Perioperative Chemo Enough in Esophageal Cancer?

Perioperative chemotherapy in locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma was not “unacceptably” inferior to neoadjuvant chemoradiotherapy, an interim analysis of the randomized Neo-AEGIS trial suggested.

At 3 years, the overall survival rate for patients receiving perioperative chemotherapy was nearly identical to those treated with the multimodal CROSS regimen, at 57% vs 56%, respectively (HR 1.02, 95% CI 0.74-1.42), reported John V. Reynolds, PhD, of St. James’s Hospital in Dublin.

“Notwithstanding, markers of pathological response and other proxy markers of oncologic benefit were significantly better in the CROSS arm, and importantly there was no difference in operative outcomes,” Reynolds said during the American Society of Clinical Oncology virtual meeting.

The CROSS arm showed “hugely significant” improvements in pathologic response, nodal downstaging, tumor regression grade, and resection status compared with chemotherapy, said Reynolds:

• Pathologic complete response: 16% vs 5% (P=0.001)
• Major pathologic response: 32% vs 12% (P<0.001)
• R0 resection: 95% vs 82% (P<0.001)
• Node-negative disease: 60% vs 44.5% (P=0.004)

“The data support clinical equipoise in decision-making at this time, and the seeming paradox of how improved rates of oncological impact in CROSS does not translate into a survival advantage may be reflected in the patterns of recurrence data, but is unclear at this time point,” said Reynolds.

When the CROSS regimen was first introduced, there were concerns that preoperative radiation therapy may increase postoperative morbidity, particularly pulmonary morbidity, and mortality, explained Reynolds.

But this was not observed in the current study. Postoperative mortality was similar between the chemotherapy and multimodal arms (1.9% vs 3%), and there were no differences for key respiratory complications such as pneumonia, respiratory failure, or venous thromboembolism, except for possibly acute respiratory distress syndrome (0.6% vs 4.3% with CROSS regimen, P=0.067).

Severity of complications, as per Clavien-Dindo score, was also no different between study arms.

Certain grade 3/4 adverse events were significantly more common in the perioperative chemotherapy arm, including neutropenia (14.1% vs 2.8%), diarrhea (10.9% vs 0), and vomiting (7.6% vs 2.8%). But there were no significant differences in toxic deaths (1.6% vs 3%, respectively) or pulmonary embolism (5% in each arm).

ASCO discussant Manisha Palta, MD, of Duke University in Durham, North Carolina, noted certain limitations with the findings, including the change in the study’s statistical design (from superiority to noninferiority) and the change in chemotherapy toward the end of the study (from modified MAGIC to FLOT).

“We don’t have clarity on the best neoadjuvant or perioperative regimen, whether that should be chemoradiation or perioperative systemic therapy, and we’ll await additional data that will be coming out from the Neo-AEGIS study, from the TOPGEAR study, and the ESOPEC study,” she said. “We do know that there’s a benefit of adjuvant immunotherapy — a clear benefit — in patients with residual disease after chemoradiation.”

The FDA recently approved nivolumab (Opdivo) as adjuvant treatment for esophageal/GEJ cancers with residual pathologic disease following neoadjuvant chemoradiotherapy and complete surgical resection, based on findings from CheckMate-577.

Neo-AEGIS randomized 184 patients with esophageal or GEJ cancers to perioperative chemotherapy with the modified MAGIC (epirubicin and cisplatin plus fluorouracil [5-FU] or capecitabine) regimen or FLOT (5-FU, leucovorin, oxaliplatin, and docetaxel) regimen and 178 patients to multimodal therapy using the CROSS regimen (paclitaxel, carboplatin, and 41.4 Gy over 23 fractions).

A modified MAGIC regimen (n=157) was used as perioperative chemotherapy from 2013-2018 and FLOT (n=27) was used from 2019-2020, following results of the German FLOT4 trial; the trial was also switched to a non-inferiority design following an initial futility analysis.

The primary endpoint of Neo-AEGIS was overall survival, and the current analysis was performed at the second futility analysis. Assessment will continue with a final analysis planned in July 2022, but Reynolds said it was highly likely that perioperative chemotherapy would remain noninferior.

Eligible patients had cT2-3 adenocarcinoma of the esophagus or esophagogastric junction (AEG I-III) with or without nodal involvement, and with primary tumor size of 8 cm or less. PET-CT was used for staging, radiotherapy quality assurance was mandated, and operative complications were defined using the Esophageal Complications Consensus Group.

Patients had a median age of 64, most were men (about 90%), and 84% had cT3 disease. Slightly more patients in the perioperative chemotherapy arm had nodal involvement (60.3% vs 56.0%). Over 75% of patients underwent transthoracic esophagectomy.