Ovarian cancer

ManagementAPRIL 12 2019

ROBYN COMEAU MD FRCSC (OBGYN, GYNECOLOGIC ONCOLOGY)

Disclosures

Educational sessions

Astra Zeneca

Merc

Objectives

Epidemiology

Screening

Symptoms based

Populations based

Low risk

High risk

Treatment

Surgery

Therapies

Genetic Screening

Clinical Scenario

62 YO G4P3

2 months

Abdominal pain

Bloating

Reflux

Early Satiety

CA 125, 875

CT scan

Omental nodules ,diaphragmatic

disease, pelvic mass, large volume

ascites

30 YO G0

Family History Malignancy

1 paternal cousin breast cancer,

living 45

Paternal Aunt breast cancer, living

70

Mother ovarian cancer, deceased

64

Would like information about

screening

Ovarian Cancer Epidemiology

2800 New cases of ovarian cancer diagnosed each year in Canada

In New Brunswick 75-80 cases per year

Incidence 1/57 ♀

50%> 65 years of age at diagnosis

75% stage III or IV at diagnosis *

Epithelial tumors most common (serous> endometrioid> Clear cell > mixed histology) 65%

Germ Cell 20%

Sex cord stromal 10%

Metastatic 5%

5 year survival: 25 to 40%

Improved survival in last 20 years due to increased surgical aggressiveness and advances in chemotherapy

Screening….SYMPTOM BASED VS..... POPULATION BASED

Symptoms of ovarian cancer

Early stage

Irregular menses

Pelvic mass

Urinary frequency

Constipation

Abdominal distension

Abdominal pain

Abdominal pressure

dyspareunia

Advanced Stage

Pelvic mass

Abdominal distension

Abdominal bloating

Constipation

Nausea

Anorexia

Early satiety

AUB

Decima Research Study – OCC

1373 women

12% – never heard of ovarian cancer

1 in 3 – pap is a screening test for ovarian cancer

96% could not identify symptoms

age > 50 – less likely to be aware

Can we make a diagnosis of OC

on Symptoms?

1725 Women

95% + symptoms before diagnosis (89% stage I-II, 97% stage III-IV)

70% abdominal pain or GI Sx

58% pain

34% Urinary symptoms

26% pelvic Discomfort

89% stage I-II, 97% stage III-IV

Goff BA, Mandel LS, Muntz HG, et al. Ovarian cancer diagnosis: results of a national

ovarian cancer survey. Cancer 2000;89:2068–2075.

Reducing time to Diagnosis,

improved outcomes?

2319 women suspected diagnosis

invasive/borderline EOC

Survey describing events leading

to diagnosis (symptoms, dates, #

of MD visits etc)

1318 women invasive cancer

71% stage III/IV

29% stage I/II

90% had at least 1 symptom, 10%

incidental

≈ 50 within 1 month of onset

70% within 2 months

90% within 6 months

≈ 8% > 6 months

Time to diagnosis:

39% < 2 months

61% < 3 months

80 % < 6 months

4% > 1 year

Australian Ovarian Cancer Study Group Journal of clinical oncology

Vol 29, No 16, June 1 2011

WHO Criteria for Population

ScreeningCondition is important health problem.

Accepted treatment for patients with recognized disease.

Facilities for diagnosis and treatment available.

Latent or early symptomatic stage.

Suitable test or examination.

Test acceptable to the population.

The natural history of the condition adequately understood.

Policy on treatment.

Cost Effective.

Case-finding continual

Options for screening

CA 125 Imaging

CA 125

Non Malignant Gyn

Benign Ovarian Neoplasm

Functional Ovarian Cyst

Endometriosis

Meig Syndrome

Adenomyosis

Uterine Leimoyomas

PID

OHSS

Pregnancy

Menstruation

Non Malignant Non Gyn Cirrhosis and other liver conditions

Ascites

Colitis

Diverticulitis

Appendiceal conditions

Pancreatitis

Pleural effusions

Pulmonary embolism

Pneumonia

CF

Pericardial disease

CHF/ myocardiopathy/ MI

Renal Insufficiency

Recent surgery

SLE/ Sarcoidosis

CA 125

Malignant

Gynecologic:

EOC: Ovary, FT, PP

Endometrial

Malignant

Non-Gynecologic:

Breast

Colon

Liver

Pancreas/ Gallbladder

Lung

Hematologic Malignancies

CA 125

CA 125: sensitivity/ Specificity 80%

Pre-operative CA 125

? Prognostic factor for recurrence/ death of disease

Pre-chemotherapy CA 125 (230-300U/mL)

? Increased PFS/ OS

CA-125 During Chemotherapy

Normalization CA 125 ≈ 3 months of treatment independent predictor or

progression of disease

Eagle et al. The Oncologist 1997 vol 2 no. 5, 324-329

Investigations for a pelvic mass

2D US: sensitivity 85.3%, specificity 87.4%

3D US: sensitivity 93.5%, specificity 91.5%

CT: sensitivity 87.2%, specificity 84.0%

MRI: sensitivity 91.9 %, specificity 88.4%

Pet Scan: sensitivity 67% , specificity 79%

Gynecologic Oncology 126 (2012) 157–166

RMI ≥ 200 suggestive of malignancy

?

• RMI I = U X M X Ca 125

– U= 0 no US or US 0

– U= 1 for US score 1

– U= 3 for US score 2-5

– M= 1 premenopausal

– M=3 Postmenopausal

– Sensitivity: 87%

– Specificity: 91%

• PPV: 73%

• NPV: 96%

• RMI II = U X M X Ca 125

– U= 0 or 1 for score 1

– U= ≥ 2 for score 4

– M= 1 premenopausal

– M=4 postmenopausal

– Sensitivity: 95 %

– Specificity: 87%

• PPV: 67%

• NPV: 98%

British Journal of Obstetrics and gynecology August 1996, Vol 3, pp. 826-831

Combined Population based

Screening Trials: CA 125 + Ultrasound

PLCO

UKTOCS

UKTFOCS

PLCO

1993-2001 (13 Yr FU) 70 000 women

Multicenter US trial

Baseline CA 125

Baseline TVUS

Compliance

85% yearly CA 125

84% TVUS

Cancer Incidence:

212 Cases Intervention

176 Usual FU

Cancer Death

118 Intervention

100 Usual Care

NO DIFFERENCE OS

NO DIFFERENCE STAGE OF

DIAGNOSIS

77% III/IV INTERVENTION

78% III/IV USUAL CARE

United Kingdom Collaborative Trial of

Ovarian Cancer Screening (UKCTOCS)

3 level screening

CA 125 Level 1

Normal: repeat 1 year

Intermediate: repeat 12 weeks +/-

US

Abnormal: US

TVUS Level 2

Normal: TVUS 1 year

Intermediate: repeat TVUS 6 weeks

Abnormal: Referral Gyn Onc

UKCTOCS

MMS 50 078 women

45 523 (90.9%) low risk

4315 (8.6%) Interm risk

240 (0.5%) high risk level II

81 Surgery

42 malignancies (8 borderline)

33/42 (78%) cases detected with on level 1 screen

Median time to surgery 75 days

Interm Risk 9/42 (21.4%) malignancy

Time to OR 273.9 days

2.3 operations per case of cancer

Sensitivity: 89.5%

Specificity: 99.8%

US 48230 women

42 416 87.9%) TVUS, 4325 (9.0%) US, 1489 (3.1%) both

42451 (88.0%) Normal scan

2774 (5.8%) Abnormal Level II

5779 (12.0%) repeat scan

775 Surgery

45 malignancies (20 borderline)

45/45 (100%) detected on level 1 screen

Median time to surgery 81.5 days

18.8 operations per case of cancer

Sensitivity 82.9%

Specificity 99.0%

28/58 (48.3% )stage I/II , 30/58 ( 52%) stage III/ IV, no survival advantage

United Kingdom Familial Ovarian

Cancer Screening study

> 10% lifetime risk of ovarian

cancer

Family History

Mutation status

4531 Women

14 623 women screen years

12 309 Scans

Women were offered preventative

surgery vs.. screening

Yearly Blood Test CA 125

4 month Blood Test CA 125

Roca CA 125

TVUS annually or if ROCA increased

Gynecologist (central referral) if Abnormal

scan or ROCA increased

Stage Screen + Screen -

I 5 0

II 3 0

III 8 0

IV 0 0

Total 16 0

Sensitivity 100%

12/16 , 75% if occult cases

classified as screen negative

Stage I/II 50% screen positive for

malignancy

Uncertain if early diagnosis

resulted in improved outcomes

High risk population (BRCA +)

improved outcomes due to

platinum sensitivity and response

to PARPi

Challenge with screening

Screening summary

Symptom Index useful for identifying patients who need

investigations

Population based Screening

PLCO, UKTOCS UKTFOCS

Screening intervention did NOT increase diagnosis at earlier stage or

decrease mortality

No evidence for routine screening

Improve sensitivity/ specificity

High risk populations recommendation: Salpingo-oophorectomy

Treatment Of Ovarian Cancer

Surgery

Genetic testing

Systemic therapy

Chemotherapy

Anti-angiogenic agents

Parp Inhibition

Suspicion Ovarian Cancer,

treatment options?

Combination Therapy/ Discussion

Points

Surgery

Chemotherapy

Genetic Testing

Surgery for suspicion/ ovarian

cancer: TAH-BSO +/- Staging

Includes pelvic nodes, Para-aortic nodes, infracolic omentectomy,

multiple biopsies

+/-Appendectomy mucinous tumors. Consider also in all epithelial

tumors if suspicious of disease

Fertility - Preserve contra lateral ovary and uterus (Borderline tumors

certain Germ cell tumors)

30% of patients upstaged – hence impact on survival

Importance of Surgical staging in

clinical stage I disease

Location %

Positive Cytology 20

Omentum 6

Diaphragm 15

Peritoneal Biopsy 13

Para-Aortic Nodes 14

Pelvic Nodes 6

JB Trimblos, Int J gyne cancer,2000

Benefits of cytoreductive surgery for advanced

ovarian carcinoma

•Removal of large bulky tumors with poor blood supply

• Improved sensitivity of residual masses to postoperative

chemotherapy

•Greater likelihood of tumour eradication before

chemoresistance develops

Meigs (1934) concept surgical debulking

Griffiths (1970)

Published paper “optimal surgical debulking” ≤ 1.5 cm optimal survival benefit

Hacker(1983)”Primary cytoreductive surgery in ovarian cancer

< 5mm optimal survival rate

Hunter (1992)

“Meta-analysis of surgery in advanced ovarian carcinoma: Is maximum cytoreductive surgery and independent determinant of prognosis?

Chi (2006, 2009, 2012)

“ Analysis of patients with bulky advanced ovarian, bal and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical periods as randomized EORTC-NCIC trial of PDS vs.. neoadjuvant

Surgery

2 cm or less

Less than 1 cm

Maximal

surgical effort

R= 0 cm residual

microscopic

residual

Median survival by residual disease

Chi DS et al. Gynecol Oncol 2006

Residual disease Number of

patients

Median Survival

(months)

Microscopic 57 81

Gross <0.5 cm 51 56

Gross 0.5-1 cm 92 47

Gross 1-2 cm 53 31

Gross > 2 CM 172 34

Cytoreductive surgery meta-analysis

Each 10% increase in maximal cytoreduction associated with 4.1% increase in median survival time

Gynecologic oncologists – OR – 25% reduction in death compared to generalists in advanced cancers (P = 0.005)

Chi DS et al. Gynecol Oncol 2006

Survival in Ovarian Cancer

Influenced by:

stage

grade

histologic type

completeness of cytoreduction

Other favourable prognostic factors:

• younger age

• good performance status

• smaller disease volume prior to any surgical cytoreduction

• absence of ascites

Neoadjuvant chemotherapy in

Ovarian Cancer

Patient Factors

Advanced Age

Poor Performance status

Medical comorbities

Disease presentation/ Tumor Factors

Histologic Type

Distribution of disease

Chest

Mediastinum

Parynchemal liver disease

Porta Hepatis

Root mesenteric involvement

Neoadjuvant Chemotherapy

• Reduction operative/ perioperative mortality and morbidity

• Increase likelihood complete surgical resection R=0

• Assess response to chemotherapy

• Poor performance status

• Increase technical skill of surgery difficult due to fibrotic changes

• Formation of resistant clones?

• Median OS

– 29 months vs..... 30 months

• Median PFS

– 12 months in both groups

• Multivariate analysis:

– Residual tumor

– Stage IIIC

– Small tumor size pre-tx

– Histologic subtype

Complications:

Post-Op Death:

2.5% vs. 0.7%

Gr ¾ Hemorrhage:

7.4% vs. 4.1%

Infection:

8.1% vs. 1.7%

VTE:

2.6% vs. 0%

Ignace Vergote, NEJM 2010

Improved Debulking

Size of

residual

disease

Chi Group

(n= 285)

EORTC

PDS arm (n=

336)

No Gross

R =0

69 (24%) 61 (19.4%)

≤ 1 cm 134 (47%) 70 (22.2%)

> 1 cm 82 (29%) 167 (53%)

Missing 0 (0%) 17 (5.4%)

• 87 % stage IIIC vs..... 76.5 EORTC

• 33% upper abdominal debunking (spleen, liver, pancreas, GB)

• 27 vs..... N/A Grade 3-5 complications

• Symptomatic Pleural Effusion

• Pancreatic leak requiring drainage

• Infection/ abscess requiring drain

• Bleeding (surgical exploration)

• Aspiration pneumonia, respiratory failure, pneumothorax, anastomotic leak, GI bleed, SBO, ischemic colitis, perforated duodenal ulcer, Cardiac Arrest: (1/ 39)

• 2 vs..... 8 deaths in post-op period

Advantages of neoadjuvant chemotherapy

followed by IDS/ Delayed Primary Reduction

Procedures

• Decrease in morbidity and mortality

• Advantage in advanced cancer

Which treatment are Gynecologic

Oncologist Choosing?

ESGO/ SGO/ GOC

NATC medically unfit/ unressectable disease

50-60% pre-operative imaging not great indicator of intra-operative

findings

25-80% believe there is sufficient evidence to support surgery

Types of neoadjuvant

chemotherapy

Platinum

Carboplatin

Cell cycle non-specific

Alkylating Agent

Covalently binds to DNA

Pain

Metabolic

Hematologic

Hypersensitivity

Weakness

Renal Impairment

Taxanes

Paclitaxel

G2 Mitotic Phase

Inhibit cell replication

Cardiovascular

Neuropathy

Alopecia

GI: N,V,D,M

Hepatic

Infection

Renal Impairment

Adjuvant Treatment

Chemotherapy Anti-Angiogenic Therapy

Parp Inhibition

Chemotherapy Options

Platinum Based regimens; single vs.. doublets

IV Regimen

Dose dense regimen vs.. a Q3 weekly regimen

IP chemotherapy

HIPEC

Intra peritoneal chemotherapy

Majority of patients have disease

confined to peritoneum on

presentation

Higher peritoneal to plasma

concentrations (1000X)

Optimal cytoreduction essential

Penetration limits a few millimeters

IP Chemotherapy

Hyperthermic Intraperitoneal

Chemotherapy

Evidence from advanced GI

tumors and IP chemotherapy

protocols

1 treatment given after

neoadjuvant chemotherapy

Centers in Canada in clinical trial

setting: Montreal, Calgary, Toronto

1 Phase 3 RCT showing benefit in

neoadjuvant Patients

Other novel therapies

Anti-angiogenic agents

Parp Inhibition

Anti-angiogenic Therapies

Bevacizumab/Avastin

Indications

First line therapy

Suboptimally debulked stage III/IV ovarian cancer +/- maintenance

therapy PFS approx 4 months

Recurrent disease

Platinum sensitive (OCEANS) 4 month PFS 8 vs.. 12 months

Platinum Refractory (AURELIA) double PFS 3.4 to 6.8 Months

Genetics: Somatic vs Germline

Mutations

Genetic Mutations in Ovarian Cancer:

15-20% Germline 5% Somatic

BRCA1

BRCA2

Peutz-Jeghers STK11

Lynch associated mutations

MLH1

MSH2

MSH6

PMS2

EPCAM gene

ARID1A

PARP inhibitors exploit synthetic lethality in tumour cells with dysfunctional

HRR1-4

1. Helleday et al. Molecular Oncology 2011 5,387-393, 2. Aly A et al. J Mol Cell Biol. 2011, 3, 66-74, 3. Girolimetti et al. Biomed Research International. 2014; 4. O’Connor MJ. Mol Cell 2015;60:547–

560

In tumour cells with defective HRR, accumulation of cytotoxic DSBs lead to cell death1

Single strand break

PARP

Double strand breaks

Homologous recombination deficient

cancer cell

Increase in double

strand breaks

Cell death

Non-functioning HR

PARP inhibitor

58

Parp Inhibition

Study 19 PFS: 3.6 months, aprox 8 months for BRCA mutations

Solo 1: 60% patient on Olaparib remained progression free at 3 years

vs. 27% on chemotherapy alone

Median PFS not reached 54 months of follow-up

Solo 2 PFS: 13.6 months

Secondary Cytoreduction for

Recurrent Ovarian Cancer

• 9 non-randomized studies

• No RCTs

• Surgical effect vs.. tumor biology

Complete cytoreduction associated with significant improvement in survival

Study showed < 1 cm cytoreduction of benefit as compared to > 1 cm ( HR 3.51)

Desktop Criteria

Residual disease at 1st surgical attempt?

Functional status/ ECOG

Ascites

Resectability of recurrence; solitary lesion vs. multiple recurrences

Platinum sensitivity

Cochrane Database systems review, Galaab et al,2013

Treating recurrent disease

GOALS

Control Disease

Maintain

Quality of Life

Extend Survival

Risk Modification of Ovarian

cancer in all women

Protection

# of pregnancies

Breastfeeding

OCP

Tubal ligation

Hysterectomy

Risk

Early Menarche/ Late menopause

Obesity

Age

Demographics/ ethnicity

Endometriosis

Clinical Scenario

62 YO G4P3

2 months

Abdominal pain

Bloating

Reflux

Early Satiety

CA 125, 1000

CT scan

Omental nodules ,diaphragmatic

disease, pelvic mass, large volume

ascites

30 YO G0

Family History Malignancy

1 paternal cousin breast cancer,

living 45

Paternal Aunt breast cancer, living

70

Mother ovarian cancer, deceased

64

Would like information about

screening

Conclusion: Management of ovarian cancer

•Need to identify ovarian cancer prior to it being

at an advanced stage

•No role for screening with screening with current

screening modalities

•Surgical staging essential for early disease

•Aggressive surgery improves survival

•There is a role for neoadjuvant chemotherapy

•Novel Therapies may play an important role in

improving progression free survival and overall survival