Gastroenterology Hepatology

Esophageal tumors

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How can I be sure that the patient has esophageal tumors?

Squamous cell carcinoma and adenocarcinoma comprise over 90% of esophageal tumors. Rarely, leiomyoma, melanoma, sarcoma, small cell carcinoma, or lymphoma may arise in the esophagus. Causes and patterns of incidence are different in these subtypes.

Overall, the incidence of esophageal cancer is increasing. Although the incidence of esophageal squamous cell carcinoma (ESCC) has stabilized or slightly declined, the incidence of esophageal adenocarcinoma (EAC) is increasing rapidly in the Western hemisphere. EAC now accounts for 60% of esophageal cancer cases in the United States even though more than 90% of all esophageal cancer cases worldwide are still ESCC. Despite improvements in both diagnostic and therapeutic techniques, esophageal cancer continues to have a poor prognosis, with 5-year survival rates of less than 20%.

Definition of esophagogastric junction (EGJ) cancer has been controversial. In the American Joint Committee on Cancer (AJCC 7th edition, 2010), tumors are classified as esophageal cancer whose midpoint is in the lower esophagus, EGJ, or within the proximal 5cm of the stomach that extends to EGJ or esophagus. Other tumors whose midpoint is lying the stomach more than 5cm distal to the EGJ, or those within 5cm but not extend into EGJ or esophagus are classified as gastric cancer.

Signs and symptoms of esophageal cancer depend on the stage of the disease. The majority of patients are unaware of the presence of early stage cancer or precancerous lesions such as Barrett's esophagus for EAC. As the cancer grows, symptoms gradually appear. It is estimated that 80% of the esophageal circumference is involved before patients experience symptoms.

Symptoms by local tumor effects

  • – Reflux

  • – Odynophagia

  • – Chest pain

  • – Back pain

  • – Weight loss

  • – Dysphagia

  • – GI bleeding

Symptoms by advanced effects

  • – Hoarseness or other voice changes by recurrent laryngeal nerve invasion

  • – Horner's syndrome by invasion of sympathetic nerve. Horner syndrome is the combination of drooping of the eyelid (ptosis) and constriction of pupil (miosis), sometimes accompanied by decreased sweating on the same side of the face. Redness of the conjunctiva of the eye may also be present.

  • – Recurrent pneumonia and severe cough from bronchoesophageal fistula

  • – Hiccups by phrenic nerve invasion

  • – Dyspnea from stricture of trachea by tumor invasion

A tabular or chart listing of features and signs and symptoms

Esophageal tumors mimic the following diseases:

  • – Esophageal varices

  • – Zenker's diverticulum

  • – Achalasia: also a risk factor for ESCC

  • – Benign tumors: papilloma, lipoma, polyp, fibrolipoma, hemangioma, neurofibroma, lhamartoma, cysts

  • – Gastroesophageal refluc disease (GERD)

  • – Reflux esophagitis

  • – Eosinophilic esophagitis

  • – Caustic esophagitis

  • – Infectious esophagitis

  • – Esophageal ulcer

  • – Boerhaave syndrome. A spontaneous esophageal perforation that is thought to arise from a rapid increase in intraluminal esophageal pressure through a patent lower-esophageal sphincter during vomiting. The sudden increase in intraluminal pressure is the result of failure of relaxation of the cricopharyngeal muscle. Transmural rupture of the esophageal wall follows, commonly in the left lateral and posterior wall of the lower third of the esophagus, 3 cm above the gastroesophageal junction.

The following conditions below have been reported as unusual initial manifestations of esophageal cancer:

  • – Brain metastases

  • – Fever of unknown origin

  • – Guillain-Barre syndrome

  • – Numb chin syndrome (NCS). NCS is sensory neuropathy presenting with numbness of the chin in the distribution of the mental nerve and the branches of the mandibular division of the trigeminal nerve. Mandibular metastasis from esophageal squamous cell cancers have presented with numb chin syndrome.

  • – Cullen's sign. Refers to the presence of periumbilical ecchymosis and is most often recognized as a manifestation of hemorrhagic pancreatitis. Patients with metastastic squamous cell carcinoma presented with Cullen's sign.

  • – Nephrotic syndrome

  • – Esophagocutaneous fistula

  • – Pseudohyperparathyroidism

  • – Hypercortisolism

How can I confirm the diagnosis?

The American Joint Committee on Cancer (AJCC 7th edition, 2010) has staged esophageal cancer using the TNM system. A major change between the 6th and the 7th editions was the development of separate stage groupings according to histology. (See Table I, Table II, and Table III.) The elements of staging are the depth of tumor penetration into or through the esophageal wall (T category), the presence and number of metastatic regional lymph nodes (N category), and distant metastases (M category). The initial treatment differs for each stage.

Table I.

TNM classification according to American Joint Committee on Cancer (AJCC), 7th edition

Table II.

Esophageal adenocarcinoma (EAC) stage grouping according to AJCC, 7th edition

Table III.

Esophageal squamous cell carcinoma (ESCC) stage grouping according to the AJCC, 7th edition

Barium esophagram

Barium esophagram can provide tumor location, tumor size, and tumor shape. In addition, the depth of tumor penetration (T factor) can be estimated by its size, shape, and stiffness. Intramucosal carcinoma (Tis-T1a) is generally not detectable by esophagram.

Upper endoscopy

Provides color, location, size, and shape of tumor. Biopsy should be taken from the tumor to confirm histology. Improper movement of the vocal cords may suggest recurrent laryngeal nerve paresis. Laryngopharyngeal cancer may coexist with esophageal squamous cell carcinoma. The depth of tumor penetration can be estimated by its color, shape, size, and flexibility of the tumor and surrounding wall. The extent of tumor can be more clearly visualized with techniques such as chromoendoscopy and with new technology such as narrow band imaging (NBI), autofluorescence (AFI), and optical coherence tomography (OCT).

Narrowband imaging

With NBI, optical interference filters are placed in front of a sequential red-green-blue illumination system for narrowing the spectral bandwidth; the depth of light penetration into the tissue is dependent on its wavelength. With this technique, the blue component of white light preferentially highlights superficial capillary networks and mucosal pit patterns. NBI improves detection of specialized columnar epithelium and dysplastic epithelium in patients with Barrett's esophagus.

Autofluorescence imaging

AFI produces real-time pseudocolor images based on the detection of natural tissue fluorescence generated from endogenous fluorophores (collagen, nicotinamide, adenine dinucleotide, flavin, and porphyrins) through emission induced by excitation light. The system can visualize lesions, including early stage cancers, by differences in tissue fluorescence properties.

Optical coherence tomography

OCT is an imaging technology that allows imaging of biologic tissues on a micrometer scale. OCT sends an optical beam of infrared light into tissue and then measures the reflected or backscattered intensity and depth of light from various tissue layers, planes, structures, and cell membranes. Currently available endoscopic OCT probes do not have the capability of providing images at the nuclear level and are applicable only for research purposes.

Endoscopic ultrasound (EUS). Useful to evaluate the depth of tumor penetration and regional lymph node size. EUS is the major modality used for T staging and is particularly helpful in distinguishing T1 from T2-4. The accuracy of EUS for T staging was 89% in a meta-analysis. For N staging, EUS-guided fine needle aspiration (FNA) of lymph nodes may aid staging and diagnosis.

Bronchoscopy. Tracheal invasion can be observed. A stent would be placed when strictures of the trachea or tracheoesophageal fistulas exist.

Computed tomography (CT). CT has difficulty in distinguishing the depth of tumor penetration between T1 and T2-4. The major role of CT for T staging is to detect local tumor invasion into adjacent structures (T4). Diagnosing metastatic lymph nodes by CT is limited because large primary esophageal tumors may obscure adjacent, involved lymph nodes. In addition, CT is not able to detect micrometastases. CT is useful for detection of distant metastatic disease such as lung and hepatic metastases. It should be an intravenous contrast-enhanced CT of the chest and abdomen.

Magnetic resonance imaging (MRI). MRI is rarely used for staging esophageal cancer because there is no real difference in staging accuracy between CT and MRI.

Positron emission tomography (PET). PET is not useful in T staging and detecting lymph nodes adjacent to primary tumor as well as CT. However, it is useful in detecting regional lymph nodes that are not near the primary tumor. PET is the most important modality for distant metastatic disease detection.

See Table I, Table II, and Table III.

What other diseases, conditions, or complications should I look for in patients with esophageal tumors?

Esophageal squamous cell carcinoma

  • – Tobacco use. Regardless of form, tobacco use is a major risk factor for ESCC. Odds ratio (OR): 2.6 (95% CI 1.5-4.6). Population attributable risk (PAR): 56.9% (95% CI = 36.6-75.1)

  • – Alcohol. Alcoholic beverages are a major risk factor for esophageal squamous cell carcinoma. OR: 4.2 (2.2-8.1), PAR: 72.4% (95% CI = 53.3-85.8)

  • – Tobacco and alcohol interaction. Heavy consumers of both alcohol and tobacco have the highest risk. Tobacco use has been shown to increase risk twofold to sevenfold for developing esophageal cancer in alcoholics compared with rates for the general population.

  • – Hot food and beverages

  • – Low fruit and vegetable intake. OR: 1.4, PAR: 15.3% (95% CI = 5.8-34.6)

  • – Male gender

Esophageal adenocarcinoma

  • – Obesity, high BMI. Increases incidence of GERD and its progression to Barrett's esophagus. OR: 2.0 (1.3 to 3.0), PAR (95%CI = 23.8-60.9)

  • – GERD

  • – Barrett's esophagus. The risk of progression to cancer increases gradually from 0.5% per year for nondysplastic Barrett's to 13% in low-grade dysplasia (LGD), to 40% in high-grade dysplasia (HGD).

  • – Tobacco use. Although smoking is a less potent cause of esophageal adenocarcinoma than squamous cell carcinoma, it is still a significant risk factor for esophageal adenocarcinoma. In addition, tobacco and obesity are the two main established risk factors for reflux. OR: 2.0, PAR: 39.7% (95% CI= 25.6-55.8)

  • – Male gender

What is the right therapy for the patient with an esophageal tumor?

Most situations that require emergent management are in inoperable patients. These are caused by tumor invasion, metastases, or as complications of cancer therapy. Treatment of these situations requires consideration of both treatment of the underlying cancer and relief of symptoms. A tissue diagnosis is necessary to confirm the presence of a malignancy before the initiation of therapy, unless there are acute airway emergencies or progressive life-threatening conditions.

Superior vena cava (SVC) syndrome. SVC syndrome is uncommon with esophageal cancer as compared to lung cancer. Initial management is supportive, such as oxygen supplementation. Minimizing hydrostatic pressure – such as fluid limitation, head elevation, diuretics, and possibly steroids – can reduce edema. Endovascular stent placement, radiation, and chemotherapy may help reduce symptoms.

Tracheoesophageal or bronchoesophageal fistula. Prognosis is very poor and most of these patients die in 1 to 2 months after developing this condition. Post-obstructive pneumonia might follow. Therapy should be supportive to maintain quality of life. Double stenting (esophagus and airway) has been proposed rather than esophageal or airway stents alone. It should be noted that radiation and chemotherapy could cause tracheo/broncho-esophageal fistula.

Aorto-esophageal fistula. Usually fatal. Successful treatment has been reported with thoracic endovascular aortic repair.

Perforated esophageal cancer. Intravenous resuscitation and broad antibiotic therapy covering oral flora, including Candida species, are indicated. Intravenous H2 blocker or proton pump inhibitors may be given to reduce acid content. Operative management could be divided into open surgery and minimal invasive surgery. Surgical options include primary repair, repair and drainage, resection, exclusion and diversion, and wide drainage. Most of these cases would be unresectable cases so that surgical options are limited. Nonoperative management, such as esophageal stent, is an option for perforated esophageal cancer.

Gastrointestinal bleeding (bleeding primarily from tumor surface). Intravenous resuscitation and blood transfusion are indicated to stabilize vital signs. Endoscopic hemostasis such as bipolar electrocoagulation or argon plasma coagulation may be useful for control of bleeding.

What is the most effective initial therapy?

Multiple approaches for treatment of locally advanced disease are available. Often, multimodality care is chosen, depending on the histology and stage as well as patient characteristics. The availability of such a variety of options further emphasizes the importance of complete and accurate staging. The recommendations that follow are stratified by both stage and histology. While some approaches are based on level I evidence, some are not. The lack of definitive evidence for each treatment category underscores the need for additional trials.

Treatment of ESCC

Early esophageal cancers are those that are classified as Tis (high-grade dysplasia) or T1 tumors, which are split into T1a and T1b subcategories, depending on the depth of invasion. However, this classification by itself is inadequate to distinguish differences in lymph node involvement among T1a versus T1b esophageal cancers.

A more detailed subclassification of early esophageal cancer has been proposed for determining prognosis and selecting treatment. Mucosal esophageal cancer (T1a) and submucosal esophageal cancer are both divided into three classes based on the depth of invasion. See Table IV.

Table IV.

Classification of mucosal and submucosal esophageal cancers

Lymph nodes metastases in esophageal cancer have correlated with the depth of tumor invasion. Mucosal esophageal cancer (T1a) has been recognized with a low rate of metastatic lymph nodes, but it is not 0%. This is a more comprehensive subclassification scheme that divides mucosal esophageal cancer into three types based on the depth of invasion: M1, M2, and M3. M1 and M2 tumors are not associated with lymph node metastases. However, the risk of lymph node metastasis rises to 10% with M3 tumors.

Whether endoscopic therapy should be considered an alternative to esophagectomy for the treatment of T1a esophageal cancer is still controversial . However, there are some benefits of endoscopic therapy compared to that of surgery: preserving the function of the digestive system, a less invasive procedure, shorter hospital stay, etc.

Stage 0 and patients with M1 and M2 and patients with M3 disease without lymphatic invasion. Esophagectomy represents the most definitive approach. Endoscopic mucosal resection (EMR) or submucosal dissection (ESD) are reasonable alternatives. The benefit of preoperative chemoradiotherapy for these patients is unclear.

Patients with submucosal cancer (T1b: SM diseases). Esophagecetomy is recommended. For patients with T1b who are high risk for esphagectomy, EMR may be used along with/without photodynamic therapy (PDT) or radiofrequency ablation (RFA).

Patients with T2-3N0 (Stage IB), stage II and III (patients with positive lymph nodes). Preoperative chemoradiotherapy followed by esophagectomy is recommended. Definitive chemoradiotherapy is a reasonable approach for patients who are not surgical candidates.

Patients with Stage IV. Palliative therapy including chemotherapy, chemoradiotherapy, radiation therapy, palliative surgery, and best supportive care.

Treatment of esophageal adenocarcinoma

Stage 0 and patients with M1 and M2 and patients with M3 disease without lymphatic invasion. Esophagectomy represents the most definitive approach, but EMR or ESD is a reasonable alternative. The benefit of preoperative chemoradiotherapy for these patients is unclear.

Patients with submucosal cancer (T1b: SM diseases). Esophagecetomy is recommended. For poor-risk surgical patients with T1b, EMR may be used along with/without PDT or RFA therapy.

Patients with T2-3N0 (Stage IB), stage II and III (including patients with positive LN). Preoperative chemoradiotherapy followed by esophagectomy is recommended. Definitive chemoradiotherapy is a reasonable approach for patients who are not surgical candidates.

Patients with Stage IV. Palliative therapy including chemotherapy, chemoradiotherapy, radiation therapy, palliative surgery, and best supportive care.

Special cases

Management of cervical esophageal cancer

Neoadjuvant chemoradiotherapy. Several studies suggest that a concurrent trimodality approach (concomitant chemoradiotherapy followed by surgery) provides a survival benefit compared to surgery alone. In addition, local control appears to be better with neoadjuvant chemoradiotherapy compared to surgery alone.

Adjuvant chemotherapy. The role of adjuvant therapy has not been studied extensively. Adjuvant chemoradiotherapy remains a possible option for patients who did not receive any neoadjuvant treatment.

Definitive chemoradiotherapy. Concurrent chemotherapy and radiation therapy has been studied as a definitive nonoperative treatment. Chemoradiotherapy alone is used in many patients who are not fit enough for surgery or those who choose to not undergo surgery. In randomized trials, definitive chemoradiation therapy has been demonstrated as the curative approach for patients with ESCC, whereas its role is not established in patients with EAC. Definitive chemoradiation for EAC has a curative potential, but randomized trials are needed for EAC.

Surgery. Surgery has been the standard treatment for resectable esophageal cancer. The most popular methods used in Western countries are the transhiatal and transthoracic approaches with two-field lymphadenectomy (mediastinal and upper abdomen). Esophagectomy with an extended (three-field) lymphadenectomy is advocated in East Asian countries. Esophagectomy is a technically difficult operation, and the complication rate is high due to the anatomic challenges of the procedure. Minimally invasive esophagectomy has been used for both staging and treatment of esophageal and EGJ cancer. The gastric conduit is usually used for reconstruction after esophagectomy. Patients who undergo esophagectomy at hospitals that perform large numbers of procedures have lower perioperative mortality rates and better early clinical outcomes than those who undergo resection at lower-volume institutions.

For cervical esophageal cancer, surgery requires removal of portions of the larynx, the pharynx, the thyroid gland, and the proximal esophagus. Incisions are made in the neck, chest, and abdomen and a permanent terminal tracheostomy is necessary. Surgery may be considered for selected patients with early stage disease; however, radiation combined with chemotherapy is preferred over surgery for patients with locally advanced disease, as survival appears to be comparable, and major operative morbidity is avoided in most patients with chemoradiotherapy.

Management of esophagogastric junction cancer

EGJ tumors were staged and treated as either esophageal or gastric cancers. The 7th edition of AJCC TNM staging criteria classifies all tumors of the EGJ in the proximal 5 cm of the stomach along with esophageal cancers.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Therapeutic approaches for potentially curable disease

Endoscopic therapy. Various endoscopic therapies are emerging as alternatives to surgical therapy in patients with high grade dysplasia and T1a esophageal cancer. Endoscopic therapies include EMR, ESD, PDT, RFA, argon plasma coagulation (APC), and laser therapy.

EMR. The neoplastic epithelium is excised without destroying the surrounding area, thus allowing for a definitive histologic diagnosis while potentially being curative. Several techniques are established, such as cap-assisted endoscopic mucosal resection (EMRC) and multiband mucosectomy (MBM). Major complications are bleeding and stricture.

EMRC and MBM. EMRC is a technique that uses a combination of submucosal injection, aspiration of tissue into a clear soft plastic cap attached to the tip of the endoscope, and snare excision. Various commercially available single-use devices have been developed that include a combination of cap and specially designed snare. Typically, the snare is opened within the distal internal rim of the cap, tissue is aspirated within the cap and snare, the snare is closed around the captured tissue, and standard snare cautery is applied to excise the tissue. In removing multiple pieces for a widespread lesion, using the EMRC technique has a number of disadvantages, such as repeated submucosal lifting and requiring changing the snare every time.

An alternative to the EMRC technique is the ligate-and-cut technique. This technique uses a trasparent cap loaded with a rubber band. Without prior submucosal lifting, the lesion is sucked into the cap and the rubber band is released, thus creating a pseudopolyp that is subsequently resected. MBM uses this ligate-and-cut technique. MBM kit consists of a standard variceal rubber band ligator cap containing six bands and a specially designed handle that allows passage of 7 Fr snare alongside the releasing wires required for releasing bands. This makes it possible to perform consecutive resections without the need to remove the endoscope. As no submucosal lifting is required and the same polypectomy snare is used for all resections, this new device allow easier and quicker piece-meal resection.

ESD. Using specially designed needle-knives for en bloc dissection of larger esophageal lesion than EMR.

PDT. PDT relies on a drug-light interaction to induce cell death. Afterinjection of a photosensitizing agent, exposure to light of anappropriate wavelength is delivered through a fiber introduced throughthe endoscope. The efficacy of PDT for treatment of patients withsuperficial esophageal cancer has not been evaluated yet.

RFA. A specialized circumferential device for delivering radiofrequency energy to ablate esophageal epithelium.

APC. APC is a noncontact electorcoagulation device that involves a high-frequency monopolar current that is conducted to the tissue by a flow of ionized argon gas.

Laser therapy. Three types of laser have been used: neodynium, potassium titanyl phosphate, and argon. The use of lasers has largely been replaced by other techniques.

Radiation therapy. External beam radiation therapy (EBRT) with/without chemotherapy and/or intraluminal brachytherapy are potentially useful alternatives to esophagectomy for patients with esophageal cancer

  • – Tumor size and radiation dose are important considerations for local-regional tumor control.

  • – EBRT with curative intent (definitive therapy) requires a total dose of 60 to 66.6 Gy using 1.8 to 2.0 Gy daily fractions, five fractions per week. Small daily fractions (1.8-2.0 Gy instead of 2.5-3.0 Gy) reduce the likelifood of late toxicity.

  • – The optimal dose for preoperative chemoradiotherapy regimens is not defined, although a total dose of 45 to 50.4 Gy administered in daily 1.8 Gy fractions, 5 days per week, produces reasonable results with acceptable toxicity.

  • – For palliative intent, a total dose of 40 to 45 Gy at 2.5 Gy daily fractions 5 days a week is a reasonable schedule for patients who require palliation of esophageal obstruction.

Brachytherapy. Permits treatment of a localized area of the esophagus with high radiation doses and relative sparing of adjacent structures. This technique may be used alone or in combination with EBRT with or without chemotherapy. Brachytherapy should be considered an alternative to stent-placement palliation of dysphagia. Consensus guidelines for brachytherapy in the treatment of esophageal cancer from the American Brachytherapy Society are listed below.

For definitive treatment

  • – High dose rate (HDR): total dose of 10 Gy, 5 Gy/fraction, 1 fraction/week, starting 2-3 weeks following completion of EBRT

  • – Low dose rate (LDR): total dose of 20 Gy single course, 0.4-1.0 Gy/hr starting 2-3 weeks after completion of EBRT.

For palliative treatment

  • – Recurrence after EBRT or short life expectancy: Brachytherapy (HDR 10-14 Gy in 1-2 fraction or LDR 20-40 Gy in 1-2 fraction at 0.4-1.0 Gy/hr)

  • – No previous EBRT: EBRT 30-40 Gy in 2-3 Gy/fraction followed by bracytherapy, (HDR 10-14 Gy in 1-2 fraction or LDR 20-25 Gy in a single course at 0.4-1.0 Gy/hr)

  • – No previous EBRT and life expectancy >6 months: follow the definitive treatment

The toxicity of radiation therapy is usually limited to the area of the patient's body that is under treatment. Toxicities include damage to the skin, mucositis (inflammation of the lining of the throat, mouth and esophagus), perforation of the esophagus with the development of fistulas (connections with other organs such as the trachea), infection, bleeding, xerostomia (dryness in the mouth) and fatigue. Changes to the esophagus and skin usually go away in 6-12 months

Surgical therapy. See Table V.

Table V.

Types of surgical therapies for esophageal cancer

Current therapy for resectable esophageal cancer: stages I, II, III

Early esophageal cancer: stage Ia. EMR or ablation is a good primary treatment options for the patient with Tis and T1a tumors, whereas esphagectomy is still the preferred treatment for T1a tumor. For patients with T1b tumors, esophagectomy is the preferred treatment option. Although data is limited, radiation therapy (EBRT) with or without concurrent chemotherapy and/or intraluminal brachytherapy are potentially useful alternatives to endoscopic therapy/esophagectomy for the stage I patient.

Resectable advanced esophageal cancer: stages Ib to III. Primary treatment options for patients with Stage Ib to III include preoperative chemoradiation therapy, perioperative chemotherapy, definitive chemoradiation therapy, and/or esophagectomy.

Preoperative chemoradiation therapy

  • – Preoperative chemoradiation: pactlitaxel and carboplatin (category 1), cisplatin and fluoropyrimidine (5-FU or capecitabine)(category 1 for EAC or ESCC)

  • – Radiation therapy regimens

The optimal dose for preoperative chemoradiotherapy regimens is not defined, although a total dose of 45 to 50.4 Gy administered in daily 1.8 Gy fractions, 5 days per week, produces reasonable results with acceptable toxicity.

Chemotherapy regimens

  • – Paclitaxel 50 mg/m2 IV on day 1 plus carboplatin AUC 2 IV on day 1; weekly for 5 weeks

    OR

  • – Cisplatin 75-100 mg/m2 IV on day 1 plus 5-FU 750-1000 mg/m2/day IV continuous infusion on days 1-4; every 28 day for 2-4 cycles

    OR

  • – Cisplatin 30 mg/m2 IV on day 1 plus capecitabine 800 mg/m2 PO b.i.d. on days 1-5; weekly for 5 weeks

    OR

  • – Cisplatin 15 mg/m2 IV on days 1-5 plus 5-FU 800 mg/m2/day IV continuous infusion on days 1-5; every 21 days for 2 cycles

Perioperative chemotherapy

Three (3) cycles preoperative and 3 cycles postoperative (only for EAC of the distal esophagus or esophagogastoric junction)

ECF (epirubicin, cisplatin, and 5-FU) (category 1)

ECF modifications (category 1)

  • – Epirubicin 50 mg/m2 IV on day 1 plus cisplatin 60 mg/m2 IV on day 1 plus 5-FU 200 mg/m2 IV continuous infusion over 24 hours; daily on days 1-21; cycled every 21 days for 3 cycles preoperatively and 3 cycles postoperatively

  • – Epirubicin 50 mg/m2 IV on day 1 plus oxaliplatin 130 mg/m2 IV on day 1 plus 5-FU 200mg/m2 IV continuous infusion over 24 hours; daily on days 1-21; cycled every 21 days for 3 cycles preoperatively and 3 cycles postoperatively

  • – Epirubicin 50 mg/m2 IV on day 1 plus cisplatin 60 mg/m2 IV on day 1 plus capecitabine 625 mg/m2 PO b.i.d. on days 1-21; cycled every 21 days for 3 cycles preoperatively and 3 cycles postoperatively

  • – Epirubicin 50 mg/m2 IV on day 1 plus oxaliplatin 130 mg/m2 IV on day 1 plus capecitabine 625 mg/m2 PO b.i.d. on days 1-21; cycled every 21 days for 3 cycles preoperatively and 3 cycles postoperatively

Definitive chemoradiation therapy

  • – Definitive chemoradiation therapy with infusional 5-FU (1000 mg/m2 per day, days 1-4 and 29-32) and cisplatin (75 mg/m2 on days 1 and 29) using radiation with a total dose of at least 50.4 Gy, administered in daily 1.8 Gy fractions, 5 days per week concurrent with chemotherapy.

    OR

  • – Cisplatin 30 mg/m2 IV on day 1 plus capecitabine 800 mg/m2 PO b.i.d. on days 1-5; weekly for 5 weeks using the radiation with a total dose of at least 50.4 Gy administered in daily 1.8 Gy fractions, 5 days per week concurrent with chemotherapy.

  • – MAGIC trial. A total of 503 patients with resectable gastric, EGJ, and distal esophageal adenocarcinomas were randomly assigned to surgery with or without perioperative chemotherapy (3 cycles of preoperative plus 3 postoperative cycles of ECF. 253 patients: surgery alone; 250 patients: perioperative chemotherapy and surgery). At a median follow-up of 4 years, overall survival was significantly superior in the perioperative chemotherapy group.

  • – CROSS trial. A total of 364 patients with potentially resectable esophageal or EGJ cancer were randomly assigned to surgery with or without preoperative chemoradiotherapy (weekly paclitaxel 50 mg/m2 plus carboplatin plus concurrent radiotherapy). Overall survival was significantly superior in the preoperative chemoradiontherapy.

As a result of these studies, definitive chemoradiotherapy with 5-FU and cisplatin using the radiation dose of 50.4 Gy was established as the standard approach for patients with resectable esophageal cancer.

Therapeutic approaches for incurable disease

Chemotherapy

Chemotherapy alone should be used in patients with unresectable disease or poor performance status. The goals of chemotherapy in patients with metastatic/recurrent cancer are to palliate symptoms and improve survival.

First line therapy. There is no consensus as to the best agent or regimen. Combination chemotherapy regimens provide higher response rates than single agents at the cost of increased toxicity. In randomized trials, the ECF (epirubicin, cisplatin, infusional 5-FU) and DCF (docetaxel, cisplatin, infusional 5-FU) combinations have emerged as standard regimens for first-line treatment. The REAL-2 trial suggests that outcomes are comparable if capecitabine is substituted for infusional 5-FU and/or if oxaliplatin is substituted for cisplatin in the ECF regimen.

First-line therapy

DCF or its modifications. (Category 1 for docetaxel, cisplatin, and fluorouracil; category 2B for docetaxel, carboplatin, and fluoouracil; category 2A for all other combinations)

DCF

  • – Docetaxel 75 mg/m2 IV on day 1 plus Cisplatin 75 mg/m2 IV on day 1 plus 5-FU 1000 mg/m2 continuous infusion over 24 hours daily on day 1-5; cycled every 28 days

ECF or its modifications. (Category 1)

ECF

  • – Epirubicin 50 mg/m2 IV on day 1 plus cisplatin 60 mg/m2 IV on day 1 plus 5-FU 200 mg/m2 continuous infusion over 24 hours daily on days 1-21; cycled every 21 days

  • – Fluoropyrimidine- or taxane-based regimens, single agent or combination therapy (category 1 for combination of fluoropyrimidine and cisplatin; category 2A for all other regimens)

Fluoropyrimidine and cisplatin

  • – Cisplatin 75-100 mg/m2 IV on day 1 plus 5-FU 750-1000 mg/m2 continuous infusion over 24 hours daily on days 1-4; cycled every 28 days

    OR

  • – Cisplatin 80 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO twice daily on days 1-14; every 21 days

    OR

  • – Cisplatin 50 mg/m2 IV on day 1 plus leucovorin 200 mg/m2 IV on day 1 plus 5-FU 2000 mg/m2/day IV on day 1; every 14 days

Fluoropyrimidine and oxaliplatin

  • – Oxaliplatin 85 mg/m2 IV on day 1 plus leucovorin 400 mg/m2 IV on day 1 plus 5-FU 400 mg/m2 IV on day 1, followed by 5-FU 2400 mg/m2 over 46 hours; every 14 days

Taxane-based regimens

  • – Paclitaxel 135 mg/m2 IV on day 1 plus cisplatin 75 mg/m2 IV on day 2; cycled every 21 days

    OR

  • – Paclitaxel 90 mg/m2 IV on day 1 plus cisplatin 50 mg/m2 IV on day 1; cycled every 14 days

    OR

  • – Paclitaxel 200 mg/m2 IV on day 1 plus carboplatin AUC 6 IV on day 1; cycled every 21 days

    OR

  • – Docetaxel 70-85 mg/m2 IV on day 1 plus cisplatin 70-75 mg/m2 IV on day 1; cycled every 21 days

    OR

  • – Docetaxel 35 mg/m2 IV on days 1 and 8 plus irrinotecan 50 mg/m2 IV on days 1 and 8; cycled every 21 days

Single-agent regimens

  • – Docetaxel 70-100 mg/m2 IV on day 1; cycled every 21 days

    OR

  • – Paclitaxel 135-175 mg/m2 IV on day 1; cycled every 21 days

    OR

  • – Paclitaxel 80 mg/m2 IV on day 1 weekly; cycled every 28 days

    OR

  • – Leucovorin 400 mg/m2 IV on day 1 plus 5-FU 400mg/m2 IVP on day 1 plus 5-FU 1200mg/m2/day IV continuous infusion over 24 hours on days 1 and 2; every 14 days

    OR

  • – 5-FU 1200 mg/m2/day IV continuous infusion over 24 hours on day 1-5; cycled every 28 days

    OR

  • – Capecitabine 1000 mg/m2 PO twice daily on days 1-14; every 21 days

Trastuzumab with chemotherapy. (Category 1 for combination with cisplatin and fluoropyrimidine; category 2B for combination with other chemotherapy agents.) For patients who are HER2-neu positive, as determined by a standard method.

  • – Trastuzumab 8 mg/m2 IV loading dose on day 1 of cycle 1, then 6 mg/m2 IV; every 21 days with chemotherapy

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Management for recurrent disease can range from aggressive intervention with curative intent in patients with locoregional relapse to therapy intended strictly for palliation in patients for whom cure is not a possibility. Local or regional recurrence after esophagectomy can be treated with chemoradiation in patients who have not received prior chemoradiation. Other options include best supportive care, surgery, or chemotherapy. Selected patients with anastomotic recurrence can undergo re-resection. When recurrence develops in patients treated with prior definitive chemoraidation therapy without surgery, salvage esophagectomy may be an option. Supportive care is recommended for medically unfit patients.

Second-line chemotherapy

There is no standard approach for second-line therapy after failure of the first-line chemotherapy regimen. Quality of Life and minimization of side effects are key considerations when choosing the therapeutic approach.

Second-line therapy

Trastuzumab with chemotherapy. (Category 1 for combination with cisplatin and fluoropyrimidine; category 2B for combination with other chemotherapy agents.) For patients who are HER2-neu positive, if not used as first-line therapy.

  • – Trastuzumab 8 mg/m2 IV loading dose on day 1 of cycle 1, then 6mg/m2 IV; every 21 days with chemotherapy

Taxane-based therapy

  • – Docetaxel 75-100 mg/m2 IV on day 1; cycled every 21 days

    OR

  • – Paclitaxel 135-175 mg/m2 IV on day 1; cycled every 21 days

    OR

  • – Paclitaxel 80 mg/m2 IV on day 1 weekly; cycled every 28 days

Irinotecan-based therapy

  • – Irinotecan 65 mg/m2 IV on day1 and 8 plus cisplatin 25-30 mg/m2 IV on days 1 and 8; cycled every 28 days

    OR

  • – Irinotecan 250 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO b.i.d. on days 1 to 14; cycled every 21 days

    OR

  • Irinotecan 180 mg/m2 IV on day 1 plus leucoborin 400 mg/m2 IV on day 1 plus 5-FU 400 mg/m2 IVP on day 1 plus 5-FU 1200 mg/m2 IV continuous infusion over 24 hours daily on day 1 and 2; cycled every 14 days

    OR

  • – Docetaxel 35 mg/m2 IV on days 1 and 8 plus irrinotecan 50 mg/m2 IV on days 1 and 8; cycled every 21 days

Trastuzumab

  • – HER2 is a member of epidermal growth factor receptor (EGFR) family that is associated with cell proliferation, migration, and differentiation. HER2 overexpression and/or amplification has been reported in EAC, along with some evidence supporting a prognostic utility. Various phase I and II trials have reported a possible benefit for HER2 blockage. Data from these trials served as the basis for a recent prospective phase III trial (ToGA) that evaluated the therapeutic benefit of blocking this target in a randomized fashion. In the ToGA tiral, more than 594 patients with HER2-positive gastric and esophageal cancer were treated with standard chemotherapy (cisplatin and either 5FU or capecitabine), either with or without trastuzumab. The tumors of the enrolled patients were either fluorescence in situ hybridization (FISH)-positive or positive for HER2 expression by immunohistochemistory (IHC). Median overall survival (the primary end point) was significantly improved with the addition of trastuzumab (13.8 vs. 11.1 months) at a median follow-up of 17.1 to 18.6 months. This established trastuzumab plus chemotherapy as a new standard of care for the treatment of patients with HER2-expressing advanced gastric and EAC.

Palliative therapy

  • – RT. Using RT alone may provide a small chance of long-term palliation. However, most experts consider that combined chemoradiotherapy provides superior palliation.

  • – Stent/dilation

  • – Feeding tubes

  • – Pain management

  • – RFA

  • – Clinical trials are preferred in all cases, with the goal of increasing survival and minimizing side effects.

Listing of these, including any guidelines for monitoring side effects.

Dysphagia

Assess the extent of disease and the functional degree of swallowing impairment and confirm the etiology of dysphagia. Dysphagia arising from esophageal cancer is commonly due to obstruction but, on occasion, may be primarily due to tumor-related dysmotility. Dysphagia and odysnophagia are common initial symptoms in patients undergoing radiotherapy. Dysphagia causes malnutrition and dehydration. For patients who need frequent intravenous hydration or who lose weight despite conservative intervention, placement of percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) tube should be considered.

Obstruction

Complete obstruction. Endoscopic lumen restoration or enhancement, gastrostomy or jejunal tube, brachytherapy, chemotherapy, surgery (selected patients)

Severe obstruction. Endoscopic dilatation, esophageal stent placement (self-expanding metal stents)

Moderate obstruction. Endoscopic lumen enhancement as necessary

Pain relief

Patients experiencing tumor-related pain should be assessed and treated. The World Health Organization (WHO) recommends the pain ladder for managing analgesia. The goal of pain management is not just control of pain but the ability of a patient to regain control of patient's psyche and maintain quality of life.

Bleeding

Acute bleeding from malignant aortoesophageal fistula is usually fatal. Surgery or external beam radiation and/or endoscopic therapy may be indicated. Bleeding from tumor itself could be treated with endoscopic therapy.

Nausea/Vomiting: Antiemesis

  • – Chemotherapy related: serotonin (5-HT3) antagonist, Steroid, and Neurokinin 1 antagonist

  • – Radiation related: same drugs above

Other potential causes

Bowel obstruction, vestibular dysfunction, brain metastasis, electrolyte imbalance, uremia, concomitant drug treatments, gastroparesis, psychophysiologic

How should I monitor the patient with an esophageal tumor?

Guidelines for post-treatment surveillance of patients who have completed curative therapy vary. In particular, indications for the use of cross-sectional imaging are poorly defined. First and foremost, follow-up and subsequent investigations must be symptom directed.

  • – All patients should be followed systematically.

  • – For asymptomatic patients, a suggested follow-up schedule is complete history and physical examination, CBC, chemistry profile and CT scan every 3 months for 2 years, then every 6 months for 3 years, then annually.

  • – Upper endoscopy and other radiologic imaging studies should be obtained as clinically indicated.

  • – Patients with Tis or T1a tumors who undergo EMR or ESD should undergo endoscopic surveillance every 3 months for 1 year and then annually.

Some patients may require dilatation of an anastomotic or a chemoradiation-induced stricture. Nutritional counseling may be valuable.

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