Ovarian CancerPedro T. Ramirez, M.D.

Associate ProfessorDirector of Minimally Invasive Research & Education

Department of Gynecologic Oncology

Epidemiology

In the United States• Estimated 21,650 new cases and 15,520

deaths for 2008• 5th most common cancer in women• Most common cause of gynecologic mortality• 1 in 70 women will develop ovarian cancer

Epidemiology: Risk Factors

• Advancing age• Infertility• Endometriosis• Application of talcum powder to perineum• Genetic susceptibility (8-13% caused by BRCA1

or BRCA2)

Epidemiology: Protective factors

• Oral contraceptive use (RR 0.7 for 2 yrs of use, 0.5 for ≥5 yrs of use)

• Parity• Tubal sterilization?• Hysterectomy?

Screening

• Routine pelvic examination NOT effective

• ACS, ACOG, SGO, NCCN do NOT recommend ovarian cancer screening for general population

• Screening with ultrasound and CA125 is recommended for women BRCA (+) mutations

Screening Tests: CA 125• CA125 elevated in 90% of epithelial ovarian cancers

• However:– CA125 levels are normal in 50% of women with early stage

ovarian cancer– CA125 levels are elevated in 2-3% of postmenopausal

women without ovarian cancer

Causes of elevated CA125

• Malignant conditionsGynecologic Cancers- Epithelial ovarian cancer- Some germ cell tumors- Some stromal tumors- Fallopian tube cancers- Endometrial cancer- Endocervical cancerNon Gynecologic Cancer- Pancreatic cancer- Lung cancer- Breast cancer- Colon cancer

• Benign conditionsGynecologic conditions- Endometriosis- Adenomyosis- Leiomyomata uteri- Ectopic pregnancy- Normal pregnancy- Pelvic inflammatory disease- MensesNongynecologic conditions- Pancreatitis- Cholecystitis- Cirrhosis- Passive liver congestion- Peritonitis- Peritoneal tuberculosis- Peritoneal sarcoidosis- Recent laparotomy

Screening Tests: Ultrasound

• Transvaginal ultrasonography most studied as modality for ovarian cancer screening

• Not very effective in diagnosing early stage ovarian cancer

• Combination of ultrasound and CA125 better sensitivity with worse false positive rate

Histology• Epithelial (85% of all ovarian cancers)

- 40-50% serous- 15-25% endometrioid- 6-16% mucinous-5-11% clear cell

• Germ cell (10% of all ovarian cancers)• Sex-cord stromal (5% of all ovarian cancers)

Diagnosis• Most present with advanced stage diseases • Symptoms are vague (abdominal pain, bloating,

gastrointestinal or urinary tract complaints)

• Studies show that most women recall having symptoms before diagnosis high index of suspicion most important

Diagnosis

• Definitive diagnosis: surgery (or biopsy)

• Laparoscopy can be used (Avoid rupture/spillage of tumor)

• Frozen section diagnosis of ovarian cancerStaging is mandatory

ACOG & SGO Joint Opinion 2002• Women who have a pelvic mass that raises suspicion for a

malignant ovarian neoplasm as suggested by at least one of the following should be referred to a Gynecologic Oncologist:

(1) Elevated CA125 level(2) Ascites(3) A nodular or fixed pelvic mass(4) Evidence of abdominal or distant metastasis (5) Family history of one or more first-degree relatives

(Ovarian or breast cancer)

Staging• Staging is surgical

• One third with presumed stage I or II disease have stage III disease when thoroughly staged

• Spread due to exfoliation of cells in peritoneal cavity (right paracolic gutterclockwise)

FIGO StagingStage Description

I Growth limited to the ovaries

IA Growth limited to one ovary; no ascites containing malignant cells present; no tumor on external surface; capsule intact

IB Growth limited to both ovaries; no ascites containing malignant cells present; no tumor on the external surface; capsule intact

IC Tumor either stage IA or IB, but with tumor on the surface of one or both ovaries, or with capsule ruptured, or with ascites containing malignant cells present, or with positive peritoneal washings

II Growth involving one or both ovaries with pelvic extension

IIA Extension or metastases or both to the uterus or fallopian tubes or both

IIB Extension to other pelvic tissues

IIC Tumor either stage IIA or IIB, but with tumor on the surface of one or both ovaries, or with capsule ruptured, or with ascites containing malignant cells present, or with positive peritoneal washings

III Tumor involving one or both ovaries with histologically confirmed peritoneal implants outside the pelvis or positive retroperitoneal or inguinal nodes or both; superficial liver metastasis equals stage III; tumor is limited to the true pelvis but with histologically confirmed

IIIA Tumor grossly limited to the true pelvis with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces, or histologically proven extension to small bowel or omentum

IIIB Tumor of one or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2cm in diameter; nodes are negative

IIIC Peritoneal metastasis beyond the pelvis larger than 2cm in diameter or positive retroperitoneal or inguinal nodes or all

IV Growth involving one or both ovaries with distant metastases; if pleural effusion is present, there must be positive cytologic findings to allot a case to stage IV; parenchymal liver metastasis equals stage IV

Epithelial Ovarian Cancer Management

• Surgical therapy is the initial form of intervention in most cases

• Stage IA, grade 1 epithelial cancer will generally not require adjuvant therapy

• Categorized into early stage disease (Stage I and IIA with no residual cancer) and advanced disease (stage IIB with residual cancer and stages III and IV)

• Early stage disease further divided into low-risk and high-risk disease

• Survival rate for properly staged early epithelial ovarian cancer is ~95%

Recommended Primary Surgical Staging Procedure for Patients with Apparently Early Ovarian Carcinoma

• Vertical incision• Multiple peritoneal washings• Total abdominal hysterectomy and bilateral salpingo-oophorectomy

(unilateral salpingo-oophorectomy may be appropriate for selected patients with stage IA disease who desire to defer definitive surgery until completion of childbearing)

• Infracolic omentectomy• Pelvic and paraaortic lymph node sampling• Peritoneal biopsies of the following:- Cul-de-sac- Rectal and bladder serosa- Right and left pelvic sidewalls- Right and left paracolic guters- Right and left diaphragm- Any adhesions

Therapy for Epithelial Ovarian Cancer

Category of Ovarian Cancer Based on Surgical Staging

Recommended (standard) Therapy

Early ovarian cancer

Low risk (stages IA and IB, grade 1) TAH, BSO

High risk (stages IA and IB, grade 2 and 3; stages IC, IIA, IIB, and IIC, no residual)

TAH, BSOAdjuvant therapy with combination carboplatin and paclitaxel chemotherapy

Advanced ovarian cancer

Stage III with optimal residual disease Maximal surgical cytoreductionCombination chemotherapy with systemic carboplatin and paclitaxel or systemic paclitaxel plus intraperitoneal cisplatinand paclitaxel

Stage IV, or suboptimal disease, or both Maximal surgical cytoreductionCombination chemotherapy with carboplatin and paclitaxel

Primary Cytoreductive Surgery• Patients who undergo “optimal” cytoreduction have

improved response rates to chemotherapy, prolonged disease-free survival, and improved overall survival

• If cytoreduction is suboptimal, there is no survival benefit to surgical debulking

• Overall survival for patients with optimally debulked advanced disease is 47-66 months compared with 33-36 months with suboptimally debulked disease

• Meta-analysis showed improved survival rates among patient referred to expert centers for primary surgery (centers where ≥75% optimal cytoreduction rate)

• Optimal cytoreduction generally defined as tumor measuring 1 cm or less, but best survival rates when no gross visible tumor remaining

SPLEEN

SPLEENHILUS

Interval Cytoreductive Surgery• Chemotherapy followed by surgery• Used in patients who are not good operative

candidates or where it is known that an optimal cytoreductive surgery can not be performed

• Helps determine patients who have chemoresistant disease and won’t be helped by surgery

• Recent European study shows no difference in survival between patients randomized to primary cytoreductive surgery and patients treated with neoadjuvant chemotherapy

Consolidation Chemotherapy

• GOG randomized trial showed improvement in progression-free survival with the administration of 1 year vs 3 months of monthly paclitaxel as consolidation

• However, study stopped before overall survival could be determined

Secondary Cytoreductive Surgery

• The use of cytoreductive surgery in the setting of recurrent disease is not well defined

• Selection should be based on disease-free interval from completion of primary therapy, the number of sites of recurrence, and the probability that cytoreduction to minimal residual disease can be achieved

Chemotherapy

• 75-80% of patient will respond to chemotherapy, but many will eventually develop resistance

• Standard therapy has been IV carboplatin and paclitaxel

• Recent GOG randomized phase III trial compared IV paclitaxel + cisplatin to IV paclitaxel + IP (intraperitoneal) cisplatin and paclitaxel in patients with optimally cytoreduced stage III ovarian cancer 50 vs 66 month overall survival NCI recommendation for IP therapy in this group of women

Chemotherapy for Persistent Disease

• ~20-25% of patients with advanced epithelial ovarian cancer will be “cured” by initial surgery and primary chemotherapy

• Platinum sensitive: Recurrence after 6 months-carboplatin and paclitaxel-carboplatin and liposomal doxorubicin

• Platinum resistant: Recurrence with 6 months -Second line chemotherapy

• These patients are candidates for experimental trials

Follow-up Care

• Year 1Every 3 months

• Year 2Every 4 months

• Year 3-5 Every 6 months

Pelvic exam & CA125 every visit

Primary Peritoneal Carcinoma

• Serous carcinoma arising from the peritoneal lining that is histologically indistinguishable from serous epithelial ovarian cancer

• Widespread abdominal disease with only surface ovarian involvement

• Responds to therapy similarly to epithelial ovarian cancer and managed in the same way

Fallopian Tube Cancer

• Resembles papillary serous carcinoma of the ovary, surgical therapy is the same, pattern of spread the same, therapy the same

• Symptoms similar to ovarian cancer

• Most common symptoms is vaginal bleeding

Ovarian Germ Cell Tumors• Diagnosed in 2nd and 3rd decades of life• Symptoms: 10% with acute episode of torsion,

hemorrhage, or rupture of the tumor• Elevated serum levels of hCG

(choriocarcinoma), alpha-fetoprotein (endodermal sinus tumors), or lactic dehydrogenase (dysgerminoma)

• Excellent (>95%) prognosis for those treated with combination adjuvant therapy

Germ Cell Tumors: Management• Complete cytoreduction and same surgical

staging as epithelial ovarian cancer• May preserve reproductive organs not

involved with the cancer in women who have not completed childbearing

• Chemotherapy with BEP (bleomycin, etoposide, and cisplatin) or taxol/carboplatin

Sex Cord Stromal Tumors

• Granulosa-cell (Adult and Juvenile)• Granulosa-theca cell• Sertoli-Leydig cell• Lipid cell tumors• Gynandroblastoma

Sex Cord Stromal Tumors

• Complete cytoreduction and same surgical staging as epithelial ovarian cancer

• May preserve reproductive organs not involved with the cancer in women who have not completed childbearing

• Chemotherapy with BEP (bleomycin, etoposide, and cisplatin) or taxol/carboplatin

MD Anderson Cancer Center