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

Gynecologic Oncology-Gynecologic Oncology-The Times They Are The Times They Are

A’Changin A’Changin

Ronald D. Alvarez, MDRonald D. Alvarez, MD

University of Alabama at BirminghamUniversity of Alabama at BirminghamDivision of Gynecologic OncologyDivision of Gynecologic Oncology

DisclosuresDisclosures

Grant supportGrant support

– Morphoteck Morphoteck

– Pfizer Pfizer

– MerrimackMerrimack

Florida Society of Florida Society of Gynecologic OncologyGynecologic Oncology

Organized 1993Organized 1993 Founders meeting 1994 Founders meeting 1994

(Holloway,Chair) (Holloway,Chair) Invited speaker at 1Invited speaker at 1stst, and , and

1010thth meetings (one with a meetings (one with a hurricane) hurricane)

Invited for 19Invited for 19thth meeting meeting (Penalver, Chair)(Penalver, Chair)

Many longterm Many longterm connections and friendsconnections and friends

Lecture OutlineLecture Outline

Thoughts on change Thoughts on change Changes in gynecologic oncologyChanges in gynecologic oncology Drivers of change Drivers of change Adapting to changeAdapting to change



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

Rapid Pace of ChangeRapid Pace of Change

Agricultural revolution Agricultural revolution 8000 yrs8000 yrs Industrial revolution Industrial revolution 120 yrs 120 yrs Light bulb Light bulb 90 yrs 90 yrs Moon landing Moon landing 22 yrs 22 yrs World wide web World wide web 9 yrs 9 yrs Human genome sequencedHuman genome sequenced

Principles of Principles of Transformational ChangeTransformational Change

Something old Something old passes awaypasses away

Something new Something new comes to becomes to be

Something stays Something stays the samethe same

Aristotle, 350 BC

Why Is Change So Threatening?Why Is Change So Threatening?

We all have a worldviewWe all have a worldview It is shaped by beliefs, It is shaped by beliefs,

values, experiencevalues, experience Change often Change often

challenges and challenges and misaligns our misaligns our worldview worldview

How Is Change Best Implemented?How Is Change Best Implemented?

Positive vision of Positive vision of abundanceabundance

Create a readiness for Create a readiness for changechange

Implement small Implement small changes that changes that stakeholders can ownstakeholders can own

Help stakeholders Help stakeholders change worldviewchange worldview

Win

Win Win

WIN

Win

Win



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

US Gynecologic Cancer Statistics US Gynecologic Cancer Statistics

New Cases Deaths

1987 2012 1987 2012

Ovary 19,000 22,280 11,700 15,550

Uterine 35,000 47,130 2,900 8,010

Cervix 12,800 12,170 6,800 4,220

Vulva NR 4,490 NR 950

Vagina NR 2,680 NR 840

Ovarian Cancer - 1987Ovarian Cancer - 1987

Risk groups not identifiedRisk groups not identified Known as the Known as the ““silentsilent”” cancer cancer Surgical debulking often suboptimalSurgical debulking often suboptimal Limited chemotherapy optionsLimited chemotherapy options Short median survivalShort median survival

Science, 1990

● Evaluated 23 families Evaluated 23 families with 146 cases of with 146 cases of breast cancer using breast cancer using linkage analysislinkage analysis

● Identified that a gene Identified that a gene for early onset breast for early onset breast cancer to be located cancer to be located near D17S74near D17S74

● Isolated by Miki et al in Isolated by Miki et al in 1994 Science paper1994 Science paper

Hereditary Ovarian Cancer – Beyond Hereditary Ovarian Cancer – Beyond the Usual Suspectsthe Usual Suspects

Swisher, 2012

Screening for Ovarian CancerScreening for Ovarian Cancer

PLCO Trial (Partridge et al, 2009)PLCO Trial (Partridge et al, 2009)– Evaluated annual CA125 and TVU vs. Evaluated annual CA125 and TVU vs.

observation in general population observation in general population – 20:1 surgery:cancer ratio20:1 surgery:cancer ratio– Most late stage/no reduction in mortalityMost late stage/no reduction in mortality

UKCTOCSUKCTOCS– Evaluating yearly CA125 vs. yearly TVU Evaluating yearly CA125 vs. yearly TVU

vs. observation in general populationvs. observation in general population– Results due 2014Results due 2014

Ovarian Pap Gene TestOvarian Pap Gene Test

Used massively Used massively parallel sequencing to parallel sequencing to assess DNA from liquid assess DNA from liquid Pap smear samples Pap smear samples from 24 ovarian and 22 from 24 ovarian and 22 endometrial cancer endometrial cancer patientspatients

Mutations detected in Mutations detected in 100% of endometrial 100% of endometrial cancers and 41% of cancers and 41% of ovarian cancersovarian cancers

Kinde et al. Sci Transl Med, 2013

Ovarian Cancer is not a Ovarian Cancer is not a ““SilentSilent”” Cancer Cancer

Symptoms Symptoms – BloatingBloating– Pelvic or abdominal painPelvic or abdominal pain– Difficulty eating or feeling full quicklyDifficulty eating or feeling full quickly– Urinary symptoms (urgency or Urinary symptoms (urgency or

frequency)frequency) Workup – Pelvic exam, sonar, CA125Workup – Pelvic exam, sonar, CA125

Achieving Maximum Debulking in Achieving Maximum Debulking in Ovarian CancerOvarian Cancer

• Debulking TAH BSODebulking TAH BSO

• OmentectomyOmentectomy

• Colon resectionColon resection

• Small bowel resectionSmall bowel resection

• SplenectomySplenectomy

• Hepatic resectionHepatic resection

• Diaphragm strippingDiaphragm stripping

• Peritoneal strippingPeritoneal stripping

The Role of Neoadjuvant Chemotherapy in The Role of Neoadjuvant Chemotherapy in Advanced Ovarian CancerAdvanced 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

New Chemotherapy Approaches New Chemotherapy Approaches in Ovarian Cancer in Ovarian Cancer

Taxane based regimensTaxane based regimens

Intraperitoneal chemotherapyIntraperitoneal chemotherapy

Dose dense taxanesDose dense taxanes

Consolidation chemotherapyConsolidation chemotherapy

Anti-angiogenic therapyAnti-angiogenic therapy

PARP inhibitorsPARP inhibitors

TCGA Project – Molecular TCGA Project – Molecular Characterization of HGSCCharacterization of HGSC

Serous 82%

Carcinosarcoma 6%

Clear cell 6%

Endometrioid 3%

Mixed 3%

BRCA1 Germline

8%BRCA2

Germline6%

BRCA1 Somatic

3%

BRCA2 Somatic

3%

BRCA1 Methylation

11%

EMSY Amplification

6%PTEN Loss

5%Other HRD7%

CCNE1 Amplification

15%

MMR Germline

2%

RB1 deletion3%

PIK3CA Amplification

4%

KRAS Amplification

3%

NF1 Deletion3% Other

21%

CGARN, Nature 2011

PACLITAXEL

CISPLATIN

AGGRESSIVESURGERY,

COMBINATIONCHEMOTHERAPY

Su

rviv

al (

mo)

Progress in Ovarian Cancer Progress in Ovarian Cancer

PACLITAXELCARBO

IP THERAPY

Endometrial Cancer - ThenEndometrial Cancer - Then

No known risk groupsNo known risk groups Poor understanding of biologyPoor understanding of biology Surgical staging rare Surgical staging rare All patients treated with radiationAll patients treated with radiation Limited use of adjuvant systemic Limited use of adjuvant systemic

therapytherapy

HNPCC and Endometrial CancerHNPCC and Endometrial Cancer

2-3% of all endometrial cancers2-3% of all endometrial cancers Due to mutations in MMR genes Due to mutations in MMR genes

– MLH1, MSH2, MSH6,EPCAM, PMS2MLH1, MSH2, MSH6,EPCAM, PMS2 Identifying patients at riskIdentifying patients at risk

– Colorectal/endometrial cancer age < 50Colorectal/endometrial cancer age < 50– MSI high histology (i.e., mucinous, signet ring, TIL)MSI high histology (i.e., mucinous, signet ring, TIL)– Abnormal MSI/IHC tumor test Abnormal MSI/IHC tumor test – 2 or more family members with HNPCC related 2 or more family members with HNPCC related

cancer, one age <50cancer, one age <50– 3 or more family members with HNPCC related 3 or more family members with HNPCC related

cancer, any agecancer, any age

Modern Surgical Management of Modern Surgical Management of Endometrial CancerEndometrial Cancer

MIS has improved surgical MIS has improved surgical outcomesoutcomes

Robotic surgery more Robotic surgery more feasible for obese patientsfeasible for obese patients

Surgical staging still Surgical staging still controversial controversial

Debulking employed more Debulking employed more with advanced stage with advanced stage cancercancer

Uterine Cancer - Uterine Cancer - Adjuvant TreatmentAdjuvant Treatment

Low risk early stage Low risk early stage – No benefit of radiationNo benefit of radiation

Intermediate risk early stageIntermediate risk early stage– Vaginal brachytherapyVaginal brachytherapy– Chemotherapy/radiationChemotherapy/radiation

High risk advanced stage/RecurrentHigh risk advanced stage/Recurrent– Chemotherapy Chemotherapy ++ radiation radiation

Advances in Endometrial CancerAdvances in Endometrial Cancer

Evolving Evolving understanding of understanding of pathogenesispathogenesis

TCGA elucidating TCGA elucidating biologybiology

Targeted therapeuticsTargeted therapeutics– AntiangiogenesisAntiangiogenesis– mTOR inhibitorsmTOR inhibitors

Cervical Cancer - 1987Cervical Cancer - 1987

Evolving understanding of Evolving understanding of etiology/natural historyetiology/natural history

Annual Pap standard of careAnnual Pap standard of care CKC, cryo, laser used for CINCKC, cryo, laser used for CIN Radical hysterectomyRadical hysterectomy Radiation alone usedRadiation alone used

New 2013 Cervical Cancer New 2013 Cervical Cancer Screening GuidelinesScreening Guidelines

Age < 21 – No screeningAge < 21 – No screening Age 21-29 – Cytology alone q Age 21-29 – Cytology alone q

3 yrs 3 yrs Age 30-65 – Cytology/HPV Age 30-65 – Cytology/HPV

testing q 5 yrs testing q 5 yrs Age > 65 – No screening with Age > 65 – No screening with

negative prior screeningnegative prior screening After hysterectomy – No After hysterectomy – No

screening unless history of screening unless history of CIN 2/3 or cervical caCIN 2/3 or cervical ca

Cervical Cancer VaccinesCervical Cancer Vaccines

All VLP basedAll VLP based– Merck - Gardasil - 16/18/6/11Merck - Gardasil - 16/18/6/11– GSK - Cervarix - 16/18 - ASO4GSK - Cervarix - 16/18 - ASO4

EfficacyEfficacy– Enhances HPV Ab responseEnhances HPV Ab response– Decreases CIN 2/3Decreases CIN 2/3– Duration of protection at Duration of protection at

least 5 yrs least 5 yrs

Modern Surgical ManagementModern Surgical Management of Cervical Cancer of Cervical Cancer

PET CT allows for PET CT allows for better preop better preop assessment assessment

MIS has improved MIS has improved surgical outcomessurgical outcomes

Fertility sparing Fertility sparing procedures – CKC, procedures – CKC, radical trachelectomyradical trachelectomy

Relative Risk Estimate of Survival from Five Chemoradiation Clinical Trials

Relative Risk-with 90% CI

Vulva CancerVulva Cancer

Triple incision Triple incision techniquetechnique

Unilateral node Unilateral node dissectiondissection

Sentinel nodeSentinel node Partial vulvectomyPartial vulvectomy ChemoradiationChemoradiation


Thoughts on change Thoughts on change Changes in gynecologic oncologyChanges in gynecologic oncology Drivers of change Drivers of change

– Scientific discovery and Scientific discovery and innovationinnovation

Adapting to changeAdapting to change

The Genomic RevolutionThe Genomic Revolution

Clinical and Surgical InnovationClinical and Surgical Innovation

Enhanced imaging Enhanced imaging technologytechnology

Minimally invasive Minimally invasive surgerysurgery

Targeted Targeted therapeuticstherapeutics

Improved Improved supportive caresupportive care



– Changing demographicsChanging demographics Adapting to changeAdapting to change

The US Population is GrowingThe US Population is Growing

The US Population is Getting OlderThe US Population is Getting Older

The Number of Patients with a The Number of Patients with a Gyn Cancer will IncreaseGyn Cancer will Increase

2010 2030

All 1.6 mil 2.3 mil

Cervix 13,000 17,000

Uterine 44,000 58,000

Ovarian 24,000 33,000

Smith et alJCO, 2009

We are More Culturally DiverseWe are More Culturally Diverse

50% nonwhite in 50% nonwhite in 20502050

Latino and Asian Latino and Asian populations will populations will tripletriple

More multiracialMore multiracial More immigrationMore immigration

We Have Disparities in Gyn CancerWe Have Disparities in Gyn Cancer

We Have an Obesity We Have an Obesity EpidemicEpidemic

CDC.gov



– Government relatedGovernment related Adapting to changeAdapting to change

Cost of Health Care in USCost of Health Care in US

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United StatesFranceSwitzerlandGermanyCanadaNetherlandsNew ZealandDenmarkSwedenUnited KingdomNorwayAustralia

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

Health Care Reform in USHealth Care Reform in US

PPACA – signed 3/23/10PPACA – signed 3/23/10 Upheld by Supreme Upheld by Supreme

Court, Presidential Court, Presidential Election 2012Election 2012

Major goals Major goals – increase the number of increase the number of

insuredinsured

– Improve qualityImprove quality

– control rising health control rising health

care care costscosts

Investment in Cancer Research Investment in Cancer Research DecliningDeclining

Funding largely flat Funding largely flat since 2000since 2000

R01 paylines lowest R01 paylines lowest since 1980’ssince 1980’s

Reliant on other Reliant on other funding sources – funding sources – industry, foundations industry, foundations philanthropyphilanthropy

NCI Cooperative Group Trials NCI Cooperative Group Trials Program is ReorganizingProgram is Reorganizing

IOM advocates changeIOM advocates change NCI develops NCTNNCI develops NCTN Funding 4 adult and 1 pediatric Funding 4 adult and 1 pediatric

operation centersoperation centers Funding 40 lead academic sitesFunding 40 lead academic sites



What and How We Learn What and How We Learn Will Be DifferentWill Be Different

Commit to life long learning Commit to life long learning Define and teach the skills Define and teach the skills

our trainees will need in the our trainees will need in the future future

Ensure continuing education Ensure continuing education and proficiency post trainingand proficiency post training

Innovative IT educational Innovative IT educational strategies strategies

We Must Revolutionize We Must Revolutionize How We Practice How We Practice

Current health care system promotes Current health care system promotes fragmented, poorer quality, high cost fragmented, poorer quality, high cost carecare

The Practice SummitThe Practice Summit− How should high quality, cost effective How should high quality, cost effective

gynecologic cancer care be delivered? gynecologic cancer care be delivered? − How should high quality gynecologic How should high quality gynecologic

cancer care be defined? cancer care be defined? − How should the delivery of high quality How should the delivery of high quality

gynecologic cancer care be fairly gynecologic cancer care be fairly compensated? compensated?

Proposed SolutionProposed Solutionfor Optimizing Deliveryfor Optimizing Delivery

Develop patient Develop patient centered medical centered medical homehome

Lead by a team Lead by a team captain and involve captain and involve many disciplinesmany disciplines

Optimize Optimize manpower manpower utilizationutilization

Proposed SolutionsProposed Solutionsfor Optimizing Qualityfor Optimizing Quality

Create uniform access to Create uniform access to best-qualified providersbest-qualified providers Better define standards for Better define standards for high-quality gynecologichigh-quality gynecologic cancer carecancer care Expand access to clinical Expand access to clinical

trialstrials Hold providers accountable Hold providers accountable

for delivering higher quality for delivering higher quality gynecologic cancer caregynecologic cancer care

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=6yceZM8o5Izf5M&tbnid=vepNq59O3IWyiM:&ved=0CAUQjRw&url=http://dealercarroofligthingsigns.com/index.php?route=product/product&product_id=272&ei=4oQNUerdPNTurAG7jIHQBg&bvm=bv.41867550,d.aWc&psig=AFQjCNFCT2a2RkFI4kJAYRVaKsyDYUq-EA&ust=1359926685247277

Proposed SolutionsProposed Solutionsto Optimizing Payment to Optimizing Payment

SystemsSystems Test episode of care Test episode of care reimbursement reimbursement systems systems

Incentivize hospitals Incentivize hospitals to become centers of to become centers of excellenceexcellence

Fairly value surgery Fairly value surgery for complicated for complicated benign gynecology benign gynecology and obstetric patientsand obstetric patients

We Must Advocate for We Must Advocate for Research in Gynecologic Research in Gynecologic

CancerCancer Enhance research training Enhance research training Set gyn cancer research Set gyn cancer research

priorities and build research priorities and build research teamsteams

Seek funding for research in Seek funding for research in prevention and high mortality prevention and high mortality gynecologic cancersgynecologic cancers

Advocate for robust clinical Advocate for robust clinical trials program and expand trials program and expand access to clinical trialsaccess to clinical trials

My Gene Therapy My Gene Therapy Scientific CollaboratorsScientific Collaborators

Hopkins/UAB Cervical SPORE

UAB Ovarian SPORE

Change Must Start with Change Must Start with the Individualthe Individual

Commit to life long learning Commit to life long learning and expand your skill setsand expand your skill sets

Work smarter and critically Work smarter and critically evaluate what you are doing evaluate what you are doing

Work collaborativelyWork collaboratively Take risks – get out of your Take risks – get out of your

comfort zonecomfort zone

When you're finished changing,

you're finished.-- Benjamin Franklin

http://en.wikipedia.org/wiki/File:BenFranklinDuplessis.jpg

Thanks for your attention - Thanks for your attention - Questions?Questions?

Ronald D. Alvarez, MDRonald D. Alvarez, MD

University of Alabama at BirminghamUniversity of Alabama at BirminghamDivision of Gynecologic OncologyDivision of Gynecologic Oncology

Documents

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