· Web view1.Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up

Research Paper

The optimal strategy of multimodality therapies for resectable gastric

cancer: evidence from a network meta-analysis

Songcheng Yin1,2,5, Pengliang Wang1,3,5, Xiaoyu Xu4, Yuen Tan1,3, Jinyu Huang1,3,

Huimian Xu1,3, *

1 Department of Surgical Oncology, First Affiliated Hospital of China Medical

University, Shenyang, China

2 Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen

University, Shenzhen, China

3 Key Laboratory of Gastric Cancer Molecular Pathology of Liaoning Province, 155

Nanjing North Street, Heping District, Shenyang, China

4 Department of Gynecology, The Seventh Affiliated Hospital of Sun Yat-sen

University, Shenzhen, China

5 These two authors contribute equally in this work

*Corresponding Author: Prof. Huimian Xu, Department of Surgical Oncology, First

Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping

District, Shenyang, 110001, China. Phone: +86-024-83283556; Fax: +86-024-

83283556; E-mail: [email protected]

1 / 48

Abstract

Background. Controversy continues regarding the optimal strategy of multimodality

therapies for resectable gastric cancer. The aim of this network meta-analysis was to

determine the efficacy of surgery combined with neoadjuvant or adjuvant

chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT) by integrating

the direct and indirect method.

Methods. A systematically search for randomized controlled trials (RCTs) was

performed through Medline, Embase, CENTRAL, and PMC databases. Overall

survival (OS) was the primary outcome of interest. A Bayesian network meta-analysis

was conducted and treatments were ranked based on their effectiveness for improving

survival.

Results. Fifty-six RCTs involving 12,435 patients were included. Overall analysis

showed that neoadjuvant CRT resulted in a statistically significantly better OS

compared with adjuvant CT, adjuvant RT, adjuvant CRT, neoadjuvant CT,

neoadjuvant RT, and surgery alone. Moreover, subgroup analysis of D2

lymphadenectomy revealed that neoadjuvant CRT was not significant superior to

neoadjuvant CT (HR = 0.67, 95% CrI 0.41–1.08), adjuvant CRT (HR = 0.67, 95% CrI

0.37–1.21), and adjuvant CT (HR = 0.60, 95% CrI 0.35–1.04). With a tendency to

survival benefit, neoadjuvant CRT had an 89% probability of being the best selection.

Conclusions. Our study showed no significant survival advantage for neoadjuvant

CRT, though the highest probability of being the best treatment was observed. Further

clinical trials are essential to determine the value of neoadjuvant CRT, especially in

2 / 48

D2 lymphadenectomy subgroup.

Keywords: gastric cancer, neoadjuvant therapy, adjuvant therapy, network meta-

analysis

3 / 48

INTRODUCTIONGastric cancer (GC) represents the fifth most prevalent malignancy and the third

leading cause of cancer mortality worldwide [1]. Surgery is still the only potential

curative treatment, and the 5‐year survival rate of patients received curative surgery

remains ranging from 24% to 45% [2, 3]. Multiple treatment options including

surgery–based neoadjuvant and/or adjuvant therapies have been applied to improve

the survival of GC patients in the past several decades.

The Southwest Oncology Group (SWOG) 9008/INT–0116 study, the milestone

trial of postoperative adjuvant treatment, laid the foundation for adjuvant

chemoradiotherapy (CRT), which became a commonly used treatment in the United

States [4]. In parts of Europe, perioperative or neoadjuvant chemotherapy (NCT) has

become the standard treatment for GC mainly based on the results of the Medical

Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial and

Federation Nationale des Centres de Luttecontre le Cancer (FNCLCC)/Federation

Francophone de Cancerologie Digestive (FFCD) trial [2, 5].Thereafter, Adjuvant

Chemotherapy trial of S-1 for Gastric Cancer (ACTS-GC) study and the Capecitabine

and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study established the

D2-lymphadenectomy-based surgery combined with adjuvant chemotherapy (CT) as

the standard treatment in Asian [6, 7].Additionally, other treatment options, including

adjuvant radiotherapy (RT), neoadjuvant RT and neoadjuvant CRT, have also been

applied in GC [8-10].

However, insufficient studies evaluated the comparison between these treatment

4 / 48

options and reported conflicting results [11, 12], the comparison among these options

remained unknown. Thus, in the current study, we designed a network meta-analysis

to evaluate the efficacy of different treatment options in treating resectable GC

patients and compared by integrating the previous trials.

METHODS

Literature Search

Medline, Embase, the Cochrane Central Register of Controlled Trials

(CENTRAL), PMC database and the abstracts from the American Society of Clinical

Oncology and European Society for Medical Oncology were systematically retrieved

up to June 30, 2017. The search strategy consisted of the medical subject headings

(MeSH) and key words for GC and treatment options. Additionally, the reference lists

from eligible trials and review studies were also screened manually. All the included

studies should be in accordance with ethical standards of the responsible committee

on human experimentation and the Helsinki Declaration of 1964 and later versions.

Two authors (SCY and PLW) conducted the process of the literature search

independently. Disagreements were resolved through the group discussion.

Study Selection

The inclusion criteria for this meta-analysis was performed as follows: (i)

prospective randomized controlled trials (RCTs); (ii) patients with pathologically

proven as gastric or esophagogastric junction cancer (EGJ); (iii) pair-wise comparison

of treatment modalities grouped as surgery combined neoadjuvant/adjuvant treatments

5 / 48

(CT, RT, or CRT), and surgery alone; (iv) sufficient data to extract hazard ratios (HRs)

to evaluate survival difference; (v) studies published in English. Patients with

unresectable, metastatic, or recurrent disease were excluded. If trials with multiple

publications were retrieved, the most recent reported one was included to obtain the

longest follow-up. We excluded the articles that enrolled esophagogastric junction

cancer along with esophageal cancer because of unextracted data of esophagogastric

junction cancer alone.

Data Extraction and Quality Assessment

The following study characteristics were recorded for each included study: (i)

basic study information, including the first author, publication year and country; (ii)

pathological and demographic characteristics, including gender, age, histopathological

type, TNM stage and lymphadenectomy information; (iii) research protocol, including

regimens compared, intervention schedules and the number of patients in each group;

(iv) outcome indicators, including follow-up information and survival data. All

articles were evaluated for risk of bias using the Cochrane Risk of Bias tool, which

classified studies into three categories.Two reviewers independently completed data

extraction and quality evaluation for each eligible study.

Statistical Analysis

Overall survival (OS) was selected as the primary endpoint which was measured

using hazard ratio (HR) with its 95% credible intervals (95% CrIs). Assessment of

treatment efficacy were derived first from direct pairwise comparisons in RevMan

6 / 48

software version 5.2 for statistical analysis. In order to obtain robust results, the

random effects model was performed. Next, a Bayesian network meta-analysis was

performed using JAGS and the GeMTC package in R software (https://drugis.org/

software/r-packages/gemtc). For studies with more than two arms, we considered the

correlation between the relative therapeutic effects using the approach reported by

Woods[13]. Consistency between direct and indirect evidence was assessed by

comparing the pooled HRs from traditional pair-wise comparisons with corresponding

results from the network meta-analyses. Moreover, the probability of each treatment

being the best was calculated by ranking the relative efficacies of all regimens based

on its posterior probabilities. All statistical tests were 2-sided with α of 0.05.

RESULTS

Description of the Included Studies

Fifty-six RCTs contained 12,435 patients were included in our meta-analysis

through the systematically literature review (Fig.1). Among the eligible studies,

patients received seven different treatment regimens containing surgery alone or

surgery-based treatment which involved in adjuvant CT, adjuvant RT, adjuvant CRT,

neoadjuvant CT, neoadjuvant RT, and neoadjuvant CRT (Fig.2). The primary features

of the included studies were summarized in Supplementary Table S1. Almost trials

were randomized with two comparator arms, in addition to one study comprising

three arms involving adjuvant CT, adjuvant RT and surgery alone [8]. The main

clinicopathologic characteristics of the enrolled patients in the included studies were

7 / 48

showed in Supplementary Table S2. There was a high degree of consistency among

the patients among the studies. The average age of the patients ranged from 55 to 65

years old; and the majority of patients were stage II-II.

Direct Comparison Meta-analysis for OS

Results of standard pairwise meta-analysis were presented in Supplementary Fig.

S1 and S2. Comparing with surgery alone, adjuvant CT (HR = 0.82, 95% CI 0.77–

0.87), adjuvant CRT (HR = 0.77, 95% CI 0.65–0.91), neoadjuvant CT (HR = 0.78,

95% CI 0.68–0.91), neoadjuvant RT (HR = 0.79, 95% CI 0.66–0.94), and neoadjuvant

CRT (HR = 0.35, 95% CI 0.15–0.81) showed significantly OS benefit. Nevertheless,

adjuvant RT resulted in a nonsignificant effect on survival (HR = 1.17, 95% CI 0.92–

1.49). When compared with adjuvant CT, there was no significantly reduced mortality

risk in patients who received adjuvant CRT (HR = 0.91, 95% CI 0.75–1.09) or

neoadjuvant CT (HR = 0.74, 95% CI 0.55–1.00), respectively. In addition, no

significant difference in OS was found between adjuvant CT and adjuvant RT (HR =

0.82, 95% CI 0.64–1.05). Similar result was found between neoadjuvant CRT and

neoadjuvant CT (HR = 0.67, 95% CI 0.41–1.08).

Network Meta-analysis for OS

A random–effect model network meta-analysis was established to compare

surgery alone, adjuvant CT, adjuvant RT, adjuvant CRT, neoadjuvant CT, neoadjuvant

RT, and neoadjuvant CRT (Fig.3a). The pooled HRs with 95% CrIs revealed that all

intervention measures resulted in a statistically significantly better OS compared with

8 / 48

surgery alone, apart from adjuvant RT (HR = 1.07, 95% CrI 0.86–1.34). In the

comparisons of adjuvant therapies, efficacy results showed that adjuvant CRT (HR =

0.71, 95% CrI 0.54–0.93) and CT (HR = 0.78, 95% CrI 0.62–0.96) were both superior

to adjuvant RT. For the comparison between adjuvant CRT and CT, the combined HR

did not favour either regimen (HR = 0.92, 95% CrI 0.78–1.08). With regard to

neoadjuvant therapies, patients who underwent neoadjuvant CRT demonstrated a

survival advantage compared with those who had neoadjuvant CT (HR = 0.61, 95%

CrI 0.39–0.96) or RT (HR = 0.56, 95% CrI 0.33–0.94). Moreover, there was no

significant difference among the comparisons of adjuvant CT, adjuvant CRT, and

neoadjuvant CT.

It is encouraging that neoadjuvant CRT was significant superiority compared

with the rest therapies (Fig. 3a). Additionally, the results of the probability of being

the most effective therapeutic schedule were as follows: neoadjuvant CRT (97.23%),

neoadjuvant CT (1.05%), adjuvant CRT (1.01%), neoadjuvant RT (0.89%), adjuvant

CT (0.01%), adjuvant RT (0.01%), and surgery alone (0%) (Fig. 3b).

Subgroup Analysis

For patients received D1 lymphadenectomy, adjuvant CT, adjuvant CRT,

neoadjuvant CT and surgery alone were researched in RCTs. Our results showed

survival advantage with adjuvant CRT (HR = 0.76, 95% CrI 0.63–0.91) and

neoadjuvant CT (HR = 0.79, 95% CrI 0.65–0.98) compared with surgery alone (Fig.

4a), whereas adjuvant CT had no survival benefit statistically (HR = 0.84, 95% CrI

0.69–1.03). There was no significant difference between adjuvant CRT and

9 / 48

neoadjuvant CT. Ranking analysis revealed that adjuvant CRT, neoadjuvant CT, and

adjuvant CT had values at 53.03%, 31.89%, and 15.08% probability of being the best

regimen, respectively (Fig. 4b).

In terms of patients underwent D2 lymphadenectomy, adjuvant CT, adjuvant

CRT, neoadjuvant CT, neoadjuvant CRT and surgery alone were applied in RCTs.

These treatment options were all associated with a survival advantage over surgery

alone (Fig. 4c). Neoadjuvant CRT tended to be superior to neoadjuvant CT (HR =

0.67, 95% CrI 0.41–1.08), adjuvant CRT (HR = 0.67, 95% CrI 0.37–1.21), and

adjuvant CT (HR = 0.60, 95% CrI 0.35–1.04) but with nonsignificant. Additionally,

neoadjuvant CRT had the highest (89.05%) probability of being the best treatment

(Fig. 4d).

Comparison of toxicity

The grade 3 and above adverse events data from 27 RCTs were showed in Table

1. In general, there was no obviously difference in the toxicity for patients treated

with adjuvant CT, adjuvant CRT, neoadjuvant CT, and neoadjuvant CRT. For patients

who received adjuvant CT had the highest rate of diarrhea (6.2%) when compared

with adjuvant CRT, neoadjuvant CT, and neoadjuvant CRT. The incidence of

leukopenia (30.0%) was the highest among the patients with adjuvant CRT.

Additionally, only one trial reported the toxicity data for neoadjuvant CRT. And the

most common adverse events were leukopenia (11.7%) and Thrombocytopenia

(5.0%).

10 / 48

Quality Assessment and Network Consistency

Minimal bias was found among majority of studies by using the Cochrane risk of

bias tool. Risk of bias summary by domain and each study was showed in

Supplementary Fig. S3. No studies showed high risk bias in the integrity of outcome

data and comprehensiveness of the report, which was impersonal and had a relatively

low bias.

We evaluated the consistency between direct and indirect comparisons with

node-split models and the results showed that no significant inconsistency for OS (all

P > 0.05, Supplementary Fig. S4).

DISCUSSION

Evidence-based multiple effective treatment modalities were applied in the

treatment of resectable GC and the prognosis of patients were also improved during

the past decades. However, the comparison of these treatment options remained

unclear. To our knowledge, this is the first study to synthesize all efficacy evidence

from 56 trials, compared different treatment options using a Bayesian network meta-

analysis. The results showed that neoadjuvant CRT resulted in a statistically

significantly better OS compared with adjuvant CT, adjuvant RT, adjuvant CRT,

neoadjuvant CT, neoadjuvant RT, and surgery alone. Subgroup analysis revealed that

neoadjuvant CRT tended to be superior to adjuvant CT, adjuvant CRT, and

neoadjuvant CT which had the highest probability of being the best treatment and

might be the best treatment strategy on the basis of D2 lymphadenectomy.

11 / 48

D2 lymphadenectomy, accepted as the standard operation for advanced GC in

both Asian and Western, is associated with lower loco-regional recurrence and cancer-

specific death [14]. Actually, surgery alone cannot achieve a biological cure for

advanced GC, even though the extended lymphadenectomy is performed. Adjuvant

and neoadjuvant therapies are generally accepted to eradicate microscopic disease,

result an additional 10%–15% survival benefit based on the curative surgical

resection[15].

Adjuvant CRT gained much popularity in the United States since the results of

INT–0116 study reported [4]. Thereafter, D2 lymphadenectomy combined with

adjuvant CT has become the standard treatment in Asia mainly based on the ACTS–

GC and CLASSIC trials [6, 7]. Our results also found that adjuvant CRT and CT were

superior to surgery alone. These results confirmed the necessity of postoperative

adjuvant treatment. For adjuvant RT, non-significant result was observed when

compared with surgery alone. Additionally, the comparison between adjuvant CRT

and adjuvant CT also showed non-significant results. Subgroup analysis showed that

adjuvant CRT was superior to surgery alone but positive results was not found in

adjuvant CT for patients with D1 lymphadenectomy. Several previous studies also

showed that the advantages of adjuvant or additional RT could be observed in patients

with lymph nodes metastasis, D1 resections and positive margins[16-18]. These

results elucidated that postoperative RT may serve as a supplementary treatment

option when combined with adjuvant CT.

The superiority of neoadjuvant CT mainly attributes to the increasing rate of R0

12 / 48

resection and controlling microscopic disease. For the comparison between

neoadjuvant CT and adjuvant CT, the results of our direct comparison and indirect

comparison analyses indicated insignificantly difference, which was consistent with

previous study [19]. However, no clinical trials evaluated the difference between

neoadjuvant CT and adjuvant CRT. Recently, a retrospective study showed that

patient received neoadjuvant CT was superior to those received adjuvant CRT in

terms of survival [20]. Nevertheless, our current study did not obtain the same results

and further study will be needed to evaluate these two treatment options.

Notably, the overall analysis indicated that neoadjuvant CRT was significantly

superior to other therapeutic strategy in terms of the rank probability of being the best

selection. However, subgroup analysis of D2 lymphadenectomy showed that patients

with neoadjuvant CRT seemed to be correlated with a better but a nonsignificant

survival advantage. With the highest probability of being the best treatment, the level

of evidence for neoadjuvant CRT was downgraded from high to moderate, as the CrI

crossed the unit [21]. Since the tumor has not changed the anatomical location and is

rich in vascularization before surgery, the neoadjuvant CRT is more effective and

sensitive. Moreover, smaller irradiated volumes and therefore less toxic reactions

were observed lead to well tolerant for patients received preoperative RT [15]. Thus,

more feasibility and safety neoadjuvant CRT resulted in higher rate of pCR and R0

resection [22-24]. In the ongoing prospective trials, TOPGEAR trial was designed to

compare neoadjuvant CRT with neoadjuvant CT followed by postoperative CT with

D2 lymphadenectomy. Until this result is available, our data presented here providing

13 / 48

an evidence of support neoadjuvant CRT.

The phase III MAGIC and FNLCC/FFCD trials confirmed that perioperative CT

was superior to surgery alone and was widely used in Europe [2, 5]. Unfortunately,

fewer than 50% patients completed the postoperative chemotherapy in these two

trials, mainly because of the surgical complications and nutrition status [5]. Even

though the higher R0 resection and pCR rates were achieved, unsatisfied recurrence

rate, especially the distant recurrence rate, were obtained in patients received

neoadjuvant CT/CRT [2, 5, 10, 25]. A previous retrospective study reported that

postoperative CT gained more survival benefit than observation for patients received

neoadjuvant CRT [26]. This result further confirmed the superiority of the

perioperative treatment pattern. Future trials should consider the difference and

evaluate the neoadjuvant and perioperative treatment properly.

Moreover, tumor location may also affect the treatment options. A study

investigated the treatment trend in the United States showed that noncardia GC

patients had different treatment pattern compared with cardia patients. Preoperative

treatment, especially the preoperative CRT, was the most commonly used treatment

among cardia patients, whereas the postoperative treatment was the most commonly

used among noncardia patients [27]. Additionally, the molecular heterogeneity and

subtypes had been explored in different tumor location and this might also affect the

response to the chemotherapy and radiotherapy [28, 29]. Thus, the effect of the tumor

location and treatment response should be considered in the future trials.

Several limitations should be acknowledged in present study. The trials included

14 / 48

in our study lasted for a long period and the improvement of treatment schedules or

technique may affect our findings. We evaluated the consistency with node-split

models and showed relatively well transitivity. Moreover, our study used all

information from published data other than individual patient data, which might

influence the accuracy of assessment, even though we obtained part of information

from previously individual patient data meta-analysis [30]. Additionally, some certain

endpoints like disease-free survival and disease-specific survival could not obtain

from published studies, which might influence our analysis. Several studies

investigated the treatment both in esophagogastric junction cancer and gastric cancer.

However, part of trials could not obtain the subgroup data for these two tumor sites.

Thus, we may not evaluate the effects of treatment in different tumor location.

Furthermore, it was difficult to implement subgroup analysis stratified by different

regions (Asia, Europe and the US). Because studies in different areas were

inadequate. Most Asian and European trials used D2 lymph node dissection, while the

US studies focused on D1 lymph node dissection. Therefore, subgroup analysis of

lymph node dissection may partly reflect the subgroup results in different regions.

CONCLUSIONS

Our findings showed a potential survival advantage conferred by neoadjuvant

CRT. Despite nonsignificant survival advantage was observed for patients with D2

lymphadenectomy, neoadjuvant CRT had the highest probability of being the best

treatment. Future direct head-to-head clinical trials are needed to identify the

effectiveness of neoadjuvant CRT in D2 lymphadenectomy subgroup.

15 / 48

ACKNOWLEDGMENTS

This work was supported by National Natural Science Foundation of China

(No.81772549 and 81572334 to HMX, No.81602522 to JYH). The funders had no

role in study design, data collection and analysis, decision to publish, or preparation

of the manuscript.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

ETHICAL STANDARDS

All procedures performed were in accordance with the ethical standards of the

responsible committee on human experimentation (institutional and national) and with

the Helsinki Declaration of 1964 and later versions. Informed consent or an

appropriate substitute was obtained from all patients prior to inclusion in the study.

REFERENCES

1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer

statistics, 2012. CA: a cancer journal for clinicians. 2015; 65: 87-108.

2. Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, et al.

Perioperative chemotherapy compared with surgery alone for resectable

gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial.

Journal of clinical oncology : official journal of the American Society of Clinical

Oncology. 2011; 29: 1715-21.

3. Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ, Welvaart K, Songun I, et

al. Extended lymph-node dissection for gastric cancer. The New England journal of

16 / 48

medicine. 1999; 340: 908-14.

4. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann

GN, et al. Chemoradiotherapy after surgery compared with surgery alone for

adenocarcinoma of the stomach or gastroesophageal junction. The New England

journal of medicine. 2001; 345: 725-30.

5. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ,

Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable

gastroesophageal cancer. The New England journal of medicine. 2006; 355: 11-20.

6. Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al.

Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. The

New England journal of medicine. 2007; 357: 1810-20.

7. Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, et al. Adjuvant

capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a

phase 3 open-label, randomised controlled trial. Lancet. 2012; 379: 315-21.

8. Hallissey MT, Dunn JA, Ward LC, Allum WH. The second British Stomach

Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric

cancer: five-year follow-up. Lancet. 1994; 343: 1309-12.

9. Zhang ZX, Gu XZ, Yin WB, Huang GJ, Zhang DW, Zhang RG. Randomized

clinical trial on the combination of preoperative irradiation and surgery in the

treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients.

International journal of radiation oncology, biology, physics. 1998; 42: 929-34.

10. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J,

et al. Phase III comparison of preoperative chemotherapy compared with

chemoradiotherapy in patients with locally advanced adenocarcinoma of the

esophagogastric junction. Journal of clinical oncology : official journal of the

American Society of Clinical Oncology. 2009; 27: 851-6.

11. Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, et al. Phase III Trial to

Compare Adjuvant Chemotherapy With Capecitabine and Cisplatin Versus Concurrent

Chemoradiotherapy in Gastric Cancer: Final Report of the Adjuvant

17 / 48

Chemoradiotherapy in Stomach Tumors Trial, Including Survival and Subset

Analyses. Journal of clinical oncology : official journal of the American Society of

Clinical Oncology. 2015; 33: 3130-6.

12. Zhu WG, Xua DF, Pu J, Zong CD, Li T, Tao GZ, et al. A randomized, controlled,

multicenter study comparing intensity-modulated radiotherapy plus concurrent

chemotherapy with chemotherapy alone in gastric cancer patients with D2 resection.

Radiotherapy and oncology : journal of the European Society for Therapeutic

Radiology and Oncology. 2012; 104: 361-6.

13. Woods BS, Hawkins N, Scott DA. Network meta-analysis on the log-hazard

scale, combining count and hazard ratio statistics accounting for multi-arm trials: a

tutorial. BMC medical research methodology. 2010; 10: 54-62.

14. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical

treatment of gastric cancer: 15-year follow-up results of the randomised nationwide

Dutch D1D2 trial. The Lancet Oncology. 2010; 11: 439-49.

15. Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer.

Lancet. 2016; 388: 2654-64.

16. Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, et al. Phase III trial

comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with

concurrent capecitabine radiotherapy in completely resected gastric cancer with D2

lymph node dissection: the ARTIST trial. Journal of clinical oncology : official

journal of the American Society of Clinical Oncology. 2012; 30: 268-73.

17. Dikken JL, Jansen EP, Cats A, Bakker B, Hartgrink HH, Kranenbarg EM, et al.

Impact of the extent of surgery and postoperative chemoradiotherapy on recurrence

patterns in gastric cancer. Journal of clinical oncology : official journal of the


18. Stumpf PK, Amini A, Jones BL, Koshy M, Sher DJ, Lieu CH, et al. Adjuvant

radiotherapy improves overall survival in patients with resected gastric

adenocarcinoma: A National Cancer Data Base analysis. Cancer. 2017; 123: 3402-9.

19. Yang Y, Yin X, Sheng L, Xu S, Dong L, Liu L. Perioperative chemotherapy more

18 / 48

of a benefit for overall survival than adjuvant chemotherapy for operable gastric

cancer: an updated Meta-analysis. Scientific reports. 2015; 5: 12850.

20. Fitzgerald TL, Efird JT, Bellamy N, Russo SM, Jindal C, Mosquera C, et al.

Perioperative chemotherapy versus postoperative chemoradiotherapy in patients with

resectable gastric/gastroesophageal junction adenocarcinomas: A survival analysis of

5058 patients. Cancer. 2017; 123: 2909-17.

21. Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JP. Evaluating the

quality of evidence from a network meta-analysis. PloS one. 2014; 9: e99682.

22. Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, et al.

Phase II trial of preoperative chemoradiation in patients with localized gastric

adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic

response. Journal of clinical oncology : official journal of the American Society of


23. Rivera F, Galan M, Tabernero J, Cervantes A, Vega-Villegas ME, Gallego J, et al.

Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-

cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric

junction adenocarcinoma. International journal of radiation oncology, biology,

physics. 2009; 75: 1430-6.

24. Pera M, Gallego R, Montagut C, Martin-Richard M, Iglesias M, Conill C, et al.

Phase II trial of preoperative chemoradiotherapy with oxaliplatin, cisplatin, and 5-FU

in locally advanced esophageal and gastric cancer. Annals of oncology : official

journal of the European Society for Medical Oncology. 2012; 23: 664-70.

25. Fields RC, Strong VE, Gonen M, Goodman KA, Rizk NP, Kelsen DP, et al.

Recurrence and survival after pathologic complete response to preoperative therapy

followed by surgery for gastric or gastrooesophageal adenocarcinoma. British journal

of cancer. 2011; 104: 1840-7.

26. Mokdad AA, Yopp AC, Polanco PM, Mansour JC, Reznik SI, Heitjan DF, et al.

Adjuvant Chemotherapy vs Postoperative Observation Following Preoperative

Chemoradiotherapy and Resection in Gastroesophageal Cancer: A Propensity Score-

19 / 48

Matched Analysis. JAMA oncology. 2018; 4: 31-8.

27. Mokdad AA, Ali A, Yopp AC, Polanco PM, Nassour I, Mansour JC, et al.

Adoption of evidence-based novel therapies in the treatment of gastric cancer: A

national observational study. Cancer. 2018; 124: 1122-31.

28. Cancer Genome Atlas Research N. Comprehensive molecular characterization of

gastric adenocarcinoma. Nature. 2014; 513: 202-9.

29. Sohn BH, Hwang JE, Jang HJ, Lee HS, Oh SC, Shim JJ, et al. Clinical

Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer

Genome Atlas Project. Clinical cancer research : an official journal of the American

Association for Cancer Research. 2017; [Epub ahead of print].

30. Ronellenfitsch U, Schwarzbach M, Hofheinz R, Kienle P, Kieser M, Slanger TE,

et al. Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal

adenocarcinoma: systematic review with meta-analysis combining individual patient

and aggregate data. European journal of cancer. 2013; 49: 3149-58.

20 / 48

Figures and figure legends:

Fig. 1PRISMA flowchart of the study selection process.

21 / 48

Fig. 2 Network of eligible comparisons for network meta-analysis. The size of each

node corresponds to the number of eligible subjects and the line thickness reflects the

number of trials for each comparison. CT adjuvant chemotherapy, RT radiotherapy,

CRT chemoradiotherapy

Fig. 3 Results ofentire network meta-analysis for overall survival. (a) Pooled hazard

ratios and 95% credible intervals from network meta-analysis. (b) Probability of being

the best treatment. CT adjuvant chemotherapy, RT radiotherapy, CRT

chemoradiotherapy

22 / 48

Fig. 4 Results of subgroup analysis for overall survival. Relative effects in combined

hazard ratios and 95% credible intervals in subgroup of D1 (a) and D2 (c)

lymphadenectomy. Probability of being the best treatment on overall survival in in

subgroup of D1 (b) and D2 (d) lymphadenectomy. CT adjuvant chemotherapy, RT

radiotherapy, CRT chemoradiotherapy

23 / 48

Supplementary Fig. S1 Pair-wise meta-analysis for overall survival.

24 / 48

Supplementary Fig. S2 Pair-wise meta-analysis for overall survival (continued).

25 / 48

Supplementary Fig. S3 Risk of bias graph for all studies included.

Supplementary Fig. S4 Consistency between direct and indirect comparisons with

26 / 48

node-split models.

27 / 48

Table 1 Major Toxic effects (grade 3 and above)

Treatment strategy No. of trials

(patients)

Number of patients (%)

Nausea/vomiting Diarrhea Anemia Leukopenia Thrombocytopenia Stomatitis/Mucositis

Adjuvant CT 23 (3277) 12.8 6.2 5.9 17.8 4.5 6.0

Adjuvant CRT 5 (549) 9.7 1.6 1.6 30.0 1.9 1.5

Neoadjuvant CT 4 (422) 9.7 2.8 4.7 11.6 2.4 3.3

Neoadjuvant CRT 1 (60) N/A N/A N/A 11.7 5.0 N/A

Abbreviations: CT, chemotherapy; RT, radiotherapy; CRT, chemoradiotherapy; N/A, not available

Supplementary Table S1. Characteristics of the included studies

28 / 48

Study Year Region Chemotherapy Radiotherapy Concurrent

Sequential

Lymph

node

resection

Intervention

Group Size

Control

Group Size

Median

follow–up

(Range), m

Adjuvant CT versus Surgery

Noh et al. [1] 2014 International Capecitabine, oxaliplatin N/A N/A D2 520 515 62.4

(54–70)

Sasako et al. [2] 2011 Japan S–1 N/A N/A D2 529 530 36

Chen et al. [3] 2011 China FAM group: fluorouracil,

doxorubicin, mitomycin;

FOLFOX group: oxaliplatin,

leucovorin, fluorouracil

N/A N/A D2 115 153 87

(25–216)

Kulig et al. [4] 2010 Poland Doxorubicin, cisplatin,

etoposide

N/A N/A D1–D3 141 154 37

(31–51)

Di Costanzo et al. [5] 2008 Italy Cisplatin, epirubicin,

leucovorin, fluorouracil

N/A N/A D1–D4 130 128 73

(46.8–81.6)

Nakajima et al. [6] 2007 Japan Uracil–tegafur N/A N/A D2 95 95 74.4

De Vita et al. [7] 2007 Italy Epirubicin, leucovorin,

fluorouracil, etoposide

N/A N/A D1 at least 112 113 60

29 / 48

Nitti et al. (EORTC)

[8]

2006 Italy Methotrexate, fluorouracil,

leucovorin, adriamycin

N/A N/A D2 103 103 79.2

Nitti et al. (ICCG) [8] 2006 Italy Fluorouracil, methotrexate,

leucovorin, epirubicin

N/A N/A N/A 91 100 76.8

Bouche et al. [9] 2005 France Fluorouracil, cisplatin N/A N/A D0–D2 127 133 97.8

Chipponi et al. [10] 2004 France Leucovorin, fluorouracil,

cisplatin

N/A N/A D1, D2 101 104 101

(43–140)

Nashimoto et al. [11] 2003 Japan Mitomycin, fluorouracil,

cytarabine

N/A N/A D2 mostly 127 123 69

Bajetta et al. [12] 2002 Italy Etoposide, adriamycin,

cisplatin, leucovorin,

fluorouracil

N/A N/A D2 137 137 66

(2–83)

Neri et al. [13] 2001 Italy Epidoxorubicin, leucovorin,

fluorouracil

N/A N/A N/A 69 68 31

(7–60)

Cirera et al. [14] 1999 Spain Mitomycin, tegafur N/A N/A N/A 76 72 37

(3–122)

Nakajima et al. [15] 1999 Japan Mitomycin, fluorouracil, uracil N/A N/A N/A 288 285 72

30 / 48

plus tegafur

Macdonald et al. [16] 1995 USA Fluorouracil, doxorubicin,

mitomycin

N/A N/A N/A 93 100 114

Lise et al. [17] 1995 International Fluorouracil, doxorubicin,

mitomycin

N/A N/A N/A 155 159 78

Chou et al. [18] 1994 Taiwan Ftorafur N/A N/A N/A 59 56 27

(8–57)

Grau et al. [19] 1993 Japan Mitomycin N/A N/A N/A 68 66 105

Krook et al. [20] 1991 USA Fluorouracil, doxorubicin N/A N/A N/A 61 64 84

Tsavaris et al. [21] 1996 Greece Fluorouracil, epirubicin,

mitomycin

N/A N/A N/A 42 42 60

Bonfanti et al. [22] 1988 Italy Semustine, fluorouracil N/A N/A N/A 75 69 81

Douglass et al. [23] 1982 USA Semustine, fluorouracil N/A N/A N/A 71 71 N/A

Engstrom et al. [24] 1985 International Fluorouracil, semustine N/A N/A N/A 91 89 64

Popiela et al. [25] 2004 Poland Fluorouracil, adriamycin,

mitomycin

N/A N/A D2 53 52 N/A

Huguier et al. [26] 1980 France Fluorouracil, vinblastine,

cyclophosphamide

N/A N/A N/A 27 26 60

31 / 48

Coombes et al. [27] 1990 International Fluorouracil, adriamycin,

mitomycin

N/A N/A N/A 133 148 68

Nakajima et al. [28] 1984 Japan Mitomycin, fluorouracil,

cytosine arabinoside

N/A N/A N/A 149 74 N/A

Schlag et al. [29] 1982 Germany Fluorouracil, carmustine N/A N/A N/A 49 54 N/A

Hallissey et al. [30] 1994 UK Mitomycin, doxorubicin,

fluorouracil

N/A N/A N/A 138 145 60

Adjuvant CRT versus Surgery

Smalley et al. [31] 2012 USA Fluorouracil, leucovorin 45 Gy in 25 fractions

for 5 weeks

Concurrent D0–D2 282 277 123.6

Moertel et al. [32] 1984 USA Fluorouracil 37.5 Gy delivered over

4 to 5 weeks

Concurrent N/A 39 23 N/A

Dent et al. [33] 1979 South Africa Fluorouracil 20 Gy in 8 fractions

over 10 days

Concurrent N/A 35 31 N/A

Adjuvant RT versus Surgery

Hallissey et al. [30] 1994 UK N/A 45 Gy in 25 fractions

over 35 days

N/A N/A 153 145 60

Adjuvant CRT versus Adjuvant CT

32 / 48

Park et al. [34] 2015 South Korea Capecitabine, cisplatin 45 Gy in 25 fractions

over 5 weeks

Concurrent D2 230 228 84

Zhu et al. [35] 2012 China Fluorouracil, leucovorin 45 Gy in 25 fractions

for 5 weeks

Concurrent D2 186 165 42.5

Kim et al. [36] 2012 South Korea Fluorouracil, leucovorin 45 Gy in 25 fractions

for 5 weeks


(60.3–116.5)

Yu et al. [37] 2012 China Fluorouracil, leucovorin 45 Gy in 25 fractions

for 5 weeks

Concurrent D1, D2 34 34 36

Kwon et al. [38] 2010 South Korea Fluorouracil, cisplatin 45 Gy in 25 fractions

over 5 weeks


(24–92.8)

Bamias et al. [39] 2010 Greece Docetaxel, cisplatin 45 Gy in 25 fractions

for 5 weeks

Sequential D0–D2 72 71 53.7

(1–77.8)

Neoadjuvant RT versus Surgery

Skoropad et al. [40] 2002 Russia N/A 20 Gy in 5 fractions

for 5 days

N/A N/A 51 51 N/A

Zhang et al. [41] 1998 China N/A 40 Gy in 20 fractions N/A N/A 153 158 128

33 / 48

for 4 weeks (89–192)

Shchepotin et al. [42] 1994 Ukrain N/A 20 Gy in 4 fractions

for 4 days

N/A N/A 98 100 N/A

Neoadjuvant CRT versus Surgery

Walsh et al. [43] 2002 Ireland Fluorouracil, cisplatin 40 Gy in 15 fractions

over 2 weeks

Concurrent N/A 16 23 60

Neoadjuvant CRT versus Neoadjuvant CT

Stahl et al. [44] 2009 Germany Fluorouracil, leucovorin,

cisplatin

30 Gy in 15 fractions

for 3 weeks

Concurrent D2 60 59 46

Neoadjuvant CT versus Surgery

Ychou et al. [45] 2011 France Fluorouracil, cisplatin N/A N/A D2 113 111 25

Cunningham et al.

[46]

2006 UK Epirubicin, cisplatin,

fluorouracil

N/A N/A D1, D2 250 253 49

Schuhmacher et al.

[47]

2010 International Cisplatin, folinic acid,

fluorouracil

N/A N/A D2 mostly 72 72 52.8

Hartgrink et al. [48] 2004 Netherlands Methotrexate, leucovorin,

doxorubicin

N/A N/A D1 29 30 83

(51–102)

Wang et al. [49] 2000 China FPLC, fluorouracil N/A N/A N/A 30 30 60

34 / 48

Zhao et al. [50] 2006 China Group 1: 5’–DFUR

Group 2: fluorouracil, calcium

folinate

N/A N/A N/A 34 20 N/A

Kelsen et al. [51] 2007 International Cisplatin, fluorouracil N/A N/A N/A 47 46 (93.6–156)

Neoadjuvant CT versus Adjuvant CT

Yonemura et al. [52] 1993 Japan Cisplatin, mitomycin,

etoposide, uracil

N/A N/A N/A 23 23 24

(6–42)

Nio et al. [53] 2004 Japan Uracil N/A N/A D0–D3 102 193 83

(37–140)

Sun et al. [54] 2011 China Docetaxel, fluorouracil,

leucovorin

N/A N/A N/A 29 26 N/A

Fazio et al. [55] 2015 International Docetaxel, cisplatin,

fluorouracil

N/A N/A D2 34 35 N/A

CT chemotherapy, RT radiotherapy, CRT chemoradiotherapy, N/A not available

References

1. Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2

gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. The Lancet Oncology. 2014; 15: 1389-96.

35 / 48

2. Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, et al. Five-year outcomes of a randomized phase III trial

comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. Journal of clinical oncology : official journal of

the American Society of Clinical Oncology. 2011; 29: 4387-93.

3. Chen S, Chen YB, Zhou ZW, Li W, Sun XW, Xu DZ, et al. No survival benefit from postoperative adjuvant chemotherapy after D2 radical

resection for the patients with stage II gastric cancer. American journal of clinical oncology. 2011; 34: 309-13.

4. Kulig J, Kolodziejczyk P, Sierzega M, Bobrzynski L, Jedrys J, Popiela T, et al. Adjuvant chemotherapy with etoposide, adriamycin and

cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial. Oncology. 2010; 78:

54-61.

5. Di Costanzo F, Gasperoni S, Manzione L, Bisagni G, Labianca R, Bravi S, et al. Adjuvant chemotherapy in completely resected gastric

cancer: a randomized phase III trial conducted by GOIRC. Journal of the National Cancer Institute. 2008; 100: 388-98.

6. Nakajima T, Kinoshita T, Nashimoto A, Sairenji M, Yamaguchi T, Sakamoto J, et al. Randomized controlled trial of adjuvant uracil-tegafur

versus surgery alone for serosa-negative, locally advanced gastric cancer. The British journal of surgery. 2007; 94: 1468-76.

7. De Vita F, Giuliani F, Orditura M, Maiello E, Galizia G, Di Martino N, et al. Adjuvant chemotherapy with epirubicin, leucovorin, 5-

fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale

(GOIM 9602 Study). Annals of oncology : official journal of the European Society for Medical Oncology. 2007; 18: 1354-8.

8. Nitti D, Wils J, Dos Santos JG, Fountzilas G, Conte PF, Sava C, et al. Randomized phase III trials of adjuvant FAMTX or FEMTX

compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG. Annals of oncology :

36 / 48

official journal of the European Society for Medical Oncology. 2006; 17: 262-9.

9. Bouche O, Ychou M, Burtin P, Bedenne L, Ducreux M, Lebreton G, et al. Adjuvant chemotherapy with 5-fluorouracil and cisplatin

compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Annals of oncology : official

journal of the European Society for Medical Oncology. 2005; 16: 1488-97.

10. Chipponi J, Huguier M, Pezet D, Basso N, Hay JM, Quandalle P, et al. Randomized trial of adjuvant chemotherapy after curative resection

for gastric cancer. American journal of surgery. 2004; 187: 440-5.

11. Nashimoto A, Nakajima T, Furukawa H, Kitamura M, Kinoshita T, Yamamura Y, et al. Randomized trial of adjuvant chemotherapy with

mitomycin, Fluorouracil, and Cytosine arabinoside followed by oral Fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology

Group 9206-1. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003; 21: 2282-7.

12. Bajetta E, Buzzoni R, Mariani L, Beretta E, Bozzetti F, Bordogna G, et al. Adjuvant chemotherapy in gastric cancer: 5-year results of a

randomised study by the Italian Trials in Medical Oncology (ITMO) Group. Annals of oncology : official journal of the European Society for

Medical Oncology. 2002; 13: 299-307.

13. Neri B, Cini G, Andreoli F, Boffi B, Francesconi D, Mazzanti R, et al. Randomized trial of adjuvant chemotherapy versus control after

curative resection for gastric cancer: 5-year follow-up. British journal of cancer. 2001; 84: 878-80.

14. Cirera L, Balil A, Batiste-Alentorn E, Tusquets I, Cardona T, Arcusa A, et al. Randomized clinical trial of adjuvant mitomycin plus tegafur

in patients with resected stage III gastric cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

1999; 17: 3810-5.

37 / 48

15. Nakajima T, Nashimoto A, Kitamura M, Kito T, Iwanaga T, Okabayashi K, et al. Adjuvant mitomycin and fluorouracil followed by oral

uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Gastric Cancer Surgical Study Group. Lancet. 1999; 354: 273-7.

16. Macdonald JS, Fleming TR, Peterson RF, Berenberg JL, McClure S, Chapman RA, et al. Adjuvant chemotherapy with 5-FU, adriamycin,

and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study.

Annals of surgical oncology. 1995; 2: 488-94.

17. Lise M, Nitti D, Marchet A, Sahmoud T, Buyse M, Duez N, et al. Final results of a phase III clinical trial of adjuvant chemotherapy with the

modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer. Journal of clinical oncology : official journal of the


18. Chou FF, Sheen-Chen SM, Liu PP, Chen FC. Adjuvant chemotherapy for resectable gastric cancer: a preliminary report. Journal of surgical

oncology. 1994; 57: 239-42.

19. Grau JJ, Estape J, Alcobendas F, Pera C, Daniels M, Teres J. Positive results of adjuvant mitomycin-C in resected gastric cancer: a

randomised trial on 134 patients. European journal of cancer. 1993; 29A: 340-2.

20. Krook JE, O'Connell MJ, Wieand HS, Beart RW, Jr., Leigh JE, Kugler JW, et al. A prospective, randomized evaluation of intensive-course 5-

fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer. Cancer. 1991; 67: 2454-8.

21. Tsavaris N, Tentas K, Kosmidis P, Mylonakis N, Sakelaropoulos N, Kosmas C, et al. A randomized trial comparing adjuvant fluorouracil,

epirubicin, and mitomycin with no treatment in operable gastric cancer. Chemotherapy. 1996; 42: 220-6.

22. Bonfanti G, Gennari L, Bozzette F. Adjuvant treatments following curative resection for gastric cancer. The Italian Gastrointestinal Tumor

38 / 48

Study Group. The British journal of surgery. 1988; 75: 1100-4.

23. Douglass H, Stablein D, Bruckner H. Controlled trial of adjuvant chemotherapy following curative resection for gastric cancer. The

Gastrointestinal Tumor Study Group. Cancer. 1982; 49: 1116-22.

24. Engstrom PF, Lavin PT, Douglass HO, Jr., Brunner KW. Postoperative adjuvant 5-fluorouracil plus methyl-CCNU therapy for gastric cancer

patients. Eastern Cooperative Oncology Group study (EST 3275). Cancer. 1985; 55: 1868-73.

25. Popiela T, Kulig J, Czupryna A, Szczepanik AM, Zembala M. Efficiency of adjuvant immunochemotherapy following curative resection in

patients with locally advanced gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese

Gastric Cancer Association. 2004; 7: 240-5.

26. Huguier M, Destroyes JP, Baschet C, Le Henand F, Bernard PF. Gastric carcinoma treated by chemotherapy after resection: a controlled

study. American journal of surgery. 1980; 139: 197-9.

27. Coombes RC, Schein PS, Chilvers CE, Wils J, Beretta G, Bliss JM, et al. A randomized trial comparing adjuvant fluorouracil, doxorubicin,

and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group. Journal of clinical oncology : official


28. Nakajima T, Takahashi T, Takagi K, Kuno K, Kajitani T. Comparison of 5-fluorouracil with ftorafur in adjuvant chemotherapies with

combined inductive and maintenance therapies for gastric cancer. Journal of clinical oncology : official journal of the American Society of


29. Schlag P, Schreml W, Gaus W, Herfarth C, Linder MM, Queisser W, et al. Adjuvant 5-fluorouracil and BCNU chemotherapy in gastric

39 / 48

cancer: 3-year results. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer. 1982; 80: 277-

83.

30. Hallissey MT, Dunn JA, Ward LC, Allum WH. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in

resectable gastric cancer: five-year follow-up. Lancet. 1994; 343: 1309-12.

31. Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, et al. Updated analysis of SWOG-directed intergroup study 0116: a

phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. Journal of clinical oncology : official


32. Moertel CG, Childs DS, O'Fallon JR, Holbrook MA, Schutt AJ, Reitemeier RJ. Combined 5-fluorouracil and radiation therapy as a surgical

adjuvant for poor prognosis gastric carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

1984; 2: 1249-54.

33. Dent DM, Werner ID, Novis B, Cheverton P, Brice P. Prospective randomized trial of combined oncological therapy for gastric carcinoma.

Cancer. 1979; 44: 385-91.

34. Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, et al. Phase III Trial to Compare Adjuvant Chemotherapy With Capecitabine and

Cisplatin Versus Concurrent Chemoradiotherapy in Gastric Cancer: Final Report of the Adjuvant Chemoradiotherapy in Stomach Tumors Trial,

Including Survival and Subset Analyses. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015; 33:

3130-6.

35. Zhu WG, Xua DF, Pu J, Zong CD, Li T, Tao GZ, et al. A randomized, controlled, multicenter study comparing intensity-modulated

40 / 48

radiotherapy plus concurrent chemotherapy with chemotherapy alone in gastric cancer patients with D2 resection. Radiotherapy and oncology :

journal of the European Society for Therapeutic Radiology and Oncology. 2012; 104: 361-6.

36. Kim TH, Park SR, Ryu KW, Kim YW, Bae JM, Lee JH, et al. Phase 3 trial of postoperative chemotherapy alone versus chemoradiation

therapy in stage III-IV gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. International journal of radiation oncology,

biology, physics. 2012; 84: e585-92.

37. Yu C, Yu R, Zhu W, Song Y, Li T. Intensity-modulated radiotherapy combined with chemotherapy for the treatment of gastric cancer patients

after standard D1/D2 surgery. Journal of cancer research and clinical oncology. 2012; 138: 255-9.

38. Kwon HC, Kim MC, Kim KH, Jang JS, Oh SY, Kim SH, et al. Adjuvant chemoradiation versus chemotherapy in completely resected

advanced gastric cancer with D2 nodal dissection. Asia-Pacific journal of clinical oncology. 2010; 6: 278-85.

39. Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, et al. A randomized phase III study of adjuvant platinum/docetaxel

chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer chemotherapy and pharmacology. 2010; 65: 1009-21.

40. Skoropad V, Berdov B, Zagrebin V. Concentrated preoperative radiotherapy for resectable gastric cancer: 20-years follow-up of a

randomized trial. Journal of surgical oncology. 2002; 80: 72-8.

41. Zhang ZX, Gu XZ, Yin WB, Huang GJ, Zhang DW, Zhang RG. Randomized clinical trial on the combination of preoperative irradiation and

surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. International journal of radiation oncology, biology,

physics. 1998; 42: 929-34.

42. Shchepotin IB, Evans SR, Chorny V, Osinsky S, Buras RR, Maligonov P, et al. Intensive preoperative radiotherapy with local hyperthermia

41 / 48

for the treatment of gastric carcinoma. Surgical oncology. 1994; 3: 37-44.

43. Walsh TN, Grennell M, Mansoor S, Kelly A. Neoadjuvant treatment of advanced stage esophageal adenocarcinoma increases survival.

Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus. 2002; 15: 121-4.

44. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, et al. Phase III comparison of preoperative chemotherapy

compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. Journal of clinical

oncology : official journal of the American Society of Clinical Oncology. 2009; 27: 851-6.

45. Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, et al. Perioperative chemotherapy compared with surgery alone for

resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. Journal of clinical oncology : official journal of

the American Society of Clinical Oncology. 2011; 29: 1715-21.

46. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery

alone for resectable gastroesophageal cancer. The New England journal of medicine. 2006; 355: 11-20.

47. Schuhmacher C, Gretschel S, Lordick F, Reichardt P, Hohenberger W, Eisenberger CF, et al. Neoadjuvant chemotherapy compared with

surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized

trial 40954. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010; 28: 5210-8.

48. Hartgrink HH, van de Velde CJ, Putter H, Songun I, Tesselaar ME, Kranenbarg EK, et al. Neo-adjuvant chemotherapy for operable gastric

cancer: long term results of the Dutch randomised FAMTX trial. European journal of surgical oncology : the journal of the European Society of

Surgical Oncology and the British Association of Surgical Oncology. 2004; 30: 643-9.

42 / 48

49. Wang XL, Wu GX, Zhang MD, Guo M, Zhang H, Sun XF. A favorable impact of preoperative FPLC chemotherapy on patients with gastric

cardia cancer. Oncology reports. 2000; 7: 241-4.

50. Zhao WH, Wang SF, Ding W, Sheng JM, Ma ZM, Teng LS, et al. Apoptosis induced by preoperative oral 5'-DFUR administration in gastric

adenocarcinoma and its mechanism of action. World journal of gastroenterology. 2006; 12: 1356-61.

51. Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, et al. Long-term results of RTOG trial 8911 (USA Intergroup

113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. Journal

of clinical oncology : official journal of the American Society of Clinical Oncology. 2007; 25: 3719-25.

52. Yonemura Y, Sawa T, Kinoshita K, Matsuki N, Fushida S, Tanaka S, et al. Neoadjuvant chemotherapy for high-grade advanced gastric

cancer. World journal of surgery. 1993; 17: 256-61; discussion 61-2.

53. Nio Y, Koike M, Omori H, Hashimoto K, Itakura M, Yano S, et al. A randomized consent design trial of neoadjuvant chemotherapy with

tegafur plus uracil (UFT) for gastric cancer--a single institute study. Anticancer research. 2004; 24: 1879-87.

54. Sun XC, Lin J, Ju AH. Treatment of Borrmann type IV gastric cancer with a neoadjuvant chemotherapy combination of docetaxel, cisplatin

and 5-fluorouracil/leucovorin. The Journal of international medical research. 2011; 39: 2096-102.

55. Fazio N, Biffi R, Maibach R, Hayoz S, Thierstein S, Brauchli P, et al. Preoperative versus postoperative docetaxel-cisplatin-fluorouracil

(TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial. Annals of

oncology : official journal of the European Society for Medical Oncology. 2016; 27: 668-73.

Supplementary Table S2. Main clinicopathologic characteristics of the enrolled patients in the included studies

43 / 48

Study Mean age

(years)

Sex Tumor stage Nodal status UICC/AJCC

stage

Male Female T1 T2 T3 T4 N0 N1 N2 N3

Noh et al. [1] 56 731 304 11 564 456 4 103 621 311 0 IB-IV

Sasako et al. [2] 63 736 323 1 575 457 26 115 577 367 0 IB-IV

Chen et al. [3] 56 183 85 0 80 198 0 198 80 0 0 IIA

Kulig et al. [4] 61 211 84 6 67 140 82 91 80 85 39 IB-IV

Di Costanzo et al. [5] 59 157 101 NA NA 124 14 42 213 I-IV

Nakajima et al. [6] 63 143 45 0 188 0 0 0 141 47 0 II

De Vita et al. [7] 63 131 94 8 37 142 38 62 77 86 0 IB-IIIB

Nitti et al. (EORTC) [8] 56 127 79 17 68 114 7 39 83 84 0 IB-IIIB

Nitti et al. (ICCG) [8] 54 125 66 6 61 107 17 34 82 75 0 IB-IV

Bouche et al. [9] 61 186 74 59 288 10 43 138 48 21 II-IV

Chipponi et al. [10] 61 129 67 NA NA NA NA 33 163 NA

Nashimoto et al. [11] 58 169 81 74 155 21 0 139 80 31 NA I-III

Bajetta et al. [12] 57 174 97 128 143 27 244 I-III

Neri et al. [13] 69 98 39 3 15 64 65 0 65 72 0 NA

44 / 48

Cirera et al. [14] 61 94 54 3 11 39 95 20 57 71 0 III

Nakajima et al. [15] NA 363 210 188 323 62 0 237 286 46 4 NA

Macdonald et al. [16] 59 123 70 NA NA NA NA NA NA NA NA I-III

Lise et al. [17] NA 202 112 12 126 144 29 NA NA NA NA II-III

Chou et al. [18] NA 67 48 NA NA NA NA NA NA NA NA II-III

Grau et al. [19] 56 88 46 4 21 109 0 51 54 29 0 NA

Krook et al. [20] 63 98 27 NA NA NA NA NA NA NA NA NA

Tsavaris et al. [21] 53 57 27 NA NA NA NA NA NA NA NA III

Bonfanti et al. [22] NA 138 75 40 70 103 89 124 NA

Douglass et al. [23] NA 100 42 NA NA NA NA 54 88 NA

Engstrom et al. [24] NA 120 60 NA NA NA NA NA NA NA NA NA

Popiela et al. [25] 58 74 31 0 80 25 0 62 43 0 III-IV

Huguier et al. [26] 60 38 15 NA NA NA NA NA NA NA NA NA

Coombes et al. [27] NA NA NA 13 97 124 45 89 119 62 8 II-III

Nakajima et al. [28] NA 141 82 NA NA NA NA 91 108 86 15 I-IV

Schlag et al. [29] 59 63 40 NA NA NA NA NA NA NA NA II-III

Hallissey et al. [30] 64 303 133 NA NA NA NA NA NA NA NA II-III

Smalley et al. [31] 60 397 159 172 342 42 83 231 242 0 IB-IV

45 / 48

Moertel et al. [32] 58 46 16 NA NA NA NA NA NA NA NA NA

Dent et al. [33] NA NA NA 4 8 46 0 22 9 27 0 NA

Park et al. [34] 56 296 162 NA NA NA NA 62 253 101 42 IB-IV

Zhu et al. [35] 56 261 90 0 0 351 50 104 123 74 IB-IV

Kim et al. [36] NA 59 31 0 33 51 6 2 25 43 20 III-IV

Yu et al. [37] 56 43 25 0 7 42 19 0 40 28 0 II-III

Kwon et al. [38] 56 44 17 NA NA NA NA NA NA NA NA III-IV

Bamias et al. [39] NA 100 43 4 26 107 6 17 74 40 11 IB-IV

Skoropad et al. [40] 55 74 28 11 27 58 6 48 37 15 2 I-IV

Zhang et al. [41] 56 NA NA NA NA NA NA NA NA NA NA I-IV

Shchepotin et al. [42] 55 NA NA 0 6 127 65 71 121 0 NA

Walsh et al. [43] NA NA NA NA NA NA NA NA NA NA NA NA

Stahl et al. [44] 60 108 11 0 0 109 10 NA NA NA NA NA

Ychou et al. [45] 63 187 37 NA NA NA NA NA NA NA NA NA

Cunningham et al. [46] 62 396 107 NA NA NA NA NA NA NA NA NA

Schuhmacher et al. [47] 57 100 44 0 0 135 9 10 92 11 2 III-IV

Hartgrink et al. [48] 60 NA NA NA NA NA NA NA NA NA NA II-III

Wang et al. [49] 54 50 10 NA NA NA NA NA NA NA NA NA

46 / 48

Zhao et al. [50] NA NA NA NA NA NA NA NA NA NA NA NA

Kelsen et al. [51] 62 NA NA NA NA NA NA NA NA NA NA NA

Yonemura et al. [52] 64 41 14 NA NA NA NA NA NA NA NA IV

Nio et al. [53] 64 211 84 NA NA NA NA NA NA NA NA I-IV

Sun et al. [54] 52 37 18 NA NA NA NA NA NA NA NA NA

Fazio et al. [55] 57 47 22 NA NA NA NA NA NA NA NA IB-IV

NA, not available

47 / 48

48 / 48

· Web view1.Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up

Documents