1 PLCO And The Current State of Screening Andrew W. Swartz, MD Family Physician Emergency Medicine Physician Flight Surgeon (Alaska ANG)

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PLCOAnd

The Current State of Screening

Andrew W. Swartz, MDFamily Physician

Emergency Medicine Physician

Flight Surgeon (Alaska ANG)

Conflicts of Interest

Biases

Am a member of a profession (and specialty) which profits from cancer screening and treatment

No financial interest in any medical patents or products

I do have a small software company, no product relation to topic today

Part of my income is derived from CRC Screening

Not trying to get any votes

Practice in fear of the legal liability associated with “missing something”

May soon be graded by how many of my patients get screened

Am a member of a society whose health care system is in financial jeopardy

Like most rational humans, I strongly desire prevention and screening to work so that my loved ones and I may live longer and suffer less

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Scientific Method

Observe the World(for apparent associations, etc)

[Re] Form Hypothesis

Test Hypothesis with Experiment

Hypothesis NOT disprovedHypothesis disproved

Test further,

Incorporate into Theory,

etc.

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Hierarchy of Evidence

Cohort Studies

Case-Control Studies

Case-Series and Reports

Expert Opinion

Non-randomized Controlled Trials

RCT’s

Observations

Experiments

Less Bias + Confounding

Reviews + Meta-analyses of RCT’s

Questionnaire

Screening Theory

DeathCancerous Mutation

Unscreened

Screened

Symptomatic Diagnosis

Early Diagnosis

Early Treatment Lifespan Gain

Holy Grail

Background

To be effective, screening must satisfy two criteria:

1. Monographs in Epidemiology and Biostatistics, Volume 19. Morrison A. Screening in Chronic Disease, 2nd Ed. 1992. Oxford University Press. New York.

1. We must be able to diagnose early.

2. Early treatment must be better than late treatment.

Background

“The evaluation of screening must be based on

measures of disease occurrence that will not be

affected by early diagnosis except to the extent

that early treatment is beneficial.1”

1. Monographs in Epidemiology and Biostatistics, Volume 19. Morrison A. Screening in Chronic Disease, 2nd Ed. 1992. Oxford University Press. New York. p16.


NO TREATMENT

Survival

Survival

Lead-time

Unscreened

Screened


Screening Diagnosis

Lead-Time Bias

Cancerous Mutation

Group-A

Group-B

Treatment Comparisons

Survival

Survival

Rx-B

Rx-A


Unscreened

Screened


Screening Diagnosis

Lead-Time Bias

Survival

Survival


Unscreened

Screened


Screening Diagnosis

Lead-Time Bias

Survival

Survival

Background

“The evaluation of screening must be based on

measures of disease occurrence that will not be

affected by early diagnosis except to the extent

that early treatment is beneficial.1”


Background

“The ultimate gains derived from a screening

program are reductions of serious illness and

death among the people screened.1”

1. Mortality

2. Morbidity


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Ground RulesValid Outcomes in Screening Trials:

1. Mortality

2. Incidence

SurvivalStaging

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Cumulative Case Plots

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Cumulative Case PlotsNo Difference

Time since Randomization

ScreenedControlScreening Period Follow-up Period

Num

ber

of C

ases

18




Num

ber

of C

ases

19

Mortality Plots


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Screen

Control

Num

ber

of D

eath

s

21




Screen

Control

Num

ber

of D

eath

s

22




Screen

Control

Num

ber

of D

eath

s

23


Incidence Plots

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Ideal

Screen

Control

Num

ber

of C

ance

rs

25




Worst-Case

Screen

Control

Overdiagnosis !!!

Num

ber

of C

ance

rs

26




Screen

Control

Num

ber

of C

ance

rs

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Screen

Control

Num

ber

of C

ance

rs

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Screen

Control

?

Num

ber

of C

ance

rs

PLCOProstate, Lung, Colorectal, and Ovarian Screening RCT

The Good,

The Bad,

And the Ugly.

PLCO

One of the most massive undertakings

in the history of medicine.• 5-year design phase (1989-1994) by the National Cancer Institute

• Patient recruitment 1994-2001

• Multi-center w/ competition for participation:1) University of Colorado Health Sciences Center, Denver, CO2) Georgetown University Medical Center, , Washington, DC3) Lombardi Cancer Research Center, Washington, DC4) Pacific Health Research Institute, Honolulu, HI5) Henry Ford Health System, Detroit, MI6) University of Minnesota, Minneapolis, MN7) Washington University School of Medicine, St. Louis, MO8) Cancer Institute of Brooklyn at Maimonides, Brooklyn, NY (discontinued 1997)9) University of Pittsburgh Cancer Institute, Pittsburgh, PA10) Satellites: Latrobe Area Hospital, Latrobe, PA11) Jameson Health System, New Castle, PA12) Trinity Health System, Steubenville, OH13) University of Utah School of Medicine, Salt Lake City, UT14) Satellite: St. Lukes Meridian Medical Center, Boise, ID15) Marshfield Medical Research and Education Foundation, Marshfield, WI16) University of Alabama at Birmingham, Birmingham, AL (added 1997)

PLCO

307 Publications4/17/2013

PLCO Design

154,900

Gender: Men + Women

Age: 55-

74

Exclusions:- PLCO Cancers- Treatment for any

cancer- Recently screened

Usual Care

Yearly DRE x 4y + PSA x 6y

Yearly CXR x 4y

Flex-Sig at 0 and 3-5y

Yearly TVU x 4y + Ca125 x 6y

77,445

Screen

Men Women

Prostate X 38,340

Lung X X 77,445

Colorectal X X 77,445

Ovarian X 39,105

77,455

Control

Randomization

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Prostate Lung

Colorectal Ovarian

Andriole GL, Crawford DE, et al. Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up. J Natl Cancer Inst. 2012;104:125–132.

Oken MM, Hocking WG, Kvale PA, et al; PLCO Project Team. Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA. 2011; 306(17):1865-1873.

Schoen R.E., Pinsky P.F., Weissfeld J.L., et al. Colorectal-Cancer Incidence and Mortality with Screening Flexible Sigmoidoscopy. N Engl J Med. 2012 Jun 21;366(25):2345-57.

Buys SS, Partridge E, Black A, et al. Effect of Screening on Ovarian Cancer Mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305(22):2295-2303.

Disease-Specific Mortality

LungProstate

Colorectal Ovarian

Screen

Control

Screen

Control

Screen

ControlControl

DRE PSA CXR

FS TVU Ca125

Screen

Control

Control

Screen

Control

Cancer Incidence

Screen

Control

LungProstate

Colorectal Ovarian

DRE PSA CXR

TVU Ca125FS

1886

1274

113

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Graph Familiarization

RR = x.xx

NNI = y.yy

NS

RR = x.xx

NNI = y.yy

PLCO Trial Results (at 10-13 years)


PLCO

1999 – 13y

400 / 399

2014 – 11.5y

13,563 / 41,092

2010 – M15y, I10y

57,254 / 113,178

2011 – 10.5

17,136 / 17,136

2012 – 11y

77,445 / 77,455

PLCO-CRC: Comparison with other RCT’s

3.2 : 1

100%77,450

* *

*

Control

CRC Mortality

Control

CRC Incidence


PLCO: Screening for Ovarian Cancer

ControlIncidence

TVU

113

83

ScreenCa125

Screen

Control

Mortality

Screenees (39,105)

NNH

False-positives: 3,285

12

Abdominal surgeries: 1,080

36

Major Surg. Comps.: 222

176

Background

To be effective, screening must satisfy two criteria:

1. Monographs in Epidemiology and Biostatistics, Volume 19. Morrison A. Screening in Chronic Disease, 2nd Ed. 1985. Oxford University Press. New York.

1. We must be able to diagnose early.

2. Early treatment must be better than late treatment.

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SCREENING

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PLCO References

Prostate

Andriole GL, Crawford DE, et al. Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and

Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up. J Natl Cancer Inst.

2012;104:125–132.

Lung

Oken MM, Hocking WG, Kvale PA, et al; PLCO Project Team. Screening by chest radiograph and lung cancer

mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA. 2011;

306(17):1865- 1873.

Colorectal

Schoen R.E., Pinsky P.F., Weissfeld J.L., et al. Colorectal-Cancer Incidence and Mortality with Screening Flexible

Sigmoidoscopy. N Engl J Med. 2012 Jun 21;366(25):2345-57.

Ovarian

Buys SS, et al. Effect of Screening on Ovarian Cancer Mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO)

Cancer Screening Randomized Controlled Trial. JAMA. 2011;305(22):2295-2303.

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Flex-Sig RCT References

Telemark

Thiis-Evensen E, Hoff GS, Sauar J, et al. Population-based surveillance by colonoscopy_ effect on the incidence of

colorectal cancer. Telemark Polyp Study I. Scand J Gastroenterol 1999; 34(4):414-20.

NORCCAP

Holme Ø, Løberg M et al. Effect of Flexible Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality: A

Randomized Clinical Trial. JAMA. 2014;312(6):606-615. doi:10.1001/jama.2014.8266.

UK

Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal

cancer: a multicentre randomised controlled trial. Lancet 375 (9726):1624-33..

SCORE

Segnan N, et al. Once-Only Sigmoidoscopy in Colorectal Cancer Screening: Follow-up Findings of the Italian

Randomized Controlled Trial—SCORE. J Natl Cancer Inst 2011;103:1310–1322.

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Thank You

Questions ?

Documents

1 PLCO And The Current State of Screening Andrew W. Swartz, MD Family Physician Emergency Medicine Physician Flight Surgeon (Alaska ANG)