The first recorded case of esophageal cancer was described in China 2,000 years ago. It was called ye ge, which seems to have been a polite way of referring to difficult swallowing (dysphagia) and belching. It is a treatable and sometimes curable cancer, although most patients have a poor prognosis because the cancer is usually advanced by the time symptoms appear.
Special attention to good nutrition is an important part of treatment, especially since people in good physical condition with minimal weight loss have a better prognosis. Overall five-year survival for cases amenable to surgery is in the range of 15 to 25 percent; however, only 25 to 40 percent of cases are amenable to surgery. Earlier diagnosis and treatment can improve survival. Recent improvements in radiation therapy and chemotherapy results are somewhat encouraging.
Esophageal cancer is relatively uncommon in the United States, with an estimated 15,560 new cases in 2007, and approximately 13,940 deaths. It is responsible for less than 1 percent of all cancers and for 6 percent of gastrointestinal cancers.
Types Fifty percent of esophageal cancers appear in the cells lining the esophageal tube (squamous cells), usually in the upper two-thirds of the esophagus. About 50 percent develop in the glands (adenocarcinoma) in the lower third. One to 2 percent are relatively rare tumors, such as melanomas, primary lymphomas, and tumors in the smooth muscles, among others.
Whereas the incidence of squamous cell cancer has been declining in the United States, the number of patients with esophageal adenocarcinomas has been increasing over the past several decades. In particular, cancers located at the bottom end of the esophagus, right at the junction between the esophagus and the stomach, have become much more frequent. These cancers, known as GE (gastroesophageal) junction cancers, are sometimes classified as esophageal cancers, sometimes as gastric cancers, and sometimes as their own unique entity. Reasons for this trend may include the increased incidence of obesity and reflux disease (heartburn), which predispose individuals to a precancerous condition called Barrett’s esophagus.
How It Spreads Carcinoma of the esophagus usually starts on the surface layer, invades the surrounding tissue, and grows to cause an obstruction that makes swallowing difficult. It spreads through the lymph system to lymph nodes. The most common sites for metastases are the lymph nodes, lungs, liver, brain, adrenal glands, and bone.
What Causes It Alcohol and tobacco abuse are the most common causes of esophageal squamous cell cancer in North America. Contributing factors in other parts of the world include exposure to environmental carcinogens such as nitrosamines and diets deficient in riboflavin, magnesium, nicotinic acid, and zinc. Betel nut chewing and bidi smoking are major factors in India.
For esophageal adenocarcinomas, the primary cause is inflammation of the lower portion of the esophagus related to a chronic backup (reflux) of stomach acid with bile (gastric reflux) causing “heartburn.” This may also develop from a malfunction of the gastroesophageal valve. The cellular changes (called metaplasia) that result from long-term bathing of the esophageal lining with stomach acid is referred to as Barrett’s esophagus. Barrett’s is a precancerous condition in which the normal squamous lining of the esophagus is replaced by glandular (columnar) epithelium resembling the intestines.
Who Gets It Esophageal cancer is much more prevalent in China, Singapore, Iran, Puerto Rico, Switzerland, and France than in North America. On this continent, it is most prevalent among men over sixty, smokers, drinkers, and blacks. In the United States, men with esophageal cancer outnumber women by more than 3 to 1. The incidence of squamous cell cancers is higher in blacks than in whites, while the reverse is true for adenocarcinomas.
Risk Factors
At Significantly Higher Risk for Squamous Cell Cancers of the Esophagus
•Men over sixty.
•Long-term drinkers, especially in whites.
•Long-term smokers (more common in blacks than in whites).
•Smokers who drink alcohol (more common in blacks than in whites).
•Other causes of esophageal injury, such as lye ingestion and, possibly, long-term consumption of very hot beverages.
•Diets low in fruits, vegetables, and certain vitamins and minerals (vitamin E, beta-carotene, selenium).
•Individuals with esophageal muscle spasm (achalasia) or chronic stricture.
•Human papillomavirus (HPV) in certain parts of the world, such as Asia and South Africa.
At Significantly Higher Risk for Adenocarcinomas of the Esophagus
•A known diagnosis of Barrett’s esophagus. Individuals with Barrett’s esophagus confirmed by endoscopy have a 30- to 125-fold increased risk of developing esophageal adenocarcinoma compared to the general population at large.
•Obesity. According to one study, the risk of developing esophageal adenocarcinoma was almost three times higher for individuals in the highest 25 percent of body mass index compared to those in the lowest 25 percent.
•Long-standing gastroesophageal reflux disease (GERD), especially manifested by reflux/heartburn symptoms at least once a week and occurring at night.
•Poor diet (similar to that seen in esophageal squamous cell cancers).
Screening
Screening is not routinely performed in North America because of the low incidence of esophageal cancer. But high-risk individuals (such as those with Barrett’s esophagus) should undergo regular screening by upper endoscopy (also called esophagogastroduodenoscopy, or EGD for short). This procedure should be performed anywhere from once every three to six months to once every two to three years, depending on the severity of the Barrett’s. Patients with Barrett’s esophagus may be cured if treated when premalignant (high-grade dysplasia) or mucosal (noninvasive) malignant changes are detected.
Common Signs and Symptoms
The most common symptom of esophageal cancer—occurring in 90 percent of patients—is difficulty or pain in swallowing foods and liquids (dysphagia). Other symptoms include weight loss, which can be severe (cachexia), heartburn, hoarseness, pain in the throat or back, vocal cord paralysis, pneumonia, and coughing up blood.
Diagnosis
Physical Examination
•Enlarged lymph nodes, particularly over the left collarbone.
•The vocal cords may be less mobile or paralyzed.
•Tapping the spinal area may cause pain in the vertebrae.
•Rarely, thickening and scaling of the palms and soles.
Blood and Other Tests
•Cells for analysis similar to a Pap smear cytology may be scraped off a swallowed balloon or obtained with a brush inserted through an endoscope or a nasogastric tube.
•Blood counts and serum chemistry profile.
•Serum liver function tests to measure alkaline phosphatase, bilirubin, transaminases, and LDH. Elevated levels may suggest metastases to the liver or bone.
•An elevated CEA (carcinoembryonic antigen) may indicate liver metastases.
•Analysis of cell DNA and DNA histograms (flow cytometry) as well as molecular biological alterations are under evaluation as investigational diagnostic tools and may help identify patients with Barrett’s esophagus who are about to develop cancer. Preliminary data suggest that a tumor with abnormal chromosomes has a poorer prognosis.
Imaging
•A barium swallow and X-ray of the esophagus may reveal abnormalities suggestive of an esophageal tumor.
•A chest X-ray can detect masses in the midchest area and the lungs.
•CT scans of the chest and abdomen can often identify the location, size, and depth of penetration of the tumor through the wall of the esophagus (T stage), as well as surrounding lymph nodes (N stage). However, endoscopic ultrasound (below) is a more accurate tool to assess T and N staging. CT scans can also evaluate for the presence or absence of metastatic lesions (e.g., in the liver or lungs).
•Endoscopic ultrasound (EUS) is a specialized procedure in which a gastroenterologist places a long flexible tube down the patient’s throat, similar to a regular upper endoscopy. However, in EUS, an ultrasound probe is present on the end of the tube, which allows for visualization and accurate assessment of the size and depth of the tumor’s invasion of the esophagus, as well as evaluation of the status of nearby lymph nodes.
•Positron-emission tomography (PET) scans are often used as part of the staging evaluation, especially to look for the presence of metastases.
Endoscopy and Biopsy
•Upper endoscopy is the key test because it allows both visualization and biopsy. A flexible fiber-optic tube is passed through the mouth and down the esophagus. A piece of tissue may be removed with forceps (punch biopsy and cytology). Twenty-five to 40 percent of patients have a narrowing of the esophagus, which does not permit an endoscope to be passed, so an esophageal dilation may be needed.
•For tumors near the place where the trachea (central air passage) divides into the right and left bronchi, it is advisable to include bronchoscopy to evaluate whether the tumor has eroded through the esophagus into the airway.
•A mediastinoscopy (inspection of the center of the chest through a thin telescope) may be needed occasionally to assist in staging, for biopsy, and to help decide on surgery.
Staging
The TNM classification system is used to describe the stage, referring to the depth of penetration through the esophageal wall (T stage), the involvement of lymph nodes near the esophagus (N stage), and the presence or absence of metastases (M stage). Clinical staging is typically arrived at through a combination of CT scanning, endoscopic ultrasound (if available), and sometimes PET scan. Laparoscopy (a minimally invasive surgical procedure in which a camera is placed in the abdomen to evaluate the abdominal contents) is used on the rare occasion. Precise staging can truly be made only from an operation in which the esophageal tumor and regional lymph nodes are removed.
Treatment Overview
The treatment of esophageal cancer typically involves a multimodality approach, in which any one or a combination of different strategies—radiation therapy, surgery, chemotherapy—are used.
Surgery Since most patients in North America have advanced (Stage III) esophageal cancer before diagnosis, only 25 to 40 percent have tumors that can be removed in an attempt at cure. Before surgery, an evaluation for metastases is performed.
Radical surgery for cure involves removing the entire esophagus (or a good part of it) and the surrounding tissues and lymph nodes. If the lesion is in the lower esophagus near the stomach, the top of the stomach has to be removed as well. Once the esophagus is removed, the stomach can be brought all the way up to bridge the gap (esophagogastrostomy). A portion of the colon may be used instead. This operation is rather demanding of both patient and surgeon. It should be performed only in major medical centers because complex care will be needed during and after surgery.
Mortality ranges from 5 to 10 percent, but the removal of the esophagus relieves swallowing problems in over 90 percent of patients and is imperative for a chance of cure.
Tumors in the upper half of the esophagus may have invaded the trachea or larynx, so reconstruction (with a high risk of complications) will be required.
In patients with Barrett’s esophagus who appear to be at very high risk for development of cancer, the esophagus may be removed as a prophylactic (preventive) measure.
Two types of surgery to replace a cancerous portion of the esophagus
Radiation Therapy Radiation therapy is used in several different settings for esophageal cancer. It is typically used concurrently with chemotherapy, as the combination of chemotherapy and radiation produces higher rates of response and better patient outcomes than radiation alone. The settings in which radiation is used include (1) before a planned operation (in combination with chemotherapy), to shrink the cancer; (2) for the definitive treatment of esophageal cancer (also in combination with chemotherapy), in patients who are not good operative candidates; and (3) for palliation, in patients who have obstructive symptoms or active bleeding from their tumor that is difficult to control (either with or without concurrent chemotherapy). Side effects of radiation therapy can include a short-term inflammation of the esophagus and the development of a benign stricture (30 percent), which can be dilated.
Very precise treatment planning using an X-ray simulator is important for the best results, with CT scans used to plan treatments accurately. This involves lying on a flat table, similar to that of an actual radiation therapy machine, and drinking oral contrast (which may taste like a sour milkshake). The radiation oncologist will then take simulation films. He or she will transfer the tumor volume from the CT scans, endoscopic ultrasound, and oral contrast onto the simulation films in order to set up a daily treatment port. This will include the primary tumor, draining lymph nodes, and a margin of healthy tissue.
Intraluminal radiation using a radiation source placed inside the esophagus (intraluminal brachytherapy) may complement external radiation in some circumstances, typically as part of palliative treatment. A radiation source (iridium-192) is inserted into the esophagus and left at the tumor site for several hours. Side effects can include inflammation of the esophagus, bleeding, and a hole from the esophagus into the lungs (esophagobronchial fistula).
Chemotherapy Chemotherapy is moderately effective in the treatment of esophageal cancer. As noted above, it is often given concurrently with radiation based on evidence that combined chemotherapy and radiation is superior to radiation by itself. The combination of two drugs, cisplatin (Platinol) and 5-fluorouracil, is the most commonly used chemotherapy regimen administered together with radiation; however, other chemotherapy agents and newer targeted therapies have also been looked at and are currently being evaluated.
Giving chemotherapy with or without radiation therapy prior to an operation for esophageal cancer (referred to as neoadjuvant therapy) remains a controversial issue. Many studies have examined this question, comparing preoperative chemotherapy and/or radiation followed by surgery, versus surgery alone. A few of these studies have shown a survival advantage by giving the preoperative treatment, but most of them have failed to demonstrate any difference. Thus, this remains an important study question. Tumors of the gastroesophageal junction are sometimes treated as esophageal cancers and sometimes as stomach cancers; in the latter case, surgery is often performed first, then chemotherapy and radiation are delivered after the patient has recovered from the operation.
Chemotherapy is also given for individuals with more extensive, advanced disease, such as those with metastases. Many different chemotherapy agents have been used, alone and in combination, including platinum agents (cisplatin, carboplatin [Paraplatin], oxaliplatin [Eloxatin]), fluoropyrmidines (5-FU, capecitabine [Xeloda]), taxanes (paclitaxel [Taxol], docetaxel [Taxotere]), irinotecan (Camptosar, CPT-11), and epirubicin (Ellence), among others. In general, using two or three drugs in combination produces higher response rates than using single drugs, although this has not been definitively proven to translate into longer survival time. Furthermore, combination regimens, predictably, are associated with greater toxicities, and so quality-of-life issues need to be balanced out.
Palliation Symptoms associated with the esophageal tumor, most commonly obstruction of the esophagus resulting in difficulty and discomfort with swallowing, can often be managed using the previously described modalities. For example, sometimes patients with moderate swallowing difficulties experience significant relief after starting chemotherapy, or with a short course of radiation. An aggressive operation purely for the goal of palliating symptoms (as opposed to trying to remove all disease) should be undertaken with caution, given that the other options available to patients are less invasive.
Mechanical dilation, most commonly using a balloon dilator, can be used to open up areas of esophageal narrowing due to tumor, or due to benign strictures that develop following an operation or postradiation. Esophageal rupture is an infrequent but serious complication of dilation. Esophageal stenting is another approach that can be used to palliate obstructive symptoms that develop from esophageal cancer. A stent is placed by a gastroenterologist (or, less commonly, by an interventional radiologist) via endoscopy. Stents may be either plastic (which have a higher rate of migrating to a wrong location after they are placed) or metallic; they are compressed onto a delivery catheter and then deployed (expanded) once in the correct location.
Endoscopic laser therapy (ELT), administered through a flexible tube inserted through the mouth, has been used to relieve swallowing problems. Lasers can vaporize the tumor and cut a hole through a blockage in the esophagus, although the hole will last only a few weeks to three months. The procedure can be repeated to keep the obstruction open, but repeated laser treatments may be more difficult. With laser therapy, there are dangers of perforation, bleeding, and fistula formation. Also, lasers can treat tumors only inside the esophagus, not tumors outside the esophageal wall. More recently, a newer technique called photodynamic therapy incorporates the intravenous administration of hematoporphyrin derivatives (photosensitizing drugs) with laser therapy to palliate symptoms of dysphagia, as well as obliterate Barrett’s esophagus and some early esophageal cancers.
Treatment by Stage
Stage 0
TNM Tis (tumor or carcinoma in situ)
This very early cancer has not spread below the lining of the first layer of esophageal tissue. It is unusual for cancer to be found at this stage in Western countries, although it’s not unusual in China, where esophageal cancer is seen frequently and screening programs are common.
Standard Treatment Early-stage esophageal cancer can be cured with surgery. Radiotherapy could be an option in poor-risk patients.
Five-Year Survival The prognosis is excellent if the tumor is treated surgically or with radiotherapy.
Stage I
TNM T1, N0, M0
The tumor does not penetrate the muscular wall, and there is no spread to lymph nodes, adjacent structures, or other organs. While patients may have some difficulty swallowing, there is usually no obstruction of the esophagus.
Standard Treatment Stage I esophageal cancer is treatable and often curable. Surgical removal of the tumor is the treatment of choice, with the highest success rate for cancer in the lower third of the esophagus. The diseased portion of the esophagus and the adjacent lymph nodes are removed. With surgery, there is a 5 to 10 percent mortality rate and a 15 to 30 percent complication rate.
For individuals who are not operative candidates for some reason, radiation therapy may effectively control and sometimes cure small tumors. As noted previously, the concurrent use of chemotherapy and radiation produces better outcomes than radiation therapy alone.
A newer approach, endoscopic mucosal resection, is being actively investigated as a less aggressive alternative to surgical resection for early-stage esophageal cancers. This is performed using a small cap with a wire loop that fits on the end of the endoscopy tube. The tumor is suctioned into the cap, and the wire loop is closed, snaring the tumor while the area is cauterized to minimize bleeding.
Five-Year Survival 40 to 80 percent
Stage IIA
TNM T2–3, N0, M0
Stage IIB
TNM T1–2, N1, M0
The cancer has not spread to adjacent organs, but may have spread to regional lymph nodes (Stage IIB).
Standard Treatment Surgery still represents the mainstay of treatment for patients with this stage of disease who are robust enough to sustain a major operation. Cure is still possible in some individuals. The potential for cure has to be counterbalanced by the significant operative risks and perioperative mortality and morbidity, including infection, leak at the surgical anastomosis site (the area where the organs are reattached), vocal cord paralysis, and stricture.
Combination therapy with chemotherapy and radiation is sometimes given prior to surgery, although, as noted above, the benefits of preoperative therapy remain controversial. The choice of chemotherapy agents that can be given in this context is expanding, with the most well-studied regimen being cisplatin and 5-fluorouracil. About 20 percent of patients treated with preoperative chemotherapy plus radiation have had a complete pathologic response at the time of surgery, meaning that no tumor was found at the time they went to operation. Patients who are found to have had a complete pathologic response have a better prognosis than those patients who have a lot of residual tumor at the time of surgery. For some individuals, especially those who are poor operative candidates, chemotherapy plus radiation, without surgery, may be the best option and may still offer the possibility of long-term survival.
Five-Year Survival 25 to 50 percent
Stage III
TNM T3–T4, N1, M0 or T4, any N, M0
The tumor has spread outside the esophagus and there is extensive lymph node involvement, but there are no metastases.
Standard Treatment The same treatment strategies apply here as discussed for Stage II disease, with the notable difference that fewer patients will be able to undergo a successful operation. Given the bulky tumor and the presence of multiple lymph nodes, there is usually more of an impetus to start with chemotherapy and radiation before attempting surgical resection, to debulk the tumor and try to eradicate as much of the cancer as possible. Prophylactic placement of a feeding tube for nutritional support is often necessary. For patients who are not appropriate surgical candidates, definitive chemotherapy and radiation is the most common approach and can sometimes produce long-term remissions.
Five-Year Survival 10 to 15 percent
Stage IV
TNM Any T, any N, M1
The tumor has spread to other organs (distant metastases).
Standard Treatment Chemotherapy represents the mainstay of care for patients with Stage IV esophageal cancer. As noted in the chemotherapy section above, a variety of chemotherapy agents have been tested in esophageal cancer, both alone and in various combinations, with varying degrees of success. Many of the combination regimens produce similar rates of response, in the range of 30 to 50 percent, each with its own unique schedule and side-effect profile. Regimens should be tailored according to a patient’s functional status as well as his or her personal preference (in terms of schedule, intravenous versus oral administration, willingness to accept particular side effects, etc.). For individuals with poorer functional status, single-agent therapy may be more appropriate.
All patients may be considered candidates for investigational protocols evaluating novel approaches to treatment, including promising chemotherapy combinations and new targeted agents in development.
While chemotherapy alone may palliate symptoms effectively, some patients may require other modalities as discussed above, such as radiation, stenting, dilation, and insertion of a feeding tube.
Five-Year Survival Less than 5 percent
Supportive Therapy
People with esophageal tumors often have a poor nutritional status. Attempts to correct weight loss may help reduce the complications of surgery, radiotherapy, chemotherapy, and combined treatments.
•A nasogastric feeding tube (if it can be passed through the obstruction) or a percutaneous (through the skin) feeding tube (gastrostomy or jejunostomy) may be used for enteral nutrition.
•Parenteral hyperalimentation (nutrition given intravenously) may be necessary for support during therapy.
•Esophageal dilation, stenting, or laser therapy to maintain an open esophagus may help maintain nutrition.
Treatment Follow-Up
Patients who have had treatment for cure should visit their physician every few months for close follow-up, including history and physical examination. Laboratory work, imaging studies (chest X-ray and CT scans), and endoscopies can be performed as indicated.
Recurrent Cancer
Depending on the location and extent of disease recurrence, chemotherapy, radiation, and local palliative procedures as described above may be considered in the treatment plan, although the likelihood of cure at this point is remote.
Prevention
•Avoid drinking alcohol and smoking.
•For Barrett’s esophagus, it is important to try to heal the esophagitis and prevent the reflux of stomach acids.
Reflux may be managed by using H-2 blockers or proton pump inhibitors to relieve symptoms, by changing the pressure in the lower esophagus with metoclopramide (Reglan), and by not eating for several hours before sleep. Proton-pump inhibitors such as Prilosec (omeprazole), Prevacid (lansoprazole), and Nexium (esomeprazole) may not only help heal esophagitis, but also heal or normalize a Barrett’s esophagus. Avoid being overweight and increase intake of fresh fruits and vegetables. Dietary restrictions—avoiding fats, caffeine (coffee), chocolate, and peppermint—and opiates, calcium-channel blockers, and anticholinergic drugs may also help control reflux.
The Most Important Questions You Can Ask
•Do I have squamous cell cancer or adenocarcinoma?
•Am I an appropriate candidate for surgery?
•What kind of surgery will be performed [remember, there are different types of operations for esophageal cancer]? How experienced is my surgeon in performing this type of operation?
•How does my stage of disease relate to the chance for cure?
•If I am being considered for surgery, would you recommend I receive chemotherapy and radiation beforehand?
•How can I obtain nutritional support?
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