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Journal Club
Benjamin Han
October 12th, 2012
Our patient is Mr. G, a 68 year old gentleman with CAD,
hypertension, hyperlipidemia, mild COPD, and chronic
back pain who presents to clinic for a physical
examination with his new primary care physician.
He recently retired from his job as a cook, and now that he
has more time on his hands he has a “new commitment
to his health.”
He recently got over a cold, but otherwise feels well.
He has just quit smoking about three months ago.
His COPD is mild, he uses albuterol rarely.
He wants every test done to make sure everything is okay,
he is especially concerned about his risk for having lung
cancer, and asks if he can have a chest x-ray.
Case Presentation
• Past Medical History:
– CAD with STEMI inferiorly with BMS x2 in 9/12/2009 with
preserved EF.
– COPD (PFTs 10/2007 – Mild)
– Hypertension
– Hyperlipidemia
– L4-L5 Disc Herniation
• Medications:
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ASA 81 mg
Simvastatin 40 mg
Toprol XL 50 mg
Albuterol PRN
Tramadol PRN
Tylenol PRN
Case Presentation
• Social History:
– Born in Boston and has lived in Roxbury entire life.
– Lives with his wife on the 3rd floor.
– Smoked ½ - 1 pack a day for 35 years. He quit on 9/12/2010,
however his wife continues to smoke.
– Drinks 6-7 beers a month.
– Distant, intermittent use of cocaine, none since STEMI.
– Sexually active with wife only.
– Worked as a cook at one of the local universities.
• Family History:
– Father with bladder cancer, CAD, died at age 64.
– Mother died of breast cancer at age 62.
Case Presentation
• Review of systems:
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Has chronic back pain that has been unchanged.
Able to walk 4 flights of stairs, without problems.
Gets bronchitis 2-3 times a year.
Negative for weight loss, dyspnea, chest pain, cough,
hemoptysis, or wheezing.
• Physical Examination:
– VS: BP 102/68, HR 61, RR 20, O2 100% RA, BMI 22.
– Cardiac and pulmonary exams are normal.
“Screen for everything!”
• Should we screen this gentleman for lung cancer?
• If so, how should we screen?
• What are the harms of screening?
• Burden of suffering caused by the condition.
• Quality of screening test (sensitivity, specificity, cost,
safety, simplicity and acceptability)
• The effectiveness, safety, and cost of treatment for
conditions identified through screening, taking into
account lead-time, length-time, and compliance biases.
• Adverse effects of screening include negative labeling,
false positive tests resulting in unnecessary follow-up,
and over-diagnosis.
• Lung cancer is the leading cause of cancer death in the
United States and worldwide.
• Lung cancer will account for more than 160,000 deaths
in the United States in 2012.
• Most patients diagnosed with lung cancer today already
have advanced disease.
• Current 5-year survival rate is only 16%.
• Previous randomized trials of screening with use of chest
x-ray with or without cytologic analysis of sputum
showed no reduction in lung-cancer mortality.
• The sensitivity of low-dose CT scan (LDCT) for detecting
lung cancer is 4 times greater than the sensitivity of
CXR. And can detect many tumors at early stages.
• However, LDCT is also associated with a greater number
of false-positive results, more radiation exposure, and
increased costs compared with CXR.
• 2004: The USPSTF concludes that the evidence is
insufficient to recommend for or against screening
asymptomatic persons for lung cancer with either low
dose computerized tomography (LDCT), chest x-ray
(CXR), sputum cytology, or a combination of these tests.
In in 12/2010, we decided not to screen Mr. G for lung
cancer.
• May 2012: The American College of Chest Physicians
and the American Society of Clinical Oncology Release
Joint Systematic Review and Clinical Practice Guideline
on the Role of CT Screening for Lung Cancer.
• Recommendation #1:
– For smokers and former smokers aged 55-74 who have smoked
>30 pack years and continue to smoke or have quit in the past
15 years, suggest annual screening with low-dose CT should be
offered.
– Grade of recommendation: 2B (weak recommendation based on
moderate quality research data).
• Recommendation #2:
– For individuals who have accumulated fewer than 30 pack years
or younger than 55 years or older than 74 years, or
individuals who quit more than 15 years ago, and for individuals
with severe co-morbidities that would preclude potentially
curative treatment, CT screening should not be performed.
– Grade of recommendation: 2C (indicating a ‘weak
recommendation based on low quality research data).
• Where are these new recommendations coming from?
• Among patients at high risk for lung cancer, does lowdose screening CT scans reduce mortality from lung
cancer when compared to screening CXRs?
• Primary outcome: Lung Cancer Deaths.
• Secondary outcomes:
– All-cause mortality.
– Lung cancer incidence.
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Multicenter, prospective, randomized, controlled trial.
Setting: 33 centers in the US.
Enrollment: 2002-2004.
Screening: Three screenings at 1-year intervals with
either LDCT or CXR.
• Analysis: Intention-to-treat.
• Follow-up: median 6.5 years.
• Funding from the National Cancer Institute.
• Inclusion Criteria:
Age 55-74 years
≥30 pack-year smoking history
Quit smoking ≤15 years prior
• Exclusion Criteria:
Lung cancer or history of lung cancer
Chest CT in prior 18 months
Recent Hemoptysis
Unexplained weight loss of ≥15 lbs in prior year
Use of home O2
Pneumonia or acute respiratory infection treated with
antibiotics in the 12 weeks prior to eligibility assessment.
• N=53,454 adults at high risk for lung cancer
– Low-dose CT scan (n=26,722)
– CXR (n=26,732).
• Rate of adherence:
– Low-dose CT scan: 95%
– CXR: 93%
• Notably, the participants were generally younger, had
higher education levels, and were more likely to be
former smokers compared to a 2002-2004 US Census
tobacco survey.
Selected Baseline Characteristics of the Study Participants.
The National Lung Screening Trial Research
Team . N Engl J Med 2011;365:395-409.
• Three screenings, one year apart (T0, T1, and T2), no
subsequent screenings for those diagnosed with lung
cancer.
– Low-dose CT group - 1.5 mSv CT scan
– Chest x-ray group
• Analysis of images:
– Single scan interpretation alone followed by
comparison to previous scans.
– Positive ("suspicious for lung cancer") if non-calcified
nodule ≥4mm (CT scan) or any non-calcified nodule
(CXR). Also adenopathy or effusions.
• Stable findings at T2 were reclassified as "minor
abnormalities“.
• Follow-up of masses: no mandated approach, guidelines
were provided. Included more imaging (PET, CT),
bronchoscopy, needle biopsy, thoracotomy,
thoracoscopy, mediastinoscopy.
• Medical record abstraction.
• Vital status questionnaire annually.
• Lost to follow-up submitted to National Death Index.
- Did not publish methods of identifying cancer-specific
deaths.
Primary Outcome
Lung cancer death:
• 247 (LDCT) vs. 309 (CXR) per 100,000 person-years
(RR 0.80; 95% CI 0.73-0.93; P=0.004).
• Relative risk reduction (RRR) in mortality from lung
cancer with low-dose CT screening of 20% (95% CI, 6.826.7; P=0.004)
• Numbers needed to treat to prevent one lung cancer
death with 3 years of screening is 308.
Secondary Outcomes
• Overall mortality:
1877 (CT) vs. 2000 (CXR) deaths (RR 93.3; 95% CI 1.213.6; P=0.02).
7.0% (CT) vs 7.5% (CXR) (RRR 6%; 95% CI 0.2-12, NNT
219)
• Lung cancer accounted for 24.1% of all deaths in the trial.
• When deaths from lung cancer were excluded from the
comparison, the reduction in overall mortality with the use
of low-dose CT dropped to 3.2% (P=0.28).
Secondary Outcomes
• Lung cancer incidence:
CT group: 645 per 100,000 person-years (1060 cancers)
CXR group: 572 per 100,000 person-years (941 cancers)
(RR 1.13; 95% CI 1.03-1.23, P not given.)
Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer.
The National Lung Screening Trial Research Team . N
Engl J Med 2011;365:395-409.
• Stage of cancer with positive screening test CT vs CXR
– IA - 51.8% vs. 32.7%
– IB - 11.2% vs. 14.9%
– II A - 4.1% vs. 5.1%
– II B - 3.1% vs. 4.0%
– III A - 9.3% vs. 12.7%
– III B - 7.7% vs. 9.8%
– IV - 12.8% vs. 20.7%
• 24.2% of CT screening tests were classified as positive.
• 6.9% of CXR screening tests were classified as positive.
Of positive tests:
- 96% in the CT group were false positives
- 95% in the CXR were false positives
• Complications following any invasive diagnostic
interventions where lung cancer confirmed CT vs CXR.
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Any complication - 28.4% vs. 23.3%
Major complication - 11.6% vs. 8.6%
Intermediate complication - 14.6% vs. 12.5%
Minor complication - 2.2% vs. 2.2%
Death ≤60 days after most invasive diagnostic intervention - 1.5%
vs. 3.9%.
Major – Acute respiratory failure, Cardiac Arrest, CVA, CHF,
Hemothorax, MI, Empyema, VTE.
• Complications following any invasive diagnostic
interventions where lung cancer NOT confirmed (CT vs
CXR)
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Any complication - 0.4% vs. 0.3%
Major complication - 0.1% vs. 0.1%
Intermediate complication - 0.3% vs. 0.2%
Minor complication - <0.1% vs. 0.1%
Death ≤60 days after most invasive diagnostic intervention - 0.1%
vs. 0.1%
– Healthy volunteers may not be representative of the
population as a whole.
– Modern scanners are more advanced than those in
the trial, which may lead to increased detection of
cancers or increased false-positives.
– The trial included institutions with radiology
departments well-regarded for their abilities and may
not be representative of the average radiology
department of other institutions.
– The reduction of death rate was only determined from
three years of scanning, yearly scanning may provide
more benefits.
– Psychosocial harm from the high number of false
positives and invasive procedures unaccounted for.
– Lack of cost-effectiveness calculations.
– Did not publish methods of identifying cancer-specific
deaths.
– Generalizability is limited.
• If 308 patients were screened (NNT=308), the NLST
results suggest that they would undergo:
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985 CT scans
18 PET scans
8 Bronchoscopies
9 Surgical Procedures
To yield 8 diagnoses of lung cancer.
And prevent 1 additional lung cancer-related dealth.
• This is expensive!
• Radiation exposure:
– Ionizing radiation releases free radicals that may
cause DNA damage .
– Cancer risks from radiation are generally
multiplicative of the background cancer risk (radiation
damage and smoking damage interact
synergistically).
• Radiation exposure (Effective dose in millisievert):
– In study average effective dose with low-dose CT
scan was 1.5 mSv.
– Average in diagnostic chest CT is ~ 8 mSv.
– CXR is 0.1 mSv.
– PET CT is ~14 mSv.
– CTPA is ~ 12 mSv.
• The average person in the U.S. receives an effective
dose of about 3 mSv per year from naturally occurring
radioactive materials and cosmic radiation from outer
space.
• In a systematic review of trial.:
– Estimated that NLST participants received
approximately 8 mSv per participant over 3 years.
– Models predict approximately 1 cancer death may be
caused by radiation from imaging per 2500 persons
screened.
Bach PB, Mirkin JN, Oliver TK, et al.
Benefits and harms of CT screening for
lung cancer: A systematic review. JAMA.
2012;307:2418-29.
Bach PB, Mirkin JN, Oliver TK, et al.
Benefits and harms of CT screening for
lung cancer: A systematic review. JAMA.
2012;307:2418-29.
• American Cancer Society, American College of Chest
Physicians, American Society of Clinical Oncology, National
Comprehensive Cancer Network sponsored a systematic
review of randomized clinical trials and cohort studies
addressing the benefits and risks of screening using low dose
CT scan.
• Yielded only three RCT.
• NLST was the largest.
• Other two showed no effect with usual care in much smaller
trials.
• Corrected NLST study of number needed to screen to prevent
1 lung cancer death to 320 (published study was 308).
• Across all studies reviewed average rate of detecting
nodules per round of screening was 20%.
• More than 90% of these nodules turned out to be benign.
• Effect on Mortality.
• CT scans are expensive as well as the diagnostic
procedures performed to evaluate abnormalities.
• Radiation.
• False-positive findings – adverse psychological effects.
• Complications.
• Incidental findings outside the lung.
• Interestingly, part of the recommendation also states that
screening should be conducted in a center similar to
those where the NLST was conducted.
– Concerns about management of screen-detected nodules?
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Is this relevant to our population?
Will you change your practice based on this study?
Do you have any hesitations/reservations?
Is this appropriate or excessive?