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10.1245/ASO.2006.03.061
Annals of Surgical Oncology 13:363-369 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Significance of Long-Term Follow-Up of Early Gastric Cancer

Chikara Kunisaki, MD, PhD1, Hirotoshi Akiyama, MD, PhD1, Masato Nomura, MD1, Goro Matsuda, MD1, Yuichi Otsuka, MD1, Hidetaka Ono, MD, PhD1, Yutaka Nagahori, MD, PhD2, Hideo Hosoi, MD, PhD2, Masazumi Takahashi, MD, PhD3, Fumihiko Kito, MD, PhD3 and Hiroshi Shimada, MD, PhD1

1 Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
2 Department of Surgery, Yokosuka Kyosai Hospital, Yokosuka, Japan
3 Department of Surgery, Yokohama Municipal Hospital, Yokohama, Japan

Correspondence: Address correspondence and reprint requests to: Chikara Kunisaki, MD, PhD; E-mail: s0714{at}med.yokohama-cu.ac.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Therapeutic outcomes for most patients with early gastric cancer are favorable. However, mortality among these patients remains a concern. Improvements in therapeutic outcomes are being sought by studying the timing and causes of death. Here, the results of surgery were evaluated to assess the appropriate treatment and follow-up schedule for early gastric cancer.

Methods: A total of 1169 patients with early gastric cancer underwent curative gastrectomy between 1992 and 1999. Survival time, prognostic factors, cause of death, and time of death were evaluated retrospectively.

Results: Multivariate analysis of disease-specific survival identified lymph node metastasis as an independent prognostic factor. The anatomical extent of lymph node metastasis and the number of metastatic lymph nodes influenced the rate of recurrence. Multivariate analysis of overall survival identified age as a prognostic factor. A total of 91 patients (7.8%) from the study group died: 56 from comorbid diseases, 21 from gastric cancer, and 14 from other second primary cancers. Death from gastric cancer was frequently observed within 5 years of surgical resection, whereas death from other diseases usually occurred after 5 years. Patients who died as a result of diseases other than gastric cancer tended to be older.

Conclusions: Appropriate lymph node dissection is necessary for patients with early gastric cancer, particularly those with risk factors associated with lymph node metastasis. Meticulous follow-up protocols that can detect second primary cancers, together with the development of treatments for comorbid diseases, are required to improve survival.

Key Words: Comorbid diseases • Early gastric cancer • Follow-up • Prognostic factors • Second primary cancers • Lymph node metastasis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Gastric cancer is the second largest cause of cancer-related deaths in Japan and throughout the world.1 Early gastric cancer was first defined by the Japanese Society of Gastroenterological Endoscopy as an adenocarcinoma confined to the mucosa or submucosa irrespective of lymph node metastasis (T1NX).2 This definition was based on a favorable prognosis of gastric cancer of this type and is commonly used in Western countries as well as in Japan. Therapeutic outcomes for Japanese patients with early gastric cancer have improved considerably with the establishment of mass screening.3,4 Early gastric cancers make up >50% of the total number of resected cancers in most institutions in Japan.5 Endoscopic mucosal resection6 and limited resection with laparoscopy (D1 plus lymph node resection along the left gastric artery or common hepatic artery)7,8 have been commonly used to treat gastric cancers in these institutions. Moreover, management guidelines have been published to standardize surgical treatments and to improve the surgical outcome for gastric cancer patients.9 A tailored therapeutic strategy for early gastric cancer is also included within these guidelines. Patients with early gastric cancer who have undergone curative resection have relatively favorable surgical outcomes. In Japan, the 5-year survival rate for these patients is ≥ 90%.10,11 Furthermore, most patients with early gastric cancer do not die of this disease but of other malignant or comorbid diseases, such as ischemic heart disease or brain infarction.12,13 Therefore, evaluating the cause of death and its timing in relation to curative surgery in patients with early gastric cancer should help to improve therapeutic outcomes. In this study, we evaluated the surgical results, including causes of death and patterns of recurrence, of patients with early gastric cancer to improve therapeutic strategies.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A series of 1169 patients from the Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Japan, and affiliated institutions who had early gastric cancer (T1: mucosal or submucosal) and had undergone potentially curative gastrectomy were entered into this study between April 1992 and December 1999 after giving their informed consent. The age of the patients (mean ± SD) was 60.7 ± 11.9 years, and more men than women (777 men and 392 women) participated in the study.

The following clinicopathologic variables were evaluated: sex, age (<70 or ≥70 years), location of tumor (lower third, middle third, upper third, or entire stomach), macroscopic appearance (protruded [I], elevated [IIa], flat [IIb], depressed [IIc], excavated [III], or mixed), tumor diameter (<30, ≥ ≥30 to <60, or ≥60 mm), histological type (differentiated: well differentiated, moderately differentiated, or papillary; undifferentiated: poorly differentiated, signet-ring cell, or mucinous), lymph node metastasis, depth of invasion (mucosa or submucosa), lymphatic invasion, and venous invasion. The clinicopathologic terminology in this article follows the Japanese classification of gastric carcinoma.14

Preoperative imaging studies were used to determine the tumor location, macroscopic appearance, tumor diameter, depth of invasion, lymph node metastasis, and distant metastasis. Imaging studies were routinely performed by using an upper gastrointestinal barium meal, endoscopic examination, abdominal ultrasonography, and computed tomography.

The Japanese Gastric Cancer Association has standardized lymph node dissections (standard D2 gastrectomy) for gastric cancer. In this study, D1 gastrectomy plus lymph node dissection along the left gastric artery or common gastric artery was used in 582 patients, whereas D2 gastrectomy was used in 587 patients. These procedures were performed in accordance with the Japanese classification of gastric carcinoma. Patients with suspected metastatic lymph nodes underwent D2 gastrectomy. Those with tumors located in the lower third of the stomach underwent distal gastrectomy. Patients with tumors in the middle third of the stomach underwent either distal gastrectomy or total gastrectomy according to the direction of the tumor invasion. Proximal gastrectomy was used for patients with tumors in the upper third of the stomach, and total gastrectomy was used for those with tumors occupying the entire stomach. In this series, distal gastrectomy was performed in 957 patients, total gastrectomy was performed in 194 patients, and proximal gastrectomy was performed in 18 patients.

Patient follow-ups were performed at the outpatient department according to our standard protocol (every 8–12 weeks for at least 5 years). At these appointments, a medical interview was conducted by the physician to review the progress and health of the patient. Patients also underwent hematological examinations every 3 months, ultrasonography or computed tomography every 6 months, and chest radiography and endoscopic examinations every year. After 5 years, the follow-ups were continued on an annual basis. The median follow-up duration was 75.5 ± 43.1 months for all registered patients.

The data were analyzed by using the SPSS statistical software program (SPSS Inc., Chicago, IL). The patient characteristics were compared by using the two-tailed Fisher’s exact test or the {chi}2 test with the Yates correction, as appropriate. Quantitative variables were compared by using the Student’s t-test and expressed as medians ± SD. The Cox proportional hazards regression model was used to identify prognostic factors. Step-forward regression was used to build a valid statistical model for the association of prognostic factors with overall or disease-specific survival among patients with complete data. Disease-specific survival was calculated by using the Kaplan-Meier estimation and examined by using the log-rank test. P values were considered to be statistically significant at the .05 level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Survival
The overall 5-year survival rate was 94.5% in all cases, and the disease-specific 5-year survival rate was 98.2% (Fig. 1Go).


Figure 1
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  		FIG. 1. Disease-specific and overall survival in registered patients according to the Kaplan-Meier method.

 
Prognostic Factors
Univariate analysis of disease-specific survival showed that macroscopic appearance, depth of invasion, lymph node metastasis, lymphatic invasion, and venous invasion significantly affected patient prognosis. Multivariate analysis of disease-specific survival revealed that only lymph node metastasis independently influenced prognosis (Table 1Go). However, the multivariate analysis of overall survival showed that both age and lymph node metastasis were independent prognostic factors (Table 2Go).


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  		TABLE 1. Prognostic factors according to univariate analysis and the Cox proportional regression hazard model with disease-specific survival
 

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  		TABLE 2. Independent prognostic factors according to the Cox proportional regression hazard model with overall survival
 
Characteristics of Patients With Lymph Node Metastasis
We compared the clinicopathologic features of 117 patients with lymph node metastasis, with and without recurrence of gastric cancer. There was a significant difference in the anatomical extent of lymph node metastasis (first, second, or third tier in the Japanese classification) and in the number of metastatic lymph nodes between patients with and without recurrence of gastric cancer (Table 3Go).


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  		TABLE 3. Characteristics of patients with lymph node metastasis
 
Predictive Factors for Lymph Node Metastasis
Of the clinicopathological factors examined, female sex, larger tumor diameter, and deeper invasion all independently predicted lymph node metastasis (Table 4Go).


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  		TABLE 4. Predictive factors for lymph node metastasis
 
Pattern of Mortality
A total of 91 patients (7.8%) from the study group died during the follow-up period. Of these, 21 patients (1.8%) died as a direct result of gastric cancer, and 70 patients (6.0%) died as a result of additional diseases, such as other cancers (n = 14) or comorbid diseases (n = 56). Of the 14 patients who died as a result of other cancers, 3 died of lung cancer, 3 of pancreatic cancer, 1 of esophageal cancer, 1 of remnant stomach cancer, 1 of hepatoma, 1 of gallbladder cancer, 1 of colon cancer, 1 of urinary bladder cancer, 1 of ovarian cancer, and 1 of cervical uterine cancer. Of the 56 patients who died of comorbid diseases, 15 died of ischemic heart disease, 9 of cerebrovascular disease, 9 of senility, 6 of respiratory disease, 5 of acute abdomen disease, 3 from accidents, 3 of renal failure, 3 of liver failure, 1 of anaphylactic shock, and 2 of unknown causes.

Characteristics of Patients With Recurrence
Of the 21 patients who died as a result of gastric cancer recurrence, 8 had no lymph node metastasis (identified as an independent prognostic factor); hematogenous recurrence was observed in 7 of these patients, and lymph node recurrence after surgery was observed in the remaining patient. No difference was observed in any of the other clinicopathologic factors among these 21 patients (Table 5Go).


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  		TABLE 5. Characteristics of patients with recurrence (n = 21)
 
Cause of Death at Different Time Points After Surgery
The causes of death after resection were classified into two groups: gastric cancer and second primary cancers or comorbid diseases. The correlation between cause of death and time of death after surgery was evaluated. Of the 21 patients who died of gastric cancer during the follow-up period, 12 (57.1%) died within 3 years, and 18 (85.7%) died within 5 years. Of the 70 patients who died of other causes, 30 (42.9%) died within 3 years, and 39 (55.7%) died within 5 years. There was a significant correlation between the cause of death and the time of death between these two groups (P = .0229). Evaluation of the relationship between cause of death and time of death in patients who died of other primary cancers or comorbid diseases showed that among patients who died of second primary cancers, 5 (35.7%) died within 3 years, and 8 (57.1%) died within 5 years; among those who died of comorbid diseases, 25 (44.6%) died within 3 years, and 31 (55.4%) died within 5 years. There was no significant correlation between cause of death and time of death in these populations (P = .3777).

Cause of Death in Relation to Age
The distribution of the cause of death in relation to age (<70 vs. ≥70 years) was evaluated. Of the 21 patients who died of gastric cancer, 15 (71.4%) were <70 years of age. In contrast, among the 70 patients who died of other causes, 32 (45.7%) were <70 years of age. Patients who died of gastric cancer were significantly younger than those who died of other causes (P = .0386). Furthermore, of the 14 patients who died of second primary cancer, 3 (21.4%) were ≥70 years. In contrast, among the 56 patients who died of comorbid diseases, 33 patients (58.9%) were ≥70 years. Patients who died of comorbid diseases were therefore significantly older than those who died of other cancers (P = .0120).

Patterns of Recurrence of Gastric Cancer
The patterns of recurrence were as follows: 15 patients had hematogenous recurrence, 5 patients had lymphatic recurrence, and 1 patient had peritoneal recurrence. However, there was no significant correlation between the type of recurrence and time elapsed since surgery (Table 6Go).


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  		TABLE 6. Patterns of recurrence
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study has shown that lymph node metastasis in early gastric cancer patients is an independent prognostic factor, as revealed by multivariate analysis of disease-specific survival. However, multivariate analysis of overall survival also identified age and lymph node metastasis as independent prognostic factors. Among the patients who died during the follow-up period, death from comorbid diseases was the most common, followed by early gastric cancer and, finally, by subsequent primary cancers. Moreover, the incidence of death caused by comorbid diseases increased with age. In Japan, the increased detection of early gastric cancer resulting from mass screening3,4 and the development of imaging modalities, such as endoscopic examination,15,16 have significantly improved therapeutic outcomes for these patients, as well as for those with more advanced gastric cancers.

Patients with early gastric cancer have an excellent prognosis after appropriate treatment, with a high survival rate and a low rate of recurrence. However, there is a risk that these patients might have other conditions, such as comorbid diseases or subsequent primary cancers as a result of aging. It is therefore important not only to follow up early gastric cancer, but also to be aware of other diseases that might affect the therapeutic outcome of gastric cancer patients.

Prognostic factors in patients with early gastric cancer are thought to include lymph node metastasis and depth of tumor invasion (mucosa vs. submucosa). 17–19 A tumor with many metastatic lymph nodes, deeper invasion, and a histologically differentiated type adversely affects prognosis. In this study, the multivariate analysis of disease-specific survival revealed that only lymph node metastasis was an independent prognostic factor. Patients with many metastatic lymph nodes or with anatomically extended lymph node metastasis frequently died of gastric cancer. In this study, most lymph node metastases recurred within 5 years of surgery. Furthermore, 50% of the patients with recurrent metastasis died within 3 years. The timing of recurrence in patients with early gastric cancer seems to be delayed compared with that in patients with advanced gastric cancer.20 Therefore, long-term, comprehensive follow-up is necessary for patients with many, or extended, metastatic lymph nodes, even in early gastric cancer. Periodic follow-up is also necessary for patients without lymph node metastasis, because hematogenous recurrence, such as liver metastasis, was sometimes observed. In this study, there was no correlation between the timing and type of recurrence, although peritoneal metastasis was infrequent. A comprehensive follow-up schedule after surgery is therefore required to detect all types of recurrence.

As mentioned previously, older age was identified as an independent prognostic factor in the multivariate analysis of overall survival. This suggests that patients with curatively resected early gastric cancer tended to die as a result of factors other than the recurrence of gastric cancer. Death due to comorbid diseases and second primary cancers was frequently observed during the 5-year follow-up. Patients aged ≥70 years frequently died of comorbid diseases or second primary cancers rather than gastric cancer. Moreover, more patients died of comorbid diseases than of second primary cancers in both age groups; this difference was statistically significant in the older age group. As a result, old age must be considered as an independent prognostic factor for overall survival. These findings are supported by the results of a previous study.21

It is still unclear whether intensive follow-up after surgery produces significant benefits in patients with gastric cancer. A previous retrospective study concluded that follow-ups were not useful.22 Other studies have reported that chemotherapeutic agents, such as S-123 or taxane derivatives,24 gave satisfactory results in the treatment of highly advanced gastric cancer. However, there have been no data to suggest that chemotherapeutic agents are useful in the treatment of recurrent gastric cancer detected during follow-up.

In conclusion, appropriate lymph node dissection is necessary in patients with early gastric cancer. In particular, lymph node dissection is essential in those with risk factors associated with lymph node metastasis (female sex, larger tumor size, and deeply invasive tumor type). To improve survival and therapeutic outcomes, a periodic follow-up schedule may be necessary to detect second primary cancers in patients with early gastric cancer. In addition, treatment of comorbid diseases may be important in older patients.

Received for publication March 4, 2005. Accepted for publication August 4, 2005.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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