Sections

Sections Esophageal Cancer Treatment Protocols
Overview
General Recommendations Based on Stage
Neoadjuvant Chemotherapy and Chemoradiotherapy, Resectable Disease
Perioperative Chemotherapy, Resectable Disease
Unresectable Nonmetastatic Disease
Postoperative Chemoradiotherapy
Postoperative Chemotherapy
Systemic Therapy for Recurrent or Metastatic Disease
Other Regimens to Consider
Show All
References

Overview

Treatment protocols for esophageal cancer are provided below, including recommendations for surgical resection and regimens for the following^[1]:

Neoadjuvant chemoradiotherapy
Perioperative chemotherapy
Definitive chemoradiotherapy
Postoperative chemoradiotherapy
Metastatic disease

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:

Tylosis with esophageal cancer (non-epidermolytic palmoplantar keratosis [PPK]; Howel-Evans syndrome), caused by mutations in RHBDF2 and associated with squamous cell esophageal carcinoma
Bloom syndrome
Fanconi anemia
Familial Barrett esophagus

For unresectable locally advanced and stage IV esophageal cancer, evaluation of the following is suggested:

Human epidermal growth factor receptor 2/neu (HER2/neu)
Microsatellite instability–high(MSI-H)/deficient mismatch repair (dMMR)
Programmed death–ligand 1 (PD-L1)
NTRK gene fusion

Evaluation can either be done via any of the following:

Traditional biopsy with immunohistochemistry
Fluorescent in situ hybridization (FISH)
Targeted polymerase chain reaction (PCR)
Next-generation sequencing (NGS)

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]

General Recommendations Based on Stage

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.

Stage 0 - Stage 1

For Tis-T1a, N0, M0 disease, treatment options are as follows:

Endoscopic resection
Ablation
Endoscopic resection followed by ablation
Esophagectomy

For T1b, N0, M0 disease, treatment options are as follows:

Endoscopic resection followed by ablation
Esophagectomy

Stage II

For T2/T3, N0, M0 disease, treatment options are as follows:

Esophagectomy
Definitive chemoradiation therapy
Neoadjuvant chemoradiotherapy followed by esophagectomy

Stage III

For T3, N1, M0 to T1-3, N2, M0 disease, chemoradiotherapy with or without esophagectomy is recommended

Stage IV

For T4, N0-2, M0-1 disease, treatment options are as follows:

T4b tumors potentially resectable
Chemoradiation
Chemotherapy
Supportive care as indicated

Neoadjuvant chemoradiotherapy

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 75-100 mg/m ² IV on Days 1 and 29 plus 5-FU 750-1000 mg/m ² continuous infusion over 24 hours daily on Days 1 to 4 and 29 to 32 of a 35-day cycle 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/m²IV 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

Neoadjuvant chemotherapy is used only for adenocarcinoma of the thoracic esophagus or esophagogastric junction (EGJ). The following is a category 2B recommendations)^[1]:

5-FU 1000 mg/m ² IV continuous infusion over 24 hours daily on Days 1-4 plus cisplatin 80 mg/m ² IV on Day 1 of a 21-day cycle for two cycles preoperatively ^[4]

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]:

Trastuzumab 4 mg/kg IV loading dose on Day 1; 2 mg/kg per week during weeks 2 to 6; and 6 mg/kg per week during weeks 7, 10, and 13 and pertuzumab 840 mg every 3 weeks

Further trials of this approach are needed.

Perioperative Chemotherapy, Resectable Disease

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]

Unresectable Nonmetastatic Disease

Definitive chemoradiotherapy is used in patients with unresectable nonmetastatic esophageal cancer. The following is an NCCN preferred regimen:

Paclitaxel 50 mg/m ² IV over 60 minutes once per day on Days 1, 8, 15, 22, and 29 plus carboplatin AUC 2 IV on Days 1, 8, 15, 22, and 29; weekly for 5 wk ^[5]

The following are NCCN category 1 regimens:

Oxaliplatin 85 mg/m ² IV on Days 1, 15, and 29 plus 5-FU 180 mg/m ²/day continuous IV infusion on Days 1 to 33 ^[20] or
Oxaliplatin 85 mg/m ² IV on Day 1 plus leucovorin 400 mg/m ² IV on Day 1 plus 5-FU 400 mg/m ²IV bolus on Day 1, then 5-FU 800 mg/m ² continuous IV infusion daily on Days 1 and 2 of a 14-day cycle for three cycles with radiation followed by three cycles without radiation ^[7] or
Oxaliplatin 85 mg/m ² IV on Days 1, 15 and 29 for 3 doses plus capecitabine 625 mg/m ² PO BID on Days 1-5, 8-12, 15-19, 22 to 26, and 29 to 33; for 5 wk ^[23] or
Cisplatin 75-100 mg/m ² IV on Day 1 plus 5-FU 750-1000 mg/m ²/day continuous IV infusion on days 1-4; every 4 wk for two cycles with radiation followed by two cycles without radiation ^{[24, 25]} or
Cisplatin 30 mg/m ² IV on Day 1 plus capecitabine 800 mg/m ² PO BID on Days 1 to 5; weekly for 5 wk ^[26] or
Paclitaxel 60 mg/m ² IV on Days 1, 8, 15, and 22 plus cisplatin 75 mg/m ² IV on Day 1 for one cycle ^[27] or
Docetaxel 60 mg/m ² IV on Days 1 and 22 plus cisplatin 80 mg/m ² IV on Days 1 and 22 for one cycle ^[28] or
Docetaxel 20-30 mg/m ² IV on Days 1, 8, 15, 22, and 29 plus cisplatin 20-30 mg/m ² IV once on Days 1, 8, 15, 22, and 29 for one cycle ^[29]

The following are NCCN category 2B regimens (ie, supported by a lower level of clinical evidence):

Irinotecan 65 mg/m ² IV on Days 1, 8, 22, and 29 plus cisplatin 30 mg/m ²IV on Days 1, 8, 22, and 29 ^{[10, 11, 12]} or
Paclitaxel 45 mg/m ² IV on Days 1, 8, 15, 22, and 29 plus 5-FU 300 mg/m ² IV continuous infusion daily on Days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33; for 5 wk ^{[13, 14]} or
Paclitaxel 45-50 mg/m ² IV once per day on Days 1, 8, 15, 22, and 29 plus capecitabine 625-825 mg/m ² PO BID on Days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and 29 to 33; weekly for 5 wk ^{[13, 16]}

Postoperative Chemoradiotherapy

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:

Leucovorin 400 mg/m ² IV on Days 1 plus 5-FU 400 mg/m ²IV bolus on Days 1 plus 5-FU 1200 mg/m ²/day continuous IV infusion on Days 1 and 2; 14-day cycle; two cycles before and four cycles after chemoradiation ^[30] or

See the list below:

5-FU 200-250 mg/m ²/day continuous IV infusion on Days 1 to 5; weekly for 5 wk with radiation ^[31] or

See the list below:

Capecitabine 750 -1000 mg/m2 PO BID on Days 1-14 of 21-day cycle; one cycle before and two cycles after chemoradiation

See the list below:

Capecitabine 625-825 mg/m ² PO BID on Days 1 to 5; weekly for 5 wk with radiation ^[32]

Postoperative Chemotherapy

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 85 mg/m ² IV on Day 1 plus leucovorin 200 mg/m ² IV on Day 1 plus 5-FU 2600 mg/m ² over 24 hr on Day 1 of a 14-day cycle

Systemic Therapy for Recurrent or Metastatic Disease

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)

Trastuzumab 8 mg/kg IV loading dose on Day 1 of cycle 1, then 6 mg/kg IV every 21 days or
Trastuzumab 6 mg/kg IV loading dose on Day 1 of cycle 1, then 4 mg/kg IV every 14 days plus

One of the following chemotherapies:

Oxaliplatin 85 mg/m ² IV on Day 1 plus leucovorin 400 mg/m ² IV on Day 1 plus 5-FU 400 mg/m ² IV bolus on Day 1, then 5-FU 1200 mg/m ² over 24 hr daily on Days 1 and 2 of a 14-day cycle or
Oxaliplatin 85 mg/m ² IV on Day 1 plus leucovorin 200 mg/m ² IV on Day 1 plus 5-FU 2600 mg/m ² over 24 hr on Day1 of a 14-day cycle or
Capecitabine 1000 mg/m ²PO BID on Days 1-14 plus oxaliplatin 130 mg/m ² IV on Day 1 of a 21-day cycle or
Capecitabine 625 mg/m ² PO BID on Days 1-14 plus oxaliplatin 85 mg/m ²IV on Day 1 of a 21-day cycle or
Cisplatin 75-100 mg/m ² IV on Day 1 plus 5-FU 750-1000 mg/m ² IV continuous infusion over 24 hr daily on Day 1-4 of a 28-day cycle ^[34] or
Cisplatin 50 mg/m ² IV daily on Day 1 plus leucovorin 200 mg/m ² IV on Day 1 plus 5-FU 2000 mg/m ² IV continuous infusion over 24 hr daily on Day 1 of a 14-day cycle or
Cisplatin 80 mg/m ² IV on Day 1 plus capecitabine 1000 mg/m2 PO BID on Days 1-14 of a 21-day cycle

HER2-negative adenocarcinoma

For tumors with PD-L1 expression ≥ 5 by Combined Positive Score (CPS), the following are NCCN category 1 regimens:

Nivolumab 360 mg IV on Day 1 plus capecitabine 1000 mg/m ² PO BID on Days 1-14 plus oxaliplatin 130 mg/m ² IV Day 1; every 21 days
Nivolumab 240 mg IV, oxaliplatin 85 mg/m ² IV, leucovorin 400 mg/m ² IV, and 5-FU 400 mg/m ² IV push (IVP) on Day 1 plus 5-FU 1200 mg/m ²/day continuous IV infusion on Days 1 and 2; every 14 d

For tumors with PD-L1 expression 1-4 by CPS, the following are NCCN category 2B regimens:

Nivolumab 240 mg IV, oxaliplatin 85 mg/m ² IV, leucovorin 400 mg/m ² IV, and 5-FU 400 mg/m ² IVP on Day 1 plus 5-FU 1200 mg/m ²/day continuous IV infusion on Days 1 and 2; every 14 d
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:

Pembrolizumab 200 mg IV every 21 days for up to 2 years plus cisplatin 80 mg/m ² IV on Day 1 plus 5-FU 800 mg/m ² 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/m ² IV on day 1 and capecitabine 1000 mg/m ² PO BID on Days 1-14 of a 21-day cycle for up to six cycles

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/m²IV 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)

Induction with IV Pembrolizumab 200 mg flat dose and IV trastuzumab 8 mg/kg loading dose. After 3 weeks, IV Pembrolizumab 200 mg flat dose, trastuzumab 6mg/kg, IV Oxaliplatin 130 mg/m ² (or IV Cisplatin 80 mg/m ²) on day 1, and PO Capecitabine 850 mg/m ² BID for 2 weeks followed by one week off (or IV 5-FU 800 mg/m ² on day 1-5), cycled every 3 weeks ^[52]

For PDL-1 positive and HER negative EGJ carcinoma (further trials ongoing)

Pembrolizumab 200 mg 30-minutes IV infusion every 3 weeks, plus Oxaliplatin IV 130 mg/m ² every 3 weeks, and S-1 PO BID for the first 2 weeks of each 3-week cycle (S-1 dose: 40 mg for body surface area (BSA) < 1.25 m ², 50 mg for BSA 1.25 to < 1.5 m ² and 60 mg for BSA ≥1.5 m ²) ^[53]

For advanced, metastatic, or recurrent disease (Further studies needed)

FOLFIRINOX: 5-FU 400 mg/m ² IV bolus, followed by 2400 mg/m ² IV continuous infusion over 46 hours plus Leucovorin 400 mg/m ², Irinotecan 180 mg/m ², and Oxaliplatin 85 mg/m ², IV on days 1 and 15 of 28-day cycles. For the ERBB2-positive group, Trastuzumab IV loading dose of 6 mg/kg for the first dose, followed by 4 mg/kg IV with subsequent treatments. ^[54]
IV Nedaplatin 90 mg/m ² on day 1, Docetaxel 35 mg/m ² on days 1 and 15, and 5‐FU 800 mg/m ² on days 1–5 of a 4‐week cycle.

For recurrent or refractory advanced adenocarcinoma with CLDN 18.2 positive cells (Further trials ongoing)

Zolbetuximab IV every 2 weeks for five infusions (3 cohort of dosages: 1300 mg/m ², 2600 mg/m ² and 3600 mg/m ²) ^[55]

For metastatic Squamous cell carcinoma (Further trials needed)

S-1 PO 40 mg/m ² divided into 2 daily doses for 14 days and Cisplatin IV at 75 mg/m ² on day 1 or 25 mg/m ² on days 1-3, repeated every 21 days with a maximum of 6 cycles ^[56]

Switch-maintenance therapy after completion of first-line chemotherapy (Further studies needed)

IV Avelumab (anti PDL-1 antibody) 10 mg/kg every 2 weeks, irrespective of PDL-1 status ^[57]

Second-line therapy

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:

Ramucirumab 8 mg/kg IV once per day on Days 1 and 15 plus paclitaxel 80 mg/m ² IV once per day on Days 1, 8, and 15 of a 28-day cycle ^[58] (category 1 for esophagogastric junction [EGJ] adenocarcinoma; category 2A for esophageal adenocarcinoma) or
Ramucirumab 8 mg/kg IV once every 2 weeks ^[59] (category 1 for EGJ adenocarcinoma; category 2A for esophageal adenocarcinoma)
Ramucirumab 8 mg/kg IV on Day 1 and irinotecan 180 mg/m ² IV on Day 1 plus leucovorin 400 mg/m ² IV on Day 1 plus 5-FU 400 mg/m ² IV bolus on Day 1 then 5-FU 1200 mg/m ²/day IV continuous infusion over 24 hours on Days 1 and 2; every 14d ^[60]

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:

Docetaxel 75-100 mg/m ² IV over 60 minutes on Day 1; every 21d ^[44] or
Paclitaxel 135-250 mg/m ² IV over 24 hours on Day 1; every 21d ^[40] or
Paclitaxel 80 mg/m ²IV weekly, every 4 weeks ^[41] or
Paclitaxel 80 mg/m ² IV over 60 minutes on Days 1, 8, 15, and 22; every 28d ^[41] or
Irinotecan 180 mg/m ² IV on Day 1 plus leucovorin 400 mg/m ² IV over 2 hours on Day 1 plus 5-FU 400 mg/m ² IV bolus on Day 1 then 5-FU 1200 mg/m ²/day IV continuous infusion over 46 hours on Days 1 and 2; every 14d ^[60] or
Irinotecan 250-350 mg/m ² IV on Day 1; every 21d ^[61] or
Irinotecan 150-180 mg/m ² IV on Day 1; every 14d ^{[62, 63]} or
Irinotecan 125 mg/m ² IV on days 1 and 8; every 21d ^{[62, 63]}
Irinotecan 65 mg/m ² IV on Days 1 and 8 plus cisplatin 25-30 mg/m ² IV on Days 1 and 8; every 21d ^{[64, 65]} or
Irinotecan 150 mg/m ² IV on Day 1 plus ramucirumab 8 mg/kg on Day 1 of a 14-day cycle or

Category 2B recommendations for second-line therapy, based on lower level of clinical evidence, include the following:

Docetaxel 35 mg/m ² IV on Days 1 and 8 plus irinotecan 50 mg/m ² on Days 1 and 8; every 21d ^[66] or

For third-line or subsequent therapy for EGJ adenocarcinoma

Tipiracil/trifluridine 35 mg/m ² PO BID with food on Days 1-5 and Days 8-12 of each 28-day cycle; not to exceed 80 mg/dose, until disease progression or unacceptable toxicity ^[67]

Regimens are only used for NTRK gene fusion-positive tumors:

Entrectinib 600 mg PO qDay or
Larotrectinib 100 mg PO BID

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]}

Pembrolizumab 200 mg IV on Day 1 of a 21-day cycle or 400 mg IV on Day1 of a 6-weeks cycle

Other new regimens (Further trials needed)

Second or third-line therapy in recurrent or metastatic squamous cell carcinoma

Intravenous infusion of Irinotecan 160 mg/m ² on day 1 and oral S-1 80–120 mg on days 1–10, repeated every 14 days (Further trials needed) ^[70]
Camrelizumab (anti-PD-1 antibody) 200 mg IV day 1 every 2 weeks ( Trial ongoing) ^[71]

Second or further-line treatment of SCC or adenocarcinoma of esophagus or EGJ

Apatinib (VEGFR2 inhibitor) monotherapy 500 mg PO daily (Further studies needed) ^[72]

GEJ carcinoma previously treated with >=2 chemotherapy regimen

Nivolumab IV infusion 3 mg /kg every 2 weeks for 6 weeks, even when PDL-1 is negative (Further studies needed) ^[73]

Chemoradiotherapy for advanced unresectable disease

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]

Other Regimens to Consider

See the list below:

Gemcitabine 1000 mg/m ² IV once on Dys 1, 8, and 15 plus leucovorin 25 mg/m ² IV once on Days 1, 8, and 15 plus 5-FU 600 mg/m ² IV on Days 1, 8, and 15; every 28d ^[75] or
Pegylated liposomal doxorubicin 20 mg/m ² IV once on Day 1 plus cisplatin 50 mg/m ² IV once on Day 1 plus 5-FU 400 mg/m ² IV bolus on Day 1 then 5-FU 600 mg/m ²/day continuous IV infusion on Days 1 and 2; every 14d ^[76] or
Mitomycin 6 mg/m ² IV once on Day 1 plus irinotecan 125 mg/m ² IV on Days 2 and 9; every 28d ^[77] or
Mitomycin 7 mg/m ² (maximum 14 mg per cycle) IV once on Day 1 plus cisplatin 60 mg/m ²IV once on Days 1 and 22 plus 5-FU 300 mg/m ²/day continuous IV infusion on Days 1 to 42; every 6 wk ^[78] or
Mitomycin 10 mg/m ² IV once per day on Days 1 and 22 plus leucovorin 500 mg/m ² IV over 2 hours once per day on Day 1 plus 5-FU 2600 mg/m ²/day continuous IV infusion over 24 hours on Days 1, 8, 15, 22, 29, and 36 for 8 wk cycle (6wk followed by 2wk off treatment) ^[79] or
Etoposide 90-120 mg/m ² on Days 1 to 3; every 28d ^{[80, 81]} or
Erlotinib 150 mg PO daily on Days 1 to 28 ^{[82, 83]} or
Cetuximab 400 mg/m ² IV over 2 hours on Day 1 of week 1, then cetuximab 250 mg/m ²IV over 60 minutes once per day on Days 8, 15, and 22; can be used as single agent or with chemotherapy ^[84]

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