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As a surrogate endpoint to measure response to treatment, Response Evaluation Criteria in Solid Tumors (RECIST) has been road-tested and found to correlate well with the Gold-Standard of Overall Survival. By offering, in essence, a surrogate estimation of tumor volume via unidimensional measurements, RECIST has provided not only an indicator of response to treatment, but also a common language in clinical trials of solid tumors. Increasingly, the use of targeted and immunotherapeutic agents has called into question the true value of RECIST, particularly in early clinical trials where go or no-go decision making is essential. Indeed, clinical trials are increasingly finding a lack of correlation with the use of RECIST to outcomes from early data. Here we explore measures of response beyond RECIST.
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Immunotherapy (IOT) agents are increasingly being used in clinical trials to treat solid tumors due to their dramatic effects on tumor response. However, the assessment of tumor response is not always straightforward given IOTs unique mechanisms of action which include enhancing immune cell infiltration of tumors, draining lymph node basins and inducing generalized systemic inflammatory changes. These inflammatory episodes can lead to radiographic pseudo-progression whereby there can be an initial worsening of radiographic lesions, often accompanied by the appearance of new lesions, followed by lesion improvement or resolution. As a result, the innate and adaptive immune system responses that immuno-therapy agents demonstrate requires unique approaches in the evaluation to reveal treatment response that can be substantially different from standard RECIST methodologies used for chemotherapeutic agents.
The Lugano Classification published in 2014 and also referred to as Cheson 2014, updated and replaced the previously utilized 2007 IWG-NHL guideline (Cheson 2007). The primary goals of the Lugano Classifications were to improve lymphoma patient evaluation, eliminate ambiguity in the assessment of response status and provide a universally applicable approach to facilitate the comparison of patients and data for clinical trial as well as regulatory purposes. Here we discuss the key features of the Lugano including what has changed from the Cheson 2007 guidelines and recommendations on the use of diagnostic CT/MRI with the evaluation of FDG-PET and a methodology to operationalize this criteria in a clinical trial.
Six years have passed since the publication of the RANO criteria. During this time, treatment options for high-grade gliomas have advanced and it is important to consider the ways in which the RANO criteria can be fine-tuned to keep pace with discovery. Here we review the basic implementation of the RANO criteria as published in 2010 and recent research and recommendations on these evolving criteria.
Immunotherapies are changing the way tumor response is defined.
Imaging Endpoints has maintained a leadership role in PET imaging services and analysis for the clinical trial industry for many years. There has been tremendous growth and innovation in recent years with PET being routinely used in clinical diagnosis and staging as well as monitoring of cancer treatment. Additionally, PET has become a very robust tool in clinical trials, where the use of PET follows two distinct approaches – qualitative assessment and quantitative assessment. A typical qualitative assessment may focus on the overall visual assessments of activity on whole body scans while quantitative assessment requires a high degree of analysis and dedication on the part of the clinical site performing PET scans and upon the reader evaluating those images in the context of the extent of disease and response following therapy. Here we discuss when to consider implementing PET imaging in a clinical trial as well as other PET agents that may be considered.
Heterogeneity is a well-recognized feature of malignancy associated with increased tumor aggression and treatment resistance. Texture analysis (TA) is an emerging image processing algorithm that can quantify heterogeneity of tumors. While tumor heterogeneity can be appreciated visually, current systems cannot adequately measure this parameter on standard of care images and much of the heterogeneity visible for example on CT represents noise. At a time of financial restraint and a need to accelerate drug development, TA maximizes the information available from images (e.g. CT, MRI) acquired during clinical trials without the need either for the requirements of additional specialized acquisition methods or the expense of further procedures or stress to patients. Here we discuss how texture analysis can be used to accelerate your product development by exploring imaging biomarker development, patient enrichment selection or treatment efficacy analysis in current, planned or retrospective clinical trials prior to advancing to the next stage of clinical development.
Tumor-associated macrophages (TAMs) have been linked to tumor development and progression. TAMs enhance proliferation of tumors through promoting growth but also survival of the tumor by preventing attack by natural killer and T cells. There is a growing interest in targeting TAMs in oncology therapeutic development, given their noted protumoral activity. Ferumoxytol has been shown to be taken up by TAMs and therefore is potentially a good imaging agent to track TAM migration into and out of tumors. Ferumoxytol (FMX), an ultra-small carbohydrate coated iron-oxide containing nanoparticle was developed to treat anemia in patients with chronic renal failure. One of the properties of this agent is its prolonged residence time within the intravascular space due to an average particle size of approximately 30 nm and slow clearance from the blood stream. When performing Magnetic Resonance Imaging (MRI) studies in subjects given this agent for off-label use for the treatment of their anemia, exquisite angiographic images can be obtained out to 24 hours post injection. The enhancement of the intravascular space following FMX administration has provided a novel approach to imaging pathologic conditions that involve the vascular tree such as in stroke, vascular malformations, chronic renal disease and tumor vascularity, even in patients without kidney disease. Here we discuss the application of FMX in clinical trials.
Choi criteria can provide a window into anti-tumor activity when traditional methods fail to reveal response outcomes that are demonstrated in improved patient outcomes. It is not uncommon that targeted therapy and precision medicine do not alter tumor size but do alter the appearance of tumors. Traditional response criteria such as RECIST 1.1 focus on changes in the size of lesions to evaluate a response outcome. Choi criteria focuses on changes in tumor enhancement (density) on CT as an indicator of response that may be observed with or without evidence of size changes in lesions on imaging. Here we discuss how Choi criteria may provide another option in evaluating efficacy in clinical trials.