- Email: [email protected]
Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent?
Radiotherapy and Oncology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Editorial
Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent? Robin Wijsman, Pètra M. Braam, Johan Bussink ⇑ Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
Stereotactic body radiation therapy (SBRT) is a well established treatment modality for inoperable patients with early stage nonsmall cell lung (NSCLC) cancer with excellent local control rates as high as 90–98% at 3 years [1–3]. Besides, thoracic SBRT is increasingly being used for the treatment of patients with metastatic disease located within the lung as local tumor control in these patients is 80–90% with 2 and 5-year overall survival rates of approximately 50% and 25%, respectively [4–6]. In general, stereotactic treatment is very well tolerated with minimal acute and late toxicity and therefore a suitable treatment option for the medically inoperable patient [7]. However, chest wall toxicity has been reported including chest wall pain (focal or neuropathic pain) and rib fracture (symptomatic and asymptomatic) [1–3,8– 11]. Chest wall toxicity is usually mild to moderate and can be treated effectively with narcotics or anti-inflammatory medication. Radiation-induced rib fracture is a late radiation effect that generally develops within 6–48 months after treatment [12,13]. It can be transient or can last for several weeks or longer. In the current issue of Radiotherapy and Oncology, Stam et al. [14] report a study assessing chest wall toxicity after SBRT for thoracic tumors. They determined a dose–effect relationship for radiation induced rib fractures after SBRT for early stage NSCLC [14]. A total of 466 patients were evaluated and 11.184 ribs were automatically delineated to generate the dose–volume histograms for all ribs individually. The majority of patients (73%) received 54 Gy in 3 fractions; there were no dose constraints on the ribs during plan optimization. Follow-up computed tomography (CT) scans were only evaluated in detail for patients that were suspected of fracture based on this CT or in case the patient reported pain. After a median follow-up of 26.1 months, 64 patients (13.7%) had 123 rib fractures on the follow-up CT scans (of whom 42 patients and 22 patients had symptomatic and asymptomatic fractures, respectively). Median time to fracture was 22 months. Multivariate analysis showed that maximum rib dose (Dmax), age and body mass index were significantly associated with rib fractures. The Dmax was used for NTCP modeling; the risk of developing a rib fracture 26 months was <5% and <50% when Dmax was below 207 Gy and 452 Gy (equivalent dose in 2 Gy fractions), respectively. Taking into account time to fracture, the risk of developing ⇑ Corresponding author. E-mail address: [email protected] (J. Bussink).
rib fractures at 26 months was <5% when Dmax < 225 Gy and <50% when Dmax < 375 Gy. The identification of (dose–volume) parameters that predict the risk of toxicity to bony structures such as the vertebral body and the ribs has been subject of research [15–18]. Regarding the chest wall, many different dose–volume parameters have been reported to be predictive for chest wall toxicity. For example, a greater incidence of chest wall toxicity in peripheral tumors treated with 60 Gy in 3 fractions has been reported compared to treatment with 50 Gy in 5 fractions (18% versus 4%) [19]. Dunlap et al. [13] demonstrated that small volumes receiving doses of 50 Gy to 60 Gy correlated strongly with the development of severe chest wall toxicity. The threshold volume of the chest wall receiving 30 Gy was a 10-fold greater than the threshold volume receiving 50–60 Gy before a 30% risk of severe chest wall toxicity was observed. They predict a 30% risk of severe chest wall toxicity when 30 cm3 of the chest wall receives 30 Gy. Stephans et al. [20] demonstrated a correlation between tumor size and dose to the chest wall in estimating the risk of chest wall toxicity. Restricting the V30 to less than 30 cm3 and the V60 to less than 3 cm3 should result in a less than 10–15% risk of chest wall toxicity. As Dunlap et al. found the greatest correlation of V30 with toxicity, Stephans et al. found an equal correlation of V30-V60. Another study by Petterson et al. also found this association between individual rib dose–volume histogram parameters [21]. The dose–response curves proved more suitable than the volume–response curves. The highest risk of fracture in the smallvolume/high-dose region, was found for the dose given by the cut-off volume of 2 cm3. The authors predict a 5% risk of rib fracture for 2 cm3 of rib receiving 27 Gy and a 50% chance of fracture when 2 cm3 of rib receives 50 Gy. Andolino et al. did not find a specific threshold volume for a dramatic increase in the risk of chest wall toxicity, but a more gradual increase in risk was observed as the volume increased [11]. They found a 30% risk of any grade chest wall toxicity when limiting the V30 to 40 cm3 and the V40 to 15 cm3, respectively. Similarly, they predicted a 10% risk of chest wall toxicity when 15 cm3 and 5 cm3 of the chest wall receives 30 Gy and 40 Gy, respectively. Corresponding to the study of Stam et al. reported in this issue, Asai et al. found that the best predictor for rib fracture was Dmax (cut-off 42.4 Gy) among 374 analyzed ribs in 116 patients treated with SBRT [22]. The Dmax has been found to be associated with chest wall toxicity in various other studies as well [11,12,22,23]. Besides the plethora of dosimetric variables
http://dx.doi.org/10.1016/j.radonc.2017.03.010 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Wijsman R et al. Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent? Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.010
2
Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent?
reported to be associated with chest wall toxicity, clinical variables such as tobacco use, higher body mass index, age, tumor to chest wall distance, gender and osteoporosis have also been reported to be associated with chest wall toxicity [24–29]. Taremi et al. combined clinical and dosimetric parameters to develop an NTCPmodel to estimate the risk of rib fracture in 46 patients (49 tumors) treated with SBRT for early stage NSCLC [23]. The model consisted of the parameters gender, age and D0.5 (minimum absolute dose received by 0.5 cm3). Although the area under the curve of the receiver operator characteristic was high (0.93), caution should be taken because of the small number of patients included in this analysis and the lacking of (both internal and external) validation. Although the different abovementioned dosimetric parameters can guide in treatment planning, dosimetric parameters alone seem less useful in risk estimation for the individual patient. In the light of shared decision making, informing the patient on individual estimated risk of chest wall toxicity after SBRT is increasingly important. Robust multivariable NTCP models developed with sophisticated parameter selection techniques are required for this purpose [30,31], as have already been developed for the prediction of radiation induced toxicity of the rectum [32], the esophagus [33] and oral mucosa [34]. The results from the chest wall toxicity studies are heterogeneous, which may be partially due to differences in toxicity grading (e.g. fracture vs pain). Differences in toxicity grading scales should be avoided. For the evaluation of chest wall toxicity discrimination has to be made between symptomatic and therewith clinically relevant and asymptomatic radiation-induced rib fractures [27]. Furthermore, differences in OAR delineation (automatically vs manually) may also have contributed to the different outcomes. In general, several different delineation guidelines are used in clinical practice [27]. Besides manual delineation [21], the chest wall can be contoured as a 3-three-dimensional expansion of the lung (excluding lung and mediastinal tissue and the anterior vertebral body) [11,13], or the arc of all ipsilateral soft tissue outside of lung tissue from the edge of the sternum circumferentially to the edge of the vertebral body [20]. To improve rib delineation consistency, an automatic segmentation method for ribs has recently been developed and was applied for rib delineation in the study of Stam et al. [14]. It proved accurate and time efficient (reducing delineation time from 2 h to 8 min per patient, for manual and automatic delineation, respectively) [35]. Other new digital radiographic techniques have been developed to evaluate the cortical thickness of the ribs using computed tomography scans and may therefore be useful in future chest wall toxicity studies as well [36]. Preferably, large patient populations are needed for NTCP model development as overfitting is less likely in case there is a substantial number of events of interest [31]. Pooling of data from different departments of radiation oncology may be useful to create such a database [37]. For future work, the abovementioned issues need to be addressed to generate consistent data that can be properly modeled. Moreover, sophisticated statistical evaluation including thorough internal and external validation is mandatory in developing generalizable multivariable NTCP models for chest wall toxicity after SBRT [31,38]. Once such a multivariable NTCP model is externally validated, it may guide both the patient and the clinician in decision making for SBRT. References [1] Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of riskadapted fractionated stereotactic radiotherapy for stage i non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;70:685–92. [2] McCammon R, Schefter TE, Gaspar LE, Zaemisch R, Gravdahl D, Kavanagh B. Observation of a dose-control relationship for lung and liver tumors after stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2009;73:112–8.
[3] Ng AW, Tung SY, Wong VY. Hypofractionated stereotactic radiotherapy for medically inoperable stage i non-small cell lung cancer–report on clinical outcome and dose to critical organs. Radiother Oncol 2008;87:24–8. [4] Rieber J, Streblow J, Uhlmann L, et al. Stereotactic body radiotherapy (sbrt) for medically inoperable lung metastases-a pooled analysis of the german working group ‘‘stereotactic radiotherapy”. Lung cancer 2016;97:51–8. [5] Van den Begin R, Engels B, Boussaer M, et al. Motion management during sbrt for oligometastatic cancer: Results of a prospective phase ii trial. Radiother Oncol 2016;119:519–24. [6] Tanadini-Lang S, Rieber J, Filippi AR, et al. Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastastic lung disease. Radiother Oncol 2017. epub ahead of print. [7] Louie AV, van Werkhoven E, Chen H, et al. Patient reported outcomes following stereotactic ablative radiotherapy or surgery for stage ia non-small-cell lung cancer: results from the rosel multicenter randomized trial. Radiother Oncol 2015;117:44–8. [8] Zimmermann FB, Geinitz H, Schill S, et al. Stereotactic hypofractionated radiotherapy in stage i (t1–2 n0 m0) non-small-cell lung cancer (nsclc). Acta Oncol 2006;45:796–801. [9] Taremi M, Hope A, Dahele M, et al. Stereotactic body radiotherapy for medically inoperable lung cancer: prospective, single-center study of 108 consecutive patients. Int J Radiat Oncol Biol Phys 2012;82:967–73. [10] Baumann P, Nyman J, Lax I, 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. Acta Oncol 2006;45:787–95. [11] Andolino DL, Forquer JA, Henderson MA, et al. Chest wall toxicity after stereotactic body radiotherapy for malignant lesions of the lung and liver. Int J Radiat Oncol Biol Phys 2011;80:692–7. [12] Aoki M, Sato M, Hirose K, et al. Radiation-induced rib fracture after stereotactic body radiotherapy with a total dose of 54–56 gy given in 9–7 fractions for patients with peripheral lung tumor: Impact of maximum dose and fraction size. Radiat Oncol 2015;10:99. [13] Dunlap NE, Cai J, Biedermann GB, et al. Chest wall volume receiving >30 gy predicts risk of severe pain and/or rib fracture after lung stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 2010;76:796–801. [14] Stam B, van der Bijl E, Peulen H, Rossi MM, Belderbos JS, Sonke JJ. Dose-effect analysis of radiation induced rib fractures after thoracic sbrt. Radiother Oncol 2017. [15] Pilz K, Hoffmann AL, Baumann M, Troost EG. Vertebral fractures – an underestimated side-effect in patients treated with radio(chemo)therapy. Radiother Oncol 2016;118:421–3. [16] Uyterlinde W, Chen C, Belderbos J, et al. Fractures of thoracic vertebrae in patients with locally advanced non-small cell lung carcinoma treated with intensity modulated radiotherapy. Radiother Oncol 2016;118:437–41. [17] Otani K, Teshima T, Ito Y, et al. Risk factors for vertebral compression fractures in preoperative chemoradiotherapy with gemcitabine for pancreatic cancer. Radiother Oncol 2016;118:424–9. [18] Wei RL, Jung BC, Manzano W, et al. Bone mineral density loss in thoracic and lumbar vertebrae following radiation for abdominal cancers. Radiother Oncol 2016;118:430–6. [19] Stephans KL, Djemil T, Reddy CA, et al. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage i non-small cell lung cancer: The cleveland clinic experience. J Thorac Oncol 2009;4:976–82. [20] Stephans KL, Djemil T, Tendulkar RD, Robinson CG, Reddy CA, Videtic GM. Prediction of chest wall toxicity from lung stereotactic body radiotherapy (sbrt). Int J Radiat Oncol Biol Phys 2012;82:974–80. [21] Pettersson N, Nyman J, Johansson KA. Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy of non-small cell lung cancer: A dose- and volume-response analysis. Radiother Oncol 2009;91:360–8. [22] Asai K, Shioyama Y, Nakamura K, et al. Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy: Risk factors and dosevolume relationship. Int J Radiat Oncol Biol Phys 2012;84:768–73. [23] Taremi M, Hope A, Lindsay P, et al. Predictors of radiotherapy induced bone injury (ribi) after stereotactic lung radiotherapy. Radiat Oncol 2012;7:159. [24] Welsh J, Thomas J, Shah D, et al. Obesity increases the risk of chest wall pain from thoracic stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2011;81:91–6. [25] Thibault I, Chiang A, Erler D, et al. Predictors of chest wall toxicity after lung stereotactic ablative radiotherapy. Clin Oncol (R Coll Radiol) 2016;28:28–35. [26] Kim SS, Song SY, Kwak J, et al. Clinical prognostic factors and grading system for rib fracture following stereotactic body radiation therapy (sbrt) in patients with peripheral lung tumors. Lung cancer 2013;79:161–6. [27] Shaikh T, Turaka A. Predictors and management of chest wall toxicity after lung stereotactic body radiotherapy. Cancer Treat Rev 2014;40:1215–20. [28] Nambu A, Onishi H, Aoki S, et al. Rib fracture after stereotactic radiotherapy for primary lung cancer: Prevalence, degree of clinical symptoms, and risk factors. BMC Cancer 2013;13:68. [29] Creach KM, Al-Lozi R, El Naqa I, et al. Dosimetric prediction of chest wall toxicity after lung sbrt. Int J Radiat Oncol Biol Phys 2010;78:S181–2. [30] El Naqa I, Bradley J, Blanco AI, et al. Multivariable modeling of radiotherapy outcomes, including dose-volume and clinical factors. Int J Radiat Oncol Biol Phys 2006;64:1275–86.
Please cite this article in press as: Wijsman R et al. Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent? Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.010
R. Wijsman et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx [31] Harrell Jr FE, Lee KL, Mark DB. Multivariable prognostic models: Issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Statistics Med 1996;15:361–87. [32] Schaake W, van der Schaaf A, van Dijk LV, Bongaerts AH, van den Bergh AC, Langendijk JA. Normal tissue complication probability (ntcp) models for late rectal bleeding, stool frequency and fecal incontinence after radiotherapy in prostate cancer patients. Radiother Oncol 2016;119:381–7. [33] Wijsman R, Dankers F, Troost EG, et al. Multivariable normal-tissue complication modeling of acute esophageal toxicity in advanced stage nonsmall cell lung cancer patients treated with intensity-modulated (chemo-) radiotherapy. Radiother Oncol 2015;117:49–54. [34] Dean JA, Wong KH, Welsh LC, et al. Normal tissue complication probability (ntcp) modelling using spatial dose metrics and machine learning methods for
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3
severe acute oral mucositis resulting from head and neck radiotherapy. Radiother Oncol 2016;120:21–7. Stam B, Peulen H, Rossi MM, Belderbos JS, Sonke JJ. Validation of automatic segmentation of ribs for ntcp modeling. Radiother Oncol 2016;118:528–34. Okoukoni C, Lynch SK, McTyre ER, et al. A cortical thickness and radiation dose mapping approach identifies early thinning of ribs after stereotactic body radiation therapy. Radiother Oncol 2016;119:449–53. Skripcak T, Belka C, Bosch W, et al. Creating a data exchange strategy for radiotherapy research: Towards federated databases and anonymised public datasets. Radiother Oncol 2014;113:303–9. Steyerberg EW, Vickers AJ, Cook NR, et al. Assessing the performance of prediction models: a framework for traditional and novel measures. Epidemiology 2010;21:128–38.
Please cite this article in press as: Wijsman R et al. Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent? Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.010
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Editorial
Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent? Robin Wijsman, Pètra M. Braam, Johan Bussink ⇑ Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
Stereotactic body radiation therapy (SBRT) is a well established treatment modality for inoperable patients with early stage nonsmall cell lung (NSCLC) cancer with excellent local control rates as high as 90–98% at 3 years [1–3]. Besides, thoracic SBRT is increasingly being used for the treatment of patients with metastatic disease located within the lung as local tumor control in these patients is 80–90% with 2 and 5-year overall survival rates of approximately 50% and 25%, respectively [4–6]. In general, stereotactic treatment is very well tolerated with minimal acute and late toxicity and therefore a suitable treatment option for the medically inoperable patient [7]. However, chest wall toxicity has been reported including chest wall pain (focal or neuropathic pain) and rib fracture (symptomatic and asymptomatic) [1–3,8– 11]. Chest wall toxicity is usually mild to moderate and can be treated effectively with narcotics or anti-inflammatory medication. Radiation-induced rib fracture is a late radiation effect that generally develops within 6–48 months after treatment [12,13]. It can be transient or can last for several weeks or longer. In the current issue of Radiotherapy and Oncology, Stam et al. [14] report a study assessing chest wall toxicity after SBRT for thoracic tumors. They determined a dose–effect relationship for radiation induced rib fractures after SBRT for early stage NSCLC [14]. A total of 466 patients were evaluated and 11.184 ribs were automatically delineated to generate the dose–volume histograms for all ribs individually. The majority of patients (73%) received 54 Gy in 3 fractions; there were no dose constraints on the ribs during plan optimization. Follow-up computed tomography (CT) scans were only evaluated in detail for patients that were suspected of fracture based on this CT or in case the patient reported pain. After a median follow-up of 26.1 months, 64 patients (13.7%) had 123 rib fractures on the follow-up CT scans (of whom 42 patients and 22 patients had symptomatic and asymptomatic fractures, respectively). Median time to fracture was 22 months. Multivariate analysis showed that maximum rib dose (Dmax), age and body mass index were significantly associated with rib fractures. The Dmax was used for NTCP modeling; the risk of developing a rib fracture 26 months was <5% and <50% when Dmax was below 207 Gy and 452 Gy (equivalent dose in 2 Gy fractions), respectively. Taking into account time to fracture, the risk of developing ⇑ Corresponding author. E-mail address: [email protected] (J. Bussink).
rib fractures at 26 months was <5% when Dmax < 225 Gy and <50% when Dmax < 375 Gy. The identification of (dose–volume) parameters that predict the risk of toxicity to bony structures such as the vertebral body and the ribs has been subject of research [15–18]. Regarding the chest wall, many different dose–volume parameters have been reported to be predictive for chest wall toxicity. For example, a greater incidence of chest wall toxicity in peripheral tumors treated with 60 Gy in 3 fractions has been reported compared to treatment with 50 Gy in 5 fractions (18% versus 4%) [19]. Dunlap et al. [13] demonstrated that small volumes receiving doses of 50 Gy to 60 Gy correlated strongly with the development of severe chest wall toxicity. The threshold volume of the chest wall receiving 30 Gy was a 10-fold greater than the threshold volume receiving 50–60 Gy before a 30% risk of severe chest wall toxicity was observed. They predict a 30% risk of severe chest wall toxicity when 30 cm3 of the chest wall receives 30 Gy. Stephans et al. [20] demonstrated a correlation between tumor size and dose to the chest wall in estimating the risk of chest wall toxicity. Restricting the V30 to less than 30 cm3 and the V60 to less than 3 cm3 should result in a less than 10–15% risk of chest wall toxicity. As Dunlap et al. found the greatest correlation of V30 with toxicity, Stephans et al. found an equal correlation of V30-V60. Another study by Petterson et al. also found this association between individual rib dose–volume histogram parameters [21]. The dose–response curves proved more suitable than the volume–response curves. The highest risk of fracture in the smallvolume/high-dose region, was found for the dose given by the cut-off volume of 2 cm3. The authors predict a 5% risk of rib fracture for 2 cm3 of rib receiving 27 Gy and a 50% chance of fracture when 2 cm3 of rib receives 50 Gy. Andolino et al. did not find a specific threshold volume for a dramatic increase in the risk of chest wall toxicity, but a more gradual increase in risk was observed as the volume increased [11]. They found a 30% risk of any grade chest wall toxicity when limiting the V30 to 40 cm3 and the V40 to 15 cm3, respectively. Similarly, they predicted a 10% risk of chest wall toxicity when 15 cm3 and 5 cm3 of the chest wall receives 30 Gy and 40 Gy, respectively. Corresponding to the study of Stam et al. reported in this issue, Asai et al. found that the best predictor for rib fracture was Dmax (cut-off 42.4 Gy) among 374 analyzed ribs in 116 patients treated with SBRT [22]. The Dmax has been found to be associated with chest wall toxicity in various other studies as well [11,12,22,23]. Besides the plethora of dosimetric variables
http://dx.doi.org/10.1016/j.radonc.2017.03.010 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Wijsman R et al. Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent? Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.010
2
Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent?
reported to be associated with chest wall toxicity, clinical variables such as tobacco use, higher body mass index, age, tumor to chest wall distance, gender and osteoporosis have also been reported to be associated with chest wall toxicity [24–29]. Taremi et al. combined clinical and dosimetric parameters to develop an NTCPmodel to estimate the risk of rib fracture in 46 patients (49 tumors) treated with SBRT for early stage NSCLC [23]. The model consisted of the parameters gender, age and D0.5 (minimum absolute dose received by 0.5 cm3). Although the area under the curve of the receiver operator characteristic was high (0.93), caution should be taken because of the small number of patients included in this analysis and the lacking of (both internal and external) validation. Although the different abovementioned dosimetric parameters can guide in treatment planning, dosimetric parameters alone seem less useful in risk estimation for the individual patient. In the light of shared decision making, informing the patient on individual estimated risk of chest wall toxicity after SBRT is increasingly important. Robust multivariable NTCP models developed with sophisticated parameter selection techniques are required for this purpose [30,31], as have already been developed for the prediction of radiation induced toxicity of the rectum [32], the esophagus [33] and oral mucosa [34]. The results from the chest wall toxicity studies are heterogeneous, which may be partially due to differences in toxicity grading (e.g. fracture vs pain). Differences in toxicity grading scales should be avoided. For the evaluation of chest wall toxicity discrimination has to be made between symptomatic and therewith clinically relevant and asymptomatic radiation-induced rib fractures [27]. Furthermore, differences in OAR delineation (automatically vs manually) may also have contributed to the different outcomes. In general, several different delineation guidelines are used in clinical practice [27]. Besides manual delineation [21], the chest wall can be contoured as a 3-three-dimensional expansion of the lung (excluding lung and mediastinal tissue and the anterior vertebral body) [11,13], or the arc of all ipsilateral soft tissue outside of lung tissue from the edge of the sternum circumferentially to the edge of the vertebral body [20]. To improve rib delineation consistency, an automatic segmentation method for ribs has recently been developed and was applied for rib delineation in the study of Stam et al. [14]. It proved accurate and time efficient (reducing delineation time from 2 h to 8 min per patient, for manual and automatic delineation, respectively) [35]. Other new digital radiographic techniques have been developed to evaluate the cortical thickness of the ribs using computed tomography scans and may therefore be useful in future chest wall toxicity studies as well [36]. Preferably, large patient populations are needed for NTCP model development as overfitting is less likely in case there is a substantial number of events of interest [31]. Pooling of data from different departments of radiation oncology may be useful to create such a database [37]. For future work, the abovementioned issues need to be addressed to generate consistent data that can be properly modeled. Moreover, sophisticated statistical evaluation including thorough internal and external validation is mandatory in developing generalizable multivariable NTCP models for chest wall toxicity after SBRT [31,38]. Once such a multivariable NTCP model is externally validated, it may guide both the patient and the clinician in decision making for SBRT. References [1] Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of riskadapted fractionated stereotactic radiotherapy for stage i non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;70:685–92. [2] McCammon R, Schefter TE, Gaspar LE, Zaemisch R, Gravdahl D, Kavanagh B. Observation of a dose-control relationship for lung and liver tumors after stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2009;73:112–8.
[3] Ng AW, Tung SY, Wong VY. Hypofractionated stereotactic radiotherapy for medically inoperable stage i non-small cell lung cancer–report on clinical outcome and dose to critical organs. Radiother Oncol 2008;87:24–8. [4] Rieber J, Streblow J, Uhlmann L, et al. Stereotactic body radiotherapy (sbrt) for medically inoperable lung metastases-a pooled analysis of the german working group ‘‘stereotactic radiotherapy”. Lung cancer 2016;97:51–8. [5] Van den Begin R, Engels B, Boussaer M, et al. Motion management during sbrt for oligometastatic cancer: Results of a prospective phase ii trial. Radiother Oncol 2016;119:519–24. [6] Tanadini-Lang S, Rieber J, Filippi AR, et al. Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastastic lung disease. Radiother Oncol 2017. epub ahead of print. [7] Louie AV, van Werkhoven E, Chen H, et al. Patient reported outcomes following stereotactic ablative radiotherapy or surgery for stage ia non-small-cell lung cancer: results from the rosel multicenter randomized trial. Radiother Oncol 2015;117:44–8. [8] Zimmermann FB, Geinitz H, Schill S, et al. Stereotactic hypofractionated radiotherapy in stage i (t1–2 n0 m0) non-small-cell lung cancer (nsclc). Acta Oncol 2006;45:796–801. [9] Taremi M, Hope A, Dahele M, et al. Stereotactic body radiotherapy for medically inoperable lung cancer: prospective, single-center study of 108 consecutive patients. Int J Radiat Oncol Biol Phys 2012;82:967–73. [10] Baumann P, Nyman J, Lax I, 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. Acta Oncol 2006;45:787–95. [11] Andolino DL, Forquer JA, Henderson MA, et al. Chest wall toxicity after stereotactic body radiotherapy for malignant lesions of the lung and liver. Int J Radiat Oncol Biol Phys 2011;80:692–7. [12] Aoki M, Sato M, Hirose K, et al. Radiation-induced rib fracture after stereotactic body radiotherapy with a total dose of 54–56 gy given in 9–7 fractions for patients with peripheral lung tumor: Impact of maximum dose and fraction size. Radiat Oncol 2015;10:99. [13] Dunlap NE, Cai J, Biedermann GB, et al. Chest wall volume receiving >30 gy predicts risk of severe pain and/or rib fracture after lung stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 2010;76:796–801. [14] Stam B, van der Bijl E, Peulen H, Rossi MM, Belderbos JS, Sonke JJ. Dose-effect analysis of radiation induced rib fractures after thoracic sbrt. Radiother Oncol 2017. [15] Pilz K, Hoffmann AL, Baumann M, Troost EG. Vertebral fractures – an underestimated side-effect in patients treated with radio(chemo)therapy. Radiother Oncol 2016;118:421–3. [16] Uyterlinde W, Chen C, Belderbos J, et al. Fractures of thoracic vertebrae in patients with locally advanced non-small cell lung carcinoma treated with intensity modulated radiotherapy. Radiother Oncol 2016;118:437–41. [17] Otani K, Teshima T, Ito Y, et al. Risk factors for vertebral compression fractures in preoperative chemoradiotherapy with gemcitabine for pancreatic cancer. Radiother Oncol 2016;118:424–9. [18] Wei RL, Jung BC, Manzano W, et al. Bone mineral density loss in thoracic and lumbar vertebrae following radiation for abdominal cancers. Radiother Oncol 2016;118:430–6. [19] Stephans KL, Djemil T, Reddy CA, et al. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage i non-small cell lung cancer: The cleveland clinic experience. J Thorac Oncol 2009;4:976–82. [20] Stephans KL, Djemil T, Tendulkar RD, Robinson CG, Reddy CA, Videtic GM. Prediction of chest wall toxicity from lung stereotactic body radiotherapy (sbrt). Int J Radiat Oncol Biol Phys 2012;82:974–80. [21] Pettersson N, Nyman J, Johansson KA. Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy of non-small cell lung cancer: A dose- and volume-response analysis. Radiother Oncol 2009;91:360–8. [22] Asai K, Shioyama Y, Nakamura K, et al. Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy: Risk factors and dosevolume relationship. Int J Radiat Oncol Biol Phys 2012;84:768–73. [23] Taremi M, Hope A, Lindsay P, et al. Predictors of radiotherapy induced bone injury (ribi) after stereotactic lung radiotherapy. Radiat Oncol 2012;7:159. [24] Welsh J, Thomas J, Shah D, et al. Obesity increases the risk of chest wall pain from thoracic stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2011;81:91–6. [25] Thibault I, Chiang A, Erler D, et al. Predictors of chest wall toxicity after lung stereotactic ablative radiotherapy. Clin Oncol (R Coll Radiol) 2016;28:28–35. [26] Kim SS, Song SY, Kwak J, et al. 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Please cite this article in press as: Wijsman R et al. Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent? Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.010