JOURNAL CLUBRanjita Pallavi MD and Josef Bautista MD

Critical Appraisal of a Guideline

THE AMERICAN ASSOCIATION FOR THORACIC SURGERY

Guidelines for Lung Cancer Screening using Low-dose

Computed Tomography Scans for Lung Cancer Survivors and other

High-risk groups

Lung Cancer Screening

• Nine million US adults should get a yearly low-dose CT yearly until age 79

• This translates to $ 27 billion dollars of yearly healthcare cost for lung cancer screening alone

The AATS Guideline

The AATS Guideline was developed by a 14-member task force and was based from the result of the NSLT trial and the current NCCN guidelines.

OVERVIEW

• The potential benefits of a guideline are only as good as the quality of the guidelines themselves

• The quality of guidelines can be extremely variable and some often fall short of basic standards

• The AGREE instrument was developed to address the variability in guideline quality

THE AGREE II INSTRUMENT

The AGREE II Instrument

GUIDELINE CONTENT

NOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINE RECOMMENDATIONS

STRENGTH OF RECOMMENDATIONS AND LEVEL OF EVIDENCE FOR THE CLINICAL PRACTICE GUIDELINE

TIER 1 GUIDELINE recommendations

• Guideline for Highest Risk Population

• Annual screening beginning age 55 for smokers and former smokers with 30-pack-year history (1a)

• Annual Screening may continue until age 79 (1a)

• Low-dose CT is the screening technology to be used (1a)

• CXR alone should not be used (1a)

• Exclusion: individuals who cannot be offered adequate treatment based on comorbidity or functional status, regardless of age (not graded)

Tier 1 AlgorithmA

ge 5

5-7

9 a

nd

> 3

0

pack y

ear

No lung nodule

Annual LDCT up to

age 79

Solid nodule See Figure 3

Ground glass

opacity

See Figure 4

TIER 2 GUIDELINE recommendations

• Guidelines for lung cancer survivors and patients with combined risk

• Annual screening for those treated for a primary lung Ca + completed 4 years of radiographic surveillance without evidence for recurrence (2b), or

• patients aged 50-79 years with a 20-pack-year smoking history + cumulative risk of developing lung Ca > 5% over the following 5 years (3)

Tier 2 Algorithm

Lu

ng

Ca S

urv

ivor;

Ag

e >

50

an

d >

20 p

ack y

ears

an

d

Ad

ded

ris

k >

5%

of

develo

pin

g C

a w

ith

in 5

years

.

No lung nodule Annual LDCT up to age 79

Solid nodule See Figure 3

Ground glass nodule See Figure 4

Management of LDCT Findings

Solid nodule

<4 mm

Annual LDCT screening to age

79

4-6 mm

LDCT in 6 mo

>6-8 mm

LDCT in 3 mo

No increase

LDCT in 6 mo

No increase

Annual LDCT

Increase

Referral to specialists

Increase

Surgery

>8 mm

Cosider PET-CT

Low suspicion High suspicion

Surgery

Solid Endobronchial

Bronchoscopy

Management of LDCT FindingsGround Glass

Nodule

< 5 mm

Stable

Annual LDCT until age 79

5-10 mm

LDCT in 6 mo

Stable

Annual LDCT until age 79

Suspicious change

Surgical excision

No lung cancer

Lung cancer

> 10 mm

LDCT in 3-6 mo

Suspicious change

Stable

LDCT 6-12 mo or Biopsy or Surgery

Management of LDCT FindingsNew nodule at

annual or followup LDCT

No suspected infection or

inflammation

Solid nodule

Ground glass nodule

Suspected infection or

inflammation

LDCT in 1-2 mo

Resolving

Radiographic follow-up to resolution

Resolved

Annual LDCT until 79

Persistent or enlarging

PET/CT

Suspicious of Ca

Surgical excision

No lung Ca

Annual LDCT until 79

Lung Ca

Biopsy

No lung Ca

Annual LDCT until 79

Lung Ca

Low suspicion

LDCT in 3 mo

APPRAISAL OF THE GUIDELINEACCORDING TO THE AGREE II

TOOL

Scope and Purpose

• Is there a utility for the use of low-dose CT scan as a lung cancer screening strategy for:

• high risk individuals defined as > 55 yo with > 30 pack years of smoking history

• lung cancer survivors

• 50-79 years with a 20 pack year smoking history and other factors producing a cumulative risk of developing lung cancer that is 5% or more over the following 5 years.

Scope and purpose

Rating: 80%

• The scope and the purpose were clearly stated

• The target population was clearly identified

• However, the expected benefits for the target population were not explicitly stated in a measureable way

• No specified way to measure cumulative smoking risk

Stakeholder Involvement• The guideline was developed by a 14-member committee.

• The task force was composed of thoracic radiologists, oncologists, thoracic surgeons, medical oncologists, a pulmonologist, an epidemiologist and a pathologist.

• The guideline mainly evolved from a well-designed single national trial, which was carried out according to a rigid protocol, without seeking views and opinions from the target population

Stakeholder Involvement

Rating: 30%

• There was no mention of the institutions where the task force members came from, and the geographical location that developed the guideline.

• No involvement of the primary care physician in the development guideline

• No participation of the target group in the development of the guideline

Rigour of Development

• The guideline was based on the NLST and the current NCCN guideline

• It referenced 16 articles

Rigour of DevelopmentRating: 50%

• No other relevant literature was presented

• There is no explicit link between the recommendations and the evidence.

• There was no statement regarding the harm of the procedure or the financial aspect of it

• No sufficient description of the external validation of the guideline

• No statement on possible update of the guideline was present

Clarity of Presentation

Rating: 81%

• The recommendations are specific and unambiguous

• Other options for management were not directly considered

• Specific algorithms for different CT findings were defined

ApplicabilityRating: 35%

• Specific algorithm on different lung findings were presented

• The guideline did not identify barriers or facilitators of the implementation process

• No potential resource implications were considered

• There were no monitoring or auditing criteria defined

Editorial Independence

Rating: 63%

• Funding body was clearly stated

• No description of competing interests

GLOBAL APPRAISAL

• The overall quality of the guideline was moderate.

DISCUSSION

Basis of Tier 1 Recommendations

The National Lung Cancer Screening Trial

Main Objective

• NLST compared two ways of detecting lung cancer: low-dose helical computed tomography (CT) and standard chest X-ray, to see if CT screening could reduce lung cancer specific mortality relative to chest X-ray.

Design• Participants were randomized to 3 annual screens with either low-dose

helical CT or single-view chest X-ray

• Multicenter, parallel-group, randomized, control trial

• N = 53,454 adults at high risk for lung Ca

• LDCT n = 26,722

• CXR n = 26732

• Setting: 33 centers in the US

• Enrollment: 2002-2004

• Analysis: Intention-to-treat

• Follow-up: Median 6.5 ( 3.5 year no-intervention followup)

Inclusion and Exclusion Criteria• Inclusion:

• 55 to 74 years of age

• Cigarette smoking history of at least 30 pack-years

• Former smokers must have quit within the past 15 years.

• Exclusion:

• Lung Cancer

• Chest CT in prior 18 months

• Hemoptysis

• Unexplained weight loss of > 15 lbs in prior year

Population• Age: Race:

• 55-59: 42.8% White 90.9%

• 60-64: 30.6% Black: 4.5%

• 65-69: 17.8% Hispanic: 1.8%

• 70-74: 8.8%

• > 74: <0.1%

• Sex: Smoking Status:• Males: 59% Current 48.1%

• Females 41% Former: 51.9%

Outcomes• Primary Outcomes:

• Lung cancer deaths: 247 vs 309 per 100,000 person-years (RR 0.80; 95% CI 0.73-0.93; p=0.004)

• Secondary Outcomes:

• All-cause mortality: 1877 vs 2000 deaths (RR 93.3; 95% CI 1.2-13.6; p=0.02)

• Lung cancer incidence: 645 vs 572 per 100,000 person-years (RR 1.13; 95% CI 1.03-1.23)

Outcomes

• Positive result: Not cancer: Cancer diagnosis:

T0 27.3% vs. 9.2% 10.2% vs. 3% 3.8% vs. 5.7%

T1 27.9% vs. 6.2% 6.1% vs. 1.8% 2.4% vs. 4.4%

T2 16.8% vs. 5.0% 5.8% vs. 1.5% 5.2% vs. 5.5%

Outcomes

Adverse Events

• Complications following any invasive diagnostic interventions where lung cancer confirmed:

• Any complication: 28.4% vs 23.3%

• Complications following any invasive diagnostic interventions where lung cancer NOT confirmed:

• Any complication 0.4% vs 0.3%

Discussion• Number needed to screen with LDCT is 320 to prevent 1

cancer death

• Good overall internal validity:

• Baseline characteristics were similar for both study groups

• Mixed external validity:

• The LDCT were read by highly trained radiologists

• Population screened was younger and had higher education

• High false-positive rate:

• Problem with overdiagnosis:

• In theory there should be the same number of lung cancers in both arms after followup. But the LDCT group had a persistent gap of 120 excress lung cancers

High Risk Population

Why 79 years?

•Peak incidence of lung cancer :70 years in US

•Average life expectancy currently at 78.6 years

•Age alone is a risk factor: Incidence increases linearly with age

Age > 79 years with good functional status

Why annual screening beyond 3 years?

Lung cancer survivors

• Patients treated for primary bronchogenic carcinoma+4 years of radiographic surveillance+No recurrence(level 3)

• HRCT obtained for 4 yrs after resection of stages IA to IIIA NSCLC foll. By annual LDCT screening starting in 5th yr.

• LDCT screening continue lifelong(funcional status+ pulmonary reserve present)

• These pts have continuing 3% risk of lung cancer diagnosis each year.

Patients with combined risk

• 50-79 yrs with 20 pack-year smoking history+cumulative risk of > 5% over 5 years(similar to NCCN)(level 2)

a) COPD (FEV1<70%)

b) Environmental/Occupational exposure: Asbestosis, Silicosis, Radon

c) Prior cancer/Thoracic Radiation therapy(Radiation risks are linear with dose, risk begins after 2 decades)

d) Genetic/Family history

• Risk calculators: To help with self assessment of risk

a) Liverpool Lung Project Model for individual absolute 5 year risk

b) Prostate,Lung,Colorectal and Ovarian Screening trial: 9 yr probability

LLP Model

PLCO Model

CONCLUSION• The guideline aimed to extend the use of NSLT results to

age 79 as extrapolated from the results of the study

• Based on our assessment using the AGREE tool, the guideline is modest in quality

• The guideline recommendations are clearly stated and specific

• There is lack of emphasis on the potential risks of the uncontrolled screening strategy in the general population.

• The rate of false positives and over-diagnosis must be addressed in subsequent updates.

• We feel that the screening strategy be offered with utmost care and only to high-risk individuals