ReviewSurvival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: A direct and adjusted indirect comparison meta-analysis
Introduction
In Western countries, about two thirds of patients with gastric cancer have locally advanced disease at diagnosis and inevitably the R0 resection rate and prognosis after surgery alone are miserable in this clinical setting.1
In many new cases of gastric cancer, adequate locoregional and systemic disease control is difficult to obtain with resection alone, therefore surgery is frequently combined with preoperative cytoreductive treatment in contemporary clinical practice. A previous meta-analysis comparing the long-term survival between preoperative chemotherapy with or without radiotherapy and surgery alone in patients with adenocarcinoma of the stomach, gastro-oesophageal junction (GOJ) or lower oesophagus suggested a survival benefit of preoperative chemotherapy.2 In this context, it should be noted that a corresponding survival benefit of preoperative radiotherapy alone has been alleged in a previous meta-analysis.3
Several phase I/II studies have presented promising results from the combination of preoperative chemotherapy and radiotherapy in patients with potentially resectable gastric cancer.4, 5, 6 Given the established validity of chemoradiotherapy for gastric cancer, the significance of preoperative radiotherapy as an adjunct to chemotherapy in patients with potentially resectable gastric cancer warrants better scientific validation. To date, however, the sole direct randomised comparison between preoperative chemoradiotherapy versus chemotherapy alone focused on patients with GOJ cancer has been reported by Stahl et al.7 This study showed a significantly higher pathologic complete response rate and a tendency toward an improved 3-year survival rate by the addition of radiotherapy.
Evidence from comparative head to head (direct) trials is often limited or unavailable, why indirect comparisons are mandated.8 This is particularly the case with chemoradio- and chemotherapy when used preoperatively. A simple but inappropriate statistical method for indirect comparison is to compare the results of individual arms from different trials as if they were from the same randomised trial. This naive type of indirect comparison has been criticised for discarding the within trial comparison, and thereby increasing the liability to bias. In contrast, the adjusted indirect comparison can take advantage of the strength of randomised clinical trials in making unbiased comparisons. In the present study, the indirect comparison of different interventions is adjusted by comparing the results of their direct comparisons with a common control group.8
The objectives of the current study were threefold: firstly, to perform a careful literature survey to assess the feasibility of performing a meta-analysis concerning outcome after preoperative treatment added to surgery compared to surgery alone in patients with gastric cancer including GOJ adenocarcinoma. Secondly, we wanted to analyse the compiled database with regard to the main outcomes of interest: postoperative morbidity, perioperative mortality and long-term survival for preoperative chemotherapy and chemoradiotherapy, separately. Finally, we aimed to clarify the differences in endpoints mentioned above between preoperative chemotherapy and chemoradiotherapy by direct and adjusted indirect comparison analyses.
Section snippets
Eligibility criteria
Eligible studies were randomised clinical trials in which patients fulfilled the following criteria: adenocarcinoma of the stomach and/or GOJ; no previous treatment; tumours clinically diagnosed as resectable. Trials comparing preoperative chemotherapy plus surgery with surgery alone, preoperative radiotherapy with or without chemotherapy [(chemo)radiotherapy] plus surgery with surgery alone, and preoperative chemoradiotherapy plus surgery with chemotherapy plus surgery were included. To be
Study selection
In total 18 studies7, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 were eligible (Fig 1). Eight were randomised comparisons of preoperative (chemo)radiotherapy versus surgery alone,21, 22, 23, 24, 25, 26, 27, 30 8 were randomised comparisons of preoperative chemotherapy versus surgery alone,15, 17, 18, 19, 20, 28, 29, 31 and 2 were randomised comparisons of preoperative chemoradiotherapy versus preoperative chemotherapy.7, 16 One study was a 3-arm study that compared
Discussion
In total 18 studies were eligible when we scrutinised the relevant literature and among these data were available from 14 of them. The subsequent meta-analysis on overall survival yielded an HR of 0.75 for preoperative (chemo)radiotherapy compared to surgery alone in resectable gastric and GOJ cancer, suggesting an important therapeutic effect. We also found that preoperative chemotherapy in resectable gastric and GOJ cancer showed a strong trend towards better long-term survival compared to
Conflict of interest statement
The authors state they have no conflict of interest to disclose regarding current manuscript.
Acknowledgements
The authors thank the European Organization for Research and Treatment of Cancer for permission to use the data from EORTC trial 40954 and thank the German Oesophageal Cancer Study Group for permission to use the data from the POET study for this meta-analysis.
References (37)
- et al.
Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: systematic review with meta-analysis combining individual patient and aggregate data
Eur J Cancer
(2013) - et al.
The impact of radiotherapy on survival in resectable gastric carcinoma: a meta-analysis of literature data
Cancer Treat Rev
(2007) - et al.
Assessing the quality of reports of randomized clinical trials: is blinding necessary?
Control Clin Trials
(1996) - et al.
Postoperative pancreatic fistula: an international study group (ISGPF) definition
Surgery
(2005) - et al.
Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial
Eur J Cancer
(2011) - et al.
Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial
Eur J Surg Oncol
(2004) - et al.
Intensive preoperative radiotherapy with local hyperthermia for the treatment of gastric carcinoma
Surg Oncol
(1994) - et al.
A prospective, randomized trial of pre-operative and intraoperative radiotherapy versus surgery alone in resectable gastric cancer
Eur J Surg Oncol
(2000) - et al.
A favorable impact of preoperative FPLC chemotherapy on patients with gastric cardia cancer
Oncol Rep
(2000) - 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)
Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial
Lancet
Cancer statistics, 2000
CA Cancer J Clin
Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma
J Clin Oncol
Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome
J Clin Oncol
Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response
J Clin Oncol
Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction
J Clin Oncol
Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews
BMJ
Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints
Stat Med
Cited by (36)
SP promotes cell proliferation in esophageal squamous cell carcinoma through the NK1R/Hes1 axis
2019, Biochemical and Biophysical Research CommunicationsCitation Excerpt :In China, esophageal squamous cell carcinoma (ESCC), as the main type of EC (approximately 90%), ranks the 4th most lethal tumour [2]. Although surgical strategies and adjuvant therapy have improved, the prognosis of ESCC patients remains poor, and the 5-year overall survival (OS) rate is only 15% ∼ 25% [3]. Substance P (SP), first discovered in 1931 [4], is composed of 11 amino acids.
4D flow MRI for the analysis of celiac trunk and mesenteric artery stenoses
2018, Magnetic Resonance ImagingCitation Excerpt :An exciting new field has emerged in the evaluation and understanding of altered vascular supply of the celiac artery (CA) after esophagectomy and gastric pull-up. This surgical procedure, in combination with radiochemotherapy, is the current gold standard for treatment of esophageal cancer in an operable stage [35–37]. However, this procedure is accompanied by high morbidity and mortality rates of up to 60% and 5%, respectively [38–41], with a major cause of the former being leakage of the anastomosis based on the compromised tissue perfusion of the proximal gastric tube [39, 41, 42].
Preoperative therapy and long-term survival in gastric cancer: One size does not fit all
2018, Surgical OncologyCitation Excerpt :The interpretation of these results could have led to the improper extension of the indication for preoperative therapy from gastroesophageal to GCs [9]. In fact, in both the MAGIC and ACCORD07 trials, the subgroup of patients with GC did not benefit from the administration of preoperative therapy [29,30]. The presence of a selective advantage of the preoperative phase of the perioperative therapy in specific subgroups of patients may explain why the preoperative therapy did not prove to be an independent prognostic factor in the entire population of the study.
Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial
2017, European Journal of CancerCitation Excerpt :The positive results of preoperative CRT were weakened by increased numbers of postoperative deaths coming from more early data with former radiation techniques. This is no longer true nowadays and in particular for AC [25]. Of note, a recent international consensus of surgeons [26] stated that postoperative mortality should no longer be reported after 30 d, only, since modern intensive care strategies largely prevent patients from early death after major surgery.
Multimodal treatments for resectable esophagogastric junction cancer: A Bayesian network meta-analysis
2023, Langenbeck's Archives of Surgery