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. 2009 Mar-Apr;3(2 Suppl 1):S6–S10.

Principles of Modern Radiation Techniques for Esophageal and Gastroesophageal Junction Cancers

Gary Y Yang 1,2,✉, Susan A McClosky 1,2, Nikhil I Khushalani 1,2
PMCID: PMC2684733  PMID: 19461922

Abstract

Esophageal cancer is a highly virulent neoplasm with high morbidity and mortality. With the benefit of radiotherapy (RT) combined with chemotherapy clearly established, the challenge is in the accurate and safe delivery of radiotherapy. Improved understanding of patterns of esophageal cancer relapse and tumor spread and of organ motion in the upper thorax and abdomen have allowed for implementation of more conformal radiation techniques, including respiratory-gated RT, imageguided RT (IGRT), and intensity-modulated RT (IMRT). At a minimum, successful implementation of conformal radiation delivery requires a detailed understanding of esophageal anatomy and radiobiological principles, an individualized assessment of organ motion, precise patient immobilization techniques, and adequate physics and dosimetry expertise. To aid the practicing clinician, the National Comprehensive Cancer Network (NCCN) has recently incorporated detailed recommendations on simulation, treatment planning, target volumes, and dose limits for select critical normal structures. The practicing clinician is urged to utilize the multitude of resources now available to ensure that optimal adjuvant radiotherapy for esophageal cancer is delivered safely and accurately.

It is estimated that 16,470 new cases of esophageal cancer were diagnosed in the United States in 2008 and 14,280 Americans died of the disease.1 Worldwide, esophageal cancer is the eighth most common malignancy.2 Dramatic increases in rates of adenocarcinoma of the esophagus and gastroesophageal junction have been observed in the United States, attributed primarily to increasing obesity and gastroesophageal reflux disease.3 Prospective data support the efficacy of concurrent chemoradiation in both the definitive and neoadjuvant settings. The Radiation Therapy Oncology Group (RTOG) 85-01 trial was a randomized controlled comparison of definitive radiotherapy alone (64 Gy), and definitive concurrent chemoradiation (50 Gy delivered concurrently with 5-fluorouracil [5-FU] and cisplatin). A statistically significant benefit was noted for overall survival among patients receiving concurrent chemoradiation.4 The Intergroup trial 0123 subsequently randomized 231 patients to receive definitive chemoradiation with 50 Gy delivered concurrently with 5-FU and cisplatin vs. 64 Gy delivered concurrently with the same chemotherapeutic regimen. No significant differences were noted in median or overall survival or locoregional control.5 Given these findings, the current standard of care for inoperable esophageal cancer is concurrent chemoradiation with 50 Gy radiotherapy and cisplatin/5-FU–based chemotherapy. Recent meta-analyses and randomized prospective data also support the efficacy of concurrent chemoradiation in the neoadjuvant setting. 6–8

While radiotherapy has a clear role in the management of esophageal carcinoma, the challenge lies in how to deliver the radiation accurately while minimizing normal tissue toxicity.

STANDARD 3D CONFORMAL RADIATION PLANNING

Prior to the advent of computed tomography (CT)-based planning, treatment fields were designed using an orally administered contrast agent and a fluoroscopic simulator. Currently, the radiation oncologist correlates diagnostic CT scan and endoscopy data to a planning CT scan to determine an appropriate treatment field. RTOG 0436 is the most recently activated RTOG trial that describes radiation treatment planning for definitive management of esophageal carcinoma.

RTOG 0436, activated in June 2008, is a phase III randomized trial examining the addition of cetuximab to paclitaxel, cisplatin, and radiotherapy for patients with esophageal cancer treated without surgery. This trial stipulates that the gross tumor volume (GTV) will include all areas of gross disease as defined by the planning CT and clinical information. Such clinical information typically includes endoscopic ultrasound, endoscopy, and diagnostic CT scan reports. Per RTOG 0436, clinical tumor volume (CTV) is defined as 4 cm proximal and distal to the GTV and 1 cm lateral to the GTV. For cervical primaries, CTV should include the supraclavicular nodes, and for distal esophageal primaries, CTV should include the celiac nodes. Recommended planning treatment volume (PTV), to account for variability in daily setup and organ motion, is between 1 and 2 cm. With CTV and PTV expansions, the treatment field is approximately 5 cm superior and inferior and 1.5 cm lateral to the GTV. The field is thus similar to what would have been designed conventionally, prior to the advent of 3-dimensional (3D) conformal planning. RTOG 0436 does not include specific guidelines regarding beam arrangement.

Field arrangements commonly used in practice are anteroposterior-posteroanterior opposed fields to 36–41 Gy followed by obliques. For the oblique component, field arrangements can include an anterior field with a left and right posterior oblique pair or opposed right anterior and left posterior obliques. The typical normal tissues in the treatment region include lung, spinal cord, heart, liver, and kidneys.

Endoscopic ultrasound (EUS) and CT have traditionally been used to aid in radiation therapy planning; however, both techniques have limitations. The reported accuracy of EUS has been 85% and 75% for primary and nodal disease, respectively.9 EUS also frequently cannot pass an obstructing lesion to give an accurate determination of tumor length. Furthermore, the distance from the incisors as reported by the endoscopist is difficult to translate when the patient is in a different position for radiation treatment planning. Visualization of tumor extent with CT scan alone is also difficult, especially at the gastroesophageal junction. Drudi et al examined surgical specimens from 22 patients undergoing surgical resection for esophageal carcinoma and correlated the pathologic length of primary carcinoma with the length determined by CT and EUS. Primary tumor length determined by esophagram and CT scan correlated with surgical specimen length in 59% and 32%, respectively.10

EMERGING DATA TO AID IN DESIGN OF RADIATION FIELDS

Better Defining the GTV: PET-CT Planning

A growing body of literature supports the use of 18F-fluoro-2-deoxy-D-glucosepositron emission tomography (FDG-PET) in esophageal radiotherapy planning. Vrieze et al assessed lymph node involvement by CT, EUS, and FDG-PET in 30 patients with advanced esophageal carcinoma.11 In 47% of patients, discordance was noted between lymph nodes detected by FDG-PET and by CT/EUS. FDG-PET failed to detect nine nodes in eight patients that were detected by CT/EUS. In three of these eight patients, failure of FDG-PET to detect CT/EUS-detected disease would have led to a reduction in the irradiated volume. Eight nodes in six patients were detected by FDG-PET that were not detected by CT/EUS. In three of these six patients, disease detected by FDG-PET would have resulted in an increase in the irradiated volume.

The authors suggested that irradiated volumes should not be reduced based on negative FDG-PET results, given the falsenegatives noted in this report. However, they suggested that FDG-PET demonstrated adequate specificity to conclude that FDGPET– positive disease should be included in the irradiated volume. As these patients received neoadjuvant chemoradiation, no histologic confirmation of discordant findings was possible.11

Konski et al performed CT and FDGPET for radiation planning in 25 patients with esophageal carcinoma; 18 of the 25 also had EUS for comparison.12 The length of the esophageal GTV and detection of regional adenopathy was compared between the three imaging modalities. Mean GTV as determined by CT scan was significantly longer than that determined by FDG-PET. Specifically, mean GTV lengths were 6.77 cm, 5.4 cm, and 5.1 cm, respectively, with CT, PET, and EUS. EUS detected more regional adenopathy than both CT and PET. The authors concluded that EUS and PET aid in precisely identifying the GTV for esophageal cancer radiation planning.12

Moureau-Zabotto et al performed FDGPET and CT for simulation purposes in 34 patients with esophageal carcinoma.13 Five fiducial markers were used to precisely coregister the CT and FDG-PET images for planning purposes. In 56% of patients, GTV modifications affected the radiotherapy treatment volume. GTV was reduced in 35% and increased in 21% of patients. The authors concluded that FDG-PET and CT image fusion affected treatment planning for esophageal cancer; however, the clinical impact was not yet demonstrated.13

Leong et al enrolled 21 esophageal carcinoma patients in a prospective trial to determine effects of PET-CT on delineation of tumor volume for radiation therapy planning. PET-CT detected disease in eight patients that was not detected by CT scan: four of these patients were found to have metastatic disease and four had regional nodal disease. In 16 of 21 patients who proceeded to the radiotherapy planning phase of the trial, 69%had PET-CT–positive disease that would have been excluded if CT alone had been used for radiation planning.14

Gondi et al performed treatment planning for 30 patients (16 with esophageal cancer and 14 with lung cancer) using both FDG-PET and non-contrast CT scans. In the patients with esophageal cancer, the mean conformality index was 0.46 and FDG-PET resulted in a smaller GTV in 62.5% of them.15

Better Defining the CTV: Assessment of Pathologic Disease Extent

Gao et al examined surgical specimens of patients undergoing surgery for squamous cell carcinoma of the esophagus (n = 34) or adenocarcinoma of the gastroesophageal junction (n = 32) to determine the CTV necessary for radiation therapy planning. 16 The mean microscopic spread beyond the gross tumor among 34 patients with esophageal squamous cell carcinoma was 10.5 ± 13.5 mm proximally and 10.6 ± 8.1 mm distally. In 32 of 34 cases, the proximal spread was < 30 mm, and in 33 of 34 cases, the distal spread was < 30 mm. The mean microscopic spread beyond the gross tumor among 32 patients with adenocarcinoma of the gastroesophageal junction was 10.3 ± 7.2 mm proximally and 18.3 ± 16.3 mm distally. In 29 of 29 evaluable cases, the proximal spread was < 30 mm, and in 27 of 32 cases, the distal spread was < 30 mm. The authors concluded that a 50 mm CTV would be necessary to cover distal microscopic spread in 94% of adenocarcinomas of the gastroesophageal junction. A 30 mm CTV would be adequate to cover microscopic disease spread in 94% of squamous cell carcinomas and for coverage of proximal microscopic spread for adenocarcinomas of the gastroesophageal junction.16

Better Defining the ITV: Assessment of Esophageal Mobility

Dieleman et al used 4-dimensional (4D) CT scans to quantify esophageal mobility during normal respiration in 29 patients with non-esophageal malignancies.17 This study sought to quantify esophageal mobility, not for treatment of esophageal cancer, but in an effort to avoid the esophagus in treatment of thoracic tumors. Margins necessary to cover esophageal medio-lateral movement were 5 mm, 7 mm, and 9 mm, respectively, for the proximal, mid, and distal esophagus. Margins necessary to cover esophageal dorso-ventral movement were 5 mm, 6 mm, and 8 mm, respectively, for the proximal, mid, and distal esophagus.17

Yaremko et al similarly used 4D CT to determine motion of distal esophageal cancers with respiration in 31 patients.18 In 95% of cases, radial and inferior tumor mobility was < 0.8 cm and < 1.75 cm, respectively. Esophageal mobility varied by location within the esophagus. Abdominal esophageal primariesmoved 1.06 ± 0.04 cm and thoracic esophageal primaries moved 0.81 ± 0.02 cm, on average. The authors suggest that these data can inform construction of an internal target volume (ITV) for esophageal cancer planning, and that methods to limit respiratorymotionmay, in the future, allow for margin reduction and thus decreases in treatment-related toxicity.18

Better Defining the PTV: Assessment of Daily Set-Up Variation

Chen et al performed megavoltage CT scans daily prior to treatment to quantify daily set-up variation among ten patients with esophageal carcinoma undergoing concurrent chemoradiation using helical tomotherapy. Using the recommendation that CTV to PTV expansion should equal the mean plus standard deviation of absolute set-up error in either direction, this series noted that anterior-posterior (AP), lateral, and superior-inferior margins of 5 mm, 11.1 mm, and 12.7 mm, respectively, would be necessary to encompass daily set-up errors in the absence of onboard imaging correction.19

INTENSITY-MODULATEDRADIATION THERAPY (IMRT)

In an attempt to improve tumor coverage and limit normal tissue toxicities, IMRT has been evaluated for treatment of esophageal carcinoma. With the exception of a small series that used IMRT to treat patients with cervical esophageal primaries, most data regarding IMRT for esophageal malignancies has been limited to dosimetric analyses.

Fu et al performed treatment planning for five patients with cervical esophageal primaries using IMRT and 3D conformal radiotherapy. 20 This series used a simultaneous integrated boost technique to deliver 67.2 Gy and 50.4 Gy, respectively, to grossly positive disease and elective nodal regions. The IMRT plans were superior in that they reduced the percent of total lung volume exceeding 20 Gy (V20) or 30 Gy (V30) while generating more conformal and homogeneous target coverage.20 Chandra et al assessed the use of IMRT in treating distal esophageal primaries.21 This was a retrospective treatment planning study in which ten patients who had undergone radiotherapy for distal esophageal cancer using a standard 3D conformal technique were also planned using a 4-, 7-, or 9-beam IMRT technique. Compared with the 3D conformal plan, IMRT plans reduced V10 by 10%, V20 by 5%, and mean lung dose by 2.5 Gy. Heterogeneity and conformality indices were improved with IMRT. No significant reductions were noted in heart, spinal cord, liver, and total body integral dose.21

A dosimetric comparison of 3D conformal and IMRT plans in five patients with esophageal carcinoma was performed by Nutting et al.22 Specifically, a 3D conformal plan using anterior, posterior, and bilateral posterior oblique fields was compared with 9-field and 4-field IMRT plans. Compared with the 3D conformal plan, although no improvements were noted for the 9-field IMRT plan, the 4-field IMRT plan resulted in reduced mean lung dose.22 Chen et al reported a dosimetric analysis of ten patients with mid-distal esophageal carcinoma planned using helical tomotherapy, step-and-shoot IMRT, and 3D conformal radiotherapy.23 Tomotherapy plans were superior in that they resulted in decreased lung V20 while generating sharper dose gradients, more conformal target coverage, and improved homogeneity index. Tomotherapy and IMRT plans, however, resulted in increased lung V10. Tomotherapy and IMRT plans resulted in decreased heart V30 and V45.23

More recently, Mayo et al examined hybrid IMRT for the treatment of patients with primary lung (n = 12) and esophageal (n = 6) cancers.24 With hybrid IMRT, the majority of dose is delivered using static beams and the remaining one third of dose is delivered using IMRT. Four plans were generated for the 18 patients, including a hybrid IMRT plan, a conventional 3D conformal plan, a 5-field IMRT plan, and a 9-field IMRT plan. Among patients with esophageal carcinoma, hybrid IMRT plans resulted in decreased contralateral lung V5, V13, and V20 (−16%, −20%, and −7%, respectively). With increasing evidence suggesting that low doses to large portions of lung can result in significant morbidity, the authors suggest that use of the hybrid technique to reduce the lung volume treated to low doses may improve clinical outcomes.24

Wang et al retrospectively reported outcomes of seven patients with upper or cervical esophageal cancer treated definitively with concurrent chemoradiation. A total radiation dose of 59.4–66 Gy (mean, 64.8 Gy) was delivered using 5–9–beam IMRT. Complete response was noted in six evaluable patients with a median follow-up of 15 months. At last follow-up, three of six patients were alive with no evidence of disease, two developed local recurrence, and two recurred distantly. Toxicities included one tracheoesophageal fistula and two esophageal strictures requiring frequent dilatation.25

CRITICAL NORMAL STRUCTURE AVOIDANCE

Beyond the difficulties associated with accurate target delineation, another challenge to the implementation of adjuvant radiation therapy is the close proximity of dose-limiting critical structures including kidneys, liver, heart, lung, and spinal cord. National Comprehensive Cancer Network (NCCN) Guidelines recommend dose limits for select critical normal structures,26 including the following: 60% of the liver should receive less than 30 Gy, at least two thirds of one kidney should not receive more than 20 Gy, the spinal cord dose should not exceed 45 Gy, and one third of the heart should receive less than 50 Gy. Although specific dose-volume histogram parameters are not provided for the lung, the Guidelines recommend keeping the lung volume and doses to a minimum.

Pulmonary Effects

Many studies have examined various dosevolume histogram predictors of pulmonary toxicity secondary to radiation. Mean lung dose has been reported to correlate with development of radiation pneumonitis in selected series.27–32 Kwa et al reported the largest series, which included 540 patients undergoing thoracic radiation for lymphoma or primary lung, esophageal, or breast carcinoma. In this series, the mean lung dose predicted for grade ≥ 2 pneumonitis. Specifically, a mean lung dose < 20 Gy correlated with acceptable pneumonitis risk of 13% to 24%.30

Graham et al examined dose-volume histogram parameters among 99 patients who received radiation to the chest for inoperable non-small cell lung cancer.29 The V20 was the only independent predictor for development of pneumonitis on multivariate analysis. Specifically, no pneumonitis was seen with V20 < 22%, 8%grade 2 pneumonitis was observed with V20 of 22% to 31%, and grade 3 pneumonitis was observed when V20 exceeded 32%. A 23% incidence of grade 3–5 pneumonitis was observed among patients with a V20 exceeding 40%. Tsujino et al also found V20 to be a significant predictor for the development of grade 2 or more pneumonitis in a series that included 75 patients receiving concurrent definitive thoracic chemoradiation.31

Although V20 and mean lung dose have been the traditional parameters used to assess plan acceptability, emerging data suggest that percent lung volume receiving even lower doses may be predictive of pulmonary toxicity.

Schallenkamp et al correlated pneumonitis risk with dose-volume histogram parameters in 92 patients receiving definitive thoracic radiation. Mean lung dose, effective lung dose, V10, V13, V15, V20, and V30 were examined for correlation with pneumonitis risk, and V10 and V13 were found to be the strongest predictors of pneumonitis.33

Lee et al correlated postoperative pulmonary complications with lung dose-volume histogram parameters in 61 esophageal cancer patients receiving neoadjuvant concurrent chemoradiation followed by surgery at M. D. Anderson Cancer Center.34 Postoperative pulmonary complications increased significantly when the V10 exceeded 40%.34 An update of this study included 110 esophageal carcinoma patients treated with neoadjuvant concurrent chemoradiation followed by surgery. The only significant predictor of pulmonary complications, defined as pneumonia or acute respiratory distress syndrome within 30 days of surgery, was volume of lung spared from doses ≥ 5 Gy.35

Cardiac Effects

Given the limited life expectancy of patients with advanced esophageal carcinoma, data are limited regarding cardiac morbidity associated with radiotherapy for this disease. An excess risk of coronary artery disease and myocardial infarction has been well documented following mantle radiotherapy for Hodgkin’s lymphoma and adjuvant radiotherapy for breast cancer before 1980.36–41 More modern series have yielded conflicting results.42

Carr et al analyzed cardiac outcomes among patients who did (n = 1,859) or did not (n = 1,860) receive radiation therapy for peptic ulcer disease at the University of Chicago between 1936 and 1965.43 It was estimated that 5% of the cardiac volume was directly in the radiation field and received a mean cumulative absorbed dose of 7.6 to 18.4 Gy. The remaining 95% of the heart received scatter dose of 1.6 to 3.9 Gy. Patients receiving radiation had a significantly increased risk for coronary heart disease mortality. Furthermore, the doses were lower than those used for modern breast cancer and lymphoma radiotherapy strategies. Based on these findings, the authors urged long-term followup of patients receiving chest radiation for assessment of cardiac toxicity.43

Wei et al retrospectively examined clinical and dosimetric predictors for the development of pericardial effusion among 101 patients receiving definitive concurrent chemoradiation for inoperable esophageal carcinoma. Pericardial effusion was noted in 27.7% of patients at a median of 5.3 months following completion of radiation. The only significant variable for the development of pericardial effusion was cardiac V30. Specifically, V30 > 46% and < 46% were associated with rates of pericardial effusion of 73% and 13%, respectively.44

Investigators at Roswell Park Cancer Institute retrospectively evaluated multiple gated acquisition (MUGA) cardiac scans obtained in 20 patients before and after receipt of neoadjuvant concurrent chemoradiation for esophageal carcinoma. A statistically significant, but clinically insignificant, decrease was noted in median post-chemoradiation ejection fraction (59% to 54%, P = .01).45

Research is ongoing regarding the optimal dosing and patient parameters for prediction of both cardiac and pulmonary toxicities secondary to radiation. As research efforts continue, every effort should be made to limit radiation dose delivery to critical normal structures.

CONCLUSION

Rates of esophageal adenocarcinoma are increasing in the United States. A recent Surveillance Epidemiology and End Results (SEER) analysis found that, among white men and women, rates of esophageal adenocarcinoma increased by 463% and 335%, respectively, from 1975–1979 to 2000– 2004.46 Many of these patients will receive neoadjuvant or definitive chemoradiation. To maximize outcomes, further utilization and study of modern radiation techniques are encouraged, including respiratory gating to account for and minimize target motion, image guidance to allow for precise target localization, and IMRT to allow for greater dose conformality. Further study of normal tissue toxicities should aid in more precisely defining safe dose parameters.

Footnotes

Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

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