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Identifying Ovarian Tumors at High Risk for Ovarian Cancer

Identifying Ovarian Tumors at High Risk for Ovarian Cancer. Frederick R. Ueland, M.D. Associate Professor Gynecologic Oncology Vice Chairman, Department of Obstetrics and Gynecology University of Kentucky Markey Cancer Center. Ovarian Cancer Epidemiology.

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Identifying Ovarian Tumors at High Risk for Ovarian Cancer

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  1. Identifying Ovarian Tumors at High Risk for Ovarian Cancer Frederick R. Ueland, M.D. Associate Professor Gynecologic Oncology Vice Chairman, Department of Obstetrics and Gynecology University of Kentucky Markey Cancer Center

  2. Ovarian CancerEpidemiology • Fifth leading cause of female cancer death in the United States • Approximately 21,500 new cases of ovarian cancer and 14,600 deaths in 2009 • Median age at diagnosis: 63 years • Incidence: 13.1 per 100,000 women • Prevalence: 176,000 women alive with a history of ovarian cancer (2006) • Lifetime risk: 1/71 (1.4%) American Cancer Society, 2007 Surveillance, Epidemiology, and End Results (SEER) Program: National Cancer Institute, 2008

  3. Cancer Incidence Rates 1975-2003 Colon and rectum Ovary Uterine Corpus Rate Per 100,000 Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006

  4. Cancer Mortality Rates1930-2003 Colon & rectum Stomach Uterus Ovary Rate Per 100,000 Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2003, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006

  5. Background • Advanced stage presentation common (70%) • Poor prognosis (50% 5-year survival) • Slowly improving outcomes • Annual mortality change: –1.4% (2002-2006) • Treatment • Comprehensive surgical staging for early disease • Cytoreduction for advanced disease • Combination chemotherapy • Clinical trials American Cancer Society: Facts & Figures, 2009. Atlanta. www. Cancer.org Hoskins WJ, Perez CA, Young RC, eds. Principles and practice of Gynecologic Oncology, 4th ed. Philadelphia: Lippincott Williams & Wilkins: 919-922, 2006

  6. Stage and Outcome American Cancer Society

  7. Ovarian Cancer Symptoms • Symptom awareness • 95% report symptoms prior to diagnosis • > 12 times monthly • Pelvic and abdominal pain (77%) • Bloating, early satiety, GI symptoms (70%) • Pelvic (26%) and urinary symptoms (34%) • Physician evaluation • Avoid diagnostic delay • Examination, imaging, laboratory testing as indicated • Sensitivity • 57% for early stage • 80% for advanced stage • Specificity • 90% if > 50yo • 86% for premenopausal women Goff B, et al. JAMA. 291:2705-12:2068-75, 2004 Olson S, et al. Obstet Gynecol. 98:212-7, 2001

  8. Challenge of Ovarian Tumors • There are 155 million women in United States • ~125 million women 13 years of age or older • 90 million are between 13 and 50 years of age • 30 million are over age 50 • 40 million women are Baby Boomers (age 41-59) • How common are ovarian tumors? • Premenopausal women • 14% annual incidence (13 million) • 30% prevalence (27 million) • Postmenopausal women • 5% annual incidence (1.5 million) • 16% prevalence (5 million) • 30% of unilocular and 45% of complex tumors typically persist • Annually, there are tens of millions of ovarian cystic tumors, but only 22,000 ovarian cancers diagnosed United States Census Bureau, 2008 Data from University of Kentucky Ovarian Cancer Screening Program, 2009 (N=27,000)

  9. Ovarian TumorsPremenopausal Women • 15% of ovarian neoplasms in premenopausal women are malignant • Non-inflammatory ovarian tumors • 70% functional cysts • 20% neoplastic • 10% endometriomas • Other • Inflammatory process, bowel

  10. Ovarian TumorsPostmenopausal Women • 50% of ovarian neoplasms in postmenopausal women are malignant • Benign epithelial tumor • Stromal tumor • Granulosa cell • Fibroma • Thecoma • Epithelial ovarian cancer • Metastatic cancer

  11. Guidelines and Algorithms • NIH Consensus Statement, 1994 • “Women with ovarian masses identified preoperatively having a significant risk of cancer should be given the option of surgery performed by a gynecologic oncologist” • Clinical algorithms • Examination, imaging, patient history, and laboratory tests • Infrequently utilized, not standardized • Challenging to evaluate

  12. Biopsy of Ovarian Tumors • Percutaneous FNA cytology of cystic ovarian tumors has low cancer sensitivity, ranging from 25% to 82% • Approximately 25-50% of ovarian cystic tumors aspirated in perimenopausal women will recur within 1 year • Aspiration of a malignant cystic tumor may disseminate the cancer, increase the stage and worsen the prognosis ACOG Practice Bulletin no 83, 2006. Mizuno M, et al. Oncology. 65:29, 2003 Sainz de la Cuesta R, et al. Obstet Gyn. 84:1, 1994

  13. Evaluation • Physical examination • Pelvic, abdominal, and lymph node survey • Imaging study • Transvaginal ultrasonography • CT scan • CA-125 • Not FDA-approved as a diagnostic test • Low sensitivity and specificity

  14. Pelvic ExaminationDetecting Ovarian Tumors • Ovarian detection on pelvic examination is infrequent in women ≥ 55 years old (30%) • Ovarian detection is exceedingly difficult in women weighing at least 200 lb (9%) • A large uterus (weight ≥ 200 g) makes ovarian palpation unlikely (16%) Ueland et al. Gyn Oncol, 2005

  15. Pelvic Exam vs. Ultrasound Ueland et al. Gyn Oncol, 2005

  16. Unilateral Simple, unilocular Septated (MI < 5) No ascites Resolution Bilateral Complex (MI ≥ 5) Solid wall abnormalities Internal papillations Ascites Persistence or growth Sonographic CharacteristicsOvarian Tumors Benign Malignant

  17. Ovarian Tumor Imaging Spanos W. Am J Obstet Gynecol, 1973

  18. Ovarian Tumor Imaging Modesitt et al, Gyn Oncol, 2003

  19. Kentucky Morphology IndexMI Score = 6 Ascites Ueland et al. Gyn Oncol, 2003

  20. Kentucky Morphology IndexHigh Risk Score (5-10) 92 83 77 38 32 20 Ueland et al. Gyn Oncol, 2003

  21. Morphology IndexPredicting Malignancy • Sensitivity 0.98 • Specificity 0.81 • Positive predictive value 0.41 • Negative predictive value 0.99 • Accuracy 0.83 Ueland et al. Gyn Oncol, 2003

  22. Ovarian Tumor Ultrasound Definition of (+) US varied with each author

  23. CA-125 • Antigen derived from: • coelomic epithelium (pericardium, pleura, peritoneum) • mullerian epithelium (tubal, endometrial, endocervical) • Two different assays • Assay I < 35 U/ml • Assay II < 20 U/ml • Expressed by 80% non-mucinous EOC • FDA-approved to monitor cancer treatment • Neither a screening nor a diagnostic test • False negative CA-125 values (low sensitivity) • 50% of early stage ovarian cancers • 20-25% of advanced stage ovarian cancers • Mixed mullerian tumors, clear cell cancers

  24. Benign ovarian cysts Uterine leiomyomata Pelvic inflammatory disease Endometriosis Adenomyosis Pregnancy Menstruation Ascites Heart failure Liver failure Renal failure Peritoneal tuberculosis Diverticulitis Pancreatitis Recent abdominal or thoracic surgery Other malignancies CA-125Non-specific

  25. Role Surgery • Proper staging for early disease • Determine adjuvant therapy • Cytoreduction for advanced disease • Radical surgery as indicated • “Optimal” ≤ 1cm • Reassessment laparotomy • Secondary debulking

  26. Staging by Specialty • Women with early stage ovarian cancer • 291 subjects • Complete surgical staging performed: • 97% gynecologic oncologists • 52% general obstetrician/gynecologists • 35% general surgeons McGowan L, et al. Obstet Gynecol;65:568-72, 1985

  27. Surgical CytoreductionAdvanced Stage Ovarian Cancer Slide courtesy of Gynecologic Cancer Foundation

  28. Surgical CytoreductionAdvanced Stage Ovarian Cancer • Meta-analysis of 53 studies • 6,885 stage III/IV patients • Cytoreduction • High volume centers have higher rates of “optimal” surgery • “Optimal” improved survival by 11 months (50% increase) • Each 10% increment in cytoreduction = 5.5% improvement in survival Median Survival (months) % Cytoreduction Bristow, J Clin Oncol 20:1248, 2002

  29. Improved Survival • Utah Cancer Registry • 848 new ovarian cancers, 1992-1998 • Only 39% were ever seen by a gyn onc • Patients with advanced disease had significant survival advantage when managed by gynecologic oncologist • median survival 26 mo vs. 15 mo, p < 0.01 Carney ME, et al. Gynecol Oncol;84:36-42, 2002

  30. Improved Survival • Medicare claims by physician specialty • SEER database • 65 years or older • 3067 surgeries for ovarian cancer • Only 33% of patients with ovarian cancer were treated by gynecologic oncologist • Improved outcomes and overall survival when managed by gynecologic oncologist Earle C.C, et al. JNCI 98:3, 2006

  31. Value of Specialists • Meta-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

  32. NCCN Guidelines • Cytoreductive surgery • all patients with stage II, III or IV ovarian cancer • “optimal” cytoreduction (no residual disease > 1 cm) • Gynecologic oncologist • perform the initial surgical procedure • Improved overall survival • Category I recommendation • Combination adjuvant chemotherapy • Most patients (>70%) relapse after 1st line therapy • Clinical trials NCCN Clinical Practice Guidelines in Oncology, 2008 Ozols et al. J Clin Oncol. 21: 3194-3200, 2003

  33. Ovarian Cancer Dilemma • Ovarian tumors are very common, particularly in young women • Women with benign tumors prefer to have their surgery close to home with their established gynecologist • Women with ovarian cancer are best managed by a gynecologic oncologist • Current methods are unreliable in differentiating benign from malignant ovarian tumors, particularly in young women and early stage disease

  34. ACOG Referral Guidelines Premenopausal Women Postmenopausal Women • CA125 >200 U/mL • Ascites • Evidence of abdominal or distant metastases • Family history one or more first-degree relatives with ovarian or breast cancer • CA125 >35 U/mL • Nodular or fixed mass • Ascites • Evidence of abdominal or distant metastases • Family history one or more first-degree relatives with ovarian or breast cancer

  35. Validation of Guidelines • Im, 2005 • Chart review with 7 tertiary centers: 1035 patients • 95% had imaging, 68% had preop CA-125, 24% had both • “SGO and ACOG referral guidelines effectively separate women with pelvic masses into two risk categories for malignancy” • Dearking, 2007 • Prospective, single-institutional trial: 837 patients • Guidelines performed well in predicting advanced-stage disease, but “poorly” in early-stage disease, and premenopausal women • Recommended modifications: • CA-125 <67 U/mL (pre), exclude FH of breast, ovarian cancer

  36. A Multi-institutional Evaluation of ACOG and SGO Referral Guidelines for an Ovarian Mass Rachel Ware, Alan Smith, Chris Desimone, Leigh Seamon, Scott Goodrich, Iwona Podzielinski, Lori Sokoll, Joseph Santoso, J.R. van Nagell Jr., Zhen Zhang, Frederick Ueland. Presented at the Society of Gynecologic Oncology Annual Meeting, 2010

  37. Results

  38. ACOG Results

  39. ACOG Results

  40. FDA NEWS RELEASE For Immediate Release: Sept. 11, 2009 Media Inquiries: Peper Long, 301-796-4671, mary.long@fda.hhs.govConsumer Inquiries: 888-INFO-FDA FDA Clears a Test for Ovarian CancerTest can help identify potential malignancies, guide surgical decisions The U.S. Food and Drug Administration today cleared a test that can help detect ovarian cancer in a pelvic mass that is already known to require surgery. The test, called OVA1, helps patients and health care professionals decide what type of surgery should be done and by whom.

  41. The OVA1 Test • Biomarker panel • CA125, transthyretin (prealbumin), apolipoprotein A1, beta 2 microglobulin, transferrin • OvaCalc software algorithm • OVA1 risk index, range 0-10

  42. OVA1 Indications • Known pelvic mass or ovarian tumor • Complete physician assessment • Examination, imaging, history, labs • Decision for surgery • OVA1 • Low risk OVA1 reassuring • High risk OVA1 referred to gyn oncologist

  43. The OVA1 Test Improves the Preoperative Assessment of Ovarian Tumors Frederick Ueland, Chris Desimone, Leigh Seamon, Rachel Ware, Scott Goodrich, Iwona Podzielinski, Lori Sokoll, Alan Smith, Joseph Santoso, J.R. van Nagell Jr., Zhen Zhang. Presented at the Society of Gynecologic Oncology Annual Meeting, 2010

  44. Methods • 27 primary care, specialty sites throughout U.S. • Preoperative evaluation • imaging to confirm ovarian tumor • serum collection for CA125 • physician assessment (Is it malignant? “yes or no”) • Centralized assay at Quest Diagnostics • Validation assays • Johns Hopkins Biomarker Discovery Center • Specialty Laboratories • Independent data analysis • Applied Clinical Intelligence

  45. OVA1 Trial

  46. OVA1 Test Alone

  47. OVA1 Sensitivity Tumor subtype Cancer stage

  48. OVA1 Results

  49. OVA1 Results

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