The time of lung cancer screening may provide the ideal setting to discuss and initiate a smoking cessation plan that includes pharmacologic aids. No studies to date have fully investigated the potential effectiveness of such combined approach.
We prospectively evaluated the biochemically verified 1-year continuous abstinence rate from smoking of 187 persistent smokers enrolled within the Multicentric Italian Lung Detection Trial (MILD), who received a pharmacologic aid to quit smoking with varenicline along with behavioral counseling. The propensity of study subjects to succeed in smoking cessation was also monitored.
At 12 months, the continuous abstinence rate from smoking was achieved in 37 out of 187 patients (19.8%), with a propensity to succeed in smoking cessation for the assisted attempt equal to 1.43, as compared to an unassisted MILD patient. At the end of the third month of therapy, 48.7% of subjects showed a continuous abstinence rate, while only 33.7% of patients were abstinent from smoking at 6 months. At baseline, the subgroup of MILD participants who were originally allocated to lung tomography showed higher smoking intensity than those allocated to no screening.
A combined smoking cessation intervention can be implemented with satisfactory results within a lung cancer screening program; this preliminary observation needs to be replicated in a prospective investigation. Clinicians should consider that lung cancer screening may be falsely reassuring for persistent smokers; therefore it should always be coupled with a smoking cessation program.
Tumori 2015; 101(3): 306 - 311
Article Type: ORIGINAL RESEARCH ARTICLE
AuthorsPaolo Pozzi, Elena Munarini, Francesca Bravi, Marta Rossi, Carlo La Vecchia, Roberto Boffi, Ugo Pastorino
- • Accepted on 02/12/2014
- • Available online on 02/04/2015
- • Published in print on 25/06/2015
This article is available as full text PDF.
Lung cancer, which annualy causes 1.4 million deaths worldwide, is the most common cause of cancer death (1). In the Early Lung Cancer Action Program study, low-dose computed tomography (LDCT) showed potential to detect early-stage lung cancer (2), and the recent National Lung Screening Trial showed that a 20% reduction in mortality from lung cancer could be achieved through LDCT screening programs (3). Low-dose computed tomography also has been shown to serve as a “teachable moment” for smoking cessation (SC) (4). In the experience of Cox et al (5) and Townsend et al (6), 1-year self-reported smoking abstinence was 14%. In the Danish Lung Cancer Screening Trial, Ashraf et al (7) described a net quit rate from smoking of 6%. In the Dutch-Belgian NELSON LDCT trial, van der Aalst et al (8) reported a 2-year SC rate of 14.5%. These trials offered only cessation advice in spite of an integrated SC intervention, although their results were encouraging when compared to the SC prevalence of an unassisted population (9). Nevertheless, it would be useful to determine whether offering lung cancer screening without SC programs could be cost-effective (10) and whether LDCT contributes to altering smoking behaviors (11). In fact, being in an active arm of LDCT screening or receiving a negative screening result may provide relief to persistent smokers (8), rather than discouraging quit attempts (12). Furthermore, due to study design, most investigations routinely regarded the point prevalence rather than continuous abstinence rate from smoking (4-5-6-7).
To our knowledge, only one small study investigated the feasibility of a SC intervention in the LDCT setting (13). The subjects received nicotine replacement therapy or varenicline before or after the LDCT screening; the investigators registered a point prevalence of SC equal to 16.7% at the end of the study and they concluded that it might be better to offer SC support before the screening test (13).
We report here the results of a combined pharmacologic and behavioral SC intervention within a prospective LDCT lung cancer screening trial; for pharmacologic support, we chose the first-line antitobacco drug varenicline (14), a partial agonist of the α-4 β-2 nicotinic acetylcholine receptor. Varenicline reduces craving and satisfaction from smoking (15) and helps smokers to continuously abstain from smoking (16), the primary objective of this study.
The Multicentric Italian Lung Detection (MILD) is a randomized prospective lung cancer screening trial launched in 2005 at the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan that included 4099 current or former smokers (17). The MILD participants could have been originally assigned either to a control group, where they received a longitudinal evaluation of respiratory function and brief advice for SC in each study visit, or to an early detection group, where they underwent the same program with the addition of LDCT; subjects in the LDCT arm were further randomized to receive computed tomography scan every 12 months (annual) or every 24 months (biennial).
The present research considered a subsample of patients already participating in the MILD trial who were enrolled in 2009-2010 to receive an intervention with varenicline plus individual behavioral counseling to promote continuous SC.
The study was designed as observational to follow the directive of the “Centro Nazionale per la Prevenzione e il Controllo delle Malattie” from the Italian Ministry of Health, which financially supported the study.
We selected a subcohort of MILD participants who satisfied the following criteria: age 49-75 years, persistent smoking despite brief advice for stopping smoking during prior MILD visits, and cumulative exposure to smoke of at least 20 pack-years. Individuals with renal, neurologic, or psychiatric disorders as well as those with a history of drug or alcohol abuse were excluded. The study was approved by the local institutional ethical committee (approval 09/49) and all subjects were asked to provide informed consent. The final population included 187 MILD participants who satisfied the eligibility criteria and signed the informed consent.
At baseline, the participants completed the Fagerström Test of Nicotine Dependence (18) and underwent a forced expiratory volume in the first second evaluation (FEV1%) according to more recent ATS/ERS guidelines (19). Moreover, basal expired carbon monoxide (eCO) through an eCO reader (Micro Smokerlyzer, Bedfont Scientific Ltd., Kent, UK) was obtained (20). Participants were subsequently instructed to take 0.5 mg/day of varenicline for days 1-3, 0.5 mg twice per day for days 4-7, and 1 mg twice per day starting on day 8 and continuing until the end of week 12. Subjects were allowed to continue smoking only until the 14th day of therapy, after which they were supposed to quit smoking. Temporal or permanent dose reduction for tolerability problems was allowed. The duration of therapy was 3 months. The drug was provided free of charge by the study investigators, as the Italian Health System does not provide any reimbursement for SC drugs.
The one-on-one cognitive behavioral support consisted of 4 telephone calls, lasting at least 10 minutes, promoted by the same counselor during the months of treatment; the psychologist provided behavioral advice about how to cope with craving, and supported the motivation and the self-efficacy of the subject to quit or remain abstinent. If required by the participant, additional contacts were scheduled.
Follow-up assessments were set at months 1, 3, 6, and 12 after enrollment. At each medical visit, participants were asked about their smoking status, and they received an eCO reading in order to confirm smoking abstinence. A patient was defined as a sustained quitter if he or she reported being abstinent from smoking at follow-up visits and had an eCO of ≤6 ppm (21). Participants who missed visits or provided no information on their smoking status were considered persistent smokers. Therapy compliance was recorded by pill counts; the occurrence of adverse events was also monitored.
The primary endpoint of the study was the rate of continuous abstinence from smoking, defined as sustained abstinence from smoking at months 3, 6, and 12, overall and in specific subgroups of subjects (basal pulmonary function and LDCT allocation arm). The point prevalence of SC and the propensity of study subjects to succeed in SC were also monitored.
Significant differences in the distributions of categorical variables were tested using the χ2 test, and continuous variables were tested by the paired
At month 12, 37 out of 187 subjects (19.8%) receiving the combined pharmacologic and psychological SC support achieved biochemically verified continuous abstinence from smoking.
baseline characteristics of 187 participants according to continuous abstinence rate from smoking at month 12
|Total (n = 187)||Quitters (n = 37, 19.8%)||Nonquitters (n = 150, 80.2%)|
|eCO = expired carbon monoxide; FTND = Fagerström Test of Nicotine Dependence; LDCT = low-dose computed tomography; MILD = Multicentric Italian Lung Detection Trial.|
|aThe sum does not add up to the total because of missing values.|
|bSubjects who did not receive active screening.|
|Age, y, n (%)|
|<55||82 (43.9)||14 (37.8)||68 (45.3)|
|55-59||62 (33.2)||14 (37.8)||48 (32.0)|
|60-64||35 (18.7)||8 (21.6)||27 (18.0)|
|≥65||8 (4.3)||1 (2.7)||7 (4.7)|
|Median (range)||55 (47-72)||57 (49-70)||55 (47-72)|
|Mean ± SD||55.9 ± 4.6||56.3 ± 4.6||55.8 ± 4.6|
|Sex, n (%)|
|Male||117 (62.6)||22 (59.5)||95 (63.3)|
|Female||70 (37.4)||15 (40.5)||55 (36.7)|
|Duration of smoking, y, n (%)|
|<40||115 (61.5)||21 (56.8)||94 (62.7)|
|≥40||72 (38.5)||16 (43.2)||56 (37.3)|
|Cigarettes per day, n, n (%)|
|<20||69 (36.9)||14 (37.8)||55 (36.7)|
|≥20||118 (63.1)||23 (62.2)||95 (63.3)|
|Pack-years of cigarettes|
|Median (range)||20.0 (0-120)||22.5 (0-90)||20.0 (0-120)|
|Mean ± SD||22.4 ± 22.0||25.5 ± 25.0||21.6 ± 21.2|
|Baseline eCO, ppm|
|Median (range)||16 (0-41)||14 (2-34)||16 (0-41)|
|Mean ± SD||16.6 ± 7.5||14.9 ± 7.8||17.0 ± 7.3|
|Median (range)||5 (0-9)||5 (0-8)||5 (0-9)|
|Mean ± SD||5.1 ± 2.0||4.7 ± 2.1||5.2 ± 2.0|
|FEV1%, n (%)|
|<90||101 (54.0)||16 (43.2)||85 (56.7)|
|≥90||86 (46.0)||21 (56.8)||65 (43.3)|
|Body mass index, n (%)a|
|<20||13 (7.0)||1 (2.7)||12 (8.0)|
|20-24.9||70 (37.4)||15 (40.5)||55 (36.7)|
|≥25||98 (52.4)||21 (56.8)||77 (51.3)|
|Median (range)||25.4 (15.6-45.0)||26.0 (19.6-37.4)||25.3 (15.6-45.0)|
|Mean ± SD||26.1 ± 5.0||25.9 ± 4.3||26.2 ± 5.2|
|MILD intervention group, n (%)|
|Controlb||81 (43.3)||19 (51.4)||62 (41.3)|
|LDCT||106 (56.7)||18 (48.7)||88 (58.7)|
|Year of enrollment (MILD), n (%)|
|2005-2006||124 (66.3)||28 (75.7)||96 (64.0)|
|2007-2010||63 (33.7)||9 (24.3)||54 (36.0)|
The point prevalence of SC was 52.4%, 48.7%, 33.7%, and 32.6% at months 1, 3, 6, and 12, respectively; 28 out 91 subjects (30.7%) who were abstinent from smoking at the end of the third month of the combined SC intervention displayed an early relapse from smoking, shortly after the end of the therapy (data not shown).
In subjects who had a similar propensity to receive the combined SC intervention within the MILD trial on the basis of several covariates (
Covariates included in the propensity score (combined smoking cessation intervention or matched mild participant)
|Mild (n = 150)||Combined intervention (n = 150)|
|FTND = Fagerström Test of Nicotine Dependence; LDCT = low-dose computed tomography; MILD = Multicentric Italian Lung Detection Trial.|
|aSubjects who did not receive active screening.|
|Age, y, n (%)|
|<55||67 (44.67)||62 (41.33)|
|55-59||52 (34.67)||50 (33.33)|
|60-64||24 (16.00)||30 (20.00)|
|≥65||7 (4.67)||8 (5.33)|
|Sex, n (%)|
|Male||90 (60.00)||93 (62.00)|
|Female||60 (40.00)||57 (38.00)|
|Duration of smoking, y, n (%)|
|<40||97 (64.67)||89 (59.33)|
|≥40||53 (35.33)||61 (40.67)|
|Cigarettes per day, n (%)|
|<20||40 (26.67)||55 (36.67)|
|≥20||110 (73.33)||95 (63.33)|
|FTND (score), mean ± SD||5 ± 2.2||5.0 ± 2.0|
|FEV1%, n (%)|
|<90||38 (25.33)||85 (56.67)|
|≥90||112 (74.67)||65 (43.33)|
|Years since enrollment, median (range)||1 (1-4)||1 (1-4)|
|MILD intervention group, n (%)|
|Controla||62 (41.33)||56 (37.33)|
|LDCT||88 (58.67)||94 (62.67)|
Smoking habits according to mild intervention group at baseline
|eCO = expired carbon monoxide; FTND = Fagerström Test of Nicotine Dependence; LDCT = low-dose computed tomography.|
|Values are mean ± SD.|
|aSubjects who did not receive active screening.|
|Controla (n = 81)||22.5 ± 22.6||4.9 ± 1.9||18.5 ± 10.8||14.9 ± 7.5|
|LDCT (n = 106)||22.3 ± 21.7||5.2 ± 2.1||20.8 ± 10.6||17.8 ± 7.2|
Side effects and therapy discontinuation
|Therapy compliance, n (%)|
|aThe sum does not add up to the total of 61 quitters and 126 nonquitters because of missing values on side effects.|
|bGastrointestinal disorders include nausea and other gastroenteric disorders.|
|cPsychiatric disorders include insomnia, irritability and abnormal dreams.|
|Totala||175||42 (24.0)||26 (14.9)||107 (61.1)|
|Yes||62||15 (24.2)||15 (24.2)||32 (51.6)|
|Type of side effectsa|
|Gastrointestinal disordersb||41||8 (19.5)||9 (22.0)||24 (58.5)|
|Psychiatric disordersc||20||7 (35.0)||5 (25.0)||8 (40.0)|
|Headache||1||0 (0.0)||1 (100.0)||0 (0.0)|
|No||113||27 (23.9)||11 (9.7)||75 (66.4)|
The present study demonstrated that combined SC support offered to persistent smokers enrolled in a lung cancer screening trial can effectively alter their smoking behaviors. By combining a 3-month course of varenicline with individual SC behavioral counseling, we were able to register a 1-year continuous abstinence rate from smoking of 19.8%.
The long-term results of our investigation are concordant with the literature (15, 16). The novelty of our study was in introducing an integrated SC intervention where it is not routinely used, as previous experiences considered only the “teachable moment” related to LDCT screening (4-5-6-7-8).
Our study confirms the feasibility data depicted by Ferketich et al (13) and supports the indication for a SC treatment in a new setting (i.e., lung cancer screening). Our study primarily examined the continuous SC rate, an innovative aspect of our study. Van der Aaslt et al (8, 12) reported sustained smoking abstinence among smokers enrolled in the NELSON trial, 14.9% and 14.6% in the screening and control arm, or 8.9% and 10.9% in smokers who received a negative or indeterminate screening result, but these were prevalent estimates with no biochemical verification. Our investigation applied a rigorous procedure (24) addressing proper duration of smoking abstinence with a strict eCO cutoff (21).
Varenicline was chosen as the study drug because it showed a nearly tripled probability to succeed in long-term SC, with respect to unassisted attempts (25); furthermore, providing a behavioral support in subjects using pharmacotherapy to stop smoking has been shown to increase their chance of success in SC (26).
Our study has several limitations, including lack of randomization to receive placebo or varenicline; application of a propensity score can reduce but not eliminate selection and other sources of bias. On the other hand, our intervention was introduced when the MILD trial had been ongoing for 4 years, resulting in two thirds of enrollees who were older MILD participants (i.e., enrolled in 2005-2006); due to this selection bias, we cannot rule out a longitudinal behavioral change that might take place in a patient who participates in several LDCT rounds (6), the effect of being treated before the LDCT screening (13), or the effect of receiving a negative/indeterminate LDCT result (12). Such a selection may result in an unpredictable outcome of our investigation.
As such, we tried to fill some gaps by applying the propensity score technique. In this scenario, the subjects of the MILD trial who received the assisted attempt had a 43% higher rate of succeeding in SC, as compared to the unassisted ones.
The present study allowed also us to further analyze the smoking habits of this MILD population. We found that, comparably to what van der Aalst et al described (8), subjects allocated to an active screening arm may perceive LDCT as a relief for their dangerous behaviour of being persistent smokers; in fact, when entering in the SC trial, LDCT participants smoked more cigarettes and showed higher eCO values than control participants, with the latter being statistically significant.
One third of subjects relapsed as soon as the active SC intervention ended; this trend was seen in other reports and represents a limitation of existing SC treatments (15, 16). Our investigation was not focused on preventing the smoking relapse by analyzing the quitting pattern of the subjects, thus we did not investigate the possible benefit of a lengthened varenicline treatment, as depicted by Hajek et al (27); on the other hand, we already demonstrated that there is a specific group of LDCT participants with a greater risk to develop lung cancer (28).
Future LDCT screening trials should include a combined SC intervention for all smokers, especially those who are actively screened for lung cancer and who may have aggressive cancers. This intervention may be designed in a prospective fashion and may consider different (e.g., nicotine replacement therapy or bupropion) or extended treatment for subjects with early relapse of smoking. Lung cancer screening should move from a moment of early detection into a dynamic process of smoking prevention.
This work was made possible by a (year) law by the Italian government which allowed Italian citizens to allocate the 5 × 1000 share of their tax payment to support a research or charitable institution of their choice. We wish to thank all those citizens who decided to donate their 5 × 1000 to IRCCS Fondazione Istituto Nazionale dei Tumori, Milan.
- Pozzi, Paolo [PubMed] [Google Scholar] 1, * Corresponding Author (Paolo.Pozzi@istitutotumori.mi.it)
- Munarini, Elena [PubMed] [Google Scholar] 1
- Bravi, Francesca [PubMed] [Google Scholar] 2
- Rossi, Marta [PubMed] [Google Scholar] 2, 3
- Vecchia, Carlo La [PubMed] [Google Scholar] 2, 3
- Boffi, Roberto [PubMed] [Google Scholar] 1
- Pastorino, Ugo [PubMed] [Google Scholar] 4
Tobacco Control Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
Department of Epidemiology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan - Italy
Department of Clinical Sciences and Community Health, University of Milan, Milan - Italy
Unit of Thoracic Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy
Paolo Pozzi and Elena Munarini contributed equally to this work.