Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

limited disease (cT1, cN0, M0)

1st line – endoscopic therapy or surgery (esophagectomy)

Back
ACUTE
|
limited disease (cT1, cN0, M0)
|
T1a disease
1st line – 

endoscopic therapy or surgery (esophagectomy)

Endoscopic therapy alone is recommended for most patients with cT1a disease (i.e., disease limited to the lamina propria and muscularis mucosae).​​[15][88]​ No further surgical treatment is required. Endoscopic resection can usually be considered curative in all T1a adenocarcinomas.[88] Esophageal squamous cell carcinomas have a higher risk of lymph node metastasis, and features such as differentiation and lymphovascular invasion should be considered. Esophagectomy is therefore indicated for patients with extensive T1a disease, particularly nodular disease that is not controlled with endoscopic therapy.​[15][88]

In a SEER database analysis of 1458 patients with T1N0 esophageal cancer, the overall survival rates were similar after treatment with surgery or endoscopic therapy, but those treated with endoscopic therapy had improved cancer-specific survival and decreased morbidity.[172]

Residual Barrett esophagus should be ablated following endoscopic therapy to minimize the risk of subsequent cancer.​[15][88]​​ Following endoscopic therapy, patients require continuous monitoring with routine interval endoscopies.

1st line – surgery (esophagectomy) or endoscopic therapy

Back
ACUTE
|
limited disease (cT1, cN0, M0)
|
T1b disease: suitable for surgery
1st line – 

surgery (esophagectomy) or endoscopic therapy

Esophagectomy is recommended for patients with cT1b disease (squamous cell carcinoma or adenocarcinoma) who are suitable for surgery.​[15][88][137][173][174]​​​​ Patients with superficial T1b adenocarcinomas may be considered for initial treatment with endoscopic therapy instead of surgery.[88] If histopathologic assessment of endoscopic resected specimens confirms superficial T1b disease (i.e., submucosa invasion <500 micrometers for adenocarcinoma), no ulceration, and the presence of low-risk lesions (i.e., no lymphovascular invasion; well differentiated histology; negative margins) then no further surgical treatment is required. The American Society for Gastrointestinal Endoscopy suggests that patients with esophageal squamous cell dysplasia or early, well-differentiated, nonulcerated esophageal squamous cell carcinoma who do not show overt signs of submucosal invasion need not undergo surgical resection.[142]​ Surgery is required if histopathologic assessment confirms deep submucosa invasion and/or high-risk lesions (i.e., lymphovascular invasion; poorly differentiated histology; positive margins).[88]

1st line – definitive chemoradiation therapy

Back
ACUTE
|
limited disease (cT1, cN0, M0)
|
T1b disease: not suitable for surgery
1st line – 

definitive chemoradiation therapy

Patients who are unsuitable for or decline surgery can be offered definitive chemoradiation therapy. The radiation component should be delivered at a dose of 50.4 Gy. The first-line regimens for the chemotherapy backbone are: carboplatin plus paclitaxel; fluorouracil plus oxaliplatin; or leucovorin plus fluorouracil plus oxaliplatin (FOLFOX). Other options include: cisplatin plus fluorouracil; cisplatin plus docetaxel or paclitaxel; irinotecan plus cisplatin; or paclitaxel plus fluorouracil.​[15][88][154]​​​[156][175][176]​​ Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

Definitive chemoradiation therapy has been shown to increase the survival of patients who have squamous cell carcinoma or adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with radiation therapy alone.[177][178]​​ The landmark RTOG 85-01 trial randomized patients to receive either chemoradiation therapy (fluorouracil plus cisplatin plus radiation therapy) or radiation therapy alone. At 5 years of follow-up, the overall survival for combined therapy was 26% (95% CI 15% to 37%) compared with 0% following radiation therapy.[178] Median survival in one phase 3 study (n=121) was 12.5 months in patients treated with chemoradiation therapy compared with 8.9 months in the patients treated with radiation therapy alone.[177]

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

paclitaxel

OR

fluorouracil

and

oxaliplatin

OR

leucovorin

and

fluorouracil

and

oxaliplatin

Secondary options

cisplatin

and

fluorouracil

OR

cisplatin

and

docetaxel

OR

cisplatin

and

paclitaxel

OR

irinotecan

and

cisplatin

OR

paclitaxel

and

fluorouracil

2nd line – endoscopic therapy

Back
ACUTE
|
limited disease (cT1, cN0, M0)
|
T1b disease: not suitable for surgery
2nd line – 

endoscopic therapy

Endoscopic therapy is an alternative to chemoradiation but only for patients with superficial adenocarcinomas.[88]

localized disease (cT2, cN0, M0): suitable for surgery

1st line – surgery (esophagectomy)

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
low-risk lesions
1st line – 

surgery (esophagectomy)

Surgery (esophagectomy) is the recommended initial treatment for patients with localized disease (cT2, cN0, M0) who are suitable for surgery.​[15][88][135]

Patients with cT2 disease and low-risk lesions (i.e., no lymphovascular invasion; tumor size <30 mm; well-differentiated histology) can be treated with surgery alone if there is confidence in the accuracy of the clinical stage.[15][135][180][181]

1st line – surgery (esophagectomy)

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: squamous cell carcinoma
1st line – 

surgery (esophagectomy)

Surgery (esophagectomy) is the recommended initial treatment for patients with localized disease (cT2, cN0, M0) who are suitable for surgery.​[15][88][135]

Plus – preoperative chemoradiation therapy

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: squamous cell carcinoma
Plus – 

preoperative chemoradiation therapy

Treatment recommended for ALL patients in selected patient group

Patients with localized squamous cell carcinoma and high-risk lesions (i.e., lymphovascular invasion; tumor size ≥30 mm; poorly differentiated histology) can be considered preoperative chemoradiation therapy followed by surgery.​[15][88]​​​[135][182]​​​ This has been shown to improve survival compared with surgery alone in patients with localized or locally advanced esophageal squamous cell carcinoma.[154]​​[182][183][184][185]

The standard regimen for preoperative chemoradiation therapy is carboplatin plus paclitaxel plus radiation therapy (41.4 Gy), based on the results from the CROSS trial (which enrolled patients with cT1, N1 disease or cT2-3, N0-1 disease).[154][184][185]​​​ The other preferred regimen is fluorouracil plus oxaliplatin plus radiation therapy.[15] Other recommended regimens include: fluorouracil plus cisplatin plus radiation therapy; irinotecan plus cisplatin plus radiation therapy; and paclitaxel plus fluorouracil plus radiation therapy.[15][175][176]​​​​ Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

paclitaxel

OR

fluorouracil

and

oxaliplatin

Secondary options

fluorouracil

and

cisplatin

OR

irinotecan

and

cisplatin

OR

paclitaxel

and

fluorouracil

Consider – postoperative nivolumab

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: squamous cell carcinoma
Consider – 

postoperative nivolumab

Treatment recommended for SOME patients in selected patient group

Patients with localized disease who have residual pathologic disease despite complete surgical resection and preoperative chemoradiation therapy (i.e., ≥ypT1 or ypN1) are at high risk for recurrence, particularly if there is lymph node involvement.[201] These patients can be considered for postoperative treatment with nivolumab, an immune checkpoint inhibitor that blocks the programmed cell death-1 receptor (PD-1).[15][202][203]

In the CheckMate 577 study, nivolumab significantly improved disease-free survival compared with placebo in patients with localized or locally advanced disease who had residual pathologic disease following complete surgical resection and preoperative chemoradiation therapy (22.4 vs. 11.0 months).[202]​ Programmed death-ligand 1 (PD-L1) testing is not required for this indication.[88]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

1st line – surgery (esophagectomy)

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: adenocarcinoma
1st line – 

surgery (esophagectomy)

Surgery (esophagectomy) is the recommended initial treatment for patients with localized disease (cT2, cN0, M0) who are suitable for surgery.​[15][88][135]

Plus – preoperative chemoradiation therapy

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: adenocarcinoma
Plus – 

preoperative chemoradiation therapy

Treatment recommended for ALL patients in selected patient group

Patients with localized esophageal adenocarcinoma (EAC) and high-risk lesions can be considered for surgery plus preoperative chemoradiation therapy or perioperative chemotherapy.​[15][88][135]​ Both approaches have been found to improve survival and R0 resection rates compared with surgery alone in patients with localized or locally advanced EAC.[154][183][184][185][186][187]​​

The standard regimen for preoperative chemoradiation therapy is carboplatin plus paclitaxel plus radiation therapy (41.4 Gy in 23 fractions), based on the results from the CROSS trial.[154][184][185]​​​ The other preferred regimen is fluorouracil plus oxaliplatin plus radiation therapy.[15] Other recommended regimens include: fluorouracil plus cisplatin plus radiation therapy; irinotecan plus cisplatin plus radiation therapy; and paclitaxel plus fluorouracil plus radiation therapy.​[15][88][175][176]​​​ Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

Patients with resectable disease should proceed to surgery even after complete clinical tumor response to preoperative chemoradiation therapy, as data for a watch-and-wait strategy are limited.[88]

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

paclitaxel

OR

fluorouracil

and

oxaliplatin

Secondary options

fluorouracil

and

cisplatin

OR

irinotecan

and

cisplatin

OR

paclitaxel

and

fluorouracil

Consider – postoperative nivolumab

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: adenocarcinoma
Consider – 

postoperative nivolumab

Treatment recommended for SOME patients in selected patient group

Patients with localized disease who have residual pathologic disease despite complete surgical resection and preoperative chemoradiation therapy (i.e., ≥ypT1 or ypN1) are at high risk for recurrence, particularly if there is lymph node involvement.[201] These patients can be considered for postoperative treatment with nivolumab, an immune checkpoint inhibitor that blocks the programmed cell death-1 receptor (PD-1).[15][202][203]

In the CheckMate 577 study, nivolumab significantly improved disease-free survival compared with placebo in patients with localized or locally advanced disease who had residual pathologic disease following complete surgical resection and preoperative chemoradiation therapy (22.4 vs. 11.0 months).[202]​ Programmed death-ligand 1 (PD-L1) testing is not required for this indication.[88]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

1st line – surgery (esophagectomy)

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: adenocarcinoma
1st line – 

surgery (esophagectomy)

Surgery (esophagectomy) is the recommended initial treatment for patients with localized disease (cT2, cN0, M0) who are suitable for surgery.​[15][88][135]

Plus – perioperative chemotherapy

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: adenocarcinoma
Plus – 

perioperative chemotherapy

Treatment recommended for ALL patients in selected patient group

Patients with localized esophageal adenocarcinoma (EAC) and high-risk lesions can be considered for surgery plus preoperative chemoradiation therapy or perioperative chemotherapy.​[15][88][135]​​ Both approaches have been found to improve survival and R0 resection rates compared with surgery alone in patients with localized or locally advanced EAC.[154][183][184][185][186][187]​​​

The preferred perioperative chemotherapy regimens for T2 tumors are fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), or a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin. The other option is fluorouracil plus cisplatin.​[15][88]

See local specialist protocol for dosing guidelines.

Primary options

fluorouracil

and

leucovorin

and

oxaliplatin

and

docetaxel

OR

fluorouracil

or

capecitabine

-- AND --

oxaliplatin

Secondary options

fluorouracil

and

cisplatin

Consider – postoperative nivolumab

Back
ACUTE
|
localized disease (cT2, cN0, M0): suitable for surgery
|
high-risk lesions: adenocarcinoma
Consider – 

postoperative nivolumab

Treatment recommended for SOME patients in selected patient group

Patients with localized disease who have residual pathologic disease despite complete surgical resection and preoperative chemoradiation therapy (i.e., ≥ypT1 or ypN1) are at high risk for recurrence, particularly if there is lymph node involvement.[201] These patients can be considered for postoperative treatment with nivolumab, an immune checkpoint inhibitor that blocks the programmed cell death-1 receptor (PD-1).[15][202][203]

In the CheckMate 577 study, nivolumab significantly improved disease-free survival compared with placebo in patients with localized or locally advanced disease who had residual pathologic disease following complete surgical resection and preoperative chemoradiation therapy (22.4 vs. 11.0 months).[202]​ Programmed death-ligand 1 (PD-L1) testing is not required for this indication.[88]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

localized disease (cT2, cN0, M0): unsuitable for surgery

1st line – definitive chemoradiation therapy

Back
ACUTE
|
localized disease (cT2, cN0, M0): unsuitable for surgery
1st line – 

definitive chemoradiation therapy

Patients with localized squamous cell carcinoma or adenocarcinoma who are unsuitable for surgery (e.g., those with tumors located in the cervical esophagus) or who decline surgery can be considered for definitive chemoradiation therapy.​[15]​​[88]

Randomized trials comparing definitive chemoradiation therapy versus surgery plus preoperative chemoradiation therapy in patients with locally advanced disease have reported similar survival outcomes, particularly among those with squamous cell carcinoma who achieved a complete response with chemoradiation therapy.[192][193][194]

Close monitoring is required following definitive chemoradiation therapy due to the risk of local tumor recurrence.[192][193]

Salvage esophagectomy can be considered in patients with persistent or progressive disease post definitive chemoradiation therapy. It has been shown to be comparable in terms of outcomes to those with planned trimodality therapy in the setting of adenocarcinoma.[88][195][196]​ However, some data suggest increased morbidity for patients with esophageal squamous cell carcinoma.[197]

Radiation therapy should be delivered at a dose of 50.4 Gy. The first-line regimens for the chemotherapy backbone are: carboplatin plus paclitaxel; fluorouracil plus oxaliplatin; or fluorouracil plus leucovorin plus oxaliplatin (FOLFOX). Other options are: cisplatin plus fluorouracil; cisplatin plus docetaxel or paclitaxel; irinotecan plus cisplatin; or paclitaxel plus fluorouracil.​[15][88][154][156][175][176]​​​ Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

paclitaxel

OR

fluorouracil

and

oxaliplatin

OR

leucovorin

and

fluorouracil

and

oxaliplatin

Secondary options

cisplatin

and

fluorouracil

OR

cisplatin

and

docetaxel

OR

cisplatin

and

paclitaxel

OR

irinotecan

and

cisplatin

OR

paclitaxel

and

fluorouracil

locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery

1st line – surgery (esophagectomy)

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
squamous cell carcinoma
1st line – 

surgery (esophagectomy)

The recommended initial treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is surgery plus preoperative chemoradiation therapy.​[15][88][135][182]​​ This has been shown to improve survival compared with surgery alone in patients with localized or locally advanced ESCC.[135][154][183][184][185]

Plus – preoperative chemoradiation therapy

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
squamous cell carcinoma
Plus – 

preoperative chemoradiation therapy

Treatment recommended for ALL patients in selected patient group

The recommended initial treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is surgery plus preoperative chemoradiation therapy.​[15][88][135][182]​​ This has been shown to improve survival compared with surgery alone in patients with localized or locally advanced ESCC.[135][154][183][184][185]

The standard regimen for preoperative chemoradiation therapy is carboplatin plus paclitaxel plus radiation therapy (41.4 Gy), based on the results from the CROSS trial (which enrolled patients with cT1, N1 disease or cT2-3, N0-1 disease).[154][184][185]​​​​ The other preferred regimen is fluorouracil plus oxaliplatin plus radiation therapy.[15] Other recommended regimens include: fluorouracil plus cisplatin plus radiation therapy; irinotecan plus cisplatin plus radiation therapy; and paclitaxel plus fluorouracil plus radiation therapy.​[15][88][175][176]​​​​ Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

paclitaxel

OR

fluorouracil

and

oxaliplatin

Secondary options

fluorouracil

and

cisplatin

OR

irinotecan

and

cisplatin

OR

paclitaxel

and

fluorouracil

Consider – postoperative nivolumab

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
squamous cell carcinoma
Consider – 

postoperative nivolumab

Treatment recommended for SOME patients in selected patient group

Patients with localized disease who have residual pathologic disease despite complete surgical resection and preoperative chemoradiation therapy (i.e., ≥ypT1 or ypN1) are at high risk for recurrence, particularly if there is lymph node involvement.[201] These patients can be considered for postoperative treatment with nivolumab, an immune checkpoint inhibitor that blocks the programmed cell death-1 receptor (PD-1).[15][202][203]

In the CheckMate 577 study, nivolumab significantly improved disease-free survival compared with placebo in patients with localized or locally advanced disease who had residual pathologic disease following complete surgical resection and preoperative chemoradiation therapy (22.4 vs. 11.0 months).[202]​ Programmed death-ligand 1 (PD-L1) testing is not required for this indication.[88]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

1st line – surgery (esophagectomy)

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
adenocarcinoma
1st line – 

surgery (esophagectomy)

The recommended initial treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is surgery plus preoperative chemoradiation therapy or perioperative chemotherapy.​[15][88]​​[135] Both approaches have been found to improve survival and R0 resection rates compared with surgery alone in patients with localized or locally advanced EAC.[154][183][184][185][186][187]

Plus – preoperative chemoradiation therapy

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
adenocarcinoma
Plus – 

preoperative chemoradiation therapy

Treatment recommended for ALL patients in selected patient group

The recommended initial treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is surgery plus preoperative chemoradiation therapy or perioperative chemotherapy.​[15][88][135]​ Both approaches have been found to improve survival and R0 resection rates compared with surgery alone in patients with localized or locally advanced EAC.[154][183][184][185][186][187]

The standard regimen for preoperative chemoradiation therapy is carboplatin plus paclitaxel plus radiation therapy (41.4 Gy in 23 fractions), based on the results from the CROSS trial.[154][184][185]​​​​ The other preferred regimen is fluorouracil plus oxaliplatin plus radiation therapy.[15] Other recommended regimens include: fluorouracil plus cisplatin plus radiation therapy; irinotecan plus cisplatin plus radiation therapy; and paclitaxel plus fluorouracil plus radiation therapy.​[15][88][175][176]​​​​ Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

Patients with resectable disease should proceed to surgery even after complete clinical tumor response to preoperative chemoradiation therapy, as data for a watch-and-wait strategy are limited.[88]

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

paclitaxel

OR

fluorouracil

and

oxaliplatin

Secondary options

fluorouracil

and

cisplatin

OR

irinotecan

and

cisplatin

OR

paclitaxel

and

fluorouracil

Consider – postoperative nivolumab

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
adenocarcinoma
Consider – 

postoperative nivolumab

Treatment recommended for SOME patients in selected patient group

Patients with localized disease who have residual pathologic disease despite complete surgical resection and preoperative chemoradiation therapy (i.e., ≥ypT1 or ypN1) are at high risk for recurrence, particularly if there is lymph node involvement.[201] These patients can be considered for postoperative treatment with nivolumab, an immune checkpoint inhibitor that blocks the programmed cell death-1 receptor (PD-1).[15][202][203]

In the CheckMate 577 study, nivolumab significantly improved disease-free survival compared with placebo in patients with localized or locally advanced disease who had residual pathologic disease following complete surgical resection and preoperative chemoradiation therapy (22.4 vs. 11.0 months).[202]​ Programmed death-ligand 1 (PD-L1) testing is not required for this indication.[88]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

1st line – surgery (esophagectomy)

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
adenocarcinoma
1st line – 

surgery (esophagectomy)

The recommended initial treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is surgery plus preoperative chemoradiation therapy or perioperative chemotherapy.​[15][88]​​[135] Both approaches have been found to improve survival and R0 resection rates compared with surgery alone in patients with localized or locally advanced EAC.[154][183][184][185][186][187]

Plus – perioperative chemotherapy

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
adenocarcinoma
Plus – 

perioperative chemotherapy

Treatment recommended for ALL patients in selected patient group

Perioperative chemotherapy is an alternative to preoperative chemoradiation therapy for locally advanced esophageal adenocarcinoma (EAC), with data strongly suggesting noninferiority.[15][88][135]​​ Both approaches have been found to improve survival and R0 resection rates compared with surgery alone in patients with localized or locally advanced EAC.[154][183][184][185][186][187]

The preferred perioperative chemotherapy regimens are fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), or a fluoropyrimidine (fluorouracil or capecitabine) plus oxaliplatin. The other option is fluorouracil plus cisplatin.​[15][88]

See local specialist protocol for dosing guidelines.

Primary options

fluorouracil

and

leucovorin

and

oxaliplatin

and

docetaxel

OR

fluorouracil

or

capecitabine

-- AND --

oxaliplatin

Secondary options

fluorouracil

and

cisplatin

Consider – postoperative nivolumab

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): suitable for surgery
|
adenocarcinoma
Consider – 

postoperative nivolumab

Treatment recommended for SOME patients in selected patient group

Patients with localized disease who have residual pathologic disease despite complete surgical resection and preoperative chemoradiation therapy (i.e., ≥ypT1 or ypN1) are at high risk for recurrence, particularly if there is lymph node involvement.[201] These patients can be considered for postoperative treatment with nivolumab, an immune checkpoint inhibitor that blocks the programmed cell death-1 receptor (PD-1).[15][202][203]

In the CheckMate 577 study, nivolumab significantly improved disease-free survival compared with placebo in patients with localized or locally advanced disease who had residual pathologic disease following complete surgical resection and preoperative chemoradiation therapy (22.4 vs. 11.0 months).[202]​ Programmed death-ligand 1 (PD-L1) testing is not required for this indication.[88]

See local specialist protocol for dosing guidelines.

Primary options

nivolumab

locally advanced disease (cT3-4, cN1-3, M0): unsuitable for surgery

1st line – definitive chemoradiation therapy

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): unsuitable for surgery
1st line – 

definitive chemoradiation therapy

Patients with locally advanced squamous cell carcinoma or adenocarcinoma who are unsuitable for surgery (e.g., those with tumors located in the cervical esophagus) or who decline surgery can be considered for definitive chemoradiation therapy.[135]

Randomized trials comparing definitive chemoradiation therapy versus surgery plus preoperative chemoradiation therapy in patients with locally advanced disease have reported similar survival outcomes, particularly among those with squamous cell carcinoma who achieved a complete response with chemoradiation therapy.[192][193][194]

Close monitoring is required following definitive chemoradiation therapy due to the risk of local tumor recurrence.[192][193]​ In the case of complete response to definitive chemoradiation therapy, a 3-month follow-up with endoscopy, biopsies, and computed tomography (CT) scan should be considered.[88]

Salvage esophagectomy can be considered in patients with persistent or progressive disease post chemoradiation therapy. It has been shown to be comparable in terms of outcomes to those with planned trimodality therapy in the setting of adenocarcinoma.[88][195][196]​ However, some data suggest increased morbidity for patients with esophageal squamous cell carcinoma.[197]

The first-line regimens for the chemotherapy backbone are: carboplatin plus paclitaxel; fluorouracil plus oxaliplatin; or fluorouracil plus leucovorin plus oxaliplatin (FOLFOX). Other options include: cisplatin plus fluorouracil; cisplatin plus docetaxel or paclitaxel; irinotecan plus cisplatin; or paclitaxel plus fluorouracil.​[15][88]​​​[154][156][175][176]​​​ Capecitabine is an alternative to fluorouracil for patients who are capable of swallowing tablets.

The radiation component of the treatment should be delivered using 3D conformal radiation treatment (RT) as a minimum, but intensity-modulated RT or volumetric arc therapy are preferred to better minimize the radiation dose to normal tissues such as the heart and lungs. There is little evidence to support the use of RT doses >50.4 Gy in the definitive treatment of esophageal cancer.[88]

If patients are unable to tolerate chemoradiation therapy they should be offered palliative radiation therapy or best supportive care.[15] 

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

paclitaxel

OR

fluorouracil

and

oxaliplatin

OR

leucovorin

and

fluorouracil

and

oxaliplatin

Secondary options

cisplatin

and

fluorouracil

OR

cisplatin

and

docetaxel

OR

cisplatin

and

paclitaxel

OR

irinotecan

and

cisplatin

OR

paclitaxel

and

fluorouracil

Consider – targeted therapy

Back
ACUTE
|
locally advanced disease (cT3-4, cN1-3, M0): unsuitable for surgery
Consider – 

targeted therapy

Treatment recommended for SOME patients in selected patient group

It is important that all patients with esophageal cancer undergo biomarker testing (e.g., for human epidermal receptor 2 [HER2], metastatic microsatellite instability-high [MSI-H], mismatch repair deficient [dMMR], and programmed death-ligand 1 [PD-L1] overexpression) to identify those suitable for targeted therapies.These agents may be used alone or in combination with chemotherapy.

Available preferred options include trastuzumab, nivolumab, and pembrolizumab. The preferred options for MSI-H/dMMR tumors include pembrolizumab (alone or in combination with fluoropyrimidine- and platinum-based chemotherapy), dostarlimab, and nivolumab (in combination with ipilimumab or fluoropyrimidine- and platinum-based chemotherapy).[15]

Trastuzumab (an anti-HER2 monoclonal antibody) is approved for use in patients with previously untreated metastatic HER2-positive adenocarcinoma, in combination with first-line platinum- and fluoropyrimidine-based chemotherapy.[15][114][158]​ In the ToGA trial, trastuzumab combined with chemotherapy (cisplatin plus either capecitabine or fluorouracil) improved survival (16.0 vs. 11.8 months) in patients with HER2-positive esophageal and gastric adenocarcinoma compared with chemotherapy alone.[114]

Pembrolizumab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) may be added to first-line therapy with a fluoropyrimidine, a platinum agent, and trastuzumab.[15][159]​​​ Pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy may be used for the first-line treatment of patients with squamous cell carcinoma or HER2-negative adenocarcinoma.​[15][88][159] In Europe, this approval is limited to patients with combined positive score (CPS) ≥10. In the KEYNOTE-859 study comprising patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma, the combination of pembrolizumab with chemotherapy has shown significant and clinically meaningful improvement in overall survival with manageable toxicity, compared with placebo.[160]

Nivolumab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) may be added to first-line treatment with fluoropyrimidine- and platinum-based chemotherapy for patients with HER2-negative advanced esophageal or esophagogastric junction adenocarcinoma.[15][159]​ The National Institute for Health and Care Excellence (NICE) in the UK recommends nivolumab after fluoropyrimidine and platinum-based therapy for the treatment of previously treated unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma in adults.[161]​ NICE further recommends nivolumab plus fluoropyrimidine-based and platinum-based therapy as an option in adults with untreated unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma whose tumors express PD‑L1 at a level of 1% or more when pembrolizumab plus chemotherapy is not found to be suitable.[162]​ Nivolumab is approved in combination with fluoropyrimidine- and platinum-based chemotherapy and in combination with ipilimumab for the first-line treatment of patients with advanced esophageal squamous cell carcinoma.[15][159]

Dostarlimab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) is approved for the treatment of patients with DNA mismatch repair-deficiency recurrent or advanced solid tumors that have progressed on or following prior treatment, who have no alternative treatment options, and who have not previously received a PD-1 or PD-L1 inhibitor.[15]

Second-line or subsequent therapy depends on prior therapy and performance status.[15]

See local specialist protocol for dosing guidelines.

Primary options

trastuzumab

OR

pembrolizumab

OR

nivolumab

OR

nivolumab

and

ipilimumab

OR

dostarlimab

metastatic (M1) disease

1st line – palliative chemotherapy

Back
ACUTE
|
metastatic (M1) disease
1st line – 

palliative chemotherapy

Patients with metastatic disease can be considered for chemotherapy, in addition to best supportive care. The decision to proceed with chemotherapy should be based on performance status, comorbidities, and patient preference.

Chemotherapy may improve symptoms, survival, and quality of life compared with best supportive care alone in patients with metastatic disease.[205][206]​ Most of the evidence supporting the use of chemotherapy in metastatic disease is extrapolated from randomized studies in patients with advanced/metastatic gastric adenocarcinoma.[205][206]

Two-drug chemotherapy regimens comprising a platinum agent (e.g., oxaliplatin or cisplatin) plus a fluoropyrimidine (e.g., fluorouracil or capecitabine) are typically recommended for first-line treatment in patients with metastatic disease.​​[15][88]​​ Studies suggest equivalence for oxaliplatin and cisplatin.[88] Oxaliplatin is usually preferred to cisplatin due to lower toxicity.[15][207]​ A reduced-dose oxaliplatin plus capecitabine regime is an option for older or frail patients who may be unsuitable for full-dose treatment.[88]

Adding a taxane (docetaxel) or anthracycline (epirubicin) to a two-drug regimen (i.e., triplet therapy) may be considered if a rapid response is required (e.g., to treat bulky and/or symptomatic disease). However, triplet therapy is associated with an increased risk of toxicity and adverse effects (e.g., myelosuppression, gastrointestinal toxicity, neuropathy, neutropenia); therefore, it is only suitable for fit patients with good performance status.[208][209][210]

Docetaxel combined with cisplatin plus fluorouracil has been shown to improve survival compared with cisplatin plus fluorouracil alone in patients with untreated advanced gastric cancer, although at the expense of increased toxicity.[209]

Epirubicin combined with cisplatin plus fluorouracil has been shown to improve survival compared with other triplet regimens (e.g., fluorouracil plus doxorubicin plus methotrexate; and mitomycin plus cisplatin plus fluorouracil) in patients with advanced esophagogastric cancer.[211][212]​​ However, there is controversy regarding the efficacy and safety of epirubicin-containing regimens, particularly when compared with standard two-drug regimens.[213]

Other triplet therapy regimens that can be considered for first-line treatment include leucovorin plus fluorouracil plus oxaliplatin (FOLFOX), and leucovorin plus fluorouracil plus irinotecan (FOLFIRI).[214][215][216]

Despite the benefits of triplet therapy, two-drug regimens are generally preferred due to lower toxicity.

Other options for first-line therapy include docetaxel plus cisplatin; paclitaxel plus cisplatin; paclitaxel plus carboplatin; or single-agent capecitabine, fluorouracil, docetaxel, or paclitaxel.[15]

Second-line and subsequent lines of treatments for metastatic disease are based on prior treatment and performance status.[15] 

See local specialist protocol for dosing guidelines.

Primary options

oxaliplatin

and

fluorouracil

OR

oxaliplatin

and

capecitabine

OR

cisplatin

and

fluorouracil

OR

cisplatin

and

capecitabine

OR

docetaxel

and

cisplatin

and

fluorouracil

OR

docetaxel

and

cisplatin

OR

paclitaxel

and

cisplatin

OR

paclitaxel

and

carboplatin

OR

fluorouracil

and

leucovorin

and

oxaliplatin

OR

fluorouracil

and

leucovorin

and

irinotecan

OR

capecitabine

OR

fluorouracil

OR

docetaxel

OR

paclitaxel

Plus – best supportive care

Back
ACUTE
|
metastatic (M1) disease
Plus – 

best supportive care

Treatment recommended for ALL patients in selected patient group

Patients may have symptoms secondary to the local and systemic effects of malignancy, such as dysphagia, esophageal obstruction, pain, bleeding, and malaise, in addition to underlying comorbidities. Palliation of symptoms and maintaining quality of life is, therefore, central to managing patients with metastatic disease.

Dysphagia and esophageal obstruction may be relieved using palliative radiation therapy (external beam radiation therapy or brachytherapy) or self-expanding metallic stent insertion, depending on the degree of dysphagia and its impact on nutrition, quality of life, performance status, and prognosis.​​[15][88][137]​​ The National Institute for Health and Care Excellence in the UK advises against routine use of external beam radiation therapy after stent placement in patients with esophageal cancer and recommends that it should only be used in those with esophageal cancer having prolonged post-interventional bleeding or a known bleeding disorder. If there is complete obstruction, endoscopic lumen restoration should be performed via simultaneous retrograde and anterograde enteroscopy.[15] Severe obstruction should be relieved with wire-guided dilation or balloon dilation and insertion of an expandable metal stent.[15] These options should be considered for moderate obstruction, balancing the associated risks and benefits.[15] Photodynamic therapy may be effective but is less commonly used due to associated photosensitivity and costs.[15] Surgery may be useful in carefully selected patients.[15]

Nutritional status should be optimized with dietetic input (including dietary advice, nutritional supplements, and, if appropriate, short-term enteral feeding).

Consider – targeted therapy

Back
ACUTE
|
metastatic (M1) disease
Consider – 

targeted therapy

Treatment recommended for SOME patients in selected patient group

It is important that all patients with esophageal cancer undergo biomarker testing (e.g., for human epidermal receptor 2 [HER2], metastatic microsatellite instability-high [MSI-H], mismatch repair deficient [dMMR], and programmed death-ligand 1 [PD-L1] overexpression) to identify those suitable for targeted therapies.These agents may be used alone or in combination with chemotherapy, depending on the drug. Available preferred options include trastuzumab, nivolumab, and pembrolizumab. The preferred treatment options for MSI-H/dMMR tumors include pembrolizumab (alone or in combination with fluoropyrimidine- and platinum-based chemotherapy), dostarlimab, and nivolumab (in combination with ipilimumab or fluoropyrimidine- and platinum-based chemotherapy).

Trastuzumab (an anti-HER2 monoclonal antibody) is approved for use in patients with previously untreated metastatic HER2-positive adenocarcinoma, in combination with first-line platinum- and fluoropyrimidine-based chemotherapy.[15][114][158]​ In the ToGA trial, trastuzumab combined with chemotherapy (cisplatin plus either capecitabine or fluorouracil) improved survival (16.0 vs. 11.8 months) in patients with HER2-positive esophageal and gastric adenocarcinoma compared with chemotherapy alone.[114]

Pembrolizumab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) may be added to first-line therapy with a fluoropyrimidine, a platinum agent, and trastuzumab for patients with HER2-positive adenocarcinoma.[15][159] Pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy may be used for the first-line treatment of patients with squamous cell carcinoma or HER2-negative adenocarcinoma.[15][88][159] In Europe, this approval is limited to patients with combined positive score ≥10. In the KEYNOTE-859 study comprising patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma, the combination of pembrolizumab with chemotherapy has shown significant and clinically meaningful improvement in overall survival with manageable toxicity, compared with placebo.[160]

Nivolumab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) may be added to first-line treatment with fluoropyrimidine- and platinum-based chemotherapy for patients with HER2-negative advanced esophageal or esophagogastric junction adenocarcinoma.[15][159] The National Institute for Health and Care Excellence (NICE) in the UK recommends nivolumab after fluoropyrimidine and platinum-based therapy for the treatment of previously treated unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma in adults.[161] NICE further recommends nivolumab plus fluoropyrimidine-based and platinum-based therapy as an option in adults with untreated unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma whose tumors express PD‑L1 at a level of 1% or more when pembrolizumab plus chemotherapy is not found to be suitable.[162] Nivolumab is approved in combination with fluoropyrimidine- and platinum-based chemotherapy and in combination with ipilimumab for the first-line treatment of patients with advanced esophageal squamous cell carcinoma.[15][159]

Dostarlimab (a PD-1-blocking monoclonal antibody [immune checkpoint inhibitor]) is approved for the treatment of patients with DNA mismatch repair-deficiency recurrent or advanced solid tumors that have progressed on or following prior treatment, who have no alternative treatment options, and who have not previously received a PD-1 or PD-L1 inhibitor.[15]

Second-line or subsequent therapy depends on prior therapy and performance status.[15] 

See local specialist protocol for choice of regimen and dosing guidelines.

Primary options

trastuzumab

OR

pembrolizumab

OR

nivolumab

OR

nivolumab

and

ipilimumab

OR

dostarlimab

ONGOING

recurrent disease

1st line – surgery or chemoradiation therapy or chemotherapy and/or palliative/best supportive care

Back
ONGOING
|
recurrent disease
|
locoregional recurrence
1st line – 

surgery or chemoradiation therapy or chemotherapy and/or palliative/best supportive care

Patients with locoregional recurrence that occurs subsequent to chemoradiation therapy can be considered for surgery if the tumor is resectable (depending on performance status and patient preference).

Patients with locoregional recurrence that occurs following surgery without the use of chemoradiation therapy can be considered for chemoradiation therapy, surgery, chemotherapy, and palliative care/best supportive care (depending on performance status and patient preference).

Patients may have symptoms secondary to the local and systemic effects of malignancy, such as dysphagia, esophageal obstruction, pain, bleeding, and malaise, in addition to underlying comorbidities. Palliation of symptoms and maintaining quality of life is, therefore, central to managing patients with metastatic disease.

Dysphagia and esophageal obstruction may be relieved using palliative radiation therapy (external beam radiation therapy or brachytherapy) or self-expanding metallic stent insertion, depending on the degree of dysphagia and its impact on nutrition, quality of life, performance status, and prognosis.​​[15][88][137]​​ The National Institute for Health and Care Excellence in the UK advises against routine use of external beam radiation therapy after stent placement in patients with esophageal cancer and recommends that it should only be used in those with esophageal cancer having prolonged post-interventional bleeding or a known bleeding disorder.[137] If there is complete obstruction, endoscopic lumen restoration should be performed via simultaneous retrograde and anterograde enteroscopy.[15] Severe obstruction should be relieved with wire-guided dilation or balloon dilation and insertion of an expandable metal stent.[15] These options should be considered for moderate obstruction, balancing the associated risks and benefits.[15] Photodynamic therapy may be effective but is less commonly used due to associated photosensitivity and costs.[15] Surgery may be useful in carefully selected patients.[15]

Nutritional status should be optimized with dietetic input (including dietary advice, nutritional supplements, and, if appropriate, short-term enteral feeding).

1st line – palliative/best supportive care

Back
ONGOING
|
recurrent disease
|
unresectable or metastatic recurrence
1st line – 

palliative/best supportive care

Patients with unresectable recurrent disease or metastatic disease that occurs following treatment can be considered for palliative/best supportive care (including systemic and targeted therapies).

Patients may have symptoms secondary to the local and systemic effects of malignancy, such as dysphagia, esophageal obstruction, pain, bleeding, and malaise, in addition to underlying comorbidities. Palliation of symptoms and maintaining quality of life is, therefore, central to managing patients with metastatic disease.

Dysphagia and esophageal obstruction may be relieved using palliative radiation therapy (external beam radiation therapy or brachytherapy) or self-expanding metallic stent insertion, depending on the degree of dysphagia and its impact on nutrition, quality of life, performance status, and prognosis.​[15][88][137]​​​ The National Institute for Health and Care Excellence in the UK advises against routine use of external beam radiation therapy after stent placement in patients with esophageal cancer and recommends that it should only be used in those with esophageal cancer having prolonged post-interventional bleeding or a known bleeding disorder.[137] If there is complete obstruction, endoscopic lumen restoration should be performed via simultaneous retrograde and anterograde enteroscopy.[15] Severe obstruction should be relieved with wire-guided dilation or balloon dilation and insertion of an expandable metal stent.[15] These options should be considered for moderate obstruction, balancing the associated risks and benefits.[15] Photodynamic therapy may be effective but is less commonly used due to associated photosensitivity and costs.[15] Surgery may be useful in carefully selected patients.[15]

Nutritional status should be optimized with dietetic input (including dietary advice, nutritional supplements, and, if appropriate, short-term enteral feeding).

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