Shu-bo Tian, Jian-chun Yu*, Wei-ming Kang, Zhi-qiang Ma, Xin Ye, Chao Yan, and Ya-kai Huang

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

ORIGINAL ARTICLE

Effect of Neoadjuvant Chemotherapy Treatment on Prognosis of Patients with Advanced Gastric Cancer: a Retrospective Study△

Shu-bo Tian, Jian-chun Yu*, Wei-ming Kang, Zhi-qiang Ma, Xin Ye, Chao Yan, and Ya-kai Huang

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

gastric cancer; neoadjuvant chemotherapy; prognosis; survival analysis

Objective To evaluate the prognostic effects of neoadjuvant chemotherapy (NAC) in patients with local advanced gastric cancer.

Methods We retrospectively analyzed prognosis in 191 patients with advanced gastric cancer, of whom 71 were treated with NAC and 120 received surgery only between February 2007 and July 2013. Postoperative complication rate was recorded. Survival by clinicopathological features, pathological T and N stages, and histopathological tumor regression was retrospectively compared between the two groups.

Results According to Response Evaluation Criteria in Solid Tumors, none of the 71 patients in the NAC followed by surgery group showed complete response, 36 showed partial response, 25 had stable disease, and 10 had progressive disease. The chemotherapy response rate was 50.7%; the disease control rate was 85.9%. Grade 3/4 adverse events were seen in less than 20% patients, with acceptable toxicities. No difference was found in the overall postoperative complication rates between the two groups (7 versus 22 cases, p=0.18). Median survival time was significantly different, at 54 months in the NAC combined with surgery group and 25 months in the surgery-only group (p=0.025).

Conclusion In patients with operable gastric adenocarcinomas, NAC can significantly improve overall survival without increasing surgical complications.

Chin Med Sci J 2015; 30(2)： 84-89

LTHOUGH the incidence and cancer-related mortality have been decreasing in recent years, Agastric cancer is still one of the most common causes of cancer death worldwide.1, 2 Adjuvant chemotherapy has been proven to be effective in Chinese patients.3 Currently, neoadjuvant chemotherapy (NAC), in order to improve patient’s survival after gastric cancer surgery, has been applied during the last decade. However, no uniform standards exist for NAC regimens and illness may be worsened in unresponsive cases and thus a delay in radical surgery can lead to poor prognosis. So, suitable NAC is important to treat advanced gastric cancer patients for better prognosis. In the current study, we retrospectively analyzed the clinical data of patients who were treated with an oxaliplatin/capecitabine regimen prior to surgery in our hospital, to assess the efficacy and safety of this treatment for resectable gastric cancer patients and to analyze the relationships between T and N stages and prognosis.

PATIENTS AND METHODS

Patient’s enrollment

Totally, 191 patients were treated for gastric cancer at our hospital between February 2007 and July 2013. Some patients received chemotherapy prior to surgery. Some basic criteria had to be met before NAC: (1) histological proof of gastric cancer and preoperative diagnosis to be curatively resectable; (2) clinically diagnosed as advanced T2-4 stage disease or metastatic disease on endoscopic ultrasound and abdominal computed tomography (CT) scans; (3) sufficient organ functions and no contraindication for chemotherapy; (4) provision of written informed consent.

Table 1. Patient’s characteristics

Treatment schedule

Patient’s status was evaluated after each course of the treatment. Chemotherapy adverse events were recorded and graded according to the National Cancer Institute Common Toxicity Criteria (version 4.0). Patients in the NAC combined with surgery group and the surgery-only group continued to receive chemotherapy after the surgery.

Surgery

Standard surgical procedure was gastrectomy and D2 lymphadenectomy. Surgical margins were evaluated after radical operation, and classified as R0 (clean surgical margin), R1 (microscopic residual cancer), or R2 (macroscopic residual cancer). The resection margins and the lymph node stations were evaluated separately. The extent of the tumor (TNM-classification) was determined according to the guidelines of the International Union Against Cancer.

Evaluation of therapeutic effect and side-effects

Assessment of response to NAC was based on reduction of primary tumor size measured by endoscopy and CT scan. Clinical response to chemotherapy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST).4Evaluation of target lesions is divided into four categories: complete remission (CR, disappearance of all lesions lasting 4 weeks), partial remission (PR, at least a 30% decrease in the sum of diameters of lesions for 4 weeks), stable disease [SD, ranged between PR and progressive disease (PD)], and PD (at least a 20% increase in the sum of diameters of the lesions, or the appearance of new lesions). The clinical response rate (RR) is (CR+PR)/measurable number of cases×100%; the disease control rate is (CR+PR+SD)/measurable number of cases× 100%.

Follow-up

All patients were followed up regularly by physical examination, abdominal CT, and routine hematological examination until December 2014. Survival time was calculated in days from the date of endoscopic pathological diagnosis.

Statistical analysis

All statistical calculations were performed using the Statistical Package for Social Services (Version 18.0). Chi-squared tests were used to compare categorical data. Survival curves were calculated by the Kaplan-Meier method and compared by the log-rank test. All tests were two-sided. P≤0.05 was considered significant.

RESULTS

Surgery and complications

After chemotherapy, 8 patients in the NAC group were not treated with surgery because of disease progression, as shown through imaging studies. The R0 resection rates did not significantly differ between the NAC arm (84.5%, 60/71) and the surgery-only arm (79.1%, 95/120; P=0.36). Surgical complications, including anastomotic leakage (2 versus 3 cases, P=0.56), incision infection (1 versus 4 cases, P=0.44), pulmonary infection (3 versus 12 cases, P=0.17), and postoperative bleeding (1 versus 3 cases, P=0.57), also did not significantly differ between the two groups. No difference was found in overall postoperative complication rates between the two groups (7 versus 22 cases, P=0.18).

Chemotherapy toxicity

The most common adverse effects of chemotherapy in 71 patients were neutropenia/leukopenia (21.1%/16.9%), and gastrointestinal toxicities, including nausea (12.7%) and diarrhea (8.5%). Other adverse effects were hepatic dysfunction (11.3%) and hand–foot skin reaction (8.5%). Grade 3 or higher hematological and non-hematological toxicities occurred in 11 and 2 patients, respectively.

Pathological analysis

Among the 71 patients in the NAC group, 36 had PRs with an overall RR of 50.7%, 25 patients had SD, and 10 had PD. The disease control rate was 85.9%. Sex, age, and tumor differentiation did not correlate with response to chemotherapy (Table 2).

Of the 63 patients who underwent both NAC and surgery, postoperative T staging showed 12 patients in stage T1, 10 in T2, 18 in T3, and 31 in T4 (Table 3). The two groups did not differ significantly in pathologic features.

The median numbers of dissected lymph nodes were 24 in the NAC group (range: 0-77) and 27 in the surgery-only group (range: 7-95), which did not significantly differ (P=0.17). However, the median number of positive lymph nodes was 1 in the NAC group (range: 0-36) and 3 in the surgery-only group (range: 0-56), which was significantly different (P=0.024). Many patients in the surgery-only group had metastatic lymph nodes.

Table 2. Relationship between clinical factors and NAC response rate

Table 3. Comparisons of surgical and pathologic results of the two groups (n)

Survival analysis

At our analysis, follow-up time ranged from 17 to 86 months. Median survival time for the NAC group (54 months) was significantly longer than that for the surgery-only group (25 months, P=0.025). Five-year survival rate was significantly higher in the NAC group (44.1%) than that in the surgery-only group (27.9%, Fig. 1A). Compared with the surgery-only group, the NAC group had a significantly higher overall survival (OR=0.58, 95% CI= 0.37-0.93, P=0.024). When data were grouped and analyzed by T stages, the NAC survival benefit was significant for patients with T3 (P=0.046; Fig. 1C) and T4 (P=0.037; Fig. 1D) disease, but not for those with T2 disease (P=0.720; Fig. 1B). Similarly, when data were analyzed by N stage, NAC showed a survival benefit among patients with positive lymph nodes (P=0.011; Fig. 2), but there was no difference in survival of patients with negative lymph nodes between the NAC group and the surgery-only group (P=0.45; Fig. 3).

When patients were analyzed by PR, SD, and PD outcomes, we found the median survival time was 72 months in the PR arm, 54 months in the SD arm, and 8 months in the PD arm, which were significantly different (P＜0.01).

Figure 1. Overall survival curves in different T stages between the NAC group and surgery-only group.

Figure 2. Overall survival curves in patients with positive lymph nodes between the NAC group and surgeryonly group.

Figure 3. Overall survival curves in patients with negative lymph nodes between NAC group and surgery-only group.

DISCUSSION

NAC can reduce primary tumor size and improve complete resection, which has become an important option among therapies for gastric cancer.5,6In this present clinical retrospective study, patients received a chemotherapy regimen based on cisplatin and fluorouracil. The NAC group did not have significantly more postoperative complications than the surgery-only group; however, most of their primary lesions were reduced and tumors were downstaged for a clinical RR of 50.7%, which is similar to studies that reported RRs of 32%-49%.7-9Median survival was longer for the NAC group than that for the surgery-only group. Patients with stage T3-4 disease or lymph node metastasis who underwent NAC had longer survival, which implies that NAC is beneficial in advanced stages. However, NAC showed no survival advantage for T2 disease, possibly because pT2 tumors have a high likelihood of lymphatic tumor dissemination. Response to chemotherapy was reported to be an independently prognostic factor in a study that found patients who benefited most from NAC were those who achieved CR and PR.10In the current study, although no patient achieved CR, survival analysis suggested that patients with PR benefited more from NAC than patients with PD and SD.

NAC, which has been proven to lead to higher resection rates, is a subject of heated discussion concerning its definite role in improving cure rate and prognosis for gastric cancer patients. The British Medical Research Council conducted the randomized control trial in patients with resectable gastric cancer that included 503 patients (perioperative chemotherapy and surgery: 250 cases; surgery-only: 253 cases, Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial, MAGIC). The results showed that perioperative chemotherapy with an epirubicin, cisplatin, and infused fluorouracil (ECF) regimen significantly reduced the size of resected tumors, but the ECF-related adverse effects and rate of postoperative complications were similar between the two groups. Compared with the surgery-only group, the perioperative chemotherapy group had higher overall and progression-free survival.11A phase Ⅲ trial performed in France including 224 patients with resectable gastroesophageal cancer showed perioperative chemotherapy that used fluorouracil plus cisplatin significantly increased radical resection rate, disease-free survival and overall survival.12However, 75% of patients had adenocarcinoma of the lower esophagus or gastroesophageal junction in above study, whereas in the MAGIC trial, 74% of patients had stomach adenocarcinoma, which might affect results. The 5-year survival of the NAC arm and control arm was also similar in the two trials. Another phase Ⅲ trial was performed by the European Organization for Research and Treatment of Cancer, which compared NAC with cisplatin, leucovorin and fluorouracil followed by surgery to surgery-only. The results showed that the NAC group had a higher R0 resection rate but failed to exhibit a survival benefit.13

A Meta-analysis including 12 randomized controlled trials demonstrated that NAC combined with surgery could down-stage the tumor, increase the R0 resection rate, and significantly improve the 3-year progression-free survival of patients with advanced gastric cancer.14However, another Meta-analysis of gastric cancer patients only (excluding esophageal carcinoma and adenocarcinoma of the esophagogastric junction) showed that NAC contributes no significant survival benefits to patients with gastric cancer, although it reduced nodal stage and resulted in a lower incidence of total mortality.15The reason may be that chemotherapy regimens and courses differed between these studies. Of course, because of differences in the quantity and quality of the included studies, their region, chemotherapy regimens and surgical variables, these studies also show some heterogeneity; further studies are needed to investigate these points.

At present, NAC for advanced gastric cancer, although often beneficial, raises some questions. First, chemotherapy evokes both hematological and non-hematological side effects. Hematological toxicity includes leucopenia, neutropenia, or thrombocytopenia, which caused by myelosuppression may increase the incidence of complications and mortality. In our study, there were acceptable toxicities of chemotherapy prior to surgery, and NAC did not increase the postoperative complications. However, this study was limited by its small sample size and single-institution data. In addition, some patients’ lack of response to NAC might have delayed their curative surgery and this treatment protocol may not be suitable for these patients. In our study, 8 patients failed to receive radical surgery. Postsurgical pathological analysis showed that they all had diffuse adenocarcinoma, so identifying patients who were not sensitive to NAC and performing aggressive surgery on them may improve the survival rate.

In conclusion, our retrospective study showed that NAC can reduce tumor load, decrease disease stage, and improve patients’ survival time, but did not increase postoperative complications. Although NAC had been widely clinical used in treating advanced gastric cancer, the drug selection, the number of regimen cycles and suitablesurgery timeframes are still controversial. Further large-scale, multicenter, and high-quality trials should be conducted to determine the best treatment strategy for patients with gastric cancer.

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for publication February 24, 2015.

Tel: 86-10-69152215, E-mail: yu-jch@163.com

△Supported by Beijing Municipal Natural Science Foundation of China (7132209) and Special Found of the Capital Health Research and Development (2014-3-4014).

Finally, 71 chemotherapy prior to surgery and 120 underwent surgery directly. Patients’ characteristics were well balanced between the two treatment groups (Table 1). In the NAC group, most tumors were of the undifferentiated type.

All patients systemic chemotherapy consisting of oxaliplatin and capecitabine. Oxaliplatin (130 mg/m2) was administered intravenously on the first day, and capecitabine was orally administered at a dose of 1000 mg/m2on days 1-14 of a 3-week regimen. Patients in the NAC group underwent a median of 4 pre-surgery chemotherapy courses (range: 2-8 cycles).

Each patient routine hematological and biochemical examinations and serum tumor marker assays. We also assessed postoperative complications such as bleeding, anastomotic leakage, wound and abdominal infections, and pulmonary infection.