Esophageal Cancer: Pharmacologic Management

Esophageal cancer accounts for 1.1% of all cancer cases and is the 11th leading cause of cancer death in the United States.^1-3 Esophageal cancer is more than 3 times more prevalent in men than in women. In 2023, 17,030 and 4530 new cases are expected to be diagnosed in men and women, respectively.³ Esophageal cancer is predominantly seen in older populations, as reflected by a median age of onset of 68 years.¹ 

Risk factors contributing to the development of esophageal cancer include older age, heavy alcohol consumption, and smoking.¹ Life expectancy for individuals with esophageal cancer depends on numerous factors, including stage of cancer at diagnosis and comorbid conditions.  Currently, the median age at death for patients with esophageal cancer is 70 years.¹ Overall survival rates for individuals with esophageal cancer have improved significantly over the past half century as a result of effective treatment modalities; however, socioeconomic disparities continue to present a barrier to patients with lower income receiving timely treatment, resulting in the highest death rates from esophageal cancer for these patients.⁴  

Esophageal cancer is typically categorized as esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAC). ESCCs originate in the upper esophagus, while EACs emanate from the gland cells of the middle to lower esophagus. Additionally, esophagogastric junction carcinomas occur in the lowest portion of the esophagus. Although a much rarer type, these malignancies are treated similarly to EACs.^1-3,5

The primary symptom of esophageal cancer is dysphagia (difficulty swallowing), mouth pain, and blood upon coughing or in the stool. The process of gastric acid coming into contact with the esophageal lining is a significant contributing factor to the development of EACs and esophagogastric junction cancer. Patients with esophageal cancer can also experience symptoms of acid reflux and other signs of stomach discomfort. Diagnosis usually occurs through endoscopy and biopsy. Although early diagnosis improves prognosis, symptoms usually only occur in advanced disease. Most pharmacologic interventions are recommended at more advanced stages of disease.^1-3,5

Staging of Esophageal Cancer

Staging for esophageal cancers depends on 3 primary features: the size and spread of the tumor (T), the extent to which the tumor has invaded the local lymph nodes (N), and whether the tumor has metastasized or spread to distant organs of the body (M). Numbers after the letter denote the severity of each feature. Generally, higher numbers indicate more severe illness. Esophageal cancer tumors also have a histologic grade. Higher grades indicate a less differentiated, more pathologic cellular morphology. Criteria for staging are similar between ESCC and EAC, but any differences will be noted below.⁶

• Stage 0: Tumor is contained to the epithelium of the esophagus. No lymph nodes have been affected, and there is no metastasis. Stage is Tis, N0, M0. Grade is 1.
• Stage I: Tumor has spread into the surrounding submucosa of the esophagus or the smooth and skeletal muscles surrounding the esophagus. No lymph nodes have been affected, and there is no metastasis. Stage is T1-T2, N0, M0. Grade is 1 for ESCC. For EAC, the grade can be 2 or 3 in T1 tumors or 1 or 2 in T2 tumors.
• Stage II: Tumor has spread into the adventitia, which is the surrounding connective tissue. No lymph nodes have been affected, and there is no metastasis. Stage is T1-4, N0, M0. Grade can be 1-3.
• Stage III: Tumor has spread extensively into the surrounding organs or it has invaded the surrounding lymph nodes. There is no metastasis. Grade is T1-4a, N1-N2, M0. N0 can occur with T4a tumors.
• Stage IV: Tumor has either extensively spread to surrounding tissues and lymph nodes or the cancer has metastasized. Staging is Tis-T4b, N0-N2, M1. EACs can have an N3 rating with more than 6 affected lymph nodes.⁶

Esophageal Cancer Treatment Types

Esophageal cancer is treated with endoscopic techniques and surgery early in the disease. As the disease progresses, chemotherapy with radiation (chemoradiation) will also be used. Treatments include:

• Neoadjuvant therapies (treatment administered before surgery),
• Perioperative therapies (treatment administered at the time of surgery),
• Postoperative or adjuvant therapies (treatment administered following surgery), and 
• Definitive therapies (treatment administered without surgery).

For any of these treatment strategies, chemotherapy, immunotherapy, and targeted therapy may be used alone as a single agent or in a regimen with other treatments. We will review medications approved by the US Food and Drug Administration (FDA), as well as those recommended by the National Comprehensive Cancer Network (NCCN).^5,7-9

Chemotherapy

Chemotherapy agents harm or inhibit DNA synthesis, causing fast-growing cells to undergo apoptosis (programmed cell death).^5,7 The following are commonly used chemotherapy agents for treating esophageal cancer:

• Capecitabine
• Carboplatin
• Docetaxel
• Fluorouracil
• Oxaliplatin
• Paclitaxel

Additionally, in treatments containing fluorouracil, leucovorin is used to help mitigate toxicity.⁵  Although carboplatin, docetaxel, fluorouracil, oxaliplatin, and paclitaxel are not approved by FDA for use in patients with esophageal cancer, they are indicated as first-line recommendations by the NCCN.⁵

Immunotherapy

Immunotherapy represents a broad category of treatments that stimulate the immune system to eliminate cancer cells. These include monoclonal antibody therapies for esophageal cancer. Nivolumab and pembrolizumab function by inhibiting the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway, which protects cancer cells from the immune system.^5,8 The following are commonly used chemotherapy agents for treating esophageal cancer:

• Ipilimumab
• Nivolumab
• Pembrolizumab

Targeted Therapy

Targeted therapy is intended to kill cancer cells by interfering with specific genetic and molecular processes. These can include monoclonal antibodies — such as ramucirumab and trastuzumab — that block pathways upregulated in certain cancers. These also include antibody-drug conjugates such as fam-trastuzumab deruxtecan-nxki.^5,9 The following targeted therapies are used for the treatment of esophageal cancer:

• Fam-trastuzumab deruxtecan-nxki
• Ramucirumabr 
• Trastuzumab

Combination Therapy

Multiple chemotherapeutic agents in combination with or without immunotherapy and targeted therapy are used for the treatment of esophageal cancer.^5,10 The following are commonly used combination therapies:

• FU-LV: Leucovorin calcium and fluorouracil
• XELIRI: Capecitabine and irinotecan hydrochloride
• Paclitaxel with carboplatin
• Fluorouracil with oxaliplatin
• FLOT: Fluorouracil, leucovorin, oxaliplatin, and docetaxel
• Fluoropyrimidine with oxaliplatin and nivolumab
• Fluoropyrimidine with oxaliplatin and trastuzumab
• Ramucirumab with paclitaxel
• Fluorouracil with irinotecan

Esophageal Cancer Treatments

Table 1. Management Guidelines for Chemotherapy for Esophageal Cancer

Drug	Dose	Administration	Treatment Duration	Recommended Use
Capecitabine	850-100 mg/m2 of body surface area taken twice daily on days 1-14 of 3-wk cycle	Oral tablets	Every 3 wk for 6 mo	Advanced stage IV disease; HER2-positive with no previous capecitabine-containing treatment
Carboplatin*	AUC 2 or AUC 5; administered with paclitaxel	IV infusion	Every wk for 5 wk	Neoadjuvant treatment during RT; advanced stage IV disease
Docetaxel†	75 mg/m2 (day 1) prior to cisplatin (day 1) and fluorouracil (daily)	IV infusion over 1 h	5-d treatment every 3 wk	Advanced disease in adenocarcinoma  in esophageal junction
Fluorouracil*	200-1200 mg/m2 daily over 24 h	IV infusion over 24 h	Every 2 wk	Stages I-IV for all types of esophageal cancer
Irinotecan hydrochloride	150 mg/m2 on day 1 for 2-wk cycle; 125 mg/m2 on days 1 and 8 of 2-wk cycle; 250-350 mg/m2 on day 1 of 3-wk cycle	IV infusion	2-wk or 3-wk cycle	See table 4
Oxaliplatin*	85 mg/m2 on day 1 of 14-d cycle	IV infusion	Every 2 wk for 3 cycles	Neoadjuvant treatment during RT
Paclitaxel*	50 mg/m2 on day 1 administered with carboplatin	IV infusion	Every wk for 5 wk	Neoadjuvant treatment during RT; advanced stage IV disease
Trifluridine and tipiracil hydrochloride	35 mg/m2 twice daily on days 1- 5 and days 8-12 of 28-d cycle	Oral tablets	Until disease worsens or toxicity is intolerable	Systemic treatment for advanced stage IV disease; used after patient has already received combination chemotherapy treatment

HER2 = human epidermal growth factor receptor-2; IV= intravenous; RT = radiation treatment; AUC = area under the curve.

*Not approved by the FDA for use in esophageal cancer but first-line recommendation by the NCCN.

†Not recommended by the NCCN.

From FDA-approved prescribing information or NCCN.^5,9-20

Table 2. Management Guidelines for Immunotherapy for Esophageal Cancer

Drug	Dose	Administration	Treatment Duration	Recommended Use
Ipilimumab	1 mg/kg	IV infusion over 30 min	Every 6 wk combined with 2-3 doses of nivolumab until disease worsens or intolerable toxicity; maximum 2 y	Advanced stage IV disease; ESCC
Nivolumab	240 mg every 2 wk or 280 mg every 4 wk; in regimen with ipilimumab 3 mg/kg every 2 wk or 360 mg total every 3 wk	IV infusion over 30 min	Every 2 wk or 4 wk if administered alone or with chemotherapy; every 2 or 3 wk if administered with ipilimumab; until disease worsens or intolerable toxicity; maximum 1 y	Adjuvant therapy in advanced stage IV disease; ESCC
Pembrolizumab	200 mg every 3 wk or 400 mg every 6 wk	IV infusion over 30 min	Every 3 or 6 wk until disease worsens or toxicity becomes intolerable; maximum 2 y	Advanced stage IV disease in combination with chemotherapy; ESCC that expresses PD-L1 and has already been treated with ≥1 systemic chemotherapy

ESCC = esophageal squamous cell carcinoma; IV= intravenous; PD-1 = programmed death-1.

From FDA-approved prescribing information.^5,21-24

Table 3. Management Guidelines for Targeted Therapy for Esophageal Cancer

Drug	Dose	Administration	Treatment Duration	Recommended Use
Fam-trastuzumab deruxtecan-nxki	6.4 mg/kg	IV infusion	Every 3 wk until disease worsens or intolerable toxicity	Stage II or III; patients with stage IV HER2-positive disease who have received trastuzumab regimen
Ramucirumab	8 mg/kg either alone or with paclitaxel	IV infusion	Every 2 wk	Stage IV gastroesophageal junction adenocarcinoma
Trastuzumab	8 mg/kg first dose followed by 6 mg/kg subsequent doses	IV infusion over 90 min for the first dose and over 30-90 min for subsequent doses	Every 3 wk	Stage IV gastroesophageal junction adenocarcinoma

HER2 = human epidermal growth factor receptor-2; IV= intravenous.

From FDA-approved prescribing information.^5,25-27

Table 4. Management Guidelines for Combination Therapy for Esophageal Cancer

Drug Regimen	Dose	Administration	Treatment Duration	Recommended Use
FU-LV	Leucovorin 400 mg/m2 on day 1, fluorouracil 400 mg/m2 IV push on day 1, and continuous IV fluorouracil 1200 mg/m2 on days 1 and 2	IV infusion except on day 1 when fluorouracil IV push is used	Every 2 wk	Stages I-IV any time fluorouracil is recommended
XELIRI*	Irinotecan 130 mg/m2 on days 1 and 15 and capecitabine 1750 mg twice daily on days 1-15	IV infusion of irinotecan; capecitabine taken orally	Every 22 d until disease worsens or intolerable toxicity	Stage IV
Paclitaxel with carboplatin†	Paclitaxel 200 mg/m2 and carboplatin AUC 5 on day 1	IV infusion	Every 3 wk	Stages I-IV with radiation
Fluorouracil with oxaliplatin†	Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and fluorouracil 500 mg/m2 IV push on day 1; continuous IV fluorouracil 1200 mg/m2 on days 1 and 2	IV infusion of oxaliplatin and leucovorin with fluorouracil IV push on day 1; continuous IV infusion of fluorouracil on days 1 and 2	Every 2 wk	Stages I-IV with radiation
FLOT†	Fluorouracil 2600 mg/m2, leucovorin 200 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2 on day 1	Continuous IV infusion of fluorouracil over 24 h; IV infusion of others	Every 2 wk	Perioperative chemotherapy for EAC stages I-III with larger T1b or T2 tumors
Fluoropyrimidine with oxaliplatin and nivolumab†	Nivolumab 360 mg and oxaliplatin 130 mg/m2 on day 1, capecitabine 850-1000 mg/m2 on days 1–14Nivolumab 240 mg, oxaliplatin 85 mg/m2, and leucovorin 400 mg/m2 IV on day 1, fluorouracil 400 mg/m2 IV push on day 1, and continuous IV fluorouracil 1200 mg/m2 on days 1 and 2	IV infusion for nivolumab, oxaliplatin, leucovorin, and continuous fluorouracil; capecitabine is taken orally; and fluorouracil IV push on day 1	Every 3 wk with capecitabine and every 2 wk with fluorouracil; up to 2 y	Stage IV
Fluoropyrimidine with oxaliplatin and pembrolizumab†	Pembrolizumab 200 mg and oxaliplatin 130 mg/m2 on day 1, capecitabine 850-1000 mg/m2  on days 1–14Pembrolizumab 200 mg, oxaliplatin 85 mg/m2, and leucovorin 400 mg/m2 on day 1, fluorouracil 400 mg/m2  IV push on day 1, and continuous IV fluorouracil 1200 mg/m2 on days 1 and 2	IV infusion for pembrolizumab, oxaliplatin, leucovorin, and continuous fluorouracil; capecitabine is taken orally; and fluorouracil IV push on day 1	Every 3 wk and up to 6 cycles with capecitabine; every 2 wk and up to 9 cycles with fluorouracil	Stage IV and PD-L1-positive
Fluoropyrimidine with oxaliplatin and trastuzumab with or without pembrolizumab†	Administered with fluoropyrimidine with oxaliplatin For capecitabine regime, trastuzumab 8 mg/kg on day 1 of cycle 1 followed by 6 mg/kg on subsequent day 1 For fluorouracil regime, trastuzumab 6 mg/kg on day 1 of cycle 1 and 4 mg/kg on subsequent day 1	IV infusion for trastuzumab, oxaliplatin, leucovorin, and continuous fluorouracil; capecitabine is taken orally; and fluorouracil IV push on day 1	Every 3 wk with capecitabine and every 2 wk with fluorouracil	Stage IV and HER-positive; pembrolizumab used if PD-L1-positive
Ramucirumab with paclitaxel†	Ramucirumab 8 mg/kg on days 1 and 15 and 80 mg/m2 on days 1, 8, and 15	IV infusion	Every 28 d	Recurrent adenocarcinomas and esophageal junction adenocarcinoma
Fluorouracil with irinotecan†	Irinotecan 180 mg/m2 and leucovorin 400 mg/m2 on day 1, fluorouracil 400 mg/m2  IV push on day 1, and continuous IV fluorouracil 1200 mg/m2 on days 1 and 2	IV infusion except fluorouracil IV push on day 1	Every 2 wk	Recurrent esophageal cancers

AUC = area under the curve; HER = human epidermal growth factor receptor; IV= intravenous; EAC = esophageal adenocarcinoma; FU-LV = leucovorin calcium and fluorouracil; XELIRI = capecitabine and irinotecan hydrochloride; FLOT = fluorouracil, leucovorin, oxaliplatin, and docetaxel; PD-L1 = programmed death ligand-1.

*Not recommended in any context by the NCCN.

†Not approved by the FDA for use in esophageal cancer but first-line recommendation by the NCCN.

From FDA-approved prescribing information.^5,10,20

Monitoring Side Effects of Esophageal Cancer Treatment

Importantly, in esophageal cancer, the FDA-approved treatments and regimens are not always best practices. Furthermore, some recommendations are given based on side-effect profiles. The following tables review the major side effects for each drug used for esophageal cancer. All of the listed drugs are approved by the FDA but not all are approved specifically in the setting of esophageal cancer.

Table 5. Side Effect Profiles for Chemotherapy for Esophageal Cancer

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug-Drug Interactions	Special Populations
Capecitabine	Palmar-planter erythrodysesthesia (hand and foot syndrome), vomiting, abdominal pain, nausea, fatigue, increased bilirubin	Pathologic blood clotting, DPD deficiency, kidney failure, hand and foot syndrome, increased bilirubin, decreased neutrophils	Anticoagulants; phenytoin; leucovorin can increase toxicity of fluorouracil in combination therapy; CYP2C9 substrates; allopurinol should be avoided	Not recommended in pregnant or lactating individuals; increased incidence of adverse events in geriatric population; individuals with kidney disease should be administered lower dose
Carboplatin*	Low platelet count, low neutrophil count, low leukocyte count, anemia, nausea, vomiting, neurotoxicity, increased alkaline phosphatase, decreased magnesium, weakness, general pain	Low platelet count, low neutrophil count, low leukocyte count, low red blood cells	Drugs processed through the kidneys should be used with caution	Could cause harm to fetus; breastfeeding is not recommended
Docetaxel	Decreased neutrophils, anemia, neutropenia-induced fever, low platelet count, nerve damage, allergic reactions, taste alterations, difficulty breathing, constipation, diarrhea, severe weight loss, nail disorders, weakness, fluid retention, hair loss, nausea, vomiting, inflammation of the mouth or stomach, skin reactions, muscle pain	Secondary cancers, severe skin reactions, neurologic disorders, eye disorders, severe weakness, alcohol consumption	Inducers, substrates, and inhibitors of cytochrome P450 3A4	Could cause harm to fetus; breastfeeding is not recommended until 1 wk after last dose; infertility possible; male and female patients should use contraception for 3 mo and 6 mo following treatment, respectively; increased risk of liver, kidney, and heart complications in geriatric population; not recommended for patients with liver disease
Fluorouracil*	Low DPD, cardiotoxicity, ammonia-induced swelling of the brain, neurologic toxicity, diarrhea, hand and foot syndrome, mouth inflammation, myelosuppression, increased risk of elevated INR with anticoagulants	Low DPD, cardiotoxicity, ammonia-induced swelling of the brain, neurologic toxicity, diarrhea, hand and foot syndrome, mouth inflammation, myelosuppression, increased risk of elevated INR with anticoagulants	Anticoagulants and CYP2C9 substrates	Could cause harm to fetus; breastfeeding is not recommended; infertility possible for both men and women; contraception is recommended for sexually active individuals; female patients should refrain from getting pregnant for 3 mo following treatment
Irinotecan hydrochloride	Abdominal pain, nausea, vomiting, diarrhea, constipation, anorexia, neutrophil deficiency, decreased leukocytes and lymphocytes, anemia, weakness, fever, weight loss, hair loss	Diarrhea, reduced bone marrow activity and blood cell count, severe allergic reaction, kidney disease, lung disease, liver disease	CYP3A4 inducers and inhibitors	Could cause harm to fetus; breastfeeding is not recommended until 7 days after final dose of treatment; infertility possible for both men and women; contraception recommended for sexually active individuals; female patients should refrain from getting pregnant for 6 mo following treatment; increased risk of diarrhea in geriatric population; not recommended for individuals with kidney or liver disease; individuals with certain UGT1A1 mutations are at increased risk for neutrophil deficiency
Oxaliplatin*	Nerve damage in the hands and feet, low neutrophil count, low platelet count, anemia, elevated transaminases and alkaline phosphatase, diarrhea, vomiting, tiredness, mouth ulcers	Nerve damage in the hands and feet, low neutrophil count, PRES, lung toxicity, liver toxicity, QT interval lengthening, rhabdomyolysis, hemorrhage	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 3 mo after final dose of treatment; not recommended for sexually active female patients until 9 mo and male patients until 6 mo after treatment; could cause infertility for both men and women; geriatric population is more susceptible to side effects
Paclitaxel*	Reduced neutrophils, low platelet count, anemia, allergic reactions, abnormal ECG, peripheral nerve damage, tiredness, nausea, vomiting, diarrhea, mouth inflammation, hair loss, elevated bilirubin, elevated alkaline phosphatase	Allergic reactions, low neutrophil count, anemia	None indicated	Not recommended during pregnancy
Trifluridine and tipiracil hydrochloride	Anemia, neutrophil deficiency, fatigue, nausea, reduced platelet count, reduced hunger, diarrhea, vomiting, fever	Severe myelosuppression	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 1 d after final dose of treatment; infertility possible for both men and women; contraception recommended for sexually active female patients for 6 mo after treatment and for male patients for 3 mo after treatment; decreased neutrophils and platelet count and increased incidence of anemia in geriatric population; reduced dose recommended for individuals with kidney disease; not recommended for individuals with moderate to severe liver disease

DPD = dihydropyrimidine dehydrogenase; INR = International normalized ratio; PRES = posterior reversible encephalopathy syndrome; ECG = electrocardiogram.

*Not approved by the FDA for use in esophageal cancer but first-line recommendation by the NCCN.

From FDA-approved prescribing information.^11-19

Table 6. Side Effect Profiles for Immunotherapy for Esophageal Cancer

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug-Drug Interactions	Special Populations
Ipilimumab	Fatigue, rash, itchy skin, diarrhea, nausea, muscle  pain, fever, cough, reduced hunger, vomiting, abdominal discomfort, difficulty breathing, upper respiratory tract infection, joint pain, headache, underactive thyroid, constipation, weight loss, dizziness	Hepatitis, rash, pituitary inflammation, adrenal insufficiency, overactive thyroid, underactive thyroid, thyroiditis, type 1 diabetes, lung inflammation, kidney dysfunction, colitis	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 3 mo after final dose of treatment; not recommended for sexually active female patients until 3 mo after treatment
Nivolumab	Fatigue, rash, itchy skin, muscle pain, diarrhea, nausea, constipation, labored breathing, cough, weakness, reduced hunger, back pain, joint pain, upper respiratory tract infection, fever, headache, abdominal discomfort, vomiting, UTI	Lung inflammation, colitis, hepatitis, adrenal insufficiency, pituitary gland inflammation, thyroiditis, overactive thyroid, underactive thyroid, type 1 diabetes, kidney dysfunction, rash, infusion reactions, reactions to stem-cell implantation	None indicated	Could cause harm to fetus; breastfeeding should only be performed 5 mo after discontinuation of use
Pembrolizumab	Fatigue, musculoskeletal discomfort, itchy skin, rash, nausea, reduced hunger, hyperglycemia, anemia, reduced lymphocytes, hypoalbuminemia, low serum sodium, elevated alkaline phosphatase, elevated creatinine, reduced phosphate, elevated AST, elevated serum potassium, low serum calcium	Lung inflammation, colitis, hepatitis, adrenal insufficiency, inflammation of the pituitary gland, thyroiditis, overactive thyroid, underactive thyroid, type 1 diabetes, kidney dysfunction, rash, infusion reactions, reactions to stem-cell implantation	None indicated	Could cause harm to fetus; breastfeeding should only be performed 4 mo after discontinuation of use

AST = aspartate aminotransferase; UTI = urinary tract infection.

From FDA-approved prescribing information.^21-24

Table 7. Side Effect Profiles for Targeted Therapy for Esophageal Cancer

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug-Drug Interactions	Special Populations
Fam-trastuzumab deruxtecan-nxki	Reduced hemoglobin, reduced white blood cells, reduced neutrophils, reduced lymphocytes, reduced platelets, nausea, decreased appetite, elevated ALT and AST, fatigue, elevated blood alkaline phosphatase, diarrhea, low serum potassium, vomiting, constipation, elevated blood bilirubin, fever, hair loss	Reduced neutrophils, LVEF, CHF	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 7 mo after final dose of treatment; check pregnancy status of female patients and advise use of contraception during treatment and for 7 mo after last dose; advise use of contraception during treatment and for 4 mo after last does for male patients
Ramucirumab	Hypertension, diarrhea	Hemorrhage, perforations in the GI tract, slow wound healing, ATEs, hypertension, IRR, worsening of liver dysfunction, PRES, proteinuria, thyroid dysfunction	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 2 mo after final dose of treatment; check pregnancy status of female patients and advise use of contraception during treatment and for 3 mo after last dose; could cause infertility in female patients; geriatric population could be more susceptible to side effects
Trastuzumab	Decreased neutrophils, diarrhea, fatigue, anemia, mouth ulcers, weight loss, upper respiratory tract infections, fever, low platelet count, mucosal inflammation, infection of nose and throat, taste disorder	Cardiomyopathy, LVEF, anaphylaxis, skin swelling, lung scarring, ARDS	Anthracyclines should be avoided for 7 mo	Could cause harm to fetus; breastfeeding is not recommended until 7 mo following treatment;  check pregnancy status of female patients and advise use of contraception during treatment and for 7 mo after last dose

ALT = elevated alanine aminotransferase; ARDS = acute respiratory distress syndrome; AST = aspartate aminotransferase; ATE = arterial thromboembolic events; CHF = congestive heart failure; GI = gastrointestinal; IRR = infusion-related reactions; LVEF = left ventricular dysfunction; PRES = posterior reversible encephalopathy syndrome.

From FDA-approved prescribing information.^25-27

Guidelines for the Management of Esophageal Cancer

Generally, early stages of esophageal cancer are treated with endoscopic procedures or esophagectomy (partial surgical resection of the esophagus). As the tumor progresses and the disease advances, neoadjuvant and adjuvant chemoradiation are recommended. Metastasized disease is treated systemically or with chemoradiation alone. For regimens involving chemotherapy, oxaliplatin is recommended over cisplatin due to tolerability. In chemotherapy recommendations that involve a fluoropyrimidine, fluorouracil or capecitabine is acceptable. Because of fluorouracil shortages, capecitabine is the preferred alternative.⁵

Stage 0

This local, nonadvanced stage is usually considered precancerous.  Endoscopic resection strategies are usually recommended for any abnormal masses in any section of the esophagus.

Stage 1

Tumors with T1 classifications can sometimes be fully eradicated via endoscopic removal; however, they usually require more invasive surgical procedures such as an esophagectomy.²⁸ If there are still cancerous cells remaining following, adjuvant therapy with chemoradiation is recommended.

Following esophagectomy of T1a and T1b tumors, ESCC and EAC are assessed for how much tumor remains following resection. R0 resections, fully removed tumors, require only postoperative surveillance. R1 resections with leftover microscopic cancer cells require adjuvant fluoropyrimidine-based (fluorouracil or capecitabine) chemoradiation. R2 resections with leftover macroscopic cancer cells or masses require either adjuvant fluoropyrimidine-based chemoradiation or palliative care.⁵

In patients with T2 tumor classifications, neoadjuvant chemoradiation is recommended prior to the esophagectomy. If the tumor measures less than 2 cm, surgery alone may be recommended²⁸ with the same resection surveillance guidance as T1a and T1b tumors.⁵ For ESCC tumors, chemoradiation alone may be recommended. For EAC tumors, chemotherapy at the time of surgery may be recommended without radiation. Patients who cannot undergo surgery may opt for chemoradiation and/or endoscopic procedures.²⁸

Squamous Cell Carcinomas

Neoadjuvant chemoradiation is preferred prior to esophagectomy of ESCC T2 tumors larger than 3 cm. Paclitaxel with carboplatin and fluorouracil with oxaliplatin are the chosen treatment regimens with radiation. In cases where definitive chemoradiation, chemoradiation alone, is necessary, the same treatment regimens are advised.⁵

Adenocarcinomas

Neoadjuvant chemoradiation is preferred prior to esophagectomy of EAC T2 tumors larger than 3 cm. Paclitaxel with carboplatin and fluorouracil with oxaliplatin are the chosen treatment regimens with radiation. If perioperative chemotherapy (performed at the time of surgery) is chosen, FLOT is recommended. This is also the recommendation for esophagogastric junction cancers. In cases where definitive chemoradiation, chemoradiation alone, is necessary, the same treatment regimens are advised.⁵

Stages II and III 

For tumors that have spread into the muscle or local lymph nodes, neoadjuvant chemoradiation followed by surgery is usually the first line of treatment. Esophagogastric junction cancers are often treated with surgery followed by adjuvant chemotherapy. EACs sometimes treated with surgery followed by adjuvant chemoradiation. ESCCs are difficult to operate on and usually require chemoradiation without surgery. For patients who cannot undergo surgery, chemoradiation or chemotherapy with immunotherapy are recommended. Esophagogastric junction tumors that are HER2-positive are eligible for pembrolizumab combined with targeted therapies and chemotherapies.

See stage I, T2 tumors for specific pharmacologic recommendations for ESCC and EAC.^5,28

Stage IV

Generally, stage IV tumors are not treated surgically. The intention behind this treatment is palliative, which is to improve longevity and quality of life. The cancers will be treated by a combination of pharmacologic and radiation interventions. Esophagogastric junction tumors may be eligible for more targeted therapies and immunotherapies.²⁸ Definitive chemoradiation using either paclitaxel with carboplatin or fluorouracil with oxaliplatin is advised.⁵

Squamous Cell Carcinomas

If there is extensive metastasis, systemic chemotherapy alone is recommended for ESCC. Fluoropyrimidine with oxaliplatin and nivolumab is the preferred treatment regimen. If the tumor is positive for PD-L1, pembrolizumab can replace nivolumab.⁵

Adenocarcinomas

If there is extensive metastasis, systemic chemotherapy alone is recommended for EAC. If the tumor is HER2-positive, fluoropyrimidine with oxaliplatin and trastuzumab is the preferred treatment regimen. If a checkpoint inhibitor has not been used yet, pembrolizumab can also be used with this regimen. If the primary tumor is HER2-negative, fluoropyrimidine with oxaliplatin and nivolumab is recommended.⁵

Recurrent Esophageal Cancer

Treatment of recurrence of esophageal cancer is dependent on the location of the recurrence and the previous interventions used. In general, local recurrences will be treated like local disease, and metastatic recurrences will be treated like stage IV, metastatic disease. Changes to the recommended treatment regimen will depend on previous treatment strategies used. Once systemic therapy is recommended, the following subsequent therapies are advised.⁵

Squamous Cell Carcinomas

Single-agent therapy of nivolumab, docetaxel, paclitaxel, and irinotecan are all appropriate as subsequent therapies for ESCC. Single-agent pembrolizumab is appropriate for patients who have tumors with high PD-L1 expression. Fluorouracil with irinotecan can be used in combination.⁵

Adenocarcinomas

Ramucirumab with paclitaxel is highly recommended for esophageal junction adenocarcinoma and also recommended for EAC. Single-agent treatment with docetaxel, paclitaxel, and irinotecan is recommended. For HER2-positive tumors, fam-trastuzumab deruxtecan-nxki is recommended. Fluorouracil with irinotecan can also be recommended as subsequent treatment.⁵

References

1. Surveillance, Epidemiology, and End Results Program.  Cancer stat facts: esophageal cancer. National Cancer Institute. Accessed May 18, 2023. https://seer.cancer.gov/statfacts/html/esoph.html#content

2. Cancer Facts and Figures 2023. American Cancer Society. Accessed May 18, 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf

3. Key statistics for esophageal cancer. American Cancer Society. Updated January 12, 2023. Accessed May 7, 2023. https://www.cancer.org/cancer/types/esophagus-cancer/about/key-statistics.html

4. Geng CS, Gudur AR, Radlinski, M, et al. Socioeconomic disparities affect outcomes in early-stage esophageal adenocarcinoma: a SEER analysis. Clin Gastroenterol Hepatol. Published online February 26, 2023. doi:10.1016/j.cgh.2023.02.011

5. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines^Ⓡ), Esophageal and Esophagogastric Junction Cancers. National Comprehensive Cancer Network. Updated March 10, 2023. Accessed May 7, 2023. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf

6. Esophageal Cancer Treatment (PDQ®)–Health Professional Version. National Cancer Institute. Updated January 20, 2023. Accessed May 2, 2023 https://www.cancer.gov/types/esophageal/hp/esophageal-treatment-pdq

7. Chemotherapy for esophageal cancer. American Cancer Society. Updated March 20, 2020. Accessed May 7, 2023. https://www.cancer.org/cancer/types/esophagus-cancer/treating/chemotherapy.html

8. Immunotherapy for esophageal cancer. American Cancer Society. Updated June 2, 2022. Accessed May 7, 2023. https://www.cancer.org/cancer/types/esophagus-cancer/treating/immunotherapy.html

9. Targeted drug therapy for esophageal cancer. American Cancer Society. Updated January 19, 2021. Accessed May 7, 2023. https://www.cancer.org/cancer/types/esophagus-cancer/treating/targeted-therapy.html

10. Drugs approved for esophageal cancer. National Cancer Institute. Updated December 27, 2022. Accessed May 7, 2023 https://www.cancer.gov/about-cancer/treatment/drugs/esophageal

11. Capecitabine. Prescribing information. Armas Pharmaceutical Inc; 1998. Accessed May 7, 2023. 

12. Capecitabine. National Cancer Institute. Updated December 21, 2022. Accessed May 7, 2023.

13. Carboplatin. Prescribing information. Fresenius Kabi USA, LLC; 2021. Accessed May 7, 2023.

14. Docetaxel. Prescribing information. Curae Pharma360 Inc; 1996. Accessed May 8, 2023.

15. Fluorouracil. Prescribing information. Spectrum Pharmaceuticals, Inc; 1962. Accessed May 7, 2023.

16. Camptosar. Prescribing information. Pfizer; 2009. Accessed May 9, 2023.

17. Oxaliplatin. Prescribing information. Actavis Pharma, Inc; 2002. Accessed May 7, 2023.

18. Paclitaxel. Prescribing information. Alembic Pharmaceutical Inc; 2022. Accessed May 7, 2023.

19. Lonsurf. Prescribing information. Taiho Pharmaceutical Co. Ltd; 2022. Accessed May 4, 2023.

20.  Oh S, Sur H, Sung H, et al. A phase II study of biweekly dose-intensified oral capecitabine plus irinotecan (bXELIRI) for patients with advanced or metastatic gastric cancer. Br J Cancer. Published online May 1, 2007. doi:10.1038/sj.bjc.6603752

21. Yervoy. Prescribing information. E.R. Squibb & Sons, LLC; 2011. Accessed May 7, 2023.

22. Opdivo. Prescribing information. E.R. Squibb & Sons, LLC; 2014. Accessed May 7, 2023. 

23. Keytruda. Prescribing information. Merck Sharp & Dohme LLC; 2014. Accessed May 7, 2023. 

24. Pembrolizumab. National Cancer Institute. Updated April 14, 2023. Accessed May 7, 2023.

25. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2019. Accessed May 8, 2023

26. Cyramza. Prescribing information. Eli Lilly and Company; 2014. Accessed May 8, 2023.

27. Herceptin. Prescribing information. Genentech, Inc; 1998. Accessed May 8, 2023.

28. Treating esophageal cancer by stage. American Cancer Society. Updated June 2, 2022. Accessed May 9, 2022. https://www.cancer.org/cancer/types/esophagus-cancer/treating/by-stage.html

Author Bio

Hannah Actor-Engel, PhD, earned a BS in Neural Science at New York University and her PhD in Neuroscience at the University of Colorado. She is a multidisciplinary neuroscientist who is passionate about scientific communication and improving global health through biomedical research.