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Pediatric Normal Tissue Effects in the Clinic (PENTEC): An International Collaboration to Assess Normal Tissue Radiation Dose-Volume-Response Relationships for Children With Cancer

2021; Elsevier BV; Volume: 119; Issue: 2 Linguagem: Inglês

10.1016/j.ijrobp.2020.10.040

1879-355X

Louis S. Constine, Arthur J. Olch, Andrew Jackson, Chia‐Ho Hua, Cécile M. Ronckers, Michael T. Milano, Karen J. Marcus, Ellen Yorke, David C. Hodgson, Rebecca M. Howell, Melissa M. Hudson, Jacqueline P. Williams, Brian Marples, Leontien C.M. Kremer, Lawrence B. Marks, Søren M. Bentzen,

Acute Lymphoblastic Leukemia research

"Every child begins the world again."—Henry David Thoreau This issue of the International Journal of Radiation Oncology, Biology, Physics includes reports from Pediatric Normal Tissue Effects in the Clinic (PENTEC),1Constine L.S. Ronckers C.M. Hua C.H. et al.Pediatric normal tissue effects in the clinic (PENTEC): An international collaboration to analyse normal tissue radiation dose-volume response relationships for paediatric cancer patients.Clin Oncol (R Coll Radiol). 2019; 31: 199-207Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar offspring of Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) and a sibling of Hy-Dose per Fraction, Hypofractionated Treatment Effects in the Clinic (HyTEC). This labor of love was born of a compassion for children with cancer and striving to cure them, with resolute recognition that their potential for long lives might be compromised by normal tissue damage and subsequent malignancies. Childhood cancer affects some 360,000 patients annually; 54% are in Asia and 28% are in Africa.2Johnston W.T. Erdmann F. Newton R. et al.Childhood cancer: Estimating regional and global incidence.Cancer Epidemiol. 2020; 101662PubMed Google Scholar With advances in multimodality therapy, the cure rates of childhood cancer approach 80%. However, the gap in life expectancy between survivors with cancer diagnosed in the 1990s and age-matched controls without cancer is still estimated at 9 years.3Fung A. Horton S. Zabih V. et al.Cost and cost-effectiveness of childhood cancer treatment in low-income and middle-income countries: A systematic review.BMJ Glob Health. 2019; 4e001825Crossref PubMed Scopus (9) Google Scholar,4Howlader N. Noone A.M. Krapcho M. et al.Seer cancer statistics review. National Cancer Institute, Bethesda, MD1975-2017https://seer.Cancer.Gov/csr/1975_2017/Date accessed: September 9, 2020Google Scholar The debilitating and sometimes fatal late adverse events of therapy responsible (at least in part) for this gap are critical to understand, mitigate, and prevent. Ionizing radiation is unique among the currently available anticancer agents because the dose can be carefully titrated and modulated in space and time. There is a strong relationship between both time-dose-fractionation and the spatial distribution of dose on the incidence of adverse events. QUANTEC summarized radiation dose/volume/outcome data for normal tissues among patients undergoing treatment for cancer as adults and identified associated uncertainties. The art of antiquity often depicted children as small versions of adults; similarly, suppositions regarding their toxicities from radiation were often derived from studies of adults. However, as outcomes for children with cancer have improved, we have discovered that their vulnerability to damage from therapy is often far greater than adults. Determining the relationship between the spatiotemporal distribution of dose and the toxicity profiles is further complicated for children because of the mosaic of tissues developing at different rates and temporal sequences.5Krasin M.J. Constine L.S. Friedman D.L. et al.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: 21-29Crossref PubMed Scopus (41) Google Scholar,6Paulino A.C. Constine L.S. Rubin P. et al.Normal tissue development, homeostasis, senescence, and the sensitivity to radiation injury across the age spectrum.Semin Radiat Oncol. 2010; 20: 12-20Crossref PubMed Scopus (37) Google Scholar In adults, we have attempted to identify the inherent structures that are critical to each organ's function, and we classified the component cells according to an overarching view of their radiation response (eg, stem vs progenitor vs terminally differentiated). Nonetheless, the radiation injury of an "adult" organ that leads to a normal tissue effect is, basically, a disruption in homeostasis, with the major contributing factors being volume and age—assessed on a sliding scale of functional reserve. However, in pediatric patients, additional factors affect the radiobiologic effects on normal tissues, including the contribution and extent of a proliferating compartment (that will vary according to the stage of maturation) and the developmental stage (eg, of brain maturation, cardiac hypertrophy, presence of bone growth spurts, gonadal evolution or involution). Normal tissue damage after radiation therapy varies across the age spectrum, but critical to children is that the sensitivity to radiation injury directly relates to the developmental dynamics and maturational status of each organ, its regenerative potential, and ultimately the extent to which it has begun to senesce—processes whose timelines vary between organs and also somewhat between patients. The late Dr Giulio J. D'Angio, a pioneering pediatric radiation oncologist, introduced study designs to investigate the adverse effects in children treated for cancer.7Breslow N.E. Norkool P.A. Olshan A. et al.Second malignant neoplasms in survivors of Wilms' tumor: A report from the National Wilms' Tumor Study.J Natl Cancer Inst. 1988; 80: 592-595Crossref PubMed Scopus (59) Google Scholar The work of his group and others demonstrates the severity of the problem. In the North American Childhood Cancer Survivor Study, the 30-year cumulative mortality for 5-year survivors was approximately 18%; those who received radiation therapy had a more than 2-fold increased risk of mortality versus those not receiving radiation, in large part because of different disease constellations affecting the need to incorporate radiation in their therapy.8Armstrong G.T. Liu Q. Yasui Y. et al.Late mortality among 5-year survivors of childhood cancer: A summary from the childhood cancer survivor study.J Clin Oncol. 2009; 27: 2328-2338Crossref PubMed Scopus (458) Google Scholar Overall, 60% to 90% of survivors of childhood cancer will develop one or more chronic health conditions, and 20% to 80% will experience severe or life-threatening complications from treatment.9Geenen M.M. Cardous-Ubbink M.C. Kremer L.C. et al.Medical assessment of adverse health outcomes in long-term survivors of childhood cancer.JAMA. 2007; 297: 2705-2715Crossref PubMed Scopus (565) Google Scholar, 10Hudson M.M. Ness K.K. Gurney J.G. et al.Clinical ascertainment of health outcomes among adults treated for childhood cancer.JAMA. 2013; 309: 2371-2381Crossref PubMed Scopus (632) Google Scholar, 11Bhakta N. Liu Q. Ness K.K. et al.The cumulative burden of surviving childhood cancer: An initial report from the St Jude Lifetime Cohort Study (SJLIFE).Lancet. 2017; 390: 2569-2582Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar Collaborative long-term observational studies and clinical research programs for survivors of pediatric and adolescent cancer provide adverse event data for follow-up periods exceeding 40 years, during which therapy has changed.10Hudson M.M. Ness K.K. Gurney J.G. et al.Clinical ascertainment of health outcomes among adults treated for childhood cancer.JAMA. 2013; 309: 2371-2381Crossref PubMed Scopus (632) Google Scholar, 11Bhakta N. Liu Q. Ness K.K. et al.The cumulative burden of surviving childhood cancer: An initial report from the St Jude Lifetime Cohort Study (SJLIFE).Lancet. 2017; 390: 2569-2582Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 12Armstrong G.T. Chen Y. Yasui Y. et al.Reduction in late mortality among 5-year survivors of childhood cancer.N Engl J Med. 2016; 374: 833-842Crossref PubMed Scopus (284) Google Scholar, 13Gibson T.M. Mostoufi-Moab S. Stratton K.L. et al.Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: A report from the childhood cancer survivor study cohort.Lancet Oncol. 2018; 19: 1590-1601Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 14Teepen J.C. van Leeuwen F.E. Tissing W.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: 2288-2298Crossref PubMed Scopus (82) Google Scholar Data analysis is challenging, however, because of the interaction between developmental and therapeutic variables and a paucity of radiation dose-volume data.15Journy N. Mansouri I. Allodji R.S. et al.Volume effects of radiotherapy on the risk of second primary cancers: A systematic review of clinical and epidemiological studies.Radiother Oncol. 2019; 131: 150-159Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar In addition, most childhood malignancies are managed with combined modality therapy, and the confounding effects of other concurrent or sequential therapies adds to the degrees of freedom from a modeling perspective. PENTEC seeks to provide a systematic overview of published radiation dose-effect data for late-occurring adverse effects in survivors of childhood cancer and, where possible, to synthesize and analyze normal tissue radiation dose/volume/outcome data and to assess the impact of chemotherapy and other risk factors (eg, genetic predispositions).1Constine L.S. Ronckers C.M. Hua C.H. et al.Pediatric normal tissue effects in the clinic (PENTEC): An international collaboration to analyse normal tissue radiation dose-volume response relationships for paediatric cancer patients.Clin Oncol (R Coll Radiol). 2019; 31: 199-207Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar One obstacle is the lack of uniform reporting standards for toxicity of therapy for childhood cancer. The quality of reporting in the literature is highly variable; even in the more complete reports, the absence of a consensus on what and how to report dose-volume-age response data often precludes a direct comparison of reports and makes a statistical synthesis of pooled data impossible. We are a volunteer research collaboration of more than 150 physicians (radiation and pediatric oncologists, subspecialists), medical physicists, mathematical modelers, and epidemiologists organized into 18 organ-specific task forces conducting critical reviews and synthesis of quantitative data from existing studies aiming to1.Establish quantitative, evidence-based dose/volume/outcome data to inform radiation treatment planning and, in turn, to improve outcomes after radiation therapy for childhood cancers.2.Estimate the quantitative effect of the most relevant risk factors for treatment-related toxicity (eg, developmental status, concurrent or sequential therapies).3.Describe specific physics and dosimetric issues relevant to pediatric radiation therapy.4.Propose dose/volume/outcome reporting standards for future studies.5.Define future research priorities. The organ-specific reports will appear electronically as they become available and ultimately as a compilation in a special supplement to this journal. The goal is to provide clinicians and scientists with an overview of dose/volume/outcome associations relevant to their treatment decisions, identify knowledge gaps, and make recommendations to facilitate future investigations. Mirroring the QUANTEC issue of this journal,16Bentzen S.M. Constine L.S. Deasy J.O. 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: S3-9Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar PENTEC will comprise 3 types of reports:1.A series of introductory reports that discuss biodevelopmental underpinnings for the genesis of radiation toxicities, mathematical modeling and epidemiologic considerations, and medical physics issues specific to radiation therapy treatment planning and delivery in children.2.Reports from the 18 organ-specific task forces that represent the heart and soul of the issue. The breadth of reports and the content of each is described in Figure 1. Each report explores challenges defining target organs, scoring organ-specific toxicities, risk factors for toxicities, and summarizes dose/volume/outcome data and associated evidence-based dose constraints for specific toxicities. Knowledge gaps and recommendations for future investigations are highlighted.3.A series of reports describing our vision for improving the future of this dynamic field by highlighting deficiencies in the quality and scope of available systematic data and recommendations to enhance data gathering, reporting, and analysis. We recognize that empirical data are, by definition, historical, and much of the data available for these reports are based on relatively primitive radiation therapy technologies compared with contemporary capabilities (owing to the long latent periods of many of the effects analyzed by PENTEC). However, most survivors of childhood cancer underwent treatment with these radiation techniques and, from a global perspective, many patients are still treated with similar techniques. Moreover, we must understand the past to predict the future. Arriving at reasonably accurate estimates of dose to various critical normal tissues can be challenging, especially without 3-dimensional treatment planning and with dose estimates based on hand calculations, single reference points, and assumed uniform tissue density. Dose estimates for tissues located out of field or in the penumbral regions (as is often the case for the gonads or lens) are especially inaccurate. Evolving changes in practice that affect the dose/volume distributions and might affect the dose/volume/outcome relationships challenge the applicability of this work to more-modern techniques.17Newhauser W.D. Berrington de Gonzalez A. Schulte R. et al.A review of radiotherapy-induced late effects research after advanced technology treatments.Front Oncol. 2016; 6: 13Crossref PubMed Scopus (44) Google Scholar For example, intensity modulated radiation therapy often results in a low-dose exposure to large volumes of tissue, raising the possibility of increased toxicities such as secondary malignancies. Similarly, emerging data from proton or light-ion therapy suggest that simple extrapolation from one radiation modality to another may not be valid. Hypofractionated radiation therapy schedules and new systemic agents such as immunobiologics might also alter the toxicity profile. Our evolving ability to better identify patient-specific genetic predispositions and to modify therapy accordingly will also affect outcomes. Pediatric cancer is a broad spectrum of complex diseases, all with their own biology and natural history. The optimal and creative integration of radiation therapy into management requires a sophisticated understanding of each disease and the specific adverse consequences of treatment. Importantly, attempts to limit risk from radiation will need to be considered carefully in the context of delivering adequate therapeutic radiation doses to cure the cancer. We recognize the limitations of available radiation toxicity data and predictive models, and it is only through more systematic data gathering and continued study that specific morbidities and patterns will be identified and interventions for treatment and prevention can be designed. The PENTEC investigators are gratified to play a role in refining and enhancing the use of radiation therapy in safely and effectively treating pediatric malignancy, and we dedicate our efforts to all future children who will be affected by this malady. We are inspired by and indebted to many pioneers in this field, including Guilio D'Angio, Sarah Donaldson, J. Robert Cassady, Bahman Emami, Edward Halperin, and Philip Rubin, who cured children with cancer, recognized the consequential therapeutic injuries, and sought to define and mitigate them. We are also thankful for the support of the American Society of Radiation Oncology, the American Association of Physicists in Medicine, our home institutions that have directly or indirectly supported this effort, and the leaders and staff at the International Journal of Radiation Oncology, Biology, Physics for working collaboratively and patiently with us on this project. The steering committee has been privileged to collaborate with talented clinicians and scientists from all over the world. In this year of tragedy, uncertainty, and fear, the collaborators of this project have risen to the occasion and persevered in their work. E-mailing published data to our colleagues in isolation during the COVID-19 crisis, and receiving from them analyses of this data, has been a humbling experience. We hope that this body of data provides valuable practical treatment planning guidance and provokes future investigators to further explore, dissect, and explain the adverse normal tissue outcomes that result from our therapies, which no doubt will be considered primitive in future decades. We pause to recognize those children who succumbed to cancer and to express gratitude to those fortunate to have survived while retaining a childlike enthusiasm for living despite the burden of malignancy. This PENTEC initiative was made possible, in part, by logistic support from the American Association of Physicists in Medicine. This special supplement to the International Journal of Radiation Oncology, Biology, Physics was supported by ASTRO. Above all else, we are indebted to the large corps of volunteer physicians and scientists who donated their time and skills to this effort (www.pentecradiation.org).