QUANTEC: Organ-Specific Paper
Radiation Dose-Volume Effects in the Esophagus

https://doi.org/10.1016/j.ijrobp.2009.05.070Get rights and content

Publications relating esophageal radiation toxicity to clinical variables and to quantitative dose and dose–volume measures derived from three-dimensional conformal radiotherapy for non–small-cell lung cancer are reviewed. A variety of clinical and dosimetric parameters have been associated with acute and late toxicity. Suggestions for future studies are presented.

Section snippets

Clinical Significance

Acute esophagitis (occurring ≤90 days after treatment initiation) is a common side effect of patients undergoing radiotherapy (RT) for thoracic tumors. Concurrent chemoradiotherapy (CCT) or hyperfractionation results in a 15–25% rate of severe (Radiation Therapy Oncology Group [RTOG] Grade 3 or greater) acute esophagitis 1, 2, 3 that can require hospitalization, invasive diagnostic tests (e.g., endoscopy), surgical intervention (e.g., percutaneous endoscopic gastrostomy tube) or RT breaks that

Endpoints

The assigned toxicity grade varies with the scoring system used, making interstudy comparisons challenging. In general, Grade 1 toxicities cause minor changes in a patient's lifestyle, and Grade 2 or greater toxicities might require medical intervention. The currently accepted grading system is the Common Terminology Criteria for Adverse Events, version 3 (9); however, the studies cited in the present report mostly used the RTOG scoring system. In the present review, Grade 2 or greater acute

Challenges Defining Volumes

The adult esophagus length is ≈25 cm and is defined by its external contour on axial computed tomography (CT) images. The esophagus remains closed when not involved in swallowing, and its lumen is often not easily identifiable throughout its entire length, particularly in the middle and caudal levels. Administration of a thick barium paste can help localize the esophagus, but the swallowing times are short (10 seconds), and the barium paste might not fully opacify the entire organ. In addition,

Review of Dose–Volume Published Data

A total 12 studies published between 1999 and January 2009 that assessed the dose–volume outcome in ≥90 patients treated for non–small cell lung cancer were reviewed 7, 8, 11, 13, 16, 17, 18, 19, 20, 21, 22, 23 (Table 1). All but one study (17) used three-dimensional planning. The endpoint was usually RTOG Grade 2 or greater or Grade 3 or greater. Two studies 7, 8 combined acute and late toxicities in a single analysis. The others either analyzed only acute 13, 16, 17, 19, 20, 22, 23 or

Factors Affecting Risk

Greater acute esophagitis rates are seen with increased RT aggressiveness (e.g., hyperfractionation, concurrent boost), the addition of CCT, and several clinical factors (e.g., pre-existing dysphagia and increasing nodal stage, with the latter likely a surrogate for larger tumors; Table 1). The incidence of Grade 3 or greater acute esophagitis is ≈1% for patients treated with once-daily RT alone. It is markedly increased with the addition of CCT (incidence, 6–24%) and is as great as 49% with

Statistical models

The statistical level of correlation between a complication and a set of variables is inadequate for treatment planning purposes. Statistical models aim to supply the missing link. They use the most significant dose–volume or dose–area variable and medical factors (e.g., CCT) as variables in a sigmoidal function. The typical functional form is%NTCP=100 exp[c0+ccctCCT+Σi(ciVdosei)]/[1+exp(c0+ccctCCT+Σi[ciVdosei])].

The summation (symbolized by Σi) represents a weighted combination of the

Special Situations

Hypofractionation for central lesions can expose parts of the esophagus to relatively large doses per fraction. Predictions using conventional fractionation should not be applied to such treatments unless they have been validated by additional study. Although a few reports have been published of serious esophageal toxicity from hypofractionation (35), no comprehensive dose–volume-based analyses have been published. Similarly, no large body of data exists on long-term esophageal toxicity of

Recommended Dose–Volume Limits

At present, it is not possible to identify a single best threshold volumetric parameter for esophageal irradiation, because a wide range of Vdose parameters correlate significantly with severe acute esophagitis. In particular, the studies we analyzed illustrate a clear trend demonstrating that volumes receiving >40–50 Gy correlated significantly with acute esophagitis (Fig. 1) (24). In particular, for high-dose conventionally fractionated non–small-cell lung cancer treatments, it is prudent to

Future Toxicity Studies

New thoracic protocols that have acute esophagitis toxicity as an endpoint should specify one or more dose–volume models to test prospectively. Future analyses of esophagitis should ideally include the time of onset, because the complication occurs from the dose accumulated during the course of therapy, usually well before the total dose has been delivered. Complication models could potentially be constructed on the basis of the dose accumulated each week and the total dose. Thus, the data

Toxicity Scoring

We recommend that the Common Terminology Criteria for Adverse Events, version 3, be used to score both acute and late injury. It is simple and consistent, and its use has been mandated by the National Cancer Institute in the cooperative group trials since October 2003 (40). Late injury might be scored under several endpoints, including necrosis, obstruction, perforation, or stricture, depending on the patient's symptoms.

References (40)

  • I. El Naqa et al.

    Multivariable modeling of radiotherapy outcomes including dose–volume and clinical factors

    Int J Radiat Oncol Biol Phys

    (2006)
  • X. Wei et al.

    Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy

    Int J Radiat Oncol Biol Phys

    (2006)
  • N. Rodriguez et al.

    Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy

    Int J Radiat Oncol Biol Phys

    (2009)
  • K. Takeda et al.

    Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy

    Int J Radiat Oncol Biol Phys

    (2005)
  • C. Langer et al.

    Do elderly patients with locally advanced non-small cell lung cancer benefit from combined modality therapy? A secondary analysis of RTOG 94-10

    Int J Radiat Oncol Biol Phys

    (2001)
  • D. Antonadou et al.

    Randomized Phase III trial of radiation treatment plus/minus amifostine in patients with advanced-stage lung cancer

    Int J Radiat Oncol Biol Phys

    (2001)
  • R. Komaki et al.

    Effect of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small cell lung cancer: Report of a randomized comparative trial

    Int J Radiat Oncol Biol Phys

    (2004)
  • C. Burman et al.

    Fitting of normal tissue tolerance data to an analytic function

    Int J Radiat Oncol Biol Phys

    (1991)
  • B. Emami et al.

    Tolerance of normal tissue to therapeutic irradiation

    Int J Radiat Oncol Biol Phys

    (1991)
  • R. Onimaru et al.

    Tolerance of organs at risk in small-volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers

    Int J Radiat Oncol Biol Phys

    (2003)

    • Cited by (0)

    Conflict of interest: none.

    View full text
    Copyright © 2010 Elsevier Inc. All rights reserved.