A new index comparable to BED for evaluating the biological efficacy of hypofractionated radiotherapy schemes on early stage non-small cell lung cancer: analysis of data from the literature.

BACKGROUND AND PURPOSE Hypofractionated radiotherapy has been the principal curative treatment option for early stage NSCLC patients who are medically inoperable or those who refuse surgery and achieved favorable clinical outcomes. Evidence demonstrated that the linear quadratic model widely used in normally fractionated radiotherapy cannot work well to fit outcome data by use of BED to predict the effect of hypofractionation schemes. New models and the related metrics need to be developed to quantify the effect of high-dose ablative regimens for early stage NSCLC. PATIENTS AND METHODS Trials using hypofractionated radiotherapy without chemotherapy to treat early stage (T1 or T2N0M0) primary NSCLC and providing information on patient numbers, age, T stage and local control rates were eligible. The endpoint was local relapse and the covariates analyzed were total radiotherapy dose, dose per fraction or combinations of the two parameters, treatment duration, T stage and median age of patients within the trial. The model used was a multivariate logistic regression. RESULTS 19 trials were included (767 patients) in which 90 patients suffered local relapse. Only total dose × dose per fraction (D × d) and stage T had statistically significant effect on local control. Smaller T stage (p=0.000) and increasing D × d (p=0.006) were associated with improved probability of local control. In contrast, BED10 had no significant impact on local control, which probably indicated that D × d might be a more effective metric than BED10 to predict tumor control rate and assess the efficacy of the large dose fractionation schemes for early stage NSCLC. CONCLUSIONS BED was not an ideal metric to estimate the effect of the schemes of high-dose ablative radiotherapy for early stage NSCLC, and total dose × fraction dose could be considered as a comparable index, though the result need to be further validated.

[1]  B. Kavanagh,et al.  Toward a unified survival curve: in regard to Park et al. (IntJ Radiat Oncol Biol Phys 2008;70:847-852) and Krueger et al. (Int J Radiat Oncol Biol Phys 2007;69:1262-1271). , 2008, International journal of radiation oncology, biology, physics.

[2]  Colin G Orton,et al.  The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery. , 2009, Medical physics.

[3]  Ping Li,et al.  Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable Stage I/II non-small-cell lung cancer. , 2006, International journal of radiation oncology, biology, physics.

[4]  K. Johansson,et al.  Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer--mature results for medically inoperable patients. , 2006, Lung cancer.

[5]  Y. Sugawara,et al.  Local control of metastatic lung tumors treated with SBRT of 48 Gy in four fractions: in comparison with primary lung cancer. , 2010, Japanese journal of clinical oncology.

[6]  Angelika Hoess,et al.  Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer (NSCLC). , 2003, International journal of radiation oncology, biology, physics.

[7]  L. Marks Extrapolating hypofractionated radiation schemes from radiosurgery data: regarding Hall et al., IJROBP 21:819-824; 1991 and Hall and Brenner, IJROBP 25:381-385; 1993. , 1995, International journal of radiation oncology, biology, physics.

[8]  J. Petersen,et al.  Prospective study on stereotactic radiotherapy of limited-stage non-small-cell lung cancer , 2005 .

[9]  Stereotactic body radiation therapy: a treatment in need of basic biological research. , 2006, Cancer journal.

[10]  V. Tombolini,et al.  Hypofractionated radical radiotherapy in elderly patients with medically inoperable stage I-II non-small-cell lung cancer. , 2010, Lung cancer.

[11]  T. Araki,et al.  Stereotactic hypofractionated high‐dose irradiation for stage I nonsmall cell lung carcinoma , 2004, Cancer.

[12]  S. Tung,et al.  Hypofractionated stereotactic radiotherapy for medically inoperable stage I non-small cell lung cancer--report on clinical outcome and dose to critical organs. , 2008, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[13]  R P Müller,et al.  Computer simulation of cytotoxic and vascular effects of radiosurgery in solid and necrotic brain metastases. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[14]  D. Brenner,et al.  We forget at our peril the lessons built into the α/β model. , 2012, International journal of radiation oncology, biology, physics.

[15]  J. Fowler Linear quadratics is alive and well: in regard to Park et al. (Int J Radiat Oncol Biol Phys 2008;70:847-852). , 2008, International journal of radiation oncology, biology, physics.

[16]  Jan Nyman,et al.  Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries , 2006, Acta oncologica.

[17]  Andrea Bezjak,et al.  Stereotactic body radiation therapy for inoperable early stage lung cancer. , 2010, JAMA.

[18]  M. Franzblau,et al.  Conflict of Interest Statement , 2004 .

[19]  Nina A. Mayr,et al.  A Generalized Linear-Quadratic Formula for High-Dose-Rate Brachytherapy and Radiosurgery , 2007 .

[20]  Takashi Aruga,et al.  Stereotactic single high dose irradiation of lung tumors under respiratory gating. , 2002, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[21]  Albert C Koong,et al.  High-dose single-fraction radiotherapy: exploiting a new biology? , 2008, International journal of radiation oncology, biology, physics.

[22]  Seung Do Ahn,et al.  Stereotactic body frame based fractionated radiosurgery on consecutive days for primary or metastatic tumors in the lung. , 2003, Lung cancer.

[23]  Yoshihiro Takai,et al.  A phase II study on stereotactic body radiotherapy for stage I non-small cell lung cancer. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[24]  Jan Nyman,et al.  Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  David Wilkins,et al.  The modified linear-quadratic model of Guerrero and Li can be derived from a mechanistic basis and exhibits linear-quadratic-linear behaviour. , 2005 .

[26]  S. Bentzen,et al.  Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: evidence of a radiation and chemotherapy dose response. , 2006, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[27]  S B Curtis,et al.  Lethal and potentially lethal lesions induced by radiation--a unified repair model. , 1986, Radiation research.

[28]  M. Scholz,et al.  The Increased Biological Effectiveness of Heavy Charged Particles: From Radiobiology to Treatment Planning , 2003, Technology in cancer research & treatment.

[29]  T. Vuong,et al.  Absence of toxicity with hypofractionated 3-dimensional radiation therapy for inoperable, early stage non-small cell lung cancer , 2006, Radiation oncology.

[30]  Lech Papiez,et al.  Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. , 2009, International journal of radiation oncology, biology, physics.

[31]  S. Ahmad,et al.  Fitting techniques of cell survival curves in high-dose region for use in stereotactic body radiation therapy , 2009, Physics in medicine and biology.

[32]  Kurt Baier,et al.  Dose-response in stereotactic irradiation of lung tumors. , 2005, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[33]  Umberto Ricardi,et al.  Stereotactic body radiation therapy for early stage non-small cell lung cancer: results of a prospective trial. , 2010, Lung cancer.

[34]  J. D. Chapman,et al.  The power of radiation biophysics-let's use it. , 2012, International journal of radiation oncology, biology, physics.

[35]  Mike Partridge,et al.  Dose escalation for non-small cell lung cancer: analysis and modelling of published literature. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[36]  Salahuddin Ahmad,et al.  Toward a unified survival curve: in regard to Kavanagh and Newman (Int J Radiat Oncol Biol Phys 2008;71:958-959) and Park et al. (IntJ Radiat Oncol Biol Phys 2008;70:847-852). , 2009, International journal of radiation oncology, biology, physics.

[37]  G. W. Snedecor Statistical Methods , 1964 .

[38]  D. Lim,et al.  Results and Prognostic Factors of Hypofractionated Stereotactic Radiation Therapy for Primary or Metastatic Lung Cancer , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[39]  Lawrence B Marks,et al.  The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery. , 2008, Seminars in radiation oncology.

[40]  M. Astrahan,et al.  Some implications of linear-quadratic-linear radiation dose-response with regard to hypofractionation. , 2008, Medical physics.

[41]  Michael Flentje,et al.  Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients. , 2004, International journal of radiation oncology, biology, physics.

[42]  M. Joiner Quantifying cell kill and cell survival , 2009 .

[43]  M. Astrahan BED calculations for fractions of very high dose: in regard to Park et al. (Int J Radiat Oncol Biol Phys 2007;69:S623-S624). , 2008, International journal of radiation oncology, biology, physics.

[44]  John Wilson Basic Clinical Radiobiology. 2nd ed , 1998 .

[45]  X Allen Li,et al.  Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy. , 2004, Physics in medicine and biology.

[46]  E. Glatstein The omega on alpha and beta. , 2011, International journal of radiation oncology, biology, physics.

[47]  Lech Papiez,et al.  Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy. , 2008, International journal of radiation oncology, biology, physics.

[48]  Quynh-Thu Le,et al.  Results of a Phase I Dose-Escalation Study Using Single-Fraction Stereotactic Radiotherapy for Lung Tumors , 2006, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[49]  I. Lax,et al.  Long-term Results after Fractionated Radiation Therapy for Large Brain Arteriovenous Malformations , 2005, Neurosurgery.

[50]  David J Brenner,et al.  The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction. , 2008, Seminars in radiation oncology.

[51]  Michael C. Joiner,et al.  Basic Clinical Radiobiology , 2009 .