Smoking as a Risk Factor 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.[1,2] 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),[3-5] 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 of 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 of 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, although 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 of 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 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. The impact of smoking on risk of a secondary lung cancer has been demonstrated in survivors of Hodgkin lymphoma.[7,12] Studies conducted in patients with primary cancers have also shown decreased risk of second malignancy and improved survival as a result of smoking cessation.[13,14]
- Gritz ER, Fingeret MC, Vidrine DJ, et al.: Successes and failures of the teachable moment: smoking cessation in cancer patients. Cancer 106 (1): 17-27, 2006. [PUBMED Abstract]
- Parsons A, Daley A, Begh R, et al.: Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ 340: b5569, 2010. [PUBMED Abstract]
- Richardson 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. [PUBMED Abstract]
- Tucker 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. [PUBMED Abstract]
- Johnson BE: Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 90 (18): 1335-45, 1998. [PUBMED Abstract]
- Ford 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. [PUBMED Abstract]
- Travis 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. [PUBMED Abstract]
- Kawahara 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. [PUBMED Abstract]
- Day 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. [PUBMED Abstract]
- Do 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. [PUBMED Abstract]
- Daniell HW: A worse prognosis for smokers with prostate cancer. J Urol 154 (1): 153-7, 1995. [PUBMED Abstract]
- Abrahamsen 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. [PUBMED Abstract]
- Chen CH, Shun CT, Huang KH, et al.: Stopping smoking might reduce tumour recurrence in nonmuscle-invasive bladder cancer. BJU Int 100 (2): 281-6; discussion 286, 2007. [PUBMED Abstract]
- Geyer SM, Morton LM, Habermann TM, et al.: Smoking, alcohol use, obesity, and overall survival from non-Hodgkin lymphoma: a population-based study. Cancer 116 (12): 2993-3000, 2010. [PUBMED Abstract]