This is an excerpt from Keosys' free eBook, "An Introduction to Peptide Receptor Radionuclide Therapy." To access the full eBook, click here.
A key challenge for peptide receptor radionuclide therapy (PRRT) using radiopharmaceuticals is to optimize the dose delivered to the tumor, while minimizing healthy tissue irradiation.
Dosimetry is how the dose of radiation that is given to sensitive organs (which need to be spared as much as possible) and tumors (which need to be killed) is determined and measured.
Beta- and gamma-emitting radionuclide 177Lu emits low levels of gamma rays on top of its higher energy beta rays, and so 177Lu-dotatate can be tracked — using imaging — inside the body.
In PRRT clinical trials, individual pre-therapeutic dosimetry was necessary for patient selection and therapy planning. This is due to the significant inter-patient differences in radiopeptide uptake between normal organs and tumors. Dosimetry suggests that only patients displaying high levels of the peptide target might benefit from PRRT.
Dosimetry in Clinical Settings
Dosimetry could help address how to increase the radiation dose for therapy whilst limiting toxicity. However, pre-treatment dosimetry in PRRT is not routinely performed, mainly due to the lack of evidence in literature and clinical implementation difficulties.
Highly specific techniques and workflows are needed to bring dosimetry into clinical settings. Fortunately, possible solutions are offered by several commercial software-assisted workflows. These include DOSISOFT / PLANET Dose, Hermes / OLINDA and MIMS. A small number of trials have used this commercial software. For example, the previously mentioned 177Lu-PMSA phase II trial in prostate cancer used dosimetry (OLINDA/EXM software) in 30 patients to ensure that the maximal mean absorbed renal dose was not exceeded10. Another study showed that organ-based absorbed dose estimations using either PLANET Dose or OLINDA software were comparable in patients treated with Lutathera.
However, dosimetry is not yet at a stage where it can be routinely used for optimized patient–individual dosing. A sub-analysis of the NETTER-1 approval trial concluded that "This dosimetry analysis did not identify predictive factors that would warrant patient-individual dosing" (presented at Annual Congress of the European Association of Nuclear Medicine 2018). Hence, personalized dosimetry is currently performed mainly to ensure safety and evaluate the absorbed dose to the tumor rather than to optimize the administered activity and to assess the dose-response relationship for individual patients. Several dosimetry-based clinical trials are underway to help improve this situation.
Project Management Considerations for Dosimetry Analyses
As well as image-based data, dosimetry relies on data obtained from a patient's blood and urine samples. Because of the importance of blood and urine data, the management of dosimetry trials includes several steps that are often not required for other imaging-based trials and require specific project management activities. These include:
Dosimetry Analysis Software
Dosimetric analyses can be run using commercial software (such as PLANET Dose) that enables the routine evaluation of radiation doses delivered to tumor and at-risk organs during PRRT. There needs to be individuals in the imaging project management team who have experience in the use of such software-mediated analyses.
SPECT Equipment Calibration
Because dosimetry requires the accurate estimation of the activity of the PRRT in the target and in at-risk organs (e.g. kidney) at several time points, the preliminary calibration (SPECT gamma-camera, dose calibrator, gamma-counter) is crucial for image quantification. Images for a given patient need to be acquired on the same scanner throughout the study, or if it is necessary to change scanners then a new calibration should take place.
It is common practice to outsource this activity to specialized providers which need to be overseen to ensure calibration takes place within agreed timelines. It is also important to check that the correct calibration factor (gamma-counter) has been used for blood and urine throughout the course of the study. Otherwise dosimetry results might be severely impacted. In this respect, close coordination with investigation sites and data management is required to ensure that only data that has been subject to source data verification (SDV) are entered into the system and used by the dosimetry team in charge.
Imaging Data Collection
Dosimetry time-points are generally performed 24 hours apart. Once images are acquired, they need to be provided to the imaging core laboratory in due time. We recommend that at least the first dosimetry time-point is uploaded onto the relevant imaging platform immediately after it is acquired. This is so that the project management team can communicate any required corrections to the investigation site in time for the next time-point. Similarly, dosing data collected from blood and urine samples for dosimetry purposes need to be available in due time. This might be necessary if, for example, dosimetry is used to address safety to allow dose escalation. It is advisable the Imaging Core Laboratory (ICL) in charge proceeds with internal data quality checks (see below) before making them available to the dosimetry team.
It's vital that the blood and urine dosing data is checked and cleaned (SDV) before it is used for dosimetry analysis. Other checks on blood and urine dosing data are needed to ensure that the data is consistent with any defined medical standards. For example, do the data follow the expected radioactivity count decrease over time? Is the volume of urine collected physiologically sound? In turn, it is important that dosimetry data are clean and complete before being communicated to the data managers on sponsor’s end. We recommend that dedicated data checks are set-up when dosimetry analyses are planned in the study protocol.
We recommend that a specific dosimetry risk management plan is generated and the plan is included in the study documentation file. To document dosimetry analyses, two key documents are necessary. First, a dosimetry operating manual is needed, which is communicated to investigation sites and contains technical recommendations regarding image as well as blood and urine collection. Second, you need a dosimetry analysis plan, which lists the methods used for dosimetry analyses including software and fitting models.