by C.H. Weaver M.D. Medical editor 5/2022
Optimal treatment of patients with esophageal cancer often requires more than one therapeutic approach. Thus, it is important for patients to be treated at a medical center that can offer multi-modality treatment involving surgeons, medical oncologists, radiation oncologists, medical gastroenterologists and nutritionists.
Patients with stage 0 - III and some patients with stage IV esophageal cancer can be treated with curative intent using surgery or by combining systemic therapy with surgery. Combined systemic therapy and radiation therapy alone is usually reserved for patients who are not able or do not wish to undergo major surgery.
Patients with stage IV or recurrent cancer are not currently considered curable with standard treatment and are typically offered treatment on clinical trials or with systemic therapy and supportive care measures.
Systemic therapy is any treatment directed at destroying cancer cells throughout the body, and may include chemotherapy or newer precision cancer medicines or immunotherapy. Treatment of patients with stage II - III or locally advanced esophageal cancer often consists of systemic treatment combined with surgery or radiation and systemic treatment is routinely used in stage IV or recurrent cancer.
Systemic Adjuvant Therapy (Treatment after Surgery)
Most patients with esophageal cancer already have small amounts of cancer that have spread beyond the esophagus that could not be removed with surgery and cannot be detected with any of the currently available tests. These undetectable areas of cancer are referred to as micrometastases and they are responsible for cancer recurrence following treatment with surgery alone. Additional systemic treatment aimed at these micrometastases can improve duration of survival and potential for a cure in some patients. The delivery of cancer treatment following local treatment with surgery is referred to as adjuvant therapy.
Neoadjuvant Therapy (Treatment before Surgery)
Some patients may receive treatment with systemic therapy (with or without radiation therapy) prior to surgery. This treatment can help to reduce the extent of cancer, making it easier to remove the cancer during surgery. Patients who receive systemic therapy prior to surgery often receive systemic therapy after surgery as well.
Types of Systemic Therapy
Systemic therapy may consist of chemotherapy, immunotherapy, or precision cancer medicines used individually or in combinations. All patients with advanced esophageal cancer should discuss the role of genomic biomarker testing for EGFR, HER2 and other targets in order to determine if they can benefit from treatment with a precision cancer medicine.
Checkpoint Inhibitor Immunotherapy
Immunotherapy medications called checkpoint inhibitors are changing how doctors treat esophageal cancer. The checkpoint inhibitors Opdivo (nivolumab) and Keytruda (pembrolizumab) both produce overall response rates of 30% in patients with PD-L1–positive, advanced esophageal cancers and improve survival when compared to chemotherapy. Keytruda and Opdivo are monoclonal antibodies work to restore the body’s immune system in fighting cancer. They create their anti-cancer effect by blocking a specific protein used by cancer cells called the programmed death-ligand 1 (PD-L1), to escape an attack by the immune system. Once PD-L1 is blocked, cells of the immune system are able to identify cancer cells as a threat and initiate an attack to destroy the cancer.
Precision Cancer Medicines
Precision cancer medicine utilizes molecular diagnostic & genomic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.
There are increasing numbers of precision cancer medicines that can target cancer driving mutations and more being developed in clinical trials. Patients with esophageal cancer should ensure their doctors perform genomic biomarker testing on their cancer and discuss the role of precision medicines in their treatment planning. Genomic testing can also be performed on a blood sample.
Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs, and can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill. Several different chemotherapy drugs are available for treatment of esophageal cancer.
- 5 - Flourouracil
- Xeloda (capecitabine)
- Lonsurf (Trifluridine/tipiracil)
- Lynparza (rubraca)
- Cyramza (ramucirumab)
Surgical Treatment of Esophageal Cancer
Surgery is an integral part of the treatment of esophageal cancer. However, since esophageal cancer is not exclusively a surgical disease, it is important for patients to be treated at a medical center that can offer multi-modality treatment involving surgeons, gastroenterologists, radiation oncologists, medical oncologists and nutritionists.
Removal of the esophagus (esophagectomy) may be utilized to prevent esophageal cancer from occurring in high-risk individuals with Barrett’s esophagus, as primary treatment for early stage cancer and as palliation to reduce side effects or symptoms from the cancer in patients with extensive disease. The primary goal of treatment (cure vs. palliation), the experience of the surgical team and the age of the patient should all be considered when making a decision about esophagectomy.
Barrett’s Esophageal With or Without Low-Grade Dysplasia
Surgery vs. Medical Management
Surgical management of patients with Barrett’s esophagus with or without low-grade dysplasia is directed at preventing reflux of stomach contents into the esophagus.
There is evidence that surgical prevention of reflux of stomach contents can prevent the progression of Barrett’s esophagus and may prevent progression to dysplasia. One clinical study demonstrated a decrease in columnar epithelium and low-grade dysplastic changes after anti-reflux surgery. In another study involving surveillance of patients with Barrett’s esophagus, none of the patients who had received anti-reflux surgery developed dysplasia.
These and other studies suggest that anti-reflux surgery can reduce symptoms and prevent progression to dysplasia. Long-term endoscopic follow-up is still required in all patients with Barrett’s esophagus after anti-reflux surgery because it is still unknown if this treatment prevents progression to cancer.
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The usual anti-reflux procedure (fundoplication) is a simple operation that does not involve cutting open the stomach or esophagus. The surgeon sews together the upper and middle parts of the stomach to prevent portions of the upper stomach from protruding above the diaphragm. This usually prevents reflux of stomach contents into the esophagus. Fundoplication can be performed through an incision in the left upper abdomen or through a laparoscope (a lighted flexible tube inserted through a small cut in the abdomen). One randomized clinical trial directly comparing the laparoscopy approach to the standard incision in the left upper abdomen demonstrated that the open operation was superior to the laparoscopic surgery for the prevention of reflux. Patient’s considering treatment with the laparoscopic procedure should inquire as to the success rate of the surgeon.
Barrett’s Esophagus with High-Grade Dysplasia
Several studies have clearly demonstrated that patients who have been diagnosed with high-grade dysplasia on endoscopic biopsy actually have a 40-50% chance of having invasive adenocarcinoma of the esophagus. In one study, one-third of patients who underwent esophagectomy for high-grade dysplasia with Barrett’s esophagus had stage I-III adenocarcinoma of the esophagus and approximately one-sixth of these patients ultimately died of adenocarcinoma. There were no deaths from cancer in patients who only had high-grade dysplasia. In a review of 85 patients who had esophagectomy as treatment for high-grade dysplasia, 41% had adenocarcinoma in the removed esophagus. These results highlight the unreliability of endoscopic biopsy in detecting early invasive cancer in patients with high-grade dysplasia of the lower esophagus in association with Barrett’s esophagus. The cure rate from surgery for high-grade dysplasia is over 90% and the cure rate for the 40-50% with adenocarcinoma depends on the stage of cancer. Esophagectomy currently appears to be the treatment of choice for patients with high-grade dysplasia occurring in Barrett’s esophagus.
Primary Surgical Treatment of Cancer of the Esophagus
Early cancers, stage 0 and I, can often be removed through an endoscope if they have not spread widely up or down the esophagus. However, the overwhelming majority of esophageal cancers require surgical removal of a large portion of the esophagus (esophagectomy).
Esophageal cancer cannot be cured in the majority of patients because the diagnosis is usually made after the cancer has spread. In addition, many patients are often too ill for aggressive surgical treatment. One of the major dilemmas facing patients with esophageal cancer is whether or not to undergo a major surgical procedure or to be treated with radiation therapy and chemotherapy without surgery.
There are several approaches to the surgical removal of the esophagus. The important considerations are to remove all of the cancer and to restore the continuity of the normal digestive system so that patients can feed themselves without excessive complications or death resulting from the surgery itself. The choice of type of surgery depends on the location of the cancer, extent of cancer, condition of the patient and the preference of the surgeon. Currently, 2 methods predominate: trans-hiatal esophagectomy and trans-thoracic esophagectomy. During an esophagectomy, the surgeon removes the portion of the esophagus containing the cancer and reattaches the remaining esophagus to the stomach.
During trans-hiatal esophagectomy, a surgeon makes two incisions, one in the cervical or neck region and the other in the upper abdomen. A third incision is made through the diaphragm, which is the breathing muscle that separates the chest from the abdomen. In contrast, a trans-thoracic esophagectomy involves a single incision in the left chest, with division of the left part of the diaphragm.
Surgical exploration of the abdomen is usually performed during all operations for removal of esophageal cancer. The sampling of lymph nodes can help determine the current stage of cancer and whether the goal of treatment is to be curative or palliative. During an esophagectomy, the esophagus is removed and then the stomach is pulled up to the neck region and is connected to the cut end of the remaining esophagus. Cancers of the lower esophagus are easier to treat than cancers of the upper esophagus because a longer portion of normal esophagus remains. Cancers of the upper esophagus can invade the larynx (voice box) and the pharynx (throat), making reconstruction of an adequate tube to the stomach difficult.
Complications of Esophagectomy
The major complications of surgery are pneumonia and leaking of digestive fluids at the site where the stomach is sewn into the remaining esophagus. The death rate from complications following esophagectomy varies from 0-17%, depending on the stage of cancer, condition of the patient and experience of the surgical team. It is important that patients planning to undergo surgery receive treatment at an institution that performs a large number of esophagectomies because the operative death rate is directly linked to the experience of the team of surgeons, anesthesiologists and nurses performing the operation. A recent clinical study evaluated deaths occurring in the first 30 days after esophagectomy in over 5,000 patients treated at various medical institutions. Following esophagectomy, 17% of patients died in hospitals that performed a few esophagectomies per year, compared to 3.4% in hospitals that performed many esophagectomies per year. This difference is even more revealing since larger centers often treat the more difficult cases. Patients should request information concerning the success and complication rates of the surgical team performing the esophagectomy at the institution where the operation is planned.
Surgery alone is the primary treatment for many patients with stage 0, I, or II esophageal cancers and results are detailed in the treatment overview sections. For more information, go to Stage 0 cancer, Stage I cancer, Stage II cancer.
Surgery for stage III cancer is somewhat controversial and is often performed after neoadjuvant chemotherapy and radiation therapy. For more information, go to Stage III cancer.
Extent of Surgery
There is currently some controversy over the extent of surgery required to eliminate all cancer in patients who have spread of cancer outside the esophagus. Some surgeons, especially in Japan, claim that survival is improved if extensive surgery is utilized to remove all of the involved lymph nodes. This is sometimes accomplished with three different surgical incisions. In general, the more extensive the surgery, the higher the complication and death rate. Some surgeons claim that less extensive surgery is acceptable. Unfortunately, no clinical trials have been performed that to directly compare more extensive surgery with less extensive surgery. In the United States, patients are more likely to be treated with chemotherapy and radiation therapy alone or before surgery (neoadjuvant therapy) and are less likely to be treated with more extensive surgery. In fact, some surgeons who have removed the esophagus through endoscopic techniques without a major surgical incision advocate minimal surgery.
Surgery in the Elderly
There are several clinical studies that suggest that advanced age alone should not preclude older patients from being treated with esophagectomy. These studies have evaluated and reported outcomes following esophagectomy in patients 70 years of age or older. In one clinical study, the in-hospital death rate was 18% for older patients and 14% for younger patients. In another study, survival at 5 years was 24% for elderly patients and 22% for younger patients. The condition of the patient and not the age should be the determining factor in pursuing an aggressive surgical approach for treatment of esophageal cancer.
Surgery for Palliation of Cancer of the Esophagus
In situations where the cancer cannot be cured, surgery is frequently utilized to improve the ability of patients to pass food through the esophagus. In one clinical study, doctors compared the outcomes of 39 patients with stage IV esophageal cancer who underwent an esophagectomy for palliation with the outcomes of 49 patients with stage IV esophageal cancer who underwent more complete removal of cancer. Both groups of patients experienced significant improvement with regard to both the quantity and quality of food intake and a reduction in the severity of eating related symptoms. After 9 months, patients in the palliative group experienced more pain and a poorer quality of life, but there were no differences in sleep, leisure activity and performance scores when compared to the other group. This study suggests that palliative esophagectomy relieves symptoms in the majority of patients with inoperable esophageal cancer. It could also be argued that both groups had palliative surgery since the majority of patients who undergo surgery with curative intent have rapid recurrence of cancer in the first year or two after surgery.
Prior to any surgical procedure, adequate preparation of the patient is important to minimize complications. Most patients with esophageal cancer are malnourished at the time of diagnosis. Aggressive nutritional support has not been shown to improve long-term survival, but it has been shown to improve survival in the immediate post-operative period. Nutrition before surgery can be enhanced by feeding through a naso-gastric tube and/or intravenous feeding. As discussed above it is important to maintain an open esophagus so that patients can feed themselves. In extreme cases, placement of a tube directly into the stomach is justified.
Radiation Therapy for Esophageal Cancer
Radiation therapy can be an integral part of the treatment of esophageal cancer. However, since esophageal cancer is not exclusively treated with radiation therapy, it is important for patients to be treated in an environment that can offer multi-modality treatment involving radiation oncologists, surgeons, gastroenterologists, medical oncologists and nutritionists.
The objective of radiation therapy to the esophagus is to kill cancer cells that could otherwise persist after therapy and cause the cancer to relapse locally. Radiation therapy uses high energy x-rays to kill cancer cells that remain in or near the esophagus and surrounding lymph nodes. Radiation therapy can be externally or internally delivered to the esophagus and surrounding lymph nodes. External beam radiation therapy (EBRT) delivers radiation from a machine outside the body, called a linear accelerator. EBRT treatments are typically delivered 5 days a week, for 2-6 weeks, depending on the overall goals of treatment and each treatment lasts between 10-15 minutes. The internal delivery of radiation therapy (brachytherapy) involves the placement of a radioactive isotope, such as iridium 192, within the esophagus.
Primary Treatment with Radiation Therapy
External beam radiation therapy alone is not usually recommended for primary treatment of esophageal cancer because radiation administered in combination with chemotherapy improves survival compared to treatment with radiation alone.
The results of radiation therapy and chemotherapy as primary treatment for esophageal cancer are presented under the treatment overviews for each stage of esophageal cancer. In general, current evidence suggests that combined chemotherapy and radiation therapy is superior to either therapy alone as primary therapy for esophageal cancer.
However, radiation therapy alone can be used to treat localized cancer in patients who cannot tolerate surgery or chemotherapy. Treatment with radiation therapy alone results in an approximate18% survival at one year, an 8% survival at two years and less than 5% survival at 5 years in patients with localized esophageal cancer (stage I-III).
Radiation therapy alone can also be used to decrease the symptoms from esophageal cancer in patients with more advanced disease who are medically unable to receive surgery or chemotherapy or for patients who have a recurrence after surgery. However, patients with locally recurrent cancer usually receive simultaneous chemotherapy.
Side Effects of Radiation Therapy
Radiation therapy may produce considerable short-term side effects such as 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. Some patients who respond to radiation therapy will develop strictures or narrowing of the esophagus that will require treatment in the future.