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A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction

Klevebro F, Alexandersson von Döbeln G, Wang N, Johnsen G, Jacobsen AB, Friesland S, et al.

Selected and commented by Prof. Florian Lordick:

In this randomized, controlled trial (referred to with the acronym NeoRes), which compared 3 cycles of cisplatin-5-fluorouracil neoadjuvant chemotherapy (nCT) with neoadjuvant chemoradiotherapy (nCRT) for oesophageal and gastro-esophageal junction carcinoma, the investigators have shown that nCRT significantly increases the proportion of complete histological response, increases the occurrence of ypN0 lymph-node status, and increases the R0 resection rate, but does so without a corresponding improvement in survival.

What are the caveats and what can we learn out of this study?

In this trial, many patients had difficulty tolerating the full three cycles of chemotherapy in the nCRT arm and consequently only 74% completed three cycles, compared with 85% in the nCT arm.

This trial also showed that complications were significantly more severe after the addition of radiotherapy, and this finding is further aggravated by the analysis of the causes of death by follow-up year, which showed significantly more deaths unrelated to disease progression in the nCRT arm during the first year of follow-up. The many early deaths not related to cancer progression in the nCRT arm illustrate the need for less toxic preoperative regimens with preserved efficacy. The CROSS regimen, which combines weekly paclitaxel and carboplatin given in moderate doses with 41.4 Gray radiation, is probably a better choice for the neoadjuvant treatment of patients with oesophageal cancer.

Interestingly, the analysis of survival by histological tumour type revealed a trend towards improved survival after the addition of radiotherapy among patients with squamous cell histology and, conversely, a trend towards poorer survival with the addition of radiotherapy among patients with adenocarcinoma. This highlights that at the time being, there are two options for the neoadjuvant treatment of adenocarcinoma of the oesophagus and oesophago-gastric junction, nCT as well as nCRT. And we cannot conclude at the time being that either of the options is better than the other one with regards to survival.

Moreover, I conclude, in accordance with the authors of the this study, that this trial does not provide any evidence in support of using complete histological response as a surrogate marker for survival in future studies.

Abstract

BACKGROUND:

Neoadjuvant therapy improves long-term survival after oesophagectomy, treating oesophageal cancer, but the evidence to date is insufficient to determine which of the two main neoadjuvant therapy types, chemotherapy (nCT) or chemoradiotherapy (nCRT), is more beneficial. We aimed to compare the effects of nCT with those of nCRT.

PATIENTS AND METHODS:

This multicentre trial, which was conducted in Sweden and Norway, recruited 181 patients with carcinoma of the oesophagus or the gastro-oesophageal junction who were candidates for curative-intended treatment. The primary end point was histological complete response after neoadjuvant treatment, which has been shown to be correlated with increased long-term survival. Study participants were randomized to nCT or nCRT, followed by surgery with two-field lymphadenectomy. Three cycles of platin/5-fluorouracil were administered in both arms, whereas 40 Gy of concomitant radiotherapy was added in the nCRT arm.

RESULTS:

The trial met the primary end point, histological complete response being achieved in 28% after nCRT versus 9% after nCT (P = 0.002). Lymph-node metastases were observed in 62% in the nCT group versus 35% in the nCRT group (P = 0.001). The R0 resection rate was 87% after nCRT and 74% after nCT (P = 0.04). There was no difference in overall survival between the treatment arms.

CONCLUSION:

The addition of radiotherapy to neoadjuvant chemotherapy results in higher histological complete response rate, higher R0 resection rate, and a lower frequency of lymph-node metastases, without significantly affecting survival.

Category: Articles, Chemotherapy & Chemoradiotherapy

Keywords: Gastric cancer; KEYNOTE-012, Pembrolizumab, phase I trial

©PubMed Central


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