Benjamin Han October 12th, 2012 Journal Club Benjamin Han October 12th, 2012

Case Presentation 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.

Case Presentation 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: Medications: 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: ASA 81 mg Simvastatin 40 mg Toprol XL 50 mg Albuterol PRN Tramadol PRN Tylenol PRN

Case Presentation Social History: Family 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: Physical Examination: 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!”

Lung Cancer Screening Should we screen this gentleman for lung cancer? If so, how should we screen? What are the harms of screening?

Screening Tests 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.

Background 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%.

Background 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.

Lung Cancer Screening 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.

Lung Cancer Screening 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.

Lung Cancer Screening 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).

Lung Cancer Screening 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).

Lung Cancer Screening Where are these new recommendations coming from?

National Lung Screening Trial

Clinical Question Among patients at high risk for lung cancer, does low-dose 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.

Study Design 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.

Study Design Population 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.

Study Design Population 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.

Screening Intervention 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

Screening Intervention 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.

Collected Data 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.

Outcomes 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, 6.8-26.7; P=0.004) Numbers needed to treat to prevent one lung cancer death with 3 years of screening is 308.

Outcomes Secondary Outcomes Overall mortality: 1877 (CT) vs. 2000 (CXR) deaths (RR 93.3; 95% CI 1.2-13.6; 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).

Outcomes 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.)

Outcomes

Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer. Figure 1. Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer. The number of lung cancers (Panel A) includes lung cancers that were diagnosed from the date of randomization through December 31, 2009. The number of deaths from lung cancer (Panel B) includes deaths that occurred from the date of randomization through January 15, 2009. The National Lung Screening Trial Research Team . N Engl J Med 2011;365:395-409.

Outcomes 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%

Screening 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 Complications following any invasive diagnostic interventions where lung cancer confirmed CT vs CXR. 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 Complications following any invasive diagnostic interventions where lung cancer NOT confirmed (CT vs CXR) 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%

Limitations 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.

Limitations 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.

Testing Burden If 308 patients were screened (NNT=308), the NLST results suggest that they would undergo: 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!

Limitations 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).

Limitations 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.

Limitations 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.

Benefits and Harms American Caner Society, American College of Chest Physicians, American Society of Clinical Oncology, National Comprehensive Cancer Network 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.

Systematic Review 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.

Systematic Review 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.

Systematic Review

Potential Benefits Effect on Mortality.

Potential Harms 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.

Screening Recommendations 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?

Discussion 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?