Chemotherapy is the preferred neoadjuvant treatment of oesophageal adenocarcinoma

The successful treatment of oesophageal adenocarcinoma (OAC) is dependent on maximizing both local and distant disease control. If the appropriate surgical approach is adopted to reduce local-regional recurrence, such as an en bloc transthoracic resection, then, to improve outcomes, all efforts should be focused on systemic treatments to prevent distant metastatic recurrence. We believe that, for locally advanced OAC, the best chance of cure is afforded by an en bloc surgical resection preceded by neoadjuvant chemotherapy (nCT), not neoadjuvant chemoradiotherapy (nCRT), in which the primary function of the cytotoxic drugs is to be radiosensitizing. Although nCT to treat OAC had been well established, the FLOT4 trial further reinforced this approach by demonstrating a significant improvement in survival by using a docetaxel-based regimen (FLOT) rather than an epirubicin-based regimen1. Although junctional and oesophageal cancers represented a minority of the cohort, the genomic similarity of these lesions to gastric adenocarcinoma suggests that they should be treated as a common entity. Indeed, one of the authors and others have shown that this approach is applicable to OAC in a multicentre study demonstrating that, with neoadjuvant FLOT combined with a transthoracic en bloc oesophagectomy, a 3-year overall survival of over 60 per cent is achievable for OAC, despite a high disease burden2. Proponents of nCRT cite improved complete resection (R0) rates and pathological complete response (pCR) compared with nCT, implying that this may result in better local control3,4. However, this is not the case, as the increased R0 rate has not translated into lower local-regional recurrence in any of the above studies. This is even though transthoracic en bloc resection, an approach that has been associated with a very low rate of local-regional recurrence, was not routinely employed in these studies. Furthermore, prospective trial data from the authors’ centre, combining modern docetaxel-based treatment with transthoracic en bloc resection, demonstrate that a very high R0 resection rate (greater than 95 per cent) is possible without radiation5. With regards to pCR, multiple randomized studies comparing nCT with nCRT have demonstrated that pCR is more common after irradiation compared with chemotherapy alone. Yet again, none of these trials has shown that this translates into improved overall survival. This was recently demonstrated in the NeoRes study, in which oesophageal cancer patients (majority with OAC) were randomized to receive either cisplatin and 5-fluorouracil with 40 Gy of radiotherapy or cisplatin and 5-fluorouracil3. An equivalent 3-year overall survival was found in OAC patients (48 versus 43 per cent after nCT and nCRT respectively), despite higher rates of pCR among those treated with radiotherapy (22 versus 7 per cent after nCRT and nCT respectively) and despite using an inferior systemic regimen to FLOT. The results from the Neo-AEGIS study further highlight the non-inferiority of nCT in comparison with nCRT, despite higher levels of pCR4. In this trial comparing nCRT (in the form of the CROSS regimen: cisplatin, paclitaxel, and 41.4 Gy of radiotherapy) with nCT (mostly MAGIC-style epirubicin-based regimens), the rate of pCR was significantly higher among patients treated with nCRT (16 versus 5 per cent after nCRT and nCT respectively). Nevertheless, the 3-year overall survival was equivalent when comparing the two arms (57 versus 56 per cent after nCT and nCRT respectively). Importantly, FLOT was only used in 15 per cent of the nCT arm. Considering the superiority of FLOT over ECF (Epirubicin, Cisplatin, 5-Fluorouracil), demonstrated in the FLOT4 trial, it is not unreasonable to imagine that survival among recipients of nCT would have been better than that among recipients of nCRT. A large international study investigating the clinical outcomes of pCR after neoadjuvant treatment of OAC found a trend towards greater 5-year overall survival in those treated with nCT in comparison with nCRT (79 versus 66 per cent after nCT and nCRT respectively; P = 0.099)6, suggesting that pCR is not a valid oncological metric when comparing these two approaches for the management of OAC. Conversely, pCR after nCRT is associated with a greater prevalence of distant recurrence (OR 2.5, 95 per cent c.i. 1.25 to 4.99) and hence a significantly lower incidence of 5-year disease-free survival (75 versus 87 per cent after nCRT and nCT respectively; P = 0.026). Poor distant control is also reflected in recurrence data from the CROSS study, in which patients with OAC originally treated in the trial with nCRT had a similar incidence of distant recurrence when compared with those who underwent upfront surgery7. The strength of nCT is derived from the improved systemic control that is associated with effective systemic neoadjuvant therapy to treat occult metastatic disease. It is important to note that data from the NeoRes study showed no difference in the incidence of recurrence when comparing nCT and nCRT (45 versus 36 per cent after nCT and nCRT respectively; P = non-significant). However, when comparing FLOT and CROSS regimens, distal recurrence appears to be higher for the latter (23.8 versus 4.8 per cent in the CROSS group and the FLOT group respectively; P = 0.026)8. The results from the German study directly comparing FLOT with CROSS regimens, the ESOPEC trial, will clarify this specific issue. Concerning local recurrence, it appears the incidence is similar after nCT and nCRT (19 versus 16 per cent after nCT and nCRT respectively; P = 0.68)3. This leads the authors to question the benefit of providing two treatment modalities, irradiation and surgery, to achieve local disease control. Therefore, in our opinion, the literature suggest that nCRT compensates for suboptimal surgery as much of the perceived benefit of nCRT is derived from studies where the incidence of transthoracic resections was low. This may be why Noordman et al.9, who carried out a retrospective review of patients treated according to the CROSS protocol stratified by transhiatal versus transthoracic oesophagectomy, concluded that the extended lymphadenectomy afforded by a transthoracic approach is not needed to achieve long-term OAC survival. The authors’ interpretation of the data in Noordman et al.9 is that radiation is not needed to achieve local control if the appropriate surgical approach is undertaken10, namely a transthoracic en bloc resection, thus allowing placement of all efforts in maximizing systemic control with nCT. In conclusion, the authors believe that nCT followed by en bloc transthoracic resection is the treatment of choice for patients with locally advanced OAC. In terms of local control, this approach can achieve a similar level of R0 resection rates as nCRT if the appropriate operation is performed. Patients with OAC often suffer from distant recurrence and, despite the best efforts of surgeons, it is effective systemic chemotherapy that ultimately prevents this. In the authors’ opinion, to deprive patients of these treatments is to deprive them of the best chance of cure. The authors have no funding to declare. The authors declare no conflict of interest.

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