cancer screening in women… update jodi friedman, md david geffen school of medicine at ucla

Cancer Screening in Cancer Screening in Women… UpdateWomen… Update

Jodi Friedman, MDDavid Geffen School of Medicine at UCLA

Principles of PreventionPrinciples of Prevention

FIRST DO NO HARM!

– asymptomatic, by definition

– predominantly healthy population

– evidence-based medicine

Principles of PreventionPrinciples of Prevention

Where do Preventive Services recommendations come from?

USPSTF, CTFPHC

• extensive review of literature

• rigorous requirements of proof of efficacy Various subspecialty organizations

What the USPSTF Grades Mean and Suggestions for Practice

Ann Intern Med 2009;151:716-726

©2009 by American College of Physicians

Principles of ScreeningPrinciples of Screening

Appropriateness of a screening test

• the disease

• the test

• the population

Potential Adverse Effects of Potential Adverse Effects of ScreeningScreening

– physical complications of the test– consequences of false positives

• anxiety

• complications from work-up

• labeling/insurability

– over treating insignificant abnormalities– financial costs

ScreeningScreening

Cervical Cancer Breast Cancer Colorectal Cancer Lung Cancer Ovarian Cancer

Cervical Cancer ScreeningCervical Cancer Screening

Since early 1970’s, mortality has decreased 74%

Largely attributable to screening with the Pap smear

Majority of disease now occurs in women with inadequate screening

Cervical CancerCervical Cancer

Progression: HPV infxn high grade lesion invasive disease

On average, initial HPV infxn to invasive cancer takes 10-20 years

Lifetime risk of acquiring at least 1 HPV infxn estimated as high as > 90%

Majority of these infections are transient

Cervical CancerCervical Cancer

Over 100 HPV types, 13 are associated with cervical intraepithelial neoplasia

Most HPV infxns never progress beyond low grade disease (CIN 1)• Women 15-25 years of age ~ 80% of HPV

infections are transient

80 -90% of low grade cervical abnormalities will regress spontaneously

HPV TestingHPV Testing

2 commercially available assays for the “oncogenic” HPV types

These 13 types account for ~ 90% of HPV types associated with HSIL and cervical cancer

HPV TestingHPV Testing

Most established role of testing is to “triage” ASCUS results• HPV + : double the probability of

HSIL (15%)• HPV - : less than 1% chance of HSIL

Role in primary screening less well-established

Current Current RecommendationsRecommendations

USPSTF (2003)• begin w/in 3 yrs of first sexual activity or 21

yo, whichever first• after 2-3 normal annual Paps, screen every 3

yrs• in women who have had adequate screening

(3 Paps in preceding 10 years) stop at 65• no screening if hysterectomy for benign

causes

Current Current RecommendationsRecommendations

ACS (2009)• begin w/in 3 yrs of first sexual activity or 21 yo,

whichever first• annual Paps until age 30 (or q 2 yrs with liquid-based

cytology)• after 3 normal annual Paps

• may begin every 2-3 yr screening • may opt for HPV and Pap testing every 3 years

• annual screening if HIV, DES exposure, or significant immunosuppression

• if adequate screening, stop at 70

Current Current RecommendationsRecommendations

ACOG (11/2009)• begin at age 21• every 2 years Paps until age 30 • Age 30 and older, after 3 consecutive normal Paps

should be screened once every 3 years• annual screening if HIV, DES exposure, or

significant immunosuppression• may stop at 65 – 70 if

• 3 negative cytology results in a row• No abnormal test in the past 10 years

Breast CancerBreast Cancer

Most prevalent cancer in women Second leading cause of cancer deaths Average lifetime risk of developing breast

cancer is 1 in 8• 40’s: 1 in 69• 50’s: 1 in 38• 60’s: 1 in 27

Breast Cancer ScreeningBreast Cancer Screening

Breast Self Exam

Clinical Breast Exam

Mammography

MRI

Breast Self Exam (BSE)Breast Self Exam (BSE)

2 RCT’s, 1 large non-RCT F/U 5-13 yrs No reductions in mortality No significant improvement in # or stage of

cancers detected 2-fold increase in biopsies (benign) in BSE

grps

Clinical Breast ExamClinical Breast Exam

No direct evidence comparing CBE alone to no screening

Reductions in mortality observed when used with mammography

Reductions in mortality in mammography trials alone similar to that using CBE with mammography

MammographyMammography

Positive predictive value

• Aged 40-49: 1-4%

• Aged 50-59: 4-9%

• Aged 60-69: 10-19%

• 70 and over: 18-20%

MammographyMammography

9 RCTs: 0-32% mortality reduction Meta-analysis shows:

• 50 yo and over: RR = 0.78 (CI, .70-.87)• 22% reduction in breast cancer mortality

• 40-49 yo: RR=0.85 (CI, .77-.97)• 15% reduction in breast cancer mortality

Only 1 study included women up to 74 yo• No statistically significant benefit in women 70-74 but

numbers small

Pooled relative risk for breast cancer mortality from mammography screening trials compared with control for women aged 39 to 49 years.CNBSS-1 = Canadian National Breast Screening Study-1; CrI = credible interval; HIP = Health Insurance

Plan of Greater New York.* Swedish Two-County trial.

Nelson H D et al. Ann Intern Med 2009;151:727-737

©2009 by American College of Physicians

NNI to Prevent 1 Breast NNI to Prevent 1 Breast Cancer DeathCancer Death

39 – 49 yo 1904

50 – 59 yo 1339

60 – 69 yo 377

Frequency of Mammographic Frequency of Mammographic ScreeningScreening

Trials range from 12-33 month intervals Decision analysis study (USPSTF)

• Biennial screening produced 81% of the benefit of annual screening

• Half the number of false positives and unnecessary biopsies

MRIMRI

14 prospective trials in hi-risk women (20-80% lifetime risk)

No studies have demonstrated MRI reduces risk of death from breast cancer

Sensitivity 71-100%• vs. 16-40% with mammo or utz

Specificity 81 – 97%• vs. 93 -99% with mammo

USPSTF Breast Cancer Screening USPSTF Breast Cancer Screening Recommendations (2009)Recommendations (2009)

The USPSTF recommends biennial screening mammography for women aged 50 to 74 years. Grade: B recommendation.

The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take patient context into account, including the patient's values regarding specific benefits and harms. Grade: C recommendation.

USPSTF Breast Cancer Screening USPSTF Breast Cancer Screening Recommendations (2009)Recommendations (2009)

The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older. Grade: I Statement.

The USPSTF recommends against teaching breast self-examination (BSE).Grade: D recommendation.

USPSTF Breast Cancer Screening USPSTF Breast Cancer Screening Recommendations (2009)Recommendations (2009)

The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of clinical breast examination (CBE) beyond screening mammography in women 40 years or older. Grade: I Statement.

The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of either digital mammography or magnetic resonance imaging (MRI) instead of film mammography as screening modalities for breast cancer. Grade: I Statement.

Other Groups’ Other Groups’ RecommendationsRecommendations

AAFP (2009) – AAFP (2009) – all recommendations in agreement with new USPSTF guidelines

ACSACS• Begin annual mammography at 40• CBE q 3 yr 20-40, yearly after 40• BSE option, beginning at 20

Screening Screening Recommendations: MRIRecommendations: MRI

ACS now recommends annual MRI (in addition to mammo) for women with lifetime risk estimate at least 20-25%

Also recommended for women with h/o chest irradiation for HD

? When to begin ? Personal h/o breast CA, LCIS, ADH

ASCO Screening ASCO Screening Recommendations for High-Risk Recommendations for High-Risk WomenWomen

Screening breast MRI appears to be more sensitive than mammography in high-risk women

BRCA 1/2 carriers should be screened with annual MRI, mammography and possibly ultrasound

The decision to use breast MRI in high-risk patients should be made on an individual basis

Colorectal Cancer (CRC)Colorectal Cancer (CRC)

Third leading cause of cancer deaths Lifetime incidence is 5%, lifetime

mortality is 2.5%• 1 first-degree relative, RR=1.7• 2 first-degree relatives, RR=2.7

Highest risk - familial polyposis syndromes and long-standing UC

Fecal occult blood testing Fecal occult blood testing (FOBT)(FOBT)

4 RCTs – all show mortality benefit

• Over 46,000 subjects ages 50-80• annual FOBT v. no screening

• 33% reduction in CRC mortality

• Biennial FOBT ages 45-74• 15% - 18% reduction in mortality

Flexible SigmoidoscopyFlexible Sigmoidoscopy

2 large case-control studies - 60% reduction in risk of death from CRC

1 RCT – showed increased detection rate of adv neoplasms and cancers compared to FOBT

Detects approx 50% of CRCs and adenomatous polyps• up to 3% of pts screened will have

advanced neoplasm that sigmoidoscopy will miss

ColonoscopyColonoscopy

No RCTs Identification and removal of adenomas is the

central element of reducing CRC incidence and mortality

One case-control study showed odds ratio for CRC mortality was 0.43

All other screening strategies include colonoscopy

Screening Recommendations Screening Recommendations (2008)(2008)

The USPSTF recommends screening for colorectal cancer (CRC) using fecal occult blood testing, sigmoidoscopy, or colonoscopy, in adults, beginning at age 50 years and continuing until age 75 years. The risks and benefits of these screening methods vary.  

Grade: A Recommendation The USPSTF recommends against routine screening for

colorectal cancer in adults age 76 to 85 years. There may be considerations that support colorectal cancer screening in an individual patient. Grade: C Recommendation

Screening Recommendations Screening Recommendations (2008)(2008)

The USPSTF recommends against screening for colorectal cancer in adults older than age 85 years. Grade: D Recommendation

The USPSTF concludes that the evidence is insufficient to assess the benefits and harms of computed tomographic colonography and fecal DNA testing as screening modalities for colorectal cancer. Grade: I Statement.

CRC ScreeningCRC Screening

Most groups agree that any strategy patient agrees to should be offered:• annual FOBT• sigmoidoscopy q 5 ys• annual FOBT + flex sig q 5 yrs• colonoscopy q 10 yrs

CRC screening is cost-effective at less than $30K per year saved regardless of strategy

Lung CancerLung Cancer

Leading cause of cancer-related death among women and men in the US.

Average 5-yr survival rates < 15%• 70% for stage I• < 5% for stage IV

USPSTF 1996 recommended against screening based on RCT data of CXR and sputum cytology screening

CXR +/- Sputum CytologyCXR +/- Sputum Cytology

6 RCTs (men only)

• varying screening intervals

• no benefit to those screened

• all studies limited by some level of screening in control groups

Mortality in randomized, controlled trials of lung cancer screening with chest radiography with or without sputum cytologic examination.

Humphrey L L et al. Ann Intern Med 2004;140:740-753

©2004 by American College of Physicians

Low Dose CT (LDCT)Low Dose CT (LDCT)

Sensitivity 4 times greater than CXR 8 cohort studies using LDCT

• lung cancer diagnosed at earlier stage

• high rate of FPs

• cannot evaluate mortality outcomes without control groups

Low Dose CT (LDCT)Low Dose CT (LDCT)

RCTs

• National Lung Screening Trial (NCI)• LDCT vs. CXR

• NELSON Trial (Dutch study)• LDCT vs. no screening

National Lung Screening National Lung Screening TrialTrial

RCT

• >53,000 current or former heavy smokers

• Age 55 – 74

• 3 annual screenings with LDCT vs. CXR

• 90% statistical power to detect 20% mortality reduction

National Lung Screening National Lung Screening TrialTrial

On October 28, 2010 the DSMB stopped the trial

A 20% reduction in lung cancer deaths was found in the LDCT screened group

6.9% reduction in all-cause mortality (secondary endpoint)

Await full publication of the results

USPSTF May, 2004USPSTF May, 2004

I Recommendation fair evidence that screening with LDCT, CXR, or sputum

cytology can detect lung cancer at an earlier stage than lung cancer would be detected in an unscreened population

poor evidence that any screening strategy for lung cancer decreases mortality

because of the invasive nature of diagnostic testing and the possibility of a high number of false-positive tests in certain populations, there is potential for significant harms from screening

Ovarian CancerOvarian Cancer

Fifth leading cause of cancer-related death in women

Low incidence in general population• overall incidence is 17 per 100,000• in women over 50, 44 per 100,000

for average risk women, an abnormal screening test will have a 1-4% positive predictive value

Ovarian Cancer ScreeningOvarian Cancer Screening

Screening is Problematic

• Low PPV (low prevalence)

• High mortality

• No well-defined precursor lesion

• FPs lead to serious morbidity

Ovarian Cancer ScreeningOvarian Cancer Screening

CA-125 Transvaginal Ultrasound 16 Fair-poor quality cohort studies:

• Sensitivities 80-100%

• False positives .6-2.5%

Ovarian Cancer ScreeningOvarian Cancer Screening

1 RCT of multimodal screening• non-statistically signif improvement in

stage 1 detection (50% vs. 5%) 2 large cohort studies of UTZ

• 59-65% diagnosed in stage 1 No evidence that detecting early stage cancer

through screening decreases mortality 3 RCTs in progress to evaluate mortality

Ovarian Cancer ScreeningOvarian Cancer Screening

USPSTF (2004): D recommendation There is no existing evidence that any screening test,

including CA-125, ultrasound, or pelvic examination, reduces mortality from ovarian cancer

existing evidence that screening can detect early-stage ovarian cancer is insufficient to indicate that this earlier diagnosis will reduce mortality

Because of the low prevalence of ovarian cancer and the invasive nature of diagnostic testing after a positive screening test, there is fair evidence that screening could likely lead to important harms

Ovarian Cancer ScreeningOvarian Cancer Screening

Routine screening NOT recommended by any professional organization

ACS• hi-risk women may benefit from screening

with CA-125 and UTZ ACOG

• stay vigilant for early sxs and w/u when present

BibliographyBibliography

Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in

young women. N Engl J Med 1998;338:423–8. Mark E. Sherman , et.al. Baseline Cytology, Human

Papillomavirus Testing, and Risk for Cervical Neoplasia: A 10-Year Cohort Analysis JNCI Journal of the National Cancer Institute 2003 95(1):46-52

Screening for Cervical Cancer, Topic Page. January 2003. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspscerv.htm

BibliographyBibliography

HD Nelson et al. Screening for Breast Cancer: An Update for the U.S. Preventive Services Task Force. Ann Intern Med 2009;151:727

USPSTF. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009;151:716

Screening for Breast Cancer, Topic Page. November 2009. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspsbrca.htm

BibliographyBibliography

Screening for Colorectal Cancer, Topic Page. March 2009. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspscolo.htm

BibliographyBibliography

The International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763-1771

Computed Tomography Screening and Lung Cancer OutcomesPeter B. Bach; James R. Jett; Ugo Pastorino; Melvyn S. Tockman; Stephen J. Swensen; Colin B. BeggJAMA. 2007;297:953-961.

BibliographyBibliography

Lung Cancer Screening, Topic Page. May 2004. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspslung.htm

Screening for Ovarian Cancer, Topic Page. May 2004. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspsovar.htm