OVARIAN CANCEROVARIAN CANCER

New NICE guidelines and the New NICE guidelines and the research behind themresearch behind them

Journal Club 20/5/11Journal Club 20/5/11Natalie Brown and Matthew ParkesNatalie Brown and Matthew Parkes

ContentContent

• Summary of NICE guidelinesSummary of NICE guidelines

• Critical appraisal of paperCritical appraisal of paper– Anderson M, Goff B, Lowe K et al. Use of Anderson M, Goff B, Lowe K et al. Use of

symptom index, CA125 and HE4 to symptom index, CA125 and HE4 to predict ovarian cancer. predict ovarian cancer. Gynecol OncolGynecol Oncol 2010 March 116(3): 378. 2010 March 116(3): 378.

• DiscussionDiscussion

NICE guidelines: Ovarian NICE guidelines: Ovarian CancerCancer• The recognition and initial management of ovarian The recognition and initial management of ovarian

cancer – published April 2011cancer – published April 2011• Guidelines produced to focus on areas of Guidelines produced to focus on areas of

uncertainty and when wide variation in clinical uncertainty and when wide variation in clinical practicepractice

• StatisticsStatistics– 5th most common cancer in women (1 in 20 5th most common cancer in women (1 in 20

cases of cancer) and risingcases of cancer) and rising– Leading cause of death from gynaecological Leading cause of death from gynaecological

cancer (4,300 women die from ovarian cancer cancer (4,300 women die from ovarian cancer each year in the UK)each year in the UK)

– Overall 5 year survival 35%Overall 5 year survival 35%– Approximately 6,700 new cases of ovarian Approximately 6,700 new cases of ovarian

cancer were diagnosed every year in United cancer were diagnosed every year in United Kingdom between 2004 and 2007Kingdom between 2004 and 2007

Clinical question: What are the Clinical question: What are the symptoms and signs of ovarian symptoms and signs of ovarian cancer?cancer?

Recognition in primary care : Recognition in primary care : when to measure CA-125when to measure CA-125

• Symptoms present particularly >12 times per Symptoms present particularly >12 times per month (especially if >50yo)month (especially if >50yo)– Persistent abdominal distension (‘bloating’)Persistent abdominal distension (‘bloating’)– Early satiety and/or loss of appetiteEarly satiety and/or loss of appetite– Pelvic or abdominal painPelvic or abdominal pain– Increased urinary urgency and/or frequencyIncreased urinary urgency and/or frequency

• Alternatively, suspect in a woman over 50 who has Alternatively, suspect in a woman over 50 who has developed ‘IBS’ symptoms in the last yeardeveloped ‘IBS’ symptoms in the last year

• Also measure if experiencing weight loss, change in Also measure if experiencing weight loss, change in bowel habit or fatigue and ovarian cancer is bowel habit or fatigue and ovarian cancer is suspectedsuspected

When to avoid CA-125 in When to avoid CA-125 in primary careprimary care

• If a woman has ascites and/or an If a woman has ascites and/or an abdominal or pelvic mass on clinical abdominal or pelvic mass on clinical examination that is ‘not obviously examination that is ‘not obviously due to uterine fibroids’due to uterine fibroids’

• Refer urgently (2 week referral) to Refer urgently (2 week referral) to secondary caresecondary care

Investigation after CA-125 Investigation after CA-125 results in primary careresults in primary care

• If CA-125 > 35, arrange USS If CA-125 > 35, arrange USS abdomen and pelvisabdomen and pelvis– If USS suggestive of ovarian cancer, If USS suggestive of ovarian cancer,

refer urgently (2ww)refer urgently (2ww)– If normal USS consider other causesIf normal USS consider other causes

• If CA-125<35, consider other causesIf CA-125<35, consider other causes

Establishing the diagnosis in Establishing the diagnosis in secondary caresecondary care

• Need to have USS or CA-125 if not Need to have USS or CA-125 if not already donealready done

• If under 40 years old, measure beta-If under 40 years old, measure beta-hCG and AFP to identify those who hCG and AFP to identify those who may not have epithelial ovarian may not have epithelial ovarian cancercancer

• Next calculate RMI score and refer to Next calculate RMI score and refer to MDT if score >250MDT if score >250

Risk of malignancy index Risk of malignancy index (RMI)(RMI)• RMI = score based on combination of USS RMI = score based on combination of USS

findings, menopausal status and CA-125 levelfindings, menopausal status and CA-125 level

• USS score; 1 point if one of the following USS score; 1 point if one of the following present, 3 points if 2-5 of the following present, 3 points if 2-5 of the following presentpresent– Multilocular cystsMultilocular cysts– Solid areasSolid areas– MetastasesMetastases– AscitesAscites– Bilateral lesionsBilateral lesions

RMI continuedRMI continued

• Menopausal statusMenopausal status– 1 point if pre-menopausal1 point if pre-menopausal– 3 points if post-menopausal3 points if post-menopausal

• CA-125CA-125– Use the value itselfUse the value itself

• Eg a post menopausal lady with ascites Eg a post menopausal lady with ascites and solid areas on USS, and CA-125 of 50 and solid areas on USS, and CA-125 of 50 has an RMI of 3 x 3 x 50 = 300has an RMI of 3 x 3 x 50 = 300

• If RMI is 250 or greater, must be referred If RMI is 250 or greater, must be referred to specialist MDTto specialist MDT

Further investigation in Further investigation in secondary caresecondary care

• If overall picture suggestive of ovarian If overall picture suggestive of ovarian cancer, needs CT pelvis, abdomen +/- cancer, needs CT pelvis, abdomen +/- thorax to assist with stagingthorax to assist with staging

• MRI not routinely advisedMRI not routinely advised• Tissue diagnosis – generally recommend Tissue diagnosis – generally recommend

if contemplating chemotherapyif contemplating chemotherapy– Percutaneous image guided biopsyPercutaneous image guided biopsy– Laparoscopic biopsyLaparoscopic biopsy

Summary of clinical Summary of clinical managementmanagement

• Stage IStage I– OophorectomyOophorectomy– Retroperitoneal lymph node assessmentRetroperitoneal lymph node assessment– 1a and 1b – no chemotherapy1a and 1b – no chemotherapy– 1c and above – adjuvant chemotherapy1c and above – adjuvant chemotherapy

• Stage II-IVStage II-IV– Surgical objective = complete removal of all Surgical objective = complete removal of all

macroscopic diseasemacroscopic disease– Intraperitoneal chemotherapy only used in Intraperitoneal chemotherapy only used in

Trials at presentTrials at present

Summary of holistic Summary of holistic managementmanagement

• FertilityFertility

• SexualitySexuality

• GeneticsGenetics

• PhysiotherapyPhysiotherapy

• Self-help strategiesSelf-help strategies

• CounsellingCounselling

• Support groupsSupport groups

Further research Further research recommendationsrecommendations

• Further research should be undertaken Further research should be undertaken on the relationship between the on the relationship between the duration and frequency of symptoms duration and frequency of symptoms in women with ovarian cancer before in women with ovarian cancer before diagnosis, the stage of disease at diagnosis, the stage of disease at diagnosis and subsequent survival.diagnosis and subsequent survival.

• Large multicentre case–control studies Large multicentre case–control studies should be conducted to compare the should be conducted to compare the accuracy of CT versus MRI for staging accuracy of CT versus MRI for staging in women with ovarian cancer.in women with ovarian cancer.

Critical Appraisal of journal Critical Appraisal of journal articlearticle

• Anderson M, Goff B, Lowe K et al. Use Anderson M, Goff B, Lowe K et al. Use of symptom index, CA125 and HE4 to of symptom index, CA125 and HE4 to predict ovarian cancer. predict ovarian cancer. Gynecol Gynecol OncolOncol 2010 March 116(3): 378. 2010 March 116(3): 378.

• Using ‘CASP’ framework via BWH Using ‘CASP’ framework via BWH Trust library homepageTrust library homepage

Did the study address a clearly Did the study address a clearly defined issue?defined issue?

• To evaluate to use of symptom index To evaluate to use of symptom index with serum HE4 or Ca-125 alone and with serum HE4 or Ca-125 alone and in combination to predict ovarian in combination to predict ovarian cancercancer

Did the authors use an Did the authors use an appropriate method to answer appropriate method to answer their question?their question?

• Prospective case-control studyProspective case-control study– 74 women with ovarian cancer74 women with ovarian cancer– 137 ‘healthy’ women as controls137 ‘healthy’ women as controls

Were the cases recruited in an Were the cases recruited in an acceptable way?acceptable way?

• Cases were recruited from a group Cases were recruited from a group that had positive imaging suggesting that had positive imaging suggesting ovarian cancer and were surveyed ovarian cancer and were surveyed prior to surgery and before receiving prior to surgery and before receiving a definitive diagnosis of ovarian a definitive diagnosis of ovarian cancercancer

Were the controls recruited in Were the controls recruited in an acceptable way?an acceptable way?

• All controls have family histories All controls have family histories consistent with inherited consistent with inherited susceptibility for ovarian cancersusceptibility for ovarian cancer

Was exposure accurately Was exposure accurately measured to avoid bias?measured to avoid bias?

What confounding factors have What confounding factors have the authors accounted for?the authors accounted for?

• Control group selection bias and the ability Control group selection bias and the ability to record and recall symptoms more to record and recall symptoms more specific to ovarian cancerspecific to ovarian cancer

• Recall bias of patients awaiting surgery Recall bias of patients awaiting surgery and ability to remember recent symptoms and ability to remember recent symptoms than a high risk control groupthan a high risk control group

• Study does not have detailed information Study does not have detailed information for imaging resultsfor imaging results

• The study did not look at case notes to see The study did not look at case notes to see if symptoms had been clinically reported – if symptoms had been clinically reported – only took results from their own surveyonly took results from their own survey

What are the results?What are the results?

• As a single marker CA-125 had the highest As a single marker CA-125 had the highest overall sensitivity 81.1% and specificity of overall sensitivity 81.1% and specificity of 95%95%

• HE4 had the highest sensitivity in high risk HE4 had the highest sensitivity in high risk cases, overall sensitivity 77% and cases, overall sensitivity 77% and specificity 95%specificity 95%

• Symptom index alone showed sensitivity Symptom index alone showed sensitivity of 63.5% and specificity of 88.3%of 63.5% and specificity of 88.3%

• Any 2 of 3 above positive sensitivity 83.8% Any 2 of 3 above positive sensitivity 83.8% and specificity of 98.5%and specificity of 98.5%

How precise are the results?How precise are the results?

• Wide confidence intervals for resultsWide confidence intervals for results

Do you believe the results?Do you believe the results?

• Unable to comment on quality and Unable to comment on quality and appropriateness of ‘survey’appropriateness of ‘survey’

• Measuring of serum markers Measuring of serum markers appropriateappropriate

Can the results be applied to Can the results be applied to the local population?the local population?

• USA studyUSA study

• Symptom reporting different across Symptom reporting different across Atlantic?Atlantic?

• Tumour markers ? Universal across Tumour markers ? Universal across populationspopulations

Do the results fit with other Do the results fit with other available evidence?available evidence?

HE4

- Consistent evidence across studies suggesting HE4 better than Ca-125

- Also suggests that the combination of HE4 and CA125 is more specific, but less sensitive than either marker in isolation.