title: 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 nonoperative therapy.
abstract: OBJECTIVE
  To identify in a multivariate analysis treatment-related factors predisposing patients (pts) with lung cancer to acute esophagitis, expressed as a severity grade or Esophagitis Index (EI).
  
  
  METHODS
  Acute esophagitis is prospectively scored as an RTOG Grade in our institution during and after thoracic radiotherapy. Charts, toxicity forms and digitally reconstructed radiographs (DRRs) of all pts with lung cancer who received thoracic radiotherapy (RT) between 11/95 and 1/99 were reviewed. Esophagitis grades for each time point were verified by review of weekly physician and nursing treatment notes, hospital discharge summaries and referring physician notes and then plotted on graph against time. The area under the curve was calculated for each patient's graph and was defined as an Esophagitis Index. The length of esophagus was measured on each anterior DRR while assuming that esophagus overlies the vertebral bodies on the anterior films and projects over the edge of the vertebral body on the oblique DRRs. This assumption was confirmed in 10 pts by digitizing esophagus on CT simulator-derived slices and visualizing its position on DRRs. To compare RT doses delivered with different fractionation schemes to standard fractionated doses, the equivalent RT doses were calculated using the linear-quadratic formula and alpha/beta ratio of 10. Univariate and multivariate analyses of several factors potentially influencing the maximum esophagitis grade, as well as EI, were performed.
  
  
  RESULTS
  A total of 277 pts were identified. Pts were included in the analysis (n = 105) if they fulfilled the following criteria: chart, toxicity form and DRRs were all available; parallel opposed fields (no multiple fields) were used for both the initial and off cord/cone down fields; and an equivalent dose of 45.0 Gy or more was delivered. Seventy-eight pts had Stage III; 32, Stage IV, and the remainder, Stages I, II, or recurrent lung cancer (85 non-small cell and 18, small cell). Seventy-four pts were treated with definitive intent. Chemotherapy was given concurrently with RT in 58 pts (in 7 pts, with twice daily, or b.i.d., RT) and as induction treatment, in 11. Only 2 pts required a treatment break of more than 1 week. Median total and equivalent RT doses, fraction size, and anterior esophageal length were as follows: 59.9 Gy, 59.9 Gy, 2.0 Gy, and 14 cm (range, 4.2-21). The following maximum grades of esophagitis were recorded: 1, in 54 pts; 2, in 17 pts; 3, in 13 pts, and 4, in 1 pt. The mean EI for all pts; pts treated with standard RT alone; induction chemotherapy and standard RT; concurrent chemotherapy and standard (QD) RT; and b.i.d. RT with concurrent chemotherapy, was 41. 5 (range, 0-317); 13.6; 24.5; 52.4; and 132.1, respectively (p < 0. 001). Three pts developed an esophageal stricture within 3 months beginning RT. In multivariate analysis, the following factors were significantly associated with increasing EI: concurrent chemotherapy with QD RT and concurrent chemotherapy with b.i.d. RT (p < 0.001, considered jointly). Both factors were also associated with increasing maximum esophagitis grade (p = 0.011). Esophageal length was not associated with increasing EI or esophagitis grade in either univariate or multivariate analyses.
  
  
  CONCLUSIONS
  Concurrent chemotherapy and twice daily radiotherapy, especially if combined together, were associated with the highest acute maximum esophagitis grade and esophagitis index in pts with lung cancer. The duration of acute esophagitis was also longest in the concurrent chemotherapy/twice daily radiotherapy group. Esophagitis Index appeared to be a more sensitive measure of acute esophagitis than the maximum esophagitis grade. The increasing length of esophagus in the radiation field did not predict for the severity of acute esophagitis.
authors.affiliation: Kimmel Cancer Center of Jefferson Medical College, Philadelphia, PA, USA. maria.werner-wasik@mail.tju.edu
authors.forename: M
authors.initials: M
authors.lastname: Werner-Wasik
authors.forename: E
authors.initials: E
authors.lastname: Pequignot
authors.forename: D
authors.initials: D
authors.lastname: Leeper
authors.forename: W
authors.initials: W
authors.lastname: Hauck
authors.forename: W
authors.initials: W
authors.lastname: Curran
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D019540:Area Under Curve; D003131:Combined Modality Therapy; D004941:Esophagitis / Q000209:etiology* / Q000473:pathology; D004947:Esophagus / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D005544:Forecasting; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011879:Radiotherapy Dosage; D012720:Severity of Illness Index; D012737:Sex Factors
chemical_list: D000970:Antineoplastic Agents