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

Introduction

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 https://jgo.amegroups.com/article/view/10.21037/jgo-22-29/rc).

Methods

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).

Results

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.

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.

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.

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.

Discussion

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.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-29/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-29/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-29/coif). 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.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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