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CHICAGO -- A perioperative regimen of four cycles of chemotherapy before and after surgery extended overall survival (OS) compared with neoadjuvant chemoradiation in patients with locally-advanced, resectable esophageal adenocarcinoma.

At a median follow-up of 55 months in the intent-to-treat population of the ESOPEC trial, the FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) perioperative protocol significantly improved median OS compared with CROSS (radiation plus paclitaxel and carboplatin) administered 4 to 6 weeks prior to surgery (66 vs 37 months, HR 0.70, P=0.012).

OS rates in the two treatment arms, respectively, were 57.4% and 50.7% at 3 years, and 50.6% and 38.7% at 5 years, Jens Hoeppner, MD, of the University of Bielefeld in Detmold, Germany, reported at the American Society of Clinical Oncology (ASCO) annual meeting.

A higher proportion of patients in the FLOT arm achieved pathological complete remission (ypT0 ypN0) compared with the CROSS arm (16.8% vs 10.0%).

Based on these results, "perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with CROSS for improving survival in resectable esophageal adenocarcinoma," said Hoeppner.

Other Options

However, new treatment approaches have emerged since the trial was conceived, Hoeppner noted. These include adjuvant immunotherapy following chemoradiation and surgery in cases when a pathologic complete response has not been achieved, as well as organ preservation and active surveillance in clinical complete responders following chemoradiation. Whether these approaches improve OS is under investigation, he said.

Invited discussant Karyn Goodman, MD, of Icahn School of Medicine at Mount Sinai in New York City, said that while the results of ESOPEC trial are impressive, the 5-year OS rate of only 50% is still suboptimal. Further, a concern of FLOT is the toxicity of the regimen and its tolerability in the esophageal cancer population.

The results of the trial of adjuvant nivolumab (Opdivo) after preoperative CROSS and surgery for patients who did not achieve a pathologic complete response (CR) must be considered, she said. CheckMate 577 showed that adjuvant nivolumab significantly decreased metastatic recurrences and doubled disease-free survival. "The use of immunotherapy seemed to address the higher systemic relapse rate associated with the low-dose chemotherapy used as part of the CROSS regimen," said Goodman. "Based on these results, it is now standard of care in the U.S. that, if using the CROSS regimen, adjuvant nivolumab is recommended for patients who do not achieve a pathologic CR. Since patients in the ESOPEC trial did not receive adjuvant nivolumab, we can't conclude that perioperative FLOT is better than CROSS and adjuvant nivolumab."

"We need to continue to focus on how we can do better for our patients," she continued. "With FLOT, we are focusing on systemic disease; and with CROSS, we are just addressing locoregional disease. Does it really have to be an either/or?"

An emerging option may be induction chemotherapy followed by personalized chemoradiation.

Adaptive therapy based on treatment response using PET imaging as a biomarker and combining the benefits of systemic and locoregional appears to be promising, as in the study.

Combining FLOT and CROSS may also be an option, said Goodman. Several ongoing trials are evaluating this approach. FLOT will likely be adopted as the standard approach in patients who are fit, she said, while CROSS is a reasonable option for patients who are not candidates for FLOT. The OS results from CheckMate 577 are eagerly awaited to determine the utility of CROSS followed by adjuvant nivolumab.

Trial Details

In the phase III trial, 438 patients with locally advanced (cT1N+ and cT2-4a, cN0/+) resectable esophageal adenocarcinoma from 25 centers across Germany were randomized to FLOT or CROSS. FLOT was administered for four cycles every 2 weeks over the course of 8 weeks, 4 to 6 weeks prior to en-bloc resection, and this was repeated 4 to 6 weeks after discharge. Patients randomized to CROSS received 41.4 Gy of radiation and five weekly cycles of paclitaxel plus carboplatin, 4 to 6 weeks prior to the same surgery.

Both approaches are considered standard of care and were recommended by guidelines for the treatment of locally advanced tumors when ESOPEC was designed in 2015, Hoeppner noted.

The mean age of study participants was 63 years, and 89% were men, reflecting the incidence of the disease in the general population. About 80% in each arm had clinical T3 or T4 tumors before treatment, and about 80% had clinically positive locoregional lymph nodes.

More than 90% started neoadjuvant treatment in each arm. The completion rate of neoadjuvant treatment was 87.3% in the FLOT arm and 67.7% in the CROSS arm. In the latter group, 98% completed the 41.4 Gy of radiotherapy and 94% received at least four cycles of concomitant chemotherapy. Some 86.0% of the FLOT arm and 82.9% of the CROSS arm received neoadjuvant treatment plus surgery.

Progression-free survival in the intent-to-treat population was also superior in the FLOT versus CROSS arm (median 38 vs 16 months, HR 0.66, P=0.001).

The R0 resection rates were 94.2% in the FLOT arm versus 95.0% in the CROSS arm. Histopathologic complete tumor regression also favored the FLOT arm (18.3% vs 13.3%).

Postoperative morbidity was similar between the two arms. The 30-day mortality rates were 1.0% in the FLOT group and 1.7% in the CROSS group.

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