Locoregional relapse
Locoregional relapse rates were 8% (15/178) and 18% (33/188) in the chemoradiotherapy-surgery and surgery arms, respectively (HR, 0.39; 95% CI, 0.21-0.72). Eighty-seven percent of those developed within 3 years of follow-up in the chemoradiotherapy arm, with the median relapse-free interval at 3.9 months. In the surgery arm, 28 of 33 relapses (85%) developed within 3 years and the median relapse-free interval was 7.1 months. Beyond 6 years, there were no further relapses in either arm.
While synchronous distant plus locoregional relapse developed in 23 of 178 patients (13%) in the chemoradiotherapy-surgery arm and in 42 of 188 patients (22%) in the surgery arm (HR, 0.43; 95% CI, 0.26-0.72), isolated distant relapse developed at similar rates (around 27.5%) in both groups. Risk of distant relapse (with or without locoregional relapse) was lower in the chemoradiotherapy-surgery arm (HR, 0.61; 95%CI, 0.45-0.84). The median relapse-free interval was 15.1 months (interquartile range, 9.3-27.6) in the chemoradiotherapy-surgery arm and 9.0 months (IQR, 5.3-19.7) in the surgery arm.
Safety and health-related quality of life
The combination of paclitaxel and carboplatin with concurrent 41.4 Gy radiotherapy before surgery seems safe in the long term and does not significantly increase the risk of toxicity-related death, the researchers stated. Within the CROSS trial, short-term and long-term health-related quality of life after neoadjuvant chemoradiotherapy plus surgery for surviving patients was comparable to that after surgery alone.
Long-term persistent overall survival benefit
Ten-year CROSS results show that “for locally advanced resectable cancer of the esophagus or esophagogastric junction, preoperative chemoradiotherapy induces a long-term persistent improvement in overall survival.” Also, neoadjuvant chemoradiotherapy does not lead to an increased risk of death from other causes, and the survival benefit of long-term survivors is not compromised, compared with surgery alone. Furthermore, neoadjuvant chemoradiotherapy plus surgery according to CROSS can still be regarded as a standard of care, the researchers added.
Dr. Eyck and colleagues are currently performing the phase II TNT-OES-1 trial. It combines FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel) chemotherapy followed by CROSS chemoradiotherapy in patients with advanced esophageal and junctional adenocarcinoma. If this regimen appears to be safe in advanced cancer, they plan to perform a phase III trial with this regimen in locally advanced cancer. In addition, they are currently evaluating the implementation of adjuvant nivolumab in clinical practice for patients with pathologically residual disease after CROSS + surgery, based on the recently published CheckMate 577 trial .
“If possible, we prefer adding better systemic therapy to chemoradiotherapy rather than replacing chemoradiotherapy with systemic therapy alone,” Dr. Eyck said in an interview. “The reason for this is that we would like to allow patients with a complete response to neoadjuvant therapy to undergo active surveillance instead of surgery in the near future. … Since the pathologically complete response rate after regimens containing radiotherapy is substantially higher, we still prefer the addition of radiotherapy.”
The study was funded by the Dutch Cancer Foundation (KWF Kankerbestrijding). Dr. Eyck reported no disclosures. Several of the coauthors reported consulting and advisory roles with a variety of pharmaceutical companies.