HISTORY
Back in the forties, the Argentinian physician Angel Roffo (1882-1947) (1) was the first to publish on tobacco as a cause of cancer. In 1950, the British Medical Journal had a key article written by Doll and Hill on this causal relationship (2). But it took 14 years before the carcinogenic effects of tobacco were highlighted for the first time in the 1964 annual Report of the American Surgeon General, by head of Public Health Service Commissioned Corps and spokesman on matters of public health for the federal government in the USA (3). In the meantime, the cigarette industry flourished and the amount of individuals smoking increased by millions every year. A new Surgeon General Report on smoking emerged in 1979 and it stated that smoking was far more dangerous than had been supposed in 1964 (4). In the early eighties, it became clear that passive smoking also increased the risk of cancer (5) and by the end of the century causal relationships between smoking and many different cancer types, heart- and lung diseases, diabetes, birth complications, and various other diseases had been established. As for oncology, 30 % of all present cancer deaths in western countries are the consequence of smoking.
RENÉ VAN HELVOIRT, Senior Consultant Radiation Oncology, Center for Cancer Treatment, Sørlandet Hospital Trust, Kristiansand, Norway
CONTENTS OF TOBACCO SMOKE AND THEIR CARCINOGENICITY
Tobacco smoke contains about 7000 different molecular substances, amongst which the highly addictive nicotine. Around 60 substances are confirmed carcinogenic, part of them in gas form and part in solid form: amongst others aldehydes, hydrocarbons, metals. Understandably, there will be direct contact between the smoke substances and the lining epithelium of the head and neck areas and the airways and lungs, but as many of the substances enter the blood in the alveoli of the lungs, all the bodies’ organs and tissues will be reached and negatively affected. In contrast to what one would think, the introduction of filter cigarettes and light cigarettes placed an even greater health risk on the smoking population, at least with regard to lung cancer. As the smoker’s body’s need for nicotine stays the same, changing over to these types of cigarettes that have a lower gain of nicotine, will make the smoker smoke more cigarettes a day and inhale the smoke more deeply. On the population basis, the incidence of lung cancer rose especially with an increase in the incidence of more peripherally located cancers (6).
PATIENTS WITH CANCER WHO CONTINUE TO SMOKE
In the past two decades, increased focus has been given to what the consequences are if a patient who is diagnosed with cancer, continues to smoke. The negative consequences are significant and much larger than previously assumed. The 2014 annual Surgeon General Report focused on this and concluded that smoking cancer patients have a higher mortality, a higher cancer specific mortality, a higher cancer recurrence risk, a higher secondary cancer risk and more acute and late treatment related toxicities (7,8).
The risk of dying from any cause is 1.5 to 5 times higher for a smoking patient, the risk of dying from cancer is 1.5 to 3 times higher, the risk of tumor recurrence up to 2 times higher and the risk of a secondary cancer can even be up to 30 times higher (9,10,11,12,13,14). With regard to treatment related toxicity, both acute toxicities (2 to 9 times more often) and late toxicities including e.g. radiation induced lung cancer (13 times more often), are without doubt more prominent in smoking patients (15,16,17). This can have implications with regard to how to treat a cancer patient who refuses to give up smoking. For instance, for the majority of smoking early-stage breast cancer patients who have been operated on with breast conserving surgery, the risk of the potentially lethal treatment induced late toxicity of lung cancer, will outweigh the benefits of postoperative radiotherapy (17).
EX-SMOKERS VERSUS NEVER SMOKERS
The risk of death and complications in cancer patients who stop smoking before the start of treatment, will still be higher compared to the risks in those who have never smoked, but the risks are definitely lower than in continuous smokers. Stopping smoking will give these patients a significant risk reduction (30 – 70%)(9,10,18).
«Stopping smoking will give these patients a significant risk reduction»
QUALITY OF LIFE AND PERFORMANCE STATUS
Besides the gain of lowering the risk of death and complications, stopping smoking will give most patients the prospect of a better overall quality of life and a better performance status (measured by either the ECOG or the Karnofsky score)(10).
PATHOPHYSIOLOGY
Several of the underlying mechanisms behind the deleterious effects of continuous smoking in cancer patients have been elucidated in the past years (9,19,20,21,22,23).
- Many different cellular receptor pathways that are involved in cell division, e.g. the EGFR pathway, are affected by tobacco smoke. As a result, the cancer cells change towards a more malignant, more dividing phenotype.
- Exposition to tobacco smoke leads to less apoptosis in cancer cells and changes them into a pro-survival phenotype.
- Lasting exposition to tobacco smoke leads to a change in cancer cell behavior in that they become more invasive and thereby give rise to more hematogenous spread.
- Immune modulating effects are observed. Several immune systemrelated pathways are negatively influenced by tobacco smoke and the immune system becomes less effective, which is beneficial for the cancer cells.
- There will be less effect of various systemic oncological treatments. Tobacco smoke induces enzymes that play a role in the breaking down of different chemotherapeutics. This increased enzyme activity leads to a quicker clearance of these drugs and lowers the serum drug levels. Also in the field of molecular targeted agents negative effects are seen, for instance a diminished action of tyrosine kinase inhibitors.
- Radiotherapy will not be as effective. In vitro experiments have shown that cancer cells that are exposed to radiation under cigarette smoke circumstances, are less likely to die from the radiation damage, compared to the same type of cancer cells that are exposed to the same amount of radiation under fresh air circumstances. In patients, less effect of radiotherapy with diminished local tumor control is seen in for instance radically treated lung cancers and head and neck cancers.
EVIDENCE BASED ONCOLOGICAL TREATMENT
Around 20-25% of newly diagnosed cancer patients are current smokers. Knowing how deleterious it is for cancer patients if they continue to smoke, all smoking patients with a reasonable life expectancy (> 4-6 months) must be informed by their treating physician about these negative consequences and must be advised to quit. As stopping smoking is difficult for the majority of smokers and as a doctor’s recommendation alone will at best make no more than 25 % of them quit, a smoking cessation program must become an integrated part of oncological treatment. With the help of a cessation program including counselling by a cessation specialist and nicotine replacement therapy and/or the nicotinic acetylcholine receptor agonist varenicline, the amount of quitters can be increased by at least 10 % (some studies even report on success rates of 50 % quitters) (9). Initiated by a recently performed study on smoking cessation in cancer patients in Norway (results pending), cessation support is now offered in most Norwegian oncology departments.
References:
(1) Proctor RN. Angel H Roffo: the forgotten father of experimental tobacco carcinogenesis. Bull World Health Organ. 2006 Jun;84(6):494-6. Epub 2006 Jun 21.
(2) DOLL R, HILL AB. Smoking and carcinoma of the lung; preliminary report. Br Med J. 1950 Sep 30;2(4682):739-48.
(3) The 1964 report of the Surgeon General on health problems attributable to tobacco use. 1964.
(4) The 1979 report of the Surgeon General on health problems attributable to tobacco use. 1979.
(5) Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan. Br Med J (Clin Res Ed). 1981 Jan 17;282(6259):183-5.
(6) Shields P.G. Tobacco smoking, harm reduction, and biomarkers. J Natl Cancer Inst. 2002 Oct 2;94(19):1435-44. doi: 10.1093/jnci/94.19.1435.
(7) 2014 Surgeon General’s Report: The Health Consequences of Smoking—50 Years of Progress
(8) Warren GW1, Alberg AJ, Kraft AS, Cummings KM. The 2014 Surgeon General’s report: «The health consequences of smoking–50 years of progress»: a paradigm shift in cancer care. Cancer. 2014 Jul 1;120(13):1914-6. doi: 10.1002/cncr.28695. Epub 2014 Mar 28.
(9) Warren et al. The biological and clinical effects of smoking by patients with cancer and strategies to implement evidence-based tobacco cessation support. Lancet Oncol. 2014 Nov;15(12):e568-80.
(10) Florou et al. Clinical significance of smoking cessation in subjects with cancer: a 30-year review. Respir Care. 2014 Dec;59(12):1924-36.
(11) Gritz et al. Tobacco use in the oncology setting: advancing clinical practice and research. Cancer Epidemiol Biomarkers Prev. 2014 Jan;23(1):3-9.
(12) Chen et al. Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 2, pp. 414–419, 2011.
(13) Foerster et al. Association of Smoking Status With Recurrence, Metastasis, and Mortality Among Patients With Localized Prostate Cancer Undergoing Prostatectomy or Radiotherapy. JAMA Oncol. 2018;4(7):953-961.
(14) Rieken et al. Association of Cigarette Smoking and Smoking Cessation with Biochemical Recurrence of Prostate Cancer in Patients Treated with Radical Prostatectomy. EUROPEAN UROLOGY 68 (2015) 949 – 956.
(15) Alsadius et al. Tobacco smoking and long-lasting symptoms from the bowel and the anal-sphincter region after radiotherapy for prostate cancer. Radiother Oncol. 2011 Dec;101(3):495-501.
(16) Sharp et al. Smoking as an independent risk factor for severe skin reactions due to adjuvant radiotherapy for breast cancer. The Breast 22 (2013) 634-638.
(17) Taylor et al. Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials. J Clin Oncol. 2017 May 20;35(15):1641-1649.
(18) Chen et al. Impact of smoking cessation on clinical outcomes in patients with head and neck squamous cell carcinoma receiving curative chemoradiotherapy: A prospective study. Head Neck. 2019 Sep;41(9):3201-3210.
(19) Sobus et al. The biologic effects of cigarette smoke on cancer cells. Cancer. 2014 Dec 1;120(23):3617-26.
(20) O’Malley et al. Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer. J Thorac Oncol. 2014 Jul;9(7):917-26.
(21) Tu et al. Cigarette smoke enhances oncogene addiction to c-MET and desensitizes EGFR-expressing non-small cell lung cancer to EGFR TKIs. Molecular Oncology 12 (2018) 705–723.
(22) Rades et al. Effect of smoking during radiotherapy, respiratory insufficiency, and hemoglobin levels on outcome in patients irradiated for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008 Jul 15;71(4):1134-42.
(23) Chen et al. Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):414-9.