Overview

Patients with stage III esophageal cancer have cancer that invades through the wall of the esophagus and has spread to the lymph nodes and/or invaded adjacent structures. This is a very common stage for presentation of esophageal cancer. Stage III cancer may also be referred to as locally advanced.

A variety of factors ultimately influence a patient’s decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient’s chance of cure, or prolong a patient’s survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of the treatment of stage III esophageal cancer. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied to your situation. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.

Optimal treatment of patients with stage III 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 medical oncologists, radiation oncologists, surgeons, medical gastroenterologists and nutritionists.

For patients with stage III esophageal cancer, there are essentially two currently available treatment choices: chemotherapy and radiation therapy before surgery or chemotherapy and radiation therapy without surgery. Surgery alone is not usually advised for patients with stage III esophageal cancer except as necessary for palliation for difficulty in swallowing. There may be some exceptions to this recommendation for patients with stage III cancer who only have minimal lymph node nodal involvement with cancer or those with minimal spread of cancer to adjacent structures.

The American Society of Radiology has published guidelines for the treatment of esophageal cancer and has recommended chemotherapy and radiation therapy and no surgery for patients with stage III esophageal cancer. However, many current clinical trials are directed at improving outcomes of patients with stage III esophageal cancer by administering chemotherapy and radiation therapy before surgery (neoadjuvant treatment). This approach assumes that chemotherapy and radiation therapy will increase the likelihood of curative surgery being performed in patients who are inoperable at diagnosis. It also presumes that surgery can eliminate residual cancer that remains after treatment with chemotherapy and radiation therapy. The major problem with this approach is the high mortality rate following surgery, which is often increased by currently utilized radiation therapy and chemotherapy programs.

Patients with stage III esophageal cancer with extensive local and lymph node spread are also often included in clinical trials along with patients with metastatic stage IV esophageal cancer to evaluate new chemotherapy regimens.

Chemotherapy and Radiation Therapy as Primary Treatment:

Chemotherapy is usually combined with radiation therapy for the treatment of patients with stage III esophageal cancer. Chemotherapy refers to anti-cancer drugs designed to treat cancer systemically. Chemotherapy and radiation therapy may act together to increase the destruction of cancer cells. Chemotherapy may also destroy cancer cells in locations not reached by radiation therapy.

The results of several clinical studies performed in esophageal cancer patients receiving concurrent chemotherapy and radiation therapy have indicated that this strategy may improve remission rates and prolong survival compared to surgery with or without radiation. In general, concurrent radiation and chemotherapy results in 3-5 year survival rates of 20-30%, with average survival rates of less than one year. The combination of radiation and chemotherapy is superior to treatment with radiation therapy alone.

For example, a randomized clinical trial involving 129 patients with stage II and III esophageal cancer compared radiation therapy alone to radiation therapy and chemotherapy. The majority of patients had squamous cell cancer. Approximately 70% of patients participating in this clinical trial had stage II and 30% had stage III esophageal cancer. Chemotherapy consisted of a combination of Platinol® and fluorouracil. The combined chemotherapy and radiation therapy treatment was associated with a 5-year survival of 27%, compared to 0% for patients receiving radiation therapy alone. The number of local recurrences and distant relapses were fewer in patients receiving combined therapy than in patients receiving radiation therapy alone.

Neoadjuvant Therapy

Chemotherapy and/or radiation therapy administered prior to surgery is referred to as neoadjuvant therapy. In theory, neoadjuvant therapy can decrease the size of the cancer, making it easier to remove with surgery.

Neoadjuvant therapy has the potential advantages of delivering immediate therapy to destroy any cancer cells that may have already spread away from the esophagus and reducing the size of the cancer, thereby allowing easier surgical resection. The role of neoadjuvant chemotherapy and radiation therapy before surgery in patients with localized esophageal cancer is controversial. In some clinical studies, patients receiving neoadjuvant chemotherapy and radiation therapy have experienced improved outcomes compared to surgery alone. Unfortunately, a higher death rate following surgery has also been reported, which may cancel out any benefit from control of cancer by this more intensive treatment approach. Clinical trials of new more effective and potentially less toxic chemotherapy regimens continue to be tested because current results of treatment with or without surgery remain unsatisfactory.

Doctors have performed a small clinical study that compared surgery alone to neoadjuvant chemotherapy followed by surgery. In this study, 74 patients with squamous cell esophageal cancer were treated with Platinol® and fluorouracil before surgery and compared to 73 patients who were treated with surgery alone. The average survival of patients treated with neoadjuvant chemotherapy before surgery was 17 months, compared to 13 months for patients treated with surgery alone. Patients who responded to chemotherapy survived an average of 42 months, which was better than the 14 months observed in the group treated with surgery alone. This small study suggested that some patients might have benefited from neoadjuvant chemotherapy administered before surgery.

In another small clinical study, 58 patients with localized esophageal cancer were randomly assigned to receive chemotherapy, radiation therapy and surgery and 55 patients were randomly assigned to receive surgery alone. The majority of these patients had stage III cancer. The results indicated that 25% of patients achieved a complete pathological response after chemotherapy and radiation therapy. The average survival was 16 months for patients receiving combined treatment and 11 months for those receiving surgery alone. The 3-year survival rate was 32% for patients receiving combined therapy and 6% for patients receiving surgery alone. This clinical trial, in addition to the previous one, suggests that combined modality treatment appears superior to treatment with surgery alone for stage III esophageal cancer.

A more recent clinical trial evaluated newer chemotherapy drugs. In this trial, 73 patients with localized (stage I-III) esophageal cancer received paclitaxel, Paraplatin® and fluorouracil chemotherapy with radiation therapy before surgery. Following chemotherapy and radiation, 81% of patients underwent surgery and 95% of these had complete resection of all visible cancer. The results indicated that 54% of patients undergoing surgery had a complete pathological response, 18% had cancer visible only under the microscope and 32% had residual cancer. Of the 14 patients who did not undergo surgery, 7 experienced a complete response. Survival at one year for all patients was 69% and at two years was 50%. The average survival was 24 months. There were no treatment related deaths during the chemotherapy and radiation therapy, but 10% of patients died from surgical complications. These results are impressive because of the 50% complete response rate, which is the best reported. However, the 10% death rate following surgery is high and it is unclear what role surgery contributed to overall survival.

Neoadjuvant and Adjuvant Treatment

Researchers have also evaluated neoadjuvant low-dose chemotherapy prior to surgery followed by additional adjuvant chemotherapy after surgery. In the largest clinical trial published, 440 patients with stage II-IV esophageal cancer received treatment with surgery alone or with low-dose neoadjuvant chemotherapy followed by surgery and additional chemotherapy. One year following treatment, the survival rate was 59% for those who received chemotherapy and 60% for those who had surgery alone; at 2 years, survival was 35% and 37%, respectively. In this clinical trial, preoperative chemotherapy with a combination of Platinol® and fluorouracil did not improve overall survival among patients with squamous or adenocarcinoma of the esophagus compared to treatment with surgery alone.

Strategies to Improve Treatment

The progress that has been made in the treatment of esophageal cancer has resulted from improved patient participation in clinical studies. Future progress in the treatment of esophageal cancer will result from continued participation in appropriate studies. Currently, there are several areas of active exploration aimed at improving the treatment of esophageal cancer.

Supportive Care: Supportive care refers to treatments designed to prevent and control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the optimal delivery of therapy at its planned dose and schedule. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that side effects resulting from cancer and its treatment are appropriately managed. For more information, go to Supportive Care.

New Adjuvant Regimens (treatment after surgery): Treatment of patients with radiation therapy, chemotherapy or both combined after surgery has not been shown to affect survival of patients with stage III esophageal cancer. Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies alone or in combination with radiation therapy for use as treatment is an active area of clinical research carried out in phase II clinical trials. Currently, the taxanes, Gemzar® and other newer chemotherapy drugs are being evaluated in patients with stage III cancer since these are among the most active agents developed for the treatment of esophageal cancer.

New Neoadjuvant Regimens (Treatment before surgery): Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies is an active area of clinical research carried out in phase II clinical trials. Neoadjuvant therapy may consist of chemotherapy alone or in combination with radiation therapy or biological agents. The potential effectiveness of neoadjuvant chemotherapy and radiation therapy is still being studied in clinical trials, which are primarily evaluating newer combination chemotherapy regimens.

Neoadjuvant and Adjuvant Treatment: Although initial clinical trials have not shown this approach to be superior to surgery alone, researchers continue to evaluate neoadjuvant chemotherapy prior to surgery followed by additional adjuvant chemotherapy after surgery. In a more recent clinical trial, 42 patients with stage II-IV esophageal cancer received treatment with low-dose neoadjuvant chemotherapy combined with radiation therapy. Following neoadjuvant treatment, 39 of the 42 patients underwent esophagectomy and only one patient died of surgery related problems. After surgery, patients received additional paclitaxel-based chemotherapy. Overall, 51% of patients were alive 2 years after treatment and 91% of the patients achieving a complete response to treatment survived. This clinical trial suggests that decreasing the dose of neoadjuvant chemotherapy may reduce mortality associated with surgery and the addition of paclitaxel adjuvant therapy could potentially improve outcomes.

Gene Therapy: Currently, there are no gene therapies approved for the treatment of esophageal cancer. Gene therapy is defined as the transfer of new genetic material into a cell for therapeutic benefit. This can be accomplished by replacing or inactivating a dysfunctional gene or replacing or adding a functional gene into a cell to make it function normally. Gene therapy has been directed towards the control of rapid growth of cancer cells, control of cancer cell death and efforts to facilitate immune mediated death of cancer cells. A few gene therapy studies are being carried out in patients with refractory esophageal cancer. If successful, these therapies could be applied to patients with earlier stages of esophageal cancer.

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