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Ovarian cancer
ManagementAPRIL 12 2019
ROBYN COMEAU MD FRCSC (OBGYN, GYNECOLOGIC ONCOLOGY)
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Disclosures
Educational sessions
Astra Zeneca
Merc
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Objectives
Epidemiology
Screening
Symptoms based
Populations based
Low risk
High risk
Treatment
Surgery
Therapies
Genetic Screening
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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
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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
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Screening….SYMPTOM BASED VS..... POPULATION BASED
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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
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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
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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.
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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
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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
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Options for screening
CA 125 Imaging
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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
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CA 125
Malignant
Gynecologic:
EOC: Ovary, FT, PP
Endometrial
Malignant
Non-Gynecologic:
Breast
Colon
Liver
Pancreas/ Gallbladder
Lung
Hematologic Malignancies
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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
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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
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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
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Combined Population based
Screening Trials: CA 125 + Ultrasound
PLCO
UKTOCS
UKTFOCS
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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
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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
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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
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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
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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
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Challenge with screening
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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
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Treatment Of Ovarian Cancer
Surgery
Genetic testing
Systemic therapy
Chemotherapy
Anti-angiogenic agents
Parp Inhibition
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Suspicion Ovarian Cancer,
treatment options?
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Combination Therapy/ Discussion
Points
Surgery
Chemotherapy
Genetic Testing
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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
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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
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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
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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
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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
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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
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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
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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
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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?
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• 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
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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
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Advantages of neoadjuvant chemotherapy
followed by IDS/ Delayed Primary Reduction
Procedures
• Decrease in morbidity and mortality
• Advantage in advanced cancer
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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
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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
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Adjuvant Treatment
Chemotherapy Anti-Angiogenic Therapy
Parp Inhibition
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Chemotherapy Options
Platinum Based regimens; single vs.. doublets
IV Regimen
Dose dense regimen vs.. a Q3 weekly regimen
IP chemotherapy
HIPEC
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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
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IP Chemotherapy
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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
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Other novel therapies
Anti-angiogenic agents
Parp Inhibition
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Anti-angiogenic Therapies
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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
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Genetics: Somatic vs Germline
Mutations
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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
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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
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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
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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
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Treating recurrent disease
GOALS
Control Disease
Maintain
Quality of Life
Extend Survival
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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
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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
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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