Cited by 1,826Advanced Radiotherapy TechniquesRadiation Therapy and DosimetryEffects of Radiation Exposure

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Use of Normal Tissue Complication Probability Models in the Clinic

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Marks, Lawrence B., Yorke, Ellen D., Jackson, Andrew, Ten Haken, Randall K., Constine, Louis S., Eisbruch, Avraham, Bentzen, Søren M., Nam, Jiho, Deasy, Joseph O.·2010·International Journal of Radiation Oncology*Biology*Physics

DOI 10.1016/j.ijrobp.2009.07.1754PMC PMC4041542

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Abstract

The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) review summarizes the currently available three-dimensional dose/volume/outcome data to update and refine the normal tissue dose/volume tolerance guidelines provided by the classic Emami et al. paper published in 1991. A "clinician's view" on using the QUANTEC information in a responsible manner is presented along with a description of the most commonly used normal tissue complication probability (NTCP) models. A summary of organ-specific dose/volume/outcome data, based on the QUANTEC reviews, is included.

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Tolerance of normal tissue to therapeutic irradiation
Emami, B., Lyman, J., Brown, A., Cola, L., Goitein, M., Munzenrider, J. E., Shank, B., Solin, L. J., & Wesson, M. (1991) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(91)90171-y · Cited by 4,488
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Fitting of normal tissue tolerance data to an analytic function
Burman, C. M., Kutcher, G. J., Emami, B., & Goitein, M. (1991) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(91)90172-z · Cited by 1,251
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Niemierko, A. (1997) · Medical Physics · doi:10.1118/1.598063 · Cited by 1,231
Clinical dose–volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC)
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Lyman, J. T. (1985) · Radiation Research · doi:10.2307/3576626 · Cited by 1,160
Histogram reduction method for calculating complication probabilities for three-dimensional treatment planning evaluations
Kutcher, G. J., Burman, C. M., Brewster, L. J., Goitein, M., & Mohan, R. (1991) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(91)90173-2 · Cited by 560
Complication Probability as Assessed from Dose-Volume Histograms
Lyman, J. T. (1985) · Radiation Research Supplement · doi:10.2307/3583506 · Cited by 537
The Linear-Quadratic Model Is Inappropriate to Model High Dose per Fraction Effects in Radiosurgery
Kirkpatrick, J. P., Meyer, J. J., & Marks, L. B. (2008) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2008.04.005 · Cited by 519
Self-citation
Treatment volume and tissue tolerance
Withers, H. R., Taylor, J. M. G., & Maciejewski, B. (1988) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(88)90098-3 · Cited by 446

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Background
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“2 Gy (RBE) in the respective brain area, maximum constraints for brain tissue [17] were not adhered to in the current evaluation.”
BackgroundMethod
Stereotactic body radiotherapy in patients with multiple lung tumors: a focus on lung dosimetric constraints
Milano, M. T., Mihai, A., Kang, J., Singh, D. P., Verma, V., Qiu, H., Chen, Y., & Kong, F. (2019) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2019.1686980 · Cited by 8
“dimensional data [38,39] – perhaps by necessity as the human brain is generally not well equipped to analyze quan-”
Background
Comparison and Evaluation of Different Radiotherapy Techniques Using Biodosimetry Based on Cytogenetics
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“For all plans, organs at risk (OARs) constraints followed the recommendations of QUANTEC [21] for prostate radiotherapy.”
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Zakem, S., Jones, B. L., Castillo, R., Castillo, E. M., Miften, M. M., Goodman, K. A., Schefter, T. E., Olsen, J. R., & Vinogradskiy, Y. Y. (2022) · Journal of Applied Clinical Medical Physics · doi:10.1002/acm2.13552 · Cited by 8
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de Oliveira, T. B., Fontes, D. M. N., Montella, T. C., Lewgoy, J., Dutra, C., & Miola, T. M. (2023) · Current Oncology · doi:10.3390/curroncol31010012 · Cited by 8
“34 Gy in 3D-radiotherapy was estimated to result in a 5–20% incidence of grade ≥ 3 esophagitis [85].”
Background
Towards Personalized Radiotherapy in Pelvic Cancer: Patient-Related Risk Factors for Late Radiation Toxicity
Nuijens, A. C., Oei, A. L., Franken, N. A. P., Rasch, C. R. N., & Stalpers, L. J. A. (2025) · Current Oncology · doi:10.3390/curroncol32010047 · Cited by 10
“Comprehensive and renowned reviews are available on radiation dose–volume effects [39–43].”
Proton Radiotherapy for Midline Central Nervous System Lesions: A Class Solution
Estabrook, N. C., McDonald, M. W., Hoene, T. A., Bartlett, G. K., Johnstone, P. A. S., McMullen, K. P., & Buchsbaum, J. C. (2015) · Oncology · doi:10.1159/000377727 · Cited by 8
Empirical estimation of beam-on time for prostate cancer patients treated on Tomotherapy
Skórska, M., & Piotrowski, T. (2013) · Reports of Practical Oncology & Radiotherapy · doi:10.1016/j.rpor.2012.12.005 · Cited by 8
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Dosimetric quantification of the incidental irradiation of the ‘true’ (deep) ano-inguinal lymphatic drainage of anal cancer patients not described in conventional contouring guidelines
Dapper, H., Habl, G., Hirche, C. R., Münch, S., Oechsner, M., Mayinger, M. C., Sauter, C., Combs, S. E., & Habermehl, D. (2018) · Acta Oncologica · doi:10.1080/0284186x.2017.1415459 · Cited by 8
“Dose constraints for organs at risk (OAR) (rectum, sigmoid, small bowel, femoral head left and right, penis/scrotum or vagina/vulva, skin of AILD, urinary bladder) orientated on Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) [16].”
Background
Statistical motion modelling for robust evaluation of clinically delivered accumulated dose distributions after curative radiotherapy of locally advanced prostate cancer
Hysing, L. B., Ekanger, C., Zolnay, A. G., Helle, S. I., Rasi, M., Heijmen, B. J. M., Sikora, M., Söhn, M., Muren, L. P., & Thörnqvist, S. (2018) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2018.06.004 · Cited by 8
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Yoder, A. K., Gunther, J. R., Milgrom, S. A., Mirković, D., Nastoupil, L. J., Neelapu, S. S., Fanale, M. A., Fowler, N. H., Westin, J. R., Lee, H. J., et al. (2018) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2018.09.002 · Cited by 8
“For all patients, dose constraints were easily achieved for the liver and bilateral kidneys [37].”
Background
Dosimetric comparison of different radiation techniques (IMRT vs. 3-dimensional) of the “true” (deep) ano-inguinal lymphatic drainage of anal cancer patients
Dapper, H., Oechsner, M., Hirche, C. R., Münch, S., Sauter, C., Borm, K. J., Peeken, J. C., Combs, S. E., & Habermehl, D. (2018) · Radiation Oncology · doi:10.1186/s13014-018-1174-z · Cited by 8
“Dose constraints for organs at risk (OAR) (rectum, sigmoid, small bowel, femoral head left & right, penis/scrotum or vagina/vulva, skin of AILD, urinary bladder) orientated on Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) [21].”
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Morshed, R. A., Wu, S. Y., Sneed, P. K., & McDermott, M. W. (2019) · Journal of Neuro-Oncology · doi:10.1007/s11060-019-03202-2 · Cited by 8
Dose–volume analysis of acute gastrointestinal complications in cervical cancer undergoing definitive concurrent chemoradiation
Kumar, A., Tudu, R., Singh, R. K., & Raina, P. (2020) · Journal of Cancer Research and Therapeutics · doi:10.4103/jcrt.jcrt_313_19 · Cited by 8
GOECP/SEOR radiotherapy guidelines for small-cell lung cancer
Couñago, F., de la Pinta, C., Gonzalo, S., Fernández, C., Almendros, P., Calvo, P., Taboada, B., Gómez‐Caamaño, A., Guerra, J. L. L., Chust, M., et al. (2021) · World Journal of Clinical Oncology · doi:10.5306/wjco.v12.i3.115 · Cited by 8
Change in dysphagia and laryngeal function after radical radiotherapy in laryngo pharyngeal malignancies — a prospective observational study
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“Constraints for OARs were largely based on Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) and standard institutional protocols [13].”
BackgroundMethod
Reasonable Timing of Radiotherapy for Stage IV Non-Small-Cell Lung Cancer During Targeted Therapy Based on Tumour Volume Change
Li, Q., Liang, N., Zhang, X., Zhang, Y., Ouyang, W., Su, S., Ma, Z., Hu, Y., Geng, Y., Chen, X., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.705303 · Cited by 8
“The simulated radiotherapy plan and its parameters represent the dose likely to control the primary tumour and the threshold to protect normal tissues from radiation injury (34, 35), while the implementation radiotherapy plan and its parameters validate and summarize the efficacy for each individual tumour and the pro…”
Background
Investigation of optimum minimum segment width on VMAT plan quality and deliverability: A comprehensive dosimetric and clinical evaluation using DVH analysis
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Retrospective Study on Left-Sided Breast Radiotherapy: Dosimetric Results and Correlation with Physical Factors for Free Breathing and Breath Hold Irradiation Techniques
Xin, X., Li, J., Zhao, Y., Wang, P., Tang, B., Yao, X., Liao, X., Ma, J., & Orlandini, L. C. (2021) · Technology in Cancer Research & Treatment · doi:10.1177/15330338211062429 · Cited by 8
Urological Cancers and Kidney Transplantation: a Literature Review
Hernández-Gaytán, C. A., Rodríguez‐Covarrubias, F., Castillejos-Molina, R., Hernández-Porras, A., Tobia, I. P., Dubin, J. M., & Autrán-Gómez, A. M. (2021) · Current Urology Reports · doi:10.1007/s11934-021-01078-2 · Cited by 8
“However, there are still concerns about nephritis and strictures, complications described with this modality [41].”
Background
Head and Neck Radiation Therapy Patterns of Practice Variability Identified as a Challenge to Real-World Big Data: Results From the Learning from Analysis of Multicentre Big Data Aggregation (LAMBDA) Consortium
Caissie, A. L., Mierzwa, M. L., Fuller, C. D., Rajaraman, M. M., Lin, A., MacDonald, A., Popple, R. A., Xiao, Y., van Dijk, L. V., Balter, P. A., et al. (2022) · Advances in Radiation Oncology · doi:10.1016/j.adro.2022.100925 · Cited by 8
“Large-scale, multi-institutional dosimetric data could be highly valuable for clinical assessment of treatment plan quality and for modeling associations with toxic effects from treatment.(9-36) As the first of its kind to assess head and neck (H&N) RT “big data,” we have formed the Learning from Analysis of Multicent…”
Background
Dosimetric and clinical predictors of radiation-induced lung toxicity in esophageal carcinoma
Zhu, S., Shen, W., Liu, Z., Li, J., Su, J., & Wang, Y. (2011) · Tumori Journal · doi:10.1177/030089161109700510 · Cited by 8
Feasibility Study of Stereotactic Radiosurgery Treatment of Glomus Jugulare Tumors via HyperArc VMAT
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Self-citation
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“This violates the heart constraint proposed by Marks et al.(24) of V30Gy ≤ 10%.”
Method
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Yu, J. I., Park, H. C., Oh, D., Noh, J. M., Jung, S. H., Kim, H. Y., Shin, S. W., Cho, S. K., Sinn, D. H., Paik, Y., et al. (2016) · International Journal of Hyperthermia · doi:10.3109/02656736.2016.1144895 · Cited by 8
“Though the RT dose prescribed in this study was not high according to quantitative analysis of normal tissue effects in the clinic (QUANTEC) [32], confirming the safety of CERT was informative because liver function and gastroduodenal integrity are commonly limited in HCC patients with cirrhosis.”
Method
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Kuo, L., Yorke, E. D., Dumane, V. A., Foster, A., Zhang, Z., Mechalakos, J., Wu, A. J.-C., Rosenzweig, K. E., & Rimner, A. (2016) · Journal of Applied Clinical Medical Physics · doi:10.1120/jacmp.v17i3.6199 · Cited by 8
Self-citation
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“In accordance with the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) data, the mean EQD2 for esophagus, heart and lung must be <34 Gy, <26 Gy and ≤7 Gy, respectively [9].”
Method
Integration of radiobiological modeling and indices in comparative plan evaluation: A study comparing VMAT and 3D-CRT in patients with NSCLC
Roy, S., Badragan, I., Ahmed, S. N., Sia, M. A., Singh, J., & Bahl, G. (2018) · Practical Radiation Oncology · doi:10.1016/j.prro.2018.02.012 · Cited by 8
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“as tissue composed of functional units arranged in parallel architecture, which is shown by an n value close to 1 [32].”
Background
Assessment and quantification of patient set-up errors in nasopharyngeal cancer patients and their biological and dosimetric impact in terms of generalized equivalent uniform dose (gEUD), tumour control probability (TCP) and normal tissue complication probability (NTCP)
Boughalia, A., Marcié, S., Fellah, M., Chami, S., & Mekki, F. (2015) · British Journal of Radiology · doi:10.1259/bjr.20140839 · Cited by 8
Volume effects in radiosurgical spinal cord dose tolerance: how small is too small?
Ma, T. M., Emami, B., Grimm, J., Xue, J., Asbell, S. O., Kubicek, G. J., Lanciano, R. M., Welsh, J. S., Peng, L. C., Gui, C., et al. (2019) · Journal of Radiation Oncology · doi:10.1007/s13566-018-0371-6 · Cited by 8
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Multimodal assessment of acute cardiac toxicity induced by thoracic radiotherapy in cancer patients. Study protocol
Merino, T., Pinto, M. P., Paz, O. M., Martínez, G., Andía, M. E., Muñoz-Schuffenegger, P., Francisco Acevedo, C., Gabrielli, L., Sanchez, C. G., & Pereira, J. I. (2021) · BMC Cancer · doi:10.1186/s12885-021-08823-3 · Cited by 7
A Comprehensive Primer on Radiation Oncology for Non-Radiation Oncologists
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“These dose constraints were empirically defined [76] and summarized in the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reports [77].”
Background
Radiation toxicity grading after chemoradiotherapy of canine urinary tract carcinomas: Comparing VRTOG to VRTOG_v2.0
Ahrens, C., Beatrice, L., Meier, V., & Bley, C. R. (2024) · Veterinary and Comparative Oncology · doi:10.1111/vco.12973 · Cited by 7
The relationship between thyroid dose and diagnosis of primary hypothyroidism in pediatric brain tumor patients receiving craniospinal irradiation
Lauro, C. F., Macy, M. E., Zeitler, P. S., Backus, J., Mettler, P., Foreman, N. K., & Liu, A. K. (2013) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2013-0063 · Cited by 7
“Presently, a normal tissue complication probability (NTCP) model for radiation-induced primary hypothyroidism does not exist (12).”
Background
Uncertainty quantification and data fusion based on Dempster-Shafer theory
He, Y. (2013) · DigiNole (Florida State University) · Cited by 7

Authors: Marks, L. B., Yorke, E. D., Jackson, A., Ten Haken, R. K., Constine, L. S., Eisbruch, A., Bentzen, S. M., Nam, J., & Deasy, J. O.
Affiliations: University of North Carolina at Chapel Hill (US)
Memorial Sloan Kettering Cancer Center (US)
University of Rochester Medicine (US)
University of Michigan (US)
University of Wisconsin–Madison (US)
Washington University in St. Louis (US)
Corresponding author: Marks, Lawrence B.
ORCID: Marks, Lawrence B.
Yorke, Ellen D.
Jackson, Andrew
Constine, Louis S.
Eisbruch, Avraham
Bentzen, Søren M.
Nam, Jiho
Deasy, Joseph O.
Venue: International Journal of Radiation Oncology*Biology*Physics
Publisher: Elsevier BV
Published: 2010-03
Volume: 76
Issue: 3
Pages: S10-S19
ISSN: 0360-3016 (ISSN-L)
DOI: 10.1016/j.ijrobp.2009.07.1754
PMC: PMC4041542
OpenAlex: W2046701188
Cited by: 1,826
References: 30
Citations by year: 2026: 92 · 2025: 110 · 2024: 125 · 2023: 132 · 2022: 130 · 2021: 160 · 2020: 138 · 2019: 146 · 2018: 164 · 2017: 122 · 2016: 108 · 2015: 102 · 2014: 112 · 2013: 87 · 2012: 55
FWCI: 56.07
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: International Journal of Radiation Oncology*Biology*Physics (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Lance Armstrong Foundation
Armstrong Foundation
National Institutes of Health
National Cancer Institute (CA69579, R29CA069579, R29CA085181, R01CA069579, R01CA129182, R01CA085181, CA85181)
Topics: Physical Sciences › Physics and Astronomy › Radiation › Advanced Radiotherapy Techniques
Physical Sciences › Physics and Astronomy › Radiation › Radiation Therapy and Dosimetry
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Keywords: normal tissue complication probability, QUANTEC, normal tissue tolerance, NTCP models
MeSH terms: Adult, Child, Dose-Response Relationship, Radiation, Humans, Models, Biological, Organ Specificity, Radiation Injuries, Radiation Tolerance, Models, Statistical, Practice Guidelines as Topic, Radiation Oncology, Dose Fractionation, Radiation

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Use of Normal Tissue Complication Probability Models in the Clinic

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