The radiopharmaceutical procedures covered in the full report are listed in Table 1, which also displays selected post-therapy imaging and measurement methods that can form the basis for verification of absorbed doses delivered. Furthermore, the possibility for administration of a tracer amount of the radiopharmaceutical itself or of a “companion diagnostic” to estimate absorbed doses “up front” are indicated. Current clinical therapy regimens vary from single administrations to multiple cycles, and prescriptions range from the delivery of a fixed amount of radioactivity to dosimetric treatment planning. The range of current practice is reported in an IDTF survey on implementation of dosimetry procedures in Europe .
In the following sections, the potential for dosimetric treatment planning are summarized for five of the most common individual therapy procedures. In the full report, a brief introduction to the disease and radiopharmaceutical is given for each procedure, followed by a brief review of the reported effectiveness of the treatment, the potential for quantitative imaging that underpins normal tissue and target dosimetry, and existing evidence for absorbed dose-effect correlations. The potential for personalized dosimetry-based treatment planning is then considered. Finally, issues specific to the treatment are considered along with questions that merit further investigation. For the individual procedures included in the present summary, these have been condensed in two paragraphs: the first presenting the therapy and current practice, followed by a second describing the dosimetric procedures and dose-effects. Resource requirements are reported in a separate section.
131I NaI for the treatment of differentiated thyroid cancer with ablative intent and in the case of recurrent disease
The amount of 131I NaI activity to administer for differentiated thyroid cancer (DTC) treatment is commonly empirically determined. Typically, a fixed activity of 131I NaI ranging between 1.11 and 7.4 GBq is given . In the case of recurrent disease, the administered activity may be calculated based on the absorbed dose constraints of the normal tissue, usually red marrow as recommended in EANM guidelines .
Radioiodine uptake in thyroid remnants and metastases can be determined with gamma camera planar imaging or with SPECT/CT which can provide more accurate quantification . Camera calibrations and radiation protection measures may be demanded due to a high photon flux . PET/CT imaging can also be performed using 124I NaI, which may be advantageous for determination of remnant mass and small metastases . Currently, in the treatment of DTC, there are no well-established values for absorbed doses to remnants and metastases which may be used as prescription values. EANM guidelines recommend the calculation of red marrow absorbed doses from whole-body and blood dosimetry , and a constraint of 2 Gy is considered when using this methodology . Additional organs at risk may include the lungs and salivary glands [10,11,12]. Issues regarding the alteration of biodistribution can occur due to the debated “stunning effect” for 131I NaI [13, 14] or due to prior administration of recombinant human thyroid-stimulating hormone (rhTSH) , which may have to be considered if treatment planning is performed.
131I mIBG for the treatment of neuroblastoma in children and young adults
The metaiodobenzylguanidine (mIBG) molecule structurally resembles norepinephrine (also called noradrenaline), and tumors expressing the norepinephrine transporter show mIBG uptake capacity. The prescription of 131I mIBG for neuroblastoma is often made according to whole-body absorbed dose, which is related to bone marrow absorbed dose and neutropenia .
If stem cell rescue is not scheduled, the main organ at risk is usually the bone marrow, with an absorbed dose constraint of 2 Gy . An increasingly common protocol is to deliver a whole-body absorbed dose of 4 Gy in two administrations of activity separated by 2 weeks, followed by stem cell rescue. The first administration is delivered according to a body mass-based prescription of 444 MBq/kg . The whole-body absorbed dose can be estimated by dose-rate measurements obtained with a probe. However, if there is bone marrow involvement, imaging is necessary to perform dosimetry. Quantitative imaging can be performed essentially as for 131I NaI, with the same technical considerations .
177Lu-DOTATATE for the treatment of neuroendocrine tumors
177Lu-DOTATATE is a radiolabelled somatostatin analog developed for the treatment of patients with somatostatin receptor-positive neuroendocrine tumors. The most frequent treatment protocol is currently to administer 7.4 GBq for up to four times with a 6 to 10-week interval between each administration . However, protocols delivering cycles of 7.4 GBq until a maximum prescribed absorbed dose to the kidneys and the bone marrow is reached are under investigation .
Although the photon yield is relatively low, the high level of activity administered makes quantitative gamma camera imaging of 177Lu possible [21, 22]. Late treatment-related kidney toxicity has not been reported for patients receiving a kidney absorbed dose over 28 Gy, a commonly used tolerance limit, indicating that this may be a conservative value . A clear correlation between tumor absorbed doses and the response to the treatment was reported in pancreatic neuroendocrine tumors . Although it has been demonstrated that patient-specific absorbed doses for 177Lu can be calculated and have a clinical benefit, the absorbed dose limits for normal tissue and the desirable absorbed dose to the tumors require further investigations.
223Ra dichloride for the treatment of bone metastases from castration-resistant prostate cancer
223Ra dichloride is an alpha-emitting radiopharmaceutical approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. Being an analog to calcium, cationic radium is taken up by areas of increased osteoblastic activity. A fractionated approach is routinely used for the delivery of this treatment with six administrations of 55 kBq/kg body weight.
The low yield of photons, combined with the low amount of activity administered, makes quantitative imaging of 223Ra challenging. However, it has been demonstrated that prolonged gamma camera imaging is feasible [25, 26] and that activity can be quantified to within 20–50%, depending on the volume imaged. A study showed that absorbed doses delivered to normal organs vary by an order of magnitude between individual patients . Uptake of 223RaCl2 in metastases has been seen to correlate with that of 99mTc MDP , demonstrating a potential for treatment planning. There is no evidence as yet of correlations between the absorbed doses delivered and effect. Besides developing reliable dosimetric methodology for this treatment, the relative biological effect is yet to be determined, and the short range of the alpha emissions necessitates investigations of microdosimetry and small-scale dosimetry.
90Y microspheres for the treatment of primary and metastatic liver cancer
Intra-arterial locoregional liver therapies have their rationale in the fact that liver lesions are fed mainly by the arterial stream, while normal parenchyma is supplied by portal vein blood flow. At present, both 90Y glass microspheres and 90Y resin microspheres are used, both licensed as medical devices to treat liver primary hepatocarcinoma (HCC) and liver metastases . Toxicity is of particular importance, as patient death from radioembolization-induced liver disease leading to liver failure can be a consequence of a standard treatment . With current recommendations, dosimetry is sometimes used as a basis for treatment planning, although methods for absorbed dose prescription vary.
Simulation scanning is performed with 99mTc-albumin macro aggregate (MAA) administered under angiographic guidance for quantitative imaging and pre-treatment dosimetry . The permanent trapping into liver capillaries of the 99mTc MAA and of the therapeutic 90Y microspheres allows dosimetry to be performed from only one scan . Post-therapy quantitative imaging can be performed by 90Y bremsstrahlung SPECT or 90Y PET with suitable corrections [31, 32]. Correlations between the absorbed doses delivered and toxicity and response have been reported both for hepatocellular carcinoma [33,34,35] and colorectal metastases [36, 37].
Implementation of dosimetry for therapy, particularly on a routine basis, has implications for infrastructure resourcing. The level of resources required will depend on the complexity of the dosimetry procedure and will vary according to local and national protocols and guidelines. Each procedure will have resource implications for both an initial setup of a dosimetry service and for ongoing support.
Resources fall into categories of equipment and staff. Whole-body dosimetry may be performed with a portable or externally mounted compensated Geiger counter which enables multiple measurements to be made by either staff or, if necessary, possibly by comforters and carers. Both the legal implications and the technical complexity should be carefully considered if the latter group is to perform such measurements. Blood dosimetry may be derived from samples measured in a well counter. Image-based dosimetry requires a gamma camera or PET system that has been set up for the radionuclide under investigation at activity levels relevant to the procedure. In addition to routine quality control procedures, this entails determination of calibration factors for image quantification and characterization of camera deadtime which is important for post-therapy imaging. For each therapeutic procedure, the required number of measurement time points (especially imaging time points) needs careful investigations as this directly affects both the dosimetric accuracy and the resource implications. Unlike many of the other resource requirements, this also impacts the time spent by the patients. Volume estimation may be acquired from radiological images or, in the case of radioiodine treatment of benign thyroid disease, from ultrasound scanning as well as from the SPECT and PET data.
As a multidisciplinary area, a range of trained staff are necessary to provide a comprehensive service. These include medical physicists for image quantification and absorbed dose calculations, nuclear medicine technologists and radiographers with experience in quantitative imaging, nuclear medicine physicians and radiologists for performing or supervising volume outlining, and possibly other specialists to contribute on patient-specific prescriptions and procedures.