First-line systemic therapy for advanced gastric cancer: a systematic review and network meta-analysis.

BACKGROUND: Systemic therapy is the standard treatment against advanced gastric cancer. Fluoropyrimidine plus platinum doublet has been recommended as the preferred first-line strategy. However, there is still a lack of a comprehensive and hierarchical evidence that compares all eligible literature simultaneously.
METHODS: Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO, and ESMO meeting library from inception to October 2018. Randomized controlled trials featuring comparisons between different first-line systemic treatments against advanced gastric cancer were eligible. Overall survival was utilized as the primary endpoint. Pairwise and network calculations were based on a random-effects model and the hierarchical ranking was numerically indicated by P-score. All procedures were conducted according to Cochrane Handbook 5.1 and PRISMA for Network Meta-analysis (Registration identifier: CRD42018084951).
RESULTS: A total of 119 studies were eligible for our pooled analysis. Concerning general analysis, 'fluoropyrimidine plus platinum-based triplet' topped the overall survival hierarchy (HR 0.91 [0.83-0.99], P-score = 0.903, p = 0.04) while it ranked in second place for progression-free survival and objective response rate. However, it displayed worse tolerability against 'fluoropyrimidine plus platinum doublet'. More specifically, 'Capecitabine plus cisplatin-based triplet plus targeted medication' topped the ranking among all fluoropyrimidine plus platinum-based regimens in additional analysis. Nevertheless, it did not reach statistical advantage against fluoropyrimidine plus oxaliplatin doublet in terms of survival benefits, while still displaying significantly worse safety profile.
CONCLUSIONS: Taken together, fluoropyrimidine plus oxaliplatin doublet (especially capecitabine or S-1) should still be considered as the preferred first-line regimen owing to its comparable survival benefits and lower toxicity.

Introduction

Gastric cancer is the third leading cause of cancer-related mortality worldwide, and more than half of the cases occur in East Asia.[1,2] It is estimated that over 950,000 cases were newly diagnosed in 2012, while 720,000 fatalities were reported, highlighting its relatively poor prognosis.[1]

For early localized gastric cancer cases, surgery has been recognized as the optimal therapeutic option owing to its curability.[3,4] Nonetheless, for those bearing incurable factors, such as locally advanced inoperable, recurrent, or metastatic gastric cancer, systemic therapy is often used as the preferred palliative treatment among cancer patients, which offers survival benefits compared with supportive treatments alone.[5]

Currently, owing to its survival benefits and satisfactory safety profile, fluoropyrimidine and platinum-based doublet is widely recommended as the preferred first-line systemic regimen against advanced gastric cancer. Specifically, fluorouracil (5-FU) or capecitabine plus cisplatin, capecitabine plus cisplatin or oxaliplatin, S-1 or capecitabine plus cisplatin, and S-1 or capecitabine plus oxaliplatin are the first choices recommended by National Comprehensive Cancer Network (NCCN),[5] European Society for Medical Oncology (ESMO),[6] Japanese,[7] and Chinese[8] guidelines, respectively. In terms of fluoropyrimidine and platinum-based triplet, no consensus has been reached despite several phase III studies reporting positive survival results when comparing fluoropyrimidine and platinum-based triplet with the doublet regimen.[9-11] Higher toxicity is the major concern about the clinical application of the three-drug regimen, therefore current guidelines only recommend the three-drug regimen for patients with better performance status (PS).[5,6] Furthermore, the addition of targeted medications displayed comparable survival benefits against fluoropyrimidine and platinum-based triplet alone,[12-15] adding more options on potential alternatives of fluoropyrimidine and platinum-based doublet in terms of preferred first-line systemic regimens.

However, comprehensive evidence of this topic is still scarce. Although three previously published high-quality systematic reviews had reported relevant results, each of them had specific imperfections. Wagner et al. updated their systematic review based on studies up to June 2016 (n = 64).[16] However, this systematic review was only quantitatively synthesized by pairwise meta-analyses rather than hierarchical network meta-analysis. Meanwhile, it only included first-line chemotherapy while excluding studies with targeted medications. Song et al. published a systematic review and pairwise meta-analysis based on studies up to December 2015 (n = 11), which was also an noncomprehensive review since it only included studies with molecular-targeted first-line therapy.[17] Moreover, Ter Veer et al. conducted a systematic review with network meta-analysis based on studies until June 2015 (n = 65).[18] Nonetheless, this systematic review contained both advanced esophageal and gastric cancer patients, while it discussed first-line chemotherapy only. Therefore, those systematic reviews were lopsided, outdated, or inadequate in their use of hierarchical rankings, which urged us to provide an updated and by far the most comprehensive systematic review and network meta-analysis.

Methods

Registration and guidelines

The protocol of our systematic review and network meta-analysis had been published in PROSPERO (CRD42018084951). The design, conduct, and writing of this systematic review and network meta-analysis was strictly in accordance with the requirements from the PRISMA Checklist for Network Meta-analysis and Cochrane Handbook 5.1. Each step was conducted by two investigators of our research group. Any discrepancy was resolved by a third investigator.

Search strategy

Electronic databases including PubMed, Web of Science, Cochrane Central Register of Controlled Trials, and Embase were examined comprehensively. In addition, we also thoroughly searched major databases for meeting abstracts, including American Society of Clinical Oncology (ASCO) and ESMO Meeting Library. The searching process started on 1 March until 4 October 2018, covering possible indexes published from inception to October 2018. Both the abstract and the main text of the retrieved entries were rigorously assessed in order to guarantee the accuracy of selection. Furthermore, in the case of omission, the reference lists of three previously published high-quality systematic reviews were also reviewed.[16-18] The full electronic search strategy is presented in the supplementary material.

Selection criteria

Studies that simultaneously met the following inclusion criteria were eligible (PICOS framework).

Participant: patients with previously untreated advanced gastric cancer, including locally inoperable, recurrent, and metastatic cases. Studies that contained both gastric and esophageal cancer cases were eligible. However, if other types of malignancies existed such as pancreatic cancer, it was not qualified unless subgroup data were offered.

Intervention: different first-line systemic treatments against advanced gastric cancer, including chemotherapy and targeted medications. Regarding chemotherapeutic types, since intraperitoneal chemotherapy was still controversial among different countries, we only included oral and intravenous chemotherapeutic regimens. Moreover, the comparisons between different regimens of chemotherapy were qualified while the comparisons between different dosages or methods of administration by the same chemotherapeutic regimen were not eligible. Comparisons between auxiliary therapeutics (such as anti-inflammatory medications, nutritional supportive methods, unspecified herbal medicine, and immunomodulators) were also not qualified.

Comparator: ‘FP2’ (fluoropyrimidine plus platinum-based doublet), ‘FC2’ (5-FU plus cisplatin doublet), and ‘XC2’ (capecitabine plus cisplatin doublet) were common comparator nodes of network meta-analysis under different scenarios.

Outcome: time-to-event overall or progression-free survival (PFS) data [hazard ratio (HR) or Kaplan–Meier curves] were mandatory, while results of objective response rate (ORR) and adverse events were dispensable.

Study design: phase II and phase III randomized controlled trials reported from inception to October 2018 without language limitations. We only included the one with the longest follow-up period among different reports of the same registered trial.

Studies were excluded from systematic review owing to the following reasons.

Could not incorporate into network calculation among unselected population.

Sequential first-line therapy (Supplementary Table 1).

Risk of bias assessment

The quality of each eligible study was evaluated by The Cochrane Risk of Bias Tool. The entire scale was constituted by seven domains, namely random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias.[19] According to the criteria in Cochrane Handbook 5.1, each domain could be judged as any of the three levels, low risk, unclear risk, or high risk of bias. If the majority of items were judged as low risk of bias, then the entire methodological design of network meta-analysis was regarded as low risk of bias, and vice versa. Here, studies were defined to be low quality if four or more items were scored as high risk of bias.

Data extraction

Predesigned forms were utilized to collect and organize the original data. General information, survival, and safety data were extracted from the main text, tables, survival curves, or supplementary materials, which had been cross-checked by two different investigators in our team before quantitative synthesis.

Nodes, baseline parameters, and endpoints

Our major principle for node classifications was to combine similar and less-significant regimens together so that sample size and the advantages of direct randomization could be enhanced, and meanwhile also individualize the clinically significant components based on their known mechanisms to lower the heterogeneity and maintain clinical availability. For general analysis among the unselected population, all nodes were in the form of alphanumeric combination. Each type of alphanumeric combination was selected based on the clinical significance and availability. Since leucovorin was routinely considered as a chemo-modulator, it was not calculated into a separate node. The node abbreviations in the general analysis were as follows: F, fluoropyrimidine; P, platinum; R, targeted medication; T, taxane; I, irinotecan; A, anthracycline; M, methotrexate; E, etoposide; Y, mitomycin-C; S, best supportive care; U, nitrosourea; 1, monotherapy; 2, doublet; 3, triplet. For example, ‘FP3R’ suggested that this regimen was a fluoropyrimidine plus platinum-based triplet plus one targeted medication, while ‘F1’ indicated that it was a fluoropyrimidine monotherapy. Meanwhile, different drugs within each regimen were orderly listed according to their clinical significance for systemic therapy (fluoropyrimidine, platinum, leucovorin, taxane, other drugs), which helped to eliminate the possible false classification of the same regimen into two different nodes. For additional analysis among unselected population, similar rationale had been applied. Moreover, since fluoropyrimidine and platinum were crucial components for gastric cancer systemic treatments with different subtypes inside each category that might function differently, we individualized diverse types of fluoropyrimidine and platinum when combining them into separate nodes. All abbreviations of nodes in additional analysis were as follows: S, S-1; C, cisplatin; X, capecitabine; R, targeted medication; O, oxaliplatin; F, 5-FU; H, heptaplatin; 1, monotherapy; 2, doublet; 3, triplet. For instance, ‘XC3’ was the node for capecitabine plus cisplatin-based triplet.

Unselected patients were those without specific pathological positivity, in contrast to those featuring specific positivity such as HER-2 positive gastric cancer. Since most studies were completed via multinational cooperation, the leading country of each study was defined by the nationality of its first corresponding author, who usually led the project. Age referred to the median age of overall population. Here, region referred to the source region of patients that had been analyzed in the studies. Western regions included Europe, North America, and Australia, while eastern regions usually referred to East Asian countries including Japan, South Korea, and China. If the study contained patients from both western and eastern regions, or patients from other areas of the world (such as South America), it was regarded as a versatile region. Visceral involvement suggested the metastatic involvement of liver and lung. In term of measurability, those nonmeasurable but assessable patients were also included as measurable cases. Owing to the potential disparity of efficacy in terms of different tumor locations and histological types, ratios between gastric cancer and gastroesophageal junction cancer, as well as intestinal type and diffused type were collected, respectively. Usually, patients with gastric cancer should significantly outnumber those with gastroesophageal junction cancer.

The primary endpoint was overall survival (OS), while secondary endpoints included PFS, ORR, hematological adverse events, and nonhematological adverse events. OS and PFS were defined as the time from randomization to death from any cause and the time from randomization to disease progression or death from any cause, respectively. ORR was the percentage of patients with complete and partial response. The hematological adverse events included leukopenia, neutropenia, anemia, thrombocytopenia, and other relevant events such as febrile neutropenia and infection with neutropenia. The remaining adverse events were categorized as nonhematological adverse events. We only counted grade 3 or higher (National Cancer Institute Common Terminology Criteria for Adverse Events) adverse events owing to their clinical significances. For early studies that failed to use this numerical grading system, we collected severe-toxicity adverse events in the nonhematological category and leukocyte count <2000/μl, platelets <50,000/μl, or hemoglobin <9.5 g/dl were collected in the hematological category.

Statistical analysis

HRs and 95% confidence intervals (95% CIs) were used as the effect size for OS and PFS. Risk ratios (RR) and 95% CIs were applied as the effect size for ORR, hematological and nonhematological adverse events. If survival data or its CI was not directly provided, we estimated the values from the Kaplan–Meier curves by methods described elsewhere.[20] In terms of adverse events, the total amount of grade 3 or higher adverse events were used for calculation, instead of the number of patients suffering grade 3 or higher adverse events.

As was known to all, the prominent strength of network meta-analysis was to provide a hierarchical ranking for multiple arms even without direct comparisons.[21] This key feature reflected on and highlighted the two fundamental assumptions of network meta-analysis, known as transitivity and consistency.[22]

When the head-to-head results of A versus C and B versus C were respectively provided, then the hypothesis of transitivity also validated a statistical comparison between A and B. However, it required comparable general features within each node as the prerequisite condition to eliminate selection bias and justify statistical connections among indirect arms.[23] Since all included studies were randomized controlled trials without significant methodological heterogeneity, the baseline parameters were the crucial factors to determine the clinical heterogeneity and therefore transitivity. We carefully compared the main baseline features of different arms within each node and eliminated those with significant differences by sensitivity analysis. Apart from clinical and methodological heterogeneity, we also evaluated statistical heterogeneity of the network meta-analysis, which was known as the overall degree of disparity within the same pairwise comparison.[24] The I2 statistic was the chief indicator of statistical heterogeneity, with values of <25%, 25–50%, and >50% indicating low, moderate, and high heterogeneity, respectively. In addition, the Q statistic of heterogeneity and its p value also facilitated the assessment of statistical heterogeneity. If the p value of the Q statistic was less than 0.05, it suggested that there was significant heterogeneity.

On the other hand, the consistency, another crucial assumption for network meta-analysis, referred to the statistically consistent results between direct and indirect effect sizes regarding the same comparison. Significant differences between direct and indirect calculations might indicate inconsistency within the network meta-analysis while also suggest the unsuitability for transitivity.[25] Here, we employed several methods to assess the network consistency, including the comparison between direct and indirect results as well as the Q statistic. We performed a pairwise meta-analysis via both fixed-effects and random-effects calculations to generate direct results before network meta-analysis. Concerning the same therapeutic comparison, the results were regarded as consistent if the 95% CI of both pairwise and network meta-analysis significantly overlapped. Meanwhile, the Q statistic of inconsistency was another statistical indicator to numerically estimate the consistency within the comparisons, whose p value (<0.05) could suggest a significant inconsistency between pairwise and network meta-analysis. Both consistency and homogeneity were crucial bases to offer reliable outcomes by network meta-analysis. If inconsistency or significant heterogeneity occurred, we deleted the original data from the most inconsistent or heterogeneous pairwise comparisons to examine whether the results remained unchanged, otherwise it was not appropriate for pooled analysis.[24,26]

For the network calculation of general analysis, ‘fluoropyrimidine plus platinum’ (FP2) was chosen as the common comparator since it was the regimen preferred by different guidelines. A network plot and comparison-adjusted funnel plot were used to display the network structure and examine the publication bias across the included trials, respectively, where the more symmetrical it was, the lower the probability of publication bias the merged results would have.[27,28] We conducted the random-effects network meta-analysis based on a frequentist model, with either HR or RR as the effect size. A network forest plot or league table were used to demonstrate the entire regimens with their relative CIs. In addition, we also utilized P-score to rank all regimens based on their network estimates. The closer the P-score moved to 1, the better the regimen. Sensitivity analysis was performed to detect the stability of pooled outcomes, which included using fixed-effects model and deleting studies with significant clinical heterogeneity. For the network calculation of additional analysis, ‘5-FU plus cisplatin’ (FC2) was chosen as the common comparator since they were recommended by NCCN guidelines, while the remaining statistical methods were similar to those of the general analysis.

Both pairwise and network meta-analysis were conducted in R software 3.4.3, assisted by STATA 14.0 in terms of graphical functions.

Role of the funding source

The sponsors had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

Literature retrieval

After screening through 15,262 preliminary records, a total of 119 randomized controlled trials were eligible for inclusion in our systematic review (Figure 1). Among 119 eligible trials, 94 studies were included in the general analysis of unselected population, 39 studies were selected into the additional analysis of unselected population (including 22 studies overlapping with general analysis), while 8 trials were systematically reviewed in terms of specific pathological positivity. Both systematic review and network meta-analysis were conducted among unselected population, irrespective of general or additional analysis. However, owing to the limited number of eligible studies, we only performed systematic review for studies concerning specific pathological positivity.

Figure 1.

Selection flow chart for network meta-analysis.

General analysis: baseline features and transitivity

Overall, 94 randomized controlled trials were included in the general analysis, containing a total of 17,976 participants. Japan (n = 19), USA (n = 15), and China (n = 12) were the top three leading countries. A total of 52 studies recruited patients from western region, while 37 and 5 studies featured patients from the eastern region and versatile region, respectively, displaying a relatively balanced geographical distribution between eastern and western regions. ‘Fluoropyrimidine plus platinum doublet’ was the most frequent node in the network (n = 45), followed by ‘fluoropyrimidine plus platinum-based triplet’ (n = 31), and ‘fluoropyrimidine monotherapy’ (n = 28). The majority of the studies featured populations with a median-age around 60 and male-dominant sex ratio. Predominantly, patients were metastatic measurable cases and had a PS of either 0 or 1. Meanwhile, the ratio of visceral or peritoneal involvement, primary locations (dominant proportion of gastric cancer cases) and histological types were largely comparable across different studies. Therefore, the demographic characteristics of included trials were generally comparable. Several studies might introduce potential heterogeneity owing to incompatible baseline features with other studies, such as recruiting elderly patients (>70 years old),[12,29-32] containing esophageal,[13-15,29,31,33-36] fake registration identifier,[37] nonmeasurable cases only,[38] and peritoneal metastasis only[39] (Table 1). The influence on pooled results by these studies was further detected in sensitivity analysis.

Table 1.

Baseline characteristics of eligible studies for general analysis (unselected population).

Study	Leading country	Registration	Phase	Enrollment	Regimen	Node	Sample size	Age	Gender (M/F)	Region	Metastatic (Y/N)	Visceral involvement (Y/N)	Peritoneal involvement (Y/N)	Prior resection (Y/N)	Measurable (Y/N)	PS (0/1/2)	Location (G/J)	Histological type (I/D)	OS-HR	PFS-HR	ORR (P/T)	hAE (E/T)	non-hAE (E/T)	Journal	PMID	Note
Yamada 2018	Japan	UMIN000007652	III	April 2012—March 2016	S-1 plus cisplatin plus docetaxel	FP3	370	Adult	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	0–1	Gastric	259/428	0.99 (95% CI, 0.85–1.16)	0.99 (95% CI, 0.86–1.15)	219/370	245/370-2	26/370-1	J Clin Oncol	J Clin Oncol 36, 2018 (suppl; abstr 4009)	Abstract
					S-1 plus cisplatin	FP2	371														208/371	140/371-2	27/371-1
Muro 2018	Japan	NCT02539225	II	October 2015—October 2017	S-1 plus oxaliplatin plus ramucirumab	FP2R	96	Adult	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	0–1	Gastric and junction	NA	NA	1.07 (95% CI, 0.86–1.33)	32/55	NA	NA	J Clin Oncol	J Clin Oncol 36, 2018 (suppl; abstr 4036)	Abstract
					S-1 plus oxaliplatin	FP2	93														27/54
Lu 2018	China	NCT01015339	III	December 2009—February 2014	Capecitabine plus paclitaxel	FT2	160	56.6	115/45	Eastern	151/9	71/89	8/152	51/109	Measurable	0–2	92/68	40/40	0.88 (95% CI, 0.69–1.13)	0.91 (95% CI, 0.71–1.16)	69/160	100/158	24/158	Gastric Cancer	29488121
					Capecitabine plus cisplatin	FP2	160	56.2	118/42		142/18	76/84	4/156	50/110			97/63	31/35			46/160	91/147	65/147
Fuchs 2018	USA	NCT02314117	III	January 2015—May 2017	5-FU/capecitabine plus cisplatin plus ramucirumab	FP2R	326	58.9	214/112	Versatile	Metastatic	NA	NA	NA	Measurable	0–2	Gastric and junction	NA	0.96 (95% CI, 0.80–1.16)	0.75 (95% CI, 0.61–0.94)	134/326	125/326-2	32/326-1	J Clin Oncol	10.1200/JCO.2018.36.4_suppl.5	Abstract
					5-FU/capecitabine plus cisplatin	FP2	319	60.1	215/104												116/319	131/319-2	5/319-1
Matsuyama 2018	Japan	UMIN000006179	II	August 2011—September 2015	S-1 plus docetaxel	FT2	30	18–75	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	Non-measurable *	0–2	Gastric	NA	0.62 (95% CI, 0.34–1.13)	0.70 (95% CI, 0.40–1.21)	NA	15/30-2	4/30-3	J Clin Oncol	10.1200/JCO.2018.36.4_suppl.119	Abstract
					S-1 plus cisplatin	FP2	31	11/31-2														10/31-3
Iqbal 2017	USA	NCT01498289	II	February 2012—March 2018	5-FU plus oxaliplatin plus leucovorin	FP2	99	Adult	NA	Western	Metastatic and locally unresectable	NA	NA	NA	Measurable	0–2	Gastric and esophageal *	NA	0.82 (95% CI, 0.61–1.10)	0.70 (95% CI, 0.52–0.93)	33/80	NA	NA	J Clin Oncol	10.1200/JCO.2017.35.15_suppl.4009	Abstract
					Docetaxel plus irinotecan	TI2	104														23/86
Li 2017	China	ChiCTR-TRC-08000167	II	April 2008—September 2012	5-FU plus leucovorin plus irinotecan	FI2	71	53	50/21	Eastern	65/6	33/38	NA	49/22	Measurable	12/25/35	Gastric	Balanced	1.23 (95% CI, 0.87–1.75)	1.23 (95% CI, 0.89–1.69)	6/54	22/71	12/71	Oncotarget	29228659
					5-FU plus oxaliplatin plus leucovorin	FP2	74	52	54/20		67/7	21/53		49/25		10/29/35					7/74	27/74	14/74
Hwang 2017	South Korea	NCT01470742	III	August 2010—October 2014	Capecitabine plus oxaliplatin	FP2	24	75 *	18/6	Eastern	15/9	NA	NA	11/13	Measurable	20/4	Gastric	NA	0.58 (95% CI, 0.30–1.12)	0.32 (95% CI, 0.17–0.61)	10/24	4/24	10/24	J Geriatr Oncol	28119041
					Capecitabine	F1	26	77 *	16/10		15/11			15/11		20/6					8/26	5/26	7/26
Hall 2017	UK	ISCTRN33934807	II	June 2009—January 2011	Capecitabine plus oxaliplatin plus epirubicin	FP3	17	74 *	13/4	Western	17/0	NA	NA	NA	NA	0/11/6	10/2/5 * -E	Balanced	1 versus 2: 1.24 (95% CI, 0.39–3.94)	1 versus 2: 0.83 (95% CI, 0.36–1.93)	5/17	NA	14/17	Br J Cancer	28095397
					Capecitabine plus oxaliplatin	FP2	19	77 *	13/6		17/2					4/10/5	5/1/11 * -E		1 versus 3: 0.84 (95% CI, 0.41–1.73)	1 versus 3: 0.64 (95% CI, 0.24–1.71)	9/19		7/19
					Capecitabine	F1	19	75 *	15/4		18/1					2/10/7	7/4/8 * -E		2 versus 3: 0.38 (95% CI, 0.14–1.03)	2 versus 3: 0.78 (95% CI, 0.34–1.79)	2/19		8/19
Li 2016	China	NA	NA	NA	5-FU plus leucovorin plus irinotecan	FI2	50	Adult	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	NA	Gastric	NA	1.23 (95% CI, 0.81–1.88)	0.87 (95% CI, 0.59–1.27)	24/50	NA	NA	World Chinese Journal of Digestology	28850174	Abstract
					Capecitabine plus oxaliplatin plus epirubicin	FP3	55														22/55
Yoon 2016	USA	NCT01246960	II	April 2011—August 2012	5-FU plus oxaliplatin plus leucovorin plus ramucirumab	FP2R	84	64.5	63/21	Western	80/4	NA	NA	NA	67/17	40/43/0	19/26/39 * -E	Balanced	1.08 (95% CI, 0.73–1.58)	0.98 (95% CI, 0.69–1.37)	38/84	27/82	65/82	Ann Oncol	27765757
					5-FU plus oxaliplatin plus leucovorin	FP2	84	60	61/23		79/5				70/14	43/41/0	20/23/41 * -E				39/84	31/80	35/80
Shah 2016	South Korea	NCT01590719	II	July 2012—May 2013	5-FU plus oxaliplatin plus leucovorin plus onartuzumab	FP2R	62	58.5	40/22	Versatile	Metastatic	NA	NA	23/39	NA	24/35/0	46/16	20/31	1.06 (95% CI, 0.64–1.75)	1.08 (95% CI, 0.71–1.63)	26/43	41/60-2	10/60-2	Oncologist	27401892
					5-FU plus oxaliplatin plus leucovorin	FP2	61	57	36/25					20/41		24/36/0	48/13	23/26			24/42	29/60-2	1/60-2
Tebbutt 2016	Australia	ACTRN12609000109202	II	April 2010—November 2011	5-FU/capecitabine plus cisplatin plus docetaxel plus panitumumab	FP3R	37	64	33/4	Western	Metastatic and locally unresectable	26/11	13/24	NA	Measurable	34/3	13/10/15 * -E	Balanced	1.02 (95% CI, 0.51–2.05)	1.08 (95% CI, 0.59–2.01)	22/37	NA	26/37	Br J Cancer	26867157
					5-FU/capecitabine plus cisplatin plus docetaxel	FP3	39	59	30/9			23/16	5/34			37/2	15/11/13 * -E				17/39		18/39
Hironaka 2016	Japan	JapicCTI-111635	II	October 2011—December 2012	S-1 plus oxaliplatin plus leucovorin	FP2	47	65	33/14	Eastern	40/7	NA	12/35	NA	Measurable	37/10/0	Gastric	24/23	1 versus 2: 0.76 (95% CI, 0.47–1.24)	1 versus 2: 0.52 (95% CI, 0.30–0.88)	31/47	25/47	28/47-3	Lancet Oncol	26640036
					S-1 plus leucovorin	F1	47	65	37/10		40/7		11/36			37/10/0		24/23	1 versus 3: 0.59 (95% CI, 0.37–0.93)	1 versus 3: 0.60 (95% CI, 0.35–1.02)	20/47	11/47	10/47-3
					S-1 plus cisplatin	FP2	48	65	38/10		41/7		14/34			38/10/0		18/30	2 versus 3: 0.77 (95% CI, 0.49–1.22)	2 versus 3: 1.08 (95% CI, 0.67–1.74)	22/48	43/48	22/48-3
Wang 2016	China	NCT00811447	III	November 2008—June 2012	5-FU plus cisplatin plus docetaxel	FP3	119	56.6	81/38	Eastern	89/30	NA	NA	46/73	Measurable	115/4	99/20	Balanced	0.71 (95% CI, 0.52–0.97)	0.58 (95% CI, 0.42–0.80)	58/119	72/119-1	31/119	Gastric Cancer	25604851
					5-FU plus cisplatin	FP2	115	55.5	88/27		89/26			39/76		108/7	86/29				39/115	11/115-1	21/115
Du 2015	China	NCT02370849	II	October 2009—February 2012	S-1 plus cisplatin plus nimotuzumab	FP2R	31	58	17/14	Eastern	22/9	6/25	4/27	8/23	Measurable	5/26/0	25/6	Balanced	1.78 (95% CI, 0.97–3.25)	2.14 (95% CI, 1.19–3.83)	17/31	8/31	6/31	Medicine	26061330
					S-1 plus cisplatin	FP2	31	53	26/5		18/13	3/28	5/26	9/22		7/24/0	25/6				18/31	4/31	1/31
Wu 2015	China	ChiCTR-TRC-13003993 *	NA	July 2009—June 2011	S-1 plus cisplatin	FP2	36	64.1	25/11	Eastern	31/5	NA	NA	16/20	Measurable	15/21/0	Gastric	21/13	0.81 (95% CI, 0.46–1.43)	0.76 (95% CI, 0.40–1.46)	19/36	25/36	30/36	Anticancer Drugs	25933246
					Cisplatin	P1	36	62.7	23/23		30/6			18/18		16/20/0		22/11			15/36	19/36	24/36
Van Cutsem 2015	Belgium	NCT00382720	II	September 2006—September 2007	5-FU plus oxaliplatin plus leucovorin plus docetaxel	FP3	89	58	61/28	Western	Metastatic and locally unresectable	63/26	17/72	35/54	77/12	87/2	75/14	NA	1 versus 2: 0.73 (95% CI, 0.48–1.09)	1 versus 2: 0.80 (95% CI, 0.55–1.18)	41/88	49/88-1	67/88	Ann Oncol	25416687
					Capecitabine plus oxaliplatin plus docetaxel	FP3	86	59	64/22			50/36	17/69	40/46	80/6	84/2	75/11		1 versus 3: 0.51 (95% CI, 0.35–0.76)	1 versus 3: 0.43 (95% CI, 0.30–0.63)	21/81	50/82-1	73/82
					Oxaliplatin plus docetaxel	PT2	79	59	51/28			55/24	7/72	23/56	69/10	77/2	70/9		2 versus 3: 0.75 (95% CI, 0.51–1.10)	2 versus 3: 0.69 (95% CI, 0.49–0.96)	18/78	52/78-1	76/78
Shen 2015	China	NCT00887822	III	March 2009—July 2010	Capecitabine plus cisplatin plus bevacizumab	FP2R	100	54.2	68/32	Eastern	95/5	39/61	NA	24/76	81/19	95/5	85/15	Balanced	1.11 (95% CI, 0.79–1.56)	0.89 (95% CI, 0.66–1.21)	33/81	54/100	66/100	Gastric Cancer	24557418
					Capecitabine plus cisplatin	FP2	102	55.5	74/28		94/8	40/62		20/82	86/16	97/5	82/20				29/86	68/101	45/101
Guimbaud 2014	France	NCT00374036	III	June 2005—May 2008	5-FU plus leucovorin plus irinotecan	FI2	207	61.4	155/52	Western	176/31	NA	NA	48/159	Measurable	71/102/27	138/63	Balanced	1.01 (95% CI, 0.82–1.24)	0.99 (95% CI, 0.81–1.21)	75/198	78/203	108/203	J Clin Oncol	25287828
					Capecitabine plus cisplatin plus epirubicin	FP3	209	61.4	154/55		173/36			54/155		61/108/36	133/73				74/189	129/200	107/200
Iveson 2014	UK	NCT00719550	II	October 2009—June 2010	Capecitabine plus cisplatin plus epirubicin plus rilotumumab	FP3R	82	61	57/25	Western	73/9	NA	NA	13/69	76/6	34/47/1	66/12	NA	0.70 (95% CI, 0.45–1.09)	0.60 (95% CI, 0.45–0.79)	30/76	56/81	68/81	Lancet Oncol	24965569
					Capecitabine plus cisplatin plus epirubicin	FP3	39	60	31/8		34/5			9/30	38/1	16/22/1	31/4				8/38	16/39	32/39
Zhang 2014	China	NA	NA	August 2010—September 2012	S-1 plus oxaliplatin plus cetuximab	FP2R	30	49	37/19	Eastern	Metastatic and locally unresectable	26/30	8/48	12/44	Measurable	3/47/6	Gastric	25/31	0.74 (95% CI, 0.42–1.30)	0.67 (95% CI, 0.38–1.18)	17/30	10/30	3/30	World J Surg Oncol	24758484
					S-1 plus oxaliplatin	FP2	26														11/26	11/26	5/26
Lu 2014	China	NA	II	January 2009—December 2011	S-1 plus oxaliplatin	FP2	47	63	34/13	Eastern	Metastatic and locally unresectable	18/29	19/28	NA	Measurable	34/8/5	Gastric	12/32	0.60 (95% CI, 0.39–0.94)	0.57 (95% CI, 0.36–0.91)	24/47	39/47	27/47	J Chemother	24621155
					S-1	F1	47	65	33/14			16/31	20/27			33/10/4		10/33			13/47	15/47	15/47
Sugimoto 2014	Japan	UMIN000000638	II	December 2004—November 2007	S-1 plus paclitaxel	FT2	51	62	38/13	Eastern	40/11	NA	NA	14/37	Measurable	39/12/0	Gastric	33/16	0.99 (95% CI, 0.64–1.52)	1.18 (95% CI, 0.79–1.79)	16/51	3/51	14/51	Anticancer Res	24511022
					S-1 plus irinotecan	FI2	51	64	38/13		40/11			14/37		41/8/2		28/22			17/51	22/48	15/48
Koizumi 2014	Japan	NCT00287768	III	September 2005—September 2008	S-1 plus docetaxel	FT2	314	65	227/87	Eastern	260/54	127/187	119/195	168/146	242/72	137/177/0	Gastric and junction	NA	0.84 (95% CI, 0.71–0.99)	0.77 (95% CI, 0.65–0.90)	92/237	208/310	130/310	J Cancer Res Clin Oncol	24366758
					S-1	F1	321	65	229/92		267/54	135/186	131/190	163/158	249/72	147/174/0					65/243	49/313	129/313
Koizumi 2013	Japan	JapicCTI-101327	II	December 2008—February 2012	S-1 plus cisplatin plus orantinib	FP2R	45	62	30/15	Eastern	39/6	19/26	15/30	NA	Measurable	28/17/0	Gastric	22/23	0.74 (95% CI, 0.46-1.19)	1.23 (95% CI, 0.74–2.05)	28/45	36/45-2	27/45	Br J Cancer	24045669
					S-1 plus cisplatin	FP2	46	63.5	35/11		39/7	24/22	15/31			30/16/0		25/20			26/46	28/46-2	14/46
Shirao 2013	Japan	NCT00149201	III	October 2002—April 2007	5-FU plus leucovorin plus methotrexate	FM2	118	59	70/48	Eastern	Metastatic	NA	118/0 *	96/22	NA	46/68/4	Gastric	26/92	0.94 (95% CI, 0.72–1.22)	NA	NA	81/116	110/116	Jpn J Clin Oncol	24014884
					5-FU	F1	119	61	66/53				119/0 *	91/28		46/69/4		25/94				13/117	77/117
Richards 2013	USA	NCT00517829	II	December 2007—April 2010	Oxaliplatin plus docetaxel	PT2	75	61.7	59/16	Western	62/13	65/10	NA	NA	Measurable	26/42/7	37/38	Balanced	0.94 (95% CI, 0.65–1.36)	1.00 (95% CI, 0.67–1.49)	18/68	53/68	25/68	Eur J Cancer	23747051
					Oxaliplatin plus docetaxel plus cetuximab	PT2R	75	64	60/15		55/20	63/12				33/33/9	34/41				27/71	58/72	46/72
Waddell 2013	UK	NCT00824785	III	June 2008—October 2011	Capecitabine plus oxaliplatin plus epirubicin plus panitumumab	FP3R	278	63	232/46	Western	244/34	NA	NA	NA	Measurable	118/144/16	78/94/106 * -E	Balanced	1.37 (95% CI, 1.07–1.76)	1.22 (95% CI, 0.98–1.52)	116/254	69/276	264/276	Lancet Oncol	23594787
					Capecitabine plus oxaliplatin plus epirubicin	FP3	275	62	226/49		250/25					117/143/15	89/75/111 * -E				100/238	137/266	190/266
Lordick 2013	Germany	EudraCT2007-004219-75	III	June 2008—December 2010	Capecitabine plus cisplatin plus cetuximab	FP2R	455	60	339/116	Versatile	439/16	NA	113/342	92/363	Measurable	237/218/0	376/71	162/76	1.00 (95% CI, 0.87–1.17)	1.09 (95% CI, 0.92–1.29)	136/455	178/446	430/446	Lancet Oncol	23594786
					Capecitabine plus cisplatin	FP2	449	59	334/115		436/12		116/333	90/359		228/220/0	371/73	149/94			131/449	234/436	278/436
Wang 2013	China	NA	II	January 2008—September 2010	S-1 plus paclitaxel	FT2	41	63	32/9	Eastern	Metastatic and locally unresectable	16/25	15/26	15/26	Measurable	31/6/4	Gastric	11/28	0.55 (95% CI, 0.34–0.90)	0.60 (95% CI, 0.37–0.97)	19/41	32/41	36/41	Clin Transl Oncol	23381898
					S-1	F1	41	61	30/11			14/27	17/24	17/24		29/9/3		10/30			10/41	13/41	14/41
Eatock 2013	UK	NCT00583674	II	December 2007—July 2009	Capecitabine plus cisplatin plus trebananib	FP2R	115	59	85/30	Western	Metastatic	NA	NA	7/108	100/15	54/60/1	76/21/18 * -E	NA	Median OS time	0.98 (95% CI, 0.67–1.43)	35/100	33/114	44/114-3	Ann Oncol	23108953
					Capecitabine plus cisplatin	FP2	56	62	45/11					5/51	49/7	29/25/2	33/11/12 * -E				17/49	24/53	22/49-3
Al-Batran 2013	Germany	NCT00737373	II	August 2007—October 2008	5-FU plus oxaliplatin plus leucovorin plus docetaxel	FP3	72	69 *	51/21	Western	50/22	33/39	14/58	18/54	Measurable	67/5	45/27	NA	0.83 (95% CI, 0.54–1.28)	0.80 (95% CI, 0.54–1.20)	35/72	59/72-2	58/72	Eur J Cancer	23063354
					5-FU plus oxaliplatin plus leucovorin	FP2	71	70 *	45/26		49/22	32/39	14/57	18/53		65/6	47/24				20/71	16/70-2	46/70
Andrić 2012	Serbia	NA	NA	2006–2009	5-FU plus doxorubicin plus mitomycin-C	FA3	25	61	18/7	Western	21/4	NA	NA	9/16	NA	3/22/0	Gastric	7/18	1.17 (95% CI, 0.55–2.47)	NA	5/25	3/25	22/25	Srp Arh Celok Lek	22826983	Serbian
					5-FU plus cisplatin plus leucovorin	FP2	25	57	20/5		20/5			10/15		6/19/0		6/19	6/25		0/25	7/25
Roy 2012	UK	NA	II	August 1999—August 2000	Docetaxel plus irinotecan	TI2	42	62	35/7	Western	40/2	NA	NA	16/26	Measurable	7/29/6	27/15	Balanced	0.79 (95% CI, 0.52–1.22)	Median PFS time	13/42	35/42-1	35/42-3	Br J Cancer	22767144
					5-FU plus docetaxel	FT2	43	60	35/8		40/3			15/28		9/22/12	19/24				11/43	30/43-1	18/43-3
Mochiki 2012	Japan	NA	II	January 2006—November 2010	S-1 plus paclitaxel	FT2	42	63.3	31/11	Eastern	Metastatic and locally unresectable	14/28	11/31	9/33	Measurable	38/4/0	Gastric	16/26	0.94 (95% CI, 0.55–1.63)	0.84 (95% CI, 0.50–1.40)	22/42	8/42	6/42	Br J Cancer	22617130
					S-1 plus cisplatin	FP2	41	63	30/11			12/29	8/33	8/33		39/2/0		16/25			20/41	8/41	7/41
Ohtsu 2011	Japan	NCT00548548	III	September 2007—December 2008	Capecitabine plus cisplatin plus bevacizumab	FP2R	387	58	257/130	Versatile	367/20	130/257	NA	110/277	311/76	365/22	333/54	NA	0.87 (95% CI, 0.73–1.04)	0.80 (95% CI, 0.68–0.93)	143/311	194/386	165/386	J Clin Oncol	21844504
					Capecitabine plus cisplatin	FP2	387	59	258/129		378/9	126/261		107/280	297/90	367/20	338/49				111/297	209/381	183/381
Jeung 2011	South Korea	NA	II	July 2005—April 2007	S-1 plus docetaxel	FT2	39	56	31/8	Eastern	29/10	10/29	14/25	12/27	Measurable	35/4	Gastric	Balanced	0.56 (95% CI, 0.35–0.88)	0.63 (95% CI, 0.38–1.05)	18/39	Description	24/39	Cancer	21523716
					Cisplatin plus docetaxel	PT2	41	60	28/13		34/7	10/31	12/29	9/32		35/6					10/41		16/41
Komatsu 2011	Japan	NA	II	August 2003—March 2005	S-1 plus irinotecan	FI2	48	70 *	34/14	Eastern	33/15	NA	NA	2/46	Measurable	38/10/0	Gastric	Balanced	0.95 (95% CI, 0.64–1.41)	0.78 (95% CI, 0.54–1.13)	12/48	21/48	30/48	Anticancer Drugs	21512394
					S-1	F1	47	63 *	37/10		33/14			4/43		35/12/0					7/47	12/47	16/47
Li 2011	China	NA	II	January 2003—December 2007	5–FU plus cisplatin plus paclitaxel	FP3	50	59	32/18	Eastern	28/22	NA	NA	NA	Measurable	24/26	Gastric	Balanced	1.02 (95% CI, 0.63–1.66)	NA	24/50	4/50-1	5/50-1	World J Gastroenterol	21448363
					5-FU plus oxaliplatin plus leucovorin	FP2	44	58	31/13		27/17					21/23					20/44	4/44-1	0/44-1
Narahara 2011	Japan	JapicCTI-050083	III	June 2004—November 2005	S-1 plus irinotecan	FI2	155	63	110/45	Eastern	129/26	110/205	105/210	93/62	Measurable	102/48/5	Gastric	61/93	0.89 (95% CI, 0.70–1.15)	0.86 (95% CI, 0.68–1.08)	39/94	89/155	98/155	Gastric Cancer	21340666
					S-1	F1	160	63	127/33		133/27			93/67		109/46/5		71/88			25/93	53/160	87/160
Tebbutt 2010	Australia	NA	II	June 2004—May 2006	5-FU plus cisplatin plus docetaxel	FP3	50	60.5	42/8	Western	48/2	32/18	10/40	NA	Measurable	21/28/1	26/13/11 * -E	Balanced	0.84 (95% CI, 0.50–1.39)	0.73 (95% CI, 0.48–1.13)	22/47	8/49	38/49-4	Br J Cancer	20068567
					Capecitabine plus docetaxel	FT2	56	59.1	42/14		51/5	43/13	6/50			31/23/2	23/13/20 * -E				14/53	2/55	23/55-4
Yun 2010	South Korea	NCT00743964	II	April 2008—October 2009	Capecitabine plus cisplatin plus epirubicin	FP3	44	55	28/16	Eastern	Metastatic and locally unresectable	12/32	26/18	17/27	Measurable	40/1	Gastric	NA	NA	0.96 (95% CI, 0.58–1.57)	16/43	31/44	40/44	Eur J Cancer	20060288
					Capecitabine plus cisplatin	FP2	45	58	34/11			19/26	23/22	20/25		41/4					17/45	22/45	32/45
Moehler 2010	Germany	NA	II	October 2003—December 2006	Capecitabine plus irinotecan	FI2	57	61	42/15	Western	Metastatic	44/13	18/39	20/37	NA	0–2	49/7	NA	0.77 (95% CI, 0.51–1.17)	1.14 (95% CI, 0.59–2.21)	20/53	33/57	50/57	Ann Oncol	19605504
					Capecitabine plus cisplatin	FP2	55	64	36/19			38/17	20/35	14/41			38/17				21/50	48/55	54/55
Ikeda 2009	Japan	NA	II	June 2005—August 2008	S-1 plus docetaxel	FT2	24	58	19/5	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	21/3	Gastric	NA	0.53 (95% CI, 0.28–0.99)	0.53 (95% CI, 0.28–0.97)	21/24	22/24-2	3/24-3	J Clin Oncol	10.1200/jco.2009.27.15s.4595	Abstract
					5-FU plus cisplatin	FP2	25	65	23/2							23/2					13/25	8/25-2	18/25-3
Boku 2009	Japan	NCT00142350	III	November 2000—January 2006	Cisplatin plus irinotecan	PI2	236	63	180/56	Eastern	190/46	NA	76/160	NA	NA	151/81/4	Gastric	102/134	1 versus (2+3): 0.82 (95% CI, 0.68–0.99)	1 versus (2+3): 0.73 (95% CI, 0.64–0.83)	68/181	152/234-1	172/234	Lancet Oncol	19818685
					S-1	F1	234	64	175/59		188/46		69/165			151/80/3		110/124			49/174	30/234-1	94/234
					5-FU	F1	234	63.5	176/58		189/45		87/147			152/79/3		111/121			15/175	36/232-1	57/232
Ridwelski 2008	Germany	NA	III	NA	Cisplatin plus docetaxel	PT2	137	62	NA	Western	243/27	NA	NA	NA	NA	0–2	Gastric	NA	1.06 (95% CI, 0.82–1.37)	1.10 (95% CI, 0.85–1.42)	32/117	56/137-1	27/137-1	J Clin Oncol	10.1200/jco.2008.26.15_suppl.4512	Abstract
					5-FU plus cisplatin plus leucovorin	FP2	133														33/117	16/133-1	38/133-1
Tesselaar 2008	Netherlands	NA	II	NA	5-FU plus leucovorin plus paclitaxel	FT2	47	NA	NA	Western	Metastatic	NA	NA	NA	Measurable	NA	Gastric and junction	NA	0.79 (95% CI, 0.52–1.20)	Median PFS time	21/47	Description	13/47	J Clin Oncol	10.1200/jco.2008.26.15_suppl.4567	Abstract
					5-FU plus cisplatin plus leucovorin	FP2	49														23/49		17/49
Jin 2008	China	NCT00202969	III	July 2005—October 2006	S-1	F1	77	57	56/21	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	65/12	Gastric	NA	(2+3) versus 1: 0.55 (95% CI, 0.36–0.83)	Median PFS time	19/77	6/77	4/77	J Clin Oncol	10.1200/jco.2008.26.15_suppl.4533	Abstract
					S-1 plus cisplatin	FP2	74	56.5	55/19							66/8					28/74	26/74	17/74
					5-FU plus cisplatin	FP2	73	58	61/12							63/10					14/73	23/73	22/73
Dank 2008	Hungary	NA	III	June 2000—March 2002	5-FU plus cisplatin	FP2	163	59	108/55	Western	155/8	91/72	41/122	66/97	Measurable	27/134/2	132/31	42/46	1.08 (95% CI, 0.86–1.35)	1.23 (95% CI, 0.97–1.57)	42/163	155/166-3	128/166	Ann Oncol	18558665
					5-FU plus leucovorin plus irinotecan	FI2	170	58	125/45		163/7	101/69	40/130	70/100		45/124/1	136/34	49/60			54/170	88/167-3	119/167
Koizumi 2008	Japan	NCT00150670	III	March 2002—November 2004	S-1 plus cisplatin	FP2	148	62	108/40	Eastern	118/30	60/88	51/97	53/95	NA	106/38/4	Gastric	45/103	0.77 (95% CI, 0.61–0.98)	0.57 (95% CI, 0.44–0.73)	47/87	127/148	88/148	Lancet Oncol	18282805
					S-1	F1	150	62	116/34		119/31	60/90	36/114	58/92		106/39/5		60/89			33/106	27/150	24/150
Park 2008	South Korea	NCT00320294	II	October 2004—November 2006	5-FU plus cisplatin plus leucovorin plus irinotecan	FP3	45	51	30/15	Eastern	Metastatic and locally unresectable	16/29	26/19	29/16	Measurable	38/7	Gastric	NA	0.84 (95% CI, 0.38–1.89)	0.72 (95% CI, 0.44–1.19)	19/45	27/45	29/45	Ann Oncol	18083691
					5-FU plus leucovorin plus irinotecan	FI2	46	55	30/16			21/25	30/16	43/3		35/11					19/46	17/45	36/45
Popov 2008	Serbia	NA	II	August 1998—September 2001	Cisplatin plus doxorubicin plus etoposide	PA3	30	57	21/9	Western	27/3	18/12	10/20	24/6	Measurable	3/22/5	21/9	Balanced	0.86 (95% CI, 0.32–2.29)	Median PFS time	10/30	Cycles	Cycles	Med Oncol	17972024
					5-FU	F1	30	55	23/7		22/8	17/13	11/19	22/8		6/19/5	19/11				3/30
Roth 2007	Switzerland	NA	II	September 1999—July 2003	5-FU plus cisplatin plus docetaxel	FP3	41	61	30/11	Western	39/2	17/24	9/32	13/28	Measurable	25/16	Gastric	NA	(1+2) versus 3: 0.96 (95% CI, 0.59–1.54)	(1+2) versus 3: 0.79 (95% CI, 0.49–1.27)	15/41	33/41-1	37/41	J Clin Oncol	17664469
					5-FU plus cisplatin plus epirubicin	FP3	40	59	30/10		33/7	16/24	5/35	7/33		24/16					10/40	24/40-1	23/40
					Cisplatin plus docetaxel	PT2	38	58	29/9		31/7	15/23	3/34	9/29		23/15					7/38	29/38-1	32/38
Lutz 2007	Germany	NA	II	January 1996—August 1999	5-FU plus cisplatin plus leucovorin	FP2	51	62	40/11	Western	45/6	NA	NA	23/28	50/1	49/2	Gastric	22/13	1 versus 2: 0.66 (95% CI, 0.42–1.06)	Median PFS time	21/46	20/51	32/51	J Clin Oncol	17577037
					5-FU plus leucovorin	F1	53	53	42/11		47/6			26/27	53/0	49/4		27/10	1 versus 3: 0.57 (95% CI, 0.35–0.94)		12/48	4/53	12/48
					5-FU	F1	37	37	30/7		29/8			22/15	36/1	34/3		20/6	2 versus 3: 0.83 (95% CI, 0.50–1.37)		2/33	5/37	12/33
Van Cutsem 2006	Belgium	NA	III	November 1999—January 2003	5-FU plus cisplatin	FP2	224	55	158/66	Western	217/6	NA	NA	71/153	Measurable	29/192/3	168/56	45/77	1.29 (95% CI, 1.02–1.63)	1.47 (95% CI, 1.19–1.82)	57/224	126/224-1	206/224-3	J Clin Oncol	17075117
					5-FU plus cisplatin plus docetaxel	FP3	221	55	159/62		213/6			68/153		28/190/3	179/42	40/92			81/221	181/221-1	197/221-3
Ajani 2005	USA	NA	II	June 1998—September 1999	5-FU plus cisplatin plus docetaxel	FP3	79	57	61/18	Western	75/4	NA	NA	28/51	Measurable	7/72/0	50/29	16/30	1.19 (95% CI, 0.83–1.69)	0.80 (95% CI, 0.52–1.22)	34/79	66/79-1	73/79-4	J Clin Oncol	16110025
					Cisplatin plus docetaxel	PT2	76	57	53/23		72/4			30/46		10/65/1	56/20	20/17			20/76	65/76-1	39//76-4
Moehler 2005	Germany	NA	II	November 2000—April 2003	5-FU plus leucovorin plus etoposide	FE2	58	63	49/9	Western	Metastatic and locally unresectable	42/16	11/47	31/27	Measurable	8/43/7	42/16	NA	1.25 (95% CI, 0.83–1.86)	1.10 (95% CI, 0.75–1.62)	14/58	45/58	31/58	Br J Cancer	15942629
					5-FU plus leucovorin plus irinotecan	FI2	56	61	40/16			46/10	10/46	29/27		4/49/3	37/19				24/56	15/56	29/56
Thuss-Patience 2005	Germany	NA	II	NA	5-FU plus docetaxel	FT2	45	62	29/16	Western	44/1	26/19	15/30	NA	Measurable	14/28/2	31/14	14/12	1.02 (95% CI, 0.68–1.54)	0.96 (95% CI, 0.63–1.48)	17/45	24/45	23/45	J Clin Oncol	15659494
					5-FU plus cisplatin plus epirubicin	FP3	45	63	36/9		44/1	20/25	20/25			16/28/1	33/12	12/19			16/45	32/45	21/45
Pozzo 2004	Italy	NA	II	January 1999—April 2000	5-FU plus leucovorin plus irinotecan	FI2	74	57	57/17	Western	68/6	33/41	13/61	28/46	57/17	11/63/0	61/12	22/34	0.56 (95% CI, 0.39–0.81)	0.41 (95% CI, 0.26–0.64)	25/74	33/74	36/74	Ann Oncol	15550582
					Cisplatin plus irinotecan	PI2	72	59	46/26		69/3	39/33	16/56	30/42	57/15	7/65/0	49/23	27/29			18/72	68/72	33/72
Bouché 2004	France	NA	II	January 1999—October 2001	5-FU plus leucovorin plus irinotecan	FI2	45	65	38/7	Western	Metastatic	41/4	9/36	23/22	Measurable	35/10	31/14	Balanced	1 versus 2: 0.93 (95% CI, 0.54–1.58)	1 versus 2: 0.84 (95% CI, 0.52–1.35)	18/45	25/45-2	24/45	J Clin Oncol	15514373
					5-FU plus cisplatin plus leucovorin	FP2	44	64	35/9			42/2	6/44	22/22		33/11	31/13		1 versus 3: 0.64 (95% CI, 0.38–1.08)	1 versus 3: 0.47 (95% CI, 0.29–0.78)	18/45	25/45-2	24/45
					5-FU plus leucovorin	F1	45	64	37/8			43/2	10/45	23/22		33/12	32/13		2 versus 3: 0.65 (95% CI, 0.39-1.10)	2 versus 3: 0.59 (95% CI, 0.36–0.97)	12/44	40/44-2	16/44
Koizumi 2004	Japan	NA	II	July 1991—December 1996	Doxifluridine plus cisplatin plus mitomycin-C	FP3	32	58	17/15	Eastern	Metastatic and locally unresectable	10/22	8/24	3/29	Measurable	5/20/6	Gastric	Balanced	0.78 (95% CI, 0.43–1.41)	NA	8/32	14/32	7/32	Anticancer Res	15330199
					Doxifluridine plus cisplatin	FP2	29	58	19/10			11/18	6/23	2/27		3/13/9					5/29	6/29	8/29
Cocconi 2003	Italy	NA	NA	May 1993—November 1999	5-FU plus cisplatin plus leucovorin plus epirubicin	FP3	98	62	67/31	Western	82/16	NA	NA	49/49	Measurable	0–2	Gastric	NA	0.90 (95% CI, 0.77–1.05)	Median PFS time	38/98	62/94	50/94	Ann Oncol	12881389
					5-FU plus doxorubicin plus methotrexate	FA3	97	62	66/31		83/14			50/47							21/97	60/93	30/93
Ohtsu 2003	Japan	NA	III	September 1992—March 1997	UFT plus mitomycin-C	FY2	70	60.5	55/15	Eastern	61/9	31/39	20/50	21/49	Measurable	63/7	Gastric	29/39	1 versus 2: 1.53 (95% CI, 1.11–2.11)	1 versus 2: 2.16 (95% CI, 1.47–3.17)	6/70	45/67-2	25/67	J Clin Oncol	12506170
					5-FU plus cisplatin	FP2	105	63	77/28		90/15	55/50	28/77	29/76		95/10		49/52	1 versus 3: 1.29 (95% CI, 0.93–1.79)	1 versus 3: 1.19 (95% CI, 0.84–1.69)	36/105	81/102-2	40/102
					5-FU	F1	105	63	75/29		90/15	49/56	23/82	27/78		95/10		47/56	2 versus 3: 0.84 (95% CI, 0.63–1.11)	2 versus 3: 0.63 (95% CI, 0.46–0.86)	12/105	15/104-2	26/104
Tebbutt 2002	UK	NA	III	July 1994—February 2001	5-FU	F1	123	72 *	94/29	Western	71/29	NA	NA	NA	NA	11/72/37	55/33/29 * -E	Balanced	0.96 (95% CI, 0.75–1.22)	1.09 (95% CI, 0.86–1.38)	19/118	17/123	59/123	Ann Oncol	12377644
					5-FU plus mitomycin-C	FY2	127	72 *	95/32		73/30					9/70/44	69/30/27 * -E				23/121	27/127	56/127
Kim 2001	South Korea	NA	III	March 1997—April 2000	5-FU plus cisplatin plus epirubicin	FP3	61	55	45/15	Eastern	57/3	32/29	NA	NA	Measurable	55/6	Gastric	NA	0.83 (95% CI, 0.42–1.61)	Median PFS time	22/61	23/61-2	32/61-3	Eur J Cancer	10.1016/S0959-8049(01)81651-8	Abstract
					5-FU plus cisplatin	FP2	60	56.5	42/18		57/3	28/32				53/7					20/60	10/60-2	10/60-3
Vanhoefer 2000	Germany	NA	III	July 1991—April 1995	5-FU plus leucovorin plus etoposide	FE2	132	59	90/38	Western	110/22	NA	NA	78/54	122/10	54/66/12	Gastric	57/45	1 versus 3: 0.95 (95% CI, 0.74–1.24)	1 versus 3: 1.02 (95% CI, 0.79–1.32)	7/79	68/129	62/129	J Clin Oncol	10894863
					5-FU plus cisplatin	FP2	134	57	91/41		113/21			73/61	125/9	43/71/20		65/43	2 versus 3: 0.98 (95% CI, 0.86–1.12)	2 versus 3: 0.94 (95% CI, 0.83–1.07)	16/81	73/127	84/127
					5-FU plus doxorubicin plus methotrexate	FA3	133	58	96/34		111/22			67/66	122/11	36/81/16		59/47			10/85	89/122	57/122
Roth 1999	Croatia	NA	NA	NA	5-FU plus cisplatin plus epirubicin	FP3	54	55	NA	Western	74/36	NA	NA	NA	Measurable	57/53	Gastric	NA	0.74 (95% CI, 0.55–0.99)	NA	16/56	Description	Description	Tumori	10587023
					5-FU plus epirubicin	FA2	56														23/54
Waters 1999	UK	NA	NA	July 1992—June 1995	5-FU plus doxorubicin plus methotrexate	FA3	130	60	110/20	Western	79/51	NA	NA	48/82	NA	97/32	73/33/24 * -E	Balanced	1.52 (95% CI, 1.19–1.95)	1.79 (95% CI, 1.40–2.29)	24/116	126/130-2	111/130	Br J Cancer	10390007
					5-FU plus cisplatin plus epirubicin	FP3	126	59	99/27		79/47			51/75		96/30	72/27/27 * -E				56/121	60/126-2	122/126
Içli 1998	Turkey	NA	III	1994–1997	5-FU plus cisplatin plus epirubicin	FP3	67	52.7	40/27	Western	53/14	NA	NA	NA	Measurable	8/38/21	Gastric	NA	1.23 (95% CI, 0.76–1.98)	1.07 (95% CI, 0.58–1.96)	9/59	4/67	15/67	Cancer	9874451
					Cisplatin plus epirubicin plus etoposide	PA3	64	52.7	44/20		53/11					6/36/22					12/59	6/64	10/64
Yamamura 1998	Japan	NA	NA	NA	5-FU plus pirarubicin plus methotrexate	FA3	37	NA	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	NA	Gastric	NA	0.88 (95% CI, 0.55–1.41)	NA	NA	Description	Description	Gan To Kagaku Ryoho	9725047	Japanese
					5-FU	F1	34
Barone 1998	Italy	NA	II	January 1993—December 1995	Cisplatin plus epirubicin plus etoposide	PA3	36	57.3	26/10	Western	Metastatic and locally unresectable	19/17	17/19	22/14	Measurable	28/8	Gastric	NA	0.89 (95% CI, 0.55–1.42)	Median PFS time	6/33	Cycles	Cycles	Cancer	9554521
					5-FU plus leucovorin	F1	36	59	24/12		17/19	18/18	20/16	28/8							7/32
Scheithauer 1996	Austria	NA	NA	NA	5-FU plus leucovorin plus doxorubicin	FA2	52	NA	NA	Western	65/38	NA	NA	NA	NA	73/30	Gastric	NA	0.49 (95% CI, 0.33–0.74)	0.31 (95% CI, 0.21–0.45)	NA	NA	NA	Ann Hematol	28850174	Abstract
					Supportive care	S	51
Colucci 1995	Italy	NA	NA	NA	5-FU plus leucovorin plus etoposide	FE2	31	56	20/11	Western	Metastatic and locally unresectable	14/17	1/30	18/13	Measurable	0–2	Gastric	NA	0.70 (95% CI, 0.42–1.16)	NA	13/31	4/31	15/31	Am J Clin Oncol	8526196
					5-FU plus leucovorin	F1	31	58	20/11			17/14	1/30	20/11							9/31	2/31	4/31
Pyrhönen 1995	Finland	NA	III	July 1986—June 1992	5-FU plus leucovorin plus epirubicin	FA2	21	58	15/6	Western	15/6	8/13	4/17	15/6	Measurable	4/15/2	Gastric	NA	0.35 (95% CI, 0.15–0.81)	0.29 (95% CI, 0.13–0.65)	6/21	12/21	13/21	Br J Cancer	7533517
					Supportive care	S	20	58	10/10		14/6	8/12	2/18	16/4		3/15/2					0/20	0/20	0/20
Coombes 1994	UK	NA	NA	August 1985—September 1988	Epirubicin	A1	36	59.9	27/9	Western	34/2	18/18	8/28	NA	Measurable	0–2	Gastric	NA	1.09 (95% CI, 0.56–2.12)	NA	3/36	3/36	25/36	Ann Oncol	8172789
					5-FU	F1	33	55.6	24/9		31/2	15/18	5/28								2/33	4/33	9/33
Cocconi 1994	Italy	NA	III	August 1988—November 1991	5-FU plus cisplatin plus leucovorin plus epirubicin	FP3	85	62	60/25	Western	78/7	NA	NA	31/21	46/6	0–3	Gastric	NA	0.69 (95% CI, 0.51–0.93)	Median PFS time	37/85	13/85	28/85	J Clin Oncol	7989945
					5-FU plus doxorubicin plus mitomycin-C	FA3	52	65	42/10		43/9			54/31	76/9						8/52	1/52	8/52
Loehrer 1994	USA	NA	NA	January 1985—January 1987	5-FU	F1	69	59	NA	Western	44/25	34/35	16/53	NA	47/22	12/34/22	Gastric	NA	1 versus 2: 0.75 (95% CI, 0.43–1.31)	1 versus 2: 0.42 (95% CI, 0.21–0.83)	5/40	21/69	48/69	Invest New Drugs	7960608
					Epirubicin	A1	26	57			15/11	11/15	5/21		17/9	7/11/5			1 versus 3: 0.98 (95% CI, 0.67–1.44)	1 versus 3: 1.02 (95% CI, 0.69–1.53)	1/16	6/26	18/26
					5-FU plus epirubicin	FA2	70	62			45/25	35/35	16/54		50/20	16/31/14			2 versus 3: 1.25 (95% CI, 0.73–2.14)	2 versus 3: 4.55 (95% CI, 2.40–8.65)	4/33	48/70	68/70
Cullinan 1994	USA	NA	NA	February 1984—March 1992	5-FU plus doxorubicin plus Me-CCNU plus triazinate	FA4	79	60	53/26	Western	Metastatic and locally unresectable	NA	NA	31/48	16/63	55/24	Gastric	Balanced	1 versus 4: 0.95 (95% CI, 0.65–1.38)	1 versus 4: 0.65 (95% CI, 0.46–0.94)	NA	47/79	47/79	J Clin Oncol	8113849
					5-FU plus cisplatin plus doxorubicin	FP3	51	61	40/11					21/30	6/45	35/16			2 versus 4: 1.17 (95% CI, 0.77–1.76)	2 versus 4: 0.84 (95% CI, 0.57–1.26)		29/51	30/51
					5-FU plus doxorubicin plus Me-CCNU	FA3	53	63	43/10					18/35	6/47	36/17			3 versus 4: 0.97 (95% CI, 0.62–1.52)	3 versus 4: 0.90 (95% CI, 0.60–1.34)		34/53	16/53
					5-FU	F1	69	63	52/17					24/45	14/55	50/19						28/69	12/69
Murad 1993	Brazil	NA	II	1988–1991	5-FU plus doxorubicin plus methotrexate	FA3	30	58	20/10	Versatile	21/9	NA	NA	13/17	Measurable	5/16/9	Gastric	NA	0.33 (95% CI, 0.17–0.64)	NA	15/30	2/30	7/30	Cancer	8508427
					Supportive care	S	10	57	7/3		6/4			3/7		3/4/3					0/10	0/10	0/10
Kim 1993	South Korea	NA	III	August 1986—June 1990	5-FU plus doxorubicin plus mitomycin-C	FA3	98	54	68/30	Eastern	Metastatic and locally unresectable	34/64	NA	22/76	57/41	75/23	Gastric	22/48	1 versus 2: 1.36 (95% CI, 0.99–1.86)	Median PFS time	14/57	Cycles	93/98-2	Cancer	8508349
					5-FU plus cisplatin	FP2	103	51	71/32			38/65		15/88	55/48	83/20		30/52	1 versus 3: 1.21 (95% CI, 0.88–1.67)		28/55		101/103-2
					5-FU	F1	94	54	66/28			33/61		10/84	54/50	76/18		26/45	2 versus 3: 0.84 (95% CI, 0.61–1.17)		14/54		44/94-2
KRGGC 1992	South Korea	NA	NA	NA	5-FU plus cisplatin plus epirubicin	FP3	25	NA	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	NA	Gastric	NA	0.57 (95% CI, 0.27–1.20)	NA	5/21	Description	Description	Anticancer Res	1295444
					5-FU plus cisplatin	FP2	22														6/22
Kelsen 1992	USA	NA	NA	June 1988—October 1990	5-FU plus leucovorin plus doxorubicin plus methotrexate	FA3	30	56	22/8	Western	19/11	16/14	2/28	NA	Measurable	0–2	Gastric and junction	NA	0.79 (95% CI, 0.42–1.46)	NA	10/30	Description	Description	J Clin Oncol	1548519
					Cisplatin plus doxorubicin plus etoposide	PA3	30	57	24/6		21/9	16/14	3/27								6/30
Kikuchi 1990	Japan	NA	NA	NA	5-FU plus cisplatin plus doxorubicin	FP3	32	NA	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	NA	Gastric	NA	0.58 (95% CI, 0.36–0.95)	NA	6/18	Description	Description	Gan To Kagaku Ryoho	2181941	Japanese
					5-FU plus doxorubicin	FA2	33														0/19
GITSG 1988	USA	NA	III	November 1981—July 1985	5-FU plus cisplatin plus doxorubicin	FP3	85	18–75	63/22	Western	Metastatic	41/44	NA	NA	31/54	58/27	Gastric	NA	1 versus 2: 0.98 (95% CI, 0.67–1.45)	NA	6/30	64/85	33/85	J Natl Cancer Inst	2900901
					5-FU plus doxorubicin plus triazinate	FA3	81		60/21			32/49			30/51	53/28			1 versus 3: 0.71 (95% CI, 0.49–1.02)		6/31	23/81	25/81
					5-FU plus doxorubicin plus Me-CCNU	FA3	81		51/30			40/41			33/48	51/30			2 versus 3: 0.71 (95% CI, 0.49–1.03)		5/33	61/81	12/81
Lacave 1987	Spain	NA	III	April 1979—June 1983	5-FU plus doxorubicin plus Me-CCNU	FA3	85	58	55/30	Western	65/20	32/53	43/42	60/25	28/57	0–3	Gastric	NA	0.82 (95% CI, 0.59–1.14)	NA	5/28	Description	Description	J Clin Oncol	3305795
					5-FU plus doxorubicin	FA2	88	59	65/23		74/14	50/38	48/40	63/25	29/59						3/29
Levi 1986	Australia	NA	NA	NA	5-FU plus doxorubicin plus BCNU	FA3	94	61	68/26	Western	Metastatic and locally unresectable	28/66	22/72	42/52	75/19	68/18	Gastric	Balanced	0.58 (95% CI, 0.43–0.77)	0.62 (95% CI, 0.30–1.28)	30/75	13/94	10/94	J Clin Oncol	3528404
					Doxorubicin	A1	93	59	68/25			26/67	17/76	41/52	70/24	63/23					9/70	5/93	14/93
De Lisi 1986	Italy	NA	III	NA	5-FU plus doxorubicin plus mitomycin-C plus BCNU	FA4	42	64	NA	Western	Metastatic and locally unresectable	NA	NA	NA	NA	NA	Gastric	NA	1.16 (95% CI, 0.26–5.15)	NA	9/41	Description	Description	Cancer Treat Rep	3516397
					5-FU	F1	42														6/41
Cullinan 1985	USA	NA	NA	NA	5-FU	F1	51	18–75	36/15	Western	32/19	NA	NA	NA	11/40	37/14	Gastric	NA	1 versus 2: 0.96 (95% CI, 0.60–1.52)	1 versus 2: 0.99 (95% CI, 0.62–1.59)	2/11	Description	Description	JAMA	2579257
					5-FU plus doxorubicin	FA2	49		37/12		31/18				10/39	33/16			1 versus 3: 0.91 (95% CI, 0.56–1.48)	1 versus 3: 1.17 (95% CI, 0.70–1.96)	3/11
					5-FU plus doxorubicin plus mitomycin-C	FA3	51		39/12		31/20				13/38	32/19			2 versus 3: 0.99 (95% CI, 0.64–1.53)	2 versus 3: 1.30 (95% CI, 0.82–2.06)	5/13
Douglass 1984	USA	NA	NA	NA	5-FU plus doxorubicin plus Me-CCNU	FA3	39	62	31/8	Western	Metastatic and locally unresectable	NA	NA	NA	Measurable	9/21/6	Gastric	Balanced	1 versus 2: 1.61 (95% CI, 0.88–2.92)	NA	11/39	14/39	3/39	J Clin Oncol	6439836
					5–FU plus doxorubicin plus mitomycin–C	FA3	46	61	35/11							11/19/13			1 versus 3: 0.72 (95% CI, 0.39–1.35)		18/46	14/46	1/46
					5-FU plus Me-CCNU	FU2	44	58	35/9							9/23/10			1 versus 4: 0.94 (95% CI, 0.54–1.64)		6/44	13/44	4/44
					Doxorubicin plus mitomycin-C	AY2	46	59.5	33/13							8/20/14			13/46		13/46	6/46
O’Connel 1984	USA	NA	NA	December 1978—March 1981	5-FU plus doxorubicin plus Me-CCNU	FA3	76	62	53/23	Western	60/16	29/41	NA	NA	16/44	18/38/20	Gastric	Balanced	1 versus 2: 0.89 (95% CI, 0.58–1.37)	NA	4/16	60/76	11/76	Cancer	6418371
					5-FU plus doxorubicin plus mitomycin-C	FA3	78	62	52/26		62/16	23/46			18/44	17/38/23			1 versus 3: 0.82 (95% CI, 0.54–1.26)		3/18	40/78	7/78
					5-FU plus doxorubicin	FA2	78	60	57/21		60/18	21/54			19/41	16/40/22			2 versus 3: 0.92 (95% CI, 0.62–1.39)		1/19	32/78	7/78
Friedman 1983	USA	NA	III	December 1977– December 1980	Tegafur plus doxorubicin plus BCNU	FA3	36	18–75	24/12	Western	27/9	NA	NA	15/21	22/14	0–3	Gastric	NA	1.03 (95% CI, 0.64–1.66)	NA	3/22	9/36	4/36	Cancer	6414682
					5-FU plus doxorubicin	FA2	38		22/16		28/10			19/19	19/19						1/19	14/38	2/38
					Tegafur plus doxorubicin plus mitomycin-C	FA3	34		22/12	Eastern	28/6			8/29	12/22				0.79 (95% CI, 0.39–1.59)	NA	1/12	10/34	0/34
					5-FU plus doxorubicin	FA2	34		21/13		27/7			5/26	22/12						3/22	5/34	1/34
O’Connel 1982	USA	NA	NA	NA	5-FU plus doxorubicin plus mitomycin-C	FA3	43	62	29/14	Western	Metastatic and locally unresectable	NA	NA	NA	12/31	18/25	Gastric	NA	1 versus 2: 1.13 (95% CI, 0.57–2.25)	Median PFS time	3/12	7/43	Description	Cancer	7037163
					5-FU plus doxorubicin plus Me-CCNU	FA3	34	59	25/9					10/24	21/13	1 versus 3: 0.69 (95% CI, 0.38–1.26)			3/10		7/34
					5-FU plus Me-CCNU plus razoxane	FU3	46	62	32/14					19/27	17/29	1 versus 4: 0.87 (95% CI, 0.46–1.64)			4/19		15/46
					5-FU plus Me-CCNU	FU2	58	64	34/24					18/40	29/29				1/18		17/58
Buroker 1979	USA	NA	II	March 1975– March 1977	5-FU plus mitomycin-C	FY2	80	18–75	NA	Western	Metastatic and locally unresectable	28/52	NA	NA	43/37	NA	Gastric	NA	0.86 (95% CI, 0.60–1.21)	NA	6/43	Cycles	Cycles	Cancer	387204
					5-FU plus Me-CCNU	FU2	88					40/48			55/33						5/54

Notes: Items that may produce significant heterogeneity are emphasized with bold-type letters and asterisks. Underlined data in PS (0/1/2) indicates that the numbers should be interpreted as PS (0 and 1) versus PS (2). The additional letter ‘E’ in certain items of ‘Location (G/J)’ suggested that there were additional esophageal cancer cases in addition to gastric and gastroesophageal junction cancer cases. The word ‘Balanced’ in ‘Histological type (I/D)’ indicated that although there was no description about the ratio of intestinal and diffused types, there were other classifications of histological grades and both arms were well balanced. In multi-arm studies, for example, ‘1 versus 2’ in survival data referred to the hazard ratio of first regimen versus the second regimen. In terms of adverse events, since the number of events sometimes surpassed the total number of patients, therefore in those situations we only calculated the most significant types of adverse event in each category. The numbers of selected types of adverse events were identified inside the cells and underlined. Moreover, the words ‘Description’ or ‘Cycles’ inside adverse events suggested that there was no quantitative data or the quantitative data was calculated by chemotherapeutic cycles rather than patient-level comparison, respectively. Regarding ‘PMID’, those studies without a specific PubMed ID were either replaced by a DOI number or the PubMed ID of previous systematic reviews carrying relevant information. Unless clarified, the hazard ratios were the results of upper arm versus lower arm in each trial.

E/T, events/total patients; G/J, gastric/junction; hAE, hematological adverse events; HR, hazard ratio; I/D, intestinal/diffused; M/F, male/female; NA, not available; non-hAE, nonhematological adverse events; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; P/T, responsive patients/total patients;

Nodes: 1, monotherapy; 2, doublet; 3, triplet; A, anthracycline; E, etoposide; F, fluoropyrimidine; I, irinotecan; M, methotrexate; P, platinum; R, targeted medication; S, best supportive care; T, taxane; Y, mitomycin-C; U, nitrosourea. Details of the rationale for organizing the nodes are described in main text.

First, all included studies were randomized controlled trials that minimized the methodological heterogeneity induced by different study designs. Second, patients in most studies shared similar and comparable baseline characteristics that guaranteed the treatment effects not to be artificially biased owing to unbalanced confounding information. For example, in most studies, patients were PS < 2, metastatic, measurable, and gastric cancer cases, without specific inclination of histological types. Other potential difference in baseline features were either unable to alter the results (such as small amount of esophagogastric junction cases) or addressed by sensitivity analysis (Table 1). All these had justified the transitivity and performance of our network meta-analysis.

General analysis: risk of bias

Overall, the included studies had low risk of bias since nearly half of the assessment parameters were scored as low risk of bias (45%), while unclear risk (39%) or high risk of bias (16%) took up relatively small proportions (Figure 2). None of the eligible studies were at high risk of bias concerning methodological design (Supplementary Table 2).

Figure 2.

Risk of bias assessment in general analysis.

Specifically, 31% and 48% of the studies were evaluated as low risk of bias concerning random sequence generation and allocation concealment, respectively, while no high risk of bias was reported in these two key domains. Largely due to the open-label design, 90% of the included trials were scored as high risk of bias in terms of blinding or participants and personnel. Meanwhile, since there was a lack of details on whether the response evaluation was independent enough, more than half of the studies (63%) were evaluated as unclear risk of bias regarding blinding of outcome assessment. In addition, because most of the studies were analyzed based on the intent-to-treat population as well as having reported enough endpoints, 79% and 72% of the eligible trials had low risk of bias in terms of incomplete outcome data and selective reporting, respectively. Moreover, since the majority of studies were completely performed without early termination and also described adequate baseline details, nearly half of the studies (48%) were appraised as low risk of bias with respect to other source of bias (Figure 2).

General analysis: primary endpoint (OS)

Network geometry

There were a total of 91 randomized controlled trials merged into the quantitative analysis, with 17,529 participants and 24 nodes of therapeutic regimen (Figure 3 and Table 1).

Figure 3.

Network structure plot of overall survival in general analysis.

Note: The size of nodes implicates the number of studies of each regimen while the width of the lines is proportional to the amount of mutual direct comparisons.

Nodes: 1, monotherapy; 2, doublet; 3, triplet; A, anthracycline; E, etoposide; F, fluoropyrimidine; I, irinotecan; M, methotrexate; P, platinum; R, targeted medication; S, best supportive care; T, taxane; U, nitrosourea; Y, mitomycin-C.

Consistency and statistical heterogeneity

In addition to the value of Q statistic (Q inconsistency: p = 0.08), the effect size and CI between direct and indirect results were highly overlapped (Supplementary Table 3), both of which suggested that results inside the entire network were consistent. In terms of statistical heterogeneity, both I2 statistic (I2 = 15.00%) and Q statistic (Q heterogeneity: p = 0.29) implied that there was no significant heterogeneity across the network.

Publication bias

There was no publication bias among the included studies owing to the symmetrical distribution of effect sizes inside the funnel plot (Supplementary Figure 1).

Network calculation

Based on P-score ranking of the network meta-analysis, ‘fluoropyrimidine plus platinum-based triplet’ (network HR 95% CI: 0.91 (0.83–0.99), P-score = 0.903) was the best ranking regimen, displaying statistical superiority against common comparator ‘fluoropyrimidine plus platinum doublet’ (p = 0.04). The network forest plot and league table are shown in Figures 4 and 5, respectively. These results were also consistent with pairwise meta-analysis, where ‘fluoropyrimidine plus platinum-based triplet’ was better than ‘fluoropyrimidine plus platinum doublet’ (random HR 95% CI: 0.86 (0.75–0.98), p = 0.03; Supplementary Table 3).

Figure 4.

Network forest plot of overall survival in general analysis.

Figure 5.

Network league table of overall survival in general analysis.

Note: Treatments are hierarchically ranked according to their P-score. The higher the position in the table a regimen is located, the better survival benefits it could offer. Values situated at the intersection of a specific column and row are the network effect sizes (HR and 95% CI) of row-defining regimen versus column-defining regimen.

Sensitivity analysis

After changing to a fixed-effects model (network HR 95% CI: 0.91 (0.84–0.98), P-score = 0.916) or removing clinically heterogeneous studies (network HR 95% CI: 0.90 (0.82–0.99), P-score = 0.903), ‘fluoropyrimidine plus platinum-based triplet’ remained as the top node with statistical advantage against ‘fluoropyrimidine plus platinum doublet’ (figures not shown).

General analysis: secondary endpoint

PFS

A total of 63 studies were included in the network calculation. ‘Fluoropyrimidine plus platinum-based triplet plus targeted medication’ became the best regimen in the entire hierarchy (network HR 95% CI: 0.75 (0.54–1.04), P-score = 0.919), closely followed by ‘fluoropyrimidine plus platinum-based triplet’ (network HR 95% CI: 0.83 (0.71–0.96), P-score = 0.881). However, only ‘fluoropyrimidine plus platinum-based triplet’ had shown statistical superiority against ‘fluoropyrimidine plus platinum doublet’ (p = 0.01) (Supplementary Figure 2).

ORR

A total of 89 studies were eligible and merged into the hierarchical comparisons. ‘Fluoropyrimidine plus platinum-based triplet plus targeted medication’ (network RR 95% CI: 1.48 (1.11–1.98), P-score = 0.964) and ‘fluoropyrimidine plus platinum-based triplet’ (network RR 95% CI: 1.20 (1.06–1.36), P-score = 0.857) again ranked as the top two nodes in the entire hierarchy, both of which demonstrated statistical advantage against common comparator ‘fluoropyrimidine plus platinum doublet’ (FP3R: p = 0.008; FP3: p = 0.004) (Supplementary Figure 3).

Hematological adverse events

A total of 74 studies were included in the network meta-analysis. ‘Best supportive care’ was certainly the most tolerable node in the rankings (network RR 95% CI: 0.16 (0.02–1.28), P-score = 0.952). Meanwhile, based on the hierarchical data, both ‘fluoropyrimidine plus platinum-based triplet plus targeted medication’ (network RR 95% CI: 1.31 (0.75–2.29), P-score = 0.414) and ‘fluoropyrimidine plus platinum-based triplet’ (network RR 95% CI: 1.55 (1.25–1.90), P-score = 0.272) had worse rankings than ‘fluoropyrimidine plus platinum doublet’ while the difference between ‘fluoropyrimidine plus platinum-based triplet’ and ‘fluoropyrimidine plus platinum doublet’ was statistically meaningful (p = 0.0001) (Supplementary Figure 4).

Nonhematological adverse events

A total of 78 studies were included in the network meta-analysis. Undoubtedly, ‘Best supportive care’ was the most tolerable node concerning nonhematological adverse events (network RR 95% CI: 0.07 (0.01–0.50), P-score = 0.993). Both ‘fluoropyrimidine plus platinum-based triplet’ (network RR 95% CI: 1.15 (0.99–1.34), P-score = 0.315) and ‘fluoropyrimidine plus platinum-based triplet plus targeted medication’ (network RR 95% CI: 1.44 (1.02–2.03), P-score = 0.176) displayed lower rankings than ‘fluoropyrimidine plus platinum doublet’ while the difference between ‘fluoropyrimidine plus platinum-based triplet plus targeted medication’ and ‘fluoropyrimidine plus platinum doublet’ was statistical meaningful (p = 0.04) (Supplementary Figure 5).

Additional analysis

Although the results from general analysis seemed to be very consistent, however, since there were several subtypes of medications included in fluoropyrimidines and platinum, we decided to perform an additional analysis by only including studies with pairwise comparisons between fluoropyrimidine plus platinum-based regimens. This not only helped to lower the heterogeneity across the network but also enhanced the clinical specificity and availability. Overall 39 randomized controlled trials were eligible for additional analysis, containing a total of 10,959 patients. ‘5-FU plus cisplatin’ (FC2) was chosen as the common comparator. Since fluoropyrimidine plus oxaliplatin doublet (especially capecitabine plus oxaliplatin) was commonly used in clinical applications, we also observed relative results between fluoropyrimidine plus oxaliplatin doublet and other alternative regimens by network league tables. Similar to that of general analysis, the majority of studies featured metastatic and measurable gastric cancer cases, exhibiting a low level of clinical heterogeneity and therefore a well transitivity (Table 2). Overall, none of the included studies were at high risk of bias regarding methodological design (Supplementary Table 4).

Table 2.

Baseline characteristics of eligible studies for additional analysis (unselected population).

Study	Leading country	Registration	Phase	Enrollment	Regimen	Node	Sample size	Age	Gender (M/F)	Region	Metastatic (Y/N)	Visceral involvement (Y/N)	Peritoneal involvement (Y/N)	Prior resection (Y/N)	Measurable (Y/N)	PS (0/1/2)	Location (G/J)	Histological type (I/D)	OS-HR	PFS-HR	ORR (P/T)	hAE (E/T)	non-hAE (E/T)	Journal	PMID	Note
Kawakami 2018	Japan	UMIN000006755	II	NA	S-1 plus cisplatin	SC2	41	68	33/8	Eastern	33/8	22/19	8/33	6/35	NA	22/19	Gastric	NA	0.78 (95% CI, 0.49–1.24)	0.76 (95% CI, 0.46–1.26)	21/41	27/39	26/39	Oncologist	30115736	New study
					Capecitabine plus cisplatin	XC2	43	64	36/7		38/5	20/23	13/30	2/41		24/19					23/43	38/43	37/43
Nishikawa 2018	Japan	NCT00140624	II	July 2011–June 2013	Capecitabine plus cisplatin	XC2	55	65	45/10	Eastern	43/12	11/44	23/32	17/38	36/19	45/8/2	Gastric	19/29	0.94 (95% CI, 0.62–1.42)	1.13 (95% CI, 0.75–1.69)	25/36	23/55	40/55	Eur J Cancer	30096702	New study
					S-1 plus cisplatin	SC2	55	65	30/25		42/13	12/43	23/32	17/38	33/22	47/7/1		26/24			14/33	16/55	39/55
Yamada 2018	Japan	UMIN000007652	III	April 2012–March 2016	S-1 plus cisplatin plus docetaxel	SC3	370	Adult	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	0–1	Gastric	259/428	0.99 (95% CI, 0.85–1.16)	0.99 (95% CI, 0.86–1.15)	219/370	245/370-2	26/370-1	J Clin Oncol	J Clin Oncol 36, 2018 (suppl; abstr 4009)	From general analysis, abstract
					S-1 plus cisplatin	SC2	371														208/371	140/371-2	27/371-1
Fuchs 2018	USA	NCT02314117	III	January 2015–May 2017	5-FU/capecitabine plus cisplatin plus ramucirumab	XC2R	326	58.9	214/112	Versatile	Metastatic	NA	NA	NA	Measurable	0–2	Gastric and junction	NA	0.96 (95% CI, 0.80–1.16)	0.75 (95% CI, 0.61–0.94)	134/326	125/326-2	32/326-1	J Clin Oncol	10.1200/JCO.2018.36.4_suppl.5	From general analysis, abstract
					5-FU/capecitabine plus cisplatin	XC2	319	60.1	215/104												116/319	131/319-2	5/319-1
Ajani 2017	USA	NCT01285557	III	April 2011–August 2014	S-1 plus cisplatin	SC2	239	56	124/115	Western	Metastatic	NA	NA	55/184	193/46	74/165/0	223/16	Balanced * -D	0.99 (95% CI, 0.76–1.28)	0.86 (95% CI, 0.65–1.14)	67/193	138/230	166/230	Ann Oncol	28911091	New study
					5-FU plus cisplatin	FC2	122	56	60/62					34/88	91/31	38/83/0	117/5				18/91	50/118	84/118
Hall 2017	UK	ISCTRN33934807	II	June 2009–January 2011	Capecitabine plus oxaliplatin plus epirubicin	XO3	17	74 *	13/4	Western	17/0	NA	NA	NA	NA	0/11/6	10/2/5 * -E	Balanced	1 versus 2: 1.24 (95% CI, 0.39–3.94)	1 versus 2: 0.83 (95% CI, 0.36–1.93)	5/17	NA	14/17	Br J Cancer	28095397	From general analysis
					Capecitabine plus oxaliplatin	XO2	19	77 *	13/6		17/2					4/10/5	5/1/11 * -E		1 versus 3: 0.84 (95% CI, 0.41–1.73)	1 versus 3: 0.64 (95% CI, 0.24–1.71)	9/19		7/19
					Capecitabine	19	75 *	15/4			18/1					2/10/7	7/4/8 * -E		2 versus 3: 0.38 (95% CI, 0.14–1.03)	2 versus 3: 0.78 (95% CI, 0.34–1.79)	2/19		8/19
Yoon 2016	USA	NCT01246960	II	April 2011–August 2012	5-FU plus oxaliplatin plus leucovorin plus ramucirumab	FO2R	84	64.5	63/21	Western	80/4	NA	NA	NA	67/17	40/43/0	19/26/39 * -E	Balanced	1.08 (95% CI, 0.73–1.58)	0.98 (95% CI, 0.69–1.37)	38/84	27/82	65/82	Ann Oncol	27765757	From general analysis
					5-FU plus oxaliplatin plus leucovorin	FO2	84	60	61/23		79/5				70/14	43/41/0	20/23/41 * -E				39/84	31/80	35/80
Shah 2016	South Korea	NCT01590719	II	July 2012–May 2013	5-FU plus oxaliplatin plus leucovorin plus onartuzumab	FO2R	62	58.5	40/22	Versatile	Metastatic	NA	NA	23/39	NA	24/35/0	46/16	20/31	1.06 (95% CI, 0.64–1.75)	1.08 (95% CI, 0.71–1.63)	26/43	41/60-2	10/60-2	Oncologist	27401892	From general analysis
					5-FU plus oxaliplatin plus leucovorin	FO2	61	57	36/25					20/41		24/36/0	48/13	23/26			24/42	29/60-2	1/60-2
Tebbutt 2016	Australia	ACTRN12609000109202	II	April 2010–January 20111	5-FU/capecitabine plus cisplatin plus docetaxel plus panitumumab	XC3R	37	64	33/4	Western	Metastatic and locally unresectable	26/11	13/24	NA	Measurable	34/3	13/10/15 * -E	Balanced	1.02 (95% CI, 0.51–2.05)	1.08 (95% CI, 0.59–2.01)	22/37	NA	26/37	Br J Cancer	26867157	From general analysis
					5-FU/capecitabine plus cisplatin plus docetaxel	XC3	39	59	30/9			23/16	5/34			37/2	15/11/13 * -E				17/39		18/39
Hironaka 2016	Japan	JapicCTI-111635	II	October 2011–December 2012	S-1 plus oxaliplatin plus leucovorin	SO2	47	65	33/14	Eastern	40/7	NA	12/35	NA	Measurable	37/10/0	Gastric	24/23	1 versus 2: 0.76 (95% CI, 0.47–1.24)	1 versus 2: 0.52 (95% CI, 0.30–0.88)	31/47	25/47	28/47-3	Lancet Oncol	26640036	From general analysis
					S-1 plus leucovorin		47	65	37/10		40/7		11/36			37/10/0		24/23	1 versus 3: 0.59 (95% CI, 0.37–0.93)	1 versus 3: 0.60 (95% CI, 0.35–1.02)	20/47	11/47	10/47-3
					S-1 plus cisplatin	SC2	48	65	38/10		41/7		14/34			38/10/0		18/30	2 versus 3: 0.77 (95% CI, 0.49–1.22)	2 versus 3: 1.08 (95% CI, 0.67–1.74)	22/48	43/48	22/48-3
Wang 2016	China	NCT00811447	III	November 2008–June 2012	5-FU plus cisplatin plus docetaxel	FC3	119	56.6	81/38	Eastern	89/30	NA	NA	46/73	Measurable	115/4	99/20	Balanced	0.71 (95% CI, 0.52–0.97)	0.58 (95% CI, 0.42–0.80)	58/119	72/119-1	31/119	Gastric Cancer	25604851	From general analysis
					5-FU plus cisplatin	FC2	115	55.5	88/27		89/26			39/76		108/7	86/29				39/115	11/115-1	21/115
Ryu 2016	South Korea	NCT01671449	III	October 2012–October 2014	S-1 plus oxaliplatin	SO2	338	56	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	172/166	331/7	Gastric and junction	NA	0.86 (95% CI, 0.66–1.11)	0.85 (95% CI, 0.67–1.07)	Description	Description	Description	J Clin Oncol	10.1200/JCO.2016.34.15_suppl.4015	New study, abstract
					S-1 plus cisplatin	SC2
Li 2015	China	NCT01198392	III	October 2008–June 2011	S-1 plus cisplatin	SC2	120	53.2	84/36	Eastern	Metastatic and locally unresectable	NA	NA	65/55	Measurable	28/85/7	98/22	Balanced	1.05 (95% CI, 0.73–1.50)	1.03 (95% CI, 0.76–1.39)	27/120	112/120	22/120	Oncotarget	26439700	New study
					5-FU plus cisplatin	FC2	116	55.3	85/31					64/52		29/83/4	106/10				25/116	41/116	20/116
Ochenduszko 2015	Poland	NCT02445209	III	September 2010–February 2014	Capecitabine plus oxaliplatin plus epirubicin	XO3	29	57.9	16/13	Western	28/1	6/23	16/13	16/13	Measurable	26/3	Gastric and junction	5/10	1.25 (95% CI, 0.72–2.18)	1.06 (95% CI, 0.63–1.80)	NA	25/29	7/29	Med Oncol	26354521	New study
					5-FU plus cisplatin plus leucovorin plus docetaxel	FC3	27	60.3	13/14		24/3	15/12	12/15	14/13		25/2		6/10				19/26	4/26
Du 2015	China	NCT02370849	II	October 2009–February 2012	S-1 plus cisplatin plus nimotuzumab	SC2R	31	58	17/14	Eastern	22/9	6/25	4/27	8/23	Measurable	5/26/0	25/6	Balanced	1.78 (95% CI, 0.97–3.25)	2.14 (95% CI, 1.19–3.83)	17/31	8/31	6/31	Medicine	26061330	From general analysis
					S-1 plus cisplatin	SC2	31	53	26/5		18/13	3/28	5/26	9/22		7/24/0	25/6				18/31	4/31	1/31
Van Cutsem 2015	Belgium	NCT00382720	II	September 2006–September 2007	5-FU plus oxaliplatin plus leucovorin plus docetaxel	FO3	89	58	61/28	Western	Metastatic and locally unresectable	63/26	17/72	35/54	77/12	87/2	75/14	NA	1 versus 2: 0.73 (95% CI, 0.48–1.09)	1 versus 2: 0.80 (95% CI, 0.55–1.18)	41/88	49/88-1	67/88	Ann Oncol	25416687	From general analysis
					Capecitabine plus oxaliplatin plus docetaxel	XO3	86	59	64/22			50/36	17/69	40/46	80/6	84/2	75/11		1 versus 3: 0.51 (95% CI, 0.35–0.76)	1 versus 3: 0.43 (95% CI, 0.30–0.63)	21/81	50/82-1	73/82
					Oxaliplatin plus docetaxel		79	59	51/28			55/24	7/72	23/56	69/10	77/2	70/9		2 versus 3: 0.75 (95% CI, 0.51–1.10)	2 versus 3: 0.69 (95% CI, 0.49–0.96)	18/78	52/78-1	76/78
Yamada 2015	Japan	JapicCTI-101021	III	January 2010–October 2011	S-1 plus oxaliplatin	SO2	318	65	240/78	Eastern	261/57	160/158	61/257	74/244	Measurable	224/91/3	Gastric	144/174	0.96 (95% CI, 0.80–1.14)	1.00 (95% CI, 0.84–1.20)	117/318	151/338-3	174/338	Ann Oncol	25316259	New study
					S-1 plus cisplatin	SC2	324	65	237/87		272/52	164/160	64/260	72/252		228/92/4		145/179			169/324	314/335-3	200/335
Shen 2015	China	NCT00887822	III	March 2009–July 2010	Capecitabine plus cisplatin	XC2R	102	55.5	74/28	Eastern	94/8	40/62	NA	20/82	86/16	97/5	82/20	Balanced	1.11 (95% CI, 0.79–1.56)	0.89 (95% CI, 0.66–1.21)	29/86	68/101	45/101	Gastric Cancer	24557418	From general analysis
					Capecitabine plus cisplatin plus bevacizumab	XC2	100	54.2	68/32		95/5	39/61		24/76	81/19	95/5	85/15				33/81	54/100	66/100
Chen 2015	China	NA	NA	August 2009–June 2011	S-1 plus oxaliplatin plus docetaxel	SO3	30	18–75	18/12	Eastern	Metastatic	NA	NA	NA	Measurable	6/20/4	Gastric	Balanced	0.97 (95% CI, 0.78–1.22)	0.97 (95% CI, 0.87–1.08)	16/30	8/30	7/30	Chinese Journal of CancerPrevention and Treatment	28850174	New study, Chinese
					5-FU plus cisplatin plus docetaxel	FC3	30	14/16								9/17/4					14/30	6/30	6/30
Iveson 2014	UK	NCT00719550	II	October 2009–June 2010	Capecitabine plus cisplatin plus epirubicin plus rilotumumab	XC3R	82	61	57/25	Western	73/9	NA	NA	13/69	76/6	34/47/1	66/12	NA	0.70 (95% CI, 0.45–1.09)	0.60 (95% CI, 0.45–0.79)	30/76	56/81	68/81	Lancet Oncol	24965569	From general analysis
					Capecitabine plus cisplatin plus epirubicin	XC3	39	60	31/8		34/5				9/30	38/1	16/22/1	31/4			8/38	16/39	32/39
Zhang 2014	China	NA	NA	August 2010–September 2012	S-1 plus oxaliplatin plus cetuximab	SO2R	30	49	37/19	Eastern	Metastatic and locally unresectable	26/30	8/48	12/44	Measurable	3/47/6	Gastric	25/31	0.74 (95% CI, 0.42–1.30)	0.67 (95% CI, 0.38–1.18)	17/30	10/30	3/30	World J Surg Oncol	24758484	From general analysis
					S-1 plus oxaliplatin	SO2	26														11/26	11/26	5/26
Li 2014	China	NA	NA	NA	S-1 plus oxaliplatin	SO2	16	42.1	9/7	Eastern	Metastatic and locally unresectable	NA	NA	NA	Measurable	0–2	Gastric	Balanced	Median OS time	0.78 (95% CI, 0.18–3.39)	9/16	2/16-1	NA	Cancer Research and Clinic	28850174	New study, Chinese
					5-FU plus oxaliplatin plus leucovorin	FO2	16	45.7	11/5												7/16	5/16-1
Koizumi 2013	Japan	JapicCTI-101327	II	December 2008–February 2012	S-1 plus cisplatin plus orantinib	SC2R	45	62	30/15	Eastern	39/6	19/26	15/30	NA	Measurable	28/17/0	Gastric	22/23	0.74 (95% CI, 0.46–1.19)	1.23 (95% CI, 0.74–2.05)	28/45	36/45-2	27/45	Br J Cancer	24045669	From general analysis
					S-1 plus cisplatin	SC2	46	63.5	35/11		39/7	24/22	15/31			30/16/0		25/20			26/46	28/46-2	14/46
Waddell 2013	UK	NCT00824785	III	June 2008–October 2011	Capecitabine plus oxaliplatin plus epirubicin plus panitumumab	XO3R	278	63	232/46	Western	244/34	NA	NA	NA	Measurable	118/144/16	78/94/106 * -E	Balanced	1.37 (95% CI, 1.07–1.76)	1.22 (95% CI, 0.98–1.52)	116/254	69/276	264/276	Lancet Oncol	23594787	From general analysis
					Capecitabine plus oxaliplatin plus epirubicin	XO3	275	62	226/49		250/25					117/143/15	89/75/111 * -E				100/238	137/266	190/266
Lordick 2013	Germany	EudraCT2007-004219-75	III	June 2008–December 2010	Capecitabine plus cisplatin plus cetuximab	XC2R	455	60	339/116	Versatile	439/16	NA	113/342	92/363	Measurable	237/218/0	376/71	162/76	1.00 (95% CI, 0.87–1.17)	1.09 (95% CI, 0.92–1.29)	136/455	178/446	430/446	Lancet Oncol	23594786	From general analysis
					Capecitabine plus cisplatin	XC2	449	59	334/115		436/12		116/333	90/359		228/220/0	371/73	149/94			131/449	234/436	278/436
Al-Batran 2013	Germany	NCT00737373	II	August 2007–October 2008	5-FU plus oxaliplatin plus leucovorin plus docetaxel	FO3	72	69 *	51/21	Western	50/22	33/39	14/58	18/54	Measurable	67/5	45/27	NA	0.83 (95% CI, 0.54–1.28)	0.80 (95% CI, 0.54–1.20)	35/72	59/72-2	58/72	Eur J Cancer	23063354	From general analysis
					5-FU plus oxaliplatin plus leucovorin	FO2	71	70 *	45/26		49/22	32/39	14/57	18/53		65/6	47/24				20/71	16/70-2	46/70
Kim 2012	South Korea	NCT00985556	II	March 2008–September 2009	S-1 plus oxaliplatin	SO2	65	60	44/21	Eastern	47/18	NA	NA	NA	53/12	11/54/0	Gastric	Balanced	1.08 (95% CI, 0.74–1.58)	1.06 (95% CI, 0.72–1.57)	21/53	29/65	17/65	Eur J Cancer	22243774	New study
					Capecitabine plus oxaliplatin	XO2	64	61	45/19		46/18				45/19	8/54/2					20/45	16/64	23/64
Ocvirk 2012	Slovenia	ISRCTN34052674	II	January 2003–March 2007	5-FU plus cisplatin plus epirubicin	FC3	45	54.7	34/11	Western	37/8	7/38	13/32	NA	NA	21/21/3	Gastric	NA	1.16 (95% CI, 0.75–1.80)	1.48 (95% CI, 0.94–2.35)	14/45	14/45	16/45	Am J Clin Oncol	21399488	New study
					Capecitabine plus cisplatin plus epirubicin	XC3	40	55.6	32/8		35/5	5/35	12/28			21/18/2					12/40	12/40	15/40
Ohtsu 2011	Japan	NCT00548548	III	September 2007–December 2008	Capecitabine plus cisplatin plus bevacizumab	XC2R	387	58	257/130	Versatile	367/20	130/257	NA	110/277	311/76	365/22	333/54	NA	0.87 (95% CI, 0.73–1.04)	0.80 (95% CI, 0.68–0.93)	143/311	194/386	165/386	J Clin Oncol	21844504	From general analysis
					Capecitabine plus cisplatin	XC2	387	59	258/129		378/9	126/261		107/280	297/90	367/20	338/49				111/297	209/381	183/381
Li 2011	China	NA	II	January 2003–December 2007	5-FU plus cisplatin plus paclitaxel	FC3	50	59	32/18	Eastern	28/22	NA	NA	NA	Measurable	24/26	Gastric	Balanced	1.02 (95% CI, 0.63–1.66)	NA	24/50	4/50-1	5/50-1	World J Gastroenterol	21448363	From general analysis
					5-FU plus oxaliplatin plus leucovorin	FO2	44	58	31/13		27/17					21/23					20/44	4/44-1	0/44-1
Ajani 2010	USA	NCT00400179	III	May 2005–March 2007	S-1 plus cisplatin	SC2	521	59	382/139	Western	497/24	NA	NA	NA	499/22	226/295/0	438/83	Balanced	0.92 (95% CI, 0.80–1.05)	0.99 (95% CI, 0.86–1.14)	117/402	254/521	295/521	J Clin Oncol	20159816	New study
					5-FU plus cisplatin	FC2	508	60	347/161		488/20				485/23	200/308/0	417/91				123/385	446/508	422/508
Lee 2009	South Korea	NA	III	July 2000–January 2004	5-FU plus heptaplatin	FH2	88	53.5	66/22	Eastern	84/3	NA	NA	68/20	Measurable	36/46/5	Gastric	NA	0.83 (95% CI, 0.61–1.11)	1.22 (95% CI, 0.84–1.77)	27/78	34/88	38/88	Cancer Res Treat	19688066	New study
					5-FU plus cisplatin	FC2	86	53.5	62/24		79/4			68/18		30/51/4					28/78	2/86	64/86
Kang 2009	South Korea	NA	III	April 2003–January 2005	Capecitabine plus cisplatin	XC2	160	56	103/57	Versatile	Metastatic and locally unresectable	94/66	30/130	40/120	Measurable	0–2	Gastric	NA	0.85 (95% CI, 0.65–1.11)	0.80 (95% CI, 0.63–1.03)	64/139	29/156	38/156	Ann Oncol	19153121	New study
					5-FU plus cisplatin	FC2	156	56	108/48			84/72	29/127		34/122						44/137	35/155	37/155
Popov 2008	Serbia	NA	NA	NA	5-FU plus oxaliplatin plus leucovorin	FO2	36	57	24/12	Western	29/7	21/15	13/23	27/9	Measurable	3/22/11	21/15	Balanced	0.70 (95% CI, 0.54–0.90)	0.66 (95% CI, 0.34–1.27)	15/36	Cycles	Cycles	J BUON	19145671	New study
					5-FU plus cisplatin plus leucovorin	FC2	36	55	26/10		28/8	20/16	14/22	25/11		6/20/10	19/17				9/36
Al-Batran 2008	Germany	NA	III	June 2003–January 2006	5-FU plus oxaliplatin plus leucovorin	FO2	112	64	64/48	Western	109/3	70/42	37/75	51/71	NA	103/9	92/20	NA	0.89 (95% CI, 0.66–1.21)	0.76 (95% CI, 0.57–0.99)	39/112	28/112	48/112	J Clin Oncol	18349393	New study
					5-FU plus cisplatin plus leucovorin	FC2	108	64	81/27					98/10	69/39	30/78	45/63		97/11	84/24
Cunningham 2008	UK	ISRCTN51678883	III	June 2000–May 2005	5-FU plus cisplatin plus epirubicin	FC3	249	65	202/47	Western	198/51	NA	NA	19/230	Measurable	220/29	90/72/87 * -E	Balanced	2 versus 1: 0.92 (95% CI, 0.76–1.11)	2 versus 1: 0.98 (95% CI, 0.82–1.17)	107/263	161/234	186/234	N Engl J Med	18172173	New study
					Capecitabine plus cisplatin plus epirubicin	XC3	241	64	194/47		185/56			18/223		211/30	102/68/71 * -E		3 versus 1: 0.96 (95% CI, 0.79–1.15)	3 versus 1: 0.97 (95% CI, 0.81–1.17)	116/250	171/234	209/234
					5-FU plus oxaliplatin plus epirubicin	FO3	235	61	191/44		181/54			18/217		215/20	87/55/93 * -E		4 versus 1: 0.80 (95% CI, 0.66–0.97)	4 versus 1: 0.85 (95% CI, 0.70–1.02)	104/245	111/225	181/225
					Capecitabine plus oxaliplatin plus epirubicin	XO3	239	62	198/41		181/58			21/217		215/24	104/53/82 * -E				117/244	112/227	197/227
Van Cutsem 2006	Belgium	NA	III	November 1999–January 2003	5-FU plus cisplatin	FC2	224	55	158/66	Western	217/6	NA	NA	71/153	Measurable	29/192/3	168/56	45/77	1.29 (95% CI, 1.02–1.63)	1.47 (95% CI, 1.19–1.82)	57/224	126/224-1	206/224-3	J Clin Oncol	17075117	From general analysis
					5-FU plus cisplatin plus docetaxel	FC3	221	55			159/62			213/6		68/153	28/190/3	179/42			40/92	81/221	181/221-1	197/221-3
Kim 2001	South Korea	NA	III	March 1997–April 2000	5-FU plus cisplatin plus epirubicin	FC3	61	55	45/15	Eastern	57/3	32/29	NA	NA	Measurable	55/6	Gastric	NA	0.83 (95% CI, 0.42–1.61)	Median PFS time	22/61	23/61-2	32/61-3	Eur J Cancer	10.1016/S0959-8049(01)81651-8	From general analysis, abstract
					5-FU plus cisplatin	FC2	60	56.5	42/18		57/3	28/32				53/7					20/60	10/60-2	10/60-3
KRGGC 1992	South Korea	NA	NA	NA	5-FU plus cisplatin plus epirubicin	FC3	25	NA	NA	Eastern	Metastatic and locally unresectable	NA	NA	NA	NA	NA	Gastric	NA	0.57 (95% CI, 0.27–1.20)	NA	5/21	Description	Description	Anticancer Res	1295444	From general analysis
					5-FU plus cisplatin	FC2	22														6/22

Notes: Items that may produce significant heterogeneity are emphasized with bold-type letters and asterisks. Underlined data in PS (0/1/2) indicates that the numbers should be interpreted as PS (0 and 1) versus PS (2). The additional letter ‘E’ in certain items of ‘Location (G/J)’ suggested that there were additional esophageal cancer cases in addition to gastric and gastroesophageal junction cancer cases. The additional letter ‘D’ in ‘Histological type (I/D)’ suggested that the study featured diffuse gastric cancer specifically. The word ‘Balanced’ in ‘Histological type (I/D)’ indicates that although there was no description about the ratio of intestinal and diffused types, there were other classifications of histological grades and both arms were well balanced. In multi-arm studies, for example, ‘1 versus 2’ in survival data referred to the hazard ratio of first regimen versus the second regimen. In terms of adverse events, since the number of events sometimes surpassed the total number of patients, therefore in those situations we only calculated the most significant types of adverse event in each category. The numbers of selected types of adverse events were identified inside the cells and underlined. Moreover, the words ‘Description’ or ‘Cycles’ inside adverse events suggested that there was no quantitative data or the quantitative data was calculated by chemotherapeutic cycles rather than patient-level comparison, respectively. Regarding ‘PMID’, those studies without a specific PubMed ID were either replaced by a DOI number or the PubMed ID of previous systematic reviews carrying relevant information. Unless clarified, the hazard ratios were the results of upper arm versus lower arm in each trial.

E/T, events/total patients; G/J, gastric/junction; hAE, hematological adverse events; HR, hazard ratio; I/D, intestinal/diffused; M/F, male/female; NA, not available; non-hAE, nonhematological adverse events; ORR, objective response rate; OS, overall survival; PFS: progression-free survival; P/T, responsive patients/total patients; Y/N, yes/no.

Nodes: 1, monotherapy; 2, doublet; 3, triplet; S, S-1; C, cisplatin; F, 5-FU; H, heptaplatin; O, oxaliplatin; R, targeted medication; X, capecitabine. Details of the rationale for organizing the nodes are described in the main text.

Primary endpoint: OS

A total of 38 studies were included in the network calculation. The pooled results were in low heterogeneity and high consistency (I2 = 0.16%, Q heterogeneity: p = 0.405, Q inconsistency: p = 0.508). ‘Capecitabine plus cisplatin-based triplet plus targeted medication’, ‘5-FU plus oxaliplatin-based triplet’, and ‘Capecitabine plus oxaliplatin-based triplet’ closely ranked as the top three regimens in the entire hierarchy, all of which displayed superiority against ‘5-FU plus cisplatin’ and ‘Capecitabine plus cisplatin’. However, none of them displayed superiority against ‘5-FU plus oxaliplatin’, ‘S-1 plus oxaliplatin’, or ‘Capecitabine plus oxaliplatin’ (Supplementary Figures 6 and 7).

Secondary endpoint: PFS

A total of 36 randomized controlled trials were merged into the pooled analysis. Again, ‘Capecitabine plus cisplatin-based triplet plus targeted medication’, ‘5-FU plus oxaliplatin-based triplet’, and ‘Capecitabine plus oxaliplatin-based triplet’ were the best three nodes in the rankings, statistically superior to ‘5-FU plus cisplatin’ and ‘Capecitabine plus cisplatin’. In addition, except for ‘Capecitabine plus cisplatin-based triplet plus targeted medication’, none of the top three regimens demonstrated enough advantage against ‘5-FU plus oxaliplatin’, ‘S-1 plus oxaliplatin’, or ‘Capecitabine plus oxaliplatin’ (Supplementary Figures 8 and 9).

Secondary endpoint: ORR

A total of 37 studies were eligible for the network calculation. ‘Capecitabine plus cisplatin-based triplet plus targeted medication’, ‘5-FU plus oxaliplatin-based triplet’, and ‘Capecitabine plus cisplatin plus targeted medication’ reigned the hierarchy with statistical advantage against ‘5-FU plus cisplatin’. However, none of them displayed superiority against ‘5-FU plus oxaliplatin’, ‘S-1 plus oxaliplatin’, or ‘Capecitabine plus oxaliplatin’ (Supplementary Figures 10 and 11).

Secondary endpoint: hematological adverse events

A total of 34 trials were included into the pooled analysis. ‘Capecitabine plus cisplatin-based triplet plus targeted medication’ appeared to have statistical inferiority against ‘5-FU plus cisplatin’, ‘5-FU plus oxaliplatin’, ‘S-1 plus oxaliplatin’, and ‘Capecitabine plus oxaliplatin’ (Supplementary Figures 12 and 13).

Secondary endpoint: nonhematological adverse events

A total of 35 studies were eligible for network meta-analysis. ‘Capecitabine plus cisplatin-based triplet plus targeted medication’ was statistically inferior to ‘S-1 plus oxaliplatin’ while comparable to ‘5-FU plus cisplatin’, ‘5-FU plus oxaliplatin,’ and ‘Capecitabine plus oxaliplatin’ (Supplementary Figures 14 and 15).

Patients with specific positivity

There were a total of eight randomized controlled trials were analyzed in this section of the systematic review, including four HER-2 positive studies, two MET-1 positive studies, one CLDN18.2 positive study, and one EGFR positive study (Table 3). None of the included studies were at high risk of bias with regard to methodological design (Supplementary Table 5).

Table 3.

Baseline characteristics of eligible studies for patients with specific positivity.

Study	Leading country	Registration	Phase	Enrollment	Regimen	Sample size	Age	Gender (M/F)	Region	Metastatic (Y/N)	Visceral involvement (Y/N)	Peritoneal involvement (Y/N)	Prior resection (Y/N)	Measurable (Y/N)	PS (0/1/2)	Location (G/J)	Histological type (I/D)	OS-HR	PFS-HR	ORR (P/T)	hAE (E/T)	non-hAE (E/T)	Journal	PMID	Note
Tabernero 2018	USA	NCT01774786	III	June 2013–January 2016	5-FU/Capecitabine plus cisplatin plus trastruzumab plus pertuzumab	388	62	294/94	Versatile	Metastatic	NA	NA	NA	351/37	162/226/0	278/110	353/18	0.84 (95% CI, 0.71–1.00)	0.73 (95% CI, 0.62–0.86)	199/351	218/385	335/385	Lancet Oncol	30217672	HER2-positive
					5-FU/Capecitabine plus cisplatin plus trastruzumab	392	61	323/69						352/40	162/229/0	294/98	350/21			170/352	220/388	241/388
Moehler 2018	Germany	NCT01123473	II	February 2011–August 2013	5-FU/Capecitabine plus cisplatin plus epirubicin plus lapatinib	14	66	12/2	Western	Metastatic	NA	NA	NA	NA	10/4/0	10/4	Balanced	0.90 (95% CI, 0.35–2.27)	0.86 (95% CI, 0.37-1.99)	6/14	7/14	11/14	Cancer Chemother Pharmacol	30105460	HER2 and/or EGFR-positive
					5-FU/Capecitabine plus cisplatin plus epirubicin	14	58	10/4							9/5/0	10/4				3/14	4/14	14/14
Hecht 2016	USA	NCT00680901	III	June 2008–January 2012	Capecitabine plus oxaliplatin plus lapatinib	249	61	189/60	Versatile	236/13	NA	NA	18/231	NA	79/149/21	214/23/12 * -E	225/9	0.91 (95% CI, 0.73–1.12)	0.84 (95% CI, 0.69–1.03)	131/249	17/270	113/270	J Clin Oncol	26628478	HER2-positive
					Capecitabine plus oxaliplatin	238	59	176/62		227/11			20/218		63/153/22	210/20/8 * -E	211/10			93/238	7/267	75/267
Bang 2010	South Korea	NCT01041404	III	September 2005–December 2008	5-FU/Capecitabine plus cisplatin plus trastruzumab	294	59.4	226/68	Versatile	284/10	NA	NA	71/223	269/25	264/30	236/58	225/26	0.74 (95% CI, 0.60–0.91)	0.71 (95% CI, 0.59–0.85)	139/294	144/294	173/294	Lancet	20728210	HER2-positive
					5-FU/Capecitabine plus cisplatin	290	58.5	218/72		280/10			62/228	257/33	263/27	242/48	213/2			100/290	134/290	140/290
Catenacci 2017	UK	NCT01697072	III	November 2012–November 2014	Capecitabine plus cisplatin plus epirubicin plus rilotumumab	304	61	205/99	Western	284/20	118/186	NA	48/256	262/42	117/187/0	227/53/24 * -E	Balanced	1.34 (95% CI, 1.10–1.63)	1.26 (95% CI, 1.04–1.51)	78/262	130/298	182/298	Lancet Oncol	28958504	MET-1 positive
					Capecitabine plus cisplatin plus epirubicin	305	59	220/85		283/22	136/169		48/257	267/38	115/189/1	195/71/39 * -E				119/267	148/299	169/299
Shah 2017	UK	NCT01662869	III	November 2012–March 2014	5-FU plus oxaliplatin plus leucovorin plus onartuzumab	279	60	188/91	Versatile	Metastatic	NA	NA	98/181	Measurable	112/162/0	214/65	136/83	0.82 (95% CI, 0.59–1.15)	0.90 (95% CI, 0.71–1.16)	84/207	124/279	101/279	JAMA Oncol	27918764	MET-1 positive
					5-FU plus oxaliplatin plus leucovorin	283	58	183/100					101/182		118/158/0	218/65	133/98			100/217	100/280	80/280
Schuler 2016	Germany	NCT01630083	II	NA	Capecitabine plus oxaliplatin plus epirubicin plus IMAB362	161	58	NA	Western	Metastatic and locally unresectable	NA	NA	NA	NA	NA	257/65	106/141	0.51 (95% CI, 0.36–0.73)	0.47 (95% CI, 0.31–0.70)	69/161	Description	Description	Ann Oncol	10.1093/annonc/mdw371.06	CLDN18.2 positive, abstract
					Capecitabine plus oxaliplatin plus epirubicin	161														45/161
Rao 2010	UK	NCT00215644	II	August 2005–November 2006	Capecitabine plus cisplatin plus epirubicin plus matuzumab	35	59	24/11	Western	Metastatic	NA	10/25	NA	NA	13/22/0	14/21 * -E	Balanced	1.02 (95% CI, 0.61–1.70)	1.13 (95% CI, 0.63–2.01)	11/35	16/35	31/35	Ann Oncol	20497967	EGFR positive
					Capecitabine plus cisplatin plus epirubicin	36	64	27/9				9/27			12/24/0	16/20 * -E				21/36	17/36	24/36

Notes: Items that may produce significant heterogeneity are emphasized with bold-type letters and asterisks. Underlined data in PS (0/1/2) indicates that the numbers should be interpreted as PS (0 and 1) versus PS (2). The additional letter ‘E’ in certain items of ‘Location (G/J)’ suggested that there were additional esophageal cancer cases besides of gastric and gastroesophageal junction cancer cases. The word ‘Balanced’ in ‘Histological type (I/D)’ indicated that although there was no description about the ratio of intestinal and diffused types, there were other classifications of histological grades and both arms were well balanced. Moreover, the words ‘Description’ or ‘Cycles’ inside adverse events suggested that there was no quantitative data or the quantitative data was calculated by chemotherapeutic cycles rather than patient-level comparison, respectively. Regarding ‘PMID’, those studies without a specific PubMed ID were either replaced by a DOI number or the PubMed ID of previous systematic reviews carrying relevant information. Unless clarified, the hazard ratios were the results of upper arm versus lower arm in each trial.

E/T, events/total patients; G/J, gastric/junction; hAE, hematological adverse events; HR, hazard ratio; I/D, intestinal/diffused; M/F, male/female; NA, not available; non-hAE, non-hematological adverse events; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; P/T, responsive patients/total patients; Y/N, yes/no.

HER-2 positive

Three studies were large-scale phase III randomized controlled trials and only one trial reported phase II results, with sample sizes ranging from 28 to 780 patients. According to Bang et al,[40] adding trastuzumab to capecitabine plus cisplatin could significantly enhance its survival benefits among HER-2 positive patients compared with capecitabine plus cisplatin alone (OS HR: 0.74 [95% CI, 0.60–0.91]; PFS HR: 0.71 [95% CI, 0.59–0.85]). Recently, Tabernero et al.[41] also confirmed that dual HER-2 targeting strategy with both pertuzumab and trastuzumab failed to generate OS benefit compared with trastuzumab-based regimen, despite the difference of OS coming close to crossing the boundary value (OS HR: 0.84 (95% CI, 0.71–1.00); PFS HR: 0.73 (95% CI, 0.62–0.86)). Moreover, either pertuzumab or trastuzumab was well tolerable compared with its control arm. On the other hand, however, adding lapatinib failed to produce survival benefits in contrast to capecitabine plus oxaliplatin alone[42] (OS HR: 0.91 [95% CI, 0.73–1.12]; PFS HR: 0.84 [95% CI, 0.69–1.03]), irrespective of gastric (p = 0.30), gastroesophageal junction (p = 0.77), or esophageal cancer subgroups (p = 0.77). Similarly, the addition of lapatinib to capecitabine-based triplet also failed to have enough survival benefit (OS HR: 0.90 [95% CI, 0.35–2.27]; PFS HR: 0.86 [95% CI, 0.37–1.99]), despite that the results were less credible owing to lower statistical power on small sample size (n = 28)[43] (Table 3).

MET-1 positive

Two large-scale phase III randomized controlled trials reported the first-line options for MET-1-positive gastric cancer patients. Based on 609 patients, Catenacci et al.[44] surprisingly described that adding rilotumumab not only failed to increase but also significantly decreased the survival time among MET-1-positive patients compared with capecitabine plus cisplatin plus epirubicin alone (OS HR: 1.34 [95% CI, 1.10–1.63]; PFS HR: 1.26 [95% CI, 1.04–1.51]). Furthermore, Shah et al.[45] reported that addition of onartuzumab also failed to display survival benefit among MET-1-positive patients compared to 5-FU plus oxaliplatin plus leucovorin alone (OS HR: 0.82 [95% CI, 0.59–1.15]; PFS HR: 0.90 [95% CI, 0.71–1.16]) (Table 3).

Others

Based on a CLDN18.2-positive 161-patient phase II trial, adding IMAB362 could significantly enhance the survival time while maintaining comparable tolerability against capecitabine plus oxaliplatin plus epirubicin alone[46] (OS HR: 0.51 [95% CI, 0.36–0.73]; PFS HR: 0.47 [95% CI, 0.31–0.70]). For EGFR-positive patients, the addition of matuzumab failed to generate survival benefits compared with capecitabine plus cisplatin plus epirubicin alone[47] (OS HR: 1.02 [95% CI, 0.61–1.70]; PFS HR: 1.13 [95% CI, 0.63–2.01]) (Table 3).

Discussion

Currently, systemic therapy is still the preferred measure against advanced inoperable gastric cancer, in which fluoropyrimidine plus cisplatin doublet is the most recommended regimen in virtue of both clinical efficacy and tolerability.[5] However, previously published systematic reviews failed to make a panoramic summary about the systemic therapy against gastric cancer, let alone a credible hierarchical ranking that fit the diversity of regimens.[16-18] Therefore, we have conducted by far the most comprehensive systematic review and network meta-analysis based on 119 high-quality randomized controlled trials, covering both chemotherapy and targeted medications.

In general, analysis among unselected population, ‘fluoropyrimidine plus platinum-based triplet’ was the top-ranking node regarding OS, which was consistent with the result of pairwise meta-analysis and was confirmed to be stable by sensitivity analysis. In terms of PFS and ORR, ‘fluoropyrimidine plus platinum-based triplet plus targeted medication’ and ‘fluoropyrimidine plus platinum-based triplet’ ranked as the top two nodes, demonstrating statistical superiority against ‘fluoropyrimidine plus platinum doublet’. However, in 2014, one ASCO expert meeting stated that a risk reduction of HR 0.80 might be clinically relevant. In addition, the ESMO clinical benefit scale even recommends that HR 0.65 is clinically relevant. Therefore, in consideration of survival efficacy and safety profile, it is still inappropriate to conclude that ‘fluoropyrimidine plus platinum doublet’ could be replaced by ‘fluoropyrimidine plus platinum-based triplet’ in terms of first-line regimens. Moreover, since the general analysis did not further clarify different subtypes inside fluoropyrimidine and platinum, we still had concerns about the statistical credibility about the pooled results and, thus, we performed a specific additional analysis.

The additional analysis that individualized different types of fluoropyrimidine and platinum gave detailed comparisons across diverse fluoropyrimidine and platinum-based regimens. Concerning survival benefits, ‘capecitabine plus cisplatin-based triplet plus targeted medication’ was the best regimen in the entire hierarchy, statistically superior against both ‘5-FU plus cisplatin’ and ‘capecitabine plus cisplatin’ while comparable with ‘5-FU plus oxaliplatin’, ‘S-1 plus oxaliplatin’, and ‘Capecitabine plus oxaliplatin’. On the other hand, it also featured unfavorable tolerability as expected, especially compared with ‘S-1 plus oxaliplatin’. However, although more specific categorizations helped to lower heterogeneity, it also raised concerns about low statistical power owing to the small sample-size in each node. In addition, the third component and targeted medication besides fluoropyrimidine and platinum were not always consistent within the same node, which could introduce heterogeneity into the final results as well. Therefore, we feel that it is more appropriate to maintain the recommendation of fluoropyrimidine plus oxaliplatin doublet (especially capecitabine or S-1) as the preferred first-line regimen, which has been widely applied in clinical settings.

Among patients with specific pathological positivity, HER-2 is the most widely investigated target against advanced gastric cancer. Based on a large-scale phase III randomized controlled trial by Bang et al.,[40] the addition of trastuzumab to fluoropyrimidine plus cisplatin doublet has been confirmed as the preferred regimen against HER-2 overexpressing metastatic gastric cancer. Despite the negative result of OS (p = 0.056), a dual HER-2-targeting strategy with both pertuzumab and trastuzumab displayed a significant benefit in terms of PFS, as well as the comparable tolerability compared with trastuzumab-based first-line regimen.[41] Since the difference in OS was quite close to statistical boundary, it hinted that other combination of dual HER-2-targeting strategy might possibly reach statistical significance in future designs. In addition, lapatinib plus capecitabine plus oxaliplatin failed to surpass capecitabine plus oxaliplatin doublet,[42] therefore fluoropyrimidine plus cisplatin plus trastuzumab is still the best regimen for HER-2 overexpressing advanced gastric cancer at present. According to two large-scale phase III studies, adding rilotumumab or onartuzumab failed to generate survival benefits among MET-1-positive patients compared with fluoropyrimidine plus platinum-based chemotherapy alone.[44,45] This suggests that fluoropyrimidine plus cisplatin may still serve as the preferred first-line regimen against MET-1-positive advanced gastric cancer. Moreover, in a phase II trial by Schuler et al.[46], the addition of IMAB362 significantly elongated survival lifespan among patients with CLDN18.2 positivity compared with capecitabine plus oxaliplatin plus epirubicin alone. Since CLDN18.2 is believed to widely exist in nearly half of gastric cancer cells, IMAB362 is a very promising medication and, thus, a phase III trial is currently ongoing.

Although our systematic review was rigorously designed and conducted, there were still some limitations within. First, this network meta-analysis was not based on individual-patient data. However, since the network was verified to be highly consistent, stable, and homogenous, conclusions of our pooled analysis were therefore also credible and applicable. Second, even though in additional analysis, several different regimens were still forced to merge into one node in order to perform the network calculations, since the third component and targeted medication in addition to fluoropyrimidine and platinum were not further specified. All these could bring potential biases into the network meta-analysis despite of the low overall statistical heterogeneity as mentioned previously. Third, the overall number of studies especially for top-ranking nodes such as ‘capecitabine plus cisplatin-based triplet plus targeted medication’ were still inadequate, which might lower the statistical power of the entire quantitative analysis.

Taken together, fluoropyrimidine plus oxaliplatin doublet (especially capecitabine or S-1) should still be considered as the preferred first-line regimen owing to its comparable survival benefits and lower toxicity.

Click here for additional data file.

Supplemental material, Supplemetary_Materials for First-line systemic therapy for advanced gastric cancer: a systematic review and network meta-analysis by Ji Cheng, Ming Cai, Xiaoming Shuai, Jinbo Gao, Guobin Wang and Kaixiong Tao in Therapeutic Advances in Medical Oncology