Evaluation of Clinical and Safety Outcomes of Neoadjuvant Immunotherapy Combined With Chemotherapy for Patients With Resectable Esophageal Cancer

Abstract

ImportanceA considerable number of clinical trials of neoadjuvant immunotherapy for patients with resectable esophageal cancer are emerging. However, systematic evaluations of these studies are lacking.ObjectiveTo provide state-of-the-art evidence and normative theoretical support for neoadjuvant immunotherapy for locally advanced resectable esophageal cancer.Data SourcesPubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for relevant original articles and conference proceedings that were published in English through April 1, 2022.Study SelectionPublished phase 2 or 3 clinical trials that included patients with resectable stage I to IV esophageal cancer who received immune checkpoint inhibitors (ICIs) before surgery as monotherapy or in combination with other therapies.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines for meta-analysis were followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 statistic >50%); otherwise, the common-effects model was used. Data analyses were conducted from April 2 to 8, 2022.Main Outcomes and MeasuresPathological complete response (pCR) rate and major pathological response (MPR) rate were considered to be the primary outcomes calculated for the clinical outcomes of neoadjuvant immunotherapy. Incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. The rate of R0 surgical resection was summarized. Subgroup analyses were conducted according to histologic subtype and ICI types.ResultsA total of 27 clinical trials with 815 patients were included. Pooled rates were 31.4% (95% CI, 27.6%-35.3%) for pCR and 48.9% (95% CI, 42.0-55.9%) for MCR in patients with esophageal cancer. In terms of safety, the pooled incidence of treatment-related severe adverse events was 26.9% (95% CI, 16.7%-38.3%). Most patients achieved R0 surgical resection (98.6%; 95% CI, 97.1%-99.6%). Regarding histologic subtypes, the pooled pCR rates were 32.4% (95% CI, 28.2%-36.8%) in esophageal squamous cell carcinoma and 25.2% (95% CI, 16.3%-35.1%) in esophageal adenocarcinoma. The pooled MPR rate was 49.4% (95% CI, 42.1%-56.7%) in esophageal squamous cell carcinoma.Conclusions and RelevanceThis study found that neoadjuvant immunotherapy with chemotherapy had promising clinical and safety outcomes for patients with resectable esophageal cancer. Randomized clinical trials with long-term follow-up are warranted to validate the findings and benefits of ICIs.

Comparison of neoadjuvant immunotherapy versus routine neoadjuvant therapy for patients with locally advanced esophageal cancer: A systematic review and meta-analysis

“…The neoadjuvant immunotherapy significantly improved pCR rates with tolerable toxicity in EC patients (14)(15)(16)(17). However, the best neoadjuvant treatment strategy for EC was still inconclusive.…”

“…The efficacy of neoadjuvant ICIs combined with nCT has been previously reported in esophageal cancer ( 12 , 13 ). Recent meta-analyses have demonstrated the neoadjuvant ICIs combined with nCT or nCRT had promising clinical result and acceptable safety outcomes for patients with locally advanced EC ( 14 – 17 ). Nevertheless, there was no any meta-analyses comparing neoadjuvant ICIs combined with nCT or nCRT with routine neoadjuvant therapy, which included nCRT and nCT.…”

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

“…Following the launch of a new era in immunotherapy (including programmed cell death-ligand 1 [PD-L1] and programmed cell death protein-1 [PD-1] inhibitors), further exploration of neoadjuvant immunotherapy alone or combined with chemotherapy or chemoradiotherapy is expected to further improve the therapeutic effect in locally advanced resectable ESCC. In a recent systematic review including 27 phase 2 or 3 clinical trials with 815 patients, the pooled pathological complete response (pCR) rate was 32.4% in ESCC after neoadjuvant chemoimmunotherapy(nCIT), with the pooled incidence of treatment-related severe adverse events of 26.9% (7). 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).…”

The genomic signature of resistance to platinum-containing neoadjuvant therapy based on single-cell data

“…Nowadays, neoadjuvant targeted therapy and immunotherapy have become new trends in preoperative adjuvant therapy for malignant tumors and have broad application prospects [5,[11][12][13][14][15]. However, owing to high price, uncertainty (still in clinical tails), and restriction (targeted and biologic therapies account for only 30% of all rst-line treatments), platinum-based chemotherapy regimens remain a rst-line treatment option or one of the components of neoadjuvant or adjuvant therapy for most of the cancers.…”