Oncology

Esophageal Cancer

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Esophageal Cancer

What every physician needs to know:

Esophageal cancer has two main histological types; squamous cell carcinoma and adenocarcinoma. Rarely, melanoma, sarcoma, small cell carcinoma, or lymphoma may arise in the esophagus. Causes and patterns of incidence are different in these types. The incidence of esophageal cancer is increasing. Although the incidence of esophageal squamous cell carcinoma has been stabilized/slightly lessened, the incidence of esophageal adenocarcinoma is increasing rapidly in the U.S. and European countries.

A marked histologic shift has occurred and esophageal adenocarcinoma now accounts for 60% of cases of esophageal cancer in the U.S. even though more than 90% of all the esophageal cancer cases worldwide are still esophageal squamous cell carcinoma. Despite improvements in both diagnostic and therapeutic techniques, esophageal cancer continues to have a poor prognosis, with 5-year survival rates less than 20%.

Are you sure your patient has esophageal cancer? What should you expect to find?

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 pre-cancerous disease such as Barrett's esophagus for esophageal adenocarcinoma. As the cancer grows, symptoms gradually appear.

Symptoms by local tumor effects (comparatively early symptoms)

  • Reflux

  • Chest pain

  • Back pain

  • Weight loss

  • Dysphagia

Symptoms by advanced effects

  • Hoarseness 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. The redness of the conjunctiva of the eye may also present.

  • Recurrent pneumonia and severe cough by bronchoesophageal fistula.

  • Hiccups by phrenic nerve invasion.

  • Dyspnea from stricture of trachea by tumor invasion.

Beware of other conditions that can mimic esophageal cancer:

  • Esophageal varices

  • Achalasia: also a risk factor of ESCC.

  • Benign tumors: Papilloma, Lipoma, polyp, fibrolipoma, hemangioma, neurofibroma, leiomioma, hamartoma, cysts.

  • GERD

  • Reflux esophagitis

  • Caustic esophagitis

  • Infectious esophagitis

  • Esophageal ulcer

  • Booerhaave syndrome: spontaneous esophageal perforation which is thought to arise from a rapid increase in intraluminal esophageal pressure through a patent lower esophageal sphincter during vomiting. The sudden increase of intraluminal esophageal pressure is the result of failure of relaxation of cricoparyngeal muscle. Then, the transmural rupture of the esophageal wall happens, commonly in the left lateral and posterior wall of the lower third esophagus, 3cm above the gastroesophageal junction.

  • Esophageal diverticulum

Which individuals are most at risk for developing esophageal cancer:

Esophageal squamous cell carcinoma

  • Tobacco use: regardless of form, tobacco use is a major risk factor for esophageal squamous cell carcinoma. 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 of esophageal squamous cell carcinoma. OR: 4.2 (2.2-8.1), PAR: 72.4% (95% CI= 53.3-85.8).

  • Tobacco and alcohol interactions: heavy consumers of both alcohol and tobacco have the highest risk. Tobacco use has shown a two-fold to seven-fold increase in risk of esophageal cancer in alcoholics compared with rates for the general population.

  • Hot food and beverage.

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

  • Male gender.

Esophageal adenocarcinoma

  • Obesity, high BMI: increased 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 non-dysplastic 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 EAC than ESCC, it is still a significant risk factor for EAC. 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 laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

The American Joint Committee on Cancer (AJCC 7th edition 2010) have staged esophageal cancer using the TNM system. The major change between the 6th and the 7th editions was the development of separate stage groupings according to histology (See Table I, Table II, Table III, Table IV, Table V, Table VI).

Table II.

The depth of tumor invasion.
Subclass The depth of invasion Lymph node metastasis (SCC) % Lymph node metastasis (EAC) %
M1 Tumor limited to epithelial layer 0 0
M2 Tumor invades lamina propria 0-5.6 0
M3 Tumor invades but not into muscularis mucosa 6-23 0
SM1 Tumor penetrates the shallowest one-third of the submucosa 27-53.1 23-27
SM2 Tumor penetrates into the intermediate one-third of the submucosa 17-53.9 4-38
SM3 Tumor penetrates the deepest one-third of the submucosa 36-75 11-78

Table III.

Types of endoscopic therapy.
EMR The neoplastic epithelium is excised without destroying the neoplastic 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 Endoscopic resection cap or cap assisted endoscopic mucosal resection (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 widespread lesion, using EMRC technique has a number of disadvantages such as repeated submucosal lifting and required changing snare every time. An alternative to the EMRC technique is the ligate-and-cut technique. This technique uses a transparent 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.
Multiband musosectomy (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 allows for 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. After injection of a photosensitizing agent, exposure to light of an appropriate wavelength is delivered through a fiber introduced through the endoscope. The efficacy of PDT for treatment of patients with superficial esophageal cancer has not been evaluated yet.
RFA A specialized circumferential device for delivering radiofrequency energy to ablate esophageal epithelium.
APC APC is a non-contact electorcoagulation device that involves a high-frequency monopolar current which 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

Table IV.

Types of esophagectomy.
Type of surgery Brief Definition Advantages Disadvantages
Transhiatal esophagectomy (THE) Laparotomy and neck incision. Thoracic esophagus is bluntly dissected through diaphragm via the neck incision. Cervical esophagogastric anastomosis. Morbidity, mortality, and recurrence rates between THE and TTE in patients with esophageal cancer have not shown any significant differences. Inability to perform a full thoracic lymphadenectomy due to lacking of visualization of the midthoracic dissection.
Transthoracic esophagectomy (TTE, The Ivor-Lewis) Laparotomy with right thoracotomy and anastomosis at thoracic cavity. Direct visualization of the thoracic esophagus. Limited proximal margin
Full two-field lymphadenectomy.
Esophagectomy with three-field lymphadenectomy Laparotomy with right thracotomy and neck incision. Three-field lymphadenectomy (cervical, mediastinal, and abdominal) Higher mortality and morbidity
Accurate staging Requires technical skill
Minimally invasive esophagectomy Using laparoscopy and thoracoscopy to perform THE or TTE. Smaller incisions Randomized trials are needed to be considered as a standard approach
Less blood loss
Less post-operative
Complications
Decrease ICU and hospital stay
Better post-operative
Pulmonary function

Table V.

Chemotherapy for metastatic/recurrence cancer.
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 75mg/m2 IV on day 1 plus cisplatin 75mg/m2 IV on day 1 plus 5-FU 1000mg/m2 continuous infusion over 24 hours daily on day 1-5; cycled every 28 days.
ECF or its modifications (Category 1)
ECF
  • Epirubicine 50mg/m2 IV on day 1 plus cisplatin 60mg/m2 IV on day 1 plus 5-FU 200mg/m2 continuous infusion over 24 hours daily on day 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 75-100mg/m2 IV on day 1 plus 5-FU 750-1000mg/m2 continuous infusion over 24 hours daily on day 1-4; cycled every 28 days.
Or
  • Cisplatin 80mg/m2 IV on day 1 plus capecitabine 1000mg/m2 PO twice daily on days 1-14; every 21 days.
Or
  • Cisplatin 50mg/m2 IV on day 1 plus leucovolin 200mg/m2 IV on day 1 plus 5-FU 2000mg/m2/day IV on day 1; every 14 days.
Fluoropyrimidine and oxaliplatin
  • Oxaliplatin 85mg/m2 IV on day 1 plus leucovolin 200mg/m2 IV on day 1 plus 5-FU 2600mg/m2 IV continuous infusion over 24hours on day 1 ; every 14 days.
Taxan-based regimens
  • Paclitaxel 135mg/m2 IV on day 1 plus cisplatin 75mg/m2 IV on day 2; cycled every 21 days.
Or
  • Paclitaxel 90mg/m2 IV on day 1 plus cisplatin 50mg/m2 IV on day 1; cycled every 14 days.
Or
  • Paclitaxel 200mg/m2 IV on day 1 plus carboplatin AUC 6 IV on day 1; cycled every 21 days.
Or
  • Docetaxel 70-85mg/m2 IV on day 1 plus cisplatin 70-75mg/m2 IV on day 1; cycled every 21 days.
Or
  • Docetaxel 35mg/m2 IV on day 1 and 8 plus Irrinotecan 50mg/m2 IV on day 1 and 8; cycled every 21 days.
Single-agent regimens
  • Docetaxel 70-100mg/m2 IV on day 1; cycled every 21 days.
Or
  • Paclitaxel 135-175mg/m2 IV on day 1; cycled every 21 days.
Or
  • Paclitaxel 80 mg/m2 IV on day1 weekly; cycled every 28 days.
Or
  • Leucovorin 400mg/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 day 1 and 2; every 14 days.
Or
  • 5-FU 1200mg/m2/day IV continuous infusion over 24 hours on day 1-5; cycled every 28 days.
Or
  • Capecitabine 1000mg/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 8mg/m2 IV loading dose on day 1 of cycle 1, then 6mg/m2 IV; every 21 days with chemotherapy.

Table VI.

Chemotherapy for metastatic/recurrence cancer: second-line therapy.
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 8mg/m2 IV loading dose on day 1 of cycle 1, then 6mg/m2 IV; every 21 days with chemotherapy.
Taxane-based therapy
  •Docetaxel 75-100mg/m2 IV on day 1; cycled every 21 days.
Or
  •Paclitaxel 135-175mg/m2 IV on day 1; cycled every 21 days.
Or
  •Paclitaxel 80mg/m2 IV on day 1 weekly; cycled every 28 days.
Irinotecan-based therapy
  •Irinotecan 65mg/m2 IV on day 1 and 8 plus cisplatin 25-30mg/m2 IV on day 1 and 8; cycled every 28 days
Or
  •Irinotecan 250mg/m 2 IV on day 1 plus capecitabine 1000mg/m2 PO BID on day 1 to 14; cycled every 21 days.
Or
  •Irinotecan 180mg/m2 IV on day1 plus leucoborin 400mg/m2 IV on day 1 plus 5-FU 400mg/m2 IVP on day 1 plus 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily on day 1 and 2; cycled every 14 days.
Or
  •Docetaxel 35mg/m2 IV on day1 and 8 plus Irrinotecan 50mg/m2 IV on day 1 and 8; cycled every 21 days.

The elements of staging esophageal cancer are: the depth of tumor into or through the esophageal wall (T category), the presence of metastatic regional lymph nodes (N category), and distant metastases (M category). The initial treatment differs for each stage.

Barium esophagram

Barium esophagogram can provide tumor location, tumor size, and tumor shape. In addition, the depth of tumor (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 examine histology. Improper movement of vocal cord may suggest recurrent laryngeal nerve paresis. Laryngopharyngeal cancer may coexist with ESCC.

The depth of tumor could be estimated by its color, shape, size, flexibility of tumor and surrounding wall. The extent of tumor can be more clearly visualized with techniques such as chromoendoscopy and with new technology such narrow band imaging (NBI), autofluorescence (AFI), and optical coherence tomography (OCT).

Narrowband imaging (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)

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)

OCT is an imaging technology that allows imaging of biologic tissues to the micrometer scale. OCT sends an optical beam of infrared light into tissues and then measures the reflected or back-scattered intensity and depth of the 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)

EUS is useful in the evaluation of the depth of tumor and regional lymph nodes. 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 percent in a meta-analysis. For N staging, EUS-guided fine needle aspiration (FNA) of lymph nodes may help staging and diagnosis less invasively.

Bronchoscopy

Tracheal invasion can be observed. Stent would be placed when strictures of the trachea or tracheoesophagea fistulas exist.

Computed tomography (CT)

CT has difficulty distinguishing the depth of tumor 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 small lymph nodes which may have 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 which are not near the primary tumor. PET is the most important modality for distant metastatic disease detection.

Staging

See Table I. TNM staging for esophageal cancer.

What therapies should you initiate immediately i.e., emergently?

Most situations which need emergent management are inoperable cases. They are caused by either tumor invasion or metastases. Complications of cancer therapy also cause these situations. Therapies for these situations need to consider both treatment of the 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 not common with esophageal cancer versus lung cancer. Initial management of this condition is supportive care such as oxygen support. Minimizing the hydrostatic pressure, such as fluid limitation, head elevation, diuretics, and possibly steroids would reduce edema. Endovascular stent placement, radiation, and chemotherapy may help reduce symptoms.

Tracheoesophageal or bronchoesophageal fistula

Prognosis is very poor and most of the patients die in a month or two after developing this condition. Post-obstructive pneumonia might follow this condition subsequently. Therapy should be supportive to maintain quality of life. Double stenting (esophagus and airways) has been proposed rather than esophageal or airways 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. Non-operative management such as esophageal stent are 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 should the initial definitive therapy for the cancer be?

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

Treatment of esophageal sqamous cell carcinoma

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

  • Stage 0 and patients with M1 and M2, as well as those with M3 disease without lymphatic invasion: esophagectomy represents the most definitive approach. Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) are reasonable alternatives. The benefit of pre-operative 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 esophagectomy, EMR may be used along with/without photodynamic therapy (PDT) or radiofrequency ablation (RFA) therapy.

  • Patients with T2-3N0 (Stage IB), stage II and III (patients with positive lymph nodes): pre-operative chemoradiotherapy following 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 as well as those with M3 disease without lymphatic invasion: esophagectomy represents the most definitive approach, but EMR or ESD are reasonable alternatives. The benefit of pre-operative chemoradiotherapy for these patients is unclear.

  • Patients with submucosal cancer (T1b: SM diseases), esophagecetomy is recommended.

  • For poor-risk 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): pre-operative chemoradiotherapy following esophagectomy is recommended. Definitive chemoradiotherapy is 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.

Therapeutic approaches

Endoscopic therapy

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

Lymph nodes metastasis in esophageal cancer have been correlated with the depth of tumor invasion. Mucosal esophageal cancer (T1a) has recognized with low rate of metastatic lymph nodes but it is not 0%. There is a more comprehensive subclassification scheme which 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 metastasis. However the risk of lymph nodes metastasis rise up to 10% with M3 tumors.

It is still controversial if endoscopic therapy should be considered an alternative to esophagectomy for the treatment of T1a esophageal cancer. However, there are some benefits of endoscopic therapy compared to that of surgery: Preserving the function of digestive system, less invasive procedure, shorter hospital stay, etc. (See Table III)

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 in 30 to 37 daily, using 1.8 to 2.0 Gy daily fractions, five fractions per week. Small daily fractions (1.8 to 2.0 Gy instead of 2.5 to 3.0 Gy) reduce the likelihood of late toxicity.

The optimal dose for pre-operative chemoradiotherapy regimens is not defined, although a total dose of 45 to 50.4 Gy administered in daily 1.8 Gy fractions, five 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 five 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 to high radiation doses with relative sparing of surrounding structures. This technique may be used alone or in combination with EBRT with/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 fracton at 0.4-1.0 Gy/hr).

  • No previous EBRT: EBRT 30-40 Gy in 2-3 Gy/fraction followed by brachytherapy, (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 greater than 6 months: follow the definitive treatment.

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.

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 non-operative treatment. Chemoradiotherapy alone is used in many patients who are not fit enough for surgery or those who choose not to 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 randomised trials are still 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 esophagogastric junction (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 peri-operative mortality rates and better early clinical outcomes than those who undergo resection at lower volume institutions. (See Table IV)

In cervical esophageal cancer, if radical surgery is performed, it requires removal of portions of the larynx, the pharynx, the thyroid gland, and portions of the proximal esophagus. The surgery requires incisions in the neck, chest, and abdomen. In addition, a permanent terminal tracheostomy is also necessary.

Surgery may be considered for selected patients with earlier 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.

Treatment of esophagogastric junction cancer:

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

Treatment regimens

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

Early esophageal cancer: stage Ia

  • EMR or ablation are good primary treatment options for patients with Tis and T1a tumors whereas esophagectomy is still the preferred treatment for T1a tumor. For patients with T1b, esophagectomy is also the preferred treatment option. Although data is limited, Radiation therapy (EBRT) with/without concurrent chemotherapy and/or intraluminal brachytherapy are potentially useful alternatives to endoscopic therapy/esophagectomy for Stage I patient.

Resectable advanced esophageal cancer: stage Ib to III

Primary treatment options for patients with Stage Ib to III include pre-operative chemoradiation therapy, peri-operative chemotherapy, definitive chemoradiation therapy, or esophagectomy.

Pre-operative chemoradiation therapy

  • 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 pre-operative chemoradiotherapy regimens is not defined, although a total dose of 45 to 50.4 Gy administered in daily 1.8 Gy fractions, five days per week, produces reasonable results with acceptable toxicity.

Chemotherapy Regimens

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

OR

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

OR

  • Cisplatin 30mg/m2 IV on day 1 plus capecitabine 800mg/m2PO BID on days 1-5; weekly for 5 weeks.

OR

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

Peri-operative chemotherapy

3 cycles pre-operative and 3 cycles post-operative (only for EAC of the distal esophagus or esophagogastoric junction).

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

  • ECF modifications (category 1)

  • Epirubicin 50mg/m2 IV on day 1 plus cisplatin 60mg/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 pre-operatively and 3 cycles post-operatively.

  • Epirubicin 50mg/m2 IV on day 1 plus oxaliplatin 130mg/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 pre-operatively and 3 cycles post-operatively.

  • Epirubicin 50mg/m2 IV on day 1 plus cisplatin 60mg/m2 IV on day 1 plus capecitabine 625mg/m2 PO BID on days 1-21 cycled every 21 days for 3 cycles pre-operatively and 3 cycles post-operatively.

  • Epirubicin 50mg/m2 IV on day 1 plus oxaliplatin 130mg/m2 IV on day 1 plus capecitabine 625mg/m2 PO BID on days 1-21 cycled every 21 days for 3 cycles pre-operatively and 3 cycles post-operatively

Definitive chemoradiation therapy

  • Definitive chemoradiation therapy with infusional 5-FU (1000mg/m2per day, days 1 to 4 and 29 to 32) and cisplatin (75mg/m2 on days 1 and 29) using the radiation with a total dose of at least 50.4 Gy administered in daily 1.8 Gy fractions, five days per week concurrent with chemotherapy.

Or

  • Cisplatin 30mg/m2 IV on day 1 plus capecitabine 800mg/m2 PO BID 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, five days per week concurrent with chemotherapy.

In the MAGIC trial, a total of 503 patients with resectable gastric, EGJ, and distal esophageal adenocarcinomas were randomly assigned to surgery with or without peri-operative chemotherapy (3 cycles of pre-operative plus 3 post-operative cycles of ECF. 253 patients: surgery alone, 250 patients: peri-operative chemotherapy and surgery). At a median follow-up of four years, overall survival was significantly superior in the peri-operative chemotherapy group.

The Herskovic trial determined that concurrent therapy with cisplatin and fluorouracil and radiation is superior to radiation therapy alone in patients with localized carcinoma of the esophagus.

The CROSS trial used a total of 363 patients with potentially resectable esophageal or EGJ cancer were randomly assigned to surgery with or without pre-operative chemoradiotherapy (weekly paclitaxel 50mg/m2 plus carboplatin plus concurrent radiotherapy). Overall survival was significantly superior in the pre-operative chemoradiotherapy.

  • After results of these studies, definitive chemoradiation therapy with 5-FU and cisplatin using the radiation therapy dose of 50.4 Gy was established as the standard approach for patients with esophageal cancer.

Other possible chemotherapy regimens include:

  • Gemcitabine 1000mg/m2 IV on day 1, 8, 15 plus Leucovorin 20mg/m2 IV on day 1, 8, 15, plus 5-FU 500mg/m2 IV on day 1, 8, 15; cycled every 28 days.

Or

  • Pegylated liposomal doxorubicin 20mg/m2 on day 1 plus cisplatin 50mg/m2 IV on day 1 plus 5-FU 500mg/m2 IVP on day 1 plus 5-FU 600mg/m2 IV continuous infusion over 24 hours daily on day 1 and 2; cycled every 14 days.

Or

  • Mitomycin 6mg/m2 IV on day 1 plus Irrinotecan 125mg/m2 IV on Day 2 and 9; cycled every 28 days.

Or

  • Mitomycin 7mg/m2 IV on day 1 plus cisplatin 60mg/m2 IV on day 1 and 22 plus 5-FU 300mg/m2 continuous infusion over 24 hours daily on day 1-42; cycled every 6 weeks.

Or

  • Mitomycin 10 mg/m2 IV on day1 and 22 plus leucovorin 500mg/m2 IV on day 1 plus 5-FU 2600mg/m2 continuous infusion over 24h daily on day 1 weekly for 6 weeks and 2 weeks off.

Or

  • Etoposide 90-120mg/m2 IV on day 1-3; cycled every 28 days.

Or

  • Erlotinib 150mg/m2 PO daily.

Or

  • Cetuximab (single-agent or with chemotherapy): Cetuximab 400mg/m2 IV on day 1 of week 1, then Cetuximab 200mg/m2 IV on day 1 weekly.

Therapy for metastatic/recurrent cancer

Chemotherapy

The goals of chemotherapy in patients with metastatic/recurrence cancer are to palliate symptoms and improve survival.

First-line

There is no consensus as to the best agent or regimen. Combination chemotherapy regimens provide higher response rates than single agents. In randomized trials, the ECF (Epirubicine, 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 when oxaliplatin is substituted for cisplatin in the ECF regimen. (See Table V)

Second-line

There is no standard approach for second-line therapy after failure of the first-line regimen. QOL and minimization of side effects are key considerations when choosing the therapeutic approach. (See Table VI)

Trastuzumab

HER2 is a member of the epidermal growth factor receptor (EGFR) family that is associated with cell proliferation, migration, and differentiation. HER2 over-expression and/or amplification have 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 immunohistochemistry (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 t 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 esophageal adenocarcinoma.

Palliative therapy

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

  • radiofrequency ablation (RFA)

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

What other therapies are helpful for reducing complications?

Dysphagia

Assess the extent of disease, 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 their 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 as above.

  • Other potential causes: bowel obstruction, vestibular dysfunction, brain metastasis, electrolyte imbalance, uremia, concomitant drug treatments, gastroparesis, psychophysiologic.

What should you tell the patient and the family about prognosis?

The goals of therapy

Stages 0-IIIA(AJCC7)

  • Curative intent: endoscopic therapy, surgery, CRT, ETC

Stage IV/recurrent

  • Palliative intent: chemotherapy

Stage 0: overall 5-year survival; greater than 90%

  • Esophagectomy: curative intent

  • Endoscopic procedure (EMR,ESD, RFA, PDT): possible curative intent for patients who are not suitable or refuse surgery.

Stage I: overall 5-year survival; 56.5%(squamous), 67%(adenocarcinoma)

  • Esophagectomy: curative intent

  • Endoscopic procedure for Stage IA: possible curative intent for patients with M1 and M2 diseases

  • Definitive chemoradiation therapy: curative intent

Stage II: over all 5-year survival; 28%(squamous), 33%(adenocarcinoma)

  • Neoadjuvant chemo/chemoradiation therapy followed by esophagectomy: curative intent

  • Esophagectomy followed by adjuvant chemo/chemoradiation therapy: possible curative intent

  • Definitive chemoradiation therapy: curative intent

Stage III: over all 5-year survival; 8%(squamous), 8%(adenocarcinoma)

  • Definitive chemoradiation therapy: curative intent

  • Neoadjuvant chemo/chemoradiation therapy followed by esophagectomy: curative intent

Stage IV and recurrence: over all 5-year survival; less than 5%

  • Chemo/chemoradiation therapy: palliative treatment

  • Esophagectomy: palliative treatment

  • Esophageal stent placement: palliative treatment

  • Brachytherapy: palliative treatment

  • Gastro/jejunostomy: palliative treatment

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 chemoradiation therapy without surgery, salvage esophagectomy may be an option. Supportive care is recommended for medically unfit patients.

What if scenarios.

  • Incorrect initial staging (from not using PET/CT and/or lap staging at presentation) may lead to misclassification for curative versus palliative intent.

  • Overly toxic pre-operative treatment may prevent curative surgery or increase complications - for instance, excessive weight loss correlates with worse operative outcomes.

  • Low volume surgery centers may have higher rates of morbidity and mortality after surgery.

  • Unexperienced multidisciplinary clinical teams/centers may affect patients' quality of life.

  • No swallowing evaluation pre-operative and/or post-operative may result in prolonged J-tube use.

Follow-up surveillance and therapy/management of recurrences.

Guidelines for post-treatment surveillance of patients who have completed curative therapy vary. In particular, indications for the use of cross-sectional imaging is 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, complete blood count (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 one year and then annually.

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

Pathophysiology

Although the environment and exposure to risk factors are both important for esophageal carcinogenesis, genetic factors also have a role. Genetic polymorphisms of certain genes have been identified that might clarify the cause of esophageal cancer.

The molecular mutation most commonly associated with cancer, including esophageal cancer, is the p53 tumor suppressor gene TP53. However, this mutation is only one of many possible aberrations that can lead to esophageal carcinogenesis.

Esophageal squamous cell carcinoma is primarily due to chronic irritation of esophageal squamous epithelium, although the exact mechanisms responsible for the formation of esophageal squamous cell carcinoma are unknown.

Smoking has a synergistic effect with heavy alcohol consumption, and heavy exposure to both increases the risk of esophageal squamous cell carcinoma by many factors. Esophageal squamous cell carcinoma appears to develop through a series of changes from dysplasia to invasive carcinoma.

Genetic variability and patterns of mutation seem to be more diverse in esophageal squamous cell carcinoma that in esophageal adenocarcinoma. There are a few identified oncogenes in the pathogenesis of esophageal squamous cell carcinoma including MDM2 gene and ETS2 gene. The mutation of tumor suppressor genes have found in esophageal squamous cell carcinoma including Rb, p53, BCL-2, e.t.c.

Many cases of esophageal adenocarcinoma are believed to arise from Barrett's Esophagus by a process known as the Barrett's-Metaplasia-Carcinoma sequence. Chronic GERD is associated with Barrett's Esophagus. Barrett's Esophagus is defined as an esophagus in which the distal portion of the normal squamous lining has been replaced by a intestinal metaplastic columnar epithelium. The intestinal metaplasia may become dysplastic and finally malignant with genetic alterations which activate proto-oncogenes and disable tumor suppressor genes.

The formation of Barrett's Esophagus in this setting is a 2-step process: transition from squamous to columnar-lined esophagus and intestinalization of cardiac mucosa. With exposure to gastric juice, squamous mucosa is injured, and over time becomes replaced by cardiac columnar mucosa.

The exact details of molecular mechanisms of this first step remain unknown. However, there is likely to be some interaction between squamous stem cells and factors in gastric juice. The second step, intestinalization of cardiac mucosa, is acquiring goblet cells which secrete mucin. Key genes responsible for this intestinal differentiation are CDX2 and SHH.

The process of metaplasia-dysplasia-carcinoma sequence is driven by genomic instability and the evolution of clones of cells with accumulated genetic errors. Regulatory genes that have been implicated in the development of EAC include cyclin D1 and p16. Activation of telomerase is detected in esophageal adenocarcinoma.

Growth factors are also present in the damaged epithelium as the mucosa tries to heal, and dysregulation of these growth factors can contribute to carcinogenesis. Epithelial growth factor (EGF) belongs to the tyrosine kinase receptor family that is responsible for stimulating cell proliferation in the gastrointestinal tract. The expression of EGF has been shown to be aberrant in both Barrett's and EAC.

Cyclooxygenase 2 (COX-2) has a role in cell adhesion, invasion, angiogenesis, and metastasis, and its expression acts as an antiapoptotic mechanism. COX-2 is expressed in 70-80 % of EAC. Mutation of tumor suppressor genes such as TP53 have also detected in EAC. For a tumor to develop, tumor needs an adequate blood supply. Vascular endothelial growth factor (VEGF) is one of such promoter of angiogenesis, and the expression of VEGF has been demonstrated in both Barrett's esophagus and esophageal adenocarcinoma.

What other clinical manifestations may help me to diagnose esophageal cancer?

These conditions below have been reported as unusual first manifestations of esophageal cancer:

  • Brain metastasis

  • Fever of unknown origin

  • Guillain-Barre syndrome

  • Numb chin syndrome: numb chin syndrome (NCS) is a 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. Metastasis of mandible from esophageal squamous cell cancers have presented with Numb chin syndrome.

  • Cullen's sign: Cullen's sign refers to the presence of periumbilical ecchymosis and is most often recognized as a manifestation of hemorrhagic pancreatitis. Patients with metastastic SCC presented with Cullen's sign.

  • Nephrotic syndrome

  • Esophagocutaneous fistula

  • Psuedohyperparathyroidism

  • Hypercortisolism

What other additional laboratory studies may be ordered?

To make the final treatment recommendation, patients should be evaluated regarding staging and physical fitness:

  • Physical activity, biological age, and comorbidities should be considered.

  • Treadmill test and spirometry should be used to objectively evaluate fitness.

  • CBC and comprehensive metabolic panel.

Tumor markers are not helpful.

What's the evidence?

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