INTRODUCTION

• Tobacco use remains one of the largest causes of cancer internationally.
• Surgeon General’s Report (SGR) on Smoking and Health recently updated in 2020 extend smoking as a major cause of cancer that can be improved or reversed with smoking cessation.

The 2020 SGR found that quitting smoking after a cancer diagnosis improved survival rates.

TOBACCO USE AND ADDICTION

• An estimated 1 billion people will die in the 21st century based on current use of projections and approximately 50% of people who use tobacco will die of tobacco-related diseases.
• Nicotine is the predominant addictive component of tobacco, which stimulates the dopaminergic system and leads to a rewarding experience.
• The introduction of low-tar and filtered cigarettes actually increased risk by promoting deeper inhalation and higher rates of addiction with no reductions in cancer risk, resulting in subsequent changes in lung cancer from centrally located squamous cell cancers to peripherally located non-squamous cell cancers.
• Smoking cessation remains the optimal approach to improving health outcomes.

DEFINING TOBACCO USE BY CANCER PATIENT

• Never smoking is defined as having smoked fewer than 100 cigarettes in a person’s lifetime and no current cigarette use.
• Categories 2 to 4 require that a person has smoked at least 100 cigarettes in their whole life.
• Former smoking is defined as no current cigarette use, but having quit for usually more than 1 year.
• Recent smoking is defined as having stopped smoking within the recent past, typically for a period of 1 week to 1 year.
• Current smoking is typically defined as actively smoking one or more cigarettes per day, every day or some days.
• Ever smoking is a combination of groups 2 to 4 that has been used to report negative associations between smoking and cancer outcomes in many studies.

SMOKING CESSATION IN THE CONTEXT OF LUNG CANCER

• The US Preventative Services Task Force (USPSTF) has supported low-dose computed tomography (LDCT) screening for lung cancer to reduce mortality risk.
• The addition of a smoking cessation program to an LDCT screening program can improve cost-effectiveness, and seven years of smoking cessation have been shown to reduce mortality.
• The SCALE collaboration acknowledges the significance of smoking cessation and Low-Dose Computed Tomography (LDCT) screening. Their ongoing efforts aim to evaluate various smoking cessation approaches while looking for the best practices for incorporating cessation into screening. This will be done by identifying the common core elements.

THE CLINICAL EFFECTS OF SMOKING ON CANCER OUTCOMES

• Overall, approximately 75% to 80% of studies in the SGR demonstrated a negative association between smoking and outcomes.
• Current smoking is linked to a higher risk of overall mortality across disease sites and treatments than former smoking. The median risk associated with former smoking is 22% compared to 51% for current smoking.
• Bittner et al. conducted research on the causes of death in prostate cancer patients and found that smoking has a significant impact beyond the development of cancer. They discovered that over 90% of prostate cancer patients died from other causes and that current smoking increased the risk of non-prostate cancer deaths by 3 to 5.5 times.
• As a result, tobacco use and cessation may be of paramount importance to cancers with high cure rates, such as prostate cancer or breast cancer, simply because patients may be at most risk of death from noncancer-related causes such as heart disease, pulmonary disease, or other diseases related to smoking and tobacco use.
• Continued smoking by cancer patients also increases the risk of developing a second primary cancer, as reviewed by the 2014 SGR.
• Combining smoking with CT or RT therapy may exacerbate risk beyond the effects of smoking alone. In ER-positive breast cancer patients, treatment with RT had no significant effect on the risk of developing contralateral breast cancer, but RT combined with current smoking increased the risk of contralateral cancer by ninefold.
• In Hodgkin disease patients, non-heavy smokers (defined as never-smokers, former smokers, or smoking less than one pack per day) had a relative risk of a second primary cancer of between four- and sevenfold when treated with CT or RT as compared with patients who received no RT or CT.
• These observations suggest that smoking combined with cytotoxic cancer therapy may increase the risk of developing a second primary cancer, perhaps through the promotion of mutations induced by CT and RT in the presence of tobacco smoke.
• Smoking cessation after diagnosis has also been shown to significantly reduce the risk of second primary cancer by up to 83%.

SMOKING, TARGETED THERAPEUTICS, AND IMMUNOTHERAPY

• Smoking can have a significant effect on mutations, cancer biology, and activation of tumour pathways, but there are relatively few studies identifying targeted approaches to patients with a current or former smoking history.
• Patients who have Human Papilloma Virus (HPV)–associated tumours typically have increased p16 expression, minimal or no prior smoking history, and often respond better to conventional cancer therapy, including RT and CT. Current smoking increased cancer mortality approximately fivefold, even in p16-positive patients treated with surgery.
• Smoking also increases the risk of developing a second primary cancer among both HPV-positive and HPV-negative patients. A similar effect is noted in lung cancer patients with EGFR or ALK-related lung cancers.
• Analysis of over 1,000 resected lung cancer specimens demonstrated that PD-L1 was associated with smoking, KRAS, poor survival, and not associated with EGFR or ALK mutations.
• A recent meta-analysis demonstrated improved response and outcomes with immunotherapy over chemotherapy in patients with a current or former smoking history.

SMOKING CESSATION GUIDELINES

• Smoking in cancer patients is also often associated with comorbid psychiatric diseases such as depression that may affect dependence. As smoking decreases the efficacy of cancer treatment, every effort should be made to stop tobacco use as soon as possible.
• Evidence-based treatment of tobacco use is fundamentally supported by Public Health Service (PHS) Guidelines.
• The principal steps in conducting effective smoking cessation interventions are referred to as the 5 A’s:
  1. Ask about tobacco use for every patient.
  2. Advise every tobacco user to quit.
  3. Assess the willingness of patients to quit.
  4. Assist patients with quitting through counselling and pharmacotherapy.

5. Arrange follow-up cessation support, preferably within the first week after the quit date.

• Promoting an effective quit strategy for cancer patients should consist of setting a quit date and removing all tobacco-related products from the environment.
• The final step in the 5A’s model of clinician-delivered smoking cessation intervention is arranging follow-up contact with the patient.
• Ideally, cancer patients will follow an immediate quit strategy, and follow-up should occur preferably within 1 to 2 weeks.

PHARMACOLOGIC TREATMENT FOR SMOKING CESSATION

• It reduces the craving associated with nicotine withdrawal and significantly increases cessation success.
• NRT (in the form of patches, lozenges, inhalers, sprays, and gum), varenicline (Chantix), and bupropion (Zyban) are the three principal first-line pharmacotherapies recommended for use either alone or in combination according to PHS Guidelines.
• Guidelines identify two non-nicotine-based medications— clonidine and nortriptyline—as second-line pharmacotherapies for tobacco dependence typically used when a smoker cannot use first-line medications due to either contraindications or lack of effectiveness.
• NRT facilitates smoking cessation by reducing the craving and withdrawal that smokers experience during abstinence. It also weans smokers off nicotine by providing a lower level and slower infusion of nicotine than smoking.
• Strong evidence from randomized clinical trials supports the use of NRT to increase the odds of quitting approximately twofold as compared with placebo. Recent evidence further shows that combination therapy, or “dual NRT” (such as a nicotine patch and lozenge), is an effective smoking cessation therapy producing high quit rates.
• Bupropion (Zyban) is currently the only FDA-approved antidepressant for the treatment of tobacco dependence that inhibits the reuptake of both dopamine and norepinephrine, thereby increasing dopamine and norepinephrine concentrations in the mesolimbic systems.
• If an abstinent smoker relapses, bupropion may function to reduce the pleasure of cigarette smoking experienced by the smoker and help to prevent further relapse. A meta-analysis found that smokers who received bupropion were twice as likely as those who received placebo to have achieved long-term abstinence at either 6- or 12-month follow-up.
• Importantly, there are situations where bupropion may interact with drug metabolism because bupropion is a cytochrome P450 (CYP) 2D6 inhibitor that may affect certain drugs affected by CYP2D6 activity, such as tamoxifen.
• Varenicline (Chantix) is an α4β2 nAChR partial agonist that produces sustained dopamine release in the mesolimbic system. In 2006, it received FDA approval for treating tobacco dependence.
• Sustained dopamine release maintains a normal systemic level of the neurotransmitter, which helps to reduce craving and withdrawal during abstinence. Varenicline also antagonizes the rewarding effects of nicotine. Because varenicline attenuates the pleasure smokers experience from smoking, it may decrease motivation to smoke and protect them from relapse. One of the initially randomized clinical trials that compared varenicline (2 mg), bupropion (300 mg), and placebo showed that varenicline was superior to bupropion and placebo, with continuous abstinence rates between 10% and 23%.
• A meta-analysis demonstrated that the 1-mg daily dose approximately doubled and the 2-mg daily dose approximately tripled the likelihood of long-term abstinence at six months as compared to placebo.
• Several meta-analyses have shown that varenicline is superior to bupropion and placebo in the general population.
• Recent findings from a randomized, double-blind, triple-dummy, placebo-controlled and active-controlled study (Evaluating Adverse Events in a Global Smoking Cessation Study [EAGLES]) demonstrated that the use of varenicline or bupropion does not increase the risk of moderate-to-severe neuropsychiatric adverse events in smokers with or without stable psychiatric disorders.
• Varenicline produced higher abstinence rates in both the nonpsychiatric and psychiatric cohorts when compared to bupropion and nicotine patches.
• Given the findings from the EAGLES study, the FDA approved the removal of the boxed warning on varenicline and bupropion regarding neuropsychiatric events.