Clinical investigation: esophagus
Combined modality radiotherapy and chemotherapy in nonsurgical management of localized carcinoma of the esophagus: A practice guideline

https://doi.org/10.1016/S0360-3016(02)04278-5Get rights and content

Abstract

Purpose:

To make recommendations regarding combined radiotherapy (RT) and chemotherapy (RTCT), compared with RT alone, when a nonsurgical approach is used for patients with localized esophageal carcinoma.

Methods and materials:

The Medline, Cancerlit, Cochrane Library databases, and abstracts published in the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology proceedings were searched for evidence. Evidence was evaluated by two members of the Gastrointestinal Cancer Disease Site Group and methodologists.

Results:

Pooling seven randomized trials detected a statistically significant survival benefit at 1 year for concomitant RTCT compared with RT alone (1-year mortality odds ratio 0.61; 95% confidence interval 0.44–0.84; p <0.00001). Local control also significantly improved with concomitant RTCT compared with RT alone for the available data (odds ratio 0.52; 95% confidence interval 0.31–0.89; p = 0.004), but a significant increase in adverse effects, including life-threatening toxicities, was shown.

Conclusion:

Concomitant RT and cisplatin-based CT is recommended over RT alone. Patients should be aware of the increased acute toxicity associated with this approach, and this recommendation should only be made after consideration of the potential risks and benefits and the patient’s general condition. Sequential RTCT is not recommended as standard practice.

Introduction

Carcinoma of the esophagus has a poor overall prognosis. The extent of disease at presentation and a patient’s performance status are the most powerful predictors of the potential for cure 1, 2. The opportunity exists to eradicate disease localized at presentation through therapy given with curative intent. The current TNM staging system (6th edition, 2002; 3) incorporated major prognostic factors, including the extent of esophageal wall involvement (T1–T4) and whether locoregional nodes are involved (N1). The extent of disease that oncologists consider amenable to curative intent is evolving. The changes in the precision and accuracy of diagnostic modalities, including the use of tools such as minimally invasive staging techniques, are improving the accuracy of clinical staging. Within this context, most would consider patients with T4 disease and extensive nodal involvement incurable. Evidence is increasing that patients with fewer than five nodes involved may have a better outcome than those with more extensive disease (4). Furthermore, the definition of nodal stations that are considered regional and still amenable to potentially curative therapies is also evolving. For the purpose of this guideline, patients with T1–T3, small volume N1, M0 were considered potential candidates for curative therapy.

Both primary surgery and radiotherapy (RT) are offered as treatment options to suitable candidates. In cervical tumors, the desire to avoid laryngoesophagectomy, together with the retrospective data supporting a better prognosis with cervical esophageal tumors, has resulted in the general acceptance of an organ-preserving approach for these patients. For patients with thoracic esophageal tumors, the recommendation for a primary surgical approach vs. a primary RT approach had predominantly been based on the patient’s medical operability, the patient’s preference, and the treating physician’s estimation of the relative morbidity of the outcomes. A well-known attempt in the United Kingdom to compare surgery and RT through a randomized study failed through the inability to accrue patients (5). Two randomized studies compared surgery alone vs. RT alone 6, 7. In 1994, Fok et al. (6) reported a four-arm study comparing surgery alone, preoperative RT and surgery, postoperative RT and surgery, and RT alone. The study was conducted in Hong Kong and included 156 patients. The median survival for surgery vs. RT was 21.6 vs. 8.2 months (p <0.001). Similarly, in 1999, Badwe et al. (7) reported a randomized study comparing surgery alone vs. RT alone. A total of 99 patients participated in this study. The overall survival was significantly superior in the surgery arm vs. the RT arm (p = 0.002). The ability to generalize these results to contemporary surgical and RT techniques and practices and the selection factors that need to be considered when choosing between these two treatment modalities are discussed in a separate guideline for the overall management of esophageal cancer that will be produced in due course.

Studies of the patterns of care of esophageal cancer in North America have shown an increase in the use of combined chemoradiotherapy (RTCT). Daly et al. (8) analyzed patterns of care using the U.S. National Cancer Database and found that the treatment modality most commonly used for esophageal cancer is combined RTCT (30.2%), followed by surgery alone (18%). The most common chemotherapy regimen used in combination with RT is 5-fluorouracil (5-FU) and cisplatin. In the Patterns of Care Study (9), the chemotherapy agents most frequently used were 5-FU (84%), cisplatin (64%), and mitomycin (9%). Youssef et al. (10) compared the management and outcome of carcinoma of the esophagus in Ontario and the United States. Controlling for age, gender, histologic type, and subsite, the rate of esophagectomy was similar, but the rate of primary RT was lower in Ontario. Practice patterns for the use of RT vs. combined RTCT and the types of chemotherapy used have not been described for Ontario or Canada.

This practice guideline report addresses the question of whether the addition of chemotherapy to a primary RT approach improves patient outcomes. A separate guideline is being prepared on the use of neoadjuvant or adjuvant therapy for resectable esophageal cancer when surgery is the primary modality (Practice Guidline 2–11: Neoadjuvant or adjuvant therapy for resectable esophageal cancer). Eventually, the Gastrointestinal Cancer Disease Site Group will consolidate both guidelines to produce a comprehensive recommendation for patients with localized carcinoma of the esophagus who are treated with curative intent.

Section snippets

Guideline development

This practice guideline report was developed by the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI), using the method of the Practice Guidelines Development Cycle (11). Evidence was selected and reviewed by two members of the CCOPGI’s Gastrointestinal Cancer Disease Site Group (Gastrointestinal Cancer DSG) and methodologists. Members of the Gastrointestinal Cancer DSG disclosed potential conflict-of-interest information.

The practice guideline report is a convenient and up-to-date

Literature search results

No fully published reports of meta-analyses were identified, although the pooling of data presented in this guideline report was published in abstract form in 1999 (23). This abstract is not discussed further, because the meta-analysis was updated for this guideline report. A related study by Smith et al. (24) was excluded because surgery was a planned option within the study design.

Ten randomized trials of concomitant RTCT met the inclusion criteria 25, 26, 27, 28, 29, 30, 31, 32, 33, 34.

Discussion

On the basis of the pooled analyses, concomitant RTCT compared with RT alone was associated with an absolute reduction of 1-year mortality from 67% to 56%, with an NNT of 9. The recurrence rate was reduced from 69% with RT alone to 55% with concomitant RTCT, with an NNT of 7. These benefits, although relatively modest, are not trivial considering the generally poor survival rates and morbidity associated with an uncontrolled primary tumor. However, these advantages are associated with a

Practice guideline

This practice guideline reflects the integration of the draft recommendations with feedback obtained from the external review process. It has been approved by the Gastrointestinal Cancer DSG and the Practice Guidelines Coordinating Committee.

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    Supported by Cancer Care Ontario and Ontario’s Ministry of Health and Long-Term Care.

    1

    The Cancer Care Ontario Practice Guidelines Initiative Gastrointestinal Cancer Disease Site Group includes J. Maroun, M.D. (Chair); O. Agboola, M.D.; M. Citron; B. Cummings, M.D.; F. G. DeNardi, M.D.; C. Earle, M.D.; A. Figueredo, M.D.; S. Fine, M.D.; B. Fisher, M.D.; C. Germond, M.D.; D. Jonker, M.D.; K. Khoo, M.D.; W. Kocha, M.D.; M. Lethbridge; W. Lofters, M.D.; R. McLeod, M.D.; M. Moore, M.D.; and V. Tandan, M.D. Please see the Cancer Care Ontario Practice Guidelines Initiative (CCOGPI) web site (http://www.ccopebc.ca/) for a complete list of current Gastrointestinal Cancer Disease Site Group members. Ottawa, ON, Canada.

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