Normal tissue complication models for clinically relevant acute esophagitis (≥ grade 2) in patients treated with dose differentiated accelerated radiotherapy (DART-bid)

Radiation Oncology

Felix Sedlmayer³  Michael Studnicka⁴  Claus Belka¹  Manfred Kranzinger⁵  Philipp Steininger³  Christoph Fussl⁵  Gerd Fastner⁵  Heinz Deutschmann³  Almut Tröller²  Karl Wurstbauer³  Ann-Katrin Exeli⁵  Matthias Söhn¹  Franz Zehentmayr³ 

[1] Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität Munich, Marchioninistr. 15, Munich, 81377, Germany;Department of Radiation Oncology, William Beaumont Health System, 3601 W. Thirteen Mile Road, Royal Oak 48073, MI, USA;Institute for Research and Development of Advanced Radiation Technologies (radART), Paracelsus Medizinische Privatuniversität, Müllner Hauptstr. 48, Salzburg, 5020, Austria;Univ.-Klinik für Pneumologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, Salzburg, 5020, Austria;Univ.-Klinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Univ.-Klinikum der Paracelsus Medizinischen Privatuniversität, Müllner Hauptstr. 48, Salzburg, 5020, Austria

关键词: NTCP (normal tissue toxicity probability) modeling;    Acute esophagitis;    Accelerated radiotherapy;    NSCLC (non-small cell lung cancer);   

Others  :  1228524
DOI  :  10.1186/s13014-015-0429-1

 received in 2015-02-22, accepted in 2015-05-25,  发布年份 2015

【 摘 要 】

Background

One of the primary dose-limiting toxicities during thoracic irradiation is acute esophagitis (AE). The aim of this study is to investigate dosimetric and clinical predictors for AE grade ≥ 2 in patients treated with accelerated radiotherapy for locally advanced non-small cell lung cancer (NSCLC).

Patients and methods

66 NSCLC patients were included in the present analysis: 4 stage II, 44 stage IIIA and 18 stage IIIB. All patients received induction chemotherapy followed by dose differentiated accelerated radiotherapy (DART-bid). Depending on size (mean of three perpendicular diameters) tumors were binned in four dose groups: <2.5 cm 73.8 Gy, 2.5–4.5 cm 79.2 Gy, 4.5–6 cm 84.6 Gy, >6 cm 90 Gy. Patients were treated in 3D target splitting technique. In order to estimate the normal tissue complication probability (NTCP), two Lyman models and the cutoff-logistic regression model were fitted to the data with AE ≥ grade 2 as statistical endpoint. Inter-model comparison was performed with the corrected Akaike information criterion (AIC_c), which calculates the model’s quality of fit (likelihood value) in relation to its complexity (i.e. number of variables in the model) corrected by the number of patients in the dataset. Toxicity was documented prospectively according to RTOG.

Results

The median follow up was 686 days (range 84–2921 days), 23/66 patients (35 %) experienced AE ≥ grade 2. The actuarial local control rates were 72.6 % and 59.4 % at 2 and 3 years, regional control was 91 % at both time points. The Lyman-MED model (D50 = 32.8 Gy, m = 0.48) and the cutoff dose model (D_c = 38 Gy) provide the most efficient fit to the current dataset. On multivariate analysis V38 (volume of the esophagus that receives 38 Gy or above, 95 %-CI 28.2–57.3) was the most significant predictor of AE ≥ grade 2 (HR = 1.05, CI 1.01–1.09, p = 0.007).

Conclusion

Following high-dose accelerated radiotherapy the rate of AE ≥ grade 2 is slightly lower than reported for concomitant radio-chemotherapy with the additional benefit of markedly increased loco-regional tumor control. In the current patient cohort the most significant predictor of AE was found to be V38. A second clinically useful parameter in treatment planning may be MED (mean esophageal dose).

【 授权许可】

   
2015 Zehentmayr et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Curran WJ, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S et al.. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011; 103(19):1452-60.
• [2]Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S et al.. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999; 17(9):2692-9.
• [3]Fournel P, Robinet G, Thomas P, Souquet PJ, Lena H, Vergnenegre A et al.. 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. 2005; 23(25):5910-7.
• [4]Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S et al.. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncology. 2015; 16(2):187-99.
• [5]Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol. 1999; 52(2):137-48.
• [6]van Baardwijk A, Wanders S, Boersma L, Borger J, Ollers M, Dingemans AM et al.. Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III non-small-cell lung cancer. J Clin Oncol. 2010; 28(8):1380-6.
• [7]Wurstbauer K, Deutschmann H, Dagn K, Kopp P, Zehentmayr F, Lamprecht B et al.. DART-bid (Dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily)–a novel approach for non-resected NSCLC: final results of a prospective study, correlating radiation dose to tumor volume. Radiat Oncol. 2013; 8:49. BioMed Central Full Text
• [8]Kong FM, Ten Haken RK, Schipper MJ, Sullivan MA, Chen M, Lopez C et al.. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys. 2005; 63(2):324-33.
• [9]Wurstbauer K, Weise H, Deutschmann H, Kopp P, Merz F, Studnicka M et al.. Non-small cell lung cancer in stages I-IIIB: long-term results of definitive radiotherapy with doses >/= 80 Gy in standard fractionation. Strahlenther Onkol. 2010; 186(10):551-7.
• [10]Werner-Wasik M, Pequignot E, Leeper D, Hauck W, Curran W. 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. Int J Radiat Oncol Biol Phys. 2000; 48(3):689-96.
• [11]Ahn SJ, Kahn D, Zhou S, Yu X, Hollis D, Shafman TD et al.. Dosimetric and clinical predictors for radiation-induced esophageal injury. Int J Radiat Oncol Biol Phys. 2005; 61(2):335-47.
• [12]Mauguen A, Le Pechoux C, Saunders MI, Schild SE, Turrisi AT, Baumann M et al.. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol. 2012; 30(22):2788-97.
• [13]Guerra JL, Gomez D, Wei Q, Liu Z, Wang LE, Yuan X et al.. Association between single nucleotide polymorphisms of the transforming growth factor beta1 gene and the risk of severe radiation esophagitis in patients with lung cancer. Radiother Oncol. 2012; 105(3):299-304.
• [14]Dikomey E. Predictive marker for acute normal tissue toxity in radiotherapy of non-small cell lung cancer. Strahlenther Onkol. 2013; 189(9):806-8.
• [15]Belderbos J, Heemsbergen W, Hoogeman M, Pengel K, Rossi M, Lebesque J. Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy. Radiother Oncol. 2005; 75(2):157-64.
• [16]Patel AB, Edelman MJ, Kwok Y, Krasna MJ, Suntharalingam M. 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. 2004; 60(4):1106-12.
• [17]Bradley J, Deasy JO, Bentzen S, El-Naqa I. Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma. Int J Radiat Oncol Biol Phys. 2004; 58(4):1106-13.
• [18]Qiao WB, Zhao YH, Zhao YB, Wang RZ. Clinical and dosimetric factors of radiation-induced esophageal injury: radiation-induced esophageal toxicity. World J Gastroenterol. 2005; 11(17):2626-9.
• [19]Singh AK, Lockett MA, Bradley JD. 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. 2003; 55(2):337-41.
• [20]Kim TH, Cho KH, Pyo HR, Lee JS, Han JY, Zo JI et al.. Dose-volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2005; 62(4):995-1002.
• [21]Wei X, Liu HH, Tucker SL, Liao Z, Hu C, Mohan R et al.. Risk factors for acute esophagitis in non-small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2006; 66(1):100-7.
• [22]Takeda K, Nemoto K, Saito H, Ogawa Y, Takai Y, Yamada S. Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2005; 62(3):626-9.
• [23]Rose J, Rodrigues G, Yaremko B, Lock M, D’Souza D. Systematic review of dose-volume parameters in the prediction of esophagitis in thoracic radiotherapy. Radiother Oncol. 2009; 91(3):282-7.
• [24]Manapov F, Sepe S, Niyazi M, Belka C, Friedel G, Budach W. Dose-volumetric parameters and prediction of severe acute esophagitis in patients with locally-advanced non small-cell lung cancer treated with neoadjuvant concurrent hyperfractionated-accelerated chemoradiotherapy. Radiat Oncol. 2013; 8:122. BioMed Central Full Text
• [25]Zehentmayr F, Wurstbauer K, Deutschmann H, Fussl C, Kopp P, Dagn K et al. DART-bid: dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily: high local control in early stage (I/II) non-small-cell lung cancer. Strahlenther Onkol. 2014. doi: 10.1007/s00066-014-0754-6.
• [26]Wurstbauer K, Deutschmann H, Kopp P, Merz F, Scholler H, Sedlmayer F. Target splitting in radiation therapy for lung cancer: further developments and exemplary treatment plans. Radiat Oncol. 2009; 4:30. BioMed Central Full Text
• [27]Wurstbauer K, Deutschmann H, Kopp P, Sedlmayer F. Radiotherapy planning for lung cancer: slow CTs allow the drawing of tighter margins. Radiother Oncol. 2005; 75(2):165-70.
• [28]Werner-Wasik M, Yorke E, Deasy J, Nam J, Marks LB. Radiation dose-volume effects in the esophagus. Int J Radiat Oncol Biol Phys. 2010; 76(3 Suppl):S86-93.
• [29]Lyman JT. Complication probability as assessed from dose-volume histograms. Rad Res Suppl. 1985; 8:S13-9.
• [30]Burman C, Kutcher GJ, Emami B, Goitein M. Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys. 1991; 21(1):123-35.
• [31]Kutcher GJ, Burman C. Calculation of complication probability factors for non-uniform normal tissue irradiation: the effective volume method. Int J Radiat Oncol Biol Phys. 1989; 16(6):1623-30.
• [32]Söhn M, Yan D, Liang J, Meldolesi E, Vargas C, Alber M. Incidence of late rectal bleeding in high-dose conformal radiotherapy of prostate cancer using equivalent uniform dose-based and dose-volume-based normal tissue complication probability models. Int J Radiat Oncol Biol Phys. 2007; 67(4):1066-73.
• [33]Hurvich CM, Tsai CL. Regression and time-series model selection in small samples. Biometrika. 1989; 76(2):297-307.
• [34]van Baardwijk A, Reymen B, Wanders S, Borger J, Ollers M, Dingemans AM et al.. Mature results of a phase II trial on individualised accelerated radiotherapy based on normal tissue constraints in concurrent chemo-radiation for stage III non-small cell lung cancer. Eur J Cancer. 2012; 48(15):2339-46.
• [35]Fowler JF, Tome WA, Fenwick JD, Mehta MP. A challenge to traditional radiation oncology. Int J Radiat Oncol Biol Phys. 2004; 60(4):1241-56.
• [36]Bradley J, Graham MV, Winter K, Purdy JA, Komaki R, Roa WH et al.. Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2005; 61(2):318-28.
• [37]Huang EX, Bradley JD, El Naqa I, Hope AJ, Lindsay PE, Bosch WR et al.. Modeling the risk of radiation-induced acute esophagitis for combined Washington University and RTOG trial 93–11 lung cancer patients. Int J Radiat Oncol Biol Phys. 2012; 82(5):1674-9.
• [38]Rodriguez N, Algara M, Foro P, Lacruz M, Reig A, Membrive I et al.. Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phys. 2009; 73(3):810-7.
• [39]Chapet O, Kong FM, Lee JS, Hayman JA, Ten Haken RK. Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer. Radiother Oncol. 2005; 77(2):176-81.
• [40]Söhn M, Alber M, Yan D. Principal component analysis-based pattern analysis of dose-volume histograms and influence on rectal toxicity. Int J Radiat Oncol Biol Phys. 2007; 69(1):230-9.
• [41]Dieleman EM, Senan S, Vincent A, Lagerwaard FJ, Slotman BJ. Four-dimensional computed tomographic analysis of esophageal mobility during normal respiration. Int J Radiat Oncol Biol Phys. 2007; 67(3):775-80.