The American Association for Cancer Research (AACR) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) recently organized a multi-disciplinary conference bringing together experts in their respective fields. The 3-day conference co-organized by Drs. C. Anderson, C. Contag and D. Piwnica-Worms covered in educational sessions, the new frontiers in molecular imaging, big data and imaging genomics, imaging and therapy nanomedicine amongst several key topics of interest. A key note session on targeting PI3K was delivered by Dr. Cantley, and Dr. R. Tsien, Nobel Laureate in Chemistry, delivered a lecture on building molecules to image and treat cancer. The role of immunotherapy imaging to measure response to therapy following T cells was eloquently presented and appear to have great prospect. Unique to the field of Nuclear Medicine is the possibility of theranostics and companion diagnostics, where imaging and therapy properties are combined in a single agent. This was reviewed from the angle of prostate cancer as well as from the use of the Ga-68/Lu-177 labeled molecules. The challenges and opportunities of imaging in clinical trials may affect the field of imaging biomarker the most. Three key abstracts from the thought-leaders in this area, Drs. D. Mankoff, A. Shields and R. Wahl, are provided below. Clearly, Molecular Imaging is moving into an implementation phase now that it has earned its value with FDG. The challenges related to standardization of equipment and quantification are being addressed, and new molecules will be added, first through clinical trials, then progressively in the day to day battle against cancer.
Invited speaker abstracts:
#18. Molecular imaging as a cancer biomarker in clinical trials. D. Mankoff; University of Pennsylvania, Philadelphia, PA
The ability to measure biochemical and molecular processes to guide cancer treatment represents a potentially powerful tool for trials of targeted cancer therapy. These assays have traditionally been performed by analysis of tissue samples. More recently, functional and molecular imaging allows in vivo assay of cancer biochemistry and molecular biology that is highly complementary to tissue-based assay. Molecular imaging can inform targeted cancer clinical trials and clinical decision making by (1) measuring regional expression of the therapeutic target, (2) testing the ability of drugs to interact with their intended targets, (3) measuring cancer response early in the course of treatment, and (4) relating response to the risk of relapse. This talk will review basic principles of molecular imaging in cancer, with an emphasis on those methods that have been tested in patients. The talk will review the current state of molecular imaging in cancer patients, including methods in routine clinical use, those undergoing advanced clinical trials, and those in early-phase testing. Current trials and future directions will be highlighted. References: 1. Farwell MD, Pryma DA, Mankoff DA. PET/CT imaging in cancer: current applications and future directions. Cancer. 2014 Nov 15;120(22):3433-45. 2. Mankoff DA, Pryma DA, Clark AS. Molecular imaging biomarkers for oncology clinical trials. J Nucl Med. 2014 Apr;55(4):525-8.
#22. Design of clinical trials and approaches to prediction and assessment of response. A.F. Shields; Barbara Ann Karmanos Cancer Institute, Detroit, MI
Imaging provides an essential element in evaluating the efficacy of cancer treatment. It continues to gain importance as we develop multiple therapeutic options for patients and treatment becomes more personalized. The oncologist is in need of better ways to predict which treatment is likely to be efficacious. Early assessment of response also becomes critical when multiple options are available for patients who fail first line therapy. Imaging using anatomic assessment, such as with CT and MR, has long been used to help stage patients and is often included in the eligibility criteria of trials. It has also been routinely used to measure the change in tumor size as treatment progresses over multiple months. Such assessments have been standardized using RECIST and other approaches, but one needs to understand the limitations of such techniques for both routine clinical care and clinical trials. This has become particularly problematic with many of the new therapeutic options. Some targeted therapies may slow tumor growth but do not result in significant shrinkage. Furthermore, even with slow growth, treatment may provide benefits for the patient. Anti-vascular agents have become commonly used in cancer therapy, both in combination with other agents and by themselves. To date we lack good predictive markers for efficacy of such agents and also need methods to demonstrate their physiologic effect. Furthermore, anti-vascular agents can lead to tumor necrosis and produce changes described as pseudo-progression. These need to be taken into account as trials are designed. The recent success of immunotherapy can also lead to pseudo-progression on anatomic imaging and many trials are now working to improve the assessment of such studies using modified RECIST criteria and other metabolic imaging assessments. The development of both older and newer targeted therapies often relies on biomarkers to predict and monitor treatment. While the presence of a tumor target may be predicted using genomic markers obtained on tumor specimens, these molecular markers can be complemented by use of imaging tools to measure activity in specific pathways and demonstrate that they have been blocked by treatment. Furthermore, regular measurements of metabolism made after therapy may provide information that adds to standard anatomic imaging methods. As new treatments are developed it is important the oncologists and imagers discuss methods to incorporate novel imaging approaches in both phase I and early phase II trials. These can be used to help understand the pharmacodynamics of the agents and provide evidence of efficacy or help in deciding that a particular therapy should not be pursued for a given tumor. The imaging methods may also find subsequent use as an integral biomarker to help select and monitor treatment as future trials are developed.
#25. Clinical applications of quantitative imaging in planning and assessing cancer therapies. R.L. Wahl; Washington University School of Medicine, St. Louis, MO
Medical images of patients with cancer have typically been interpreted in a mainly qualitative manner with quantitative assessments usually limited to manual determinations of tumor size in one or two dimensions. Medical images from a variety of cross sectional methods are intrinsically quantitative, comprised of voxels representing tumors and normal tissues spatially with continuous data reflecting aspects of tumor biology. While qualitative image interpretation remains a cornerstone of interpretation, increasingly quantitative results are being reported, often extracted using semi-automated or automated methodologies. In CT, tumor volumes can now be calculated with increasing reliability using automated software tools. In MRI, methods to assess a variety of tumor physiological characteristics have been developed, including assessments of diffusion of water, vascular flow and permeability, and metabolite concentrations in addition to size metrics. With PET, a wide range of methods can be applied, including assessments of tumor glucose metabolism in a small region of a tumor, an entire tumor, or through the entire body. Other aspects of tumor biology can be assessed using PET including amino acid transport, flow, hypoxia, receptor or transporter expression, and proliferation, among other characteristics. Combining methodologies to secure a multi-parametric signal, such as with PET/CT, PET/MRI or SPECT/CT, has become a more common approach lending increased certainty to diagnosis. Quantitative imaging can allow assessments to include tumor detection, lesion characterization, and treatment response assessment at varying time points into treatment. End of therapy and intratherapy assessments are both applied with increased frequency. The applications of quantitative imaging are broad, but the PERCIST 1.0 response criteria for FDG PET will be discussed, as well as the RECIST and modified RECIST criteria. In addition, criteria and experience with PET and FDG for monitoring response in lymphoma, including the Deauville criteria (semiquantitative), will be discussed. Through this lecture, the move from qualitative and subjective to quantitative and objective tumor imaging and treatment response assessments will be highlighted, as well as opportunities moving forward.
For all the abstracts go to: http://jnm.snmjournals.org/content/56/Supplement_1/3A?etoc
There is a lot more information than an image in every medical scan… but most of the time that information is not harnessed.
Great progress are being made now both in imaging hardware and image processing to extract that information. The RSNA, the Radiological Society of North America, is leading the way with the QIBA initiative, or Quantitative Imaging Biomarkers Alliance, in which key researchers and scientists not only exploring the boundaries but also setting up guidelines to help others. Look at features such as comparison of images to baseline to extract severity, degree or changes in disease status. In cancer in particular, as stated by Dr. Macura (Johns Hopkins), quantitative imaging has the potential to bring out the value in biomarkers — as measurable characteristics used to indicate a biological state and where imaging can contribute quantifiable data, for example, as surrogate end-points to evaluate treatment response, and especially to detect early failure of potentially toxic treatments or to predict patient outcome. The FDA has well recognized the impact that biomarkers could have (J. Woodcock, “Biomarkers: Physiological & Laboratory Markers of Drug Effect”, 2011).
Quantitative Imaging Accelerates Clinical Research, http://rsna.org/NewsDetail.aspx?id=12002
Janet Woodcock: http://www.cc.nih.gov/training/training/principles/slides/Biomarkers-2010-2011-3slides.pdf
In an editorial of Molecular Imaging this month, Dr. Bob Atcher, past President of the Society of Nuclear Medicine in 2008, covers with clarity the complexities associated with the success of molecular imaging agents in the US: “Is Molecular Imaging Due for a Fallow Period?”
Molecular imaging has a great potential to change the way Medicine is delivered today, such as (1) incorporating imaging biomarkers to better identify patients at high risk of diseases, or for appropriate targeted therapy, (2) following patients response to treatment much closer to therapy, especially when helping in the determination for when to use more potent (but also more toxic) treatment should/could be used, and (3) monitoring patients for recurrences with high sensitive whole body tests.
In his editorial, Dr. Atcher outlines the intricacies associated with imaging agents and the difficulties in bringing a new compound into routine clinical use despite the highly visible promises that are seen very early on. As long as the process remains divisive rather than inclusive to an integrated healthcare plan, as long as one pitches the individual costs which are certainly high to the impact on society, the value of such new technology will take a seat back in the US. Other countries, such as South Korea and Denmark for example, have embraced Molecular Imaging and are now observing the impact of its value to the society in terms of socio-economic markers such as quality of life and more efficient return to the workforce.
For the full editorial, please visit: http://www.molecularimaging.net/topics/practice-management/molecular-imaging-due-fallow-period
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