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Smoking in Cancer Care (PDQ®)
- Smoking as a Primary Risk Factor
- Poorer Treatment Response in Cancer Patients
- Smoking as a Risk for Second Malignancy
- Effects of a Cancer Diagnosis on Quitting Smoking and Remaining Abstinent
- Smoking Intervention With Cancer Patients
- Pharmacological Treatment
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This summary briefly covers smoking as a primary risk factor for cancer, but the main focus is on the effect of smoking on recurrence or on diagnosis of a second primary cancer; patterns of quitting and continued smoking in cancer patients; and recommendations for smoking intervention for cancer patients. This information will assist health professionals caring for patients during and after treatment. Substantial material on cancer prevention and smoking cessation in the general population is available elsewhere. Because virtually all the available evidence pertains to cigarettes rather than other forms of tobacco such as snuff or chewing tobacco, reference is made to smoking cigarettes rather than to tobacco use.
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
Smoking as a Primary Risk Factor
The relationship between tobacco use and cancers of the lung and head and neck has been established for almost 50 years. Of the estimated 53,000 cases of head and neck cancer diagnosed each year, 85% are associated with tobacco use. The relative attributable risk for morbidity from smoking for lung cancer is more than 90%; it is between 60% and 70% for other smoking-related cancers (larynx, oral cavity, esophagus, bladder, kidney, pancreas, and other urinary cancers). Evidence suggests that smoking before age 30 years is a strong risk for colorectal cancer, with the risk appearing after a very long induction period (>35 years) in both men  and women.
Smokers may also be at increased risk of regional and metastatic disease at diagnosis. In one study, smoking worsened the course or outcome of acute myeloid leukemia, particularly in younger patients and those with unfavorable karyotypes. A study of renal cell carcinoma patients suggests that improvement in renal cell carcinoma risk following smoking cessation may be relatively linear but may take more than 20 years to reduce risk to that of a nonsmoker.
Smoking contributes to cancer development by causing mutations in tumor suppressor genes and dominant oncogenes and by impairing mucociliary clearance in the lungs and decreasing immunologic response. (Refer to the PDQ summary on Lung Cancer Prevention for more information.)1Shopland DR, Burns DM, Garfinkel L, et al.: Monograph 8: Changes in Cigarette-Related Disease Risks and Their Implications for Prevention and Control. Bethesda, Md: National Institutes of Health, National Cancer Institute, NIH Publ No 97-4213, 1997.2Giovannucci E, Rimm EB, Stampfer MJ, et al.: A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. men. J Natl Cancer Inst 86 (3): 183-91, 1994.3Giovannucci E, Colditz GA, Stampfer MJ, et al.: A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. women. J Natl Cancer Inst 86 (3): 192-9, 1994.4Kobrinsky NL, Klug MG, Hokanson PJ, et al.: Impact of smoking on cancer stage at diagnosis. J Clin Oncol 21 (5): 907-13, 2003.5Chelghoum Y, Danaïla C, Belhabri A, et al.: Influence of cigarette smoking on the presentation and course of acute myeloid leukemia. Ann Oncol 13 (10): 1621-7, 2002.6Parker AS, Cerhan JR, Janney CA, et al.: Smoking cessation and renal cell carcinoma. Ann Epidemiol 13 (4): 245-51, 2003.7Carbone D: Smoking and cancer. Am J Med 93 (1A): 13S-17S, 1992.
Poorer Treatment Response in Cancer Patients
Evidence exists for substantial medical advantage to an individual quitting smoking once cancer is diagnosed. There is substantial evidence that continued smoking may reduce the effectiveness of treatment and increase the likelihood of a second cancer. (Refer to the Smoking as a Risk for Second Malignancy section of this summary for more information.) Continued smoking may also worsen side effects of treatment, although the direct evidence for this is surprisingly limited because few studies have evaluated this issue.
If one extrapolates from the extensive evidence of the effects of smoking on cardiovascular disease, pulmonary functioning, immunosuppression, and wound healing due to vasoconstriction and the fairly rapid reduction of some effects following smoking cessation, these results might also apply to cancer patients, particularly if surgical management or lung functioning is involved. For example, one study outlined a model of cardiopulmonary toxicities in response to various antineoplastic therapies that may be potentiated by tobacco use. More specifically, smokers treated with bleomycin or carmustine showed higher levels of pulmonary fibrosis and restrictive lung disease, and the anthracyclines led to higher risk of cardiomyopathy in smokers.
In a study of advanced head and neck cancer patients receiving radiation therapy, patients who continued to smoke during radiation therapy suffered mucositis for a longer time (23.4 weeks) than did patients who quit at the time of radiation therapy and remained abstinent (13.6 weeks) or patients who remained abstinent for at least a month after treatment (18.3 weeks). Extended mucositis may be associated with permanent alteration in appearance. In one study, patients receiving induction chemotherapy for acute myeloid leukemia who continued to smoke were more likely to experience severe pulmonary infection (26% vs. 18%), although overall survival rates did not differ in adults older than 60 years. Following radiation therapy for laryngeal carcinoma, patients who continue to smoke may be less likely to regain satisfactory voice quality.
Another area of reasonable concern for patients who continue to smoke is the rate of general complications following any type of surgery. It is documented that wound healing postsurgery is slowed in smokers because both nicotine and carbon monoxide cause vasoconstriction, inhibition of epithelization, and creation of cellular hypoxia. In one study of predictors of complications following resection in lung cancer patients, a history of smoking doubled the likelihood of complications, but smoking at the time of admission for surgery did not. However, no detailed information on the time since smoking had ceased was provided.
One study found decreased response rates and survival rates in patients with head and neck cancer who continued to smoke during treatment. Patients who continued to smoke had a significantly lower rate of complete response to radiation therapy (45% vs. 74%) and 2-year survival (39% vs. 66%). Recent quitters were more similar to long-term quitters than to continued smokers in survival likelihood at 18 months.
Another study also showed an effect of continued smoking on survival rates in patients with head and neck cancer. Those who stopped smoking doubled their chance of survival, irrespective of extent of disease at diagnosis; after 2 years, survival of quitters approached that of nonsmokers. Relative risk for recurrence in quitters was about double that in nonsmokers; in those who continued to smoke after diagnosis, relative risk for recurrence quadrupled, regardless of the amount they smoked. One study failed to find significant differences in prognosis in resected stage I non-small cell lung cancer patients on the basis of smoking status; the recurrence and death rates in both former and current smokers did not differ but were double to triple the rates in newer smokers. These differences failed, however, to reach statistical significance because of the small number of newer smokers; in addition, the lack of differences between former versus current smokers was hard to interpret because no definitions were provided.
In another study, a consistent trend was found in patients with small cell cancer: continued smokers had the poorest survival, followed by patients who quit at diagnosis, then by patients who had quit on average 2.5 years before diagnosis. Although survival curves of recent ex-smokers did not differ statistically from continued smokers, perhaps because of small numbers, no continued smokers (n = 57) survived past 131 weeks, whereas six of those who quit at diagnosis (n = 35) were in complete remission at 1 and 2 years.
The relationships between smoking, disease recurrence, and mortality rates for prostate cancer have been examined. Studies have found an association between continued smoking and earlier recurrence  and increased mortality. In a study of 1,416 men who underwent radical prostatectomy, recurrence occurred after a mean of 7.3 years in 34.3% of current smokers, 14.8% of former smokers, and 12.1% of those who had never smoked. Another study found higher 5-year mortality rates in patients with stage D2 disease (88% vs. 63%) and non–stage A disease (39% vs. 17%). In a prospective observational study of 5,366 men, prostate cancer–specific death rates were 15.3 per 1,000 person-years for current smokers versus 9.6 per 1,000 person-years for those who had never smoked. Prostate cancer patients who quit smoking for 10 years or longer had mortality rates similar to those of nonsmokers.1Des Rochers C, Dische S, Saunders MI: The problem of cigarette smoking in radiotherapy for cancer in the head and neck. Clin Oncol (R Coll Radiol) 4 (4): 214-6, 1992.2U.S. Department of Health and Human Services.: The Health Benefits of Smoking Cessation. A Report of the Surgeon General. Rockville, Md: 1990. DHHS Publ No. (CDC) 90-8416.3U.S. Department of Health and Human Services.: A Report of the Surgeon General: How Tobacco Smoke Causes Disease: What It Means to You. Atlanta, Ga: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010. Also available online. Last accessed May 7, 2013.4Tyc VL, Hudson MM, Hinds P, et al.: Tobacco use among pediatric cancer patients: recommendations for developing clinical smoking interventions. J Clin Oncol 15 (6): 2194-204, 1997.5Rugg T, Saunders MI, Dische S: Smoking and mucosal reactions to radiotherapy. Br J Radiol 63 (751): 554-6, 1990.6Chelghoum Y, Danaïla C, Belhabri A, et al.: Influence of cigarette smoking on the presentation and course of acute myeloid leukemia. Ann Oncol 13 (10): 1621-7, 2002.7Karim AB, Snow GB, Siek HT, et al.: The quality of voice in patients irradiated for laryngeal carcinoma. Cancer 51 (1): 47-9, 1983.8Gritz ER, Kristeller J, Burns DM: Treating nicotine addiction in high-risk groups and patients with medical co-morbidity. In: Orleans CT, Slade J, eds.: Nicotine Addiction: Principles and Management. New York, NY: Oxford University Press, 1993, pp 279-309.9U.S. Department of Health and Human Services.: The Health Consequences of Smoking: Cardiovascular Disease. A Report of the Surgeon General. Rockville, Md.: DHHS Publication No. (PHS) 84-50204, 1983.10Kearney DJ, Lee TH, Reilly JJ, et al.: Assessment of operative risk in patients undergoing lung resection. Importance of predicted pulmonary function. Chest 105 (3): 753-9, 1994.11Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993.12Stevens MH, Gardner JW, Parkin JL, et al.: Head and neck cancer survival and life-style change. Arch Otolaryngol 109 (11): 746-9, 1983.13Gail MH, Eagan RT, Feld R, et al.: Prognostic factors in patients with resected stage I non-small cell lung cancer. A report from the Lung Cancer Study Group. Cancer 54 (9): 1802-13, 1984.14Johnston-Early A, Cohen MH, Minna JD, et al.: Smoking abstinence and small cell lung cancer survival. An association. JAMA 244 (19): 2175-9, 1980.15Daniell HW: A worse prognosis for smokers with prostate cancer. J Urol 154 (1): 153-7, 1995.16Joshu CE, Mondul AM, Meinhold CL, et al.: Cigarette smoking and prostate cancer recurrence after prostatectomy. J Natl Cancer Inst 103 (10): 835-8, 2011.17Kenfield SA, Stampfer MJ, Chan JM, et al.: Smoking and prostate cancer survival and recurrence. JAMA 305 (24): 2548-55, 2011.
Smoking as a Risk for Second Malignancy
Persons who initially present with both smoking-related and non–smoking-related malignancy face increased risk of a second malignancy at the same site or another site if they continue to smoke. When prognosis is more favorable for the initial cancer, the evidence is even stronger that continued smoking increases the risk of new primary cancers for up to 20 years after original diagnosis. In two studies of survivors of small cell lung cancer (SCLC) (mostly stage I and II), risk of a second cancer (mostly non-SCLC [NSCLC]) was 3.5-fold to 4.4-fold higher than in the general population. In those who continued to smoke, the risk was far higher, particularly in those who also received chest irradiation (relative risk [RR] = 21.0) and alkylating agents (RR = 19.0). In individuals who stopped smoking at the time of diagnosis, the risk was no higher than in those who had stopped smoking at least 6 months before diagnosis.
In a study of breast cancer survivors who subsequently developed lung cancer, the risk for subsequent lung cancer in those who were treated with thoracic radiation therapy (XRT) alone was negligible, whereas the risk attributable to smoking was substantial (adjusted odds ratio [OR] = 5.6) and even higher for a combination of XRT and smoking (unadjusted OR = 9.0, P < .05; adjusted OR = 8.6, P = .08). Even higher multiplicative risk for subsequent lung cancer from radiation treatment and smoking (RR = 20.2) was identified in a study of Hodgkin lymphoma survivors, which found higher multiplicative effects (RR = 49.1) for a combination of radiation and alkylating agents in moderate to heavy smokers compared with other cases. Another study in Japan confirmed that patients with SCLC who survive at least 2 years greatly reduced their likelihood of a second cancer if they quit smoking.
Patients with oral and pharyngeal cancers who smoke also have an exceptionally high rate of second primary cancers. A follow-up study of more than 1,000 patients with oral cancers found that the risk of a second cancer increased with continued smoking up to almost five times as much (OR = 4.7) for all aerodigestive cancers among long-term heavy smokers (two packs or more per day), even after controlling for alcohol, which carries its own excess risk. No effect was seen for quitting within 2 years, but risk decreased significantly after 5 years' cessation. Another study  confirmed this increased risk, though at a somewhat lower level. More than 1,000 patients with early-stage head and neck squamous cell carcinoma were examined for the joint effects of tobacco and alcohol exposure on second primary tumors (SPT) up to 6 years after initial diagnosis. SPT cases were more likely to be current smokers (27.5% vs. 18.8%) who smoked more for a longer period and used forms of tobacco other than cigarettes or in combination with cigarettes. Overall risk for SPT was approximately double for smokers. Most increased risk was associated with continued smoking (RR = 2.1) and alcohol intake (RR = 1.3) after diagnosis, although no interaction effect was evident.
The relationship between smoking and progression of prostate cancer has also been documented. One study found a much higher 5-year tumor-specific mortality rate among smokers with stage D2 disease (88% vs. 63%) or non–stage A disease (39% vs. 17%), which was attributed to immunosuppressive effects of continued smoking. Finally, the impact of smoking on risk of a secondary lung cancer has been demonstrated in survivors of Hodgkin lymphoma.1Wynder EL, Mushinski MH, Spivak JC: Tobacco and alcohol consumption in relation to the development of multiple primary cancers. Cancer 40 (4 Suppl): 1872-8, 1977.2Blum A: Cancer prevention: preventing tobacco-related cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, pp 545-557.3Richardson GE, Tucker MA, Venzon DJ, et al.: Smoking cessation after successful treatment of small-cell lung cancer is associated with fewer smoking-related second primary cancers. Ann Intern Med 119 (5): 383-90, 1993.4Tucker MA, Murray N, Shaw EG, et al.: Second primary cancers related to smoking and treatment of small-cell lung cancer. Lung Cancer Working Cadre. J Natl Cancer Inst 89 (23): 1782-8, 1997.5Johnson BE: Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 90 (18): 1335-45, 1998.6Ford MB, Sigurdson AJ, Petrulis ES, et al.: Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer 98 (7): 1457-64, 2003.7Travis LB, Gospodarowicz M, Curtis RE, et al.: Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst 94 (3): 182-92, 2002.8Kawahara M, Ushijima S, Kamimori T, et al.: Second primary tumours in more than 2-year disease-free survivors of small-cell lung cancer in Japan: the role of smoking cessation. Br J Cancer 78 (3): 409-12, 1998.9Day GL, Blot WJ, Shore RE, et al.: Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst 86 (2): 131-7, 1994.10Do KA, Johnson MM, Doherty DA, et al.: Second primary tumors in patients with upper aerodigestive tract cancers: joint effects of smoking and alcohol (United States). Cancer Causes Control 14 (2): 131-8, 2003.11Daniell HW: A worse prognosis for smokers with prostate cancer. J Urol 154 (1): 153-7, 1995.12Abrahamsen JF, Andersen A, Hannisdal E, et al.: Second malignancies after treatment of Hodgkin's disease: the influence of treatment, follow-up time, and age. J Clin Oncol 11 (2): 255-61, 1993.
Effects of a Cancer Diagnosis on Quitting Smoking and Remaining Abstinent
Most patients with a smoking-related cancer stop smoking or make serious efforts to quit at the time of diagnosis. One study reported that approximately half of a group of patients with oral and pharyngeal cancers quit at or after diagnosis; heavier smokers were substantially more likely to quit. Another study found a 12-month abstinence rate of 64.6% among head and neck cancer patients. A quit rate of 52% was reported in 115 head and neck cancer patients just before diagnosis, suggesting that an increase in smoking and cancer-related symptoms drives a substantial part of the decision to quit smoking, in addition to knowledge of the diagnosis.
Even patients who continue to smoke may remain motivated to quit. In a group of stage I small cell lung cancer patients, almost 90% had made one or more attempts to quit smoking, although 60% of survivors still smoked at 2 years. In another study, 84% of the sample had made at least one attempt to quit since surgery, and 69% had made multiple attempts. These studies found that while 80% of larynx and pharynx cancer patients remained abstinent after surgery, only 20% of those with oral cavity cancers did so. Patients who had undergone less intensive treatment (in particular, radiation therapy) were more likely to remain smokers; if they quit, they were 2.46 times more likely to resume tobacco use, even after controlling for severity. Higher relapse rates have also been associated with less radical treatment of head and neck cancers.
Such a relationship between continued smoking and less severe disease has also been found in cardiac patients. Another group in which secondary prevention may be particularly important is survivors of childhood cancer. In pediatric cancer survivors, initiation of smoking may be as high as in a group of healthy peers. An excellent review of the findings and recommendations in addressing smoking in this population has been published.1Gritz ER, Nisenbaum R, Elashoff RE, et al.: Smoking behavior following diagnosis in patients with stage I non-small cell lung cancer. Cancer Causes Control 2 (2): 105-12, 1991.2Gritz ER, Carr CR, Rapkin D, et al.: Predictors of long-term smoking cessation in head and neck cancer patients. Cancer Epidemiol Biomarkers Prev 2 (3): 261-70, 1993 May-Jun.3Ostroff JS, Jacobsen PB, Moadel AB, et al.: Prevalence and predictors of continued tobacco use after treatment of patients with head and neck cancer. Cancer 75 (2): 569-76, 1995.4Vander Ark W, DiNardo LJ, Oliver DS: Factors affecting smoking cessation in patients with head and neck cancer. Laryngoscope 107 (7): 888-92, 1997.5Day GL, Blot WJ, Shore RE, et al.: Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst 86 (2): 131-7, 1994.6Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993.7Gritz ER, Schacherer C, Koehly L, et al.: Smoking withdrawal and relapse in head and neck cancer patients. Head Neck 21 (5): 420-7, 1999.8Ockene J, Kristeller JL, Goldberg R, et al.: Smoking cessation and severity of disease: the Coronary Artery Smoking Intervention Study. Health Psychol 11 (2): 119-26, 1992.9Tyc VL, Hudson MM, Hinds P, et al.: Tobacco use among pediatric cancer patients: recommendations for developing clinical smoking interventions. J Clin Oncol 15 (6): 2194-204, 1997.
Smoking Intervention With Cancer Patients
Surprisingly few smoking intervention studies have been conducted with cancer patients. Many patients report quitting smoking at the time of diagnosis, and many others have comorbidities that prevent enrollment in clinical trials, yet little is known about routine smoking cessation services in an oncology setting. Thus, a smoking cessation feasibility study reported on implementation issues. In this study, 14,514 adult cancer patients were screened as potential participants, with fewer than 2% of patients determined to be eligible. Barriers to enrollment and exclusion criteria included the following:
- Nonsmoker status (83%).
- Contraindicated medical history (e.g., serious cardiovascular problem) (5%).
- Not interested in quitting smoking (4%).
- Current psychiatric condition (e.g., alcohol dependence, any Axis I disorder) (0.1%).
- Other (e.g., unreachable by phone, too far to travel, died, non-English speaker, current medication contraindicated) (7.2%).
Eighty-four percent of eligible patients enrolled. Compared to those who enrolled, those who declined were more likely to have advanced disease. Those who enrolled had extensive smoking histories (mean, 38 years), scored very high on measures of nicotine dependence, and averaged about seven drinks per week; about one-quarter of enrollees reported clinical levels of depressive symptoms. Researchers concluded that integrating a smoking cessation program into routine clinical care is feasible, although challenging, and that particular attention should be given to the subpopulation of smokers who also experience depression.
Another study found that when consistent intervention was provided to a group of head and neck cancer patients, about 65% were able to quit and remain abstinent, including about half of those who expressed little interest in quitting at baseline.[Level of evidence: I] A large intervention study with head and neck cancer patients used surgeon- or dentist-delivered advice to stop smoking, contracted quit dates, written materials, and booster advice sessions. Partially because of a high drop-out rate, a significant intervention effect was not detected, though differences were in the expected direction. A similar study [Level of evidence: I] also failed to find beneficial effects for very brief (<5 minutes) physician-delivered interventions based on the Ask, Advise, Assist, Arrange model outlined below. More than 400 cancer patients with a range of diagnoses were randomly assigned to receive either intervention or usual care. Approximately half had been diagnosed within the previous 6 months, 46.3% had tried to quit in the previous 6 months, and 84% were considering quitting in the following 6 months. Patients randomly assigned to the intervention group acknowledged receiving advice and resources from their physician consistent with the protocol; however, there were no significant differences in quit rates at either 6-month follow-up (11.9% vs. 14.4%) or 12-month follow-up (13.6% vs. 13.3%). Patients were more likely to quit smoking if they had been diagnosed with head and neck cancer or lung cancer, were lighter smokers, expressed a strong desire to quit, and used additional intervention resources. These results suggest that very brief physician counseling for this high-risk group is not adequate to improve quit rates.
A case-controlled retrospective study [Level of evidence: III] examined the effects of referral to a nicotine dependence center for more than 200 smokers diagnosed with lung cancer compared with smokers without a lung cancer diagnosis. Most lung cancer patients were less likely to have made previous attempts to quit but expressed higher motivation to quit smoking than did individuals without lung cancer. Although the likelihood of being abstinent at 6 months postintervention was higher among lung cancer patients (22% vs. 14%), after adjusting for demographic variables and level of motivation, there was no statistically significant difference. Patients who were closer to diagnosis at the time of intervention were far more likely to be abstinent at 6 months (27.3% vs. 0% for 3–6 months vs. 7% for >6 months, P = .01). In general, a brief smoking intervention consisting of approximately 1 hour of tailored intervention, including prescription of pharmacologic treatment, showed relatively little impact in this high-risk population. However, referral sooner after diagnosis may increase the likelihood of quitting. This study is limited by the self-selection of patients and lack of a nonintervention comparison group.
Considerable work has been done, however, with other patient groups—particularly cardiac patients—in establishing the valuable role of physicians and other health care providers in providing smoking intervention in the context of medical care. Specific recommendations for intervening in tobacco use have been published in several contexts. On the basis of outcomes from six major clinical trials of physician-delivered smoking intervention conducted in the late 1980s, the Ask, Advise, Assist, Arrange model was developed. In this model, the physician provides a brief intervention that entails asking about smoking status at every visit, advising abstinence, assisting by setting a quit date, providing self-help materials, recommending the use of nicotine replacement therapy, and arranging for a follow-up visit. See the list below for brief and expanded intervention outlines. The Patient-Centered Counseling Key Elements list below provides detailed questions that may be asked in the assist phase in a patient-centered counseling format that is brief enough (5–7 minutes) to be delivered within the context of a usual office visit.[Level of evidence: I]
These recommendations form the core of the Public Health Service–sponsored Clinical Practice Guideline [Level of evidence: IV]; that extended the recommendations by strongly supporting the value of referral to more intensive counseling. Furthermore, in addition to the documented value of nicotine replacement therapy (using gum, lozenge, patch, nasal spray, or inhaler), there is now clear evidence for the value of the antidepressant bupropion HCl (Wellbutrin SR and Zyban), 150 mg twice a day, as an adjunct for treatment; however, these adjunctive pharmacological treatments have not been tested in cancer patients. Individuals should be advised to check with their physicians.
Not all smokers are equally motivated to stop smoking. One of the most useful models for physicians in understanding the motivational issues in stopping smoking and actually quitting is the Stages of Change Model. Most individuals attempting to change a complex behavior such as smoking go through several predictable stages, from precontemplation to contemplation to preparation and, finally, to action. One of the goals of brief physician counseling is to move patients along these stages, until they are more motivated to quit. In addition, especially for first-time quitters, relapsing and cycling through these stages one or more times is common, until the person develops better behavioral skills.
The most common triggers for relapse are stressful situations and social triggers for smoking. One study found that the patterns of relapse in head and neck cancer patients were comparable to patterns of relapse in quitters in the general population.[Level of evidence: II] Smokers should be encouraged to anticipate such situations and develop strategies for handling them, as part of developing a new identity as a nonsmoker. It may take more than a year for even motivated smokers to successfully make these changes. The Stages of Change Model is well described and summarized  and is outlined as part of the Ask, Advise, Assist, Arrange Key Elements list below. Other important information such as smoking history (e.g., amount smoked or previous attempts to quit) can be efficiently collected by asking patients to complete a brief set of self-assessment forms in the waiting room. Nicotine addiction can be assessed using the Fagerstrom Test for Nicotine Dependence, and behavioral patterns (e.g., tendency to smoke when under stress) can be assessed using the online Quit Guide. When talking to patients about smoking cessation, providers can use a fact sheet available from the Centers for Disease Control and Prevention.
Psychiatric disorders and alcohol abuse may be complicating factors in the treatment of smoking, regardless of the population. Smoking prevalence is notably higher among those with mental or alcohol disorders, and response to treatment is poorer.
A comprehensive longitudinal study  of all patients (N = 1,425) seen over a 3-year period at the MD Anderson Cancer Center Tobacco Treatment Program identified individuals with major depression (n = 194), an anxiety disorder (n = 53), alcohol abuse (n = 92), or combinations of these disorders (n = 255), with the remainder (n = 831) having no psychiatric diagnosis. Across groups, individuals smoked an average of one pack per day. Patients received an individually tailored behavioral intervention, generally consisting of an in-person initial evaluation and an average of eight treatment sessions over 3 to 4 months, either in person or by phone, with follow-up at 6 months. Smoking-related pharmacotherapy was part of treatment for 88% of participants; about 15% also received a consultation with the program's addiction psychiatrist.
Individuals with no psychiatric diagnosis had abstinence rates of 44% at the end of the program and 45.1% at 6 months. Abstinence rates for clinical groups at 6 months varied, as follows:
- 30.2% for those with combined anxiety, depression, and alcohol abuse.
- 33.7% for those with alcohol abuse alone.
- 37.6% for those with major depression.
- 45.3% for those with only an anxiety disorder.
Regardless of the diagnosis, the best predictor of extended abstinence was the Fagerstrom Test for Nicotine Dependence (FTND) (overall average score, 4.9 [standard deviation, 2.2]; group range, 4.7 [no diagnosis] to 5.4 [major depression]). The overall conclusion is that in an intensive comprehensive program for cancer patients who are smokers, such as the program offered here, individuals with an anxiety disorder are likely to do as well as individuals without any diagnosis, but those with major depression or alcohol abuse may do more poorly, particularly if their FTND scores are higher.
Tailoring intervention for specific populations may also be important, although this has not been examined specifically in cancer patients. A study of the effects of self-help intervention materials designed for an African American population showed higher quit rates (25%) among those receiving the tailored materials than among those receiving the standard materials (15.4%) at 12 months postintervention.[Level of evidence: I]
Other investigators have begun to examine intervention approaches specific to patients at high risk for developing lung cancer, through the use of genetic biomarker feedback (presence of the CYP2D6 genetic abnormality, which increases the risk of developing lung cancer twofold to fourfold) in otherwise healthy smokers. Adding information on genetic risk for cancer to the usual counseling approaches increased initial quit rates significantly, but this effect was not maintained; such an approach may be a useful motivational component to add to a more comprehensive intervention but may not be sufficient in itself.[Level of evidence: I]
- Ask, Advise, Assist, Arrange Key Elements
- Ask/Assessment:Minimal assessment: Screen for smoking status at every visit or at admission.Augmented assessment: Assess characteristics of smoking history and patterns.Amount smoked.Quit history.Stage of change:Precontemplator: Is not seriously considering stopping smoking.Contemplator: Is seriously considering stopping within 3 to 6 months.Preparation: Is seriously considering stopping within the next week to month, and has already made changes such as cutting back.Action: Has recently stopped smoking (within last 6 months).Relapse: Has quit for at least 48 hours but is smoking again.Maintenance: Has quit for at least 6 months but may still be vulnerable to a relapse up to 1 year.Nicotine addiction: Fagerstrom Test for Nicotine Dependence. Behavioral patterns: Online Quit Guide.
- Advise:Minimal advice: “As your physician, I must advise you that smoking is bad for your health, and it would be important for you to stop.” Augmented advice: “Because of your (__________) condition, it is particularly important for you to stop. If you stop now, (briefly educate patient about basic health benefits from quitting).”
- Assist/Counsel:Minimal assistance: Provide self-help materials; assess interest in quitting; assess interest in and appropriateness of pharmacological aids. Augmented assistance: Provide brief 5- to 7-minute patient-centered counseling. See the list below for an outline of the counseling content.
- Arrange follow-up support:Minimal follow-up support: Arrange for single follow-up contact by visit or by telephone in about 2 weeks; provide referral to a smoking counselor or group.Extended follow-up support: Establish quit-smoking contract with quit date. Arrange three or more follow-up contacts by visit or by telephone.
- Patient-Centered Counseling Key Elements
- Motivation:Basic question:“How do you feel about your smoking?”Follow-up questions:“How do you feel about stopping smoking?” “Have you ever tried to stop before?” “What happened?” “What do you like about smoking?” “What do you not like about smoking?”
- Anticipated problems:Basic question:“What problems will you have if you stop smoking?”Follow-up questions:“Anything else?”According to your Craving Journal (available through the online Quit Guide), your craving level was highest when you were (_____). How do you think you can handle that type of situation?”
- Resources for coping with problems:Basic question:“How do you think you can handle that?”Follow-up questions:“What else could you do?” “How do you expect your (family/spouse/friends) to help you?”
The following information is based on the successful use of pharmacological agents in the cessation of smoking in the general population. None of the following agents have been studied in large placebo-controlled studies in cancer patients for aid in smoking cessation. Dosage adjustments or titrations may be required when administering these agents to oncology patients. (Refer to Tables 1 through 7 for more information.)
Nicotine Replacement Therapies
Nicotine replacement therapies are designed to aid in the treatment of withdrawal symptoms associated with nicotine. Several precautions must be considered before therapy is initiated, but these precautions do not constitute absolute contraindications.
- Patients who are pregnant or nursing should obtain advice from a health care professional before using these products.
- Patients should be advised to not use these products if they continue to smoke, chew tobacco, use snuff, or use other nicotine-containing products.
- Patients should be instructed to consult a physician before using these products if they are younger than 18 years, have heart disease or an irregular heartbeat, have high blood pressure not controlled by medication, have a history of or currently have esophagitis or peptic-ulcer disease, use insulin for diabetes, or take prescription medications for depression or asthma.
Varenicline is a nicotinic acetylcholine receptor partial agonist and the first U.S. Food and Drug Administration (FDA)-approved prescription pharmacologic agent targeted to these nicotinic receptors.[Level of evidence: I] Although specific mechanisms of action are unknown, it is thought that the agonist properties result in reduced craving and withdrawal by stimulating release of dopamine, and the antagonist properties prevent inhaled nicotine from binding at the nicotinic receptor sites.
There have been at least 12 published randomized, controlled trials evaluating varenicline versus placebo (or other approved agents for smoking cessation) for its ability to affect abstinence rates related to smoking or the use of smokeless tobacco. All studies were relatively large (129–607 patients per arm) and involved multiple sites and countries. In all studies, varenicline was statistically better in achieving abstinence rates by self-report and carbon monoxide measures than was placebo, and was often better than the other approved smoking cessation comparator arm. Abstinence rates at 12 weeks can be expected to range from 44% to 49% for varenicline, compared to 11% to 17% for placebo; longer-term rates (52 weeks) range from 14% to 22% for varenicline versus 4% to 8% for placebo.
Most studies evaluated varenicline 1 mg twice a day, using a 1-week titration of 0.5 mg daily for 3 days, 0.5 mg twice a day for 4 days, and then 1 mg twice a day for 11 weeks. However, a few studies evaluated different doses, such as 0.3 mg or 0.5 mg daily or 0.5 mg twice a day, and one study evaluated a flexible dosing schedule during weeks 2 to 12 after all participants were titrated up to 1 mg twice a day in an open-label fashion. From these data, varenicline 0.5 mg twice a day appears to be the minimum dose required to achieve statistically significantly better abstinence rates over placebo.
Most studies included healthy smokers, i.e., those without significant comorbidities such as cardiovascular disease or psychiatric disease. One study evaluated varenicline in patients with chronic obstructive pulmonary disease, and another study focused on patients with stable cardiovascular disease. However, no studies have evaluated varenicline use in cancer populations.
More than 3,000 patients in clinical trials received varenicline 1 mg twice a day for 12 to 24 weeks. The side effect profile across these 12 studies  was very consistent (although incidence varied) and comprised the following:
- Nausea (13%–52%).
- Insomnia (10%–35%).
- Headache (8%–24%).
- Abnormal dreams (6%–22%).
- Flatulence (6%–12%).
- Dyspepsia (6%–13%).
- Constipation (7%–12%).
- Fatigue or somnolence (6%–10%).
Cardiovascular events often occurred as frequently in the placebo and nicotine replacement arms as in the varenicline arm and overall were rare.
Only one study evaluated varenicline in patients with stable cardiovascular disease. At week 24, this study demonstrated 7-day abstinence rates of 34.9% for varenicline versus 15.9% for placebo (P < .0001); at week 52, these rates were 27.9% for varenicline and 15.9% for placebo (P = .0001). The prevalence of any adjudicated cardiovascular event was 7.1% in the varenicline arm and 5.7% in the placebo arm, for a difference of 1.4%.
A boxed warning for varenicline addresses the risk of neuropsychiatric events—specifically, suicidal ideation or behavior, agitation or hostility, depressed mood, and uncharacteristic behavior or thinking. For patients with significant comorbidities, the risks of smoking and varenicline use must be weighed against the benefits of smoking cessation. The dose-finding trial and package insert provide evidence that the incidence of adverse events is somewhat dose dependent. It is not known, however, whether cardiovascular risks—in particular, in patients with cardiac comorbidities—are dose related because the study evaluating varenicline in patients with stable cardiovascular disease studied varenicline at only the dose of 1 mg twice a day. This is an area in need of investigation.
In June 2011, the FDA updated the prescribing information label for varenicline to warn that the drug may increase the risk of cardiovascular adverse events in patients who have cardiovascular disease. In December 2012, the FDA updated the drug safety information for varenicline to include the results of a large meta-analysis that evaluated cardiovascular adverse events in patients who received either varenicline or placebo. Although a higher occurrence of adverse cardiovascular events that was not statistically significant was reported, there was an increased risk in patients using varenicline over those treated with placebo.
In a pooled analysis of two randomized studies (total N = 2,052) in which varenicline was directly tested against bupropion SR and a placebo, results showed continuous abstinence rates of 44% with varenicline, 29.7% with bupropion SR, and 17.7% with placebo at weeks 9 through 12. Abstinence rates were followed through week 52 at study end, with varenicline at 22.4%, bupropion SR at 15.4%, and placebo at 9.3%. Factors found in previous studies to predict better quit rates—such as being older, being male, having a lower level of nicotine dependence, smoking fewer baseline cigarettes, and having the first cigarette of the day at a later time—were not found to be predictive of higher quit rates in this pooled analysis.Table 5. VareniclineBrandDoseSide EffectsWarning/Precautionabid = twice a day; Rx = prescription.aIt is recommended that clinicians closely monitor all patients taking varenicline and bupropion hydrochloride (HCl). The premarketing smoking cessation studies of these medications excluded patients with serious psychiatric illness (e.g., schizophrenia, bipolar disorder, and major depressive disorder), suggesting that the safety of these medications for these patients has not been investigated. Therefore, during smoking cessation, it is important to especially monitor patients with preexisting psychiatric illness who are receiving varenicline and bupropion HCl for smoking cessation.RxChantix0.5 mg/d, days 1–3; 0.5 mg bid, days 4–7; then 1.0 mg bid through week 12Nausea, insomniaRisk of toxicity higher in patients with impaired renal function.Not tested in children and pregnant women.
Bupropion Hydrochloride (HCl)
Also used as an antidepressant, bupropion HCl (Zyban) is a non-nicotine aid to smoking cessation. It is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine and does not inhibit monoamine oxidase. The exact mechanism by which bupropion HCl enhances the ability of patients to abstain from smoking is unknown; however, it is presumed that this action is mediated by noradrenergic or dopaminergic mechanisms. One study [Level of evidence: I] failed to find any additional value of bupropion HCl in reducing relapse in individuals using the nicotine patch compared with a placebo either as part of a relapse prevention program (after the end of successful patch therapy) or as a second-level treatment for individuals who were still smoking after nicotine-patch therapy.
There are concerns that varenicline and bupropion HCl may be associated with an increased risk of depression and other neuropsychiatric events, including suicidal behaviors. This concern is based on postmarketing reports and post hoc analyses. Attempted and completed suicides have also been reported in patients taking these medications. These neuropsychiatric events have been reported in patients with or without preexisting psychiatric illness.
In July 2009, the FDA required the manufacturers of both varenicline and bupropion HCl to add a boxed warning to the product labeling, based on the continued review of postmarketing adverse event reports. The warning describes the risk of the following neuropsychiatric events from postmarketing reports:
- Changes in mood (including depression and mania).
- Homicidal ideation.
- Suicidal ideation, suicide attempts, and completed suicides.
The warning acknowledges that nicotine withdrawal related to smoking cessation may contribute to these neuropsychiatric events. The warning also acknowledges that causality between the medication exposure and these events cannot be conclusively established and states that the risks of these medications should be weighed against the potential health benefits of quitting smoking.
Patients can be carefully matched to specific smoking cessation strategies. Some smokers can quit with the help of counseling or psychological interventions, while others might need nicotine replacement therapies. Some smokers might need medications to successfully quit smoking. Given the significant health benefits derived from smoking cessation, medications can be used in these patients with careful monitoring.Table 6. Bupropion HClBrandDose Side EffectsWarning/Precautiona HCl = hydrochloride; Rx = prescription.aIt is recommended that clinicians closely monitor all patients taking varenicline and bupropion HCl. The premarketing smoking cessation studies of these medications excluded patients with serious psychiatric illness (e.g., schizophrenia, bipolar disorder, and major depressive disorder), suggesting that the safety of these medications for these patients has not been investigated. Therefore, during smoking cessation, it is important to especially monitor patients with preexisting psychiatric illness who are receiving varenicline and bupropion HCl for smoking cessation.Rx Zyban150 mg/d × 3 days, then increase to 300 mg/d × 7–12 weeksInsomnia, dry mouth, dizziness, rhinitis Do not take with Wellbutrin or Wellbutrin SR.Higher incidence of seizures in patients treated for bulimia or anorexia.Do not prescribe >300 mg/d for patients being treated for bulimia.
Although bupropion HCl (Zyban) is the only FDA-approved antidepressant for smoking cessation, fluoxetine HCl (Prozac) has been studied and shown to be effective.[Level of evidence: I] However, fluoxetine HCl also carries a boxed warning describing an increased risk of suicidality in adults younger than 25 years. (Refer to the Depression and Suicide section in the PDQ summary on Pediatric Supportive Care for more information.)Table 7. Fluoxetine HClBrand Dose Side Effects CommentsHCl = hydrochloride; Rx = prescription.RxProzac 30–60 mg/d Insomnia, dizziness, anorexia, sexual dysfunction, confusion Limited data available on use in combination with cognitive-behavioral therapy.
Lobeline (Bantron) is classified as a category III agent by the FDA (safe but no proven effectiveness). This product is not recommended for use in any smoking cessation program because of its lack of efficacy.
- Continued smoking substantially increases the likelihood of recurrence or occurrence of a second cancer in survivors, particularly in those who received radiation therapy.
- Most patients with smoking-related cancer appear motivated to quit smoking at the time of diagnosis.
- A stepped-care approach is recommended, with strong physician advice and brief counseling to quit and provision of basic information to all patients at each contact during the first month of diagnosis, followed by more intensive treatment (pharmacologic and counseling by a smoking specialist) for those having difficulty quitting or remaining abstinent.
Changes to This Summary (05/08/2013)
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Added text about the U.S. Food and Drug Administration safety review update of varenicline and risk of cardiovascular adverse events (cited U.S. Food and Drug Administration as reference 17).
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