Gynecologic Cancer– Uterus, Ovary, and Cervix – the Role of the Cancer Registry: A Clinical Perspective

Gynecologic Cancer– Uterus, Ovary, and Cervix – the Role of the Cancer Registry: A Clinical Perspective Michael R. Milam, MD, MPH Assistant Professor Division of Gynecologic Oncology Department of Obstetrics, Gynecology, and Women’s Health University of Louisville Medical Center

Presentation Outline 1. Background of uterine cancer in the United States 2. Background of ovarian cancer in the United States 3. Background of cervical cancer in the United States 4. Kentucky Cancer Registry - Future directions in gynecologic cancer

Gynecologic Cancer: An Overview # of Cases New Cases Dead from Disease Cervix Vulvar/Vaginal Ovarian Uterine JemalA, Siegel R, XuJ, Ward E. Cancer statistics, 2010. CA Cancer J Clin;60:277-300.

Uterine Cancer- Staging • IA Tumor confined to the uterus, no or < ½ myometrial invasion • IB Tumor confined to the uterus, > ½ myometrial invasion • II Cervical stromal invasion, but not beyond uterus • IIIA Tumor invades serosa or adnexa • IIIB Vaginal and/or parametrial involvement • IIIC1 Pelvic node involvement • IIIC2 Para-aortic involvement • IVA Tumor invasion bladder and/or bowel mucosa • IVB Distant metastases including abdominal metastases and/or inguinal lymph nodes Uterine sarcomas were staged previously as endometrial cancers, which did not reflect clinical behavior. Therefore, a new corpus sarcoma staging system was developed based on the criteria used in other soft tissue sarcomas…This is described as a best guess staging system, so data will need to be collected and evaluated for further revision. http://www.medscape.com/viewarticle/722721

Uterine Cancer: Who’s Getting It? • Characteristic • Nulliparous • Obesity • > 30 pounds • > 50 pounds • Late Menopause • “Bloody” Menopause • Diabetes • Hypertension • Unopposed Estrogen • Complex Atypical Hyperplasia Relative Risk 2.0 3.0 10.0 2.4 4.0 2.8 1.5 9.5 29.0

Uterine Cancer: Disease Categories Feature Unopposed Estrogen Menopausal Status Hyperplasia ? Race Grade Myometrial Invasion Histology Clinical Behavior Type I Present Pre - or Peri- Present White Low Minimal Secretory, Endometrioid Stable Type II Absent Post Absent Black High Deep Adenosquamous Serous, Clear Cell Progress

Minimally Invasive Procedures Insufflation sites Laparoscope 10/12 mm trocar 5 mm trocar 5 mm trocar 10/12 mm trocar

GOG LAP-2 Protocol LAVH/BSO + pelvic & para-aortic LND R A N D O M I Z E Endometrial adenocarcinoma or uterine sarcoma Clinical stage I, IIA Grade 1, 2, 3 TAH/BSO + pelvic & para-aortic LND

GOG LAP-2 • N = 1434 enrolled • 109 of 957 (11.3%) converted (laparotomy) • Poor exposure • Technical difficulty • Equipment failure • Bleeding • Rare intraoperative or postoperative complications • 3% vascular injuries • 14 PE’s • 74 Deaths • 32 cancer-related • 9 treatment related • 6 PE

Is There A Role for Lymphadenectomy? • ASTEC • Phase III • Early stage • preop • CONSORT (n = 537) • Phase III • Early stage • Preop: clinical stage I • Intraop: myometrial invasion and adenocarcinoma • Excluded stage IB G1 • Age ≤ 75 • 10/96 – 3/06

Mayo Criteria 1) Grade 1-2 2) DOI ≤ 50% 3) Tumor Size ≤ 2 cm Frozen & Final Pathology Methods MMC – GOG study 1) Grade 1-2 2) DOI < 50% 3) Tumor Size < 2 cm Final Pathology Only Must have all 3 criteria to be considered low risk for lymph node metastasis Incidence of Nodal Metastasis in Endometrioid Endometrial Cancer Risk Groups: A Gynecologic Oncology Group Multicenter Review. Milam MR, Java J, Walker JL, Metzinger DS, Parker LP, Coleman RL. 42nd Annual Meeting of the Society of Gynecologic Oncologists, Orlando, FL March 2011.

Consort Diagram Incidence of Nodal Metastasis in Endometrioid Endometrial Cancer Risk Groups: A Gynecologic Oncology Group Multicenter Review. Milam MR, Java J, Walker JL, Metzinger DS, Parker LP, Coleman RL. 42nd Annual Meeting of the Society of Gynecologic Oncologists, Orlando, FL March 2011.

Table 3: Patient Characteristics by Presence of Nodal Metastasis *Numbers after percents are frequencies.

Table 4: Nodal Metastasis by Risk-Group Membership * Significance accepted when P<0.05 Incidence of Nodal Metastasis in Endometrioid Endometrial Cancer Risk Groups: A Gynecologic Oncology Group Multicenter Review. Milam MR, Java J, Walker JL, Metzinger DS, Parker LP, Coleman RL. 42nd Annual Meeting of the Society of Gynecologic Oncologists, Orlando, FL March 2011.

Ovarian Cancer Staging • Stage I - limited to one or both ovaries • IA - involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings • IB - involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings • IC - tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings • Stage II - pelvic extension or implants • IIA - extension or implants onto uterus or fallopian tube; negative washings • IIB - extension or implants onto other pelvic structures; negative washings • IIC - pelvic extension or implants with positive peritoneal washings • Stage III - microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum • IIIA - microscopic peritoneal metastases beyond pelvis • IIIB - macroscopic peritoneal metastases beyond pelvis less than 2 cm in size • IIIC - peritoneal metastases beyond pelvis > 2 cm or lymph node metastases • Stage IV - distant metastases to the liver or outside the peritoneal cavity http://en.wikipedia.org/wiki/Ovarian_cancer

BRCA 1 or 2 carrier Female relative with ovarian cancer Older age (>70) Infertility Nulligravida Obesity Early menarche / late menopause Early parity/breastfeeding Prior hysterectomy / BTL Prior OCP use Ovarian Cancer Estimated Risk Risk Factor Estimated Relative Risk

Ovarian Cancer: Scope of Problem • Estimated incidence and mortality in theUS (2009)1 • 21,550 new cases • 14,600 deaths • Stage III/IV: 70-75% • Most recur: PFS: 10-26 mos • 5-yr survival: 44% overall2 1. ACS Cancer Facts and Figures, 2009 2. Hoskins P, et al. J Clin Oncol. 1998;16:2233. Huang, Cancer 112:2289, 2008

Ovarian Tumor Origin • The majority of tumors derive from epithelial cells on the ovary surface • New data to support fallopian tube origin particularly in Type I cancers • Incessant ovulation • Sex steroid driven malignant transformation • Mullerian hypothesis: HOX and others (PI3K, MAPK, P53)

Ovarian Cancer Stats

Ovarian Carcinoma Screening Assumptions YES YES ? NO NO

Screening for Ovarian Cancer Physical Exam Family Hx Biomarkers Ultrasound TVS Serial Risk Assessment (ROC) CA-125, Ultrasound Healthy Women ≤ 50 years R “Routine Care”

Symptoms as an Early Detection Tool for Ovarian Carcinoma: Odds Ratio *Frequency >12 times/month. CI=confidence interval. Goff. Cancer. 2007;109:221.

CA-125: Poor Screening Performance

TV-US: Morphology Indexing • Cystadenocarcinoma • More challenging in younger age menstruating women • TV-US alone in low prevalent populations associated with high rates of unnecessary surgery

Ovarian Cancer Staging: Surgery • Vertical skin incision • Cytologic washings • Intact tumor removal • Complete abdominal exploration • Aggressive cytoreduction • Omentectomy • Lymphatic evaluation • Liberal peritoneal biopsies

First-line Therapy: Standard Treatment Options

Primary Cytoreduction • Meta-analysis: 53 studies (1989-98) • 81 cohorts (Stage III/IV) • N = 6885 patients • Results • Expert centers have high optimal rates • Optimal vs. not: 11 mos (50% increase) • Each 10%  in cytoreduction = 5.5%  in survival • Platinum intensity = NS Bristow, J Clin Oncol 20:1248, 2002

Chemotherapy Principle Approach: Iº Therapy - - - Paclitaxel/Cisplatin Cytoxan/Cisplatin OS PFS McGuire New Engl J Med (1996) 334:1 Ozols, J ClinOncol (2003) 21:3194 Armstrong New Engl J Med (2006) 354:34

Carcinoma of the Cervix • IA1 Confined to the cervix, diagnosed only by microscopy with invasion of < 3 mm in depth and lateral spread < 7 mm • IA2 Confined to the cervix, diagnosed with microscopy with invasion of > 3 mm and < 5 mm with lateral spread < 7mm • IB1 Clinically visible lesion or greater than A2, < 4 cm in greatest dimension • IB2 Clinically visible lesion, > 4 cm in greatest dimension • IIA1 Involvement of the upper two-thirds of the vagina, without parametrial invasion, < 4 cm in greatest dimension • IIA2 > 4 cm in greatest dimension • IIB With parametrial involvement • IIIA/B Unchanged • IVA/B Unchanged http://www.medscape.com/viewarticle/722721

Cervical Cancer • Worldwide second most common cause of cancer-related deaths among women • 500,000 cases and 280,000 deaths in 2006 • United States • 11,150 cases and 3,670 deaths in 2007 • 10 women die each day from cervical cancer World Health Organization, Jemal A, et al. CA Cancer J Clin 2007. Slomovitz, BM Cervical Cancer Background , 2008 SGO presentation , Tampa, FL

Cervical Cancer: Worldwide Prevalence, Incidence, and Mortality Estimates World Health Organization. Geneva, Switzerland; 2003:1–74. Slomovitz, BM Cervical Cancer Background , 2008 SGO presentation , Tampa, FL

Cervical Cancer Courtesy of Thomas C. Wright, Columbia University. Slomovitz, BM Cervical Cancer Background , 2008 SGO presentation , Tampa, FL

Decreasing Trends of Cervical Cancer Incidence in the U.S. • With the advent of the Pap smear, the incidence of cervical cancer has dramatically declined. • The curve has been stable for the past decade because we are not reaching the unscreened population. Reprinted by permission of the American Cancer Society, Inc. Slomovitz, BM Cervical Cancer Background , 2008 SGO presentation , Tampa, FL

Cervical Cancer: US Trends in Incidence and Mortality National Cancer Institute. Bethesda, Md: National Cancer Institute; 2004. American Cancer Society. Atlanta, Ga: American Cancer Society; 2003:1–48. Slomovitz, BM Cervical Cancer Background , 2008 SGO presentation , Tampa, FL

Regions in US with High Cervical Cancer IncidenceCancer Mortality Rates by County (Age-adjusted 1970 U.S. Population)Cervix Uteri: All Races, Females, 1970-1989 Slomovitz, BM Cervical Cancer Background , 2008 SGO presentation , Tampa, FL

Relationship Between HPV and Cervical Cancer Lowy et al.,J. Clin. Invest. 116:1167-1173 (2006). Slomovitz, BM Cervical Cancer Background , 2008 SGO presentation , Tampa, FL

Kentucky Cancer Registry:The population-based central cancer registry for the Commonwealth of Kentucky http://www.kcr.uky.edu/

Female Genital System, 2004-2008 http://cancer-rates.info/ky/index.php

Corpus Uteri, 2004-2008 http://cancer-rates.info/ky/index.php

Email Trail…. Dr. Tucker - My name is Michael Milam and I am a faculty member at the University of Louisville. I had a meeting with ReitaPardee and she recommended speaking with you regarding a joint project with the KCR and the University of Louisville…

Abstract to be submitted to national meeting – Society of Gynecologic Oncology Overtreatment in Early Stage Low Risk Endometrial Cancer is Associated with Increased Mortality: A Statewide Cancer Registry Analysis Michael R. Milam1, Bin Huang2, 3, Lynn P. Parker1, Dan Metzinger1, Thomas Tucker3 1Division of Gynecologic Oncology, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky 2.Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, Kentucky .3Kentucky Cancer Registry, Markey Cancer Center, University of Kentucky, Lexington, Kentucky

Overtreatment in Early Stage Low Risk Endometrial Cancer is Associated with Increased Mortality: A Statewide Cancer Registry Analysis Objective: National Comprehensive Cancer Network (NCCN) guidelines state that patients with early stage low risk endometrial cancer (defined with 2009 criteria as stage IA endometrioid endometrial cancer) may be managed with observation with consideration of adjuvant therapy. The premise of this study is to review the patterns of care of those patients who received adjuvant therapy and its impact on survival.

Gynecologic Cancer– Uterus, Ovary, and Cervix – the Role of the Cancer Registry: A Clinical Perspective