Jaishankar 10-29-12

8/11/2019 Jaishankar 10-29-12

1/64

ONCOLOGY FOR THE INTERNIST

CANCER SCREENING

Devapiran Jaishankar

Associate ProfessorETSU

8/11/2019 Jaishankar 10-29-12

2/64

Disclosures

No disclosures

8/11/2019 Jaishankar 10-29-12

3/64

Questions? Questions? Questions?

Is there a guideline ?

What is the guideline ?

Has there been a change ?

Why ?

How do I adopt it for the patient in front of me ?

8/11/2019 Jaishankar 10-29-12

4/64

Cancers to Screen ?

Cervical cancer

Lung cancer

Colon cancer

Breast cancer

Prostate cancer

8/11/2019 Jaishankar 10-29-12

5/64

USPSTF Grades of Recommendation

Annals of Internal Medicine ; June 2012

8/11/2019 Jaishankar 10-29-12

6/64

Levels of

Certainty

High

Consistent results

Moderate

Sufficient evidence,confidence constrained,

future recommendations

may alter

Low

Insufficient evidence

not generalizable

8/11/2019 Jaishankar 10-29-12

7/64

Why we screen for cervical cancer

Annual incidence: 6.6 per 100,000 women

12,000 new cases in 2010 in the US

4200 deaths in 2010 in the US

Dramatic decrease in mortality

Most cases in the US related to inadequate screening

8/11/2019 Jaishankar 10-29-12

8/64

Cervical cancer

Who should we screen

All women with a cervix regardless of sexual history

Women aged 21-65

The guidelines do not apply to the following patients

1. High grade precancerous lesion

2. Prior cervical cancer

3. In utero exposure to DES (diethylstilbestrol)

4. Immuno compromised status - HIV positive patients

8/11/2019 Jaishankar 10-29-12

9/64

Cervical cancer screening

Guidelines Summary

Annals of Internal Medicine; June 2012

8/11/2019 Jaishankar 10-29-12

10/64

Cervical cancer screening methodology

Conventional cytology as good as liquid based cytology

HPV testing slightly more sensitive but with higher false

positives

HPV testing positive more often in younger women

( age < 30-35 years)

Cervical cancer common in older women (age 35-55)

8/11/2019 Jaishankar 10-29-12

11/64

Cervical cancer

Potential harms to screening - treatment

Surveillance vs Surveillance and Immediate colposcopy

Pain: 15% vs 39%

Bleeding: 17% vs 47%

Discharge: 9% vs 34%

Cervical conization or Loop electrosurgical excision

Pain: 67%

Bleeding 83%

Discharge 63%

Adverse outcomes with future pregnancies

(preterm delivery < 40 weeks, low birth weight and perinatal mortality)

8/11/2019 Jaishankar 10-29-12

12/64

What is adequate cervical screening

history in the elderly ?

Current guidelines define adequate screening as

3 consecutive negative cytology results or

2 consecutive negative HPV tests

Within the ten year period before stopping cervical cancer screening

With the most recent test performed within the last 5 years

Screening women who have never been screened reducesmortality by 74% ( even if age > 65 )

29% of all invasive cervical carcinoma in women neverscreened

50% of invasive cervical carcinoma in women never screenedor not screened in the last 5 years

8/11/2019 Jaishankar 10-29-12

13/64

Cervical cancer biology

Invasive cervical carcinoma is almost universally linked to

HPV infection

HPV infection of the cervix is generally transient

When this infection is not cleared by the immune system

And the HPV strain happens to be an oncogenic strain

Incorporation of the oncogenic HPV genome into the host

Development of precancerous lesions: CIN

Invasive cervical carcinoma

Long preclinical phase: Infection Pre cancer Invasive cancer

8/11/2019 Jaishankar 10-29-12

14/64

Lung Cancer Screening

USPSTF:Recommendation I :Insufficient evidence for or against screening of asymptomatic

patients with

Low dose helical CT

CXR Sputum cytology

American Cancer Society: Interim guidance:

To discuss the NLST results in the appropriate setting

NCCN:mentions possible mortality benefit in the right settingbut makes no concrete recommendations

8/11/2019 Jaishankar 10-29-12

15/64

Lung Cancer Screening

What is the right setting ?

NLST and I- ELCAP: 2 landmark screening trials

NLST National Lung Cancer Screening Trial:

Eligibility criteria

Patients aged 55-70

More than 30 pack year history of smoking

Smokers and non-smokers ( quit within last 15 years)

No metallic implants in chest or back

No prior history of lung cancer or symptoms suggestive of

Not home O2 dependent

8/11/2019 Jaishankar 10-29-12

16/64

NLSTNational Lung Cancer Screening Trial

53,454 patients at 33 US medical centers

High risk patients

August 2002 through April 2004

Randomized to 3 annual screenings

Low dose CT vs CXR (PA view)

And then surveillance for another 3.5 years

Data collected through Dec 31st2009

8/11/2019 Jaishankar 10-29-12

17/64

Baseline

characteristicsof patients

Overall patients were

Younger

Better educated

Former smokers

Compared to the 2002-

2004 US census survey

NEJM 365;5 Aug 4th 2011

8/11/2019 Jaishankar 10-29-12

18/64

NLST

Results

Low dose CT

24% positive test result

Of which 96% false positive

1060 cancers

645 per 100,000 person years

247 deaths/ 100,000 person-

years

CXR

6.9% positive test results

Of which 94% false positive

941 cancers

572 per 100,000 person years

309 deaths per 100,000 person-

years

8/11/2019 Jaishankar 10-29-12

19/64

NLST

What is a positive test ?

Non calcified nodule: CXR

Non calcified nodule > 4mm in size: CT

Adenopathy, Pleural effusion

NEJM; August 4th 2011

8/11/2019 Jaishankar 10-29-12

20/64

NLST

Follow up of positive test results

Low dose CT

18,146 positive results

CT chest: 8,807 (50%)

PET: 1,471 (8.3%)

Per cut bx: 322 (1.8%)

Bronch: 671 (3.8%)

Surg bx: 713 (4.0%)

Lung cancer 649 (3.6%)

CXR

5043 positive results

CT chest: 3,003 (60%)

PET: 397 (8.0%)

Per cut bx: 172 (3.5%)

Bronch: 225 (4.5%)

Surg bx: 239 (4.8%)

Lung cancer 279 (5.5%)

8/11/2019 Jaishankar 10-29-12

21/64

NLST

Complication rate

Lung cancer diagnosed

Low dose CT: (649)

None = 71% (465)

Major = 11% (75)Mod = 14% (95)

Death = 1.5% (10)

CXR group: (279)

None = 76% (214)

Major = 8.6% (24)

Mod = 12.5% (35)

Death = 3.9% (11)

No lung cancer diagnosed

Low dose CT: (17,053)

None = 99.6% (16,992)

Major = 0.1% (12)Mod = 0.3% (44)

Death = 0.1% (11)

CXR group: ( 4,674)

None = 99.7% (4,658)

Major = 0.1% (4)

Mod = 0.2% (9)

Death = 0.1% (3)

8/11/2019 Jaishankar 10-29-12

22/64

NLST

Stage and Screening

Low dose CT

Stage

IA 416/1040 40%

IB 10%

IIA 3.4%

IIB 3.7% IIIA 9.5%

IIIB 11.7%

IV 21.7%

CXR

Stage

IA 90/519 21.1%

IB 10%

IIA 3.4%

IIB 4.5% IIIA 11.7%

IIIB 13.1%

IV 36.1%

8/11/2019 Jaishankar 10-29-12

23/64

NLST

Final Results

Diagnosis of lung cancer

645 cases vs 572

low dose CT vs CXR

Rate ratio, 1.13;

95% confidence interval (CI)1.03 to 1.23

Cancer related mortality

247 deaths per 100,000

person years vs 309Relative reduction of 20%95% CI (6.8 to 26.7)P = 0.004

NEJM August 4th2011

8/11/2019 Jaishankar 10-29-12

24/64

NLST

Mortality statistics

Al l cause mortali ty Lung cancer mortali ty

CT 1865/ 26722 = 6.9% 427/26722 = 1.59%

CXR 1991/26732 = 7.4% 503/26732 = 1.88%

NEJM August 4th2011

8/11/2019 Jaishankar 10-29-12

25/64

Lung cancer screening

Summary

Low dose helical CT does detect more lung cancer

These lung cancers are at an earlier stage

High false positive rate Lower lung cancer death rate

Relative risk reduction 20%

Absolute risk reduction < 1%

Lower lung cancer death rate offset by higher cardio-respiratory complications and death

All cause mortality marginally better with screening

8/11/2019 Jaishankar 10-29-12

26/64

Colon cancer

Screening

Colorectal cancer is the third most common type of cancer

Leading cause of cancer death in the US

Current levels of screening lag other effective cancer screeningtests

Effective screening can save over 18,000 lives a year

Screening guidelines do not apply to Lynch syndrome, FAP syndrome

Inflammatory Bowel Disease

8/11/2019 Jaishankar 10-29-12

27/64

Date of download:10/13/2012

Copyright The American College of Physicians.All rights reserved.

From: Screening for Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement

Ann Intern Med. 2008;149(9):627-637. doi:10.7326/0003-4819-149-9-200811040-00243

Screening for colorectal cancer: clinical summary of a U.S. Preventive Services Task Force (USPSTF) recommendation.For a

summary of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and

supporting documents, please go to http://www.preventiveservices.ahrq.gov. FOBT= fecal occult blood testing.

*These recommendations do not apply to individuals with specific inherited syndromes (the Lynch syndrome or familial

adenomatous polyposis) or those with inflammatory bowel disease.

Figure Legend:

8/11/2019 Jaishankar 10-29-12

28/64

Colon cancer

Screening Tools

Fecal Occult Blood Test: FOBT Hemoccult II / SENSA

Fecal Immunochemical Test: FIT

Sigmoidoscopy

Colonoscopy

Not recommended CT Colonography

Fecal DNA test

8/11/2019 Jaishankar 10-29-12

29/64

Colon Cancer Screening

Stool Tests

Overall sensitivity for cancer = 70%

Specificity > 90% ; less than 10% false positive rate

Hemoccult tests for peroxidase activity of heme

Dietary heme (fruits and vegetables especially if raw)

Red meat

Vitamin C

FIT: Fecal Immunochemical Test tests for human heme

Fecal DNA tests for denovo/ somatic mutations in the mucosallining of the bowel

8/11/2019 Jaishankar 10-29-12

30/64


Endoscopic tests

Colonscopy

Perforation: 3.8/ 10,000

M. Bleeding: 12.3/ 10,000

Serious complic: 25/ 10,000 Perforation

Major bleeding

Diverticulitis

Sev abdominal pain Hospital admission

Cardiovascular events

Death

Sigmoidoscopy

Perforation: 4.6/ 10,000

Point estimate

Serious complic: 3.4/ 10,000

8/11/2019 Jaishankar 10-29-12

31/64

Untoward andUnexpected side

effects of ..

colon cancerscreening

8/11/2019 Jaishankar 10-29-12

32/64


Net Benefit

Annual high sensitivity fecal occult blood testing

256-259 life years gained for every 1,000 persons screened

2654 colonoscopies per 1,000 persons over 10 years

Flex- Sig every 5 yrs + FOBT every 3 yrs

257 life years gained for every 1,000 persons screened

1655 colonoscopies per 1,000 persons over 10 years

Colonoscopy every 10 years

271 life years gained for every 1,000 persons screened

3756 total colonoscopies per 1,000 persons over 10 years

8/11/2019 Jaishankar 10-29-12

33/64


Summary

Start- age 50 : stop- age 75

Screening vs Surveillance guidelines

Do not recommend routine screening: ages 75-85 Recommend against any screening after age 85

Subsets where screening guidelines do not apply

Positive resultcolonoscopy : gold standard

CT colonography, Fecal DNA: Grade I recommendations

8/11/2019 Jaishankar 10-29-12

34/64

Breast Cancer Screening

Commonest cancer in women worldwide

Most common cause of cancer related death world wide

Second most common cause of cancer death in the US

Lifetime risk in the US: 1 in 8

Screening guidelines not applicable > 20-25% lifetime risk

Based on genetic testing Strong family history

Prior chest wall irradiation

8/11/2019 Jaishankar 10-29-12

35/64

Risk factors for

Breast Cancer

Risk assessment tools

Gail model

Claus model

NEJM September 15th2011

8/11/2019 Jaishankar 10-29-12

36/64



From: Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement


Screening for breast cancer using film mammography: clinical summary of USPSTF recommendation.For a summary of the

evidence systematically reviewed in making these recommendations, the full recommendation statement, and supporting

documents, please go to www.preventiveservices.ahrq.gov.

Figure Legend:

8/11/2019 Jaishankar 10-29-12

37/64

Risks of Screening Mammography

False positive results

More common in younger women ( 49% over 10 years)

Short term anxiety

possible small but significant risk of long term effects

Other associations

False negatives

Insufficient data

Radiation risk

86 cancers and 11 deaths / 100,0000 women screened

Over diagnosis ?

8/11/2019 Jaishankar 10-29-12

38/64



From: Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement


Screening for breast cancer using methods other than film mammography: clinical summary of USPSTF recommendation.For a

summary of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and

supporting documents, please go to www.preventiveservices.ahrq.gov.

Figure Legend:

8/11/2019 Jaishankar 10-29-12

39/64

Incidence of Breast Cancer

SEER data: NCI 2010

8/11/2019 Jaishankar 10-29-12

40/64

Risk reduction in Breast cancer

Relative or Absolute

NEJM 365:11

8/11/2019 Jaishankar 10-29-12

41/64

Breast cancer screening groups

Annals of Internal Medicine; 17 November 2009

8/11/2019 Jaishankar 10-29-12

42/64

Models &

Screening

strategyPercentage of breast cancer

mortality reduction

vs

Number of mammograms

Per 1,000 women


8/11/2019 Jaishankar 10-29-12

43/64

Breast cancer screening

Annual vs Biennial

Annals of Internal Medicine; November 2009

8/11/2019 Jaishankar 10-29-12

44/64

Risk vs Rewards

Age and breast cancer screening


G id li G l

8/11/2019 Jaishankar 10-29-12

45/64

Guidelines Galore

Warner E. N Engl J Med 2011;365:1025-1032.

NEJM: September 15, 2011

8/11/2019 Jaishankar 10-29-12

46/64

8/11/2019 Jaishankar 10-29-12

47/64

Breast Cancer Screening

Summary

Do not screen prior to age 40

Discuss screening age 40 -49

Routine screening age 50 onwards: every 1-2 years

Possibly stop screening at age 75 Encourage Breast awareness

May consider clinical breast exam ? Annual ? Start age 40

Do not hesitate to exam and image the breast, no matter whatage, if cl ini cal symptoms or signs warrant i t

8/11/2019 Jaishankar 10-29-12

48/64

Prostate cancer

overview

Annual data in the US

240,000 new diagnoses

28,000 deaths

Median age at diagnosis: 67 years

Median age at death: 81 years

Autopsy studies reveal occult prostate cancer 30% of men older than 50 years

70% of men older than 70 years

8/11/2019 Jaishankar 10-29-12

49/64

Prostate Cancer

The Big Picture

NEJM November 2011

8/11/2019 Jaishankar 10-29-12

50/64

The case for or

against the PSA

90 % of cases diagnosed in

the US are due to screening

Lifetime risk doubles

9% to 16% with PSA

Causes of raised PSA

BPH, infection,

ejaculation, perineal traumainstrumentation, cancer

NEJM November 2011

8/11/2019 Jaishankar 10-29-12

51/64

Prostate cancer screening

The guideline wars

NEJM November 2011

8/11/2019 Jaishankar 10-29-12

52/64

European Randomized Study of

Screening for Prostate Cancer

ERSPC

8/11/2019 Jaishankar 10-29-12

53/64

ERSPC

Cancer diagnoses

8.2 % screening group

4.8% control group

Cancer death2.8 per 1000: screening

3.5 per 1000: control

20% relative risk reduction

To prevent 1 deathneed to screen 1410 pts

need to dx 48 cancers

over 9 years

NEJM March 2009

PLCO

8/11/2019 Jaishankar 10-29-12

54/64

PLCO

Project

1993-2001: 76,693 patientsAnnual PSA + DRE

vs

Usual care

2820 cancers: screen

2322 cancers: control

50 deaths: screen

44 deaths: control

Contamination rate: 40%

NEJM March 2009

PLCO P j

8/11/2019 Jaishankar 10-29-12

55/64

PLCO Project

Prostate Lung Colon Ovarian

NEJM March 2009

SPCG

8/11/2019 Jaishankar 10-29-12

56/64

SPCG

Scandinavian Prostate Cancer Group

Enrolled 1989-1999follow up through 2009

695 patients

Localized prostate cancer

T1-T2 lesions

PSA < 50

Negative bone scan

Predominantly diagnosed with symptoms and not PSA

screening

8/11/2019 Jaishankar 10-29-12

57/64

PIVOT

8/11/2019 Jaishankar 10-29-12

58/64

PIVOT

Prostate cancerintervention vs observation

trial

1994-2002

44 V.A and 8 NCI sites

Any grade histology

Median age: 67

Median PSA: 7.8

T1c disease: 50%

Gleason >/= 7: 48%

NEJM July 2012

8/11/2019 Jaishankar 10-29-12

59/64

PIVOTProstate Cancer Intervention vs Observation Trial

All cause mortality

171 (47%) vs 183( 49.9%)

HR: 0.88, p=0.22

Prostate cancer mortality

21 (5.8%) vs 31 (8.4%)

HR: 0.63, p=0.09

Median survival 13 yrs

Subgroup analysis showed benefit

in PSA > 10 and

NEJM July 2012

T t t l t d T i it

8/11/2019 Jaishankar 10-29-12

60/64

Treatment related Toxicity

Prostate Cancer

NEJM July 2012

P t t i

8/11/2019 Jaishankar 10-29-12

61/64

Prostate cancer screening

Summary

NEJM November 2011

8/11/2019 Jaishankar 10-29-12

62/64

8/11/2019 Jaishankar 10-29-12

63/64

Cancer screening summary

Cervical cancer: Screening works. Target the unscreened

Colon cancer: Screening works. Needs larger adoption.

Lung cancer: Not ready for mainstream?

Target high risk groups.Fraught with issues

Breast cancer: Screening works butwho and how often.Benefits are possibly more modest than

expected.

Prostate cancer: Screening unlikely to decrease mortality.

8/11/2019 Jaishankar 10-29-12

64/64

THANK YOU

Documents

Jaishankar 10-29-12