The distance of proximal resection margin dose not significantly influence on the prognosis of gastric cancer patients after curative resection

Despite the continued medical and surgical advancement in the treatment of gastric cancer, gastric cancer is still the main cause of death in Korea and other countries [1, 2, 3, 4, 5, 6]. In the surgical treatment, the complete surgical resection with an adequate resection margin length is well known for the most effective treatment of gastric cancer [7, 8, 9]. Especially, the negative resection margin is considered critical as the most important treatment based on the philosophy that minimal residual cancer cells have the possibility of recurrence.

Under the conventional rule, most surgeons try very hard to achieve a sufficient proximal resection margin length more than 2-3 cm in early gastric cancer, and 5-6 cm in advanced gastric cancer. In practice however, we are experiencing that the intraoperative measurement of proximal margin length may quite different from the pathologic measurement for a variety of reasons. In rare cases, the involvement of proximal margin was determined by pathology report.

In these cases, many surgeons are wondering what to perform a reoperation to achieve a negative resection margin or sufficient proximal resection margin length. Therefore, this study was designed to investigate the impact of the involvement of proximal resection margin and the discrepancy of proximal margin length on the prognosis of overall survival and the recurrence pattern.

Eighteen hundred eighty-eight patients were included in this study. Seventeen patients had the involvement of proximal margin after surgery by pathologic report. Their 5-year survival rate was 5.9%. Although there were significant differences in the extent of lymph node dissection, distribution of pathologic T and N staging, and histologic type between patients with positive margin and negative margin, their survival rate was very low compared to the result of patients with negative proximal margin. In patient with negative proximal margin, twelve hundred thirty-two patients (65.8%) were male. A mean age was 56.8 ± 11.8 years at surgery. Four hundred twenty-nine patients (22.9%) underwent total gastrectomy and most patients (98.4%) underwent D2 or more lymph node dissections. According to variables, there were some significant differences between each group (proximal margin length ≤1 cm vs. >1 cm, ≤2 cm vs. >2 cm, and ≤3 cm vs. >3 cm) (Table 1).

Table 1
Clinical characteristics and overall survival rate according to the distance of proximal margin

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According to the type of surgery, there was significant difference of 5-year survival rate between proximal margin length ≤3 cm group and >3 cm group in patients who underwent subtotal gastrectomy (≤3 cm group vs. >3 cm group; 86.3% vs. 78.5%; P = 0.011). In subtotal gastrectomy patients, there was also significant difference in distribution of pathologic T staging (≤2 cm group vs. >2 cm group, P = 0.006) (Table 2).

Table 2
Clinical characteristics, 5-year survival rate and overall survival between TG and STG groups

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According to the pathologic T staging, our statistical analyses did not reveal a significant difference in 5-year survival rate. According to the histologic type, there was significant difference between proximal margin length ≤2 cm and >2 cm in patients with undifferentiated adenocarcinoma (≤2 cm group vs. >2 cm group; 66.5% vs. 72.9%; P = 0.022). (Tables 3, 4)

Table 3
Clinical characteristics, 5-year survival rate and overall survival among T1, T2, T3, and T4 groups

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Table 4
Clinical characteristics, 5-year survival rate and overall survival between WD and PD groups

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In patients who having poor prognostic factors, multivariate Cox proportional hazard analysis for pathologic T and N staging and these prognostic factors was performed. As a result, the 5-year survival rate was not affected by the discrepancy of proximal margin length (with 2 cm in undifferentiated adenocarcinoma, and 3 cm in subtotal gastrectomy) (Table 5).

Table 5
Multivariate analysis of factors associated with overall survival

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In subsets of patients who having same pathologic T staging, there was no significant difference of 5-year survival rate in proximal margin length ≤2 cm and >5 cm, and ≤5 cm and >5 cm (Table 6).

Table 6
Clinical characteristics, 5-year survival rate and overall survival according to the distance of proximal margin

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After 88.0 months' median follow-up (1-235), local recurrence occurred in 16 patients (0.9%). Local recurrence analysis by Kaplan-Meier test didn't show the significant difference in patients with different proximal margin length (Table 7).

Table 7
Kaplan-Meier estimates of local recurrence by proximal margin length in the same staging group

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The TNM staging system is most important prognostic factor for predicting overall survival in gastric cancer patients. With this system, the degree of differentiation of tumor cells, tumor size, tumor location, and presence of lymphovascular invasion are known as independent prognostic factors [14, 15, 16, 17, 18, 19, 20, 21].

Recently, many studies have been carried out to explore the impact of prognostic factors on overall survival. Especially in patients with the involvement of proximal margin, many reports suggested different philosophies, consequences, and needs for reoperation [22, 23, 24, 25]. Also, in the cardiac or middle-third gastric cancer patients, there is a great chasm between the need for total gastrectomy and for subtotal gastrectomy [26, 27]. Some surgeons recommended that total gastrectomy is standard treatment to decrease local recurrence rate in the cardiac cancer or middle-third of the stomach cancer because of the short proximal resection margin length.

Before we begin our study, we could not find satisfactory evidences regarding safe proximal margin length from Web search and PubMed. Conventionally, a 2- to 3-cm proximal resection margin is regarded as the safety proximal margin length for early gastric cancer and a 5- to 6-cm is safe for advanced gastric cancer. Several investigators reported various lengths of safety proximal margin [28, 29]. According to the Japanese gastric cancer guidelines 2010, a gross resection margin of 2 cm should be done in T1 gastric cancer. More than 3 cm of proximal margin length is recommended in advanced gastric cancer with expansive growth pattern, and more than 5 cm is recommended in infiltrative advanced gastric cancer [30].

In practical, all surgeons try very hard to achieve the recommended proximal margin length from tumor due to intramural infiltration spreading in the proximal direction. However, it is often very difficult to secure a recommended proximal margin length depending on the situation such as patient's general condition, and the advancement of cancer stage. Also, there are times when we have no way to demarcate the tumor boundary on intraoperative findings through the use of palpation and inspection techniques. Besides, the distinction in proximal margin length between intraoperative findings and pathologic findings can occur depending on the tumor characteristics and the process of formalin fixation. Even, the prevalence rates of positive margin were reported from 0.8% to 2.0% in patients who underwent gastrectomy with curative intent [4, 22, 23, 24, 25].

Therefore, our study was planned to explore the impact of the involvement and length of proximal margin on overall survival. Although there were significant differences in the ratio of total gastrectomy, distribution of tumor depth, nodal staging, and tumor cell differentiation between proximal margin positive group and negative group, the 5-year survival rate (5.9%) of positive proximal margin group was very low compared to the rate (75.0%) of negative proximal margin group (Table 1). This result supports curative resection margin should be done. But in practice, we often have trouble securing proximal resection margin in total gastrectomy case. In our study, we can identify that there were more patients with positive resection margin in total gastrectomy. In our institution, we have a policy to perform a reoperation in patients with positive resection margin. Although positive proximal margin was confirmed by pathologic report, we did not additional reoperation in patients who refuse reoperation because of their general condition and far advanced stage.

In patients with negative proximal margin, univariate analysis showed a significant difference of overall survival rate in subtotal gastrectomy group (proximal margin length ≤3 cm vs. >3 cm; 86.3% vs. 78.5%; P = 0.011). And, there was significant difference in patients with undifferentiated adenocarcinoma group (proximal margin length ≤2 cm vs. >2 cm; 66.5% vs. 72.9%; P = 0.022) (Tables 2, 4). However, a multivariate analysis of these prognostic factors and others (depth of tumor invasion, and nodal staging) didn't show statistical significance (Table 5). Therefore, the discrepancies of proximal margin length have little to predict overall survival compared to those of depth of tumor invasion, and lymph node metastasis. Also, Table 6 showed that an extension of proximal margin length doesn't help the improvement of overall survival. Based on these results, reoperation to achieve an additional proximal margin length offers nothing to improve overall survival.

And, it is considered that the proximal margin length is related to local recurrence in gastric cancer patients. Our study showed that the discrepancies of proximal margin length do not affect the local recurrence rate in gastric cancer patients with negative proximal margin (Table 7). We speculate that the discrepancies of proximal margin length have little effect on local recurrence rate in patients with gastric cancer. In other words, the impact of proximal margin length on oncologic outcomes is relatively lower than other factors such as depth of tumor invasion and lymph node metastasis.

In this study, we are not arguing that clear resection margin is enough for surgical treatment of gastric cancer, regardless of the proximal margin length. Also, we feel the need to explore the safety of proximal margin length 1 cm in T4 gastric cancer, and the impact of subcentimeter on prognosis, because of a small number of patients. We also expect that future studies through large volume can lead to the resolution of these problems.

In conclusion, surgeons should try to secure the negative proximal margin in the surgical treatment because of a poor prognosis of positive proximal margin and a philosophy of the possibility of residual cancer cells. Based on our analyses for the impact of the proximal margin length on overall survival and local recurrence, it is clear that reoperation to achieve an additional proximal margin length does nothing to improve oncologic outcomes.