Survival Advantages in Gastric Cancer Patients Receiving Preoperative SOX Regimen Chemotherapy

Abstract

Objective:

This study addressed whether preoperative chemotherapy (PECT) plus surgery prolongs overall survival (OS) compared with surgery plus postoperative chemotherapy (POCT) among gastric cancer (GC) patients in Northwest China.

Materials and Methods:

The authors included 157 GC patients confirmed histologically or by gastroscopic pathological examination treated at the General Hospital of Ningxia Medical University of China between 2012 and 2018. All patients were followed up by telephone in January 2019 within a 2-week period. The endpoint was death due to GC or its complications.

Results:

Thirty-eight patients received PECT, 41 patients received POCT, 40 patients received surgery alone, and 38 patients received chemotherapy alone. Surgery was performed with R0 resection and subsequent extended lymph node dissection. Chemotherapy was performed with the S-1, oxaliplatin capecitabine regimen. Patients who received PECT had longer OS than those with POCT treatment (hazard ratio = 2.409, p = 0.037). The 5-year OS rate was 32.7% higher in the PECT group than in the POCT group.

Conclusions:

PECT was associated with better OS in GC patients and should be considered by clinicians in GC treatment, although prospective studies are needed for confirmation.

Introduction

Gastric cancer (GC) is the third leading cause of cancer death worldwide, with an estimated 783,000 deaths in 2018.¹ Over half of the GC deaths worldwide occur in East Asia.¹ In Japan, the 5-year survival of patients with GC was 50.5% in 2000, and it increased to 60.3% in 2014.² In China, the 5-year survival rate of GC, which was about 30.2% in 2000 increased by 5.7% in 2014.² Although it is promising to see that the overall survival (OS) rate has been enhanced due to early detection techniques and progress in therapeutics, GC is still a heavy health burden. This burden inspires researchers and clinicians to discover more effective therapeutic strategies worldwide, especially in China.^2
–4

Preoperative chemotherapy (PECT), which was first applied to advanced breast cancer in London in the 1970s, can downsize locally advanced (inoperable) disease, and improve resectability.⁵ PECT has been employed in the treatment of locally advanced GC, especially in Europe, since the early 1990s.⁶ In 2006, Cunningham et al. randomly assigned 503 stomach cancer patients in the United Kingdom to either PECT plus surgery or surgery alone to compare the efficacy of each treatment.⁷ They found that patients who received PECT had a higher 5-year survival rate (13%) than patients treated with surgery alone, which meant PECT could prolong the survival of GC patients in some extent. In 2010, Qu et al. selected 76 Chinese GC patients and found that the 2-year survival rates in the PECT group and the postoperative chemotherapy (POCT) group were 59.0% and 28.2%, respectively, which suggested that PECT was superior to POCT for GC patients.⁸ However, some other reports have shown that PECT can improve the R0 resection rate and reduce tumor staging, but it has no obvious advantage in terms of the long-term survival rate.^9
–11 Therefore, more investigations in different GC populations, especially in high-incidence GC areas, are still warranted.

This study aimed to evaluate the survival benefit for GC patients treated with PECT compared with GC patients treated with POCT, surgery alone, and chemotherapy alone to optimize the treatment strategy on the basis of collected data. All patients were selected from the Ningxia region, a high-incidence area for GC in Northwest China.¹²

Materials and Methods

Patients

A total of 170 patients with GC confirmed histologically or by gastroscopic pathological examination treated at the General Hospital of Ningxia Medical University of China between 2012 and 2018 were retrospectively enrolled in this study. All data were obtained from the patients' medical records at the General Hospital of Ningxia Medical University.

A total of 53 datum, including sex, age, cigarette smoking, alcohol drinking, family history, Borrmann's type, clinical stage, tumor localization, surgical procedures, pathological diagnosis, and other relevant information pertaining to patients with primary gastric carcinoma, were collected for further analyses.

GC patients were eligible for this study if they (1) had histologically proven stage IB-IVA GC (as defined by the American Joint Committee on Cancer, 8th edition), (2) had primary GC, (3) had been treated according to the National Comprehensive Cancer Network (NCCN) guidelines, and (4) had no synchronous or metachronous cancer. Patients with gastroesophageal junction carcinoma were excluded if they were treated with PECT and esophagectomy according to the guidelines for esophageal cancer. The data of 157 GC patients were retrospectively examined after excluding 13 patients who did not meet these criteria.

Informed consent was obtained in all cases, and this study was approved by the Ethics Committee of Ningxia Medical University of China.

Treatment

Patients could be treated with no chemotherapy, PECT, or POCT. Likewise, patients could undergo or forego surgery. Thirty-eight patients received PECT and surgery, 38 patients received chemotherapy alone, 40 patients received only surgery, and 41 patients received surgery and POCT. The authors compared survival outcomes based on the different therapies.

Chemotherapy

Patients were treated with any combination of chemotherapy (administered orally, intravenously, or intraperitoneally). Chemotherapy regimens were classified into two types: (1) S-1, oxaliplatin (SOX) regimen: For SOX therapy, S-1 80 mg/m² was administered from days 1 to 14 and oxaliplatin 130 mg/m² was administered on day 1. (2) oxaliplatin, capecitabine (XELOX) regimen: For XELOX therapy, patients received oxaliplatin 130 mg/m² on day 1 and capecitabine 1000 mg/m² twice daily from days 1 through 14.

Surgery

Surgical treatment consisted of proximal subtotal gastrectomy, total gastrectomy and subsequent extended lymph node dissection (D2 resection), radical resection of cardiac carcinoma, and palliative subtotal gastrectomy. The operations were in accordance with the NCCN guidelines.

Follow-up

The initial event of this study was admission to the hospital for treatment. The endpoint of this study was cause of death due to GC or complications while in or after discharge from the hospital. Patients who were lost to follow-up or alive at the end of follow-up were censored. OS was calculated from the time of first treatment to the date of death or the last follow-up. All selected patients were followed up by telephone in January 2019 within a 2-week period. The purpose of the phone calls was to collect survival information. Additional phone calls or messages were made to patients who could not initially be contacted. Nine patients were lost to follow-up, so there were follow-up data from 148 patients: 40 patients who were alive and 108 patients who died from GC. The causes of missing information included discontinued phone service, number change, and no response.

Statistical analyses

All analyses were performed using SPSS 24.0 software (IBM Corporation, Armonk, NY). The distribution of baseline characteristics was compared with Pearson's Chi-square (χ²) test or Fisher's exact test. Patient survival was first estimated with the Kaplan–Meier method. To identify independent prognostic factors of GC, a multivariate Cox proportional hazards model was then conducted on the basis of meaningful and clinically relevant factors extracted from univariate analysis. The most appropriate statistic for evaluating primary endpoints (time-to-event outcomes) was the hazard ratio (HR). p < 0.05 was considered statistically significant. All tests were two sided.

Results

Patients' characteristics

From 2012 to 2018, a total of 170 GC patients were treated at their hospital. After assessment of eligibility, 157 patients remained. The included patients' demographic information and clinicopathological characteristics are shown in Table 1. There was no significant difference in the demographic or clinical characteristics among the four groups over the period studied.

Table 1.

Basic Information and Clinicopathological Characteristics of Gastric Cancer Patients Enrolled During 2012–2018 (N = 157)

Variables	PECT (N = 38), n (%)	POCT (N = 41), n (%)	Surgery (N = 40), n (%)	CT (N = 38), n (%)	χ²	p
Age
<55	15 (39.5)	8 (20.0)	10 (26.3)	10 (25.4)	4.096	0.253
≥55	23 (60.5)	32 (80.0)	28 (73.7)	31 (75.6)
Sex
Male	31 (81.6)	27 (67.5)	27 (71.1)	33 (80.5)	3.062	0.394
Female	7 (18.4)	13 (32.5)	11 (28.9)	8 (19.5)
Cigarette smoking
No	22 (57.9)	26 (65.0)	21 (55.3)	20 (48.8)	2.224	0.254
Yes	16 (42.1)	14 (35.0)	17 (44.7)	21 (51.2)
Alcohol drinking
No	31 (81.6)	34 (85.0)	30 (78.9)	35 (85.4)	0.761	0.866
Yes	7 (18.4)	6 (15.0)	8 (21.1)	6 (14.6)
Tumor size
≥5 cm	21 (60.0)	24 (61.5)	16 (53.3)	—	4.158	0.246
<5 cm	14 (40.0)	15 (38.5)	14 (46.7)	3 (100.0)
Tumor site
Proximal	11 (39.3)	10 (25.0)	7 (20.6)	13 (33.3)	12.828	0.044
Middle	17 (39.3)	18 (45.0)	10 (20.6)	16 (41.0)
Pyloric	6 (21.4)	12 (30.0)	20 (58.8)	10 (25.6)
Histological subtype
Adenocarcinoma	26 (72.2)	33 (82.5)	33 (89.2)	35 (92.1)	5.952	0.104
Other types	10 (27.8)	7 (17.5)	4 (10.8)	3 (7.9)
Differentiation
High	1 (3.2)	3 (7.9)	2 (5.6)	2 (6.9)	1.246	0.988
Medium	13 (41.9)	15 (39.5)	13 (36.1)	12 (41.4)
Low	17 (54.8)	20 (52.6)	21 (58.3)	15 (51.7)
Borrmann's type
I	5 (13.9)	6 (15.0)	2 (5.4)	1 (6.3)	9.963	0.368
II	7 (19.4)	5 (12.5)	3 (8.1)	2 (12.5)
III	7 (19.4)	15 (37.5)	9 (24.4)	6 (37.5)
IV	17 (47.2)	14 (35.0)	23 (62.2)	7 (43.8)
cT stage
T1	—	1 (2.5)	1 (2.9)	—	10.783	0.203
T2	5 (13.2)	5 (12.5)	1 (2.9)	1 (2.4)
T3	7 (18.4)	5 (12.5)	5 (14.3)	12 (29.3)
T4	26 (68.4)	29 (72.5)	28 (80.0)	28 (68.3)
cN stage
N0	9 (25.0)	5 (12.8)	3 (8.3)	3 (8.6)	4.868	0.172
N+	27 (75.0)	34 (87.2)	33 (91.7)	32 (91.4)
Clinical stage
I+II	10 (26.3)	10 (25.0)	8 (22.2)	10 (24.4)	0.174	0.987
III	28 (73.7)	30 (75.0)	28 (73.7)	31 (75.6)
Type of resection
Radical surgery	35 (92.1)	39 (97.5)	35 (92.1)	—	5.128	0.051
Other types	3 (7.9)	1 (2.5)	3 (7.9)	—

cN stage, clinical N stage; cT stage, clinical T stage; CT, chemotherapy; PECT, preoperative chemotherapy; POCT, postoperative chemotherapy.

Survival analysis

In this retrospective study, the survival status of all GC patients was compared by both univariate and multivariate analysis (Tables 2 and 3). The median follow-up time for the entire cohort was 12.0 months (0.4–74.2 months). The 1-, 3-, and 5-year OS rates in the PECT group were 68.8%, 55.1%, and 51.0%, respectively, which were significantly higher than the corresponding OS rates in the POCT group (60.0%, 30.5%, and 18.3%, respectively), the surgery group (50.0%, 11.8%, and 15.0%, respectively), and the chemotherapy group (60.5%, 11.8%, and 0%, respectively) (Table 4). PECT (Fig. 1A–D, all p < 0.05), age younger than 55 years (Fig. 1E, p = 0.049), tumor site in the middle (Fig. 1F, p = 0.003), Stage I and II (Fig. 1G, p = 0.001), and radical surgery (Fig. 1H, p = 0.012) were shown to be significant predictors of good survival in GC patients. The Kaplan–Meier curves are provided in Figure 1. Then, to analyze the survival efficacy of the different treatments, they compared the outcomes of patients undergoing PECT, POCT, chemotherapy, and surgery and significant differences were noted. It was shown that there existed statistical differences in the survival of patients undergoing PECT compared with those undergoing other treatments (PECT vs. POCT: p = 0.048, PECT vs. surgery: p < 0.001, PECT vs. chemotherapy: p = 0.008; Fig. 1B–D). The statistical differences were also found in age, tumor site, N stage, clinical stage, and type of resection (Table 2, all p < 0.05). The results of the Cox regression analysis, in which the type of treatment, cigarette smoking, lymph node metastasis, and tumor site were included to identify prognostic factors are shown in Table 3. The type of treatment (HR = 2.409, 95% confidence interval [CI] = 1.056–5.494, p = 0.037), cigarette smoking (HR = 2.067, 95% CI = 1.022–4.180, p = 0.043), and lymph node metastasis (HR = 4.946, 95% CI = 1.438–17.012, p = 0.011) all showed to be significant, independent prognostic factors for OS in GC patients.

FIG. 1.

Survival curves of four treatments and clinically related factors in gastric cancer patients. (A–D) Survival curves of four treatments (A), PECT and POCT (B), PECT and surgery (C), PECT and CT (D). (E–H) The survival curves of age (E), tumor site (F), clinical stage (G), and the type of resection (H). CT, chemotherapy; PECT, preoperative chemotherapy; POCT, postoperative chemotherapy. Color images are available online.

Table 2.

Univariate Analysis of Overall Survival of Gastric Cancer Patients

Variables	Total mortality (%)	P	PECT	POCT	Surgery	CT	PECT vs.
			PECT	POCT	Surgery	CT	POCT	Surgery	CT
			Mortality (%)				p	p	p
Total	108 (68.7)		15 (46.8)	28 (70.0)	35 (92.1)	30 (78.9)	0.048	<0.001	0.008
Age
<55	24 (58.5)	0.049	6 (46.2)	6 (66.7)	9 (90.0)	3 (33.3)	0.349	0.002	0.005
≥55	84 (78.5)		9 (47.4)	22 (71.0)	26 (92.9)	27 (93.1)
Sex
Male	85 (75.2)	0.677	13 (48.1)	20 (74.1)	26 (96.3)	26 (81.2)	0.258	0.002	0.056
Female	23 (65.7)		2 (40.0)	8 (61.5)	9 (81.8)	4 (66.7)
Cigarette smoking
No	54 (66.7)	0.344	6 (35.3)	17 (65.4)	18 (85.7)	13 (76.5)	0.211	0.001	0.043
Yes	54 (80.6)		9 (60.0)	11 (78.6)	17 (100.0)	17 (81.0)
Alcohol drinking
No	90 (57.3)	0.374	13 (50.0)	23 (67.6)	28 (93.3)	26 (81.2)	0.273	0.002	0.055
Yes	18 (73.8)		2 (33.3)	5 (83.3)	7 (87.5)	4 (66.7)
Tumor size
≥5 cm	37 (73.8)	0.472	10 (52.6)	17 (80.8)	10 (100.0)	-	0.264	0.001	0.042
<5 cm	28 (63.6)		4 (33.3)	10 (66.7)	11 (78.6)	3 (100.0)
Tumor site
Proximal	31 (91.6)	0.003	5 (55.6)	7 (60.0)	7 (100.0)	12 (100.0)	0.104	<0.001	0.001
Middle	33 (57.9)		4 (26.7)	13 (72.2)	9 (90.0)	7 (90.0)
Pyloric	34 (80.9)		3 (60)	8 (66.7)	14 (90.0)	9 (50.0)
Histological subtype
Adenocarcinoma	90 (74.4)	0.254	9 (42.9)	25 (73.5)	31 (93.9)	25 (75.8)	0.071	0.001	0.44
Other types	13 (59.1)		4 (44.4)	3 (50.0)	3 (75.0)	3 (100.0)	0.071	0.001	0.44
Differentiation
High	5 (75.7)	0.773	1 (100.0)	1 (33.3)	1 (50.0)	2 (100.0)	0.264	0.001	0.042
Medium	36 (73.5)		4 (40.0)	12 (80.0)	13 (100.0)	7 (63.6)
Low	53 (62.5)		6 (42.9)	15 (75.0)	20 (95.2)	12 (80.0)
Borrmann's type
I	10 (76.9)	0.138	2 (50.0)	6 (100.0)	1 (50.0)	1 (100.0)	0.239	0.005	0.423
II	8 (50.0)		2 (33.3)	2 (40.0)	3 (100.0)	1 (50.0)
III	22 (61.1)		1 (16.7)	8 (53.3)	9 (100.0)	4 (66.7)
IV	49 (84.5)		10 (66.7)	12 (85.7)	22 (95.7)	5 (72.3)
cT stage
T1	— (—)	0.497	—	—	—	—	0.445	<0.001	0.141
T2	6 (54.5)		2 (50.0)	3 (60.0)	1 (100.0)	—
T3	20 (74.1)		3 (50.0)	3 (60.0)	5 (100.0)	9 (81.8)
T4	81 (76.4)		10 (46.5)	22 (75.9)	28 (96.6)	21 (78.9)
cN stage
N0	9 (47.4)	0.009	2 (22.2)	3 (60.0)	3 (100.0)	1 (76.6)	0.037	0.001	0.031
N+	89 (75.4)		12 (57.1)	24 (70.6)	30 (91.0)	23 (50.0)
Clinical stage
I+II	20 (51.3)	0.001	3 (25.0)	5 (50.0)	7 (87.5)	5 (55.6)	0.066	0.001	<0.001
III	87 (81.3)		12 (60.0)	23 (76.7)	27 (96.4)	25 (86.2)
Type of resection
Radical surgery	72 (69.8)	0.013	13 (43.3)	27 (69.2)	32 (91.4)	—	0.002	<0.001	—
Other types	6 (100.0)		2 (100.0)	1 (100.0)	3 (100.0)	—

Table 3.

Multivariate Analysis of Gastric Cancer Patients

Variables	Hazard ratio (95% confidence interval)	p
Treatment
PECT	1.000
POCT	2.409 (1.056–5.494)	0.037
Cigarette smoking
No	1.000
Yes	2.067 (1.022–4.180)	0.043
Tumor site
Proximal	1.000
Middle	0.835 (0.373–1.873)	0.662
Pyloric	1.142 (0.448–2.913)	0.781
Lymph node metastasis
N0	1.000
N+	4.946 (1.438–17.012)	0.037

Table 4.

The Overall Survival of Four Treatments of Gastric Cancer Patients

OS	PECT (%)	POCT (%)	Surgery (%)	CT (%)	p
1-Year	68.8	60.0	50.0	60.5	0.520
3-Year	55.1	30.5	11.8	18.8	0.015
5-Year	51.0	18.3	0	15.0	0.070
Total	53.2	30.0	7.9	21.1	0.001

OS, overall survival.

Discussion

This study directly compared the survival benefit of PECT with other treatments in GC patients and demonstrated that patients who received PECT plus gastrectomy had a higher 5-year OS rate than those who received surgery plus POCT (55.1% vs. 30.5%), surgery only (55.1% vs. 15.0%), or chemotherapy alone (55.1% vs. 0%). The results from this study are consistent with those of two previous investigations from Fazio et al.¹³ and Kano et al.,¹⁴ who showed that the survival rates of GC patients undergoing PECT were higher compared with patients undergoing POCT (44.1% vs. 29.4% and 80.0% vs. 58.7%, respectively).

The survival improvement observed with PECT might be related to tumor regression. Spoerl et al.¹⁵ assessed the tumor response to PECT and confirmed that pathological regression identified on PECT is an important prognostic marker for survival in stomach cancer. In that study, TRG1a (defined as no residual cancer found on histological examination of the specimen) was achieved in 8.8% of patients treated with PECT, and TRG1b (subtotal regression, <10% residual tumor) was achieved in 27.3% of patients treated with PECT. These patients had a more favorable prognosis (3-year survival rates: 82.8% and 71.3%, respectively) when regression was accompanied by a decrease in maximum infiltrative depth, referred to as tumor shrinkage. More importantly, in the remaining 63.9% of patients whose tumors did not recede, the survival rates were lower, although still above 37.9%. Therefore, patients who had a complete or partial response had significantly better OS than nonresponding patients or the immediate surgery group.^16

–19

The reasons for tumor shrinkage after PECT are manifold. First, PECT is generally better tolerated than POCT. Therefore, patients are most likely to receive sufficient treatment dosage and have the highest probability of receiving multimodal treatment if the treatment starts before surgery. This is also true for primarily resectable cancer.²⁰ Second, tumor resection can induce the production of tumor cell growth-stimulating factors, which make tumor cells grow rapidly and be less responsive to antichemotherapy agents.²¹ Accordingly, noncurative reduction of the tumor increases proliferation of the residual tumor. This can be prevented by administering PECT instead of POCT.²² Last, many patients with advanced cancer may theoretically undergo complete tumor resection, and PECT may allow for safer surgical intervention.²³ However, if the tumor spread is extensive and/or the general condition of the patient is poor, the risk of preoperative mortality may outweigh any potential benefits. Furthermore, postsurgical complications usually result in the delay of postoperative therapy, which negatively impacts treatment outcomes.

PECT may be conducted on the basis of different treatment modalities. Because there are fewer tumor cells in patients with early stage disease, the proliferation rate is high and doubling time is relatively short. In contrast, more advanced tumor cells with a low proliferation rate will have a prolonged doubling time and a decreased sensitivity to chemotherapeutic drugs.²⁴ Therefore, using a drug that does not target the cell cycle can reduce the tumor volume and improve the proliferation rate, thereby increasing the sensitivity to cell cycle-specific chemotherapeutic drugs.²⁵ Recently, many new drugs, including SOX and XELOX, have been administered as PECT. Xue et al. suggested that there was no significant difference in survival in patients receiving SOX and XELOX (5-year survival rates: 78% and 66%, respectively). According to Samaratunga et al.,²⁶ the SOX regimen induced a relatively high number of pathologically complete responses without increasing morbidity and mortality. This study showed that, in patients receiving SOX or XELOX, the 5-year survival rate of patients receiving PECT was 32.7% higher compared with patients receiving POCT. Therefore, it is not surprising that the SOX regimen is considered to be one of the most effective chemotherapy treatments for GC, particularly in China and Japan^27

–30 (it is not available in most other countries). However, it is still controversial whether PECT based on SOX or XELOX is more advantageous than POCT.

In addition, curative resection with D2 lymphadenectomy is recommended for advanced GC, according to the Japanese,³¹ Korean,³² British,³² German,³³ and Italian guidelines.³⁴ In this study, because of the large number of patients with advanced GC having lymph node metastases, D2 lymphadenectomies were performed in more than 90% of cases. Therefore, there was no difference in the extent of lymph node dissection between the PECT and POCT groups. However, the benefits of PECT on lymph node dissection were assessed by a group from the European Institute of Oncology in Milan.³⁵ Their study indicated that the median number of metastatic lymph nodes (1 vs. 5) and the median number of excised lymph nodes (20 vs. 26) were lower in patients who received PECT than in patients who received POCT. The investigation by Chao et al.³⁶ concluded that extensive lymph node dissection after preoperative therapy confers a strong survival benefit. PECT has also been confirmed to eliminate micrometastases and improve the success rate of surgery.³⁷ Therefore, it is reasonable to assume that patients receiving PECT have fewer metastatic lymph nodes. These benefits were reflected in their study (5-year OS rate of PECT vs. POCT: 55.1% vs. 30.5%).

However, this study has some limitations. It is a retrospective study, and only early outcomes were observed. That the OS of the PECT group was longer compared with the other treatment groups may not necessarily be because the mortality was higher in the other groups. The results also depend on the quality of data collection. Furthermore, there were only 38 patients in the PECT group, and the effect of PECT still needs to be verified in a larger study. Additionally, evaluation of PECT efficacy was hampered by patient withdrawal during the treatment process, mainly due to transfer to another hospital or no longer receiving the same therapy. Despite controlling for many important factors that can influence long-term survival and cancer recurrence, there are inevitably other confounding variables that were not studied. Nonetheless, this study highlights the important finding that PECT has survival advantages over other therapies in patients with stage IB to III GC.

Conclusion

In summary, these data from a high GC incidence area of China showed that PECT with D2 gastrectomy had a better outcome than the surgery-first approach for patients with cStage IB to III GC. Therefore, PECT should be considered by clinicians in GC treatment, and SOX regimen should be considered preferentially for the preoperative treatment, although more prospective studies are needed for confirmation.

Footnotes

Acknowledgments

The authors thank Wiley for the linguistic assistance during the preparation of this article. They thank all of the participants of this study.

Authors' Contributions

Guarantor of integrity of the entire study: W.Y. and Z.C. Study concepts and design: Q.Z., Qinghua Z., J.C., W.W., D.Z., X.Z., J.W., and W.Y. Literature research: Qinghua Z., H.Y., and Y.Y. Clinical studies: N/A. Experimental studies/data analysis: N/A. Statistical analysis: Q.Z. and J.C. Article preparation: Q.Z., W.Y., and Z.C. Article editing: Q.Z., W.Y., and Z.C.

Disclosure Statement

No competing financial interests exist.

Funding Information

W.Y. was supported by grants from National Natural Science Foundation of China [Grant Nos. NSFC 81760525, 81160249, and 81860426].

References

Bray

, Ferlay

, Soerjomataram

, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018; 68:394.

Allemani

, Matsuda

, Di Carlo

, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): Analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet, 2018; 391:1023.

Van Cutsem

, Sagaert

, Topal

, et al. Gastric cancer. Lancet, 2016; 388:2654.

Leung

, Wu

, Kakugawa

, et al. Screening for gastric cancer in Asia: Current evidence and practice. Lancet Oncol, 2008; 9:279.

Rubens

, Sexton

, Tong

, et al. Combined chemotherapy and radiotherapy for locally advanced breast cancer. Eur J Cancer, 1980; 16:351.

Wilke

, Preusser

, Fink

, et al. Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: A phase II study with etoposide, doxorubicin, and cisplatin. J Clin Oncol, 1989; 7:1318.

Cunningham

, Allum

, Stenning

, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med, 2006; 355:11.

, Shi

, Liu

, et al. [A clinical study of paclitaxel combined with FOLFOX4 regimen as neoadjuvant chemotherapy for advanced gastric cancer]. Zhonghua Wei Chang Wai Ke Za Zhi, 2010; 13:664.

Gianni

, Panzini

, Tassinari

, et al. Meta-analyses of randomized trials of adjuvant chemotherapy in gastric cancer. Ann Oncol, 2001; 12:1178.

10.

Schuhmacher

, Fink

, Becker

, et al. Neoadjuvant therapy for patients with locally advanced gastric carcinoma with etoposide, doxorubicin, and cisplatinum. Closing results after 5 years of follow-up. Cancer, 2001; 91:918.

11.

Mirza

, Pritchard

, Welch

. The postoperative component of MAGIC chemotherapy is associated with improved prognosis following surgical resection in gastric and gastrooesophageal junction adenocarcinomas. Int J Surg Oncol, 2013; 2013:781742.

12.

Zhengzheng

, Donggeng

, Jianhua

, et al. Analysis of mortality trend of digestive system malignant tumors in Ningxia region. Shanghai Med J, 2007:1:61. [In Chinese].

13.

Fazio

, Biffi

, Maibach

, et al. Preoperative versus postoperative docetaxel-cisplatin-fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial. Ann Oncol, 2016; 27:668.

14.

Kano

, Hayano

, Hayashi

, et al. Survival Benefit of Neoadjuvant Chemotherapy with S-1 Plus Docetaxel for Locally Advanced Gastric Cancer: A Propensity Score-Matched Analysis. Ann Surg Oncol, 2019; 26:1805.

15.

Spoerl

, Novotny

, Al-Batran

, et al. Histopathological regression predicts treatment outcome in locally advanced esophagogastric adenocarcinoma. Eur J Cancer, 2018; 90:26.

16.

Kelsen

, Winter

, Gunderson

, et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): A random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol, 2007; 25:3719.

17.

Law

, Fok

, Chow

, et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: A prospective randomized trial. J Thorac Cardiovasc Surg, 1997; 114:210.

18.

Roth

, Pass

, Flanagan

, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg, 1988; 96:242.

19.

Schlag

. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Arch Surg, 1992; 127:1446.

20.

Heinrich

, Lang

. Neoadjuvant therapy of pancreatic cancer: Definitions and benefits. Int J Mol Sci, 2017; 18.

21.

Chen

, Guo

, Shi

, et al. Efficacy of adjuvant chemotherapy combined with immunotherapy with cytokine-induced killer cells for gastric cancer after d2 gastrectomy. Int J Clin Exp Med, 2015; 8:7728.

22.

Fisher

, Gunduz

, Saffer

. Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res, 1983; 43:1488.

23.

Leary

, Cowan

, Chi

, et al. Primary surgery or neoadjuvant chemotherapy in advanced ovarian cancer: The Debate Continues…. Am Soc Clin Oncol Educ Book, 2016; 35:153.

24.

Song

, Wu

, Yang

, et al. Progress in the treatment of advanced gastric cancer. Tumour Biol, 2017; 39:1010428317714626.

25.

Neves

, de Sant'Ana

, Nunes

, et al. Histopathological regression of gastric adenocarcinoma after neoadjuvant therapy: A critical review. APMIS, 2017; 125:79.

26.

Samaratunga

, Samaratunga

, Dunglison

, et al. Alpha-fetoprotein-producing carcinoma of the renal pelvis exhibiting hepatoid and urothelial differentiation. Anticancer Res, 2012; 32:4987.

27.

Zhong

, Wu

, Wang

, et al. Combination chemotherapy with S-1 and oxaliplatin (SOX) as first-line treatment in elderly patients with advanced gastric cancer. Pathol Oncol Res, 2015; 21:867.

28.

Liu

, Tang

, Li

, et al. S-1-based combination therapy vs S-1 monotherapy in advanced gastric cancer: A meta-analysis. World J Gastroenterol, 2014; 20:310.

29.

Shi

, Chen

, Shen

, et al. Paclitaxel combined with oxaliplatin as first-line chemotherapy for locally advanced or metastatic gastric cancer. Expert Rev Anticancer Ther, 2015; 15:595.

30.

Yang

, Yang

, Qin

, et al. Evaluation of the optimal dosage of S-1 in adjuvant SOX chemotherapy for gastric cancer. Oncol Lett, 2015; 9:1451.

31.

Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer, 2017; 20:1.

32.

Lee

, Kim

, Jung

, et al. Clinical practice guidelines for gastric cancer in Korea: An evidence-based approach. J Gastric Cancer, 2014; 14:87.

33.

Meyer

, Holscher

, Lordick

, et al. [Current S3 guidelines on surgical treatment of gastric carcinoma]. Chirurg, 2012; 83:31.

34.

De Manzoni

, Marrelli

, Baiocchi

, et al. The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015. Gastric Cancer, 2017; 20:20.

35.

Biffi

, Fazio

, Luca

, et al. Surgical outcome after docetaxel-based neoadjuvant chemotherapy in locally-advanced gastric cancer. World J Gastroenterol, 2010; 16:868.

36.

Chao

, Liu

, Hsieh

, et al. Lymph node dissection after chemoradiation in esophageal cancer: A subgroup analysis of patients with and without pathological response. Ann Surg Oncol, 2012; 19:3500.

37.

Matsuda

, Takahashi

, Fukada

, et al. Phase I study of neoadjuvant chemoradiotherapy with S-1 plus biweekly cisplatin for advanced gastric cancer patients with lymph node metastasis: -KOGC04-. Radiat Oncol, 2014; 9:9.