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Radiation Dose-Volume Effects in the Esophagus

      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.

      1. 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 (
      • Curran Jr., W.
      • Scott C.
      • Langer C.
      • et al.
      Phase III comparison of sequential vs. concurrent chemoradiation for patients with unresected stage III non-small cell lung cancer: Initial report of RTOG 9410.
      ,
      • Furuse K.
      • Fukuoka M.
      • Kawahara M.
      • et al.
      Phase III study of concurrent vs. sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small cell lung cancer.
      ,
      • Cox J.D.
      • Pajak T.F.
      • Asbell S.
      • et al.
      Interruptions of high-dose radiation therapy decrease long-term survival of favorable patients with unresectable non-small cell carcinoma of the lung: Analysis of 1244 cases from 3 RTOG trials.
      ) that can require hospitalization, invasive diagnostic tests (e.g., endoscopy), surgical intervention (e.g., percutaneous endoscopic gastrostomy tube) or RT breaks that could lower local tumor control.
      Late injury is less commonly reported, perhaps because the patients might not live long enough to manifest toxicity (e.g., the disease-specific survival is relatively short for many thoracic cancers). Dose escalation of standard fractionated RT and hypofractionated RT regimens (
      • Timmerman R.
      • McGarry R.
      • Yiannoutsos C.
      • et al.
      Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancers.
      ,
      • Onishi H.
      • Shirato H.
      • Nagata Y.
      • et al.
      Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: Updated results of 257 patients in a Japanese multi-institutional study.
      ) can increase the risk of late esophageal toxicity, especially if the survival rates improve. Esophageal stricture often requires periodic dilation, usually with good results (
      • Choi G.B.
      • Shin J.H.
      • Song H.Y.
      • et al.
      Fluoroscopically guided balloon dilation for patients with esophageal stricture after radiation treatment.
      ). Death related to late esophageal injury (e.g., tracheoesophageal fistula or esophageal perforation) has been reported in only 0.4–1% of patients (
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ).

      2. 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 (

      CTC/CTCAE Codes. Available from: www.ctep.info.nih.gov/reporting/ctc.html. Last accessed December 15, 2009.

      ); however, the studies cited in the present report mostly used the RTOG scoring system. In the present review, Grade 2 or greater acute esophagitis (because it constituted the endpoint of many studies) and any late esophagitis (Grade 1 or greater), independent of the duration of the late symptoms, were considered clinically significant.
      Acute esophagitis occurs during RT and often persists for several weeks after RT. The symptoms of severe esophagitis (Grade 3 or greater) typically peak 4–8 weeks from the beginning of RT (
      • Werner-Wasik M.
      • Scott C.
      • Curran Jr., W.J.
      • et al.
      Correlation between acute esophagitis and late pneumonitis in patients (pts) with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent thoracic radiotherapy (RT) and chemotherapy: A multivariate analysis of the Radiation Therapy Oncology Group (RTOG) database [Abstract].
      ). Late esophageal damage, typically stricture and associated dysphagia, develops ∼3–8 months (range, 5–40) after RT (
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ). Abnormal esophageal motility can be noted within 3–4 weeks from RT alone and as early as 1 week after starting concurrent chemoradiotherapy (
      • Goldstein H.M.
      • Rogers L.F.
      • Fletcher G.H.
      • et al.
      Radiological manifestations of radiation-induced injury to the normal upper gastrointestinal tract.
      ).
      Some of the pitfalls in assigning the acute esophagitis grade are as follows:
      • 1.
        Esophageal infection can mimic treatment (RT or concurrent chemoradiotherapy)-related esophagitis. Candidiasis (usually suggested by co-existing oral candidiasis) or, rarely, herpes simplex esophagitis are the main culprits.
      • 2.
        Pre-existing gastroesophageal reflux can worsen the symptoms of esophagitis and should be treated. Constant burning, unrelated to the act of swallowing, and localized in the lower part of the esophagus is more likely related to the reflux than to the treatment-related esophagitis.
      • 3.
        Incidental irradiation of the stomach, and associated gastritis symptoms, can occur when a lower lobe lung mass has been treated.
      • 4.
        The assignment of Grade 2 (brief intravenous fluid for ≤24 hours) vs. Grade 3 (hospitalization) esophagitis might be physician-dependent.

      3. 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, high-contrast barium can affect the heterogeneity-corrected dose calculations. It is recommended that the entire length of the esophagus, from the cricoid cartilage to the gastroesophageal junction, be identified, requiring that a portion of the neck and upper abdomen be included in the planning CT scan. In some of the studies (
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ,
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ,
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ), the cephalad (“cervical”) esophagus was not included, causing the absolute esophageal volume to be ∼20% smaller than if its entirety had been contoured.
      The esophagus is slightly mobile. In a study of 29 patients undergoing four-dimensional CT scans three times during RT, the cephalad, middle, and caudal esophagus can move ≤5, 7, and 9 mm in the combined anteroposterior and craniocaudal directions, respectively (
      • Dieleman E.M.T.
      • Senan S.
      • Vincent A.
      • et al.
      Four-dimensional computed tomographic analysis of esophageal mobility during normal respiration.
      ). Thus, dose–volume analyses using the planning CT scan (as was done in the studies we reviewed), could have some inaccuracies, although no specific margin recommendations can be given at this time.
      The esophageal circumference varies markedly on sequential axial CT images, a reflection of the swallowing act. This appearance does not reflect the anatomic reality of a relatively uniform circumference (
      • Kahn D.
      • Zhou S.
      • Ahn S.-J.
      • et al.
      Anatomically correct dosimetric parameters may be better predictors for esophageal toxicity than are traditional CT-based metrics.
      ). Thus, conventional dose–volume histograms (DVHs) might not accurately reflect the partial volume doses. In the single study to consider this issue, the predictive value of metrics that were “corrected” for this anatomic reality were slightly better predictors of outcome than were the “traditional” DVH-based metrics (
      • Kahn D.
      • Zhou S.
      • Ahn S.-J.
      • et al.
      Anatomically correct dosimetric parameters may be better predictors for esophageal toxicity than are traditional CT-based metrics.
      ). Nevertheless, the use of alternative three-dimensional dosimetric parameters (e.g., dose–surface-area, dose–circumference histograms, “anatomically corrected” DVHs) as improved predictors of outcome is of unclear utility (
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ,
      • Kahn D.
      • Zhou S.
      • Ahn S.-J.
      • et al.
      Anatomically correct dosimetric parameters may be better predictors for esophageal toxicity than are traditional CT-based metrics.
      ,
      • Bradley J.
      • Deasy J.O.
      • Bentzen S.
      • et al.
      Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma.
      ).

      4. 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 (
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ,
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ,
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ,
      • Bradley J.
      • Deasy J.O.
      • Bentzen S.
      • et al.
      Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma.
      ,
      • Werner-Wasik M.
      • Pequignot E.
      • Leeper D.
      • et al.
      Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: A multivariate analysis of patients with lung cancer treated with non-operative therapy.
      ,
      • Maguire Sibley GS.
      • Zhou S.M.
      • et al.
      Clinical and dosimetric predictors of radiation-induced esophageal toxicity.
      ,
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ,
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • El Naqa I.
      • Bradley J.
      • Blanco A.I.
      • et al.
      Multivariable modeling of radiotherapy outcomes including dose–volume and clinical factors.
      ,
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      ,
      • Rodriguez N.
      • Algara M.
      • Foro P.
      • et al.
      Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.
      ) (Table 1). All but one study (
      • Werner-Wasik M.
      • Pequignot E.
      • Leeper D.
      • et al.
      Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: A multivariate analysis of patients with lung cancer treated with non-operative therapy.
      ) used three-dimensional planning. The endpoint was usually RTOG Grade 2 or greater or Grade 3 or greater. Two studies (
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ) combined acute and late toxicities in a single analysis. The others either analyzed only acute (
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ,
      • Bradley J.
      • Deasy J.O.
      • Bentzen S.
      • et al.
      Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma.
      ,
      • Werner-Wasik M.
      • Pequignot E.
      • Leeper D.
      • et al.
      Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: A multivariate analysis of patients with lung cancer treated with non-operative therapy.
      ,
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ,
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      ,
      • Rodriguez N.
      • Algara M.
      • Foro P.
      • et al.
      Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.
      ) or analyzed acute and late toxicity separately (
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ,
      • Maguire Sibley GS.
      • Zhou S.M.
      • et al.
      Clinical and dosimetric predictors of radiation-induced esophageal toxicity.
      ). The studies found a correlation with these endpoints for a variety of dose–volume factors.
      Table 1Summary of large published series investigating treatment-related esophagitis in patients with NSCLC
      Series/investigatorPatients (n)Prescription dose (Gy) range [median]
      All doses at standard fractionation of 1.8–2.2 Gy/d, 5 d/wk, unless otherwise stated.
      (special fractionations)
      CCT (%)Endpoint
      Unless otherwise specified, RTOG grading was used; RTOG Grade 2, moderate dysphagia or odynophagia, requiring narcotic agents or liquid diet; RTOG Grade 3, severe dysphagia or odynophagia with dehydration or weight loss, requiring nasogastric feeding.
      (rate)
      Univariate significant factorsMultivariate significant factors
      Duke/Maguire et al.
      • Maguire Sibley GS.
      • Zhou S.M.
      • et al.
      Clinical and dosimetric predictors of radiation-induced esophageal toxicity.
      , 1999
      9164–86 [79]
      Clinical calculations and prescriptions done without inhomogeneity correction; doses for study retrospectively corrected for inhomogeneity and tabulated above.
      (64% twice daily, 1.25–1.6 Gy/fx)
      47Acute G ≥3 (G3, 11%; G4-5, 0%)NoneNone
      Any late,
      Late complications determined from fraction of patients assessable for late toxicity.
      18% (G1, 9%; G2, 6%; G3, 3%)
      V50, A50, length of 100% circumference >50 GyGender, pre-RT dysphagia, V50, maximum percentage of circumference >80 Gy
      Thomas Jefferson/Werner-Wasik et al.
      • Werner-Wasik M.
      • Pequignot E.
      • Leeper D.
      • et al.
      Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: A multivariate analysis of patients with lung cancer treated with non-operative therapy.
      , 2000
      No three-dimensional conformal RT but correlation with irradiated esophagus length inferred from length of spine in field was investigated.
      10545–70 [60] (7% twice daily)
      All twice-daily patients also underwent CCT.
      ,
      Doses were fraction size-corrected using linear-quadratic model and α/β = 10 Gy.
      55Acute G ≥3 (G3, 12%; G4, 1%)CCT, twice-daily treatment, female genderCCT, twice-daily treatment
      Washington University/Singh et al.
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      , 2003
      20760–74 [70]
      Doses reported without tissue heterogeneity correction.
      25.6Acute G ≥3 (G3, 4.3% G4, 0.5%) and/or
      Acute and Late complications analyzed together.
      late G ≥3 (G3, 4.8%; G4, 0.5%; G5, 0.5%)
      Percentage of late complications from raw numbers (e.g., 4.8% = 10 patients of 207 patients).
      CCT, Dmax ≥58 Gy, mean dose >34 Gy, subcarinal nodes, raceCCT, Dmax ≥58 Gy
      Washington University/Bradley et al.
      • Bradley J.
      • Deasy J.O.
      • Bentzen S.
      • et al.
      Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma.
      , 2004
      Same patients analyzed by El Naqa et al.(21).
      16660–74 [70]
      Various treatment techniques and fractionation schedules used; most common was standard fractionation for 45 Gy to clinical target volume with cone-down to 66 Gy total to gross target volume; dose range quoted was overall dose to isocenter, corrected for tissue heterogeneity.
      24.7Acute G ≥2 (G2, 22.3%; G3, 4.2%; G4, 0.6%)CCT, aA range (aA5–aA70), aA55
      Lowest p value.
      , aV range (aV5–aV70), aV60
      Lowest p value.
      CCT and aV60; CCT, aV60, and aV80; CCT and aA55; CCT, aA55, and aA80 “volume and area equally predictive”
      Duke/Ahn et al.
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      , 2005
      Some patients analyzed by Ahn et al.(10) were also analyzed by Maguire et al.(18).
      25430–86 [66]
      Same patients analyzed by El Naqa et al.(21).
      (39% twice daily, 1.25–1.6 Gy/fx)
      12.6Acute G ≥3 (G3, 8.7%; G4, 0.4%)Twice daily; nodal stage; pretreatment dysphagia; Dmax; mean dose; V50; length of 50%, 75%, or 100%; circumference ≥50 Gy; maximal percentage circumference ≥50, 60, 70 GyTwice daily RT, nodal stage, pretreatment dysphagia
      Any late
      Late complications determined from fraction of patients assessable for late toxicity.
      (G2, 2%; G3, 2%; G4, 1%)
      Length with 75% circumference ≥70 Gy, length with 100% circumference ≥50, 55 Gy; maximal percentage circumference ≥60–80 GyPrevious acute toxicity dominated all dosimetric factors
      NKI/Belderbos et al.
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      , 2005
      156Group 1 (n = 88), 50–95 at 2.25/fx
      Doses were fraction size-corrected using linear-quadratic model and α/β = 10 Gy.
      Doses were heterogeneity corrected.
      Esophagus constraint on treatment plan.
      Group 2 (n = 68), 66 at 2.75/fx
      Doses were fraction size-corrected using linear-quadratic model and α/β = 10 Gy.
      Doses were heterogeneity corrected.
      23.7
      All CCT patients were in 66-Gy group, a randomized trial of concurrent vs. sequential chemotherapy; they constituted 54% of that group but only 23.7% of total.
      Acute G ≥2 (G2, 20%; G3, 6%; G4, 0.6%)Lyman NTCP
      Found Lyman NTCP model parameters that gave visually good fit to data; significance not stated.
      , V range (V20–V60); V35
      Lowest p value.
      , percentage of length, 100%; circumference ≥40 Gy or ≥66 Gy; treatment group (column 3); CCT worse than sequential C/RT or RT only; sequential C/RT worse than RT alone; T stage and nodal stage; age
      Not specified whether toxicity was more likely at older age.
      V35, CCT
      University of Michigan/Chapet et al.
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      , 2005
      10165–103
      Doses were fraction size-corrected using linear-quadratic model and α/β = 10 Gy.
      Doses were heterogeneity corrected.
      Esophagus constraint on treatment plan.
      0Acute G ≥2 (G2, 13%; G3, 3%)Nodal stage, V range (V40–V70), Dose-percentage volume range (D5–D60), D30
      Lowest p value.
      , D1 cc, 2.5 cc, 5 cc
      Lyman model NTCP with study-specific parameters
      Goyang/Kim et al.
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      , 2005
      12454–66 [60]
      Doses were fraction size-corrected using linear-quadratic model and α/β = 10 Gy.
      Doses were heterogeneity corrected.
      60Acute G ≥3-4 (G3, 12%; G4, 0.8%)CCT, V range (V58–V63), Dmax,

      Lyman model NTCP (Burman et al.
      • Takeda K.
      • Nemoto K.
      • Saito H.
      • et al.
      Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy.
      parameters)
      CCT, V60 (in patients with CCT)
      Harbin University/Qiao et al.
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      , 2005
      20860–72 [70]
      Doses reported without tissue heterogeneity correction.
      26Acute G ≥3 (G3, 5%; G4, 0.5%; G5, 1%) and/or late G ≥3 (G3, 5%; G4, 0.5%)CCT, Dmax ≥60 Gy, mean dose ≥40 Gy, subcarinal lymph nodesCCT, Dmax ≥60 Gy
      MDACC/Wei et al.
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      , 2006
      21560–70 [63]
      Doses were heterogeneity corrected.
      (16% twice daily, 1.2 Gy/fx)
      100Acute G ≥3
      Grading by institutional modification of RTOG.
      (G3, 20%; G4, 0.5%)
      aV range (aV15–V45); V range (V10–V45); mean dose ≥34.5 GyV20
      Barcelona/Rodriquez et al.
      • Rodriguez N.
      • Algara M.
      • Foro P.
      • et al.
      Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.
      , 2009
      10055–65 [62]100Acute G ≥1 (G2, 29%; G3, 4%) esophagitis index
      See Rodriguez et al.(23) for definition.
      V50–V55NA
      Abbreviations: NSCLC = non–small-cell lung cancer; CCT = concurrent chemotherapy; fx = fraction; G = grade; Vdose (e.g., V20) = relative volume receiving specified dose or more (e.g., ≥ 20 Gy); RT = radiotherapy; Dmax = maximal dose; Adose = relative surface area receiving specified dose or greater; aVdose, aAdose = absolute volume (V) or area (A) receiving specified dose or greater; D# = dose encompassing hottest percentage of esophagus. D #cc = dose encompassing hottest cubic centimeters of esophagus; NTCP = normal tissue complication probability; RTOG = Radiation Therapy Oncology Group.
      All doses at standard fractionation of 1.8–2.2 Gy/d, 5 d/wk, unless otherwise stated.
      Unless otherwise specified, RTOG grading was used; RTOG Grade 2, moderate dysphagia or odynophagia, requiring narcotic agents or liquid diet; RTOG Grade 3, severe dysphagia or odynophagia with dehydration or weight loss, requiring nasogastric feeding.
      Clinical calculations and prescriptions done without inhomogeneity correction; doses for study retrospectively corrected for inhomogeneity and tabulated above.
      § Late complications determined from fraction of patients assessable for late toxicity.
      No three-dimensional conformal RT but correlation with irradiated esophagus length inferred from length of spine in field was investigated.
      || All twice-daily patients also underwent CCT.
      # Doses were fraction size-corrected using linear-quadratic model and α/β = 10 Gy.
      ∗∗ Doses reported without tissue heterogeneity correction.
      †† Acute and Late complications analyzed together.
      ‡‡ Percentage of late complications from raw numbers (e.g., 4.8% = 10 patients of 207 patients).
      §§ Same patients analyzed by El Naqa et al.
      • El Naqa I.
      • Bradley J.
      • Blanco A.I.
      • et al.
      Multivariable modeling of radiotherapy outcomes including dose–volume and clinical factors.
      .
      ¶¶ Various treatment techniques and fractionation schedules used; most common was standard fractionation for 45 Gy to clinical target volume with cone-down to 66 Gy total to gross target volume; dose range quoted was overall dose to isocenter, corrected for tissue heterogeneity.
      |||| Lowest p value.
      ## Some patients analyzed by Ahn et al.
      • Werner-Wasik M.
      • Scott C.
      • Curran Jr., W.J.
      • et al.
      Correlation between acute esophagitis and late pneumonitis in patients (pts) with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent thoracic radiotherapy (RT) and chemotherapy: A multivariate analysis of the Radiation Therapy Oncology Group (RTOG) database [Abstract].
      were also analyzed by Maguire et al.
      • Maguire Sibley GS.
      • Zhou S.M.
      • et al.
      Clinical and dosimetric predictors of radiation-induced esophageal toxicity.
      .
      ∗∗∗ Doses were heterogeneity corrected.
      ††† Esophagus constraint on treatment plan.
      ‡‡‡ All CCT patients were in 66-Gy group, a randomized trial of concurrent vs. sequential chemotherapy; they constituted 54% of that group but only 23.7% of total.
      §§§ Found Lyman NTCP model parameters that gave visually good fit to data; significance not stated.
      ¶¶¶ Not specified whether toxicity was more likely at older age.
      |||||| Grading by institutional modification of RTOG.
      ### See Rodriguez et al.
      • Rodriguez N.
      • Algara M.
      • Foro P.
      • et al.
      Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.
      for definition.
      The maximal esophagus dose had significant univariate correlation (p ≤ .05), with severe esophagitis in all the studies that included it as a variable (
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ,
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ,
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ,
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      ). However, it only remained significant in multivariate analyses in some of them (
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ,
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ).
      Ten studies (
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ,
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ,
      • Bradley J.
      • Deasy J.O.
      • Bentzen S.
      • et al.
      Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma.
      ,
      • Maguire Sibley GS.
      • Zhou S.M.
      • et al.
      Clinical and dosimetric predictors of radiation-induced esophageal toxicity.
      ,
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ,
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • El Naqa I.
      • Bradley J.
      • Blanco A.I.
      • et al.
      Multivariable modeling of radiotherapy outcomes including dose–volume and clinical factors.
      ,
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      ,
      • Rodriguez N.
      • Algara M.
      • Foro P.
      • et al.
      Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.
      ,
      • Takeda K.
      • Nemoto K.
      • Saito H.
      • et al.
      Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy.
      ) searched for correlations between severe acute esophagitis and either the absolute volume (aVdose), absolute area (aAdose), or percentage of a reference volume (Vdose), or reference area (Adose) receiving more than a specified dose. Eight of these studies (
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ,
      • Bradley J.
      • Deasy J.O.
      • Bentzen S.
      • et al.
      Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma.
      ,
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ,
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • El Naqa I.
      • Bradley J.
      • Blanco A.I.
      • et al.
      Multivariable modeling of radiotherapy outcomes including dose–volume and clinical factors.
      ,
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      ,
      • Rodriguez N.
      • Algara M.
      • Foro P.
      • et al.
      Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.
      ,
      • Takeda K.
      • Nemoto K.
      • Saito H.
      • et al.
      Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy.
      ) found significant univariate correlations with exposure over a wide dose range (10–80 Gy; Table 1 and Fig. 1). Multivariate analysis (
      • Bradley J.
      • Deasy J.O.
      • Bentzen S.
      • et al.
      Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma.
      ,
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ,
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      ,
      • Takeda K.
      • Nemoto K.
      • Saito H.
      • et al.
      Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy.
      ) identified fewer dose–volume combinations. Because of the diverse reporting metrics, we could not find a consensus for the dose–volume thresholds. For example, one study (
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ) found V35 was the only dosimetric predictor of RTOG Grade 2 or greater acute esophagitis on multivariate analysis, both with and without CCT, and another study (
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      ) found V20 to be the only multivariate significant factor for 215 patients receiving CCT. However, a third study (
      • Bradley J.
      • Deasy J.O.
      • Bentzen S.
      • et al.
      Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma.
      ) found a much greater dose region (aA55 and aA80 or aV60 and aV80) to be significant.
      Figure thumbnail gr1
      Fig. 1Correlations between acute esophagitis and Vx values (volume greater than x Gy). p Values correlated with relative or absolute volumes (in cubic centimeters); relative volumes used except as noted for 2006 data from Wei et al.
      (
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      )
      . Lower values indicate better correlations with outcomes. As the wide variety of correlation shapes suggests, there does not appear to be any singular “threshold” dose above which a toxic effect is observed.
      Some studies found circumferential metrics (e.g., esophageal length receiving full circumference dose >40–66 Gy [
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ] or 50–65 Gy [
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ]) to be significant, although not superior to simpler volume or area metrics.
      Four studies (
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      ,
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ,
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ,
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      ) found a univariate correlation with the mean dose greater than levels ranging from 34 Gy (
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      ) to 40 Gy (
      • Qiao W.-B.
      • Zhao Y.-H.
      • Zhao Y.-B.
      • et al.
      Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity.
      ). A 34-Gy mean dose recommendation was adopted in the RTOG Phase III comparison of 60 Gy vs. 74 Gy with CCT in Grade III non–small-cell lung cancer (RTOG 0617).
      Dose–volume histogram parameters describing cumulative dose >50 Gy have been identified as highly statistically significantly correlated with acute esophagitis in several studies. Some studies (Fig. 1), however, have shown the strongest statistically significant correlations with esophagitis at lower doses (as low as V30), perhaps owing to technique differences. V30 was also implicated in a multivariate modeling study by El Naqa (
      • El Naqa I.
      • Bradley J.
      • Blanco A.I.
      • et al.
      Multivariable modeling of radiotherapy outcomes including dose–volume and clinical factors.
      ). Overall, the data are consistent with some risk of acute esophagitis at intermediate doses (30–50 Gy) and an increasing effect for greater doses.
      A main obstacle to obtaining definitive dosimetric recommendations from the published data is the variety of volumetric metrics—the absolute volume or area, relative volume or area, and circumferential measures—all have been analyzed. Reports describing relative metrics might have used different reference volumes (

      CTC/CTCAE Codes. Available from: www.ctep.info.nih.gov/reporting/ctc.html. Last accessed December 15, 2009.

      ,
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ). Differences in the way other technical factors were handled have less effect. For example, adjusting DVHs for conventional fraction size and the type of tissue heterogeneity correction used are likely to have only minor effect, the latter because the esophagus is embedded in bulky soft tissue and anteroposterior/posteroanterior beams are the main component in many treatment plans. Several studies have provide enough information to estimate the incidence of esophagitis to dosimetric parameters (Fig. 2). There does appear to be a dose–response relationship, although the interstudy variations have been large. Nevertheless, the data are somewhat consistent, with rates of acute Grade 2 or greater esophagitis increasing to >30% as V70 exceeds 20%, V50 exceeds 40%, and V35 exceeds 50%.
      Figure thumbnail gr2
      Fig. 2Incidence of acute esophagitis according to Vx (volume receiving more than x Gy). x-Axis values estimated according to range of doses reported. Each curve annotated as follows: Vdose (investigator, number of patients, percentage with concurrent chemotherapy [CCT]. Percentage of patients who received sequential chemotherapy in studies by Ahn et al.
      (
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      )
      , Belderbos et al.
      (
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      )
      , and Kim et al.
      (
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      )
      was 44%, 38%, and 15%, respectively. Data for V50 (Ahn et al.
      [
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ]
      ) at 15, 45, and 75 Gy represent reported rates of Grade 2 or greater acute esophagitis plotted in dose bins at <30%, 30–60%, and >60%, respectively. Similarly, for V70 (Ahn et al.
      [
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ]
      ), V50 (Rodriguez et al.
      [
      • Rodriguez N.
      • Algara M.
      • Foro P.
      • et al.
      Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.
      ]
      ), and V60 (Kim et al.
      [
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      ]
      ), each symbol represents rates of acute esophagitis at <10% vs. 11–30% vs. 31–64%, and ≤30% vs. ≥30%, and ≤30 vs. >30%, respectively. Dashed horizontal lines reflect dose ranges ascribed to each data point. Upper x-axis range of greatest data point for V50 (Rodriguez et al.
      [
      • Rodriguez N.
      • Algara M.
      • Foro P.
      • et al.
      Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.
      ]
      ), V50 (Ahn et al.
      [
      • Ahn S.-J.
      • Kahn D.
      • Zhou S.
      • et al.
      Dosimetric and clinical predictors for radiation- induced esophageal injury.
      ]
      ), and V60 (Kim et al.
      [
      • Kim T.H.
      • Cho K.H.
      • Pyo H.R.
      • et al.
      Dose–volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy.
      ]
      ), are indefinite according to data (light-gray dotted bars). Solid and open symbols represent reported rates of Grade 2 or greater acute esophagitis and Grade 3 or greater acute esophagitis, respectively. Thicker and thinner solid lines represent higher and lower doses of Vx, respectively (i.e., thicker line for V70 and thinner line for V20).

      5. 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 concurrent gemcitabine. The Continuous Hyperfractionated Accelerated Radiation Therapy regimen (
      • Saunders M.I.
      • Dische S.
      • Barrett A.
      • et al.
      Randomized multicentre trials of CHART vs. conventional radiotherapy in head and neck and non-small cell lung cancer: An interim report.
      ) reported a 19% rate of severe (Grade 3 or greater) esophagitis. Older patients (>70 years of age) were more likely than younger patients to experience high-grade esophagitis in a secondary analysis of the RTOG 94-10 study (
      • Langer C.
      • Hsu C.
      • Curran W.
      • 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.
      ).
      Several studies have assessed the putative radioprotector amifostine. Three single-institution Phase III studies (
      • Antonadou D.
      • Coliarakis N.
      • Synodinou M.
      • et al.
      Randomized Phase III trial of radiation treatment plus/minus amifostine in patients with advanced-stage lung cancer.
      ,
      • Leong S.S.
      • Tan E.H.
      • Fong K.W.
      • et al.
      Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small cell lung cancer.
      ,
      • Komaki R.
      • Lee J.S.
      • Milas L.
      • 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.
      ) suggested a significant benefit (
      • Antonadou D.
      • Coliarakis N.
      • Synodinou M.
      • et al.
      Randomized Phase III trial of radiation treatment plus/minus amifostine in patients with advanced-stage lung cancer.
      ,
      • Leong S.S.
      • Tan E.H.
      • Fong K.W.
      • et al.
      Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small cell lung cancer.
      ) or a trend (
      • Komaki R.
      • Lee J.S.
      • Milas L.
      • 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.
      ) for amifostine in lowering Grade 2 or greater esophagitis. However, the findings are difficult to interpret because of the small patient numbers and low (
      • Leong S.S.
      • Tan E.H.
      • Fong K.W.
      • et al.
      Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small cell lung cancer.
      ) or unknown (
      • Antonadou D.
      • Coliarakis N.
      • Synodinou M.
      • et al.
      Randomized Phase III trial of radiation treatment plus/minus amifostine in patients with advanced-stage lung cancer.
      ) incidence of Grade 3 or greater esophagitis. These results were not confirmed in a large cooperative group Phase III randomized study of 243 patients (RTOG trial 98-01) (
      • Movsas B.
      • Scott C.
      • Langer C.
      • et al.
      Phase III study of amifostine in patients with locally advanced non-small cell lung cancer receiving intensive chemoradiation: Radiation Therapy Oncology Group 98-01.
      ).

      6. Mathematical/Biologic Models

       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 patient-specific values of the significant dose–volume variables, Vdosei. CCT can be handled by an extra term or by having different sets of coefficients for patients with and without CCT. The model coefficients, ci, are chosen to best match the observed complication rates, and coefficient values are given in the cited studies. The simplest models (probably too simple) use a single dose–volume variable (e.g., V35[
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ], V20, or mean dose [
      • Wei X.
      • Liu H.H.
      • Tucker S.L.
      • et al.
      Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy.
      ]). Others use several DVH-based variables (e.g., a four-variable model [
      • El Naqa I.
      • Bradley J.
      • Blanco A.I.
      • et al.
      Multivariable modeling of radiotherapy outcomes including dose–volume and clinical factors.
      ] selected absolute area points with doses from 30 to 85 Gy). Such statistical models are more sensitive to the DVH shape than those based on a single Vdose point.

       Lyman-Kutcher-Burman model

      Two recent studies (
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ,
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ) used the maximum likelihood method to find the Lyman-Kutcher-Burman model parameters that correlated well with the incidence of Grade 2 or greater acute esophagitis in their respective populations of patients without CCT. Both studies applied tissue inhomogeneity and linear-quadratic corrections to 2-Gy equivalent regimens but used different reference esophageal lengths. Chapet et al.(
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ) excluded the cervical esophagus; thus, their reference length was approximately 20% shorter than that of Belderbos et al.(
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ). Table 2 lists the parameters from these two studies and, for comparison, the 1991 parameters (
      • Burman C.
      • Kutcher G.J.
      • Emami B.
      • et al.
      Fitting of normal tissue tolerance data to an analytic function.
      ). Because the 1991 endpoint was a very severe and, in modern times very rare, toxicity of clinical stricture or perforation, it is not surprising that the 1991 Lyman-Kutcher-Burman parameters are different from those from the more recent studies for which the endpoint was RTOG Grade 2 or greater acute esophagitis. Both recent parameterizations (
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      ,
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      ) yielded mid-size n values, consistent with the correlation with a wide range of significant dose–volume factors noted in the section, “Review of Dose–Volume Published Data.” The Lyman parameters of the two studies agreed within their broad 95% confidence intervals.
      Table 2Three parameterizations of Lyman-Kutcher-Burman model for esophageal complications
      InvestigatorTD50 (Gy)nm
      Burman et al.
      • Burman C.
      • Kutcher G.J.
      • Emami B.
      • et al.
      Fitting of normal tissue tolerance data to an analytic function.
      , 1991
      680.060.11
      Chapet et al.
      • Chapet O.
      • Kong F.-M.
      • Lee J.S.
      • et al.
      Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer.
      , 2005
      51 (29–82)0.44 (0.11–1.41)0.32 (0.19–0.57)
      Belderbos et al.
      • Belderbos J.
      • Heemsbergen W.
      • Hoogeman M.
      • et al.
      Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.
      , 2005
      47 (41–60)0.69 (0.18–6.3)0.36 (0.25–0.55)
      Abbreviation: TD50 = median toxic dose.
      Burman values derived from “Emami” estimates for more severe endpoint.

       Relative Seriality Model

      Parameters for relative seriality model were derived (
      • Källman P.
      • Agren A.
      • Brahme A.
      Tumor and normal tissue responses to fractionated non-uniform dose delivery.
      ) from partial irradiation tabulation of Emami et al.(
      • Emami B.
      • Lyman J.
      • Brown A.
      • et al.
      Tolerance of normal tissue to therapeutic irradiation.
      ). Recent planning study (
      • Ragazzi G.
      • Cattaneo G.M.
      • Fiorino C.
      • et al.
      Use of dose–volume histograms and biophysical models to compare 2D and 3D irradiation techniques for non-small cell lung cancer.
      ) found this model/parameter combination predicted a complication rate similar to Lyman model using Burman et al.(
      • Burman C.
      • Kutcher G.J.
      • Emami B.
      • et al.
      Fitting of normal tissue tolerance data to an analytic function.
      ) parameters. However, because both were parameterized to fit the Emami data, neither might be relevant to the studies and milder endpoints reviewed in section “Review of Dose–Volume Published Data.”

       General comments

      Because acute esophagitis events occur mainly during a course of therapy, the rapidity of dose accumulation might be more important than the final overall dose (much of which is delivered after the complication risk has peaked). No current models account for the course of a complication relative to the number of fractions delivered. It also follows that existing models and dose–volume parameters should not be applied to regimens in which the number of fractions is much different from 30–35 Gy without careful additional study.

      7. 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 (
      • Onimaru R.
      • Shirato H.
      • Shimizu S.
      • et al.
      Tolerance of organs at risk in small-volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers.
      ), no comprehensive dose–volume-based analyses have been published. Similarly, no large body of data exists on long-term esophageal toxicity of other altered fractionation schemes (e.g., hyperfractionation; in-field boost).

      8. 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) (
      • Takeda K.
      • Nemoto K.
      • Saito H.
      • et al.
      Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy.
      ). In particular, for high-dose conventionally fractionated non–small-cell lung cancer treatments, it is prudent to ensure that the dose to even small volumes of the esophagus does not exceed the prescription dose. This is a particular risk of intensity-modulated RT if no esophagus constraints are imposed in the planning process and the radiation dose is “dumped” inadvertently in the region of the esophagus. The ongoing Phase III Intergroup trial (RTOG 0617) has recommended (but has not mandated) that the mean dose to the esophagus be kept to <34 Gy and that the esophageal V60 be calculated for each patient enrolled in the trial. These recommendations were based on the Washington University experience (
      • Singh A.K.
      • Lockett M.A.
      • Bradley J.D.
      Predictors of radiation-induced esophageal toxicity in patients with non-small cell lung cancer treated with three-dimensional conformal radiotherapy.
      ) (Table 2). An inability to provide specific “dose limits” for the esophagus in this large cooperative group trial illustrates the lack of evidence that any absolute limits can be imposed on the basis of current published data. However, from the clinical reports without detailed dosimetric esophageal dose correlates, it appears safe to give doses as great as 74 Gy to a segment of the esophagus with concurrent carboplatin and paclitaxel (
      • Xiao Y.
      • Werner-Wasik M.
      • Michalski D.
      • et al.
      Comparison of three IMRT-based treatment techniques allowing partial esophagus sparing in patients receiving thoracic radiation therapy for lung cancer.
      ,
      • Stichcombe T.
      • Lee C.
      • Moore D.T.
      • et al.
      Long-term follow-up of a phase I/II trial of dose escalating three-dimensional conformal thoracic radiation therapy with induction and concurrent carboplatin and paclitaxel in unresectable stage IIIA/B non-small cell lung cancer.
      ,
      • Schild S.E.
      • McGinnis W.L.
      • Graham D.
      • et al.
      Results of a phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non–small-cell lung cancer.
      ).
      In the section “Mathematical/Biologic Models,” we described several mathematical models that correlate with the incidence of Grade 2 or greater acute esophagitis for specific study populations. Clinicians with appropriate treatment planning resources might find such models interesting and useful, particularly when making decisions between competing treatment plans. However, it is important to recognize that, at present, these models are tentative as best. A prudent approach to using any mathematical model is to first do a retrospective “test drive” to determine whether predictions are in qualitative agreement with the complications observed at one's own center, subject to local contouring protocols, treatment beam arrangements, and patient populations.

      9. 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 analysis would not be a continual cycle of hypothesis/model generation, such as is commonly the case today.
      Peer-reviewed treatment planning and outcomes data should be pooled and made permanently available. This might enable a single analysis to confidently uncover the factors that lead to such an array of dose–volume correlations, such as seen in Fig. 1, to derive robust parameter sets for the Lyman or relative seriality models or to derive new semimechanistic models.
      The exclusion of the entire esophageal length/volume from the high-dose radiation region is extremely difficult; however, reducing the radiation dose delivered to a part of esophageal circumference might be feasible. Intensity-modulated RT seems well suited for that purpose, with its ability to deliver concave-shaped RT dose distributions around organs at risk (
      • Blackstock A.W.
      • Ho C.
      • Butler J.
      • et al.
      Phase IA/IB chemo-radiation trial of gemcitabine and dose-escalated thoracic radiation in patients with stage III A/B non-small cell lung cancer.
      ). Studies to better understand the importance of the spatial distribution of the dose (and hence the utility of partial circumferential sparing) would be useful.
      Additional study is needed to understand the utility of radioprotectors.
      A prospective assessment of the dose and volume and other factors relating to esophageal injury after hypofractionation is needed, given the growing interest in this approach.
      The identification of biologic markers of radiation sensitivity will be important to explain individual variations in patients' reactions.

      10. 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 (
      • Colevas A.D.
      • Setser A.
      The NCI Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 is the new standard for oncology clinical trials.
      ). Late injury might be scored under several endpoints, including necrosis, obstruction, perforation, or stricture, depending on the patient's symptoms.

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