Introduction

Several epidemiological studies have emphasized the fundamental role of tobacco and alcohol in the appearance of head and neck squamous cell carcinomas (HNSCC) [1, 2]. Smoking and drinking cessation is generally actively encouraged after diagnosis and treatment of a HNSCC, but a number of patients persist in consuming these substances [3–5].

The possible development of a second neoplasm in HNSCC patients who achieve control of the disease is a matter of major concern. The criteria to consider a tumor as a second neoplasm were defined by Warren and Gates in1932 [6]. They stated that each tumor must be confirmed histologically, that there must be no submucous connection between the two tumors, and the possibility that one of the tumors is a metastasis of the other must be ruled out. The index tumor is the first tumor diagnosed, and a second neoplasm is any malignant tumor discovered thereafter. From a chronological point of view, the second neoplasm is synchronous if it is diagnosed within 6 months after the diagnosis of the index tumor and metachronous if it is diagnosed after 6 months.

More than 70% of these second neoplasms are located in the aerodigestive tract, again in locations epidemiologically related to tobacco and alcohol use [7, 8]. All authors agree that the intensity and duration of tobacco and alcohol consumption prior to the diagnosis of the HNSCC index tumor has a significant influence on the risk of appearance of a second neoplasm [8–10].

However, the results of some studies analyzing the influence of continued tobacco smoking and alcohol drinking after treatment of a HNSCCC index tumor in the risk of appearance of a second neoplasm are contradictory. Several studies have found that continuing tobacco and alcohol use does not influence the risk of a second neoplasm [11–14], whereas others have found a relation between such persistence and the appearance of second neoplasm [15–19].

The objective of the present work was to perform a case–control study in an extensive cohort of HNSCC patients with a long follow-up to evaluate the influence of persistent tobacco smoking and alcohol drinking on the risk of appearance of a second metachronous neoplasm in the aerodigestive tract.

Material and methods

The data used in this study were obtained retrospectively from a database that prospectively collects information about the clinical status, tumor characteristics, treatment, and follow-up of all patients with a malignant head and neck tumor diagnosed in our hospital since 1985.

The study initially included all patients diagnosed between 1985 and 2000 with a HNSCC located in the oral cavity, oropharynx, hypopharynx, or larynx, with a minimum follow-up of three years and without antecedents of previous malignant tumors. Patients with synchronous tumors were excluded because it was considered that their appearance would not be related to persistence of tobacco and alcohol use. Patients with a second neoplasm outside the aerodigestive tract were also excluded. Warren and Gates’ [6] criteria for defining a second tumor were followed.

The routine follow-up program in our hospital consists of evaluation of recent medical history and loco-regional examinations at bimonthly intervals during the first year, every three months in the second year, every four months between the third and fifth years, and every six months thereafter. All patients undergo annual chest radiography. At follow-up visits the patients are questioned about tobacco and alcohol use and the information is included in the medical records. The follow-up visits are carried out alternately by the departments involved in the treatment of the patients: Otorhinolaryngology, Radiotherapy, and Medical Oncology.

From 1985 to 2000, 1,676 patients fulfilled the inclusion criteria. Prior to 2003, 265 of these patients developed a metachronous second neoplasm in the aerodigestive tract. Eight patients were excluded from the study as we were unable to retrieve their clinical records. The study group thus consisted of 257 patients who had a HNSCC index tumor located in the oral cavity, oropharynx, hypopharynx, or larynx, and presented a second metachronous neoplasm in the aerodigestive tract during the follow-up. The second neoplasm was located in the lung (137 cases), head and neck (91 cases), or esophagus (29 cases).

A control patient was selected from among the 1,411 patients who had not developed a second neoplasm to match each case patient. The control subjects were individually matched to the case by location of the index tumor, tumor stage according to the 5th TNM edition, sex, tobacco consumption prior to diagnosis of the index tumor, alcohol consumption prior to diagnosis of the index tumor, age (categorized at five-year intervals), general health status measured according to the Karnofsky index, treatment, and follow-up period. All control patients had a follow-up that was at least as long as the interval between the index tumor and the second neoplasm in the case group.

Table 1 shows the distribution of the patients included in case and control groups according to the variables considered in the matching. The tobacco and alcohol exposure levels prior to treatment of the head and neck index tumor were slightly higher in case patients, but there were no significant differences between case and control patients in any of the variables used in the matching process.

Table 1 Patient characteristics in relation to variables used in the matching
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Our database includes systematic information about tobacco and alcohol consumption prior to the diagnosis of the index head and neck tumor, but it does not include information about persistence in the use of these substances after treatment. Data concerning tobacco and alcohol use after treatment of the index HNSCC was obtained from a retrospective review of the patients’ records. Tobacco consumption after treatment for the index HNSCC was classified as: none, 1–10 cigarettes/day, 11–20 cigarettes/day, or >20 cigarettes/day. Alcohol consumption was categorized as: none, ≤50 gr/day, or >50 gr/day.

Persistent tobacco smoking and alcohol drinking after diagnosis of the index tumor was the only information collected retrospectively. A validation study was performed to determine bias in collecting this information. The retrospective information taken from the review of the clinical records was compared with prospective information from a study that was carried out in our center in a cohort of 582 consecutive patients to evaluate the use of tobacco and alcohol after treatment of a HNSCC [5]. One hundred and twenty-seven of the patients included in the present case–control study were also evaluated in this prospective study. A patient was defined as concordant when both the retrospective and the prospective information was the same. There was a concordance between retrospective and prospective information on 119 occasions (94%). Inconsistency between the two studies was attributed to eight patients with a metachronous second neoplasm who persisted in using tobacco or alcohol in the interval between the treatment of the index tumor and the diagnosis of the second neoplasm. All eight patients stopped using these substances when the metachronous second neoplasm was diagnosed and were included in the prospective study at this moment.

Univariable comparison of patients’ characteristics between groups was conducted using the chi-square test or Fisher’s exact test for qualitative variables and the student’s t-test or the nonparametric Mann–Whitney test for quantitative variables, as appropriate. We calculated the odds ratio (OR) for appearance of a second metachronous tumor in the aerodigestive tract in relation to persistent use of tobacco and alcohol, considering that it was a matched case–control study. A multivariate model (logistic regression) was used, considering the appearance of a second neoplasm as the dependent variable, and continued tobacco and alcohol use after treatment of the index tumor as independent variables.

Finally, we evaluated the attributable risk of persistent tobacco and alcohol use after treatment of HNSCC index tumor in the appearance of a second neoplasm tumor using the method in case–control studies proposed by Cox [20].

Results

Influence of persistence of tobacco smoking

Table 2 shows the distribution of tobacco consumption after treatment of the index tumor in the case and control groups, the OR for a second neoplasm according to the intensity of continued tobacco smoking, and the OR for a second neoplasm according to the intensity of continued tobacco smoking adjusted for the alcohol consumption. The percentage of patients who continued smoking in the case group was 33.5% and 14% in the control group (p = 0.001). The intensity of use was higher in the case group than in the control group (p = 0.001).

Table 2 Odds ratio for the appearance of a second neoplasm according to persistence in tobacco use after treatment of the head and neck index tumor
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Patients who continued smoking moderately (less than 10 cigarettes/day) had no greater risk of appearance of a second neoplasm. The incidence of a second neoplasm was significantly greater for patients who continued smoking more than 10 cigarettes/day. The OR for a second metachronous tumor in the aerodigestive tract in the total group of patients who continued smoking after treatment of the index tumor in relation to those who did not was 2.9 (95% CI OR 1.8–4.1).

Influence of persistence of alcohol drinking

Table 3 shows the distribution of alcohol consumption after treatment of the index tumor in the case and control groups, the OR for a second neoplasm according to the intensity of continued alcohol drinking, and the OR for a second neoplasm according to the intensity of continued alcohol drinking adjusted for the tobacco consumption. The percentage of patients who continued to drink alcohol was 44% in the case group and 13% in the control group (p = 0.001). In the case of persistence, the intensity of alcohol consumption was greater in the case group than in the control group (p = 0.02).

Table 3 Odds ratio for the appearance of a second neoplasm according to persistence in alcohol use after treatment of the head and neck index tumor
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There was a significant increase in the risk of appearance of a second neoplasm for patients who persisted drinking alcohol after treatment of the index tumor. The OR ratio for a second metachronous tumor in the aerodigestive tract for patients who continued to use alcohol after treatment of the index tumor in relation to patients who did not was 5.2 (95% CI OR 3.3–7.9).

Association between tobacco and alcohol

There was a strong association between the persistence of tobacco smoking and alcohol drinking after treatment of the index tumor in both case and control groups. In the case group, 92% of the patients who continued smoking also continued drinking, and 70% of the patients who persisted with alcohol consumption were simultaneously tobacco users. In the control group, 90% of the patients who persisted in smoking were also alcohol users, and 100% of the patients who continued drinking alcohol were also tobacco users. Considering tobacco and alcohol use jointly, the intensity of consumption of both substances was higher in the case group than in the control group (data not shown).

Table 4 shows patient classification in function of tobacco smoking and alcohol drinking after treatment of the index tumor according to three categories: no consumption (absence of tobacco and alcohol use); moderate consumption (<10 cigarettes/day and/or <50 gr alcohol/day); and high consumption (≥10 cigarettes/day or ≥50 gr alcohol/day). The table also shows the OR for appearance of a second neoplasm for each category. Considering patients who did not use alcohol or tobacco after treatment of the index tumor as the reference category, the risk ratio of appearance of a second neoplasm was 1.6 higher (95% CI 0.9–2.5) for patients with moderate consumption, and 11.2 higher (95% CI 5.6–22.4) for patients with high consumption.

Table 4 Odds ratio for appearance of a second neoplasm in relation to persistence in both tobacco and alcohol consumption after treatment of the head and neck index tumor
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Attributable risk

According to the estimate of the attributable risk, persistence in tobacco smoking and/or alcohol drinking after treatment would be responsible for 33% of the second neoplasms in the patients with a HNSCC index tumor (95% CI 26–37%).

Discussion

Development of a second neoplasm is a significant factor in survival of patients who achieve control of a HNSCC [21]. Several studies have shown second neoplasms develop at a steady rate throughout the follow-up period after a HNSCC, with an incidence of between 2% [22] and 5% [23] per year. Around 75% of these second neoplasms are carcinomas located in the aerodigestive tract, in locations that are epidemiologically related to tobacco and alcohol use. All authors appear to agree that the risk of developing a second primary tumor in the aerodigestive tract is clearly correlated with tobacco and alcohol abuse prior to the diagnosis of the index tumor [8–10]. Some studies have found a significant relationship between the intensity of tobacco and alcohol exposure prior to the diagnosis of the index tumor and the incidence of second neoplasm [22, 24]. Nevertheless, there is no unanimity about the role of continued tobacco smoking and alcohol drinking after treatment of the HNSCC index tumor in the appearance of a second neoplasm.

Table 5 summarizes the results of several studies analyzing the influence of continuing tobacco smoking after treatment of a HNSCC index tumor on the development of a second neoplasm.

Table 5 Studies relating persistence of tobacco smoking with the appearance of a second neoplasm
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In 1965, Moore [25] first reported the relationship between persistence in tobacco smoking after treatment of a HNSCC and appearance of a second neoplasm. The same author later carried out a longitudinal study in 203 HNSCC patients with a follow-up of 3–18 years, finding that the frequency of second neoplasm in the group with persistence of tobacco smoking was 40% as compared to 6% for the group of quitters (p < 0.001) [17].

In a retrospective matched case–control study, Wynder et al. [16] found that the frequency of persistence in use of tobacco after treatment of a HNSCC index tumor was significantly greater in the group of patients who developed a second head and neck carcinoma. These authors found that persistence in alcohol drinking was also greater in patients with a second neoplasm, but in this case the differences did not reach statistical significance.

Finally, in two prospective longitudinal studies in patients with index tumors in the oral cavity and head and neck, Silverman et al. [15, 18] found a relation between continued tobacco use and the development of a second oral or oropharyngeal carcinoma.

However, other authors found no such relation between persistence in tobacco smoking and alcohol drinking and the risk of second neoplasm. In a retrospective case–control-matched study in patients with oral cavity and pharynx carcinomas, Day et al. [13] did not find the cessation of tobacco or alcohol consumption after treatment of a HNSCC to be associated with a reduction in the risk of second neoplasm. Similarly, according to the results obtained in two retrospective studies carried out by Castigliano [11] and Tomek et al. [14], and in one prospective study by Schottenfeld et al. [12], cessation of tobacco smoking or alcohol consumption did not significantly reduce the incidence of second neoplasm.

It is clear that there is no conclusive evidence from these studies. The discrepancies may be due to differences in design and methodology. Some of the studies included a limited number of patients [11, 22], with information derived from telephone interviews in some cases [12, 13, 18], with a limited follow-up period [11–13, 15], or without considering the alcohol consumption after the treatment of the index tumor [11, 15, 17, 18].

For ethical reasons it is not feasible to carry out an experimental study evaluating the influence of the persistence of tobacco and alcohol use after treatment of a HNSCC. From a theoretical point of view, the best design to evaluate this topic would be a prospective longitudinal study with a large number of patients and a long follow-up.

Do et al. [26] recently published the results of such a study that analyzed 1,190 patients with an early (stages I–II) HNSCC tumor included in a chemoprevention clinical trial. The median time from index tumor diagnosis to randomization to 13-cis-retinoic acid or placebo was 1.0 year (range 0.4–4.5 years), and median follow-up duration from the time of randomization was 4.9 years (range 0–9.9 years). A second primary tumor was diagnosed in 248 patients (20.8%) and it was located in a smoking-related location in 70% of cases. According to the results of a multivariate study, the risk of second neoplasm in a tobacco-related location was significantly greater in the group of patients who continued smoking after treatment of the index tumor. Considering the group of never-smoker patients as the reference category, the risk of a tobacco-related second primary tumor was more than three times greater (RR 3.28; 95% CI 1.69–6.38) in the group of patients who persisted smoking after treatment of the index tumor. Former smokers (patients who quit smoking >12 months before the clinical trial) and recent quitters (patients who quit smoking <12 months before clinical trial and remained abstinent during follow-up) were approximately 1.5 times more likely to develop a second primary neoplasm (RR for former smokers 1.41, 95% CI 0.79–2.50; RR for recent quitters 1.77, 95% CI 0.93–3.39).

In a previous study with the same cohort of patients [19], it could be appreciated that the risk of second neoplasm was greater for patients who continued drinking alcohol after treatment of the index tumor. Considering never-drinkers as the reference category, patients who continued alcohol use after treatment of the index tumor had a 1.3 higher risk of second neoplasm (RR 1.3, 95% CI 1.0–1.7).

It is widely accepted that tobacco and alcohol use prior to diagnosis of a HNSCC index tumor plays a role in the appearance of a second neoplasm. In the present study, whose aim was to evaluate the influence of continued tobacco and alcohol use in the appearance of a second neoplasm, one of the main challenges was to recruit a control group of patients without second neoplasm but with a similar exposure to tobacco and alcohol prior to diagnosis of the index tumor. Table 1 shows that case patients had a slightly greater exposure to tobacco and alcohol prior to diagnosis of the index tumor than control patients. However, as there were no significant differences between groups, we consider the two were comparable in relation to tobacco and alcohol exposure.

One of the limitations of our study was the retrospective character of the data about persistence in tobacco smoking and alcohol drinking after treatment of the index tumor. In contrast, all the other information has been prospectively recorded in our center from 1985 [27]. To verify the accuracy of the retrospective data, a validation study was carried out with data prospectively obtained in a study about persistence in tobacco and alcohol use after treatment of a HNSCC [5]. The results of this validation study allowed us to check the adequacy of the information about persistence in tobacco and alcohol use obtained retrospectively from the clinical records.

The results obtained showed that persistence in the use of both tobacco and alcohol after treatment of a HNSCC index tumor was related with the development of a second neoplasm in the aerodigestive tract. In agreement with Do et al. [26], the results of our study showed that continuing smoking increased the risk of second neoplasm almost threefold. Continuing alcohol use also increased the risk of a second neoplasm in a significant way. We should point out that there was a clear association between tobacco and alcohol consumption, making it difficult to separate the individual contribution of persistence of each in the risk of second neoplasm. However, the multivariate analysis showed that the persistence of both tobacco smoking and alcohol drinking after treatment of a head and neck index tumor were significant independent risk factors in the appearance of a second neoplasm.

The attributable risk is used to provide a measure of the effect of exposure to a risk factor on the occurrence of a disease. There are no data in the studies that consulted about the attributable risk of continuing to smoke and drink in the appearance of a second neoplasm in HNSCC patients. According to our results, one-third of the second neoplasms after treatment of an index HNSCC would be attributable to the persistence of consumption of these substances.

The results of a previous study in our center showed that 13% of patients continued smoking and 21% continued drinking alcohol after treatment of a HNSCC [5]. According to the results of the present study, persistence in tobacco smoking and alcohol drinking had a significant influence on the appearance of a second neoplasm, and would be responsible for one-third of these tumors. It therefore stands to reason that tobacco and alcohol cessation should be a major goal after diagnosis and treatment of a HNSCC in order to decrease the incidence of second neoplasm and to improve survival in this group of patients.