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LETTERS Prevalence of non-cancer-related abnormalities on low-dose spiral computer tomography versus chest radiograph in a screening population We recently reported the presence of noncancer-related abnormalities seen on chest radiographs (CXR) among subjects enrolled in a lung cancer screening trial.1 More than 70 000 men and women enrolled in the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial received annual CXR screens for 4 years. Radiologists reported the presence of nodules/ masses suspicious for cancer as well as other, non-cancer-related abnormalities. In an average of 3.3 CXR screens, 5.8% of subjects had chronic obstructive pulmonary disease (COPD), 16.8% had scarring, 17.5% had granuloma, 9.1% had cardiac abnormalities and 0.7% had pleural fluid reported on at least one examinaton. Controlling for smoking status, sex and age, we found increased hazard ratios (HRs) associated with COPD (HR = 1.8) and scarring (HR = 2.0) for diagnosis of lung cancer over a 3-year period after the screen. In addition, COPD (HR = 1.7), scarring (HR = 1.4), cardiac abnormalities (HR = 2.1) and pleural fluid (HR = 2.3) were associated with significantly increased HRs for non-lungcancer mortality. These results suggest that the above abnormalities found on CXR may have clinical relevance. Low-dose spiral computed tomography (LDCT) is currently being evaluated as a screening modality for lung cancer. Studies have shown that LDCT identifies nodules/ masses in roughly twice as many people as CXR, and can identify 3–4 times as many cancers at baseline screening as CXR.2 3 This increased positivity rate and sensitivity, although possibly indicative of an increased ability of LDCT (over CXR) to detect lung cancers while they are still curable, also results in an increased burden of follow-up for LDCT. LDCT may also identify a greater number of non-cancer abnormalities (eg, COPD, scarring, cardiac abnormalities) than CXR. To the extent that these abnormalities are followed up, this could result in a further increased burden of follow-up for LDCT as compared with CXR, although it could also possibly lead to increased useful interventions. The Lung Screening Study was a pilot study designed to assess the feasibility of conducting a randomised trial of LDCT versus CXR. The Lung Screening Study randomised a total of 3409 current and former male and female smokers aged 55–74 years with at least 30 pack years of smoking at six screening centres to either CXR or LDCT.4 The technical parameters for LDCT were a 120–140 kV peak, 60 mA current, 1 s scan time, 5 mm collimation and a pitch of 2 or equivalent. The CXR was posterior–anterior only. Radiologists reported specific non-cancer abnormalities as well as nodules/ masses on the baseline screening form.
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Table 1 shows the proportion of screened subjects with various non-cancer abnormalities reported on the baseline screen by study arm; for comparison, the proportion with nodules/ masses is also shown. For most abnormalities, the relative risk (RR) for LDCT versus CXR is close to that for nodules/masses of 2.1. The exceptions are cardiac abnormalities, which were almost 5 times as common in the LDCT arm, bone lesions, which were much less common (RR = 0.24) on LDCT, and pleural fluid, which was reported about equally in each arm (RR = 1.2, p = NS). The type of cardiac abnormality was further examined using the year one screening results. At this screen, radiologists reported non-cancer findings only in an ‘‘other specify’’ category requiring a verbatim response. Analysis of these responses showed that coronary calcification was reported for 19% of LDCT subjects compared with 0.7% of CXR subjects, whereas cardiomegaly was reported for 0.4% of LDCT subjects versus 2.1% of CXR subjects. It is not clear whether the increased risks for lung cancer and/or non-lung-cancer mortality observed for various abnormalities reported on CXR will hold to the same extent for those abnormalities as reported on LDCT. However, there seems to be a potential for increased burden of follow-up associated with noncancer abnormalities for high-risk subjects undergoing screening with LDCT as compared with CXR. Paul Pinsky Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
Matthew Freedman Lombardi Cancer Center, Georgetown University, Washington, D C, USA
Martin Oken Hubert Humphrey Cancer Center, North Memorial Hospital, Minneapolis, Minnesota, USA
Paul Kvale Henry Ford Health System, Detroit, Michigan, USA
Neal Caporaso Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
Table 1 Study
John Gohagan Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA Correspondence to: Dr P Pinsky, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd, Bethesda, MD 20892, USA;
[email protected]
doi: 10.1136/thx.2006.073288 Competing interests: None declared.
References 1 Pinsky PF, Freedman M, Kvale P, et al. Abnormalities on chest radiograph reported in subjects in a cancer screening trial. Chest 2006;130:688–93. 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 Sone S, Shodayu T, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242–5. 4 Gohagan JG, Marcus P, Fagerstrom R, et al. Baseline findings of a randomized feasibility trial of lung cancer screening with spiral CT scan versus chest radiograph. Chest 2004;126:114–21.
When in doubt should we cut it out? The role of surgery in nonsmall-cell lung cancer We wish to clarify a comment made in the editorial regarding our systematic review.1 In an otherwise insightful piece, Holty and Gould2 considerably played down the importance of complete mediastinal lymph node dissection (CMLND) in reducing locoregional and distant relapse after lung cancer resection because of what they called ‘‘stage migration’’. They are correct that about 10% of participants were excluded from analysis after randomisation and minor breaches of intention-to-treat principles occurred in two of the three trials analysed. These, however, should not be confused with the Will Rogers phenomenon,3 where more accurate staging results in better apparent survival for each stage subgroup. This is the problem with every retrospective or stage-matched series comparing CMLND with
Prevalence of abnormalities at baseline, by study arm, Lung Screening
Nodule/mass Granuloma Scarring/pulmonary fibrosis COPD Pleural fibrosis Pleural fluid Bone/soft tissue Cardiac abnormality
CXR n = 1550
LDCT n = 1586
%
%
RR* (95% CI)
7.7 8.5 12.5
16.1 17.2 28.5
2.1 (1.9–2.4) 2.0 (1.8–2.3) 2.3 (2.1–2.5)
10.3 3.7 0.26 6.1 3.3
24.9 9.5 0.32 1.5 13.9
2.4 (2.2–2.6) 2.6 (2.2–3.0) 1.2 (0.5–2.9) 0.24 (0.17–0.37) 4.2 (3.7–4.8)
COPD, chronic obstructive pulmonary disease; CXR, chest x ray radiograph; LDCT, low-dose spiral computed tomography. *RR is rate in the LDCT arm divided by rate in the CXR arm.
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systematic sampling, but is avoided in trials with patients prospectively randomised and analysed on an intention-to-treat basis. We emphasise that we did not perform any stagebased subanalyses, but compared the whole CMLND population with the systematic sampling group. The exclusions after randomisation clearly should not have occurred, but were adequately reported. In all, 25 patients had small-cell cancer or a non-malignant pathology, 48 had incomplete primary resection, 5 turned out to have metastatic deposits from other sites and 15 were excluded because of upstaging to IIIB or IV only. The exclusions were well matched, with 52 occurring in the CMLND group and 41 in the systematic sampling group. We therefore believe this had little effect on the overall analysis. It should also be mentioned that in one of the trials, only patients with cT1N0 adenocarcinoma of (2 cm diameter were randomised. Mechanistically, the authors hypothesised that this is the group least likely to benefit from CMLND; however, their inclusion in the pooled analysis still resulted in a clear benefit in favour of CMLND. In fact, the pooled hazard ratio of 0.78 is superior to that of adjuvant chemotherapy meta-analyses4 that have created such enthusiasm in lung cancer circles of late. Therefore, we are concerned that as a result of this editorial, groups treating lung cancer may not demand from their surgeons that which they are demanding from their medical oncologists—an evidence-based improvement in survival with an adjuvant intervention. We also await the results of the ACOSOG Z30 trial,5 which will address this question for patients in clinical stage I. This will also allow a pooled analysis of 1959 patients, which should be able to put this question to rest after 50 years of controversy. Until then, the level I evidence is that CMLND should be performed as part of the surgical treatment of patients with stage I–IIIA non-small-cell lung cancer.
Gavin M Wright Correspondence to: G M Wright, St Vincent’s Hospital, 55 Victoria Parade Fitzroy, Melbourne 3065, Victoria, Australia;
[email protected] Competing interests: None declared.
References 1 Wright G, Manser RL, Byrnes G, et al. Surgery for non-small cell lung cancer: systematic review and meta-analysis of randomised controlled trials. Thorax 2006;61:597–603.
2 Holty J-EC, Gould MK. When in doubt should we cut it out? The role of surgery in non-small cell lung cancer. Thorax 2006;61:554–6. 3 Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985;312:1604–8. 4 Pignon JP, Tirbodet H, Scagliotti GV, et al. Lung Adjuvant Cisplatin Evaluation: a pooled analysis of five randomised clinical trials including 4,584 patients. Proc Am Soc Clin Oncol 2006;24(Part 1):No 188, 7008. 5 Allen MS, Darling GE, Pechet TT, et al. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 2006;81:1013–19.
Authors’ reply We thank Dr Wright for his comments, but respectfully disagree. Although it is certainly possible that complete mediastinal lymph node dissection (CMLD) might improve survival in non-small-cell lung cancer (NSCLC), all three of the studies performed to date were limited by stage migration and other biases. Although overall exclusions were matched, we do not know whether exclusions due to upstaging were necessarily matched between study arms. In fact, limited data from the studies suggest that they were not. In the study by Wu et al,1 after post-randomisation exclusions, there were more patients with stage I (42% v 24%) and fewer with stage IIIa (28% v 48%) in the lymph node sampling group than in the CMLD group. Furthermore, the authors of one of the other three included studies concluded that stage migration might have resulted in an observed survival benefit for patients undergoing CMLD,2 and a previous systematic review on CMLD in NSCLC also concluded that stage migration existed for two of the three included studies.3 In addition, there are other limitations. For example, because the study by Sugi et al4 included only patients with peripheral NSCLC ,2 cm, the results are not generalisable to all patients with early-stage disease. The study by Wu et al had unequal follow-up between study arms.1 3 The study by Izbicki et al2 had significantly more patients with squamous cell carcinoma in the lymph node sampling group (53%) than in the CMLD group (32%, p = 0.03). Finally, two of the three studies were unblinded during follow-up.1 4 Even if a small survival benefit exists, this must be weighed against the substantially higher morbidity for patients undergoing CMLD reported in two of the three included studies.2 4 The results of the ACOSOG Z30 trial should help address these trade-offs.5
J-E C Holty Center for Primary Care and Outcomes Research, Stanford, University, Stanford, California, USA
M K Gould VA Palo Alto Health Care System, Palo Alto, California, USA; Stanford University Medical Center, Palo Alto, California, USA; Center for Primary Care and Outcomes Research, Stanford University, Stanford, California, USA Correspondence to: Dr J-E C Holty, Division of Pulmonary and Critical Care Medicine, University School of Medicine, 300 Pasteur Drive, H3143, Stanford, CA 94305-5236, USA;
[email protected] Competing interests: None declared.
References 1 Wu YL, Huang ZF, Wang SY, et al. A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer 2002;36:1–6. 2 Izbicki J, Passlick B, Pantel K, et al. Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial. Ann Surg 1998;227:138–44. 3 Barnard J, Dunning J, Musleh G, et al. Is there a role for the use of radical lymph node dissection in the surgical management of resectable non-small cell lung cancer? Interact Cardiovasc Thorac Surg 2004;3:294–9. 4 Sugi K, Nawata K, Fujita N, et al. Systematic lymph node dissection for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter. World J Surg 1998;22:290–5. 5 Allen MS, Darling GE, Pechet TTV, et al. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 2006;81:1013–20.
CORRECTION doi: 10.1136/thx.2006.063271corr1 The authors of the article entitled ‘‘Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis’’ (Barr RG, Bourbeau J, Camargo CA, et al. Thorax 2006;61:854–62), published in the October issue, have noticed an error in figure 1. Reference 26 in figure 1 should refer to a paper not in the reference list: Witek TJ Jr, Mahler DA. Minimal important difference of the transition dyspnoea index in a multinational clinical trial. Eur Respir J 2003;21:267–72. Where reference 26 is cited in the text this correctly refers to the paper listed in the reference list.
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