Benefit of preop chemotherapy for 10 years


Among patients with locally advanced resectable esophageal cancer or junction cancer, the overall survival benefit conferred by preoperative chemotherapy persists for at least 10 years, according to the long-term results of the Chemotherapy for esophageal cancer followed by a surgery study (CROSS). As a result of previous publication of CROSS data, chemoradiotherapy followed by surgery has become one of the standards of care for patients with locally advanced resectable esophageal cancer, according to lead author Ben M. Eyck, MD, Erasmus University Medical Center, Rotterdam. Netherlands and colleagues in the Journal of Clinical Oncology.

In the multicenter, randomized trial, initiated in 2004, 178 randomized patients undergoing chemoradiotherapy with subsequent surgery and 188 randomized patients with surgery alone were followed, with overall survival as primary and cause-specific survival and relapse risks. locoregional and distant as secondary. end points. Chemoradiotherapy consisted of 5 weekly cycles of carboplatin (area under the curve of 2 mg / mL / min) i paclitaxel (50 mg / m2 body surface area on days 1, 8, 15, 22 and 29) with simultaneous radiotherapy (41.4 Gy in 23 fractions, 5 days a week. The mean age was 60 years (around 78% male), with squamous cell carcinoma (23%) and adenocarcinoma (75%) as predominant histologies.

The first analysis showed low short-term toxicity and 2-year survival increased from 50% only in patients who received surgery to 67% of neoadjuvant chemotherapy plus surgery. Five-year follow-up data were consistent with initial reports. According to researchers, the long-term benefits and harms of this scheme are still unclear. The side effects of neoadjuvant chemoradiotherapy could lead to long-term death from causes other than esophageal cancer, and they may not be preventing, but simply postponing, dying from cancer. The aim of the current analysis was to determine whether the observed benefits persisted for more than five years.

As of December 31, 2018, 117/178 patients had died in the chemotherapy-surgery arm and 144/188 in the surgery arm. The mean follow-up of surviving patients was 147 months. Patients in the chemoradiotherapy surgery arm had better overall survival than patients in the surgery arm (risk ratio, 0.70; 95% confidence interval, 0.55-0.89; Pg = 0.004), with an overall 10-year survival of 38% (95% CI, 31–45) and 25% (95% CI, 19–32), respectively. No significant subgroup differences were observed for overall survival. There was also no evidence of a time-dependent effect of neoadjuvant chemoradiotherapy on overall survival. The main effect of neoadjuvant chemoradiotherapy, according to the emblematic analyzes, was during the first 5 years of follow-up, with the effect on overall survival stabilized afterwards, with a risk ratio of approximately 1.00.

Mortality due to specific cause

Eighty-four of 178 patients in the chemotherapy and surgery group died of esophageal cancer, and 32 died of other causes. In the arm of surgery, 121/188 died of esophageal cancer and 22 other causes. The risk ratio of death from esophageal cancer in the chemotherapy and surgery group was 0.60 (95% CI, 0.46 to 0.80), with absolute 10-year risks of 47% (95 CI %, 40-54) and 64% (95% CI), 57-71), respectively, in both arms. Death from other causes was comparable, with absolute risks at 10 years of 15% (95% CI, 10-21) and 11% (95% CI, 7-16), respectively, for chemotherapy. surgery versus surgery alone.

Locoregional relapse

Locoregional relapse rates were 8% (15/178) and 18% (33/188) in the chemotherapy-surgery and surgery arms, respectively (HR, 0.39; 95% CI, 0.21- 0.72). Eighty-seven percent of those who developed within 3 years of chemoradiotherapy arm follow-up, with a relapse-free interval at 3.9 months. In the surgery arm, 28 of 33 relapses (85%) developed in 3 years and the mean interval without relapses was 7.1 months. Beyond 6 years, there were no further relapses on either arm.

While the most locoregional distance synchronous relapse occurred in 23 of 178 patients (13%) in the chemotherapy and surgery arm and in 42 of 188 patients (22%) in the surgery arm (HR, 0.43; 95% CI, 0.26-0.72), isolated relapse relapsed at similar rates (around 27.5%) in both groups. The risk of distant relapse (with or without locoregional relapse) was lower in the chemotherapy-surgery arm (HR, 0.61; 95% CI, 0.45-0.84). The mean no-relapse interval was 15.1 months (interquartile range, 9.3–27.6) in the chemotherapy-surgery arm and 9.0 months (IQR, 5.3–19.7) in the surgery arm.

Quality of life related to safety and health

The combination of paclitaxel and carboplatin with concurrent 41.4 Gy radiotherapy before surgery appears safe in the long term and does not significantly increase the risk of toxicity-related death, the researchers said. Within the CROSS trial, the quality of life related to short- and long-term health after neoadjuvant chemoradiotherapy plus surgery for surviving patients was comparable to that of surgery alone.

Overall long-term persistent survival benefit

CROSS ‘s ten – year results show that “for locally advanced resectables esophageal cancer or esophagogastric junction, preoperative chemotherapy induces a persistent long-term improvement in overall survival. “In addition, neoadjuvant chemotherapy does not carry an increased risk of death from other causes, and the long-term survival benefit of survivors is not compromised. In addition, neoadjuvant chemoradiotherapy plus surgery according to CROSS can still be considered a standard. of attention, the researchers added.

Eyck and colleagues are currently conducting the Phase II TNT-OES-1 trial. Combines FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel) chemotherapy followed by CROSS chemoradiotherapy in patients with advanced esophageal adenocarcinoma and junction. 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 the adjuvant nivolumab in clinical practice for patients with pathologically residual disease after CROSS + surgery, based on the recently published CheckMate 577 test.

“If possible, we prefer to add better systemic therapy to chemotherapy rather than replacing chemotherapy with systemic therapy alone,” 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 go through active surveillance rather than surgery in the near future … Because the pathologically complete response rate after regimens that contain radiotherapy is substantially higher, we still prefer the addition of radiotherapy “.

The study was funded by the Dutch Cancer Foundation (KWF Kankerbestrijding). Eyck did not report any disclosures. Several of the co-authors reported consulting and advisory functions with various pharmaceutical companies.

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