Carcinoma of the Esophagus Part 2: Adjuvant Therapy

Introduction

Two general approaches are used to treat esophageal cancer: primary treatment (surgical or nonsurgical) or adjuvant treatment (preoperative or postoperative). Primary treatments include surgery alone, radiation therapy alone, and radiation therapy plus chemotherapy (combined- modality therapy). Adjuvant therapies include preoperative or postoperative radiation therapy, preoperative chemotherapy, and preoperative combined-modality therapy. The first part of this two-part review, which appeared in last month’s issue, focused on primary therapy for esophageal cancer. This second part examines the rationale for and results of adjuvant therapy.

Adjuvant Radiation Therapy Without Chemotherapy

The rationale for using adjuvant radiation therapy is based on the patterns of failure following potentially curative surgery in patients with clinically resectable esophageal cancer. Unfortunately, few surgical series have reported these data.

The rates of local failure in the surgical control arms from the preoperative radiation therapy randomized trials of Mei et al[50] and Gignoux et al[51] were 12% and 67%, respectively. Local failure rates in the surgical control arm from the postoperative radiation therapy randomized trial of Teniere et al[52] were 35% for patients with negative locoregional lymph nodes and 38% for patients with positive nodes.

The surgical control arm of the intergroup INT 0113 trial provides a modern, more relevant baseline for the results of surgery alone. As discussed in part 1 of this article, the rate of local failure was 31% in patients with an R0 resection, and the total rate of local failure (including the additional 30% of patients with persistent disease) was 61%.

In summary, although the majority of patients with esophageal cancer die of distant metastasis, the incidence of local failure following surgery alone is high enough to examine the use of adjuvant radiation therapy.

Preoperative Radiation Therapy

Six randomized trials have assessed the value of preoperative radiation therapy in patients with clinically resectable disease.[16,50,51,53-55] The studies of Launois et al,[53] Gignoux et al,[51] and Nygaard et al[16] were limited to patients with squamous cell carcinoma. Arnott et al included patients with both squamous cell carcinoma and adenocarcinoma.[54] The series of Huang et al[55] and Mei et al[50] did not mention the histology.

Overall, preoperative radiation therapy did not increase the resectability rate. Only two series reported local failure rates. Although Mei and colleagues[50] found no difference in local failure, Gignoux et al[51] did report a significant decrease in local failure (46% vs 67%) in patients who received preoperative radiation therapy compared with those treated with surgery alone.

Two series showed an improvement in survival. The study by Nygaard and associates was a four-arm trial in which patients were randomized to chemotherapy (cisplatin (Platinol)/bleomycin (Blenoxane) × 2 cycles), radiation therapy, combined-modality therapy, or surgery alone.[16] Patients who received preoperative radiation therapy (with or without chemotherapy) demonstrated a significant improvement in overall 3-year survival rate compared with those who did not receive radiation (18% vs 5%; P = .009). Of the 48 patients given preoperative radiation therapy without chemotherapy, 20% were alive at 3 years; however, this benefit did not reach statistical significance. Therefore, this was not a pure radiation study, and the benefit may have been due, in part, to the chemotherapy.

Huang et al reported a similar improvement in survival in patients who received preoperative radiation therapy vs those who did not undergo such therapy (46% vs 25%); however, a statistical analysis was not performed.[55] A recent meta-analysis from the Oesphageal Cancer Collaborative Group also showed no clear evidence of a survival advantage with preoperative radiation.[56]

There have been many criticisms of the randomized trials of preoperative radiation therapy. For example, conventional doses of radiation therapy were not used. Also, none of these trials allowed an adequate interval between the completion of radiation therapy and surgery. In general, a 4- to 6-week interval is recommended. The use of these unconventional techniques precludes a meaningful analysis of radiation-related morbidity from being performed.

In summary, since only two of the six series of preoperative radiation therapy have reported local failure rates, it is difficult to draw firm conclusions regarding the influence of this therapy on local control. Two series have reported an improvement in survival; in one of these studies, half of the patients received chemotherapy, and the other series did not perform a statistical analysis. Four of the six series found no advantage of preoperative radiation with respect to overall survival. Nonrandomized trials from Yadava et al[57] and Sugimachi and associates[58] also report no survival benefit.

Thus, based on the available randomized, albeit limited, trials, preoperative radiation therapy does not appear to significantly decrease local failure or improve survival.

Postoperative Radiation Therapy

Nonrandomized trials have reported encouraging results with postoperative radiation therapy. For example, in a study by Kasai et al, patients with lymph node–negative disease had a 5-year survival rate of 88%.[59] Yamamoto et al reported a 2-year local control rate of 94% in node-positive patients.[60]

Only two randomized trials have been published that were limited to patients treated in the adjuvant setting. Teniere and colleagues[52] reported 221 patients with squamous cell esophageal carcinoma randomized to surgery alone or surgery plus postoperative radiation therapy (4,500 to 5,500 cGy at 180 cGy/fraction). With a minimum follow-up of 3 years, postoperative radiation had no significant impact on survival.

The second randomized trial, by Fok et al,[61] included patients with squamous cell carcinoma and adenocarcinoma. It should be emphasized that patients with both curative and palliative resections were included in this series. Although the total dose of radiation was conventional, the dose per fraction (350 cGy/fraction) was not. The addition of postoperative radiation therapy did not significantly decrease local or distant failure or improve median survival.

Postoperative radiation therapy is sometimes recommended for patients with positive locoregional lymph nodes. Although the data from Teniere et al[52] support the use of postoperative radiation therapy for decreasing local failure, the benefit was limited to patients with negative lymph nodes. In this subset of patients, postoperative radiation therapy decreased the local failure rate from 35% to 10%. There was no significant effect of postoperative radiation in patients with positive nodes.

In summary, although the limited available data suggest that adjuvant postoperative radiation therapy may decrease local failure in node-negative patients, it has no impact on overall survival. The only established role for postoperative radiation therapy is in patients with positive margins. In patients selected for treatment with postoperative radiation, based on the positive survival results from combined-modality therapy trials, such as Radiation Therapy Oncology Group (RTOG) 85-01, it is reasonable to combine systemic chemotherapy with radiation.[5,6]

Preoperative Chemotherapy

Given the advantage in local control and survival when systemic chemotherapy is added to radiation therapy, two randomized trials were designed to examine the role of preoperative chemotherapy compared with surgery alone in patients with clinically resectable disease. In the Dutch trial, patients who received two cycles of preoperative cisplatin(Drug information on cisplatin) and etoposide(Drug information on etoposide) experienced a significant increase in median survival over those treated with surgery alone (19 vs 11 months; P = .002).[46]

These results contrasted with those of the INT 0113 trial (RTOG 89-11), which randomized patients who underwent an R0 resection to receive two cycles of preoperative fluorouracil(Drug information on fluorouracil) (5-FU)/cisplatin or surgery alone. This trial found no differences between the two groups with respect to median survival (15 vs 16 months), overall survival at 2 years (35% vs 37%) or 5 years (20% vs 20%), incidence of postoperative death (7% vs 6%), or local failure (32% vs 31%).[47]

In summary, preoperative chemotherapy as delivered in the above randomized trials, shows no survival benefit. At present, therefore, preoperative chemotherapy remains investigational.