We would like to thank Drs. Bedenne, Le Malicot and Drouillard for their commentary on our recently published networked meta-analysis (1). There is no worldwide agreement on the best perioperative oncological management of this disease so we are pleased this article has encouraged debate. It is notable the small amount of randomised evidence directly comparing CT with CRT as a neoadjuvant therapy in resectable oesophageal cancer (2,3).
Since the publication of most recent meta-analysis by Sjoquist et al. (4) four trials enrolling almost 1,100 patients have reported conflicting results (1). This meta-analysis only considered neoadjuvant therapies, but there is much debate about the efficacy of adjuvant therapies in resectable oesophago-gastric cancers. The diverse evidence in the literature allowed us an opportunity to compare adjuvant and neoadjuvant treatments with chemotherapy (CT), radiotherapy (RT), or chemoradiotherapy (CRT) using a novel ‘network’ meta-analysis. The advantage of this analysis over conventional direct meta-analysis is it allows the evaluation of treatments that have not been compared directly or indirectly by using a common reference that is part of all the RCTs, i.e., surgery alone (e.g., comparison of B versus C, using data from trials comparing A versus B and A versus C). Further, it ranks multiple treatments based simultaneously on their efficacy; and it pools together direct and indirect evidence within mixed comparisons improving the precision of estimates (5).
Different approaches to data interpretation are sometimes required to gain insight in to their clinical application and these analyses can be hypothesis-generating and inform the design of RCTs. For example, SUCRA (Surface Under the Cumulative RAnking) is Bayesian statistical approach interested in treatment efficacy rather than comparative statistics. It ranks different treatments rather than comparing. This is in contrast to frequentist statistics which uses hazard ratios (HR) to compare treatment effect.
We decided not to include Ychou et al. paper (6) as there were very few cases with oesophageal cancer included (decisional rule stated in our methods) (1). The omission of this study reduced number of patients by roughly 25, which will not have affected the power of our meta-analysis; which due to the networked approach is actually more complicated issue which is best accounted for by heterogeneity rather than simply the number of patients included.
Considering the available evidence, we were not able to draw conclusions on best neoadjuvant approach and recommend completing the several CT vs. CRT trial using contemporary RT techniques and latest chemotherapeutic drugs. The available evidence suggests CRT significantly increases the pathCR response rate and this may confer a survival advantage; but not always (3,7). In other studies, there was the cost of an increased peri-operative morbidity and mortality, which offsets the survival gains (2).
Clearly, better designed pragmatic randomised trial evidence is required comparing these two neoadjuvant techniques in oesophageal cancer. Fortunately, three further high quality trials are currently recruiting patients (8-10) (Table 1). Although these will take time to be recruited and be published, it is hoped that they will clarify whether the increased rates of pathCR and potential survival gains from CRT are worth the risks of toxicity and potential peri-operative morbidity and mortality.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Pasquali S, Yim G, Vohra RS, et al. Survival After Neoadjuvant and Adjuvant Treatments Compared to Surgery Alone for Resectable Esophageal Carcinoma: A Network Meta-analysis. Ann Surg 2017;265:481-91. [Crossref] [PubMed]
- Hamilton E, Vohra RS, Griffiths EA. What is the best neoadjuvant regimen prior to oesophagectomy: chemotherapy or chemoradiotherapy? Int J Surg 2014;12:196-9. [Crossref] [PubMed]
- Klevebro F, Alexandersson von Döbeln G, Wang N, et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol 2016;27:660-7. [Crossref] [PubMed]
- Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011;12:681-92. [Crossref] [PubMed]
- Mills EJ, Thorlund K, Ioannidis JP. Demystifying trial networks and network meta-analysis. BMJ 2013;346:f2914. [Crossref] [PubMed]
- Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29:1715-21. [Crossref] [PubMed]
- Favi F, Bollschweiler E, Berlth F, et al. Neoadjuvant chemotherapy or chemoradiation for patients with advanced adenocarcinoma of the oesophagus? A propensity score-matched study. Eur J Surg Oncol 2017;43:1572-80. [Crossref] [PubMed]
- Nakamura K, Kato K, Igaki H, et al. Three-arm phase III trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, NExT study). Jpn J Clin Oncol 2013;43:752-5. [Crossref] [PubMed]
- Reynolds JV, Preston SR, O'Neill B, et al. ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS). BMC Cancer 2017;17:401. [Crossref] [PubMed]
- Hoeppner J, Lordick F, Brunner T, et al. ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286). BMC Cancer 2016;16:503. [Crossref] [PubMed]