Emerging treatments

Tislelizumab

Tislelizumab is an anti-programmed cell death-1-receptor (PD-1) monoclonal antibody. It has been shown to improve overall survival compared with chemotherapy (investigator's choice of the following single-agent chemotherapies: paclitaxel, docetaxel, or irinotecan) and is a promising second-line agent.[15]​[217][218]​​​​​ Tislelizumab monotherapy has been approved by the Food and Drug Administration (FDA) for adults with unresectable or metastatic esophageal squamous cell carcinoma who have received prior systemic chemotherapy that did not include a programed death-ligand 1 (PD-L1) inhibitor. It is approved in Europe as monotherapy for adults with unresectable, locally advanced, or metastatic esophageal squamous cell carcinoma after prior platinum-based chemotherapy. According to one randomized phase 3 trial, first-line treatment with tislelizumab plus chemotherapy has better overall survival with a manageable safety profile than placebo plus chemotherapy in patients with advanced esophageal squamous cell carcinoma.[219][220]​ 

Bemarituzumab

Bemarituzumab is a monoclonal antibody against fibroblast growth factor receptor 2b (FGFR2b). The FDA has granted bemarituzumab breakthrough therapy designation for the first-line treatment of patients with FGFR2b-overexpressing and HER2-negative metastatic and locally advanced gastric and esophagogastric adenocarcinoma in combination with modified FOLFOX6 (fluoropyrimidine, leucovorin, and oxaliplatin). In the phase 3 FIGHT trial, bemarituzumab plus FOLFOX6 demonstrated clinically significant and substantial improvements in the primary endpoint of progression-free survival compared with FOLFOX6 alone in patients with FGFR2b+, non-HER2-positive frontline advanced gastric or esophagogastric cancer.[221][222]

Toripalimab

Toripalimab is an anti-PD-1 monoclonal antibody. In one phase 3 trial of patients with treatment-naive advanced esophageal squamous cell carcinoma, toripalimab plus paclitaxel and cisplatin was associated with a significantly longer progression-free and overall survival compared with treatment with chemotherapy alone.[223]​ It is approved in Europe for the treatment of unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma, in combination with paclitaxel and cisplatin. It is not approved in the US for this indication as yet.

Camrelizumab

Camrelizumab is an anti-PD-1 monoclonal antibody. Treatment with camrelizumab plus chemotherapy (paclitaxel and cisplatin) was associated with longer overall and progression-free survival, compared with treatment with placebo plus chemotherapy, in one phase 3 trial of treatment-naive patients with unresectable, locally advanced or recurrent esophageal squamous cell carcinoma.[224]

Tegafur/gimeracil/oteracil (S-1)

Tegafur/gimeracil/oteracil (S-1) is an oral prodrug of fluorouracil with a prolonged half-life. Perioperative chemotherapy with S-1 and oxaliplatin has been associated with improved 3-year disease-free survival in patients with locally advanced esophagogastric junction adenocarcinoma, compared with perioperative chemotherapy with capecitabine and oxaliplatin.[225] Older people may tolerate S-1 better than other chemotherapeutic agents. One phase 3 trial found that chemoradiation therapy with S-1 was associated with improved 2-year overall survival, compared with radiation therapy alone, in older patients with locally advanced or metastatic esophageal cancer (median age 77 years).[226]

Robotic esophagectomy

Results from a single-center randomized trial of patients with resectable intrathoracic esophageal cancer suggest that robot-assisted minimally invasive thoracolaparoscopic esophagectomy (RAMIE) reduces overall surgery-related and cardiopulmonary complications compared with open transthoracic esophagectomy (OTE).[227] The 5-year disease-free survival rate did not differ with surgical approach (42% in the RAMIE group and 43% in the OTE group); no statistically significant difference in recurrence rate nor recurrence pattern was observed.[228] Further research is warranted.

Iodine-125 (125-I) brachytherapy

Small observational studies suggest that 125-I seed implantation may be of some benefit in patients with lymph node metastases or recurrence.[229][230] Further research is required.

Intensity-modulated radiation therapy (IMRT)

An advanced form of 3D conformal radiation therapy (3D-CRT) that changes the intensity of radiation in different parts of a single beam whilst the treatment is being delivered. This enables simultaneous treatment of multiple areas within the target area with different dose levels, potentially reducing cardiopulmonary toxicity. Retrospective studies comparing 3D-CRT with IMRT for patients with esophageal cancer have shown superior dose conformity and homogeneity as well as a reduction of radiation therapy dose delivered to the lungs and heart with IMRT.[231][232]​​​​​ One phase 2 trial of postoperative IMRT with concurrent chemotherapy for node-positive esophageal squamous cell cancer showed this regimen to be safe and effective with 1-year overall survival and progression-free survival rates of 91.2% and 80.4%, respectively. There were no unexpected cases of serious adverse events or treatment-related deaths.[233]​ Two phase 3 trials have safely employed IMRT with concurrent chemotherapy as definitive treatment for esophageal cancer.[234][235]​​​ A possible disadvantage of IMRT is the prolonged time for each treatment compared with other treatment techniques.

Proton beam therapy (PBT)

A highly targeted radiation therapy technique that may limit cardiopulmonary toxicity and is associated with lower rates of postoperative complications, including pulmonary, cardiac, gastrointestinal, and wound complications, as well as reduced length of hospital stays.[236][237]​​​​​ One phase 2B trial that randomized 145 patients to receive IMRT or PBT reported that PBT reduced the risk and severity of adverse events while maintaining similar rates of 3-year progression-free survival (50.8% for IMRT and 51.2% for PBT) and 3-year overall survival (44.5% for both).[238]​ An ongoing phase 3 study comparing PBT to photon therapy for patients with esophageal cancer is recruiting patients.[239] National Comprehensive Cancer Network (NCCN) guidelines currently recommend that patients with esophageal cancer be treated with PBT within a clinical trial.[15]

Intensity-modulated proton beam therapy (IMPT)

Another emerging radiation therapy technique that uses magnets to steer the proton beam, potentially reducing toxicity to nontarget tissues. Studies have shown significant reductions in mean radiation therapy dose to the heart, lungs, kidneys, liver, and small bowel.[236][240]​​​ Clinical outcomes of IMPT for esophageal cancer are needed, as current evidence is limited to dose comparisons.[15]

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