By: Matthew A. Hoover, MBA, CNMT, NMTCB(CT), PET
Introduction
Pharmaceutical clinical trials are essential for the development and evaluation of new drugs and therapies for various diseases and conditions. One of the key aspects of early phase clinical trials is assessing efficacy and safety of the intervention, which requires the use of appropriate response criteria. Response criteria are standardized methods for measuring and categorizing the changes in the disease status or the clinical outcome of the patients after receiving the intervention. Response criteria can be based on different types of data such as clinical symptoms, laboratory tests, biomarkers, or imaging endpoints. Imaging endpoints are particularly useful for diseases that affect the structure or function of organs and tissues, such as cancer, neurodegenerative disorders, cardiovascular diseases, and inflammatory diseases. Imaging endpoints can provide objective, quantitative, and reproducible information on the anatomical, physiological, metabolic, or molecular changes induced by the intervention. However, not all imaging endpoints may provide equally reliable, sensitive, or specific data for the evaluation of the intervention. In this blog post, we will review the various response criteria based on imaging endpoints and compare the advantages, disadvantages, and opportunities for improvement for each one. This post focuses on how imaging endpoints often rely on structural imaging and physical changes to be visualized on computed tomography (CT) or magnetic resonance imaging (MRI), compared to the functional imaging and cellular changes visualized on positron emission tomography (PET) images.
Structural imaging response criteria are the most widely used and accepted methods for assessing the efficacy of interventions in clinical trials, especially for solid tumors. These criteria are based on the measurement of the size and number of the lesions or tumors on CT or MRI images, which reflect the anatomical changes caused by the intervention. The most common structural imaging response criteria are the Response Evaluation Criteria in Solid Tumors (RECIST) (Eisenhauer, 2009), the World Health Organization (WHO) criteria, the Choi criteria (Choi, 2007), and the modified RECIST (mRECIST) (Lencioni, 2010) for hepatocellular carcinoma. These criteria have different definitions and thresholds for the categories of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), which are used to determine the overall response rate (ORR), the disease control rate (DCR), and the progression-free survival (PFS) of the patients. The main advantages of structural imaging response criteria are their simplicity, standardization, and reproducibility, which facilitate the comparison and interpretation of the results across different trials and settings. Moreover, structural imaging response criteria have been validated and correlated with the survival outcomes of the patients in many studies and are endorsed by several regulatory agencies and professional organizations.
However, structural imaging response criteria also have several limitations and challenges that may affect their accuracy and reliability (Grimaldi, 2018). First, structural imaging response criteria may not capture the true biological effects of the intervention, especially for novel therapies that target the molecular pathways, the immune system, or the microenvironment of the disease. For example, some therapies may induce tumor necrosis, inflammation, or edema, which may increase the size of the lesion or tumor on CT or MRI images, but actually reflect a positive response. This phenomenon is known as pseudoprogression, and may lead to the underestimation of the efficacy of the intervention and premature discontinuation of the treatment. On the other hand, some therapies may cause tumor shrinkage without affecting the viability of the tumor cells, which may result in a false positive response. This phenomenon is known as pseudoresponse (Gatto, 2021) , and may lead to the overestimation of the efficacy of the intervention and the delay of the switch to a more effective treatment. Second, structural imaging response criteria may not be sensitive or specific enough to detect the subtle or heterogeneous changes in the lesions or tumors, especially for diseases that have complex or irregular morphology, such as liver cancer, brain cancer, or bone metastases. For example, some lesions or tumors may have a partial or mixed response, which may not be adequately reflected by the measurement of the longest diameter or the sum of diameters of the lesions or tumors (Rauwerdink, 2020). Moreover, some lesions or tumors may be difficult to measure or identify on CT or MRI images, due to the low contrast, the anatomical location, or the presence of artifacts or noise. Third, structural imaging response criteria may not be timely or consistent enough to monitor the changes in the disease status or the clinical outcome of the patients, especially for diseases that have a rapid or variable progression (Villaruz, 2013), such as lymphoma, leukemia, or sarcoma. For example, some lesions or tumors may have a delayed or transient response which may not be captured by the fixed or arbitrary time intervals or cut-off points of the structural imaging response criteria. Furthermore, some lesions or tumors may have a discordant or paradoxical response, which may not be accounted for by the unidimensional or bidimensional measurement of the lesions or tumors.
Functional imaging response criteria are emerging and promising methods for assessing the efficacy of interventions in clinical trials, especially for diseases that affect the function or metabolism of organs and tissues such as cancer, neurodegenerative disorders, cardiovascular diseases, and inflammatory diseases. These criteria are based on the measurement of the intensity and distribution of the radiotracer uptake or signal on PET images, which reflect the physiological, metabolic, or molecular changes induced by the intervention. The most common functional imaging response criteria are the European Organization for Research and Treatment of Cancer (EORTC) criteria, the PET Response Criteria in Solid Tumors (PERCIST), the Deauville criteria (Meignan, 2009), and the Lugano criteria (Cheson, 2014). These criteria have different definitions and thresholds for the categories of CR, PR, SD, and PD, which are used to determine the ORR, the DCR, and the PFS of the patients. The main advantages of functional imaging response criteria are their sensitivity, specificity, and early prediction of the response to the intervention, which may improve the selection and stratification of the patients, the optimization and personalization of the treatment, and the evaluation and validation of the novel therapies. Moreover, functional imaging response criteria have been correlated and prognostic of the survival outcomes of the patients in many studies and are increasingly recognized and recommended by several regulatory agencies and professional organizations.
However, functional imaging response criteria also have several limitations and challenges that may affect their accuracy and reliability. First, functional imaging response criteria may not capture the true anatomical effects of the intervention, especially for therapies that cause tumor shrinkage or disappearance without affecting the function or metabolism of the tumor cells. Similar to the examples outlined in the structural imaging criteria, some therapies may induce tumor necrosis, inflammation, or edema, which may decrease the radiotracer uptake or signal on PET images, but actually reflect a negative response. This phenomenon is known as pseudoregression, and may lead to the overestimation of the efficacy of the intervention and the delay of the switch to a more effective treatment. On the other hand, some therapies may cause tumor stabilization or growth without affecting the function or metabolism of the tumor cells, which may result in a false negative response. This phenomenon is known as pseudostability, and may lead to the underestimation of the efficacy of the intervention and the premature discontinuation of the treatment (Wahl, 2009). Second, functional imaging response criteria may not be standardized or reproducible enough to compare and interpret the results across different trials and settings. For example, some functional imaging response criteria may have different or unclear definitions or thresholds for the categories of CR, PR, SD, and PD, which may introduce variability or ambiguity in the assessment of the response to the intervention. Moreover, some functional imaging response criteria may depend on the choice or availability of the radiotracer, the PET scanner, the acquisition protocol, the reconstruction algorithm, the image analysis, or the quality control, which may introduce bias or error in the measurement of the radiotracer uptake or signal on PET images (Sunderland, 2015). Third, functional imaging response criteria may not be validated or correlated enough with the clinical outcomes of the patients, especially for diseases that have a complex or multifactorial etiology, pathogenesis, or progression, such as cancer, neurodegenerative disorders, cardiovascular diseases, and inflammatory diseases. For example, some functional imaging response criteria may not reflect the overall or long-term response or survival of the patients, but only the short-term or partial response or survival of the patients. Furthermore, some functional imaging response criteria may not account for the heterogeneity (Fourcade, 2022) or dynamics of the disease, such as the presence of multiple or different subtypes or phenotypes of the disease, or the emergence of resistance or recurrence of the disease.
In conclusion, response criteria based on imaging endpoints are valuable and indispensable tools for the assessment of the efficacy and safety of interventions in pharmaceutical clinical trials. However, not all imaging endpoints may be equally reliable, sensitive, or specific for the evaluation of the intervention and may require specific attention to detail when interpreting the images (Therasse, 2000). Structural imaging response criteria, which rely on the measurement of the size and number of the lesions or tumors on CT or MRI images, are the most widely used and accepted methods, but they may not capture the true biological effects of the intervention, and they may not be sensitive or specific enough to detect the subtle or heterogeneous changes in the lesions or tumors. Functional imaging response criteria, which rely on the measurement of the radiotracer uptake or signal on PET images, are emerging and promising methods, but they may not capture the true anatomical effects of the intervention, and they may not be standardized or reproducible enough to compare and interpret the results across different trials and settings. Therefore, there is a need for the development and validation of new or improved response criteria that can integrate the structural and functional imaging information, and that can provide a more accurate, comprehensive, and personalized assessment of the response to the intervention in pharmaceutical clinical trials (Benz, 2008; Shankar, 2006).
Moving forward, it may be beneficial to ensure that all functional imaging is reviewed in conjunction with structural imaging. Imaging systems such as PET/CT, PET/MRI, and SPECT/CT, may provide a solution that allows researchers to ensure that they have access to functional and structural imaging, all in one dataset. Additionally, the development of specialty radiopharmaceuticals such as CD8 ImmunoPET, an investigational imaging agent, may provide additional value as tools to potentially bridge the knowledge gap between standard imaging modalities and other modalities such as biopsy and immunohistochemistry staining, providing enhanced insights into the tumor microenvironment.
Disclaimer: This content is for individuals in the pharma or biotech industry and is for educational purposes only. CD8 ImmunoPET is an investigational product and has not yet been approved by the FDA.
