Key points
- Esophageal cancer has two main types, squamous cell carcinoma and adenocarcinoma, which differ in their causes, location and treatment [1, 2].
- Worldwide, about 85% of cases are squamous cell carcinoma [3]; northeastern Iran (Golestan province) has one of the highest rates of this type in the world [4].
- In Golestan, smoking opium, drinking very hot tea, eating little fruit and vegetables, using unpiped water and being exposed to indoor smoke have been linked to a higher risk, and about 75% of cases have been attributed to the combination of these factors [4].
- Difficulty swallowing that keeps getting worse, together with weight loss, is the most important warning sign and should be checked with an endoscopy [1].
- Newer treatments, including chemoradiotherapy or FLOT chemotherapy before surgery, nivolumab after surgery, and immunotherapy (nivolumab or pembrolizumab) combined with chemotherapy for advanced disease, have improved treatment outcomes [5, 6, 7, 8, 23].
What is esophageal cancer?
The esophagus is the muscular tube that carries food from the throat to the stomach. Esophageal cancer is really two different diseases that occur in the same organ: squamous cell carcinoma, which arises from the cells lining the surface of the esophagus, and adenocarcinoma, which develops from glandular tissue, usually on a background of “Barrett’s esophagus” at the lower end of the esophagus [1]. Adenocarcinoma usually affects the lower part of the esophagus, whereas the squamous cell type is more often located at or above the point where the windpipe divides; the two types differ in cause, pathology, tumor location, treatment and prognosis [1, 2].
According to GLOBOCAN estimates for 2024, esophageal cancer is the seventh leading cause of cancer death worldwide [21]. Most cases are squamous cell carcinoma, and in the 2020 estimates the incidence in men was 2 to 3 times that in women [3]. While the squamous cell type is declining in most parts of the world, adenocarcinoma has increased rapidly in developed countries over the past four decades [1].
Esophageal cancer in Iran and Golestan province
Squamous cell esophageal cancer is especially common in a region known as the “esophageal cancer belt,” which stretches from northern China through the Central Asian republics to northern Iran [1]. Northeastern Iran has one of the highest reported rates of esophageal squamous cell carcinoma in the world [4].
To find the reasons for this, the Golestan Cohort Study enrolled more than 50,000 people aged 40 to 75 between 2004 and 2008 and followed them for about 10 years; during this time, 317 people developed this cancer [4]. The good news is that survival in this region has improved dramatically over the past two decades: 5-year survival rose from 3.3% in earlier reports to 23% in patients diagnosed between 2007 and 2018, and it was 37% in patients who received cancer treatment versus 4% in those who were not treated [9].
Signs and symptoms
Because the esophagus is muscular and can stretch, symptoms caused by the tumor often do not appear until the disease has reached a locally advanced or even metastatic stage [1]. Warning signs include [1]:
- Difficulty or pain when swallowing (dysphagia or odynophagia), usually with solid foods at first
- Unintentional, progressive weight loss
- Hoarseness or cough (which may be a sign that the nerve to the voice box is involved or that food is entering the airway)
- Sometimes vomiting blood or black stools
- Tiredness from anemia caused by chronic, hidden bleeding
Before diagnosis, most patients have had difficulty swallowing, trouble eating and loss of appetite, leading to significant weight loss and fatigue [1].
When should I contact my doctor?
If you feel food getting stuck in your chest, have to wash food down with water, or find that swallowing solid food is getting harder day by day, especially if you have lost weight, don’t wait: see a doctor for an evaluation and possibly an endoscopy. Most of these symptoms have a benign cause, but diagnosing esophageal cancer earlier greatly improves the chance of successful treatment.
Risk factors and prevention
| Risk factor | Associated type | Evidence |
|---|---|---|
| Drinking very hot tea (60 °C or higher) | Squamous cell | In the Golestan cohort, a measured tea temperature of 60 °C or higher was associated with a 41% increase in risk (HR 1.41) [10] |
| Opium use | Squamous cell | Opium smoking: HR 1.85 in the Golestan cohort [4]; IARC has classified opium consumption as a Group 1 carcinogen and rated the evidence for esophageal cancer as “limited” [11] |
| Tobacco and alcohol | Squamous cell (and tobacco for adenocarcinoma) | Cigarette smoking increases the risk of the squamous cell type 5- to 9-fold, and smoking and alcohol have a synergistic effect; in high-risk areas, these two factors play a smaller role [1] |
| Low intake of fruit and vegetables, tooth loss, unpiped water, indoor smoke | Squamous cell | Each was independently associated with increased risk (HR between 1.48 and 2.04) [4] |
| Gastroesophageal reflux (chronic heartburn) | Adenocarcinoma | With recurrent reflux, the odds ratio was 7.7, and with severe, long-standing reflux it was 43.5; reflux was not associated with the squamous cell type [12] |
| Barrett’s esophagus, abdominal obesity, male sex | Adenocarcinoma | Adenocarcinoma arises mainly from Barrett’s mucosa; after reflux, obesity is the strongest risk factor [1] |
Many of these factors can be changed; having several risk factors together multiplies the risk.
- Let your tea cool a little. In Golestan, drinking tea less than 2 minutes after it was poured was linked to a much higher risk; wait a few minutes until your tea is no longer hot [13, 10].
- Give up opium and cigarettes. Opium is not “safe” and increases the risk of several cancers [14].
- Eat more fresh fruit and vegetables, and take good care of your mouth and teeth [4].
- If you have chronic reflux or are overweight, talk to your doctor about treatment and weight loss [1].
Diagnosis and staging
Diagnostic pathway for esophageal cancer
- 1
Endoscopy and biopsy
Endoscopy is the mainstay of the evaluation: the exact location, length and degree of obstruction of the tumor are recorded, and at least 6 biopsies are recommended to confirm the histology and determine the type (squamous cell carcinoma or adenocarcinoma) [1].
- 2
CT scan
All patients should first have a CT scan to rule out distant metastases [1].
- 3
Endoscopic ultrasound (EUS) and PET-CT
EUS is more accurate than CT in determining how deeply the tumor has invaded (T stage) and allows biopsy of suspicious lymph nodes. In candidates for surgery, PET-CT can reveal hidden metastases in about 15% of patients [1].
- 4
Additional tests
Diagnostic laparoscopy for more advanced tumors of the gastroesophageal junction; bronchoscopy for tumors at or above the level of the tracheal bifurcation; and, in squamous cell carcinoma with a history of smoking and alcohol use, evaluation for synchronous head and neck tumors [1].
- 5
- 6
Treatment by stage and type of disease
Very early cancer (confined to the mucosa)
For a tumor confined to the mucosa without metastasis (T1a N0), endoscopic resection (EMR or ESD) has replaced surgical removal of the esophagus; it is less invasive and safer, with a similar long-term prognosis [1].
Locally advanced: squamous cell type
Chemoradiotherapy before surgery (the CROSS regimen: weekly carboplatin and paclitaxel with radiotherapy for 5 weeks) [5, 15]; or definitive chemoradiotherapy without surgery, which is recommended for tumors in the neck portion of the esophagus and is also a standard option in the middle and lower esophagus [1]. In Japan, three-drug chemotherapy before surgery improved survival [16].
Locally advanced: adenocarcinoma
FLOT chemotherapy (every 2 weeks; 4 cycles before and 4 cycles after surgery) is the preferred approach based on the ESOPEC trial and the ESMO guideline; chemoradiotherapy before surgery is for patients who are not suitable for FLOT [6, 17]. In tumors of the gastroesophageal junction, adding durvalumab to FLOT has improved overall survival [26].
After surgery with residual disease
If cancer cells remain in the surgical specimen after chemoradiotherapy and surgery, one year of nivolumab roughly doubled the time without the disease coming back (disease-free survival) [7]; however, in the final analysis, the difference in length of life (overall survival) was not statistically significant [22].
Advanced disease: squamous cell type
Advanced disease: adenocarcinoma
Treatment is similar to that of stomach cancer: in HER2-negative tumors with PD-L1 of 1 or higher, nivolumab or pembrolizumab plus chemotherapy [19, 18, 24]; in HER2-positive tumors, trastuzumab plus chemotherapy [1], and in gastroesophageal junction tumors with PD-L1 of 1 or higher, the addition of pembrolizumab [24]. In PD-L1-negative tumors, two-drug chemotherapy is the backbone of treatment, and if the tumor is positive for claudin 18.2, zolbetuximab is a newer option [24].
After diagnosis: nutrition and supportive care
Because most patients have lost weight before diagnosis due to difficulty swallowing, attention to nutritional status is an important part of treatment; malnourished patients are at higher risk of complications and death after surgery, and in patients who are candidates for surgery and need nutritional support, a feeding tube into the small intestine (jejunostomy) is preferred over a stent [1].
When the disease cannot be treated with curative intent, difficulty swallowing caused by the tumor can be relieved with radiotherapy or stent placement, and systemic therapy is used to control the disease [1]. In locally advanced or metastatic disease, systemic therapy can relieve symptoms, improve survival and/or enhance quality of life [2].
Frequently asked questions
Frequently asked questions
Does drinking tea cause esophageal cancer?
The problem is not tea itself, but its very high temperature. In the Golestan studies, drinking tea at 60 °C or higher, and drinking it less than 2 minutes after it was poured, were linked to a higher risk of esophageal cancer [13, 10]. All you need to do is wait a few minutes for your tea to cool a little.
Does opium really increase the risk of cancer?
Yes. In the Golestan Cohort Study, regular opium use was associated with an increased risk of cancers of the esophagus, stomach, lung, bladder and larynx [14], and the International Agency for Research on Cancer has classified opium consumption as “carcinogenic to humans” [11].
Can heartburn (reflux) turn into esophageal cancer?
Is esophageal cancer curable?
Who is immunotherapy suitable for?
In advanced disease, immunotherapy combined with chemotherapy has improved survival, and the benefit is greater in tumors with higher PD-L1 expression [8, 18, 23]. After surgery, too, nivolumab reduces the risk of the cancer coming back in patients who still have some cancer cells left after chemoradiotherapy [7]. The final decision is made with your care team, based on the type and stage of the disease.
Will I be able to eat again after esophageal surgery?
Yes. After the esophagus is removed, the stomach is usually pulled up to take its place, and patients gradually go back to eating by mouth. In the first months, small, frequent meals and avoiding lying down right after eating help. Your care team and a dietitian will support you through this period.
Recent evidence and advances (for physicians)
For physicians
Neoadjuvant therapy
In the CROSS trial (366 patients; 75% adenocarcinoma and 23% squamous cell carcinoma), preoperative weekly carboplatin and paclitaxel with 41.4 Gy radiotherapy increased the R0 resection rate from 69% to 92%, and a pathologic complete response occurred in 29% of patients who underwent resection; median overall survival (OS) was 49.4 vs 24.0 months (HR 0.657) [5]. At a median follow-up of 147 months, the absolute 10-year survival benefit was 13% (38% vs 25%; HR 0.70) [15].
In adenocarcinoma, the phase 3 ESOPEC trial (438 patients) showed that perioperative FLOT, compared with CROSS, improved 3-year OS (57.4% vs 50.7%; HR 0.70) and 3-year progression-free survival (51.6% vs 35.0%; HR 0.66); 90-day postoperative mortality was 3.1% vs 5.6% [6]. A median OS of 66 vs 37 months has been reported, and the 2025 ESMO guideline update recommends FLOT for locally advanced adenocarcinoma of the esophagus and gastroesophageal junction [I, A] [17]. For junctional tumors, the MATTERHORN trial (gastric and gastroesophageal junction adenocarcinoma) showed that adding durvalumab to perioperative FLOT significantly improves OS (HR 0.78; 95% CI 0.63–0.96) [26].
In squamous cell carcinoma, the Japanese JCOG1109 NExT trial (601 patients) showed that preoperative triplet chemotherapy with docetaxel, cisplatin and fluorouracil increased 3-year OS from 62.6% to 72.1% compared with the doublet regimen (HR 0.68), whereas adding radiotherapy to the doublet regimen provided no significant benefit (HR 0.84) [16].
Adjuvant therapy
In CheckMate 577 (794 patients with residual pathologic disease after chemoradiotherapy and R0 resection), nivolumab for up to 1 year increased median disease-free survival (DFS) from 11.0 to 22.4 months (HR 0.69); grade 3 or 4 treatment-related adverse events occurred in 13% vs 6% [7]. In the final OS analysis (minimum follow-up of 5 years), median OS was 51.7 vs 35.3 months and 5-year OS was 46% vs 41%, but the difference was not statistically significant (HR 0.85; 95% CI 0.70–1.04); the DFS benefit was maintained (HR 0.76) [22].
First-line immunotherapy in advanced disease
In CheckMate 648 (970 patients with squamous cell carcinoma), both nivolumab + chemotherapy and nivolumab + ipilimumab improved OS compared with chemotherapy; in patients with tumor-cell PD-L1 ≥1%, median OS was 15.4 and 13.7 months vs 9.1 months (HR 0.54 and 0.64, respectively) [8]. With a minimum follow-up of 5 years, the OS HR in this group was 0.62 for both regimens [20]. In KEYNOTE-590 (749 patients, both histologic types), pembrolizumab + chemotherapy increased median OS in squamous cell carcinoma with CPS ≥10 from 8.8 to 13.9 months (HR 0.57) and in all patients from 9.8 to 12.4 months (HR 0.73) [18]; at 5-year follow-up, 5-year OS in all patients was 10.6% vs 3.0% (HR 0.72) [23]. In esophageal adenocarcinoma, the CheckMate 649 trial (which also included gastric and gastroesophageal junction cancer) showed that nivolumab + chemotherapy improves OS in patients with CPS ≥5, and this benefit was maintained with a minimum follow-up of 5 years (HR 0.71; 5-year OS 16% vs 6%) [19]. The ASCO guideline (2026) recommends immunotherapy plus doublet chemotherapy for tumors with PD-L1 of 1 or higher; patients with higher PD-L1 expression are more likely to benefit [24]. In advanced squamous cell carcinoma, the ESMO guideline also recommends tislelizumab plus chemotherapy for tumors with PD-L1 TAP ≥5% (EMA-approved) [17].
Treatment regimens and dosing (for physicians)
Treatment regimens and doses: index13 regimens
- DPD deficiency: Testing for DPYD gene variants is recommended before starting fluorouracil or capecitabine (unless immediate treatment is necessary); avoid use in patients with variants that result in complete DPD deficiency [36, 37].
- Taxane premedication: Paclitaxel requires premedication (a corticosteroid, diphenhydramine and an H2 antagonist) per the label [40]. The docetaxel label recommends premedication with an oral corticosteroid (such as dexamethasone 8 mg twice daily for 3 days, starting one day before the infusion), and docetaxel should not be given if the neutrophil count is below 1500 cells/mcL or bilirubin is above the upper limit of normal [39].
- Cisplatin: Dose-related, cumulative nephrotoxicity; use IV hydration, and give the next dose only after renal function has returned to normal; audiometry before starting and before each dose [38].
- Capecitabine and renal function: Reduce the dose by 25% for CrCl 30–50 mL/min; no dose has been established for CrCl below 30; monitor INR in patients taking warfarin [36].
- Oxaliplatin: Acute sensory neuropathy exacerbated by cold, and persistent neuropathy; for CrCl below 30, use a dose of 65 mg/m² [41].
- PD-1 and PD-L1 inhibitors (nivolumab, pembrolizumab, durvalumab, tislelizumab): Monitor liver enzymes, creatinine and thyroid function before starting and periodically; withhold the drug for severe (grade 3) immune-mediated adverse reactions and permanently discontinue it for life-threatening (grade 4) reactions; dose reduction is not recommended [27, 28, 29]. Immune-mediated adverse reactions with tislelizumab are managed in the same way as with other PD-1 inhibitors, and dose reduction is not recommended [30].
For physicians
Locally advanced disease: treatment with curative intent
Preoperative chemoradiotherapy (CROSS regimen)
Resectable cancer of the esophagus or gastroesophageal junction (squamous cell carcinoma or adenocarcinoma); in adenocarcinoma, for patients who are not suitable for FLOTCycle length: Weekly
Resectable cancer of the esophagus or gastroesophageal junction (squamous cell carcinoma or adenocarcinoma); in adenocarcinoma, for patients who are not suitable for FLOT
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Carboplatin | AUC 2 mg/mL/min | IV | Weekly (Days 1, 8, 15, 22 and 29) |
| Paclitaxel | 50 mg/m² | IV | Weekly (Days 1, 8, 15, 22 and 29) |
| Concurrent radiotherapy | 41.4 Gy in 23 fractions | External beam radiotherapy | 5 days per week |
Regimen from the CROSS trial [5]. The carboplatin dose is calculated in mg (not based on body surface area) using the Calvert formula: total dose = target AUC × (GFR + 25) [42]. In CROSS, the most common severe adverse events were leukopenia (6%) and anorexia (5%) [5].
Evidence: CROSS (2012)
Perioperative FLOT (ESOPEC trial)
Resectable adenocarcinoma of the esophagus or gastroesophageal junction, clinical stage cT1 cN+ or cT2–cT4a with any N status, no distant metastasesCycle length: Every 14 days
Resectable adenocarcinoma of the esophagus or gastroesophageal junction, clinical stage cT1 cN+ or cT2–cT4a with any N status, no distant metastases
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Docetaxel | 50 mg/m² | IV | Day 1 |
| Oxaliplatin | 85 mg/m² | IV | Day 1 |
| Leucovorin | 200 mg/m² | IV | Day 1 |
| Fluorouracil | 2600 mg/m² | IV, 24-hour infusion | Day 1 |
FLOT doses as in the FLOT4 trial [33]; in ESOPEC, grade 3 or higher adverse events occurred in 58% with FLOT vs 50% with CROSS [6].
Evidence: ESOPEC (2025), FLOT4 (2019)
Durvalumab + FLOT (MATTERHORN trial)
Resectable adenocarcinoma of the gastroesophageal junction (or stomach), stage II–IVA, ECOG PS 0–1
Resectable adenocarcinoma of the gastroesophageal junction (or stomach), stage II–IVA, ECOG PS 0–1
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| 2 cycles before and 2 cycles after surgery | |||
| Durvalumab | 1500 mg (body weight below 30 kg: 20 mg/kg) | IV | Day 1 |
| FLOT | Standard FLOT doses (see regimen above) | IV | Days 1 and 15 |
| Maintenance: up to 10 cycles | |||
| Durvalumab | 1500 mg (body weight below 30 kg: 20 mg/kg) | IV | Day 1 |
Durvalumab dose and schedule from the FDA label (approved for gastric and gastroesophageal junction adenocarcinoma) [29]; the doses of the FLOT components are not specified separately in the label, and the standard FLOT4 doses serve as the basis [33].
Evidence: FLOT4 (2019)
Preoperative DCF (Japanese JCOG1109 NExT trial)
Resectable locally advanced squamous cell carcinoma, age 20–75 years, ECOG PS 0–1Cycle length: Every 21 days
Resectable locally advanced squamous cell carcinoma, age 20–75 years, ECOG PS 0–1
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Docetaxel | 70 mg/m² | IV | Day 1 |
| Cisplatin | 70 mg/m² | IV | Day 1 |
| Fluorouracil | 750 mg/m²/day | IV | Days 1–5 |
Doses from the JCOG1109 trial [16]. Grade 3 or higher febrile neutropenia occurred in 16% of patients, and 9% discontinued treatment because of adverse events [16].
Evidence: JCOG1109 NExT (2024)
Definitive chemoradiotherapy: cisplatin + fluorouracil with 50.4 Gy (INT 0123 / RTOG 94-05)
Nonsurgical treatment of T1–T4, N0/1, M0 esophageal cancer (squamous cell carcinoma or adenocarcinoma); preferred approach for tumors of the cervical esophagus
Nonsurgical treatment of T1–T4, N0/1, M0 esophageal cancer (squamous cell carcinoma or adenocarcinoma); preferred approach for tumors of the cervical esophagus
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Fluorouracil | 1000 mg/m² per 24 hours | IV, continuous infusion | Days 1–4 |
| Cisplatin | 75 mg/m² | IV (bolus) | Day 1 |
| Concurrent radiotherapy | 50.4 Gy | External beam radiotherapy | Concurrent with chemotherapy |
Regimen from the INT 0123 trial; escalating the radiation dose to 64.8 Gy did not improve survival or local control, and 50.4 Gy is the standard dose with this chemotherapy [34].
Adjuvant nivolumab (CheckMate 577 trial)
Esophageal or gastroesophageal junction cancer (squamous cell carcinoma or adenocarcinoma) with residual pathologic disease after neoadjuvant chemoradiotherapy and complete (R0) resection; in the trial, randomization 4 to 16 weeks after surgery
Esophageal or gastroesophageal junction cancer (squamous cell carcinoma or adenocarcinoma) with residual pathologic disease after neoadjuvant chemoradiotherapy and complete (R0) resection; in the trial, randomization 4 to 16 weeks after surgery
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Weeks 1–16 | |||
| Nivolumab | 240 mg | IV (30 minutes) | Every 2 weeks |
| From Week 17 | |||
| Nivolumab | 480 mg | IV (30 minutes) | Every 4 weeks |
Schedule from the trial and the FDA label; the label allows 240 mg every 2 weeks or 480 mg every 4 weeks throughout the 1-year course [7, 27].
Evidence: CheckMate 577 (2021)
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Advanced or metastatic disease, first-line: squamous cell carcinoma (KEYNOTE-590 in both types)
Nivolumab + cisplatin and fluorouracil (CheckMate 648 trial)
Unresectable, advanced or metastatic esophageal squamous cell carcinoma, no prior systemic therapy; FDA label: tumor-cell PD-L1 ≥1%Cycle length: Every 28 days
Unresectable, advanced or metastatic esophageal squamous cell carcinoma, no prior systemic therapy; FDA label: tumor-cell PD-L1 ≥1%
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Nivolumab | 240 mg on Days 1 and 15 (or 480 mg every 4 weeks) | IV (30 minutes) | Days 1 and 15 |
| Fluorouracil | 800 mg/m²/day | IV | Days 1–5 |
| Cisplatin | 80 mg/m² | IV | Day 1 |
Doses from the FDA label (description of CheckMate 648) [27].
Pembrolizumab + cisplatin and fluorouracil (KEYNOTE-590 trial)
Esophageal or gastroesophageal junction cancer (epicenter 1 to 5 cm above the junction), squamous cell carcinoma or adenocarcinoma, not amenable to surgical resection or definitive chemoradiotherapy; FDA label: PD-L1 CPS ≥1 (greater benefit with CPS ≥10)Cycle length: Every 21 days
Esophageal or gastroesophageal junction cancer (epicenter 1 to 5 cm above the junction), squamous cell carcinoma or adenocarcinoma, not amenable to surgical resection or definitive chemoradiotherapy; FDA label: PD-L1 CPS ≥1 (greater benefit with CPS ≥10)
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 200 mg (or 400 mg every 6 weeks) | IV (30 minutes), before chemotherapy | Day 1 |
| Cisplatin | 80 mg/m² (maximum 6 cycles) | IV | Day 1 |
| Fluorouracil | 800 mg/m²/day | IV, continuous infusion | Days 1–5 |
Doses from the FDA label (description of KEYNOTE-590) and the 5-year follow-up publication [28, 23].
Evidence: KEYNOTE-590 (2025)
Nivolumab + ipilimumab without chemotherapy (CheckMate 648 trial)
Unresectable, advanced or metastatic esophageal squamous cell carcinoma; FDA label: tumor-cell PD-L1 ≥1%Each drug’s schedule in the table
Unresectable, advanced or metastatic esophageal squamous cell carcinoma; FDA label: tumor-cell PD-L1 ≥1%
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Nivolumab | 3 mg/kg every 2 weeks or 360 mg every 3 weeks | IV (30 minutes) | Every 2 or 3 weeks |
| Ipilimumab | 1 mg/kg | IV | Every 6 weeks |
Doses from the FDA label [27].
Tislelizumab + doublet chemotherapy (RATIONALE-306 trial)
Unresectable or metastatic esophageal squamous cell carcinoma, first-line; FDA label: PD-L1 ≥1; ESMO guideline: PD-L1 TAP ≥5% (EMA approval)Cycle length: Every 21 days
Unresectable or metastatic esophageal squamous cell carcinoma, first-line; FDA label: PD-L1 ≥1; ESMO guideline: PD-L1 TAP ≥5% (EMA approval)
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Tislelizumab | 200 mg every 3 weeks (or 150 mg every 2 weeks, 300 mg every 4 weeks, 400 mg every 6 weeks) | IV | Day 1 |
| Platinum + fluoropyrimidine | |||
| Cisplatin or oxaliplatin | Cisplatin 60–80 mg/m² or oxaliplatin 130 mg/m² | IV | Day 1 |
| Fluorouracil or capecitabine | Fluorouracil 750–800 mg/m²/day (Days 1–5) or capecitabine 1000 mg/m² twice daily (Days 1–14) | IV / oral | Days 1–5 or 1–14 |
| Or platinum + paclitaxel | |||
| Platinum + paclitaxel | Platinum as above (Day 1 or 2) + paclitaxel 175 mg/m² | IV | Day 1 |
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Advanced or metastatic disease, first-line: adenocarcinoma
HER2-negative adenocarcinoma: nivolumab + CAPOX or mFOLFOX6 (CheckMate 649 trial)
Advanced HER2-negative adenocarcinoma of the esophagus, gastroesophageal junction or stomach; FDA label: PD-L1 ≥1 (greatest benefit with CPS ≥5). Pembrolizumab + chemotherapy (KEYNOTE-590 regimen) is another alternative
Advanced HER2-negative adenocarcinoma of the esophagus, gastroesophageal junction or stomach; FDA label: PD-L1 ≥1 (greatest benefit with CPS ≥5). Pembrolizumab + chemotherapy (KEYNOTE-590 regimen) is another alternative
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| 3-week regimen (CAPOX) | |||
| Nivolumab | 360 mg | IV (30 minutes) | Day 1 |
| Oxaliplatin | 130 mg/m² | IV | Day 1 |
| Capecitabine | 1000 mg/m² twice daily | Oral | Days 1–14 |
| Or 2-week regimen (FOLFOX) | |||
| Nivolumab | 240 mg | IV (30 minutes) | Day 1 |
| Oxaliplatin | 85 mg/m² | IV | Day 1 |
| Leucovorin | 400 mg/m² | IV | Day 1 |
| Fluorouracil | 400 mg/m² bolus on Day 1, then 1200 mg/m² per day continuous infusion on Days 1–2 | IV | Days 1–2 |
Nivolumab dose from the FDA label [27] and chemotherapy doses from the primary CheckMate 649 publication [35]; 5-year follow-up [19]. In PD-L1-negative tumors, doublet chemotherapy alone is the backbone of treatment [24].
Evidence: CheckMate 649 (2026), CheckMate 649 (2021)
HER2-positive adenocarcinoma: trastuzumab + cisplatin + fluoropyrimidine, ± pembrolizumab (ToGA and KEYNOTE-811)
Advanced HER2-positive adenocarcinoma; trials and FDA label in gastric and gastroesophageal junction tumors; add pembrolizumab if PD-L1 CPS ≥1Cycle length: Every 21 days
Advanced HER2-positive adenocarcinoma; trials and FDA label in gastric and gastroesophageal junction tumors; add pembrolizumab if PD-L1 CPS ≥1
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Trastuzumab | First dose 8 mg/kg (90 minutes), then 6 mg/kg (30–90 minutes) | IV | Day 1 |
| Cisplatin | 80 mg/m² | IV | Day 1 (6 cycles) |
| Capecitabine or fluorouracil | Capecitabine 1000 mg/m² twice daily (Days 1–14) or fluorouracil 800 mg/m²/day continuous infusion (Days 1–5) | Oral / IV | Days 1–14 or 1–5 |
| Pembrolizumab (if CPS ≥1) | 200 mg (or 400 mg every 6 weeks) | IV, before trastuzumab and chemotherapy | Day 1 |
Doses from the FDA labels for trastuzumab (ToGA) [31] and pembrolizumab (KEYNOTE-811; CAPOX was also permitted in this trial: oxaliplatin 130 mg/m² on Day 1 for 6 to 8 cycles + capecitabine) [28]. Monitor LVEF before starting and every 3 months; withhold trastuzumab for an absolute decrease of 16% or more, or for an LVEF below the lower limit of normal with a decrease of 10% or more [31].
Evidence: KEYNOTE-811 (2023), ToGA (2010)
CLDN18.2-positive adenocarcinoma: zolbetuximab + mFOLFOX6 or CAPOX (SPOTLIGHT and GLOW)
Advanced HER2-negative, CLDN18.2-positive adenocarcinoma (moderate to strong staining in 75% or more of tumor cells); FDA label in gastric and gastroesophageal junction tumors; particularly with PD-L1 below 1Each drug’s schedule in the table
Advanced HER2-negative, CLDN18.2-positive adenocarcinoma (moderate to strong staining in 75% or more of tumor cells); FDA label in gastric and gastroesophageal junction tumors; particularly with PD-L1 below 1
Before prescribing: Shared safety points| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Zolbetuximab | First dose 800 mg/m²; then 600 mg/m² every 3 weeks or 400 mg/m² every 2 weeks | IV, before chemotherapy | First dose on Day 1; then every 3 weeks or every 2 weeks, depending on the dose |
| With one of two regimens | |||
| mFOLFOX6 | Oxaliplatin 85, leucovorin 400, fluorouracil 400 bolus and 2400 mg/m² continuous infusion | IV | Every 2 weeks (up to 12 treatments) |
| CAPOX | Oxaliplatin 130 mg/m² on Day 1 (up to 8 cycles) + capecitabine 1000 mg/m² twice daily on Days 1–14 | IV / oral | Every 3 weeks |
Doses from the zolbetuximab FDA label [32] and the ASCO guideline [24]. Premedication with a combination of antiemetics (an NK-1 and/or 5-HT3 receptor antagonist) is required before each infusion; the infusion is started at a slow rate, and dose reduction is not recommended [32].
Evidence: SPOTLIGHT (2023), GLOW (2023), GLOW (2023)
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Scientific evidence
Key studies
13 itemsPreoperative chemoradiotherapy for esophageal or junctional cancer
Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer
Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial
Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer
Pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer: 5-year extended follow-up for the randomized phase III KEYNOTE-590 study
Nivolumab plus chemotherapy as first-line treatment for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 5-year follow-up results from CheckMate 649
Individual and Combined Effects of Environmental Risk Factors for Esophageal Cancer Based on Results From the Golestan Cohort Study
A prospective study of tea drinking temperature and risk of esophageal squamous cell carcinoma
Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study
Nivolumab plus chemotherapy or ipilimumab versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: 5-year follow-up results from CheckMate 648
Perioperative durvalumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable gastric and gastro-oesophageal junction adenocarcinoma (MATTERHORN): final results of overall survival and event-free survival by pathological response in a global, randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study
Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma
Clinical guidelines
3 itemsNCCN Guidelines® Insights: Esophageal and Esophagogastric Junction Cancers, Version 4.2026
Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update
ESMO Clinical Practice Guideline interim update on the treatment of locally advanced oesophageal and oesophagogastric junction adenocarcinoma and metastatic squamous-cell carcinoma
References
42 referencesShow all references, 25 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
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- 9Improvement of esophageal cancer survival in Northeast Iran: A two-decade journey in a high-risk, low-resource region
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- 11Carcinogenicity of opium consumption
- 12Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma
- 13Tea drinking habits and oesophageal cancer in a high risk area in northern Iran: population based case-control study
- 14Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study
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- 20Nivolumab plus chemotherapy or ipilimumab versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: 5-year follow-up results from CheckMate 648
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- 25Gastric and oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
- 26Perioperative durvalumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable gastric and gastro-oesophageal junction adenocarcinoma (MATTERHORN): final results of overall survival and event-free survival by pathological response in a global, randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
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- 33Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial
- 34INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy
- 35First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial
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- 37Fluorouracil injection, for intravenous use: Prescribing Information
- 38Cisplatin injection: Prescribing Information
- 39Docetaxel injection, for intravenous use: Prescribing Information
- 40Paclitaxel injection: Prescribing Information
- 41Oxaliplatin injection, for intravenous use: Prescribing Information
- 42Carboplatin injection: Prescribing Information
This page is based on reputable scientific sources and was last updated on 21 October 2026. The content of this website is for educational and informational purposes only and does not replace consultation, diagnosis or treatment by a specialist physician. Consult your treating physician about any treatment decision.