Does lung cancer screening with low-dose computerised tomography (LDCT) improve disease-free survival
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《血管的通路杂志》
a Department of Thoracic Surgery, Guy's Hospital, St Thomas Street, London, UK
b Information Scientist, Royal College of Surgeons of England, Lincolns Inn Fields, London, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether screening an asymptomatic person with a low-dose computerised tomography (LDCT) would detect lung cancer early and most importantly improve that person's disease-free survival from lung cancer. Altogether 354 papers were identified using the search below. Ten papers presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of the papers are tabulated. We conclude that the current observational and prevalence studies on the role of LDCT screening has failed to establish whether LDCT really impacts on improved disease-free survival, despite consistently higher early detection rates of lung cancer.
Key Words: Evidence-based medicine; Thoracic surgery; Lung cancer screening
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
You are in the out-patient department seeing a 77-year-old patient with lung cancer when the patient's son mentions his concerns about getting lung cancer. He is a wealthy 50-year-old smoker and though currently well with no symptoms of respiratory disease wonders if he could be ‘screened’ for lung cancer and have a CT scan from time to time.
3. Three part question
In [asymptomatic patients with risk factors for lung cancer] is the use of [Low-dose Computerised Tomography] beneficial in terms of [improving disease-free survival].
4. Search strategy
Medline 1966–Feb 2006 and Embase 1980–Feb 2006 using the Dialog Datastar interface [Lung-Neoplasms#.DE. OR Lung-Tumor#.DE. OR (Lung NEAR (Neoplasm$ OR Cancer$ OR Carcinoma$ OR Adenocarcinoma$ OR Angiosarcoma$ OR Chrondosarcoma$ OR Sarcoma$ OR Teratoma$ OR Lymphoma$ OR Blastoma$ OR Microcytic$ OR Carcinogenesis OR Tumor$ OR Tumour$ OR Metast$4)).TI,AB. OR NSCLC.TI,AB. OR SCLC.TI,AB.] AND [Mass-Screening.DE. OR Cancer-Screening.DE. OR (Screen$3 OR Case ADJ Finding OR Casefinding OR Case-Finding).TI,AB.] AND [Tomography-X-Ray-Computed#.DE. OR Tomography-Spiral-Computed.DE. OR Computer-Assisted-Tomography#.DE. OR (Comput$2 ADJ Tomograph$2 OR CT ADJ Scan$3 OR HRCT). limit to English. This search was repeated in Cochrane Central Register of Controlled Trials
5. Search outcome
A total of 354 papers were identified of which nine were deemed to be relevant. No RCT was found and all systematic reviews included observational cohort studies. No meta-analysis has been attempted. The reviews analysed on average 6 to 8 papers including many of the same studies, though in total the three reviews identified 13 observational studies. The larger individual observational studies are presented for clarity. In addition, one retrospective study examining the incidental lung cancers at autopsy was included as the issue of overdiagnosis in lung cancer screening is regarded as important to the debate on CT screening.
6. Comments
Many of the LDCT screening studies have come from Japan where historically screening programmes have been conducted since the 1980s with large numbers of both high- and low-risk men and women over the age of 40 years. LDCT based on the observational and prevalence studies so far conducted appears to detect smaller nodules than chest X-ray [7,10,11]. Sone [4] reported that in over 5000 participants LDCT detected lung cancer in 0.48% as compared to 0.03–0.05% in a similar number of persons screened with chest X-ray and sputum cytology. Amongst all studies reported, the detected prevalence for lung cancer using CT ranged from 0.40 to 2.70% [7,10,11]. In studies that have compared CT with CXR, CT screening of asymptomatic individuals for lung cancer results in an approximately 3-fold higher detection rate than screening with CXR [10]. In addition, from both Japanese and American studies it appears the higher detection rate of CT scan compared to CXR is mainly as a result of increased stage I tumour detection [11].
Bepler [9] reported the rate of non-calcified pulmonary nodules ranged from 5.1 to 51.4%, with the smallest diameter of detectable lesions being <3 mm. The PPV was variable, but better in an older group and comparable in range to that of mammography in breast cancer screening. Henschke [2,3] in the Early Lung Cancer Action Project (ELCAP) detected non-calcified nodules in 23% of participants compared to 7% with chest X-ray. However, in the 23% with nodules only around 3% had lung cancer. The rate of false positive results in the LDCT screened patients remained consistently high leading to the risk of potentially invasive further tests for essentially benign nodules. The ELCAP study incorporated a protocol for dealing with suspicious nodules involving repeat LDCT surveillance that essentially separated the evaluation of the diagnostic aspect of screening from that of the subsequent treatment. This limited the use of invasive tissue diagnosis and has been adopted elsewhere [13].
As with CXR screening, LDCT screening has faced several methodological problems related to inherent biases, most noticeably the issue of overdiagnosis, sometimes referred to as ‘pseudodisease’. Overdiagnosis can occur when screening leads to the detection of cancers that would not have become symptomatic or be diagnosed clinically before that individual died of other causes. Its importance remains a matter of intense debate [7,11,13]. Manser [12] in a recent retrospective review of coronial autopsies found that in individuals that died of natural causes 28% of lung cancers detected at autopsy were incidental, and were typically stage 0 or I. The ELCAP protocol protects against this by requiring assessment of growth prior to biopsy of nodules <15 mm in diameter and review by a panel of expert lung pathologists [2,3,13].
All the reviews of LDCT lung cancer screening concluded that the efficacy on disease-specific and overall mortality cannot be accurately assessed on current available evidence. Bepler [9] highlighted several deficiencies; the reported follow up periods on the observational studies are too short for a meaningful comparison with global age-adjusted lung cancer mortality data; participants in the screening studies represent a particular population, and are not necessarily representative of the general population; and finally lack of an RCT to examine the impact of LDCT screening on lung cancer mortality (Table 1).
7. Clinical bottom line
The current observational and prevalence studies on the role of LDCT screening has failed to establish whether LDCT really impacts on improved disease-free survival, despite consistently higher early detection rates of lung cancer.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact J Cardiovasc Thoracic Surg 2003; 2:405–409.
Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, Libby DM, Pasmantier MW, Koizumi J, Altorki NK, Smith JP. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999; 354:99–105.
Henschke CI, Naidich DP, Yankelevitz DF, McGuinness G, McCauley DI, Smith JP, Libby D, Pasmantier M, Vazquez M, Koizumi J, Flieder D, Altorki N, Miettinen OS. Early lung cancer action project: initial findings on repeat screenings. Cancer 2001; 92:153–159.
Sone S, Takashima S, Li F, Yang Z, Honda T, Maruyama Y, Hasegawa M, Yamanda T, Kubo K, Hanamura K, Asakura K. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998; 351:1242–1245.
Sobue T, Moriyama N, Kaneko M, Kusumoto M, Kobayashi T, Tsuchiya R, Kakinuma R, Ohmatsu H, Nagai K, Nishiyama H, Matsui E, Eguchi K. Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol 2002; 20:911–920.
Swensen SJ, Jett JR, Sloan JA, Midthun DE, Hartman TE, Sykes AM, Aughenbaugh GL, Zink FE, Hillman SL, Noetzel GR, Marks RS, Clayton AC, Pairolero PC. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002; 165:508–513.
Bach PB, Kelley MJ, Tate RC, McCrory DC. Screening for lung cancer: a review of the current literature. Chest 2003; 123:72S–82S.
Bach PB, Niewoehner DE, Black WC. Screening for lung cancer: the guidelines. Chest 2003; 123:83S–88S.
Bepler G, Goodridge CD, Djulbegovic B, Clark RA, Tockman M. A systematic review and lessons learned from early lung cancer detection trials using low-dose computed tomography of the chest. Cancer Control 2003; 10:306–314.
Lung cancer screening: recommendation statement. Ann Intern Med 2004; 140:738–739.
Manser RL, Irving LB, de Campo MP, Abramson MJ, Stone CA, Pedersen KE, Elwood M, Campbell DA. Overview of observational studies of low-dose helical computed tomography screening for lung cancer. Respirology 2005; 10:97–104.
Manser RL, Dodd M, Byrnes G, Irving LB, Campbell DA. Incidental lung cancers identified at coronial autopsy: implications for overdiagnosis of lung cancer by screening. Respir Med 2005; 99:501–507.
Henschke CI, Shaham D, Yankelevitz DF, Altorki NK. CT screening for lung cancer: past and ongoing studies. Semin Thorac Cardiovasc Surg 2005; 17:99–106.(Ian Hunt, Mayroon Siva, R)
b Information Scientist, Royal College of Surgeons of England, Lincolns Inn Fields, London, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether screening an asymptomatic person with a low-dose computerised tomography (LDCT) would detect lung cancer early and most importantly improve that person's disease-free survival from lung cancer. Altogether 354 papers were identified using the search below. Ten papers presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of the papers are tabulated. We conclude that the current observational and prevalence studies on the role of LDCT screening has failed to establish whether LDCT really impacts on improved disease-free survival, despite consistently higher early detection rates of lung cancer.
Key Words: Evidence-based medicine; Thoracic surgery; Lung cancer screening
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
You are in the out-patient department seeing a 77-year-old patient with lung cancer when the patient's son mentions his concerns about getting lung cancer. He is a wealthy 50-year-old smoker and though currently well with no symptoms of respiratory disease wonders if he could be ‘screened’ for lung cancer and have a CT scan from time to time.
3. Three part question
In [asymptomatic patients with risk factors for lung cancer] is the use of [Low-dose Computerised Tomography] beneficial in terms of [improving disease-free survival].
4. Search strategy
Medline 1966–Feb 2006 and Embase 1980–Feb 2006 using the Dialog Datastar interface [Lung-Neoplasms#.DE. OR Lung-Tumor#.DE. OR (Lung NEAR (Neoplasm$ OR Cancer$ OR Carcinoma$ OR Adenocarcinoma$ OR Angiosarcoma$ OR Chrondosarcoma$ OR Sarcoma$ OR Teratoma$ OR Lymphoma$ OR Blastoma$ OR Microcytic$ OR Carcinogenesis OR Tumor$ OR Tumour$ OR Metast$4)).TI,AB. OR NSCLC.TI,AB. OR SCLC.TI,AB.] AND [Mass-Screening.DE. OR Cancer-Screening.DE. OR (Screen$3 OR Case ADJ Finding OR Casefinding OR Case-Finding).TI,AB.] AND [Tomography-X-Ray-Computed#.DE. OR Tomography-Spiral-Computed.DE. OR Computer-Assisted-Tomography#.DE. OR (Comput$2 ADJ Tomograph$2 OR CT ADJ Scan$3 OR HRCT). limit to English. This search was repeated in Cochrane Central Register of Controlled Trials
5. Search outcome
A total of 354 papers were identified of which nine were deemed to be relevant. No RCT was found and all systematic reviews included observational cohort studies. No meta-analysis has been attempted. The reviews analysed on average 6 to 8 papers including many of the same studies, though in total the three reviews identified 13 observational studies. The larger individual observational studies are presented for clarity. In addition, one retrospective study examining the incidental lung cancers at autopsy was included as the issue of overdiagnosis in lung cancer screening is regarded as important to the debate on CT screening.
6. Comments
Many of the LDCT screening studies have come from Japan where historically screening programmes have been conducted since the 1980s with large numbers of both high- and low-risk men and women over the age of 40 years. LDCT based on the observational and prevalence studies so far conducted appears to detect smaller nodules than chest X-ray [7,10,11]. Sone [4] reported that in over 5000 participants LDCT detected lung cancer in 0.48% as compared to 0.03–0.05% in a similar number of persons screened with chest X-ray and sputum cytology. Amongst all studies reported, the detected prevalence for lung cancer using CT ranged from 0.40 to 2.70% [7,10,11]. In studies that have compared CT with CXR, CT screening of asymptomatic individuals for lung cancer results in an approximately 3-fold higher detection rate than screening with CXR [10]. In addition, from both Japanese and American studies it appears the higher detection rate of CT scan compared to CXR is mainly as a result of increased stage I tumour detection [11].
Bepler [9] reported the rate of non-calcified pulmonary nodules ranged from 5.1 to 51.4%, with the smallest diameter of detectable lesions being <3 mm. The PPV was variable, but better in an older group and comparable in range to that of mammography in breast cancer screening. Henschke [2,3] in the Early Lung Cancer Action Project (ELCAP) detected non-calcified nodules in 23% of participants compared to 7% with chest X-ray. However, in the 23% with nodules only around 3% had lung cancer. The rate of false positive results in the LDCT screened patients remained consistently high leading to the risk of potentially invasive further tests for essentially benign nodules. The ELCAP study incorporated a protocol for dealing with suspicious nodules involving repeat LDCT surveillance that essentially separated the evaluation of the diagnostic aspect of screening from that of the subsequent treatment. This limited the use of invasive tissue diagnosis and has been adopted elsewhere [13].
As with CXR screening, LDCT screening has faced several methodological problems related to inherent biases, most noticeably the issue of overdiagnosis, sometimes referred to as ‘pseudodisease’. Overdiagnosis can occur when screening leads to the detection of cancers that would not have become symptomatic or be diagnosed clinically before that individual died of other causes. Its importance remains a matter of intense debate [7,11,13]. Manser [12] in a recent retrospective review of coronial autopsies found that in individuals that died of natural causes 28% of lung cancers detected at autopsy were incidental, and were typically stage 0 or I. The ELCAP protocol protects against this by requiring assessment of growth prior to biopsy of nodules <15 mm in diameter and review by a panel of expert lung pathologists [2,3,13].
All the reviews of LDCT lung cancer screening concluded that the efficacy on disease-specific and overall mortality cannot be accurately assessed on current available evidence. Bepler [9] highlighted several deficiencies; the reported follow up periods on the observational studies are too short for a meaningful comparison with global age-adjusted lung cancer mortality data; participants in the screening studies represent a particular population, and are not necessarily representative of the general population; and finally lack of an RCT to examine the impact of LDCT screening on lung cancer mortality (Table 1).
7. Clinical bottom line
The current observational and prevalence studies on the role of LDCT screening has failed to establish whether LDCT really impacts on improved disease-free survival, despite consistently higher early detection rates of lung cancer.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact J Cardiovasc Thoracic Surg 2003; 2:405–409.
Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, Libby DM, Pasmantier MW, Koizumi J, Altorki NK, Smith JP. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999; 354:99–105.
Henschke CI, Naidich DP, Yankelevitz DF, McGuinness G, McCauley DI, Smith JP, Libby D, Pasmantier M, Vazquez M, Koizumi J, Flieder D, Altorki N, Miettinen OS. Early lung cancer action project: initial findings on repeat screenings. Cancer 2001; 92:153–159.
Sone S, Takashima S, Li F, Yang Z, Honda T, Maruyama Y, Hasegawa M, Yamanda T, Kubo K, Hanamura K, Asakura K. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998; 351:1242–1245.
Sobue T, Moriyama N, Kaneko M, Kusumoto M, Kobayashi T, Tsuchiya R, Kakinuma R, Ohmatsu H, Nagai K, Nishiyama H, Matsui E, Eguchi K. Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol 2002; 20:911–920.
Swensen SJ, Jett JR, Sloan JA, Midthun DE, Hartman TE, Sykes AM, Aughenbaugh GL, Zink FE, Hillman SL, Noetzel GR, Marks RS, Clayton AC, Pairolero PC. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002; 165:508–513.
Bach PB, Kelley MJ, Tate RC, McCrory DC. Screening for lung cancer: a review of the current literature. Chest 2003; 123:72S–82S.
Bach PB, Niewoehner DE, Black WC. Screening for lung cancer: the guidelines. Chest 2003; 123:83S–88S.
Bepler G, Goodridge CD, Djulbegovic B, Clark RA, Tockman M. A systematic review and lessons learned from early lung cancer detection trials using low-dose computed tomography of the chest. Cancer Control 2003; 10:306–314.
Lung cancer screening: recommendation statement. Ann Intern Med 2004; 140:738–739.
Manser RL, Irving LB, de Campo MP, Abramson MJ, Stone CA, Pedersen KE, Elwood M, Campbell DA. Overview of observational studies of low-dose helical computed tomography screening for lung cancer. Respirology 2005; 10:97–104.
Manser RL, Dodd M, Byrnes G, Irving LB, Campbell DA. Incidental lung cancers identified at coronial autopsy: implications for overdiagnosis of lung cancer by screening. Respir Med 2005; 99:501–507.
Henschke CI, Shaham D, Yankelevitz DF, Altorki NK. CT screening for lung cancer: past and ongoing studies. Semin Thorac Cardiovasc Surg 2005; 17:99–106.(Ian Hunt, Mayroon Siva, R)