Multidisciplinary treatment for locally advanced gastric cancer: A systematic review and network meta-analysis

Abstract

Introduction:

This study aimed to evaluate the efficacy of multidisciplinary treatment for patients with locally advanced gastric cancer (LAGC) who underwent radical gastrectomy.

Patients and Methods:

Randomised controlled trials (RCTs) comparing the effectiveness of surgery alone, adjuvant chemotherapy (CT), adjuvant radiotherapy (RT), adjuvant chemoradiotherapy (CRT), neoadjuvant CT, neoadjuvant RT, neoadjuvant CRT, perioperative CT and hyperthermic intraperitoneal chemotherapy (HIPEC) for LAGC were searched. Overall survival (OS), disease-free survival (DFS), recurrence and metastasis, long-term mortality, adverse events (grade ≥3), operative complications and R0 resection rate were used as outcome indicators for meta-analysis.

Results:

Forty-five RCTs with 10077 participants were finally analysed. Adjuvant CT had higher OS (hazard ratio [HR] = 0.74, 95% credible interval [CI] = 0.66–0.82) and DFS (HR = 0.67, 95% CI = 0.60–0.74) than surgery-alone group. Perioperative CT (odds ratio [OR] = 2.56, 95% CI = 1.19–5.50) and adjuvant CT (OR = 0.48, 95% CI = 0.27–0.86) both had more recurrence and metastasis than HIPEC + adjuvant CT, while adjuvant CRT tended to have less recurrence and metastasis than adjuvant CT (OR = 1.76, 95% CI = 1.29–2.42) and even adjuvant RT (OR = 1.83, 95% CI = 0.98–3.40). Moreover, the incidence of mortality in HIPEC + adjuvant CT was lower than that in adjuvant RT (OR = 0.28, 95% CI = 0.11–0.72), adjuvant CT (OR = 0.45, 95% CI = 0.23–0.86) and perioperative CT (OR = 2.39, 95% CI = 1.05–5.41). Analysis of adverse events (grade ≥3) showed no statistically significant difference between any two adjuvant therapy groups.

Conclusion:

A combination of HIPEC with adjuvant CT seems to be the most effective adjuvant therapy, which contributes to reducing tumour recurrence, metastasis and mortality – without increasing surgical complications and adverse events related to toxicity. Compared with CT or RT alone, CRT can reduce recurrence, metastasis and mortality but increase adverse events. Moreover, neoadjuvant therapy can effectively improve the radical resection rate, but neoadjuvant CT tends to increase surgical complications.

INTRODUCTION

Gastric cancer, the third leading cause of cancer deaths and the fifth most frequently diagnosed cancer, has over 1 million new cases and 700,000 deaths worldwide each year.[1-3] Radical resection is the primary therapy for gastric cancer patients to obtain cure and long-term survival. With advances in diagnostic and surgical techniques, the early diagnosis rate and complete resection rate of gastric cancer have been greatly improved. The 5-year survival rate of patients with early gastric cancer has already exceeded 90%.[3-5] Owing to high malignancy and rapid progression, however, locally advanced gastric cancer (LAGC) has a poor prognosis even experienced radical gastrectomy and D2+ lymphadenectomy. Therefore, multidisciplinary therapy including chemotherapy (CT) and radiotherapy (RT) has been adopted to improve the treatment outcomes of patients with LAGC.[4,5]

Multidisciplinary treatment modality combining surgery with CT or RT has become the standard regimen for LAGC.[4,6,7] Multidisciplinary therapy can be divided into neoadjuvant (pre-operative) therapy, adjuvant (post-operative) therapy and perioperative (pre-operative and post-operative) therapy according to different intervention time points and divided into CT, RT, chemoradiotherapy (CRT) and hyperthermic intraperitoneal chemotherapy (HIPEC) according to different combination and application methods. At present, adjuvant CT, adjuvant RT, adjuvant CRT, neoadjuvant CT, neoadjuvant RT, neoadjuvant CRT, perioperative CT and HIPEC have emerged as multidisciplinary therapeutic methods for LAGC.[8-52] Over the past decade, numerous studies evaluated the efficacy of multidisciplinary therapy, whereas it has not reached a consensus on the most efficient multidisciplinary therapy for LAGC.[4-7]

In a mesh meta-analysis conducted by Yin et al., neoadjuvant CRT resulted in a statistically significantly better overall survival (OS) compared with neoadjuvant CT, neoadjuvant RT, adjuvant CRT, adjuvant CT, adjuvant RT and surgery alone.[6] However, Cai et al. found that perioperative CT tended to be the best therapy in terms of OS.[7] Published meta-analysis of LAGC focused on OS without analysing disease-free survival (DFS), recurrence and metastasis, long-term mortality or adverse events, resulting in insufficient evidence. Moreover, HIPEC, as a hot topic of discussion in recent years, was not included as a multidisciplinary therapy. Therefore, we collected published randomised controlled trials (RCTs) on the comparison of different multidisciplinary therapies in the treatment of LAGC. Subsequently, we conducted a comprehensive comparative analysis with 5-year OS and DFS, recurrence and metastasis, long-term mortality, adverse events (grade ≥3), operative complication and R0 resection rate as outcome indicators using meta-analysis.

PATIENTS AND METHODS

This study was designed and implemented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement,[53] and it has been registered in the PROSPERO database (Registration no. CRD42021287159).

Search strategy

PubMed, Embase and Cochrane Library databases were searched for studies of multidisciplinary therapies in the treatment of LAGC until October 2021, and language was limited to English. Subject words including ‘Stomach Neoplasms’, ‘Neoadjuvant Therapy’, ‘Radiotherapy’, ‘Drug Therapy’ and ‘Randomised Controlled Trial’ with random words were combined for retrieval. Besides, relevant references in the literature were also manually searched. The preliminary screening of collected studies was conducted by reading titles and abstracts. Then, the full text was read to identify the studies that meet the inclusion criteria.

Inclusion and exclusion criteria

Studies meeting the following criteria were included: (1) RCTs; (2) gastric cancer with TNM I–IV (M0) stage; (3) LAGC patients received radical gastrectomy; (4) intervention and control groups treated with different therapies, respectively, which included surgery alone, adjuvant CT, adjuvant RT, adjuvant CRT, neoadjuvant CT, neoadjuvant RT, neoadjuvant CRT, perioperative CT and HIPEC; (5) studies published in English; and (6) basic data of patients and treatments in two groups were comparable.

Exclusion criteria were as follows: (1) case–control studies, cohort studies, review articles, case reports or meta-analysis; (2) repeated studies; (3) inoperable, recurrent or metastatic gastric cancer; and (4) required outcome indicators were not reported, such as 5-year OS and DFS, recurrence and metastasis, long-term mortality, adverse events (grade ≥3), operative complication or R0 resection rate.

Data extraction and quality assessment

Two investigators independently carried out data extraction and quality assessment. We discussed further or asked for the opinion of a third investigator when both sides hold different opinions. The method reported by Hozo et al. was used to convert the median and numerical range to mean and standard deviation.[54] Since all the included studies were RCTs, the Cochrane risk-of-bias tool was used to evaluate literature quality.[55]

Statistical analysis

Pairwise meta-analysis was implemented by using Review Manager 5.3 software (The Cochrane Collaboration, Software Update, Oxford, UK). Hazard ratio (HR) with 95% confidence intervals (CI) was given in the literature and combined by the inverse variance method. Heterogeneity was tested using both the Chi-square test and I² index, and heterogeneity was considered significant when P < 0.1 and I² >50%. Network meta-analysis, which is based on the multiple regression method, was implemented to incorporate direct and indirect evidence using Stata SE 15 software. Network graphs were plotted to show a comparative relationship between each procedure, with nodes representing therapies. Cumulative ranking probabilities were computed using the surface area under cumulative ranking curves (SUCRA), to show the possibility of each intervention becoming the best. The possibility of publication bias presented in a funnel plot and literature quality assessment was implemented by using Review Manager 5.3 software.

RESULTS

Study selection and study characteristics

A total of 8376 studies were identified based on retrieval strategy, and 893 repetitive articles were excluded by using NoteExpress software. After reading the titles and abstracts, 524 studies were left. Then, we read the remaining studies in full, and included the 10,077 patients from 45 RCTs[8-52] in this network meta-analysis. The flow diagram of literature screening is shown in Figure 1. Only one of the 45 studies was a three-arm study,[22] while the remaining 44 studies were all dual-arm studies.[8-21,23-52] In addition, 12 studies[9,26,29,31,34,38,43-45,50-52] from China and 8 studies[8,10,13,15,19,39,42,47,49] from Japan, and the above 20 studies account for almost half of the included studies. The characteristics of the included studies are shown in Table 1. Network graphs were plotted for primary outcomes [Figure 2]. The results of the literature quality assessment based on the Cochrane risk-of-bias tool are shown in Figure 3.

Figure 1.

Flow diagram of literature screening and selection

Table 1.

Characteristics of included studies

Author year	Country	Sample size (intervention/control)	Age (years) (intervention/control)	Chemotherapy	Radiotherapy	UICC/AJCC stage	Lymph node resection	Median follow-up (months)
Adjuvant CT plus surgery versus surgery alone
Moon et al., 2017[8]	Japan	113/116	63 (36–77)/64 (34–79)	5-FU, 5’- DFUR or UFT (PO)	NA	I B–III A	NA	66
Noh et al., 2014[9]	China, Korea	520/515	56.1±11.1/55.8±11.6	Capecitabine (PO); oxaliplatin (IV)	NA	I B–IV	D2	62.4/62.6b
Sasako et al., 2011[10]	Japan	529/530	63 (27–80)/63 (33–80)	S-1 (PO)	NA	II–III B	D1–D3	60
Kulig et al., 2010[11]	Poland	141/154	61 (58–67)/64 (61–66)	Etoposide, doxorubicin, cisplatin (IV)	NA	IB–IV	D1–D3	37
Di Costanzo et al., 2008[12]	Italy	130/128	59 (32–73)/64 (18–71)	Cisplatin, epirubicin, leucovorin, 5-FU (IV)	NA	I B–IV	D1–D4	67.2/70.8b
Nakajima et al., 2007[13]	Japan	93/95	63/64	UFT (PO)	NA	II	D2–D4	74.4
Chipponi et al., 2004[14]	France	93/103	59/63	Leucovorin, 5-FU, cisplatin (IV)	NA	NA	D1–D2	101
Nashimoto et al., 2003[15]	Japan	127/123	58.4 (33–75)/57.5 (25–75)	MMC, 5-FU, cytarabine (IV); 5-FU (PO)	NA	I–III	D1–D4	69
Bajetta et al., 2002[16]	Italy	135/136	57 (23–70)/57 (31–70)	Etoposide, doxorubicin, cisplatin, 5-FU, leucovorin (IV)	NA	I–III	D2	66
Neri et al., 2001[17]	Italy	69/68	62 (37–73)/64 (35–74)	Epidoxorubicin, leucovorin, 5-FU (IV)	NA	NA	D1–D2	NA
Cirera et al., 1999[18]	Spain	76/72	61.2±8.7/60.7±10.5	MMC (IV); tegafur (PO)	NA	III	NA	37
Nakajima et al., 1999[19]	Japan	288/285	NA	MMC, 5-FU (IV); UFT (PO)	NA	NA	NA	72
Lise et al., 1995[20]	Italy	155/159	NA	Doxorubicin, MMC, 5-FU (IV)	NA	II–III	D1–D3	78
Grau et al., 1993[21]	Spain	68/66	56 (34–70)/57 (30–70)	MMC (IV)	NA	NA	NA	105
Adjuvant RT plus surgery versus adjuvant CT plus surgery versus surgery alone
Hallissey et al., 1994[22]	UK	153/138/145	65 (55–69)/63 (58–68)/63 (57–69)	Doxorubicin, MMC, 5-FU (IV)	45 Gy in 25 fractions over 35 days	II - IV	NA	60
Adjuvant CRT plus surgery versus surgery alone
Smalley et al., 2012[23]	USA	282/277	NA	5-FU, leucovorin (IV)	45 Gy in 25 fractions for 5 weeks	I B–IV	D0–D2	123.6
Moertel et al., 1984[24]	USA	39/23	58 (40–72)/56 (41–67)	5-FU	37.5 Gy delivered over 4 to 5 weeks	NA	NA	NA
Adjuvant CRT plus surgery versus adjuvant CT plus surgery
Park et al., 2021[25]	South Korea	183/181	61 (27–77)/58 (31–79)	S-1, oxaliplatin (IV)	45 Gy in 25 fractions over 5 weeks	II–III	D2	47
Wang et al., 2021[26]	China	63/63	55.44±5.71a	Oxaliplatin, 5-FU, calcium folinate (IV)	NA	II–III	NA	36
Yu et al., 2015[27]	Korea	230/228	56 (28–76)/56 (22–77)	Capecitabine, cisplatin	45 Gy in 25 fractions	IB–IV	D2–D3	59.3/58b
Kim et al., 2012[28]	Korea	46/44	NA	5-FU, leucovorin (IV)	45 Gy in 25 fractions for 5 weeks	IIIA–IV	D2	86.7
Yu et al., 2012[29]	China	34/34	56/57	5-FU, leucovorin (IV)	45 Gy in 25 fractions for 5 weeks	II–III	D1–D2	36
Kwon et al., 2010[30]	Korea	31/30	56 (23–73)/49 (29–70)	5-FU, cisplatin (IV)	45 Gy in 25 fractions over 5 weeks	IIIA–IV	D2	77.2
Neoadjuvant RT plus surgery versus surgery alone
Zhang et al., 1998[31]	China	171/199	55.8 (39–66)/56.1 (32–65)	NA	40 Gy in 20 fractions for 4 weeks	I–IV	NA	128/123b
Neoadjuvant CT plus surgery versus surgery alone
Ramachandra et al., 2019[32]	India	30/30	50.7±9.5/51.8±9.8	Cisplatin, 5-FU (IV)	NA	I–III	D2	NA
Hashemzadeh et al., 2014[33]	Iran	22/52	58.3±9.1/59.7±8.7	Docetaxel, cisplatin, 5-FU (IV)	NA	I B–IV	D1–D2	NA
Zhao et al., 2013[34]	China	40/45	59 (29–77)/57 (33–73)	Capecitabine (PO); oxaliplatin (IV)	NA	IIB–IIIC	NA	23.5
Schuhmacher et al., 2010[35]	International	72/72	56 (38–70)/58 (26–69)	Cisplatin, folinic acid, 5-FU (IV)	NA	III–IV	D1–D2	56.4/49.2b
Hartgrink et al., 2004[36]	Netherlands	27/29	60 (34–75)a	Methotrexate, 5-FU, leucovorin (IV)	NA	I–IV	D1	83
Neoadjuvant CT plus surgery versus adjuvant CT plus surgery
Fazio et al., 2016[37]	International	34/35	57 (25–75)/59 (39–76)	Docetaxel, cisplatin, 5-FU (IV)	NA	I B–IV	D2–D3	120
Sun et al., 2011[38]	China	29/26	52.6 (33–72)a	Docetaxel, 5-FU, leucovorin (IV)	NA	NA	NA	NA
Yonemura et al., 1993[39]	Japan	23/23	64.1±8.34/56.4±9.6	Cisplatin, uracil, MMC, etoposide (IV)	NA	IV	NA	24
Neoadjuvant CRT plus surgery versus adjuvant CRT plus surgery
Saedi et al., 2014[40]	Iran	12/13	62.7/58.5	Cisplatin, 5-FU, leucovorin, epirubicin, capecitabine (IV)	45 Gy in 20 fractions for 4 weeks	II–III	NA	36
Perioperative CT plus surgery versus neoadjuvant CT plus surgery
Monti et al., 2020[41]	Italy	45/46	66 (33–75)/63 (39–74)	Docetaxel, oxaliplatin, capecitabine (IV)	NA	NA	D1–D2	55
Perioperative CT plus surgery versus adjuvant CT plus surgery
Iwasaki et al., 2021[42]	Japan	139/147	64 (30–75)/62 (28–75)	S-1 (PO); cisplatin (IV)	NA	I B–IV	D2–D3	54
Zhao et al., 2020[43]	China	223/290	NA	Oxaliplatin (IV); S-1 (PO)	NA	II A–III C	D2	23.5
Zhao et al., 2017[44]	China	50/52	59 (39–77)/58.5 (34–77)	Oxaliplatin (IV); S-1 (PO)	NA	II B–III C	NA	9.6
HIPEC plus surgery versus surgery alone
Beeharry et al., 2019[45]	China	40/40	59±10/58±10	Cisplatin (IP)	NA	II A–III C	D2	32
Yu et al., 2001[46]	Korea	125/123	54/55	MMC, 5-FU (IP)	NA	I A–IV	D2–D3	36
Fujimoto et al., 1999[47]	Japan	71/70	58.5±8.1/59.2±9.1	MMC (IP)	NA	NA	NA	NA
Sautner et al., 1994[48]	Austria	33/34	62.2±10/63.5±11	Cisplatin (IP)	NA	III–IV	NA	72.5
Hamazoe et al., 1994[49]	Japan	42/40	56.5±10.4/63.4±9.6	MMC (IP)	NA	I–IV	NA	NA
HIPEC and adjuvant CT plus surgery versus adjuvant CT plus surgery
Gong et al., 2019[50]	China	69/70	56.0±11.1/58.3±11.0	5-FU (IP); docetaxel, oxaliplatin, 5-FU (IV)	NA	II–III	D2	78
Cui et al., 2014[51]	China	48/48	NA	Cisplatin, 5-FU (IP); paclitaxel, cisplatin, tegafur (IV)	NA	IIIA–IIIB	NA	NA
Zuo et al., 2004[52]	China	46/36	53/52	Cisplatin, 5-FU (IP); calcium folinate, 5-FU, mitoxantrone, cisplatin (IV)	NA	II–IV	NA	NA

^aResults based on the whole sample, ^bResults based on intervention group/control group. Data are reported as numbers, mean±SD, median (range). SD: Standard deviation, CT: Chemotherapy, RT: Radiotherapy, CRT: Chemoradiation therapy, HIPEC: Hyperthermic intraperitoneal chemotherapy, 5-FU: 5-Fluorouracil, PO: Per os, IV: Intravenous, IP: Intraperitoneal, UFT: Uracil-tegafur, MMC: Mitomycin C, NA: Not available, UICC: Union for International Cancer Control, AJCC: American Joint Committee on Cancer

Figure 2.

(a) Network graphs of included studies for recurrence and metastasis, (b) long-term mortality. CT: chemotherapy, RT: radiotherapy, CRT: chemoradiation therapy, HIPEC: hyperthermic intraperitoneal chemotherapy

Figure 3.

Results of bias assessed with the Cochrane risk-of-bias tool

Pairwise meta-analysis for overall survival and disease-free survival

Nine studies[8-13,15,16,18,19] evaluated the OS and DFS between adjuvant CT and surgery alone. No obvious heterogeneity was presented between the included studies, so a fixed effect model was adopted. The analysis results showed that the adjuvant CT group had a higher OS (HR = 0.74, 95% CI = 0.66–0.82) [Figure 4a] and DFS (HR = 0.67, 95% CI = 0.60–0.74) [Figure 4b] than surgery-alone group.

Figure 4.

(a) Pairwise meta-analysis between adjuvant CT plus surgery and surgery alone for OS, and (b) DFS. CT: chemotherapy, CRT: chemoradiation therapy, OS: Overall survival, DFS: Disease-free survival

Network meta-analysis

Primary outcomes

As network meta-analysis showed, neoadjuvant RT (OR = 1.90, 95% CI = 1.23–2.94), HIPEC + adjuvant CT (OR = 3.37, 95% CI = 1.58–7.16), HIPEC (OR = 2.32, 95% CI = 1.61–3.34), adjuvant CT (OR = 1.63, 95% CI = 1.01–2.63) and adjuvant CRT (OR = 2.18, 95% CI = 1.21–3.93) groups all had less patients with recurrence and metastasis than surgery-alone group. Compared with HIPEC + adjuvant CT group, perioperative CT (OR = 2.56, 95% CI = 1.19–5.50) and adjuvant CT (OR = 0.48, 95% CI = 0.27–0.86) had higher morbidity of recurrence and metastasis. Besides this, adjuvant CRT tended to have a lower risk of recurrence and metastasis than adjuvant CT (OR = 1.76, 95% CI = 1.29–2.42), even compared with adjuvant RT (OR = 1.83, 95% CI = 0.98–3.40) [Table 2]. The rank probability analysis showed that the possible order of recurrence and metastasis from least to most is HIPEC + adjuvant CT (SUCRA = 90.6), adjuvant CRT (SUCRA = 85.6), HIPEC (SUCRA = 68.7), neoadjuvant RT (SUCRA = 52.0), neoadjuvant CT (SUCRA = 45.7), adjuvant CT (SUCRA = 41.0), adjuvant RT (SUCRA = 37.7), perioperative CT (SUCRA = 25.6) and surgery alone (SUCRA = 3.2) [Figure 5a].

Table 2.

Efficacy estimates table (primary outcomes) from network meta-analysis: Mean odds ratio (95% credible interval)

Recurrence	Surgery alone
	1.32 (0.66–2.62)	Perioperative CT
	1.90 (1.23–2.94)	1.44 (0.64–3.27)	Neoadjuvant RT
	1.73 (0.59–5.02)	1.31 (0.45–3.84)	0.91 (0.29–2.88)	Neoadjuvant CT
	3.37 (1.58–7.16)	2.56 (1.19–5.50)	1.77 (0.74–4.24)	1.95 (0.64–5.95)	HIPEC + adjuvant CT
	2.32 (1.61–3.34)	1.76 (0.80–3.90)	1.22 (0.69–2.16)	1.34 (0.43–4.18)	0.69 (0.29–1.61)	HIPEC
	1.57 (0.77–3.22)	1.19 (0.58–2.48)	0.83 (0.36–1.92)	0.91 (0.31–2.71)	0.47 (0.21–1.03)	0.68 (0.30–1.54)	Adjuvant RT
	1.63 (1.01–2.63)	1.24 (0.75–2.03)	0.86 (0.45–1.64)	0.94 (0.36–2.44)	0.48 (0.27–0.86)	0.70 (0.38–1.30)	1.03 (0.61–1.77)	Adjuvant CT
	2.18 (1.21–3.93)	1.51 (0.86–2.66)	1.66 (0.61–4.53)	3.63 (0.77–17.02)	0.85 (0.44–1.65)	1.24 (0.74–2.07)	1.83 (0.98–3.40)	1.76 (1.29–2.42)	Adjuvant CRT
Mortality	Surgery alone
	5.40 (0.59–49.25)	Perioperative CT
	1.54 (0.87–2.73)	0.29 (0.03–2.80)	Neoadjuvant RT
	10.02 (1.05–95.61)	1.86 (0.82–4.19)	6.50 (0.63–66.63)	Neoadjuvant CT
	2.11 (0.12–36.52)	0.39 (0.05–2.80)	1.37 (0.07–25.08)	0.21 (0.03–1.59)	Neoadjuvant CRT
	12.87 (1.35–123.12)	2.39 (1.05–5.41)	8.35 (0.81–85.80)	1.29 (0.51–3.27)	6.10 (0.81–45.96)	HIPEC+adjuvant CT
	1.71 (1.12–2.62)	0.32 (0.03–3.01)	1.11 (0.54–2.27)	0.17 (0.02–1.70)	0.81 (0.05–14.46)	0.13 (0.01–1.32)	HIPEC
	3.58 (0.37–34.37)	0.66 (0.29–1.52)	2.32 (0.23–23.95)	0.36 (0.14–0.92)	1.70 (0.22–12.83)	0.28 (0.11–0.72)	2.09 (0.21–20.92)	Adjuvant RT
	5.73 (0.66–49.62)	1.06 (0.66–1.71)	3.72 (0.40–34.68)	0.57 (0.30–1.10)	2.71 (0.40–18.29)	0.45 (0.23–0.86)	3.35 (0.37–30.26)	1.60 (0.82–3.14)	Adjuvant CT
	0.56 (0.17–1.80)	4.28 (0.47–39.16)	0.66 (0.32–1.35)	10.53 (1.02–108.36)	3.13 (0.47–20.58)	0.51 (0.25–1.06)	3.86 (0.44–34.15)	1.84 (0.88–3.85)	1.15 (0.86–1.55)	Adjuvant CRT

OR: Odds ratio, CT: Chemotherapy, RT: Radiotherapy, CRT: Chemoradiation therapy, HIPEC: Hyperthermic intraperitoneal chemotherapy

Figure 5.

(a) Rank probabilities of the different therapies for tumour recurrence and metastasis. A: adjuvant CRT, B: adjuvant CT, C: adjuvant RT, D: HIPEC, E: HIPEC + adjuvant CT, F: neoadjuvant CT, G: neoadjuvant RT, H: perioperative CT, I: surgery, (b) Rank probabilities of the different therapies for long-term mortality. A: adjuvant CRT, B: adjuvant CT, C: adjuvant RT, D: HIPEC, E: HIPEC + adjuvant CT, F: neoadjuvant CRT, G: neoadjuvant CT, H: neoadjuvant RT, I: perioperative CT, J: surgery. CRT: chemoradiation therapy, CT: chemotherapy, RT: radiotherapy, HIPEC: hyperthermic intraperitoneal chemotherapy

Regarding patient mortality during follow-up time, it was lower in neoadjuvant CT (OR = 10.02, 95% CI = 1.05–95.61), HIPEC + adjuvant CT (OR = 12.87, 95% CI = 1.35–123.12) and HIPEC (OR = 1.71, 95% CI = 1.12–2.62) groups compared with surgery-alone group. HIPEC + adjuvant CT had lower mortality than adjuvant RT (OR = 0.28, 95% CI = 0.11–0.72), adjuvant CT (OR = 0.45, 95% CI = 0.23–0.86) and perioperative CT (OR = 2.39, 95% CI = 1.05–5.41). In addition, the mortality of the adjuvant CRT group (OR = 0.45, 95% CI = 0.23–0.86) was lower than that of the neoadjuvant CT group (OR = 10.53, 95% CI = 1.02–108.36) [Table 2]. In rank probability analysis, the order of mortality from lowest to highest is HIPEC + adjuvant CT (SUCRA = 94.4), neoadjuvant CT (SUCRA = 86.9), adjuvant CRT (SUCRA = 71.2), adjuvant CT (SUCRA = 59.2), perioperative CT (SUCRA = 55.7), surgery alone (SUCRA = 33.5), adjuvant RT (SUCRA = 32.1), neoadjuvant CRT (SUCRA = 24.1), HIPEC (SUCRA = 23.9) and neoadjuvant RT (SUCRA = 19.0) [Figure 5b].

Secondary outcomes

Adverse events (grade ≥3) associated with toxicity were more common in perioperative CT (OR = 0.18, 95% CI = 0.03–0.91) and adjuvant CT (OR = 0.20, 95% CI = 0.08–0.49) compared with surgery-alone group. Moreover, no statistically significant difference was found between any other two groups [Table 3]. Rank probability analysis showed that the possible order of adverse events (grade ≥3) from least to most was surgery alone (SUCRA = 96.6), HIPEC + adjuvant CT (SUCRA = 55.5), neoadjuvant CT (SUCRA = 55.3), adjuvant CT (SUCRA = 41.1), perioperative CT (SUCRA = 34.2) and adjuvant CRT (SUCRA = 17.3).

Table 3.

Efficacy estimates table (secondary outcomes) from network meta-analysis: Mean odds ratio (95% credible interval)

Adverse events (grade≥3)	Surgery alone
	0.18 (0.03–0.91)	Perioperative CT
	0.29 (0.05–1.65)	1.60 (0.21–12.37)	Neoadjuvant CT
	0.28 (0.06–1.35)	1.56 (0.24–10.36)	0.97 (0.13–7.19)	HIPEC +adjuvant CT
	0.20 (0.08–0.49)	1.14 (0.29–4.48)	0.71 (0.16–3.23)	0.73 (0.20–2.68)	Adjuvant CT
	0.72 (0.14–3.73)	0.71 (0.04–12.62)	0.45 (0.08–2.63)	0.46 (0.09–2.26)	0.64 (0.26–1.56)	Adjuvant CRT
Operative complications	Surgery alone
	0.20 (0.07–0.56)	Perioperative CT
	2.92 (0.93–9.12)	14.86 (3.15–70.18)	Neoadjuvant RT
	0.61 (0.33–1.12)	3.09 (1.31–7.26)	0.21 (0.06–0.76)	Neoadjuvant CT
	0.63 (0.36–1.10)	3.18 (0.96–10.54)	0.21 (0.06–0.77)	1.03 (0.45–2.38)	HIPEC
	0.18 (0.04–0.81)	0.90 (0.30–2.68)	0.06 (0.01–0.40)	0.29 (0.07–1.17)	0.28 (0.06–1.43)	Adjuvant CT
R0 resection	Surgery alone
	0.49 (0.19–1.26)	Perioperative CT
	0.40 (0.25–0.64)	0.83 (0.29–2.39)	Neoadjuvant RT
	0.48 (0.30–0.77)	0.99 (0.43–2.26)	1.20 (0.61–2.34)	Neoadjuvant CT
	2.00 (1.40–2.84)	0.63 (0.16–2.44)	2.41 (0.89–6.57)	2.01 (0.95–4.24)	Adjuvant CT

OR: Odds ratio, CT: Chemotherapy, RT: Radiotherapy, CRT: Chemoradiation therapy, HIPEC: Hyperthermic intraperitoneal chemotherapy

In terms of operative complications, it was more common in perioperative CT (OR = 0.20, 95% CI = 0.07–0.56) and adjuvant CT (OR = 0.18, 95% CI = 0.04–0.81) groups compared with surgery-alone group. Perioperative CT had a higher risk of operative complications than neoadjuvant RT (OR = 14.86, 95% CI = 3.15–70.18) and neoadjuvant CT (OR = 3.09, 95% CI = 1.31–7.26). What’s more, patients with neoadjuvant RT experienced less operative complications than those with neoadjuvant CT (OR = 0.21, 95% CI = 0.06–0.76), HIPEC (OR = 0.21, 95% CI = 0.06–0.77) and adjuvant CT (OR = 0.06, 95% CI = 0.01–040) [Table 3]. Rank probability analysis showed that the possible order of operative complications from least to most was neoadjuvant RT (SUCRA = 99.0), surgery alone (SUCRA = 77.9), HIPEC (SUCRA = 50.0), neoadjuvant CT (SUCRA = 49.7), perioperative CT (SUCRA = 12.1) and adjuvant CT (SUCRA = 11.3).

The R0 resection rate of the surgery-alone group, as showed by network meta-analysis, was lower than that of neoadjuvant RT (OR = 0.40, 95% CI = 0.25–0.64) and neoadjuvant CT (OR = 0.48, 95% CI = 0.30–0.77) groups [Table 3]. The result of rank probability analysis showed that the R0 resection rate from highest to lowest was neoadjuvant RT (SUCRA = 83.0), perioperative CT (SUCRA = 69.5), neoadjuvant CT (SUCRA = 68.6), adjuvant CT (SUCRA = 14.6) and surgery alone (SUCRA = 14.2).

Publication bias

A funnel plot was drawn for recurrence and metastasis as an outcome indicator, and it was found that the left and right distributions of each study site were asymmetrical, suggesting the possible existence of publication bias [Figure 6].

Figure 6.

Funnel plot for recurrence and metastasis as an outcome indicator. CT: chemotherapy, RT: radiotherapy, CRT: chemoradiation therapy, HIPEC: hyperthermic intraperitoneal chemotherapy

DISCUSSION

Currently, surgery as the core, supplemented by CT, RT or CRT, is still the main treatment mode for LAGC.[5-7] Neoadjuvant therapy is used to degrade or decrease tumour stage and improve the R0 resection rate of surgery,[4,5] while HIPEC and adjuvant therapy mainly aim to reduce tumour recurrence and metastasis, and prolong the survival time of patients.[31-36] As shown by pairwise meta-analysis, the OS and DFS of patients in the adjuvant CT group were both significantly higher than that in the surgery-alone group. The therapeutic effects of the pre-operative and post-operative intervention on patients’ operation results and prognosis needed to be further evaluated.[37-39] Compared with RT or CT alone, CRT not only may enhance the therapeutic effect but also increase the risk of complications and side effects.[40] Whether the effect of HIPEC is better than traditional oral or intravenous infusion CT,[45-49] and whether the combination of HIPEC with adjuvant CT leads to better results,[50-52] are issues that needed further discussion.

Analysis results of recurrence and metastasis showed that HIPEC + adjuvant CT seemed to be the best therapy, while surgery alone to be the worst. Serosal invasion and operation contribute to the appearance of free cancer cells in the abdominal cavity, causing intraperitoneal tumour metastases and local recurrence. The peritoneum is the main site of distant metastasis of advanced gastric cancer. Even underwent R0 resection, gastric cancer could be accompanied by undetectable peritoneal implantation and metastasis.[3,56] In the HIPEC procedure, CT drugs are mixed with a large amount of perfusate and heated and then the mixture is continuously injected into the patient’s abdominal cavity at a constant temperature and maintained for a fixed time. The synergistic effect of hyperthermia CT, in HIPEC, associated with the flushing effect of perfusion, could effectively kill and remove cancer cells and small metastasis tumours in the abdominal cavity, to prevent and treat intraperitoneal metastasis of gastric cancer.[45,57] Besides this, dual-approach therapy HIPEC + adjuvant CT tends to reduce the risk of tumour recurrence and metastasis than systemic intravenous CT or HIPEC alone. Therefore, for LAGC cases with suspected peritoneal metastasis, intraperitoneal micrometastases, residual tumour tissue or free tumour cells, HIPEC + adjuvant CT is considered. In addition, CRT seems more effective than CT or RT alone in reducing the incidence of recurrence and metastasis. Previous researches have shown that numerous CT drugs can not only suppress tumours systematically but also enhance tumour sensitivity to RT.[25,26] Therefore, the combination of adjuvant CT and RT can further improve the local control rate of advanced gastric cancer while reducing the RT dose.

Tumour recurrence and metastasis is the most common and serious complication after stomach cancer surgery, as well as the most common cause of death.[3,58] Similar to the analysis result of recurrence, therefore, patients in the HIPEC + adjuvant CT group also appeared to experience the lowest mortality during post-operative follow-up. In addition, owing to the existence of the blood-peritoneal barrier, a high concentration of drugs in the abdominal cavity will not lead to increased drug concentration in blood circulation.[50] Based on this, a combination of HIPEC will not significantly increase the incidence of severe adverse events related to CT toxicity. Next, the combination of RT and CT could reduce mortality by reducing the incidence of tumour recurrence and metastasis, as shown in this mortality analysis. However, because of the dual effects of radiation and CT drugs imposed on the body, severe adverse events risk of CRT is higher than CT or RT. Hence, the general condition of patients should be concerned during CRT procedure, and positive and adequate nutritional support should be carried out to increase the tolerance of the patient’s body.[28-30,59]

The concept of neoadjuvant therapy was first proposed by Frei, mainly including neoadjuvant CT and neoadjuvant RT, which has been conducted in the treatment of gastric cancer for nearly 40 years. Compared with adjuvant therapy, its main advantages consist in the reduction of tumour volume and staging, improvement of surgical resection rate and early treatment of tumour micrometastases.[31,37] Therefore, the radical resection (R0 resection) rate of the neoadjuvant RT and neoadjuvant CT groups was significantly better than that of the adjuvant CT and surgery-alone groups. Neoadjuvant therapy helps to reduce tumour size and relieve related symptoms caused by a tumour, thus reducing surgical difficulty and trauma, and further reducing the incidence of bleeding, pain and other surgery-related complications.[32,58] RT, classified as a local treatment, could act on site-specific tumours with relative precision, so produces a little harmful effect on the whole system of the body. Furthermore, with the application of high-precision techniques such as three-dimensional conformal RT), toxicity associated with RT can be reduced by reducing exposure of normal tissues around the lesion.[60] Previously reported neoadjuvant CT is mostly systemic intravenous CT regimens, which is not accurate enough to inhibit local tumours but weaken the immune and anti-injury function of the body. Therefore, patients in the neoadjuvant CT group are accompanied by a decreased tolerance to surgical stimulation, resulting in an increased risk of surgical complications. Some studies showed that interventional CT had a stronger ability to kill tumour cells directly and lower systemic toxicity than traditional CT, but further research is needed.[61] To sum up, neoadjuvant therapy is recommended when a tumour is difficult to be completely resected by surgery alone. The effectiveness of neoadjuvant CRT on anti-tumour, toxicity and improvement of post-operative prognosis is also the direction of further research. Analysis of perioperative CT showed that perioperative CT had no distinct advantage in reducing tumour recurrence and metastasis, and long-term mortality, but increased the risk of surgical complications and adverse events related to toxicity. However, the lack of direct comparison of perioperative CT makes the results inconclusive.

Although this study systematically collected published RCTs on the comparison between various multidisciplinary therapies for LAGC and analysed as many outcome indicators as possible, there still remain lots of limitations. First, the absence of direct comparison between many multidisciplinary therapies may lead to inconsistencies between direct and indirect evidence, affecting the accuracy of analysis results. Second, although recruited gastric cancer patients were in locally advanced stages without distant metastasis (AJCC I–IV), studies based on a particular stage are needed. Third, CT regimens in each study were not identical, leading to heterogeneity amongst different studies. Finally, the follow-up time for each included study was inconsistent or unclear, causing the different incidences of long-term outcomes such as recurrence and mortality amongst the studies. Therefore, more high-quality, large-scale and long-term follow-up studies are needed.

CONCLUSION

This network meta-analysis comprehensively evaluated the effects of different multidisciplinary therapies in the treatment of LAGC. Adjuvant CT combined with surgery improved OS and DFS than surgery alone. A combination of HIPEC with adjuvant CT seems to be the most effective adjuvant therapy, which significantly reduces the incidence of tumour recurrence and metastasis, and mortality – without increasing the risk of surgical complications and severe adverse events related to toxicity. Compared with CT or RT alone, CRT can reduce recurrence and metastasis, and mortality, but increase severe adverse events. Neoadjuvant RT and CT both can improve R0 resection rate, but neoadjuvant CT tends to increase surgical complications. In the future, high-quality, large-scale and long-term follow-up RCTs based on specific tumour stages, uniform lymph node resection and unified CT drug regimens are needed to compare different multidisciplinary therapies for LAGC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.