Tobacco Use and the Cancer Patient



Tobacco Use and the Cancer Patient


Graham W. Warren

Benjamin A. Toll

Irene M. Tamí-Maury

Ellen R. Gritz



INTRODUCTION

Tobacco is commonly described as the largest preventable cause of cancer. Over 50 years ago, tobacco was increasingly recognized as the primary cause of lung cancer, with definitive recognition for tobacco use as a causative factor in the seminal 1964 U.S. Surgeon General’s Report (SGR) on Smoking and Health.1 Recent editions of the SGR have described the widespread adverse health effects of tobacco on a spectrum of diseases, including as a causative agent for a spectrum of cancers.2,3 Tobacco use is an addiction usually initiated in youth prior to the age of 18 and is driven by the highly addictive drug, nicotine.4 As related to the cancer patient, considerable work has been conducted to associate tobacco use with the risk of developing cancer and how tobacco cessation can substantially reduce cancer risks. However, there is a relative paucity of effort that has been put forth to identify the effects of smoking on outcomes for cancer patients or to establish methods to help cancer patients quit smoking. Fortunately, in recent years, the importance of tobacco use by the cancer patient has been increasingly recognized as an important health behavior, including a National Cancer Institute (NCI)-sponsored conference on tobacco use in 2010, a joint sponsored NCI-American Association of Cancer Research (AACR)-sponsored workshop at the Institute of Medicine in 2012, and recent recommendations by the AACR and the American Society of Clinical Oncology (ASCO) to address tobacco use in cancer patients.5,6 The recently released 2014 SGR now provides substantial evidence behind the effects of smoking by cancer patients with the following conclusions7:



  • In cancer patients and survivors, the evidence is sufficient to infer a causal relationship between cigarette smoking and adverse health outcomes. Quitting smoking improves the prognosis of cancer patients.


  • In cancer patients and survivors, the evidence is sufficient to infer a causal relationship between cigarette smoking and increased all-cause mortality and cancer-specific mortality.


  • In cancer patients and survivors, the evidence is sufficient to infer a causal relationship between cigarette smoking and increased risk for second primary cancers known to be caused by cigarette smoking, such as lung cancer.


  • In cancer patients and survivors, the evidence is suggestive but not sufficient to infer a causal relationship between cigarette smoking and the risk of recurrence, poorer response to treatment, and increased treatment-related toxicity.

The overall objective of this chapter is to discuss tobacco use by cancer patients, the clinical effects of smoking in cancer patients, methods to address tobacco use by cancer patients, and areas of needed research.


NEUROBIOLOGY OF TOBACCO DEPENDENCE

Nicotine is the primary addictive component of tobacco that increases extracellular concentrations of dopamine in the nucleus accumbens and stimulates the mesolimbic dopaminergic system,8,9 resulting in nicotine’s rewarding effect experienced by tobacco users.10,11,12 Dopaminergic neurotransmission may also be involved in the assignment of incentive salience, or stimulus for a pleasure based reward, to tobacco use-related environmental cues13,14 that may become conditioned reinforcers of tobacco use behaviors. For example, an individual who smokes while drinking their morning coffee may associate coffee, or even holding a coffee cup in their hand, with the reward from smoking. Thus, cigarette smoking is directly linked to external nontobacco-based behavioral stimuli. Activation of the nucleus accumbens has further been implicated in drug reinstatement or relapse.15,16 Individuals who have quit tobacco use for years have restarted a tobacco habit simply by sitting next to a smoker and being exposed to secondhand smoke. Substantial work has been conducted on the addictive nature of tobacco and nicotine, and readers are referred to several comprehensive reviews on this topic.9,12,17


TOBACCO USE PREVALENCE AND THE EVOLUTION OF TOBACCO PRODUCTS

Much of the discussion on tobacco use epidemiology and carcinogenesis is presented in Chapter 4. In brief, the prevalence of cigarette smoking among adults in the United States decreased to 19.0% as compared with 22.8% in 2001, but it did not meet the Healthy People 2010 objective to reduce smoking prevalence to 12%.18,19 There have been substantial changes in the landscape of tobacco use over time as a direct consequence of cigarette-centered policies and regulations aiming to reduce the harmful effects and number of deaths caused by smoking.20,21,22 Under this new landscape, novel and reemergent noncigarette tobacco products such as cigars, cigarillos, snuff, chewing tobacco, water pipes (hookahs), and other forms of tobacco consumption have been growing in demand as a consequence of aggressive and sophisticated marketing by the tobacco industry.23 Consumption patterns have also changed due to efforts by the tobacco industry to make cigarettes appear safer, such as low tar or filtered cigarettes, and the inclusion of flavoring (menthol, vanilla, fruits, etc.).24 Although these efforts may have changed consumption patterns, they have not reduced cancer risk. Large patient cohorts demonstrate that 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,24,25 resulting in subsequent changes in lung cancer from centrally located squamous cell cancers to peripherally located nonsquamous cell cancers.

The relatively recent introduction of electronic cigarettes (i.e., e-cigarettes, e-cigs, nicotine vaporizers, or electronic nicotine delivery systems [ENDS]) is noteworthy. These electronic or battery-powered devices activate a heating element that vaporizes a liquid solution contained in a cartridge, and then the user inhales this vapor. Levels of nicotine as well as other chemical additives and flavors in the cartridge are uncertain and vary according to the brand.26 Although there are no research studies that have evaluated the potential harmful effects of the use of e-cigarettes for
cancer patients,27 organizations such as the World Health Organization have already expressed concerns about the safety of these increasingly popular products.28,29 To date, e-cigarettes have not been approved by the U.S. Food and Drug Administration (FDA) as therapeutic devices to aid in quitting smoking.26 Readers are referred to a recent editorial on the use of e-cigarettes by cancer patients27; however, it will likely be several years before evidence-based health information is available.


TOBACCO USE BY THE CANCER PATIENT

The prevalence of current smoking among long-term adult cancer survivors appears to have declined in the past decade,30 but data suggest higher rates of smoking among cancer survivors than in the general population.30,31,32 These data are often biased by the fact that assessments in cancer patients may not include cancer patients who were current smokers at the time of death. As a result, estimates of smoking rates in cancer survivors may be misleading and may underestimate true tobacco use patterns for cancer patients. Furthermore, alternative tobacco products are often not assessed in cancer patients. Data from the Childhood Cancer Survivor Study and the 2009 Behavioral Risk Factor Surveillance System indicate that approximately 3% to 8% of cancer survivors use smokeless tobacco products.33,34 Patients may be attracted to these alternative products due to less social stigma and the nonevidence-based perception that these products are healthier alternatives compared to cigarette smoking.

Continued tobacco use by cancer patients often represents a combined failure by the patient to recognize the need to stop smoking even after a cancer diagnosis and the effort by health-care providers to address tobacco use with evidence-based assessments and tobacco cessation support. Approximately 30% of all cancer patients use tobacco at the time of cancer diagnosis with higher rates in traditionally tobacco-related disease sites, such as head and neck or lung cancers, and lower rates in traditionally nontobacco-related disease sites, such as breast or prostate cancers.35,36,37,38,39,40,41,42,43,44 However, findings from several studies indicate that cancer patients are receptive to smoking cessation interventions even as they continue to smoke.35,38,45,46,47,48,49,50

A cancer diagnosis can be used as a window of opportunity, or teachable moment, to intervene and provide assistance in the quitting process.51 A recent study in 12,000 cancer patients, including 2,700 patients who smoked, capitalized on the teachable moment and demonstrated that less than 3% of patients who were contacted by the cessation program rejected tobacco cessation assistance.45 However, only 1.2% of patients who received a mailed invitation participated in the program. This highlights the idea that patients may be interested in quitting, but methods such as mailed tobacco cessation information may not yield effective participation by cancer patients. Once enrolled, patients and clinicians must realize that although relapses in the general population usually occur within 1 week of cessation, relapses in cancer patients may be delayed due to cancer treatment-related variables such as surgical or other posttreatment healing.52 Consequently, it is important to continue offering tobacco assessments and cessation support for cancer survivorship efforts.


Defining Tobacco Use by the Cancer Patient

In dealing with tobacco use by cancer patients, it is important to note that virtually all of the evidence associating tobacco with cancer treatment outcomes deals with smoking. Few studies report associations between other forms of tobacco use (e.g., smokeless, cigars, cigarillos) and outcomes in cancer patients. Furthermore, the definition of smoking across published studies varies substantially.53 In studies of cancer patients, smoking has been defined as current (e.g., smoking after diagnosis, at diagnosis, in the weeks before diagnosis, within the 12 months prior to diagnosis, after diagnosis, within the past 10 years), former (e.g., recent, intermediate-, or long-term quit for 1 month, 3 month, 6 month, 12 month, 2 years, 5 years, 10 years), never, quitting after diagnosis, and according to exposure (e.g., multiple pack year cutoffs, Brinkman index, years of smoking, years of smoking within a predefined period of time such as 5 years prior to diagnosis). Though the nonstandard method of addressing tobacco use in cancer patients has been observed in several reports,54,55,56,57 there are no current standard recommendations for the definition of tobacco use by any national organization. There are four primary categories for smoking status:



  • Never smoking is typically defined as having smoked less than 100 cigarettes in a person’s lifetime and no current cigarette use. These patients are generally considered as a reference group in many studies. Categories 2 through 4 require that a person has smoked at least 100 cigarettes in their lifetime.


  • Former smoking is typically defined as no current cigarette use, usually within the past year.


  • Recent smoking (or recent quit) is generally 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 smoking one or more cigarettes per day every day or some days.

Ever smoking is a combination of categories 2 through 4 (i.e., former, recent, and current smokers) that has been used to report negative associations between smoking and cancer outcomes in a number of studies.58,59,60,61,62,63,64,65,66,67,68,69,70 Defining smoking according to ever smoking status limits the ability to interpret the effects of current smoking on a clinical outcome, and nothing can be done to address a prior tobacco use history. However, defining exposure according to current smoking status allows for the analysis of potentially reversible effects as well as for the potential implementation of smoking cessation to prevent the adverse outcomes of smoking on cancer patients. The primary focus for the remainder of this chapter will be on current smoking and will include a discussion of methods to address tobacco use with the cancer patient through accurate assessments and structured tobacco cessation support.


THE CLINICAL EFFECTS OF SMOKING ON THE CANCER PATIENT

Cancer treatment is generally defined according to disease site, stage, treatment type (e.g., surgery, chemotherapy [CT], radiotherapy [RT], or biologic therapy), and primary treatment objective, such as cure or palliation. A comprehensive discussion of the effects of smoking on cancer patients is beyond the scope of a single chapter, but the 2014 SGR provides an excellent evidence base, concluding that “the evidence is sufficient to infer a causal relationship between cigarette smoking and adverse health outcomes.”7 Overall, approximately 75% to 80% of studies in the SGR demonstrated a negative association between smoking and outcome, with approximately 65% to 70% of studies demonstrating statistically significant negative associations. This chapter will provide an illustrative review of studies that demonstrate the adverse effects of tobacco across disease sites and treatment modalities (e.g., surgery, CT, RT), and effects will be discussed across the categories of mortality, recurrence and cancer-related mortality, toxicity, and risk of a second primary cancer. Evidence for the benefits of smoking cessation will also be presented within each section.


The Effect of Smoking on Overall Mortality

Substantial evidence demonstrates that current smoking by cancer patients increases the risk of overall mortality across virtually all cancer disease sites and for all treatment modalities. Currently smoking significantly increased the risk of overall mortality by
between 17% to 38% as compared with never, former, and recent quit smokers in a large cohort of patients across 13 disease sites.71 Similar but larger observations were noted in elderly current smokers from a separate cohort (hazard ratio [HR], 1.72, 95% confidence interval [CI], 1.23 to 2.42).72 A large analysis of over 20,000 patients treated with surgery demonstrated that current smoking increased mortality by 62% in gastrointestinal cancer patients and by 50% in thoracic cancer patients with a nonsignificant trend in urologic cancer patients.73 Several larger studies with at least 500 patients demonstrated that current smoking increases mortality in head and neck cancer,74,75,76,77 breast cancer,78,79,80,81 gastrointestinal cancers,82,83 prostate cancer,84,85,86,87 renal cancer,88 gynecologic cancers,89,90 and lung cancer.91,92,93,94,95,96,97,98,99,100,101,102 Smaller studies demonstrate similar effects for hematolymphoid cancers such as leukemia and lymphoma.103,104 Studies suggest that the effects of current smoking on mortality may be dose and time dependent, with higher risks in heavier smokers105,106 and lesser risks in patients whose time since quitting was longer.105

Whereas many reports rely on retrospective chart reviews, several prospective studies demonstrate that current smoking increases mortality.71 Browman et al.107 was one of the first prospective studies to demonstrate that current smoking increased mortality by 2.3-fold in patients who continued to smoke during RT as compared with nonsmokers. Results from Radiation Therapy Oncology Group (RTOG) 9003 and 0129 cooperative group trials demonstrated that current smoking increased mortality in advanced head and neck cancer patients treated with RT or concurrent chemoradiotherapy (CRT),108 with a similar effect noted in 165 cervical cancer patients treated with CRT.109 In the randomized retinoid chemoprevention trial of 1,190 early stage head and neck cancer patients, current smoking increased mortality by 2.5-fold.110

Numerous studies have demonstrated that current smoking increases overall mortality as compared with former and never smokers combined.72,75,76,101,102,107,108 The adverse effects of smoking compared with former and never smokers not only reflect the negative effects of smoking on mortality as a whole, but also demonstrate that the effects of smoking are reversible. Current smoking increased mortality risk as compared with patients who quit within the year71 or 1 to 3 months prior to diagnosis.111,112 Furthermore, in 284 limited-stage small-cell lung cancer patients, patients who quit smoking at or following a cancer diagnosis had a 45% reduction in mortality as compared with current smokers.113 These studies suggest that the effects of smoking on mortality are reversible.

Collectively, these studies provide significant data associating current smoking with increased overall mortality across most disease sites, tumor stages, treatment modalities, and in both traditionally tobacco-related as well as nontobacco-related cancers. The potential significance of smoking is perhaps best exemplified by Bittner et al.,114 who analyzed causes of death in prostate cancer patients and demonstrated that more than 90% died of causes other than prostate cancer, but that current smoking increased the risks of non-prostate cancer deaths between 3- and 5.5-fold. 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 the most risk of death from noncancer-related causes such as heart disease, pulmonary disease, or other diseases related to smoking and tobacco use.


The Effect of Smoking on Cancer Recurrence and Cancer-Related Mortality

The primary objective of cancer therapy is to cure cancer and prevent recurrence. However, smoking has been shown to increase cancer recurrence and cancer-related mortality. Across a broad spectrum of cancer patients, current smoking increased cancer mortality as compared with former and never smokers.71 Current smoking has been shown to increase cancer mortality in patients with head and neck cancer,108,115,116,117,118 breast cancer,78,119 gastrointestinal cancers,82,120,121 prostate cancer,41,84,122 gynecologic cancers,89,90,106,123,124,125 and lung cancer.126 Cancer recurrence, whether local or metastatic, is a key driver behind cancer-related mortality. Several studies demonstrate that current smoking increases the risk of recurrence and decreases response across multiple disease sites.76,84,107,127,128 The effects of smoking on increasing recurrence or cancer-related mortality have also been reported in several relatively rare cancers.120,129 In a remarkable report of patients with recurrent head and neck cancers treated with salvage surgery, continued smoking after salvage treatment continued to increase the risk of yet another recurrence by 42%.130 The striking nature of this last study highlights the continued risks even in recurrent cancer patients and the resilience with which some cancer patients will continue to smoke.

The effects of smoking are also noted in premalignant lesions. In patients with high-grade vulvar intraepithelial neoplasia, current smoking increased the risk of persistent disease after therapy by 30-fold.131 In a prospective trial of progesterone to treat cervical intraepithelial neoplasia (CIN), current smoking increased the risk of progression as compared with former and never smokers combined.132 A prospective trial of 516 low-grade cervical intraepithelial neoplasia patients demonstrated that current smoking decreased response by 36%, although a similar effect was also noted in former smokers.133

As noted with overall mortality, several studies demonstrated that the effects of current smoking are worse than the effects of former smoking76,86,89,109,127,134,135,136,137 and that the effects of smoking may be acutely reversible. Several studies also demonstrate that current smoking increases recurrence or cancer mortality, whereas former smoking has no significant effect.41,78,82,84,85,119,122,123,124,138 The acutely reversible effects of smoking were shown by Browman et al.139 who demonstrated that continued smoking increased the risk of cancer-related mortality by 23% as compared with patients who quit within 12 weeks of starting RT. In 284 colorectal cancer patients, smoking at the first postoperative visit increased the risk of cancer mortality by 2.5-fold as compared with all other patients suggesting that smoking after treatment significantly predict for adverse outcome.121 In a notable study of over 1,400 prostate cancer patients treated with surgery, continued smoking 1 year after treatment increased the risk of recurrence 2.3-fold, but quitting smoking 1 year after treatment did not confer an increased risk of recurrence.128 Chen et al.138 demonstrate that patients who continue to smoke before and following a bladder cancer diagnosis have an increased risk of recurrence as compared with patients who quit in the year prior to diagnosis or within the first 3 months after diagnosis. The reversible effects of smoking on recurrence and mortality are consistent with observations on overall mortality and continue to emphasize the benefit of tobacco cessation for cancer patients who smoke at diagnosis.


The Effect of Smoking on Cancer Treatment Toxicity

Discussion of the effects of smoking on cancer treatment toxicity is highly dependent upon disease site, treatment modality (e.g., surgery, CT, RT), and timing of toxicity. Across disease sites and treatments, current smoking has been shown to increase complications from surgery,140,141,142,143,144,145,146,147,148,149 pulmonary complications,150,151 toxicity from RT,117,152,153,154,155,156 mucositis,157 hospitalization,158 and vasomotor symptoms.159 One of the largest recent studies in over 20,000 gastrointestinal, pulmonary, and urologic patients demonstrates that former or current smoking increased the risk of surgical site infection, pulmonary complications, or 30-day mortality in a site-specific manner.73 The effects of current smoking were most significant for pulmonary complications where former smoking had a lesser or nonsignificant effect. In 13,469 lung cancer patients treated with surgery, current smoking increased the risk of postoperative death with no increased risk in former smokers.160 Current
smoking increased the risk of complications, morbidity, or reoperation following esophagectomy, pancreatectomy, or colorectal surgery.161,162,163 A study of 836 prostate cancer patients treated with RT demonstrated that current smoking increased abdominal cramps, rectal urgency, diarrhea, incomplete emptying, and sudden emptying between two- and nine-fold,164 with similar effects noted in 3,489 cervical cancer patients who smoked more than 1 pack per day (PPD).156

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Jun 28, 2016 | Posted by in ONCOLOGY | Comments Off on Tobacco Use and the Cancer Patient

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