Klaveren, R.J. van

Mass spectrometry analyses of κ and λ fractions result in increased number of complementarity-determining region identifications (Article)

2012-01-01T00:00:00Z

Sera from lung cancer patients contain antibodies against tumor-associated antigens. Specific amino acid sequences of the complementarity-determining regions (CDRs) in the antigen-binding fragment (Fab) of these antibodies have potential as lung cancer biomarkers. Detection and identification of CDRs by mass spectrometry can significantly be improved by reduction of the complexity of the immunoglobulin molecule. Our aim was to molecular dissect IgG into κ and λ fragments to reduce the complexity and thereby identify substantially more CDRs than by just total Fab isolation. We purified Fab, Fab-κ, Fab-λ, κ and λ light chains from serum from 10 stage I lung adenocarcinoma patients and 10 matched controls from the current and former smokers. After purification, the immunoglobulin fragments were enzymatically digested and measured by high-resolution mass spectrometry. Finally, we compared the number of CDRs identified in these immunoglobulin fragments with that in the Fab fragments. Twice as many CDRs were identified when Fab-κ, Fab-λ, κ and λ (3330) were combined than in the Fab fraction (1663) alone. The number of CDRs and κ:λ ratio was statistically similar in both cases and controls. Molecular dissection of IgG identifies significantly more CDRs, which increases the likelihood of finding lung cancer-related CDR sequences.

Association of the transfer coefficient of the lung for carbon monoxide with emphysema progression in male smokers (Article)

2011-11-01T00:00:00Z

A decreased transfer coefficient of the lung for carbon monoxide (KCO) is associated with emphysema. We evaluated whether in heavy smokers, baseline KCO was associated with the progression of computed tomography (CT)-detected emphysema, and the progression of airflow limitation. Heavy smokers, mean±SD 41.3±18.7 pack-yrs, participating in a lung cancer screening trial underwent diffusion testing and CT scanning of the lungs. CT scanning was repeated after median (25th-75th percentile) 2.8 (2.7-3.0) yrs and emphysema was assessed by lung densitometry using the 15th percentile. The association between KCO at baseline with progression of emphysema and lung function decline was assessed by multiple linear regression, correcting for baseline CT-quantified emphysema severity and forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), age, height, body mass index, pack-yrs and smoking status (current or former smoker). 522 participants aged 60.1±5.4 yrs were included. Mean±SD 15th percentile was -938±19, absolute FEV1/FVC was 71.6±9% and KCO was 1.23±0.25, which is 81.8±16.5% of predicted. By interpolation, a one SD (0.25) lower KCO value at baseline predicted a 1.6 HU lower 15th percentile and a 0.78% lower FEV1/FVC after follow-up (p<0.001). A lower baseline KCO value is independently associated with a more rapid progression of emphysema and airflow limitation in heavy smokers. Copyright

Identification of chronic obstructive pulmonary disease in lung cancer screening computed tomographic scans (Article)

2011-10-26T00:00:00Z

Context: Smoking is a major risk factor for both cancer and chronic obstructive pulmonary disease (COPD). Computed tomography (CT)-based lung cancer screening may provide an opportunity to detect additional individuals with COPD at an early stage. Objective: To determine whether low-dose lung cancer screening CT scans can be used to identify participants with COPD. Design, Setting, and Patients: Single-center prospective cross-sectional study within an ongoing lung cancer screening trial. Prebronchodilator pulmonary function testing with inspiratory and expiratory CT on the same day was obtained from 1140 male participants between July 2007 and September 2008. Computed tomographic emphysema was defined as percentage of voxels less than -950 Hounsfield units (HU), and CT air trapping was defined as the expiratory:inspiratory ratio of mean lung density. Chronic obstructive pulmonary disease was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 70%. Logistic regression was used to develop a diagnostic prediction model for airflow limitation. Main Outcome Measures: Diagnostic accuracy of COPD diagnosis using pulmonary function tests as the reference standard. Results: Four hundred thirty-seven participants (38%) had COPD according to lung function testing. A diagnostic model with CT emphysema, CT air trapping, body mass index, pack-years, and smoking status corrected for overoptimism (internal validation) yielded an area under the receiver operating characteristic curve of 0.83 (95% CI, 0.81-0.86). Using the point of optimal accuracy, the model identified 274 participants with COPD with 85 false-positives, a sensitivity of 63% (95% CI, 58%-67%), specificity of 88% (95% CI, 85%-90%), positive predictive value of 76% (95% CI, 72%-81%); and negative predictive value of 79% (95% CI, 76%-82%). The diagnostic model showed an area under the receiver operating characteristic curve of 0.87 (95% CI, 0.86-0.88) for participants with symptoms and 0.78 (95% CI, 0.76-0.80) for those without symptoms. Conclusion: Among men who are current and former heavy smokers, low-dose inspiratory and expiratory CT scans obtained for lung cancer screening can identify participants with COPD, with a sensitivity of 63% and a specificity of 88%.

A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03) (Article)

2011-10-01T00:00:00Z

Background: EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung cancer (NSCLC), not progressing following standard 1st-line chemotherapy. Methods: Patients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250 mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11-14.1 months (HR = 0.78) and planned to randomise 598 patients to observe 514 deaths. Results: After inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib (n = 86) and placebo (n = 87) arms were well balanced. After a median follow up of 41 months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4 months, HR 0.83 [95% confidence interval (95% CI) 0.60-1.15]; p = 0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9 months, HR = 0.61, [95% CI 0.45, 0.83]), p = 0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo). Conclusions: Despite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study (NCT00091156).

The role of the (18)F-fluorodeoxyglucose-positron emission tomography scan in the Nederlands Leuvens Longkanker Screenings Onderzoek lung cancer screening trial (Article)

2011-10-01T00:00:00Z

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%.

CT-quantified emphysema in male heavy smokers: Association with lung function decline (Article)

2011-09-01T00:00:00Z

Background: Emphysema and small airway disease both contribute to chronic obstructive pulmonary disease (COPD), a disease characterised by accelerated decline in lung function. The association between the extent of emphysema in male current and former smokers and lung function decline was investigated. Methods: Current and former heavy smokers participating in a lung cancer screening trial were recruited to the study and all underwent CT. Spirometry was performed at baseline and at 3-year follow-up. The 15th percentile (Perc15) was used to assess the severity of emphysema. Results: 2085 men of mean age 59.8 years participated in the study. Mean (SD) baseline Perc15 was -934.9 (19.5) HU. A lower Perc15 value correlated with a lower forced expiratory volume in 1 s (FEV1) at baseline (r=0.12, p<0.001). Linear mixed model analysis showed that a lower Perc15 was significantly related to a greater decline in FEV1 after follow-up (p<0.001). Participants without baseline airway obstruction who developed it after follow-up had significantly lower mean (SD) Perc15 values at baseline than those who did not develop obstruction (-934.2 (17.1) HU vs -930.2 (19.7) HU, p<0.001). Conclusion: Greater baseline severity of CT-detected emphysema is related to lower baseline lung function and greater rates of lung function decline, even in those without airway obstruction. CT-detected emphysema aids in identifying non-obstructed male smokers who will develop airflow obstruction.

Lung cancer screening (Article)

2011-09-01T00:00:00Z

Chairperson's introduction (Article)

2011-09-01T00:00:00Z

Long-term effects of lung cancer computed tomography screening on health-related quality of life: The NELSON trial (Article)

2011-07-01T00:00:00Z

The long-term effects of lung cancer computed tomography (CT) screening on health-related quality of life (HRQoL) have not yet been investigated. In the Dutch-Belgian Randomised Lung Cancer Screening Trial (NELSON trial), 1,466 participants received questionnaires before randomisation (T0), 2 months after baseline screening (screen group only; T1) and at 2-yr follow-up (T2). HRQoL was measured as generic HRQoL (12-item short-form questionnaire and EuroQoL questionnaire), anxiety (Spielberger State-Trait Anxiety Inventory) and lung cancer-specific distress (impact of event scale (IES)). Repeated measures of ANOVA were used to analyse differences between the screen and control groups, and between indeterminate (requiring a follow-up CT) and negative screening result groups. At T0 and T2 there were no significant differences in HRQoL scores over time between the screen and control groups, or between the indeterminate or negative second-round screening result group. There was a temporary increase in IES scores after an indeterminate baseline result (T0: mean 4.0 (95% CI 2.8-5.3); T1: mean 7.8 (95% CI 6.5-9.0); T2: mean 4.5 (95% CI 3.3-5.8)). At 2-yr follow-up, the HRQoL of screened subjects was similar to that of control subjects, the unfavourable short-term effects of an indeterminate baseline screening result had resolved and an indeterminate result at the second screening round had no impact on HRQoL. Copyright

The impact of a lung cancer computed tomography screening result on smoking abstinence (Article)

2011-06-01T00:00:00Z

Receiving a lung cancer computed tomography screening result might be a teachable moment for smoking cessation, but it might also unintentionally reassure smokers to continue smoking. The objective of the present study was to investigate whether test results were associated with smoking abstinence in the Dutch-Belgian Randomised Controlled Lung Cancer Screening Trial (NELSON trial). Two random samples of male smokers who had received either only negative test results (n=550) or one or more indeterminate test result (n=440) were sent a questionnaire 2 yrs after randomisation. Smokers with an indeterminate result reported more quit attempts (p=0.02), but the prolonged abstinence rate in smokers receiving a negative test (46 (8.9%) out of 519 subjects) was comparable with the abstinence rate in smokers with one or more indeterminate results (48 (11.5%) out of 419 subjects) (p=0.19). A statistically insignificant increase was found after one or more indeterminate test result (10.9 and 15.0%, respectively) compared with receiving only negative test results (8.9%) (p=0.26). In conclusion, the outcome of the screening test had no impact on future smoking abstinence in male smokers, although all results suggest more favourable implications after one or more follow-up recommendations. Screening test outcomes could be used as a teachable moment for smoking cessation. Copyright

Ultrafast selective quantification of methotrexate in human plasma by high-throughput MALDI-isotope dilution mass spectrometry (Article)

2011-06-01T00:00:00Z

Background: A new analytical MS method using isotope dilution combined with MALDI-triple quadrupole MS/MS has been developed and validated for the determination of methotrexate and 7-hydroxymethotrexate in plasma. Methotrexate, methotrexate-d3, 7-hydroxymethotrexate and 7-hydroxymethotrexate-d3 were monitored by selected reaction monitoring using the transitions m/z 455.2→308.2, 458.2→311.2, 471.2→324.2 and 474.2→327.2 for methotrexate, methotrexate-d3, 7-hydroxymethotrexate and 7-hydroxymethotrexate- d3, respectively. Results: The LLOQ was 1 nmol/l for methotrexate and 7-hydroxymethotrexate while the limit of detection was 0.3 nmol/l for both analytes. The new developed method was cross-validated by a fluorescence polarization immunoassay and tested for its clinical feasibility by measuring plasma samples from patients suffering from acute lymphoblastic leukemia. Plasma methotrexate concentrations ranged between 66.0 and 954 nmol/l and observed 7-hydroxymethotrexate/methotrexate ratios ranged between 0.1 and 32.4, respectively. Conclusion: The new method showed comparable analytical performances as the fluorescence polarization immunoassay, but analyte specificity and sensitivity of the newly developed method were significantly better.

Lung cancer screening: What is the benefit and what do we do about it? (Article)

2011-03-01T00:00:00Z

Is CT screening for lung cancer ready for prime time? (Article)

2011-02-01T00:00:00Z

Screening and early detection of lung cancer (Article)

2011-01-01T00:00:00Z

Lung cancer with an estimated 342,000 deaths in 2008 (20% of total) is the most common cause of death from cancer, followed by colorectal cancer (12%), breast cancer (8%), and stomach cancer (7%) in Europe. In former smokers, the absolute lung cancer risk remains higher than in never-smokers; these data therefore call for effective secondary preventive measures for lung cancer in addition to smoking cessation programs. This review presents and discusses the most recent advances in the early detection and screening of lung cancer. An overview of randomized controlled computerized tomography-screening trials is given, and the role of bronchoscopy and new techniques is discussed. Finally, the approach of (noninvasive) biomarker testing in the blood, exhaled breath, sputum, and bronchoscopic specimen is reviewed. Copyright

Informed decision making does not affect health-related quality of life in lung cancer screening (NELSON trial) (Article)

2010-12-01T00:00:00Z

Background: It is believed that making an informed decision about (screening) participation is associated with better health-related quality of life (HRQoL) outcomes. This is the first study in cancer screening to explore this association in subjects participating in a lung cancer computed tomography (CT) screening trial. Methods: Participants that made either an informed decision to participate (n = 155) or not (n = 133) were selected for this study. Differences in HRQoL, measured as generic HRQoL (Short Form 12 [SF-12] and EuroQol questionnaire [EQ-5D]), anxiety/distress (State-Trait Anxiety Inventory [STAI-6], Impact of Event Scale [IES] and Consequences of Screening-Lung Cancer [COS-LC]), were tested with Mann-Whitney U tests and ANOVA at three assessment points (when deciding about participation, before trial randomisation and 2 months after receiving the CT result). Results: Subjects who made an informed decision to participate had no better scores than those who did not make an informed decision for 23 out of 24 HRQoL comparisons, except for a better mean score for mental health (Mental Component Summary (MCS) = 53.9 ± 9.2 versus 51.0 ± 10.1, p = 0.003) before randomisation. For subjects with an indeterminate CT result (n = 64), no significant differences were found between subjects with (n = 35) or without (n = 29) an informed decision. Conclusion: Subjects who did not make an informed decision to participate in lung cancer CT screening trial did not experience worse HRQoL during screening than subjects who did make an informed decision, either in general or after receiving an indeterminate result.

A new ultrafast and high-throughput mass spectrometric approach for the therapeutic drug monitoring of the multi-targeted anti-folate pemetrexed in plasma from lung cancer patients (Article)

2010-12-01T00:00:00Z

An analytical assay has been developed and validated for ultrafast and high-throughput mass spectrometric determination of pemetrexed concentrations in plasma using matrix assisted laser desorption/ionization-triple quadrupole-tandem mass spectrometry. Patient plasma samples spiked with the internal standard methotrexate were measured by multiple reaction monitoring. The detection limit was 0.4 fmol/μL, lower limit of quantification was 0.9 fmol/μL, and upper limit of quantification was 60 fmol/μL, respectively. Overall observed pemetrexed concentrations in patient samples ranged between 8.7 (1.4) and 142.7 (20.3)∈pmol/μL (SD). The newly developed mass spectrometric assay is applicable for (routine) therapeutic drug monitoring of pemetrexed concentrations in plasma from non-small cell lung cancer patients.

Pemetrexed and cisplatin with concurrent radiotherapy for locally advanced non-small cell and limited disease small cell lung cancer: Results from 2 phase I studies (Article)

2010-09-01T00:00:00Z

Background: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival. Patients and methods: Treatment naïve patients received 1 cycle of cisplatin 80mg/m2in study I (stage III NSCLC), 75mg/m2in study II (LD-SCLC) and pemetrexed 500mg/m2before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60-80mg/m2), pemetrexed doses (400-500mg/m2) and concurrent escalating radiotherapy doses (66Gy in 33-27 fractions). In study II, patients were treated with cisplatin 75mg/m2and escalating pemetrexed doses (400-500mg/m2) with concurrent escalating radiotherapy doses (50-62Gy). Results: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed. Conclusions: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66. Gy (33 × 2. Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy.

Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer (Article)

2010-09-01T00:00:00Z

As the incidence of stage I non-small cell lung cancer (NSCLC) increases among octogenarians and only selected patients are surgical candidates, an alternative treatment is necessary. This manuscript evaluates the overall survival, local tumor control rate, and treatment-related toxicity after stereotactic body radiotherapy (SBRT) in 38 octogenarians with stage I NSCLC. Treatment consisted of 45. Gy (n= 4) or 60. Gy (n= 25) in 3 fractions for patients with peripheral tumors. A risk adaptive schedule of 45-60. Gy in 3-6 fractions was used for central (n= 7) or large peripheral tumors (n= 2).An overall survival rate of 65% at 1 year and 44% at 2 years was achieved in octogenarians after SBRT. The local tumor control rate was excellent (100% at 2 years) and no grade 4 or 5 treatment-related toxicity occurred. Despite the high incidence of comorbidity in these octogenarians (Charlson score ≥5 in 16% of patients), an approach that merely provides supportive care cannot always be justified. SBRT offers octogenarians with stage I NSCLC a good treatment alternative.

Does participation to screening unintentionally influence lifestyle behaviour and thus lifestyle-related morbidity? (Article)

2010-08-01T00:00:00Z

Cancer is a leading cause of death worldwide and the burden could be reduced by evidence-based strategies for the primary prevention of cancer, the early detection of malignancies and more adequate treatment of cancer patients. Previous research has shown that lifestyle factors are associated with common cancers and that several cancer screening programmes are cost-effective in reducing cancer-specific mortality. But, some recent studies reported that participants of screening programs might unintentionally change their lifestyle. Cancer screening might be a teachable moment or, on the other hand, have a false health certificate effect. Despite that the evidence is scarce, cancer screening might have opportunities for lifestyle improvements, although a possible health certificate effect still remains. Integrated approaches to combine primary and secondary prevention have the potential to optimise the efforts to improve cancer prevention and survival. More research is warranted to investigate evidence-based approaches.

Lung cancer screening and smoking abstinence: 2 Year follow-up data from the Dutch - Belgian randomised controlled lung cancer screening trial (Article)

2010-07-01T00:00:00Z

Background: Lung cancer screening may provide a new opportunity for attempts to quit among smokers or might delay smoking cessation, but studies to date failed to provide evidence for this. This study investigated the effect of lung cancer screening on smoking abstinence in male smokers participating in the Dutch - Belgian randomised controlled lung cancer screening trial (NELSON trial). Methods: In the NELSON trial, 50- to 75-year-old participants at high risk for developing lung cancer were randomised to either lung cancer screening or no screening. Smoking behaviour was evaluated in two random samples of male smokers in the screen (n=641) and control arm (n=643) before (T0) and 2 years after randomisation (T1). In addition, the data were also analysed by intention-to-treat (ITT) analysis, as recommended in smoking cessation intervention trials, although non-response in screening trials can also be due to reasons other than continued smoking. Results: Almost 17% (16.6%) of the trial participants quit smoking, which is higher than the 3-7% found in the general adult population. However, screening was associated with a lower prolonged abstinence rate (14.5%) compared with no screening (19.1%) (OR 1.40, 95% CI 1.01 to 1.92; p<0.05). No stastistically significant difference was found after performing an ITT analysis. Conclusions: This study showed that all trial participants were inclined to stop smoking more than average, which suggests that screening is a teachable moment to improve smoking behaviour. In those who underwent screening the smoking abstinence rate was significantly lower than for the control group, although the difference was modest. After ITT analysis this difference was no longer observed. Clinical trial number: ISRCTN63545820.

Sequencing and quantifying igg fragments and antigen-binding regions by mass spectrometry (Article)

2010-06-01T00:00:00Z

In cancer and autoimmune diseases, immunoglobulins with a specific molecular signature that could potentially be used as diagnostic or prognostic markers are released into body fluids. An immunomics approach based on this phenomenon relies on the ability to identify the specific amino acid sequences of the complementarity-determining regions (CDR) of these immunoglobulins, which in turn depends on the level of accuracy, resolution, and sensitivity that can be achieved by advanced mass spectrometry. Reproducible isolation and sequencing of antibody fragments (e.g., Fab) by high-resolution mass spectrometry (MS) from seven healthy donors revealed 43 217 MS signals: 225 could be associated with CDR1 peptides, 513 with CDR2 peptides, and 19 with CDR3 peptides. Seventeen percent of the 43 217 MS signals did not overlap between the seven donors. The Fab isolation method used is reproducible and fast, with a high yield. It provides only one Fab sample fraction for subsequent characterization by high-resolution MS. In 17% and 4% of these seven healthy donors, qualitative (presence/absence) and quantitative (intensity) differences in Fab fragments could be demonstrated, respectively. From these results, we conclude that the identification of a CDR signature as biomarker for autoimmune diseases and cancer without prior knowledge of the antigen is feasible.

A randomized phase II study comparing two schedules of the 21-day regimen of gemcitabine and carboplatin in advanced non-small cell lung cancer (Article)

2010-06-01T00:00:00Z

Purpose: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m2on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3-4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether toxicity of gemcitabine/carboplatin could be reduced by administering carboplatin on day 8 instead of day 1 without a decrease in response rate (RR). Methods: Patients received gemcitabine 1,250 mg/m2on days 1 and 8, carboplatin AUC 5 on day 1 (arm A) or day 8 (arm B). Drugs were administered over a 21-day cycle. Toxicity and RR were evaluated weekly and every second cycle, respectively. Results: 71 patients were enrolled into the study. We found 79% (95% CI 61-91%) grade 3-4 toxicity (neutropenia and thrombocytopenia) in arm A and 50% (95% CI 32-68%) in arm B; 66% grade 3-4 thrombocytopenia in arm A and 26% in arm B. We observed 30% grade 4 hematological toxicity in arm A and 3% in arm B. In arm A an overall RR of 20% (95% CI 7.7-38.6%) was seen, and 18.2% (95% CI 7-35.5%) in arm B. Conclusions: Although the study was prematurely closed, the current data are of interest. The schedule with carboplatin on day 8 is associated with substantially lower grade 3-4 neutropenia and thrombocytopenia with comparable dose intensity and RR.

Screening for lung cancer with digital chest radiography: Sensitivity and number of secondary work-up CT examinations (Article)

2010-05-01T00:00:00Z

Purpose: To estimate the performance of digital chest radiography for detection of lung cancer. Materials and Methods: The study had ethics committee approval, and a nested case-control design was used and included 55 patients with lung cancer detected at computed tomography (CT) and confirmed with histologic examination and a sample of 72 of 4873 control subjects without nodules at CT. All patients underwent direct-detector digital chest radiography in two projections within 2 months of the screening CT. Four radiologists with varying experience identified and localized potential cancers on chest radiographs by using a confidence scale of level 1 (no lesion) to 5 (definite lesion). Localization receiver operating characteristic (ROC) analysis was performed. On the basis of the assumption that suspicious lesions seen at chest radiography would lead to further work-up with CT, the number of work-up CT examinations per detected cancer (CT examinations per cancer) was calculated at various confidence levels for the screening population (cancer rate in study population, 1.3%). Results: Tumor size ranged from 6.8 to 50.7 mm (median, 11.8 mm). Areas under the localization ROC curve ranged from 0.52 to 0.69. Detection rates substantially varied with the observers' experience and confidence level: At a confidence level of 5, detection rates ranged from 18% at one CT examination per cancer to 53% at 13 CT examinations per cancer. At a confidence level of 2 or higher, detection rates ranged from 94% at 62 CT examinations per cancer to 78% at 44 CT examinations per cancer. Conclusion: A detection rate of 94% for lung tumors with a diameter of 6.8-50.7 mm found at CT screening was achievable with chest radiography only at the expense of a high false-positive rate and an excessive number of work-up CT examinations. Detection performance is strongly observer dependent.

Quality of Life After Stereotactic Radiotherapy for Stage I Non-Small-Cell Lung Cancer (Article)

2010-05-01T00:00:00Z

Purpose: To determine the impact of stereotactic radiotherapy on the quality of life of patients with inoperable early-stage non-small-cell lung cancer (NSCLC). Overall survival, local tumor control, and toxicity were also evaluated in this prospective study. Methods and Materials: From January 2006 to February 2008, quality of life, overall survival, and local tumor control were assessed in 39 patients with pathologically confirmed T1 to 2N0M0 NSCLC. These patients were treated with stereotactic radiotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 and the QLQ LC13 lung cancer-specific questionnaire were used to investigate changes in quality of life. Assessments were done before treatment, at 3 weeks, and at 2, 4, 6, 9, and 12 months after treatment, until death or progressive disease. Toxicity was evaluated using common terminology criteria for adverse events version 3.0. Results: Emotional functioning improved significantly after treatment. Other function scores and QLQ C30 and QLQ LC13 lung symptoms (such as dyspnea and coughing) showed no significant changes. The overall 2-year survival rate was 62%. After a median follow-up of 17 months, 1 patient had a local recurrence (3%). No grade 4 or 5 treatment-related toxicity occurred. Grade 3 toxicity consisted of thoracic pain, which occurred in 1 patient within 4 months of treatment, while it occurred thereafter in 2 patients. Conclusions: Quality of life was maintained, and emotional functioning improved significantly after stereotactic radiotherapy for stage I NSCLC, while survival was acceptable, local tumor control was high, and toxicity was low.

Comparing coronary artery calcium and thoracic aorta calcium for prediction of all-cause mortality and cardiovascular events on low-dose non-gated computed tomography in a high-risk population of heavy smokers (Article)

2010-04-01T00:00:00Z

Background: Coronary artery calcium (CAC) and thoracic aorta calcium (TAC) can be detected simultaneously on low-dose, non-gated computed tomography (CT) scans. CAC has been shown to predict cardiovascular (CVD) and coronary (CHD) events. A comparable association between TAC and CVD events has yet to be established, but TAC could be a more reproducible alternative to CAC in low-dose, non-gated CT. This study compared CAC and TAC as independent predictors of all-cause mortality and cardiovascular events in a population of heavy smokers using low-dose, non-gated CT. Methods: Within the NELSON study, a population-based lung cancer screening trial, the CT screen group consisted of 7557 heavy smokers aged 50-75 years. Using a case-cohort study design, CAC and TAC scores were calculated in a total of 958 asymptomatic subjects who were followed up for all-cause death, and CVD, CHD and non-cardiac events (stroke, aortic aneurysm, peripheral arterial occlusive disease). We used Cox proportional-hazard regression to compute hazard ratios (HRs) with adjustment for traditional cardiovascular risk factors. Results: A close association between the prevalence of TAC and increasing levels of CAC was established (p<0.001). Increasing CAC and TAC risk categories were associated with all-cause mortality (p for trend=0.01 and 0.001, respectively) and CVD events (p for trend <0.001 and 0.03, respectively). Compared with the lowest quartile (reference category), multivariate-adjusted HRs across categories of CAC were higher (all-cause mortality, HR: 9.13 for highest quartile; CVD events, HR: 4.46 for highest quartile) than of TAC scores (HR: 5.45 and HR: 2.25, respectively). However, TAC is associated with non-coronary events (HR: 4.69 for highest quartile, p for trend=0.01) and CAC was not (HR: 3.06 for highest quartile, p for trend=0.40). Conclusions: CAC was found to be a stronger predictor than TAC of all-cause mortality and CVD events in a high-risk population of heavy smokers scored on low-dose, non-gated CT. TAC, however, is stronger associated with non-cardiac events than CAC and could prove to be a preferred marker for these events.

Pulmonary ground-glass nodules: Increase in mass as an early indicator of growth (Article)

2010-04-01T00:00:00Z

Purpose: To compare manual measurements of diameter, volume, and mass of pulmonary ground-glass nodules (GGNs) to establish which method is best for identifying malignant GGNs by determining change across time. Materials and Methods: In this ethics committee - approved retrospective study, baseline and follow-up CT examinations of 52 GGNs detected in a lung cancer screening trial were included, resulting in 127 GGN data sets for evaluation. Two observers measured GGN diameter with electronic calipers, manually outlined GGNs to obtain volume and mass, and scored whether a solid component was present. Observer 1 repeated all measurements after 2 months. Coefficients of variation and limits of agreement were calculated by using Bland-Altman methods. In a subgroup of GGNs containing all resected malignant lesions, the ratio between intraobserver variability and growth (growth-to-variability ratio) was calculated for each measurement technique. In this subgroup, the mean time for growth to exceed the upper limit of agreement of each measurement technique was determined. Results: The κ values for intra- and interobserver agreement for identifying a solid component were 0.55 and 0.38, respectively. Intra- and interobserver coefficients of variation were smallest for GGN mass ( P<.001). Thirteen malignant GGNs were resected. Mean growth-to-variability ratios were 11, 28, and 35 for diameter, volume, and mass, respectively ( P = .03); mean times required for growth to exceed the upper limit of agreement were 715, 673, and 425 days, respectively ( P = .02). Conclusion: Mass measurements can enable detection of growth of GGNs earlier and are subject to less variability than are volume or diameter measurements.

Pulmonary ground-glass nodules: Increase in mass as an early indicator of growth (Article)

2010-04-01T00:00:00Z

The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema (Article)

2010-03-01T00:00:00Z

Rationale: Genome-wide association studies have identified genetic variants in the nicotinic acetylcholine receptor (nAChR) on chromosome 15q24/25 as a risk for nicotine dependence, lung cancer, and chronic obstructive pulmonary disease (COPD). Assessment of bronchial obstruction by spirometry, typically used for diagnosing COPD, fails, however, to detect emphysema. Objectives: To determine the association of the 15q24/25 locus with emphysema. Methods: The rs1051730 variant on 15q24/25 was genotyped in two independent white cohorts of 661 and 456 heavy smokers. Participants underwent pulmonary function tests and computed tomography (CT) of the chest, and took questionnaires assessing smoking behavior and health status. Measurements and Main Results: The rs1051730 A-allele correlated with reduced FEV1 and with increased susceptibility for bronchial obstruction with a pooled odds ratio (OR) of 1.33 (95% confidence interval [CI] = 1.11-1.61; P = 0.0026). In both studies a correlation between the rs1051730 A-allele and lung diffusing capacity (DLCO) and diffusing capacity per unit alveolar volume (KCO) was observed. Consistently, the rs1051730 A-allele conferred increased risk for emphysema as assessed by CT (P = 0.0097 and P = 0.019), with a pooledORof 1.39 (CI = 1.15-1.68; P = 0.00051). Visualemphysema scores and scores based on densities quantified on CT were more pronounced in A-allele carriers, indicating that rs1051730 correlates with the severity of emphysema. Conclusions: The 15q24/25 locus in nAChR is associated with the presence and severity of emphysema. This association was independent of pack-years smoking, suggesting that nAChR is causally involved in alveolar destruction as a potentially shared pathogenic mechanism in lung cancer and COPD.

The authors reply (Article)

2010-01-01T00:00:00Z

Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON) (Article)

2010-01-01T00:00:00Z

Background: In lung cancer CT screening, participants often have an indeterminate screening result at baseline requiring a follow-up CT. In subjects with either an indeterminate or a negative result after screening, we investigated whether health-related quality of life (HRQoL) changed over time and differed between groups in the short term.Methods: A total of 733 participants in the NELSON trial received four questionnaires: T0, before randomisation; T1, 1 week before the baseline screening; T2, 1 day after the screening; and T3, 2 months after the screening results but before the 3-month follow-up CT. HRQoL was measured as generic HRQoL (the 12-item Short Form, SF-12; the EuroQol questionnaire, EQ-5D), anxiety (the Spielberger State-Trait Anxiety Inventory, STAI-6), and lung-cancer-specific distress (the Impact of Event Scale, IES). For analyses, repeated-measures analysis of variance was used, adjusted for covariates.Results: Response to each questionnaire was 88% or higher. Scores on SF-12, EQ-5D, and STAI-6 showed no clinically relevant changes over time. At T3, IES scores that were clinically relevant increased after an indeterminate result, whereas these scores showed a significant decrease after a negative result. At T3, differences in IES scores between the two baseline result groups were both significant and clinically relevant (P<0.01).Conclusion: This longitudinal study among participants of a lung cancer screening programme showed that in the short term recipients of an indeterminate result experienced increased lung-cancer-specific distress, whereas the HRQoL changes after a negative baseline screening result may be interpreted as a relief.

Volumetric measurement of pulmonary nodules at low-dose chest CT: Effect of reconstruction setting on measurement variability (Article)

2010-01-01T00:00:00Z

Objective: To assess volumetric measurement variability in pulmonary nodules detected at low-dose chest CT with three reconstruction settings. Methods: The volume of 200 solid pulmonary nodules was measured three times using commercially available semi-automated software of low-dose chest CT data-sets reconstructed with 1 mm section thickness and a soft kernel (A), 2 mm and a soft kernel (B), and 2 mm and a sharp kernel (C), respectively. Repeatability coefficients of the three measurements within each setting were calculated by the Bland and Altman method. A three-level model was applied to test the impact of reconstruction setting on the measured volume. Results: The repeatability coefficients were 8.9, 22.5 and 37.5% for settings A, B and C. Three-level analysis showed that settings A and C yielded a 1.29 times higher estimate of nodule volume compared with setting B (P=0.03). The significant interaction among setting, nodule location and morphology demonstrated that the effect of the reconstruction setting was different for different types of nodules. Low-dose CT reconstructed with 1 mm section thickness and a soft kernel provided the most repeatable volume measurement. Conclusion: A wide, nodule-type-dependent range of agreement between volume measurements with different reconstruction settings suggests strict consistency is required for serial CT studies.

Distribution of emphysema in heavy smokers: Impact on pulmonary function (Article)

2010-01-01T00:00:00Z

Purpose: To investigate impact of distribution of computed tomography (CT) emphysema on severity of airflow limitation and gas exchange impairment in current and former heavy smokers participating in a lung cancer screening trial. Materials and Methods: In total 875 current and former heavy smokers underwent baseline low-dose CT (30 mAs) in our center and spirometry and diffusion capacity testing on the same day as part of the Dutch-Belgian Lung Cancer Screening Trial (NELSON). Emphysema was quantified for 872 subjects as the number of voxels with an apparent lowered X-ray attenuation coefficient. Voxels attenuated <-950 HU were categorized as representing severe emphysema (ES950), while voxels attenuated between -910 HU and -950 HU represented moderate emphysema (ES910). Impact of distribution on severity of pulmonary function impairment was investigated with logistic regression, adjusted for total amount of emphysema. Results: For ES910 an apical distribution was associated with more airflow obstruction and gas exchange impairment than a basal distribution (both p < 0.01). The FEV1/FVC ratio was 1.6% (95% CI 0.42% to 2.8%) lower for apical predominance than for basal predominance, for Tlco/VAthe difference was 0.12% (95% CI 0.076-0.15%). Distribution of ES950 had no impact on FEV1/FVC ratio, while an apical distribution was associated with a 0.076% (95% CI 0.038-0.11%) lower Tlco/VA(p < 0.001). Conclusion: In a heavy smoking population, an apical distribution is associated with more severe gas exchange impairment than a basal distribution; for moderate emphysema it is also associated with a lower FEV1/FVC ratio. However, differences are small, and likely clinically irrelevant.

Management of lung nodules detected by volume CT scanning (Article)

2009-12-03T00:00:00Z

BACKGROUND: The use of multidetector computed tomography (CT) in lung-cancer screening trials involving subjects with an increased risk of lung cancer has highlighted the problem for the clinician of deciding on the best course of action when noncalcified pulmonary nodules are detected by CT. METHODS: A total of 7557 participants underwent CT screening in years 1, 2, and 4 of a randomized trial of lung-cancer screening. We used software to evaluate a noncalcified nodule according to its volume or volume-doubling time. Growth was defined as an increase in volume of at least 25% between two scans. The first-round screening test was considered to be negative if the volume of a nodule was less than 50 mm3, if it was 50 to 500 mm3 but had not grown by the time of the 3-month follow-up CT, or if, in the case of those that had grown, the volume-doubling time was 400 days or more. RESULTS: In the first and second rounds of screening, 2.6% and 1.8% of the participants, respectively, had a positive test result. In round one, the sensitivity of the screen was 94.6% (95% confidence interval [CI], 86.5 to 98.0) and the negative predictive value 99.9% (95% CI, 99.9 to 100.0). In the 7361 subjects with a negative screening result in round one, 20 lung cancers were detected after 2 years of follow-up. CONCLUSIONS: Among subjects at high risk for lung cancer who were screened in three rounds of CT scanning and in whom noncalcified pulmonary nodules were evaluated according to volume and volume-doubling time, the chances of finding lung cancer 1 and 2 years after a negative first-round test were 1 in 1000 and 3 in 1000, respectively. (Current Controlled Trials number, ISRCTN63545820.). Copyright

Oral UFT, etoposide and leucovorin in recurrent non-small cell lung cancer: A non-randomized phase II study (Article)

2009-12-01T00:00:00Z

Background: Oral treatment regimens with few side effects are appealing in the 2nd or 3rd line treatment of non-small cell lung cancer (NSCLC) patients. Purpose: The aim was to investigate the efficacy and toxicity of the oral combination etoposide, Uracil-Tegafur (UFT) and leucovorin in 2nd or 3rd line in Caucasian patients with advanced NSCLC. Methods: Etoposide 50 mg/m2, UFT 250 mg/m2and leucovorin 90 mg (fixed dose) were dosed in 3 gifts approximately 8 h apart for 14 days followed by 1 week rest every 3 weeks until progressive disease (PD). Primary endpoint was response rate (RR), secondary endpoints toxicity and time to progression (TTP). Results: The median number of cycles was 3.5 (95% CI 2-5); 9 patients received ≥6 cycles, 4 > 10 cycles. The median dose intensities for etoposide and UFT were 223 mg/m2/week (95% CI 213-232) and 1092 mg/m2/week (95% CI 1032-1167), the relative dose intensities 92% and 90%, respectively. Grade 3/4 neutropenia was observed in 12% (4/32), grade 3/4 thrombocytopenia in 15% (5/32), without febrile neutropenia. Non-hematological toxicity grade 3 included hepatic toxicity (6%), lethargy (15%), diarrhea (3%) and nausea (3%). One patient developed grade 4 arterial ischemia. Fourteen percent (95% CI 4-33%) (4/28) had a confirmed partial response, 57% (95% CI 44-81%) (16/28) stable disease and 28% (95% CI 19-56%) (8/28) progressive disease. The median TTP was 3 months (95% CI 1.3-4.4), the median overall survival 6.7 months (95% CI 4.0-9.3). Conclusion: The combination of UFT, etoposide and leucovorin is active in 2nd or 3rd line therapy of Caucasian NSCLC patients and because of its favourable toxicity profile this treatment warrants further investigation.

Nitric oxide diffusing capacity versus spirometry in the early diagnosis of emphysema in smokers (Article)

2009-12-01T00:00:00Z

The diffusion capacity for nitric oxide (DLNO) is independent of pulmonary capillary blood volume and equals the membrane diffusing capacity. Therefore the DLNO could be more sensitive in detecting alveolar destruction than the DLCO. We measured flow-volumes curves, DLNO, DLCO, the transfer coefficients KNO (DLNO/VA) and KCO (DLCO/VA) and performed computed tomography (CT) scans in 263 randomly selected heavy smokers. Subjects with areas ≥1% of the total lung volume showing an attenuation <-950 Hounsfield Units were considered to have emphysema. In 36 subjects emphysema was diagnosed with CT, a low KNO was present in 94 subjects, and in 95 subjects a FEV1/FVC ratio <70% was seen. The area under the ROC curve for detection CT-based emphysema was 0.894 for the KNO, 0.822 for the KCO and 0.795 for FEV1/FVC, meaning that the KNO has a slightly higher sensitivity to detect emphysema than the KCO and FEV1/FVC. The positive predictive value of KNO however was low (34.7%), while the negative predictive value of KNO was very high (98.2%), indicating an emphysema exclusion test. The DLNO/DLCO ratio is significantly higher in the study group compared to normal subjects.

Non-cross resistant sequential single agent chemotherapy in first-line advanced non-small cell lung cancer patients: Results of a phase II study (Article)

2009-12-01T00:00:00Z

Background. sequential chemotherapy can maintain dose intensity and preclude cumulative toxicity by increasing drug diversity. Purpose. to investigate the toxicity and efficacy of the sequential regimen of gemcitabine followed by paclitaxel in first line advanced stage non-small cell lung cancer (NSCLC) patients with good performance status (PS). Patients and methods. gemcitabine 1250mg/m2was administered on day 1 and 8 of course 1 and 2; Paclitaxel 150mg/m2on day 1 and 8 of course 3 and 4. Primary endpoint was response rate (RR), secondary endpoints toxicity and time to progression (TTP). Results. Of the 21 patients (median age 56, range 38-80 years; 62 males, 38 females) 10 (2/21) had stage IIIB, 90 (19/21) stage IV, 15% PS 0, 85 PS 1. 20 of patients had a partial response, 30 stable disease, 50 progressive disease. Median TTP was 12 weeks (range 6-52 weeks), median overall survival (OS) 8 months (range 1-27 months), 1-year survival was 33. One patient had grade 3 hematological toxicity, 2 patients a grade 3 peripheral neuropathy. Conclusions. sequential administration of gemcitabine followed by paclitaxel in first line treatment of advanced NSCLC had a favourable toxicity profile, a median TTP and OS comparable with other sequential trials and might, therefore, be a treatment option for NSCLC patients with high ERCC1 expression.

Lung cancer screening with low dose computed tomography: Where do we stand today? (Article)

2009-09-01T00:00:00Z

Informed participation in a randomised controlled trial of computed tomography screening for lung cancer (Article)

2009-09-01T00:00:00Z

The actual lung cancer (screening) knowledge, attitudes, risk perceptions, reasons to participate in or decline participation, and informed decisions of subjects who decided to or decided not to participate in the Dutch-Belgian randomised controlled trial for lung cancer screening in high-risk subjects (the NELSON trial) were evaluated. A total of 2,500 high-risk subjects were asked to complete a questionnaire 3 weeks after they had received a brochure with information about the trial. Differences in knowledge, attitude and risk perception between participants and nonparticipants were analysed with logistic regression analyses adjusted for sex and smoking status. The questionnaire response of trial participants was 80% (n=889) whereas the response of nonparticipants was low (7%, n=97) and selective. Participants' responses to knowledge items on lung cancer as a disease were on average more often correct (mean±SD 68±17%) than items on lung cancer screening (49±29%). Participants had adequate knowledge on lung cancer screening (51%) more often than the nonparticipants (38%; p=0.009). Of the decisions regarding participation, 49% were uninformed, mainly due to insufficient knowledge. Most of the participants (99%) and 64% of the nonparticipants had a positive attitude towards lung cancer screening. Additional efforts are required to improve the knowledge and understanding of subjects who are in the process of decision-making regarding participation in a lung cancer screening trial. Copyright

Role of baseline nodule density and changes in density and nodule features in the discrimination between benign and malignant solid indeterminate pulmonary nodules (Article)

2009-06-01T00:00:00Z

Purpose: To retrospectively evaluate whether baseline nodule density or changes in density or nodule features could be used to discriminate between benign and malignant solid indeterminate nodules. Materials and methods: Solid indeterminate nodules between 50 and 500 mm3(4.6-9.8 mm) were assessed at 3 and 12 months after baseline lung cancer screening (NELSON study). Nodules were classified based on morphology (spherical or non-spherical), shape (round, polygonal or irregular) and margin (smooth, lobulated, spiculated or irregular). The mean CT density of the nodule was automatically generated in Hounsfield units (HU) by the Lungcare©software. Results: From April 2004 to July 2006, 7310 participants underwent baseline screening. In 312 participants 372 solid purely intra-parenchymal nodules were found. Of them, 16 (4%) were malignant. Benign nodules were 82.8 mm3(5.4 mm) and malignant nodules 274.5 mm3(8.1 mm) (p = 0.000). Baseline CT density for benign nodules was 42.7 HU and for malignant nodules -2.2 HU (p = ns). The median change in density for benign nodules was -0.1 HU and for malignant nodules 12.8 HU (p < 0.05). Compared to benign nodules, malignant nodules were more often non-spherical, irregular, lobulated or spiculated at baseline, 3-month and 1-year follow-up (p < 0.0001). In the majority of the benign and malignant nodules there was no change in morphology, shape and margin during 1 year of follow-up (p = ns). Conclusion: Baseline nodule density and changes in nodule features cannot be used to discriminate between benign and malignant solid indeterminate pulmonary nodules, but an increase in density is suggestive for malignancy and requires a shorter follow-up or a biopsy.

Pre-operative pulmonary evaluation of lung cancer patients: A review of the literature (Article)

2009-05-01T00:00:00Z

Complete anatomical resection of the primary tumour is still the standard of care in patients with early stage lung cancer. Because these patients are usually smokers who also suffer from chronic obstructive pulmonary disease, regional differences in pulmonary function due to lung tissue destruction exist. he purpose of the present article is to evaluate the currently available guidelines and to discuss novel methods for the pre-operative functional and anatomical pulmonary evaluation in lung cancer patients. espite the fact that knowledge on the pre-operative evaluation of the pulmonary function has substantially increased during the past decade, the majority of the studies are small, underpowered and, with exception of a proposed algorithm, not prospectively validated in independent cohorts.The future harmonisation of guidelines is required and novel imaging techniques should be incorporated in the pre-operative evaluation in chronic obstructive pulmonary disease patients with borderline pulmonary function. Copyright

Stem cells and the natural history of lung cancer: Implications for lung cancer screening (Article)

2009-04-01T00:00:00Z

Lung cancer is not simply a single disease, but a collection of several phenotypically very diverse and regionally distinct neoplasias. Its natural history is complex and not yet fully understood. Stem cells and the complex interaction with the microenvironment of the tumor and the immune system play an important role in tumor progression and metastasizing capacity. This finding explains why lung cancer does not always follow the multistep carcinogenetic and exponential growth model and why small lesions do not always equate to early-stage disease. Despite the fact that volume doubling times are increasingly used as surrogate markers for the natural history of lung cancer and as estimates for the proportion of overdiagnosed cases, it is only a momentary impression. At baseline screening especially, screen-detected lung cancer cases are preferably detected when they are in the indolent phase of their growth curve (length-biased sampling), from which it can by no means be concluded that they may not progress or metastasize at a later stage. Because the natural history of lung cancer is only partly elucidated, conclusions on the impact of overdiagnosis in lung cancer screening are premature.

Limited contamination in the Dutch-Belgian randomized lung cancer screening trial (NELSON) (Article)

2009-01-01T00:00:00Z

Purpose of this study was to determine the rate of contamination, defined as lung cancer screening in the control arm, of the Dutch-Belgian randomized lung cancer screening trial (NELSON) as contamination adversely affects the power of a trial. The NELSON cohort includes 15,822 high-risk current and former smokers, aged 50-75 years, equally randomized to the screen and control arm. Questionnaires were sent to a sample of 1460 male subjects of the control arm, stratified on smoking determinants. The response rate was 73.0%. The participants were asked whether they received a chest X-ray or CT scan in the last 4 years and, if so, when and for what reason it had been performed. Examinations performed after randomization because of "Precaution" or "No examination was offered by NELSON" were regarded as contamination. In the first 24 months after randomization 3.1% (2.3-3.8%) of the respondents received a lung cancer screening examination. Contamination reached a non-significant peak within the first 3 months after randomization, with a lower limit of 2.5 and an upper limit of 3.1 per 1000 person-months. This screening rate did not differ from the background rates in the last 18 months before randomization. No significant differences were observed between current and former smokers. In conclusion, the rate of contamination among male subjects of the control arm of the NELSON trial is low and is not likely to jeopardize the power of the trial.

Smooth or attached solid indeterminate nodules Detected at baseline CT screening in the NELSON study: Cancer risk during 1 year of follow-up (Article)

2009-01-01T00:00:00Z

Purpose: To retrospectively determine whether baseline nodule characteristics at 3-month and 1-year volume doubling time (VDT) are predictive for lung cancer in solid indeterminate noncalcified nodules (NCNs) detected at baseline computed tomographic (CT) screening. Materials and Methods: The study, conducted between April 2004 and May 2006, was institutional review board approved. Patient consent was waived for this retrospective evaluation. NCNs between 5 and 10 mm in diameter (n = 891) were evaluated at 3 months and 1 year to assess growth (VDT < 400 days). Baseline assessments were related to growth at 3 months and 1 year by using x2and Mann-Whitney U tests. Baseline assessments and growth were related to the presence of malignancy by using univariate and multivariate logistic regression analyses. Results: At 3 months and at 1 year, 8% and 1% of NCNs had grown, of which 15% and 50% were malignant, respectively. One-year growth was related to morphology (P < .01), margin (P < .0001), location (P < .001), and size (P < .01). All cancers were nonspherical and purely intra-parenchymal, without attachment to vessels, the pleura, or fissures. In nonsmooth unattached nodules, a volume of 130 mm3or larger was the only predictor for malignancy (odds ratio, 6.3; 95% confidence interval [CI]: 1.7, 23.0). After the addition of information on the 3-month VDT, large volume (odds ratio, 4.9; 95% CI: 1.2, 20.1) and 3-month VDT (odds ratio, 15.6; 95% CI: 4.5, 53.5) helped predict malignancy. At 1 year, only the 1-year growth remained (odds ratio, 213.3; 95% CI: 18.7, 2430.9) as predictor for malignancy. Conclusion: In smooth or attached solid indeterminate NCNs, no malignancies were found at 1-year follow-up. In nonsmooth purely intraparenchymal NCNs, size is the main baseline predictor for malignancy. When follow-up data are available, growth is a strong predictor for malignancy, especially at 1-year follow-up.

High affective risk perception is associated with more lung cancer-specific distress in CT screening for lung cancer (Article)

2008-12-01T00:00:00Z

Screening for cancer can cause distress. People who perceive their risk of cancer as high may be more vulnerable to distress. This study evaluated whether participants of a lung cancer Computed Tomography (CT) screening trial with a high affective risk perception of developing lung cancer had a higher level of lung cancer-specific distress during CT screening. Furthermore, we evaluated whether participants perceived their risk of developing lung cancer differently 6 months after screening compared with 1 day before screening. A total of 351 subsequent participants of the NELSON-trial (Dutch-Belgian randomized controlled trial for lung cancer screening in high-risk subjects), who were randomized to the screen arm, were asked to fill in questionnaires 1 day before and 6 months after screening. Lung cancer-specific distress (Impact of Event Scale (IES)), generic health-related quality of life (SF-12) and affective risk perception were assessed. One day before screening, the participants with a high affective risk perception (n = 47/321, 14.6%) had significantly higher (i.e., worse) median IES scores than participants with a low affective risk perception (11.5 vs. 2.0, p < 0.01). Although median IES scores were significantly lower 6 months after screening than 1 day before screening, participants with a high affective risk perception still showed significantly higher IES scores than participants with a low affective risk perception (6.5 vs. 1.0, p < 0.01). Six months after screening, significantly less participants (10.5%) felt that their risk of developing lung cancer was high than 1 day before screening (14.5%) (p < 0.01). Levels of distress were not severe, but were elevated compared to participants with a low affective risk perception, and therefore, attention for this group is recommended.

Limited value of shape, margin and CT density in the discrimination between benign and malignant screen detected solid pulmonary nodules of the NELSON trial (Article)

2008-11-01T00:00:00Z

Purpose: To evaluate prospectively the value of size, shape, margin and density in discriminating between benign and malignant CT screen detected solid non-calcified pulmonary nodules. Material and methods: This study was institutional review board approved. For this study 405 participants of the NELSON lung cancer screening trial with 469 indeterminate or potentially malignant solid pulmonary nodules (>50 mm3) were selected. The nodules were classified based on size, shape (round, polygonal, irregular) and margin (smooth, lobulated, spiculated). Mean nodule density and nodule volume were automatically generated by software. Analyses were performed by univariate and multivariate logistic regression. Results were presented as likelihood ratios (LR) with 95% confidence intervals (CI). Receiver operating characteristic analysis was performed for mean density as predictor for lung cancer. Results: Of the 469 nodules, 387 (83%) were between 50 and 500 mm3, 82 (17%) >500 mm3, 59 (13%) malignant, 410 (87%) benign. The median size of the nodules was 103 mm3(range 50-5486 mm3). In multivariate analysis lobulated nodules had LR of 11 compared to smooth; spiculated nodules a LR of 7 compared to smooth; irregular nodules a LR of 6 compared to round and polygonal; volume a LR of 3. The mean nodule CT density did not predict the presence of lung cancer (AUC 0.37, 95% CI 0.32-0.43). Conclusion: In solid non-calcified nodules larger than 50 mm3, size and to a lesser extent a lobulated or spiculated margin and irregular shape increased the likelihood that a nodule was malignant. Nodule density had no discriminative power.

Effect of nodule characteristics on variability of semiautomated volume measurements in pulmonary nodules detected in a lung cancer screening program (Article)

2008-08-01T00:00:00Z

Purpose: To retrospectively assess volume measurement variability in solid pulmonary nodules (volume, 15-500 mm3) detected at lung cancer screening and to quantify the independent effects of nodule morphology, size, and location. Materials and Methods: This retrospective study was a substudy of the screening program that was approved by the Dutch Ministry of Health, and all participants provided written informed consent. Two independent readers used semiautomated software to measure the volume of pulmonary nodules detected in 6774 participants aged 50-75 years (5917 men). Nodules were classified according to their location (purely intraparenchymal, pleural based, juxtavascular, or fissure attached), morphology (smooth, polylobulated, spiculated, or irregular), and size (<50 mm3or >50 mm3). The level of agreement was expressed by using the absolute values of the relative volume differences (RVDs). Multivariate logistic regression analysis was performed, and odds ratios (ORs) were computed to quantify the independent effects of morphology, location, and size on RVD categories. Results: Altogether, 4225 nodules in 2239 participants were included. Complete agreement in volume was obtained for 3646 (86%) of the nodules. Disagreement was small (absolute value of RVD < 5%) for 173 (4%) nodules, moderate (absolute value of RVD ≥ 5% but < 15%) for 232 (6%), and large (absolute value of RVD ≥ 15%) for 174 (4%). Multivariate analysis showed that the ORs of volume disagreement were 15.7, 3.1, and 1.9 for irregular, spiculated, and polylobulated nodules, respectively; 3.5, 2.6, and 2.1 for juxtavascular, pleural-based, and fissure-attached nodules, respectively; and 1.3 for large nodules compared with smooth, purely intraparenchymal, and small reference nodules. Conclusion: Nodule morphology, location, and size influence volume measurement variability, particularly for juxtavascular and irregular nodules.

Impact of computed tomography screening for lung cancer on participants in a randomized controlled trial (NELSON trial) (Article)

2008-07-15T00:00:00Z

BACKGROUND. Computed tomography (CT) screening is an important new tool for the early detection of lung cancer. In the current study, the authors assessed the discomfort associated with CT scanning and the subsequent wait for results and health-related quality of life (HRQoL) over time. METHODS. A total of 351 participants in the Dutch-Belgian randomized controlled trial for lung cancer screening in high-risk subjects (the NELSON trial) who had an appointment for a baseline CT scan were asked to complete questionnaires regarding their experienced discomfort and HRQoL before, 1 day after, and approximately 6 months after the CT scan. HRQoL was measured as generic HRQoL (12-item Short Form [SF-12] and EuroQol questionnaire [EQ-5D]), generic anxiety (State-Trait Anxiety Inventory [STAI-6]), and lung cancer-specific distress (Impact of Event Scale [IES]). Approximately 76.9% of the participants completed all 3 questionnaires. RESULTS. Approximately 87% to 99% of participants reported experiencing no discomfort related to the CT scan. The median SF-12, EQ-5D, STAI-6, and IES scores did not appear to change relevantly over time. Approximately 46.0% and 51.3%, respectively, of the participants reported discomfort in connection with having to wait for the results of the CT scan and dreading those results. These patients had relevantly higher STAI-6 and IES scores (P < .01) (unfavorable) at all 3 assessments. CONCLUSIONS. The current evaluation of the potential adverse effects of CT screening for lung cancer on HRQoL demonstrated no negative effects. However, waiting for the CT scan results was reported to be discomforting by approximately half of the participants. Minimizing the waiting time for the test results is merefore recommended.

Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: Results of an international expanded access program (Article)

2008-07-01T00:00:00Z

Introduction:: Pemetrexed has established efficacy, and is the backbone for chemotherapy in patients with malignant pleural mesothelioma (MPM). An International Expanded Access Program provided >3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed plus platinum analogs (cisplatin or carboplatin) in 13 countries. In this article, we report the safety and efficacy data of MPM patients who were treated with single-agent pemetrexed (n = 812). Methods:: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed (500 mg/m) once (day 1) every 21 days with standard premedication and vitamin supplementation. Investigator-determined response and survival data were recorded at the end of study participation. Myelosuppression data were also collected. Results:: All 812 MPM patients (319 chemonaïve; 493 pretreated) received single-agent pemetrexed (≥1 dose) and were evaluated for safety. A total of 643 patients (247 chemonaïve, 396 pretreated) were evaluated for efficacy. Of the chemonaïve patients evaluated for efficacy (n = 247), the overall response rate was 10.5%, median time to progressive disease (TTPD) was 6.0 months, and median survival was 14.1 month. Of the pretreated patients evaluated for efficacy (n = 396), the overall response rate was 12.1%, median TTPD was 4.9 months, and the median survival was not estimable due to high censoring. Common terminology criteria grade 3/4 hematologic toxicity was mild in both groups, with neutropenia (<18%) as the main toxicity. Conclusions:: In the present expanded access program, single-agent pemetrexed demonstrated promising activity in MPM in both chemonaïve and pretreated patients, with TTPD of 6.0 and 4.9 months, respectively, 1-year survival ≥54.7%, and mild hematologic toxicity. Copyright

How to deal with incidentally detected pulmonary nodules less than 10 mm in size on CT in a healthy person (Article)

2008-05-01T00:00:00Z

The high frequency of non-calcified pulmonary nodules (NCN) <10 mm incidentally detected on a multi-detector CT (MDCT) of the chest raises the question of how clinicians and radiologists should deal with these nodules. Management algorithms for solitary pulmonary nodules >10 mm do not carry across to sub-centimeter lesions. Purpose of this review is to provide a 10-step approach for routinely detected sub-centimeter NCN on a MDCT in healthy persons in order to be able to make an optimal discrimination between benign and malignant NCNs. Recommendations are primarily based on individual cancer risk, the presence or absence of calcifications and nodule size. In nodules >4-5 mm nodule consistency, margin and shape should be taken into account. Next steps in the nodule evaluation are the assessment of localization, nodule number, presence or absence of growth and volume doubling time. Growth is defined as a volume doubling time of 400 days or less, based on volumetry. For nodules <4 mm, a follow-up CT at 12 months is recommended in high risk persons, whilst for low-risk persons no follow-up is needed. If no growth is observed at 12 months, no further follow-up is required. For solid, smooth or attached indeterminate NCN between 5 and 10 mm we recommend an annual repeat scan, whilst for purely intra-parenchymal nodules a 3-month repeat scan should be made to assess growth. Growing lesions with a volume doubling time <400 days require further work-up and diagnosis, otherwise an annual repeat scan to assess growth is recommended.

Response (Article)

2008-04-01T00:00:00Z

Monitoring of smoking-induced emphysema with CT in a lung cancer screening setting: Detection of real increase in extent of emphysema (Article)

2007-09-01T00:00:00Z

Purpose: To retrospectively establish the minimum increase in emphysema score (ES) required for detection of real increased extent of emphysema with 95% confidence by using multi-detector row computed tomography (CT) in a lung cancer screening setting. Materials and Methods: The study was a substudy of the NELSON project that was approved by the Dutch Ministry of Health and the ethics committee of each participating hospital, with patient informed consent. For this substudy, original approval and informed consent allowed use of data for future research. Among 1684 men screened with low-dose multi-detector row CT (30 mAs, 16 detector rows, 0.75-mm section thickness) between April 2004 and March 2005, only participants who underwent repeat multi-detector row CT with the same scanner after 3 months because of an indeterminate pulmonary nodule were included. Extent of emphysema was considered to remain stable in this short period. Extent of low-attenuation areas representing emphysema was computed for repeat and baseline scans as percentage of lung volume below three attenuation threshold values (-910 HU, -930 HU, -950 HU). Limits of agreement were determined with Bland-Altman approach; upper limits were used to deduce the minimum increase in ES required for detecting increased extent of emphysema with 95% probability. Factors influencing the limits of agreement were determined. Results: In total, 157 men (mean age, 60 years) were included in the study. Limits of agreement for differences in total lung volume between repeat and baseline scans were -13.4% to +12.6% at -910 HU, -4.7% to +4.2% at -930 HU, and -1.3% to +1.1% at -950 HU. Differences in ES showed weak to moderate correlation with variation in level of inspiration (r = 0.20-0.49, P < .05). Scanner calibration could be excluded as a factor contributing to variation in ES. Conclusion: Increase in ES required to detect increased extent of smoking-related emphysema with 95% probability varies between 1.1% of total lung volume at -950 HU and 12.6% at -910 HU for low-dose multi-detector row CT.

Neglectable benefit of searching for incidental findings in the Dutch-Belgian lung cancer screening trial (NELSON) using low-dose multidetector CT (Article)

2007-06-01T00:00:00Z

The purpose of this study was to prospectively determine the frequency and spectrum of incidental findings (IFs) and their clinical implications in a high risk population for lung cancer undergoing low-dose multidetector computed tomography (MDCT) screening for lung cancer. Scans of 1,929 participants were evaluated for lung lesions and IFs by two radiologists. IFs were categorised as not clinically relevant or possibly clinically relevant. Findings were considered possibly clinically relevant if they could require further evaluation or could have substantial clinical implications. All possibly clinically relevant IFs were reviewed by a third radiologist, who determined its clinical relevance. Of all 1,929 participants, 1,410 (73%) had not clinically relevant IFs and 163 (8%) had possibly clinically relevant IFs of which 129 (79%) were indeed considered clinically relevant. Additional imaging was performed mainly by ultrasound (112 of 118, 96%). All but one lesion were concluded to be benign, mostly cysts (n = 115, 80%). Only 21 (1%) participants had findings with clinical implications. In one participant a malignancy was found, yet without any clinical benefit since no curative treatment was possible. Based on our results, we advise against systematically searching for and reporting of IFs in lung cancer screening studies using low-dose MDCT.

Risk-based selection from the general population in a screening trial: Selection criteria, recruitment and power for the Dutch-Belgian randomised lung cancer multi-slice CT screening trial (NELSON) (Article)

2007-02-15T00:00:00Z

A method to obtain the optimal selection criteria, taking into account available resources and capacity and the impact on power, is presented for the Dutch-Belgian randomised lung cancer screening trial (NELSON). NELSON investigates whether 16-detector multi-slice computed tomography screening will decrease lung cancer mortality compared to no screening. A questionnaire was sent to 335,441 (mainly) men, aged 50-75. Smoking exposure (years smoked, cigarettes/day, years quit) was determined, and expected lung cancer mortality was estimated for different selection scenarios for the 106,931 respondents, using lung cancer mortality data by level of smoking exposure (US Cancer Prevention Study I and II). Selection criteria were chosen so that the required response among eligible subjects to reach sufficient sample size was minimised and the required sample size was within our capacity. Inviting current and former smokers (quit ≤ 10 years ago) who smoked >15 cigarettes/day during >25 years or >10 cigarettes/day during >30 years was most optimal. With a power of 80%, 17,300-27,900 participants are needed to show a 20-25% lung cancer mortality reduction 10 years after randomisation. Until October 18, 2005 11,103 (first recruitment round) and 4,325 (second recruitment round) (total = 15,428) participants have been randomised. Selecting participants for lung cancer screening trials based on risk estimates is feasible and helpful to minimize sample size and costs. When pooling with Danish trial data (n = ±4,000) NELSON is the only trial without screening in controls that is expected to have 80% power to show a lung cancer mortality reduction of at least 25% 10 years after randomisation.

Lessons to learn from EORTC study 08981: A feasibility study of induction chemoradiotherapy followed by surgical resection for stage IIIB non-small cell lung cancer (Article)

2007-01-01T00:00:00Z

The present EORTC phase II feasibility study in stage IIIB (T4-N3) NSCLC was conducted to investigate whether an induction regimen with concurrent chemoradiotherapy followed by surgery after restaging by re-mediastinoscopy and/or fluorodeoxyglucose-positron emisson tomography (FDG-PET) was feasible in a multicenter setting. Unfortunately, the study closed prematurely because of poor accrual. The combination of more stringent selection criteria, the incorrect prevailing view of Ethical Boards that a tri-modality approach is too toxic, competing studies in the participating centers and the fact that patients with N3 disease could only be enrolled if a re-mediastinoscopy could be performed, underlie the low accrual. Although this study illustrates that the conduct of a tri-modality study across Europe appeared to be difficult at that time, the number of centers with highly qualified and experienced specialists involved in this kind of multi-modality approaches is rapidly increasing. Future initiatives should, therefore, certainly be encouraged. Minimally invasive procedures such as EUS and EBUS should preferably be used for up-front mediastinal staging, mediastinoscopy with or without EUS should preferably be reserved for restaging, and especially right-sided pneumonectomies should be avoided. Though evident, the feasibility to complete this kind of studies within a reasonable time period is still a condition sine qua non.

High relapse-free survival after preoperative and intraoperative radiotherapy and resection for sulcus superior tumors (Article)

2003-01-01T00:00:00Z

STUDY OBJECTIVES: Relapse-free survival in patients with sulcus superior tumors. DESIGN: Prospective registration study. SETTING: Department of surgical oncology of a university hospital. PATIENTS: Twenty-one patients treated with preoperative radiotherapy (46 Gy), lobectomy and chest-wall resection, and intraoperative radiotherapy (10 Gy). RESULTS: After a median follow-up of 18 months, 18 patients (85%) were free from locoregional relapse, while 8 patients were still alive. CONCLUSIONS: The results show that this protocol can achieve excellent local tumor control and can even be used for palliative treatment.