# 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

## TL;DR

Extending eligibility criteria for a cancer treatment regimen leads to lower survival rates, but the treatment can still be safely used in real-world settings.

## Contribution

This study evaluates the impact of extending the CROSS regimen criteria on treatment outcomes in locally advanced esophageal cancer patients.

## Key findings

- Extending the CROSS criteria was associated with lower overall survival.
- The lower survival was attributed to higher age, weight loss, and WHO performance score in the extended group.
- The regimen can be safely implemented in real-world settings with individual factors considered.

## Abstract

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.

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.

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.

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.

•Extending the criteria had no significant impact on DFS, pCR, surgical radicality, and post-operative mortality.•Extending the original CROSS criteria was associated with a lower OS.•The lower OS in the E-CROSS was caused by higher age, weight loss >10%, and higher WHO performance score.•Present enlargement of the original CROSS criteria can be implemented safely in practice.•Individual factors that may contribute to OS should be considered in decision-making.

Extending the criteria had no significant impact on DFS, pCR, surgical radicality, and post-operative mortality.

Extending the original CROSS criteria was associated with a lower OS.

The lower OS in the E-CROSS was caused by higher age, weight loss >10%, and higher WHO performance score.

Present enlargement of the original CROSS criteria can be implemented safely in practice.

Individual factors that may contribute to OS should be considered in decision-making.