Annals of Oncology Advance Access published online on February 23, 2007
Annals of Oncology, doi:10.1093/annonc/mdm005
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© 2007 European Society for Medical Oncology
Maximal neutropenia during chemotherapy and radiotherapy is significantly associated with the development of acute radiation-induced dysphagia in lung cancer patients
1 Department of Radiotherapy, MAASTRO clinic, GROW, University Hospital Maastricht, Maastricht, The Netherlands
2 Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
3 Department of Radiotherapy and Oncology, Jolimont Hospital, La Louvière, Belgium
4 Department of Pulmonology, University Hospital Maastricht, Maastricht
5 Department of Pulmonology, Atrium Medical Centre, Heerlen
6 Department of Pulmonology, Maasland Hospital, Sittard
7 Department of Pulmonology, Laurentius Hospital, Roermond
8 Department of Pulmonology, Sint Jans Hospital, Weert, The Netherlands
* Correspondence to: Dr D. De Ruysscher, Department of Radiotherapy, University Hospital Maastricht, Dr Tanslaan 12, 6229 ET Maastricht, The Netherlands. Tel: +31-88-445-57-00; Fax: +31-88-445-57-73; E-mail: dirk.deruysscher{at}maastro.nl
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Abstract |
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Background: Acute dysphagia is a distressing dose-limiting toxicity after concurrent chemoradiation or high-dose radiotherapy for lung cancer. We therefore identified factors associated with the occurrence of acute dysphagia in lung cancer patients receiving radiotherapy alone or combined with chemotherapy.
Patients and methods: Radiotherapy, chemotherapy and patient characteristics were analyzed using ordinal regression analysis as possible predictors for acute dysphagia (CTCAE 3.0) in 328 lung cancer patients treated with curative intent.
Results: The most significant association was seen between the maximal grade of neutropenia during chemoradiation and dysphagia, with an odds ratio increasing from 1.49 [95% confidence interval (CI) 0.63–3.54, P = 0.362] for grade 1–2 neutropenia to 19.7 (95% CI 4.66–83.52, P < 0.001) for patients with grade 4 neutropenia. Twice-daily schedule, mean esophageal dose and administration of chemotherapy were significant predictive factors. By combining these factors, a high-performance predictive model was made. On an individual patient level, 64% of patients were correctly classified and only 1.2% of patients were misclassified by more than one grade.
Conclusions: The maximal neutrophil toxicity during concurrent chemotherapy and radiotherapy is strongly associated with the development of acute dysphagia. A multivariate predictive model was developed.
chemotherapy, esophagitis, lung cancer, neutropenia, predictive factors, radiotherapy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Concurrent chemotherapy and radiotherapy has become the first choice regimen for patients with more advanced lung cancer as several trials have shown a superior survival compared with the sequential approach, at the expense however, of acute radiation-induced dysphagia which has become dose limiting [1–9]. It is therefore of great clinical importance to determine clinical and biological factors associated with the occurrence of this side-effect. Improved understanding of the radiation pathology of normal tissue side-effects may lead not only to improved prediction of these but also to the identification of potential strategies for reducing or preventing toxicity [10]. Many research groups have identified radiobiological factors such as the irradiated surface, the volume and length of the irradiated esophagus, the use of concurrent chemotherapy and the overall treatment time of radiotherapy [11–20]. However, combined chemotherapy and radiotherapy risk factors for dysphagia in concurrent chemoradiation schedules are less well studied.
We therefore investigated the importance of both radiotherapy and chemotherapy parameters for acute radiation-induced dysphagia in patients treated for lung cancer. Here we show that maximal neutrophil granulocyte toxicity during radiotherapy is strongly associated with acute radiation-induced dysphagia in combined modality therapy.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patient population
All patients with histological or cytological proven lung cancer (both non-small-cell and small-cell carcinoma) referred for radiotherapy with curative intent to MAASTRO clinic (Maastricht, The Netherlands) or Jolimont Hospital (La Louvière, Belgium) from 1 January 2001 to 31 December 2004 were reviewed. Three hundred and twenty-eight patients were identified, 192 from MAASTRO clinic and 136 from Jolimont hospital. The inclusion criteria were: T1-4N0-3M0 (International Union Against Cancer staging system) non-small-cell lung cancer (NSCLC) or limited stage small-cell lung cancer (SCLC), World Health Organization performance status of zero to one, weight loss
10% in the 6 months preceding lung cancer diagnosis and a reasonable lung function. Patients receiving preoperative chemoradiotherapy or postoperative radiation were excluded from this analysis.
treatment schedules
Patients were treated in accordance to different a priori defined radiation and chemotherapy protocols according to the stage and the histology (NSCLC versus SCLC) of the disease.
Group 1: radiotherapy without chemotherapy.
The schedules used were: (i) Radiotherapy once-daily (QD), 2 Gy per day, 5 days per week, to a total dose of 60 Gy–74Gy or (ii) radiotherapy b.i.d., two fractions of 1.8 Gy per day, 5 days per week, to a total dose of 61.2 Gy or 64.8 Gy.
Group 2: induction chemotherapy (carboplatin or cisplatin, gemcitabine), followed by radiotherapy as in group 1.
Group 3: concurrent chemotherapy and radiotherapy.
- Daily cisplatin together with radiotherapy QD, 2 Gy per day, 5 days per week, to a total dose of 60 Gy–74Gy. Cisplatin and radiotherapy both started at day 1 of radiotherapy.
- Cisplatin and etoposide together with radiotherapy QD, 2 Gy per day, 5 days per week, to a total dose of 60 Gy–74Gy. Radiotherapy started during the first cycle of chemotherapy.
- Carboplatin and etoposide together with radiotherapy b.i.d., 1.5 Gy per fraction, 5 days per week, to a total dose of 45 Gy. Radiotherapy started during the first cycle of chemotherapy.
radiotherapy
For radiotherapy planning, a computed tomography scan of the thorax was carried out that extended from the cricoid to the second lumbar vertebra using a maximal slice thickness of 5 mm. The esophagus was delineated from the laryngeal cricothyroid cartilage junction to the gastroesophageal junction. Neither the Gross Tumor Volume (GTV) nor the Planning Target Volume (PTV) was subtracted from this volume [21].
In order to reduce contouring variability, the esophagus was recontoured by three of the authors (RHB, FK, JFR). The treatment plans were recalculated on bases of the recontoured esophagus to obtain appropriate new dose–volume histograms (DVH). From the DVH's, the volume of the esophagus covered by the 95% isodose (‘irradiated esophageal volume’), the maximal esophageal dose (Dmax) and the mean esophageal dose were derived. The radiotherapy planning was carried out with a Focus CMS (Computerized Medical Systems, St Louis, Missouri, USA) system in MAASTRO clinic and with an ISIS (Curie Institute, Paris, France) system in the Jolimont Hospital, both using inhomogeneity corrections on the basis of a convolution algorithm. In both centers, planning was carried out according to ICRU 50 guidelines [22]. The lungs were contoured automatically by the treatment planning system. Three to six coplanar photon fields with beam energies ranging from 6 MV to 15 MV from linear accelerators were used. In b.i.d., 8 h interval between the fractions was respected. Irradiation was delivered 5 days per week, and each field was treated with every fraction.
As a measure of the intensity of chest radiotherapy, we used the equivalent dose in 2-Gy fractions [23]. Adjustment for dose per fraction was made as follows:
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= 10 Gy.
chemotherapy
In case of chemotherapy followed by radiotherapy, the chemotherapy consisted of carboplatin [area under the curve (AUC) 5 mg/ml/min)] on day 1 and gemcitabine 1250 mg/m2 on day 1 and 8 in all Dutch centers and of cisplatin 80 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on day 1 and 8 in Jolimont Hospital. Cycles were repeated every 21 days for a total of three cycles.
Radiotherapy started no sooner than 21 days after the last chemotherapy infusion.
For concurrent chemotherapy, three schedules were used: cisplatin 6 mg/m2 all days of QD radiotherapy, cisplatin 60 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1–3 every 4 weeks during QD radiotherapy and carboplatin (AUC 5) on day 1 and etoposide 120 mg/m2 on days 1–3 every 3 weeks during b.i.d. radiotherapy.
No hematopoietic growth factors were used.
monitoring of the patients during radiotherapy
Patients were seen and their early side-effects evaluated at least once a week during radiotherapy and weekly thereafter by either the radiation oncologist or the chest physician until resolution of the dysphagia.
toxicity scoring
The CTCAE 3.0 system was used (Table 1). Toxicity was scored independently by three of the authors (RHB, FK, JFR) by reviewing all the patient charts independently. In case of a discrepancy between the three, a fourth author (DDR) was the referee. Discrepancies, however, only occurred in six of 328 patients, all in the nonconcurrent chemoradiation groups, and only involving G1 versus G2 dysphagia. In all cases, G2 was ultimately scored.
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Reviewing all blood counts taken typically weekly during the course of radiotherapy, derived the hematological toxicity during radiation or concurrent chemoradiation.
The minimum follow-up was 2 months. Toxicity data were available from all patients and no mortality was observed within the first 2 months after treatment.
statistical analysis
The following parameters that potentially could affect the incidence and the severity of acute dysphagia were investigated: age, gender, total equivalent radiation dose, overall treatment time of the chest radiotherapy, the irradiated esophageal volume, the maximal esophageal dose, the mean esophageal dose, the nadir of the neutrophilic granulocytes during chest radiotherapy, the delivery of chemotherapy or not, sequential chemotherapy and radiotherapy or concurrent chemoradiation and the delivery of radiotherapy QD or b.i.d. The five treatment groups mentioned above were compared in terms of dysphagia score and hematological toxicity score using Wilcoxon's signed-rank test. Two-tailed P values <0.05 were considered statistically significant.
A multivariate ordinal regression was carried out to analyze the dependence of the maximum grade of dysphagia on the parameters mentioned above. The use of this method for analysis of graded toxicity data has been discussed previously [24]. Briefly, grade of dysphagia is an ordinal variable, i.e. higher grades correspond to more severe side-effects. No numerical relationship is, however, assumed between these ordered categories. Using the ordinal outcome instead of reducing this outcome to a binary response improves the statistical power. In this case the proportional odds model (PLUM, SPSS version 11.5) was used. This model assumes that the odds ratio for each predictor is constant across all possible collapsing of the response variable. The test of parallel lines was used to check if this assumption was met. A stepwise backward procedure was used to eliminate variables from the model if the P value was 
0.05. Calibration plots were made to assess the performance of the model. Ratios for several coefficients were calculated to estimate how a change in one covariate could be compensated by a corresponding change in another. The confidence interval (CI) for a ratio of parameter estimates was calculated using Fieller's method. Statistical tests were carried out with SPSS 11.5 and 14.0 for windows; graphs were made with Origin 7.5.
ethics
According to Dutch and Belgian law and regulations of the Medical Ethical Committees, no informed consent was required for this study.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patient characteristics
Three hundred and twenty-eight patients fulfilled the inclusion criteria. Among these, 118 (36%) received only radiotherapy (group 1), 85 (26%) sequential chemotherapy and radiotherapy (group 2) and 125 (38%) concurrent chemotherapy and radiotherapy (group 3). Of the latter 125 patients, 65 were treated with daily cisplatin and radiotherapy (group 3a), 26 with cisplatin, etoposide and QD radiotherapy (group 3b) and 34 with carboplatin, etoposide and b.i.d. radiation (group 3c) (Table 2).
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acute dysphagia
As expected, patients receiving concurrent chemotherapy and radiotherapy experienced significantly more grade 3 dysphagia than those without chemotherapy or treated with sequential chemotherapy and radiotherapy (12.8% versus 1.7% versus 4.7%, P < 0.001 concurrent versus no chemotherapy versus sequential chemoradiation) (Table 3). In the concurrent group, patients having chemotherapy and b.i.d. radiotherapy had a significantly higher incidence of grade 3 dysphagia than the two QD radiation groups (29.4% versus 6.2% versus 7.7%, P < 0.001 b.i.d. versus QD). In all patients, the acute dysphagia resolved within 4 weeks after radiotherapy.
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late esophageal toxicity.
At the time of analysis, no symptomatic late dysphagia was observed.
timing of the occurrence of acute dysphagia and neutropenia.
Counting from the first day of thoracic radiotherapy, for all patients, maximal acute dysphagia occurred after a mean of 24.6 days ± 6.7 days [standard deviation (SD)]. For the 125 patients treated with concurrent chemoradiation, i.e. the only group in which neutropenia occurred, maximal acute dysphagia occurred after a mean of 22.0 days ± 6.0 days (SD) and maximal neutropenia after a mean of 7.0 days ± 9.2 days (SD); the difference being significantly different (P < 0.001). For all grades of toxicity, maximal neutropenia always preceded maximal dysphagia: grade 1: 2.9 days ± 1.0 days and 19.2 days ± 0.9 days, grade 2: 8.0 days ± 1.2 days and 22.2 days ± 0.6 days, grade 3: 15.2 days ± 2.1 days and 28.3 days ± 1.6 days, grade 4: 18.3 days ± 1.5 days (no grade 4 dysphagia occurred); all differences P <0.001 (Figure 1).
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toxicity of the polymorphonuclear neutrophils (granulocytes) during radiotherapy
Neutropenia was observed during radiotherapy only in patients treated with concurrent chemoradiation (Table 4).
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In the concurrent b.i.d. radiotherapy group, only one out of 34 patients had a dose reduction to 75% of all drugs in cycle 2, however, without delay of the chemotherapy. The mean ± SD total chemotherapy dose for cycles 1 and 2 (during which thoracic radiotherapy was given) in this group was 99.63% ± 2.12% (range 87.5%–100%), the chemotherapy dose intensity 99.63% ± 2.12% (range 87.5%–100%), with no patients requiring a delay.
risk factors for the development of acute dysphagia
The initial multivariate model included age, gender, total equivalent radiation dose, chemotherapy, hematological toxicity, the maximum esophageal dose, the mean esophageal dose, the irradiated esophageal volume, number of fractions per day (QD versus b.i.d.) and the overall treatment time of radiotherapy. Using a stepwise backward procedure to remove statistically nonsignificant factors from the model, the final model consisted of chemotherapy, hematological toxicity, the mean esophageal dose and the BID versus QD schedule (Table 5). The model fit to the data was highly significant (P < 0.001) and the assumption of proportional odds was not rejected (test of parallel lines P = 0.596). Nagelkerke R2 was 0.315, indicating a good fit. This final model had a good performance. On an individual patient level, 206/327 (63.04%) patients were correctly classified and only four of 327 (1.2%) patients were misclassified by more than one grade. Looking at the predictive power of the model, among the 11 patients predicted to develop grade 3 dysphagia, 64% (95% CI 31% to 90%) actually did so. The remaining patients in this group developed grade 2 dysphagia. There were few false negatives in the group predicted to develop grade 1 dysphagia, with only 2.2% (95% CI 0.1% to 4.3%) of these patients developing a grade 3 reaction. Also the patients predicted to develop grade 2 dysphagia, had a fairly low risk 8% (95% CI 5% to 14%) of developing a grade 3 dysphagia.
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To illustrate the performance of the model on the group level rather than on an individual patient level, the whole group was split into five subgroups. For grade 3 toxic effects the split was on the basis of the predicted probability, which ranged from 2% for the lowest group to 64% for the highest group. This resulted in subgroups with different numbers of patients. For grade 2 and 3 toxic effects added together the whole group was split into five subgroups of the same size, resulting in predicted probabilities ranging from 19% for the lowest group to 83% for the highest group. The observed versus the predicted probability to develop dysphagia on basis of the final model showed a very good correlation, both for grade 3 dysphagia alone and for grade 2 and 3 dysphagia together (R = 0.98 and 0.99, respectively; Figure 2A and B).
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The most significant risk factor for dysphagia was the maximal grade of neutropenia during chemoradiation, with higher grades of maximal neutropenia correlating with higher maximal esophageal toxicity (odds ratio: G1–2: 1.49, 95% CI 0.63–3.54, P = 0.362; G3: 5.19, 95% CI 1.24–21.71, P = 0.024; G4: 19.74, 95% CI 4.66–83.52, P < 0.001; Figure 3).
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Also a higher mean esophageal dose, chemotherapy and a b.i.d. schedule led to a higher incidence of dysphagia (Table 5).
In Figure 4A and B, examples of probability curves for developing grade 3 dysphagia with radiotherapy combined with chemotherapy, according to the mean esophageal dose and increasing neutrophilic toxicity, either for a QD or a twice-daily (b.i.d.) radiation schedule, are depicted.
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In addition, ratio's for several model parameters were calculated in order to quantify the trade-off between various treatment characteristics. The addition of chemotherapy to radiotherapy alone increased the probability for dysphagia to the same extent as an increase of the mean esophageal dose by 16 Gy (95% CI 4–32 Gy). To obtain the same toxicity probability with a b.i.d. schedule compared with a QD schedule, the mean esophageal dose would be decreased with 23 Gy (95% CI 15–28 Gy).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The intensity of concurrent chemotherapy and radiotherapy for advanced nonresectable NSCLC and limited stage SCLC is limited by acute esophagitis [1–9]. The identification of clinically useful predictive factors for the development of acute esophagitis is therefore of great interest. Although several authors have found various dose–volume radiation parameters, the use of concurrent chemoradiation and the overall treatment time to be related to early radiation-induced esophagitis remains unclear, which combined chemotherapy and radiotherapy factors are associated with the development of acute esophagitis [11–20].
We therefore built a multivariate model incorporating radiation and chemotherapy factors potentially associated with the development of acute radiation dysphagia.
The final model included mean esophageal dose, chemotherapy, b.i.d. versus QD schedule and hematological toxicity. The model showed a very good correlation between observed and predicted probability, both for grade 3 dysphagia alone and for grade 2 and 3 dysphagia together (R = 0.98 and 0.99, respectively). The most significant parameter for developing dysphagia was the maximal grade of neutropenia during chemoradiation, with higher grades of maximal neutropenia correlating with higher maximal dysphagia. Also a higher mean esophageal dose, a b.i.d. radiation schedule and chemotherapy were associated with a higher incidence of dysphagia. This agrees with several published series [11–20]. The overall treatment time of radiotherapy was not significant in our model. This may be explained by the fact that the b.i.d. schedules, which was a significant variable, were administered in short overall treatment times [25, 26]. The patient's age, gender or the irradiated volume of the esophagus was not statistically significant in the multivariate model.
This model allowed estimating the relationship between the dysphagia probability and the mean esophageal dose, while correcting for the influence of the other significant parameters.
As our model is on the basis of patients with a mean esophageal dose ranging from 0.2 Gy to 64 Gy, calculations using higher or lower values should be interpreted cautiously. Moreover, some graphs and calculations come up with an estimated probability of 0% for developing dysphagia. In practice, there will be individuals who will develop side-effects, even at very low doses of radiotherapy and/or at very extended overall treatment times and without hematological toxicity.
It may seem surprising that after adjusting for chemotherapy in the model, there is no additional significant effect of giving concurrent chemotherapy. However, when we applied a logistic instead of an ordinal regression analysis using dysphagia as a dichotomous outcome (grade 1–2 versus grade 3), our results agree with literature, showing a statistically significant effect for concurrent chemotherapy. Moreover, the nadir of the neutrophil granulocytes during treatment is strongly associated with developing esophagitis, and this may pick up some of the effect from concurrent administration of the two modalities.
The importance of the nadir neutrophilic granulocyte count during radiotherapy for the development of subsequent early dysphagia is an important, new finding. The neutrophil nadir was not related to the actual given dose of chemotherapy, as nearly all patients received their planned chemotherapy dose without reductions or delays in cycles 1 and 2 (during which radiotherapy was delivered).
Several hypotheses could explain the higher incidence of dysphagia in patients with severe neutropenia. First, it is possible that patients with a pronounced neutrophil toxicity simply were exposed to a higher biological dose of chemotherapy as a result of interindividual variation in pharmacokinetics and pharmacodynamics. In this case, not only the neutrophils but also the esophageal mucosa could be exposed to a higher biological effect from the chemotherapy. Interindividual differences in the metabolism of cytotoxic agents have been described [27]. Secondly, it may be that neutrophil granulocytes themselves are needed for the protection and/or repair of the esophageal mucosa. Low levels of neutrophils will therefore lead to a higher incidence of esophageal damage. In that case, neutrophil support with growth factors may lower the incidence of severe acute dysphagia. Thirdly, infections, e.g. with fungi, of the injured esophagus may occur more frequently in patients with a low neutrophil count and hence lead to severe dysphagia. Also in this hypothesis, neutrophil growth factors may be useful. Finally, severe neutropenia may reflect a profound depletion of bone marrow stem cells, which may play a role in the recovery of radiation-induced esophageal damage [28, 29]. Obviously, a combination of all these factors could be involved. As a consequence, predictive or correlative parameters for the development of acute radiation-induced dysphagia may also be dependent on the type of chemotherapy.
Studies are in progress addressing these possibilities and these could lead to new therapeutic interventions in the pathogenesis of dysphagia. In the mean time, as maximal neutropenia precedes maximal dysphagia, patients receiving concurrent platinum, etoposide and radiation and who develop grade 3–4 neutropenia are at high risk for severe dysphagia and might be considered for prophylactic placement of nasogastric or Percutaneous Endoscopic Gastric (PEG) feeding tubes.
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Footnotes |
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These authors equally contributed to the study. 
Received for publication September 28, 2006. Revision received December 28, 2006. Accepted for publication January 8, 2007.
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References |
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1. Curran WJ, Scott CB, Langer CJ, et al. (2003) Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemoradiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 22:621.
2. Fournel P, Robinet G, Perol M, et al. (2005) Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d‘Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol 23:5910–5917.
3. Furuse K, Fukuoka M, Kawahara M, et al. (1999) Phase III study of concurrent versus sequential radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small cell lung cancer. J Clin Oncol 17:2692–2699.
4. Zatloukal P, Petruzelka L, Zemanova M, et al. (2004) Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46:87–98.[CrossRef][Web of Science][Medline]
5. Takada M, Fukuoka M, Kawahara M, et al. (2002) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20:3054–3060.
6. Murray N, Coy P, Pater JL, et al. (1993) Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11:336–344.
7. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. (2006) The time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited disease small cell lung cancer. J Clin Oncol 24:1057–1063.
8. De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, et al. (2006) Systematic review and meta-analysis of randomised controlled trials of timing of chest radiotherapy in patients with limited stage small cell lung cancer. Ann Oncol 17:543–552.
9. Turrisi AT, Kim K, Blum R, et al. (1999) Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265–271.
10. Bentzen SM. (2006) Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer 6:702–713.[CrossRef][Web of Science][Medline]
11. Hirota S, Tsujino K, Endo M, et al. (2001) Dosimetric predictors of radiation esophagitis in patients treated for non-small lung cancer with carboplatin/paclitaxel/radiotherapy. Int J Radiat Oncol Biol Phys 51:291–295.[Web of Science][Medline]
12. Maguire PD, Sibley GS, Zhou S, et al. (1999) Clinical and dosimetric predictors of radiation-induced esophageal toxicity. Int J Radiat Oncol Biol Phys 45:97–103.[Medline]
13. Werner-Wasik M, Pequinot E, Leeper D, et al. (2000) Predictors of severe esophagitis include use of concurrent chemotherapy, but not length of irradiated esophagus: a multivariate analysis of patients with lung cancer treated with nonoperative therapy. Int J Radiat Oncol Biol Phys 48:689–696.[CrossRef][Web of Science][Medline]
14. Bradley J, Deasy JO, Bentzen SM, et al. (2004) Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma. Int J Radiat Oncol Biol Phys 58:1106–1113.[CrossRef][Web of Science][Medline]
15. Belderbos J, Heemsbergen W, Hoogeman M, et al. (2005) Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy. Radiother Oncol 75:157–164.[CrossRef][Web of Science][Medline]
16. Chapet O, Kong FM, Lee JS, et al. (2005) Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer. Radiother Oncol 77:176–181.[CrossRef][Web of Science][Medline]
17. Wei X, Liu HH, Tucker SL, et al. (2006) Risk factors for acute esophagitis in non–small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 66:100–107.[CrossRef][Web of Science][Medline]
18. Patel AB, Edelman MJ, Kwok Y, et al. (2004) Predictors of acute esophagitis in patients with non small cell lung carcinoma treated with concurrent chemotherapy and hyperfractionated radiotherapy followed by surgery. Int J Radiat Oncol Biol Phys 60:1106–1112.[CrossRef][Web of Science][Medline]
19. Qiao WB, Zhao YH, Zhao YB, et al. (2005) Clinical and dosimetric factors of radiation-induced esophageal injury: radiation-induced esophageal toxicity. World J Gastroenterol 11:2626–2629.[Medline]
20. Singh AK, Lockett M, Bradley JD. (2003) Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 55:337–341.[CrossRef][Web of Science][Medline]
21. Senan S, De Ruysscher D, Giraud P, et al. (2004) Literature-based recommendations for treatment planning and execution for high-precision radiotherapy in lung cancer. Radiother Oncol 71:139–146.[CrossRef][Web of Science][Medline]
22. ICRU Report 50. Prescribing, Recording, and reporting Photon Beam Therapy. International Commission on Radiation Units and Measurements. (1993) (Oxford University Press, Oxford, UK).
23. Hendry JH, Bentzen SM, Dale RG, et al. (1996) A modelled comparison of the effects of using different ways to compensate for missed treatment days in radiotherapy. Clin Oncol (R Coll Radiol) 8:297–307.
24. Bentzen SM, Dorr W, Anscher MS, et al. (2004) Normal tissue effects: reporting and analysis. Semin Radiat Oncol 13:189–202.
25. Bentzen SM, Saunders MI, Dische S, et al. (2001) Radiotherapy-related early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial. Radiother Oncol 60:123–135.[CrossRef][Web of Science][Medline]
26. Bentzen SM, Saunders MI, Dische S. (2002) From CHART to CHARTWEL in non-small cell lung cancer: clinical radiobiological modelling of the expected change in outcome. Clin Oncol (R Coll Radiol) 14:372–381.
27. Kishi S, Yang W, Boureau B, et al. (2004) Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia. Blood 103:67–72.
28. Epperly MW, Shen H, Jefferson M, et al. (2004) In vitro differentiation capacity of esophageal progenitor cells with capacity for homing and repopulation of the ionizing irradiation-damaged esophagus. In Vivo 18:675–685.
29. Epperly MW, Guo H, Shen H, et al. (2004) Bone marrow origin of cells with capacity for homing and differentiation to esophageal squamous epithelium. Radiat Res 162:233–240.[CrossRef][Web of Science][Medline]
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