Smoking Cessation, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

Peter G. Shields; Roy S. Herbst; Douglas Arenberg; Neal L. Benowitz; Laura Bierut; Julie Bylund Luckart; Paul Cinciripini; Bradley Collins; Sean David; James Davis; Brian Hitsman; Andrew Hyland; Margaret Lang; Scott Leischow; Elyse R. Park; W. Thomas Purcell; Jill Selzle; Andrea Silber; Sharon Spencer; Tawee Tanvetyanon; Brian Tiep; Hilary A. Tindle; Reginald Tucker-Seeley; James Urbanic; Monica Webb Hooper; Benny Weksler; C. Will Whitlock; Douglas E. Wood; Jennifer Burns; Jillian Scavone

doi:10.6004/jnccn.2016.0152

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Smoking Cessation, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

Authors:

Peter G. Shields

Peter G. Shields
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Roy S. Herbst

Roy S. Herbst
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MD, PhD

Douglas Arenberg

Douglas Arenberg
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MD, MS

Neal L. Benowitz

Neal L. Benowitz
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Laura Bierut

Laura Bierut
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Julie Bylund Luckart

Julie Bylund Luckart
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DNP, AOCNP, FNP

Paul Cinciripini

Paul Cinciripini
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Bradley Collins

Bradley Collins
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Sean David

Sean David
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James Davis

James Davis
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Brian Hitsman

Brian Hitsman
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Andrew Hyland

Andrew Hyland
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Margaret Lang

Margaret Lang
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Scott Leischow

Scott Leischow
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Elyse R. Park

Elyse R. Park
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W. Thomas Purcell

W. Thomas Purcell
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Jill Selzle

Jill Selzle
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Andrea Silber

Andrea Silber
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Sharon Spencer

Sharon Spencer
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Tawee Tanvetyanon

Tawee Tanvetyanon
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Brian Tiep

Brian Tiep
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Hilary A. Tindle

Hilary A. Tindle
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Reginald Tucker-Seeley

Reginald Tucker-Seeley
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James Urbanic

James Urbanic
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Monica Webb Hooper

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Benny Weksler

Benny Weksler
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C. Will Whitlock

C. Will Whitlock
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Douglas E. Wood

Douglas E. Wood
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Jennifer Burns

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Jillian Scavone

Jillian Scavone
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Volume/Issue:: Volume 14: Issue 11

Online Publication Date:: Nov 2016

DOI:: https://doi.org/10.6004/jnccn.2016.0152

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Cigarette smoking has been implicated in causing many cancers and cancer deaths. There is mounting evidence indicating that smoking negatively impacts cancer treatment efficacy and overall survival. The NCCN Guidelines for Smoking Cessation have been created to emphasize the importance of smoking cessation and establish an evidence-based standard of care in all patients with cancer. These guidelines provide recommendations to address smoking in patients and outlines behavioral and pharmacologic interventions for smoking cessation throughout the continuum of oncology care.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

An estimated 42.1 million adults in the United States currently smoke cigarettes, accounting for approximately 18% of the adult population.¹ Cigarette smoking results in more than 480,000 premature deaths yearly, and 1 in every 5 deaths are smoking-related.² Tobacco smoking has been implicated in causing cancers of the mouth, lips, nose, sinuses, larynx, pharynx, esophagus, stomach, pancreas, kidney, bladder, uterus, cervix, colon/rectum, and ovary, and myeloid leukemia.³ Moreover, tobacco use causes at least 30% of all cancer deaths.³

These guidelines emphasize the importance of smoking cessation in all patients with cancer and seek to establish evidence-based, standard-of-care recommendations tailored to the unique needs and concerns of patients with cancer. The recommendations contained herein describe interventions for cessation of cigarette smoking. However, the panel recommends that patients with cancer be encouraged to discontinue use of all combustible products (eg, cigars, hookah, marijuana) as well as smokeless tobacco products.

In a 2014 report from the Surgeon General, “The Health Consequences of Smoking—50 Years of Progress,” a comprehensive review of the evidence revealed the following important findings for patients with cancer and cancer survivors²:

Sufficient evidence exists to infer a causal relationship between cigarette smoking and adverse health outcomes, increased all-cause mortality (ACM), and cancer-specific mortality.
Sufficient evidence exists to infer a causal relationship between cigarette smoking and second primary cancer.
Evidence is suggestive of a causal relationship between cigarette smoking and risk of recurrence, poorer response to treatment, and increased treatment-related toxicity.

Although the harmful effects of smoking after a cancer diagnosis have been clearly demonstrated, many patients continue to smoke cigarettes during treatment and beyond. The prevalence of continued smoking among those who have received a cancer diagnosis has been examined in recent studies. The

rate of smoking postdiagnosis varies widely by cancer type and with other factors, such as sex, race, and age.

Smoking Prevalence in Patients With Cancer

Using data from the National Health and Nutrition Examination Survey, of the 566 cancer survivors who regularly smoked prior to their diagnosis, 64% continued to smoke postdiagnosis. Those identified as being at higher risk for continued smoking included female, younger, and Hispanic individuals.⁴ In the Cancer Care Outcomes Research and Surveillance cohort of patients with lung (n=2,456) and colorectal (n=3,063) cancers, 90% of those with lung cancers and 55% with colorectal cancer reported a history of smoking. At diagnosis, 39% of those with lung and 14% with colorectal cancer were current smokers, and of these individuals, 14% with lung and 9% with colorectal cancer continued to smoke at 5 months after diagnosis.⁵

Smoking often persists beyond cancer treatment and well into survivorship. In a population-based study using the Behavioral Risk Factor Surveillance System, survivors of tobacco-related cancers had a smoking prevalence of 27% compared with 16% and 18% for other cancer survivors and those without a history of cancer, respectively.⁶ Based on prospectively collected data from 772 individuals with cancer in the Cancer Prevention Study-II Nutrition Cohort, persistent smoking was observed in 68.7% and 57% of the cohort at 2 and 4 years postdiagnosis, respectively.⁷ One study revealed smoking prevalence to be highest among survivors of bladder, lung, and ovarian cancers.⁸ Other studies have found high prevalence of continued smoking in survivors of cervical cancers.⁹

Health Care Community Response

Given the adverse health effects and prevalence of smoking in patients with cancer and survivors, several leading national organizations have called on the oncology community for improved smoking cessation efforts. In 2013, the American Association for Cancer Research (AACR) released a policy statement calling for provision of evidence-based smoking cessation assistance to all patients with cancer, outlining the following objectives:

“Universal assessment and documentation of tobacco use by cancer patients in all clinical settings…;
Development of universal standards for measurement of tobacco use and exposure in clinical and research settings;
Incorporation of evidence-based tobacco interventions into review criteria used by research and health care quality and accreditation bodies; and
Recognition and support of the value of tobacco cessation interventions by health systems, payers, and research funders through provision of appropriate incentives for infrastructure development and intervention delivery.”¹⁰

Additionally, in a recent policy statement update, ASCO called on oncology professionals to treat tobacco dependence as aggressively and compassionately as cancer and to advocate for the wide availability of tobacco cessation services.¹¹

However, despite general consensus on the importance of smoking cessation, particularly for patients with cancer, many cancer centers and oncology practices report that they fall short of providing consistent, high-quality smoking cessation services. In a survey of 58 NCI-designated cancer centers, 20% reported offering no smoking cessation services for their patients, 38% did not routinely provide tobacco education materials to patients, and only half reported that they effectively identified tobacco use in their patients.¹² The AACR Task Force on Tobacco and Cancer found that few cancer care institutions use systematic and consistent mechanisms to foster cessation among patients with cancer.¹⁰

Several studies have linked increased patient satisfaction to the delivery of smoking cessation advice or intervention.^13,14 Data from large surveys of oncologists practicing in academic medical centers, nonacademic hospitals, and oncology practices depict generally high rates of smoking assessment and providing initial advice to quit.^15–18 However, smoking assessment rates were weaker outside of the academic/university setting (ie, for those practicing in a hospital-based, nonacademic, or private setting).¹⁸ Regardless of work setting, only 30% to 44% of respondents reported discussing specific interventions or providing subsequent follow-up. Moreover, the majority of respondents report inadequate training and/or a lack of confidence in ability to provide effective smoking cessation counseling and intervention.^15–18 A dearth of smoking assessment and documentation has also been demonstrated in oncology trials.^19,20

Issues regarding insurance coverage and provider reimbursement for smoking cessation assessment, counseling, and cessation aids have also presented a challenge for the oncology community in the past. However, implementation of the Affordable Care Act has led to changes designed to increase access to smoking cessation interventions.²¹

Barriers to Smoking Cessation in Oncology Patients

Although more than 68.8% of current smokers in the United States express a desire to quit and 52.5% report making a quit attempt within the past year, only 6.2% report recent smoking cessation.²² In the general population, individuals who smoke report a number of different barriers to quitting, including stress; dependence; home, work, and social environmental factors; and lack of resources and support for quitting.²³ Importantly, patients and providers in the oncology setting face additional life challenges that can amplify the magnitude of these barriers.

In a population-based analysis of individuals recently diagnosed with cancer who actively smoked, health professional–provided cessation counseling was provided to only 52% of individuals in the past 12 months.²⁴ Surveys of oncology providers have identified common themes among barriers to smoking cessation for patients with cancer. Inadequate provider training and lack of time are often cited by oncology providers as barriers to successful intervention.¹⁶ Providers have also cited patient-related factors, such as inability to quit, lack of motivation, or resistance to treatment.^15,16 However, pain, second-hand smoke exposure, guilt over smoking, fear of stigmatization, and fatalism regarding disease also represent obstacles unique to oncology patients, particularly those with advanced disease.^25–30

Notably, clinical trial research on smoking cessation for patients with cancer is limited, particularly for patients thought to have non–tobacco-related cancers. Barriers that limit or prevent enrollment in smoking cessation trials include smoking rate, medical history, contraindicated medications, lack of interest, and language barriers.³¹

Given the complexity of smoking cessation interventions for patients with cancer, there is a great need for resources that provide guidance on smoking cessation specifically for this patient population. The inaugural NCCN Guidelines for Smoking Cessation have been created to establish a standard of care for smoking cessation in patients with cancer. The NCCN Guidelines panel has developed these guidelines to facilitate implementation of this standard, allow for quality control monitoring, fill a gap among existing treatment guidelines, and ultimately, improve the health and outcomes for patients with cancer.

Literature Search Criteria and Guidelines Update Methodology

Prior to the development of this inaugural version of the NCCN Guidelines for Smoking Cessation, an electronic search of the PubMed database was performed to obtain key literature in smoking cessation for patients with cancer, published from August 2014 through November 2015, using the following search terms: smoking cessation[Title/Abstract]) AND (cancer[Title/Abstract] OR oncology[Title/Abstract]. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes only peer-reviewed biomedical literature.³²

The search results were narrowed by selecting studies in humans published in English. The PubMed search resulted in 216 citations, and their potential relevance was examined. The data from key PubMed articles selected by the panel for review during the update meeting as well as articles from additional sources deemed relevant to these guidelines and discussed by the panel have been included in this version of the Discussion section (eg, e-publications ahead of print, meeting abstracts). Recommendations for which high-level evidence is lacking are based on the panel's review of lower-level evidence and expert opinion.

The complete details of the development and update of the NCCN Guidelines are available on NCCN.org.

General Principles of the Smoking Cessation Guidelines

The recommendations in these guidelines apply to cessation of cigarette smoking for patients with cancer; however, the panel strongly recommends that patients also discontinue use of all combustible products, including cigars, hookah, and marijuana, as well as smokeless tobacco products. Smoking cessation has health benefits even after a cancer diagnosis, regardless of stage or prognosis—namely improvement in cancer treatment outcomes, disease recurrence, and secondary cancers. Importantly, a diagnosis of cancer may present a teachable moment and valuable opportunity for providers to encourage smoking cessation.^7,33,34 It is the view of the NCCN Guidelines panel that it is never too late for patients with cancer at any stage to stop smoking cigarettes.

Because smokers with cancer often demonstrate high-level nicotine dependence, the panel recommends a multimodal approach to cessation therapy. The NCCN panel recommends that treatment plans for all smokers with cancer include the following 3 tenets: evidence-based motivational strategies and behavior therapy (counseling), which can be brief; evidence-based pharmacotherapy; and close follow-up with retreatment as needed.

The panel asserts that a smoking cessation approach combining pharmacologic therapy and behavior therapy is the most effective and leads to the best results for smoking cessation. The 2 most effective pharmacotherapies are combination nicotine replacement therapy (NRT) and varenicline. There is a dose–response relationship for the success of counseling; high-intensity behavior therapy with multiple counseling sessions is most effective, but at least a minimum of brief counseling is needed and effective.^35–38

The panel also emphasizes the importance of documenting smoking status and treatment plans in the patient health record. Patient health records should be updated at regular intervals to indicate changes in smoking status, quit attempts made, and interventions used.

The panel emphasizes that smoking relapse and brief slips are common. Providers should discuss this with patients and provide guidance and support to encourage continued smoking cessation attempts despite slips. Additionally, providers should be aware that smoking slips do not necessarily indicate a need for an alternative intervention. More than one quit attempt with the same therapy may be necessary to achieve long-term cessation.

Finally, smoking cessation interventions should be offered and continued throughout the oncology care continuum, including during end-of-life care. Emphasis on patient preferences and values is important when considering the best approach to fostering smoking cessation in that setting.

Smoking-Associated Risks for Patients With Cancer

Exposing cancer cells to cigarette smoke has been shown to promote a more malignant phenotype through its effects on angiogenesis and cell proliferation, migration, invasion, and survival. Sobus and Warren³⁹ provide a review of the preclinical data. These data have been corroborated by clinical studies. Per the Surgeon General's Report, The Health Consequences of Smoking—50 Years of Progress,² sufficient evidence exists to support a causal relationship between smoking and adverse health outcomes, increased ACM and cancer-specific mortality, and increased risk for secondary primary cancers. Additionally, existing evidence suggests a link between smoking and increased risk of cancer recurrence, poor treatment response, and increased treatment-related toxicity.

NCCN recommends that providers inform patients of the potential benefits of smoking cessation, including improved survival, treatment outcomes, and health-related quality of life, as well as decreased treatment-related toxicity, drug side effects, and surgical complications. Patients should receive education on the specific risks of smoking during treatment for their particular cancer and should be encouraged to stop smoking as far in advance as possible before initiating cancer treatment. Prior to initiating treatment, when making decisions regarding treatment selection, dosage, and timing of initiation, providers should consider patient smoking status and potential smoking-related effects.

Overall Survival and Mortality

Smoking has been linked not only to the development of disease in tobacco-related cancers but also to prognosis at diagnosis and risk of death during treatment. Evidence suggests that current smoking increases risk of death and negatively impacts survival for patients with cancer in a variety of disease sites, including bladder,^40–42 breast,^43,44 cervix,^45,46 colon/rectum,^47,48 endometrium,⁴⁹ esophagus,^50,51 head and neck,^52–54 kidney,^55,56 lung,^57–60 ovarian,⁶¹ pancreas,⁶² and prostate,⁶³ as well as hematologic malignancies.⁶⁴

Prospective studies of smoking at cancer diagnosis offer insight into the negative effects of smoking on overall survival, disease-specific mortality, and ACM. In the 2014 Surgeon General's report, a comprehensive review of the data assessing smoking and ACM in patients with cancer revealed that 87% of the studies (139/159) indicated increased risk, whereas 62% of all studies (99/159) demonstrated a statistically significant risk increase.² Also, more than half of the reviewed studies found at least a 50% increase in risk of death.² Additionally, among the studies examining overall survival in patients with cancer who smoke, 77% (48/62) were indicative of shortened survival, with 42% (26/62) revealing statistical significance.² Finally, smoking in patients with cancer was associated with higher disease-specific mortality in 79% of studies reviewed (46/58), with a statistically significant link between cancer-related mortality and patients' smoking status in 59% (34/59).²

Risk of Recurrence or Secondary Primary Tumor

A number of studies have linked cigarette smoking and heightened risk of recurrence (ie, recurrent cancer in the same anatomic location as the original primary cancer). The 2014 Surgeon General's Report identified a positive association between smoking and risk of recurrence in 82% of the reviewed studies (42/51), with 53% of studies revealing significantly increased risk.² Among the studies that compared relative risk (RR) of recurrence between never-smokers, former smokers, and current smokers, the median RR was 1.42 and 1.15 for current and former smokers, respectively.²

Disease sites with data linking current patient smoking to increased risk of recurrence include the anus,⁶⁵ bladder,^40,66,67 breast,⁶⁸ lung,⁵⁷ stomach,⁶⁹ and prostate.^63,70–72

Studies have also examined the impact of continued smoking in patients with cancer on the risk of second primary tumor formation. The 2014 Surgeon General's Report identified a positive association between smoking and risk of second primary tumor in all studies examined (n=26). The association was strongest when considering the effects of smoking on RR of developing a smoking-related second primary cancer (eg, lung cancer). Among 5 studies classifying smoking status into “never,” “former,” and “current,” the median elevated RR of a second primary tumor was 1.20 and 2.20 for former and current smokers, respectively. Data from a large retrospective series and pooled data analyses have continued to provide support for smoking and increased risk of second primary malignancy, especially smoking-associated cancers.^73,74 Additionally, data also suggest that smoking interacts synergistically with radiation therapy (RT) to elevate the risk of second primary cancers.^2,75,76

Smoking-Related Effects on Treatment Efficacy, Side Effects, and Outcomes

Most of the existing data establishes and supports the detrimental impact of persistent smoking during cancer treatment. In a 2014 report from the Surgeon General, 80% of the evaluated studies (66/82) demonstrated a statistically significant association between active smoking and increased anticancer treatment–related toxicity.² Smoking has implications across the spectrum of cancer treatment, including surgical outcomes, RT efficacy and toxicity, chemotherapy metabolism and side effects, and overall symptom burden. This discussion also addresses the developing evidence base for the benefits of smoking cessation after receiving a cancer diagnosis.

Smoking-Associated Risks: Surgery: Smoking has been shown to negatively impact outcomes from cancer surgery, affecting postoperative complications, quality of life, length of hospital stay, and mortality risk.

In lung cancer, studies show that smoking impacts the success of surgical resection, decreases postoperative quality of life, and increases persistent dyspnea and thoracic pain at 12 months postoperatively.^77,78 Analysis of data from 7,990 patients who had primary resections for lung cancer (Society of Thoracic Surgeons General Thoracic Surgery Database) revealed increased risk of hospital death and pulmonary complications associated with smoking.⁷⁹

The adverse effects of smoking on postoperative outcomes was examined in more than 20,000 patients with gastrointestinal (n=12,432), lung (n=4,490), and urinary tract cancers (n=3,491) using the Veteran's Health Administration Surgical Quality Improvement Program database for 2002 through 2008.⁸⁰ Surgical complications examined included surgical site infections, vascular complications (venous thromboembolism, stroke/cerebrovascular accident, myocardial infarction), and composite pulmonary outcomes (CPOs; pneumonia, failure to wean from ventilator more than 48 hours, or reintubation for cardiorespiratory failure). Across all 3 cohorts, never-smokers had fewer complications than former and current smokers. Compared with prior smokers, current smokers in the gastrointestinal cancer cohort had higher postoperative rates of pneumonia, failure to wean from ventilator, reintubation, and CPO. In the lung cancer cohort, current smokers had higher rates of pneumonia, failure to wean from the ventilator, reintubation, CPO, and return to surgery compared with former smokers. Current smoking status was associated with an increased hospital stay across all cancer sites when compared with never-smokers; never-smokers and prior smokers did not differ on this measure.

Postsurgical outcomes (ie, incisional infections, infectious and major complications, and mortality at 30 days) were compared between cohorts of never-smokers, former smokers, and current smokers using data from more than 26,000 patients with colorectal cancer in the American College of Surgeon's National Surgical Quality Improvement Program database (2005–2010). Postoperative morbidity and mortality rates were higher among current smokers, and a significant dose-dependent effect was observed when stratifying risk of major complications by pack-years of smoking.⁸¹

In patients undergoing hematopoietic stem cell transplantation to treat acute leukemias, pulmonary complications and longer postoperative hospital stays were more commonly observed in patients who smoked.⁸²

Smoking can also impair wound healing and predispose patients to surgical complications for those undergoing reconstructive surgeries after cancer treatment. Among patients with breast cancer who underwent transverse rectus abdominis myocutaneous flap breast reconstruction surgery, smoking was associated with significantly higher risk of flap complications and delayed healing,^83,84 and evidence suggested that complication risk was reduced by smoking cessation of at least 4 weeks prior to surgery.⁸³ In patients with stage III or IV squamous cell carcinoma of the head and neck, serum cotinine concentration was dose-dependently linked to increased risk of wound complications after reconstructive head and neck surgery.⁸⁵

Radiation: Studies have shown that prior smoking and active smoking during RT may decrease treatment response and increase complication rates, particularly for patients with head and neck cancers, but also in those with cervical, lung, breast, or prostate cancers.

In patients with head and neck cancer receiving RT, current smokers had poorer rates of locoregional control.^53,86 In another cohort, patients with head and neck cancer who continued to smoke during RT had lower rates of complete response and worse survival times than nonsmokers or those who quit prior to treatment.⁸⁷ Continued smoking during RT in patients with head and neck cancer has also been shown to increase the rates of treatment-related complications. In patients with laryngopharyngeal cancers, smoking during treatment was associated with significantly elevated incidence of osteoradionecrosis and hospitalization during treatment.⁸⁸ Another study demonstrated a significantly greater decline in several health-related quality-of-life measures in patients who continued to smoke during therapy compared with those who quit beforehand.⁸⁹

Among 3,489 patients receiving RT as part of treatment for stage I or II cervical cancer, heavy smoking (defined as ≥1 pack/day) was the strongest independent factor in predicting long-term major bladder, rectal, or small bowel complications, with even light/moderate smoking (<1 pack/day) predisposing patients to small bowel complications.⁹⁰ In another study of 565 patients with cervical cancer who were receiving primary RT, patients who smoked during treatment had lower cure rates, higher frequency of RT side effects, and higher rates of severe, irreversible complications.⁹¹

Smoking during RT for non–small cell lung cancer was associated with significantly decreased locoregional control.⁹² Active smoking may also decrease the efficacy of RT for prostate cancers and increase the prevalence of long-lasting treatment related effects on the bowel and anal sphincter.^93–95 Concurrent smoking and RT increased the risk of cardiovascular disease in 4,414 10-year survivors of breast cancer.⁹⁶

Chemotherapy/Systemic Therapy:Data on the impact of smoking on chemotherapy are much more limited than those for surgery and RT, partly because smoking quantity during treatment is often left out of the medical record.¹⁹ Many of the purported effects of smoking during chemotherapy are extrapolated from what is known about the impact of chemotherapy and smoking as individual factors of health. Smoking has the potential to exacerbate the risk of anticancer drug-related pulmonary and cardiac toxicities, such as cardiomyopathy and pulmonary fibrosis.⁹⁷ Combining neoplastic agents with radiation while smoking may lead to further toxicity. Additionally, cancer drug side effects such as weight loss, cachexia, and fatigue may also be increased by smoking during treatment.^97,98

Many systemic anticancer agents result in some degree of immune suppression/compromise, and smoking during chemotherapy may further compromise immune function in an already vulnerable patient population.^19,97 Preclinical and clinical studies suggest that smoking and nicotine exposure can be detrimental to the function of both the adaptive^99–102 and innate immune system.^103–107 Similarly, cigarette smoking may increase the incidence of infection, particularly for smoking-related infectious diseases such as pneumonia and influenza.¹⁰⁸

Preclinical studies also suggest a potential link between nicotine exposure from smoking and the development of chemoresistance,^109–113 although no clinical data are currently available to support these findings.

Smoking can also impact the metabolism of certain cytotoxic chemotherapies and other systemic therapy. Smoking effects on cytochrome P450 enzymes may alter drug clearance time and plasma concentration, potentially impacting the efficacy of certain drugs for patients who smoke.¹¹⁴ Providers should consider whether patients are at risk for altered drug metabolism due to smoking and determine whether medication or dose adjustments may be required.

Drugs with metabolisms that are known to be affected include erlotinib and irinotecan. Rapid drug clearance has been observed in smokers who were receiving erlotinib therapy, such that higher doses may be required to achieve equivalent systemic exposure to standard dosing in nonsmokers.^115,116 Similarly, smoking increases the clearance time of irinotecan, potentially lessening systemic exposure.^115,117 Given the narrow therapeutic index of systemic therapy for lung cancer, small changes in drug exposure due to smoking could affect treatment efficacy and patient outcomes.¹¹⁵ Bendamustine metabolism is also likely to be impacted by smoking, resulting in decreased drug plasma concentration and increased concentration of its active metabolites.^118,119 However, smoking does not appear to alter the pharmacokinetic properties of taxane chemotherapeutics (eg, docetaxel, paclitaxel) despite its paradoxical protective effects on drug-induced neutropenia and leukopenia.¹²⁰

Symptom Burden: In a study of 947 patients who were undergoing chemotherapy and/or RT, smoking during treatment was linked to a higher overall burden of symptoms commonly experienced among patients with cancer. In analyses that controlled for age, sex, race, education, occupation, treatment, cancer site, and Karnofsky performance score, current smokers had a significantly higher symptom burden compared with nonsmokers, both during treatment and 6 months afterwards.¹²¹ Active smoking in patients with advanced lung cancer was associated with greater symptom burden on diagnosis and poorer health-related quality of life post-diagnosis.¹²² Additional studies suggest that current smokers with cancer may experience more severe or frequent pain than nonsmoking counterparts.^123–126

Benefits of Smoking Cessation for Patients With a Cancer Diagnosis: For many smokers, the benefits of smoking cessation can be appreciated immediately through reduced blood carbon monoxide levels, decreased irritative respiratory symptoms (eg, cough, shortness of breath), and improved lung function. In the long term, cessation is associated with reduced risk of smoking-related disease, development of malignancy, and smoking-related mortality.¹²⁷ Although the deleterious effects of smoking after a cancer diagnosis are well documented and understood, research on the benefits of cessation post-diagnosis is much more limited.^10,128 For patients with cancer, the potential benefits and risk reductions associated with cessation are of critical importance.

Studies have begun to assess the impact of smoking cessation at or near the time of a cancer diagnosis by comparing outcomes of patients who continue to smoke during cancer treatment to those who quit prior to treatment (“recent quitters”). Studies generally show that recent quitters have survival outcomes intermediate to that of never-smokers and current-smokers, suggesting a measurable benefit of cessation post-diagnosis. The data to support this survival pattern are derived primarily from cohorts of patients with lung or head and neck cancers,^{57,59,87,129–131} but similar patterns have been observed for other disease sites.^59,132

A prospective longitudinal study examined the impact of smoking at diagnosis in 5,185 patients with cancer across 13 disease sites over the course of at least 12 years.⁵⁹ In this study, recent quitters were examined as a specific subset of former smokers who quit within 1 year of the study's structured smoking assessment, allowing for comparisons to individuals who actively smoked during cancer treatment. For disease sites with larger recent quit cohorts (ie, lung, head /neck cancers), recent quitters had lower overall mortality risk compared with continued smokers (current smoker vs recent quitter: lung cancer hazard ratio [HR], 1.38–1.42; head/neck cancer HR, 2.11–2.15).⁵⁹ Similarly, a systematic review and meta-analysis of 10 observational studies indicated a 5-year survival benefit for patients with lung cancer who quit smoking compared with patients who continued smoking (70% vs 33%).⁵⁷ In a comprehensive cancer center study that controlled for disease characteristics, smoking history, and patient demographics, 250 patients with lung cancer who quit smoking had statistically improved survival time of 9 months over those who continued to smoke through treatment and beyond.¹³³

Smoking cessation is linked to reduced risk of recurrence and second primary tumor formation. Data from patients with lung and head and neck cancers showed that rates of second primary cancers were lower for patients who quit smoking than for those who continued to smoke after diagnosis.^130,134,135 In a cohort of patients with colon cancer, active smokers were at significantly greater risk for baseline metastasis, but interestingly, rates among former smokers and never-smokers were similar and significantly less in comparison.¹³⁶

Cessation at or near cancer diagnosis appears to reduce treatment-related complications compared with patients who continued smoking. In patients undergoing lung cancer resection, preoperative cessation mitigated the risk of pulmonary complications and in-hospital mortality. Risk-adjusted odds ratios for mortality and pulmonary complications decreased as preoperative cessation time increased from 14 days to 1 month, to 1 to 12 months, and to more than 12 months.⁷⁹ A retrospective study of 188 patients undergoing reconstructive surgery after treatment for head and neck cancer revealed that preoperative smoking cessation of at least 3 weeks led to lower incidence of wound healing complications than among patients who continued smoking.¹³⁷

Cessation has been shown to lead to improvements in various measures of general health and well-being for patients with cancer. Smoking cessation improved performance status at 6 and 12 months post–lung cancer diagnosis compared with continued smokers when adjusting for disease stage, patient demographics, therapy, and comorbidity.¹³⁸ Additionally, patients with cancer who quit smoking benefited from lower rates of smoking-related cardiovascular and pulmonary disease.¹³⁹

Evaluation and Assessment of Patient Smoking

These guidelines highlight the importance of evaluating and assessing smoking status and history in patients with cancer. In a recent policy statement, the AACR emphasized the need for universal assessment and documentation of tobacco use by patients with cancer both in the standard clinical setting and in oncology clinical trials.¹⁰ The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force recently published proposed core and extension items to be used for the assessment of tobacco use in patients with cancer enrolled in research trials.¹⁴⁰ However, current practice is suboptimal, as inadequate or inconsistent assessment and documentation of smoking status has been reported both in the care setting and in the context of clinical trials.^12,20

Despite the demonstrated adverse effects of smoking during cancer treatment, a large proportion of cancer clinical trials do not collect adequate, up-to-date information regarding patient smoking status and history, particularly for malignancies other than well-known tobacco-related cancers (eg, lung, head and neck cancers).^19,20 Such assessments are needed to make evidence-based determinations of the impact of smoking on patients, treatment efficacy, and side effects.

In a large study conducted at a comprehensive cancer center, a smoking assessment questionnaire was integrated into the electronic health record (EHR) in order to automatically identify and refer appropriate candidates for onsite cessation services. The smoking assessment items incorporated into the EHR were refined based on analysis of responses from an initial patient screen containing 23 items. Response analysis revealed that the most effective questions for generating referrals included whether (1) patients smoked cigarettes every day, some days, or not at all; and (2) if/what other types of tobacco products were used. For former smokers, it was important to assess the last time a patient smoked a cigarette, “even a puff,” and for established enrollees to the cessation program, what types of cessation aids were being used.¹⁴¹ The study revealed that just 3 assessment questions made it possible to efficiently and accurately identify the vast majority (>98%) of current smokers or those at risk for smoking relapse.

Determining Smoking Status

The NCCN Guidelines for Smoking Cessation advocate for smoking status to be updated in the patient's health record at regular intervals to indicate any status changes or quit attempts. To do so, the panel recommends the providers initially ascertain whether (1) the patient has ever smoked, and if so, then initially and at regular intervals; (2) the patient is a current smoker; and (3) the patient has smoked within the past 30 days. All information should be recorded in the medical record. As a follow-up to the initial evaluation, these guidelines direct providers to a tailored patient assessment based on smoking status and history. Specific algorithms for current smokers (patient smoked within the last 30 days) and recent quitters/former smokers (>30 days since patient last smoked) are included. For never-smokers or longer-term former smokers, providers should urge patients to remain smoke-free, providing them with the benefits for remaining smoke-free.

Assessing Smokers: In patients who are current smokers (or those who have smoked in the last 30 days), providers should assess nicotine dependency to understand the chances for success and risk of relapse, and document the findings in the patient's health record. To assess nicotine dependency, providers should query patients regarding the number of cigarettes smoked per day, how soon the patient smokes after waking up in the morning, whether the patient uses other forms of tobacco (eg, pipes, cigars, snuff, e-cigarettes), and if so, what quantity. The Fagerstrom Test for Nicotine Dependence is an alternative standardized tool for assessing nicotine dependence.¹⁴² However, the panel has opted to recommend a more streamlined assessment for use in the oncology setting.

In order to best tailor treatment, providers should also gather information regarding the patient's history of quit attempts and why they were or weren't successful. Specifically, providers should ascertain the longest period of abstinence achieved, the date of the most recent quit attempt, what cessation aids were used, and why these failed. It is important to document the patient's previous experience with smoking cessation aids, including any medications, behavior therapy, e-cigarettes, quit-lines, Web sites, smart phone applications, or other media aids. The patient's perspective on why these aids were unsuccessful—such as medication side effects, continued cravings, or inefficacy—are important pieces of information.

Patient readiness to quit within the next month should be determined. Providers are encouraged to engage patients in a motivation dialog about smoking and to ensure patients are aware of the disease-specific risks of smoking and benefits of quitting. Educational resources should be provided. The panel recommends that clinicians provide patients with reasons, ideas, and needs for smoking cessation, emphasizing the importance of both encouragement and directness with patients who smoke. When incorporating motivational interviewing (MI) to promote willingness to quit, the panel emphasized the importance of the following general principles: (1) express empathy, (2) develop discrepancy, (3) roll with resistance, and (4) support self-efficacy.^143,144 For a summary of the methods and data on MI for smoking cessation, see “Principles of Behavior Therapy,” page 1459.

If patients are not ready to quit within the next month, providers should assess and address patient-reported barriers and concerns regarding cessation. When possible, providers should work with patients to set a near-future quit date and/or consider smoking reduction with the goal of cessation in the near future. The panel encourages immediate initiation of pharmacotherapy for targeted smoking reduction with a goal of cessation in the near future. A meta-analysis of 10 randomized trials in 3,760 patients with cancer found quit rates to be comparable when comparing abrupt cessation versus gradual smoking reduction.^145,146 Therefore, both options can be used after discussions with the patient. Trial data since then have continued to mirror this trend of comparable success rates with abrupt cessation and gradual reduction.¹⁴⁷ At each visit, providers should reassess readiness to quit and engage in motivational dialog as indicated.

Assessing Former Smokers/Recent Quitters: To evaluate patients who recently quit at least 30 days prior, providers should assess and document the patient's risk of relapse. The panel suggests the following characteristics to identify patients at high risk for relapse: frequent/intense cravings; elevated anxiety, stress, or depression; cohabitating or working with smokers; quitting within the past year; use of ongoing smoking cessation treatment; and drug/alcohol use or abuse. The panel considers patients demonstrating at least one of these characteristics to be at higher risk for relapse and recommends a management plan tailored to prevent relapse. Providers should discuss risk of relapse with patients and provide guidance and support to promote continued smoking cessation attempts. As indicated, patients with anxiety and/or depression should be to a specialist to manage psychiatric comorbidities.

Management of patients who demonstrate an elevated risk of relapse includes behavior therapy with counseling on relapse risk factors and relapse prevention. Short-acting NRT can be considered to promote maintenance of abstinence. Providers should review smoking-associated risks for patients with cancer and the health benefits of abstinence. All management plans and counseling should be documented in the patient health records. For patients deemed to be at low risk for relapse, providers should reinforce success and highlight the importance of continued abstinence. Risk of relapse should be re-evaluated at subsequent visits.

It is important to regularly reevaluate patients' smoking status and risk of relapse, which can be accomplished in person or by phone. If relapse occurs, patients should be evaluated per the recommendations for current smokers. Additionally, providers should remain aware that patient self-report of smoking status may underestimate the rate of active smoking among patients with cancer, as is evidenced by research comparing self-reported and objective measures.^148–150 Patients who remain smoke-free should regularly undergo reevaluation with documentation of any risk factor changes.

Smoking Cessation During Cancer Treatment

Devising a Treatment Plan

Following assessments, providers should establish a personalized quit plan for each patient that takes into account the patient's nicotine dependency, prior quit attempts and any cessation aids used, and smoking cessation therapy options. Providers should work with patients to set a quit date as soon as possible. Risk of relapse and smoking slips should be discussed with the patient, along with reassurance and support for continued cessation efforts should slips occur.

Smoking Cessation and Cancer Surgery: Smoking has been shown to increase the risk of pulmonary complications, surgical site infection, and poor wound healing in patients undergoing surgery. For an overview of the data, see “Smoking-Related Effects on Treatment Efficacy, Side Effects, and Outcomes, page 1448. Study findings generally support the benefits of preoperative smoking cessation, which has been shown to reduce postoperative morbidity in patients undergoing surgery for various cancer types.^79,151,152

For patients with planned cancer surgery, cessation should occur as far in advance as is feasible. Although longer periods of preoperative smoking cessation may confer better surgical outcomes,¹⁵³ the panel emphasizes that patient smoking should not delay appropriate timing for cancer resection, and access to cancer surgery should not be restricted based on smoking status. Preoperative smoking cessation interventions that combine pharmacotherapy with behavioral therapy may be most effective.^154–157 NRT at the normal doses has not been shown to negatively affect acute wound healing,^158–160 and therefore functions as a valuable adjunct to perioperative smoking cessation.

Elective procedures, such as plastic surgery reconstruction, may benefit from delaying surgery for a period of time after smoking cessation. Currently, consensus on an optimal time period of preoperative cessation has not been demonstrated through the existing literature.¹⁵³ Providing surgery-specific resources and advice for smoking cessation may facilitate smoking reduction or cessation in patients undergoing elective (noncancer) surgery.^161,162

Preferred Primary Therapy Options

Based on clinical trial data of smoking cessation in patients with cancer, the panel recommends a combination frontline approach including pharmacotherapy and behavior therapy for smoking cessation for patients with cancer. Population studies and meta-analyses of randomized or quasi-randomized trial data support the addition of behavior therapy to pharmacotherapy to enhance the rate of success.^163–165

Preferred primary therapy options in these guidelines are (1) combination NRT (combined long- and short-acting NRT); or (2) varenicline (typical initial duration of 12 weeks). The combination NRT approach includes the use of nicotine patch plus a short-acting NRT (eg, for breakthrough craving), such as nicotine gum, lozenge, inhaler, or nasal spray. As a general principle, the panel recommends trying both preferred primary therapy approaches (combination NRT and varenicline) before proceeding to any of the subsequent pharmacotherapy options. See “Treatment for Persistent Smoking or Relapse,” on this page, for additional details. Pharmacotherapy regimens should always be paired with behavioral counseling.

Providers should note that nausea is a common side effect of varenicline and may need to be managed in patients with cancer who are receiving chemotherapy. Additionally, varenicline (and bupropion) should be avoided in patients with brain metastases due to increased seizure risk. For discussion of the evidence for individual pharmacotherapeutic regimens, see “Principles of Pharmacotherapy,” page 1455.

Follow-up

Assessment of smoking status and toxicity of pharmacotherapy should be performed within 2 to 3 weeks of initiating therapy and on a periodic basis moving forward, but at no more than 12-week intervals, including within approximately 12 weeks after completion of pharmacotherapy. Nicotine withdrawal symptoms typically peak within 1 to 2 weeks of cessation before subsiding. Initial follow-up within 2 weeks of initiating smoking cessation therapy is important in order to assess efficacy and toxicity of pharmacotherapy. Providers should encourage continued treatment adherence through brief slips, with adjustments to dose or behavior therapy frequency as indicated. Undesirable side effects may also warrant dose adjustments.

When possible, in-person follow-up during planned clinical visits or individual/group therapy sessions is preferred. To minimize the burden on patients in active cancer therapy, behavior therapy can be provided by a trained member of the health care team during oncology visits. Alternatives include phone contact. During follow-up, providers should assess risk of relapse and, as indicated, consider adjusting the dose and/or type of pharmacotherapeutic. Patients may slip or relapse, which is expected and can be managed. Close follow-up should be maintained through the duration of therapy. At 12 weeks, assessment of smoking status should be made in person or by phone. For pharmacotherapy courses exceeding 12 weeks, assessment should be repeated at the end of the course of therapy.

If patients remain smoke-free, additional follow-up should occur at 6 and 12 months, either in person or by phone. Motivational strategies should be used to promote continued abstinence. Patients who experience smoking relapse can be considered for second-line therapy.

Treatment for Persistent Smoking or Relapse

For patients who continue to smoke or experience relapse, the panel recommends continuation of initial pharmacotherapy or switching to the alternate preferred option (combination NRT or varenicline). Regimens should always be paired with continued behavior therapy. Both preferred primary therapy approaches (combination NRT and varenicline) should be tried before proceeding to any of the subsequent pharmacotherapy options.

Subsequent options for pharmacotherapy include combination NRT with bupropion or bupropion alone (category 2B). Bupropion should be avoided in patients with brain metastases due to increased seizure risk. For further relapse, extended duration of pharmacotherapy can be considered. Additional or more intensive behavior therapy is also an option.

After switching therapy or adjusting the dose of an existing regimen, follow-up should occur within 2 weeks, after 12 weeks, and at the end of therapy if extended beyond that point. Smoking status should be reevaluated at the end of each course of prescribed pharmacotherapy, with additional follow-up at 6 and 12 months after successful quitting.

Principles of Pharmacotherapy

General

A minimum of 12 weeks of combination NRT or varenicline is recommended for the initial quit attempt. Duration of therapy can be extended to promote continued cessation, but providers should attempt to avoid unnecessarily long treatment duration when possible. Research suggests that longer courses of certain cessation regimens may be associated with higher rates of 7-day point-prevalence abstinence.¹⁶⁶

Follow-up is recommended 2 weeks after starting pharmacotherapy but can be extended to 3 weeks to coordinate with scheduled oncology appointments. For relapse or continued smoking, options include continuation of the initial agent or a switch to the alternative preferred agent. Dose adjustments should be considered as clinically indicated. Attempts at smoking reduction should be tracked. If reduction efforts stall or complete abstinence seems unlikely, providers should consider an alternative pharmacotherapy regimen.

In most circumstances, the side effects related to primary smoking cessation medications are minimal and considered an acceptable risk compared with smoking. A review of post-marketing case reports on adverse neuropsychiatric effects from smoking cessation medications generated some safety concerns in the past,¹⁶⁷ but recent large-scale analyses of the data support the safety of these regimens.^168,169 Although serious side effects of primary cessation approaches are extremely rare, providers should refer to manufacturer inserts for exhaustive lists of potential side effects and warnings.

Adherence to pharmacotherapy is important to promote optimal outcomes and success, and numerous studies have tested interventions designed to promote and improve medication adherence.¹⁷⁰

Below, data from various clinical trials are discussed. Included in this discussion are findings from a 2013 Cochrane network meta-analysis that included data on pharmacologic interventions across 267 individual studies in 101,804 participants.¹⁷¹ The authors characterized positive treatment outcome as continuous or prolonged abstinence at least 6 months from the start of smoking cessation therapy. Harm outcomes were measured by the incidence of serious adverse events associated with treatment.

Primary Therapy Options

For patients with cancer, the guidelines recommend primary therapy with either combination NRT or varenicline. If smoking persists or relapse occurs while a patient is on an initial primary therapy regimen, providers should continue therapy with that initial regimen or switch to the alternate primary therapy option. Both preferred primary therapy options should be used before trying any subsequent therapy options. The efficacy and safety data on preferred primary regimens are summarized herein.

Combination Nicotine Replacement Therapy:

Efficacy: NRT offers an alternative nicotine delivery method and can be used to ameliorate nicotine withdrawal symptoms during cessation attempts. Combination NRT incorporating long-term and fast-acting NRT offers the greatest potential benefits for smokers.^{154,171–173} Cochrane network meta-analysis data published in 2013 support the superiority of combination NRT over single forms of NRT, such as nicotine patch (odds ratio [OR], 1.43; 95% CI, 1.08–1.91), nicotine gum (OR, 1.63; 95% CI, 1.21–2.2), and various other forms that collectively include inhaler, lozenge, spray, or tablets (OR, 1.34; 95% CI, 1.0–1.8).¹⁷¹ All forms of NRT were superior to placebo, but smokers using combination NRT were almost 3 times as likely to succeed (OR, 2.73; 95% CI, 2.07–3.65).¹⁷¹ Compared with single forms of NRT, combination NRT using a patch plus short-acting NRT improved the odds of quitting (OR, 1.34; 95% CI, 1.18–1.51).^171,174

The success of NRT may be contingent on concurrent behavior therapy to support cessation. In a large population study, over-the-counter NRT resulted in similar rates of cessation as no use of aid. The addition of behavior therapy to NRT increased the odds of success nearly 3-fold.¹⁶³

Safety: The safety of combination NRT for use in humans has been demonstrated and benefits are considered to outweigh potential risks.¹⁷⁵ Importantly, providers should be aware that blood nicotine levels from NRT, including combination NRT, are significantly less than those from smoking cigarettes.^176–178 Therefore, providers and smokers should not be dissuaded from using NRT to foster quitting and long-term cessation. Recent reviews of the data suggest that NRT is not linked to increased serious cardiovascular adverse events when used for smoking cessation.¹⁷⁹ Although myocardial infarction has rarely been reported in NRT users, there is insufficient evidence that NRT increases the risk of myocardial infarction or cardiovascular disease.^174,180 Data from large case series have not shown elevated risk with the use of NRT in patients with acute coronary syndromes.^181,182

In the past, the safety of NRT has been evaluated in light of the bioactivity of nicotine and evidence that this drug can promote cell growth in certain types of cancer cells.¹⁸³ Some in vitro data suggested that nicotine increased the malignant potential of small cell lung cancer cells¹⁸⁴; induced chemoresistance in models using lung cancer cells^109–111 and nasal epithelial cells¹¹²; and promoted chemoresistance and metastasis in pancreatic cancer cell and mouse models.¹¹³ However, other studies suggested no effects of physiologic levels nicotine exposure on tumorigenesis in mouse lung cancer models.^185,186 Moreover, there is insufficient evidence that NRT causes cancer in humans.^185–189 Evaluation of data from 3,320 participants in the Lung Health Study, which recorded in-study NRT use and smoking exposure, found that NRT was not a significant predictor of lung cancer, whereas smoking was.¹⁸⁸

Varenicline:

Efficacy: Varenicline is a nonnicotinic partial agonist of the alpha4beta2 subtype of the nicotinic acetylcholine receptor. Varenicline partially mimics the effects of nicotine in the brain's reward center and competitively inhibits the binding of nicotine from cigarettes.¹⁹⁰

Systematic reviews/meta-analyses have identified varenicline as the most effective single pharmacotherapy option for smoking cessation.^171,191,192 Cochrane network meta-analysis data report that varenicline increases the odds of smoking cessation by almost 3-fold compared with placebo (OR, 2.88; 95% CI, 2.40–3.47).¹⁷¹ Direct comparison of the cumulative data suggest that varenicline was more efficacious than bupropion (OR, 1.59; 95% CI, 1.29–1.96) and single forms of NRT, such as nicotine patch, nicotine gum, and other formulations (OR, 1.57; 95% CI, 1.29–1.91).¹⁷¹ Varenicline appeared to be equally as likely to promote smoking cessation as combined treatment with more than one form of NRT (OR, 1.06; 95% CI, 0.75–1.48), so that both may be offered, depending on patient circumstances.¹⁷¹

Results recently published from the double-blind EAGLES randomized clinical trial (RCT) (n=8144) revealed that varenicline-treated patients achieved higher abstinence rates than patients receiving placebo (OR, 3.61; 95% CI, 3.07–4.24), nicotine patch (OR, 1.68; 95% CI, 1.46–1.93), and bupropion (OR, 1.75, 95% CI, 1.52–2.01).¹⁹³ A recent study investigated the efficacy of varenicline specifically for patients with cancer, revealing 84% retention and 40% abstinence at 12 weeks. Side effect profiles mimicked those observed in the general population, and abstinence improved cognitive function and reduced negative affect over time.¹⁹⁴

Varenicline may also be efficacious for smoking reduction. A clinical trial enrolling 1,510 individuals revealed that a 24-week course of varenicline effectively promoted smoking cessation in patients who were unwilling to quit but willing to gradually reduce cigarette consumption.¹⁹⁵ Therefore, this agent provides an alternative for patients who cannot or will not attempt abrupt cessation. A clinical trial in 1,236 smokers showed that an additional 12 weeks of varenicline maintenance therapy helped sustain continued abstinence in those who successfully quit during initial treatment.¹⁹⁶

One study examined whether varenicline dose increases would boost treatment efficacy in patients who had a low or no response to standard dosing. A double-blind RCT of 503 smokers found no evidence to suggest that gradual dose titration beyond the standard 2-mg dose (up to a maximum 5 mg/d) lessened frequency of urges and nicotine withdrawal symptoms, or increased cessation rates.¹⁹⁷ However, nausea and vomiting were increased in the treatment group receiving more than 2 mg/d. Additionally, another RCT showed that varenicline was effective and well-tolerated for re-treating patients who had previously received this agent (n=498).¹⁹⁸

A recent RCT (n=1,246) examined whether a biomarker of nicotine clearance (nicotine metabolite ratio [NMR]) was predictive of nicotine patch versus varenicline efficacy in “slow” versus “normal” metabolizers of nicotine. The findings showed that varenicline was more effective than nicotine patch in normal metabolizers, but varenicline superiority was not observed among slow metabolizers, suggesting the possibility in the future to optimize treatment selection based on this biomarker.¹⁹⁹

Safety: Varenicline safety has been extensively examined to determine the risk of adverse effects, particularly serious cardiovascular events and neuropsychiatric changes. Initial phase III studies found varenicline to be safe and generally well-tolerated compared with bupropion or placebo; common side effects included nausea, insomnia, and abnormal dreams, with rates of approximately 28% to 29%, 14%, and 10% to 13%, respectively.^200,201

Concerns regarding neuropsychiatric adverse effects of varenicline have been extensively investigated in smokers with comorbid mental illness.¹⁷¹ Despite reviews of case reports that raised concern,¹⁶⁷ a 2015 systematic review and meta-analysis of 39 randomized controlled smoking cessation trials identified no evidence to suggest that varenicline increases risk of suicide or suicide attempts, suicidal ideation, depression, or death.¹⁶⁹ Another trial showed that varenicline increased smoking cessation rates without exacerbating anxiety and depression symptoms in adults with stably treated current or past depression.²⁰² Results were recently published from a large double-blind RCT (EAGLES trial) that enrolled 2 cohorts: individuals with psychiatric disorders (n=4,116) and those without psychiatric disorders (n=4,028). No significant increase in neuropsychiatric events was observed for varenicline relative to nicotine patch or placebo. Varenicline was associated with significantly higher abstinence rates than bupropion plus nicotine patch, as well as placebo.¹⁹³

Cardiovascular risks have also been examined. Importantly, recent systematic reviews and meta-analyses of RCT data have not identified a significant link between varenicline and increased risk of serious cardiovascular adverse events.^{171,179,203,204} However, the cardiovascular safety of varenicline has remained a topic of interest and concern.^205–207

In a 2015 retrospective review of 164,766 individuals who received pharmacotherapy for smoking cessation (varenicline, n=51,450; NRT, n=106,759; bupropion, n=6,557), neither varenicline nor bupropion posed an elevated risk of cardiovascular or neuropsychiatric (depression, self-harm) events compared with NRT.²⁰⁸ Based on the current evidence base for safety risks, the panel considers varenicline to be safe and to have a favorable risk/benefit ratio for use in patients with cancer who smoke.

Although rare, elevated seizure risk is a concern with varenicline therapy.^209,210 In patients with brain metastases who have a history or elevated risk of seizure, varenicline should be avoided.

Subsequent Therapy Options

Recommended subsequent therapy options in these guidelines include combination NRT with bupropion or bupropion alone (category 2B). Currently, other regimens are not recommended in this treatment setting. However, the panel acknowledges ongoing evaluation of alternative regimens (eg, varenicline plus combination NRT, varenicline plus bupropion, nortriptyline, or clonidine). The panel regularly reviews the evidence base for alternative regimens when updating these guidelines. The data for various regimens are summarized herein.

Recommended Regimens:

Bupropion Plus NRT: A large trial in the United Kingdom (n=1,071) examined the efficacy of NRT alone, bupropion alone, and NRT plus bupropion.²¹¹ All participants received 7 weeks of behavior therapy support in addition to the pharmacologic interventions. Abstinence rates at 6-months' follow-up ranged from 24.2% to 27.9% and did not differ significantly between cohorts. Several unwanted side effects were more common with bupropion than with NRT (eg, disturbed sleep, dry mouth, headaches, nausea), and side effects of combination therapy were not significantly different versus bupropion alone. Five serious adverse events occurred in the bupropion group, including allergic reaction (n=3), neuropsychiatric symptoms (n=1), and chest pain (n=1). A trend toward improved efficacy of bupropion in patients with a history of depression was noted (χ²=2.86; P=.091).

A double-blind RCT compared bupropion plus NRT, bupropion alone, nicotine patch alone, and placebo in 893 individuals who smoked at least 15 cigarettes per day. At 12 months, the highest abstinence rates were observed for the bupropion plus NRT group (35.5%) and bupropion-only group (30.3%), although these groups did not differ significantly.²¹² A smaller RCT studying the addition of bupropion to combination NRT and behavior therapy in patients with schizophrenia suggested that combination pharmacotherapy promoted smoking reduction and cessation, but also demonstrated a high relapse rate after discontinuation of treatment.²¹³ A 2014 meta-analysis of 12 trials examining this combination revealed a nonsignificant trend in improved cessation with the addition of NRT to bupropion.²¹⁴

Bupropion: Bupropion was first approved to treat depression, but its efficacy as a cessation aid also became apparent. In addition to its effects on the dopaminergic and adrenergic systems, this agent also acts as an inhibitor of nicotinic acetylcholingeric receptors. A 2014 Cochrane review of 44 trials examined bupropion efficacy, revealing an RR of 1.62 (95% CI, 1.49–1.76).²¹⁴ Recent results from the EAGLES trial (n=8,144) revealed that patients receiving bupropion achieved superior abstinence rates compared with placebo (OR, 2.07; 95% CI, 1.75–2.45).¹⁹³ Efficacy was similar to nicotine patch but less than that for varenicline. Some evidence suggests that bupropion may be particularly beneficial as a smoking cessation agent for persons with depression.^211,215 Additionally, longer duration of bupropion treatment may help prevent relapse in those who have successfully quit.²¹⁶

Bupropion reduces the seizure threshold and meta-analyses of trial data have found a 0.1% seizure risk among those receiving the drug for smoking cessation.²¹⁴ In patients with brain metastases who have a history or elevated risk of seizure, bupropion should be avoided.

Neuropsychiatric effects have also been identified as a safety concern with bupropion, although to a lesser extent than varenicline.¹⁶⁷ However, recent systematic reviews of the data have found that serious neuropsychiatric adverse events were rarely associated with bupropion prescribed for smoking cessation, including studies of bupropion in patients with mental illness.^171,217 In the EAGLES trial, no significant increase in neuropsychiatric events was observed for bupropion relative to nicotine patch or placebo.¹⁹³

Similarly, regarding risk of serious adverse cardiovascular effects, recent meta-analyses do not show elevated risk as a result of bupropion use for smoking cessation.^171,179,214

Other Regimens: Several other pharmacotherapy regimens for smoking cessation have been studied in clinical trials but are not currently recommended by the panel based on the existing data. Data from these studies are summarized below for information purposes.

Varenicline Plus NRT: A study in 435 smokers found that the addition of nicotine patch to varenicline therapy significantly increased the cessation rates at the end of treatment (12 weeks), 24 weeks, and at 6-month follow-up.²¹⁸ No significant differences were noted for side effect incidence between varenicline/NRT and varenicline/placebo with the exception of skin reactions, which were increased with combination therapy (14.4% vs 7.8%; P=.03). However, one RCT of 341 smokers did not find enhanced cessation rates at 12 and 24 weeks follow-up among individuals receiving a combination of varenicline and nicotine patch, versus varenicline alone.²¹⁹ The addition of nicotine patch to varenicline did not cause significant changes in side effect profiles. Similarly, a trial in 117 participants did not find evidence that the addition of NRT to varenicline increased abstinence rates at 1, 4, or 12 weeks after the targeted quit date, and no between-group differences in adverse effects were found.²²⁰

Varenicline Plus Bupropion: In an RCT of smokers who demonstrated an inadequate response to front-line nicotine patch treatment (n=222), combination therapy with varenicline and bupropion appeared to be more efficacious than varenicline alone as a second-line therapy option.²²¹ This observation was more pronounced among male smokers and those with a high level of nicotine dependency. Although no significant differences in side effects were observed between varenicline and bupropion versus varenicline alone, dose reductions were required for 11.5% and 24.8% of patients, respectively. Common side effects were vivid dreams, change in taste perception, thirst, insomnia, and irritability. Another study of varenicline plus bupropion therapy versus varenicline alone (n=316) demonstrated that combination therapy increased prolonged abstinence but did not affect 7-day point prevalence at 12 and 26 weeks follow-up, and no significant differences were observed between the groups at 52 weeks.²²² In this study, anxiety (7.2% vs 3.1%; P=.04) and depressive symptoms (3.6% vs 0.8%; P=.03) occurred more frequently in patients receiving combination therapy versus varenicline alone.

Nortriptyline and Clonidine: Studies have also suggested some efficacy of off-label use of nortriptyline, a tricyclic antidepressant, as well as the antihypertensive agent clonidine.

A Cochrane network review identified 6 trials comparing nortriptyline with placebo, finding a pooled RR of 2.03 (95% CI, 1.48–2.78).^102,133 However, as an adjunct to NRT, clear cut benefits were not observed.^171,223

Clonidine is recommended as a third-line smoking cessation option. Although several studies have produced data in favor of clonidine as a cessation aid versus placebo, not all study data reveal a statistically significant effect. Additionally, clonidine's benefits can be counteracted by dose-dependent increases in drug side effects. A 2013 Cochrane network review of data from 6 studies resulted in a pooled RR of 1.63 (95% CI, 1.22–2.18).¹⁰²

Principles of Behavior Therapy

General Principles

The guidelines provide the following guiding principles on behavior therapy, which have been developed in consideration of the existing evidence base, clinical practice guidelines, and expert consensus.^164,165,175

The panel recommends a combination of behavior therapy with pharmacotherapy for best outcomes. In fact, studies suggest that counseling for smoking cessation may enhance patient satisfaction.^13,14 A 2012 systematic review of 41 studies provided support for the efficacy of this approach.¹⁶⁴ The “real-world effectiveness” of adding a behavior therapy component to smoking cessation therapy was further supported by a large population study published in 2014.¹⁶³ Additionally, a 2016 meta-analysis of data from 1,239 patients with head and neck cancer showed improved smoking cessation rates with the addition of counseling to usual care (NRT).²²⁴

Behavior therapy may enhance motivation and support optimal medication strategies and adherence to pharmacotherapy. When possible, therapy should be provided by a tobacco treatment specialist or dedicated staff member (eg, nurse, medical assistant, health educator) with training in motivational and behavior strategies for smoking cessation.

As a general principle, more intensive behavior therapy is preferred over brief advice or counseling.¹⁶⁵ The evidence supports a measurable dose-response effect of behavior therapy, with more numerous and/or longer sessions delivering improved outcomes. The panel defines intensive behavioral therapy as at least 4 sessions within 12 weeks (in person; group or individual) lasting at least 10 minutes, but typically 30 minutes or longer. As patients progress through multiple lines of pharmacotherapy, behavior therapy should be progressively intensified with referral to specialty care (eg, psychiatrist, psychologist) as indicated. Studies have also demonstrated additional benefit in relapse prevention of extending behavioral therapy for 6 months or more.^225–227 Importantly, if intensive therapy is not feasible, brief counseling should still be given. Studies have demonstrated a small but significant benefit of counseling lasting only a few minutes.^35-38

The most successful behavior therapy strategies use practical counseling, which addresses problem-solving and skills training, as well as social support and MI (see “Motivational Interviewing,” page 1460) as elements of the treatment plan.^144,175 Optimally, behavior therapy plans should take into account a patient's nicotine dependence levels, previous quit attempts, and cessation aids used. In doing so, patients can be equipped with tailored strategies to cope with nicotine withdrawal symptoms, environmental smoking triggers, and stressful situations. For instance, the addition of a cognitive behavior therapy program designed to improve stress management improved cessation rates over controls receiving standard smoking cessation therapy.²²⁸

Providers should prepare patients for nicotine withdrawal symptoms, which typically peak at several days to 2 weeks after cessation before gradually subsiding.^229–231

A number of modalities can be used to deliver behavior therapy to patients. Counseling can take place in a variety of settings, such as in person, remotely by telephone,²³² or through Web-based interventions.²³³ Effective in-person counseling can occur as an individual session or in the group therapy setting.^234,235 Additionally, print materials²³⁶ and mobile telephone “apps”^237–239 can be used to deliver behavior therapy. However, providers should be aware that media-based behavioral interventions, particularly those using mobile telephones, may vary in the degree to which they comply with clinical practice guidelines.²⁴⁰

A recent study investigated preferences for the provision of smoking cessation information among Canadian patients with cancer. Patients most often preferred print materials (45%), followed by telephone support (39%), speaking with a clinician (29%), Web site–based information (15%), and support groups (11%). Younger patients (age ≤45 years) were more likely to prefer cessation advice via telephone, whereas older patients preferred print materials.²⁴¹ Selection of a particular modality or modalities should be guided by patient preference, medical history, and resource availability.

For patients who are unable to quit, referral to a smoking cessation clinic is encouraged when available. If specialized resources are limited, effective behavior counseling can still be provided. For instance, brief counseling by providers has been shown to generate a small but important increase in quit rates.^35–37 Additionally, quitlines can provide essential behavioral support in the absence of in-person counseling resources.²³² For instance, the addition of combination NRT to quitline counseling improved cessation outcomes.²⁴²

Tailoring Behavior Therapy for Patients With Cancer

As resources allow, specialized treatment centers should provide tailored smoking cessation therapy programs that address the unique needs of patients with cancer. For patients in active cancer treatment, behavior therapy can be provided during scheduled oncology visits to obviate the need for additional appointments. Beneficial services might include individual and group therapy focusing on the challenges specific to cancer treatment and survival, which would ideally be provided by clinicians experienced in working with patients with cancer.

The prevalence of mental disorders or serious emotional issues in patients with cancer is high, with several large studies reporting rates between 30% and 40%.^243–245 The high rates of anxiety, depression, and stress can present a significant challenge for patients with cancer who attempt to quit smoking in the face of these common smoking/relapse triggers. Patients with cancer, particularly those experiencing psychiatric comorbidity, may benefit significantly from behavior therapy programs tailored to manage cancer-related issues that predispose patients to relapse. Referral to specialized smoking cessation programs may be necessary so that these patients have access to staff trained to treat comorbid substance dependence and mental health disorders.

Motivational Interviewing

MI is beneficial for all patients, including those who are currently ambivalent or unwilling to quit. MI is typically performed by a provider trained in strategic questioning and listening, and uses a series of directive and nondirective approaches.^143,144 Through this approach to counseling, the provider seeks to understand the patient's values (eg, health, parenting, fitness) and highlights discrepancies between these values and continued smoking. Direct advice is given but is tied specifically to the patient's previously stated values and supports the patient's autonomy to decide whether they want to quit. In MI, self-efficacy is emphasized by asking about and acknowledging the patient's strengths to make change.

A 2015 Cochrane database review of 28 studies examined the efficacy of MI for smoking cessation, revealing a modest but significant increase in chance of quitting with MI versus brief advice or usual care.²⁴⁶ MI by a primary care physician appeared to be somewhat more successful than that administered by counselors, although both were effective. Notably, one-time short MI sessions of less than 20 minutes had demonstrated efficacy.²⁴⁶ A recent systematic review summarized the evidence supporting MI for behavioral change, including smoking cessation, in patients with cancer.²⁴⁷

In order to promote willingness to quit smoking, the US Preventive Services Task Force (USPSTF) recommends a model of MI that uses the “5 R's” of relevance, risks, rewards, roadblocks, and repetition.¹⁷⁵ This model encourages that motivational information be relevant to the individual patient, and that clinicians and patients work together to identify personalized risks of smoking and potential rewards of cessation. By having the patient identify perceived roadblocks to quitting, providers can suggest tailored treatments to address patient-reported concerns. Finally, this model recommends repetition of MI at each patient visit, coupled with reminders that repeated quit attempts may be necessary to achieve long-term cessation.

Alternative Treatment Approaches

The panel has reviewed the available evidence for alternative smoking cessation treatment approaches. Particular attention has been paid to the discussion of e-cigarettes for smoking cessation, given their increasing popularity and widespread use. Limited data are available on the safety and efficacy of these approaches, specifically for patients with cancer; data have been drawn primarily from studies in the general population.

The panel has found insufficient evidence to support the use of alternative therapies alone or in combination with standard smoking cessation methods, and use of alternative therapies is not recommended. The guidelines recommend that patients use evidence-based cessation methods to avoid any delay in achieving smoking abstinence. Smoking slips and relapse are common, and prior unsuccessful quit attempts with conventional therapies do not justify the use of unproven alternative cessation methods. When discussing alternative therapies, providers should counsel patients on potential interactions with evidence-based cessation methods and/or cancer treatments.

Electronic Cigarettes/Electronic Nicotine Delivery Systems

The popularity of electronic cigarettes, “e-cigarettes,” and their various derivatives is a recent phenomenon, and, as such, the available literature is new and relatively limited, particularly within specific subpopulations such as patients with cancer. Electronic nicotine delivery systems (ENDS) are not FDA-approved smoking cessation devices. Currently, the panel does not recommend use of e-cigarettes, and instead recommend that known effective methods for smoking cessation be offered. This section discusses the current data and expert opinions on e-cigarettes for smoking cessation.

Several healthcare organizations have released similar policy statements concerning ENDS, high-lighting the urgent need for research on the safety of these devices and efficacy as a cessation aid. The American Heart Association, AACR, and ASCO recognize the potential for ENDS to alter existing smoking behaviors, as well as the lack of definitive data regarding associated benefits and harms.^248,249 Experts in the field generally acknowledge that ENDS may offer an attractive approach for smoking reduction and/or cessation in certain populations. However, these policy statements also highlight the unknown potential for ENDS to affect nicotine addiction, combustible tobacco product use, and renormalization of smoking behaviors.

In the September 2015 Final Recommendation Summary, the USPSTF concluded “that the current evidence is insufficient to recommend [ENDS] for tobacco cessation…The USPSTF recommends that clinicians direct patients who smoke tobacco to other cessation interventions with established effectiveness and safety.”²⁵⁰

One study examined e-cigarette use in 1,074 patients with cancer who enrolled in a tobacco treatment program at a comprehensive cancer center.²⁵¹ The study revealed a marked increase in e-cigarette use from 10.6% to 38.5% between 2012 and 2013. E-cigarette users, most often patients with thoracic or head and neck cancers, were more nicotine-dependent and had greater numbers of prior quit attempts. At follow-up (6–12 months after intake), e-cigarette users were no more likely to have quit than nonusers (OR, 1.0; 95% CI, 0.5–1.7), calling into question the potential benefits of e-cigarettes as a cessation agent for patients with cancer.

High-quality data on e-cigarette use for smoking cessation are limited. In the largest RCT to date, 657 individuals were randomized to receive nicotine e-cigarettes, placebo e-cigarettes, or nicotine patch. Abstinence rates were unexpectedly low across all groups, with no statistically significant differences in biochemically verified smoking abstinence between treatment groups at 6 months.²⁵²

Systematic reviews have summarized the data from the general population to determine the potential efficacy of e-cigarettes as a smoking cessation aid, noting a limited overall pool of data and heterogeneous measures. More individuals reduced cigarette consumption with nicotine e-cigarettes versus placebo (RR, 1.31; 95% CI, 1.02–1.68), and one study suggested that nicotine e-cigarettes improved reduction over nicotine patch (RR, 1.41; 95% CI, 1.20–1.670).²⁵³ Across all 13 studies examined, no serious adverse events were reported.²⁵³ Similarly, a 2015 systematic review and meta-analysis of data from 1,242 participants suggested that nicotine-containing e-cigarettes were more effective cessation aids than non–nicotine-containing e-cigarettes (RR, 2.29; 95% CI, 1.05–4.97).²⁵⁴ E-cigarette use over a minimum of 6 months was associated with an 18% reported smoking cessation rate (effect size, 0.20; 95% CI, 0.11–0.28), and e-cigarette use was also associated with smoking reduction.²⁵⁴

A large cross-sectional study of 5,863 adults in the United Kingdom assessed the “real-world effectiveness” of e-cigarettes for smoking cessation compared with NRT and unaided quitting, revealing that e-cigarette users were more likely to report abstinence compared with the other cohorts (e-cigarettes vs NRT: OR, 2.23; 95% CI, 1.70–2.93; e-cigarettes vs no aid: OR, 1.38; 95% CI, 1.08–1.76).²⁵⁵ These observations persisted when adjusting for measures of nicotine dependence across the cohorts.

However, e-cigarette use did not decrease cigarette smoking in a cross-sectional study in 106 patients with head and neck cancers seeking to quit. Nonusers of e-cigarettes had a significantly greater rate of cessation compared with e-cigarette users (72% vs 39%; P=.0057).²⁵⁶

Other Alternative Approaches

Very limited data exist to support exercise-based interventions; small study size, inadequate controls, and insufficient exercise intensity limit the ability to make conclusions based on the existing evidence.²⁵⁷ Sufficient efficacy data are also lacking to support the use of alternative therapies, such as acupuncture, hypnosis, and nutritional supplements. A 2014 systematic review of the data on acupuncture, acupressure, and laser therapy revealed no consistent, bias-free evidence to support these methods for smoking cessation, although pooled evidence was suggestive of possible short-term benefits.²⁵⁸ Acupuncture was less effective than NRT and there was no evidence to support the benefit of electrostimulation for smoking cessation. Similarly, systematic reviews of the data on hypnosis for smoking cessation revealed inadequate high-quality evidence to support this approach.^259,260 Claims of efficacy data for hypnosis from several studies were not substantiated by the review of RCT data. Controlled studies are needed to provide higher-quality evidence on these interventions, both in the general population and among patients with cancer.

Individuals Disclosures for the NCCN Smoking Cessation Panel

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Smoking Cessation, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

NCCN Categories of Evidence and Consensus

Overview

Smoking Prevalence in Patients With Cancer

Health Care Community Response

Barriers to Smoking Cessation in Oncology Patients

Literature Search Criteria and Guidelines Update Methodology

General Principles of the Smoking Cessation Guidelines

Smoking-Associated Risks for Patients With Cancer

Overall Survival and Mortality

Risk of Recurrence or Secondary Primary Tumor

Smoking-Related Effects on Treatment Efficacy, Side Effects, and Outcomes

Evaluation and Assessment of Patient Smoking

Determining Smoking Status

Smoking Cessation During Cancer Treatment

Devising a Treatment Plan

Preferred Primary Therapy Options

Follow-up

Treatment for Persistent Smoking or Relapse

Principles of Pharmacotherapy

General

Primary Therapy Options

Combination Nicotine Replacement Therapy:

Varenicline:

Subsequent Therapy Options

Recommended Regimens:

Principles of Behavior Therapy

General Principles

Tailoring Behavior Therapy for Patients With Cancer

Motivational Interviewing

Alternative Treatment Approaches

Electronic Cigarettes/Electronic Nicotine Delivery Systems

Other Alternative Approaches

References