ACOFP 55th Annual Convention & Scientific Seminars

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Cancer Treatment Centers of America:Supercharge Your Knowledge: A Focus

on Breast, Cervical and Prostate Screening Guidelines and Controversies

Anthony Perre, MD

3/14/2018

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Cancer Screening – guidelines and controversies

Anthony Perre MD

Chief, Division of Outpatient Medicine, Cancer Treatment Centers of America

Disclosures

• none

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Objectives

• Discuss characteristics of an ideal screening test

• Review current guidelines and data supporting screening for several cancer types in the average risk patient including:

– Breast cancer

– Prostate cancer

– Cervical Cancer

– Lung cancer

Screening test

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Prevention

Characteristics of an Ideal Screening Test

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Characteristics of an ideal screening Test

Characteristics of an Ideal Screening Test

• What are the metrics to determine effectiveness of a screening test?

– Relative risk and relative risk reduction

– Gain in life expectancy

– Cost per case detected

– Cost per life saved

– Gain in quality-adjusted life years (QALYs)

– Cost of Life years gained (LYG)

– Number needed to screen (NNS)

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Total national health expenditures as a percent of Gross Domestic Product, 1970-2016

Cost

• Out-of-pocket spending

• Out-of-pocket expenditures have grown steadily since 1970, averaging $1,093 per capita in 2016, up from $119 per capita in 1970 ($590 in 2016 dollars)

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Life expectancy

© 2017 Rising Tide

Localized Regional Distant Unknown

61%31%

6%

2%

Breast Cancer Overview

12ACS. Cancer Facts & Figures 2016. http://bit.ly/1SHGJ3rBreastcancer.org US Breast Cancer Statistics. http://bit.ly/1l92g3W

Leading Sites of New Cancer Cases & Deaths: 2016 Estimates

Percent of Cases by Stage

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© 2017 Rising Tide

SCREENING CONTROVERSIES

• Appropriate age to begin screening ?

• Frequency of mammograms (annual vs biennial) ?

• Age to discontinue screening mammograms?

• Clinical breast exam (CBE)?

• Self breast exam (SBE)?

• Approach in women with increased breast density?

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Risk Assessment

• Women who have a personal history of breast cancer, a confirmed or suspected genetic mutation known to increase risk of breast cancer (eg, BRCA1 or BRCA2), or a history of previous radiotherapy to the chest between ages 10 and 30 are at high risk

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© 2017 Rising Tide

Breast Cancer Risk Assessment Tool

15 NCI. Breast Cancer Risk Assessment Tool.

https://www.cancer.gov/BCRISKTOOL

© 2017 Rising Tide

Risk Assessment

• For women with any family history of breast, ovarian, tubal, or peritoneal cancer, in order to identify those who need a referral for genetic counseling and possible genetic testing for deleterious BRCA1 or BRCA2 gene mutations, and a referral to consider chemoprevention, prophylactic surgery and screening recommendations, the USPSTF recommends one of five simple screening tools:

●Ontario Family History Risk Assessment Tool ●Manchester scoring system ●Referral Screening Tool ●Pedigree Assessment Tool ●Family History Screen

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Breast Cancer Screening

Breast Cancer Screening

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Breast Cancer Screening < 40

Breast Cancer Deaths Avoided

40-49Y 50-59Y 60-69Y 70-74Y

Breast Cancer deaths avoided

3 8 21 13

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Harms of One-Time Mammography Screening

Ages 40–49 y Ages 50–59 y Ages 60–69 y Ages 70–74 y

False-positive mammograms (false alarms)

1212 932 808 696

Breast biopsies 164 159 165 175

False-negative mammograms (missed cancers)

10 11 12 15

Benefits vs. HarmsVariable Ages 40–74 y Ages 50–74 y

Fewer breast cancer deaths 8 (5–10) 7 (4–9)

Life-years gained 152 (99–195) 122 (75–154)

False-positive tests 1529 (1100–1976) 953 (830–1325)

Unnecessary breast biopsies 213 (153–276) 146 (121–205)

Overdiagnosed breast tumors

21 (12–38) 19 (11–34)

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Annual vs. Biennial

Variable Ages 50–74 y, Annual Screening

Ages 50–74 y, Biennial Screening

Fewer breast cancer deaths 9 (5–10) 7 (4–9)

Life-years gained 145 (104–180) 122 (75–154)

False-positive tests 1798 (1706–2445) 953 (830–1325)

Unnecessary breast biopsies 228 (219–317) 146 (121–205)

Over diagnosed breast tumors

25 (12–68) 19 (11–34)

False PositivesStart at Age 40 y Start at Age 50 y

Annual Screening

Biennial Screening

Annual Screening

Biennial Screening

False-positive test result, %

61.3 (59.4–63.1)

41.6 (40.6–42.5)

61.3 (58.0–64.7)

42.0 (40.4–43.7)

False-positive biopsy recommendation, %

7.0 (6.1–7.8)

4.8 (4.4–5.2)

9.4 (7.4–11.5)

6.4 (5.6–7.2)

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Breast Cancer ScreeningGROUP FREQUENCY 40-49 50-69 >70

USPSTF (2016) Q2 Y DISCUSSION YES YES, TO 74

CANADIAN TF Q2-3 RECOMMENDAGAINST

YES YES, TO 74

UK NHS Q3 YES, START AT 47 YES YES, TO 73

ROYAL AUSTRALIAN COLLEGE OF GENERAL PRACTITIONERS Q2 NO YES NO

ACOG Q1-2 DISCUSSION YES YES, AT LEAST UNTIL 75

ACP Q1-2 DISCUSSION YES YES, TO 74

AAFP Q2 DISCUSSION YES YES, TO 74

ACS Q1 45-55,THEN Q2

START AT 45 YES YES, LIFE EXPECTANCY > 10Y

ACR Q1 YES YES YES,INDIVIDUALIZE

NCCN Q1 YES YES YES

SBE

ACS USPSTF ACOG

NO NO NO*

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CBE

ACOG NCCN ACS

Yes - C Insufficient evidence NO

Breast Density

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Breast Density

• Screening options

- Film vs. Digital

– Digital breast tomosynthesis (DBT)

– Hand-held ultrasound vs. automated ultrasound

– MRI

ASTOUND STUDY

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Breast density

• Barriers to implement screening US:

– Impractical to expect radiologist to perform screening as in ACRIN study

– Lack of standardized training for technologist in the USA

– Increased out of pocket cost for patients

– DBT much easier to implement

Cost/Benefit

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Cost/Benefit

Cost/Benefit

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Cost/Benefit

© 2017 Rising Tide

Leading Sites of New Cancer Cases and Deaths: 2016 Estimates

36ACS. Cancer Facts & Figures 2016. http://bit.ly/1SHGJ3r

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© 2017 Rising Tide

Identifying High Risk Patients

• African American

• Family history

– Patients with one or more first-degree relative diagnosed with prostate cancer earlier than age 65

• Inherited gene mutations

– BRCA1 and BRCA2

– Lynch Syndrome

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Digital Rectal Examination (DRE)

• No controlled studies have shown a reduction in the morbidity or

mortality of prostate cancer when detected by DRE at any age

• Most cancers detected by DRE are advanced

• Studies have estimated that PSA elevations can precede clinical

disease by 5-10 years

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Prostate-specific Antigen (PSA)

Prostate Cancer Screening

PSA Velocity

Free PSA

[-2]ProPSA

Intact PSAKallikrein – related peptidase 2

Pca 3

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Prostate Cancer screening

© 2017 Rising Tide

PSA or no PSA?

• May 2012: USPSTF recommends AGAINST prostate-specific antigen (PSA)-based screening for prostate cancer (D)

• 2017 USPSTF - The USPSTF recommends that clinicians inform men ages 55 to 69 years about the potential benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer. (C)

42USPSTF. http://bit.ly/2hWs9Gi

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Prostate Cancer Screening

• Based on 2 large studies

– European Randomized Study of Screening for Prostate Cancer (ERSPC)

– Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO)

AHRQ rated as fair quality

ERSPC

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Prostate Cancer

PLCO

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Goteborg

USPSTF

• What changed?

• Additional follow up showed a reduction in mortality (1 man per 1000 screened) after follow up of 13 years. Also harms may have been mitigated by active surveillance

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American Urologic Association

• The AUA recommends that beginning at age 55 and to age 69, men engage in shared decision-making with their doctors about whether to undergo PSA screening. The AUA doesn’t recommend routine PSA screening for men over age 70, or for any man with less than a 10-to 15-year life expectancy

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American Urologic Association

• PSA Screening in men under the age of 40 is not recommended.

• Routine screening for men between 40-54 years old AT AVERAGE RISK is not recommended.

• Screening intervals of two years vs. one year are preferred.

• PSA screening is NOT recommended for men over the age of 70 with less than a 10-15 year life expectancy.

50

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American Cancer Society (ACS)

• The ACS recommends that men consult with their doctors to make a decision about PSA testing. According to the ACS, men should explore the risks and benefits of the PSA test starting at age 50 if they are at average risk of prostate cancer and have at least a 10-year life expectancy, at age 45 if they are at high risk and at age 40 if they are at very high risk (those with several first-degree relatives who had prostate cancer at an early age).

Prostate Cancer Screening

• Key questions

– Does the effectiveness of PSA-based screening vary by subpopulation/risk factor (e.g., age, race/ethnicity, family history, and clinical risk assessment)?

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COST?

• The incremental cost per quality-adjusted life-year (QALY) for PSA screening was A$147,528. However, for years of life gained (LYGs), PSA-based screening (A$45,890/LYG) appeared more favorable.

• Optimized AS (active surveillance)improved cost utility to A$45,881/QALY

Cervical Cancer

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• Small, non-enveloped DNA viruses that infects only stratified epithelial tissues

– Over 140 have been identified in humans, only 40 are known to infect the oral and ano-genital tract and a small subset of these have been linked to cervical cancer

• 79 million Americans are currently infected with HPV and 14 million new cases occur each year1

– Most common sexually transmitted virus in the U.S.

• HPV infection is the most important risk factor for cervical cancer

– Odds ratio of cervical cancer if HPV16+ versus HPV- is 4352

– Odds ratio of lung cancer in male smokers versus non smokers is 831. http://www.cdc.gov/std/HPV/STDFact-HPV.htm; accessed 1/13/2015

2. Munoz et al. (2003). NEJM3. The World Health Report 1999: Chapter 5 and Statistical Annex and CDC

Human Papillomavirus

Cervical Cancer

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How well does cytology based screening perform?

1. Leyden WA, et al. J Natl Cancer Inst 2005; 97:675683; 2. Andrae B, et al. J Natl Cancer Inst 2008; 100:622629. •ICC, invasive cervical carcinoma.

Cause, n (%)Kaiser

study(1)Swedish study(2)

No recent screen 464 (56%) 789 (64%)

Cytology detection failure 263 (32%) 300 (24%)

Failure of follow-up of abnormal cytology

106 (13%) 91 (7%)

What is wrong with cytology alone?

• Cytology has low sensitivity ( FN) for detecting CIN2 or worse1

• Cytology is less effective in detecting AIS and adenocarcinoma2

• Highly variable cytology results between cytopathologists and between laboratories3

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HPV arm Cytology arm

When found CIN3 Cancer CIN3 Cancer

Round one 98 7 47 9

Round two 8 0 17 9

In total 106 7 64 18

Results from two rounds of HPV DNA testing versus cytology screening:

Italian study = 94,000 women screened twice 3 years apart

•Ronco G, et al. Lancet Oncol 2010; 11:249–257. •Italian women aged 2560 at recruitment.

WITH HPV TESTING, CIN3/cancer found sooner

Sensitivity of cytology vs. HPV DNA for ≥CIN2

•Whitlock EP, et al. Ann Intern Med. 2011; 155:687697, W2145. •Studies performed in developed countries

in women 30 years and older.

Average

increase

35.7%

Bigras(N=13,842)

Cardenas(N=1,850)

Coste(N=3,080)

Kulasingam(N=774)

Mayrand(N=9,977)

Petry(N=7,908)

0

20

40

60

80

100

Cytology HPV DNA Test

Sen

sit

ivit

y*

for

≥C

IN2 (

%)

Cytology has low sensitivity for detecting CIN2 or worse

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•Ronco G et al. Lancet. 2013. www.thelancet.com Published online 11/03/13 http://dx.doi.org/10.1016/S0140-6736(13)62218-7

Low sensitivity of pap results in decreased protection from getting cervical cancer compared to HPV screening

Cu

mu

lati

ve d

etec

tio

n r

ate

of

cerv

ical

can

cer

(10

6 )

0

10

20

30

40

50

60

70

80

90

100

Time since negative test at entry (Years)0 2 4 6 8

Pap

HPV

• 2013 review of 4 trials, >176,000 women:1. The reduction in cancer is 70% greater for women in HPV testing arms 2. The trust in the negative result “lasts longer”

70%

Cervical Cancer Screening

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Screening option #1Cytology screening

Pap

Rescreen 3 yrs

HPV Test

Colposcopy

Pap-

ASC-US

>ASC-US

Rescreen 3 yrs

Colposcopy

HPV-

HPV+

Women 21-29: Recommended screening method*Women 30 and above – an option

‡

‡

*Per 2011 ACS, ASCCP, ASCP screening guidelines and ACOG Practice Bulletin1,2

‡ Management strategy may be different for women 21-24 years of age3

1. Saslow et al. (2012). AJCP2. ACOG practice bulletin 131 (2012)3. Massad et al. (2013). JLGTD

Screening option #2HPV & Pap co-testing

Women 30-65: Preferred screening option*

Pap

Rescreen 5 yrs†

HPV Test

ColposcopyASC-US/HPV+

>ASC-US‡

Rescreen 1 yr

ColposcopyHPV16/18+

NILM/HPV+

NILM/HPV-

ASC-US/HPV-

HPV16/18

Rescreen 1 yrHPV16/18-OR

*Per 2011 ACS, ASCCP, ASCP screening guidelines and ACOG Practice Bulletin1,2

† ASC-US/HPV-: co-test at 3 years3

‡ LSIL/HPV-: repeat co-testing at 1 year is preferred3

1. Saslow et al. (2012). AJCP2. ACOG practice bulletin 131 (2012)3. Massad et al. (2013). JLGTD

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Pap

Rescreen 3 yrs

Colposcopy

Rescreen 1 yr

Colposcopy

HPV16/18+

12 other hrHPV+

cobas HPV Test

HPV16/18

HPV-

ASC-US

NILM

Screening option #3 Primary HPV screening

Women 25 years of age (ASCCP ALGORITHM)

Alternative option to current cytology-based screening methods per SGO/ASCCP Interim clinical guidance

ASCCP Algorithms (2015)

Cost

• QALY 15-35,000 dollars depending on method

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Lung Cancer Screening

Lung Cancer Screening

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Lung Cancer Screening

Lung Cancer

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Lung Cancer Screening

Lung Cancer

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Lung Cancer Screening

Lung Cancer Screening

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Lung Cancer screening

Lung Cancer Screening

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Lung Cancer Screening

Lung Cancer Screening

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Lung Cancer Screening

Lung Cancer

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Lung Cancer Screening

Lung Cancer Screening

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Lung Cancer Screening

Lung Cancer Screening