Japanese Journal of Clinical Oncology 32:S10-S12 (2002)
© 2002 Foundation for Promotion of Cancer Research
The Strategy for Esophageal Cancer Control in High-risk Areas of China
1Department of Epidemiology, Cancer Institute and Hospital (CI/H), Chinese Academy of Medical Sciences (CAMS), 2Department of Surgery of Head and Neck Cancers, CI/H, CAMS, 3Chinese National Office of Cancer Prevention and Treatment and 4Department of Endoscopy, CI/H, CAMS, Beijing, China
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPRIMARY PREVENTIONSECONDARY PREVENTIONTAIHANG ANTI-CANCER CAMPAIGNPERSPECTIVESREFERENCES |
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Even though the mortality from esophageal cancer has decreased during the last two decades nationwide in China, the mortality from esophageal cancer in high-risk areas is still at a high level. Moreover, the 5-year survival rate of patients with resectable esophageal cancer after treatment ranges between 20 and 30%, as majority of patients with esophageal cancer were diagnosed in late stages. Therefore, esophageal cancer control in high-risk areas in China remains a critical task. A strategy is proposed that the high-risk population would be screened by endoscopy with mucosal iodine staining and biopsy of all unstained lesions and diagnosis of severe dysplasia carcinoma in situ, and intra-mucosal carcinoma could be cured by radical mucosectomy. A pilot study showed that the strategy is feasible and cost-effective for the high prevalence of premalignant lesions and carcinomas in early stages. It would be expected that the mortality from esophageal cancer could be decreased in high-risk areas if the proposed strategy is carried out on a large scale.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPRIMARY PREVENTIONSECONDARY PREVENTIONTAIHANG ANTI-CANCER CAMPAIGNPERSPECTIVESREFERENCES |
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In the late 1970s, a Chinese mortality survey (1973–75) was conducted nationwide among the population of 850 million. Two decades later (1990–92), another mortality survey was conducted based on random stratified cluster samples that encompassed 10% of the total population of 1.2 billion. Cancer mortalities between these two surveys were compared and analyzed (1). It was shown that in the 1990s the total cancer mortality rate was 108.26/100 000, accounting for 17.94% of all deaths. It increased by 11.56% from 1970 to 1990 and became the second leading cause of all deaths, just below respiratory diseases. At present, about 1.3 million Chinese are expected to die of cancer each year; they include stomach cancer (302 000), liver cancer (244 000), lung cancer (210 000) and esophageal cancer (209 000). These four types of cancers account for 74% of all cancer deaths. Whereas the mortality rates of stomach and liver cancers have remained stable at a high level, the mortality rate of lung cancer has significantly increased, i.e. doubled (111.85%). The mortality rates of cervical, nasopharyngeal and esophageal cancer decreased by 69.00, 34.62 and 21.32%, respectively. However, there is controversy about the change in esophageal cancer, because the classification of diseases applied in the 1970s and 1990s were different. In the 1970s gastric cardia cancer was classified in esophageal cancer, but in the 1990s it was included in gastric cancer. At least the mortality of esophageal cancer remains at a high level (80–120/100 000) in high-risk areas around the Taihang Mountains, including Linxian in Henan Province, Cixian in Hebei Province and Yangcheng in Shanxi Province. Moreover, since the majority of patients with esophageal cancer have a tendency to be diagnosed at a late stage, the 5-year survival rate of patients with resectable esophageal cancer after treatment remains at a low value, ranging from 20 to 30%. Among 15 476 inpatients with esophageal cancer in Anyang Cancer Hospital in Henan Province from 1975 to 1998, only 4.3% of cases were at an early stage according to clinical standards. Therefore, esophageal cancer control remains a critical task in high-risk areas of China.
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PRIMARY PREVENTION |
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TOPABSTRACTINTRODUCTIONPRIMARY PREVENTIONSECONDARY PREVENTIONTAIHANG ANTI-CANCER CAMPAIGNPERSPECTIVESREFERENCES |
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Comprehensive studies on the etiology and carcinogenesis of esophageal cancer in high-risk areas have been carried out (2) during the past 40 years, based on a multidisciplinary approach of clinical, laboratory and field investigations. In contrast to Western counties, where the consumption of tobacco and alcoholic beverages has been implicated as a contributory factor in esophageal cancer, the causative factors in esophageal cancer in high-risk areas of China were summarized as follows: 1) nutrition deficiency, 2) N-nitrosamines, 3) fungitoxins and 4) genetic factors. A primary prevention study of nutrition intervention trials in Linxian (3) was conducted in 1985 by scientists from the Cancer Institute and Hospital, Chinese Academy of Medical Sciences in China and the National Cancer Institute in the USA. Four different nutrient supplements were tested with 29 584 participants from the general population. At the end of the 6-year intervention, the group receiving a supplement with selenium, ß-carotene and vitamin E was found to give a statistically significant reduction of 9% in all causes of mortality. Mortality and incidence of the combined category of esophageal and gastric cardia cancers were reduced by 10 and 6%, respectively. A further study based on nutrition intervention trials led to a conclusion that higher serum selenium is associated with lower esophageal and gastric cardia cancer rates (4). Hence there is a suggestion that selenium supplementation, either alone or in conjunction with other nutrients, should be started in high-risk areas. However, primary prevention such as improving nutritional status and health education would take a long time to decrease esophageal cancer deaths and would bring benefit mainly to younger generations. At present, secondary prevention may be more practical for decreasing overall esophageal cancer deaths within a relatively short term.
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SECONDARY PREVENTION |
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TOPABSTRACTINTRODUCTIONPRIMARY PREVENTIONSECONDARY PREVENTIONTAIHANG ANTI-CANCER CAMPAIGNPERSPECTIVESREFERENCES |
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The occurrence and development of esophageal cancer are processes affected by multi-factors, multi-steps and multi-genes. It will need more than 10 years to develop from premalignant lesions to carcinoma. Generally, histologically proven squamous dysplasia could be considered as premalignant lesions of esophageal cancer. Also, dysplasia with higher grades was associated with a significantly increased risk of developing esophageal cancer; the probability of developing cancer within 3.5 years from mild, moderate or severe dysplasia was reported to be 5, 25 and 65%, respectively (5). In practice, severe dysplasia is considered as premalignant lesions, which have similar degrees of risk as carcinoma in situ. Usually, esophageal carcinoma in situ and intra-mucosal carcinoma are considered as esophageal cancers at an early stage with a 5-year survival rate of more than 95%, whereas submucosal carcinoma and carcinoma invaded into muscle layers are considered as esophageal cancers at a late stage with 5-year survival rates of 60 and 25%, respectively. With regard to symptoms, among 753 early cases confirmed with pathological examinations, only 82 cases (10.9%) had mild swallowing difficulty and pain (personal communication). Since most cases are asymptomatic, the lesion is frequently unresectable when the patients visit medical facilities. The fact that most patients are diagnosed at a late stage of the disease is the principal reason for the poor prognosis of esophageal carcinoma. Therefore, at present, cancer screening, early detection and early treatment are the only choices for esophageal cancer control in high-risk areas.
The early detection of esophageal cancer was started in the 1950s with a balloon cytology sampler, which was established by Professor Shen. From 1958 to 1988, in a mass survey, esophageal balloon cytology was performed over 150 000 times (6) and esophageal cancer was found at an overall frequency of 2%, of which 84% belonged to esophageal cancer at an early stage. Among 204 operated cases with early esophageal cancer, postoperative survival at 20 years was 50.9%. Hence balloon cytology made a great contribution to the early detection and the recognition of the developing process of esophageal cancer. However, in a recent report, it was found that the sensitivity of balloon cytology for detecting biopsy-proven esophageal cancer was only 44% (7). During the past 20 years, endoscopic examinations were carried out in 20 505 high-risk adults over 40 years old and 766 cases with early esophageal cancer were diagnosed, including 498 (65.0%) carcinoma in situ and 49 (6.4%) minute cancer foci <0.5 cm in diameter. On endoscopic examination, 2.5% iodine solution was routinely applied for mucosal staining. The normal mucosa were stained brownish black, whereas carcinomatous or dysplastic mucosa were negative. The contrast in coloration between the lesions and normal mucosa was very conspicuous and the lesions were easily localized and proved by biopsy.
When more cases with esophageal cancer at an early stage can be detected, earlier treatment could be achieved, leading to longer survival and lower mortality. Since 1995, more than 140 cases have been treated with mucosectomy through endoscopy. Among these, 47 were treated with a result of 100% 3-year survival rate. Intra-mucosal carcinoma, carcinoma in situ and severe dysplasia were considered to be suitable for mucosectomy with lesions of diameter <3 cm and circumference <50%. Our clinical experience of more than 10 years indicates that endoscopic examination with iodine staining and biopsy of all unstained lesions is the most effective method for the early detection of esophageal cancer and mucosectomy following endoscopy plays an important role in early treatment.
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TAIHANG ANTI-CANCER CAMPAIGN |
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TOPABSTRACTINTRODUCTIONPRIMARY PREVENTIONSECONDARY PREVENTIONTAIHANG ANTI-CANCER CAMPAIGNPERSPECTIVESREFERENCES |
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Based on the effective and successful methods for early detection and early treatment of esophageal cancer, a strategy for esophageal cancer control in high-risk areas was proposed. It was named the ‘Taihang Anti-cancer Campaign’, because the high-risk areas of esophageal cancer are around the Taihang Mountains. As the first step of the campaign, three stations in Linxian in Henan Province, Cixian in Hebei Province and Yangchen in Shanxi Province were chosen for field studies, with a general population of 300 000. Since the level of cases with esophageal cancer in the population <40 years old is only ~2%, the high-risk population is defined as those
40 years old, accounting for 22.5% of the general population (67 500). The total population is divided into two groups, half as a control group without intervention and the other half as an intervention group; in the latter, the high-risk adults would be screened by endoscopy with iodine staining and multiple biopsy. To avoid biases, the intervening rate should be >50% (the intervening rate is equal to the screening rate multiplied by the treatment rate). The incidence and mortality rate of esophageal cancer would be followed up in these two groups. After screening, adults with normal, mild and moderate dysplasia would be followed up and examined again 5, 5 and 3 years later, respectively. The cases with severe dysplasia, carcinoma in situ and intra-mucosal carcinoma would be treated by mucosectomy and the cases with esophageal cancer in a later stage would be treated with the conventional method. A pilot study was carried out; 2213 high-risk adults were screened with endoscopy and among 1770 cases under the inclusion criteria, there were 61 (3.5%) cases with esophageal cancer, 15 (0.9%) cases with gastric cardia cancer and 147 (8.3%) cases with severe dysplasia. Among these cancers, 89.5% were found to belong to an early stage. Overall, about 10% of participants was judged to need early treatment. It is also necessary to evaluate the cost-effectiveness of the strategy, because the living standards are low in these areas. The cost of treatment for a case with esophageal cancer at a late stage is calculated to be about $800, while the cost for each examination with endoscopy is only $10. It is obvious that 100 high-risk adults could be screened with the same cost as one esophageal cancer patient at a late stage and that 10 out of 100 high-risk cases would be found to have severe dysplasia or early cancer, which could be radically cured with a better quality of life. In addition, there has been a study to predict the effectiveness for reducing the incidence and mortality of esophageal cancer using endoscopic technology for early detection and treatment. It was shown that the incidence and mortality rate would be decreased markedly during 5–8 years (8). A new mechanism for running the campaign was proposed; the cost for each examination will be divided into three parts, one for equipment supported by government, one from the participant and one from social donations. In summary, the proposed strategy could decrease the mortality from esophageal cancer, clarify the natural history of esophageal cancer and provide a method for the analysis of cost-effectiveness in detail. Finally, this could lead to the establishment of a medical insurance system for esophageal cancer control in high-risk areas.
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PERSPECTIVES |
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TOPABSTRACTINTRODUCTIONPRIMARY PREVENTIONSECONDARY PREVENTIONTAIHANG ANTI-CANCER CAMPAIGNPERSPECTIVESREFERENCES |
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At present, methods for early detection and treatment are not yet fully established. Endoscopic examination with iodine staining and multi-biopsy could identify and localize lesions, but the invasion depth is evaluated only by clinical experience. Endoscopy with an ultrasonic probe had been tested, but the results were inconclusive. A new technique, optical coherence tomography (OCT) (9,10), so-called optical biopsy, would be a good approach to solving the problem. For early treatment, mucosectomy is applied to a single lesion. Since about one-third of patients have multi-lesions, photodynamic and coagulation therapy are used. Unfortunately, some reoccurrence was observed and it is essential to improve these techniques.
For most cases with mild and moderate dysplasia, chemoprevention would be the logical approach. A mixture of Chinese herbs, anti-tumor B, was tested and some reduction in the rate of cancer development was observed. A clinical trial with selecoxib and selenium is in progress in Linxian. Since there are many candidates for chemopreventive drugs, further clinical trials would be necessary.
The protocol of following up the cases with different grades of dysplasia was based on clinical experience. When the natural history of esophageal cancer is clarified, the protocol could be improved to become more effective. However, it is frequently found that the risk of the development of esophageal cancer is not always associated with the grade of dysplasia. Based on the progress of the Human Genome Project, it is reasonable to postulate that there are possibilities for developing biological markers or DNA chips, which could predict the risk of developing esophageal cancer in individuals. When the dream comes true, the strategy for esophageal cancer control based on early detection and treatment would reach its most effective level.
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FOOTNOTES |
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+ For reprints and all correspondence: Zhiwei Dong, Department of Epidemiology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Panjiayuan 17, Chaoyang District, Beijing 100021, China
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPRIMARY PREVENTIONSECONDARY PREVENTIONTAIHANG ANTI-CANCER CAMPAIGNPERSPECTIVESREFERENCES |
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Received September 11, 2000; accepted August 7, 2001.
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