Dr. Minsky provides an excellent review of the current status of primary and adjuvant therapy in patients with carcinoma of the esophagus. Although the treatment of esophageal cancer remains a hotly debated issue, recent results clearly show the superiority of combined-modality therapy, especially when surgical resection is not planned.
Before 1980, the standard treatment of locally advanced esophageal cancer was surgery if the patient had an operable tumor, or radiotherapy for those who had inoperable disease or refused to undergo resection. The median reported survival was 9 months, the 2-year survival rate was 10%, and the 5-year survival rate was approximately 5%. Surgery had a high mortality (³ 20%), which may reflect the selection of patients and/or postoperative support.[1-3]
More importantly, only about 40% of all patients were considered to have operable disease, and only 70% of those who underwent surgery had resectable tumors. Furthermore, not all resections could be performed with disease-free margins and/or curative intent.
Early Trials of Combined-Modality Therapy
Dissatisfaction with the results of standard treatment and the high incidence of systemic failure in these patients stimulated the exploration of combined-modality therapy, achieved with the addition of systemic chemotherapy. The first trial of this approach, conducted at Wayne State University, used a regimen that had proved successful in patients with anal canal cancers. It consisted of two courses of fluorouracil(Drug information on fluorouracil) (5-FU) 3 weeks apart with one dose of mitomycin(Drug information on mitomycin) (Mutamycin) concurrent with 3,000 cGy of radiation, followed by attempts at surgical resection 3 to 6 weeks after the completion of radiotherapy. The next report came from the same institution, with cisplatin(Drug information on cisplatin) (Platinol) substituted for mitomycin and administered with 5-FU in two courses.
Many more phase II preoperative chemoradiation trials followed.[6-8] The majority of these trials used 3,000 cGy of radiation, which today would be considered inadequate. Despite this limitation, the results were very encouraging. Median survival improved to 14 months and the 2-year survival rate exceeded 20%. These favorable results may reflect, in part, the need for better selection of patients, although mortality was still unacceptably high (> 10%).
Many lessons learned from these early phase II trials of preoperative chemoradiotherapy are still true today. Patients with grossly or microscopically positive margins, or those with disease in the pathology specimen and negative margins, received additional chemotherapy and/or radiotherapy. Despite attempts to perform resection and the addition of postoperative treatment, very few patients survived for 2 years. The best survival was seen in those with a histologically negative surgical resection; these patients constitute about 20% to 30% of those treated with preoperative chemoradiation.
The question asked at that time was: Do we need planned surgery, or does its effect on prognosis depend on the results of initial treatment? This question remains very pertinent today.
More Recent Phase II Trials
Many other phase II trials of total concurrent chemoradiotherapy without planned surgical resection,[9-14] preoperative chemotherapy,[15-23] preoperative and postoperative chemotherapy, and higher-dose preoperative irradiation (4,000 to 4,500 cGy) administered concurrently with chemotherapy have been reported over the last 15 years. These reports failed to show an improvement over the results of the initial studies with limited preoperative chemoradiotherapy. This is especially true when one looks at the best 5-year survival rate reported, which was approximately 30% regardless of the criteria used to select patients, type of treatments given, histology, and whether or not surgery was planned.
The most recent studies of surgery alone in locally advanced esophageal carcinomas, which used better patient selection criteria and included a larger number of patients with adenocarcinoma, resulted in a higher 5-year survival rate (20%) and lower mortality (< 8%). Also, another conclusion that emerged from all of the trials of combined-modality therapy was that the combination of cisplatin and infusional 5-FU is the most commonly used, widely accepted, best tolerated chemotherapy regimen (without the addition of other agent[s]), whether administered as the sole modality or in combination with irradiation. Total chemoradiotherapy without planned surgery yielded the best possible 5-year survival results (30%), and neither preoperative nor postoperative chemotherapy improved on the 5-year survival rate achieved with surgery alone (20%).[23-28] This last conclusion was recently confirmed by a phase III, randomized, intergroup trial.
Dr. Minsky reviews the six randomized trials that have compared standard radiotherapy to concurrent chemoradiotherapy in patients with locally advanced esophageal carcinoma. The phase III, randomized studies led by the Eastern Cooperative Oncology Group (ECOG)[30,31] and Radiation Therapy Oncology Group (RTOG)[32,33] are worthy of further comment.
ECOG Phase III Trial
Patients participating in the ECOG trial were not stratified on the basis of any important prognostic factors. Also, this trial used the combination chemotherapy regimen of mitomycin and an 5-FU infusion and, after the preoperative treatment phase, left the question of whether to perform surgery up to the investigators. In addition, a larger percentage of patients were not considered to be evaluable.
Despite these possible deficiencies in the design of this study, the median survival duration in patients treated with radiotherapy was 9 months, while survival time in those treated with the combined approach was 50% longera difference that was statistically significant. These findings confirmed the initial results of the phase II trials of preoperative limited chemoradiotherapy, as well as the trials of total chemoradiotherapy.
RTOG Phase III Trial
The most important phase III, randomized study confirming these results was that led by the RTOG.[32,33] Patients were stratified by weight loss, histology, and tumor size and were then randomized to either total chemoradiotherapy or irradiation only, without planned surgery. The radiation dose used in the combined-modality arm was 5,000 cGy, while that used in the radiation-alone arm was 6,400 cGy, both of which were very acceptable. Two courses of cisplatin (75 mg/m² to a maximum dose of 150 mg) and 5-FU (1,000 mg/m²/d infused over 96 hours) 4 weeks apart were administered concurrently with radiotherapy.
The reason for reducing the doses of chemotherapy and radiotherapy and for prolonging the time between chemotherapy courses was twofold: (1) in an effort to avoid unacceptable toxicities, and (2) this exact treatment had never been investigated before on a cooperative group level.
Also, two additional courses of the same chemotherapy were given following radiation treatment, 3 weeks apart. Again, the addition of adjuvant chemotherapy had not previously been studied on the local institution or group level.
This randomized trial was closed early due to the highly significant results (P < .003) in favor of the combined approach. Additional patients were treated with total chemoradiotherapy on a nonrandomized basis.
The initial results showed significant improvements in local and regional control, incidence of systemic metastasis, disease-free survival, 2-year survival, and overall survival in the combined-modality group. These results were further confirmed in the additional nonrandomized patients treated with the combination regimen. Again, median survival time with radiotherapy alone was 9 months, the 2-year survival rate was 10%, and no patient survived beyond 3 years. Median survival duration was 14 months in the patients randomized to combined-modality treatment and 17 months in the nonrandomized group. The 2-year survival rate in all patients on the randomized combined-modality arm was much higher than that reported in the phase II studies, and the 5-year survival rate in these patients was 27%.
A recent update of this important trial continued to show the same significant results.
Many questions still need to be investigated and answered. Is adjuvant chemotherapy necessary? How should we intensify chemotherapy (by dose, duration, number of courses, or the addition of newer and active agent[s]? Can radiation therapy be intensified? What are the roles of brachytherapy, hyperfractionated radiation, or hyperfractionated accelerated radiotherapy? Some of these questions are being addressed in active clinical trials, which Dr. Minsky reviews.
The most important question that needs to be answered is the role of planned surgery in this disease, especially when combined with concurrent chemoradiotherapy. Unfortunately the cooperative groups appear to be reluctant to address this issue.
In summary, the treatment of locally advanced esophageal carcinomas has evolved over the last 25 years. Significant improvements have been seen in median survival; local, regional, and systemic control; disease-free survival; and 2- and 5-year survival rates (38% and 27% respectively). These improvements have been achieved with concurrent chemoradiotherapy. The majority of patients (< 90%) can be treated effectively with total chemoradiotherapy without planned surgical resection. The most commonly used chemotherapy combination is cisplatin and infusional 5-FU.
The results with surgery alone also have improved. The rate of survival at 5 years has increased to 20%, and postoperative mortality has decreased markedly. However, fewer than one-third of patients are eligible for surgery.
Finally, we strongly believe that the role of planned surgery as part of combined-modality treatment needs to be addressed in phase III, randomized trials.