Treatment protocols for esophageal cancer are provided below, including recommendations for surgical resection and regimens for the following[1] :
Tumors involving the mucosa of the esophagus, but not the submucosa (Tis or T1) may be treated with endoscopic resection methods: endoscopic mucosal resection (EMR); and the newer, more extensive technique, endoscopic submucosal dissection (ESD), which is preferred for deeper tumors. For early and some locoregional cancers, surgery is the primary treatment. Esophagectomy may be performed using either the standard open approach or a minimally invasive procedure.
Early age at onset, multiple family members with the same or related cancer, and the occurrence of multiple primary cancers are common signs suggesting hereditary cancer. In these scenarios, a genetic risk assessment should be performed to identify syndromes whose presence may affect treatment, such as the following:
For unresectable locally advanced and stage IV esophageal cancer, evaluation of the following is suggested:
Evaluation can either be done via any of the following:
NGS: When limited tissue is available for testing or if the patient cannot undergo traditional biopsy, the use of limited molecular diagnostic panels may quickly exhaust the sample. In these scenarios, comprehensive genomic profiling via a validated NGS assay may be used to identify above- mentioned mutations and amplification.
Liquid biopsy: The genomic alterations of solid cancers can be identified by evaluating circulating tumor DNA (ctDNA) in the blood This procedure is used more in patients who cannot undergo traditional biopsy, but can also be performed in other patients to gather more evidence for management.
For chemotherapy, two-drug cytotoxic regimens that include a platinum agent are generally preferred for first-line therapy. Second-line and subsequent therapy may involve single agents (eg, taxanes) or molecular therapy, such as ramucirumab to target vascular endothelial growth factor (VEGF) receptor or trastuzumab for metastatic adenocarcinoma that overexpresses HER2.[1]
Radiation therapy is often given with chemotherapy. External beam radiation therapy (EBRT) is used. Proton beam therapy may be used in the future, as it has lesser adverse effects and similar efficacy. [2]
A study by Fogh et al of induction chemoradiotherapy followed by surgery, a strategy that is widely used in treating esophageal cancer, found that perioperative morbidity and mortality with this approach was not significantly different in patients aged 70 years or older compared with younger patients. Consequently, these authors suggest using this strategy in elderly patients.[3]
The following recommendations are based on tumor/node/metastasis (TNM)–based stages. Stage I, II, and III esophageal cancers are all potentially resectable. T4b tumors involving pericardium, pleura, diaphragm are also potentially resectable.
For Tis-T1a, N0, M0 disease, treatment options are as follows:
For T1b, N0, M0 disease, treatment options are as follows:
For T2/T3, N0, M0 disease, treatment options are as follows:
For T3, N1, M0 to T1-3, N2, M0 disease, chemoradiotherapy with or without esophagectomy is recommended
For T4, N0-2, M0-1 disease, treatment options are as follows:
Neoadjuvant chemoradiotherapy appears to be associated with better survival than local therapy or surgery alone.[4] Regimens are listed below according to National Comprehensive Cancer Network (NCCN) categories of evidence: Category 1 recommendations are based on high-level evidence, while category 2A recommendations are based on lower-level evidence. With both categories, there is uniform NCCN consensus that the intervention is appropriate. Category 2B recommendations are based on lower-level evidence and there is NCCN consensus that the interventions are appropriate.
Category 1 regimens include the following:
Paclitaxel 50 mg/m2 IV on Days 1, 8, 15, 22, and 29 plus carboplatin, area under the curve (AUC) 2 IV (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator) on Days 1, 8, 15, 22, and 29 of a 5-week cycle[5, 6] or
Oxaliplatin 85 mg/m2 IV on Day 1 plus leucovorin 400 mg/m2 IV on Day 1 plus 5-FU 400 mg/m2 IV bolus, then 800 mg/m2/day IV over 24 hours on Days 1 and 2 of a 14-day cycle for three cycles with radiation [7] or
Fluorouracil (5-FU) 300 mg/m2 IV continuous infusion over 96 hours (4 days) weekly plus oxaliplatin 85 mg/m2 IV on Day 1 of a 14-day cycle for three cycles with radiation
Oxaliplatin 85 mg/m2 IV on Days 1, 15, and 29 for 3 doses plus capecitabine 625 mg/m2 PO BID on Days 1-5 weekly for 5 weeks or
Cisplatin 15 mg/m2 IV on Day 1 to 5 plus 5-FU 800 mg/m2/day continuous IV infusion on Days 1 to 5 of a 21-day cycle for two cycles[8, 9] or
Cisplatin 30 mg/m2 IV on Day 1 plus capecitabine 800 mg/m2 PO BID on Days 1-5 weekly for 5 weeks
Category 2B regimens include the following:
Irinotecan 65 mg/m2 IV on Days 1, 8, 22, and 29 plus cisplatin 30 mg/m2 IV once per day on Days 1, 8, 22, and 29[10, 11, 12] or
Paclitaxel 45 mg/m2 IV once per day on Days 1, 8, 15, 22, and 29 plus 5-FU 300 mg/m2 IV continuous infusion on Days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33; weekly for 5 wk[13, 14] or
Paclitaxel 45-50 mg/m2 IV once per day on Days 1, 8, 15, 22, and 29 plus capecitabine 625-825 mg/m2 PO BID on Days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33; weekly for 5 wk[15, 13, 16]
Neoadjuvant chemotherapy is used only for adenocarcinoma of the thoracic esophagus or esophagogastric junction (EGJ). The following is a category 2B recommendations)[1] :
In resectable HER2-positive esophageal adenocarcinoma, a phase II study demonstrated the feasibility of supplementing standard neoadjuvant chemoradiotherapy (carboplatin and paclitaxel and 41.4 Gy of radiotherapy) with the following[17] :
Further trials of this approach are needed.
Perioperative chemotherapy with regimens such as ECF (epirubicin, cisplatin, 5-FU) has led to significant improvement in overall survival in patients with operable lower esophageal adenocarcinomas.[18] With the FLOT regimen (5-FU, oxaliplatin, leucovorin, docetaxel), however, patients experienced higher rates of partial or complete remission and were less likely to experience at least 1 grade 3-4 adverse event. Therefore, ECF is no longer recommended in this setting. The following are NCCN category 1 regimens (ie, supported by high-level evidence):
FLOT regimen: 5-FU 2600 mg/m2 IV continuous infusion over 24 hours on Day 1 plus leucovorin 200 mg/m2 IV on Day 1 plus oxaliplatin 85 mg/m2 IV on day 1 plus docetaxel 50 mg/m2 IV Day 1 of 14-day cycle for four cycles preoperatively and four cycles postoperatively [19] or
Oxaliplatin 85 mg/m2 IV on Day 1 plus leucovorin 400 mg/m2 IV on Day 1 plus 5-FU 400 mg/m2 IV push on Day 1 plus 5-FU 1200 mg/m2 IV continuous infusion over 24 hr daily on Days 1 and 2 of a 14-day cycle for three cycles preoperatively and three cycles postoperatively[20] or
Oxaliplatin 85 mgm2 IV on Day 1 plus leucovorin 200 mg/m2 on Day 1 plus 5-FU 2600 mg/m2 IV continuous infusion over 24 hours on Day 1 of a 14-day cycle for three cycles preoperatively and three cycles postoperatively[21] or
Capecitabine 1000 mg/m2 PO BID on Days 1-14 plus oxaliplatin 130 mg/m2 IV on Day 1 of a 21-day cycle for three cycles preoperatively and three cycles postoperatively[22]
The following is an NCCN other preferred regimen:
5-FU 2000 mg/m2 IV continuous infusion over 48 hours on Day 1-2 plus cisplatin 50 mg/m2 IV on Day 1 of 14-day cycle for four cycles preoperatively and four cycles postoperatively[8]
Definitive chemoradiotherapy is used in patients with unresectable nonmetastatic esophageal cancer. The following is an NCCN preferred regimen:
The following are NCCN category 1 regimens:
The following are NCCN category 2B regimens (ie, supported by a lower level of clinical evidence):
Surgery can be the initial treatment of choice for patients with esophagogastric junction adenocarcinoma; however, it is advisable to treat these patients with postoperative chemoradiotherapy because of an evidence-based increase in survival.
The following are NCCN category 1 regimens:
See the list below:
See the list below:
See the list below:
The following are NCCN category 1 regimens:
Nivolumab 240 mg IV every 14 days for 16 weeks followed by nivolumab 480 mg IV every 28 days; maximum treatment duration of 1 year (only after preoperative chemoradiation with R0 resection and residual disease)
Other NCCN recommended regimens:
Capecitabine 1000 mg/m2 PO BID on Days 1-14 plus oxaliplatin 130 mg/m2 IV on Day 1 of a 21-day cycle or
Oxaliplatin 85 mg/m2 IV over 2 hours on Day 1 plus leucovorin 400 mg/m2 IV over 2 hours on Day 1 plus 5-FU 400 mg/m2 IV bolus on Day 1, then 5-FU 1200 mg/m2 over 24 hr on Days 1 and 2 of a 14-day cycle or
Oxaliplatin is preferred over cisplatin due to lower toxicity. Trastuzumab should be added to first-line chemotherapy for metastatic adenocarcinomas that overexpress HER2. However, it is not recommended for use with anthracyclines.[1]
Fluorouracil or capecitabine plus oxaliplatin plus nivolumab, in cases with programmed cell death ligand 1 (PD-L1) expression levels by Combined Positive Score (CPS) of 5 or greater)[1, 33]
The following are NCCN preferred regimens:
HER2 overexpression positive adenocarcinoma (trastuzumab with chemotherapy)
One of the following chemotherapies:
HER2-negative adenocarcinoma
For tumors with PD-L1 expression ≥ 5 by Combined Positive Score (CPS), the following are NCCN category 1 regimens:
For tumors with PD-L1 expression 1-4 by CPS, the following are NCCN category 2B regimens:
Nivolumab 360 mg IV on Day 1 plus capecitabine 1000 mg/m2 PO BID on Days 1–14 plus oxaliplatin 130 mg/m2 IV on Day 1; every 21 days
For tumors with a PD-L1 CPS 1-9, the following are NCCN category 2B regimens:
Pembrolizumab 200 mg IV every 21 days for up to 2 years plus capecitabine 1000 mg/m2 PO BID on Days 1-14 and oxaliplatin 130 mg/m2 IV on Day 1 of a 21-day cycle for up to six cycles (total of 18 weeks)
Pembrolizumab 200 mg IV every 21 days for up to 2 years plus oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV, and 5-FU 400 mg/m2 IVP on Day 1 plus 5-FU 1200 mg/m2/day continuous IV infusion daily on Days 1 and 2 of a 14-day cycle for up to nine cycles (total of 18 weeks)
Pembrolizumab 200 mg IV every 21 days for up to 2 years plus cisplatin 80 mg/m2 IV on Day 1 and 5-FU 800 mg/m2 IV continuous infusion over 24 hours daily on Days 1-5 of a 21-day cycle for up to six cycles
Pembrolizumab 200 mg IV every 21 days for up 2 years plus cisplatin 80 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO BID on Days 1-14 of a 21-day cycle for up to six cycles
HER2-negative adenocarcinoma or squamous cell carcinoma
For tumors with a PD-L1 CPS ≥10, the following are NCCN category 1 regimens:
The following are NCCN category 2B regimens for tumors with PD-L1 CPS 1-9 and preferred regimens for tumors with PD-L1 CPS ≥10:
Pembrolizumab 200 mg IV every 21 days for up to 2 years plus capecitabine 1000 mg/m2 PO BID Days 1-14 and oxaliplatin 130 mg/m2 IV on Day 1 of a 21-day cycle for up to six cycles (total of 18 weeks) or
Pembrolizumab 200 mg IV every 21 days for up to 2 years plus oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV, and 5-FU 400 mg/m2 IVP on Day 1, plus 5-FU 1200 mg/m2/day continuous IV infusion daily on Days 1 and 2 of a 14-day cycle for up to nine cycles (total of 18 weeks) or
Pembrolizumab 200 mg IV every 21 days for up to 2 years plus cisplatin 80 mg/m2 IV on Day 1 and 5-FU 800 mg/m2 IV continuous infusion over 24 hours daily on Days 1-5 of a 21-day cycle for up to six cycles or
Pembrolizumab 200 mg IV every 21 days for up 2 years plus cisplatin 80 mg/m2 IV on Day 1 and capecitabine 1000 mg/m2 PO BID on Days 1-14 of a 21-day cycle for up to six cycles
The following are NCCN other preferred regimens:
Irinotecan 180 mg/m2 IV, leucovorin 400 mg/m2, and 5-FU 400 mg/m2 IVP on Day 1, plus 5-FU 1200 mg/m2 IV continuous infusion over 24 hours daily on Days 1 and 2, cycled every 2 weeks[35] or
Irinotecan 80 mg/m2 IV on Day 1, leucovorin 500 mg/m2 on day 1, and 5-FU 2000 mg/m2 IV continuous infusion over 24 hours on day 1, weekly for 6 weeks followed by 2 weeks off treatment[36] or
Paclitaxel 135-200 mg/m2 IV on Day 1 and cisplatin 75 mg/m2 on Day 2, cycled every 3 weeks[37] or
Paclitaxel 90 mg/m2 IV and cisplatin 50 mg/m2 IV on Day 1, cycled every 2 weeks[38] or
Paclitaxel 200 mg/m2 IV and carboplatin AUC 5 IV on Day 1, cycled every 3 weeks[39] or
Paclitaxel 135-250 mg/m2 IV on Day 1, cycled every 3 weeks[40] or
Paclitaxel 80 mg/m2 IV on Day 1, cycled every 4 weeks[41] or
Docetaxel 70-85 mg/m2 IV and cisplatin 70-75 mg/m2 IV on Day 1, cycled every 3 weeks[42, 43] or
Docetaxel 75-100 mg/m2 IV on Day 1, cycled every 3 weeks[44, 45] or
Leucovorin 400 mg/m2 IV on Day 1, 5-FU 500 mg/m2 IVP on Day 1, and 5-FU 1200 mg/m2 IV continuous infusion over 24 hours daily on Days 1 and 2, cycled every 14 days[46] or
5-FU 800 mg/m2 IV continuous infusion over 24 hours daily on Days 1-5, cycled every 4 weeks[47] or
Capecitabine 1000-1250 mg/m2 PO BID on days 1-14, cycled every 3 weeks[48] or
Docetaxel 40 mg/m2 IV, leucovorin 400 mg/m2 IV, and 5-FU 400 mg/m2 IV on Day 1 plus 5-FU 1000 mg/m2 IV continuous infusion over 24 hours on Days 1 and 2 plus cisplatin 40 mg/m2 IV on Day 3, cycled every 2 weeks,[49] , or
Docetaxel 50 mg/m2 IV on Day 1, oxaliplatin 85 mg/m2 IV on Day 1, and 5-FU 1200 mg/m2 IV continuous infusion over 24 hours on Days 1 and 2, cycled every 2 weeks[50] or
Docetaxel 75 mg/m2 IV on Day 1, carboplatin AUC 6 IV on Day 2, and 5-FU 1200mg/m2 IV continuous infusion over 24 hours on Days 1-3, cycled over 3 weeks[51] or
Other new regimens:
First-line regimen for HER2 positive adenocarcinoma (further trials ongoing)
For PDL-1 positive and HER negative EGJ carcinoma (further trials ongoing)
For advanced, metastatic, or recurrent disease (Further studies needed)
For recurrent or refractory advanced adenocarcinoma with CLDN 18.2 positive cells (Further trials ongoing)
For metastatic Squamous cell carcinoma (Further trials needed)
Switch-maintenance therapy after completion of first-line chemotherapy (Further studies needed)
Category 1 recommendations for second-line therapy, based on high level of clinical evidence, are as follows:
Second-line therapy for esophageal squamous cell carcinoma
Nivolumab 240 mg IV on Day 1 of a 14-day cycle or 480 mg IV on Day 1 of a 28-day cycle
Second-line therapy for esophageal squamous cell carcinoma with PD-L1 expression levels by CPS ≥10 or third-line or subsequent therapy for esophageal and EGJ adenocarcinoma with PD-L1 expression levels by CPS ≥1
Pembrolizumab 200 mg IV on Day 1 of a 21-day cycle or 400 mg IV on Day1 of a 6-weeks cycle
Second-line therapy for adenocarcinoma only:
Second-line therapy for HER2-overexpression positive adenocarcinoma
Fam-trastuzumab deruxtecan-nxki 6.4 mg/kg IV on Day 1 of a 21-day cycle
Other regimens:
Category 2B recommendations for second-line therapy, based on lower level of clinical evidence, include the following:
For third-line or subsequent therapy for EGJ adenocarcinoma
Regimens are only used for NTRK gene fusion-positive tumors:
Regimen used for second-line or subsequent therapy for high microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) tumors; for third-line or subsequent therapy for PD-L1–positive esophageal and EGJ adenocarcinoma) [68, 69]
Other new regimens (Further trials needed)
Second or third-line therapy in recurrent or metastatic squamous cell carcinoma
Second or further-line treatment of SCC or adenocarcinoma of esophagus or EGJ
GEJ carcinoma previously treated with >=2 chemotherapy regimen
DCF-R therapy: Intravenous infusion of l60 mg/m2 docetaxel and 60 mg/m2 of Cisplatin on day 1, and 600 mg/m2 of 5-FU on days 1-5; 2 courses administered within a 4-week interval. With radiation (Further studies needed to confirm efficacy) [74]
See the list below: