* 1999-01 4911 89.3 18.6 49.7 Int. J Gynecol Obstet 2006 (Suppl 1)
  18. 18. Ovarian Cancer Surgical exploration <ul><li>Diagnostic </li></ul><ul><li>Vertical incision </li></ul><ul><li>Peritoneal fluid  cytology (or saline irrigation) </li></ul><ul><li>Scrupulous inspection - right diaphragm </li></ul><ul><li>- liver, serosa, parenchyma </li></ul><ul><li>Biopsies of contralateral ovary, retroperitoneal LN and suspicious changes on the peritoneum, omentum </li></ul><ul><li>Therapeutic </li></ul><ul><li>Early disease – TAH + BSO, omentectomy, LND </li></ul><ul><li>Advanced disease – debulking surgery </li></ul>
  19. 19. Risk Groups in Early Ovarian Cancer <ul><li>Low risk </li></ul><ul><li>Grade I </li></ul><ul><li>Intact capsule </li></ul><ul><li>No tumor ext. surface </li></ul><ul><li>Negative washings </li></ul><ul><li>No ascites </li></ul><ul><li>Growth confined to </li></ul><ul><li>ovaries </li></ul><ul><li>High risk </li></ul><ul><li>Grade 2-3 </li></ul><ul><li>Ruptured capsule </li></ul><ul><li>Tumor on ext. surface </li></ul><ul><li>Positive washings </li></ul><ul><li>Ascites </li></ul><ul><li>Growth outside ovaries </li></ul>
  20. 20. DFS in Low-Risk Early Ovarian Cancer Surgery only <ul><li>All patients had stage I a/b, grade I </li></ul><ul><li>Bolis et al, 1989 95% </li></ul><ul><li>Young et al, 1990 98% </li></ul><ul><li>Trimbos et al, 1990 100% </li></ul>
  21. 21. ICON1 + ACTION Two Parallel Randomised Phase III Trials of Adjuvant Chemotherapy in Patients with Early Stage Epithelial Ovarian Cancer ICON1 (International Collaborative Ovarian Neoplasm studies) launched in 1991 ACTION (EORTC: Adjuvant Clinical Trial In Ovarian Neoplasm) launched in 1990
  22. 22. Results in High-Risk Early Ovarian Cancer Adjuvant platinum-based Chemotherapy 105 460 75 465 Events Total Adjuvant chemotherapy No adjuvant chemotherapy S u r v i v a l 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months from randomisation 0 12 24 36 48 60 72 84 96 108 120 HR=0.64; P=0.001 HR=0.68; P=0.01 Recurrence-free survival Overall survival ICON1 + ACTION 140 460 98 465 Events Total Adjuvant chemotherapy No adjuvant chemotherapy P e r c e n t a g e 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months from randomisation 0 12 24 36 48 60 72 84 96 108 120
  23. 23. Management of Advanced-Stage Ovarian Cancer Stages IIb-III (IV) <ul><li>Upfront radical cytoreductive surgery </li></ul><ul><li>In case this is not possible, a second attempt should be made </li></ul><ul><li>Platinum-based chemotherapy </li></ul><ul><li>Six cycles </li></ul><ul><li>No second-look </li></ul>Consensus meeting, 1998 Bergen (the Netherlands)
  24. 24. Advanced Ovarian Cancer 1998-2011 treatment <ul><li>Paclitaxel + Carboplatin (TC) </li></ul><ul><ul><li>Generally agreed standard </li></ul></ul><ul><ul><li>“ Control Arm” of all recent randomized trials </li></ul></ul><ul><ul><li>No other regimen shown to outperform it </li></ul></ul><ul><li>However, results far from perfect: </li></ul><ul><ul><li>Median TTP: 15-18 mo </li></ul></ul><ul><ul><li>Median OS: <3 yrs </li></ul></ul>
  25. 25. Recurrent Ovarian Cancer: Important Issues <ul><li>Presentation (asymptomatic 55-70%; TFI*) </li></ul><ul><li>Realistic goals </li></ul><ul><li>When to treat </li></ul><ul><li>How to treat </li></ul><ul><li>New combinations and compounds </li></ul><ul><li>*<6 months; 6-12 months; <12 months </li></ul>
  26. 26. Realistic Goals of Second-line Therapy in Ovarian Cancer <ul><li>Improve cancer-related symptoms </li></ul><ul><li>Optimize overall quality of life </li></ul><ul><li>Delay time to symptomatic disease progression </li></ul><ul><li>Prolong overall survival </li></ul><ul><li>Achieve an “objective response” </li></ul><ul><li>Markman M, 2002 </li></ul>
  27. 27. When to Treat? Harries and Gore, 2002
  28. 28. Trial Design Ovarian cancer in complete remission after first-line platinum based chemotherapy and a normal CA125 CA125>2 x upper limit of normal RANDOMIZED Early treatment Clinician and patient informed Delayed treatment Clinician not informed , treatment delayed until clinically indicated REGISTER Blinded CA125 measured every 3 months Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
  29. 29. Overall Survival HR=1.00 (95%CI 0.82-1.22) p=0.98 Early Delayed Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%) Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
  30. 30. Conclusions <ul><li>In early treatment arm based on rise in CA125 </li></ul><ul><ul><li>Second-line chemotherapy started a median of 4.8 months earlier </li></ul></ul><ul><ul><li>Third-line chemotherapy started a median of 4.6 months earlier </li></ul></ul><ul><li>This early treatment did not improve overall survival </li></ul><ul><ul><ul><li>HR=1.00, 95% CI 0.82-1.22, p=0.98 </li></ul></ul></ul><ul><ul><ul><li>Absolute difference at 2 years 0.1% (95%CI -6.8, 6.3%) </li></ul></ul></ul><ul><li>Early chemotherapy does not improve Qol </li></ul>
  31. 31. Single Agent Chemotherapy in ROC Relationship with platinum sensitivity Agent Response rates (%; range) Refractory Resistant Sensitive Platinum < 10 27-34 59-77 Paclitaxel 3-22 11-37 22-55 Topotecan 6-11 15-18 19-33 Gemcitabine 15-20 19-27 34 Epirubicin 11 a 14 36 Liposomal dox 11 9-15 18-37 Vinorelbine 15-30 21-33 29 Etoposide 27 27 34 Altretamine 10-14 40 Conte PF, 2000; Vermorken JB 2000 ( a PFI < 3 mo) Johnston & Gore 2001, Stebbing & Gaya 2002
  32. 32. Chemotherapy Options in Platinum-Sensitive Recurrent Ovarian Cancer (ROC) <ul><li>Traditionally, ROC patients with TFI > 6 mo have been retreated with platinum-based chemotherapy ICON-4 trial: Platinum/paclitaxel > Pt-alone (PFS, OS  ) </li></ul><ul><li>Cumulative toxicity from primary therapy (neuro) can preclude retreatment with paclitaxel/carboplatin </li></ul><ul><ul><li>AGO OVAR 2.5: carbo/ gemcitabine vs carbo (PFS  ) </li></ul></ul><ul><ul><li>OCEANS: carbo/ gemcitabine ± bevacizumab (study) </li></ul></ul><ul><ul><li>CALYPSO: carbo/ PLD vs carbo/paclitaxel (PFS  ) </li></ul></ul>
  33. 33. Chemotherapy Options in Platinum-Resistant Recurrent OC or for those with Partially Platinum-Sensitive Disease (TFI 6-12 mo) <ul><li>Numerous agents are available that can be used as a single agent: </li></ul><ul><ul><li>gemcitabine, PLD, topotecan, paclitaxel, docetaxel, oral etoposide, altretamine, trabectedin, and hormonal agents </li></ul></ul><ul><li>Take into consideration the patient’s anticipated tolerability and cumulative toxicity from front-line therapy </li></ul>
  34. 34. Ovarian Cancer – Conclusions Take-home messages <ul><li>Early disease: comprehensive surgery </li></ul><ul><li>high-risk patients  ACT </li></ul><ul><li>Advanced disease: debulk optimally </li></ul><ul><li>6 cycles of paclitaxel / carbo </li></ul><ul><li>Recurrent disease: palliative therapy </li></ul><ul><li>use all options on indication </li></ul><ul><li>How far shall we go? </li></ul>

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