Lung cancer smokers: quit smoking is a component of treatment| Tabaccologia

Abstract

n 2020 lung cancer has been the leading cause of cancer death, with an estimated 1.8 million deaths (18% of cancer deaths). Tobacco smoking is the cause of 90% of lung cancers cases. Despite advances in lung cancer treatment, tobacco control remains the most effective measure for curbing the lung cancer epidemic. Smoking cessation, at all stages of the cancer process, is associated with benefits in terms of cure, increased life expectancy and quality of life for patients, and reduced medical, surgical, and critical care complications. It reduces risks of recurrence and of second primary cancer. Smoking cessation pharmacotherapies combined with psychological support facilitate smoking cessation. Stopping smoking is an essential component of lung cancer treatment. Research is needed into the best methods for managing smoking cessation in lung cancer patients. Healthcare professionals involved in the care of cancer patients must be trained in smoking cessation support.

Introduction

In 2020, the International Agency for Research on Cancer (IARC) [1] recorded 19.3 million new cases of cancer and 10 million deaths. Lung cancer (representing 11.4% of new cancer cases) is the leading cause of cancer deaths (representing 18% of all cancer deaths). Despite advances in treatment, five-year survival for all stages combined is only 17%. Incidence continues to rise worldwide. And it is highest in the developed countries of North America, Europe and Asia. Moreover, in recent years, significant increases in lung cancer incidence have been observed among women and in emerging countries, whose populations are affected by the smoking epidemic and are more exposed to all lung cancer risk factors [1]. Lung cancer is a major public health issue, whose incidence is expected to rise by 47% from 2020 to 2040 [1]. The paradox of this cancer lies in the fact that smoking, the main cause, is preventable [2,3]. A global tobacco control policy is more essential than ever [4]. Smoking cessation at the time of lung cancer diagnosis is associated with a multitude of benefits. Therefore, smoking cessation management of smokers with lung cancer is a component of cancer treatment and must involve health providers [5,6].

Smoking and lung cancer risk

1. Many risk factors for lung cancer

Occupational exposure to carcinogens is thought to account for 5-10% of lung cancers cases [7]. Asbestos is the most frequently implicated carcinogen [8]. The International Agency for Research on Cancer (IARC) [9] has identified several “human carcinogens”, including chemicals agents (arsenic, cadmium, beryllium, chromium, diesel fumes) or radioactive agents (uranium), implicated in the onset of cancer. Outdoor air pollution, including particulate pollution (PM_2.5; PM₁₀) and nitrogen dioxide (NO₂) [10], exposure to coal combustion and heating or cooking fuels are risk factors for the occurence of lung cancer, as well as exposure to radon gas [7]. Other risk factors are suspected: use of estrogens, presence of chronic respiratory pathologies, pulmonary infections, Human papillomavirus infections (HPV) or infection with Human immunodeficiency virus (HIV) [7]. They could be implicated in the occurrence of lung cancer in non-smokers [11]. The association of smoking has apotentiating effect on the risk of lung cancer [2,7,8].

2. Smoking: the leading risk factor for lung cancer

1. Cigarette smoke contains thousands of compounds, including over 60 carcinogens: polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, aromatic amines, aldehydes, volatile organic hydrocarbons and metals [2,7]. Metabolites of these substances are more concentrated in the urine of smokers than in non-smokers. Most of the carcinogens contained in cigarette smoke, including PAHs, require a metabolic activation process, generally catalyzed by cytochrome P-450 enzymes to form DNA adducts, which are essential to the process of carcinogenesis. Levels of DNA adducts in the lungs are higher in smokers than in non-smokers, and there is a link between the extent of their levels and the probability of developing cancer. If cellular repair systems eliminating DNA adducts or controlling cell growth are overwhelmed, the likelihood of developing somatic mutations and lung cancer increases. Polymorphisms in CYP1A1 and deletion of the glutathione-s-transferase (GSTM1) gene are associated with high levels of DNA adducts, suggesting that variations in metabolic pathways condition the individual response to carcinogens [1,2]. A specific relationship between DNA adducts caused by carcinogens and the types of somatic mutations is observed. Microsomal epoxide hydrolase (MEH) can act as an activator or detoxifier of carcinogens. As an activator, MEH is involved in the metabolism of PAH epoxides and may be associated with lung cancer risk; a low activity in detoxifying environmental pollutants may be implicated in cancer in non-smokers. N-nitrosamines and aldehydes are implicated in carcinogenesis, cocarcinogens or tumor promoters increase carcinogenicity; tobacco smoke, activating EGFR, is involved in cell proliferation [2].
2. Nicotine is not a carcinogen, but it increases the risk of cancer in smokers, by inducing dependence and prolonging the smoking habit. The presence of nicotinic acetylcholine receptors (nAChR) on the cell membranes of lung cancer cell lines has been identified [3,12]. Mutations in the q24-25 region of chromosome 15 (SNP rs16969968) containing the CHRNA5-CHRNA3-CHRNB4 gene cluster encoding α5, α3, β4 nAChRs, increase nicotine dependence and vulnerability to lung cancer [12]. A recent article [13] points out that nAChRs are involved in various functions depending on their location. On the one hand, in cognition, addiction and cell they are involved in non-neural tissue, and on the other, in inflammation, immunity and cell growth regulation in other tissues. Thus, dysregulation of nAChRs and their downstream signaling pathways could contribute to the development of diseases, including cell proliferation, neoangiogenesis, cancer development and tumor metastasis.
3. A 2006 Report by the US Surgeon General [14] on the health consequences of involuntary exposure to tobacco smoke revealed a causal relationship between such exposure and lung cancer in non-smokers, with an estimated 25% increase in risk. Cannabis, the most frequently inhaled drug after tobacco, whether used exclusively or combined with tobacco, delivers the same carcinogenic agents as tobacco smoke, increasing the risk of lung cancer [15].
4. All these facts explains why almost 90% of lung cancers are linked to smoking. Active smokers have an eleven-fold higher risk of lung cancer compared with never smokers: RR = 10.92 (95% CI: 8.28-14.40) [16]. The duration of exposure to tobacco smoke is a greater determinant of cancer risk than the total number of cigarettes smoked [2].
5. Advances in lung cancer treatment has made possible by those of surgical technique or medical thérapies [17]. Surgical video-assisted techniques give better quality of life and an equal survival at 5 years (80–90% Non Small Cell Lung Cancer – NSCLC – stage IA to 60% NSCLC stage IIB) compared with open lobectomy; perioperative chemotherapy found a survival benefit of 5.4 to 6.9% at 5 years for patients with NSCLC stage IB–IIIA. Approxymately 70% of patients with advanced NSCLC can benefit of a molecular targeted therapy [17]. The most research in gene mutations (EGFR, ALK, BRAF, MET, ROS1, KRAS, HER2, etc.) [19], leading to tumor growth have been conducted in NSCLC in order to determine whether patients can benefit of molecular targeted therapeutic. EGFR mutation-positive occur in 10-20% of NSCLC. Randomised controlled trials (RCTs) has established the superiority of EGFR Tyrosine kinase inhibitors (EGFR-TKIs: erlotinib, etc.) as the first-line treatment in EGFR mutated NSCLC in terms of response rate, progression-free survival, quality of life compared with chemotherapy. Lung cancer progression involve genomics, molecular properties of cancer cells and interaction with the immune system [17]. Vaccines immunothérapy have been proven ineffective. Approaches focused on ligands and receptors inhibiting or stimulating inhibitory checkpoint molecules generated upon T-cell activation, that regulate the immunological synapse between T cells and tumour cells hampering immune rejection are targets for immunotherapy [19]. Monoclonal antibodies directed to the PD receptor (nivolumab, etc.) or its ligand PD-L1 (atezolizumab, etc.) have shown rapid and durable responses in about 20% of patients with advanced NSCLC, playing a major role in treatment of this cancer.
6. Despite this advances in lung cancer treatment the best way to avoid this cancer is to never start smoking, or to quit as soon as possible.

Smoking cessation in lung cancer patients

Benefits of smoking cessation

a) Short term benefits

Smoking cessation is accompanied by short-term benefits [5]: improving cognitive performance, tissue oxygenation, increasing activity level, mood and appetite, reducing tiredness, breathlessness and cough, normalizing cardiovascular parameters.

b) Benefits in the longer term

Continued smoking in the early stages of NSCLC, is associated with increased risks of all-cause mortality (HR = 2.94; 95% CI: 1.15-7.54) and recurrence (HR = 1.8 ; 95% CI: 1.01-3.41). In cases of limited-stage SCLC, continuing smoking is associated with increased all-cause mortality (HR = 1.86; 95% CI: 1.33-2.59), recurrence (HR = 1.26; 95% CI: 1.06-1.50), and development of a second primary cancer (HR = 4.31, 95% CI: 1.09-16.98) [20].

On the other hand, smoking cessation at the time of diagnosis of early-stage lung cancer, improves prognosis: for NSCLC, 5-year survival is 33% for patients who continued to smoke versus 70% for those who quit smoking; for non-disseminated SCLC, 29% of smokers survive versus 63% of abstainers [20]. A prospective study [21] recruited 517 current smokers with NSCLC (IA-IIIA) and demonstrated a reduced risk of all-cause mortality (HR = 0.67; 95% CI: 0.53-0.85) and disease progression (HR = 0.70; 95% CI: 0.56-0.89), with 5-year overall survival (60.6% vs. 48.6%; P = 0.001) and progression-free survival (54.4% vs. 43.8%; P = 0.004) higher in patients who have given up smoking than in those who continued to smoke.

Smoking cessation enhances chemotherapy efficacy. On the contrary, continued smoking can induced interferences of pharmacodynamic or pharmacokinetic nature that may induce accelerated metabolism of irinotécan or erlotinib and increase in adverse events with cysplatin-based chemotherapy; stopping smoking corrects these disorders [3,5,22].

Perioperative complications (respiratory, cardiac, critical care), are more frequent (OR = 1.62; 95% CI: 1.25-2.11), one-year mortality is higher (OR = 1.50; 95% CI: 1.17-1.92) length of hospital stay longer (9.0% p < 0.001) in smokers compared with non-smokers [23]. Smoking cessation as soon as possible, at best 4 weeks before surgery, reduces these risks (19% less per week) [3,22]. Smokers have a poorer response to radiotherapy, with a higher risk of radiation pneumonia, lung infection and shorter life expectancy [3,5]. Finally, smoking cessation improves patients’ quality of life (QoL), irrespective of the lung cancer treatment and the QoL assessment method [3,5,24].

Smoking cessation management

1.The announcement of the diagnosis: a teachable moment

Announcement of lung cancer is a teachable moment and to advice stopping smoking, a component of lung cancer treatment [3]. Smokers with lung cancer have a higher level of motivation to quit than other patients (p < 0.003) and the abstinence rate at 6 months is higher (22% vs. 14 % ; p < 0.024). However, 10% to 20% of individuals are still smoking 6 months after diagnosis. Factors predictive of continued smoking have been identified: highly dependent smokers, depressive disorders, smoking of the spouse (OR = 9,57; 95% CI: 2,50-36,44) [3].

2. Counselling reinforces Stopping smoking

Practitioners provide empathy, avoid smoker stigmatization and specify benefits of quitting, increasing the patient’s self-efficacy sense. The five steps of the “5 A’s” strategy can help counselling: Ask (Identify tobacco use), Advise (urge smoker to quit), Assess (appreciate if smoker is ready to make a quit attempt), Assist (help smoker willing to quit to performe quit attempt ), Arrange (schedule follow up after the quit date); as well as the “5 R’s” method using open-ended questions can help patients to implement quit smoking: Relevance (encouraging smokers to give their reasons for quitting), Risks (helping them to identify the negative effects of smoking), Rewards (asking them about benefits when quitting smoking), Roadblocks (making them specify the obstacles to quit), Repetitions (repeating this motivational interview at each consultation) [3,5,25,26]. Simple reduction in consumption does not reduce the risk of all-cause mortality but using pharmacotherapies can prepare complete cessation [3,5,25,26].

3. Stopping smoking intervention

The smoker’s dependence on tobacco, motivation to quit and desire for therapeutic treatment are assessed. An intervention strategy is proposed and explained to the patient. Combining behavioural and cognitive therapies with smoking cessation pharmacotherapy gives the best results for smoking cessation [3,5]. Most smokers believe that they are able to quit on their own and are sceptical about the value of assistance to quit smoking. Smokers with cancer deserve treatment guidance from medical practitionners. They should be advised to stop smoking and informed of the evidence-based treatment methods that have been shown to increase cessation outcomes compared to unassisted quitting [25,26].

4. Cognitive and behavioral therapies (CBT)

Cognitive and behavioral therapies (CBT) are conducted at each step of follow-up, increase the efficacy of médications, reinforce the patient’s sense of self-efficacy, therapeutic compliance, enable better control of craving [3,5,25-27]. Long-distance support (telephone counselling) reinforce patients abstinence, as well as smoke-free home [3,5,25,26,28,29].

5. Pharmacotherapies

a) Primary option

Nicotine replacement therapy (NRT). Combination of short-acting NRT (gum, lozenge, spray) and long-acting NRT (patch) with a duration of 12 to 24 weeks, increases the odds of success nearly 3-fold compared with placebo (OR = 2.73; 95% CI: 2.07-3.65). No carcinogenic effects of NRT have been reported or demonstrated in humans [5,25,26], and the risk of overdose is very rare [25,30].

Varenicline, an α4β2-AChR partial agonist, is the most effective treatment with the odds of smoking cessation by almost 3-fold compared with placebo (OR = 2.88; 95% CI: 2.40-3.47) with a duration of 12 to 24 weeks. It does not interact with other medications. Side effects (nausea, vomiting, insomnia, vivid dream) can be troublesome for patients undergoing chemotherapy and require dose adjustment [5,25,26]. Varenicline has been taken off the market and this decision represents a loss of chance to quit smoking for lung cancer smokers.

b) Alternative options

Bupropion is a dopamine and norepinephrine reuptake inhibitor, effective in smoking cessation (OR = 2.07; 95% CI: 1.75-2.45). It may require dose adjustments in patients with hepatic or renal insufficiency. It can reduces the convulsive threshold, making it contraindicated in patients with epilepsy or brain metastases [5,25,26].

Combination of pharmacotherapies (NRT and bupropion, varenicline and NRT or bupropion) can increase cessation rate and decrease nicotine withdrawal symptoms and craving in high dependent smokers [3,5,25,26,31].

New option.

c) Cytisine

Cytisine is a plant-based alkaloid that binds selectively to α4β2AChR, used in some European countries to aid smoking cerssation; its lower cost may make it an affordable smoking cessation medication that could save millions of lives world-wide, particularly in low income countries. Pre-clinical studies have shown that it has a wide range of effects in alcohol addiction, mood regulation, food intake, motor activity, autonomatic cardiovascular system [32]. A double-blind, placebo-controlled, randomized trial compared 2 durations of cytisin (cytisinicline) treatment (3 mg, 3 times daily) 6 or 12 weeks vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily, wanted to quit has [33]. For the 6-week course of treatment vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 [OR = 8.0 (95% CI: 3.9-16.3); p < 0.001] and 8.9% vs 2.6% during weeks 3 to 24 [OR = 3.7 (95% CI: 1.5-10.2); P = 0.002]. For the 12-week course of treatment vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 [OR = 6.3 (95% CI, 3.7-11.6); p < 0.001] and 21.1% vs 4.8% during weeks 9 to 24 [OR= 5.3 (95% CI: 2.8-11.1); p < 0.001]. Adverse events occured in less than 10% of participants (nausea, abnormal dreams, insomnia), and 2,9% of participants discontinued cytisine due to an adverse event. Cytisine appears an efficient and well tolerate smoking cessation treatment.

How to improve the results of the quit attempt?

Smoker’s particularities

Specific smoking cessation difficulties give rise specific interventions:

1. Precarious smokers, with multiple co-morbidities and often psychiatric disorders, are at greater risk of not completing pre-operative home rehabilitation prior to resection for NSCLC [34], programs with NRT (combination of patch and oral forms) and a greater number of follow-up consultations help them quit smoking [35].
2. Transgender people are more likely than general population to suffer from precarious living conditions, higher prevalence of smoking and substance abuse, depressive disorders and numerous barriers to healthcare ; spcific tobacco cessation management must include specific information, motivation intervention, social support, action planning, and relapse prevention [36].
3. HIV-infected people often have high level of nicotine dependence and difficulty to quit smoking ; varenicline has been shown to be an effective smoking cessation treatment for these smokers [37].
4. Smoking is responsible for 9 out of 10 deaths related to chronic obstructive pulmonary disease (COPD), lung cancer is a major cause of these deaths. Smokers with COPD often have a high level of nicotine dependence, frequent depressive disorders and find difficult to quit [3,26]. The use of NRT, bupropion or varenicline, alone or in combination for 12, 24 weeks or more has been shown to be effective in helping patients quit smoking. Varenicline appears to be more effective in smoking cessation than other single medications. The combination of behavioural therapy and pharmacotherapy is superior to monotherapy in achieving smoking cessation. To optimize the effectiveness of pharmacotherapy, medication can also be introduced a few weeks before quitting [3, 38].
5. Tobacco consumption is strongly associated with various psychiatric disorders; this may explain the higher prevalence of smoking and lung cancer among people with psychiatric disorders, as well as the difficulty these people have in quitting smoking. The mechanisms linking mental health problems and smoking are diverse (genetic and environmental factors, nicotine’s action on the brain, nicotinic receptor abnormalities, redox phenomena, emotional regulation disorders, etc.) [39]. A study comparing the relative risk of neuropsychiatric safety and efficacy of varenicline, bupropion, the nicotine patch and placebo in smokers with and without psychiatric disorders showed no significant increase in neuropsychiatric adverse events attributable to the drugs or placebo. Varenicline was more effective than placebo, the nicotine patch and bupropion in helping smokers achieve abstinence; bupropion and the nicotine patch were more effective than placebo [40].

Electronic-cigarette (e-cig)

Despite a lack of knowledge regarding long-term safety and a lack of evidence about effectiveness for smoking cessation in smokers with lung cancer, electronic cigarette (e-cig.) is becoming increasingly popular. It might be safer than combustible cigarette, but long-term toxicity is not unlikely [41]. In lung cancer patients who continue to smoke, e-cig in an exclusive use, could be an alternative way to quit smoking [42,43]. A study focused at e-cig beliefs and use in a sample of smokers with cancer [44]. It has showm that 42% of the sample initiated e-cig use after cancer diagnosis; smoking cessation was the most frequently endorsed reason for initiating (81%) and maintaining (60%) e-cig use. Most participants (70%) reported no plans to stop using e-cig within the next year, and a third had plans to stop use within the next 6 months. Compared with combustible cigarettes, although NRT was rated as less addictive, less likely to generate cravings, less likely to result in negative social impressions, and more likely to be recommended by their oncology provider, participants viewed e-cig as less expensive, more satisfying, and more convenient. Participants also viewed e-cig as more useful for smoking cessation (p < 0.05) and more effective at reducing cancer-related stress than NRT (p < 0 .05). The most common source of information about e-cig was from friends (41%), and information rarely came from health professionnals (1.6%); participants reported that oncology providers were more likely to recommend NRT than e-cig (p < 0.001). Another study [45] recruited smokers with cancer (lung: n = 210 {19.8%], head and neck: n = 103 [9.7%], breast: n = 158 [14.9%], genitourinary: n = 85 [8%]), into a smoking cessation program at a cancer center (demographics, smoking history and smoking cessation follow-up outcomes were assessed). Compared with non-users, e-cig users were more addicted to nicotine, had made more attempts to quit smoking, and more often had lung, head or neck cancer. E-cig users were twice as often smokers during follow-up than non-users (OR = 2.0; 95% CI: 1.2-3.3); these results raise doubts about the usefulness of e-cig to quit smoking in cancer patients. Further studies are needed to verify the value of e-cig for smoking cessation in smokers with cancer.

What about heated tobacco products?

The tobacco industry reports that heated tobacco products (HTPs) reduce the risk of tobacco use and can replace combustible cigarettes; however, HTPs produce aerosols containing nicotine and toxic chemicals. Current evidence is insufficient to determine whether HTPs are less harmful than combustible cigarettes and may represent an alternative in persistent smokers with lung cancer. Hirata et al. [46] have investgate the effects of cigarette smoke extract from HTPs on lung cancer stem cells. They found that they induced proliferation and increased expression levels of stem cell markers. These results suggest that HTPs can induce lung cancer in vitro.

According to Braznell et al [47], there is an urgent need to explore the risks of lung cancer posed by HTPs, via clinical trials and epidemiological studies, and to confirm these risks using appropriate biomarkers.

Lung cancer screening and smoking cessation?

Several studies concluded that lung cancer screening using low-dose CT scans, aimed at patients aged between 50 and 80 who have smoked at least 20 pack-years, could reduce more than 20% lung cancer mortality, false-positive rate is less than 5% when the diameter of nodules is greater than 5 mm, suggesting the possibility of a more conservative surgical resection [17]. Lung cancer screening can help to raise smokers’ awareness of the need to stop smoking and to implement smoking cessation in a cost-effective manner [48,49]. However, in 2015, a survey conducted in US screening centers highlighted that only 36.6% of these sites provided optimal tobacco cessation services [50].

Improving smoking cessation management in cancer centers?

A cross-sectional study, conducted by the Cancer Center Cessation Initiative to clarify factors that improve smoking cessation has involved 28 centers and 692,662 patients [49]. Median smoking prevalence was 7.4%, evidence-based smoking cessation assistance was provided in 15.4%, and median 7-day abstinence at month 6 was 18.4%. The best results were achieved by centers with a smoking treatment protocol and the best resources, including expert professionals to support smokers [51].

All providers involved in oncology care must advise smokers to quit and support them during cessation, even if some of them have greater expertise. The organization of care for smokers and training for professionals in smoking cessation must be improved [52].

Conclusion

Smoking is the main cause of lung cancer. Smoking cessation is a component of cancer treatment and brings benefits to patients. The management of smoking cessation in the treatment of lung cancer patients needs to be improved. All healthcare professionals caring for lung cancer patients must be involved and trained in smoking cessation support.

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