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Esophageal Cancer

Esophageal Cancer Treatment: The Role of Combined Radiation and Chemotherapy  
  Submitted By: Samir V  Sejpal, MD. MPH

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The Role of Combined Radiation and Chemotherapy in the Treatment of Esophageal Cancer

Authored by: Samir V Sejpal, MD. MPH (1), Mary F. Mulcahy, MD (2), William Small Jr., MD (1)

Northwestern University


Introduction

Esophageal cancer, including cancer arising from the gastro-esophageal junction, is a challenging disease worldwide. At diagnosis, approximately 50% of patients present with disease that extends beyond the site of origin in the esophagus(1). Patients who are not medically fit for surgery or who have disease that cannot be completely removed by surgery will need aggressive treatment with a combination of chemotherapy and radiation therapy. In patients with esophageal cancer that can be completely removed with surgery, the use of chemotherapy and radiotherapy before or after surgery may be needed to achieve a cure. Treatment with chemotherapy alone or chemotherapy plus radiotherapy are strategies that continue to be explored in investigational clinical trials. With improvement in surgical techniques and the use of multi-modality therapy, the overall five-year survival of esophageal cancer has improved from 4% in the 1970s to 14% today(2). New treatment strategies include identification of and directed treatment at specific molecular targets that are involved in the growth or spread of esophageal cancer cells. This article will highlight the role of combined chemotherapy and radiation therapy in the treatment of esophageal cancer with an emphasis on results from randomized, controlled clinical trials.

Incidence

The American Cancer Society estimates that in 2005, approximately 14,520 Americans will be diagnosed with esophageal cancer and 13,570 will die from it(3). Esophageal cancer is the ninth most common cancer in the world(1).

Natural History of Esophageal Cancer

The esophagus is a thin walled tube that carries food from the back of the throat to the stomach. Esophageal cancer spreads by local growth into adjacent tissues, by spread into lymph nodes, and by invasion of the blood stream with spread to distant organs. Lack of a thick outer covering on the esophagus allows esophageal cancer to spread into adjacent blood vessels and organs such as the trachea (windpipe). The lymphatic drainage of the esophagus is a system of interconnecting vessels that allows for spread of cancer to a widely range of lymph nodes(4). Lymph node dissemination varies by site of origin of the cancer: cancers of the mid and lower esophagus initially spread to lymph nodes in the middle of the chest and the abdomen, while those arising at the junction of the esophagus and stomach spread mainly to abdominal lymph nodes with frequent involvement of lymph nodes near the liver and spleen(5).

Epidemiology

Squamous cell carcinoma and adenocarcinoma account for 90% of all esophageal cancers.2 Before 1970, adenocarcinomas accounted for less than 5% of all esophageal cancers in the Western Hemisphere.6 Adenocarcinoma has now surpassed squamous cell carcinoma as the most common type of esophageal cancer. The lower third of the esophagus, where 75% of all adenocarcinomas are found, is the most common site of esophageal carcinoma (1,2).

The incidence of esophageal cancer varies considerably among racial lines and geographic regions. In the last two decades, the incidence of esophageal adenocarcinoma has risen by 10% per year in white males in the U.S., an increase which exceeds that of any other malignancy in this population.6 Great Britain, Australia, the Netherlands, and the United States are considered high incidence areas (6,7). Squamous cell carcinoma remains more common among African-Americans, with a frequency five times higher than in Caucasians (7)

Risk Factors

Several studies have described risk factors associated with esophageal cancer. Alcohol intake, especially in combination with smoking, causes chronic irritation and inflammation of the inner lining of the esophagus and predisposes to the development of squamous cell carcinoma (2). Other risk factors for squamous cell cancers include: food preservatives such as nitrosamines, achalasia (a narrowing of the lower esophagus that causes chronic retention of food), caustic injury, and genetic predisposition (4,8). Due to a high incidence of tobacco use, these patients will often present with concurrent or subsequent cancers of the upper aerodigestive track such as lung cancer or head and neck cancer (8).

Barrett’s esophagus, a pre-cancerous condition caused by long-standing acid reflux into the esophagus from the stomach, is the strongest risk factor for the development of esophageal adenocarcinoma (6). Obesity and the frequent use of antacids, H2-blocking drugs, and drugs that relax the gastro-esophageal sphincter are felt to increase gastro-esophageal reflux and may be implicated in the development of adenocarcinoma (2).


Clinical Presentation

Difficulty with swallowing is the most common presenting symptom and occurs in 90% of patients. This symptom is usually progressive and may lead to gradual weight loss. Up to 50% of patients complain of pain with swallowing. Advanced cancers may cause hoarseness (due to cancer compressing the nerve to the vocal cords), persistent cough (due to cancer eroding into the windpipe), or bloody vomiting or dark stools (due to bleeding from the cancer) (9,10).

Diagnostic Studies

The outcome of esophageal cancer is strongly associated with pretreatment stage or extent of disease. Extent of tumor growth through the esophageal wall (T stage), involvement of lymph nodes near the esophagus (N stage), and spread to distant lymph nodes (celiac axis and supraclavicular) or other organs (M stage) each contribute independently to prognosis. Endoscopic ultrasound (EUS), computed tomography (CT) and positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) each have distinct advantages and limitations in determining the extent of disease.

Endoscopic Ultrasound (EUS)

EUS is considered the test of choice to evaluate local tumor growth in the esophagus, depth of invasion, and spread of cancer to adjacent lymph nodes. A high frequency ultrasound transducer can provide images of the esophageal wall as a five-layer structure. T stage is determined by the extent of disruption of the various layers. Lymph node involvement can be determined by the ultrasound characteristics of the lymph nodes near the esophagus, either in the middle of the chest or in the upper abdomen. N stage can be confirmed with EUS fine needle aspiration (FNA) biopsy of the involved lymph node (11). FNA is discouraged for lymph nodes directly adjacent to the main cancer, but can be invaluable in identifying disease in lymph nodes away from the primary cancer (e.g. celiac axis lymph nodes). The accuracy of EUS staging is approximately 90% for T stage and close to 80% for N stage (12).

Computed Tomography (CT) and Positron Emission Tomography (PET)

Distant metastases (M stage) are detected with CT and PET scans. CT scans aid in detecting extent of invasion of surrounding structures by the primary cancer. However, CT scans are limited by their inability to identify cancer in normal-sized lymph
nodes (13).

The advantage of PET scans lies in their ability to detect the uptake of glucose (sugar) in malignant cells with the use of the radioactive tracer FDG. A recent analysis of many studies evaluating the staging performance of PET scans in esophageal cancer found that FDG-PET had a moderate level of accuracy for the detection of regional lymph node spread of the cancer (sensitivity = 51% and specificity = 84%), and reasonably better accuracy for the detection of more distant spread (sensitivity = 67% and specificity = 97%) (13).

Treatment Options:

Surgery alone

The goal of surgery is to achieve a complete removal of the cancer, and it is considered the standard treatment approach in early stage esophageal cancer. Over 95% of patients with stage 0 disease who have had complete surgical removal of their cancer are alive 5 years after surgery. However, the percentage of patients alive 5 years after surgery alone decreases dramatically with higher stage disease (50% to 80% for stage I disease, 30% to 40% for stage IIA disease, 10% to 30% for stage IIB disease, and 10% to 15% for stage III disease) (2). If a patient is considered medically fit to undergo surgery (has the ability to tolerate major abdominal and chest surgery), and has a cancer that can potentially be completely removed, treatment with surgery alone will result in an average survival time of approximately 17 months (14). The addition of chemotherapy and radiation to surgery has been studied extensively in an attempt to improve survival and will be discussed later.

Palliative surgery (solely for the relief of symptoms) for cancer that can not be completely removed is discouraged.1 Palliative treatment is aimed at relieving symptoms such as difficulty with swallowing. Placement of an expandable metal stent (tube) within the esophagus, balloon dilation of the esophagus, and laser ablation of tumor within the esophagus are procedures that can promptly improve a patient’s ability to swallow (2,15). The role of chemotherapy and radiation therapy in the setting of advanced disease is addressed later.

Radiation Therapy Before or After Surgery

When radiation therapy alone is given for esophageal cancer, less than 20% of patients are alive 2 years after treatment (16,17). Five randomized clinical trials have compared treatment with radiation therapy before surgery to surgery alone. None of these trials have shown a survival advantage for patients treated with radiation therapy before surgery (4,18). Two randomized clinical trials have compared treatment with surgery alone to surgery plus radiation therapy after surgery (19,20). Neither of these trials has shown that radiation therapy given after surgery improved survival or the occurrence of distant spread of the cancer, although one trial did show a significant improvement in control of the cancer around the esophagus in patients treated with radiation therapy after surgery (19).

Chemotherapy Before or After Surgery

Two randomized clinical trials have compared treatment with chemotherapy before surgery to surgery alone in patients with esophageal cancer that could potentially be completely removed. The Intergroup 0113 trial showed that patients who received chemotherapy with 3 cycles of cisplatin plus 5-fluorouracil (5-FU) prior to surgery and 2 cycles after surgery, did no better in terms of survival when compared to patients who had surgery alone. The percentage of patients alive 2 years after treatment was 35% and 37%, respectively (21). A British study involving 802 patients suggested that patients treated with chemotherapy (cisplatin plus 5-FU) before surgery lived an average of 3.5 months longer than those treated with surgery alone (16.8 months vs 13.3 months) (22). This trial has been criticized for problems with its experimental design and at this time the National Comprehensive Cancer Network (NCCN) Guidelines Panel does not recommend treatment with chemotherapy before surgery as the standard of care for patients with esophageal cancer that can potentially be completely removed (1). The role of chemotherapy after surgery has not been established(1).

Combined Modality Treatment

Given the suboptimal survival results with surgery alone, the limited success of radiation therapy in given before or after surgery, and the demonstrated activity of chemotherapy in patients with advanced disease, treatment strategies combining radiation therapy and chemotherapy given at the same time have been investigated. When radiation therapy and chemotherapy are given together, they work together to allow for maximal tumor control. Radiation therapy works to control disease at the local site within the esophagus and middle of the chest. Chemotherapy not only works to control microscopic spread of the disease throughout the body, but it also acts as a radiation sensitizer, allowing the radiation to be more effective at the local site of disease. Combined modality strategies, using combinations of chemotherapy, radiation therapy, and surgery, have been explored to improve symptoms related to the primary tumor in patients with advanced disease, to achieve disease control for patients with locally advanced cancer, and to improve the duration of survival and rate of cure for patients with disease that can potentially be completely removed.

Disease that Cannot be Completely Removed with Surgery

The Radiation Therapy Oncology Group (RTOG) study 85-01 compared treatment with 4 cycles of cisplatin plus 5-FU with radiation therapy (50 Gy in 25 fractions) to radiation therapy (64 Gy in 32 fractions) in patients with local-regional thoracic esophageal cancer (T1-3, N0-1, M0) (23) Ninety percent of the patients had squamous cell carcinoma. Patients treated with both chemotherapy and radiation therapy had a significantly better average duration of survival (14 months vs 9 months, p < 0.0001) and more of these patients were alive 5 years after treatment (27% vs 0 %, p < 0.0001) (23,24). At 8 years, 22% of patients who received combined modality treatment remained alive (25)

RTOG 85-01 was important for several reasons. Combined chemotherapy plus radiotherapy became the new standard of care for patients with esophageal cancer that was not amenable to surgical removal. Even for patients with localized esophageal cancer, the percentage of patients alive 5 years after treatment with chemotherapy plus radiation therapy (27%) was comparable to that achieved with surgery alone(26). This implies that surgical and non-surgical therapy may be equivalent, especially considering that patients treated with combined modality therapy generally have more advanced disease and are less medically fit than patients who are treated with surgery alone.

Despite the positive results of the patients treated with combined modality therapy in RTOG 85-01, there was a high rate of locally persistent or recurrent disease with 47% of patients experiencing recurrence of cancer at the primary site as the first site of treatment failure (27). The Intergroup 0123 trial was designed to evaluate the optimal dose of radiation therapy in patients with esophageal cancer not amenable to surgrey (27). Patients with stage T1-4, Nx, M0 squamous cell or adenocarcinoma of the esophagus were eligible. All patients received chemotherapy with cisplatin plus 5-FU in a similar schedule as RTOG 85-01 and were randomly assigned to receive either high-dose radiation therapy (64.8 Gy in 36 fractions) or moderate-dose radiation therapy (50.4 Gy in 28 fractions) at the same time as the chemotherpay. The higher dose of radiation treatment did not result in any benefit. For patients receiving high-dose versus moderate-dose radiation treatments, the average duration of survival was 13 months vs 18 months, survival rate at 2 years was 31% vs 40%, and the percentage of patients with persistence or progression of cancer in the chest was 56% vs 52%, respectively.

Disease that Can be Completely Removed with Surgery

Both surgical removal of esophageal cancer and combined modality chemotherapy plus radiotherapy are associated with an unacceptably high rate of local, regional and distant recurrence. For the medically fit patient with a tumor that can potentially be completely removed, tri-modality therapy with surgery, chemotherapy, and radiotherapy has been evaluated in an attempt to improve outcome. At least eight randomized clinical trials have investigated the benefit of giving radiation therapy and chemotherapy prior to surgery (2) These trials are hampered by inconsistent evaluation of the extent of disease (staging), mixed histologic types of esophageal cancer (squamous cell vs adenocarcinoma), and small numbers of patients included in the trials. Only one trial is considered statistically positive, demonstrating a benefit for treatment with chemotherapy and radiotherapy prior to surgery(28).
In the Irish trial by Walsh, 113 patients with esophageal adenocarcinoma that could be surgically removed were randomized to be treated with either chemotherapy with cisplatin plus 5-FU with radiation therapy (40 Gy in 15 fractions) at the same time prior to surgery or surgery alone. The percentage of patients alive 3 years after treatment was better in the patients receiving multimodality therapy compared to those having surgery alone (32% vs 6%, p = 0.01). This trial, however, has been criticized for including small numbers of patients and for having an unusually poor surgical outcome. Most other surgical series report that 20% to 30% of patients survive for at least 3 years after surgery alone(14).
Investigators from the University of Michigan randomized 100 patients to be treated with either chemotherapy with 5-FU, cisplatin, and vinblastine plus concurrent radiation therapy (45 Gy in 1.5 Gy fractions, given twice a day for three weeks) prior to surgery or surgery alone (29). At 3 years from treatment, the survival rate favored the combined modality group (30% vs 16%, p = 0.15). However, due to the small number of patients included in the trial, this result did not reach statistical significance and, therefore, the trial is considered to show no difference between the treatments. Nevertheless, the results suggest that there may be some benefit to giving chemotherapy plus radiotherapy prior to surgery.

Treatment with chemotherapy plus radiotherapy before surgery can increase the ability to completely remove the primary cancer and can eliminate microscopic spread of the cancer. For example, in the University of Michigan study, 28% of patients who received chemotherapy plus radiotherapy before surgery had no evidence of residual disease in the pathological specimen removed at the time of surgery. These patients had significantly better chance for being alive 3 years after treatment than did patients with residual disease in the surgical specimen (64% vs 19%, p = 0.01)(29).

A recent retrospective study from the Fox Chase Cancer Center also showed that patients treated with chemotherapy plus radiotherapy before surgery who had no evidence of residual cancer in the surgical specimen had a better chance of being alive 5 years after treatment than those who did have residual disease at surgery (62% vs 31%, p = 0.02).30 Moreover, patients in whom all disease could be removed had a significantly better chance of being alive 5 years after treatment than those in whom all disease could not be removed (35% vs 10%, p < 0.0001) (30). Given the significantly prolonged survival in patients who achieved a complete disappearance of cancer or who had complete removal of visible cancer, investigators at the Fox Chase Cancer Center advocate the use of chemotherapy plus radiation therapy followed by the definitive surgical removal of all visible and microscopic cancer(31).
Putting it all together: The RTOG/Intergroup Trial and the Combined Modality Trials

The RTOG and Intergroup studies demonstrated a benefit with combined chemotherapy plus radiotherapy to achieve local control, but no benefit with increased radiation doses. Multiple studies of tri-modality therapy with chemotherapy, radiation, and surgery suggest a survival benefit over surgery alone, especially when a complete response is achieved, but a definitive regimen of pre-surgical treatment has not been defined. These results provide a rational for the use and continued study of surgery after combined chemotherapy and radiation therapy to enhance local control in patients with tumors that can be completely removed who are medically fit to undergo surgery.

The use of chemotherapy before surgery allows greater drug concentrations to be delivered, which should theoretically improve the chance of eradicating microscopic disease outside the planned radiation field. In a completed phase II study, six weeks of chemotherapy with carboplatin and paclitaxel were given either before or after therapy with carboplatin, paclitaxel and concurrent radiation therapy (50.4 Gy in 28 fractions) followed by surgery (32). Not only was the rate of complete disappearance of tumor greater in the patients who received chemotherapy before definitive treatment, but their rate of overall survival was also greater. This study was not large enough to definitely compare the study treatments, but it does lend support to the notion of additional chemotherapy prior to definitive treatment.

At Northwestern Memorial Hospital, we are about to initiate a phase II clinical trial of chemotherapy with capecitabine and oxaliplatin given as before and during radiation therapy (50.4 Gy in 28 fractions) prior to surgery in patients with esophageal and gastroesophageal junction adenocarcinoma that can potentially be completely removed. The combination of oxaliplatin and capecitabine given concurrently with radiation has been investigated in a phase I/II trial in patients with rectal cancer before surgery. This combination had a favorable side-effect profile, a substantial rate of tumor shrinkage, and no unexpected surgical complications (33). The primary aim of our phase II study is to determine the rate of clearance of the cancer with treatment given before surgery.

Some areas of controversy

The role of surgery following combination chemotherapy and radiotherapy remains an area of significant controversy (14). If combination therapy can achieve complete disappearance of disease and offer the same chance for survival as surgery, is surgical removal of the esophagus necessary if there is no evidence of residual cancer? Should patients who have only partial shrinkage of the cancer continue with further chemotherapy and radiotherapy or undergo surgery? Is there a role for salvage surgery if there is worsening of disease during chemotherapy and radiation therapy? Quantifying a patient’s response to therapy is challenging. Endoscopy, EUS and CT scans are inaccurate in re-evaluating the extent of disease after chemotherapy and radiation therapy. Over-staging is common with EUS since it is difficult to differentiate residual tumor from scarring and inflammation that occurs after radiotherapy.11 The role of PET scanning in the re-evaluation of patients is under investigation. At this time, surgery remains the only means of accurately deciphering the response to initial therapy

The role of chemotherapy and radiation therapy in the metastatic setting

Patients with disease that has spread to distant organs (stage IV) treated with chemotherapy have an average duration of survival of less than 1 year (2). Chemotherapy with cisplatin and 5-FU is the most commonly used regimen in this setting, providing significant shrinkage of cancer in 20% to 50% of patients.1 Other active chemotherapy drugs include irinotecan (CPT-11), paclitaxel, docetaxel, and oxaliplatin used in combination or as single-agents.1 Chemotherapy can achieve relief of symptoms due to the primary esophageal tumor and to other sites of disease spread. Significant improvements in the duration of survival have not been demonstrated with any particular chemotherapy regimen and the specific treatment used for an individual patient needs to be balanced against the potential side-effects and benefits that are expected..

Palliative irradiation can provide symptomatic relief of pain and difficulty swallowing in up to 80% of patients. Brachytherapy is a minimally invasive procedure in which radioactive material is placed directly into or near the cancer.15 The radiation source is sealed in wires, needles, seeds, or catheters. The advantage of brachytherapy lies in its ability to deliver high doses of radiation directly to the tumor while sparing normal surrounding tissues from excess radiation. Shortened treatment time, improved patient convenience, and quicker palliation are other advantages of brachytherapy when compared to standard radiation therapy.

Brachytherapy in the treatment of esophageal cancer involves the use of a catheter with radioactive seeds placed through the nose and into the esophagus. It can be used both in the curative and the palliative settings. In the latter case, local control rates vary from 25% to 35% (34). A recent randomized clinical trial from the Netherlands compared single-dose brachytherapy (12 Gy in one fraction) to the placement of metal stents (tubes) for palliation of esophageal obstruction. Even though the placement of a stent resulted in a more rapid improvement in swallowing, complications were more frequent, particularly due to a greater risk of bleeding. Long-term relief of swallowing problems was also better in the patients treated with brachytherapy (35).

Summary

Combined modality therapy plays an important role in the treatment of patients with esophageal cancer. In patients with esophageal cancer that can potentially be surgically removed, multi-modality therapy with chemotherapy, radiotherapy, and surgery is a common practice. However, many questions remain as to the optimal management of patients with this disease and participation in clinical trials is encouraged. Definitive chemotherapy plus radiation therapy is the standard of care in patients who are unable to tolerate surgery or who have disease that cannot be completely removed. The use of chemotherapy or chemotherapy plus radiotherapy prior to surgery continues to be studied in clinical trials. For patients with disease that has spread to distant organs, stenting or balloon dilation of the esophagus, chemotherapy, radiation therapy with external beam treatments or brachytherapy, or a combination of these modalities are all options for providing symptomatic relief.

Future Directions

Treatment directed at specific molecular targets will expand treatment options for patients with esophageal cancer. Potential targets and markers for esophageal squamous cell carcinoma and gastroesophageal adenocarcinoma include angiogenesis factors that allow tumors to develop blood supplies, such as vascular endothelial growth factor (VEGF), growth stimulating molecules, such as epidermal growth factor receptor (EGFR), inflammatory markers, such as COX-2, and regulators of cell death (apoptosis), such as p53 (36) Many targeted therapies for esophageal cancer are currently being tested in phase I and II clinical trials. Future trials will evaluate the addition of targeted therapies to combined chemotherapy plus radiotherapy in patients with locally advanced disease and to chemotherapy in patients with advanced, metastatic esophageal cancer.

1. Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, 251 E. Huron, LC-178, Chicago, Illinois 60611

2. Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, 676 North Saint Clair Suite 850, Chicago, Illinois 60611

Corresponding Author:

William Small Jr., M.D.
Department of Radiation Oncology
Northwestern Memorial Hospital
251 E. Huron, LC-178
Chicago, IL 60611
Phone: 312-926-2520
Fax: 312-926-6374
E-mail: w-small@northwestern.edu




 


 


Additional Authors:  

Works Cited:  
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