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 Ovarian Cancer Incidence/Mortality  Ovarian Cancer Incidence/Mortality

Ovarian Cancer Incidence/Mortality - PowerPoint Presentation

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Ovarian Cancer Incidence/Mortality - PPT Presentation

Improvement in 5 Year Survival Race 1975 1989 2014 All 36 38 47 White 35 38 48 African American 42 34 39 Noone AM Howlader N Krapcho M et al eds SEER Cancer Statistics Review 19752015 National Cancer Institute Bethesda MD wwwseercancergovcsr197 ID: 776623

cancer ovarian therapy maintenance cancer ovarian therapy maintenance pfs stage treatment day guidelines nccn disease clinical national line chemotherapy

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Slide1

Slide2

Ovarian Cancer Incidence/Mortality

Slide3

Improvement in 5 Year Survival:

Race197519892014All36%38%47%White35%38%48%African American42%34%39%

Noone

AM,

Howlader

N,

Krapcho

M, et al. (eds). SEER Cancer Statistics Review, 1975-2015, National Cancer Institute, Bethesda, MD, www.seer.cancer.gov/csr/1975_2015/, based on November 2017 SEER data submission, posted to the SEER website April 2018.

Slide4

Ovarian Cancer Facts and Figures

5 year overall survival (OS) rate across ALL stages of ovarian cancer: 47%

If diagnosed with advanced disease: 28%

Slide5

Ovarian Cancer Risk Factors

Not a comprehensive list of risk factors for ovarian cancer; BRCA = breast cancer susceptibility gene; BMI = body mass index; HRT = hormone replacement therapy.

1. What are the risk factors for ovarian cancer?. Atlanta, GA: American Cancer Society. Last revised February 4, 2016. http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-risk-factors. Accessed July 24, 2017. 2. Wei JJ, et al. Int J

Gynecol

Pathol

.

2011;30:553-568.

Age

Obesity

Genetics

Family history (1

st

degree relatives)

BRCA

Lynch syndrome

Peutz-Jeghers

syndrome

Cowden syndrome

Endometriosis

Medications

Hormone replacement therapy

Protective factors:

Birth control pills, childbirth before age 26, tubal ligation

Slide6

~20%–22% of patients with ovarian cancer14%–15% are associated with hereditary germline BRCA1 or BRCA2 mutations (gBRCAmut)1~6%–7% are associated with somatic BRCA mutations (sBRCAmut)1 Risk of Ovarian Cancer among BRCA carriers: 39% of BRCA1 develop ovarian cancer by age 703,411%–17% of BRCA2 develop ovarian cancer by age 703,41% lifetime risk for the general female population1

BRCA Mutations

Konstantinopoulos PA et al.

Cancer Discov.

2015;5:1137-54; Liu JF et al.

Gynecol Oncol

. 2014;133:362-369; Antoniou A et al.

Am J Hum Genet

. 2003;72:1117-1130; Chen S, Parmigiani G.

J Clin Oncol

. 2007;25:1329-1333.

Slide7

CA125

Best known marker in ovarian cancer

Present in 79%

90% of advanced cases

50% of early cases

Also elevated in benign conditions

Endometriosis, benign breast changes, inflammatory conditions

Can be elevated in other cancers

Slide8

Screening?

Slide9

Screening?

NCCN=National Comprehensive Cancer NetworkAmerican Congress of Obstetricians and Gynecologists (ACOG) Committee Opinion. http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/The-Role-of-the-Obstetrician-Gynecologist-in-the-Early-Detection-of-Epithelial-Ovarian-Cancer. Accessed March 24, 2015.

The FDA, US Preventative Services Task Force, American College

of Obstetrics and Gynecologists, Society of Gynecologic Oncology,

and NCCN recommend AGAINST ovarian cancer screening

Slide10

Signs and Symptoms:

American Society of Clinical Oncology. https://www.cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer/symptoms-and-signs

Most Common SymptomsBloating Pelvic or abdominal painor pressure Trouble eating or feeling full quickly Urinary symptoms(urgency or frequency)

Other Nonspecific SymptomsFatigue Upset stomach Back pain Constipation Pain with intercourse Menstrual changes Abdominal swelling Weight loss

Slide11

Diagnostic Work-up

CA-125 = cancer antigen 125; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography. 1. American Society of Clinical Oncology. https://www.cancer.net/cancer-types/ovarian-fallopian-tube-and-peritoneal-cancer/symptoms-and-signs. Accessed Oct 21,2019;

Imaging1Transvaginal ultrasoundCT or MRI scanPET-CT scan Chest imagingPelvic or abdominal ultrasonography

CA-1251Serum tumor markerLow predictive value for detecting ovarian cancer in women without special risk factors2 Nonspecific for ovarian cancer3Along with other tumor markers (e.g. CA 19-9) can be used to aid diagnosis

Summary1Ovarian cancer has largely nonspecific symptoms3 Initial diagnosis is made by: Physical exam Tumor markersLaboratory tests Radiology imaging Biopsy usually done at time of first surgeryStaging is done at the time of surgery

Physical Exam

Abdominal / pelvic exam

Mass

Ascites

Distension

Slide12

WHO = World Health Organization.

1. Ehdaivand S. WHO classification of ovarian neoplasms. Pathology Outlines. Revised May 19, 2016. http://www.pathologyoutlines.com/topic/ovarytumorwhoclassif.html. Accessed August 17, 2017. 2. Bodurka DC, et al. Cancer. 2012;118(12):3087-3094. 3. Prat J. Ann Oncol. 2012;23(Suppl 10):x111-117.

Histological Subtypes

Germ cells

Epithelium

Stroma

WHO histological typing of ovarian cancer is based on cell lineage

1

Epithelial cells

Germ cells

Sex chord and stromal cells

Endometrioid 10%

Clear-Cell 10%

Epithelial Ovarian Carcinoma Subtypes

High-grade Serous 70%

Mucinous 3%

Low-grade Serous <5%

Other 2%

Ovarian tumor cell lineage

Slide13

Serous ovarian tumors are typically graded using a 2-tier system

2

Slide14

FIGO Staging

FIGO=International Federation of Gynecology and Obstetrics.1. Society of Gynecologic Cancer. https://www.sgo.org/wp-content/uploads/2012/09/FIGO-Ovarian-Cancer-Staging_1.10.14.pdf. Accessed July 12, 2016; 2. College of American Pathologists. http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/pdf/cp-ovary-fallopian-16protocol-1000.pdf. Accessed July 12, 2016.

Histologic grade is included as criteria for staging of all subtypes except clear cell and serous ovarian cancer2

FIGO Stage

1

Description

I

The cancer is confined to the ovaries or fallopian tube(s)

II

The cancer is in one or both of the ovaries and

has spread below the pelvis

III

The cancer

is in one or both of the ovaries and has spread in the peritoneal area outside of the pelvis and surrounding nodes

IV

The cancer has spread

to organs beyond the ovaries and the peritoneal area

Slide15

5 Year Survival by Stage

Surveillance, Epidemiology, and End Results (SEER) Program Cancer Statistics Factsheets: Ovary Cancer. Bethesda, MA: National Cancer Institute, 2017. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed August 18, 2017.

Majority of ovarian cancer cases are diagnosed at an advanced stage*

Stage at Diagnosis

5-Year Survival by Stage

15

19

6

60

Survival rate

declines as stage at diagnosis increases

92.5

73.0

28.9

25.1

Slide16

Despite advances in treatment 85% of those diagnosed with advanced stage Ovarian Cancer will recur.

Slide17

Adapted from Ovarian Cancer National Alliance. http://www.ovariancancer.org/about/treatment/. Accessed July 13, 2016. Ushijima K. J Oncol. 2010;2010:497429.

10

30

70-90

90-95

Recurrence Rates by Stage of Diagnosis

~70%

of all patients diagnosed with ovarian cancer (all stages) will have a recurrence

1

Recurrent ovarian cancer is

treatable but not curable

Slide18

After Each Subsequent Treatment, Median Progression-Free Survival (PFS) Shortens During Watchful Waiting

*PFS was calculated from the day of randomization (day of first cycle of chemotherapy) to the first disease progression.PFS = progression-free survival; L = line. Hanker LC, et al. Ann Onc. 2012;23:2605-2612. Lorusso D, et al. Int J Surg Oncol. 2012;2012:613980.

1L

RECURRENCE

Diagnosed with ovarian cancer

2L

6L

3L

4L

5L

RECURRENCE

RECURRENCE

RECURRENCE

RECURRENCE

Median PFS

~18

mo

Median PFS*

10.2

mo

(9.6–10.7)

Median PFS*

6.4

mo

(5.6–7.0)

Median PFS*

5.6

mo

(4.8–6.2)

Median PFS*

4.4

mo

(3.7–4.9)

Median PFS*

4.1

mo

(3.0–5.1)

Ovarian cancer recurs, receives active line of treatment

Slide19

Overview of Ovarian Cancer Treatment

Systemic Treatment

-before surgery (neoadjuvant)

Goal

Reduce tumor burden prior to surgery

Surgery

-Staging

-Primary debulking surgery (PDS)

-Interval debulking surgery (pre and post chemo)

Goal-Curative intent-Reduce tumor burden

Systemic Treatment

-First-line/adjuvant therapy -Recurrence therapy-Maintenance therapy-Clinical trialsGoal-Curative intent-Control symptoms-improve QOL

Supplemental Therapy

-Observation – “watch and wait” -Maintenance therapyGoalExtend platinum –sensitivityExtend chemotherapy-free interval-Extend disease-free int.

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2019). Accessed Oct. 2019.

Slide20

NCCN Guidelines: First-line Treatment

*Stage IA or IB, Grade 1;

†Stage IA or IB, Grade 3 or Stage IC, any grade. Stage IA or IB, Grade 2 has choice of either no treatment (observation) or adjuvant chemotherapy.Chemo=chemotherapy; CR=complete response; NCCN=National Comprehensive Cancer Network; PD=progressive disease; PR=partial response; SD=stable disease; SOC=standard of care.National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018)

Ovarian cancer classification

Current SOC

Less commonly used

Clinical trial

Observation

OR

Achieved CR

OR

Persistent or Recurrent Disease

PR, SD or PD

Clinical relapse

Surgery

Neoadjuvant therapy

Locally Advanced

Stages II & III

Metastatic

Stage IV

Primary (adjuvant) chemo

“Interval debulking”

Surgery

Adjuvant chemo

No treatment (observation)

Low grade*

High grade

Localized

Stage I

Monitoring & follow-up

M

aintenance

therapy

Slide21

Surgery

Slide22

Chemotherapy

Neoadjuvant

Adjuvant

Metastatic

Intraperitoneal

Slide23

First-line Treatment: Stage I

Intraperitoneal/Intravenous Regimen Level of Evidence/RecommendationIntravenous regimensPaclitaxel + Carboplatin day 1. Repeat q3wk × 3-6 cycles (preferred)Category 2ACarboplatin + pegylated liposomal doxorubicin every 4 weeks for 3-6 cyclesCategory 2ADocetaxel + Carboplatin day 1. Repeat q3wk × 6 cycles Category 2A

NCCN=National Comprehensive Cancer Network;

IV=intravenous; IP=intraperitoneal; q3wk=every 3 weeks.

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018)

Slide24

First-line Treatment: Stage II-IV

Intraperitoneal/Intravenous Regimen Level of Evidence/RecommendationIntraperitoneal/Intravenous regimensPaclitaxel IV day 1; Cisplatin IP day 2 after IV Paclitaxel; Paclitaxel IP day 8. Repeat q3wk × 6 cycles Category 2AIntravenous regimensPaclitaxel + Carboplatin day 1. Repeat q3wk × 6 cycles Category 2ADose-dense Paclitaxel days 1, 8, and 15, followed by Carboplatin day 1.Repeat q3wk × 6 cycles Category 2APaclitaxel + Carboplatin day 1. Weekly for 18 weeks Category 2ADocetaxel + Carboplatin day 1. Repeat q3wk × 6 cycles Category 2ACarboplatin + pegylated liposomal doxorubicin every 4 weeks for 6 cyclesCategory 2ABevacizumab-containing regimens per ICON-7 and GOG-218Paclitaxel IV + Carboplatin IV + bevacizumab IV day 1. Repeat q3wk × 5–6 cycles. Continue bevacizumab up to 12 additional cycles for maintenance Category 2APaclitaxel IV + Carboplatin IV day 1. Repeat q3wk × 6 cycles Starting day 1 of cycle 2, give bevacizumab IV q3wk up to 22 cycles Category 2A

NCCN=National Comprehensive Cancer Network;

IV=intravenous; IP=intraperitoneal; q3wk=every 3 weeks.

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018)

Slide25

Intraperitoneal chemotherapy HIPEC - Hyperthermic

Most of OC have spread to peritoneum by the time of diagnosis Intraperitoneal (IP) chemotherapy prolonged survival time and reduced the risk of death. Higher rate of adverse events and the frequency of discontinuation hampered adoption Abdominal pain, Nausea, Vomiting, Fatigue, Infection, IleusHyperthermia enhanced cancer cell destruction HIPEC-based regimens might  PFS and OS for patients with advanced primary ovarian cancer. Benefit still under debate

Zhang, G., Zhu, Y., Liu, C. 

et al.

 The prognosis impact of

hyperthermic

intraperitoneal chemotherapy (HIPEC) plus cytoreductive surgery (CRS) in advanced ovarian cancer: the meta-analysis. 

J Ovarian Res

 

12, 

33 (2019) doi:10.1186/s13048-019-0509-1

Slide26

Definition of Response to First-Line Chemotherapy: NCCN Guidelines

CT=computed tomography; ULN=upper limit of normal.National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018); Nishino M et al. AJR Am J Roentgenol. 2010;195:281-289.

Complete response (CR):

Negative physical exam

Negative CA-125 Negative CT with <1cm lymph nodes

Partial response (PR)

:

≥ 30% reduction in the sum of diameters compared to baseline Persistence of 1 or more non-target lesions AND/ORCA-125 above ULN

Progressive disease (PD)

:

≥ 20% increase in the sum of diameters of target lesions

The sum must demonstrate an absolute increase of

≥ 5mm

OR

Appearance of one or more new lesions

Slide27

Then what???

Slide28

BRCA mutation in Ovarian Cancer

BRCA is tumor suppressor gene involved in repair of DNA double strand breaks

When mutated that mechanism is damaged

Germ-line BRCA (

gBRCAmut

)

improved PFS and OS

In relapse setting: improved response to 2

nd

line therapy even if early relapse

Platinum and non platinum

Non

gBRCAmut

who respond to multiple lines likely to have somatic BRCA mutation (

sBRCAmut

) or other mutations

Slide29

Genetic Mutations Beyond BRCA Mutations May Lead to Homologous Recombination Deficiency (HRd)

OTHER (may be HR deficient via upregulation of miRNAs or other mechanisms)

HR DEFICIENT

HR PROFICIENT

POSSIBLY HR DEFICIENT

HR=homologous recombination; NER=nucleotide excision repair; MMR=mismatch repair; PTEN=phosphatase and tensin homolog.

Konstantinopoulos PA et al.

Cancer Discov

. 2015;5:1137-54; Liu JF et al.

Gynecol Oncol

. 2014;133:362-369; Antoniou A et al.

Am J Hum Genet

. 2003;72:1117-1130; Chen S, Parmigiani G.

J Clin Oncol

. 2007;25:1329-1333.

Slide30

Homologous Recombination (HRd)

DNA errors in replication common

DNA damage repair through the highest fidelity mechanism = homologous recombination

HRd

or

HRp

In

BRCAmut

: part of the mechanism is absent =

HRd

PARPs required

Slide31

PARP inhibitors

Poly ADP ribose polymerase - enzymes involved in DNA repair through

HR

Single strand DNA breaks

PARP inhibitors block the ability of PARPs to participate in DNA damage repair

Most effective in

BRCAmut

and

HRd

Oral agents: dosed

qd

or bid

Slide32

PARP inhibitors

QOL similar between PARP and placebo

Side effects depend on which PARP

Nausea / vomiting

Fatigue

Thrombocytopenia, neutropenia, anemia

Slide33

HRd

HRp

HRd

HRd

+ PARP

Slide34

Maintenance

Avastin in maintenance if used with 1L

PARPs Previously indicated after recurrence and subsequent chemotherapy

Stretched the PFS after 2L in special populations

Some for

gBRCA

Some for

gBRCA

or

tBRCA

(same as

sBRCA

)

Some for

HRd

Some showed activity in

HRp

Newest data shows advantage in 1L maintenance

Goal: to maintain platinum sensitivity, increase PFS

Slide35

Goal: Increase PFS with each subsequent line

*PFS was calculated from the day of randomization (day of first cycle of chemotherapy) to the first disease progression.PFS = progression-free survival; L = line. Hanker LC, et al. Ann Onc. 2012;23:2605-2612. Lorusso D, et al. Int J Surg Oncol. 2012;2012:613980.

1L

Diagnosed with ovarian cancer

2L

3L

RECURRENCE

RECURRENCE

Median PFS

Median PFS*

Ovarian cancer recurs, receives active line of treatment

Slide36

NCCN Guidelines: Maintenance Therapy

†Pazopanib is recommended as single-agent maintenance therapy if complete clinical remission following primary therapy for stage II-IV disease, if no prior bevacizumab (category 3).*Rucaparib, Olaparib, Niraparib are approved in the US for a non-maintenance indication. Ledermann JA, Raja FA, Fotopoulou C, et al. Annals of Oncology. 2013;24(Supp 6):vi24-vi32; Ledermann JA, Sessa C, Colombo N. eUpdate-Ovarian Cancer Treatment Recommendations. Updated on: Sep. 21, 2016; http://www.esmo.org/Guidelines/Gynaecological-Cancers/Non-Epithelial-Ovarian-Cancer/eUpdate-Treatment-Recommendations; National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2018).

For those with platinum-sensitive disease who have completed two or more lines of platinum-based therapy, consider niraparib maintenance therapy if partial or complete response

For those with BRCA1/2 mutations who have completed

one or more lines of platinum-based therapy, consider olaparib maintenance therapy if partial or complete response

For platinum-sensitive recurrent disease, if response after chemotherapy, bevacizumab can be continued as maintenance therapy until disease progression or unacceptable toxicity

Niraparib

Olaparib

Bevacizumab

For those with platinum-sensitive disease who have completed two or more lines of platinum-based therapy, consider rucaparib maintenance therapy if partial or complete response

Rucaparib*

Slide37

Clinicaltrials.gov

2,498 Ovarian Cancer Trials

764 Phase I

1,011 Phase II

233 Phase III

Slide38

What about check point inhibitors?

Slide39

Ovarian Cancer Clinical Trials

Ovarian cancer thought to be “cold” tumor

Can it be “warmed up”?

Combination trials with

PARPi

+ immunotherapy agents

Combination trials of

avastin

+

PARPi

Trials on

rechallenging

with a PARP +

Slide40

Paradigm Shift

2011: 2 trials showed benefit of bevacizumab with first line therapy

2018: SOLO1 trial showed benefit of

PARPi

in

gBRCAmut

in 1L maintenance

Only 44% adopted

2019: ESMO – 3 trials showing benefit of

PARPi

in 1L maintenance in various populations (high risk,

HRd

,

HRp

, adding to chemo upfront and then following with maintenance, adding to

bev

)

“PARPs Made the biggest splash”

“Game changer”

PARPs in 1L treatment, 1L maintenance, 2L maintenance, 3+L treatment.

Slide41

Thank You!