1. Gynecologic Oncology- The Times They Are A’Changin Ronald D. Alvarez, MD University of Alabama at Birmingham Division of Gynecologic Oncology Gynecologic Oncology- The Times They Are A’Changin Ronald D. Alvarez, MD University of Alabama at Birmingham Division of Gynecologic Oncology

2. Disclosures Grant support Grant support –Morphoteck –Pfizer –Merrimack

3. Florida Society of Gynecologic Oncology Organized 1993 Organized 1993 Founders meeting 1994 (Holloway,Chair) Founders meeting 1994 (Holloway,Chair) Invited speaker at 1 st, and 10 th meetings (one with a hurricane) Invited speaker at 1 st, and 10 th meetings (one with a hurricane) Invited for 19 th meeting (Penalver, Chair) Invited for 19 th meeting (Penalver, Chair) Many longterm connections and friends Many longterm connections and friends

4. Lecture Outline Thoughts on change Thoughts on change Changes in gynecologic oncology Changes in gynecologic oncology Drivers of change Drivers of change Adapting to change Adapting to change

5. Lecture Outline Thoughts on change Thoughts on change Changes in gynecologic oncology Changes in gynecologic oncology Drivers of change Drivers of change Adapting to change Adapting to change

6. There is nothing permanent except change. - Heraclitus, c. 500 BC

7. Rapid Pace of Change Agricultural revolution 8000 yrs Agricultural revolution 8000 yrs Industrial revolution 120 yrs Industrial revolution 120 yrs Light bulb 90 yrs Light bulb 90 yrs Moon landing 22 yrs Moon landing 22 yrs World wide web 9 yrs World wide web 9 yrs Human genome sequenced Human genome sequenced

8. Principles of Transformational Change Something old passes away Something old passes away Something new comes to be Something new comes to be Something stays the same Something stays the same Aristotle, 350 BC

9. Why Is Change So Threatening? We all have a worldview We all have a worldview It is shaped by beliefs, values, experience It is shaped by beliefs, values, experience Change often challenges and misaligns our worldview Change often challenges and misaligns our worldview

10. How Is Change Best Implemented? Positive vision of abundance Positive vision of abundance Create a readiness for change Create a readiness for change Implement small changes that stakeholders can own Implement small changes that stakeholders can own Help stakeholders change worldview Help stakeholders change worldview Win WIN Win

11. Lecture Outline Thoughts on change Thoughts on change Changes in gynecologic oncology Changes in gynecologic oncology Drivers of change Drivers of change Adapting to change Adapting to change

12. Personal Perspective Born – 1957 Born – 1957 High school – 1975 High school – 1975 College and married – 1979 College and married – 1979 Medical school – 1983 Medical school – 1983 Children -1984, 1987, 1992 Children -1984, 1987, 1992 Residency -1987 Residency -1987 Fellowship -1990 Fellowship -1990 Division Director – 2003 Division Director – 2003 First grandchild, SGO President - 2012 First grandchild, SGO President - 2012

13. US Gynecologic Cancer Statistics New CasesDeaths 1987201219872012 Ovary19,00022,28011,70015,550 Uterine 35,00047,1302,9008,010 Cervix12,80012,1706,8004,220 VulvaNR4,490NR950 VaginaNR2,680NR840

14. Ovarian Cancer - 1987 Risk groups not identified Risk groups not identified Known as the “silent” cancer Known as the “silent” cancer Surgical debulking often suboptimal Surgical debulking often suboptimal Limited chemotherapy options Limited chemotherapy options Short median survival Short median survival

15. Science, 1990 ● Evaluated 23 families with 146 cases of breast cancer using linkage analysis ● Identified that a gene for early onset breast cancer to be located near D17S74 ● Isolated by Miki et al in 1994 Science paper

16. Hereditary Ovarian Cancer – Beyond the Usual Suspects Swisher, 2012

17. Screening for Ovarian Cancer PLCO Trial (Partridge et al, 2009) PLCO Trial (Partridge et al, 2009) –Evaluated annual CA125 and TVU vs. observation in general population –20:1 surgery:cancer ratio –Most late stage/no reduction in mortality UKCTOCS UKCTOCS –Evaluating yearly CA125 vs. yearly TVU vs. observation in general population –Results due 2014

18. Ovarian Pap Gene Test Used massively parallel sequencing to assess DNA from liquid Pap smear samples from 24 ovarian and 22 endometrial cancer patients Used massively parallel sequencing to assess DNA from liquid Pap smear samples from 24 ovarian and 22 endometrial cancer patients Mutations detected in 100% of endometrial cancers and 41% of ovarian cancers Mutations detected in 100% of endometrial cancers and 41% of ovarian cancers Kinde et al. Sci Transl Med, 2013

19. Ovarian Cancer is not a “Silent” Cancer Symptoms Symptoms –Bloating –Pelvic or abdominal pain –Difficulty eating or feeling full quickly –Urinary symptoms (urgency or frequency) Workup – Pelvic exam, sonar, CA125 Workup – Pelvic exam, sonar, CA125

20. Achieving Maximum Debulking in Ovarian Cancer Debulking TAH BSO Debulking TAH BSO Omentectomy Omentectomy Colon resection Colon resection Small bowel resection Small bowel resection Splenectomy Splenectomy Hepatic resection Hepatic resection Diaphragm stripping Diaphragm stripping Peritoneal stripping Peritoneal stripping

21. The Role of Neoadjuvant Chemotherapy in Advanced Ovarian Cancer EORTC 55971 From 1998-2006, 718 randomized between PDS vs. neoadjuvant chemo with IDS after 3 cycles Only 46% optimal in PDS arm Not all patients treated with taxane Morbidity and mortality higher in the PDS arm

22. New Chemotherapy Approaches in Ovarian Cancer Taxane based regimens Taxane based regimens Intraperitoneal chemotherapy Intraperitoneal chemotherapy Dose dense taxanes Dose dense taxanes Consolidation chemotherapy Consolidation chemotherapy Anti-angiogenic therapy Anti-angiogenic therapy PARP inhibitors PARP inhibitors

23. TCGA Project – Molecular Characterization of HGSC CGARN, Nature 2011

24. PACLITAXEL CISPLATIN AGGRESSIVE SURGERY, COMBINATION CHEMOTHERAPY Survival (mo) Progress in Ovarian Cancer PACLITAXEL CARBO IP THERAPY

25. Endometrial Cancer - Then No known risk groups No known risk groups Poor understanding of biology Poor understanding of biology Surgical staging rare Surgical staging rare All patients treated with radiation All patients treated with radiation Limited use of adjuvant systemic therapy Limited use of adjuvant systemic therapy

26. HNPCC and Endometrial Cancer 2-3% of all endometrial cancers 2-3% of all endometrial cancers Due to mutations in MMR genes Due to mutations in MMR genes –MLH1, MSH2, MSH6,EPCAM, PMS2 Identifying patients at risk Identifying patients at risk –Colorectal/endometrial cancer age < 50 –MSI high histology (i.e., mucinous, signet ring, TIL) –Abnormal MSI/IHC tumor test –2 or more family members with HNPCC related cancer, one age <50 –3 or more family members with HNPCC related cancer, any age

27. Modern Surgical Management of Endometrial Cancer l MIS has improved surgical outcomes l Robotic surgery more feasible for obese patients l Surgical staging still controversial l Debulking employed more with advanced stage cancer

28. Uterine Cancer - Adjuvant Treatment Low risk early stage Low risk early stage –No benefit of radiation Intermediate risk early stage Intermediate risk early stage –Vaginal brachytherapy –Chemotherapy/radiation High risk advanced stage/Recurrent High risk advanced stage/Recurrent –Chemotherapy + radiation

29. Advances in Endometrial Cancer Evolving understanding of pathogenesis Evolving understanding of pathogenesis TCGA elucidating biology TCGA elucidating biology Targeted therapeutics Targeted therapeutics –Antiangiogenesis –mTOR inhibitors

30. Cervical Cancer - 1987 Evolving understanding of etiology/natural history Evolving understanding of etiology/natural history Annual Pap standard of care Annual Pap standard of care CKC, cryo, laser used for CIN CKC, cryo, laser used for CIN Radical hysterectomy Radical hysterectomy Radiation alone used Radiation alone used

31. New 2013 Cervical Cancer Screening Guidelines Age < 21 – No screening Age < 21 – No screening Age 21-29 – Cytology alone q 3 yrs Age 21-29 – Cytology alone q 3 yrs Age 30-65 – Cytology/HPV testing q 5 yrs Age 30-65 – Cytology/HPV testing q 5 yrs Age > 65 – No screening with negative prior screening Age > 65 – No screening with negative prior screening After hysterectomy – No screening unless history of CIN 2/3 or cervical ca After hysterectomy – No screening unless history of CIN 2/3 or cervical ca

32. Cervical Cancer Vaccines All VLP based All VLP based –Merck - Gardasil - 16/18/6/11 –GSK - Cervarix - 16/18 - ASO4 Efficacy Efficacy –Enhances HPV Ab response –Decreases CIN 2/3 –Duration of protection at least 5 yrs

33. Modern Surgical Management of Cervical Cancer l PET CT allows for better preop assessment l MIS has improved surgical outcomes l Fertility sparing procedures – CKC, radical trachelectomy

34. Relative Risk Estimate of Survival from Five Chemoradiation Clinical Trials Relative Risk-with 90% CI

35. Vulva Cancer Triple incision technique Triple incision technique Unilateral node dissection Unilateral node dissection Sentinel node Sentinel node Partial vulvectomy Partial vulvectomy Chemoradiation Chemoradiation

36. Lecture Outline Thoughts on change Thoughts on change Changes in gynecologic oncology Changes in gynecologic oncology Drivers of change Drivers of change –Scientific discovery and innovation Adapting to change Adapting to change

37. The Genomic Revolution

38. Clinical and Surgical Innovation Enhanced imaging technology Enhanced imaging technology Minimally invasive surgery Minimally invasive surgery Targeted therapeutics Targeted therapeutics Improved supportive care Improved supportive care

39. Lecture Outline Thoughts on change Thoughts on change Changes in gynecologic oncology Changes in gynecologic oncology Drivers of change Drivers of change –Changing demographics Adapting to change Adapting to change

40. The US Population is Growing

41. The US Population is Getting Older

42. The Number of Patients with a Gyn Cancer will Increase 20102030 All1.6 mil2.3 mil Cervix13,00017,000 Uterine44,00058,000 Ovarian24,00033,000 Smith et al JCO, 2009

43. We are More Culturally Diverse 50% nonwhite in 2050 50% nonwhite in 2050 Latino and Asian populations will triple Latino and Asian populations will triple More multiracial More multiracial More immigration More immigration

44. We Have Disparities in Gyn Cancer

45. We Have an Obesity Epidemic CDC.gov

46. Lecture Outline Thoughts on change Thoughts on change Changes in gynecologic oncology Changes in gynecologic oncology Drivers of change Drivers of change –Government related Adapting to change Adapting to change

47. Cost of Health Care in US Total expenditures on health as % of GDPAverage spending on health per capita The U.S. spends 2.4x the average of all developed countries and 60% more per capita than the next highest spenders

48. Health Care Reform in US PPACA – signed 3/23/10 PPACA – signed 3/23/10 Upheld by Supreme Court, Presidential Election 2012 Upheld by Supreme Court, Presidential Election 2012 Major goals Major goals –increase the number of insured –Improve quality –control rising health care costs

49. Investment in Cancer Research Declining Funding largely flat since 2000 Funding largely flat since 2000 R01 paylines lowest since 1980’s R01 paylines lowest since 1980’s Reliant on other funding sources – industry, foundations philanthropy Reliant on other funding sources – industry, foundations philanthropy

50. NCI Cooperative Group Trials Program is Reorganizing IOM advocates change IOM advocates change NCI develops NCTN NCI develops NCTN Funding 4 adult and 1 pediatric operation centers Funding 4 adult and 1 pediatric operation centers Funding 40 lead academic sites Funding 40 lead academic sites

51. Lecture Outline Thoughts on change Thoughts on change Changes in gynecologic oncology Changes in gynecologic oncology Drivers of change Drivers of change Adapting to change Adapting to change

52. What and How We Learn Will Be Different Commit to life long learning Commit to life long learning Define and teach the skills our trainees will need in the future Define and teach the skills our trainees will need in the future Ensure continuing education and proficiency post training Ensure continuing education and proficiency post training Innovative IT educational strategies Innovative IT educational strategies

53. We Must Revolutionize How We Practice Current health care system promotes fragmented, poorer quality, high cost care Current health care system promotes fragmented, poorer quality, high cost care The Practice Summit The Practice Summit −How should high quality, cost effective gynecologic cancer care be delivered? −How should high quality gynecologic cancer care be defined? −How should the delivery of high quality gynecologic cancer care be fairly compensated?

54. Proposed Solution for Optimizing Delivery Develop patient centered medical home Develop patient centered medical home Lead by a team captain and involve many disciplines Lead by a team captain and involve many disciplines Optimize manpower utilization Optimize manpower utilization

55. Proposed Solutions for Optimizing Quality Create uniform access to Create uniform access to best-qualified providers best-qualified providers Better define standards for Better define standards for high-quality gynecologic high-quality gynecologic cancer care cancer care Expand access to clinical trials Expand access to clinical trials Hold providers accountable for delivering higher quality gynecologic cancer care Hold providers accountable for delivering higher quality gynecologic cancer care

56. Proposed Solutions to Optimizing Payment Systems Test episode of care reimbursement systems Test episode of care reimbursement systems Incentivize hospitals to become centers of excellence Incentivize hospitals to become centers of excellence Fairly value surgery for complicated benign gynecology and obstetric patients Fairly value surgery for complicated benign gynecology and obstetric patients

57. We Must Advocate for Research in Gynecologic Cancer Enhance research training Enhance research training Set gyn cancer research priorities and build research teams Set gyn cancer research priorities and build research teams Seek funding for research in prevention and high mortality gynecologic cancers Seek funding for research in prevention and high mortality gynecologic cancers Advocate for robust clinical trials program and expand access to clinical trials Advocate for robust clinical trials program and expand access to clinical trials

58. My Gene Therapy Scientific Collaborators Hopkins/UAB Cervical SPORE UAB Ovarian SPORE

59. Change Must Start with the Individual Commit to life long learning and expand your skill sets Commit to life long learning and expand your skill sets Work smarter and critically evaluate what you are doing Work smarter and critically evaluate what you are doing Work collaboratively Work collaboratively Take risks – get out of your comfort zone Take risks – get out of your comfort zone

60. When you're finished changing, you're finished. -- Benjamin Franklin

61. Thanks for your attention - Questions? Ronald D. Alvarez, MD University of Alabama at Birmingham Division of Gynecologic Oncology Thanks for your attention - Questions? Ronald D. Alvarez, MD University of Alabama at Birmingham Division of Gynecologic Oncology