Elsevier

The Lancet Oncology

Volume 16, Issue 9, September 2015, Pages 1090-1098
The Lancet Oncology

Articles
Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial

https://doi.org/10.1016/S1470-2045(15)00040-6Get rights and content

Summary

Background

Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years.

Methods

Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2–3N0–1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m2 of body-surface area] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed.

Findings

Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1–116·8, IQR 70·7–96·6), median overall survival was 48·6 months (95% CI 32·1–65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2–33·7) in the surgery alone group (HR 0·68 [95% CI 0·53–0·88]; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2–116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4–26·7) in the surgery alone group (HR 0·48 [95% CI 0·28–0·83]; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9–61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0–41·2) in the surgery alone group (HR 0·73 [95% CI 0·55–0·98]; log-rank p=0·038).

Interpretation

Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer.

Funding

Dutch Cancer Foundation (KWF Kankerbestrijding).

Introduction

Oesophageal cancer is an aggressive disease, characterised by a high degree of locoregional and distant recurrence after primary surgical resection and poor 5-year overall survival that rarely exceeds 40%.1, 2, 3 Much effort has been put into improving tumour resectability, long-term locoregional control, and overall survival, through the addition of chemotherapy, radiotherapy, or both, to surgery, in a neoadjuvant or adjuvant setting.2, 3, 4, 5 However, many studies have not shown a significant long-term survival benefit of such approaches.6, 7

Research in context

Evidence before this study

Based on the extensive meta-analysis by Sjoquist and colleagues in 2011, at the initiation of the CROSS trial in 2004, the results from four previous randomised trials comparing neoadjuvant concurrent chemoradiotherapy plus surgery to surgery alone had been reported. Chemotherapy in these trials consisted of cisplatin and fluorouracil (and also vinblastine in one trial), with a total concurrent radiation dose ranging from 40 to 45 Gy. However, these trials included only small numbers of patients and showed opposing results. Our previous non-randomised phase 2 feasibility trial tested a regimen of weekly administrations of carboplatin and paclitaxel with 41·4 Gy concurrent radiotherapy and showed a radical resection percentage of 100%, with low treatment-related toxicity. These promising short-term results provided the rationale to assess this CROSS neoadjuvant chemoradiotherapy regimen in a subsequent randomised phase 3 trial.

Added value of this study

At long-term follow-up, the CROSS trial has now shown that treatment of locally advanced oesophageal or junctional cancer with carboplatin, paclitaxel, and concurrent radiotherapy followed by surgery significantly improves 5-year overall and progression-free survival, compared with treatment with surgery alone.

Implications of all the available evidence

Despite the favourable results of the initial CROSS trial, preoperative or perioperative chemotherapy is still regarded as standard of care in some countries for patients with oesophageal and junctional cancer. This perspective is mainly the consequence of the results of the MAGIC trial, which compared perioperative chemotherapy—consisting of epirubicin, cisplatin, and infused fluorouracil—plus surgery versus surgery alone. However, only a few included patients had distal oesophageal cancers (14%) or junctional cancers (12%), which raises questions about the applicability of these results for oesophageal and junctional cancers. Furthermore, the MAGIC trial, which was published in 2006 after a minimum follow-up of less than 2 years, has not yet reported its long-term results, which makes it unclear whether or not the initially reported survival benefit of perioperative chemotherapy is sustained at long-term follow-up. The ongoing Japanese randomised NExT trial (JCOG1109) and the Irish randomised Neo-AEGIS trial (ICORG 10-14; NCT01726452) will probably provide more definitive evidence about the optimum preoperative or perioperative treatment for oesophageal squamous cell carcinoma and adenocarcinoma, respectively. Future research should focus on more personalised treatment strategies, such as watchful waiting protocols after neoadjuvant therapy, in which surgery is offered only to those patients in whom locoregional disease is detected (in the absence of signs of distant dissemination). Additionally, newer, more effective combinations of systemic agents need to undergo further study, such as the addition of targeted therapy to existing chemoradiotherapeutic treatment regimens.

The randomised controlled ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial8 compared neoadjuvant chemoradiotherapy plus surgery versus surgery alone. The trial enrolled 368 patients between March 30, 2004, and Dec 2, 2008, from eight Dutch participating centres (five academic centres and three large non-academic teaching hospitals). Initial results were published in 2012 after a minimum follow-up of 24 months (median follow-up 45 months [range 25·2–80·9, IQR 32·6–60·6]). We recorded an absolute benefit in 5-year overall survival in favour of the multimodality group. The neoadjuvant chemoradiotherapy regimen was completed by 162 (95%) of 171 patients who received any neoadjuvant chemoradiotherapy, with a low occurrence of grade 3 or adverse events for this setting (29 [17%] of 171 patients). Furthermore, a microscopically radical resection (ie, no vital tumour present at <1 mm from the proximal, distal, or circumferential resection margins) was achieved in 148 (92%) of 161 patients in the multimodality group, compared with 112 (69%) of 162 in the surgery alone group (p<0·001).

In this Article, we investigate the consistency of longer-term results with our previous findings and analyse secondary endpoints, such as progression-free survival and disease recurrence patterns.

Section snippets

Study design and participants

Full details of patients' eligibility criteria and the procedures of this open-label, multicentre, randomised controlled trial have been reported previously.8, 9 In brief, eligible patients were aged 75 years or younger; had adequate haematological, renal, hepatic, and pulmonary function; and a WHO performance score of 2 or better, without a past or present history of other malignancy. Only patients with locally advanced (clinical stage T1N1M0 or clinical stage T2–3N0–1M0, according to the

Results

368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled in the study. 180 patients were randomly assigned to the neoadjuvant chemoradiotherapy plus surgery group (of whom two later withdrew consent and were not included in the analysis), and 188 were randomly assigned to the surgery alone group (figure 1). Baseline characteristics were well balanced between the two treatment groups (table 1). One

Discussion

These long-term results, after a median follow-up for surviving patients of 84 months, confirm the initially reported survival benefit for neoadjuvant chemoradiotherapy plus surgery compared with surgery alone. The improvement in distant disease control occurred within the first 2 years after initiation of treatment, whereas the improvement in locoregional control continued for a longer period. These findings further support the clinical value of this multimodality treatment strategy.

The

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