Ovarian Cancer

1. Epidemiology
   1. Incidence: 26,800 new cases in U.S. in 1997
      1. Lifetime Risk: 1 in 70 (1.4%)
      2. Age adjusted risk: overall 12.5 cases per 100,000 women
         1. Age under 20 years: 0.7 per 100,000 women
         2. Age 20 to 50 years: 6.6 per 100,000 women
         3. Age 50 to 64 years: 26.9 per 100,000 women
         4. Age over 64 years: 48.6 to 55.6 per 100,000 women
   2. Mortality: 14,200 deaths in U.S. in 1997
      1. Accounts for 3% of cancer deaths in women
      2. Fifth most common cause of cancer death in women (lung, Breast, colon, Pancreas are more common)
2. Risk Factors
   1. Age over 40 years (most occur over age 50 years)
   2. Nulliparity
   3. Estrogen Replacement Therapy for more than 5 years
   4. Endometriosis
   5. Family History (accounts for up to 12% of Ovarian Cancer cases)
      1. Ovarian Cancer (2 to 20 fold increased risk)
         1. One affected first degree relative: 3 fold risk
         2. Two or more relatives affected: 40% risk
      2. Endometrial Cancer (Uterine Cancer)
      3. Colon Cancer
         1. (Lynch II syndrome)
      4. Breast Cancer
         1. BRCA1 and BRCA2 account for 10% of Ovarian Cancers
         2. BRCA1 confers 44% lifetime risk of Ovarian Cancer and typically present in the mid-40s
         3. BRCA2 typically presents in the mi-60s
   6. Past Medical History
      1. Endometrial Cancer
      2. Colon Cancer
      3. Breast Cancer
3. Risk Factors: Hereditary Ovarian Cancer Syndromes
   1. Breast-Ovarian Cancer Syndrome
   2. Site-specific Ovarian Cancer Syndrome
   3. Hereditary Nonpolyposis Colorectal Cancer (Lynch II Syndrome)
      1. Non-polyposis Colorectal Cancer
      2. Endometrial Cancer
      3. Ovarian Cancer (12% lifetime risk)
      4. Upper Gastrointestinal Tract Cancer
      5. Urinary Tract Cancer (Kidney Pelvis and Ureter)
4. Pathophysiology: Ovarian Cancer types
   1. Epithelial cell (over 85% of all overian cancers, most patients are over age 50)
      1. Subtypes
         1. Serous (40% of all Ovarian Cancers)
         2. Mucinous (25% of all Ovarian Cancers)
         3. Endometrioid (20% of all Ovarian Cancers)
   2. Stromal cell
      1. Subtypes
         1. Granulosa-theca cell
         2. Sertoli-Leydig (androblastoma)
   3. Germ cell
      1. Subtypes
         1. Endodermal sinus
         2. Embryonal
         3. Mature (commonly benign such as dermoid cysts)
   4. Krukenburg tumor (metastasis to ovary from Breast or gastrointestinal tract)
5. Evaluation: Findings that may prompt further Ovarian Cancer screening
   1. Family History suggestive of a cancer syndrome (BRCA1, BRCA2 or Lynch II) - see above
      1. Breast Cancer: Bilateral, pre-Menopause or inrences a male relative (BRCA)
      2. Ovarian Cancer in two or more first or second degree relatives (BRCA)
      3. Colon Cancer or Endometrial Cancer (ask about Lynch II cluster)
   2. Symptoms: Cluster of 6 symptoms for more than 12 days per month for less than a year (56% Test Sensitivity in early Ovarian Cancer)
      1. Pelvic Pain
      2. Abdominal Pain
      3. Increased abdominal size
      4. Abdominal bloating
      5. Difficulty eating
      6. Early satiety
   3. Exam
      1. Abdominal mass or Adnexal Mass on bimanual rectovaginal examination
         1. Ovary >10 cm, irregularity or nodularity should prompt further evaluation
         2. Palpable ovary 3-5 years after Menopause should also undergo further evaluation (ovaries should become non-palpable after Menopause)
      2. Inguinal Lymphadenopathy (although retroperitoneal involvement is more common)
      3. Sister Mary Joseph Nodule (periumbilical deep Subcutaneous Nodule associated with metastases)
   4. References
      1. Goff (2007) Cancer 109(2): 221-7
      2. Roett (2009) Am Fam Physician 80(6): 609-18
6. Imaging
   1. Transvaginal Ultrasound
      1. See Pelvic Ultrasound Ovarian Mass Findings
      2. Indication: First line evaluation of Adnexal Mass
      3. Test Sensitivity: 86%
      4. Test Specificity: 91%
      5. Findings on Ultrasound suggestive of Ovarian Cancer
         1. Increased cyst size
         2. Increased cyst wall thickness
         3. Intracystic papillary formations
         4. Intracystic solid areas
         5. Intracystic septation (complex cyst)
   2. CT Abdomen and CT Pelvis
      1. Indication: Preoperative evaluation of Adnexal Mass; monitoring post-treatment
      2. Test Sensitivity: 90%
      3. Test Specificity: 75%
   3. MRI Abdomen and Pelvis
      1. Indication: Further characterize indeterminate Adnexal Mass
      2. Test Sensitivity: 91%
      3. Test Specificity: 88%
   4. PET Scan Abdomen and Pelvis
      1. Indication: Ovarian Cancer metastases or recurrence where implants are not detectable on CT imaging alone
      2. Test Sensitivity: 67%
      3. Test Specificity: 79%
   5. References
      1. Funt (2002) Radiol Clin North Am 40(3): 591-608
7. Labs: Diagnosis of epithelial cell tumors (>85% of Ovarian Cancer)
   1. CA-125 Radioimmunoassay
      1. Low Test Specificity and low Test Sensitivity (especially in early disease and pre-Menopause)
      2. Indications to refer to gynecologic oncology
         1. Premenopause: CA-125 >200 units/ml
         2. Post-Menopause: CA-125>35 units/ml
8. Labs: Diagnosis of germ cell tumors (younger patients)
   1. Beta hCG
   2. Serum Alpha-fetoprotein
   3. Neuron-sepcific enolase
   4. Lactate Dehydrogenase
9. Labs: Other supportive labs
   1. Complete Blood Count
   2. Comprehensive metabolic panel
10. Staging
    1. Stage I: Ovary only (25% of Ovarian Cancer diagnosis)
       1. Stage IA: One ovary involved
       2. Stage IB: Both ovaries involved
       3. Stage IC: Stage IA or IB with below:
          1. Tumor on surface of ovary or
          2. Ovarian capsule ruptured or
          3. Malignant Ascites or
          4. Peritoneal cytology positive
    2. Stage II: Pelvic Extension
       1. Stage IIA: Spread to Uterus or fallopian tubes
       2. Stage IIB: Spread to other pelvic tissues
       3. Stage IIC: Stage IIA or IIB with below
          1. Tumor on surface of ovary or
          2. Ovarian capsule ruptured or
          3. Malignant Ascites or
          4. Peritoneal cytology positive
    3. Stage III: Peritoneal implants
       1. Stage IIIA: Microscopic seeding to peritoneum
       2. Stage IIIB: Abdominal peritoneal implants <2 cm
       3. Stage IIIC: Abdominal implants >2cm or positive nodes
    4. Stage IV: Distant Metastasis
11. Management: Surgical resection
    1. Standard resection
       1. Protocol
          1. Total abdominal Hysterectomy
          2. Bilateral salping-oopherectomy
          3. Pelvic and para-aortic Lymph node resection
          4. Omentum resection
          5. Appendectomy (in mucinous Ovarian Cancer)
       2. Efficacy: Radical surgical resection improves survival
          1. Benefit most significant in carcinomatosis
          2. Cliby (2006) Obstet Gynecol 107:77-85
    2. Fertility-sparing procedures
       1. Indications: Stage I Ovarian Cancer in age 30-50 years
       2. Protocol
          1. Unilateral salpingo-oophorectomy
          2. Consider later total Hysterectomy and contralateral salpingoopherectomy
          3. Adjuvant Chemotherapy in these lower risk cases only if residual disease post-resection
12. Management: Adjuvant Chemotherapy q3 weeks x6 cycles (70% respond)
    1. Medications: Protocols combine Platinum with Taxane
       1. Platinum Agents
          1. Cisplatin
             1. Significant Nausea and Vomiting
             2. Significant nephrotoxicity and neurotoxicity
             3. Administered over 24 hours with IV fluids
          2. Carboplatin
             1. Equivalent efficacy to Cisplatin
             2. Much less toxicity than with Cisplatin
             3. Can be administered outpatient over 3 hours
       2. Taxane Agents
          1. Paclitaxel (Taxol)
             1. Arthralgias and myalgias may be significant
             2. Risk of Peripheral Neuropathy
          2. Docetaxel
             1. Significant Neutropenia and nadir fever
             2. Less risk of adverse effects seen with Taxol
             3. May be preferred in pre-existing Neuropathy
    2. Intravenous (all 3 protocols with similar efficacy)
       1. Protocol 1: Cisplatin and Paclitaxel (Taxol)
       2. Protocol 2: Carboplatin and Paclitaxel
       3. Protocol 3: Carboplatin and Docetaxel
    3. Intraperitoneal (Regional) Chemotherapy
       1. Cisplatin is currently being used
       2. Carboplatin appears safe but efficacy not proven
    4. Current protocol recommended by NCI
       1. Cisplatin and Taxol Intraperitoneal and IV
       2. Armstrong (2006) NEJM 354:34-43
    5. References
       1. Markman (2003) Hematol Oncol Clin North Am 17:957
13. Prognosis
    1. Median survival: 32 months
    2. Five year survival
       1. Overall five year survival: 40%
       2. Five year survival for advanced Ovarian Cancer: 20%
    3. Predictors of better outcome
       1. Low-grade, Stage I Epithelial cell tumor (typically in premenopausal women): 95-99% ten year survival
    4. Predictors of worse outcome
       1. Age >75 contrasted with age <45 (Hazard ratio 2.8)
       2. Residual tumor >1 cm (Hazard ratio 1.72)
       3. FIGO stage 4 versus stage 1 (Hazard ratio 11.75)
       4. Clear cell or mucinous cell tumors
    5. References
       1. Tingulstad (2003) Obstet Gynecol 101:885-91
14. Prevention: Factors associated with a decreased risk of Ovarian Cancer development
    1. More than one full-term pregnancy (risk decreases with each successive pregnancy)
    2. Oral Contraceptive use (extended use beneficial)
    3. Surgeries that reduce uterine and ovarian blood flow (Hysterectomy, Tubal Ligation)
    4. Late Menarche and early Menopause
    5. Low Fat Diet
15. Prevention: High Risk Patients (Hereditary Ovarian Cancer Syndromes - BRCA1, BRCA2, Lynch II)
    1. Prophylactic Oophorectomy (preferred)
       1. Oophorectomy at age 35 or when childbearing complete
       2. Estrogen Replacement after oophorectomy
       3. Efficacy
          1. Reduces Ovarian Cancer risk
          2. Peritoneal Primary papillary serous tumors may occur
    2. Surveillance (alternative for those who forestall oophorectomy)
       1. BRCA: Transvaginal Ultrasound and CA-125 every 6 months during days 1-10 of Menstrual Cycle
       2. Lynch II: Transvaginal Ultrasound annually
       3. Onset of screening
          1. Age 35 years or
          2. Start 5-10 years earlier than the earliest case in the family
       4. Efficacy
          1. Test Sensitivity: 50-71%
          2. Test Specificity: 91%
16. References
    1. Barney (2008) Med Clin North Am 92(5): 1143-61
    2. Nahhas (1997) Postgrad Med 102(3): 112-20
    3. Roett (2009) Am Fam Physician 80(6): 609-18
    4. Teneriello (1995) CA Cancer J Clin 45(2):71-87