Journal of Thoracic Oncology:
The Role of the (18)F-Fluorodeoxyglucose-Positron Emission Tomography Scan in the Nederlands Leuvens Longkanker Screenings Onderzoek Lung Cancer Screening Trial
van't Westeinde, Susan C. MD*†; de Koning, Harry J. PhD†; Thunnissen, Frederik B. MD‡; Oudkerk, Matthijs PhD§; Groen, Harry J. M. PhD∥; Lammers, Jan-Willem J. PhD¶; Weenink, Carla MD#; Vernhout, Rene MD*; Nackaerts, Kristiaan PhD**; Mali, Willem PhD††; van Klaveren, Rob J. PhD*
*Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam; †Department of Public Health, Erasmus MC Rotterdam, Rotterdam; ‡Department of Pathology, VUMC Amsterdam, Amsterdam; §Department of Radiology, UMC Groningen, Groningen; ∥Department of Pulmonary Medicine, UMC Groningen, Groningen; ¶Department of Pulmonary Medicine, UMC Utrecht, Utrecht; #Department of Pulmonology, Kennemer Gasthuis Haarlem, RC, The Netherlands; **Department of Pulmonology, UZ Gasthuisberg, Leuven, Belgium; and ††Department of Radiology, UMC Utrecht, Utrecht, The Netherlands.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Susan C. van 't Westeinde, MD, Erasmus MC, Department of Pulmonary Medicine's, Gravendijkwal 230, Rotterdam 3000 CA, The Netherlands. E-mail: firstname.lastname@example.org
Background: In computed tomography lung cancer screening programs, up to 30% of all resections are futile.
Objective: To investigate whether a preoperative positron emission tomography (PET) after a conclusive or inconclusive nonsurgical workup will reduce the resection rate for benign disease in test-positive participants of a lung cancer screening program.
Methods: (18)F-Fluorodeoxyglucose-PET scans were made in 220 test positives. Nodules were classified as positive, indeterminate, or negative based on visual comparison with background activity. Gold standard for a positive PET was the presence of cancer in the resection specimen or the detection of cancer during more than 2 years follow-up. Sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were calculated at participant level and 95% confidence intervals (CIs) constructed.
Results: The sensitivity of PET to detect cancer was 84.2% (95% CI: 77.6–90.7%), the specificity 75.2% (95% CI: 67.1–83.3), the positive predictive value 78.9% (95% CI: 71.8–86.0), and the NPV 81.2% (95% CI: 73.6–88.8). The resection rate for benign disease was 23%, but 26% of them had a diagnosis with clinical consequences. A preoperative PET after an inconclusive nonsurgical workup reduced the resection rate for benign lesions by 11 to 15%, at the expense of missing 12 to 18% lung cancer cases. A preoperative PET after a conclusive nonsurgical workup reduced the resection rate by 78% at the expense of missing 3% lung cancer cases.
Conclusion: A preoperative PET scan in participants with an inconclusive nonsurgical workup is not recommended because of the very low NPV, but after a conclusive nonsurgical workup, the resection rate for benign disease can be decreased by 72%.
The utility of low-dose multidetector low-dose computed tomography (CT) screening is being investigated in several nonrandomized1–5 and randomized trials.6–9 Two large randomized screening trials investigate whether CT screening leads to a reduction in lung cancer mortality. The largest one, the National Lung Screening Trial has randomized 53,476 smokers between annual CT screening or chest x-ray for three annual screening rounds.6 The “Nederlands Leuvens Longkanker Screenings Onderzoek” (NELSON) is the second largest randomized lung cancer screening trial in which CT screening in year 1, 2, 4, and 6.5 is compared with a control population without screening. The nodule management strategy used in the NELSON trial is based on the volume of new noncalcified nodules and the volume doubling time (VDT) of previously existing ones, without need for additional evaluations by fine needle aspirate, positron emission tomography (PET), or radiological evaluation after antibiotics.10 As a result of this management strategy, 27% and 19% of the surgical resections performed at baseline and second round screening, respectively, have been performed for benign disease.7 Question is, whether a PET scan could be used to reduce the resection rate for benign disease in a lung cancer screening setting.
The purpose of this study was to investigate whether a preoperative PET after either an inconclusive or a conclusive nonsurgical workup, which included a physical examination, standard CT with contrast, and a bronchoscopy, will reduce the resection rate for benign disease.
METHODS AND MATERIALS
NELSON trial participants were current and former smokers at high risk for lung cancer. Detailed information on the inclusion and exclusion criteria has been reported before.11 The prospective screening study was approved by the Dutch Minister of Health and by the Medical Ethical Boards of each of the four participating hospitals. Written informed consent was obtained from all participants, which included the ability to use data for future research, including the current prospective side study. In this study, participants have been included with a positive baseline or second round test result between April 2004 and October 2008.
CT Data Acquisition and Image Reading
Data acquisition and image reading were as described before.10 In brief, all four participating screening sites used 16-detector CT scanners (Sensation-16, Siemens Medical Solutions, Forchheim, Germany Mx8000 IDT or Brilliance 16P, Philips Medical Systems, Cleveland, OH). Scan data were obtained in a spiral mode, with 16 × 0.75 mm collimation and 1.5 pitch. No contrast was administered. Data acquisition and scanning conditions were standardized and equal for baseline and repeat screening. Digital workstations (Leonardo, Siemens Medical Solutions, Erlangen, Germany) were used in all screening sites with commercially available software for semiautomated volume measurements (LungCare, Siemens Medical Solutions, version Somaris/5: VA70C-W).12,13
Nodule Management and Diagnostic Workup
At baseline, a scan was considered positive if any noncalcified nodule had a solid component more than 500 mm3 (>9.8 mm in diameter) or indeterminate if the volume of the largest solid nodule or the solid component of a partially solid nodule was 50 to 500 mm3 (4.6–9.8 mm in diameter) or more than 8 mm in diameter for nonsolid nodules.10 Subjects with an indeterminate result had a follow-up scan 3 months later to assess growth. Significant growth was defined as a change in volume between the first and second scan of ≥25%. Subjects with positive screening tests were referred to a chest physician for workup and diagnosis.7 If lung cancer was diagnosed, the participant was treated for the disease and went off screening; if no lung cancer was found, the regular second round CT scan was scheduled 12 months after the baseline scan.
For participants with one or more new nodules on the second round scan, the result (positive or negative) was based on size of the nodule, as for round one; in case of an indeterminate result, a follow-up scan was performed 6 weeks later.10 For participants with previously detected nodules, the second round result was based on the VDT. If there was no growth or if the VDT was more than 600 days, the screen was declared negative.7 If the VDT was less than 400 days or if a new solid component had emerged in a previously nonsolid nodule, the scan was considered to be positive. When the VDT was 400 to 600 days, the test was indeterminate, and a follow-up scan was done 1 year after the second round. With a VDT less than 400 days, the final result was considered to be positive, otherwise negative. If both new and existing nodules were present, the nodule with the largest volume or fastest growth determined the result. All participants with a negative second round result were invited to undergo the third screening round 2 years after the second round.
Workup and staging were standardized for all screening sites according to (inter-) national guidelines and included a physical examination, a standard CT scan with contrast of the chest and upper abdomen, a bronchoscopy, and (18)F-fluorodeoxyglucose-PET (FDG-PET).10,14,15 After a negative nonsurgical workup, subjects were referred for surgery to obtain histology of the suspicious nodule. Bronchoscopies were done for the evaluation of the central airways and (if possible) to diagnose lung cancer or benign disease. PET scans were made for preoperative staging purposes in cases the nodule turned out to be malignant during surgery. Pulmonologists were not blinded to the PET result. Therefore, PET results may have influenced the decision to resect nodules, although the NELSON protocol asked for resection irrespective of the outcome of the PET scan. National and international pathology review panels evaluated all cytological and histological specimens. A procedure was classified as surgical if it was a mediastinoscopy, video-assisted thoracoscopy (VATS), or thoracotomy. Resections for benign disease were in this study limited to thoracotomies or VATS procedures for benign lung lesions.16,17 A clinical relevant benign diagnosis was defined as a new benign diagnosis that influenced subsequent patient management, including medication and/or treatment changes.
FDG-PET scans were performed by Siemens ECAT ACCEL PET (Haarlem), Siemens ECAT EXACT PET 962 (Groningen), Siemens Biograph 2-slice PET/CT (Haarlem, Leuven), and Philips Allegro PET scanner (Utrecht). Each of the four centers used different FDG-PET protocols. All patients were asked to fast for at least 6 hours before the PET/CT scan. After administering 300 to 400 MBq radiotracer, the images were obtained. The uptake time after injection of FDG was standard for each center (90 minutes for Groningen and 60–75 minutes in the other centers). The PET data were acquired in three-dimensional mode (Leuven, Haarlem) and 2D mode (Groningen, Utrecht). PET-acquisition time was 4 to 5 minutes per table position, with a complete scan time of approximately 30 minutes. The whole-body (CT) PET extended from the head to the upper tights. PET images were reconstructed by the ordered subset expectation maximization algorithm, with attenuation correction in all centers, with the exception of Utrecht where Row Action Maximum Likelihood Algorithm was used. No respiratory gating was used.
Standard uptake values (SUV) have not been used because different PET cameras were used, and no standard reference values were available.18 At each institution, the nuclear physicians used always the same work stations (Dicom or Siemens work station) at standard settings. FDG-PET scans were classified as positive, indeterminate, or negative based on visual comparison with the background activity after single reading at each of the four centers. The FDG-PET results were matched with the suspicious nodule on CT or, in case no nodules were present, a pulmonary mass (>3 cm in diameter), a (postobstructive) infiltrate, or an atelectatic area.
For this retrospective analysis, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FDG-PET was calculated for four different groups; all participants with a positive baseline or second round test result; participants with a negative noninvasive workup; participants with a positive test result and a suspicious nodule more than 500 mm3; and participants with a positive test result and a suspicious nodule with a VDT less than 400 days. In the first analysis, PET positive and indeterminate test results were taken together and considered PET positive, in the second analysis PET indeterminate and negative results were taken together and considered PET negative. Gold standard for the outcome of FDG-PET was the pathological diagnosis of the suspicious lesion or if no surgical resection was performed, the presence or absence of cancer during at least 2 years of follow-up. If a subject was diagnosed with lung cancer after an initial benign diagnosis and the interval between the first PET scan and the second workup was more than 200 days, this new cancer was not included in the calculation of the diagnostic value of PET because of the long time interval; 95% confidence intervals (CIs) were constructed by SPSS software package version 15.0. In the absence of normal distribution, data were presented as medians with a range.
Participant and Nodule Characteristics
In total, 324 subjects had a positive test result after baseline and second round screening. Their median age was 62 years (range: 50–75 years), the median number of pack-years smoked was 43 (range: 21–160 pack-years), and 20% were women. The characteristics of the suspicious nodules detected in these test-positive participants are listed in Table 1. In 95 test-positive participants, no PET scan was made: 29 were not referred for workup, and in 66 participants (55 + 11), this was a tumor board decision (Figure 1). Nodule size was significant larger in the group who underwent a PET scan, but there were no significant differences in VDT or nodule consistency between the two groups. The mean nodule size of the 293 solid nodules was 648 mm3 (28–5486 mm3), of the 16 nodules with mixed attenuation 526 mm3 (169–4610 mm3), and of the four pure ground-glass nodules 452 mm3 (135–638 mm3).
In total, 240 test-positive participants were referred to a chest physician for nonsurgical workup, which included a bronchoscopy and a standard dose CT with contrast. The diagnostic procedures performed during bronchoscopy were washings (65%), brushings (25%), endobronchial biopsies (7%), transbronchial biopsies (3%), and transbronchial punctions (1%) but no lavages. The role of bronchoscopy and CT scan with intravenous contrast made during evaluation by the pulmonologist will be described separately. In 93 participants, nonsurgical workup was conclusive and in 147 inconclusive. In case of regression or disappearance of a nodule on CT with intravenous contrast, the workup was terminated and considered as benign. All 147 subjects with an inconclusive nonsurgical workup were referred for surgery (Figure 1).
In 11 of 147 participants with an inconclusive nonsurgical workup, no PET scan was made (tumor board decision). In 46% (5/11), these resections were done for benign disease; in one of them (1/5), the diagnosis had clinical consequences (Langerhans cell histiocytosis) (Figure 1). The remaining 136 patients underwent a PET scan and were subsequently operated upon. Twenty-three percent (31/136) of these resections were done on benign nodules (Figure 1). In these 31 patients, five VATS procedures and 26 thoracotomies (15 wedge resections, seven lobectomies, and four histological true-cut biopsies) have been performed. Twenty-six percent (8/31) of the resections for benign disease had clinical consequences with respect to follow-up or initiation of treatment and included latent tuberculosis (2), active tuberculosis (1), aspergilloma (2), tumorlet (2), and atypical adenomatous hyperplasia (1). Nine subjects were diagnosed with malignancies other than lung cancer after surgery: pulmonary metastasis from colon (3), prostate (2), oral cavity (1), esophagus (1), a thymoma, and maltoma of the lung (Figure 1).
The median time between PET and surgery was 28 days (range: 5–203 days). In Tables 2 and 3, the lung cancer diagnoses and nodule characteristics are presented. Of the 109 lung cancers detected, 17% was PET negative, 79% positive, and 4% indeterminate (Table 3). Of the PET positive, negative, and indeterminate lung cancers, 20%, 53%, and 17%, respectively, was less than 500 mm3. The one pure ground-glass nodule was PET negative and the four partial solid lesions PET positive, except for the carcinoid, which was PET negative.
For all test-positive subjects (n = 229), the sensitivity, specificity, PPV, and NPV of PET was 84%, 75%, 79%, and 81%, respectively, when the indeterminate test results were considered PET positive. In 25% (27/109), PET was false positive (Table 4). When the indeterminate test results were considered PET negative, the sensitivity, specificity, PPV, and NPV were 77%, 88%, 88%, and 77%, respectively. In 12% (13/109), PET was false positive (Table 4). During follow-up, eight subjects were diagnosed with lung cancer after an initial negative workup during baseline or second round screening (Table 5). The median time interval between the first and second workup was 716 days (259–974 days). Based on this retrospective information, the sensitivity, specificity, PPV, and NPV of the initial PET were 80%, 75%, 80%, and 75%, respectively, when the indeterminate test results were considered PET positive. When the most recent PET was taken, these values were 84%, 75%, 81%, and 78%, respectively.
The role of PET was also investigated for all test-positive subjects in whom the suspicious nodule was larger than 500 mm3 (>9.6 mm in diameter) (n = 156); these data are presented in Table 4.
Finally, we investigated the role of a preoperative PET in 137 patients who underwent surgical resection of the suspicious nodule after an inconclusive nonsurgical workup. The sensitivity, specificity, PPV, and NPV were 85%, 47%, 84%, and 48%, respectively, when the indeterminate test results were considered PET positive (Table 4). When the indeterminate test results were considered PET negative, the sensitivity, specificity, PPV and NPV were 77%, 66%, 88%, and 47%, respectively (Table 4).
In this study, we evaluated the role of PET in 229 subjects with a positive baseline or second round test result. The prevalence of cancer in this population was 52%. The sensitivity of PET to detect cancer 84.2% (95% CI: 77.6–90.7%), the specificity 75.2% (95% CI: 67.1–83.3), the PPV 78.9% (95% CI: 71.8–86.0), and the NPV 81.2% (95% CI: 73.6–88.8). For subjects with nodules larger than 500 mm3, the sensitivity was 90.9% (95% CI: 84.9–96.6%), the specificity 66.2% (95% CI: 55.2–77.2%), the PPV 76.9% (68.8–85.0%), and the NPV 85.5% (95% CI: 76.1–94.8%). The resection rate for benign lesions was 23%; a preoperative PET after an inconclusive nonsurgical workup reduced the futile resection rate with 11 to 15%, at the expense of missing 12 to 18% lung cancer cases. A preoperative PET after a conclusive nonsurgical workup reduced the futile resection rate by 78% at the expense of missing 3% lung cancer cases.
Several investigators evaluated the role of PET in a lung cancer screening setting. FDG-PET was part of their CT screening protocol for nodules ≥7 mm (4), more than 8 mm, and growing nodules less than 8 mm19 or nodules ≥10 mm and growing nodules more than 7 mm.20 Pastorino et al.4 reported on the results of 42 PET scans, Bastarrika et al.20 on 25, and Veronesi et al.19 on 157 PET scans. Sensitivities and specificities of PET in these settings ranged between 69 to 90% and 81 to 93%, respectively.4,19,20 They concluded that a combination of CT and PET effectively detects lung cancer and may help to reduce unnecessary surgeries for benign lesions4,19,20 Veronesi et al.19 reported an overall specificity of 93% for PET but with a wide range between 68% and 100%. For nodules ≥10 mm, the sensitivity was 91% at a specificity of 68%. The other two authors did not report on the value of PET in larger nodules only. Also, Lindell et al.21 investigated the role of PET. They found that 32% of the lung cancers were PET negative. This might be due to the fact that they are usually smaller (mean size 10 mm) and/or low-grade lung cancers.21 Our false-negative lung cancers rate was with 16% lower, probably because the median nodule size of all cancers detected was above 14 mm (Table 3). The overall sensitivity in our study was comparable with the aforementioned studies,4,19,20 but the specificity was lower. For nodules ≥9.6 mm, however, our results are comparable with those reported by Veronesi et al. for nodules ≥10 mm.
Question is whether the sensitivities and specificities of PET found in lung cancer screening setting differ from nonscreening series. Wahidi et al.22 reviewed 17 studies on PET for the evaluation of solitary pulmonary nodules. The median specificity in these studies was 82.6% (range: 40–100%), with a corresponding sensitivity of 87% (range: 80–100%). In a meta-analysis of 40 studies on pulmonary nodules and mass lesions, a sensitivity of 97% at a specificity of 83.3% was found.23 The sensitivities and specificities in a lung cancer screening setting are thus slightly lower than in a nonscreening setting, most likely because of smaller tumor sizes, differences in the a priori lung cancer probability, and distribution in tumor histology in lung cancer screening. When the use of PET was limited in our study to subjects with suspicious nodules ≥500 mm3 (>9.6 mm), the specificity remained very low with only a slight increase in sensitivity. This can be explained by the fact that many of the new and growing nodules ≥500 mm3 and with a VDT less than 400 days were false PET positive and represent enlarged lymph nodes, hyperplastic lymphoid tissue, or granulomas.
In a multidetector CT lung cancer screening setting, the resection rate for benign lesions at baseline varied between 0% and 43% with a median value of 19%,3–5,8,9,20,24–30 This demonstrates that by using the NELSON nodule management strategy, in which the number of recall CT scans was strictly limited to only 1 per screening round and in which volumetric software evaluation replaced FNA, PET, or evaluations after antibiotics, similar resection rates for benign disease were found in comparison with the literature.10 Although there is no consensus what an acceptable resection rate for benign lesions is, a rate between 10% and 20% can be regarded as acceptable. This means that the resection rate for benign disease in the NELSON lung cancer screening trials was too high but after adjustment for clinical relevant disease (17%), within the acceptable range.
Question was, whether a preoperative PET scan could help to reduce the resection rate for benign lesions after a negative nonsurgical workup. In the scenario that PET negative and indeterminate test results are regarded as PET negative (Table 4) instead of 137 subjects, only 92 participants would have been operated with a reduction in the resection rate for benign disease from 23% (31/137) to 8% (11/137). If PET positive and PET indeterminates are taken together (Table 4), the resection rate for benign disease would have been 12% (17/137). Thus, a preoperative PET can help to reduce the resection rate for benign disease but at the expense of missing, respectively, 24 and 16 lung cancer cases, which is unacceptable due to the low NPV of PET in this setting, and should not be recommended. Also, other investigators demonstrated that lung cancer can show faint FDG uptake, which should not be neglected.31 In small malignant pulmonary nodules less than 20 mm and less than 10 mm, 19% and 20% was PET negative, respectively.32,33
In contrast, the role of PET after a conclusive nonsurgical workup was evident; the resection rate for benign disease in this group decreased from 84% (78/93) to 12% (11/93) at the expense of only 3% (3/92) additional missed cancers because of the very high NPV of 96% (Table 4). Thus, after a conclusive nonsurgical workup, the resection rate for benign disease can be decreased by 72%.
Limitation of our study was that there was no standardized FDG-PET protocol, which could have been a potential source of bias, although it reflects our daily practice of evaluating pulmonary nodules. Differences in FDG-uptake and imaging time may have led to differences in FDG-uptake in tumor to background ratio and, thus, may have influenced the PET results. No second reading was done, which may have led diminished the reproducibility. Another limitation of our study is that, we were not able to calculate SUVs because there were no national standards available for comparison between the institutes at the time of the study.15 Nevertheless, several authors recommended qualitative analysis over quantitative analysis31,34,35 because no improvement in accuracy was observed by semiquantitative approaches over visual analysis of pulmonary nodules 10 to 30 mm31 or ≥7 mm.35 The same was found for nodules with a SUV less than 2.5.34 The classical threshold of SUV 2.5 may be inappropriate for diagnosing malignancies with low FDG-uptake,36,37 and a lower cutoff of 1.5 to 2 might be more appropriate.4,19 Another important limitation of the study is that, although the PET was made for staging purposes in case the nodule turned out to be malignant at surgery, the investigators were not blinded to the outcome of the PET result with respect to the uptake by the suspicious nodule. Therefore, outcome of the nonsurgical workup (conclusive or inconclusive) may have been influenced by the outcome of the PET result. Our nodule management strategy was based on VDT and nodule size only and did not include the use of transthoracic needle biopsies (7). This should not be regarded as limitation of this study but rather the result of our NELSON nodule management strategy based on which the workup of nodules was performed. In conclusion, a preoperative PET scan in participants with an inconclusive nonsurgical workup is not recommended because of the very low NPV, but after a conclusive nonsurgical workup, the resection rate for benign lesions can be decreased by 72%.
Supported by Zorg Onderzoek Nederland-Medische Wetenschappen (ZonMw), KWF Kankerbestrijding, Stichting Centraal Fonds Reserves van Voormalig Vrijwillige Ziekenfondsverzekeringen (RvvZ), G. Ph. Verhagen Foundation, Rotterdam Oncologic Thoracic Study Group (ROTS), Erasmus Trust Fund, Stichting tegen Kanker (België), Vlaamse Liga tegen Kanker and LOGO Leuven and Hageland. The authors thank Siemens Germany for providing four digital workstations and Roche Diagnostics for an unrestricted research grant. Legacy gift of Jan and Josephine De Rijke.
The authors thank John Bemelmans (UMC Utrecht), J. Pruim (UMC Groningen), A Zwijnenburg (Kennemer Gasthuis Haarlem), and Prof. Deroose (UZ Gasthuisberg Leuven) of the Departments of Nuclear Medicine for providing the data on FDG-PET. The authors thank Roel Faber, ICT-manager, for his assistance and Linda van Dongen for her support in data management. In addition, they thank the local data managers: Henk Pruiksma (Haarlem), Liesbet Peeters (Leuven), Saskia van Amelsvoort - van de Vorst (Utrecht), and Ria Ziengs (Groningen).
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© 2011International Association for the Study of Lung Cancer
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