Efficacy and safety of XELOX combined with neoadjuvant radiotherapy verus neoadjuvant chemotherapy in locally advanced gastric cancer

doi:10.21203/rs.3.rs-3212052/v1

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Research Article

Efficacy and safety of XELOX combined with neoadjuvant radiotherapy verus neoadjuvant chemotherapy in locally advanced gastric cancer

https://doi.org/10.21203/rs.3.rs-3212052/v1

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Objective

The work aimed to compare the efficacy and safety of XELOX regimen combined with neoadjuvant radiotherapy (CRT) and neoadjuvant chemotherapy (CT) in locally advanced gastric cancer.

Methods

The clinical data of patients with locally advanced gastric cancer were retrospectively included. They underwent radical gastrectomy with D2 lymph node dissection in our center from January 2019 to December 2020. We compared the postoperative pathology, adverse reactions and DFS and OS after XELOX regimen combined with CRT and RT. Inverse probability weighting was used as the statistical method to deal with confounding factors.

Results

369 people (90.2%) were included in the CT group and 40 people (9.8%) were in the CRT group. The negative conversion rate was 38.1% in tumor marker CEA-positive patients in the CRT group after neoadjuvant therapy. It was significantly higher than 11.8% of the CT group (P < 0.001). The rate of PCR in the RT group was 15.8%, which was significantly higher than that of the CT group (4.7%) (P = 0.017). The ypN0 rate was significantly higher the CRT group (60.3%) than that in the CT group (39.8%) (P = 0.024). The CRT group was 100%, and the CT group was 96.5% (P = 0.001) after the R0 resection rate was weighted by inverse probability. No statistically significant difference existed in nerve invasion, vascular tumor embolus, and peritoneal invasion between the two groups. The median follow-up time of the whole group was 25.1 months. The DFS and OS of the CRT group were significantly higher than those of the CT group (P < 0.001) after weighting by IPTW. No significant difference existed between the CRT group and the CT group in adverse reactions, postoperative complications and average hospitalization time.

Conclusion

XELOX regimen combined with CRT had good downstaging effects. It showed better short-term pathological curative effects and survival benefits after surgery compared with CT. The surgical safety was equivalent between the two groups.

Locally advanced gastric cancer

neoadjuvant chemoradiotherapy

perioperative chemotherapy

short-term efficacy

Gastric cancer (GA) is one of the most common malignant tumors in China. 70.8% of the patients were at the locally advanced stage when first diagnosed [1–3]. The MAGIC [4] and FLOT4-AIO studies [5] confirm that preoperative neoadjuvant chemotherapy has significant downstaging effects for locally advanced gastric cancer. An R0 resection rate of 85% resulted in improved survival outcomes. The CROSS study [6] shows that preoperative chemoradiation (CRT) for cancer of the esophagus and esophagogastric junction achieves a pathological complete response rate (PCR) of 29%. It is translated into survival benefits.

Several international phase-II clinical trials [7–9] have shown that the rate of PCR of GA patients is higher after receiving preoperative CRT. However, it is still inclusive whether perioperative CT plus concurrent radiotherapy improves the curative effects of patients with locally advanced GA. The work compared the efficacy and safety of XELOX regimen combined with concurrent radiotherapy and perioperative chemotherapy in patients with resectable GA. The evidence strength was low as retrospective studies were susceptible to factors of bias. We adopted propensity score matching and inverse probability weighting for analysis. Consequently, the bias was reduced between the two groups, and the statistical power was improved to provide a basis for clinical selection.

Research objects and data collection

All data came from patients with newly diagnosed advanced gastric cancer or esophagogastric junction adenocarcinoma. They were diagnosed with pathology in our center from January 2019 to December 2020. Inclusion criteria: 1) Patients with clinical stage III gastric adenocarcinoma confirmed by MDT consultation (the 8th edition of the American Joint Committee on Cancer (AJCC)). The same was for those with esophagogastric junction adenocarcinoma. 2) Patients without serious medical complications and tumors of poor prognosis while with neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy. Their ECOG score ≤ 2. 3) All patients received radical gastrectomy with D2 lymph node dissection. 4) No history of other concurrent malignancies and chemoradiotherapy.

Exclusion criteria: 1) Patients receiving palliative surgery. 2) Patients with double primary malignant tumors. Grouping: Cases were screened according to inclusion and exclusion criteria and divided into the neoadjuvant chemotherapy group (CT group) and neoadjuvant chemoradiotherapy group (CRT group). The clinical and pathological characteristics of all patients were recorded in detail in the surgical and medical records (e.g., age, sex, stage, tumor location, CEA, CA199, CA724 before and after neoadjuvant therapy, postoperative pathology, and length of hospital stay).

Radiotherapy technology and target area delineation

The radiotherapy treatment was intensity-modulated radiation therapy (IMRT) or volume-modulated arc therapy (VMAT) implemented by a 6MV linear accelerator. All patients received radiation doses of 39.6–50.4 Gy/1.8-2.0 Gy/22–28 times/5–6 weeks. The clinical target volume (CTV) included tumor and regional lymph node drainage/metastasis areas determined by enhanced CT, PET/CT, or endoscopic ultrasonography. The delineation was from the expert consensus of ASTRO [10] and EORTC-ROG [11].

CTV delineation of the primary tumor included at least 3 cm of mucosa proximal to the tumor. Regional lymph-node CTV selectively included perigastric, abdominal cavity, splenic hilum and artery, hepatic duodenum or hepatic hilar, and some retropancreatic and para-aortic lymph nodes according to the lesion location. The planning target volume (PTV) was 0.5 cm outside the CTV and optimized to ensure the PTV with the prescribed dose exceeded 95%. The average dose per kidney was < 18 Gy, and that to the liver was < 25 Gy. Small bowel volume ≤ 195 cm3 receiving > 45 Gy, and maximal spinal cord dose ≤ 45 Gy. The radiotherapy plan was decided by two clinicians with more than 10 years of experience in radiotherapy. The irradiation field, irradiation dose, and tumor imaging were reviewed before treatment. We had daily cone-beam CT (CBCT) position verification.

Chemotherapy regimen

All patients in the CT group received 2–6 cycles of neoadjuvant chemotherapy and 4–12 cycles of postoperative adjuvant chemotherapy. Chemotherapy regimen included single-drug S-1; oxaliplatin + capecitabine (XELOX), oxaliplatin + S-1 (SOX), paclitaxel + cisplatin (TP), oxaliplatin + fluorouracil (FOLFOX); docetaxel + oxaliplatin + S-1 (DOS), docetaxel + oxaliplatin + fluorouracil (FLOT). 1–2 cycles of concurrent XELOX chemotherapy were given during radiotherapy, and 2–6 cycles of adjuvant chemotherapy were offered with the same program after surgery in the CRT group.

Follow-up and short-term efficacy evaluation

All patients were followed up from the date of diagnosis until death. Follow-up was performed every 3 months for the first 2 years, then every 6 months until 5 years, and annually thereafter. It was conducted through outpatient follow-up or telephone follow-up. Repeated examinations included a complete taking of medical history, physical examination, serum tumor biomarkers, CT scans from neck to pelvic, and intermittent endoscopy. Local recurrence was defined as recurrence in the anastomotic stoma, duodenal stump, tumor bed, residual stomach, and lymph nodes in the abdominal cavity. Distant metastasis was defined as metastasis of distant lymph nodes, distant organs, or sites outside the abdominal cavity. Peritoneal metastases were excluded [12].

OS was defined from the start of treatment to death from any cause. Short-term curative effect observation indicators included changes in tumor markers before and after surgery, TRG grade, rate of pN0, nerve invasion, vascular tumor embolus, peritoneal invasion, and surgical margin. Long-term curative effect observation indicators included overall survival (OS) and disease-free survival (DFS). The safety evaluation included hematological toxicity of chemoradiotherapy, gastrointestinal reactions, postoperative complications, and length of hospital stay.

Statistical methods

All statistical analysis was performed using R language software (version 4.2.2). Continuous variables conforming to a normal distribution were expressed as mean ± standard deviation. Continuous variables not normally distributed were represented by median and quartile M (P 25, P 75). Significant differences between groups were tested with Mann-Whitney U, and the χ2 test was used for categorical variables.

The work adopted propensity score matching (PSM) and inverse probability weighting (IPTW) to reduce the potential bias between the two groups. The influence of confounding factors was balanced to baseline data on the prognostic comparison. Propensity values were calculated by a multivariate logistic regression model. Included independent variables contained potential confounding factors affecting survival outcomes (e.g., "gender", "age", "T stage", "N stage", "primary tumor site", and "CEA, CA199, and CA724 before the treatment").

Standardized mean difference (SMD) was used to evaluate the balance of confounding variables weighted by the inverse probability of samples of the two groups. SMD ≤ 10 and 20% were considered to be ideally balanced and within an acceptable range, respectively. Statistical analysis was performed using the weighted chi-square test or weighted rank sum test for inter-group comparisons of surgical outcomes after inverse probability weighting. It was supported by the survey package of the R language. The Kaplan-Meier survival curve was drawn using the survminer package, and the test method was the log-rank test. Two-sided P < 0.05 was considered the difference was statistically significant.

Clinical features and treatment

We collected cases of 3,976 patients with esophagogastric junction adenocarcinoma and gastric adenocarcinoma diagnosed by MDT. Patients with distant metastases, recurrences, and those lost to follow-up were excluded. We made 1211 cases undergo radical or palliative (bleeding, obstruction) gastrectomy. Preoperative neoadjuvant therapy was used to treat 409 cases among them, and they were analyzed. CT was applied in 369 (90.2%), and CRT was in 40 (9.8%) in the entire cohort. Four patients in the CRT group received radiotherapy doses of less than 40 Gy, and the rest received radiotherapy doses of more than 40 Gy. Six cases (15%) received one cycle of the XELOX regimen concurrently with chemotherapy, and the rest completed two cycles of the XELOX regimen concurrently.

We made 187 cases (50.7%) for the SOX scheme and 71 cases (19.2%) for the FLOT scheme in the CT group. Fifty-two cases (14.1%) adopted the FOLFOX regimen, and 32 cases (8.7%) adopted the XELOX regimen. Nineteen cases (5.1%) adopted the DOS regimen, six cases (1.6%) adopted the TP regimen, and two cases (0.6%) adopted single drug S-1. The median follow-up time was 25.1 months. Baseline covariates (gender, age, T stage, N stage, tumor location, and tumor markers) were controlled for confounding by PSM and IPTW, respectively. The SMD values decreased to less than 0.2, and the balance between groups was improved after IPTW compared with PSM. Therefore, the research results refer to the IPTW method (Fig. 1). Table 1 shows the comparison of the raw data of 409 patients with gastric cancer receiving neoadjuvant therapy and the baseline status after IPTW.

Changes in tumor markers after neoadjuvant therapy

The negative rate of tumor marker CEA-positive patients was 38.1% in the CRT group after neoadjuvant chemoradiotherapy. It was higher than 11.8% of the CT group, and the difference was statistically significant (P < 0.001). No significant difference existed in the changes of tumor markers CA199 and CA724 before and after neoadjuvant therapy between the two groups (Table 2 Comparison of the short-term efficacy of gastric cancer patients after neoadjuvant therapy before and after inverse probability weighting).

Table 1

Comparison of the raw data of patients and the baseline status after IPTW.
	IPTW before			IPTW after
	CRT (n = 40)	CT (n = 369)	P-value	CRT (n = 388.2)	CT (n = 408.6)	P-value
Gender, n(%)			0.199			0.721
Male	28 (70.0%)	291(78.9%)		292.0 (75.2%)	317.7 (77.8%)
Female	12 (30.0%)	78 (21.1%)		96.2 (24.8%)	90.9 (22.2%)
Age (SD)	59.62(8.63)	61.20(8.85)	0.286	61.44 (9.12)	61.04 (8.93)	0.818
Site, n(%)			0.115			0.849
EGJ	13 (32.5%)	168 (45.5%)		179.4(46.2%)	181.5(44.4%)
GA	27 (67.5%)	201 (54.5%)		208.8 (53.8%)	227.1 (55.6%)
T Stage, n(%)			0.024			0.636
T2	0 (0.0%)	5 (1.4%)		0.0 (0.0%)	5.0 (1.2%)
T3	17(42.5%)	142(38.5%)		162.0 (41.7%)	159.5 (39.0%)
T4a	16(40.0%)	201(54.5%)		200.1 (51.6%)	216.9 (53.1%)
T4b	7 (17.5%)	21 (5.7%)		26.0 (6.7%)	27.2 (6.7%)
N Stage, n (%)			0.911			0.939
N0	1 (2.5%)	13 (3.5%)		10.3 (2.7%)	14.0(3.4%)
N1	38(95.0%)	344(93.2%)		368.3 (94.9%)	381.6(93.4%)
Nx	1 (2.5%)	12 (3.3%)		9.6 (2.5%)	13.0 (3.2%)
CEA [IQR]	4.96 [2.24,7.07]	3.24 [1.85,6.66]	0.177	3.93 [2.20,6.59]	3.23 [1.82,6.52]	0.224
CA199 [IQR]	11.66 [2.99,32.68]	11.64 [5.74,32.67]	0.564	11.93 [2.99,30.13]	11.65 [5.72,32.76]	0.625
CA724 [IQR]	2.38 [1.28,7.95]	2.63 [1.30,7.01]	0.914	2.02 [1.11,5.11]	2.63 [1.29,7.05]	0.343

Table 2

Comparison of short-term efficacy in patients receiving neoadjuvant therapy for GC before and after IPTW.
	IPTW before			IPTW after
	CT (n = 369)	CRT (n = 40)	P-Value	CT (n = 408.6)	CRT (n = 388.2)	P-Value
ypT, n(%)			0.001			0.031
T0	17(4.6%)	5(12.5%)		19.4(4.7%)	61.5 (15.8%)
T1	32(8.7%)	9(22.5%)		35.8(8.8%)	76.4 (19.7%)
T2	116(31.4%)	6(15.0%)		127.7(31.2%)	59.9 (15.4%)
T3	125(33.9%)	17 (42.5%)		137.4(33.6%)	154.0(39.7%)
T4	79 (21.4%)	3 (7.5%)		88.4 (21.6%)	36.4 (9.4%)
ypN, n (%)			0.079			0.06
N0	146(39.6%)	23(57.5%)		162.7(39.8%)	234.2(60.3%)
N1	76 (20.6%)	5 (12.5%)		83.4 (20.4%)	41.0(10.6%)
N2	83 (22.5%)	4 (10.0%)		91.1 (22.3%)	36.5 (9.4%)
N3	64 (17.3%)	8 (20.0%)		71.4 (17.5%)	76.6(19.7%)
TRG, n (%)			＜0.001			0.003
N0	17 (4.6%)	5 (12.5%)		19.4 (4.7%)	61.5 (15.8%)
N1	72 (19.5%)	18(45.0%)		80.2 (19.6%)	172.6(44.5%)
N2	186(50.4%)	13(32.5%)		206.1(50.4%)	109.5(28.2%)
N3	94 (25.5%)	4 (10.0%)		103.0(25.2%)	44.6 (11.5%)
Margin, n (%)			0.228			0.001
Negative	356(96.5%)	40(100.0%)		394.4(96.5%)	388.2(100.0%)
Positive	13(3.5%)	0 (0.0%)		14.2 (3.5%)	0.0 (0.0%)
PNI, n (%)			0.089			0.234
Negative	197(53.4%)	27(67.5%)		219.2(53.6%)	251.6(64.8%)
Positive	172(46.6%)	13(32.5%)		189.4(46.4%)	136.5(35.2%)
LVI, n (%)			0.018			0.066
Negative	186(50.4%)	28(70.0%)		207.1(50.7%)	264.8(68.2%)
Positive	183(49.6%)	12(30.0%)		201.5(49.3%)	123.4(31.8%)
PTI, n (%)			0.101			0.103
Negative	359(97.3%)	37(92.5%)		397.6(97.3%)	358.4(92.3%)
Positive	10(2.7%)	3(7.5%)		11.1 (2.7%)	29.7(7.7%)
Mean LN Removed, [IQR]	24.00 [19.00,31.00]	17.00 [16.00,19.25]	＜0.001	24.00 [19.00, 31.00]	17.00 [16.00,20.00]	＜0.001
CEA^*, [n, %]	43 (11.7%)	17 (42.5%)	＜0.001	48.1 (11.8)	148.0 (38.1)	＜0.001
CA199^*, [n, %]	46 (12.5%)	7 (17.5%)	0.368	52.1 (12.7)	51.0 (13.1)	0.95
CA724^*, [n, %]	44 (11.9%)	5 (12.5%)	0.915	48.5 (11.9)	46.5 (12.0)	0.984
Perineural invasion(PNI); lymphovascular invasion(LVI); Peritoneal invasion(PTI); ^*Negative conversion rate of CEA、CA199 or CA724 seropositive patients

Short-term curative effects

R0 resection rate was processed by inverse probability weighting. The rate was 100% in the CRT group and 96.5% in the CT group, and the difference was statistically significant (P = 0.001). The average number of lymph node dissection was 24 in the CT group, which was significantly higher than that in the CRT group (17). The difference was statistically significant (P < 0.001). Both groups in the propensity score-matching cohort had similar preoperative clinical stages. However, patients receiving CRT had significantly lower final pathological stages. Additionally, patients accounted for 35.5% of the CRT group at the postoperative pathological stages of ypT0 and T1. It was significantly better than that in the CT group (13.5%), and the difference was statistically significant (P = 0.031).

The ypN0 rate was 60.3% in the CRT group and 39.8% in the CT group, and the difference was statistically significant (P = 0.024). The pathological response was better in the CRT group, and the patients with TRG0 and 1 accounted for 60.3%. It was significantly higher than that in the CT group (24.3%), and the difference was statistically significant (P = 0.003). The overall rate of PCR in the CRT group was 15.8%, which was significantly higher than that in the CT group (4.7%). The difference was statistically significant (P = 0.017). No significant differences existed in nerve invasion, vascular tumor embolus, and peritoneal invasion between the two groups. Table 2 shows the comparison of the short-term curative effects of gastric cancer patients in the two groups receiving neoadjuvant therapy before and after inverse probability weighting.

4. Survival analysis: The median follow-up time was 25.1 months in the whole group. We found that the DFS of patients in the CRT group was significantly higher (P < 0.001; Fig. 2A) after adopting the IPTW method. Besides, the OS of patients in the CRT group was also significantly higher than that in the CT group after 2 years (P < 0.001; Fig. 2B). Figure 2 shows a survival comparison of gastric cancer patients receiving neoadjuvant therapy after inverse probability weighting.

Adverse reactions and surgery-related complications

Adverse reactions were similar between the two groups after IPTW matching (e.g., myelosuppression, nausea, vomiting, esophagitis, and diarrhea), and no statistical difference existed. All patients in the group were followed up. One patient died in the CT group and 0 in the CRT group. There were 9 cases of pneumonia, 3 cases of obstruction, 7 cases of fistula, 14 cases of pleural effusion, and 1 case of abdominal infection in the CT group. Two cases of anastomotic leakage and 2 cases of pleural and peritoneal effusion existed in the CRT group.

The incidence of postoperative pneumonia was higher in the CT group than that in the CRT group, and the difference was statistically significant (P = 0.004). The average postoperative hospital stay was 13 days in the CRT group and 12 days in the CT group. No statistical difference existed between the two groups (P = 0.274). Table 3 shows the comparison of adverse reactions and postoperative complications in the two groups of gastric cancer patients receiving neoadjuvant therapy before and after inverse probability weighting.

Surgery is currently the only possible cure for gastric cancer. The prognosis of patients undergoing surgical resection is better than that of unresectable patients even in locally advanced gastric cancer. The resection rate of gastric cancer is significantly related to the survival of patients. Three ways can increase the surgical resection rate of gastric cancer: 1. The rate of early diagnosis is increased. 2. The technical level of surgeons is improved. 3. Certain measures are used to reduce the size of locally advanced lesions. We can change the unresectable to resectable, and the unresectable to curable, and finally improve the curative effects. Neoadjuvant therapy plays a key role in the latter.

Table 3

Details of complications in the samples before matching and after IPTW in the two groups.
	IPTW before			IPTW after
	CT (n = 369)	CRT (n = 40)	P-Value	CT (n = 40)	CRT (n = 40)	P-Value
Myelosuppression (n, %)			< 0.001			< 0.001
0	179 (48.5)	3 ( 7.5)		197.7 (48.4)	24.4 ( 6.3)
1	101 (27.4)	22 ( 55.0)		111.2 (27.2)	201.5 ( 51.9)
2	61 (16.5)	14 ( 35.0)		68.0 (16.6)	149.9 ( 38.6)
3	24 ( 6.5)	1 ( 2.5)		27.3 ( 6.7)	12.4 ( 3.2)
4	4 ( 1.1)	0 ( 0.0)		4.5 ( 1.1)	0.0 ( 0.0)
Nausea (n, %)	36 ( 9.8)	5 ( 12.5)	0.583	40.0 ( 9.8)	39.0 ( 10.1)	0.957
Vomit (n, %)	30 ( 8.1)	4 ( 10.0)	0.684	33.2 ( 8.1)	33.5 ( 8.6)	0.918
Esophagitis (n, %)	7 ( 1.9)	3 ( 7.5)	0.029	8.3 ( 2.0)	26.6 ( 6.8)	0.072
Diarrhea (n, %)	48 (13.0)	6 ( 15.0)	0.724	53.7 (13.1)	74.0 ( 19.1)	0.401
Postoperative complications
Pneumonia (n, %)	9 ( 2.4)	0 ( 0.0)	0.318	9.9 ( 2.4)	0.0 ( 0.0)	0.004
Obstruction (n, %)	3 ( 0.8)	0 ( 0.0)	0.567	3.3 ( 0.8)	0.0 ( 0.0)	0.095
Leak (n, %)	7 ( 1.9)	2 ( 5.0)	0.204	7.6 ( 1.8)	30.8 ( 7.9)	0.077
Effusion (n, %)	14 ( 3.8)	2 ( 5.0)	0.709	15.4 ( 3.8)	19.9 ( 5.1)	0.703
Celiac infection (n, %)	2 ( 0.5)	0 ( 0.0)	0.641	2.2 ( 0.5)	0.0 ( 0.0)	0.171
Death (n, %)	1 ( 0.3)	0 ( 0.0)	0.742	1.0 ( 0.3)	0.0 ( 0.0)	0.332

The role of preoperative CRT and CT is to reduce the primary tumor volume to improve the R0 resection rate. They are for reducing the spread of tumor cells upon surgical resection to lower the rate of subsequent local recurrence. Meanwhile, neoadjuvant chemotherapy can control micro-metastases and screen out patients with early postoperative recurrence for high invasiveness during neoadjuvant therapy. Surgical survival benefits are minimal in these patients. Some patients with esophagogastric junction adenocarcinoma were collected in the surgery study after chemoradiotherapy for esophageal cancer (CROSS trial [6]). The pCR rate is 23% and the R0 resection rate is 92%. It shows the benefit of preoperative CRT on overall survival in patients with esophagogastric junction adenocarcinoma.

A phase-III clinical study conducted by Germany's Stahl [13] compared the efficacy and adverse reactions of preoperative chemoradiotherapy and preoperative chemotherapy. It is in patients with cT3-4NanyM0 esophagogastric junction adenocarcinoma. The study plans to enroll 354 cases, and 126 cases are finally included for the slow enrolment. Preoperative chemoradiotherapy tends to prolong the survival of patients with locally advanced esophagogastric junction adenocarcinoma. Besides, neither group of patients receives adjuvant chemotherapy after surgery. Therefore, it is still inconclusive if perioperative chemoradiotherapy improves the curative effects of patients with locally advanced gastric cancer. No large randomized controlled study exists on preoperative CRT for GA. Consequently, we used inverse probability weighting to process the results of the retrospective work after neoadjuvant CRT and neoadjuvant CT in patients with locally advanced GA.

The retrospective work in our center showed that patients with ypT0 and ypT1 receiving preoperative CRT accounted for 35.5% in the CRT group. It was significantly better than that in the CT group (13.5%). The overall rate of PCR was 15.8% in the CRT group, which was significantly higher than 4.7% in the CT group. This was consistent with the rate of PCR of 15.6% reported by Stahl et al. [13] for preoperative chemoradiotherapy for esophagogastric junction cancers. It was the same for the rate of PCR of 16% for gastric adenocarcinoma patients in a phase-II clinical study led by Maurel in Spain [14]. Nearly 60% of the cases included in the work were T4 patients. Retrospective studies by Martin et al.[15]showed that R0 resection was an independent prognostic factor for T4 patients.

Ikoma [16] found that both cN0 and ypN0 patients have better survival than N + patients. Therefore, the status of ypN0 obtained after neoadjuvant therapy is an important symbol reflecting the curative effects of preoperative treatment on gastric cancer. The R0 resection rate is 100% in the CRT group. Patients undergoing CRT have significantly less visible lymph node dissection intraoperatively than patients undergoing CT. The pN0 rate (60.3%) in the CRT group is significantly higher than that in the CT group (39.8%). Neoadjuvant CRT has better downstaging effects than CT. These factors may play an important role in reducing the local recurrence rates and affecting survival [16–18].

Some studies suggest that postoperative serum CEA and CA19-9 levels are independent prognostic factors for overall survival [19–21]. The reason for it is the possible residual micro-metastases after radical gastrectomy and total lymph node dissection [22, 23]. Suenaga et al. analyzed serum CEA and CA199 levels of GA patients in multiple medical institutions. Patients with normalized CEA levels postoperatively have a better prognosis than those with high postoperative CEA levels. However, the survival curve of the population with normalized CA 19 − 9 levels after surgery is almost the same as that of patients with normal CA19-9 levels before and after surgery [24].

The normalization rate of CEA after neoadjuvant therapy was significantly higher in the CRT group than that in the CT group in the work. It further supported that the CRT group had a better prognosis. The follow-up time was insufficient, and the median survival time had not yet been reached in the two groups. However, the DFS and OS of the CRT group were significantly better than those of the CT group after IPTW weighting. Statistical differences existed and had a certain correlation with the good pathological response of the CRT group.

We found no statistically significant differences in surgical complications and surgery-related mortality between patients receiving CRT and those receiving CT considering surgery-related adverse reactions. Postoperative hospital stay was not significantly longer in the CRT group than that in the CT group. This was consistent with the results reported by Ikoma et al. [25] that preoperative chemoradiotherapy for gastric cancer does not increase postoperative anastomotic leakage rates or peritoneal effusion. Additionally, the safety of preoperative CRT was also confirmed in the TOPGEAR trial [26], a phase-III clinical study of gastric cancer.

The work was a retrospective study, and the analysis suffers from the following limitations. Good results were obtained in the current GA treatment in the MAGIC trial ^[4] and the FLOT4-AIO study [5]. The preoperative CRT was currently at the exploratory stage. Additionally, most surgeons worried that edema after radiotherapy increased the difficulties in surgery as well as postoperative complications. As a consequence, far more patients existed with neoadjuvant CT in conventional care than those with CRT. A large difference occurred in the number of cases of the two groups. PSM and IPTW were used to exert confounding control on baseline covariates (gender, age, patients undergoing CT far more than those of CRT, T stage, N stage, tumor location, and tumor markers) to admin confounding factors.

The SMD values decreased to less than 0.2 after IPTW compared with PSM, and the balance between groups was improved. Therefore, the research results referred to the IPTW method. It was used to correct the imbalance of the baseline data. Some confounding factors remained to affect the results. The whole group of patients with gastric cancer did not undergo diagnostic laparoscopy at the initial diagnosis. However, the coincidence was only 60%-70% between preoperative clinical staging and pathological staging [27–29].

We used the same MDT team combined with CT, PET-CT, and ultrasonography to conduct clinical staging on the baseline status in the two groups of patients. However, the bias of staging existed, which affected the selection of treatment decisions. Finally, we could not assess and grasp the physical and economic status of patients, the choice of chemotherapy regimens by doctors, and the completeness of the whole treatment in collecting retrospective data. All of these have affected the results. The work used single-center data, and IPTW could not replace prospective RCT. The comparison of curative effects of neoadjuvant therapy should be confirmed by RCT for gastric cancer.

In summary, neoadjuvant CRT for locally advanced GA had better short-term curative effects and survival benefits than perioperative CT in postoperative pathology. It was comparable to the CT group concerning the safety of treatment. The ongoing multicenter phase-III randomized controlled TOPGEAR and CRITICS-II trials were used to observe the curative effects and long-term survival of perioperative CT and CRT. The trials are expected to collectively provide valuable and high-quality data for determining optimal neoadjuvant therapy for gastric cancer.

CRT Neoadjuvant radiotherapy

CT Neoadjuvant chemotherapy

GA Gastric cancer

PCR Complete response rate

AJCC American Joint Committee on Cancer

IMRT Intensity-modulated radiation therapy

VMAT Volume-modulated arc therapy

CTV Clinical target volume

PTV Planning target volume

CBCT Daily cone-beam CT

XELOX Oxaliplatin + Capecitabine

SOX Oxaliplatin + S-1

TP Paclitaxel + Cisplatin

FOLFOX Oxaliplatin + Fluorouracil

DOS Docetaxel + Oxaliplatin + S-1

FLOT Docetaxel + Oxaliplatin + Fluorouracil

OS Overall survival

DFS Disease-free survival

PSM Propensity score matching

IPTW Inverse probability weighting

SMD Standardized mean difference

Acknowledgements

Not applicable.

Authors' contributions

XS W, N D and SS B designed this research. SS B, SY W and T W Collected the clinical data of patients, analyzed the data. SY W, N D and H G drew the figures and drafted this manuscript. ZD Z, XC T and C S helped check the manuscript and figures. All authors read and approved the final manuscript.

Funding

This work was supported by grants from Henan province science and technology research (202102310093).

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

We performed a retrospective review of data from patients at the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital under a study approved by the ethics committee of The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China, in accordance with the guidelines of the Declaration of Helsinki (S-K899). Informed consent was obtained from all patients.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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No competing interests reported.

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Efficacy and safety of XELOX combined with neoadjuvant radiotherapy verus neoadjuvant chemotherapy in locally advanced gastric cancer

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Abstract

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Methods

Results

Conclusion

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Introduction

Materials and methods

Research objects and data collection

Radiotherapy technology and target area delineation

Chemotherapy regimen

Follow-up and short-term efficacy evaluation

Statistical methods

Results

Clinical features and treatment

Changes in tumor markers after neoadjuvant therapy

Short-term curative effects

Adverse reactions and surgery-related complications

Discussion

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