Radioactive iodine-131 (RAI) therapy of metastatic well-differentiated thyroid cancer (mDTC) has been a cornerstone of nuclear medicine practice since it was first conceptualized in the 1940s by Saul Hertz and Arthur Roberts. RAI continues to be an important part of the therapeutic armamentarium for advanced thyroid cancer in both adults and children.
Practical RAI dosimetry as a clinical tool
In a recent article published in EJNMMI [
1], we introduced an approach to define a PET imaging–based single-timepoint biomarker for estimation of radiation-absorbed dose (cGy) of mDTC RAI for advanced disease. Our methodology could guide the selection of the amount of radioactivity (MBq) needed to achieve a desired lesion dose (in cGy), based on standard uptake value (SUV)
124I at 48 h post-oral administration of 6 mCi Na[
124I]I. The method employs a regression model relating the 48-h
124I lesion SUV measurements to the radiation-absorbed doses for these same lesions, and is illustrated on 208 individual lesions in 21 patients (our learning set). The model is derived from fitting a pharmacokinetic “gold-standard” radioactivity retention curve for each lesion based on four serial
124I PET images conducted at the nominal imaging times of 4, 24, 48, and 120 h post-radiotracer administration. If the performance of the approach is validated, the prescribing physician will be able to select an activity (MBq) to safely administer to patients with multiple metastatic lesions of heterogenous radioiodine avidity, to treat a desired fraction of the lesions to a specified radiation-absorbed dose.
The use of these results, such as those presented in both Fig. 2 and Table 3 from our aforementioned article [
1], would facilitate treatment planning. Figure 2 contains data obtained by imaging the group of 21 mDTC patients to characterize individual lesion uptake and retention, to determine integrated retained radiation over time as recommended by the MIRD Committee. Table
1 shows, for the given SUVs at 48 h, the amount of radioactivity of
131I in GBq (mCi) estimated to produce at least 2000 cGy per lesion in 90%, 95%, and 97.5% of all lesions.
Table 1
Using the SUV at 48 h to guide recommendations for administered activity based on the likelihood that a fixed percent of metastatic lesions will receive a lesional dose >2000 cGy* (learning set)
15 | 10.8 | (292) | 13.2 | (355) | 15.4 | (416) |
20 | 8.1 | (218) | 9.4 | (255) | 11.4 | (307) |
30 | 5.7 | (153) | 6.6 | (179) | 7.5 | (203) |
The individual lesion SUVs provide valuable information about intra-individual tumor heterogeneity, allowing clinicians to prescribe an administered activity that will optimize the therapeutic efficacy of RAI while bearing in mind the risks associated with RAI therapy. For example, if the vast majority of the clinically significant metastatic lesions demonstrate an SUV of 30 at 48 h and only one dominant lesion demonstrates an SUV of 15, we may choose to prescribe an administered activity of 7.5 GBq (203 mCi) to deliver >2000 cGy to most of the metastatic lesions with a plan for surgical resection or external beam irradiation of the dominant metastatic lesion—rather than administering 15.4 GBq (416 mCi), which would be required to achieve 2000 cGy in the dominant lesion. These decisions are made by a multidisciplinary team that develops multimodality treatment plans to achieve an optimal balance between therapeutic efficacy and risks, with the understanding that RAI can be used in concert with other treatment modalities for any individual patient.
At MSK, we routinely perform whole-body dosimetry on candidates for RAI therapy, to determine “maximum tolerated activity” (MTA), principal dose-limiting tissue being the blood (<200 cGy) [
1]. The MTA offers a safety net to prevent excess toxicity (“
primum non nocere”). But it is equally important to identify the minimum effective amount of radiation for tumor treatment despite heterogeneity of tumor uptake. In our RAI-treated mDTC population [
1], among 15 patients, the
124I estimated cGy radiation-absorbed dose in 168 metastatic tumors was evaluated in relationship to the prescribed >2000 cGy therapy threshold. We determined that 96% of lesions received the predicted cGy radiation-absorbed dose >2000 cGy from the total amount of RAI administered, even though cGy heterogeneity varied over ~2 logs around the median lesion dose of ~22,000 cGy. Although currently our work is proof of principle, we find these initial observations encouraging enough to warrant effort to optimize our approach to make it suitable for clinical practice. We intend to (1) increase our learning set of patients (and thus the number of individual lesions) by approximately three-fold, and (2) obtain a validation set to evaluate effectiveness of treatment, including tumor size reduction with loss of
131I uptake, reduction of thyroglobulin, long-term survival, and, ultimately, cure.
NET and prostate RPT—lesion and patient radiation dosimetry
Dosimetry estimates in relationship to tumor response and toxicity of normal tissues are beginning to appear for [
177Lu]Lu-PSMA-617 and [
177Lu]Lu-DOTATATE. For [
177Lu]Lu-DOTATATE, as for other forms of RPT, wide inter- and intra-patient variability of tumor-absorbed doses has been reported for similar cumulative administered activities, making the dosimetry representation with the range more meaningful than with median values: doses may range from 1–2 to more than 5,000 cGy/GBq. It is clear that many tumors receiving less than 1000 cGy are gravely undertreated [
6]. For many years, skepticism toward the predictive value of dosimetry prevailed, probably related to the limited understanding of tumor dose variability, scarcity of data correlating tumor dose with response, and lack of consideration of the role of radiosensitivity in radiation response [
7]. More recently, prospectively acquired dose response curves have consistently shown a correlation between tumor-absorbed dose and lesion volume reduction assessed by CT, especially significant for lesions >4 cm when quantitative SPECT reconstruction with accurate partial volume corrections could be applied [
8].
While the long-established skepticism has delayed the planning of large prospective randomized dosimetry trials to assess the advantages of dosimetry-based treatments, available dose response curves seem to indicate that, optimally, tumor doses of 12,000–13,000 cGy are necessary to effectively treat NETs [
9]. Implementing faster dosimetry protocols (e.g., single- or double-point) will facilitate the practicality, acceptance, and inclusion of dosimetry as an integral part of treatment to verify that tumor doses fall within the expected therapeutic range and exposed dose-limiting tissues within the constraints for normal organ toxicity. In parallel, measurement of the radiation doses to tumor and normal organs will both improve our understanding of lesion radiosensitivity through the correlation with response [
10] and help better define the dose-limiting toxicity to organs such as the kidney and salivary gland, resulting from RPT. Prostate cancer tumor radiation dose response to RPT has been reported by Hoffman and colleagues, using 50% reduction in circulating PSA as a response parameter. A median effective radiation-absorbed dose is approximately 1100 cGy, and these higher doses are correlated with a 50% drop in PSA, compared to those patients with no PSA decline (median ~900 cGy). Heterogeneity of 20- to 30-fold has also been reported for the variation in individual lesion cGy, with upper bounds not quite reaching 10,000 cGy [
11]. Recently, the dosimetric results of the VISION trial sub-study were presented, indicating mean absorbed doses of 5.4 (range, 0.13–45) Gy/GBq for bone and 9.7 (0.99–55) Gy/GBq for nodes, in line with prior literature [
12]. No dose response correlations have yet been presented, although one could infer that the higher absorbed doses correlate with more favorable radiological PFS, as reported in the main study [
13].
For both [177Lu]Lu-DOTATATE and [177Lu]Lu-PSMA-617, kidney and bone marrow toxicity were seen in a small percentage of patients, which appeared to be the dose-limiting organs. To help with patient selection, a proposed criterion for pre-treatment with [177Lu]Lu-PSMA-617 has been a ratio of 1.5 for [68Ga]Ga-PSMA-11 SUV in tumor/liver, predicting beneficial response when [68Ga]Ga-PSMA-11 is used prior to [177Lu]Lu-PSMA-617 therapy.
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