99mTc SPECT-CT, Consensus QIBA Profile

The quantification of 99mTc labeled biomarkers can add unique value in many different settings, ranging from clinical trials of investigation new drugs to the treatment of individual patients with marketed therapeutics. For example, goals of precision medicine include using companion radiopharmaceutical diagnostics as just-in-time, predictive biomarkers for selecting patients to receive targeted treatments, customizing doses of internally administered radiotherapeutics, and assessing responses to treatment. This Profile describes quantitative outcome measures that represent proxies of target concentration or target mass in topographically specific volumes of interest (VOIs). These outcome measures are usually expressed as the percent injected dose (i.e., radioactivity) per mL of tissue (%ID/mL), a standard uptake value ratio (SUVr), or a target-to-background ratio (TBR). In this profile, targeting is not limited to any single mechanism of action. Targeting can be based on interaction with a cell surface protein, an intracellular complex after diffusion, protein-mediated transport, endocytosis, or mechanical trapping in a capillary bed, as in the case of transarterial administration of embolic microspheres. Regardless, the profile focuses on quantification in well-defined volumes of interest. Technetium-99m based dopamine transporter imaging agents, such as TRODAT, are nearly direct links with some aspects of the predecessor profile on 123I-ioflupane for neurodegenerative disorders. (See www.qibawiki.rsna.org ) Cancer is often a base case of convenience for new material in this profile, but the intent is to create methods that can be useful in other therapeutic areas where the diseases are characterized by spatially-limited anatomical volumes, such as lung segments, or multifocal aggregations of targets, such as white blood cell surface receptors on pulmonary nodules in patients with sarcoidosis. Neoplastic masses that can be measured with x-ray computed tomography (CT) or magnetic resonance imaging (MRI) are the starting point. However, the intent is to create a profile that can be extrapolated to diseases in other therapeutic areas that are also associated with focal, or multi-focal pathology, such as pulmonary granulomatous diseases of autoimmune or infectious etiology, non-oncological diseases of organs such as polycystic kidney disease, and the like. The criteria for measurability are based on the current resolution of most SPECT-CT systems in clinical practice, and are independent of criteria for measurability in other contexts. For this SPECT profile, conformance requires that a “small” VOI must be greater than 30 mL to be measurable. It is understood that much smaller VOIs can sometimes exhibit high conspicuity on SPECT, but these use cases are beyond the scope of this profile and will not be tested for conformance in this version. It is left to individual stakeholders to show the extent to which they can achieve conformance when measuring VOIs less than 30 mL. The detection of smaller changes during clinical trials of large groups can be achieved by referring to the QIBA companion guidance on powering trials. The Claims (Section 2) asserts that compliance with the specifications described in this Profile will produce cross sectional estimates of the concentration of radioactivity [kBq/mL] in a volume of interest (VOI) or a target-to-background ratio (TBR) within a defined confidence interval (CI), and distinguish true biological change from system variance (i.e., measurement error) in individual patients or clinical trials of many patients who will be studied longitudinally with 99mTc SPECT agents. Both claims are founded on observations that target density varies between patients with the same disease as well as within patients with multi-focal disease. The Activities (Section 3) describes the requirements that are placed on the Actors who need to achieve the Claim. Section 3 specifies what the actors must do in order to estimate the amount of radioactivity in a volume of interest, expressed in kBq/mL (ideal) or as a TBR (acceptable) within a 95% CI surrounding the true value. Measurands such as %ID/mL are targets for nonclinical studies in animal models that use terminal sacrifice to establish ground truth for imaging studies. TBRs can be precarious, as the assumptions that depend on the physiology of the background regions matching the volume of interest can be hard to accept sometimes. It is up to each individual stakeholder to qualify the background regions used in their own use case. This profile qualifies only a few in some very limited contexts as examples. The Assessment Procedures (Section 4) for evaluating specific requirements are defined as needed. The requirements are focused on achieving sufficient accuracy and avoiding unnecessary variability of the measurements. The clinical performance target is to achieve a 95% confidence interval for concentration in units of kBq/mL (kilobequerels per milliliter) or %ID/mL (percent injected dose per milliliter) or TBR with both a reproducibility and a repeatability of +/- 8% within a single individual under zero-biological-change conditions. This document is intended to help clinicians basing decisions on these biomarkers, imaging staffs generating measurements of these biomarkers, vendors who are developing related products, purchasers of such products, and investigators designing trials. Note that this document only states requirements to achieve the claims, not “requirements on standard of care” nor compliance with any particular protocol for treating participants in clinical trial settings. Conformance to this Profile is secondary to properly caring for patients or adhering to the requirements of a protocol. QIBA Profiles addressing other imaging biomarkers using CT, MRI, PET and Ultrasound can be found at www.qibawiki.rsna.org.