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Ovarian Cancer: Diagnosis and Screening in Primary Care

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Ovarian Cancer: Diagnosis and Screening in Primary Care

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    1. Ovarian Cancer: Diagnosis and Screening in Primary Care Elise M. Hughes-Watkins, M.D. November 30, 2001

    2. 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% The “silent killer”: asymptomatic in early stages 75% diagnosed with advanced stage disease; 5-year survival only 10-28% Woman’s lifetime risk of dying from ovarian cancer is 1.1%

    3. Cancer Incidence and Deaths in U.S.Women in 2000 Adapted from Paley,P, Screening for the major malignancies affecting women: Current guidelines. Am J Obstet Gynecol 2001;184:

    4. Types of Ovarian Tumors Functional Follicle cyst Corpus luteum cyst Theca lutein cyst Inflammatory Tubo-ovarian abscess Benign tumors/cysts* Endometriotic cyst Brenner tumor Benign teratoma (dermoid cyst) Fibroma *Rare or very rare potential for malignancy Malignant (or malignant potential) Malignant teratoma Endometrioid carcinoma Dygerminoma Secondary ovarian tumor Cystadenoma, cystadenocarcinoma (>50% for serous, ~5% for mucinous) Granulosa cell tumor (15-20%) Arrhenoblastoma (<20%) Theca cell tumor (<1%)

    5. Epithelial Ovarian Cancer Overall 5-year survival rate is 75-95% if cancer confined to ovaries; decreases to 10-17% if distant metastases Survival improved when cancer detected in early stage Only 25% diagnosed in Stage I

    6. 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

    7. The challenge Natural history of ovarian cancer not well understood No well-defined precursor lesion Length of time from localized tumor to dissemination is unknown Multiple efforts underway to develop effective screening method for early detection

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

    9. Risk factors: Heredity Up to 10% of epithelial ovarian cancer cases are familial 3 familial syndromes: familial breast-ovarian cancer syndrome, site-specific ovarian cancer, and cancer family syndrome (Lynch type II) Familial breast-ovarian cancer and site-specific ovarian 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

    10. 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 late menopause Fertility drugs prolonged use of Clomid, especially without achieving pregnancy 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 Half of all ovarian cancers are diagnosed in women > 65yoHalf of all ovarian cancers are diagnosed in women > 65yo

    11. 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

    12. 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

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

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

    15. Diagnostic approach If premenopausal and asymptomatic, with unilateral, mobile, simple cystic mass <8-10cm and no family history, can observe for 4-6 weeks and then repeat TVUS and pelvic exam. If resolved, no further work-up necessary If larger or unchanged, or if character of mass has changed on TVUS, surgical evaluation required

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

    17. Surgical Evaluation Refer to Gyn-Onc specialist 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

    18. 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

    19. Stages Ia, Ib, Ic Stage I: confined to ovary or ovaries IA: unilateral, capsule intact, no tumor on ext surface. No ascites. IB: bilateral, same as above IC: 1 or both ovaries with ruptured capsule, surface tumor, + ascites or + peritoneal washingStage I: confined to ovary or ovaries IA: unilateral, capsule intact, no tumor on ext surface. No ascites. IB: bilateral, same as above IC: 1 or both ovaries with ruptured capsule, surface tumor, + ascites or + peritoneal washing

    20. Stages IIa, IIb, IIc Stage II: Pelvic extension IIA: involvement of uterus or fallopian tubes, (-) peritoneal washings IIB: involvement of other pelvic tissues (bladder, sigmoid colon, rectum), (-) peritoneal washings IIC: IIA or IIB with ruptured capsule, surface tumor, + peritoneal washings or ascitesStage II: Pelvic extension IIA: involvement of uterus or fallopian tubes, (-) peritoneal washings IIB: involvement of other pelvic tissues (bladder, sigmoid colon, rectum), (-) peritoneal washings IIC: IIA or IIB with ruptured capsule, surface tumor, + peritoneal washings or ascites

    21. Stages IIIa, IIIb, IIIc Stage III: Peritoneal implants outside pelvis or + retroperitoneal or inguinal LN IIIA: grossly limited to true pelvis with microscopic seeding of abdom peritoneum IIIB: Implants on abdom peritoneum < or = 2cm diam IIIC: Implants on abdom peritoneum > 2cm or + retroperitoneal or inguinal LNStage III: Peritoneal implants outside pelvis or + retroperitoneal or inguinal LN IIIA: grossly limited to true pelvis with microscopic seeding of abdom peritoneum IIIB: Implants on abdom peritoneum < or = 2cm diam IIIC: Implants on abdom peritoneum > 2cm or + retroperitoneal or inguinal LN

    22. Stage IV Stage IV: distant mets (liver, lungs), + pleural fluidStage IV: distant mets (liver, lungs), + pleural fluid

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

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

    25. Chemotherapy and Radiation Usually 6 cycles of chemotherapy Cisplatin (or Carboplatin) plus Paclitaxel most commonly used combination therapy XRT

    26. Screening Strategies Ultrasound (transvaginal vs transabdominal) Color-flow doppler CA-125 Other tumor markers

    27. 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

    28. Color-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

    29. CA-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 malignancies as well as benign conditions) CA-125 elevated in: Malignant conditions Ovarian CA of various types Cervical CA Fallopian tube CA Endometrial CA Pancreatic CA Colon CA Breast CA Lymphoma Mesothelioma Benign conditions: Endometriosis Uterine fibroids PID Pregnancy Diverticulitis Pancreatitis Liver disease Renal failure Menstruation Appendicitis Inflammatory bowel disease CA-125 elevated in: Malignant conditions Ovarian CA of various types Cervical CA Fallopian tube CA Endometrial CA Pancreatic CA Colon CA Breast CA Lymphoma Mesothelioma Benign conditions: Endometriosis Uterine fibroids PID Pregnancy Diverticulitis Pancreatitis Liver disease Renal failure Menstruation Appendicitis Inflammatory bowel disease

    30. CA-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

    31. Lysophosphatidic acid (LPA) Tumor marker being investigated for screening Phospholipid with mitogenic and growth factor-like 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 2 of 9 with Stage I disease

    32. 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

    33. Screening Guidelines– cont’d NIH Consensus Conference (1994) women with presumed hereditary cancer syndrome should undergo annual pelvic exams, CA-125 measurements, 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

    34. Screening, cont’d 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”

    35. 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 indicator and if elevated, TVUS used for secondary testing LPA (phospholipid with mitogenic and GF-like actions) may be more sensitive than CA-125 in detecting early stage cancers

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

    37. Take home points Screening not indicated at this time ASK about family history of cancers LISTEN when women present with non-specific 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

    38. References American Cancer Society. Guidelines for the cancer-related checkup: 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 DePriest 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 Hensley ML, Castiel M, Robson ME. Screening for ovarian cancer: what we know, what we need to know. Oncology (Huntingt) 2000;14(11):1601-1607 Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol 2000;19(1):3-10 6. Jacobs IJ, Skates SJ, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999;353(9160):1207-1210

    39. References, cont’d 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 Analysis-Report of the Radiology Diagnostic Oncology Group. Radiology 1999;212(1):19-27 NIH Consensus Development Conference Statement. Ovarian cancer: screening, treatment, and follow-up. Gynecol Oncol 1994;55(3 Pt2):S4-14. Paley P. Screening for the major malignancies affecting women: Current guidelines. Am J Obstet Gynecol 2001;184:1021-1030. 10. Rollins G. Developments in Cervical and Ovarian Cancer Screening: Implications for Current Practice. Ann Int Med 2000;133: 1021-1024

    40. References, cont’d 11. Ryan: Kistner’s Gynecology & Women’s Health, 7th ed. Mosby, Inc., 1999. 12. Tierney LM, McPhee SJ, Papadakis MA, editors. Current Medical Diagnosis and Treatment, 39th edition. Lange Medical Books/ McGraw-Hill, 2000. 13. 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 Gynaecol 1996;103(8):826-831 U.S. Preventive Services Task Force, Guidelines from Guide to Clinical Preventive Services, (Second Edition) 1996. 15. Zanotti K, Kennedy A. Screening for Gynecologic Cancer. Med Clin N Am 1999;83:

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