Comparison of neoadjuvant regimens for resectable gastroesophageal junction cancer: a systematic review of randomized clinical trials across three decades
Review Article

Comparison of neoadjuvant regimens for resectable gastroesophageal junction cancer: a systematic review of randomized clinical trials across three decades

Go Nishikawa1^, Pratyusha Banik1, Rajat Thawani2, Adel Kardosh2, Stephanie G. Wood3, Nima Nabavizadeh4, Emerson Y. Chen2^

1Department of Medicine, Oregon Health & Science University, Portland, OR, USA; 2Division of Hematology/Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; 3Division of Gastrointestinal and General Surgery, Oregon Health & Science University, Portland, OR, USA; 4Department of Radiation Medicine, Oregon Health & Science University, Portland, OR, USA

Contributions: (I) Conception and design: EY Chen; (II) Administrative support: G Nishikawa, P Banik, EY Chen; (III) Provision of study materials or patients: G Nishikawa, P Banik, EY Chen; (IV) Collection and assembly of data: G Nishikawa, P Banik, EY Chen; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

^ORCID: Go Nishikawa, 0000-0003-2253-7274; Emerson Y. Chen, 0000-0003-3035-4478.

Correspondence to: Emerson Y. Chen, MD, MCR. Assistant Professor of Medicine, Division of Hematology/Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Email:

Background: The optimal perioperative treatment for adenocarcinoma of gastroesophageal junction (GEJ) tumor remains uncertain. The systematic review aims to assess the best neoadjuvant modality, namely chemotherapy (CT) versus chemoradiotherapy (CRT) based on randomized controlled trials (RCTs) for resectable gastric, esophageal and GEJ tumors.

Methods: We performed a comprehensive PubMed database and Cochrane Library search to identify relevant RCTs related to neoadjuvant treatment for resectable GEJ adenocarcinoma. We included all published RCTs (phase 2 or 3) that tested specific neoadjuvant therapies (CT or CRT) if the patient population included GEJ tumors. We applied the Version 2 Cochrane risk-of-bias tool (RoB 2) to all the eligible studies. Outcomes examined included R0 resection and pathological response based on intention-to-treat (ITT) analysis, surgical outcomes, notable adverse events, and overall survival (OS). Each randomized group of every study was noted to be neoadjuvant CRT, CT, or surgery alone in order to compare the outcomes among these treatment approaches.

Results: We identified 25 RCTs with 7,855 patients published from 1996 to 2019. Seven studies tested preoperative CT versus surgery alone, 7 tested preoperative radiotherapy (RT) or CRT versus surgery alone, 4 tested preoperative RT or CRT versus preoperative CT, and 7 tested other combinations. The R0 resection ranged 47–100% and the 3-year OS ranged 6–66.1% in all the study arms. In an exploratory analysis, CRT strategies showed a superior R0 resection rate [80.2%; 95% confidence interval (CI): 79.8–80.6%] to surgery alone (60.9%; 95% CI: 60.4–61.3%; P<0.01) and to preoperative CT (63.9%; 95% CI: 63.6–64.2%; P<0.01). When comparing 3- and 5-year OS, improvement was noted when comparing CRT to surgery alone (P<0.01), and perioperative CT to surgery alone (P<0.01), but no definite difference was noted between CRT versus CT.

Discussion: Preoperative CRT showed improvement in R0 resection rate to surgery alone and preoperative CT. However, there is no significant difference in OS between CRT and CT. Both neoadjuvant strategies remain clinically meaningful options for patients with resectable GEJ tumors. Lack of patient-level data and inconsistent reporting of key outcomes across studies were the main limitations of our study.

Keywords: Gastric cancer; esophageal cancer; gastroesophageal junction (GEJ) cancer; neoadjuvant chemotherapy (CT); neoadjuvant radiation

Submitted Jan 11, 2022. Accepted for publication Apr 13, 2022.

doi: 10.21037/jgo-22-29


Esophageal cancer is a significant contributor to cancer-related mortality worldwide. It ranks sixth at 544,000 deaths a year, or 1 in every 18 cancer deaths (1). Encouragingly, the relative 5-year survival rate has improved from 5% to approximately 20% over the past five decades (2). While the incidence of squamous cell histology has declined in recent years, especially in the United States, the incidence of adenocarcinoma histology continues to increase, perhaps as a result of the increased prevalence of obesity, gastroesophageal reflux disease, and Western diet and lifestyle factors (3). Recently, there has been also better molecular and genetic characterization of gastroesophageal junction (GEJ) tumors over traditional anatomical classification, namely unique DNA methylation signatures, mRNA and microRNA expression patterns (4,5). However, despite improvements in diagnostics and curative and life-prolonging treatments for esophageal and gastric adenocarcinoma, the optimal perioperative treatment remains uncertain for operable adenocarcinoma of the GEJ.

Surgical resection is the mainstay of treatment for locally advanced resectable GEJ adenocarcinoma, and patients with GEJ cancer are generally included in studies on either esophageal or gastric cancer. Over the last 20 years, randomized controlled trials (RCTs) have shown that both adjunctive chemoradiotherapy (CRT) and chemotherapy (CT) can improve overall survival (OS) compared to surgery alone (6,7). However, there is insufficient evidence to demonstrate the superiority of one neoadjuvant approach over another.

Furthermore, there are varied multimodal approaches that are largely guided by institutional practice and physician preference. Thus, an updated, comprehensive evidence review is needed comparing and contrasting the available multimodal treatment options for GEJ tumors. A 2016 meta-analysis of 325 patients compared CRT to CT in resectable esophageal cancer with subgroup analysis for adenocarcinoma; it demonstrated improved pathologic complete response (pCR) and margin-negative (R0) resection rates with CRT but no difference in 3-year OS rates (8). Another recent meta-analysis analyzed both RCTs and retrospective cohorts among 18,260 patients with similar findings, where CRT had favorable pCR and R0 resection results without any gain in 5-year OS rate compared to CT strategies (9).

We conducted an up-to-date comprehensive systematic review of RCTs across 3 decades to summarize the clinical outcomes of neoadjuvant CRT versus neoadjuvant or perioperative CT in resectable GEJ adenocarcinoma. We present the following article in accordance with the PRISMA reporting checklist (available at


Search strategy and study selection

This study is a systematic review of RCTs investigating neoadjuvant CT and radiotherapy (RT) approaches to improve clinical outcomes in resectable GEJ cancers. We performed a systematic search on Medline (PubMed) for eligible RCTs from January 1, 1946 to August 3, 2020 and on Cochrane Library from January 1, 1946, to September 1, 2020. Additional RCTs from references of eligible trials and published systematic reviews were also included. The literature search method is detailed in Tables S1,S2 (Appendix 1).

Criteria for inclusion/exclusion of studies were established before the search. We included all RCTs that tested preoperative cancer-directed interventions, such as neoadjuvant CT, induction CT, neoadjuvant RT or CRT, or combinations of these therapies. Other notable search terms or filters included phase 2 and phase 3 trials, esophageal and GEJ adenocarcinoma, and full-text English-language articles. Studies with squamous cell or mixed histology and gastric cancer were included only if patients with GEJ adenocarcinoma were included in the overall population of the RCTs. We excluded non-randomized studies, non-CT and non-RT treatment interventions, unresectable or metastatic clinical scenarios, non-English publications, and abstract-only articles. Studies were selected by two independent reviewers: GN and either EYC or PB. Discrepancies were resolved by at least two reviewers. Reasons for exclusion are detailed in Table S3 (Appendix 1). PRISMA guidelines were followed.

Data extraction and quality assessment

All data were independently extracted and agreed upon by GN and EYC, with partial review by PB and AK. Data related to study publication, trial design, patient population, therapy strategy, duration, and clinical outcomes were all collected. The main outcomes of interest were rate of definitive surgery, R0 resection rates, and OS. We applied the Version 2 Cochrane risk-of-bias tool (RoB 2) to all the eligible studies.

Statistical analysis

We tabulated the proportion of GEJ tumors for every eligible study. Data of distal third or lower esophagus tumors were included as GEJ if a GEJ tumor was not reported based on Siewert classification or if it was not clearly delineated. When both lower esophagus and GEJ Siewert type 1 were reported separately, we included only the GEJ group but did not include the distal or lower esophagus group. GEJ site tumors with squamous cell histology were not considered to be GEJ adenocarcinoma when presented in an eligible trial.

We combined the proportion of surgery and R0 resection across all eligible trials. Survival data were summarized because patient-level data were not available. If specific survival data were not available in the publication, graphic measurements were used to estimate 1-, 3- and 5-year OS. We resolved discrepancies in data interpretation was resolved by both GN and EYC. or counted as missing data. The proportion of surgery with R0 resection and pCR rates were calculated based on intention-to-treat (ITT) analysis. Notable adverse event data were also analyzed. Data regarding postoperative complication rates were extracted from all trials that evaluated preoperative treatment modalities. Trials evaluating only postoperative CT or postoperative CRT were excluded. Complications analyzed included 30-day mortality, total postoperative mortality, anastomotic leakage, and infectious, cardiac, and respiratory complication rates. Proportions were obtained directly if values were already reported in the studies or indirectly by taking the number of patients with a particular complication and dividing by the number of subjects that underwent surgical resection. Results were reported as a range of complications reflecting all included trials. The results of the survival and R0 resection rate were first reported for each of the five analysis groups with 25 studies (groups A: preoperative CT versus CT; group B: preoperative CT versus surgery alone; group C: preoperative RT or CRT versus surgery; group D: preoperative CRT versus CT; and group E: induction CT with CRT versus CRT) and then for three groups that included all 50 study arms (group i: perioperative CT; group ii: CRT; and group iii: surgery alone). Groups A–E compared trial to trial, whereas groups i–iii compared one study arm of a trial to another.

An exploratory analysis was done to compare all 50 study arms with group i, ii, and iii. An unweighted analysis using a Mann-Whitney test was used to compare the mean R0 resection rates and 1-, 3-, and 5-year OS among these three groups. A similar weighted analysis accounting for the sample size and reported proportions for these four outcomes was completed using the Fisher Exact test, with 95% confidence interval (CI).


Characteristics of the included studies

From the initial literature search from Medline (n=1,758) and Cochrane (n=624), 48 publications were fully screened to yield 40 total published articles from 25 specific RCTs testing preoperative therapy approaches in resectable GEJ cancers (Figure 1). In these 25 studies, 6 (24%, group A) were preoperative CT versus preoperative CT, 7 (28%, group B) were preoperative CT versus surgery alone, 7 (28%, group C) were preoperative RT or preoperative CRT versus surgery alone, 4 (16%, group D) were preoperative CRT versus preoperative CT, and 1 (4%, group E) was induction CT with preoperative CRT versus preoperative CRT alone. When organizing into randomized groups (50 groups in 25 studies), 23 randomized groups tested preoperative CT, 13 randomized groups tested preoperative RT or CRT, and 14 randomized groups were surgery alone. The years studied were from 1978 to 2012 (start of accrual) and from 1989 to 2015 (end of accrual period), respectively. The number of patients per RCT (including both randomized arms) ranged from 43 to 1,063 subjects. The median age of the participants ranged from 56 to 72 years old. The proportion of GEJ cancer and adenocarcinoma histology in the studies was from 10–100% and 53–100%, per study arm, respectively. The median follow-up ranged from 10 months to 10 years. The characteristics of the included studies are summarized in Table 1. The risk of bias of the included studies was evaluated based on the Cochrane RoB 2 tool shown in Table S4 (Appendix 1).

Figure 1 PRISMA flowchart.

Table 1

Characteristics of included RCTs by groups A–E

Author, year Study period Experimental arm/control arm No. of patients Median age GEJ cancer (%) Adeno-carcinoma (%) Therapy strategy
Preoperative CT versus CT (group A)
   Cunningham, 2017 2007–2014 CT 533 63 49.7 100 Three preoperative cycles of epirubicin, cisplatin and capecitabine, preoperatively and postoperatively
CT 530 64 51.1 100 Three preoperative cycles of epirubicin, cisplatin, capecitabine and bevacizumab, preoperatively and postoperatively
   Al-Batran, 2019 2010–2015 CT 360 62 55.6 100 Three cycles of epirubicin, cisplatin, and fluorouracil or capecitabine, preoperatively and postoperatively
CT 356 62 55.6 100 Three cycles of docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil, preoperatively and postoperatively
   Cats, 2018 2007–2015 CT 393 62 17.3 100 Three cycles of epirubicin, cisplatin, or oxaliplatin, and capecitabine, preoperatively and postoperatively
CT 395 63 17 100 Three cycles of epirubicin, cisplatin, or oxaliplatin, and capecitabine preoperatively and cisplatin, capecitabine and 45 Gy in 25 fractions postoperatively
   Stahl, 2018 2010–2013 CT 80 60 41.3 100 Three cycles of epirubicin, cisplatin, capecitabine and panitumumab, preoperatively and postoperatively
CT 80 61 45 100 Three cycles of epirubicin, cisplatin, and capecitabine, preoperatively and postoperatively
   Alderson, 2017 2005–2011 CT 451 62 100 100 Three cycles of cisplatin and 5-fluorouracil, and capecitabine
CT 446 62 100 100 Three cycles of epirubicin, cisplatin and capecitabine
   Lorenzen, 2013 2007–2008 CT 22 71.5 22.7 100 Four cycles of oxaliplatin, leucovorin, and 5-fluorouracil
CT 21 69 42.9 100 Four cycles of oxaliplatin, leucovorin, docetaxel and 5-fluorouracil
Preoperative CT versus surgery alone (group B)
   Ychou, 2011 1995–2003 CT 113 63 61.9 100 Two or three cycles of cisplatin and 5-fluorouracil preoperatively, and three to four cycles postoperatively
None 111 63 66.7 100 Surgery alone
   Schuhmacher, 2010 1999–2004 CT 72 56 51.4 100 Two cycles of cisplatin and d-L-folinic acid, and 5-fluorouracil
None 72 58 54.2 100 Surgery alone
   Cunningham, 2006 1994–2002 CT 250 62 11.2 100 Three cycles of epirubicin, cisplatin, and 5-fluorouracil, preoperatively and postoperatively
None 253 62 11.9 100 Surgery alone
   Biffi, 2010 1999–2005 CT 34 57 23.5 100 Four cycles of docetaxel, cisplatin, and 5-fluorouracil preoperatively
   Fazio, 2016 None 35 59 25.7 100 Four cycles of docetaxel, cisplatin, and 5-fluorouracil postoperatively
   Kelsen, 1998 1990–1995 CT 213 62 no 54 Three cycles of cisplatin, 5-fluorouracil preoperatively
   Kelsen, 2007 None 227 61 no 53.3 Surgery alone
   MRC, 2002 1992–1998 CT 400 63 10 66.3 Two cycles of cisplatin and 5-fluorouracil preoperatively
   Allum, 2009 None 402 63 10.4 66.7 Surgery alone
   Basi, 2013 2011–2012 CT 32 62.63 17.9 100 Three cycles of docetaxel, cisplatin, 5-fluorouracil preoperatively
None 27 61.22 23.1 100 Surgery alone
Preoperative chemoradiation or RT versus surgery (group C)
   van Hagen, 2012 2004–2008 CRT 178 60 22 75.3 Five cycles of carboplatin, paclitaxel, and 41.4 Gy in 23 fractions
   Shapiro, 2015 None 188 60 26.1 75 Surgery alone
   Tepper, 2008 1997–2000 CRT 30 59.9 no 76.7 Two cycles of cisplatin and 5-fluorouracil, and 54 Gy in 26 fractions
None 26 62.2 no 73.1 Surgery alone
   Walsh, 1996 1990–1996 CRT 58 65 41.8 100 Two cycles of cisplatin, 5-fluorouracil and 40 Gy in 15 fractions preoperatively
None 55 65 27.6 100 Surgery alone
   Urba, 2001 1989–1994 CRT 50 62 92 74 Two cycles of cisplatin, 5-fluorouracil, vinblastine, and 45 Gy in 30 fractions preoperatively
None 50 64 92 76 Surgery alone
   Burmeister, 2005 1994–2000 CRT 128 61 77.3 62.5 One cycle of cisplatin, 5-fluorouracil, and 35 Gy in 15 fractions preoperatively
None 128 62 81.3 60.9 Surgery alone
   Zhao, 2015 2012–2013 CRT 36 61 100 100 Two cycles of capecitabine, oxaliplatin, and 45 Gy in 25 fractions preoperatively
None 40 57 100 100 Surgery alone
   Zhang, 1998 1978–1989 RT 171 55.8 no 100 40 Gy in 20 fractions preoperatively
None 199 56.1 no 99.5 Surgery alone
Preoperative chemoradiation versus CT (group D)
   Klevebro, 2016 2006–2013 CRT 90 63 16.7 72.2 Three 3-weekly cycles of cisplatin, fluorouracil, and 40 Gy in 20 fractions
   von Dobeln, 2019 CT 91 63 18.6 72.5 Three 3-weekly cycles of cisplatin and fluorouracil
   Leong, 2017 2009–2014 CRT 60 no 26.7 100 Three cycles of epirubicin, cisplatin, 5-fluorouracil or capecitabine, and 45 Gy in 25 fractions
CT 60 no 26.7 100 Three cycles of epirubicin, cisplatin, and 5-fluorouracil or capecitabine
   Stahl, 2009 2000–2005 CRT 60 60.6 100 100 Twelve weekly 5-fluorouracil, folinic acid, cisplatin, etoposide and 30 Gy in 15 fractions
   Stahl, 2017 CT 59 56 100 100 Twelve weekly 5-fluorouracil, folinic acid and biweekly and three weekly cisplatin
   Burmeister, 2011 2000–2006 CRT 39 60 no 100 Two cycles of cisplatin, 5-fluorouracil, and 35 Gy in 15 fractions
CT 36 63 no 100 Two cycles of cisplatin and 5-fluorouracil
Induction CT (and/or chemoradiation) versus CRT (or RT) (group E)
   Ajani, 2013 2005–2011 CRT 63 60 96.8 96.8 Five weeks of oxaliplatin, 5-fluorouracil, and 50.4 Gy in 28 fractions preoperatively
Induction CT and CRT 63 60 96.8 96.8 Two cycles of induction oxaliplatin, 5-fluorouracil, and five weeks of oxaliplatin, 5-fluorouracil, 50.4 Gy in 28 fractions preoperatively

RCTs, randomized controlled trials; GEJ, gastroesophageal junctional cancer; CT, chemotherapy; CRT, chemoradiotherapy; RT, radiotherapy.

Surgical and pathologic outcome

Surgery occurred 61.8–100% of patients according to ITT analysis among these 25 trials (Table 2). R0 resection in ITT analysis ranged 47–100% in all trials. When reorganizing the randomized arm data into the group i, ii and iii, surgery occurred 67.6–97.2% in CT arms, 73.3–100% in CRT arms, and 61.8–100% in surgery-only arms. R0 resection occurred 47–85.3% in CT arms, 71.7–100% in CRT arms, and 53.4–91.4% in surgery-only arms. The rate of pCR in ITT analysis ranged 0–33.3% in all trials. When reorganizing study arms into group i, ii, and iii, pCR ranged 0–11.8% in CT arms and 11.1–33.3% in CRT arms.

Table 2

Surgical and survival outcomes of included RCTs by groups A–E

Author, year Number of patients GEJ (%) Adeno-carcinoma (%) Rate of surgery in ITT (%) R0 resection rate in ITT (%) pCR in ITT (%) 1 year OS (%) 3 years OS (%) 5 years OS (%)
Preoperative CT versus CT (group A)
   Cunningham, 2017 533 49.7 100 85.7 60.2 3.9 78 50.3 40.2
530 51.1 100 82.6 57.5 2.1 77.1 48.1 35.6
   Al-Batran, 2019 360 55.6 100 87.2 77.5 80.1 48 36
356 55.6 100 94.4 84.6 84.9 57 45
   Cats, 2018 393 17.3 100 78.9 63.1 77.1 53.3 42
395 17 100 82.5 67.6 77.1 51.4 40
   Stahl, 2018 80 41.3 100 93.8 80 79.7 49
80 45 100 92.5 82.5 89.2 62
   Alderson, 2017 451 100 100 85.8 47 77.1 39.1 29.1
446 100 100 81.6 50 77.7 42 31.4
   Lorenzen, 2013 22 22.7 100 77.3 68.2 0 82.5
21 42.9 100 71.4 66.7 9.5 84.9
Preoperative CT versus surgery alone (group B)
   Ychou, 2011 113 61.9 100 89.4 84.1 2.7 81.8 47.6 38
111 66.7 100 89.2 73 71.3 35 24
   Schuhmacher, 2010 72 51.4 100 97.2 81.9 6.9 87.2 65.4 51.3
72 54.2 100 94.4 68.1 82.7 51.3 47.4
   Cunningham, 2006 250 11.2 100 67.6 69.5 44.3 36.3
253 11.9 100 65.6 65.2 30.4 23
   Biffi, 2010 34 23.5 100 91.2 85.3 11.8 88.2 64.5 47
   Fazio, 2016 35 25.7 100 97.1 91.4 85.5 57.9 46
   Kelsen, 1998 213 54 76.1 62.4 2.3 59 23 18.8
   Kelsen, 2007 227 53.3 89.4 59.5 60 26 21.1
   MRC, 2002 400 10 66.3 84.5 58.3 60.1 33.8 23
   Allum, 2009 402 10.4 66.7 82.1 53.4 54.7 26.4 17.1
   Basi, 2013 32 17.9 100 87.5 75 85.7
27 23.1 100 96.3 59.3 84.6
Preoperative chemoradiation or RT versus surgery (group C)
   van Hagen, 2012 178 22 75.3 90.4 83.1 81 58 47
   Shapiro, 2015 188 26.1 75 86.2 59 70 44 33
   Tepper, 2008 30 76.7 73.3 33.3 88.7 66.1 39
26 73.1 88.5 79.1 20.3 16
   Walsh, 1996 58 41.8 100 87.9 23.6 52 32
55 27.6 100 100 44 6
   Urba, 2001 50 92 74 94 28 72 30 20.2
50 92 76 90 58 16 10.1
   Burmeister, 2005 128 77.3 62.5 82 80.5 12.5 72.6 35.7 26.6
128 81.3 60.9 85.9 59.4 63.5 32 23.7
   Zhao, 2015 36 100 100 100 100 16.7
40 100 100 100 80
   Zhang, 1998 171 100 80.1 80.1 70.9 36.8 30.1
199 99.5 61.8 61.8 61.5 27.4 20.26
Preoperative chemoradiation versus CT (group D)
   Klevebro, 2016 90 16.7 72.2 86.7 75.6 24.4 76.9 51.9 42.2
   von Dobeln, 2019 91 18.6 72.5 85.7 63.7 7.7 72.6 46.6 39.6
   Leong, 2017 60 26.7 100 80
60 26.7 100 86.7
   Stahl, 2009 60 100 100 75 71.7 11.7 75.4 47.4 39.5
   Stahl, 2017 59 100 100 83.1 67.8 1.7 69.5 27.7 24.4
   Burmeister, 2011 39 100 84.6 84.6 12.8 72.7 52 45
36 100 91.7 80.6 0 76 49 36
Induction CT (and/or chemoradiation) versus chemoradiation (or RT) (group E)
   Ajani, 2013 63 96.8 96.8 87.3 73 11.1 87.4 51.9 48.9
63 96.8 96.8 85.7 79.4 22.2 85.2 60.7 50.4

RCTs, randomized controlled trials; GEJ, gastroesophageal junctional cancer; ITT, intention-to-treat analysis; pCR, pathologic complete response; OS, overall survival.

In the exploratory unweighted analysis, there was an improvement in R0 resection for CRT compared to surgery alone (P=0.02) and a similar non-statistically significant trend comparing CRT and CT arms (P=0.05). With regard to weighted analysis, CRT strategies clearly demonstrated superior R0 resection rates (80.2%; 95% CI: 79.8–80.6%) to surgery alone (60.9%; 95% CI: 60.4–61.3%; P<0.01), and compared to CT strategies (63.9%; 95% CI: 63.6–64.2%; P<0.01), as presented in Table 3.

Table 3

Weighted analysis of R0 resection and survival outcomes among preoperative CRT, CT, and surgery alone strategies

Treatment type R0 resection 1-year OS 3-year OS 5-year OS
Preoperative (chemo)radiotherapy (n=1,026) 80.2%;
(95% CI: 79.8–80.6%); reference
(95% CI: 75.0–76.1%); reference
(95% CI: 45.7–47.1%); reference
(95% CI: 37.5–38.8%); reference
Preoperative CT (n=5,027) 63.9%;
(95% CI: 63.6–64.2%); P<0.01
(95% CI: 75.8–76.2%); P=0.47
(95% CI: 45.9–46.4%);
(95% CI: 35.1–35.5%); P=0.09
Surgery alone (n=1,813) 60.9%;
(95% CI: 60.4–61.3%); P<0.01
(95% CI: 62.9–63.7%); P<0.01
(95% CI: 30.1–31.0%); P<0.01
(95% CI: 22.9–23.7%); P<0.01

CRT, chemoradiotherapy; CRT, chemotherapy.

Adverse effects

The 30-day mortality rate in the preoperative CRT group was 0–10.2%, 0–10% in CT group, and 0–10% in surgery alone. The total mortality rates (sum of 30- and 90-day mortality rates) in the group i, ii, and iii had similar ranges as the 30-day postoperative mortality rates. Anastomotic leakage rates in the CRT, CT, and surgery alone groups were 0–22%, 1.9–6.0%, and 0–30%, respectively. The rate of respiratory complications was 2.7–54.9%, 1.9–16%, and 0–58.2%, respectively. Cardiac complication rates were 4.2–27.4%, 4–17%, and 4–23.6% respectively. Finally, the rates of infectious complications were 1.9–13%, 3–12.2%, and 1.8–12.5%. Postoperative complications are summarized in Table S5 (Appendix 1).

Survival outcome

In all the trials, the 1-year OS was 44–89.2%, the 3-year OS was 6–66.1%, and the 5-year OS was 10.1–51.3% (Table 2). When reorganizing the study arm data into group i, ii, and iii, the 1-year OS was 59–89.2% in group i, 52–88.7% in group ii, and 44–85.5% in group iii. The 3-year OS was 23–65.4% in group i, 30–66.1% in group ii, and 6–57.9% in group iii. The 5-year OS was 18.8–51.3% in group i, 20.2–50.4% in group ii, and 10.1–47.4% in group iii.

In the exploratory analysis, with regards to unweighted analysis, there was an improvement in 3- and 5-year OS when comparing preoperative CRT or perioperative CT to surgery alone (all P<0.05) but no difference when comparing neoadjuvant CRT versus CT strategies. In the weighted analysis seen in Table 3, CRT strategies showed a 3-year OS of 46.4% (95% CI: 45.7–47.1%) and a 5-year OS of 38.2% (95% CI: 37.5–38.8%), which were not statistically different from preoperative CT, 3-year OS (46.2%; 95% CI: 45.9–46.4%), and 5-year OS (35.3%; 95% CI: 35.1–35.5%). Both neoadjuvant strategies had superior survival outcomes to surgery alone with 3-year OS (30.5%; 95% CI: 30.1–31.0%), and 5-year OS (23.3%; 95% CI: 22.9–23.7%), all comparisons P<0.01. Finally, Figure 2 conceptually summarizes the advantages and challenges of preoperative CT, preoperative CRT, and surgery alone based on results presented here.

Figure 2 Summary of preoperative CT, preoperative chemoradiation, and surgery alone. CT, chemotherapy; pCR, pathologic complete response; CRT, chemoradiotherapy.


In our weighted exploratory analysis, both preoperative CRT and perioperative CT for resectable GEJ cancer demonstrated a statistically significant survival advantage for 3- and 5-year OS (46% and 35–38%, respectively) compared to upfront surgical resection (31% and 23%, respectively). In this review, both neoadjuvant approaches showed similar survival outcomes despite CRT showing a superior R0 resection rate to CT. In both esophageal and gastric cancer trials for these two treatment strategies, distant metastatic recurrence represented the most common reason for disease relapse, ranging from 22–36% (7,10). Some of the preoperative CRT study arms may have used inadequate systemic treatment and varied radiation treatment doses, fields, and schedules, resulting in a wide range of disease relapse patterns and explaining why CRT trials achieved only comparable OS to perioperative CT trials, despite better R0 resection and pCR (11). For example, radiation in the CROSS study involved the regional lymph nodes while in CALBG 80803 the celiac axis was always included for lower esophageal or GEJ cancers (6,12). Additionally, various CT regimens can explain why the pCR in the preoperative CRT was not higher compared to preoperative CT (13). Our results are also similar to Petrelli et al.’s (9) recent systematic review and meta-analysis of 18,260 subjects in 22 RCTs and retrospective studies on GEJ tumors. Their results showed that preoperative CRT showed improvement in pCR (95% CI: 2.27–3.47; P<0.001) but did not reduce the risk of death (HR =0.95; 95% CI: 0.84–1.07; P=0.41) or distant metastases (OR =0.81; 95% CI: 0.59–1.11; P=0.19) compared to perioperative CT. Our study is the first systematic review to include only RCTs with no retrospective studies and to focus on the modality of the preoperative regimen for resectable GEJ tumors or esophageal adenocarcinomas.

Until a head-to-head clinical trial reports the final analysis, the best preoperative management of gastroesophageal cancers remains a debate, especially for GEJ tumors, which are included historically in both gastric and esophageal cancer trials. Among studies that included only GEJ tumors, preoperative RT or preoperative CRT have shown better R0 resection rates and OS without compromising surgical safety and morbidity compared to surgery alone (14-16). Interestingly, in the Partial Oral Treatment of Endocarditis (POET) trial, OS showed a trend in favor of adding preoperative CRT to CT compared to CT alone (HR =0.65; 95% CI: 0.42–1.01; P=0.055) (16). It is possible that optimizing systemic treatment may further decrease risk of distant relapse, and optimizing CRT could improve R0 resection and decrease local-regional relapse (8–18%) (10), both of which are vital to maintaining long-term survival. On the contrary, there is one randomized phase 2 trial that showed no survival advantage for adding induction CT to CRT despite increased higher pCR rates and common real-world practice (12,17).

Recently, the CheckMate-577 trial demonstrated that adjuvant immunotherapy with nivolumab can improve disease-free survival (median 22.4 versus 11.0 months, HR =0.69, P<0.001) after neoadjuvant CRT and surgery achieving negative margins (18). Immunotherapy checkpoint inhibitors represent a new class of drugs that could improve survival outcomes, as there may not be a difference between CT and CRT. Induction CT before CRT and postoperative CT have not proven helpful. Therefore, ongoing neo-adjuvant and perioperative therapy trials testing immunotherapy (NCT03604991, NCT04592913) may change the future therapy landscape. The ongoing EOSPEC trial (NCT02509286), will put to rest the debate of CRT versus CT, but many researchers in the field would expect these strategies to have the same result with regard to OS.

Recently, the Neo-AEGIS trial, which directly compared the preoperative CRT “CROSS” regimen (preoperative carboplatin/paclitaxel and 41.4 Gy RT) to the perioperative CT “MAGIC” or “FLOT” regimen (epirubicin/cisplatin/5-fluorouracil or docetaxel/5-fluorouracil/leucovorin/oxaliplatin, respectively), reported its first survival analysis. This important clinical trial from Ireland was compromised with the advent of FLOT prompting a significant protocol change in the perioperative CT regimen. Regardless, similar to our data analysis, the R0 resection was higher in the CROSS arm compared to the CT arm (95% versus 82%) and the 3-year OS was similar (56% versus 57%, HR =1.02), with the data safety monitoring board suggesting early recruitment closure due to futility in December 2020 (19). This RCT result validates our analysis and supports how high-quality systematic review can indeed predict research questions that may take long intervals and tremendous effort. Another ongoing RCT is the RACE trial (NCT04375605) which compares the preoperative FLOT (5-fluorouracil/folinic acid/oxaliplatin/docetaxel) to the preoperative FLOT followed by radiochemotherapy (5-fluorouracil/oxaliplatin and radiation). Tian et al. (20) also recently published a study that compared neoadjuvant CRT versus surgery alone for GEJ tumors. The pCR was 97.0% versus 87.7% (P<0.05) and the OS times was 39 versus 30 months (P=0.01) in the neoadjuvant CRT versus surgery only, which is consistent with our result. Once the final reports of these ongoing trials are available, an updated analysis including all of the relevant studies is warranted.

Several study limitations were notable. First, as patient-level data were not available from published literature, we estimated data for the 1-, 3-, and 5-year OS from the graphic measurement presented in the published figures to minimize missing data. Second, we found that the data presented in the studies may not have been accurately presented in published figures comparing text and figure (21). Third, the definition of a GEJ tumor has been inconsistent across studies, and it is difficult to account for these differences. Before the Siewert classification for GEJ was proposed in 2006, most studies used various, heterogeneous definitions that prevented consistent anatomical definition in our systematic review. Fourth, while we focused on and compared what treatment modality was conducted preoperatively, our review also included studies that performed additional postoperative management that could affect the survival outcome in those studies. And without patient-level data, we could only conduct an exploratory estimation of important outcomes comparing RT and CT approaches. Lastly, we have performed a comprehensive review by including studies for the past three decades from the 1990s. As there has been advancement in surgical intervention and supportive care for CT and radiation treatment over time, the datasets between the older and newer trials may be heterogeneous. We encourage other interested researchers to repeat similar analyses, especially with the results release of several upcoming RCTs.

In conclusion, this comprehensive review found that both the preoperative CRT and the perioperative CT approaches demonstrate similar OS advantages despite differences in short-term surrogate endpoints like R0 resection rates. While several head-to-head RCTs are ongoing, we anticipate these definitive trials will confirm findings from the historical data presented in this systematic review. The preliminary non-inferiority results from the Neo-AEGIS trials also highlight the importance of de-identified patient-level data sharing from past trials for high-quality systematic review because such research can often address research questions that may be costly or cumbersome when utilizing RCTs. In the future, use of immunotherapy checkpoint inhibitors as neoadjuvant or post-operative therapy will also likely change how we treat resectable GEJ tumors.


Funding: None.


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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at EYC reports research support from Taiho Oncology, Inc. for investigator initiated trial as co-investigator, and Honoraria for lectures from Horizon CME. The other authors have no conflicts of interest to declare.

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  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
  2. He H, Chen N, Hou Y, et al. Trends in the incidence and survival of patients with esophageal cancer: A SEER database analysis. Thorac Cancer 2020;11:1121-8. [Crossref] [PubMed]
  3. Kong CY, Nattinger KJ, Hayeck TJ, et al. The impact of obesity on the rise in esophageal adenocarcinoma incidence: estimates from a disease simulation model. Cancer Epidemiol Biomarkers Prev 2011;20:2450-6. [Crossref] [PubMed]
  4. Alabi N, Sheka D, Siddiqui A, et al. Methylation-Based Signatures for Gastroesophageal Tumor Classification. Cancers (Basel) 2020;12:1208. [Crossref] [PubMed]
  5. Barra WF, Moreira FC, Pereira Cruz AM, et al. GEJ cancers: gastric or esophageal tumors? searching for the answer according to molecular identity. Oncotarget 2017;8:104286-94. [Crossref] [PubMed]
  6. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84. [Crossref] [PubMed]
  7. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20. [Crossref] [PubMed]
  8. Deng HY, Wang WP, Wang YC, et al. Neoadjuvant chemoradiotherapy or chemotherapy? A comprehensive systematic review and meta-analysis of the options for neoadjuvant therapy for treating oesophageal cancer. Eur J Cardiothorac Surg 2017;51:421-31. [PubMed]
  9. Petrelli F, Ghidini M, Barni S, et al. Neoadjuvant chemoradiotherapy or chemotherapy for gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis. Gastric Cancer 2019;22:245-54. [Crossref] [PubMed]
  10. Eyck BM, van Lanschot JJB, Hulshof MCCM, et al. Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol 2021;39:1995-2004. [Crossref] [PubMed]
  11. Heeren PA, Kelder W, Blondeel I, et al. Prognostic value of nodal micrometastases in patients with cancer of the gastro-oesophageal junction. Eur J Surg Oncol 2005;31:270-6. [Crossref] [PubMed]
  12. Goodman KA, Hall N, Bekaii-Saab TS, et al. Survival outcomes from CALGB 80803 (Alliance): A randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer. J Clin Oncol 2018;36:4012. [Crossref]
  13. Cai Z, Yin Y, Zhao Z, et al. Comparative Effectiveness of Neoadjuvant Treatments for Resectable Gastroesophageal Cancer: A Network Meta-Analysis. Front Pharmacol 2018;9:872. [Crossref] [PubMed]
  14. Zhao Q, Li Y, Wang J, et al. Concurrent Neoadjuvant Chemoradiotherapy for Siewert II and III Adenocarcinoma at Gastroesophageal Junction. Am J Med Sci 2015;349:472-6. [Crossref] [PubMed]
  15. Zhang ZX, Gu XZ, Yin WB, et al. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. Int J Radiat Oncol Biol Phys 1998;42:929-34. [Crossref] [PubMed]
  16. Stahl M, Walz MK, Riera-Knorrenschild J, et al. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. Eur J Cancer 2017;81:183-90. [Crossref] [PubMed]
  17. Ajani JA, Xiao L, Roth JA, et al. A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer. Ann Oncol 2013;24:2844-9. [Crossref] [PubMed]
  18. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med 2021;384:1191-203. [Crossref] [PubMed]
  19. Reynolds JV, Preston SR, O'Neill B, et al. Neo-AEGIS (Neoadjuvant trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Preliminary results of phase III RCT of CROSS versus perioperative chemotherapy (Modified MAGIC or FLOT protocol). J Clin Oncol 2021;39:4004. [Crossref]
  20. Tian Y, Wang J, Qiao X, et al. Long-Term Efficacy of Neoadjuvant Concurrent Chemoradiotherapy for Potentially Resectable Advanced Siewert Type II and III Adenocarcinomas of the Esophagogastric Junction. Front Oncol 2021;11:756440. [Crossref] [PubMed]
  21. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462-7. [Crossref] [PubMed]
Cite this article as: Nishikawa G, Banik P, Thawani R, Kardosh A, Wood SG, Nabavizadeh N, Chen EY. Comparison of neoadjuvant regimens for resectable gastroesophageal junction cancer: a systematic review of randomized clinical trials across three decades. J Gastrointest Oncol 2022;13(3):1454-1466. doi: 10.21037/jgo-22-29

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