Carcinoma of the Esophagus Part 1: Primary 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 will examine the rationale for and results of primary therapy for esophageal cancer. Part 2, which will appear in next month’s issue, deals with adjuvant therapy.

The epidemiology of esophageal cancer has changed during the past decade. The most notable change has been an increase in the incidence of adenocarcinoma, most commonly occurring at the gastroesophageal junction.[1] Therefore, histology should be considered when comparing the results of various treatment approaches. Adenocarcinoma is seen more frequently in middle-aged males with a history of gastroesophageal reflux, whereas squamous cell cancers occur more commonly in the proximal and middle esophagus of older patients who have a history of smoking and alcohol(Drug information on alcohol) abuse.

At present, the available data are conflicting with respect to histology. Some series report different results according to histology, whereas other series report no such difference. Fortunately, the National Cancer Institute–sponsored, intergroup, randomized trials are now stratified by histology. Until these stratified results are available, the impact of histology cannot be adequately assessed, and it is reasonable to treat both histologies in a similar fashion.

Selection Bias in Trials of Primary Therapy

Surgical and nonsurgical approaches have had similar results when used as primary therapy for esophagel cancer. However, it must be emphasized that the patient population selected for treatment with each modality is usually different, resulting in a selection bias against nonsurgical therapy.

First, patients with poor prognostic features, including those who have medical contraindications to surgery and those with primary unresectable or metastatic disease, are more commonly selected for nonsurgical therapy. Second, surgical series report results based on pathologically staged patients, whereas nonsurgical series report results based on clinically staged patients. Pathologic staging has the advantage of excluding some patients with metastatic disease. Third, since some patients who receive nonsurgical therapy are treated palliatively rather than for cure, the intensity of chemotherapy and the doses and techniques of radiation therapy can be suboptimal.

Nonsurgical Primary Therapy

Radiation Therapy Alone

Many series have reported the results of external-beam radiation therapy alone. Most of these series include patients with unfavorable features, such as clinical T4 disease and positive lymph nodes. For example, in the series by De-Ren, 184 of the 678 patients had stage IV disease.[2] Overall, the 5-year survival rate for patients treated with radiation therapy alone is 0% to 10%.[2-4]

The use of radiation therapy as a potentially curative modality requires doses of at least 5,000 cGy administered at 180 to 200 cGy per fraction. Furthermore, given the large size of many unresectable esophageal cancers, doses of ³ 6,000 cGy are probably required. However, even in the radiation therapy-alone arm of the Radiation Therapy Oncology Group (RTOG) trial 85-01, in which patients received 6,400 cGy of radiation delivered with modern techniques, all patients were dead from esophageal cancer by 3 years.[5,6]

There is one report of radiation therapy alone for patients with clinically early-stage disease. The trial by Sykes et al was limited to 101 patients (90% of whom had squamous cell carcinoma) with tumors < 5 cm who received 4,500 to 5,250 cGy in 15 to 16 fractions. The 5-year survival rate was 20%.[7]

In summary, radiation therapy alone should be reserved for palliation or for patients who are medically unable to receive chemotherapy. As will be discussed below, combined-modality therapy has had more favorable results and represents the standard of care.

Combined-Modality Therapy

Conventional Approaches—Numerous single-arm, nonrandomized trials have evaluated combined-modality therapy alone in patients with esophageal cancer.[8-12] Selected series are summarized in Table 1.

The series reported by Coia and associates is the only one in which patients with early-stage disease (clinical stages I and II) were analyzed separately from those with more advanced disease.[9] These patients were treated with flourouracil (5-FU) and mitomycin(Drug information on mitomycin) (Mutamycin) administered concurrently with 6,000 cGy of radiation. Combining clinical stages I and II, the local failure rate was 25%, the 5-year actuarial local relapse-free survival rate was 70%, and the 5-year actuarial survival rate was 30%.

The Southwest Oncology Group (SWOG) 9060 trial reported by Poplin et al included 32 patients who received 5-FU/cisplatin (Platinol) concurrently with 5,000 cGy of radiation, followed by two cycles of 5-FU/cisplatin.[13] Since the choice of further management (observation, radiation, chemotherapy, and/or surgery) was based on tumor response, this trial cannot be considered a pure combined-modality therapy series. Although the median survival was 20 months, the authors concluded that the complexity and toxicity of this combined-modality program precluded its further use.

Six randomized trials have compared radiation therapy alone with combined-modality therapy (Table 2).[5,14-19] Of the six trials, five used suboptimal doses of radiation and three employed inadequate doses of systemic chemotherapy.

For example, in the series by Araujo and colleagues,[14] patients received only one cycle of 5-FU, mitomycin, and bleomycin(Drug information on bleomycin) (Blenoxane). The European Organization for Research and Treatment of Cancer (EORTC) trial used subcutaneous methotrexate(Drug information on methotrexate).[15] In the Scandinavian trial reported by Nygaard and associates, patients received low doses of chemotherapy (cisplatin [20 mg/m²] and bleomycin [10 mg/m²] for a maximum of two cycles).[16]

In the Eastern Cooperative Oncology Group (ECOG) EST-1282 trial, patients who received combined-modality therapy had significantly increased median survival, compared with those treated with radiation alone (15 vs 9 months; P = .04), but showed no improvement in 5-year survival (9% vs 7%). However, this was not a pure nonsurgical trial since approximately 50% of patients in each arm underwent surgery after receiving 4,000 cGy of radiation. Furthermore, this decision depended on the individual investigator’s preference. Operative mortality was 17%.

Lastly, the Pretoria trial reported by Slabber and colleagues, which was limited to a total of 70 patients with T3 squamous cell cancers, used a low-dose (4,000-cGy) split-course radiation schedule.[18]

The only trial designed to deliver adequate doses of systemic chemotherapy with concurrent radiation therapy was the RTOG 85-01 trial reported by Herskovic et al (Figure 1).[5,17] This intergroup trial primarily included patients with squamous cell carcinoma. They received four cycles of 5-FU (1,000 mg/m²/24 h × 4 days) and cisplatin(Drug information on cisplatin) (75 mg/m² on day 1). Radiation therapy (5,000 cGy at 200-cGy/d) was given concurrently with day 1 of chemotherapy. Curiously, cycles 3 and 4 of chemotherapy were delivered every 3 weeks (weeks 8 and 11) rather than every 4 weeks (weeks 9 and 13). This intensification may explain, in part, why only 50% of the patients finished all four cycles of chemotherapy. The control group received radiation therapy alone, albeit at a higher dose (6,400 cGy) than patients in the combined-modality therapy arm.

Patients who received combined-modality therapy demonstrated a significant improvement in median survival (14 vs 9 months) and 5-year survival (27% vs 0%; P < .0001), compared with radiation alone.[17] The actuarial incidence of local failure as the first site of failure was also significantly decreased in the combined-modality group (45% vs 68%; P = .0123).

The protocol was closed early due to these positive results. Following this early closure, an additional 69 patients were treated with the same combined-modality therapy regimen, and similar results were seen (3-year survival rate of 30%).

Toxicity—Although combined-modality therapy achieves better results than radiation alone, it is associated with a higher incidence of toxicity. In the RTOG 85-01 trial, patients who received combined-modality therapy had more acute grade 3 toxicity (44% vs 25%) and acute grade 4 toxicity (20% vs 3%) than patients given radiation therapy alone. Including the one treatment-related death (2%), the total incidence of acute grade 3+ toxicity in this trial was 66%. Although the acute grade 3+ radiation-related toxicity was higher with combined-modality therapy than with radiation therapy alone (35% vs 12%), there was little difference in late toxicity (29% vs 23%).

Based on the positive results of the RTOG 85-01 trial, the conventional nonsurgical treatment for esophageal carcinoma is combined-modality therapy. These results notwithstanding, the local failure rate in the RTOG 85-01 combined-modality therapy arm was 45%. Thus, there is room for improvement, and new approaches, such as intensification of combined-modality therapy and escalation of the radiation dose, have been developed in an attempt to improve upon these results.