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Dose Tolerance for Stereotactic Body Radiation Therapy
Volume 26, Number 2
April 2016
Dose Tolerance for Stereotactic Body Radiation Therapy
N
ormal tissue complication probability (NTCP) results were detailed in the July 2001 issue of Seminars in Radiation Oncology1 for conventionally fractionated radiation therapy. After 7 years, an extensive collection of stereotactic ablative body radiotherapy (SABR) or stereotactic body radiation therapy (SBRT) dose-tolerance limits was presented in the October 2008 issue of Seminars in Radiation Oncology,2 but estimates of risk were not yet available. We now have sufficient data to combine the 2: NTCP for SBRT. Physicians need a single parameter to make a clinical decision for each critical structure in the treatment plan. Ideally, this parameter would be directly associated with the expected outcome like NTCP. If every patient's tumor control probability (TCP) was 99% or higher, and if every patient's NTCP was 1% or lower, we would not need surrogate metrics like the conformality index, tumor coverage, and dosetolerance limits. Note that in 3 consecutive sentences, we went from “need” to “ideally” to “if,” and in reality TCP and NTCP are often still uncertain, and are rarely as good as 99% and 1%, so we usually are highly dependent on the surrogate metrics of plan quality. In this issue of Seminars, we focus on both clinical practice and rigorous statistics, spending as little time in the middle as possible. Maximum likelihood parameter fitting and other statistical methods are required to obtain reliable estimates of risk, but the focus of this work is on the clinical utility. Dose-tolerance limits are the stable bridge between clinical practice and rigorous estimation theory. Even as estimates of NTCP are continually updated with every new publication containing toxicity estimates, the same dose-tolerance limits can usually still be maintained, as long as the new estimate of NTCP is not dramatically different than the current expectations. This strategy of a constant dose limit is more stable than attempting to maintain a fixed NTCP limit, as estimates of NTCP continue to evolve in each new study. The selection criteria for data in this issue of Seminars are the complete opposite of the criteria for the American Association of Physicists in Medicine (AAPM) SBRT Working Group (WGSBRT). The WGSBRT manuscripts are named High Dose per Fraction, Hypofractionated Treatment http://dx.doi.org/10.1016/j.semradonc.2015.12.001 1053-4296//& 2016 Elsevier Inc. All rights reserved.
Effects in the Clinic (HyTEC). Many members of WGSBRT were authors of Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC),3 and they used the same primary ground rule: all data must already exist in the peerreviewed literature. In that endeavor for SBRT, however, many anatomical critical structures were found to have too few published dose-response models to evaluate. The selection criteria for this issue of Seminars, therefore, are the complete opposite: each of these articles after the introduction presents new data and dose-response modeling from an institution, for a critical structure that previously did not have many published dose-response models for SBRT, or where an additional new model could supplement the information that had been sparse. We hope that both projects provide enduring value to the field. SBRT and other high dose per fraction techniques have now been in clinical use for more than 20 years4–7 but initially the number of patients was small and it has taken most institutions quite some time to publish long-term statistical outcomes data for normal tissue tolerance. In 2002, the first Radiation Therapy Oncology Group (RTOG) trial for SBRT, RTOG 0236,8 was instituted. This was followed by several other RTOG trials 0618,9 0631,10 0813,11 0915,12 and 1021,13 as well as the European co-operative trials such as CHART14 and ROSEL.15 The statistical outcomes data from these trials and several institutional studies are now emerging. To help navigate this transition from expert opinion to statistical knowledge, the Dose-Volume Histogram (DVH) Risk Map16,17 includes a variety of information to show the state of the literature for each critical structure. For a given dose descriptor, the DVH Risk Map includes a plot of all published dose-tolerance limits in 1-5 fractions. From among those, for each fractionation, the highest commonly used limit is selected as the “high-risk” limit. From the remaining limits below a margin of safety, another limit is selected as the “low-risk” limit. Estimates of the risk level of the dose-tolerance limits are interpolated from statistical analysis of clinical data. For relatively acceptable toxicity like grade 1-3 rib fractures and chest wall pain,17 the high-risk limits have 50% risk and the low-risk limits have 5% risk. The Emami et al18 work used 87
J. Grimm
88 50% and 5% risk levels for all critical structures whereas this effort used clinically acceptable ranges for each: in structures like aorta19 or spinal cord20 where complications must be avoided, the high risk limits are closer to 3% and the low risk limits have about 1% risk in this issue of Seminars. These statistically based guidelines can help clinicians gauge the level of safety for each patient. This issue of Seminars in Radiation Oncology is different from all previous issues, in that each institution's article contains a new clinical dataset that has never before been published, each of which has NTCP for SBRT, and almost all have a DVH Risk Map. Aside from those additional features, the articles still have the high-quality insightful and visionary reviews that you can expect from Seminars throughout the past quarter of a century. Jimm Grimm, PhD Bott Cancer Center, Holy Redeemer Hospital, Meadowbrook, PA
References 1. Ten Haken RK: Introduction. Semin Radiat Oncol 11(3):181-183, 2001 2. Timmerman RD: An overview of hypofractionation and introduction to this issue of seminars in radiation oncology. Semin Radiat Oncol 18:215-222, 2008 3. Marks LB, Ten Haken RK, Martel MK: Guest editor’s introduction to QUANTEC: a users guide. Int J Radiat Oncol Biol Phys 76(3 Suppl): S1-S2, 2010 4. Leksell L: Sterotaxic radiosurgery in trigeminal neuralgia. Acta Chir Scand 137(4):311-314, 1971 5. Lutz W, Winston KR, Maleki N: A system for stereotactic radiosurgery with a linear accelerator. Int J Radiat Oncol Biol Phys 14(2):373-381, 1988 6. Lax I, Blomgren H, Näslund I, et al: Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects. Acta Oncol 33 (6):677-683, 1994 7. Accuray Adler JR, Inc A. Neurosurgical business case study. Cureus 1(9): e1, 2009. http://dx.doi.org/10.7759/cureus.1. 8. Timmerman R, Paulus R, Galvin J, et al: Stereotactic body radiation therapy for inoperable early stage lung cancer. J Am Med Am 303:1070-1076, 2010
9. Timmerman RD, Pass H, Galvin J, et al: A phase II trial of stereotactic body radiation therapy (SBRT) in the treatment of patients with operable stage I/ II non-small cell lung cancer. Radiatation Therapy Oncology Group 0618. Available at: 〈https://www.rtog.org/ClinicalTrials/ProtocolTable.aspx〉. 10. Ryu S, Gerszten P, Yin F, et al: Phase II/III study of image-guided radiosurgery/SBRT for localized spine metastasis. Radiatation Therapy Oncology Group 0631. Available at: 〈https://www.rtog.org/ClinicalTrials/ ProtocolTable.aspx〉. 11. Bezhak A, Bradley J, Gaspar L, et al: Seamless phase I/II study of stereotactic lung radiotherapy (SBRT) for early stage, centrally located, non-small cell lung cancer (NSCLC) in medically inoperable patients. Radiation Therapy Oncology Group 0813. Available at: 〈https://www. rtog.org/ClinicalTrials/ProtocolTable.aspx〉. 12. Videtic G, Singh A, Chang J, et al: A randomized phase II study comparing 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable patients with stage I peripheral non-small cell lung cancer. Radiation Therapy Oncology Group 0915. Available at: 〈https://www.rtog.org/ClinicalTrials/ProtocolTable.aspx〉. 13. Fernando H, Meyers B, Timmerman R, et al: RTOG 1021 A randomized phase III study of sublobar resection (+/ brachytherapy) versus stereotactic body radiation therapy in high risk patients with stage I non-small cell lung cancer (NSCLC). Available at: 〈https://www.rtog.org/ ClinicalTrials/ProtocolTable.aspx〉. 14. Hatton MQ, Hill R, Fenwick JD, et al: Continuous hyperfractionated accelerated radiotherapy-Escalated dose (CHART-ED): A phase I study. Radiother Oncol. 2015. (in press) 15. Louie AV, van Werkhoven E, Chen H, et al: Patient reported outcomes following stereotactic ablative radiotherapy or surgery for stage IA nonsmall-cell lung cancer: Results from the ROSEL multicenter randomized trial. Radiother Oncol. 117(1):44-48, 2015 16. Srivastava R, Asbell SO, LaCouture T, et al: Low toxicity for lung tumors near the mediastinum treated with stereotactic body radiation therapy (SBRT). Pract Radiat Oncol 3(2):130-137, 2013 17. Asbell SO, Grimm J, Xue J, et al: Dose volume histogram (DVH) clinical overview: The DVH Risk Map. Semin Radiat Oncol 26(2): 89-96, 2016 18. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21(1):109-122, 1991 19. Xue J, Kubicek G, Patel A, et al: Validity of current stereotactic body radiation therapy dose constraints for aorta and major vessels. Semin Radiat Oncol 26(2):135-139, 2016 20. Grimm J, Sahgal A, Soltys SG, et al: Estimated risk level of unified stereotactic body radiation therapy dose tolerance limits for spinal cord. Semin Radiat Oncol 26(2):165-171, 2016
April 2016
Dose Tolerance for Stereotactic Body Radiation Therapy
N
ormal tissue complication probability (NTCP) results were detailed in the July 2001 issue of Seminars in Radiation Oncology1 for conventionally fractionated radiation therapy. After 7 years, an extensive collection of stereotactic ablative body radiotherapy (SABR) or stereotactic body radiation therapy (SBRT) dose-tolerance limits was presented in the October 2008 issue of Seminars in Radiation Oncology,2 but estimates of risk were not yet available. We now have sufficient data to combine the 2: NTCP for SBRT. Physicians need a single parameter to make a clinical decision for each critical structure in the treatment plan. Ideally, this parameter would be directly associated with the expected outcome like NTCP. If every patient's tumor control probability (TCP) was 99% or higher, and if every patient's NTCP was 1% or lower, we would not need surrogate metrics like the conformality index, tumor coverage, and dosetolerance limits. Note that in 3 consecutive sentences, we went from “need” to “ideally” to “if,” and in reality TCP and NTCP are often still uncertain, and are rarely as good as 99% and 1%, so we usually are highly dependent on the surrogate metrics of plan quality. In this issue of Seminars, we focus on both clinical practice and rigorous statistics, spending as little time in the middle as possible. Maximum likelihood parameter fitting and other statistical methods are required to obtain reliable estimates of risk, but the focus of this work is on the clinical utility. Dose-tolerance limits are the stable bridge between clinical practice and rigorous estimation theory. Even as estimates of NTCP are continually updated with every new publication containing toxicity estimates, the same dose-tolerance limits can usually still be maintained, as long as the new estimate of NTCP is not dramatically different than the current expectations. This strategy of a constant dose limit is more stable than attempting to maintain a fixed NTCP limit, as estimates of NTCP continue to evolve in each new study. The selection criteria for data in this issue of Seminars are the complete opposite of the criteria for the American Association of Physicists in Medicine (AAPM) SBRT Working Group (WGSBRT). The WGSBRT manuscripts are named High Dose per Fraction, Hypofractionated Treatment http://dx.doi.org/10.1016/j.semradonc.2015.12.001 1053-4296//& 2016 Elsevier Inc. All rights reserved.
Effects in the Clinic (HyTEC). Many members of WGSBRT were authors of Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC),3 and they used the same primary ground rule: all data must already exist in the peerreviewed literature. In that endeavor for SBRT, however, many anatomical critical structures were found to have too few published dose-response models to evaluate. The selection criteria for this issue of Seminars, therefore, are the complete opposite: each of these articles after the introduction presents new data and dose-response modeling from an institution, for a critical structure that previously did not have many published dose-response models for SBRT, or where an additional new model could supplement the information that had been sparse. We hope that both projects provide enduring value to the field. SBRT and other high dose per fraction techniques have now been in clinical use for more than 20 years4–7 but initially the number of patients was small and it has taken most institutions quite some time to publish long-term statistical outcomes data for normal tissue tolerance. In 2002, the first Radiation Therapy Oncology Group (RTOG) trial for SBRT, RTOG 0236,8 was instituted. This was followed by several other RTOG trials 0618,9 0631,10 0813,11 0915,12 and 1021,13 as well as the European co-operative trials such as CHART14 and ROSEL.15 The statistical outcomes data from these trials and several institutional studies are now emerging. To help navigate this transition from expert opinion to statistical knowledge, the Dose-Volume Histogram (DVH) Risk Map16,17 includes a variety of information to show the state of the literature for each critical structure. For a given dose descriptor, the DVH Risk Map includes a plot of all published dose-tolerance limits in 1-5 fractions. From among those, for each fractionation, the highest commonly used limit is selected as the “high-risk” limit. From the remaining limits below a margin of safety, another limit is selected as the “low-risk” limit. Estimates of the risk level of the dose-tolerance limits are interpolated from statistical analysis of clinical data. For relatively acceptable toxicity like grade 1-3 rib fractures and chest wall pain,17 the high-risk limits have 50% risk and the low-risk limits have 5% risk. The Emami et al18 work used 87
J. Grimm
88 50% and 5% risk levels for all critical structures whereas this effort used clinically acceptable ranges for each: in structures like aorta19 or spinal cord20 where complications must be avoided, the high risk limits are closer to 3% and the low risk limits have about 1% risk in this issue of Seminars. These statistically based guidelines can help clinicians gauge the level of safety for each patient. This issue of Seminars in Radiation Oncology is different from all previous issues, in that each institution's article contains a new clinical dataset that has never before been published, each of which has NTCP for SBRT, and almost all have a DVH Risk Map. Aside from those additional features, the articles still have the high-quality insightful and visionary reviews that you can expect from Seminars throughout the past quarter of a century. Jimm Grimm, PhD Bott Cancer Center, Holy Redeemer Hospital, Meadowbrook, PA
References 1. Ten Haken RK: Introduction. Semin Radiat Oncol 11(3):181-183, 2001 2. Timmerman RD: An overview of hypofractionation and introduction to this issue of seminars in radiation oncology. Semin Radiat Oncol 18:215-222, 2008 3. Marks LB, Ten Haken RK, Martel MK: Guest editor’s introduction to QUANTEC: a users guide. Int J Radiat Oncol Biol Phys 76(3 Suppl): S1-S2, 2010 4. Leksell L: Sterotaxic radiosurgery in trigeminal neuralgia. Acta Chir Scand 137(4):311-314, 1971 5. Lutz W, Winston KR, Maleki N: A system for stereotactic radiosurgery with a linear accelerator. Int J Radiat Oncol Biol Phys 14(2):373-381, 1988 6. Lax I, Blomgren H, Näslund I, et al: Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects. Acta Oncol 33 (6):677-683, 1994 7. Accuray Adler JR, Inc A. Neurosurgical business case study. Cureus 1(9): e1, 2009. http://dx.doi.org/10.7759/cureus.1. 8. Timmerman R, Paulus R, Galvin J, et al: Stereotactic body radiation therapy for inoperable early stage lung cancer. J Am Med Am 303:1070-1076, 2010
9. Timmerman RD, Pass H, Galvin J, et al: A phase II trial of stereotactic body radiation therapy (SBRT) in the treatment of patients with operable stage I/ II non-small cell lung cancer. Radiatation Therapy Oncology Group 0618. Available at: 〈https://www.rtog.org/ClinicalTrials/ProtocolTable.aspx〉. 10. Ryu S, Gerszten P, Yin F, et al: Phase II/III study of image-guided radiosurgery/SBRT for localized spine metastasis. Radiatation Therapy Oncology Group 0631. Available at: 〈https://www.rtog.org/ClinicalTrials/ ProtocolTable.aspx〉. 11. Bezhak A, Bradley J, Gaspar L, et al: Seamless phase I/II study of stereotactic lung radiotherapy (SBRT) for early stage, centrally located, non-small cell lung cancer (NSCLC) in medically inoperable patients. Radiation Therapy Oncology Group 0813. Available at: 〈https://www. rtog.org/ClinicalTrials/ProtocolTable.aspx〉. 12. Videtic G, Singh A, Chang J, et al: A randomized phase II study comparing 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable patients with stage I peripheral non-small cell lung cancer. Radiation Therapy Oncology Group 0915. Available at: 〈https://www.rtog.org/ClinicalTrials/ProtocolTable.aspx〉. 13. Fernando H, Meyers B, Timmerman R, et al: RTOG 1021 A randomized phase III study of sublobar resection (+/ brachytherapy) versus stereotactic body radiation therapy in high risk patients with stage I non-small cell lung cancer (NSCLC). Available at: 〈https://www.rtog.org/ ClinicalTrials/ProtocolTable.aspx〉. 14. Hatton MQ, Hill R, Fenwick JD, et al: Continuous hyperfractionated accelerated radiotherapy-Escalated dose (CHART-ED): A phase I study. Radiother Oncol. 2015. (in press) 15. Louie AV, van Werkhoven E, Chen H, et al: Patient reported outcomes following stereotactic ablative radiotherapy or surgery for stage IA nonsmall-cell lung cancer: Results from the ROSEL multicenter randomized trial. Radiother Oncol. 117(1):44-48, 2015 16. Srivastava R, Asbell SO, LaCouture T, et al: Low toxicity for lung tumors near the mediastinum treated with stereotactic body radiation therapy (SBRT). Pract Radiat Oncol 3(2):130-137, 2013 17. Asbell SO, Grimm J, Xue J, et al: Dose volume histogram (DVH) clinical overview: The DVH Risk Map. Semin Radiat Oncol 26(2): 89-96, 2016 18. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21(1):109-122, 1991 19. Xue J, Kubicek G, Patel A, et al: Validity of current stereotactic body radiation therapy dose constraints for aorta and major vessels. Semin Radiat Oncol 26(2):135-139, 2016 20. Grimm J, Sahgal A, Soltys SG, et al: Estimated risk level of unified stereotactic body radiation therapy dose tolerance limits for spinal cord. Semin Radiat Oncol 26(2):165-171, 2016