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Ann Thorac Surg 1998;65:1529-1534
© 1998 The Society of Thoracic Surgeons

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Original articles: general thoracic

Multiple Primary Cancers in Esophageal Squamous Cell Carcinoma: Incidence and Implications

^a Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Accepted for publication December 23, 1997.

Address reprint requests to Dr Wong, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. The occurrence of multiple primary cancers in the aerodigestive tract is a well-known phenomenon. This study aims to elucidate the incidence and the therapeutic and prognostic implications of a nonesophageal primary cancer in patients with squamous cell carcinoma of the esophagus.

Methods. Between 1982 and 1996, 1,055 patients with esophageal squamous cell carcinoma treated at our institution were reviewed for the presence of an additional primary cancer. The effects of the nonesophageal cancer on treatment of the esophageal carcinoma and survival were analyzed.

Results. Among 1,055 patients, 114 nonesophageal primary cancers were documented in 100 patients (9.5%), 70% of which were aerodigestive tract cancers. Forty-seven patients had antecedent tumors and 43 had synchronous tumors. Treatment strategies for esophageal carcinoma in these patients were similar to patients without multiple tumors, not influenced by the nonesophageal tumor except in 6 patients. The overall survival of patients with antecedent tumors, synchronous tumors, and without multiple tumors was similar (median survival, 8.6, 8.5, and 8.8 months, respectively) (p = 0.84). Subsequent primary cancers developed in 10 patients (0.9%), 9 of them with previous curative resection of esophageal cancer, and all died of the subsequent cancer.

Conclusions. There is a high incidence of multiple primary cancers in patients with esophageal carcinoma but the treatment and prognosis of these patients are primarily determined by the esophageal carcinoma itself. Subsequent cancer is, however, a significant cause of death among patients cured of esophageal carcinoma.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The association of multiple primary cancers in the aerodigestive tract is a well-known phenomenon that has been explained by the concept of "field cancerization" (ie, exposure of the epithelium of the head and neck, lung, and esophagus to common carcinogenic agents leads to multiple carcinomas in these regions) [1]. There is strong epidemiologic evidence to implicate tobacco as the main carcinogen, and alcohol appears to act as a promoter for carcinogenesis [2, 3].

Many investigators have reported the occurrence of multiple tumors in patients with head and neck cancer with an incidence of about 10% [4–9]. Metachronous or synchronous esophageal cancer has been identified in 1% to 2% of patients with head and neck cancer [8, 9]. There are, however, very few reports in the literature regarding the incidence of a nonesophageal primary cancer in patients with esophageal carcinoma as the index tumor, and the clinical significance of such a tumor in these patients remains unknown. In this review we studied the incidence of multiple primary cancers in patients with squamous cell carcinoma of the esophagus and their effects on treatment and survival of these patients.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Esophageal carcinomas are common among the Chinese population in Hong Kong, and most are squamous cell in origin. Between January 1982 and June 1996, 1,055 patients with histologically confirmed squamous cell carcinoma of the esophagus were managed in the Department of Surgery, The University of Hong Kong at Queen Mary Hospital. Follow-up was complete in 988 patients (93.6%). The occurrence of an additional cancer was documented in a prospectively collected database and 100 patients were found to have an antecedent, synchronous, or subsequent nonesophageal primary tumor, whereas the remaining patients had esophageal carcinoma alone. Demographic data of these two groups of patients including drinking and smoking habits, and data related to esophageal cancer including treatment and survival were extracted from the prospectively collected database and analyzed. Smokers and drinkers were classified into heavy or moderate according to their daily consumption of cigarettes (1 pack/day or <1 pack/day) and alcohol (6 units/day or <6 units/day) (Table 1). Data related to second primary tumors were obtained from review of medical records.

The observed number of patients with an additional primary cancer at a specific site was compared with the number expected in a sample of the general population with the same age and sex distribution in Hong Kong. The expected number of nonesophageal primary cancers was calculated using the person-years method described by Schoenberg and Myers [11]. The number of person-years of observation for each patient was calculated from the date of birth to the date of death or last follow-up so that antecedent, synchronous, or subsequent tumors could all be included in the analysis. Age- and sex-specific incidence rates of each cancer in the general population obtained from the Hong Kong Cancer Registry 1991 were used in the calculation [12]. The Hong Kong Cancer Registry is a population-based registry with data relating to cancer patients managed in all public and private hospitals in Hong Kong being collected and analyzed. It provides reliable incidence rates of various cancers in the Hong Kong population. The observed/expected ratios (O/E ratios) give an estimate of the relative risk of having an antecedent, synchronous, or subsequent nonesophageal cancer in patients with esophageal carcinoma when compared with the general population. The statistical significance of O/E ratios was tested on the basis of Poisson distribution. An O/E ratio with a 95% confidence interval that does not include a ratio of 1.0 is regarded as a significant ratio.

Comparisons between groups were performed using Student’s t test for numerical variables, and ² test (or Fisher’s exact test when the numbers were small) for nominal variables. Actuarial survival curves were analyzed using the life-table method and comparison of survival between groups was performed using Wilcoxon test. A p value of less than 0.05 was regarded as statistically significant.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Multiple primary cancers were found in 100 of 1,055 patients (9.5%) with squamous cell carcinoma of the esophagus. Fourteen patients had a third primary cancer, giving a total of 114 nonesophageal primary cancers. Forty-seven patients had antecedent tumors, 43 had synchronous tumors diagnosed simultaneously (32 patients) or within 6 months (11 patients) of diagnosis of the esophageal carcinoma, and subsequent tumors developed in 10 patients. Of the 114 nonesophageal primary cancers, 80 (70%) were aerodigestive tract cancers and 34 (30%) occurred at other sites.

The age and sex ratio of patients with or without multiple cancers were similar (Table 1). There were more smokers in the former group, but the difference was not statistically significant. However, among patients with multiple cancers, there were significantly more heavy smokers (p < 0.05). A significantly greater proportion of patients with multiple primary cancers were alcohol drinkers, and there were significantly more heavy drinkers (p < 0.05). All patients with multiple aerodigestive tract cancers were smokers and 90% were drinkers. The distribution of the esophageal tumors was similar between the two groups, the most common site being the middle third of the esophagus (Table 1).

The incidence of nonesophageal cancers at various sites of the aerodigestive tract and elsewhere in the three subgroups of patients is shown in Table 2. Of 45 synchronous tumors, 39 (87%) were aerodigestive tract cancers, whereas only 60% of the antecedent or subsequent tumors occurred in the aerodigestive tract. Table 3 shows the observed numbers, expected numbers, and O/E ratios of the nonesophageal primary cancers. The O/E ratios were statistically significant for primary cancers in the pharynx, oral cavity, larynx, colon, stomach, and bladder, but not in the lung. The O/E ratio for the total number of nonesophageal primary cancers was 9.0 (p < 0.01).

Treatment strategies for esophageal cancer in patients with antecedent or synchronous cancers and patients without multiple cancers are shown in Table 4. No significant difference was found between these three groups. Treatment of the esophageal cancer was influenced by the nonesophageal tumor in only 4 patients with antecedent tumors and 2 patients with synchronous tumors, who were treated with nonsurgical palliative measures in the presence of advanced incurable nonesophageal cancers despite a potentially resectable esophageal cancer. The disease stages of resected esophageal cancers were similar in patients with or without multiple cancers (Table 5).

View larger version (21K): [in this window] [in a new window]   Fig 1. Survival of patients with antecedent cancers, with synchronous cancers, and without multiple cancers.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Patients with aerodigestive tract cancers are known to have an increased risk of multiple primary cancers, but the risk is site specific and varies with different anatomic locations of the index tumor [5]. Very few investigators have studied the incidence of multiple primary cancers in patients with esophageal carcinoma, and the reported incidence ranges from 8.3% to 12.6% [13–16]. Our series represents a prospectively collected registry of patients with esophageal squamous cell carcinoma in a single institution managed by the same group of surgeons, and the occurrence of multiple primary cancers was well documented. The incidence of multiple primary cancers including antecedent, synchronous, and subsequent tumors was 9.5%. The overall O/E ratio of multiple primary cancers in these patients was 9.0, indicating a risk nine times greater than the general population. Patients with a known primary cancer have closer clinical surveillance that the general population and additional tumors may be discovered more frequently. This is a potential source of bias in the estimation of risk compared with the general population. The use of the cancer incidence rates from the Cancer Registry for 1 year (1991) for calculation could also have limited the accuracy of the O/E ratios as the incidence of the cancers might have changed depending on the year. However, the O/E ratios still provide a useful and reasonably reliable estimate of the relative risk of developing multiple primary cancers in our patients compared with the general population.

In concordance with findings in Western reports, smoking and drinking were important causative factors for multiple cancers in our patients. Information on the quantity of cigarette and alcohol consumption in our database was not sufficiently detailed for a more precise dose–response analysis but it was apparent that heavy smoking and drinking had a stronger association with multiple cancers than moderate smoking and drinking. A dose–response relationship between cumulative exposure of tobacco and alcohol and the occurrence of aerodigestive tract cancers has been demonstrated by a previous study [17].

Aerodigestive tract cancers accounted for 70% of the multiple primary cancers in this series. The risks of having an additional primary cancer in the pharynx, oral cavity, or larynx were substantially higher in our patients compared with the general population. There were also more lung cancers in our patients than expected in the general population, but the O/E ratio was not statistically significant. Lung cancer is the most common cancer in Hong Kong, and the incidence in the general population is high, even in female nonsmokers [12]. The number of patients in this series may not be large enough to give a statistically significant difference. A high incidence of lung cancers in patients with head and neck cancers has been reported [5]. In our series, there was a significantly increased risk of having a primary cancer in the stomach, colon, or bladder. The association of bladder cancer with smoking is well known, and the association of tobacco with gastric cancer has also been reported [18]. The causative link with colonic cancer is probably related to alcohol, as there is epidemiologic evidence of an increased risk of colorectal cancer with alcohol consumption [19].

Panendoscopy is important in the diagnosis of asymptomatic synchronous aerodigestive tract tumors in patients with head and neck cancer [6, 20]. Our data suggest that it is equally useful in the diagnosis of asymptomatic synchronous cancers in patients presenting with esophageal carcinoma. All of our patients with newly diagnosed esophageal carcinoma underwent routine direct laryngoscopy, bronchoscopy, and esophagogastroscopy, and a synchronous aerodigestive tract cancer was incidentally found in 10 patients (0.9%), the majority being at an early curable stage.

The presence of multiple tumors often poses a dilemma to surgeons in therapeutic decision making. The treatment for esophageal carcinoma in the 90 patients with additional primary cancers before or synchronous with esophageal carcinoma in our series was largely determined by the stage of esophageal carcinoma per se. Patients with potentially curable esophageal lesions underwent curative resection, and patients with incurable lesions underwent palliative resection if possible as this was considered the best mode of palliation. In 6 patients with advanced or metastatic antecedent or synchronous cancers, palliative nonsurgical measures were offered despite potentially resectable esophageal carcinoma. The long-term survival of these 90 patients with antecedent or synchronous cancers was comparable to that of patients without multiple cancers. In contrast, the presence of multiple tumors, irrespective of their time of occurrence, was found to have an adverse effect on the survival of patients with head and neck cancer [21]. This difference could be attributed to the presentation of most patients with esophageal carcinoma at an advanced stage, and their prognosis was poor irrespective of whether another primary cancer was present. Even after curative resection, the 5-year survival rate was only 23% for esophageal carcinoma in a recent review [22], which is much worse than almost all other primary cancers. The majority of patients in this series eventually died of esophageal cancer rather than of other primary cancers.

The incidence of a subsequent tumor in our series was only 0.9% (10 to 1,055 patients), much lower compared with the 6% to 12% incidence of a subsequent primary cancer reported for head and neck cancers [4, 7]. Unlike patients with head and neck malignancy, most patients with esophageal carcinoma did not survive long enough to develop a new cancer. Even in patients who underwent curative resection, the incidence was only 3% (9 of 281 patients). However, 5 of these 9 patients developed a subsequent cancer 5 years or more after resection of esophageal cancer, constituting 10% of the 5-year survivors of the whole group, and these patients died of the new cancer. Hence, a subsequent cancer is a major cause of death among patients cured of esophageal cancer.

Smoking and drinking are important factors in the development of multiple aerodigestive tract cancers, and discontinuing smoking and drinking has been reported to decrease the risk of subsequent primary cancers [2]. Recently, the focus has been turned to the use of retinoids as cytostatic agents to prevent epithelial carcinogenesis, and a prospective study has shown its effectiveness in preventing subsequent tumors in patients with carcinoma of the head and neck [23]. Early diagnosis of a subsequent cancer at a curable stage by regular follow-up with thorough examination and early attention to new symptoms and signs may also help decrease deaths from a subsequent primary cancer in patients cured of esophageal carcinoma.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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