Tim Broadhead Consultant Gynaecologist & Gynaecological Oncologist Ovarian Cancer Tim Broadhead Consultant Gynaecologist & Gynaecological Oncologist

Ovarian Cancer Introduction Pathology Aetiology Staging Symptoms & Examination Tests Treatment Future Developments

Introduction 6700 cases in UK each year 5th commonest cancer in women Lifetime risk 1 in 48 Higher incidence in postmenopausal women

Introduction Poor prognosis & rarely cured 4300 die each year Leading cause of death from gynae cancer Advanced disease at presentation Median PFS ~1 to 2 years Median OS ~ 2.5 years 5yr survival ~ 30% 1090 patients Leeds Cancer Centre 1990-2005

Pathology Ovarian cancer subtypes Primary peritoneal cancer Epithelial (90%) Serous Endometrioid Mucinous Clear cell Germ cell tumours (10%) Sex-cord stromal cell tumours (rare) Primary peritoneal cancer

Aetiology Most cases sporadic “Incessant Ovulation Theory” Diet Pregnancy / COCP protective Diet Animal fat / Galactose / Alcohol Environmental factors Talc exposure Hysterectomy / Tubal Ligation

Aetiology Hereditary 5-10% Breast / Ovarian Cancer Syndrome BRCA1 (up to 60% lifetime risk) BRCA2 (up to 25% lifetime risk) Tumour suppressor genes HNPCC syndrome Mutations of mismatch repair genes

FIGO Staging I – confined to ovary II – confined to pelvis

FIGO Staging III - abdominal extension or lymph nodes IV - distant metastases

Staging Importance of stage 5 year survival Stage 1 - 90% 60% 20% 1090 patients Leeds Cancer Centre 1990-2005

Symptoms “Silent Killer” 1 case every 5 years 1 every 25,000 consultations

Symptoms “Ovarian cancer is not silent, rather its sound is going unheard”

Symptoms Earlier diagnosis and correct pathway sooner - improved survival?

Symptoms Carry out tests if any of the following on a frequent basis – more than 12 times a month (esp if >50 years old) Persistent abdo distension Feeling full, loss of appetite or both Pelvic or abdo pain Increased urinary urgency, frequency or both

Symptoms Carry out appropriate tests for ovarian cancer in any woman of 50 or over who has experienced symptoms within the last 12 months that suggest irritable bowel syndrome (IBS) “ITS NOT IBS, ITS OVARIAN CANCER”

Symptoms Consider tests if: Unexplained weight loss Fatigue Changes in bowel habit Advise any woman who is not suspected of having ovarian cancer to return to her GP if her symptoms become more frequent and/or persistent

Examination Abdo / pelvic examination Pelvic mass → Ascites Abdo mass Refer the woman urgently if physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids) →

Which Tests ? CA125 tumour associated antigen normal level <35 iu/ml  85% epithelial ovarian cancer but also in benign conditions (fibroids, PID, endometriosis)  in only 50% of stage 1 ovarian cancer

Which Tests? If CA125 >35 arrange USS abdo / pelvis Benign Malignant

First tests in primary care Measure serum CA125 35 IU/ml or greater Less than 35 IU/ml Assess carefully: are other clinical causes of symptoms apparent? Ultrasound of abdomen and pelvis Normal NOTES FOR PRESENTERS: Key points to raise: Detection in primary care (see also algorithm on page 7 of the QRG) This slide relates to the key priorities for implementation about asking the right questions Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer. The majority of women with symptoms suggestive of ovarian cancer will not have ovarian cancer, so symptoms alone are not sufficient to refer to secondary care. An initial test using an objective and standardised assessment in symptomatic women reduces observer variability. Serum tumour markers fulfil these criteria. CA125 is currently the most widely used and reliable ovarian cancer tumour marker. The clinical evidence demonstrated that no single test on its own adequately selected a manageable number of women for referral to secondary care. The combination of raised serum CA125 and sequential ultrasound of the abdomen and pelvis reduced significantly the number of women who would be referred, although a greater proportion of symptomatic women would be directed to the right pathway in a more timely fashion. Additional information: There is considerable variation in practice across the UK as to what tests are currently performed in primary care. In addition, many women are being referred to other specialists in error. Recommendations in full: KPIs Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see section 1.1.1) [1.1.1.2] • If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis. [1.1.2.2] • For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound: assess her carefully for other clinical causes of her symptoms and investigate if appropriate if no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent [1.1.2.4] Related recommendation: If the ultrasound suggests ovarian cancer, refer the woman urgently1 for further investigation2 [1.1.2.3] 1 An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2 weeks. 2 See also ‘Referral guidelines for suspected cancer’ (NICE clinical guideline 27; available at www.nice.org.uk/guidance/CG27) for recommendations about the support and information needs of people with suspected cancer. Suggestive of ovarian cancer Yes No Refer urgently Investigate Advise to return to GP if symptoms become more frequent and/or persistent 21

Detection in primary care Women presents to GP Ascites and/or pelvic or abdominal mass GP assesses symptoms Support and information Tests in primary care NOTES FOR PRESENTERS: Key points to raise: In this next section we will now discuss ‘awareness of symptoms and signs’ and the first tests outlined in the guideline. For a more detailed algorithm on ‘detection in primary care’ see page 7 of the QRG. A podcast explaining primary care tests and clinical case scenarios has been produced to support implementation of the guidance – see slide 27 Suspicion of ovarian cancer Urgent referral: assessment in secondary care 23

Establishing the diagnosis CT scan Complex pelvic mass Omental cake Liver surface deposits

Establishing the diagnosis Discuss in MDT Suspected early stage disease → local cancer unit Advanced disease → cancer centre

Treatment of Early Ovarian Cancer

Surgery Suspected early stage disease Staging Laparotomy TAH / BSO Infracolic omentectomy Pelvic / PA node sampling Peritoneal washings Biopsies of peritoneum Fertility sparing surgery Laparoscopic surgery

Surgery

Staging Stage important in prognosis and treatment 5 year survival 60% 20% 5 year survival Stage 1 - 90% Stage 2 - 65% Stage 3 - 35% Stage 4 - 10% 1090 patients Leeds Cancer Centre 1990-2005

Treatment of Advanced Disease Surgery or Primary Chemotherapy?

Surgery for advanced disease “Debulking surgery” Complete debulking - aim to leave no macroscopic disease Optimal debulking <1cm Bowel resection / stoma / splenectomy / peritoneal stripping / pelvic & PA lymphadenectomy

Surgery for advanced disease MDT review Disease considered resectable Medically fit → debulking surgery

Surgery Volume of residual disease directly determines survival Optimal debulking 39 months (median survival) Sub-optimal debulking 17 months (median survival) Surgical skill or tumour biology?

“Inoperable disease”

Neoadjuvant Chemotherapy and Interval Debulking Surgery Disease not resectable Medically unfit Scan guided core biopsy 3 cycles chemo → IDS → 3 cycles chemo

Neoadjuvant Chemotherapy and Interval Debulking Surgery Future standard of care? Reduced morbidity and mortality Results of CHORUS awaited

Chemotherapy Early stage disease

Early stage disease Stage I & II Died Alive

Early stage disease Stage I & II Adjuvant Chemotherapy - Increase chance of cure Died Cured by chemo Alive ICON1/Action: JNCI 2003

Early stage disease Current practice Likely benefit Uncertainty Stage 1c or higher Grade 3 Clear cell histology Uncertainty Peri-operative rupture (surgical 1c) Inadequate staging Chemotherapy vs repeat staging procedure

Chemotherapy Advanced disease

Chemotherapy Stage III & IV disease Control cancer Prolong life Improve symptoms First line Highly effective 70-80% response rate Median Progression Free Survival 1-2 years Median Overall Survival 3 years 30% 5 year survival Some long term survivors Palliative

Epithelial Ovarian Cancer First-line chemotherapy Carboplatin & Paclitaxel 6 cycles - 3-weekly 18 weeks - weekly (low dose) Carboplatin

Chemotherapy Side effects Fatigue Nausea & vomiting Myelosupression Anaemia, risk of infection Hair loss Neuropathy Mucositis Skin & nail changes Allergic reactions

Future Developments Prevention Screening for early disease Surgery Risk reducing surgery for BRCA mutations Reduced to 1% (PPC) / Breast Ca reduced 50% Screening for early disease Unknown Awaiting results of UKTOCSS / UKFOCSS Surgery Ultra-radical or IDS

Future Developments Chemotherapy Improved systemic therapy Increased dose intensity Biological agents e.g. VEGF inhibitors Improved therapy delivery Intraperitoneal chemo

Future developments Intra-peritoneal chemotherapy Suggestion of improved survival Increase in side effects

Summary Poor prognosis due to late presentation Early disease curable Advanced disease treatable but not curable

Summary Will NICE guidelines make any difference? Investment in additional tests in primary care Increase in referrals to secondary care Improved outcomes due to earlier diagnosis? Less likely to present with advanced cancer? Reduced referrals to other specialties? ITS NOT IBS, ITS OVARIAN CANCER!!

Thank You tim.broadhead@leedsth.nhs.uk