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The Oncologist® is devoted to medical and practice issues for medical, hematological, radiation, gynecologic, and surgical oncologists and is designed specifically for the busy practitioner entrusted with the care of adult or pediatric cancer patients. The Oncologist® has been continuously published since 1995. The Journal is published 12 times annually. The Oncologist® is owned, published, and trademarked by AlphaMed Press, 318 Blackwell Street, Suite 260, Durham, North Carolina, 27701. © 2007 by AlphaMed Press, all rights reserved. Print ISSN: 1083-7159. Online ISSN: 1549-490X.

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Low-Dose Computed Tomography Screening for Lung Cancer and Pleural Mesothelioma in an Asbestos-Exposed Population: Baseline Results of a Prospective, Nonrandomized Feasibility TrialAn Alpe-Adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002) Gianpiero Fasola, Ornella Belvedere, Marianna Aita, Tina Zanin, Alessandro Follador, Paolo Cassetti, Stefano Meduri, Vincenzo De Pangher, Giusto Pignata, Valentina Rosolen, Fabio Barbone and Francesco Grossi Oncologist 2007;12;1215-1224 DOI: 10.1634/theoncologist.12-10-1215

located on the World Wide Web at: http://www.TheOncologist.com/cgi/content/full/12/10/1215

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The Oncologist® is devoted to medical and practice issues for medical, hematological, radiation, gynecologic, and surgical oncologists and is designed specifically for the busy practitioner entrusted with the care of adult or pediatric cancer patients. The Oncologist® has been continuously published since 1995. The Journal is published 12 times annually. The Oncologist® is owned, published, and trademarked by AlphaMed Press, 318 Blackwell Street, Suite 260, Durham, North Carolina, 27701. © 2007 by AlphaMed Press, all rights reserved. Print ISSN: 1083-7159. Online ISSN: 1549-490X.

The

Oncologist

®

Lung Cancer

GIANPIERO FASOLA,a ORNELLA BELVEDERE,a MARIANNA AITA,a TINA ZANIN,d ALESSANDRO FOLLADOR,a PAOLO CASSETTI,e STEFANO MEDURI,b VINCENZO DE PANGHER,f GIUSTO PIGNATA,g VALENTINA ROSOLEN,c FABIO BARBONE,c FRANCESCO GROSSIh Departments of aMedical Oncology and bRadiology and cInstitute of Hygiene and Epidemiology, University Hospital of Udine, Udine, Italy; dUnit of Occupational Health and Departments of eRadiology, fOncology, and gSurgery, San Polo Hospital, Monfalcone, Italy; hMedical Oncology A, Disease Management Team - Lung Cancer, National Institute for Cancer Research, Genoa, Italy Key Words. Occupational exposure • Asbestos • Screening • Spiral computed tomography • Lung cancer Malignant pleural mesothelioma Disclosure: P.C. received an honorarium for his contribution to the study. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe the current status of LDCT screening for lung cancer among high-risk individuals. 2. Discuss the potential and drawbacks of LDCT for the early detection of lung cancer in asbestos-exposed individuals. 3. Describe the limits and possibilities of LDCT for detecting pleural abnormalities and malignant pleural mesothelioma in asbestos workers and former workers. CME

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com

ABSTRACT Objective. To evaluate the feasibility of using low-dose computed tomography (LDCT) for the early diagnosis of lung cancer and malignant pleural mesothelioma in an asbestos-exposed population. Methods. Between February 2002 and October 2003,

1,045 volunteers already enrolled in a surveillance program for asbestos-exposed workers and former workers were recruited. The main eligibility criteria were: written informed consent, definite exposure to asbestos, age 40 –75, no prior cancer or severe concomitant condi-

Correspondence: Gianpiero Fasola, M.D., Department of Medical Oncology, University Hospital of Udine, P.le S. M. Misericordia 15, 33100 Udine, Italy. Telephone: 39-0432-552-750; Fax: 39-0432-552-751; e-mail: [email protected] Received July 9, 2007; accepted for publication August 21, 2007. ©AlphaMed Press 1083-7159/2007/$30.00/0 doi: 10.1634/theoncologist.12-10-1215

The Oncologist 2007;12:1215–1224 www.TheOncologist.com

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Low-Dose Computed Tomography Screening for Lung Cancer and Pleural Mesothelioma in an Asbestos-Exposed Population: Baseline Results of a Prospective, Nonrandomized Feasibility Trial—An Alpe-Adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002)

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LDCT Screening in Asbestos-Exposed Individuals

all, LDCT identified nine cases of non-small cell lung cancer— eight stage I, one stage IIA—and one thymic carcinoid, corresponding to 1% of the enrolled population. All cases were radically treated. None had been detected by CXR. No pleural mesothelioma was diagnosed. There were 11 false-positive results. Conclusions. Our findings first suggest that LDCT may be at least as useful in asbestos workers as in heavy smokers for the early diagnosis of lung cancer; this benefit is evident even in a poor-risk population, with low rates of smoking prevalence and a previous history of radiological surveillance. The role of spiral tomography in screening for pleural mesothelioma remains uncertain. The Oncologist 2007; 12:1215–1224

INTRODUCTION

worth in other high-risk populations, such as asbestosexposed individuals. Yet, the causal relationship between asbestos exposure and both malignant mesothelioma [11] and lung cancer [12, 13] is well established; cigarette smoking and asbestos may also exert a joint, less than multiplicative but supra-additive effect on lung cancer risk [14]. In the coastal area of Trieste and Monfalcone in northeastern Italy, standardized incidence rate ratios of malignant mesothelioma, as compared with those from Italy as a whole, are approximately ninefold and fivefold higher in men and women, respectively [15–17]. Most of the cases are observed among shipyard workers and their wives, with a well-known history of asbestos exposure. The corresponding ratio for lung cancer is about 1.3 for both sexes, and the population fraction of lung cancer attributable to possible or definite exposure to asbestos has been estimated to be 20% (95% confidence interval [CI], 11.5%–28.5%) [18]. Considering the relevance of asbestos-related malignancies in that area and the current lack of evidence about LDCT screening in this risk setting, we designed a prospective, nonrandomized trial to evaluate the feasibility of baseline and annual repeat screening with LDCT among asbestos-exposed workers and former workers. Results are reported for the prevalence phase of the study.

The incidence of malignant pleural mesothelioma (MPM) began to rise in the 1940s, and it is still growing in most industrialized countries; this 5%–10% annual increase is likely to continue well into the current century, at least until 2020 [1]. As for lung cancer, while incidence and mortality rates for men have dropped in the last decade, a similar trend has not occurred in women, or in older age groups [2]. The most important prognostic factor in both malignancies is disease stage. Long-term survival may be ⬎80% in early-stage non-small cell lung cancer (NSCLC), but these rates fall to ⬍5% in more advanced cases. Also, selected patients with early MPM may experience a better outcome with aggressive multimodal treatments. In some centers, this approach has led to median survival times of about 2 years [3, 4]. Overall, both lung cancer (worldwide) and pleural mesothelioma (in selected areas) would be suitable targets for screening: they represent a significant public health issue, have a long asymptomatic natural history, and may benefit from early therapeutic intervention [5]. In the 1970s, randomized trials of lung cancer screening with chest X-ray (CXR) and sputum cytology failed to show a significant reduction in disease-specific mortality among high-risk male smokers [6 –9]. Interest in screening was renewed at the turn of this century with the introduction of low-dose spiral computed tomography (LDCT). Several studies in the past 10 years have reported encouraging results, showing that LDCT is four times as sensitive as CXR in detecting small, potentially resectable lung cancers [10], whereas its mortality benefit has not yet been fully elucidated. If feasibility trials of LDCT screening in heavy smokers have been widely conducted, data are missing about its

PARTICIPANTS AND METHODS Participant Selection Eligibility criteria were: definite exposure to asbestos, written informed consent, age 40 –75 years, no prior cancer (other than nonmelanoma skin cancer) or severe concomitant conditions, no clinical suspicion of lung cancer, no chest CT scan during the previous 2 years. CXR before

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tions, no chest CT scan in the past 2 years. A smoking history was not required. After a structured interview, chest X-ray (CXR) and LDCT were performed. Participants with negative examinations were assigned to annual LDCT. Participants with positive findings received high-resolution CT and additional diagnostic workup as appropriate. Results. Baseline characteristics of the screened population were: median asbestos exposure time, 30 years; median age, 58; median pack-years in smokers/former smokers, 18.5. Thirty-four percent had never smoked. On LDCT, 834 noncalcified nodules were identified in 44% of participants, versus 43 nodules in 4% on CXR. Pleural abnormalities were observed in 44% and 70% of participants by CXR and LDCT, respectively. Over-

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study entry was accepted. A smoking history was not required. A surveillance program for asbestos-exposed workers and former workers has been active since 1994 at the Unit of Occupational Health in Monfalcone. Enrolled participants—representing an estimated one third of all the asbestos-exposed workers of the region—annually undergo a physical examination, respiratory function tests, and a CXR. Program participants were considered possible but not exclusive candidates for our study. At enrolment, eligible individuals underwent a structured interview about medical and family history, demographics, residential history, military service, diet, smoking, and alcohol consumption. Occupational history was recorded in detail: participants were asked about place(s) of employment, exact tasks, type and duration of asbestos exposure, use of protective equipment, and cleaning of contaminated clothing. The study protocol was approved by the local ethical committee.

Screening Procedures Blood samples were collected from each participant and stored for future analyses. Respiratory function tests were also performed at baseline. Participants underwent CXR and LDCT. Posterior–anterior and lateral chest radiographs were obtained according to standard protocols. Helical LDCT scans were performed with a GE Medical System scanner (GE Medical Systems, Tokyo, Japan) at 120 kV, 40 mA, 0.8 second/rotation, and 2:1 pitch with a slice thick-

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ness of 5 mm. Scans were obtained from the level of the apex to the diaphragm in a single 20-second breath-hold at end inspiration, after 1 minute of hyperventilation. Image reconstruction was performed with a standard algorithm at intervals of 5 mm. All LDCT images were independently reviewed by two radiologists. Their findings were individually recorded and then discussed, and the consensus findings were documented. When nodules were identified, the defined characteristics of each were recorded: size, location, benign calcifications, shape, and edge. Matching of LDCT findings with CXR was checked for each nodule. Radiologists were asked to classify abnormalities other than nodules into the following categories: pleural thickening/plaque, pleural effusion, parenchymal focal opacity, endobronchial lesion, fibrosis/scar, bone/soft tissues lesion, cardiac abnormality, emphysema/ chronic obstructive broncopneumopathy, other. Positive baseline exams (Fig. 1 and Fig. 2) were defined as follows: noncalcified nodules (NCNs), calcified nodules ⬎20 mm or with malignant pattern, and pleural thickening ⬎10 mm or with scissural or circumferential involvement. Participants with negative baseline exams were proposed for annual repeat LDCT. Those with positive findings underwent high resolution CT (HRCT) and additional diagnostic workup as appropriate. If HRCT showed calcifications unidentified by LDCT, the nodule was classified as benign and the subject was assigned to annual LDCT. Otherwise further investigation was established in a multidisciplinary setting according to nodule size (Fig. 1), as recommended in the Early Lung

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Figure 1. Diagnostic algorithm for pulmonary nodules. Abbreviations: FNAB, fine-needle aspiration biopsy; FU, follow-up; HRCT, high-resolution computed tomography; LDCT, low-dose computed tomography; VATS, video-assisted thoracoscopic surgery.

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Table 1. Radiological findings at baseline, according to CXR and LDCT Radiological findings CXR LDCT Calcified nodules ⱕ20 mm ⬎20 mm Noncalcified nodules ⱕ5 mm 6–10 mm ⱖ11 mm Pleural abnormalities Pleural effusion Individuals with ⱖ1 nodule Individuals with pleural abnormalities

43

477 0 38 464

79 2 750 73 11 880 0 521 736

Abbreviations: CXR, chest X-ray; LDCT, low-dose computed tomography.

Cancer Action Project (ELCAP) protocol [19]. CT-guided biopsy, video-assisted thoracoscopic surgery (VATS), and bronchoscopy were all allowed for pathological confirmation of suspected malignant cases. If malignant and resectable disease was diagnosed, radical surgery on the primary lesion was coupled with mediastinal lymph-node dissection and labeling of all lymph-node locations. All cytological and histological

Figure 3. LDCT results and subsequent diagnostic workup. Abbreviations: HRCT, high-resolution computed tomography; LDCT, low-dose computed tomography.

findings from any biopsy and surgical procedure were documented.

Statistical Considerations The baseline phase of the study was designed to show a 9% higher rate for CT-diagnosed tumors compared with annual CXR, assuming a lung cancer probability in the study group

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Figure 2. Diagnostic algorithm for pleural abnormalities. *While for NCN a decisional algorithm had been developed already [19], no corresponding evidence was available for the workup of pleural findings. Thus, the decision to further investigate LDCT-screened pleural abnormalities was based on radiologists’ and pathologists’ expertise and on several, though unconfirmed, clinical observations. Abbreviations: FU, follow-up; HRCT, high-resolution computed tomography; LDCT, low-dose computed tomography; VATS, video-assisted thoracoscopic surgery.

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Table 2. Histological findings Type of surgery

pTN

Asbestos exposure (years)

Smoking (pack-years)

BAC BAC BAC BAC Adenocarcinoma Thymic carcinoid Adenocarcinoma Adenocarcinoma NSCLC-NOS Carcinosarcoma

T1N0 T1N0 T1N0 T1N0 T1N0 T2bNX T2N0 T1N0 T1N1 T2N0

17 15 23 34 17 37 42 29 41 22

13 14 0 5 64.5 19 41 31.5 6 12.5

Anthracotic lymph node Inflammatory pseudotumor Anthracotic lymph node Bronchiectasis Anthracotic lymph node Anthracotic lymph node Lymphoid infiltrate Adenoma Atypical adenomatous hyperplasia Round atelectasis

NA NA NA NA NA NA NA NA NA NA

23 8 32 33 9 33 37 27 28 26

38 25 0 15 18 40 0 15 10 25

Abbreviations: BAC, bronchioloalveolar carcinoma; NA, not applicable; NSCLC-NOS, non-small cell lung cancer, not otherwise specified; pTN, pathologic tumor and node stage; VATS, video-assisted thoracoscopic surgery.

at least as high as in the ELCAP study [19]. Using a onesided, 0.05-level test, the enrolment of at least 832 subjects was required to obtain a statistical power of 80%.

RESULTS From February 2002 to October 2003, 1,045 eligible individuals agreed to enter the screening program and were enrolled. Baseline characteristics of the screened population were as follows: the median age at admission was 58 years (range, 44 –75); 1,015 (97%) were men; 360 (34%) had never smoked; and the median number of pack-years was 18.5 (range, 0.5–120) in 527 (50%) and 160 (15%) former and current smokers, respectively. The median duration of asbestos exposure was 30 years (25th–75th percentile, 26 – 34). In 80% of the participants, the duration of asbestos exposure was 18 –36 years; 75% were exposed for the first time at least 32 years prior to baseline. The median duration of participation in the surveillance program was 12 months. Three hundred eighty-seven (37% of the enrolled population) had received a CXR within the previous 2 years. Table 1 shows the results of baseline CXR and LDCT.

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CXR identified 43 nodules. Thirty-four participants had one nodule, three had two nodules, and only one had three nodules. LDCT detected 834 NCNs (750 were ⬍5 mm, 73 were 6 –10 mm, and 11 were ⬎10 mm) and 81 calcified nodules. Two hundred sixty participants had one NCN, 187 had 2–5, and 13 had 6 –9. Overall, 460 subjects had at least one NCN. The right lung was involved more frequently than the left. Four hundred seventy-seven pleural abnormalities were detected in 44% of the participants with CXR, versus 880 in 70% of the participants with LDCT. No pleural effusion was identified with either technique. According to baseline evaluation (Fig. 3), 517 subjects (recall rate, 49.5%) underwent HRCT; of these, 108 (21%) were found negative and were assigned to annual LDCT and 395 (76.4%) were assigned to HRCT control at 3, 6, 12, and 24 months—243 for suspicious nodules only, 77 for pleural abnormalities, and the remaining for both findings; 10 (1.9%) underwent immediate invasive diagnostic procedures and four (0.8%) refused them despite indications. Eleven patients who received follow-up HRCT eventually underwent diagnostic surgery, because interim growth was

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Positive findings Lobectomy Lobectomy Lobectomy VATS wedge resection Bilobectomy Sternotomy Lobectomy Lobectomy Lobectomy Pneumonectomy Negative findings VATS wedge resection VATS lobectomy VATS wedge resection VATS wedge resection VATS wedge resection VATS lobectomy VATS wedge resection VATS wedge resection Thoracotomy wedge resection VATS wedge resection

Diagnosis

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Table 3. Age, smoking, and duration of asbestos exposure/time since first exposure as predictors of nodules according to LDCT and CXR LDCT CXR Individuals with NCNs Yes

No

ORa

95% CI

Yes

No

ORa

95% CI

1 1.07 0.75 0.90

– 0.77–1.48 0.52–1.09 0.60–1.35

5 13 15 5

279 311 232 185

1 2.23 3.12 1.31

– 0.77–6.43 1.07–9.11 0.35–4.83

1 1.03 1.08 1.49

– 0.72–1.50 0.79–1.49 1.06–2.09

10 5 9 14

350 176 274 201

1 1.10 1.13 2.38

– 0.37–3.30 0.45–2.84 1.03–5.49

1 0.93 0.88 0.98

– 0.64–1.36 0.61–1.27 0.68–1.41

12 8 8 10

213 238 306 250

1 .67 .56 .68

– 0.26–1.74 0.22–1.46 0.28- 1.63

1 1.09 1.24 1.32 1.17

– 0.68–1.74 0.75–2.05 0.77–2.27 0.66–2.08

2 10 10 8 8

93 336 209 176 192

1 1.27 1.78 1.31 1.35

– 0.27–6.01 0.37–8.55 0.26–6.70 0.25–7.29

aFrom a logistic regression model including terms for age, smoking, and, alternatively, duration of asbestos exposure or years since first asbestos exposure. bThe total number of participants is 1,039 instead of 1,045, because data are lacking for three participants and three of them were pipe/cigar smokers. Abbreviations: CI, confidence interval; CXR, chest X-ray; LDCT, low-dose computed tomography; NCN, noncalcified nodule; OR, odds ratio.

observed. Of eight subjects with pleural thickenings ⬎1 cm, five were excluded from invasive procedures because of a substantial risk as a result of medical conditions or the location of the thickening; three were proposed for CTguided biopsy, but only one agreed. Overall 21 subjects were assigned to invasive diagnostic procedures. Table 2 shows the results of invasive diagnostic procedures for both benign lesions and malignancies. We identified 11 benign lesions (2.1% of recalls): four anthracotic lymph nodes, one lymphoid infiltrate, one inflammatory pseudotumor, one round atelectasis, one bronchiectasis, one adenoma, one atypical adenomatous hyperplasia, and one hyaline plaque. Among the malignancies, we found four cases of bronchioloalveolar carcinoma (BAC), three adenocarcinomas, one NSCLC not otherwise specified

(NOS), one carcinosarcoma, and one thymic carcinoid. No case of MPM was recorded. The median time from first radiological finding to definite diagnosis was 136 days. The median duration of asbestos exposure was 26 years. All malignant cases, except for one, were current (n ⫽ 3) or former (n ⫽ 6) smokers, with a median smoking history of 13.5 pack-years. Three had received a CXR within the 2 years before study enrolment. Seven cases also showed pleural abnormalities at LDCT. BAC, adenocarcinomas, and the NSCLC-NOS were treated with lobectomy, except for one case of BAC, in which surgery was limited to wedge resection; the carcinosarcoma was treated with right pneumonectomy, while the thymic carcinoid was resected in sternotomy en bloc with

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Age ⬍55 127 157 55–59 153 171 60–64 97 150 ⱖ65 83 107 Smoking (pack-years)b Never-smoker 148 212 ⬍10 77 104 10–24 124 159 ⱖ25 110 105 Duration of asbestos exposure (years) ⬍25 100 125 25–29 109 137 30–34 135 179 ⱖ35 116 144 Years since first asbestos exposure ⬍30 39 56 30–34 149 197 35–39 100 119 40–44 87 97 ⱖ45 84 116

Individuals with nodules

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Table 4. Age, smoking, and duration of asbestos exposure/time since first exposure as predictors of pleural abnormalities according to LDCT and CXR LDCT CXR Individuals with pleural abnormalities

Individuals with pleural abnormalities Yes

No

95% CI

Yes

No

ORa

95% CI

1 1.61 2.35 3.25

– 1.14–2.27 1.57–3.52 2.01–5.27

86 129 128 121

198 195 119 69

1 1.37 2.23 3.49

– 0.97–1.95 1.53–3.26 2.29–5.32

1 1.57 2.02 1.95

– 1.06–2.34 1.41–2.90 1.31–2.88

133 78 137 114

227 103 146 101

1 1.52 1.72 1.97

– 1.04–2.23 1.24–2.40 1.38–2.82

1 0.80 0.87 1.29

– 0.53–1.22 0.58–1.31 0.83–2.00

113 91 115 145

112 155 199 115

1 0.76 0.78 1.13

– 0.51–1.12 0.54–1.14 0.78–1.64

1 1.74 2.37 2.85 2.98

– 1.08–2.79 1.41–3.98 1.60–5.10 1.56–5.70

22 125 100 87 130

73 221 119 97 70

1 1.96 2.66 2.39 3.64

– 1.14–3.34 1.51–4.47 1.32–4.35 1.94–6.83

aFrom a logistic regression model including terms for age, smoking, and, alternatively, duration of asbestos exposure or years since first asbestos exposure. bThe total number of participants is 1,039 instead of 1,045, because data are lacking for three participants and three of them were pipe/cigar smokers. Abbreviations: CI, confidence interval; CXR, chest X-ray; LDCT, low-dose computed tomography; OR, odds ratio.

pericardium. All cases, except for one NSCLC case, were stage I; the remaining one was stage IIA. Overall LDCT identified 10 thoracic malignancies (0.96% of the enrolled participants, 1.9% of recalls), nine lung cancers, and one thymic carcinoid. None of the malignancies had been identified by initial CXR. Because of the small number of lesions and the high level of homogeneity in asbestos exposure among study participants, no association could be found between the 10 screen-diagnosed malignancies and age, smoking, duration of asbestos exposure, and time since first exposure. NCNs according to LDCT and CXR are displayed in Table 3. NCNs were not associated with age or with asbestos exposure, a somehow expected result because

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these factors are risk indicators for malignancy and most of the nodules were benign. Notably, the prevalence odds ratio for at least 25 pack-years is 1.49 (95% CI, 1.06 – 2.09). Table 4 shows a direct association between pleural abnormalities and age, smoking, and time since first asbestos exposure, but not exposure duration.

DISCUSSION Recent observational studies have shown promising accuracy and sensitivity of LDCT for detecting early-stage lung cancer in smokers [10]. Few data are currently available with respect to the value of LDCT screening in other high-risk populations. In the prevalence phase of a study that screened 602 asbestos

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Age ⬍55 161 123 55–59 227 97 60–64 190 57 ⱖ65 158 32 Smoking (pack-years)b Never-smoker 226 134 ⬍10 126 55 10–24 216 67 ⱖ25 165 50 Duration of asbestos exposure (years) ⬍25 167 58 25–29 157 89 30–34 203 111 ⱖ35 209 51 Years since first asbestos exposure ⬍30 48 47 30–34 218 128 35–39 158 61 40–44 145 39 ⱖ45 167 33

ORa

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chosen for a number of reasons. Following a multidisciplinary evaluation, most nodules were found to be easier to manage with a surgical approach. We considered that, in many centers, the expertise needed for fine-needle aspiration biopsy (FNAB) of small and deeply located lesions is still unavailable, as well as techniques like positron-emission tomography. Besides, in a patient with a new, solitary, NCN ⬎5 mm, surgical resection may be the ideal approach, as it is both diagnostic and therapeutic [26]. FNAB is obviously less invasive, but it can be, at best, diagnostic only. While its sensitivity for malignancy can be ⬎60%, the false-negative rate is 3%–29%, and the incidence of pneumothorax is up to 30% [27]. Finally, the sensitivity of bronchoscopy for detecting a malignant process in a solitary pulmonary nodule ⬍1.5 cm in diameter is only 10% [27]. Beyond the choice of the most appropriate diagnostic tool, the adoption of a less stringent diagnostic algorithm would have been of benefit. Notably, Henscke and colleagues recently updated the ELCAP original protocol [28], recognizing that, in modern CT screening for lung cancer, NCNs ⬍5 mm detected at baseline do not justify immediate workup, but only annual repeat screening to determine interim growth. In our study, the rate of detection of NCNs corresponded to 80% of the enrolled population, whereas that of nodules ⬎5 mm was only 8%. We estimated that the modified algorithm would have reduced the rate of unnecessary invasive procedures by ⬎30%. In any case, none of the participants suffered complications from the diagnostic procedures. Our findings do not seem to support the use of LDCT in the early diagnosis of pleural mesothelioma, although some caution is needed when interpreting these data: the current MPM incidence rate in the study area is approximately 10 per 100,000 per year, corresponding to an absolute number of eight cases. Even if we assumed that the risk for MPM for individuals exposed to asbestos was much higher (e.g., 10 times) than in the general population, and that LDCT could screen a prevalence of 2 per 1,000 versus a prevalence of 0.5 per 1,000 with CXR, with an ␣ error of 0.05 and a power of 80%, the minimum sample size would be approximately 4,200 subjects. Indeed, considering the sample size and lifetime risk for MPM in asbestos-exposed individuals, less than one case was expected at baseline. The study detected a very high number of pleural abnormalities, with LDCT showing a considerably higher accuracy rate than CXR. Pleural thickening and pleural plaques are commonly seen in patients without lung disease, but there is some controversy about their relationship with asbestos exposure indexes and with the risk for malignant evolution in the absence of asbestosis [29]. Annual repeat LDCT screening could provide useful in-

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workers using both CXR and LDCT, five cases of lung cancer were detected— one stage II, two stage IIIB, and two stage IV. One case had been originally misinterpreted as negative. Overall, the study showed some inaccuracy in the diagnostic workup of suspicious findings and incongruity in their treatment [20]. More recently, two small studies were conducted, each including an asbestos-exposed cohort of ⬍200 individuals [21, 22]. Notably, in all three cases, study participants were mostly smokers/former smokers (97%, 99%, and 100%, respectively). To date, no LDCT screening study has been reported among asbestos workers with a sample size comparable with that of the original ELCAP trial [19]. Our study has met its primary endpoint, showing that, in asbestos-exposed individuals, LDCT, as compared with CXR, significantly increases the likelihood of detecting small NCNs, and thus lung cancer, at an earlier, more curable stage. Indeed, we detected NCNs 19 times more frequently with LDCT than with CXR. None of the 10 CTdetected malignancies had been identified by initial CXR. All of them could be radically resected; no death or major complications occurred, confirming previous observations of a more favorable morbidity profile of early lung cancer resection, compared with resection of symptomatic, more advanced cases [23, 24]. The proportion of lung cancer cases was apparently only in the range of those from other screening trials (0.4%– 2.7%) [10]. Study participants had already entered a surveillance program, and more than one third had undergone a CXR before enrolment; in other words, they represented a highly selected population, somewhat resembling an incidence rather than a prevalence group. In addition, they were a relatively low-risk cohort: the median age was 58, 34% had never smoked, and the median exposure for smokers and former smokers was 18.5 pack-years. Thus, our results compare very favorably with those of previous screening studies, whose rate of lung cancer detection among individuals with a median exposure of 40 – 45 pack-years was in the range of 1.1%–2.7% [19, 23–25]. As with any screening intervention, this encouraging outcome should be balanced against the possibility that aggregate harm to screened individuals may exceed the benefit conferred to those who have lung cancer detected [10]. In particular, harm may result from the high costs of screening and follow-up, and the morbidity associated with falsepositive results. In our experience, the false-positive rate was about 1%; indeed, 52% of all invasive procedures were performed for benign conditions, a proportion that largely exceeds the 25% rate reported in other studies. This is mainly a result of our choice of using VATS for a definite pathological diagnosis of suspicious nodules. VATS was

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Fasola, Belvedere, Aita et al.

CONCLUSION At present, a heated debate surrounds the issue of lung cancer screening in heavy smokers using LDCT [30]. Doubtless, LDCT may greatly increase the rate of detection of small and resectable lung cancers [31]. The evidence is weaker on whether the finding of early-stage disease results in a lower risk for death from lung cancer [32]. The U.S. National Lung Screening Trial randomized

50,000 high-risk smokers to have either CXR or CT scans, with results expected by 2011, while in the Netherlands and Belgium, 16,000 individuals have been randomized to receive CT or usual care, with results due in 2016. Only these trials could establish whether a true reduction in lung cancer mortality results from screening with LDCT [30]. The obvious result of our study is that 1% of the participants did in fact have a previously unrecognized malignancy that was small enough to allow definitive treatment. This benefit was evident even in a poor-risk, low smoking, and already surveyed population. Should ongoing screening trials demonstrate a decrease in lung cancer mortality, the finding that LDCT may capture at least an equal proportion of lung cancers in asbestos workers as in heavy smokers could provide the rationale to perform well-designed validation trials in the former risk group as well.

ACKNOWLEDGMENTS This study was supported by a grant from the Compagnia di San Paolo, Turin, Italy (Programma Oncologia 2002), a grant from the Provincia di Gorizia, Italy, and a grant from the Fondazione Cassa di Risparmio di Gorizia, Italy. The study sponsors had no role in the design of the study, the collection, analysis, and interpretation of data, the writing of the paper, and the decision to submit it for publication. The authors gratefully acknowledge the excellent contribution of the study data manager, Dr. Marica Gaiardo. We would also like to thank Dr. Claudio Rieppi, Prof. Claudio Bianchi, Dr. Alessandro Brollo, Dr. Giovanni Pilati, Dr. Danilo Spazzapan, and Dr. Manuela Baccarin for their valuable support in conducting the study. We thank the patients and their families for their confidence and collaboration. G.F. and O.B. contributed equally to the study.

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LDCT Screening in Asbestos-Exposed Individuals

Low-Dose Computed Tomography Screening for Lung Cancer and Pleural Mesothelioma in an Asbestos-Exposed Population: Baseline Results of a Prospective, Nonrandomized Feasibility TrialAn Alpe-Adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002) Gianpiero Fasola, Ornella Belvedere, Marianna Aita, Tina Zanin, Alessandro Follador, Paolo Cassetti, Stefano Meduri, Vincenzo De Pangher, Giusto Pignata, Valentina Rosolen, Fabio Barbone and Francesco Grossi Oncologist 2007;12;1215-1224 DOI: 10.1634/theoncologist.12-10-1215 This information is current as of October 28, 2007 Updated Information & Services

including high-resolution figures, can be found at: http://www.TheOncologist.com/cgi/content/full/12/10/1215

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