Dose tolerance limits and dose volume histogram evaluation for stereotactic body radiotherapy

Jimm Grimm, Tamara LaCouture, Raymond Croce, Inhwan Yeo, Yunping Zhu, Jinyu Xue, Jimm Grimm, Tamara LaCouture, Raymond Croce, Inhwan Yeo, Yunping Zhu, Jinyu Xue

Abstract

Almost 20 years ago, Emami et al. presented a comprehensive set of dose tolerance limits for normal tissue organs to therapeutic radiation, which has proven essential to the field of radiation oncology. The paradigm of stereotactic body radiotherapy (SBRT) has dramatically different dosing schemes but, to date, there has still been no comprehensive set of SBRT normal organ dose tolerance limits. As an initial step toward that goal, we performed an extensive review of the literature to compare dose limits utilized and reported in existing publications. The impact on dose tolerance limits of some key aspects of the methods and materials of the various authors is discussed. We have organized a table of 500 dose tolerance limits of normal structures for SBRT. We still observed several dose limits that are unknown or not validated. Data for SBRT dose tolerance limits are still preliminary and further clinical trials and validation are required. This manuscript presents an extensive collection of normal organ dose tolerance limits to facilitate both clinical application and further research.

References

    1. Papiez L, Timmerman R. Hypofractionation in radiation therapy and its impact. Med Phys 2008;35(1):112–18.
    1. Barnett GH, Linskey ME, Adler JR, et al. Stereotactic radiosurgery – an organized neurosurgery‐sanctioned definition. J Neurosurg. 2007;106(1):1–5.
    1. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic radiation. Int J Radiat Oncol Biol Phys. 1991;21(1):109–122.
    1. Carey Sampson M, Katz A, Constine LS. Stereotactic body radiation therapy for extracranial oligometastases: does the sword have a double edge? Semin Radiat Oncol. 2006;16(2):67–76.
    1. Elia A, Shih H, Lloeffler J. Stereotactic radiation treatment for benign meningiomas. Neurosurg Focus. 2007;23(4):E5.
    1. Chang BK, Timmerman RD. Stereotacticbody tadiation therapy: a comprehensive review. J Clin Oncol. 2007;30(6):637–44.
    1. Sahgal A, Larson D, Chang E. Stereotactic body radiosurgery for spinal metastases: a critical review. Int J Radiat Oncol Biol Phys. 2008;71(3):652–65.
    1. Timmerman RD. An overview of hypofractionation and introduction to this issue of seminars in radiation oncology. Semin Radiat Oncol. 2008;18(4):215–22.
    1. Barendsen GW. Dose fractionation, dose rate and iso‐effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys. 1982;8(11):1981–97.
    1. Dale RG. The application of the linear‐quadratic dose effect equation to fractionated and protracted radiotherapy. Br J Radiol. 1985;58(690):515–28.
    1. Douglas BG, Fowler JF. Fractionation schedules and a quadratic dose‐effect relationship [Letter]. Br J Radiol. 1975;48(570):502–04.
    1. Ellis F. Dose time and fractionation. A clinical hypothesis. Clin Radiol. 1969;20(1):1–7.
    1. Withers HR, Thames HD, Peters LJ. A new isoeffect curve for change in dose per fraction. Radiother Oncol. 1983;1(2):187–91.
    1. Barton M. Tables of equivalent dose in 2 Gy fractions: a simple application of the linear quadratic formula. Int J Radiat Oncol Biol Phys. 1995;31(2):371–78.
    1. Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1980;6(1):1–9.
    1. National Cancer Institute . Common Terminology Criteria for Adverse Events, version 3.0. 2006.
    1. Leber KA, Bergloff J, Pendl G. Dose‐response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg. 1998;88(1):43–50.
    1. Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;58(4):1017–21.
    1. Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy and single‐fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2008;72(3):678–86.
    1. Rahimian J, Chen JC, Rao AA, Girvigian MR, Miller MJ, Greathouse HE. Geometrical accuracy of the Novalis stereotactic radiosurgery system for trigeminal neuralgia. J Neurosurg. 2004;101 Suppl 3:351–55.
    1. Solberg TD, Goetsch SJ, Selch MT, Melega W, Lacan G, DeSalles AA. Functional stereotactic radiosurgery involving a dedicated linear accelerator and gamma unit: a comparison study. J Neurosurg. 2004;101 Suppl 3:373–80.
    1. Grimm J, Grimm S, Das I, et al. A quality assurance method with submillimeter accuracy for stereotactic linear accelerators. J Appl Clin Med Phys. 2011. [In press]
    1. Hoppe BS, Laser B, Kowalski AV, et al. Acute skin toxicity following stereotactic body radiation therapy for stage I non‐small‐cell lung cancer: who's at risk? Int J Radiat Oncol Biol Phys. 2008;72(5):1283–86.
    1. Rhu S, Gerszten P, Yin F, et al. Phase II/III study of image‐guided radiosurgery/SBRT for localized spine metastasis. Radiation Therapy Oncology Group 0631. Accessed at
    1. 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 from:
    1. Molinelli S, de Pooter J, Méndez Romero A, et al. Simultaneous tumour dose escalation and liver sparing in Stereotactic Body Radiation Therapy (SBRT) for liver tumours due to CTV‐to‐PTV margin reduction. Radiother Oncol. 2008;87(3):432–38.
    1. Roth J, Chang J, Komaki R, Kresl J. International randomized study to compare CyberKnifeR stereotactic radiotherapy with surgical resection in stage I non‐small cell lung cancer (STARS). Accessed at
    1. Chang J, Balter P, Dong L, et al. Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non–small‐cell lung cancer. Int J Radiat Oncol Biol Phys. 2008;72(4):967–71.
    1. Takayama K, Nagata Y, Negoro Y, et al. Treatment planning of stereotactic radiotherapy for solitary lung tumor. Int J Radiat Oncol Biol Phys. 2005;61(5):1565–71.
    1. Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys. 2005;63(5):1427–31.
    1. 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. Accessed at
    1. Loeffler JS, Siddon RL, Wen PY, Nedzi LA, Alexander E 3rd. Stereotactic radiosurgery of the brain using a standard linear accelerator: a study of early and late effects. Radiother Oncol. 1990;17(4):311–21.
    1. Alexander E 3rd, Siddon RL, Loeffler JS. The acute onset of nausea and vomiting following stereotactic radiosurgery: correlation with total dose to area postrema. Surg Neurol. 1989;32(1):40–44.
    1. Gerszten PC, Ozhasoglu C, Burton SA, et al. CyberKnife frameless single‐fraction stereotactic radiosurgery for tumors of the sacrum. Neurosurg Focus. 2003;15(2):E7.
    1. Hsu IC, Shinohara K, Pouliot J, et al. Phase II trial of combined high dose rate brachytherapy and external beam radiotherapy for adenocarcinoma of the prostate. Radiation Therapy Oncology Group 0321. Accessed at
    1. Greven KM, Corn BW, Burke TW. A phase II study of adjuvant postoperative irradiation combined with cisplatin/taxolchemotherapy following TAH/BSO for patients with high‐risk endometrial cancer. Radiation Therapy Oncology Group 9708. Available from:
    1. Fuller DB, Lee C. CyberKnife radiosurgery for low & intermediate risk prostate cancer: emulating HDR brachytherapy dosimetry. 2008. Available from:
    1. Fuller DB, Naitoh J, Lee C, Hardy S, Jin H. Virtual HDR CyberKnife treatment for localized prostatic carcinoma: dosimetry comparison with HDR brachytherapy and preliminary clinical observations. Int J Radiat Oncol Biol Phys. 2008;70(5):1588–97.
    1. Mould RF, Schulz RA, Bucholz RD, et al. Robotic radiosurgery ‐ Volume 1. Sunnyvale, CA: Cyberknife Society Press; 2005.
    1. Freidland J, Kaplan I, Meier R, et al. Prostate Cancer CyberKnife Consortium‐PC3 A Multi‐institutional Phase I Feasibilty Study. 2007. Accessed at
    1. Meier R, Kaplan I, Sanda M. CyberKnife radiosurgery for organ‐confined prostate cancer: homogenous dose distribution. 2008. Accessed at
    1. Small M, Levenback C, Iyer R, Hymes SR. A two‐part phase I/II study of extended field external irradiation and intracavitary brachytherapy combined with chemotherapy (weekly cisplatin–arm 1) and amifostine (weekly cisplatin and amifostine‐arm 2) in carcinoma of the cervix with positive para‐aortic or high common iliac lymph nodes. Radiation Therapy Oncology Group 0116. Available from:
    1. Kwon JS, Schefter T, Stuhr K, et al. A phase II study of bevacizumab in combination with definitive radiotherapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma. Radiation Therapy Oncology Group 0417. Accessed at
    1. Gaffney DK, Dicker AP, Miller B. A phase I/II study of cox‐2 inhibitor, Celebrex™ (Celecoxib), and chemoradiation in patients with locally advanced cervical cancer. Radiation Therapy Oncology Group 0118. Accessed at
    1. Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi‐institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol. 2009;27(10):1579–84.
    1. 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. 2009. May 8. [Epub ahead of print]
    1. 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(3):360–68.
    1. Dawson LA, Eccles C, Craig T. Individualized image guided iso‐NTCP based liver cancer SBRT. Acta Oncol. 2006;45(7):856–64.
    1. Heron DE, Ferris RL, Karamouzis M, et al. Stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: results of a phase I dose‐escalation trial. Int J Radiat Oncol Biol Phys. 2009. 1;75(5):1493–500.
    1. Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer. 2009;115(3):665–72.
    1. Choi BO, Choi IB, Jang HS, et al. Stereotactic body radiation therapy with or without transarterial chemoembolization for patients with primary hepatocellular carcinoma: preliminary analysis. BMC Cancer. 2008;8:351.
    1. Takeda A, Kunieda E, Sanuki N, et al. Dose distribution analysis in stereotactic body radiotherapy using dynamic conformal multiple arc therapy. Int J Radiat Oncol Biol Phys. 2009;74(2):363–69.
    1. Urschel HC, Kresl JJ, Luketich JD, Timmerman RD, eds. Treating tumors that move with respiration. Berline: Springer‐Verlag; 2007.
    1. Méndez Romero A, Wunderink W, Hussain SM, et al. Stereotactic body radiation therapy for primary and metastatic liver tumors: a single institution phase I‐II study. Acta Oncol. 2006;45(7):831–37.
    1. Wulf J, Hädinger U, Oppitz U, Thiele W, Ness‐Dourdoumas R, Flentje M. Stereotactic radiotherapy of targets in the lung and liver. Strahlenther Onkol. 2001;177(12):645–55.
    1. Wulf J, Guckenberger M, Haedinger U, et al. Stereotactic radiotherapy of primary liver cancer and hepatic metastases. Acta Oncol. 2006;45(7):838–47.
    1. Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2008;26(4):657–64.
    1. Martinez AA, Pataki I, Edmundson G, Sebastian E, Brabbins D, Gustafson G. Phase II prospective study of the use of conformal high‐dose‐rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: A feasibility report. Int J Radiat Oncol Biol Phys. 2001;49(1):61–69.
    1. King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC Jr. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int J Radiat Oncol Biol Phys. 2008. Aug 26. [Epub ahead of print]
    1. Herfarth KK, Debus J, Lohr F, et al. Stereotactic single‐dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol. 2001;19(1):164–70.
    1. Baisden JM, Reish AG, Sheng K, Larner JM, Kavanagh BD, Read PW. Dose as a function of liver volume and planning target volume in helical tomotherapy, intensity‐modulated radiation therapy‐based stereotactic body radiation therapy for hepatic metastasis. Int J Radiat Oncol Biol Phys. 2006;66(2):620–25.
    1. Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE. A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J Radiat Oncol Biol Phys. 2005;62(5):1371–78.
    1. Kavanagh BD, Schefter TE, Cardenes HR, et al. Interim analysis of a prospective phase I/II trial of SBRT for liver metastases. Acta Oncol. 2006;45(7):848–55.
    1. 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. Radiation Therapy Oncology Group 0618. Available from:
    1. Sinha B, McGarry RC. Stereotactic body radiotherapy for bilateral primary lung cancers: the Indiana University experience. Int J Radiat Oncol Biol Phys. 2006;66(4):1120–24.
    1. Gomez DR, Hunt MA, Jackson A, et al. Low rate of thoracic toxicity in palliative paraspinal single‐fraction stereotactic body radiation therapy. Radiother Oncol. 2009;93(3):414–18.
    1. Wulf J, Haedinger U, Oppitz U, Thiele W, Mueller G, Flentje M. Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients. Int J Radiat Oncol Biol Phys. 2004;60(1):186–96.
    1. Koto M, Takai Y, Ogawa Y, et al. A phase II study on stereotactic body radiotherapy for stage I non‐small cell lung cancer. Radiother Oncol. 2007;85(3):429–34.
    1. Uno T, Aruga T, Isobe K, et al. Radiation bronchitis in lung cancer patient treated with stereotactic radiation therapy. Radiat Med. 2003;21(5):228–31.
    1. Gerszten PC, Burton SA, Welch WC, et al. Single‐fraction radiosurgery for the treatment of spinal breast metastases. Cancer. 2005;104(10):2244–54.
    1. Yamada Y, Bilsky MH, Lovelock DM, et al. High‐dose, single‐fraction image‐guided intensity‐modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys. 2008;71(2):484–90.
    1. Lee M, Kalani Y, Cheshier S, Gibbs IC, Adler JR, Chang SD. Radiation therapy and CyberKnife radiosurgery in the management of craniopharyngiomas. Neurosurg Focus. 2008;24(5):E4.
    1. Stafford SL, Pollock BE, Leavitt JA, et al. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2003;55(5):1177–81.
    1. Iwai Y, Yamanaka K, Yoshioka K. Radiosurgery for nonfunctioning pituitary adenomas. Neurosurgery. 2005;56(4):699–705.
    1. Romanelli P, Muacevic A, Striano S. Radiosurgery for hypothalamic hamartomas. Neurosurg Focus. 2008;24(5):E9.
    1. Tishler RB, Loeffler JS, Lunsford LD, et al. Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys. 1993;27(2):215–21.
    1. Adler JR Jr, Gibbs IC, Puataweepong P, Chang SD. Visual field preservation after multisession cyberknife radiosurgery for perioptic lesions. Neurosurgery. 2006;59(2):244–54.
    1. Pham CJ, Chang SD, Gibbs IC, Jones P, Heilbrun MP, Adler JR Jr. Preliminary visual field preservation after staged CyberKnife radiosurgery for perioptic lesions. Neurosurgery. 2004;54(4):799–810.
    1. Muacevic A, Nentwich M, Wowra B, Staerk S, Kampik A, Schaller U. Development of a streamlined, non‐invasive robotic radiosurgery method for treatment of uveal melanoma. Technol Cancer Res Treat. 2008;7(15):369–74.
    1. Gerszten PC, Ozhasoglu C, Burton SA, et al. CyberKnife frameless single‐fraction stereotactic radiosurgery for benign tumors of the spine. Neurosurg Focus. 2003;14(5):E16.
    1. Borst GR, Ishikawa M, Nijkamp J, et al. Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy. Radiother Oncol. 2009;91(3):307–13.
    1. Friedman W, Buatti J, Bova F, Mendenhall W. Linac radiosurgery: a practical guide. New York: Springer‐Verlag; 1998.
    1. Mehta VK, Lee QT, Chang SD, Cherney S, Adler JR Jr. Image guided stereotactic radiosurgery for lesions in proximity to the anterior visual pathways: a preliminary report. Technol Cancer Res Treat. 2002;1(3):173–80.
    1. Romanelli P, Wowra B, Muacevic A. Multisession CyberKnife radiosurgery for optic nerve sheath meningiomas. Neurosurg Focus. 2007;23(6):E11.
    1. Ryu S, Jin JY, Jin R, et al. Partial volume tolerance of the spinal cord and complications of single‐dose radiosurgery. Cancer. 2007;109(3):628–36.
    1. Sahgal A, Ma L, Gibbs I, et al. Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2009. Sep 16. [Epub ahead of print]
    1. Gerszten PC, Burton SA, Ozhasoglu C, McCue KJ, Quinn AE. Radiosurgery for benign intradural spinal tumors. Neurosurgery. 2008;62(4):887–95; discussion 895–96.
    1. Gibbs IC, Kamnerdsupaphon P, Ryu MR, et al. Image‐guided robotic radiosurgery for spinal metastases. Radiother Oncol. 2007;82(2):185–90.
    1. Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine. 2007;7(2):151–60.
    1. Dodd RL, Ryu MR, Kamnerdsupaphon P, Gibbs IC, Chang SD Jr, Adler JR Jr. CyberKnife radiosurgery for benign intradural extramedullary spinal tumors. Neurosurgery. 2006;58(4):674–85; discussion 674–85.
    1. Gerszten PC, Ozhasoglu C, Burton SA, et al. CyberKnife frameless stereotactic radiosurgery for spinal lesions: clinical experience in 125 cases. Neurosurgery. 2004;55(1):89–98.
    1. Porceddu SV, Rosser B, Burmeister BH, et al. Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment–“Hypo Trial”. Radiother Oncol. 2007;85(3):456–62.
    1. Yamada Y, Lovelock DM, Yenice KM, et al. Multifractionated image‐guided and stereotactic intensity‐modulated radiotherapy of paraspinal tumors: a preliminary report. Int J Radiat Oncol Biol Phys. 2005;62(1):53–61.
    1. Chang E, Shiu AS, Lii MF, et al. Phase I clinical evaluation of near‐simultaneous computed tomographic image‐guided stereotactic body radiotherapy for spinal metastases. Int J Radiat Oncol Biol Phys. 2004;59(5):1288–94.
    1. Shiu AS, Chang EL, Ye JS, et al. Near simultaneous computed tomography image‐guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol Biol Phys. 2003;57(3):605–13.

Source: PubMed

3
Tilaa