Safety and efficacy of neoadjuvant treatment with immune checkpoint inhibitors in esophageal cancer: real-world multicenter retrospective study in China

Abstract

Summary Immune checkpoint inhibitors (ICIs) have shown a powerful benefit in the neoadjuvant therapy for esophageal cancer, but evidence for its safety and efficacy is limited and may not reflect real-world practice. We retrospectively reviewed the database of treatment-naive patients from 15 esophageal cancer centers in China who received ICIs as neoadjuvant treatment for locally advanced esophageal cancer from May 2019 to December 2020. The primary endpoints were rate and severity of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs). Secondary endpoints included pathologically complete response (pCR) rate, R0 resection rate, mortality and morbidity. Among the 370 patients, 311 (84.1%) were male with a median age of 63 (range: 30–81) years and stage III or IVa disease accounted for 84.1% of these patients. A total of 299 (80.8%) patients were treated with ICIs and chemotherapy. TRAEs were observed in 199 (53.8%) patients with low severity (grade 1-2, 39.2%; grade 3-4, 13.2%; grade 5, 1.4%), and irAEs occurred in 24.3% of patients and were mostly of grade 1-2 severity (21.1%). A total of 341 (92.2%) patients had received surgery and R0 resection was achieved in 333 (97.7%) patients. The local pCR rate in primary tumor was 34.6%, including 25.8% of ypT0N0 and 8.8% of ypT0N+. The rate of postoperative complications was 41.4% and grade 3 or higher complications occurred in 35 (10.3%) patients. No death was observed within 30 days after surgery, and three patients (0.9%) died within 90 days postoperatively. This study shows acceptable toxicity of neoadjuvant immunotherapy for locally advanced esophageal cancer in real-world data. Long-term survival results are pending for further investigations.

Efficacy and safety of neoadjuvant immunotherapy in resectable esophageal or gastroesophageal junction carcinoma: A pooled analysis of prospective clinical trials

“…A recently published real-world multicenter retrospective study in China which mainly included patients with locally advanced ESCC reported a pCR rate of 42.3% and 25.5% after neoadjuvant immunochemoradiotherapy and immunochemotherapy, respectively, which was approximative to the prospective outcomes in this study (12). In standard NCRT, the addition of radiotherapy to chemotherapy could significantly promote tumor shrinkage (33).…”

“…For safety, it should be cautious that the addition of ICIs to NCRT could increase the risk of severe even lethal complications. Compared with this pooled analysis of trials, grade 3-4 AEs were less frequently reported in the real-world practice, with 23.3% and 12.7% in neoadjuvant immunochemoradiotherapy and immunochemotherapy, respectively (12). The disagreements on safety evaluation may resulted from the different nature of two studies, and we tended to hold the opinion that severe AEs were underestimated in real-world data possibly due to non-standardized medical records and potential selective preference to patients with good performance or few comorbidities.…”

“…However, for patients treated with neoadjuvant immunotherapy, frequently occurred severe complications might partly diminish the potential survival benefit from immunotherapy, which needed to be confirmed by large-scale RCTs with long follow-up. Particularly, immune-related death occurred in patients with neoadjuvant immunochemoradiotherapy mainly due to esophageal bleeding or pneumonitis (12). To decrease the risk of lethal complications, radiation oncologists could consider the feasibility of reducing radiation dose, shrinking target area, and involving field irradiation when radiotherapy and ICIs were combined.…”

“…Prospective treatment outcomes of neoadjuvant immunotherapy in resectable esophageal or GEJ carcinoma were only investigated in small-scale phase 1 or 2 non-randomized clinical trials (9)(10)(11), with ambiguous and inaccurate efficacy outcomes and safety profiles due to limited sample size. A recently published real-world retrospective study mainly investigating neoadjuvant immunochemotherapy in resectable esophageal or GEJ carcinoma showed a pathologically complete response (pCR) rate of 25.8% (ypT0N0) and acceptable safety profile (12). It is worth noting that real-world outcomes, especially safety profiles, may be potentially confounded by selection biases and incomplete medical records.…”

Perioperative outcomes of neoadjuvant chemotherapy plus camrelizumab compared with chemotherapy alone and chemoradiotherapy for locally advanced esophageal squamous cell cancer

“…Zhu et al reported that neoadjuvant immunochemoradiotherapy could not improve the pCR rate than neoadjuvant chemoradiotherapy (nCRT) for ESCC, but significantly increased the risk of severe adverse events (8). Another multicenter retrospective study that included 370 ESCC patients showed that the pCR rates of mono-immunotherapy, nCIT, and nCRT plus immunotherapy were 12.1%, 25.5%, and 42.3%, respectively (9). Hence, neoadjuvant PD-1/PD-L1 inhibitors in combination with chemotherapy or chemoradiotherapy are becoming a new therapeutic frontier for resectable ESCC with promising clinical outcomes.…”