Prognostic selection and long-term survival analysis to assess overdiagnosis risk in lung cancer screening randomized trials.

OBJECTIVES: Overdiagnosis in low-dose computed tomography randomized screening trials varies from 0 to 67%. The National Lung Screening Trial (extended follow-up) and ITALUNG (Italian Lung Cancer Screening Trial) have reported cumulative incidence estimates at long-term follow-up showing low or no overdiagnosis. The Danish Lung Cancer Screening Trial attributed the high overdiagnosis estimate to a likely selection for risk of the active arm. Here, we applied a method already used in benefit and overdiagnosis assessments to compute the long-term survival rates in the ITALUNG arms in order to confirm incidence-excess method assessment. METHODS: Subjects in the active arm were invited for four screening rounds, while controls were in usual care. Follow-up was extended to 11.3 years. Kaplan-Meyer 5- and 10-year survivals of "resected and early" (stage I or II and resected) and "unresected or late" (stage III or IV or not resected or unclassified) lung cancer cases were compared between arms. RESULTS: The updated ITALUNG control arm cumulative incidence rate was lower than in the active arm, but this was not statistically significant (RR: 0.89; 95% CI: 0.67-1.18). A compensatory drop of late cases was observed after baseline screening. The proportion of "resected and early" cases was 38% and 19%, in the active and control arms, respectively. The 10-year survival rates were 64% and 60% in the active and control arms, respectively (p = 0.689). The five-year survival rates for "unresected or late" cases were 10% and 7% in the active and control arms, respectively (p = 0.679). CONCLUSIONS: This long-term survival analysis, by prognostic categories, concluded against the long-term risk of overdiagnosis and contributed to revealing how screening works.

Prevalence and number of circulating tumour cells and microemboli at diagnosis of advanced NSCLC.

PURPOSE: Timing and magnitude of blood release of circulating tumour cells (CTC) and circulating tumour microemboli (CTM) from primary solid cancers are uncertain. We investigated prevalence and number of CTC and CTM at diagnosis of advanced non-small cell lung cancer (NSCLC). METHODS: Twenty-eight consecutive patients with suspected stage III-IV lung cancer gave consent to provide 15 mL of peripheral blood soon before diagnostic CT-guided fine-needle aspiration biopsy (FNAB). CTC and CTM (clusters of ≥3 CTC) were isolated by cell size filtration (ScreenCell), identified and counted by cytopathologists using morphometric criteria and (in 6 cases) immunostained for vimentin. RESULTS: FNAB demonstrated NSCLC in 26 cases. At least one CTC/3 mL blood (mean 6.8 ± 3.7) was detected in 17 (65 %) and one CTM (mean 4.5 ± 3.3) in 15 (58 %) of 26 NSCLC cases. No correlation between number of CTC or CTM and tumour type or stage was observed. Neoplastic cells from both FNA and CTC/CTM were positive for vimentin but heterogeneously. CONCLUSIONS: CTC can be detected in two-thirds and CTM in more than half of patients with advanced NSCLC at diagnosis. Reasons underlying lack of CTC and CTM in some advanced lung cancers deserve further investigations.

Lung cancer associated with cystic airspaces.

OBJECTIVE: This study aimed to define computed tomographic morphologic features of lung cancer associated with cystic airspaces, their modifications in serial computed tomographic scans, and 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography uptake. METHODS: Computed tomographic scans and 18F-FDG positron emission tomography in 24 patients with lung cancer (17 adenocarcinomas, 7 squamous cell carcinomas, 12 stage I and 12 stage II to IV) associated with cystic airspaces were reviewed. RESULTS: Mean diameter of airspace was initially 17.6 mm (range, 5-30 mm), and 4 morphologic patterns were recognized: solid nodule protruding externally (type I, n = 5) or internally (type II, n = 4) from the cyst wall; circumferential thickening of the cyst wall (type III, n = 8); and tissue intermixed within clusters of cysts (type IV, n = 7). With tumor growth, airspace size decreased in 9, increased in 6, and was unchanged in 9 cases. Five cases evolved from type III to type I, and 5 lesions became completely solid. 18F-fluoro-2-deoxy-D-glucose uptake was initially absent to mild in 7 and moderate to marked in 14 lesions. CONCLUSIONS: Progressive wall thickening or appearance/increase of a nodule inside or outside a cystic airspace should raise suspicion of lung cancer irrespective of FDG uptake.

Initial LDCT appearance of incident lung cancers in the ITALUNG trial.

OBJECTIVES: To characterize early features of lung cancers detected with low-dose computed tomography (LDCT) screening. MATERIALS AND METHODS: Two radiologists reviewed prior LDCTs in 20 incident cancers diagnosed at annual repeat screening rounds and 83 benign nodules observed in the ITALUNG trial. RESULTS: No abnormality was observed in 3 cancers. Focal abnormalities in prior LDCT were identified in 17(85%) cancers (14 adenocarcinomas; 14 stage I). Initial abnormalities were intra-pulmonary in 10, subpleural in 4 and perifissural in 3. Average mean diameter was 9mm (range 4.5-18mm). Nine exhibited solid, 4 part-solid and 4 non-solid density. The margins were smooth and regular in 5 cases, lobulated in 6, irregular with spiculations in 3 and blurred in 3. Ten (59%) initial focal abnormalities had a round or oval nodular shape, but 7(41%) had a non-nodular complex (n=5) or "stripe-like" (n=2) shape. Bronchus sign was observed in 3 cases and association with cystic airspace in 2 cases. Non-solid density, complex or "stripe-like" shape, bronchus sign and association with cystic airspace had a specificity higher than 90%, but positive predictive value of every feature of incident lung cancers was low (range 10.4-50%). CONCLUSIONS: The vast majority of cancers diagnosed at annual repeat show corresponding focal lung abnormalities in prior LDCTs. Perifissural location and non-nodular shape do not exclude the possibility of early lung cancer. Since specificity of the early features of incident lung cancer is incomplete and their positive predictive value is low, all focal pulmonary abnormalities detected in screened subjects should be re-evaluated in subsequent LDCTs.

Feasibility of evaluating quality cancer care using registry data and electronic health records: a population-based study.

OBJECTIVE: To evaluate the quality of patients care, a set of indicators of the standards of cancer care were defined. PARTICIPANTS: We developed a set of indicators to assess the implementation in daily practice of recommendation produced by a regional network (Istituto Toscano Tumori). This set was tested in a retrospective study in the resident population of the Tuscany Region; the regional health system is organized on 12 local health authorities which refer to three macro areas (Area Vasta). The study included incident colorectal, lung and breast cancer cases listed in 2004 for the Tuscan Cancer Registry, a population-based registry which collected tumor cases diagnosed in all residents in Tuscany. Electronic data from registry database were used to determine the compliance with each indicator for patients in 2004. To validate the results, an ad hoc clinical survey including the same geographical area for the year 2006 was performed. INTERVENTION: None. MAIN OUTCOME MEASURES: The proportion of patients who fulfilled each of the indicators. RESULTS: Our study showed the feasibility of the evaluation of the quality of cancer care using cancer registry population-based data and major computerized information systems. The estimation of the selected indicators confirmed a good homogeneity among areas, and globally revealed a good intraregional performance. CONCLUSIONS: Further work is needed to develop specific quality measures, particularly about structural data and to continually revise indicators of quality of care. Data from a cancer registry, however, can be useful to evaluate quality of cancer care.

Changes in volume-corrected whole-lung density in smokers and former smokers during the ITALUNG screening trial.

PURPOSE: To evaluate with a volume-corrected whole-lung approach changes in lung density over 2 years consistent with progression of pulmonary emphysema in smokers and former smokers enrolled in the ITALUNG trial of lung cancer screening using low-dose computed tomography (LDCT). MATERIALS AND METHODS: A total of 103 subjects (mean age 63±4 y with a pack-year history of at least 20) underwent 2 whole-lung LDCT examinations 2 years apart. Visual assessment was made independently by 2 experienced observers on the initial LDCT examination with a 0 to 4 grading system for each of 6 regions (right and left upper, mid, and lower lung). The whole-lung 15th percentile of attenuation coefficient and relative area (RA) at -910 HU, both corrected to the individual lung volume (Perc15v and RA910v), were measured on the 2 LDCT examinations. The intrasubject variability of Perc15v and RA910v was previously determined in 32 other subjects of the trial examined using the same scanner and technique twice over a 3-month interval for suspicious nodules. RESULTS: The 2 operators agreed on the presence of mild to severe emphysema (visual score ≥1 in at least 1 region) at initial LDCT examination in 24 (23%) of the 103 subjects. Fifteen subjects (15%) showed a Perc15v change between the 2 examinations exceeding the lower 95% limit of agreement, indicating progression of emphysema with a mean difference in lung density of -14.7%±2.6%. Ten of the 15 were identified as showing emphysema progression by RA910v as well. No association was observed between progression of emphysema and visual evidence of emphysema at initial LDCT examination, smoking status, or pack-years at baseline, or intervening changes in smoking habits. CONCLUSION: Once variations in inspiratory lung volumes are taken into account, changes in lung density over 2 years consistent with progression of pulmonary emphysema in elderly smokers and former smokers are uncommon.

Prevalence and correlates of pulmonary emphysema in smokers and former smokers. A densitometric study of participants in the ITALUNG trial.

We assessed with computed tomography (CT) densitometry the prevalence of emphysema in 266 (175 men and 91 women; mean age 64 +/- 4 years) smokers and former smokers enrolled in the ITALUNG trial of lung cancer screening with low-dose thin-slice CT. Whole-lung volume and the relative area at -950 Hounsfield units (RA(950)) and mean lung attenuation (MLA) in 1 of every 10 slices (mean, 24 slices per subject) were measured. Lung volume, MLA and RA950 significantly correlated each other and with age. Average RA950 >6.8% qualifying for emphysema was present in 71 (26.6%) of 266 subjects, with a higher prevalence in men than in women (30.3% vs 19.8%; p = 0.003). Only in smokers was a weak (r = 0.18; p = 0.05) correlation between RA950 and packs/year observed. In multiple regression analysis, the variability of RA950 (R2 = 0.24) or MLA (R2 = 0.34) was significantly, but weakly explained by age, lung volume and packs/year. Other factors besides smoking may also have a significant role in the etiopathogenesis of pulmonary emphysema.

Prognostic variability among nonsmall cell lung cancer patients with pathologic N1 lymph node involvement. Epidemiological figures with strong clinical implications.

BACKGROUND: Patients who have nonsmall cell lung cancer with N1 lymph node status are an intermediate group of patients who have a variable prognosis. Differences in lymph node level (hilar or pulmonary lymph nodes) may influence patient survival. The authors retrospectively analyzed the factors that influenced prognosis, including the level of N1 lymph node involvement. METHODS: The authors used the Tuscan Cancer Registry archives to retrieve records on 2523 patients who had lung tumors diagnosed during the period from 1996 and 1998 in the provinces of Florence and Prato, central Italy. To analyze the survival of patients according to the level of lymph node involvement, the prognoses of patients with nonsmall cell lung cancer who had N1 lymph node status were compared in a population-based case series. Among 112 patients with pathologic N1 status, the following variables were analyzed for their influence on postoperative survival: gender, age, cell type, pathologic tumor status, the number of metastatic lymph nodes, the level of metastatic lymph nodes (hilar or pulmonary), and the type of surgical resection. RESULTS: The 5-year survival rates for patients who had involvement of pulmonary and hilar lymph nodes were 41.2% and 21.8%, respectively (P =.005). A Cox proportional hazards model analysis indicated that the presence of hilar lymph node involvement was an independent prognostic factor. CONCLUSIONS: N1 pathologic lymph node status was identified in a combination of subgroups with different prognoses, and the presence of hilar lymph node disease had prognostic significance. This difference in survival may lead to the use of different therapies for these subgroups of patients with pathologic N1 non-small cell lung cancer.

Risk-benefit analysis of X-ray exposure associated with lung cancer screening in the Italung-CT trial.

OBJECTIVE: Prior analyses of X-ray exposures in lung cancer screening with CT considered the basic acquisition technique in single-detector scanners and the effects of a lifetime screening regimen, whereas the potential benefit in terms of lives saved was not addressed. MATERIALS AND METHODS: We determined the total-body effective dose of different acquisition techniques for one single-detector and one MDCT scanner and made projections about the cumulative radiation exposure to smokers undergoing four annual CT examinations on the same scanners in the Italung-CT Trial. Combining these data with estimates of radiation-induced fatal cancer and of the benefit of screening, we calculated the risk-benefit ratio for participants in the trial, ex-smokers, and never-smokers. RESULTS: The cumulative effective doses per 1,000 subjects were 3.3 Sv using an MDCT scanner and 5.8 or 7.1 Sv using a single-detector scanner. Potential fatal cancers associated with radiation exposure were 0.11 per 1,000 subjects for MDCT scanners and 0.20 or 0.24 for single-detector scanners, which is about 10-100 times lower than the number of expected lives saved by screening assuming a 20-30% lung cancer-specific mortality reduction in current smokers. They were, however, of similar magnitude to the lives saved by screening in never-smokers and former smokers assuming a 10% efficacy of screening. CONCLUSION: MDCT is associated with lower radiation doses than single-detector CT technology. The risk of radiation dose in the Italung-CT Trial is compensated for by the expected benefit. CT screening for lung cancer should not be offered to never-smokers, whereas its recommendation in former smokers is debatable.