Cristiano Rampinelli

Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study.

BACKGROUND Lung cancer screening may detect cancer that will never become symptomatic (overdiagnosis), leading to overtreatment. Changes in size on sequential low-dose computed tomography (LDCT) screening, expressed as volume-doubling time (VDT), may help to distinguish aggressive cancer from cases that are unlikely to become symptomatic. OBJECTIVE To assess VDT for screening-detected lung cancer as an indicator of overdiagnosis. DESIGN Retrospective estimation of the VDT of cancer detected in a prospective LDCT screening cohort. SETTING Nonrandomized, single-center screening study involving persons at high risk for lung cancer enrolled between 2004 and 2005 who received LDCT annually for 5 years. PATIENTS 175 study patients diagnosed with primary lung cancer. MEASUREMENTS VDT was measured on LDCT and classified as fast-growing (<400 days), slow-growing (between 400 and 599 days), or indolent (≥600 days). RESULTS Fifty-five cases of cancer were diagnosed at baseline, and 120 were diagnosed subsequently. Of the latter group, 19 cases (15.8%) were new (not visible on previous scans) and fast-growing (median VDT, 52 days); 101 (84.2%) were progressive, including 70 (58.3%) fast-growing and 31 (25.8%) slow-growing (15.0%) or indolent (10.8%) cases. Lung cancer-specific mortality was significantly higher (9.2% per year) in patients with new compared with slow-growing or indolent (0.9% per year) cancer. Sixty percent of fast-growing progressive cancer and 45% of new cancer were stage I, for which survival was good. LIMITATIONS This is a retrospective study. Volume-doubling time can only indicate overdiagnosis and was estimated for new cancer from 1 measurement (a diameter of 2 mm assumed the previous year). CONCLUSION Slow-growing or indolent cancer comprised approximately 25% of incident cases, many of which may have been overdiagnosed. To limit overtreatment in these cases, minimally invasive limited resection and nonsurgical treatments should be investigated. PRIMARY FUNDING SOURCE Italian Association for Cancer Research.

Lung Cancer Risk Prediction to Select Smokers for Screening CT—a Model Based on the Italian COSMOS Trial

Screening with low-dose helical computed tomography (CT) has been shown to significantly reduce lung cancer mortality but the optimal target population and time interval to subsequent screening are yet to be defined. We developed two models to stratify individual smokers according to risk of developing lung cancer. We first used the number of lung cancers detected at baseline screening CT in the 5,203 asymptomatic participants of the COSMOS trial to recalibrate the Bach model, which we propose using to select smokers for screening. Next, we incorporated lung nodule characteristics and presence of emphysema identified at baseline CT into the Bach model and proposed the resulting multivariable model to predict lung cancer risk in screened smokers after baseline CT. Age and smoking exposure were the main determinants of lung cancer risk. The recalibrated Bach model accurately predicted lung cancers detected during the first year of screening. Presence of nonsolid nodules (RR = 10.1, 95% CI = 5.57–18.5), nodule size more than 8 mm (RR = 9.89, 95% CI = 5.84–16.8), and emphysema (RR = 2.36, 95% CI = 1.59–3.49) at baseline CT were all significant predictors of subsequent lung cancers. Incorporation of these variables into the Bach model increased the predictive value of the multivariable model (c-index = 0.759, internal validation). The recalibrated Bach model seems suitable for selecting the higher risk population for recruitment for large-scale CT screening. The Bach model incorporating CT findings at baseline screening could help defining the time interval to subsequent screening in individual participants. Further studies are necessary to validate these models. Cancer Prev Res; 4(11); 1778–89. ©2011 AACR.

Difficulties encountered managing nodules detected during a computed tomography lung cancer screening program

OBJECTIVE The main challenge of screening a healthy population with low-dose computed tomography is to balance the excessive use of diagnostic procedures with the risk of delayed cancer detection. We evaluated the pitfalls, difficulties, and sources of mistakes in the management of lung nodules detected in volunteers in the Cosmos single-center screening trial. METHODS A total of 5201 asymptomatic high-risk volunteers underwent screening with multidetector low-dose computed tomography. Nodules detected at baseline or new nodules at annual screening received repeat low-dose computed tomography at 1 year if less than 5 mm, repeat low-dose computed tomography 3 to 6 months later if between 5 and 8 mm, and fluorodeoxyglucose positron emission tomography if more than 8 mm. Growing nodules at the annual screening received low-dose computed tomography at 6 months and computed tomography-positron emission tomography or surgical biopsy according to doubling time, type, and size. RESULTS During the first year of screening, 106 patients underwent lung biopsy and 91 lung cancers were identified (70% were stage I). Diagnosis was delayed (false-negative) in 6 patients (stage IIB in 1 patient, stage IIIA in 3 patients, and stage IV in 2 patients), including 2 small cell cancers and 1 central lesion. Surgical biopsy revealed benign disease (false-positives) in 15 cases (14%). Positron emission tomography sensitivity was 88% for prevalent cancers and 70% for cancers diagnosed after first annual screening. No needle biopsy procedures were performed in this cohort of patients. CONCLUSION Low-dose computed tomography screening is effective for the early detection of lung cancers, but nodule management remains a challenge. Computed tomography-positron emission tomography is useful at baseline, but its sensitivity decreases significantly the subsequent year. Multidisciplinary management and experience are crucial for minimizing misdiagnoses.

Screening-Detected Lung Cancers: Is Systematic Nodal Dissection Always Essential?

Background: To address whether systematic lymph node dissection is always necessary in early lung cancer, we identified factors predicting nodal involvement in a screening series and applied them to nonscreening-detected cancers. Methods: In the 97 patients with clinical T1–2N0M0 lung cancer (<3 cm), enrolled in the Continuous Observation of Smoking Subjects computed tomography (CT) screening study, who underwent curative resection with radical mediastinal lymph node dissection, we examined factors associated with hilar extrapulmonary and mediastinal nodal involvement. Nodule size plus positive/negative positron emission tomography (PET)-CT (usually as maximum standard uptake value [maxSUV]) were subsequently evaluated retrospectively for their ability to predict nodal involvement in 193 consecutive patients with nonscreening-detected clinical stage I lung cancer. Results: Among Continuous Observation of Smoking Subjects patients, 91 (94%) were pN0, and six (6.2%) were pN+. All patients with maxSUV <2.0 (p = 0.08) or pathological nodule ≤10 mm (p = 0.027) were pN0 (62 cases). Nodal metastases occurred in 6 cases among the 29 (17%) patients with lung nodule >10 mm and maxSUV ≥2.0 (p = 0.002 versus the other 62 cases). In the nonscreening series, 42 of 43 cases with negative PET-CT (usually maxSUV <2.0) or nodule ≤10 mm were pN0; 33 of 149 (22%) cases with positive PET-CT (usually maxSUV ≥ 2.0) and nodule >10 mm were pN+ (p = 0.001 versus the 43 cases). Conclusions: This limited experience suggests that in early-stage clinically N0 lung cancers with maxSUV <2.0 or pathological nodule size ≤10 mm, systematic nodal dissection can be avoided as the risk of nodal involvement is very low.

Diagnostic performance of low-dose computed tomography screening for lung cancer over five years.

Introduction: Low-dose computed tomography (LD-CT) screening can reduce lung cancer mortality; however, it is essential to improve nodule management protocols. We analyze the performance of the diagnostic protocol of the Continuous Observation of SMOking Subjects single-center screening study, after long-term follow-up. Methods: Between 2004 and 2005, 5203 asymptomatic high-risk individuals (≥20 pack-years, aged 50 years or older) were enrolled to undergo annual LD-CT for 5 years. Nodules 5 mm or smaller underwent repeat LD-CT a year later. Nodules larger than 5.0 mm and 8.0 mm or smaller received LD-CT 3 to 6 months later. Nodules larger than 8.0 mm or growing underwent CT-positron emission tomography. True positives were any stage prevalent lung cancer, progressing nodules diagnosed at stage 1, localized multifocal cancer, or new nodules diagnosed at any stage. False negatives were progressing nodules diagnosed at stage >1. False positives were benign nodules resected surgically. Results: Compliance was 79% over 5 years; 175 primary lung cancers were detected (0.76% per year), 136 (77.7%) were N0M0 and three were interval cancers. Eleven second primary lung cancers were diagnosed. Resectability was 87.4%; postoperative mortality 0.6%. Recall was 6.4% overall, 10.1% at baseline. False negatives were 14 of 175 (8%). Protocol sensitivity was 158 of 175 (90%); specificity 4994 of 5028 (99.4%); positive predictive value was 158 of 187 (84.5%); and negative predictive value was 4994 of 5016 (99.7%). Twenty-nine of 204 (14.2%) benign lesions were diagnosed surgically. Five-year overall and cancer-specific survival were 78% (95% confidence interval, 72–84) and 82% (95% confidence interval, 76%–88%) respectively. Conclusions: The performance of the CT protocol was satisfactory with an acceptable number of benign lesions biopsied surgically, low recall rate, and good oncological outcomes. However, interval and advanced cancers, and misdiagnoses, need to be reduced, perhaps by risk modeling and use of serum markers.

In vivo repeatability of automated volume calculations of small pulmonary nodules with CT.

OBJECTIVE The objectives of our study were to evaluate the in vivo reproducibility of automated volume calculations of small lung nodules with both low-dose and standard-dose CT and to assess whether repeatability within each technique varies according to the diameter, site, or morphology of the nodule or to percentage of emphysema. SUBJECTS AND METHODS Sixty-six subjects with 83 solid pulmonary nodules between 5 and 10 mm in diameter were enrolled in this prospective study. Four consecutive MDCT data sets, two low dose and two standard dose, were obtained for each nodule on separate breath-holds during the same session. The volume of each nodule was calculated by automated software. Repeatability was evaluated by Bland-Altmans approach and the coefficient of repeatability. Associations of the percentage of volume variation between two measurements with nodule diameter, emphysema percentage, nodule site, and nodule morphology were assessed by Spearmans correlation coefficient and the Kruskal-Wallis test. A p value of < 0.05 was considered statistically significant. RESULTS The range of variation of the volumes of pulmonary nodules between two subsequent measurements was -38% +/- 60% for low-dose CT and -27% +/- 40% for standard-dose CT. No significant statistical association was found between variation in volume measurements and nodule site, nodule diameter, nodule morphology, or emphysema percentage by semiautomated calculation of lung density. CONCLUSION Automated volume calculations of small pulmonary nodules can significantly differ between two subsequent breath-holds with both low-dose and standard-dose CT techniques; in clinical practice we recommend that a volume variation of greater than 30% for nodules between 5 and 10 mm should be confirmed by follow-up CT to be sure that a nodule is actually growing.

Evolution of emphysema in relation to smoking

PurposeWe have little knowledge about the evolution of emphysema, and relatively little is understood about its evolution in relation to smoking habits. This study aims to assess the evolution of emphysema in asymptomatic current and former smokers over 2 years and to investigate the association with subjects’ characteristics. The study was approved by our Ethics Committee and all participants provided written informed consent.Materials and methodsWe measured emphysema by automatic low-dose computed tomography densitometry in 254 current and 282 former smokers enrolled in a lung-cancer screening. The measures were repeated after 2 years. The association between subjects’ characteristics, smoking habits and emphysema were assessed by chi-squared and Wilcoxon tests. Univariate and multivariate odds ratios (OR) with 95% confidence intervals (CI) were calculated for the risk of emphysema worsening according to subjects’ characteristics. We assessed the trend of increasing risk of emphysema progression by smoking habits using the Mantel-Haenszel chi-squared test.ResultsThe median percentage increase in emphysema over a 2-year period was significantly higher in current than in former smokers (OR 1.8; 95% CI 1.3–2.6; p < 0.0001). The risk of worsening emphysema (by 30% in 2 years) in current smokers increased with smoking duration (p for trend <0.02).ConclusionAs emphysema is a known risk factor for lung cancer, its evaluation could be used as a potential factor for identification of a high-risk population. The evaluation of emphysema progression can be added to low-dose CT screening programmes to inform and incite participants to stop smoking.

Role of operator experience in ultrasound-guided fine-needle aspiration biopsy of the thyroid

PurposeThyroid nodules are commonly encountered in clinical practice, and ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the gold standard in diagnosing the pathological nature of undetermined thyroid nodules. The aim of this study was to evaluate whether operator experience influences the diagnostic accuracy of US-guided FNAB.Materials and methodsA total of 700 consecutive US-guided FNAB done by a single radiologist between 2000 and 2007 were retrospectively analysed. The same freehand technique and capillary-action technique with 22- or 25-gauge needles was used for all nodules, All specimens were prepared and fixed without the cytologist on site and were subsequently analysed by two expert cytologists. The procedures were chronologically divided into seven groups and classified as diagnostic or nondiagnostic.ResultsThe rate of nondiagnostic procedures for each group was 32% in group 1, 13% in group 2, 17% in group 3, 11% in group 4, 10% in group 5, 5% in group 6 and 8% in group 7. No major complications were recorded.ConclusionsThe rate of nondiagnostic US-guided FNAB is heavily dependent on the operator’s experience. We estimated that at least 200 procedures need to be performed in order to achieve the levels of diagnostic accuracy reported in the literature. We therefore suggest specific training before operators routinely perform this procedure in clinical practice.RiassuntoObiettivoI noduli tiroidei costituiscono un riscontro comune nella pratica clinica e la biopsia con ago sottile (FNAB)-ecoguidata rappresenta il gold standard diagnostico nella valutazione di pazienti con noduli indeterminati. L’obiettivo di questo studio è valutare quanto l’esperienza dell’operatore influisca sull’accuratezza diagnostica degli agoaspirati tiroidei ecoguidati.Materiali e metodiSono state valutate retrospettivamente 700 FNAB-ecoguidate consecutive eseguite da un singolo radiologo dal 2000 al 2007, effettuate con tecnica a mano libera per capillarità con aghi da 22 G o 25 G, preparati ed allestiti senza citologo. Tutti i prelievi sono stati analizzati successivamente da due citologi esperti. Le procedure sono state stratificate cronologicamente in 7 gruppi e classificate come diagnostiche o non diagnostiche.RisultatiLe procedure non diagnostiche di ogni singolo Gruppo sono: 32% nel Gruppo 1, 13% nel Gruppo 2, 17% nel Gruppo 3, 11% nel Gruppo 4, 10% nel Gruppo 5, 5% nel Gruppo 6 e 8% nel Gruppo 7. Non sono state riportate complicanze maggiori.ConclusioniLa percentuale non-diagnostica di FNAB-ecoguidate tiroidee è fortemente dipendente dall’esperienza dell’operatore. Abbiamo stimato che siano necessarie almeno 200 procedure prima di raggiungere valori di accuratezza diagnostica riportati in letteratura. Suggeriamo pertanto uno specifico training dell’operatore prima di intraprendere questa procedura nella pratica clinica.

Exposure to low dose computed tomography for lung cancer screening and risk of cancer: secondary analysis of trial data and risk-benefit analysis

Objective To estimate the cumulative radiation exposure and lifetime attributable risk of cancer incidence associated with lung cancer screening using annual low dose computed tomography (CT). Design Secondary analysis of data from a lung cancer screening trial and risk-benefit analysis. Setting 10 year, non-randomised, single centre, low dose CT, lung cancer screening trial (COSMOS study) which took place in Milan, Italy in 2004-15 (enrolment in 2004-05). Secondary analysis took place in 2015-16. Participants High risk asymptomatic smokers aged 50 and older, who were current or former smokers (≥20 pack years), and had no history of cancer in the previous five years. Main outcome measures Cumulative radiation exposure from low dose CT and positron emission tomography (PET) CT scans, calculated by dosimetry software; and lifetime attributable risk of cancer incidence, calculated from the Biological Effects of Ionizing Radiation VII (BEIR VII) report. Results Over 10 years, 5203 participants (3439 men, 1764 women) underwent 42 228 low dose CT and 635 PET CT scans. The median cumulative effective dose at the 10th year of screening was 9.3 mSv for men and 13.0 mSv for women. According to participants’ age and sex, the lifetime attributable risk of lung cancer and major cancers after 10 years of CT screening ranged from 5.5 to 1.4 per 10 000 people screened, and from 8.1 to 2.6 per 10 000 people screened, respectively. In women aged 50-54, the lifetime attributable risk of lung cancer and major cancers was about fourfold and threefold higher than for men aged 65 and older, respectively. The numbers of lung cancer and major cancer cases induced by 10 years of screening in our cohort were 1.5 and 2.4, respectively, which corresponded to an additional risk of induced major cancers of 0.05% (2.4/5203). 259 lung cancers were diagnosed in 10 years of screening; one radiation induced major cancer would be expected for every 108 (259/2.4) lung cancers detected through screening. Conclusion Radiation exposure and cancer risk from low dose CT screening for lung cancer, even if non-negligible, can be considered acceptable in light of the substantial mortality reduction associated with screening.

Positron emission tomography in the diagnostic work-up of screening-detected lung nodules

Low-dose computed tomography (CT) screening for lung cancer can reduce lung cancer mortality, but overdiagnosis, false positives and invasive procedures for benign nodules are worrying. We evaluated the utility of positron emission tomography (PET)-CT in characterising indeterminate screening-detected lung nodules. 383 nodules, examined by PET-CT over the first 6 years of the COSMOS (Continuous Observation of Smoking Subjects) study to diagnose primary lung cancer, were reviewed and compared with pathological findings (surgically-treated patients) or follow-up (negative CT for ⩾2 years, considered negative); 196 nodules were malignant. The sensitivity, specificity and accuracy of PET-CT for differentially diagnosing malignant nodules were, respectively, 64%, 89% and 76% overall, and 82%, 92% and 88% for baseline-detected nodules. Performance was lower for nodules found at repeat annual scans, with sensitivity ranging from 22% for nonsolid to 79% for solid nodules (p=0.0001). Sensitivity (87%) and specificity (73%) were high for nodules ⩾15 mm, better (sensitivity 98%) for solid nodules ⩾15 mm. PET-CT was highly sensitive for the differential diagnosis of indeterminate nodules detected at baseline, nodules ⩾15 mm and solid nodules. Sensitivity was low for sub-solid nodules and nodules discovered after baseline for which other methods, e.g. volume doubling time, should be used. PET-CT is good at differentially diagnosing large, solid and baseline-detected lung nodules in the screening setting http://ow.ly/A1amh