Epithelial Ovarian Cancer

Epithelial Ovarian Cancer Fred Ueland, MD University of Kentucky Gynecologic Oncology

Risk Factors Incessant ovulation Early menarche, late menopause, low parity Family history Acquired genetic mutations BRCA-1,2 and HNPCC Fertility drugs Clomid, Pergonal High fat diet Western hemisphere Talc

Incidence and Mortality Ovarian Cancer

Ovarian Cancer Incidence and Mortality Data from the American Cancer Society 200 deaths in Kentucky in 2006

Incidence

Mortality

Classification Ovarian Cancer

Histology

Low Malignant Potential

Serous Ovarian Cancer

Endometrioid Ovarian Cancer

Undifferentiated Ovarian Cancer

Metastasis

Familial Ovarian Cancer Ovarian Cancer

Familial Ovarian Cancer Site-specific ovarian cancer 2 or more 1 st degree relatives Ovarian cancer only Breast-ovarian cancer syndrome BRCA 1,2 Over 50% develop cancer by age 70 Lynch II syndrome HNPCC

Genetic Mutations Ovarian Cancer Tumor Suppressor Genes P53 most frequent (60-70%), poor px P16 in 15% BRCA-1 1 17q (5%), BRCA-2 2 13q (3%) Autosomal dominant, 80% penetrance 90% are frame shift, 10% missense Ashkenazi Jews 5-105 x risk of mutations PTEN in endometrioid cell type

Tumor Suppressor Genes 1. Discovered in 1980 s 2. Inhibitory 3. Heritable, early in genesis Knudson s two-hit hypothesis 4. Loss of heterozygosity (LOH) 5. Gate keepers inhibit cell proliferation, promote apoptosis RB (13q), p53 (17p), APC (5q21) BRCA1 (17q), BRCA2 (13q)

BRCA-1,2 Tumor suppressor gene common to all DNA repair gene Over 600 mutations known BRCA 1 (17q21), BRCA 2 (13q12) Ashkenazi Jew 2.3% 5 fold + increase 16-60% 60% get ovarian cancer 8 to 30 fold increase 36-85% get breast cancer 3 to 7 fold increase

p53 Regulates cell cycle Guardian of the genome 17p13 p53 wild type is the functional gene Activated with DNA damage blocks replication and allows for repair For irreversible DNA damage, p53 initiates apoptosis Mutated p53 can not initiate cellular arrest or apoptosis Cell replicates the aberrant DNA

p53 Present in 50% of all cancers Li-Fraumeni 50 different mutations Risk for osteo and soft tissues sarcomas, breast, brain, adrenal cancers, leukemias Bladder cancer 20-40% Breast cancer 20-40%

Oncogenes Genetic Mutations Ovarian Cancer Her-2/neu (20-30%), poor px C-myc (20-30%) K-ras (5%) 50% of mucinous tumors LMP (20-50%)

Genetic Mutations DNA Repair Genes Ovarian Cancer Mismatch repair genes MSH 2, MLH 1, MSH 6, PMS 1, PMS 2 HNPCC syndrome 5-10% will develop OC Breast cancer not linked

DNA Repair Genes I. Autosomal dominant, 80% penetrance II. Maintain genomic integrity by repairing mismatched DNA before replication III. MSH 2, MLH 1, MSH 6, PMS 1, PMS 2 IV. HNPCC syndrome (Lynch II) Proximal colorectal 80% lifetime risk Endometrial 40% Gastric 20% Ovarian 9% Hepatobiliary Urinary

Staging Ovarian Cancer

Stage Distribution and Outcome Stage I II III IV Overall Percent 24 6 55 15 Survival 95% 65% 15-30% 0-20% 50% American Cancer Society

Stage I Confined to ovaries Stage IA: Confined to one ovary Stage IB: Both ovaries Stage IC: One or both ovaries and: Surface involvement Capsule ruptured (+) washings from the abdomen/pelvis

Stage II Confined to Pelvis Stage IIA: Involvement of uterus or the fallopian tubes, or both. Stage IIB: Adjacent pelvic organs bladder, sigmoid colon, or the rectum. Stage IIC: IIA or IIB with (+) washings

Stage III Extrapelvic Disease Stage IIIA: Microscopic disease of upper abdomen Stage IIIB: Upper abdominal involvement, but less than 2 cm in size Stage IIIC: Lymph node involvement. Upper abdominal disease 2 cm

Stage IV Distant Spread Stage IV: Distant metastasis Liver parenchyma Lungs Pleural fluid Other distant organs located outside of the peritoneal cavity

Surgery Ovarian Cancer

Ovarian Cancer

Epithelial Ovarian Cancer

Role Surgery Proper staging for early disease Adjuvant therapy Cytoreduction of advanced disease Optimal 1cm Reassessment laparotomy Secondary debulking

GOG Surgical Procedures Manual Adequate abdominal incision Estimate volume of peritoneal fluid. If no fluid, obtain washings from pelvis and abdomen if suspected stage I or II Inspect all peritoneal surfaces Infra-colic omentectomy At minimum, a biopsy must be obtained

GOG Surgical Procedures Manual If possible, extrafascial TAH with BSO. Unilateral SO if patient desires fertility and cancer appears stage I Resect all remaining gross disease in abdomen pelvis Selective pelvic and para-aortic aortic lymph node sampling Not required if stage IIIc or IV, except for cytoreduction If no gross disease, perform peritoneal biopsies Cul-de de-sac Vesical peritoneum Right and left pelvic sidewalls Right and left paracolic gutters Right hemidiaphragm

Cytoreduction Ovarian Cancer Slide courtesy of Gynecologic Cancer Foundation

Value of Specialists Meta-analysis analysis (18 studies) concluded marked benefit with Gynecologic Oncologist (Giede 2005) Complete surgical staging with early stage disease Optimal cytoreductive surgery with advanced disease Improved median and overall survival Others supporting GO involvement: NCCN guidelines SGO, ACOG SOGC clinical practice guidelines NIH consensus statement London Medical Advisory statement

Overall Survival IA IB IC IIA IIB IIC IIIA IIIB IIIC IV 92.7% 85.4% 84.7% 78.6% 72.4% 64.4% 50.8% 42.4% 31.5% 17.5%

Improving Survival

Conclusions 1. Advanced stage presentation 50% overall five-year survival 2. Serous histology most common 3. Familial ovarian cancer site-specific specific breast ovarian Lynch II syndrome

Conclusions 1. Always prepared for surgical staging 2. Optimal surgical debulking improves overall patient survival 3. Early involvement of gynecologic oncologist improves overall patient survival