Outcomes of lung cancers manifesting as nonsolid nodules

Lung Cancer 97 (2016) 35–42

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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan

Review

Outcomes of lung cancers manifesting as nonsolid nodules Rowena Yip a,∗ , Andrea Wolf b , Kathleen Tam a , Emanuela Taioli c , Ingram Olkin d , Raja M. Flores b , David F. Yankelevitz a , Claudia I. Henschke a a

Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States Departments of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States Departments of Population Health Science and Policy and Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States d Department of Statistics, Stanford University, Stanford, CA, United States b c

a r t i c l e

i n f o

Article history: Received 10 February 2016 Received in revised form 4 April 2016 Accepted 6 April 2016 Keywords: Survival Surgery Surveillance Screening Lung neoplasm

a b s t r a c t This is a comprehensive review and re-analysis of available literature to assess the outcome of lung cancer presenting as nonsolid nodules (NSNs), a more indolent form of cancer. PubMed and EMBASE were searched for articles reporting on CT-detected lung cancers manifesting as NSNs published in English on or before July 17, 2015. Only studies including clinicopathologic data, lung cancer-specific survival, or overall survival were included. Data extraction was performed by three independent reviewers using prespecified criteria. Twenty-four articles from 5 countries met criteria and they included 704 subjects with 712 lung cancers manifesting as NSNs. Each article reported from 2 to 100 lung cancer cases with a median follow up of 18–51 months. All NSNs were Stage I adenocarcinoma without pathologic nodal involvement upon resection, except for one case in which the NSN progressed to become part-solid nodule after 6 years of follow-up. The five-year lung cancer-specific survival rate was 100%. These findings suggest an indolent course for lung cancers manifesting as NSNs. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction With advances in computed tomography(CT) scanner technology, nonsolid nodules (NSNs), which are nodules that have no solid components other than blood vessels, are being identified with increasing frequency on chest CT scans performed in programs of CT screening for lung cancer as well as for other indications [1]. NSNs have also been described as ground-glass opacities (GGOs), pure ground-glass opacities (pGGOs), or as pure ground-glass nodules (pGGNs). Studies have reported excellent surgical outcomes for lung cancers manifesting as NSNs when treated [2], which raised the possibility that these outcomes were not only the result of potentially curative surgery, but also that these lung cancers might have an indolent course even in the absence of treatment [1,3–5]. As a result, concerns have been raised about the possibility that resec-

tion may represent ‘overtreatment’ [1,6]. However, most of these studies are based on a small number of patients with limited followup [7]. Combined with rapid advances in CT technology, and the wide spread use of CT for lung cancer screening [8,9], the frequency of detecting NSNs will significantly increase and further knowledge as to the best approach to manage them is urgently needed. A review of available literature is needed to confirm the indolent nature of these cancers as well as to ensure that no harm is caused to the patient by delaying a potentially lifesaving opportunity to resect a cancer before it progresses to higher stage disease.

2. Methods 2.1. Data sources and searches

Abbreviations: AIS, Adenocarcinoma-in-situ; CT, Computed tomography; GGO, Ground-glass opacities; IQR, Interquartile range; LN, Lymph node; MLND, Mediastinal lymph node dissection; NSNs, Nonsolid nodules; MIA, Minimally invasive adenocarcinoma; PGGO, Pure ground-glass opacities; VDT, Volume doubling time. ∗ Corresponding author at: Department of Radiology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, United States. E-mail address: [email protected] (R. Yip). http://dx.doi.org/10.1016/j.lungcan.2016.04.005 0169-5002/© 2016 Elsevier Ireland Ltd. All rights reserved.

The PubMed/MEDLINE and EMBASE databases were searched for all studies and clinical trials on CT-detected lung cancers published in English on or before July 17, 2015. Search strategies are listed in Appendix A. Furthermore, reference lists of all identified relevant articles and important reviews in this topic were manually searched.

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2.2. Study selection Titles and abstracts (and in ambiguous cases, full text) of the articles were reviewed by two independent reviewers (RY, KT) for eligibility of studies. Inclusion criteria were: cohort, controlled or randomized studies performed in humans; lung cancers manifesting as NSNs using CT; and studies that reported on at least one of the following outcomes of interest: (i) lung cancer-specific survival, (ii) overall survival, (iii) lymph node involvement, (iv) invasion, (v) clinical/pathologic stage, or (vi) recurrence. Studies that did not meet the inclusion criteria and non-English published studies were excluded. Also excluded were those studies that included GGO with less than a 100% ground glass component(part-solid) in which we were unable to determine the outcomes for those cases with “pGGO.” 2.3. Data extraction Data were extracted independently by three reviewers(RY, AW, and KT). In cases of discord, final decision was decided by a fourth reviewer(DY or CH). When available, information on first author, country of participants and year of the study were extracted. Other study characteristics collected were the number of lung cancer cases manifesting as NSNs, initial size, size at time of diagnosis for nonsolid cancers, type of surgery, lung cancer histology, stage of cancer at diagnosis(clinical/pathological), number of cases with mediastinal lymph node dissection(MLND)/sampling, positive lymph node(LN) metastasis, length of post-operative hospital stay, recurrence, overall and lung cancer-specific, and duration of follow-up. 2.4. Pathologic classification For the review, the updated classification for adenocarcinoma proposed by Travis et al. [10,11] was used, in which the term “bronchioloalveolar features” was replaced by the term “lepidic.” The updated description used adenocarcinoma-in-situ(AIS) to replace adenocarcinoma with bronchioloalveolar features, which by definition has no evidence of invasion. Minimally invasive adenocarcinoma(MIA) was used for cases of invasive adenocarcinoma with 90–99% lepidic subtype(formerly bronchioloalveoalar features) with less than 5 mm of invasion. For invasive adenocarcinomas, the subtype was classified by predominant component: lepidic, acinar, papillary, micropapillary, or solid. Summary of these changes has been previously reported [12,13]. 2.5. Data synthesis and analysis Frequencies and descriptive statistics were obtained for all variables. A resampling method [14] with 1000 iterations was used for estimating the sampling distribution of the percentage of noninvasive adenocarcinoma. Such resampling provides for more robust estimates and the summary statistics from the 1000 samples were given. 2.6. Bias All 24 studies included in this review were retrospective observational studies. As anticipated, there are no published randomized clinical trials in which the effects of surgery on the long term lung cancer survival among cancers manifesting as NSNs were studied. Since all included studies are observational and consisted of mostly resected cases, selection bias may have been introduced when deciding which patients should undergo surgery. It is possible that management of NSNs may be different among different countries, institutions and surgeons and this may have

played a role in the decision to perform surgery. Among the 24 studies, 22 [2,6,7,15–33] included only institutions in Asia (618 of 704 patients), one study included institutions in 8 countries, predominantly in the United States, but also in Europe, Japan and China [1] (84 of 704 patients) and one study [34] included 2 of the 704 cases from Germany. In 3 studies [16,18,25] accounting for a total of 48(7%) resected cases, only patients who underwent limited resection were included. Average tumor size of the cases was relatively small, ranging between 7.9 mm to 16.6 mm. Tumor size was one of the inclusion criteria in some of the studies; inclusion was restricted to subcentimeter(< = 1 cm) tumors in 3 studies [2,17,33] and to ≤2 cm in 4 studies [21,22,30,35], for a total of 80(11%) and 148(21%) resected cases respectively. No standard measuring methods or CT acquisition parameters were used in the 24 included studies; the time from the initial identification of the NSN to the time of resection was not reported. Of the 18 studies (495 cases) in which the median follow-up time after surgery was reported, median follow-up time ranged from 12 to 78 months of which 12 studies (339 or 68% of total cases) had a median follow up of more than 3 years, and 2 studies (134 or 28% of total cases) had more than 5 years follow-up. In 2 studies, only persistent NSNs after ≥2 years of follow-up after the initial identification were included (45 or 9% of total cases). 2.7. Confounders The year of study conduct may be important as CT scanner and surgical techniques may have changed over time. However, lung cancer survival was consistently at 100% in the 24 included studies without any changes over time according to year of publication. Our review confirms the excess of females and non-smokers as has been noted in prior studies [2]. 3. Results The PubMed/MEDLINE and EMBASE search identified 775 potential articles (Fig. 1). Studies were selected according to the inclusion and exclusion criteria. Eighty studies were obtained from this search and six additional publications were identified by a manual search of the bibliographies of the relevant articles. A total of 30 articles reporting on 24 unique studies were included in this review [1,2,6,7,15–34,36–41]. Table 1 summarizes the 24 studies conducted from 1991 to 2014. Most studies were conducted in China, Taiwan, Korea, or Japan, with one multi-institutional study in the USA and one in Germany. A total of 704 patients with 712 lung cancers manifesting as NSNs were reported. All 712 were resected except two: one patient declined surgery due to the presence of lesions in all lobes [15] and one patient chose radiation therapy instead [1]. The average age of participants ranged from 53 to 68. The number of participants with lung cancer manifesting as NSNs in each study ranged from 2 to 100, with median follow-up after surgery ranged from 18 to 78 months. Among the 24 included studies, CT acquisition parameters were reported in 18 studies. CT images were being acquired at 2.5 mm or less in 5 studies, 2.0 mm or less in 7, and 1.0 mm or less in 6. Of the 24 studies, 2 studies included only screendetected NSNs [1,6], both screen-detected and incidental detected NSNs in 3 [15,16,31], and the remaining 19 did not specify but it is presumed that non-screen detected nodules were included. Among the studies in which the type of resection was reported for all resected lung cancers, the extent of surgery varied by country of study. The frequency of sublobar resection was 63–100% in Japanese studies but lower in Korea and China (27–41%). The only multi-institutional study which included institutions in the United

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Fig. 1. Summary of search and selection strategy (PRISMA diagram).

Table 1 Description of 24 studies on lung cancer manifesting as nonsolid nodules (NSNs) in programs of CT screening for lung cancer, listed by year of publication. Author

Year

Casesa

MLNR n (%)d

Med LN mets

Stage I n (%)

Sublobar resection n (%)d

Recurrence

Lung cancer death

Median time of follow up (mo)

Kodama et al. [15] Watanabe et al. [16] Asamura et al. [2] Kakinuma et al. [6] Kishi et al. [17] Nakamura et al. [18] Nakata et al. [19] Ohta et al. [20] Ohtsuka et al. [21] Suzuki et al. [22] Seki et al. [23] Park et al. [24] Sagawa et al. [25] Tao et al. [26] Chang et al. [6] Cho et al. [27] Lederlin et al. [34] Lim et al. [28] Matsuguma et al. [29] Ichinose et al. [30] Sim et al. [31] Ye et al. [32] Sakurai et al. [33] Yankelevitz et al. [1]

2002 2002 2003 2004 2004 2004 2004 2006 2006 2006 2008 2009 2009 2011 2013 2013 2013 2013 2013 2014 2014 2014 2015 2015

6 17 19 8 11 27 20 37 10 22 38 58 4 2 11 28 2 46 16 100f 48 40 50 84

NR None 2 (11) NR NR None NR NR NR NR NR NR NR NR NR NR NR 34 (74) NR NR 42 (88) 40 (100) NR NR

0 NR 0 0 0 0 0 NR NR 0 0 0 0 0 1 0 NR 0 NR NR 0 0 0 0

NR NR 19 (100) 8 (100) NR 27 (100) 20 (100) NR NR 22 (100) 38 (100) NR 4 (100) NR 10 (91) NR NR 46 (100) NR NR NR 40 (100) 50 (100) 84 (100)

5 (100) 17 (100) 12 (63) NR NR 27 (100) 13 (65) NR 8 (67) NR NR 20 (34) 4 (100) NR 3 (27) NR NR 19 (41) NR NR NR NR 41 (82) 26 (31)

0 0 0 NR 0 0 1b 0 0 0 0 0 0 NR NR 0 0 0 0 NR 0 NR 0 0

0 0 0 NR 0 0 NR 0 NR 0 0 0 0 0 0 NR 0 0 NR NR 0 NR 0 0

NA 32 47.9 NA 35.5(mean) NA 27.7 18e 44 30e 36e 21 38e 12.3e (mean) 51 NA 48.5e (mean) 51.5 52 NA 39 NA 76.8e 78

Total

704

LN mets = Lymph node metastasis; NR = Not reported; MLNR = Mediastinal Lymph Node Resection. Number of subjects with cancers manifesting as NSNs. Distant recurrence reported in one patient with Stage IB disease, author did not specify the type of GGO (pure or mixed). c Pathologic stage if resected, otherwise clinical stage. d Percentage out of number of patients who had resection. e Summary statistics reported by the article included cases other than lung cancers manifesting as NSNs. f Authors did not specify number of subjects with cancers, but rather number of cancerous lesions. a

b

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States, Canada, Europe, Israel, Japan, and China [1] reported a rate of 31% for sublobar resection. The mean tumor size on pathology reported by the 24 studies ranged from 7.9 mm to 16.6 mm. Of the 24 studies, 22 reported lung cancer histology while 2 did not [22,26]. Among 688 (712-22-2) resected cancers (Table 2), the diagnosis was either non- or minimally-invasive adenocarcinoma in 507 (74%) (402 AIS and 105 MIA/well-differentiated adenocarcinoma), adenocarcinoma with lepidic features in 67 (10%), adenocarcinoma with acinar and papillary in 24 (3%) and unspecified in 90 (13%). Using the resampling method (Fig. 2), repeated sampling of the 507 cases out of the 688 total cases resulted in a median of 73.8% (range: 67.9%-79.7%); this was similar to the observed frequency (73.7%) of non- or minimally-invasive adenocarcinoma (AIS or MIA). Four studies [2,28,31,32] reported on the number of subjects underwent MLND or sampling. Among the cases with pathologic assessment of mediastinal LNs, none had LN metastasis. The number of cases with pathologic assessment was not reported in 20 studies but no evidence of LN metastasis was documented. In the single remaining study [7], one of the 11 patients who underwent surgery because of a growing NSN had N2 LN metastasis. On initial CT, this patient had a 5 mm NSN in the right upper lobe, which grew to 14 mm and developed a solid component after 68-month followup prior to resection. It is not clear based on the report how long the solid component had been present prior to resection. By the time of resection, the nodule had grown to more than 3 cm in greatest dimension with a preoperative clinical staging of T2aN0. Surgical pathology revealed a single metastasis in a right lower paratracheal LN. The patient was alive at the end of the study period (Median post-surgical follow-up time: 51 months, range:10–75 months). None of the 24 studies reported any local or distant recurrence and none reported any lung cancer deaths. Thus, 5-year lung-cancer-specific survival rate was 100%. Several studies also reported all cause survival rates [17–19,26,33,34] and disease-free survival rates [2,17,19,20,23,28,33,34]; both rates were 100%.

4. Discussion This review was conducted to provide information about the prognosis of lung cancer manifesting as NSNs. The results show that the lung-cancer-specific survival rate of these cancers is 100%. Of the 704 patients with resected lung cancers manifesting as NSNs, the nodule remained nonsolid at time of resection in 703 and none had LN metastases. Only 1 patient with a nodule that was initially a NSN but had progressed to become a part-solid nodule at some point during the 68 months of follow up, had LN metastasis and this patient was still alive at the end of the study period with median post-op follow-up time of 51 months. None of the 24 studies reviewed reported death due to lung cancer, confirming previous reports that these cancers have an excellent prognosis. In fact, even studies that included cancers manifesting as part-solid nodules showed an all-cause survival rate over 90% [42–45] with no deaths due to lung cancer [44,46,47] and no recurrences [2,44,46]. Previous literature [2,40] reported that MLND or sampling was performed in approximately 25% of patients who underwent resection for cancers manifesting as NSNs. Among the 24 studies, 18 reported on the results of LN resection which demonstrated no metastases while the information is not available in the remaining 6 studies. The only case with LN metastasis was in a patient whose NSN had progressed to become part-solid, and had surgery more than 68 months after first being identified; it was unclear when the transition occurred [7]. This corroborates previous reports about the absence of LN metastasis in lung cancers manifesting as NSNs [31,48]. When MLND or sampling was performed in these patients,

none had metastases [28,31,32]. These results suggest that LN metastases are exceedingly rare among lung cancers manifesting as NSNs. This raises the question as to whether LN dissection is necessary in patients undergoing resection for lung cancer manifesting as a NSN. This review confirms that cancers manifesting as NSNs are predominantly AIS or MIA with 74% of resected NSN cancers representing one of these subtypes. Less than 3% of the cases were adenocarcinoma with acinar or papillary while 13% were unspecified. Because most studies did not report on the time between the NSN identification on CT and the date of surgery, it is possible that these NSNs had already developed a solid component by the time of surgery. This progression was observed in one study in which 22 of the 84 cancers manifesting as NSNs had developed a solid component before treatment [1]. Increase in density and development of a solid component was also observed in 2 of 8 cases reported by Kakinuma et al. in 2004, of which one case was later diagnosed as adenocarcinoma, mixed subtype [6]. In 2013, Yamaguchi [49] reported one case of small cell carcinoma among 38 resected small NSNs. However, the description of this nodule as nonsolid is questionable; small cell carcinoma has not previously been reported to manifest as a NSN and no further follow up or radiologic acquisition techniques or verification of the nodule consistency about the case in Yamaguchi’s report was provided. Given the limited information in that report, the study was excluded from our review, but it should be noted that, if accurate, a small cell lung cancer presenting as an NSN 277, would be an exceptional occurrence. The CT appearance of a lung cancer has significant prognostic implications [41]. In these studies, among nodules that remained nonsolid, between 60% and 100% were non- or minimally-invasive AIS or MIA upon diagnosis with reported survival as high as 100%. The appearance of nodules on CT depends in part on CT acquisition parameters including section thickness. All 18 of the 24 studies that reported the acquisition parameters had CT images of 2.5 mm thickness or less, which might not be adequate for the identification of NSNs, as it is now recommended to use no more than 1 mm slice thickness [50,51]. According to the I-ELCAP’s, Lung-RADS guideline’s and the British Thoracic Society guideline’s recommendations, annual follow-up with CT surveillance is a reasonable alternative to surgery for NSNs [1,22,41,51–53]. The current review lends support to the indolent nature of lung cancers manifesting as NSNs. Previous studies have reported that some noninvasive cancers might evolve into invasive ones over time [1,6,31,54,55] and others have developed prediction models [35,56–60] which, however, are not yet validated [7]. The average time for a lung cancer manifesting as a NSN to progress to become part-solid or solid is not well documented. Of 84 nonsolid lung cancers reported by Yankelevitz et al. [1], a solid component developed in 22 cases of initial NSNs prior to surgery; the median time for progression from NSN to part-solid was 25 months(2.1 years) with an interquartile range(IQR) of 13–39 months. Several studies [54,60] have reported mean time for progression between 3.6 and 4.5 years for resected adenocarcinomas that changed from NSN to part-solid while others [6,15,61] have reported no change in 10 years of follow-up. Several reports on lung tumor volume doubling time(VDT) support the findings of the current review as well as those of I-ELCAP that NSNs found in low-dose CT lung cancer screening cases can be managed with active surveillance given their relatively indolent natural course [1]. In a study by Hasegawa et al. [62], investigators found that the mean of the VDT for small lung cancers manifesting as NSNs was 813 days. Aoki et al. [55] reported that 5/6(83%) Noguchi types A or B (BAC/MIA) detected as focal NSN on high resolution CT exhibited a tumor VDT of >1 year. A recent study [60] with long term follow-up of 438 solitary NSNs ≤ 5 mm reported a median

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Table 2 Pathologic diagnosis of resected cancers manifesting as NSNs by cell-type of diagnosis. BAC/WD/AIS/MIA

AD-lepidic

n

(%)

n

Kodama et al. [15] Watanabe et al. [16] Asamura et al. [2] Kakinuma et al. [6] Kishi et al. [17] Nakamura et al. [18] Nakata et al. [19] Ohta et al. [20] Ohtsuka et al. [21] Suzuki et al. [22] Seki et al. [23] Park et al. [24] Sagawa et al. [25] Tao et al. [26] Chang et al. [6] Cho et al. [27] Lederlin et al. [34] Lim et al. [28] Matsuguma et al. [29] Ichinose et al. [30] Sim et al. [31] Ye et al. [32] Sakurai et al. [33] Yankelevitz et al. [1]

4 17

(80) (100)

7 10 27 20 35 12 NR 38 58 4 NR 8 25

(88) (91) (100) (100) (95) (100)

(73) (89)

1 3

NR (9) (11)

28 16 86 28 32 42 10

(61) (100) (86) (51) (80) (84) (12)

18

(39)

1 20 5

(1) (36) (13)

Totalc

421

19a

(%)

AD-acinar

AD-papillary

AD-unspecified

n

n

n

(%)

1

(20)

1 1

19 (13) (9)

2

(5)

(%)

(%)

(100)

NR

NR

NR

NR

Total

5 17 8 11 27 20 37 12

22

(100) (100) (100)

38 58 4 NR

2

NR (18)

NR

11 28 2

(72)

66

(11)

2 4

6

(2) (7)

(1)

2

10 3 3

6

(10) (5) (8)

(1)

(100)

1

(1)

8b 74

(16) (88)

46 16 100 55 40 50 84

89

(15)

712

BAC = Bronchioalveolar carcinoma; MIA = Minimally invasive adenocarcinoma; AIS = Adenocarcinoma-in-situ; WD = Well-differentiated adenocarcinoma. a 19 AD with BAC, including 100% BAC. b 8 not specified. c Percentage out of total number of tumors in which cell-types was reported (n = 712-22-2 = 688).

Fig. 2. Resampling results of the percentage of noninvasive adenocarcinoma.

2

40

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VDT of 375 days (IQR: 267–784 days) for resected adenocarcinomas. While cancers manifesting as NSNs have an indolent course, it is clear that they need to be followed carefully for development of a solid component [1]. This review may be limited: the search was only performed using PubMed and EMBASE. Thus, it is possible that some existing studies, particularly those in non-English journals, may not have been identified. Also, the predominance of studies from Asian countries may reflect unique patient cohorts and may limit generalizability of the results to other populations. Recent publications from large North American studies reported similar findings [1,63] which suggests that the reports evaluated in this review are generalizable to additional populations. Due to the sparsity of studies with focus on outcomes of lung cancers manifesting as NSNs, five of the 24 included studies had sample sizes <10 [6,15,25,26,34]. Median follow-up time in each study ranged from 12 to 78 months, 12 studies with median follow up of more than 3 years and 2 studies with more than 5 years follow-up. Follow-up time might not be long enough to observe lung cancer death among these early stage lung cancers, but no recurrences occurred during the follow-up of these 24 reported studies. In addition, information on operative morbidity and mortality, length of observation prior to resection and indication of surgery was limited in these studies. Most retrospective studies focused on long-term survival for surgically resected lung cancers manifesting as subsolid nodules, thus lacked a control group making it difficult to explore whether the favorable outcomes were due to indolent disease or surgical treatment. The uniformly good outcome across these studies makes it impossible to detect differences in populations and nodules that may ultimately be important considerations in decision making. Regardless, it is possible that earlier surgery in these patients (operating when the NSNs were even smaller) would not provide additional benefit, and that surgery, if considered, could be postponed until solid component appears [27]. Moreover, this review confirms the indolent nature of NSNs, and that lung cancers manifesting as NSNs generally do not metastasize to lymph nodes or other organs. In addition, prognosis remained favorable in the subset of patients who did not undergo surgery [15]. Large registries and long-term outcomes from prospective cohort studies with patients whose lung cancer manifests as an NSN and who do not undergo surgery will provide additional insights about the appropriate management of these indolent NSNs. Acknowledgements Partial support from a generous gift by Sonia Lasry Gardner given in loving memory of her father, Moise Lasry to support lung cancer research, outreach, and treatment. The study sponsor has no involvement in the study design, data collection, analysis and interpretation of the data, writing or the decision of manuscript publication. Appendix A. : Search strategies For PubMed/MEDLINE Search 1. Solitary Pulmonary Nodule/or nonsolid.mp. 2. subsolid.mp. or Solitary Pulmonary Nodule/ 3. ground glass.mp. 4. ground-glass.mp. 5. 1 or 2 or 3 or 4 6. Disease-Free Survival/or Survival Analysis/or Survival/or Survival Rate/or survival.mp. 7. Hospital Mortality/or Mortality/or mortality.mp. 8. Recurrence/or Neoplasm Recurrence, Local/or recurrence.mp.

9. metastasis.mp. or Neoplasm Metastasis/ 10. metastases.mp. or Neoplasm Metastasis/ 11. fatality.mp. 12. fatalities.mp. 13. 6 or 7 or 8 or 9 or 10 or 11 or 12 14. cancer.mp. or Neoplasms/ 15. cancers.mp. or Neoplasms/ 16. carcinoma.mp. or Carcinoma/or Carcinoma, Small Cell/or Carcinoma, Non-Small-Cell Lung/or Carcinoma, Squamous Cell/or Carcinoma, Adenosquamous/ 17. carcinomas.mp. or Carcinoma/ 18. tumor.mp. or Neoplasms/ 19. tumors.mp. or Neoplasms/ 20. 14 or 15 or 16 or 17 or 18 or 19 21. lung.mp. or Lung/ 22. pulmonary.mp. 23. 21 or 22 24. 20 and 23 25. Lung Neoplasms.mp. or Lung Neoplasms/ 26. 24 or 25 27. CT scan.mp. 28. CT scans.mp. 29. CAT scan.mp. 30. CAT scans.mp. 31. Tomography, X-Ray Computed/or computed scan.mp. 32. Tomography, X-Ray Computed/or computed scans.mp. 33. Tomography, X-Ray Computed/or computed assisted tomography.mp. 34. computerized scan.mp. 35. computerized scans.mp. 36.] 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 37. 5 and 13 and 26 and 36 For EMBASE Search: 1. (nonsolid or subsolid or ground glass).mp. [mp = title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 2. lung cancer/ 3. lung tumor/ 4. ((lung or pulmonary) and (cancer or cancers or tumor or tumors or carcinoma or carcinomas or neoplasm or neoplasms)).mp. [mp = title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 5. 2 or 3 or 4 6. mortality/or cancer mortality/ 7. disease free survival/or cancer survival/or disease specific survival/or event free survival/or cancer specific survival/or long term survival/or metastasis free survival/or survival/or overall survival/ 8. recurrent disease/ 9. metastasis/or lung metastasis/ 10. (mortality or survival or recurrence or metastasis or metastases or death rate or relapsing disease or relapse).mp. [mp = title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 11. 6 or 7 or 8 or 9 or 10 12. computer assisted tomography/ 13. (CT scan or CT scans or CAT scan or cat scans).mp. [mp = title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 14. (Comput$ adj3 Tomography).mp. [mp = title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 15. 12 or 13 or 14 16. 1 and 5 and 11 and 15

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