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Lung cancer is the leading cause of cancer death in the US. About 50% of lung cancer patients are current smokers at the time of diagnosis and up to 83% continue to smoke after diagnosis. A recent study suggests that people who continue to smoke after a diagnosis of early-stage lung cancer almost double their risk of dying. Despite a growing body of evidence that continued smoking by patients after a lung cancer diagnosis is linked with less effective treatment and a poorer prognosis, the belief prevails that treating tobacco dependence is useless. With improved cancer treatments and survival rates, smoking cessation among lung cancer patients has become increasingly important. There is a pressing need to clarify the role of smoking cessation in the care of lung cancer patients.
This paper will report on the benefits of smoking cessation for lung cancer patients and the elements of smoking cessation treatment, with consideration of tailoring to the needs of lung cancer patients.
Given the significant benefits of smoking cessation and that tobacco dependence remains a challenge for many lung cancer patients, cancer care providers need to offer full support and intensive treatment with a smoking cessation program that is tailored to lung cancer patients’ specific needs.
A tobacco dependence treatment plan for lung cancer patients is provided.
Lung cancer is the leading cause of cancer death in the United States . Two or 3 out of every 100 men and 1 or 2 out of every 100 women, who are now 60 years old, will get lung cancer sometime during the next 10 years . Cigarette smoking is responsible for an estimated 90% of all lung cancers . The estimates for the prevalence of smoking at the time of lung cancer diagnosis have ranged from 24 to 60%, compared with 12–29% among the general US population [3,4,5,6,7]. Up to 83% of all smokers continue to smoke after a diagnosis of lung cancer [5, 8, 9]. Parsons et al.  found in a review of 10 studies that people who continue to smoke after a diagnosis of early stage lung cancer almost double their risk of dying. Despite a growing body of evidence that smoking cessation after a lung cancer diagnosis is linked to more effective treatment and a better prognosis, the belief prevails that treating tobacco dependence is useless .
Survival rates for lung cancer are improving every year; currently the expected 5-year survival for non-small cell lung cancer (NSCLC) is 60–75% for stage I and 36–60% for stage II disease . New anticancer agents, including angiogenesis and epidermal growth factor receptor inhibitors, have the potential to increase the number of lung cancer survivors . As lung cancer patients experience longer survival times they are more likely to benefit from the quality of life (QOL) improvements that abstinence from smoking can provide [14, 15]. In the past, smoking cessation has not been considered an integral part of the treatment of cancer but, with improved cancer treatments and survival rates, smoking cessation among cancer patients has become increasingly important . There is a pressing need to clarify the role of smoking cessation in the care of lung cancer patients. This paper will report on the benefits of smoking cessation for lung cancer patients and the elements of effective smoking cessation treatment, with consideration of tailoring to the needs of lung cancer patients.
Smoking cessation programs for lung cancer patients have long been thought to have more cost than benefit. Slatore et al.  developed a decision analysis model to evaluate the cost effectiveness of a smoking cessation intervention initiated immediately before surgical lung resection. The smoking cessation program was found to be cost-effective at both 1 and 5 years postsurgery. Smoking cessation for lung cancer patients yields both immediate and long-term benefits. There are significant positive effects of smoking cessation on the health of lung cancer patients: decreased risk of disease, increased survival time, decreased postoperative complications, increased efficacy of chemotherapy, decreased radiation therapy complications, and improved QOL.
The immediate benefits of cessation include improved oxygenation, lowered blood pressure, improved smell, taste, circulation and breathing, increased energy, and improved immune response . Smoking cessation is associated with improved cognitive function, psychological well-being, and self-esteem [18, 19]. Lung cancer patients report after successful smoking cessation all of the same benefits plus decreased fatigue and shortness of breath, increased activity level, and improved performance status, appetite, sleep, and mood [18, 20, 21]. These benefits are of special import because patients with lung cancer have a greater symptom burden than patients with other cancers .
Patients with pulmonary neoplasms have an increased risk of developing a second tumor of the lung, either at the same time or at a later time. The second tumor can represent an independent primary or a recurrence/metastasis . Smoking cessation can decrease the risk of synchronous multiple primary lung cancer tumors , metachronous lung cancers in small cell lung cancer survivors , and second primary tumors [25,26,27,28,29].
Nicotine induces polycyclic aromatic hydrocarbons (PAHs), products of incomplete combustion, which are some of the major lung carcinogens found in tobacco smoke . PAHs are also potent inducers of hepatic enzymes . Many drugs are substrates for hepatic CYP1A2, and their metabolism can be induced in smokers, resulting in a clinically significant decrease in pharmacologic effects. Thus, smokers may require higher doses of drugs that are CYP1A2 substrates. It is important to recognize that these pharmacokinetic drug interactions are caused by the PAHs in tobacco smoke, not the nicotine. Pharmacodynamic drug interactions with tobacco smoke are largely due to nicotine. Because it activates the sympathetic nervous system, nicotine can counter the pharmacologic actions of certain drugs . Nicotine replacement therapy does not contribute to the pharmacokinetic drug interactions discussed in this article .
Nicotine itself is not carcinogenic, but it has been shown that, in vivo, nicotine can induce the proliferation of lung cancer cell lines, promote angiogenesis, and promote resistance to apoptosis (cell death) induced by chemotherapeutic agents . These events are mediated through the nicotinic acetylcholine receptors (nAChRs) on lung cancer cells which impact on the efficacy of cisplatin, a frequently used chemotherapeutic agent . Nicotine can contribute to the progression of lung cancers because nicotine can promote anchorage-independent growth in NSCLCs and induce morphological changes characteristic of a migratory, invasive phenotype in NSCLCs .
Tucker  found that, compared to the general population, the risk of all second cancers among NSCLC patients was increased 3.5 times. Among those who received chest irradiation, second lung cancer risk was increased 13-fold in comparison to a 7-fold increase among nonirradiated patients. The risk was highest among current smokers; an interaction was present between chest irradiation and continued smoking (RR = 21), and a 19-fold risk increase was found among current smokers treated with alkylating agents. A synergism between chest radiation therapy and smoking in the development of second lung cancers was also found .
Gritz et al.  studied smoking behavior in 840 adults with stage I NSCLC; at the time of diagnosis, 60% of the patients were smokers. Two years after diagnosis, 40% of the smokers had quit smoking. According to this study, smoking cessation at the time of diagnosis of lung cancer may reduce the rate of development of metachronous tumors. Richardson et al.  found that the relative risk of developing a second lung cancer following curative-intent therapy for squamous cell lung cancer was lower for those who had stopped smoking.
Smoking cessation after a diagnosis of lung cancer has been linked to increased survival time [36, 37]. In a review of smoking cessation after diagnosis of a primary lung tumor, Parsons et al.  showed that the associated increase in risk of continuing to smoke is modest at around 20%; the adjusted estimates, however, suggested a more than doubling of the risk of death from continued smoking. Fox et al.  found that, among NSCLC patients diagnosed with early-stage disease, current smokers had a poorer prognosis for survival after radiation therapy. In their sample of 237 patients treated with definitive radiation or chemoradiation, 2-year overall survival was calculated from the time of initiation of treatment. Among those with stage I/II disease, current smokers had a 2-year survival rate of 41% and a median survival of 13.7 months while nonsmokers had a 2-year survival rate of 56% and a median survival of 27.9 months (p = 0.01). In a study of 5,229 patients with NSCLC and squamous cell lung cancer, the median survival times among those who had never smoked, former smokers, and current smokers with NSCLC were 1.4, 1.3, and 1.1 years, respectively (p < 0.01). The relative risk per 10 years of smoking abstinence was 0.85, demonstrating a direct biological effect of smoking on survival .
In a 2003 retrospective review (covering a 10-year period) of studies using a concurrent chemoradiotherapy regimen for patients with limited small cell lung cancer, those who continued to smoke during chemoradiotherapy had poorer survival rates than those who did not . Tammemagi et al.  found that current smoking at diagnosis was an important independent predictor of shortened lung cancer survival after adjusting for the baseline covariates age, gender, illicit drug use, adverse symptoms, histology, and stage. The relative risk for smoking (current vs. former/never) was 1.37 (95% CI 1.18–1.59; p < 0.001).
In 2010, Parsons et al.  conducted a systematic review with meta-analysis on evidence that smoking cessation after diagnosis of a primary lung tumor affects prognosis. The review revealed evidence that smoking cessation after diagnosis of early-stage lung cancer improves prognostic outcomes and most of the gain is likely due to reduced cancer progression.
Nonsmokers are at decreased risk of postoperative complications compared with smokers . Yildizeli et al.  assessed operative morbidity and mortality on NSCLC patients that underwent a sleeve lobotomy. Current smoking had a significant effect on the development of postoperative complications including infection, bronchopleural fistula , and morbidity and mortality .
In a 2005 prospective study of patients with primary or secondary lung cancer who were undergoing anatomical lung resection, the 4 groups studied were: nonsmokers (21%), past quitters of >2 months’ duration (62%), recent quitters of <2 months’ duration (13%), and ongoing smokers (4%). Overall pulmonary complications occurred in 8, 19, 23, and 23% of patients in these groups, respectively, with a significant difference between nonsmokers and all smokers (p < 0.03) . The risk of pneumonia was significantly lower in nonsmokers (3%) compared to all smokers (average 11%; p < 0.05), with no difference detected among subgroups of smokers (p < 0.17). When comparing recent quitters with ongoing smokers, no differences in pulmonary complications of pneumonia were found (p < 0.67). A smoking history of >60 pack-years (OR 2.54; 95% CI 1.28–5.04; p < 0.0008) was independently associated with overall pulmonary complications. In patients undergoing thoracotomy for primary lung cancer or metastatic cancer to the lung, there was no evidence of an increase in pulmonary complications among those who quit smoking within 2 months of having undergone surgery .
Both chemotherapy and radiation treatment are likely to produce fewer complications and less morbidity among nonsmokers than smokers [5, 45]. Smoking can have detrimental effects on the efficacy of chemotherapy including chemoresistance, chemoinsensitivity, and altered chemotherapeutic levels . Smoking can significantly affect the pharmacokinetics and toxicity profile of some drugs (e.g. irinotecan) . NSCLC patients with constitutional symptoms (i.e. fever, anorexia, and weight loss) and more pack-years of smoking are less likely to respond to chemotherapy .
As previously mentioned, some elements of cigarette smoke are known to affect drug metabolizing CYP enzymes and therefore affect treatment outcome. Nicotine in tobacco smoke can decrease the efficacy of certain drugs because of an increase in the metabolism of the drugs through the induction of hepatic enzymes . Van der Bol et al.  found that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Shepherd et al.  found that twice the normal dose of erlotinib was required to produce the necessary circulating levels of the drug in smokers compared to never-smokers. In a survival analysis, treatment with erlotinib (p < 0.001) and never having smoked (p < 0.01) were associated with longer progression-free survival. The interaction between smoking status and treatment was significantly predictive of a differential effect on survival . Studies have suggested that exposure to nicotine might negatively impact on the apoptotic potential of chemotherapeutic agents, including cisplatin .
Lung cancer patients who smoke have a 20% greater chance of experiencing radiation pneumonitis . The number of packages per year of cigarette smoking is significantly positively associated with infection in patients with NSCLC during radiotherapy . Fox et al.  found that, among NSCLC patients diagnosed with early stage disease, current smokers had a poorer prognosis for survival after radiation therapy.
The cessation of smoking after a lung cancer diagnosis has been consistently linked to an increase in QOL [7, 20, 26,27,28,29, 52]. Garces et al.  found that persistent cigarette smoking after a lung cancer diagnosis negatively impacted QOL scores. The adjusted mean total Lung Cancer Symptom Scale (LCSS) scores for never-smokers and persistent smokers were 17.6 and 28.7, respectively (p < 0.0001), with higher scores indicating greater severity of symptoms. Myrdal et al.  found that patients who smoked after surgery experienced impaired QOL compared with nonsmokers, and they had significantly lower scores for mental health and vitality than former smokers who stopped smoking at the time of surgery or before and than those who had never smoked.
Performance status is an important factor in QOL. In a recent study, records were reviewed for 206 patients with NSCLC; those who quit smoking after the diagnosis maintained a better performance status at 6 and 12 months, regardless of disease stage, age, race, sex, therapy types, and comorbidities, than those who continued to smoke. Those who quit smoking maintained a better performance status at 0–6 months (OR 7.09; 95% CI 1.99–25.3) and at 0–12 months (OR 6.99; 95% CI 1.76–27.7) than those who continued smoking .
Although the benefits of cessation are extensive, they are not generally known to lung cancer patients and their clinicians. The specific benefits of smoking cessation (both immediate and long-term) that relate to lung cancer symptom distress need to be incorporated into smoking cessation interventions. Tobacco dependence should be treated at the time of diagnosis of lung cancer, during treatment, and posttreatment.
Given the critical negative health effects of smoking on lung cancer survival and the major health benefits of smoking cessation, it is important that cancer care providers adopt the role of tobacco cessation treatment providers. The following section presents the clinical practice guidelines for treating tobacco dependence with a specific focus on the cancer care providers’ role.
Current guidelines for treatment of tobacco dependence have been published by the US Public Health Service in 2000 and updated in 2008 . The guidelines recommend use of the ‘5 A'ss’: clinicians should ask all patients about tobacco use, advise smokers to quit, assess willingness to make a quitting attempt, assist patients with quitting smoking, and arrange follow-up (table (table11).
In addition to counseling, all smokers attempting cessation should receive pharmacotherapy . First-line, FDA-approved medications for smoking cessation include nicotine replacement therapies (NRT), bupropion sustained release (SR), and varenicline (Chantix) (table (table2).2). An excellent resource that provides accurate, up-to-date pharmacotherapy information for smoking cessation treatment, including dosing, precautions, side effects, and costs is: ‘Rx for Change’, sponsored by the University of California, San Francisco School of Pharmacy (http://rxforchange.ucsf.edu). Rx for Change for Cancer Care Providers is a brief curriculum designed specifically for treating tobacco dependence in cancer patients and survivors.
There have been case reports of neuropsychiatric symptoms (behavior changes, agitation, depressed mood, and suicidal ideation or behavior) and reports of worsening of preexisting psychiatric illness. These reports are rare in comparison to the total number of patients using the medication . Clinicians need to closely monitor for neuropsychiatric symptoms while patients are using varenicline and bupropion as smoking cessation aids .
Patients with cancer may have higher levels of nicotine dependence, higher levels of co-morbidity, or more difficulty quitting, as well as poorer health and physical functioning, and more stress and emotional distress, suggesting the need for more intense or tailored programs [67, 68]. Given the impact of smoking on treatment (surgery, radiation, and chemotherapy), a patient's smoking status should be considered as part of the treatment decisions. Systematic advice received from multiple providers is more effective than advice from a single provider . A stepped care approach may be useful for patients experiencing difficulty with quitting . Schnoll et al.  highlighted the need for motivational smoking cessation interventions for cancer patients. They investigated the difference between cancer patients who enroll in smoking cessation programs and those that do not. Decliners were significantly more likely to have head and neck cancer (vs. lung cancer) and report a lower readiness to quit smoking. There are few randomized clinical trials investigating tobacco dependence treatment for lung cancer patients .
Tobacco dependence is a chronic disease and relapse is intrinsic to this disease. Lung cancer patients who smoke are, more often than not, highly dependent smokers. For the highly dependent smoker, tailored intensive interventions that combine behavioral interventions with pharmacologic cessation aides may be helpful . Combination pharmacotherapy has also been found to be effective with highly dependent smokers . Intensive interventions, however, may not be appropriate for all lung cancer patients, so other innovative interventions need to be considered. The use of telephone counseling has been shown to be effective among the general population and is now available in every state throughout the US (1-800-Quit-Now) . Evidence has shown that proactive counseling helps motivated smokers stay abstinent and that 3 or more calls increase the odds of quitting compared with standard self-help or brief health care provider advice .
Other literature that can inform tailored cessation counseling for lung cancer patients includes studies that have targeted older smokers. The mean age of lung cancer patients is 70 years . Hall et al.  purport that treatment for older smokers needs to conceptualize tobacco dependence as a chronic disease; most smokers have multiple quitting attempts and relapse is the norm [75, 76]. Hall et al. achieved abstinence rates with older smokers of more than 55% at 24, 52, 64, and 104 weeks using bupropion and extended cognitive behavioral treatment.
Only 3 smoking cessation intervention studies have been conducted with diagnosed lung cancer patients [45, 77, 78]. In 1997, a smoking cessation intervention was evaluated among patients with lung cancer during hospitalization. Upon admission, 87% of the subjects expressed intent to quit smoking in the next month. The intervention included only 15 subjects and consisted of 3 daily 20- to 30-min visits and 5 weekly follow-up phone calls. At 6 weeks postintervention, 14 (93%) subjects reported making at least 1 quitting attempt and 40% were confirmed abstinent. The finding suggested that a more intensive intervention can succeed and would be of interest to lung cancer patients . Browning et al.  evaluated the effectiveness of a smoking cessation intervention that included face-to-face and phone follow-up behavioral interventions with 14 patients with lung cancer. The number of subjects using NRT was not noted and only 3 subjects used bupropion. Cox et al.  found that nicotine dependence treatment is effective for patients with a lung cancer diagnosis and that the majority of lung cancer patients were motivated to quit smoking. The 6-month tobacco abstinence rate was 22% for the lung cancer patients compared with 14% for the control patients (p = 0.024). The intervention involved a brief consultation with a cessation counselor and a treatment plan individualized to the patient's needs. Data on the type of recommended interventions and whether patients adhered to these recommendations were not entered into the database. None of the interventions studied in the literature met the US Public Health Service Guidelines recommendation for a combination of both behavioral and pharmacologic treatment .
There are several additional features based on the 2008 guidelines for smoking cessation  to consider when treating tobacco dependence in patients with lung cancer.
The lung cancer experience is unique in many ways (with issues of self-blame and stigma, anticipated short survival time, and increased symptom burden and distress), the lung cancer patient who smokes is highly dependent on tobacco while faced with an urgent life crisis; research is needed to develop effective and tailored smoking cessation interventions. Given the prevalence of lung cancer patients who smoke and the significant benefits of smoking cessation, cancer care providers need to offer full support and tobacco dependence treatment that is tailored to patients’ specific needs. Intensive and extended tobacco cessation programs, including counseling with behavioral therapy and the use of nicotine replacement and combined pharmacology with extended follow-up, are highly efficacious, cost-effective, and a critical component of quality lung cancer care.
This research was supported by California Tobacco-Related Disease Research Program (TRDRP) grants 16RT-0149 and 17RT-0077, National Institute of Drug Addiction grant K23-DA018691, and National Institute of Nursing Research grant NR011934-01.
The content is solely the responsibility of the authors and does not represent the official views of the California TRDRP or NIDA. No Human Subject issues are involved, and there is no review board application.