September 2015 Tucson Pulmonary Journal Club: Genomic Classifier for Lung Cancer

Silvestri GA, Vachani A, Whitney D, et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N Engl J Med. 2015;373(3):243-51. [CrossRef] [PubMed]

Pulmonary lesions are a common diagnostic dilemma for clinicians. Current literature describes the sensitivity of bronchoscopic techniques to be between 34 and 88%; which varies significantly depending on size and location of the biopsied lesion (1). Previously described gene expression patterns have been found to be associated with malignancy in healthy epithelial cells of the proximal airways\(2). The primary aim of this study was to prospectively validate a specific gene expression classifier in patients undergoing bronchoscopic biopsy for suspected lung cancer.

The study involved two independent, prospective, multicenter, observational studies (AEGIS-1 and AEGIS-2) conducted in the U.S., Canada and Ireland at 28 sites. Patients were excluded if they were never smokers, under age 21, or current cancer or former lung cancer patients. Patients were followed for 12 months after bronchoscopy or until a diagnosis was established. A wide array of bronchoscopic and surgical techniques were used to ultimately make a diagnosis. Prior to undergoing invasive diagnostic testing, the treating physician was asked to estimate the patient’s pre-test probability of cancer.

The overall prevalence of lung cancer in the two cohorts was 76.5%. Bronchoscopy alone had 74% sensitivity (95% CI, 68 to 79) in AEGIS-1 and 76% (CI 95%, 71 to 81) in AEGIS-2 with a combined specificity of 100%. When combining the gene classifier with bronchoscopy, the sensitivity increased to 96% (95% CI, 93 to 98) in AEGIS-1 and 98% (95% CI, 96 to 99) in AEGIS-2 with a combined specificity of 47.9%.

The poor specificity of the gene classifier limits its clinical utility as an adjunct to bronchoscopy. Although the sensitivity was high, the low specificity makes this additional test of low diagnostic value for definitively ruling in cancer. When bronchoscopy was negative, the prevalence of lung cancer remained high, approximately 45%, and the resulting post-test probability of a positive gene-classifier test was 58% and the post-test probability of a negative test was 16%. Neither value is sufficiently predictive to avoid further invasive testing to definitely determine the presence or absence of cancer in this intermediate risk population. The racial composition of study participants was predominately white with a majority being males.  The age range of study participants was between 55 and 71. Because of that, the generalizability is more limited.  However, the gene classifier might have limited clinical utility for patients who are poor candidates for additional invasive testing.  A positive result might tilt the balance in favor of additional testing whereas a negative result might warrant watchful waiting. Overall, this dual approach to diagnostic assessment for lung nodules suspicious of being lung cancer is not ready for widespread implementation. 

Joshua Dill DO; Joe Gerald, MD, Ph.D.; Christian Bime MD, MSc and James Knepler MD.

University of Arizona

Tucson, Arizona USA

References

1. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:Suppl 5: e142S-e165S. [CrossRef] [PubMed]
2. Spira A, Beane JE, Shah V, et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med. 2007;13:361-6. [CrossRef] [PubMed] 

Cite as: Dill J, Gerald J, Bime C, Knepler J. September 2015 Tucson pulmonary journal club: genomic classifier for lung cancer. Southwest J Pulm Crit Care. 2015;11(3):119-20. doi: http://dx.doi.org/10.13175/swjpcc125-15 PDF

March 2014 Phoenix Pulmonary Journal Club: Palliative Care

Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010 Aug 19;363(8):733-42. [CrossRef] [PubMed]

The March journal club focused on the role of palliative care in respiratory diseases such as chronic obstructive lung disease (COPD) and lung cancer. Palliative care is specialized care that focuses on life threatening disease and the relief of pain and stress. Although often initiated near the end of life, palliative care should not be  considered as end of life care. This study reviewed the impact of introducing palliative care in conjunction with oncologic care in the treatment of metastatic non-small cell lung cancer versus oncologic care alone. This was a nonblinded, randomized control trial of 151 patients done at the Massachusetts General Hospital.  Seventy-seven patients were randomly assigned to early palliative care + oncologic care (P + O) and 74 patients were assigned to oncologic care only (O). P + O patients were seen by palliative care services within 3 weeks of enrollment and met with services monthly until their death. Primary outcome was quality of life at baseline and at 12 weeks. The results showed that P + O patients had less depressive symptoms (16% P + O vs. 38% O), received less aggressive end of life care (33% P + O vs. 54% O) , and lived 2.7 months longer (11.6 m P + O vs. 8.9 m O). Although this was a small, nonblinded study it showed that palliative care does not need to be exclusive of ongoing oncologic care and that early referral and involvement can help foster goals of therapy and better symptom control.

Carlucci A, Guerrieri A, Nava S. Palliative care in COPD patients: is it only an end-of-life issue? Eur Respir Rev. 2012 Dec 1;21(126):347-54.  [CrossRef] [PubMed]

The role of palliative care in COPD is underutilized and rarely initiated until the end stages of disease. This review on the role of palliative care in COPD emphasizes that COPD is often a more debilitating disease than lung cancer with even higher rates of anxiety and depression. Palliative care should not be considered as transitional or end of life care, but integrated early to improve symptom control and quality of life. The timing as to when to get palliative care services involved in the outpatient COPD population is debatable, as the resources are limited. This paper suggests that looking at parameters that delineate a decreased 5 year survival in COPD, such as THE BODE INDEX, may be useful.  Patients that have a BODE index score of 7 or more would certainly be good candidates and perhaps starting with a score of 5 or more may even be more appropriate. Palliative care should be considered an integrated and complimentary tool in the management of advanced COPD.

Manoj Mathew, MD FCCP MCCM

Reference as: Mathew M. March 2014 Phoenix pulmonary journal club: palliative care. Southwest J Pulm Crit Care. 2014;8(3):194. doi: http://dx.doi.org/10.13175/swjpcc034-14 PDF

December 2013 Phoenix Pulmonary Journal Club: Lung Cancer Screening

During this month’s pulmonary journal club we reviewed several of the sentinel studies looking at lung cancer screening. Since the National Lung Screening Research Team (NLSRT) (1) published the impressive results showing a 20% reduction in lung cancer mortality, the debate on when and if to initiate a national lung cancer screening program has been at the forefront of debate. The American Lung Association and American Cancer Society have issued statements that are not guidelines, but did offer insight on the price we pay for earlier lung cancer detection and reduction in mortality…which is the increased rates of false positives detected and increased rates of biopsies.

The US Task Force on Lung Cancer Screening has yet to decide on a screening program and have yielded a statement that neither supports nor refutes the current level of evidence. Prior to the NLSRT study there were others that showed conflicting results on lung cancer screening. The PLCO Cancer Screening Trial (2) was a large randomized prospective trial that recruited 77,464 patients and used chest X-rays at yearly intervals for 3 years in patients aged 55-74. This study included nonsmokers. The results are ongoing but the preliminary data showed that a total of 564 cancers were detected with 87% as non-small cell. Further data on outcomes will be reported in 2015.

The PANCAN and BCCA Study were 2 prospective cohort studies (3) done to see which CT detected incident nodules on more likely to be malignant. The results of the 2 combined studies showed that out of the 12029 incident nodules detected only 142 were biopsy proven malignant.  Nodules were more likely to be malignant if the size was greater than 1cm, spiculated, multiple nodules, and more upper lobe predominant. In addition a nodule along the perifissure region was highly unlikely to be cancer. The study also noted that biopsy of the largest nodule was often not the malignant nodule in 20% of cases. Subsequent image with volumetric imaging may help with this.

The results of the 2 year incidence screening results (4) demonstrated that the low dose CT screening was superior to chest radiography in detecting earlier stage cancers as well as showing lower incidence rates of lung cancer when the initial CT screening was negative. The highest rates of lung cancer were detected at the T2 interval screening due detection of enlarging nodules. Overall the 2 year incidence study showed that the use of CT screening was superior to chest Radiography in detecting earlier stage non-small cell lung cancers.

The review of the prior papers yielded a healthy discussion on where do we go as clinicians in offering lung cancer screening to patients. There was a consensus that nearly all curable lung cancers have been found incidentally, and that it makes sense to have a screening process. What this screening process should be is still uncertain.  By limiting the screening option to smokers with a significant 30 pack year history and limiting the initial screening age to 55 we have set initial targets to look at.  The price of CT screening will inevitably result in higher costs and higher rates of false positives. Future algorithms will need to be adjusted to limit rates of false positives by looking more at volumetric analysis and nodule characteristics to limit unnecessary biopsies.

Manoj Mathew, MD FCCP MCCM

References

1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. [CrossRef] [PubMed]
2. Hocking WG, Hu P, Oken MM, Winslow SD, Kvale PA, Prorok PC, Ragard LR, Commins J, Lynch DA, Andriole GL, Buys SS, Fouad MN, Fuhrman CR, Isaacs C, Yokochi LA, Riley TL, Pinsky PF, Gohagan JK, Berg CD; PLCO Project Team. Lung cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. J Natl Cancer Inst. 2010;102(10):722-31. [CrossRef] [PubMed]
3. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, Yasufuku K, Martel S, Laberge F, Gingras M, Atkar-Khattra S, Berg CD, Evans K, Finley R, Yee J, English J, Nasute P, Goffin J, Puksa S, Stewart L, Tsai S, Johnston MR, Manos D, Nicholas G, Goss GD, Seely JM, Amjadi K, Tremblay A, Burrowes P, MacEachern P, Bhatia R, Tsao MS, Lam S. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med. 2013;369(10):910-9. [CrossRef] [PubMed]
4. Aberle DR, DeMello S, Berg CD, Black WC, Brewer B, Church TR, Clingan KL, Duan F, Fagerstrom RM, Gareen IF, Gatsonis CA, Gierada DS, Jain A, Jones GC, Mahon I, Marcus PM, Rathmell JM, Sicks J; National Lung Screening Trial Research Team. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med. 2013;369(10):920-31. [CrossRef] [PubMed] 

Reference as: Mathew M. December 2013 Phoenix pulmonary journal club: lung cancer screening. Southwest J Pulm Crit Care. 2013;7(6):363-4. doi: http://dx.doi.org/10.13175/swjpcc180-13 PDF

June 2013 Pulmonary Journal Club

National Lung Screening Trial Research Team, Church TR, Black WC, Aberle DR, Berg CD, Clingan KL, Duan F, Fagerstrom RM, Gareen IF, Gierada DS, Jones GC, Mahon I, Marcus PM, Sicks JD, Jain A, Baum S. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013;368(21):1980-91. [CrossRef]  [PubMed]

This paper serves as a follow up on the results of the first round of testing using low dose computed tomography in screening for lung cancer.  A full review on the initial results can be referenced from the August 2011 Pulmonary Journal Club (1).

The study was performed at 33 centers from 2002 – 2004. A total of 53454 patients were enrolled. Inclusion criteria were age 55-74 and a 30 pack-year smoking history. All patients were randomized to receive either low dose screening CT scan (LDCT) or a chest x-ray.

The results of the first year of screening showed that the LDCT group had 7191 patients with a positive result. Out of these 7191 patients 270 patients (3.75%) were diagnosed with lung cancer. In the chest x-ray group a total of 2387 patients had a positive result and 136 patients (5.7%) were diagnosed with lung cancer. There were more stage 1A cancers diagnosed in the LDCT group (132 patients) compared to the chest x-ray group (46 patients).

The results of the study support that there is a higher prevalence in stage 1A lung cancer within the LDCT screening arm. However this comes at a cost of a substantial number of false positives which often result in additional tests, procedures and costs. In addition when we look at the overall prevalence of lung cancer between the LDCT and chest x-ray groups the difference is only 1% in the LDCT group compared to 0.7% in the chest x-ray group.  

Further information as the screening process continues will be needed to see if CT scanning is cost effective in screening for lung cancer.

Manoj Mathew, MD MCCM, FCCP

Reference

1. Mathew M. August 2011 pulmonary journal club. Southwest J Pulm Crit Care. 2011;3:52-3.

Reference as: Mathew M. June 2013 pulmonary journal club. Southwest J Pulm Crit Care. 2013;6(6):308. doi: http://dx.doi.org/10.13175/swjpcc086-13 PDF

August, 2011 Pulmonary Journal Club

Reference as: Mathew M. August 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;3:52-3. (Click here for a PDF version)

The National Lung Screening Research Team. Reduced lung cancer mortality with low dose computed tomographic screening. N Engl J Med 2011;365:395-409.

Lung cancer remains the number one cause of cancer related deaths among men and women. It is more fatal than colon, breast and prostate cancer combined. The poor prognosis is largely due to advanced cancer stage at the time of diagnosis. More than 75% of lung cancer cases are diagnosed with a stage 2 or higher and greater than 50% are diagnosed with stage 4. The best prognosis is early stage 1 with a 5 year survival of greater than 65%. Unfortunately the large bulk of early stage 1 cases come as incidental findings when patients receive either a chest x-ray or computerized tomography scan for an unrelated evaluation. Prior studies looking at lung cancer screening with chest x-rays and sputum cytology have not been shown to improve mortality due to poor sensitivity. Prior studies with low dose computed tomography (LDCT) show markedly improved sensitivity when compared to chest x-ray but failed to show improved mortality mainly due to lack of randomization and a control group (1-7). This study performed by the National Lung Screening Research Team was to date the largest randomized, controlled trial looking at low dose computed tomography as a lung cancer screening modality. The study performed from 2002 – 2007 was to determine whether screening with low LDCT improved lung cancer mortality. Inclusion criteria were age 55-74, smoking history of 30 pack/years and former smokers who have quit within the past 15 years. Patients with a prior history of lung cancer or had a LDCT scan within the past 18 months were excluded. A total 53,454 pts were enrolled and with 26732 received screening with a chest x-ray annually for 3 years and 26722 received screening with LDCT annually for 3 years. The results showed that there were significantly more abnormalities detected in the screening LDCT scan and this led to higher rates of evaluation and subsequently showed a 20% reduction in lung cancer mortality. The number needed to screen with LDCT to prevent 1 death from lung cancer was 320 patients. To put his into perspective the number of screening colonoscopies needed to prevent 1 death is 492 and the number of screening mammographies needed to prevent 1 death from breast cancer is 1224 (8). The study was well done and it did accomplish its primary objective. Although the results look promising additional validation is needed before a mass screening program is initiated. Several factors need to be addressed on subsequent studies, mainly who does the radiographic interpretation and a detailed cost analysis. A radiologist with a special interest in chest radiology may need to be designated before a screening program is released. Furthermore we still do not know the long term effects of even low dose radiation. In the accompanying editorial by Harold Sox it was well noted that patients seeking a screening LDCT may also need additional counseling on smoking cessation. Since lung cancer remains for the most part a preventable smoking related illness an equally aggressive (if not more aggressive) approach to smoking cessation needs to be implemented in conjunction with any screening program.

Manoj Mathew, MD, FCCP MCCM

Associate Editor, Pulmonary Journal Club

References

1. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242-5.
2. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99-105.
3. Swensen SJ, Jett JR, Sloan JA, et al. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002;165:508-13.
4. Nawa T, Nakagawa T, Kusano S, Kawasaki Y, Sugawara Y, Nakata H. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest 2002;122:15-20.
5. Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile lowdose spiral computed tomography scanner. Br J Cancer 2001;84:25-32.
6. Jett JR. Spiral computed tomography screening for lung cancer is ready for prime time. Am J Respir Crit Care Med 2001;163:812, discussion 814-5.
7. Diederich S, Wormanns D, Semik M, et al. Screening for early lung cancer with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology 2002;222:773-81.
8. Humphrey LL. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task F