Second head and neck cancers and tobacco usage

Materials and methods 

Records from the Wake Forest University—Baptist Medical Center Tumor Registry were reviewed for the years 1985 through 2000. Ninety-one patients who had had an index head and neck tumor and who developed a second independent head and neck primary tumor were identified. These cases were grouped into synchronous (different sites within 6 months) and metachronous (different site after 6 months or same site after 3 years) second tumors and were examined with respect to smoking history—specifically whether smoking had continued or ceased after the diagnosis of the index tumor. Other factors, such as alcohol use and gastroesophageal reflux disease, were not considered or controlled for.

Results 

Of the 91 patients identified with double head and neck tumors, 88 were tobacco users, and 3 neither smoked nor used smokeless tobacco. Thirty-seven of the 91 patients (41%) had synchronous double primary head and neck cancers. All 37 were tobacco users, with 18 having greater than a 40 pack-year history of cigarette use. Distributed within the group of 54 with metachronous second primaries were 51 smokers—25 who had continued and 26 who had ceased tobacco use. Of the 26 patients who had quit smoking but had developed a second primary, 13 had stopped smoking even before the index primary was diagnosed. The remaining 13 had stopped after the index primary was treated. No statistically significant difference existed between the group of patients who continued to smoke and those who discontinued smoking, and no statistical difference in frequency of occurrence of a second primary was found between discontinuing smokers who had stopped smoking before the index lesion and those who stopped upon treatment of the index lesion.

Discussion 

As expected, the data support an overwhelming association of tobacco use with double occurrences of head and neck cancer. This association was manifested in 97% of the simultaneous and metachronous double primaries studied for this report. Reasonably effective (50%) smoking cessation efforts were noted for patients in this group. These data from all patients with double head and neck mucosal cancers reinforced the surprising findings of our previous study of patients with laryngeal cancer only. Equal numbers of second cancers occurred in patients who had ceased to smoke, compared with those who continued to smoke, and half (13 out of 26) of those who had stopped smoking actually stopped before the index lesion appeared. These observations imply that once a critical level of damage has occurred at the cellular level, the effects are long lasting. A continued insult (such as persistence in smoking) after the development of a certain degree of cellular damage—often manifested as an index lesion—may not have any greater impact than the cumulative initial exposure that precipitated the index lesion. The high incidence of synchronous double lesions also speaks to a critical cumulative damage level likely to occur simultaneously at various sites.

Schwartz et al reviewed the cases of 162 patients with second head and neck carcinomas occurring between 1978 and 1990.3 Interestingly, the percentages of patients with synchronous and metachronous lesions were identical to those of our study (41% and 59%, respectively).

Molecular and cellular events that occur as a result of carcinogenic exposure include DNA-adduct formation, inactivation of tumor suppressor genes (p53 protein), loss of heterozygosity and chromosomal loci encoding p53 and p16 genes), and loss of control of the cell cycle.4 Genetic polymorphisms for enzymes that metabolize tobacco smoke products have been reported to determine susceptibilities to second smoking-related cancers.5, 6 Several polymorphic glutathione S-transferase enzymes are involved in the detoxification of active metabolites of many potential carcinogens from tobacco smoke. An enzyme deficiency, either naturally occurring or induced, may be important in modulating susceptibility to smoking-related cancers. Jourenkova et al7 suggest that glutathione S-transferase GSTP1 and GSTT1 gene polymorphisms specifically modulate susceptibility to smoking-related cancers of the oral cavity and pharynx. Environment-gene interaction studies related to smoking exposure have demonstrated NAT1 Star 10 genotype interaction with environmental factors and possible gene-environment interactions for certain carcinogen-metabolizing enzymes.8

This review has looked only at tobacco use relative to second head and neck tumors. What has not been examined are tobacco's other health risks, such as detrimental effects on pulmonary and vascular systems, which may well continue to be additive and, in the final measure, cause a greater effect on long-term survival of second head and neck primary tumor patients. For this reason, continued tobacco use cessation efforts may well be beneficial. This conclusion is also suggested by the work of Zambon et al,9 who demonstrated a decreased cancer risk among patients with a long-term history of smoking cessation (more than 10 years), although these workers also found that such individuals still had a significantly higher risk for later cancer development (1.5-fold higher occurrence rate), compared with nonsmokers. A 10-year life expectation is often problematic for these usually elderly patients with multisystem disease related to prior and continued tobacco use. Our data question the ability of tobacco cessation efforts with a predominantly elderly population group to significantly decrease the incidence of second head and neck primary tumors after an index cancer has developed. This concern is supported by a National Institutes of Health study, which concluded that cessation of tobacco use appears to reduce the risk of oral cancers only gradually.10

Van Oijen et al11 have demonstrated persistently increased proliferation indices in ex-smokers, and Szyfter et al12 have demonstrated that the persistence of genetic defects are reliable markers of former exposure to tobacco genotoxins. They point out a better long-term risk estimate must consider proto-oncogene and tumor suppressor gene DNA lesions and the efficiency of DNA repair. Cheng et al13 also agree that individuals with reduced DNA repair capacity may be at increased risk for developing head and neck cancers. Modulating host-specific factors such as DNA repair capacity may moderate an individual's susceptibility to tobacco carcinogens. Tobacco cessation efforts should continue to be a high priority, but such efforts may have the most benefit for patients who have a limited history of smoking and who have not yet developed a tobacco-associated index cancer. In the prevention of second head and neck mucosal lesions, the quest for an agent that reverses cellular-level genetic damage may prove more important than efforts at smoking cessation.

Summary 

A review of 91 patients with double head and neck primary tumors indicates that the frequency of second tumors developing in patients who continued to smoke after diagnosis of their index cancers was not different from that of a group of patients who stopped smoking. Tobacco exposure is postulated to trigger a critical level of cellular damage independent of continued tobacco use. When this level of cellular damage is reached, a patient becomes at risk for not only an index cancer, but also additional synchronous and metachronous mucosal head and neck cancer, even if tobacco use ceases. Tobacco cessation efforts may be most beneficial for cancer prevention before the critical cellular level of damage occurs and certainly before, rather than after, development of the tobacco-related index cancer. Efforts to promote repair of tobacco-associated DNA injury at a cellular level may prove even more beneficial than smoking cessation in the prevention of second head and neck cancers. Smoking cessation efforts remain important to prevent the progression of other multisystem diseases.