Impact of extending the original criteria in the Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) regimen on treatment outcome in locally advanced esophageal cancer patients

Abstract

Background: The Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) regimen is currently offered to locally advanced esophageal cancer patients beyond the original eligibility criteria. This national population-based study assessed the safety in implementation regarding treatment outcome when extending these criteria.

Patients and methods: Locally advanced esophageal cancer (cT1N+/T2-4aN0-3/M0) patients (n = 5061) from the Netherlands Cancer Registry treated according to the neoadjuvant chemoradiotherapy (nCRT) CROSS regimen between 2015 and 2022 were analyzed. A total of 1958 complied with the original criteria (O-CROSS group) and 1348 with one or more extended criteria (tumor length >8 cm, age >75 years, WHO score >2 and/or weight loss >10%) (E-CROSS group), eventually followed by resection in 1342 O-CROSS patients and 852 E-CROSS patients. Primary outcome was overall survival (OS), i.e. time interval from onset of nCRT (OS-nCRT) and from date of surgery (OS-surgery) until death or last follow-up. Secondary outcomes were disease-free survival, pathological complete response (pCR), surgical radicality, post-operative morbidity and mortality. Data were analyzed using the Kaplan-Meier method and Cox proportional hazards models.

Results: OS-nCRT was significantly lower in the E-CROSS compared with the O-CROSS (median of 30.3 months, 95% confidence interval 27.2-33.5 months versus 45.9 months, 95% CI 38.4-53.4 months, P < 0.001). Similarly, differences were observed in OS-surgery. When OS-nCRT and OS-surgery were adjusted for baseline covariates, however, no difference was found between both groups. Moreover, no differences were observed in disease-free survival, surgical radicality, and pCR. While not affecting post-operative mortality, significantly more anastomotic leakages and thromboembolic post-operative complications were seen in the O-CROSS group.

Conclusion: Extending the CROSS criteria was associated with lower OS, which was caused by the higher age, weight loss >10% and WHO score in the E-CROSS group. The CROSS regimen can be used in a 'real-world' setting but individual factors that may contribute to OS should be considered in decision-making.

Keywords: esophageal carcinoma; neoadjuvant chemoradiotherapy; pathological response; surgery; survival; treatment outcome.

Figure 1

CONSORT flow diagram of patients included in the original versus extended CROSS group. CROSS, Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study; nCRT, neoadjuvant chemoradiotherapy. ^aIncluded in the nCRT analyses. ^bIncluded in the surgical analyses.

Figure 2

The overall and disease-free survival in the original (O-CROSS) versus extended (E-CROSS) CROSS group, from first date of neoadjuvant chemoradiotherapy (nCRT) (A, B); from date of surgery (C, D). CROSS, Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study.

Figure 3

Separate histopathological analysis of the overall and disease-free survival in the original (O-CROSS) versus extended (E-CROSS) CROSS group, from first date of neoadjuvant chemoradiotherapy (nCRT) and from date of surgery in esophageal adenocarcinoma (EAC) (A, B); in esophageal squamous cell carcinoma (ESCC) (C, D). CROSS, Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study; DFS, disease-free survival.

Supplementary Fig S1

Surgical subanalyses of patients who underwent surgery, within16weeks and16sixteen weeks. Overall survival (a); and disease-free survival (b) in the O-CROSS vs. E-CROSS group.

Supplementary Fig S4

The overall and disease-free survival in the original versusextended CROSS group versusthe undefined group. From first date of neoadjuvant chemoradiotherapy (a,b); from date of surgery (c,d); from date of surgery performed within sixteen weeks (e,f); from date of surgery performed later than sixteen weeks (g,h).