Ovarian cancer Management APRIL ROBYN COMEAU MD FRCSC (OBGYN, GYNECOLOGIC ONCOLOGY)

Transcription

1 Ovarian cancer Management APRIL ROBYN COMEAU MD FRCSC (OBGYN, GYNECOLOGIC ONCOLOGY)

2 Disclosures Educational sessions Astra Zeneca Merc

3 Objectives Epidemiology Screening Symptoms based Populations based Low risk High risk Treatment Surgery Therapies Genetic Screening

4 Clinical Scenario 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 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

5 Ovarian Cancer Epidemiology 2800 New cases of ovarian cancer diagnosed each year in Canada In New Brunswick 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

6 Screening. SYMPTOM BASED VS... POPULATION BASED

7 Symptoms of ovarian cancer Early stage Advanced Stage Irregular menses Pelvic mass Pelvic mass Abdominal distension Urinary frequency Abdominal bloating Constipation Constipation Abdominal distension Nausea Abdominal pain Anorexia Abdominal pressure Early satiety dyspareunia AUB

8 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

9 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:

10 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

11 WHO Criteria for Population Screening Condition 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

12 Options for screening CA 125 Imaging

13 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

14 CA 125 Malignant Gynecologic: EOC: Ovary, FT, PP Endometrial Malignant Non-Gynecologic: Breast Colon Liver Pancreas/ Gallbladder Lung Hematologic Malignancies

15 CA 125 CA 125: sensitivity/ Specificity 80% Pre-operative CA 125? Prognostic factor for recurrence/ death of disease Pre-chemotherapy CA 125 ( U/mL)? Increased PFS/ OS CA-125 During Chemotherapy Normalization CA months of treatment independent predictor or progression of disease Eagle et al. The Oncologist 1997 vol 2 no. 5,

16 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)

17 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 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: 87% Specificity: 91% Sensitivity: 95 % Specificity: 87% PPV: 73% NPV: 96% PPV: 67% NPV: 98% British Journal of Obstetrics and gynecology August 1996, Vol 3, pp

18 Combined Population based Screening Trials: CA Ultrasound PLCO UKTOCS UKTFOCS

19 PLCO (13 Yr FU) women Multicenter US trial Baseline CA 125 Baseline TVUS Compliance 85% yearly CA % 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

20 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

21 28/58 (48.3% )stage I/II, 30/58 ( 52%) stage III/ IV, no survival advantage UKCTOCS MMS women (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 days 2.3 operations per case of cancer Sensitivity: 89.5% Specificity: 99.8% US women %) TVUS, 4325 (9.0%) US, 1489 (3.1%) both (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%

22 United Kingdom Familial Ovarian Cancer Screening study > 10% lifetime risk of ovarian cancer Family History Mutation status 4531 Women women screen years Scans Women were offered preventative surgery vs.. screening Yearly Blood Test CA month Blood Test CA 125 Roca CA 125 TVUS annually or if ROCA increased Gynecologist (central referral) if Abnormal scan or ROCA increased

23 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

24 Challenge with screening

25 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

26 Treatment Of Ovarian Cancer Surgery Genetic testing Systemic therapy Chemotherapy Anti-angiogenic agents Parp Inhibition

27 Suspicion Ovarian Cancer, treatment options?

28 Combination Therapy/ Discussion Points Surgery Chemotherapy Genetic Testing

29 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

30 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

31 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

32 R= 0 cm residual microscopic residual Maximal surgical effort Less than 1 cm Hunter (1992) Surgery 2 cm or less 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 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

33 Median survival by residual disease Residual disease Number of patients Median Survival (months) Microscopic Gross <0.5 cm Gross cm Gross 1-2 cm Gross > 2 CM Chi DS et al. Gynecol Oncol 2006

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

35 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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40 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

41 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?

42 Median OS 29 months vs 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

43 Improved Debulking Size of residual disease No Gross R =0 Chi Group (n= 285) EORTC PDS arm (n= 336) 69 (24%) 61 (19.4%) 87 % stage IIIC vs EORTC 33% upper abdominal debunking (spleen, liver, pancreas, GB) 27 vs... N/A Grade 3-5 complications 1 cm 134 (47%) 70 (22.2%) > 1 cm 82 (29%) 167 (53%) Missing 0 (0%) 17 (5.4%) 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

44 Advantages of neoadjuvant chemotherapy followed by IDS/ Delayed Primary Reduction Procedures Decrease in morbidity and mortality Advantage in advanced cancer

45 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

46 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

47 Adjuvant Treatment Chemotherapy Anti-Angiogenic Therapy Parp Inhibition

48 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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50 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

51 IP Chemotherapy

52 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

53 Other novel therapies Anti-angiogenic agents Parp Inhibition

54 Anti-angiogenic Therapies

55 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

56 Genetics: Somatic vs Germline Mutations

57 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

58 PARP inhibitors exploit synthetic lethality in tumour cells with dysfunctional HRR 1-4 In tumour cells with defective HRR, accumulation of cytotoxic DSBs lead to cell death 1 PARP inhibitor PARP Increase in double strand breaks Single strand break Double strand breaks Homologous recombination deficient cancer cell Non-functioning HR Cell death 1. Helleday et al. Molecular Oncology , , 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:

59 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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61 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 1 st surgical attempt? Functional status/ ECOG Ascites Resectability of recurrence; solitary lesion vs. multiple recurrences Platinum sensitivity Cochrane Database systems review, Galaab et al,2013

62 Treating recurrent disease Control Disease GOALS Maintain Quality of Life Extend Survival

63 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

64 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

65 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