Pediatric Normal Tissue Effects in the Clinic (PENTEC): An International Collaboration to Analyse Normal Tissue Radiation Dose–Volume Response Relationships for Paediatric Cancer Patients

Published:January 19, 2019DOI:


      • Radiotherapy for paediatric cancer can cause long-term adverse normal tissue effects.
      • Radiation damage depends on the radiation dose and volume, and developmental status.
      • For some organs, chemotherapy can exacerbate the effects of radiation.
      • PENTEC seeks to increase knowledge about paediatric radiotherapy dose constraints for organs.
      • Radiation dosimetric data should be precisely reported in paediatric radiotherapy studies.


      With advances in multimodality therapy, childhood cancer cure rates approach 80%. However, both radiotherapy and chemotherapy can cause debilitating or even fatal late adverse events that are critical to understand, mitigate or prevent. QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) identified radiation dose constraints for normal tissues in adults and pointed out the uncertainties in those constraints. The range of adverse events seen in children is different from that in adults, in part due to the vulnerability/characteristics of radiation damage to developing tissues, and in part due to the typical body sites affected by childhood cancer that lead to collateral irradiation of somewhat different normal tissues and organs compared with adults. Many childhood cancer survivors have a long life expectancy and may develop treatment-induced secondary cancers and severe organ/tissue injury 10, 20 or more years after treatment. Collaborative long-term observational studies and clinical research programmes for survivors of paediatric and adolescent cancer provide adverse event data for follow-up periods exceeding 40 years. Data analysis is challenging due to the interaction between therapeutic and developmental variables, the lack of radiation dose–volume data and the fact that most childhood malignancies are managed with combined modality therapy. PENTEC (Pediatric Normal Tissue Effects in the Clinic) is a volunteer research collaboration of more than 150 physicians, medical physicists, mathematical modellers and epidemiologists organised into 18 organ-specific working groups conducting a critical review and synthesis of quantitative data from existing studies aiming to: (1) establish quantitative, evidence-based dose/volume/risk guidelines to inform radiation treatment planning and, in turn, improve outcomes after radiation therapy for childhood cancers; (2) explore the most relevant risk factors for toxicity, including developmental status; (3) describe specific physics and dosimetric issues relevant to paediatric radiotherapy; and (4) propose dose–volume outcome reporting standards for publications on childhood cancer therapy outcomes. The impact of other critical modifiers of normal tissue radiation damage, including chemotherapy, surgery, stem cell transplantation and underlying genetic predispositions are also considered. The aims of the PENTEC reports are to provide clinicians with an analysis of the best available data to make informed decisions regarding radiation therapy normal organ dose constraints for planning childhood cancer treatment, and to define future research priorities.

      Key words

      To read this article in full you will need to make a payment


      Subscribe to Clinical Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bentzen S.M.
        Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology.
        Nat Rev Cancer. 2006; 6: 702-713
        • Krasin M.J.
        • Constine L.S.
        • Friedman D.L.
        • Marks L.B.
        Radiation-related treatment effects across the age spectrum: differences and similarities or what the old and young can learn from each other.
        Semin Radiat Oncol. 2010; 20: 21-29
        • Paulino A.C.
        • Constine L.S.
        • Rubin P.
        • Williams J.P.
        Normal tissue development, homeostasis, senescence, and the sensitivity to radiation injury across the age spectrum.
        Semin Radiat Oncol. 2010; 20: 12-20
        • Oeffinger K.C.
        • Mertens A.C.
        • Sklar C.A.
        • Kawashima T.
        • Hudson M.M.
        • Meadows A.T.
        • et al.
        Chronic health conditions in adult survivors of childhood cancer.
        N Engl J Med. 2006; 355: 1572-1582
        • Armstrong G.T.
        • Liu Q.
        • Yasui Y.
        • Neglia J.P.
        • Leisenring W.
        • Robison L.L.
        • et al.
        Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study.
        J Clin Oncol. 2009; 27: 2328-2338
        • Geenen M.M.
        • Cardous-Ubbink M.C.
        • Kremer L.C.
        • van den Bos C.
        • van der Pal H.J.
        • Heinen R.C.
        • et al.
        Medical assessment of adverse health outcomes in long-term survivors of childhood cancer.
        JAMA. 2007; 297: 2705-2715
        • Hudson M.M.
        • Ness K.K.
        • Gurney J.G.
        • Mulrooney D.A.
        • Chemaitilly W.
        • Krull K.R.
        • et al.
        Clinical ascertainment of health outcomes among adults treated for childhood cancer.
        JAMA. 2013; 309: 2371-2381
        • Bhakta N.
        • Liu Q.
        • Ness K.K.
        • Baassiri M.
        • Eissa H.
        • Yeo F.
        • et al.
        The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE).
        Lancet. 2017; 390: 2569-2582
        • Cohen L.
        • Creditor M.
        Iso-effect tables for tolerance of irradiated normal human tissues.
        Int J Radiat Oncol Biol Phys. 1983; 9: 233-241
        • Stovall M.
        • Weathers R.
        • Kasper C.
        • Smith S.A.
        • Travis L.
        • Ron E.
        • et al.
        Dose reconstruction for therapeutic and diagnostic radiation exposures: use in epidemiological studies.
        Radiat Res. 2006; 166: 141-157
        • Lee C.
        • Jung J.W.
        • Pelletier C.
        • Pyakuryal A.
        • Lamart S.
        • Kim J.O.
        • et al.
        Reconstruction of organ dose for external radiotherapy patients in retrospective epidemiologic studies.
        Phys Med Biol. 2015; 60: 2309-2324
        • Sigurdson A.J.
        • Ronckers C.M.
        • Mertens A.C.
        • Stovall M.
        • Smith S.A.
        • Liu Y.
        • et al.
        Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case–control study.
        Lancet. 2005; 365: 2014-2023
        • Newhauser W.D.
        • Berrington de Gonzalez A.
        • Schulte R.
        • Lee C.
        A review of radiotherapy-induced late effects research after advanced technology treatments.
        Front Oncol. 2016; 6: 13
        • Hawkins M.M.
        • Wilson L.M.
        • Burton H.S.
        • Potok M.H.
        • Winter D.L.
        • Marsden H.B.
        • et al.
        Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer.
        J Natl Cancer Inst. 1996; 88: 270-278
        • Boice Jr., J.D.
        • Blettner M.
        • Kleinerman R.A.
        • Stovall M.
        • Moloney W.C.
        • Engholm G.
        • et al.
        Radiation dose and leukemia risk in patients treated for cancer of the cervix.
        J Natl Cancer Inst. 1987; 79: 1295-1311
        • Breslow N.E.
        • Norkool P.A.
        • Olshan A.
        • Evans A.
        • D'Angio G.J.
        Second malignant neoplasms in survivors of Wilms' tumor: a report from the National Wilms' Tumor Study.
        J Natl Cancer Inst. 1988; 80: 592-595
        • Stovall M.
        • Donaldson S.S.
        • Weathers R.E.
        • Robison L.L.
        • Mertens A.C.
        • Winther J.F.
        • et al.
        Genetic effects of radiotherapy for childhood cancer: gonadal dose reconstruction.
        Int J Radiat Oncol Biol Phys. 2004; 60: 542-552
        • Alziar I.
        • Bonniaud G.
        • Couanet D.
        • Ruaud J.B.
        • Vicente C.
        • Giordana G.
        • et al.
        Individual radiation therapy patient whole-body phantoms for peripheral dose evaluations: method and specific software.
        Phys Med Biol. 2009; 54: N375-N383
        • Bentzen S.M.
        • Tucker S.L.
        Quantifying the position and steepness of radiation dose-response curves.
        Int J Radiat Biol. 1997; 71: 531-542
        • Bentzen S.M.
        • Thames H.D.
        • Travis E.L.
        • Ang K.K.
        • Van der Schueren E.
        • Dewit L.
        • et al.
        Direct estimation of latent time for radiation injury in late-responding normal tissues: gut, lung, and spinal cord.
        Int J Radiat Biol. 1989; 55: 27-43
        • Tucker S.L.
        • Dong L.
        • Bosch W.R.
        • Michalski J.
        • Winter K.
        • Mohan R.
        • et al.
        Late rectal toxicity on RTOG 94-06: analysis using a mixture Lyman model.
        Int J Radiat Oncol Biol Phys. 2010; 78: 1253-1260
        • Yasui Y.
        • Liu Y.
        • Neglia J.P.
        • Friedman D.L.
        • Bhatia S.
        • Meadows A.T.
        • et al.
        A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancers.
        Am J Epidemiol. 2003; 158: 1108-1113
        • Silber J.H.
        • Littman P.S.
        • Meadows A.T.
        Stature loss following skeletal irradiation for childhood cancer.
        J Clin Oncol. 1990; 8: 304-312
        • Merchant T.E.
        • Kiehna E.N.
        • Li C.
        • Shukla H.
        • Sengupta S.
        • Xiong X.
        • et al.
        Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma.
        Int J Radiat Oncol Biol Phys. 2006; 65: 210-221
        • Wallace W.H.
        • Thomson A.B.
        • Saran F.
        • Kelsey T.W.
        Predicting age of ovarian failure after radiation to a field that includes the ovaries.
        Int J Radiat Oncol Biol Phys. 2005; 62: 738-744
        • Teepen J.C.
        • van Leeuwen F.E.
        • Tissing W.J.
        • van Dulmen-den Broeder E.
        • van den Heuvel-Eibrink M.M.
        • van der Pal H.J.
        • et al.
        Long-term risk of subsequent malignant neoplasms after treatment of childhood cancer in the DCOG LATER study cohort: role of chemotherapy.
        J Clin Oncol. 2017; 35: 2288-2298
        • Bentzen S.M.
        • Constine L.S.
        • Deasy J.O.
        • Eisbruch A.
        • Jackson A.
        • Marks L.B.
        • et al.
        Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues.
        Int J Radiat Oncol Biol Phys. 2010; 76: S3-S9
      1. Cochrane childhood cancer. Available at:

        • Kremer L.C.
        • Mulder R.L.
        • Oeffinger K.C.
        • Bhatia S.
        • Landier W.
        • Levitt G.
        • et al.
        A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
        Pediatr Blood Cancer. 2013; 60: 543-549