Ovarian Cancer: Diagnosis and Screening in Primary Care

Elise M. Hughes-Watkins, M.D. HughesNovember 30, 2001

Ovarian Cancer: Burden of suffering

4th leading cause of cancer death in women in the U.S. (after lung, breast and colon) Overall 5-year survival rate is 35% 5 The silent killer: asymptomatic in early stages 75% diagnosed with advanced stage disease; 55year survival only 10-28% 10 Womans lifetime risk of dying from ovarian cancer is 1.1%

Cancer Incidence and Deaths in U.S.Women in 2000

Cancer type Lung Breast Colon Ovarian Endometrial Cervical

# new cases 74,600 182,800 50,400 23,100 36,100 12,800

# of deaths 67,600 40,800 24,600 14,000 6,500 4,600

Adapted from Paley,P, Screening for the major malignancies affecting women: Current guidelines. Am J Obstet Gynecol 2001;184:

Types of Ovarian Tumors

Functional
Follicle cyst Corpus luteum cyst Theca lutein cyst

Malignant (or malignant potential)

Malignant teratoma Endometrioid carcinoma Dygerminoma Secondary ovarian tumor Cystadenoma, cystadenocarcinoma (>50% for serous, ~5% for mucinous) Granulosa cell tumor (15(1520%) Arrhenoblastoma (<20%) Theca cell tumor (<1%)

Inflammatory
Tubo-ovarian abscess Tubo Benign tumors/cysts* Endometriotic cyst Brenner tumor Benign teratoma (dermoid cyst) Fibroma *Rare or very rare potential for malignancy

Epithelial Ovarian Cancer

Overall 5-year survival rate is 75-95% if 575cancer confined to ovaries; decreases to 1010-17% if distant metastases Survival improved when cancer detected in early stage Only 25% diagnosed in Stage I

Early Detection and Mortality

No direct evidence that women with early stage cancer found on screening have lower mortality than women with more advanced disease Indirect evidence supports benefits of early detection:
Most important prognostic factor in patients with advanced ovarian cancer is tumor burden after initial debulking Surgical debulking and chemo more effective when cancer detected early

The challenge
Natural history of ovarian cancer not well understood
No well-defined precursor lesion well Length of time from localized tumor to dissemination is unknown

Multiple efforts underway to develop effective screening method for early detection

Risk factors
The majority of women with ovarian cancer have no known risk factors Most significant risk factor is genetic predisposition

Risk factors: Heredity

Up to 10% of epithelial ovarian cancer cases are familial 3 familial syndromes: familial breast-ovarian breastcancer syndrome, site-specific ovarian cancer, and sitecancer family syndrome (Lynch type II) Familial breast-ovarian cancer and site-specific breastsiteovarian cancer syndromes both associated with mutations of the BRCA1 suppressor gene; account for 90% of familial ovarian cancers
Rollins,G. Ann Int Med 2000;133:1021-1024 2000;133:1021-

Additional Risk Factors

Age
Women over age 50 account for ~80% of all cases (ave. age at dx is 61)

Reproductive history
early menarche, nulliparity or age >30 at first child-bearing, and childlate menopause

Personal history of breast cancer Hormone replacement therapy > 10 years

May be associated with 30% increased risk

Talcum powder
Some studies have shown slightly increased risk in women who use talc powder on genital area
American Cancer Society, 2001

Fertility drugs
prolonged use of Clomid, especially without achieving pregnancy

Protective factors
Multiparity: First pregnancy before age 30 Oral contraceptives: 5 years of use cuts risk nearly in half Tubal ligation Hysterectomy Lactation Bilateral oopherectomy

Delays in Diagnosis
Lack of severity and specificity of early symptoms
Early signs/symptoms may include bloating, gas, indigestion, abdominal fullness or discomfort, constipation, pelvic pressure, urinary frequency, abnormal vaginal bleeding, fatigue, back pain, leg pain

Early stage tumors difficult to detect on pelvic exam

Diagnostic tools
History Pelvic Exam (including rectal) Transvaginal Ultrasound detection of masses and mass characteristics Tumor markers CA-125, LPA (plasma CAlysophosphatidic acid) CT assess spread to LN, pelvic and abdominal structures MRI best for distinguishing malignant from benign tumors

WorkWork-up of Adnexal Mass

Must first categorize as functional, benign neoplastic or potentially malignant Diagnostic approach depends on:
Age Size of mass Unilateral vs. bilateral CA-125 levels CA Ultrasound configuration Color-flow Doppler flow Color Presence of symptoms

Diagnostic approach
If premenopausal and asymptomatic, with unilateral, mobile, simple cystic mass <8<810cm and no family history, can observe for 4-6 weeks and then repeat TVUS and pelvic exam.
If resolved, no further work-up necessary work If larger or unchanged, or if character of mass has changed on TVUS, surgical evaluation required

Diagnostic Approach
If postmenopausal and asymptomatic, with unilateral simple cyst <5cm AND normal CACA-125, can follow closely with repeat TVUS All other postmenopausal women with ovarian mass require surgical evaluation

Surgical Evaluation
Refer to Gyn-Onc specialist Gyn Exploratory laparotomy has been the gold standard and includes:
Peritoneal washings for cytology Evaluation of frozen section Complete staging procedure if borderline or malignant tumor on frozen section

Surgical Evaluation
Laparoscopy can be considered in premenopausal woman with ovarian mass small enough to remove via laparoscopic approach; not recommended if high suspicion for malignancy

Stages Ia, Ib, Ic

Stages IIa, IIb, IIc

Stages IIIa, IIIb, IIIc

Stage IV

Treatment
Depends on staging, tumor type, age, desire for future fertility Can include surgery, chemotherapy and/or radiation therapy Clinical trials are ongoing

Surgical treatment
Primary debulking and cytoreduction; may include:
Bilateral salpingo-oopherectomy salpingo Hysterectomy Lymphadenectomy (para-aortic, inguinal) (para Omentectomy brushing of diaphragm, examination of liver

Chemotherapy and Radiation

Usually 6 cycles of chemotherapy Cisplatin (or Carboplatin) plus Paclitaxel most commonly used combination therapy XRT

Screening Strategies
Ultrasound (transvaginal vs transabdominal) Color-flow doppler ColorCA-125 CAOther tumor markers

Ultrasound
Both tranabdominal and transvaginal techniques identify enlarged ovaries or abnormal morphology; TVUS has better resolution One large study of TVUS underway has reported sensivity of 81% and specificity of 98.9% Major limitations are poor PPV in asymptomatic women and inability to detect malignances when ovaries are normal size Allows earlier stage detection

ColorColor-flow Doppler
Used in conjunction with TVUS Measures resistance in blood vessels supplying the ovaries May provide additional information to help distinguish malignant from benign masses

CACA-125
Sustained elevation in 82% of women with advanced ovarian cancer, but fewer than 1% of healthy women Poor sensitivity (elevated in only 50% of women with Stage I disease) Poor specificity (elevated in many gynecologic and non-gynecologic nonmalignancies as well as benign conditions)

CACA-125
Malignant conditions Cervical CA Fallopian tube CA Endometrial CA Pancreatic CA Colon CA Breast CA Lymphoma Mesothelioma
Benign conditions Endometriosis/Menses Uterine fibroids PID Pregnancy Diverticulitis Pancreatitis Liver disease Renal failure Appendicitis IBD

Lysophosphatidic acid (LPA)

Tumor marker being investigated for screening Phospholipid with mitogenic and growth factorfactorlike actions In 1 small study LPA was detected in 9 of 10 patients with Stage I ovarian CA, 24/24 with advanced cancer, and 14/14 with recurrent cancer. Only 28 of 47 pts had elevated CA-125, including CA2 of 9 with Stage I disease

Current Screening Guidelines

Routine screening for ovarian cancer by ultrasound, the measurement of serum tumor markers, or pelvic examination is not recommended. There is insufficient evidence to recommend for or against the screening of asymptomatic women at increased risk of developing ovarian cancer.
U.S.Preventive Services Taskforce, Guidelines from Guide to Clinical Preventive Services, 2nd edition, 1996

Screening Guidelines contd Guidelines

NIH Consensus Conference (1994)
women with presumed hereditary cancer syndrome should undergo annual pelvic exams, CA-125 CAmeasurements, and TVUS until childbearing is complete or at age 35, at which time prophylactic bilateral oopherectomy is recommended.

ACP
counsel high risk women about potential harms and benefits of screening

Screening, contd
American Cancer Society, AAFP and ACOG do not recommend screening for ovarian cancer in the general population Canadian Task Force on Periodic Health Examination
insufficient evidence to recommend for or against screening in high-risk women high-

Where do we go from here?

Several strategies for screening currently under investigation
TVUS as primary screening method Multimodal strategy using CA-125 as initial CAindicator and if elevated, TVUS used for secondary testing LPA (phospholipid with mitogenic and GF-like GFactions) may be more sensitive than CA-125 in CAdetecting early stage cancers

Ovarian Cancer Screening Trials

1. The United Kingdom Collaborative Trial of Ovarian Cancer Screening: will compare TVUS and multimodal screening to control 2. The European Study: RCT to screen women with TVUS at 18-month or 3-year intervals 1833. The NIH Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: 10-year study 10using multimodal strategy

Take home points

Screening not indicated at this time ASK about family history of cancers LISTEN when women present with nonnonspecific GI complaints; include OC in DDx DO perform careful bimanual exam and rectal exam as part of pelvic exam Refer women with + Family Hx to GynOnc

References
1. 2. 3. American Cancer Society. Guidelines for the cancer-related cancercheckup: and update. Atlanta: American Cancer Society, 1993. Daly M, Obrams GI. Epidemiology and risk assessment for ovarian cancer. Semin Oncol 1998;25(3):255-264 1998;25(3):255DePriest PD, Gallion HH, van Nagell JR Jr et al. Transvaginal sonography as a screening method for the detection of early ovarian cancer. Gynecol Oncol 1997;65(3):408-414 1997;65(3):408Hensley ML, Castiel M, Robson ME. Screening for ovarian cancer: what we know, what we need to know. Oncology (Huntingt) 2000;14(11):16012000;14(11):1601-1607 Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol 2000;19(1):3-10 2000;19(1):3Jacobs IJ, Skates SJ, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999;353(9160):1207-1210 1999;353(9160):1207-

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References, contd
7. Kurtz AB, Tsimikas JV, et al. Diagnosis and Staging of Ovarian Cancer: Comparative Values of Doppler and Conventional US, CT and MR Imaging Correlated with Surgery and Histopathologic AnalysisAnalysis-Report of the Radiology Diagnostic Oncology Group. Radiology 1999;212(1):19-27 1999;212(1):19NIH Consensus Development Conference Statement. Ovarian cancer: screening, treatment, and follow-up. Gynecol Oncol follow1994;55(3 Pt2):S4-14. Pt2):S4Paley P. Screening for the major malignancies affecting women: Current guidelines. Am J Obstet Gynecol 2001;184:1021-1030. 2001;184:1021Rollins G. Developments in Cervical and Ovarian Cancer Screening: Implications for Current Practice. Ann Int Med 2000;133: 1021-1024 1021-

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References, contd
11. 12. Ryan: Kistners Gynecology & Womens Health, 7th ed. Mosby, Inc., 1999. Tierney LM, McPhee SJ, Papadakis MA, editors. Current Medical Diagnosis and Treatment, 39th edition. Lange Medical Books/ McGrawMcGraw-Hill, 2000. Tingulstad S, Hagen B, et al. Evaluation of a risk of malignancy index based on serum CA125, ultrasound findings and menopausal status in the pre-operative diagnosis of pelvic masses. Br J Obstet preGynaecol 1996;103(8):826-831 1996;103(8):826U.S. Preventive Services Task Force, Guidelines from Guide to Clinical Preventive Services, (Second Edition) 1996. Zanotti K, Kennedy A. Screening for Gynecologic Cancer. Med Clin N Am 1999;83:

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