Nanda Horeweg, Carlijn M. van der Aalst, Erik Thunnissen, Kristiaan Nackaerts, Carla Weenink, Harry J.M. Groen, Jan-Willem J.

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1 Characteristics of lung cancers detected in the randomized NELSON lung cancer screening trial Nanda Horeweg, Carlijn M. van der Aalst, Erik Thunnissen, Kristiaan Nackaerts, Carla Weenink, Harry J.M. Groen, Jan-Willem J. Lammers, Joachim G. Aerts, Ernst Th. Scholten, Joost van Rosmalen, Willem Mali, Matthijs Oudkerk, Harry J. de Koning ONLINE DATA SUPPLEMENT: TEXT AND TABLES 1

2 Table E1. Predictive value of histological subtype for cancer stage at diagnosis in the 209 lung cancers; results of univariate and multivariate categorical logistic regression analyses Thresholds for All significant histological Adeno Large cell Small cell Mixed LCSC NSCLC-NOS significant histological subtypes subtypes Stage IA to IB Stage IB to IIA Stage IIA to IIIA Stage IIIA to IIIB Stage IIIB to IV Histological Univariate log regression analyses Multivariate log regression analysis subtypes Estimate 95% CI P-value Estimate 95% CI P-value Adeno Bronchoalveolar Squamous cell * * *

3 Adenosquamous Large cell Large cell neuroendocrine Small cell < <0.001 Mixed large/small cell Pleiomorph Non-small cell, NOS Carcinoid * * * No histological diagnosis The thresholds in the columns adenos, large cell, small cell, mixed LCSC and NSCLC_NOS are parameters for the effect of the variable on the cancer stage (like; the distance between the stages) in four separate univariate logistic categorical regression analysis. There is no threshold for stage IIA to stage IIB because none of the participants were diagnosed with stage IIB lung 3

4 . The threshold column all significant histological subtypes represents the threshold for the multivariate (adeno, large cell, small cell, mixed and NSCLC-NOS) logistic categorical regression model. Abbreviations: Mixed LCSL = mixed large cell and small cell lung, NSCLC-NOS = non-small cell lung, not otherwise specified, 95% CI = 95% confidence interval of the estimate * Both the bronchoalveolar s and the carcinoïds were all diagnosed in stage IA, which caused separation, therefore no estimate or p- value could be calculated 4

5 Table E2a. Histology and disease stage of the 74 screen-detected lung cancers in round one Disease stage* Ia Ib IIa IIb IIIa IIIb IV Overall Histology N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Adeno 21 (60.0) 2 (5.7) 4 (11.4). 4 (11.4) 3 (8.6) 1 (2.9) 35 (47.3) Bronchoalveolar Squamous cell Adenosquamous 2 (100.0) (2.7) 9 (60.0). 2 (13.3). 3 (20.0). 1 (6.7) 15 (20.3) 2 (100.0) (2.7) Large cell 2 (40.0) 1 (20.0).. 2 (40.0).. 5 (6.8) Large cell neuroendocrine 1 (33.3) 1 (33.3).. 1 (33.3).. 3 (4.1) Small cell (100.0) 1 (1.4) Mixed large/small cell Pleiomorph (100.0) 1 (1.4).. 1 (100.0) (1.4) 5

6 Non-small cell, NOS (50.0) 1 (50.0) 2 (2.7) Carcinoïd 4 (100.0) (5.4) No histological diagnosis 3 (100.0) (4.1) Total 44 (59.5) 4 (5.4) 7 (9.5). 10 (13.5) 4 (5.4) 5 (6.8) 74 (100.0) * 7 th edition TNM staging system 2009 (E1) According to IARC Tumours of the Lung, Pleura and Heart (E2) NOS = not otherwise specified In three participants no histological diagnosis was established because biopsies were unsuccessful or not performed and the patient did not undergo thoracic surgery because of poor pulmonary function (N = 2) and poor heart function (N = 1). = 0 (0.0) 6

7 Table E2b. Histology and disease stage of the 58 screen-detected lung cancers in round two Disease stage* Ia Ib IIa IIb IIIa IIIb IV Overall Histology N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Adeno 29 (82.9) 1 (2.9) 3 (8.6). 2 (5.7).. 35 (60.3) Bronchoalveolar Squamous cell Adenosquamous 3 (100.0) (5.2) 2 (66.7)... 1 (33.3).. 3 (5.2) 1 (50.0). 1 (50.0) (3.4) Large cell 5 (50.0)... 2 (20.0) 2 (20.0) 1 (10.0) 10 (17.2) Large cell neuroendocrine Small cell (50.0). 1 (50.0) 2 (3.4) Mixed large/small cell Pleiomorph 7

8 Non-small cell, NOS Carcinoïd No histological diagnosis 3 (100.0) (5.2) Total 43 (74.1) 1 (1.7) 4 (6.9). 6 (10.3) 2 (3.4) 2 (3.4) 58 (100.0) * 7 th edition TNM staging system 2009 (E1) According to IARC Tumours of the Lung, Pleura and Heart (E2) NOS = not otherwise specified In 3 participants no histological diagnosis was established because biopsies were unsuccessful or not performed and the patient did not undergo thoracic surgery because of poor pulmonary function (N = 1), metastasized prostate (N = 1) and death due to mesenteric ischemia before intended surgery (N = 1).. = 0 (0.0) 8

9 Table E2c. Histology and disease stage of the 77 screen-detected lung cancers in round three Disease stage* Ia Ib IIa IIb IIIa IIIb IV Overall Histology N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Adeno 25 (67.6) 6 (16.2) 1 (2.7). 3 (8.1) 1 (2.7) 1 (2.7) 37 (48.1) Bronchoalveolar Squamous cell Adenosquamous 6 (100.0) (7.8) 10 (62.5). 1 (6.3). 4 (25.0). 1 (6.3) 16 (20.8) Large cell (100.0).. 2 (2.6) Large cell neuroendocrine 1 (100.0) (1.3) Small cell (80.0). 1 (20.0) 5 (6.5) Mixed large/small cell Pleiomorph (100.0).. 1 (1.3) 9

10 Non-small cell, NOS Carcinoïd 2 (100.0) (2.6) No histological diagnosis 6 (85.7). 1 (14.3) (9.1) Total 50 (64.9) 6 (7.8) 3 (3.9). 14 (18.2) 1 (1.3) 3 (3.9) 77 (100.0) * 7 th edition TNM staging system 2009 (E1) According to IARC Tumours of the Lung, Pleura and Heart. (E2) NOS = not otherwise specified In 7 participants no histological diagnosis was established because biopsies were unsuccessful or not performed and the patient did not undergo thoracic surgery because of poor pulmonary function (N = 4), poor general condition (N = 1), radiotherapy because of participation in other clinical trial (N = 1) and refusal (N = 1).. = 0 (0.0) 10

11 Table E3a. Histology and disease stage of the 175 screen-detected lung cancers in 166 men Disease stage* Ia Ib IIa IIb IIIa IIIb IV Overall Histology N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Adeno 58 (66.7) 8 (9.2) 8 (9.2). 7 (8.0) 4 (4.6) 2 (2.3) 87 (49.7) Bronchoalveolar Squamous cell Adenosquamous 8 (100.0) (4.6) 17 (56.7). 3 (10.0). 8 (26.7). 2 (6.7) 30 (17.1) 1 (50.0). 1 (50.0) (1.1) Large cell 6 (40.0) 1 (6.7).. 5 (33.3) 2 (13.3) 1 (6.7) 15 (8.6) Large cell neuroendocrine 2 (66.7) 1 (33.3) (1.7) Small cell (62.5). 3 (37.5) 8 (4.6) Mixed large/small cell Pleiomorph... 1 (50.0). 1 (50.0) 2 (1.1).. 1 (100.0) (0.6) 11

12 Non-small cell, NOS (50.0) 1 (50.0) 2 (1.1) Carcinoïd 4 (100.0) (2.3) No histological diagnosis 12 (92.3). 1 (7.7) (7.4) Total 108 (61.7) 10 (5.7) 14 (8.0). 26 (14.9) 7 (4.0) 10 (5.7) 175 (100.0) * 7 th edition TNM staging system 2009 (E1) According to IARC Tumours of the Lung, Pleura and Heart (E2) NOS = not otherwise specified In 13 participants no histological diagnosis was established because biopsies were unsuccessful or not performed and the patient did not undergo thoracic surgery because of poor pulmonary function (N = 7), poor heart function (N = 1), poor general condition (N = 1), metastasized prostate (N = 1), death due to mesenteric ischemia before intended surgery (N = 1), radiotherapy because of participation in other clinical trial (N = 1) and refusal (N = 1).. = 0 (0.0) 12

13 Table E3b. Histology and disease stage of the 34 screen-detected lung cancers in 34 women Disease stage* Ia Ib IIa IIb IIIa IIIb IV Overall Histology N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Adeno 17 (85.0) 1 (5.0).. 2 (10.0).. 20 (58.8) Bronchoalveolar Squamous cell Adenosquamous 3 (100.0) (8.8) 4 (100.0) (11.8) 2 (100.0) (5.9) Large cell 1 (50.0)... 1 (50.0).. 2 (5.9) Large cell neuroendocrine (100.0).. 1 (2.9) Small cell Mixed large/small cell Pleiomorph 13

14 Non-small cell, NOS Carcinoïd 2 (100.0) (5.9) No histological diagnosis Total 29 (85.3) 1 (2.9).. 4 (11.8).. 34 (100.0) * 7 th edition TNM staging system 2009 (E1) According to IARC Tumours of the Lung, Pleura and Heart. (E2). = 0 (0.0) 14

15 Table E4. Predictive value of histological subtype for cancer stage at diagnosis; results of univariate and multivariate categorical logistic ordinal regression analyses Thresholds Gender Age BMI Pack-years All Stage IA to IB Stage IB to IIA Stage IIA to IIIA Stage IIIA to IIIB Stage IIIB to IV Univariate log regression analyses Multivariate log regression analysis Parameter Estimate 95% CI P-value Estimate 95% CI P-value Gender , Age BMI Pack-years The thresholds in the columns gender (male is the reference), age, BMI and pack-years are parameters for the effect of the variable on the cancer stage (like; the distance between the stages) in four separate univariate logistic categorical regression analysis. There is no threshold for stage IIA to stage IIB because none of the participants were diagnosed with stage IIB lung. The threshold column all represents the threshold for the multivariate (gender and BMI) logistic categorical regression model. Abbreviations: BMI = body-mass index, 95% CI = 95% confidence interval of the estimate 15

16 REFERENCES E1. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol Aug;2(8): E2. Travis WD, Brambilla, E., Muller-Hermelink, H.K. Pathology and Genetics. Tumours of the Lung, Pleura and Heart. IARC Press

17 ONLINE DATA SUPPLEMENT: Figure E1 Title and subscript

18 Title: Figure E1. Time from positive screen to first consultation and to lung cancer diagnosis Subscript of online data supplemental figure E1: Time to screening result, referral and diagnosis The dotted line represents the deadline according to the NELSON-protocol in the first box plot and the deadline according to the national guideline in the other three box plots.(e1) Panel A: The median time to the final screening result for the 200 participants with screen-detected lung cancer was twelve days (IQR:8-16) and 87.5% (175/200) waited 3 weeks. Panel B: Thereafter, the median time to the first consultation by a pulmonologist was 13 days (IQR: ) and 27.5% (55/200) had their first consult in 5 work-days. Panel C: In subjects who did not undergo a mediastinoscopy as part of the diagnostic work-up (N=162), was the median time from the first consultation to the lung cancer diagnosis 42 days (IQR: ), 17.9% was diagnosed in 3 weeks. Panel D: When mediastinoscopy was performed (N=38) the median time to diagnosis was 49 days (IQR: ) and 28.9% was diagnosed in 5 weeks. Analyses showed that neither a delayed final scan result (p=0.39) nor a delayed first consultation (p=0.19) was related to a more unfavorable cancer stage at diagnosis. Moreover, the participants with a delayed lung cancer diagnosis had a significantly lower disease stage than the persons without a delay (p<0.001).

19 Outliers Three participants had an extremely long lead-time between the positive scan and the first consultation (marked with a * in panel A). One participant (134 days) refused to go to the pulmonologist before a planned stay abroad. The two other participants (106 and 100 days) were delayed because of an administrative error. Fifteen subjects had an extremely long lead-time between the first consultation and the diagnosis (marked with a * in panel B). Reasons were: watchful waiting approach by the pulmonologist (N=9), delay caused by the participant (N=2), comorbidity that required immediate treatment (N=2), malignant nodule missed by wedge-resection; requiring a second procedure to perform a lobectomy (N=1) and treatment of another benign nodule first (N=1). In total, eleven of the 200 (5.5%) participants had symptoms suspicious of lung cancer before they were diagnosed. Symptomatic participants Five participants had already symptoms suspicious of lung cancer before the screening scan was made: days before the third round scan: dyspnoe and cough days after the pre-randomization questionnaire and 15 days before the baseline scan: dyspnoe, cough and thoracic pain days before the second round scan: start weight loss >10% days before the baseline scan: start weight loss >10% and thoracic pain

20 days after the pre-randomization questionnaire and 124 days before the baseline scan: fatigue Three participants got their first symptoms suspicious of lung cancer in the interval between the positive scan and the first consultation: 1. weight loss >10% and fatigue (interval was 15 days) 2. hemoptoe and thoracic pain (interval was 4 days) 3. cough (interval was 10 days) Three other participants developed symptoms suspicious of lung cancer in the interval between the first consultation and the diagnosis date: 1. cough (interval was 278 days, delay due to cardiac valve replacement that had to be performed before lung surgery) 2. weight loss >10% (interval was 131 days, delay due to a false-positive N3 on the PET-scan, which required CT-guided punction and mediastinoscopy, that were both negative) 3. hemoptoe (interval was 30 days, no delay) E1. van Meerbeeck JP, Koning CC, Tjan-Heijnen VC, Boekema AG, Kaandorp CJ, Burgers JS. [guideline on 'non-small cell lung ; staging and treatment'] richtlijn 'niet-kleincellig longcarcinoom; stadiering en behandeling'. Ned Tijdschr Geneeskd 2005;149:72-77.

21 A B C time from scan (t=0) to final scan result (days) time from final result (t=0) to first consultation pulmonologist (days) D time from final first consultation pulmonologist (t=0) to diagnosis (days) no mediastinoscopy time from final first consultation pulmonologist (t=0) to diagnosis (days) mediastinoscopy Figure E1