Treatment of Stage II - III Esophageal Cancer
Medically reviewed by C.H. Weaver M.D. 8/2018
Optimal treatment of patients with stage II - 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 surgeons, medical oncologists, radiation oncologists, medical gastroenterologists and nutritionists.
The treatment of patients with stage II - III or locally advanced esophageal cancer may consist of surgery, radiation, chemotherapy or a combination. The goal of treatment is cure and this currently requires surgical removal of the cancer.
- Stage II esophageal cancer invades into or through the muscular wall of the esophagus, but not into nearby local structures (IIA). When there is regional lymph node involvement with any extent of primary cancer but no invasion of local structures, this is called stage IIB.
- Stage III esophageal cancer invades through the wall of the esophagus and has spread to the lymph nodes and/or invaded adjacent structures.
Some patients with stage III esophageal cancer with extensive local and lymph node spread cannot be treated with surgery and are often included in clinical trials along with patients with metastatic stage IV esophageal cancer to evaluate new chemotherapy regimens.
Patients with stage II - III esophageal cancer can be treated with curative intent using either a primary surgical or a primary combined chemotherapy and radiation therapy approach. However, combined chemotherapy and radiation therapy is usually reserved for patients who are not able or do not wish to undergo major surgery.
Primary Treatment with Surgery Alone
It is difficult to get accurate information about outcomes for patients with stage II esophageal cancer, as most published clinical studies have pooled together the results of patients with stage I-III cancer. In one large clinical study of 160 patients, the average survival duration was 11 months following treatment with surgery alone. In another study involving 110 patients with squamous cell cancer and 124 with adenocarcinoma, the average survival was 16 months, the 5-year survival rate was 20% and 6% of patients died from complications of surgery. The results of this trial indicate that in general, patients with stage IIA cancer experience a better than 20% survival and patients with stage IIB cancer experience a slightly worse outcome. In one study from Japan, the average survival of 14 patients with stage II esophageal cancer following surgery alone was 25 months.
Neoadjuvant Therapy (Treatment before Surgery)
Chemotherapy and/or radiation therapy administered prior to surgery is referred to as neoadjuvant therapy. The goal of neoadjuvant therapy is to decrease the size of the cancer, making it easier to remove with surgery. The major problems with this approach are the higher mortality rates that occur when radiation therapy and/or chemotherapy are administered before surgery and the delay of surgery for some patients who do not respond to therapy. In most but not all studies, chemotherapy alone, radiation therapy alone or both therapies delivered before surgery have not consistently improved survival following surgery in patients with stage II esophageal cancer. Many current clinical trials are directed at improving outcomes of patients with stage II esophageal cancer by administering newer neoadjuvant treatment regimens containing taxane-based chemotherapy and/or radiation therapy.
In one large clinical trial evaluating neoadjuvant treatment, 300 patients with stage I-II squamous esophageal cancer were randomly assigned to receive surgery alone or chemotherapy and radiation therapy before surgery. There were fewer recurrences of cancer in patients treated with radiation therapy and chemotherapy before surgery. However, this benefit was balanced out by an increase in deaths following surgery in patients who had received chemotherapy and radiation therapy. The average survival was 1.5 years for both groups. Survival at 3 years was approximately 35% for both groups. The presence of lymph node involvement (stage IIB) was associated with a poor outcome, as was the inability to surgically remove all cancer.
In another clinical trial, paclitaxel, Paraplatin® and fluorouracil chemotherapy were given with radiation therapy to 73 patients with localized (stage I-III) esophageal cancer. Eighty-one percent of all patients underwent surgery and 95% of these had complete resection of all visible cancer. Fifty-four percent of patients undergoing surgery had a complete pathological response, 18% had cancer visible only under the microscope and 32% had residual cancer. A complete pathological response means that no cancer cells were present in the resected cancer specimen. A complete clinical response was observed in 7 of the 14 patients not undergoing surgery. Survival at one year for all patients was 69%, with 50% of patients alive at two years. There were no treatment-related deaths during the chemotherapy and radiation therapy, but 10% of patients died from surgical complications. These results showed that paclitaxel, Paraplatin® and fluorouracil was a very active drug combination producing a complete clinical and pathologic response in half the patients. However, the 10% death rate following surgery is high and it is unclear what role surgery contributed to overall survival.
With the development of new chemotherapy regimens there will continue to be new clinical trials of neoadjuvant therapy performed in patients with stage II - III cancer of the esophagus undergoing esophagectomy. The goal of these trials is to develop an effective regimen of chemotherapy and radiation therapy that does not increase the death rate following surgery, but increases survival.
Neoadjuvant and Adjuvant Treatment
Researchers have also evaluated the combination of 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, pre-operative 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.
Radiation Therapy and Chemotherapy as Primary Treatment
Patients with stage II esophageal cancer who cannot or who do not want to undergo surgery may be treated with combined chemotherapy and radiation therapy. Chemotherapy consists of anti-cancer drugs that have the ability to kill cancer cells. Chemotherapy and radiation therapy may act together to increase the destruction of cancer cells. The results of several clinical studies using concurrent chemotherapy and radiation therapy in esophageal cancer patients have suggested that this strategy may improve remission rates and prolong survival. However, there have been no clinical studies directly comparing combined chemotherapy and radiation therapy with surgery alone for the treatment of patients with stage II esophageal cancer.
In one clinical trial, stage II esophageal cancer patients who received combined chemotherapy and radiation therapy experienced a 5-year survival rate of 20% with local cancer recurrences occurring in 45% of patients. In another clinical trial, 129 patients with stage II and III esophageal cancer were randomly assigned to receive radiation therapy alone or radiation therapy and chemotherapy. The majority of patients had squamous cell cancer and approximately 70% had stage II cancer of the esophagus. Chemotherapy consisted of the combination 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. The results of this trial indicate that the survival of stage II patients receiving combined therapy is slightly better than 20% and that survival of patients with stage III cancer receiving combined therapy would be worse.
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.
New Combination Regimens: Several newer chemotherapeutic drugs have demonstrated an ability to kill esophageal cancer cells in patients with advanced cancer. Research is ongoing to develop and explore single or multi-agent chemotherapy regimens including the taxanes, Gemzar® and other newer chemotherapy drugs with or without radiation in patients with stage II cancer.
New Adjuvant Regimens: 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. Treatment of patients with radiation therapy, chemotherapy or both therapies after surgery has not been shown to affect survival of patients with stage II cancer of the esophagus. 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.
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 low-dose 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. Thirty-nine of the 42 patients underwent esophagectomy and only one patient died of surgery related problems. After surgery, additional paclitaxel based chemotherapy was given. 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.