PET and SPECT molecular imaging as biomarkers in cancer therapeutic trials
Authors: Richard L. Wahl
Journal: Clinical Cancer Research (2010)

Abstract Molecular imaging tools using radiopharmaceuticals are assuming a growing role in cancer treatment clinical trials and in the practice of oncology. Imaging is moving from a qualitative to a quantitative process. PET imaging is estimated to be used in about 2 million people worldwide/year, typically as a hybrid imaging tool including fused CT scans (PET-CT). While glucose metabolism is commonly probed, as glucose utilization is a common downstream marker of a variety of biological processes, other tracers evaluating key aspects of cancer are growing in use. PET techniques are non invasive and deliver only modest radiation doses to patients due to the short half life of the radioisotopes. PET methods offer precise quantitation of radioactivity concentrations in vivo. Single photon methods include bone scans, antibody and peptide based imaging, and imaging of the normal heart, kidneys, lungs and brain, among other tissues. Single photon agents have longer half lifes, are somewhat harder to quantify, but are well suited to slower biological processes which occur over days. SPECT imaging can be combined with CT imaging as SPECT/CT. Both of these imaging methods can be applied at several points in cancer trials. Both PET and SPECT methods are also highly applicable in small animal imaging and relatively easily translated to humans. Initially, imaging may be done to select for a group of patients with limited or extensive disease (staging) and may extend to selecting for biological characteristics of tumors such as estimates of glycolytic or proliferative rates, hypoxia, blood flow, or receptor expression among others. Such tools may make for a more homogenous entering population. Once treatment has begun, the imaging tests may be repeated to assess for treatment effect. As an example, early FDG PET scans assessing the tumor SUV (glucose utilization rate) may be predictive of a good or bad prognosis in groups of patients. Similarly, in an individual drug trial, a change in the PET tracer signal between the baseline and follow up PET image may be indicative of the drug hitting a desired target. Assessments after therapy is complete may give a better sense of treatment effect than anatomic methods. Quantitative data with PET agents structurally similar or identical to the therapeutic agent may be used to estimate dose of the treatment agent, such as in radiopharmaceutical dosimetry based trials. A rapid read out of the efficacy of the treatment using imaging may be used to intensify, or deintensify, dose in specific patients in the form of response adaptive therapies. Greater attention must be paid to secure accurate quantitative than qualitative images, however such data appear to be more reproducibly assessed than estimates of tumor size. Criteria for response by PET have been proposed, such as the PERCIST 1.0 criteria that may help lead to increased standardization of quantitative PET metrics for response but will need further validation and refinement after exploration in clinical trials. The fractional decline in FDG uptake from baseline on PET following chemotherapy has been proposed to the FDA as a possible quantitative biomarker due to a substantial number of studies showing the power of this metric as a surrogate for outcomes. It is clear than imaging biomarkers will evolve of a variety of types and it is expected that their rational use will enhance the process of development of cancer therapeutics both preclinically and in man.