ONCOLOGY FOR THE INTERNISTCANCER SCREENING

Devapiran JaishankarAssociate Professor

ETSU

Disclosures

• No disclosures

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 ?

Cancers to Screen ?

• Cervical cancer

• Lung cancer

• Colon cancer

• Breast cancer

• Prostate cancer

USPSTF Grades of Recommendation

Annals of Internal Medicine ; June 2012

Levels of CertaintyHighConsistent results

ModerateSufficient evidence, confidence constrained, future recommendations may alter

LowInsufficient evidence not generalizable

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

Cervical cancerWho 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

Cervical cancer screeningGuidelines Summary

Annals of Internal Medicine; June 2012

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)

Cervical cancerPotential 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)

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 reduces mortality by 74% ( even if age > 65 )

• 29% of all invasive cervical carcinoma in women never screened

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

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

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 setting but makes no concrete recommendations

Lung Cancer ScreeningWhat 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

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 31st 2009

Baseline characteristics of patients

Overall patients were

Younger

Better educated

Former smokers

Compared to the 2002-2004 US census survey

NEJM 365;5 Aug 4th 2011

NLSTResults

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

NLST What is a positive test ?

• Non calcified nodule: CXR• Non calcified nodule > 4mm in size: CT• Adenopathy, Pleural effusion

NEJM; August 4th 2011

NLSTFollow up of positive test results

Low dose CT18,146 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%)

CXR5043 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%)

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)

NLSTStage 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%

NLSTFinal Results

Diagnosis of lung cancer645 cases vs 572 low dose CT vs CXR Rate ratio, 1.13; 95% confidence interval (CI) 1.03 to 1.23

Cancer related mortality247 deaths per 100,000 person years vs 309Relative reduction of 20% 95% CI (6.8 to 26.7) P = 0.004

NEJM August 4th 2011

NLSTMortality statistics

All cause mortality Lung cancer mortalityCT 1865/ 26722 = 6.9% 427/26722 = 1.59%CXR 1991/26732 = 7.4% 503/26732 = 1.88%

NEJM August 4th 2011

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

Colon cancerScreening

•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 screening tests•Effective screening can save over 18,000 lives a year

•Screening guidelines do not apply to – Lynch syndrome, FAP syndrome– Inflammatory Bowel Disease

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:

Colon cancerScreening Tools

• Fecal Occult Blood Test: FOBT– Hemoccult II / SENSA

• Fecal Immunochemical Test: FIT

• Sigmoidoscopy• Colonoscopy

• Not recommended– CT Colonography– Fecal DNA test

Colon Cancer ScreeningStool 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 mucosal lining of the bowel

Colon Cancer ScreeningEndoscopic 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

Untoward and Unexpected side effects of …..

colon cancer screening

Colon Cancer ScreeningNet 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

Colon Cancer Screening 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 result colonoscopy : gold standard

• CT colonography, Fecal DNA: Grade I recommendations

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

Risk factors for Breast Cancer

Risk assessment tools

Gail model

Claus model

NEJM September 15th 2011

Date of download: 10/13/2012

Copyright © The American College of Physicians. All rights reserved.

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

Ann Intern Med. 2009;151(10):716-726. doi:10.7326/0003-4819-151-10-200911170-00008

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:

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 ?

Date of download: 10/13/2012

Copyright © The American College of Physicians. All rights reserved.

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

Ann Intern Med. 2009;151(10):716-726. doi:10.7326/0003-4819-151-10-200911170-00008

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:

Incidence of Breast CancerSEER data: NCI 2010

Risk reduction in Breast cancerRelative or Absolute

NEJM 365:11

Breast cancer screening groups

Annals of Internal Medicine; 17 November 2009

Models & Screening strategy

Percentage of breast cancer mortality reduction

vs

Number of mammograms

Per 1,000 women

Annals of Internal Medicine; 17 November 2009

Breast cancer screeningAnnual vs Biennial

Annals of Internal Medicine; November 2009

Risk vs Rewards Age and breast cancer screening

Annals of Internal Medicine; 17 November 2009

Guidelines Galore

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

NEJM: September 15, 2011

Breast Cancer ScreeningSummary

• 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 what age, if clinical symptoms or signs warrant it

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

Prostate CancerThe Big Picture

NEJM November 2011

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 trauma

instrumentation, cancerNEJM November 2011

Prostate cancer screeningThe guideline wars

NEJM November 2011

European Randomized Study of Screening for Prostate Cancer

• ERSPC

ERSPC

Cancer diagnoses 8.2 % screening group 4.8% control group

Cancer death 2.8 per 1000: screening 3.5 per 1000: control 20% relative risk reduction

To prevent 1 deathneed to screen 1410 ptsneed to dx 48 cancersover 9 years

NEJM March 2009

PLCO Project1993-2001: 76,693 patients

Annual PSA + DRE

vs

Usual care

2820 cancers: screen

2322 cancers: control

50 deaths: screen

44 deaths: control

Contamination rate: 40%

NEJM March 2009

PLCO ProjectProstate Lung Colon Ovarian

NEJM March 2009

SPCGScandinavian Prostate Cancer Group

• Enrolled 1989-1999 follow up through 2009

• 695 patients

• Localized prostate cancer – T1-T2 lesions

– PSA < 50

– Negative bone scan

• Predominantly diagnosed with symptoms and not PSA screening

SPCG-4

Radical prostatectomy vs Watchful waiting695 pts12.8 years

347 166 55348 201 81

Prostate cancer related mortality 14.6 % vs 20.7%

Need to treat = 15

NEJM May 2011

PIVOT

Prostate cancer intervention 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

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

Treatment related ToxicityProstate Cancer

NEJM July 2012

Prostate cancer screeningSummary

NEJM November 2011

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 but who and how often. Benefits are possibly more modest than expected.

• Prostate cancer: Screening unlikely to decrease mortality.

THANK YOU