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SAN FRANCISCO -- Perioperative chemotherapy for locally advanced esophageal/gastroesophageal junction (GEJ) cancer led to outcomes similar to those achieved with more intensive multimodal therapy, according to a randomized trial reported here.

Patients assigned to chemotherapy before and after surgery had a 3-year overall survival (OS) of 55% compared with 57% for patients who received multimodal therapy (chemoradiation and surgery). Surprisingly, rates of pathologic complete response (pCR), major pathologic response (mPR), clear surgical margins, and nodal downstaging all favored multimodal therapy.

Complication rates and mortality did not differ between groups, suggesting no adverse effect of radiotherapy, said Maeve Lowery, MD, of Trinity College Dublin in Ireland, at the ASCO Gastrointestinal Cancers Symposium.

"Future analysis of pattern-of-recurrence data may inform as to why improved proxies of oncologic outcome in the [multimodal] arm do not translate into a survival advantage," she concluded.

In the words of David Ilson, MD, of Memorial Sloan Kettering Cancer Center in New York City, the effects of chemotherapy in the trial were "mind boggling."

"What is striking to me is that five doses of carboplatin and paclitaxel [with multimodal therapy] achieved the same survival as 4 months of [perioperative] chemotherapy, so what does that tell us about what chemotherapy accomplishes and what should be the new directions, looking at other systemic therapies? To me, it's really mind boggling," said Ilson, who was not involved in the trial.

"Obviously, we look forward to the recurrence patterns, but the improvement in pathologic outcomes didn't seem to translate into a survival benefit, [and] it really questions whether more chemotherapy is any better," he added.

Responding to Ilson, Lowery said that only 40% of patients randomized to the Neo-AEGIS regimen received adjuvant chemotherapy and fewer still received all planned doses of adjuvant therapy.

"So I would agree with you completely [about more chemotherapy]," she said.

Lowery reported findings from the multicenter , which was designed to address the question of whether radiotherapy is necessary, in addition to chemotherapy, before complete resection and radical lymphadenectomy for esophageal/GEJ cancer. The question arose in the aftermath of the , which demonstrated the superiority of neoadjuvant chemoradiation followed by surgery versus surgery alone. An had shown improved OS with perioperative chemotherapy (no radiotherapy) and surgery.

Lowery and colleagues randomized 540 patients to Neo-AEGIS (three or four cycles of chemotherapy, depending on the regimen, before and after surgery) or to the CROSS regimen of neoadjuvant chemotherapy and radiotherapy prior to surgery. Eligible patients had stages 2-3 disease with any nodal involvement. The primary endpoint was OS, and the trial had statistical power to demonstrate non-inferiority.

Patients assigned to the control arm received the CROSS neoadjuvant chemotherapy regimen plus a radiotherapy dose of 41.4 Gy in 23 fractions.

Toxicity and grade 3/4 adverse events occurred more often with the Neo-AEGIS regimen -- primarily neutropenia, diarrhea, and vomiting.

Oncologic outcomes favored the control arm, including the proportion of patients who achieved ypN0 status (60% vs 43.8%, P=0.004), pCR (17.3% vs 5.1%, P=0.001), and mPR (42% vs 12.1%, P<0.001). Additionally, significantly more patients in the CROSS arm achieved R0 surgical status (95% vs 82%, P<0.001). The two groups did not differ with respect to frequency or severity of operative complications.

After a median follow-up of 34.2 months, the primary analysis yielded a hazard ratio of 1.03 (95% CI 0.77-1.38) for the comparison of survival between the Neo-AEGIS and CROSS treatment groups. Survival curves overlapped throughout follow-up, said Lowery.

Patients who receive chemoradiation in accordance with the CROSS trial can receive adjuvant nivolumab (Opdivo), which doubled disease-free survival in , noted Salma Jabbour, MD, of Rutgers Cancer Institute of New Jersey in New Brunswick. The evidence shows that residual disease after surgery (R1 margin status) is associated with higher rates of local and distant failure and is an indication for adjuvant radiation.

"The rates of downstaging are important and were improved [in Neo-AEGIS] with the CROSS regimen compared to perioperative chemotherapy," added Jabbour, who is a clinical expert for the American Society for Radiation Oncology. "Studies such as the suggest that the patients who have better responses to chemoradiation can achieve improved outcomes, so maximizing the response rates from preoperative therapy are important for improving long-term outcomes for patients. Chemoradiation appears to have a better preoperative response rate compared to chemotherapy."

Correction: This article has been updated with the correct 3-year OS and to clarify the discussion that followed the presentation.

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