Louis S. Constine

Improving normal tissue complication probability models: the need to adopt a "data-pooling" culture.

Clinical studies of the dependence of normal tissue response on dose-volume factors are often confusingly inconsistent, as the QUANTEC reviews demonstrate. A key opportunity to accelerate progress is to begin storing high-quality datasets in repositories. Using available technology, multiple repositories could be conveniently queried, without divulging protected health information, to identify relevant sources of data for further analysis. After obtaining institutional approvals, data could then be pooled, greatly enhancing the capability to construct predictive models that are more widely applicable and better powered to accurately identify key predictive factors (whether dosimetric, image-based, clinical, socioeconomic, or biological). Data pooling has already been carried out effectively in a few normal tissue complication probability studies and should become a common strategy.

SP-0171: Pediatric Normal Tissue Effects in the Clinic (PENTEC): An international collaboration

Elevation of tissue response markers after radiotherapy may occur in patients classified using clinical scoring as ‘non responders’ suggesting that the difference in cell and molecular phenotype between ‘responders’ and ‘non responders’ is not understood and that there may in fact be a spectrum of subclinical changes at the tissue level across the two groups. Identification of biomarkers used as simple biological endpoints of normal tissue toxicity may therefore be useful in the following settings: 1) A tool for scoring or characterisation of established late normal tissue effects which could be used in conjunction with clinical score. 2) To assess response to therapy. 3) To improve classification between ‘responders’ and ‘non responders’ in terms of radiotherapy toxicity. 4) As response markers, involved mechanistically in the radiation response, to improve understanding underlying molecular pathology or phenotype.

RELATING THREE DIMENSIONAL DOSE/VOLUME DATA TO CLINICAL OUTCOMES: AN OVERVIEW OF THE QUANTEC EFFORT

Historically, RT fields/doses were selected based on clinical experience and intuition. Clinicians generally recognized the imprecision of these empiric guidelines, as they did not reflect the underlying three-dimensional anatomy, physiology, and dosimetry. A great promise afforded by 3D imaging was an improved quantitative relationship between 3D doses/volumes and outcomes. When 3D dosimetric information became more widely available (late 80s-early 90s), 3D guidelines were needed.

WE‐E‐BRA‐02: Methodological Issues and Key Results in the QUANTEC 2010 Review of Radiation‐Induced Normal Tissue Toxicity

The QUANTEC review of radiation‐induced normal tissue toxicity provides an attempt to synthesize published knowledge about normal tissue dose volume effects for many endpoints of clinical importance. In this review, I will briefly review the methods used by the QUANTEC group, limitations of the data, and some of the key findings. The QUANTEC reviews, although valuable, were constrained by several important limitations, for example: lack of access to the original data for joint analyses, differences in reporting methods, differences in dose calculation methods, differences in endpoint definitions, differences in endpoint measurement methods, etc. Despite these problems, some clinical recommendations have already been tested in separate data sets and shown to have validity. The solidity of the underlying data and clinical recommendations therefore necessarily varies. I will also briefly discuss recommended future directions to improve NTCP model predictions, including biomarker development, machine learning modeling, and pooled data analyses. Educational goals include: 1. Understanding the main methods and structure of the QUANTEC reviews 2. Understanding the variability of the review results 3. Reviewing the main results, and caveats regarding their clinical use.

WE‐E‐BRA‐03: Therapy Symposium: A Clinicianˈs View of Quantec

Historically, RT fields/doses were selected based on clinical experience and intuition. Clinicians generally recognized the imprecision of these empiric guidelines, as they did not reflect the underlying three‐dimensional anatomy,physiology, and dosimetry. A great promise afforded by 3D imaging was an improved quantitative relationship between 3D doses/volumes and outcomes. When 3D dosimetric information became more widely available (late 80s‐early 90s), 3D guidelines were needed. In 1991, multiple investigators pooled the available, albeit sometimes limited, information regarding leading to the often‐quoted “Emami paper” (IJROBP 1991). During the last 20 years, additional 3D dose/volume/outcome data has become available. A central goal of QUANTEC is to summarize this information in a clinically useful manner. For each organ, the literature providing meaningful dose/volume/outcome data is reviewed. Clinical/treatment variables that may impact the application of the data is discussed. Where available, NTCP‐model parameters are provided. We hope this information will improve patient care by providing clinicians and treatment planners with the tools necessary to determine the “optimal” 3D dose distribution for each individual case. Nevertheless, the information provided herein is not ideal, and care must be taken to apply it correctly. Unfortunately, the data are incomplete for essentially almost every organ. The user must recognize the limitations inherent in extracting/pooling literature data. For some complications, some studies summarize their findings in terms of models that can be used to estimate risk. Extreme care should be taken when such models are applied clinically, especially when clinical dose/volume parameters are beyond the range used to generate the model. Models that rely on DVH data discard all spatial information (and hence inherently assume that all regions of an organ are functionally equally important), and often do not consider variations in fraction size (a particular concern with the increasing use of hypo‐fractionated schedules). Similarly, the increasing use of RT combined with concurrent chemotherapy, with rapidly evolving drugs/doses, questions the validity of historic data to modern times. For essentially all patients with curative cancers, a marginal miss is a more serious complication than is a normal tissue injury. Care must be taken not to compromise target coverage to reduce the normal tissue risks. A clinical balance is needed. Further, palliation in patients with recurrent/metastatic/incurable disease, with limited expected survival, often requires one to exceed “tolerances”, as concern for late effects may not be applicable (e.g. RT fields for locally advanced lungcancer may include large volumes of lung and heart and withholding RT due to the risk of pericarditis, or pneumonitis, may not be “therapeutically rational”). These concerns are most applicable to our youngest generation of recently‐trained radiation oncologists. Such individuals have become accustomed to having 3D dosimetric information available for every case, and rely on such data for many of their clinical decisions. These physicians may be uncomfortable in clinical settings wherein large radiation fields need to be applied in a relatively rapid fashion (i.e. without 3D dosimetry) in order to provide effective palliation. Educational Objectives 1. To understand the rationale, methodology and background of QUANTEC (QUAntitative Normal Tissue Effects in the Clinic) 2. To broadly understand the clinical organ‐specific findings in QUANTEC 3. To understand the differences between the QUANTEC review and the prior Emami review. 4. To recognize the limitations of QUANTEC and the opportunities for improvement in predicting normal tissue toxicity from radiation therapy