Journal of Chemotherapy
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer in a Chinese population Shuai Dong, Ji-Ren Yu, Qin Zhang & Xiao-Sun Liu To cite this article: Shuai Dong, Ji-Ren Yu, Qin Zhang & Xiao-Sun Liu (2016) Neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer in a Chinese population, Journal of Chemotherapy, 28:1, 59-64, DOI: 10.1179/1973947815Y.0000000028 To link to this article: http://dx.doi.org/10.1179/1973947815Y.0000000028
Published online: 16 Mar 2016.
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Date: 06 June 2016, At: 23:38
Anticancer Original Research Paper
Neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer in a Chinese population Shuai Dong, Ji-Ren Yu, Qin Zhang, Xiao-Sun Liu
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Department of General Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, China This study aimed to evaluate the efficacy of FOLFOX6, SOX and XELOX as neoadjuvant chemotherapy for advanced gastric cancer. The study retrospectively assessed clinicopathological data of patients who received a radical D2 gastrectomy for gastric cancer from January 2010 to January 2013.The patients were either not administered neoadjuvant chemotherapy (control) or were given FOLFOX6, SOX and XELOX prior to surgery. The metastatic rate was also higher for the control group compared with the three chemotherapy regimens in N2 station lymph nodes (P v0.001). The SOX group had significantly lower metastatic total and N2 station lymph nodes than FOLFOX6 and XELOX (Pv0.01). The frequency of metastatic lymph nodes relative to total lymph nodes examined was 9.9, 6.6, 3.9 and 5.3% for control, FOLFOX6, SOX and XELOX groups, respectively. In conclusion, SOX may be the most effective of these treatments as preoperative chemotherapy for Chinese patients with advanced gastric cancer. Keywords: Neoadjuvant chemotherapy, Gastric cancer, FOLFOX6, XELOX, SOX
Introduction Despite a decrease in frequency, gastric cancer is still the third for men and fifth for women cause of cancer-related deaths worldwide.1 About two-thirds of these cases occur in developing countries with 42% of them being reported in China.1 The prognosis for locally advanced gastric cancer is poor with the overall survival rate being between 20 and 60%, depending upon the country.2,3 Locally advanced gastric cancer is cancer that has invaded the submucosa or myometrium, and/or the serosa, but has not invaded the surrounding tissue or metastasised to other parts of the body. The outcome among patients with gastric cancer is dependent on the disease stage at diagnosis, and the high mortality rate likely reflects the fact that diagnosis is commonly late with the majority of cases having locally advanced gastric cancer.4 After tumour cells penetrate the submucosa, the risk of lymph node metastasis increases and the long-term survival diminishes; in Western countries, the 5-year survival rate of advanced gastric cancer is about 20–30%.5,6 Complete radical resection with D2 nodal dissection is the primary treatment for resectable gastric cancer.4,7,8 In addition to surgery, neoadjuvant
Correspondence to: Shuai Dong, Department of General Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China. Email: [email protected]
ß 2016 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947815Y.0000000028
chemotherapy (adjuvant chemotherapy administered preoperatively) reduces the number of metastatic lymph nodes and improves prognosis and is currently used worldwide as an initial therapy for locally advanced gastric cancer.6,9–11 Advantages to preoperative chemotherapy include that it is generally more tolerated than adjuvant chemotherapy even when the same chemotherapy agents are used, and that it also can shrink tumours potentially improving the prognosis.4 Published data indicate that neoadjuvant chemotherapy does not increase post-operative morbidity and mortality, and increases the rate of R0 resection.4,12,13 Although neoadjuvant chemotherapy is the preferred treatment for gastric cancer, the choice of the optimal regimen is controversial. A number of studies have evaluated a given neoadjuvant chemotherapy but these were not controlled studies that compared different regimens.6,8,11,14–18 One non-controlled study compared the efficacy of two different regimens (FOLFOX and EOX) as neoadjuvant chemotherapies in patients with advanced gastric cancer by evaluating clinicopathological characteristics in Chinese patients,19 in which EOX was found to be more effective than FOLFOX as neoadjuvant chemotherapy in reducing cancer invasion, tumour regression and lymph node metastasis. The aim of this retrospective study was to evaluate the efficacy of FOLFOX6 [oxaliplatin, leucovorin, and
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fluorouracril (5-FU)], SOX [S-1 (tegafur/gimeracil/oteracil) and oxaliplatin] and XELOX (capecitabine plus oxaliplatin), three commonly used neoadjuvant chemotherapy regimens in China, and control (no chemotherapy). The main outcome was the number of post-operative metastatic lymph nodes following neoadjuvant chemotherapy, as several studies found that the presence and number of post-operative metastatic lymph nodes are predictive of the prognosis for gastric cancer.20–23
Materials and Methods Study design
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This was a retrospective observational study using clinicopathological data of patients who received a radical D2 gastrectomy for gastric cancer from January 2010 to January 2013 at the First Affiliated Hospital, College of Medicine, ZheJiang University, HangZhou, China. The study was done in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital.
Study population Eligible patients were aged 30–70 years and had pathologically diagnosed Borrman type II/III gastric cancer with no evidence of distant metastasis including the surrounding organs. We limited the population to this age group and cancer stage because patients aged v30 years have very poor prognosis since the gastric cancer tends to have a high rate of metastasis in this age group. The Borrman type II/ III was chosen as it is the most common stage of cancer found in clinical practice and has better prognosis than Borrman type intravenous (IV) cancer. The cancer stage was determined following surgery. Patients with a history of malignancy, immunological disorder, or other major diseases were excluded. Patients received two to three courses of neoadjuvant chemotherapy once in every 3 weeks followed by radical D2 gastrectomy. Before each round of chemotherapy, abdominal CT was performed to evaluate the tumour and lymph node sizes. For most patients, three rounds of chemotherapy were necessary to effectively reduce the size of tumour and lymph nodes necessary for surgery. In a few cases, only two rounds of chemotherapy were necessary. The following neoadjuvant chemotherapy regimens were administered: FOLFOX6, XELOX or SOX. For FOLFOX6 on day 1, oxaliplatin 100 mg/m2 and leucovorin 400 mg/m2 were administered IV infusion over 2 hours, and 5-Fu 400 mg/m2 was given by IV injection. 5-Fu 2400 mg/m2 was administered for maintenance by continuous IV infusion over 46 hours. A total of 14 days were included in each course of FOLFOX6 chemotherapy, which was
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performed once in every 3 weeks. For XELOX on day 1, patients received oxaliplatin 130 mg/m2 and on days 1–14 were administered capecitabine 1000 mg/m2 twice daily (BID). XELOX therapy was performed once in every 3 weeks. For SOX therapy, S-180 mg/m2 was administered from days 1 to 14 and xaliplatin 130 mg/m2 was administered on day 1. SOX therapy was given once in every 3 weeks. In the control group, patients received only surgical intervention and had no neoadjuvant chemotherapy before surgery. The decision for neoadjuvant chemotherapy or surgery was physician preference based on their judgement following abdominal CT scan of the size of the tumour and possibly affected lymph nodes. There was no clear standard. In addition, for ethical reasons, it was also a decision of the patient to receive neoadjuvant chemotherapy or surgery first. For the chemotherapy, patients were randomly assigned to one of the treatment groups (FOLFOX6, XELOX or SOX). Patients who had progressive disease or serious toxicity with neoadjuvant treatment were excluded from surgery. The number of metastatic total and N2 station lymph nodes and the frequency of metastatic lymph nodes were determined. The post-operative TNM stage was confirmed on the basis of TNM staging system developed by UICC/AJCC in 2010 (N0: no regional lymph node metastasis; N1: metastasis to one to two regional lymph nodes; N2: metastasis to three to six regional lymph nodes; N3: metastasis to more than seven regional lymph nodes)
Statistical analysis Patient demographics, clinical characteristics, and treatment response were summarised as n (%) for categorical variables and median [interquartile range (IQR): first, third quartiles) for continuous variables whose data were not normally distributed. Differences among groups were compared using Pearson Chi-square test for categorical data. Kruskall–Wallis test with a pair-wise comparison and Mann–Whitney U test were used for data, including total lymph nodes and N2 station lymph nodes, which were not normally distributed. Metastasis rates were calculated as the number of patients with total or N2 station lymph node metastasis versus no metastasis. All statistical analyses were two-tailed and considered significantly different at Pv0.05. An adjusted significance level of Pv0.01 (P50.05/4) was also considered for the post hoc pair-wise comparisons. Statistical analyses were performed using SPSS 18.0 statistics software (SPSS Inc, Chicago, IL, USA).
Results A total of 603 patients were enrolled into this study of which 141 were treated only with surgery
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(control group), 157 received FOLFOX6, 160 were given SOX and 145 were administered XELOX. The majority of patients were male (w84%) and the median age was about 54 years. The baseline demographics and clinical characteristics were similar among the four treatment groups. There were also a similar number of patients with stage T2 (n5303) and stage T3 (n5300) tumours, and the number of neoadjuvant chemotherapy cycles did not differ across the three groups. The FOLFOX, XELOX and SOX groups had similar treatment response (P50.752) with more than 90% of patients achieving sustained disease control (Table 1). For each patient, the number of resected lymph nodes was w25: a mean of 33 lymph nodes for stage T2 gastric cancer patients and mean of 34 lymph nodes for stage T3 gastric cancer patients. Following chemotherapy, most patients (w94%) in the three treatment groups had sustained disease response. For all treatment groups, about 33 lymph nodes were evaluated (Table 2). Comparison of the rate of metastasis for total lymph nodes between control and the three different chemotherapy groups indicated that the control group had significantly higher number of patients with at least one metastatic lymph node compared
Efficacy of neoadjuvant chemotherapy
with the FOLFOX6, SOX and XELOX groups (all Pv0.01) (Table 2). The number of lymph nodes with metastasis differed across treatment groups with the SOX and XELOX groups, but not the FOLFOX6 group, having significantly fewer metastatic lymph nodes compared with control (Pv0.001) (Table 2). The frequency of metastatic lymph nodes relative to total lymph nodes was 9.9, 6.6, 3.9 and 5.3% for control, FOLFOX6, SOX and XELOX groups, respectively (Table 3). We did a post hoc pair-wise comparison of treatments using a post hoc adjusted significance (significance level Pv0.01) (Table 2). We found that SOX treatment may result in a lower frequency of metastasis than FOLFOX6 or XELOX (Pv0.001 versus FOLFOX6, P50.005 versus XELOX). There was no difference in frequency of total metastasis between treatment groups (all P value w0.01); although there were difference between treatments at the Pv0.05 significance levels (P50.047 for FOLFOX6 versus SOX; P50.034 for FOLFOX6 versus XELOX). The number of N2 station lymph nodes evaluated for each group was approximately 16 (Table 2). A significantly higher percentage of patients in the control group (90.8%) had at least one metastatic
Table 1 Patients’ demographics, clinical characteristics and treatment response among groups (N5603) Variables
Control (n5141)
FOLFOX6 (n5157)
SOX (n5160)
XELOX (n5145)
P value
Sex, males; n (%) Age, median (IQR) (years) Macroscopic Borrmann types, n (%) II III Tumour location; n (%) Lower Middle Upper Cycles of neoadjuvant therapya, n (%) 2 3 Response to treatmenta,b, n (%) Partial response Sustained disease Post-operative TNM stage, n (%) T2N0-3M0 T2N0M0c T2N1M0c T2N2M0c T2N3M0c T3N0-3M0 T3N0M0c T3N1M0c T3N2M0c T3N3M0c
119 (84.4) 54 (49, 61)
136 (86.6) 54 (50, 61)
143 (89.4) 53 (50, 61)
128 (88.3) 54 (51, 62)
0.600 0.519
94 (66.7) 47 (33.3)
114 (72.6) 43 (27.4)
111 (69.4) 49 (30.6)
102 (70.3) 43 (29.7)
0.734
114 (80.9) 12 (8.5) 15 (10.6)
128 (81.5) 14 (8.9) 15 (9.6)
132 (82.5) 13 (8.1) 15 (9.4)
119 (82.0) 12 (8.3) 14 (9.7)
1.000
– –
6 (3.8) 151 (96.2)
6 (3.8) 154 (96.3)
4 (2.8) 141 (97.2)
0.854
– –
6 (3.8) 151 (96.2)
9 (5.6) 151 (94.4)
7 (4.8) 138 (95.2)
0.752
79 (50.3) 12 45 21 1 78 (49.7) 9 42 27 0
80 (50) 17 48 15 0 80 (50) 18 48 14 0
73 (50.3) 19 39 15 0 72 (49.7) 13 42 17 0
1.000
71 (50.4) 3 40 21 7 70 (49.6) 0 33 29 8
Difference among groups were compared using Pearson Chi-square test for categorical data; Kruskall–Wallis test with a pair-wise comparison, Mann–Whitney U test for those continuous data without normal distribution. IQR: interquartile range; TNM: tumour node metastasis. a Only patients who received FOLFOX6, XELOX and SOX were considered. b Disease progression was evaluated 1 week after to three courses of chemotherapy. Reduction in tumour size on CT images was defined as partial response. c Data were represented as numbers of patients for a given sub-category of TNM stage.
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Table 2 Comparison of the total lymph nodes and lymph nodes for N2 station by group (N5603) Control (n5141)
FOLFOX6 (n5157)
SOX (n5160)
138 (97.9) 2 (2, 4.5) 33 (31, 36)
136 (86.6)c 2 (1, 3)c 33 (31, 35)
128 (90.8%) 2 (1, 3) 16 (15, 17)
82 (52.2)c 1 (0, 1)c 16 (15, 17)
Variables Total lymph nodes Total metastasis ratea, n (%) Number of total metastatic LN, median (IQR) Number of total LN N2 lymph nodes N2 metastasis rateb, n (%) Number of metastatic N2 LN, median (IQR) Number of N2 LN, median (IQR)
XELOX (n5145)
P value
125 (78.1)c 1 (1, 2)c,d 33 (32, 36)
112 (77.2)c 2 (1, 2)c,e 33 (32, 35)
v0.001* v0.001* 0.356
43 (26.9)c,d 0 (0, 1)c,d 16 (15, 17)
61 (42.1)c,e 0 (0, 1)c,e 16 (15, 17)
v0.001* v0.001* 0.963
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IQR: interquartile range; LN: lymph nodes.Differences among groups were compared using Kruskall–Wallis test with a pair-wise comparison, Mann–Whitney U test for those continuous data without normal distribution. All statistical analyses were two-tailed and considered significantly different at Pv0.05. An adjusted significance level of 0.01 (50.05/4) was used for the post hoc pair-wise comparisons of treatments. a Total metastasis rate was calculated as the percentage of patients having at least one metastatic lymph node. b N2 metastasis rate was the percentage of patients having at least one metastatic N2 station lymph node. * Pv0.05 indicates significantly different among four groups. c Pv0.01 versus control. d Pv0.01 versus FOLFOX6. e Pv0.01 versus SOX.
N2 station lymph node compared with FOLFOX6 (52.2%), SOX (26.9%) and XELOX (42.1%) (all Pv0.01) (Table 2). Patients in the control group also had significantly higher number of N2 station lymph nodes with metastasis compared with the chemotherapy groups (all v0.01). Similar to assessment of total lymph nodes, the SOX group had significantly lower metastasis of N2 lymph nodes than FOLFOX6 and XELOX (Pv0.01). The frequency of metastatic lymph nodes relative to the full number of N2 station lymph nodes was 12.1, 4.5, 1.7 and 3.0% for control, FOLFOX6, SOX and XELOX groups, respectively (Table 3).
Safety Most patients experienced adverse events (AEs) associated with the neoadjuvant therapy. The most common AEs were leukopenia/neutropaenia and nausea/vomiting (Table 4). FOLFOX6 was associated with a greater incidence of liver dysfunction and constipation or pain than SOX or XELOX (Pj0.044). Both nausea/vomiting and leukopenia/ neutropaenia resolved after symptomatic therapies. Table 3 Summary of the number of total lymph nodes and lymph nodes for N2 station in each of groups. Total number of lymph nodes examined Total number of lymph nodes with metastasis Rate of metastatic lymph nodes relative to total lymph nodes (%) Total number of lymph nodes for N2 station examined Total number of lymph nodes with metastasis for N2 station Rate of metastatic lymph nodes relative to total lymph nodes for N2 station (%)
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5251
>5418
4850
480
345
210
256
9.9
6.6
3.9
5.3
2296
2567
2591
2344
278
116
45
71
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1.7
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Table 4 Summary of the toxicity for the chemotherapies (N5462). FOLFOX6 (n5157)
SOX (n5160)
XELOX (n5145)
P value
Leukopenia/neutropenia None 53 (33.8) 68 (42.5) 63 (43.4) 0.078 Level 1 55 (35.0) 63 (39.4) 58 (40) Level 2 37 (23.6) 21 (13.1) 18 (12.4) Level 3 12 (7.6) 8 (5.0) 6 (4.1) Level 4 0 (0) 0 (0) 0 (0) Nausea/vomiting None 61 (38.9) 70 (43.8) 65 (44.8) 0.293 Level 1 41 (26.1) 51 (31.9) 46 (31.7) Level 2 32 (20.4) 26 (16.3) 23 (15.9) Level 3 23 (14.6) 13 (8.1) 11 (7.6) Level 4 0 (0) 0 (0) 0 (0) Stomatitis None 143 (91.1) 155 (96.9) 140 (96.6) 0.166 Level 1 9 (5.7) 4 (2.5) 3 (2.1) Level 2 5 (3.2) 1 (0.6) 2 (1.4) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Diarrhea None 144 (91.7) 140 (87.5) 122 (84.1) Level 1 11 (7.0) 14 (8.8) 15 (10.3) Level 2 2 (1.3) 6 (3.8) 8 (5.5) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Liver dysfunction (increase in transaminase or bilirubin) None 136 (86.6) 152 (95.0) 139 (95.9) 0.026* Level 1 15 (9.6) 5 (3.1) 4 (2.8) Level 2 6 (3.8) 3 (1.9) 2 (1.4) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Cardiotoxicity (sinus tachycardia) None 149 (94.9) 157 (98.1) 142 (97.9) 0.205 Level 1 8 (5.1) 3 (1.9) 3 (2.1) Level 2 0 (0) 0 (0) 0 (0) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Neurotoxicity (constipation or pain) None 143 (91.1) 156 (97.5) 142 (97.9) 0.044* Level 1 9 (5.7) 3 (1.9) 2 (1.4) Level 2 5 (3.2) 1 (0.6) 1 (0.7) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Data were represented as n (%) by group; between group differences were compared using Fisher’s exact test. * Pv0.05 indicates significantly different among three groups.
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Discussion This retrospective study investigated the effectiveness of three different regimens of neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer. The study compared the efficacy of FOLFOX, XELOX, SOX and control (without any chemotherapy before surgery) by evaluating the number of post-operative metastatic lymph nodes. More than 90% of patients had sustained disease control in the FOLFOX, XELOX and SOX groups with no significant differences across treatments. Compared with control, the chemotherapy regimens had a lower frequency of lymph nodes with metastasis (9.9 versus v7%). Patients who received neoadjuvant chemotherapy had lower metastatic rate and fewer metastatic lymph nodes, including N2 station lymph nodes, than control. Among the three different chemotherapy regimens, SOX appeared to be the most effective regimen, as it was associated with significantly fewer metastatic lymph nodes compared with FOLFOX6 and XELOX. The most common AEs were nausea/ vomiting and leukopenia/neutropaenia. FOLFOX6 was associated with a greater incidence of liver dysfunction and neurotoxicity (constipation or pain) than SOX and XELOX. Only one other study has compared the efficacy between neoadjuvant chemotherapy regimens for gastric cancer. The aim of the prior study was to attempt to identify the optimal preoperative neoadjuvant chemotherapy for this disease.19 A retrospective study by Chen et al. (2014)19 compared the efficacy of FOLFOX and EOX as neoadjuvant chemotherapy regimens in treating patients with advanced gastric cancer. The study included 87 patients treated with FOLFOX and 26 administered EOX prior to surgery, which was scheduled 1–2 weeks following the completion of the neoadjuvant chemotherapy. Clinicopathological characteristics, pathological response and tumour regression were compared between groups. Unlike our study, there was no control group. They found that a lower number of patients had deeper invasive cancer (P50.047) and metastatic lymph nodes (P50.000) in the EOX compared with the FOLFOX group. In addition, a greater percentage of patients showed tumour regression in the EOX (38.5%) than in the FOLFOX (19.5%) group (P50.047). R0 resection rate was also higher with the EOX (84.6%) than with FOLFOX (79.3%). The authors conclude that the EOX regimen is potentially more effective compared with FOLFOX as neoadjuvant chemotherapy in treating advanced gastric cancer. The explanation for the effectiveness of FOLFOX being comparable to XELOX or SOX as neoadjuvant chemotherapy for gastric cancer is unknown. Additional well-designed clinical studies are necessary to further assess the preferred
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neoadjuvant chemotherapy for treating resectable advanced gastric cancer. There are several limitations to this study that should be considered when interpreting the results. The study was a retrospective observational study and no sample size calculation was determined. Due to the retrospective nature, the findings of this study should be assessed with caution and the conclusions should be considered as exploratory. Prospectively designed trials are needed to confirm these findings. The study did not evaluate tumour regression, tumour invasion or other important clinical outcomes such as overall survival and progression-free survival. Previous findings indicate that clinical response based on World Health Organisation RECIST criteria is highly inaccurate in predicting gastric cancer prognosis particularly the use of different imaging techniques.24 The use of evaluating the number and frequency of metastatic lymph nodes for measuring the actual efficacy of chemotherapeutic agents was previously demonstrated.25 In conclusion, we compared the efficacy of FOLFOX6, SOX and XELOX in treating gastric cancer. We found that the three chemotherapy regimens were associated with fewer metastatic lymph nodes compared with control and that SOX may be the most effective of the treatments analysed as preoperative chemotherapy for Chinese patients with advanced gastric cancer. Larger, prospective, well designed, multi-centre clinical trials are necessary to further evaluate the optimum neoadjuvant chemotherapy for treating this disease.
Acknowledgements This work was financially supported by the Department of Health of Zhejiang Province (No. 201234615).
Disclaimer Statements Contributors Guarantor of integrity of the entire study: Shuai Dong Study design: Shuai Dong Clinical studies: Shuai Dong; Ji-Ren Yu; Qin Zhang Experimental studies: Qin Zhang; Xiao-Sun Liu Data acquisition: Shuai Dong; Qin Zhang; Xiao-Sun Liu Data analysis: Shuai Dong; Xiao-Sun Liu Statistical analysis: XiaoSun Liu Manuscript editing: Shuai Dong Manuscript review: Ji-Ren Yu. Funding This work was financially supported by the Department of Health of Zhejiang Province (No. 201234615). Conflicts of interest None. Ethics approval The study was done in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital.
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14 Tsuburaya A, Mizusawa J, Tanaka Y, Fukushima N, Nashimoto A, Sasako M, et al. Neoadjuvant chemotherapy with S1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis. Br J Surg. 2014;101(8):653–60. 15 Takahashi T, Saikawa Y, Yoshida M, Kitagawa Y, Otani Y, Kubota T, et al. A pilot study of combination chemotherapy with S-1 and low-dose cisplatin for highly advanced gastric cancer. Anticancer Res. 2006;26(2B)):1631–5. 16 Barone C, Cassano A, Pozzo C, D’Ugo D, Schinzari G, Persiani R, et al. Long-term follow-up of a pilot phase II study with neoadjuvant epidoxorubicin, etoposide and cisplatin in gastric cancer. Oncology. 2004;67(1):48–53. 17 Persiani R, Rausei S, Pozzo C, Biondi A, Barone C, Cananzi FC, et al. 7-Year survival results of perioperative chemotherapy with epidoxorubicin, etoposide, and cisplatin (EEP) in locally advanced resectable gastric cancer: up-to-date analysis of a phase-II study. Ann Surg Oncol. 2008;15(8):2146–52. 18 Kinoshita T, Sasako M, Sano T, Katai H, Furukawa H, Tsuburaya A, et al. Phase II trial of S-1 for neoadjuvant chemotherapy against scirrhous gastric cancer (JCOG 0002). Gastric Cancer. 2009;12(1):37–42. 19 Chen W, Shen J, Pan T, Hu W, Jiang Z, Yuan X, et al. FOLFOX versus EOX as a neoadjuvant chemotherapy regimen for patients with advanced gastric cancer. Exp Ther Med. 2014;7(2):461–7. 20 Koh YW, Park YS, Ryu MH, Ryoo BY, Park HJ, Yook JH, et al. Postoperative nodal status and diffuse-type histology are independent prognostic factors in resectable advanced gastric carcinomas after preoperative chemotherapy. Am J Surg Pathol. 2013;37(7):1022–9. 21 Chen CQ, Wu XJ, Yu Z, Bu ZD, Zuo KQ, Yook JH, et al. Prognosis of patients with gastric cancer and solitary lymph node metastasis. World J Gastroenterol. 2013;19(46):8611–8. 22 Lee JH, Choi MG, Min BH, Noh JH, Sohn TS, Bae JM, et al. Predictive factors for lymph node metastasis in patients with poorly differentiated early gastric cancer. Br J Surg. 2012;99(12):1688–92. 23 Huang JY, Xu YY, Li M, Sun Z, Zhu Z, Song YX, et al. The prognostic impact of occult lymph node metastasis in node-negative gastric cancer: a systematic review and metaanalysis. Ann Surg Oncol. 2013;20(12):3927–34. 24 Brown WA, Thomas J, Gotley D, Burmeister BH, Lim KH, Martin I, et al. Use of oesophagogastroscopy to assess the response of oesophageal carcinoma to neoadjuvant therapy. Br J Surg. 2004;91(2):199–204. 25 Wang LB, Teng RY, Jiang ZN, Hu WX, Dong MJ, Yuan XM, et al. Clinicopathologic variables predicting tumor response to neoadjuvant chemotherapy in patients with locally advanced gastric cancer. J Surg Oncol. 2012;105(3):293–6.
ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20
Neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer in a Chinese population Shuai Dong, Ji-Ren Yu, Qin Zhang & Xiao-Sun Liu To cite this article: Shuai Dong, Ji-Ren Yu, Qin Zhang & Xiao-Sun Liu (2016) Neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer in a Chinese population, Journal of Chemotherapy, 28:1, 59-64, DOI: 10.1179/1973947815Y.0000000028 To link to this article: http://dx.doi.org/10.1179/1973947815Y.0000000028
Published online: 16 Mar 2016.
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Date: 06 June 2016, At: 23:38
Anticancer Original Research Paper
Neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer in a Chinese population Shuai Dong, Ji-Ren Yu, Qin Zhang, Xiao-Sun Liu
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Department of General Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, China This study aimed to evaluate the efficacy of FOLFOX6, SOX and XELOX as neoadjuvant chemotherapy for advanced gastric cancer. The study retrospectively assessed clinicopathological data of patients who received a radical D2 gastrectomy for gastric cancer from January 2010 to January 2013.The patients were either not administered neoadjuvant chemotherapy (control) or were given FOLFOX6, SOX and XELOX prior to surgery. The metastatic rate was also higher for the control group compared with the three chemotherapy regimens in N2 station lymph nodes (P v0.001). The SOX group had significantly lower metastatic total and N2 station lymph nodes than FOLFOX6 and XELOX (Pv0.01). The frequency of metastatic lymph nodes relative to total lymph nodes examined was 9.9, 6.6, 3.9 and 5.3% for control, FOLFOX6, SOX and XELOX groups, respectively. In conclusion, SOX may be the most effective of these treatments as preoperative chemotherapy for Chinese patients with advanced gastric cancer. Keywords: Neoadjuvant chemotherapy, Gastric cancer, FOLFOX6, XELOX, SOX
Introduction Despite a decrease in frequency, gastric cancer is still the third for men and fifth for women cause of cancer-related deaths worldwide.1 About two-thirds of these cases occur in developing countries with 42% of them being reported in China.1 The prognosis for locally advanced gastric cancer is poor with the overall survival rate being between 20 and 60%, depending upon the country.2,3 Locally advanced gastric cancer is cancer that has invaded the submucosa or myometrium, and/or the serosa, but has not invaded the surrounding tissue or metastasised to other parts of the body. The outcome among patients with gastric cancer is dependent on the disease stage at diagnosis, and the high mortality rate likely reflects the fact that diagnosis is commonly late with the majority of cases having locally advanced gastric cancer.4 After tumour cells penetrate the submucosa, the risk of lymph node metastasis increases and the long-term survival diminishes; in Western countries, the 5-year survival rate of advanced gastric cancer is about 20–30%.5,6 Complete radical resection with D2 nodal dissection is the primary treatment for resectable gastric cancer.4,7,8 In addition to surgery, neoadjuvant
Correspondence to: Shuai Dong, Department of General Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China. Email: [email protected]
ß 2016 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947815Y.0000000028
chemotherapy (adjuvant chemotherapy administered preoperatively) reduces the number of metastatic lymph nodes and improves prognosis and is currently used worldwide as an initial therapy for locally advanced gastric cancer.6,9–11 Advantages to preoperative chemotherapy include that it is generally more tolerated than adjuvant chemotherapy even when the same chemotherapy agents are used, and that it also can shrink tumours potentially improving the prognosis.4 Published data indicate that neoadjuvant chemotherapy does not increase post-operative morbidity and mortality, and increases the rate of R0 resection.4,12,13 Although neoadjuvant chemotherapy is the preferred treatment for gastric cancer, the choice of the optimal regimen is controversial. A number of studies have evaluated a given neoadjuvant chemotherapy but these were not controlled studies that compared different regimens.6,8,11,14–18 One non-controlled study compared the efficacy of two different regimens (FOLFOX and EOX) as neoadjuvant chemotherapies in patients with advanced gastric cancer by evaluating clinicopathological characteristics in Chinese patients,19 in which EOX was found to be more effective than FOLFOX as neoadjuvant chemotherapy in reducing cancer invasion, tumour regression and lymph node metastasis. The aim of this retrospective study was to evaluate the efficacy of FOLFOX6 [oxaliplatin, leucovorin, and
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fluorouracril (5-FU)], SOX [S-1 (tegafur/gimeracil/oteracil) and oxaliplatin] and XELOX (capecitabine plus oxaliplatin), three commonly used neoadjuvant chemotherapy regimens in China, and control (no chemotherapy). The main outcome was the number of post-operative metastatic lymph nodes following neoadjuvant chemotherapy, as several studies found that the presence and number of post-operative metastatic lymph nodes are predictive of the prognosis for gastric cancer.20–23
Materials and Methods Study design
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This was a retrospective observational study using clinicopathological data of patients who received a radical D2 gastrectomy for gastric cancer from January 2010 to January 2013 at the First Affiliated Hospital, College of Medicine, ZheJiang University, HangZhou, China. The study was done in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital.
Study population Eligible patients were aged 30–70 years and had pathologically diagnosed Borrman type II/III gastric cancer with no evidence of distant metastasis including the surrounding organs. We limited the population to this age group and cancer stage because patients aged v30 years have very poor prognosis since the gastric cancer tends to have a high rate of metastasis in this age group. The Borrman type II/ III was chosen as it is the most common stage of cancer found in clinical practice and has better prognosis than Borrman type intravenous (IV) cancer. The cancer stage was determined following surgery. Patients with a history of malignancy, immunological disorder, or other major diseases were excluded. Patients received two to three courses of neoadjuvant chemotherapy once in every 3 weeks followed by radical D2 gastrectomy. Before each round of chemotherapy, abdominal CT was performed to evaluate the tumour and lymph node sizes. For most patients, three rounds of chemotherapy were necessary to effectively reduce the size of tumour and lymph nodes necessary for surgery. In a few cases, only two rounds of chemotherapy were necessary. The following neoadjuvant chemotherapy regimens were administered: FOLFOX6, XELOX or SOX. For FOLFOX6 on day 1, oxaliplatin 100 mg/m2 and leucovorin 400 mg/m2 were administered IV infusion over 2 hours, and 5-Fu 400 mg/m2 was given by IV injection. 5-Fu 2400 mg/m2 was administered for maintenance by continuous IV infusion over 46 hours. A total of 14 days were included in each course of FOLFOX6 chemotherapy, which was
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performed once in every 3 weeks. For XELOX on day 1, patients received oxaliplatin 130 mg/m2 and on days 1–14 were administered capecitabine 1000 mg/m2 twice daily (BID). XELOX therapy was performed once in every 3 weeks. For SOX therapy, S-180 mg/m2 was administered from days 1 to 14 and xaliplatin 130 mg/m2 was administered on day 1. SOX therapy was given once in every 3 weeks. In the control group, patients received only surgical intervention and had no neoadjuvant chemotherapy before surgery. The decision for neoadjuvant chemotherapy or surgery was physician preference based on their judgement following abdominal CT scan of the size of the tumour and possibly affected lymph nodes. There was no clear standard. In addition, for ethical reasons, it was also a decision of the patient to receive neoadjuvant chemotherapy or surgery first. For the chemotherapy, patients were randomly assigned to one of the treatment groups (FOLFOX6, XELOX or SOX). Patients who had progressive disease or serious toxicity with neoadjuvant treatment were excluded from surgery. The number of metastatic total and N2 station lymph nodes and the frequency of metastatic lymph nodes were determined. The post-operative TNM stage was confirmed on the basis of TNM staging system developed by UICC/AJCC in 2010 (N0: no regional lymph node metastasis; N1: metastasis to one to two regional lymph nodes; N2: metastasis to three to six regional lymph nodes; N3: metastasis to more than seven regional lymph nodes)
Statistical analysis Patient demographics, clinical characteristics, and treatment response were summarised as n (%) for categorical variables and median [interquartile range (IQR): first, third quartiles) for continuous variables whose data were not normally distributed. Differences among groups were compared using Pearson Chi-square test for categorical data. Kruskall–Wallis test with a pair-wise comparison and Mann–Whitney U test were used for data, including total lymph nodes and N2 station lymph nodes, which were not normally distributed. Metastasis rates were calculated as the number of patients with total or N2 station lymph node metastasis versus no metastasis. All statistical analyses were two-tailed and considered significantly different at Pv0.05. An adjusted significance level of Pv0.01 (P50.05/4) was also considered for the post hoc pair-wise comparisons. Statistical analyses were performed using SPSS 18.0 statistics software (SPSS Inc, Chicago, IL, USA).
Results A total of 603 patients were enrolled into this study of which 141 were treated only with surgery
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(control group), 157 received FOLFOX6, 160 were given SOX and 145 were administered XELOX. The majority of patients were male (w84%) and the median age was about 54 years. The baseline demographics and clinical characteristics were similar among the four treatment groups. There were also a similar number of patients with stage T2 (n5303) and stage T3 (n5300) tumours, and the number of neoadjuvant chemotherapy cycles did not differ across the three groups. The FOLFOX, XELOX and SOX groups had similar treatment response (P50.752) with more than 90% of patients achieving sustained disease control (Table 1). For each patient, the number of resected lymph nodes was w25: a mean of 33 lymph nodes for stage T2 gastric cancer patients and mean of 34 lymph nodes for stage T3 gastric cancer patients. Following chemotherapy, most patients (w94%) in the three treatment groups had sustained disease response. For all treatment groups, about 33 lymph nodes were evaluated (Table 2). Comparison of the rate of metastasis for total lymph nodes between control and the three different chemotherapy groups indicated that the control group had significantly higher number of patients with at least one metastatic lymph node compared
Efficacy of neoadjuvant chemotherapy
with the FOLFOX6, SOX and XELOX groups (all Pv0.01) (Table 2). The number of lymph nodes with metastasis differed across treatment groups with the SOX and XELOX groups, but not the FOLFOX6 group, having significantly fewer metastatic lymph nodes compared with control (Pv0.001) (Table 2). The frequency of metastatic lymph nodes relative to total lymph nodes was 9.9, 6.6, 3.9 and 5.3% for control, FOLFOX6, SOX and XELOX groups, respectively (Table 3). We did a post hoc pair-wise comparison of treatments using a post hoc adjusted significance (significance level Pv0.01) (Table 2). We found that SOX treatment may result in a lower frequency of metastasis than FOLFOX6 or XELOX (Pv0.001 versus FOLFOX6, P50.005 versus XELOX). There was no difference in frequency of total metastasis between treatment groups (all P value w0.01); although there were difference between treatments at the Pv0.05 significance levels (P50.047 for FOLFOX6 versus SOX; P50.034 for FOLFOX6 versus XELOX). The number of N2 station lymph nodes evaluated for each group was approximately 16 (Table 2). A significantly higher percentage of patients in the control group (90.8%) had at least one metastatic
Table 1 Patients’ demographics, clinical characteristics and treatment response among groups (N5603) Variables
Control (n5141)
FOLFOX6 (n5157)
SOX (n5160)
XELOX (n5145)
P value
Sex, males; n (%) Age, median (IQR) (years) Macroscopic Borrmann types, n (%) II III Tumour location; n (%) Lower Middle Upper Cycles of neoadjuvant therapya, n (%) 2 3 Response to treatmenta,b, n (%) Partial response Sustained disease Post-operative TNM stage, n (%) T2N0-3M0 T2N0M0c T2N1M0c T2N2M0c T2N3M0c T3N0-3M0 T3N0M0c T3N1M0c T3N2M0c T3N3M0c
119 (84.4) 54 (49, 61)
136 (86.6) 54 (50, 61)
143 (89.4) 53 (50, 61)
128 (88.3) 54 (51, 62)
0.600 0.519
94 (66.7) 47 (33.3)
114 (72.6) 43 (27.4)
111 (69.4) 49 (30.6)
102 (70.3) 43 (29.7)
0.734
114 (80.9) 12 (8.5) 15 (10.6)
128 (81.5) 14 (8.9) 15 (9.6)
132 (82.5) 13 (8.1) 15 (9.4)
119 (82.0) 12 (8.3) 14 (9.7)
1.000
– –
6 (3.8) 151 (96.2)
6 (3.8) 154 (96.3)
4 (2.8) 141 (97.2)
0.854
– –
6 (3.8) 151 (96.2)
9 (5.6) 151 (94.4)
7 (4.8) 138 (95.2)
0.752
79 (50.3) 12 45 21 1 78 (49.7) 9 42 27 0
80 (50) 17 48 15 0 80 (50) 18 48 14 0
73 (50.3) 19 39 15 0 72 (49.7) 13 42 17 0
1.000
71 (50.4) 3 40 21 7 70 (49.6) 0 33 29 8
Difference among groups were compared using Pearson Chi-square test for categorical data; Kruskall–Wallis test with a pair-wise comparison, Mann–Whitney U test for those continuous data without normal distribution. IQR: interquartile range; TNM: tumour node metastasis. a Only patients who received FOLFOX6, XELOX and SOX were considered. b Disease progression was evaluated 1 week after to three courses of chemotherapy. Reduction in tumour size on CT images was defined as partial response. c Data were represented as numbers of patients for a given sub-category of TNM stage.
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Table 2 Comparison of the total lymph nodes and lymph nodes for N2 station by group (N5603) Control (n5141)
FOLFOX6 (n5157)
SOX (n5160)
138 (97.9) 2 (2, 4.5) 33 (31, 36)
136 (86.6)c 2 (1, 3)c 33 (31, 35)
128 (90.8%) 2 (1, 3) 16 (15, 17)
82 (52.2)c 1 (0, 1)c 16 (15, 17)
Variables Total lymph nodes Total metastasis ratea, n (%) Number of total metastatic LN, median (IQR) Number of total LN N2 lymph nodes N2 metastasis rateb, n (%) Number of metastatic N2 LN, median (IQR) Number of N2 LN, median (IQR)
XELOX (n5145)
P value
125 (78.1)c 1 (1, 2)c,d 33 (32, 36)
112 (77.2)c 2 (1, 2)c,e 33 (32, 35)
v0.001* v0.001* 0.356
43 (26.9)c,d 0 (0, 1)c,d 16 (15, 17)
61 (42.1)c,e 0 (0, 1)c,e 16 (15, 17)
v0.001* v0.001* 0.963
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IQR: interquartile range; LN: lymph nodes.Differences among groups were compared using Kruskall–Wallis test with a pair-wise comparison, Mann–Whitney U test for those continuous data without normal distribution. All statistical analyses were two-tailed and considered significantly different at Pv0.05. An adjusted significance level of 0.01 (50.05/4) was used for the post hoc pair-wise comparisons of treatments. a Total metastasis rate was calculated as the percentage of patients having at least one metastatic lymph node. b N2 metastasis rate was the percentage of patients having at least one metastatic N2 station lymph node. * Pv0.05 indicates significantly different among four groups. c Pv0.01 versus control. d Pv0.01 versus FOLFOX6. e Pv0.01 versus SOX.
N2 station lymph node compared with FOLFOX6 (52.2%), SOX (26.9%) and XELOX (42.1%) (all Pv0.01) (Table 2). Patients in the control group also had significantly higher number of N2 station lymph nodes with metastasis compared with the chemotherapy groups (all v0.01). Similar to assessment of total lymph nodes, the SOX group had significantly lower metastasis of N2 lymph nodes than FOLFOX6 and XELOX (Pv0.01). The frequency of metastatic lymph nodes relative to the full number of N2 station lymph nodes was 12.1, 4.5, 1.7 and 3.0% for control, FOLFOX6, SOX and XELOX groups, respectively (Table 3).
Safety Most patients experienced adverse events (AEs) associated with the neoadjuvant therapy. The most common AEs were leukopenia/neutropaenia and nausea/vomiting (Table 4). FOLFOX6 was associated with a greater incidence of liver dysfunction and constipation or pain than SOX or XELOX (Pj0.044). Both nausea/vomiting and leukopenia/ neutropaenia resolved after symptomatic therapies. Table 3 Summary of the number of total lymph nodes and lymph nodes for N2 station in each of groups. Total number of lymph nodes examined Total number of lymph nodes with metastasis Rate of metastatic lymph nodes relative to total lymph nodes (%) Total number of lymph nodes for N2 station examined Total number of lymph nodes with metastasis for N2 station Rate of metastatic lymph nodes relative to total lymph nodes for N2 station (%)
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5251
>5418
4850
480
345
210
256
9.9
6.6
3.9
5.3
2296
2567
2591
2344
278
116
45
71
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Table 4 Summary of the toxicity for the chemotherapies (N5462). FOLFOX6 (n5157)
SOX (n5160)
XELOX (n5145)
P value
Leukopenia/neutropenia None 53 (33.8) 68 (42.5) 63 (43.4) 0.078 Level 1 55 (35.0) 63 (39.4) 58 (40) Level 2 37 (23.6) 21 (13.1) 18 (12.4) Level 3 12 (7.6) 8 (5.0) 6 (4.1) Level 4 0 (0) 0 (0) 0 (0) Nausea/vomiting None 61 (38.9) 70 (43.8) 65 (44.8) 0.293 Level 1 41 (26.1) 51 (31.9) 46 (31.7) Level 2 32 (20.4) 26 (16.3) 23 (15.9) Level 3 23 (14.6) 13 (8.1) 11 (7.6) Level 4 0 (0) 0 (0) 0 (0) Stomatitis None 143 (91.1) 155 (96.9) 140 (96.6) 0.166 Level 1 9 (5.7) 4 (2.5) 3 (2.1) Level 2 5 (3.2) 1 (0.6) 2 (1.4) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Diarrhea None 144 (91.7) 140 (87.5) 122 (84.1) Level 1 11 (7.0) 14 (8.8) 15 (10.3) Level 2 2 (1.3) 6 (3.8) 8 (5.5) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Liver dysfunction (increase in transaminase or bilirubin) None 136 (86.6) 152 (95.0) 139 (95.9) 0.026* Level 1 15 (9.6) 5 (3.1) 4 (2.8) Level 2 6 (3.8) 3 (1.9) 2 (1.4) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Cardiotoxicity (sinus tachycardia) None 149 (94.9) 157 (98.1) 142 (97.9) 0.205 Level 1 8 (5.1) 3 (1.9) 3 (2.1) Level 2 0 (0) 0 (0) 0 (0) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Neurotoxicity (constipation or pain) None 143 (91.1) 156 (97.5) 142 (97.9) 0.044* Level 1 9 (5.7) 3 (1.9) 2 (1.4) Level 2 5 (3.2) 1 (0.6) 1 (0.7) Level 3 0 (0) 0 (0) 0 (0) Level 4 0 (0) 0 (0) 0 (0) Data were represented as n (%) by group; between group differences were compared using Fisher’s exact test. * Pv0.05 indicates significantly different among three groups.
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Discussion This retrospective study investigated the effectiveness of three different regimens of neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer. The study compared the efficacy of FOLFOX, XELOX, SOX and control (without any chemotherapy before surgery) by evaluating the number of post-operative metastatic lymph nodes. More than 90% of patients had sustained disease control in the FOLFOX, XELOX and SOX groups with no significant differences across treatments. Compared with control, the chemotherapy regimens had a lower frequency of lymph nodes with metastasis (9.9 versus v7%). Patients who received neoadjuvant chemotherapy had lower metastatic rate and fewer metastatic lymph nodes, including N2 station lymph nodes, than control. Among the three different chemotherapy regimens, SOX appeared to be the most effective regimen, as it was associated with significantly fewer metastatic lymph nodes compared with FOLFOX6 and XELOX. The most common AEs were nausea/ vomiting and leukopenia/neutropaenia. FOLFOX6 was associated with a greater incidence of liver dysfunction and neurotoxicity (constipation or pain) than SOX and XELOX. Only one other study has compared the efficacy between neoadjuvant chemotherapy regimens for gastric cancer. The aim of the prior study was to attempt to identify the optimal preoperative neoadjuvant chemotherapy for this disease.19 A retrospective study by Chen et al. (2014)19 compared the efficacy of FOLFOX and EOX as neoadjuvant chemotherapy regimens in treating patients with advanced gastric cancer. The study included 87 patients treated with FOLFOX and 26 administered EOX prior to surgery, which was scheduled 1–2 weeks following the completion of the neoadjuvant chemotherapy. Clinicopathological characteristics, pathological response and tumour regression were compared between groups. Unlike our study, there was no control group. They found that a lower number of patients had deeper invasive cancer (P50.047) and metastatic lymph nodes (P50.000) in the EOX compared with the FOLFOX group. In addition, a greater percentage of patients showed tumour regression in the EOX (38.5%) than in the FOLFOX (19.5%) group (P50.047). R0 resection rate was also higher with the EOX (84.6%) than with FOLFOX (79.3%). The authors conclude that the EOX regimen is potentially more effective compared with FOLFOX as neoadjuvant chemotherapy in treating advanced gastric cancer. The explanation for the effectiveness of FOLFOX being comparable to XELOX or SOX as neoadjuvant chemotherapy for gastric cancer is unknown. Additional well-designed clinical studies are necessary to further assess the preferred
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neoadjuvant chemotherapy for treating resectable advanced gastric cancer. There are several limitations to this study that should be considered when interpreting the results. The study was a retrospective observational study and no sample size calculation was determined. Due to the retrospective nature, the findings of this study should be assessed with caution and the conclusions should be considered as exploratory. Prospectively designed trials are needed to confirm these findings. The study did not evaluate tumour regression, tumour invasion or other important clinical outcomes such as overall survival and progression-free survival. Previous findings indicate that clinical response based on World Health Organisation RECIST criteria is highly inaccurate in predicting gastric cancer prognosis particularly the use of different imaging techniques.24 The use of evaluating the number and frequency of metastatic lymph nodes for measuring the actual efficacy of chemotherapeutic agents was previously demonstrated.25 In conclusion, we compared the efficacy of FOLFOX6, SOX and XELOX in treating gastric cancer. We found that the three chemotherapy regimens were associated with fewer metastatic lymph nodes compared with control and that SOX may be the most effective of the treatments analysed as preoperative chemotherapy for Chinese patients with advanced gastric cancer. Larger, prospective, well designed, multi-centre clinical trials are necessary to further evaluate the optimum neoadjuvant chemotherapy for treating this disease.
Acknowledgements This work was financially supported by the Department of Health of Zhejiang Province (No. 201234615).
Disclaimer Statements Contributors Guarantor of integrity of the entire study: Shuai Dong Study design: Shuai Dong Clinical studies: Shuai Dong; Ji-Ren Yu; Qin Zhang Experimental studies: Qin Zhang; Xiao-Sun Liu Data acquisition: Shuai Dong; Qin Zhang; Xiao-Sun Liu Data analysis: Shuai Dong; Xiao-Sun Liu Statistical analysis: XiaoSun Liu Manuscript editing: Shuai Dong Manuscript review: Ji-Ren Yu. Funding This work was financially supported by the Department of Health of Zhejiang Province (No. 201234615). Conflicts of interest None. Ethics approval The study was done in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital.
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