Dosimetric Quantities in Neuroendocrine Tumors over Treatment Cycles with 177Lu-DOTATATE

Abstract

Tumor dosimetry was performed for ¹⁷⁷Lu-DOTATATE with the aims of better understanding the range and variation of the tumor-absorbed doses (ADs), how different dosimetric quantities evolve over the treatment cycles, and whether this evolution differs depending on the tumor grade. Such information is important for radiobiologic interpretation and may inform the design of alternative administration schemes. Methods: The data came from 41 patients with neuroendocrine tumors (NETs) of grade 1 (n = 23) or 2 (n = 18) who had received between 2 and 9 treatment cycles. Dosimetry was performed for 182 individual lesions, giving a total of 880 individual AD assessments across all cycles. Hybrid planar-SPECT/CT imaging was used, including quantitative SPECT reconstruction, voxel-based absorbed-dose-rate calculation, semiautomatic image segmentation, and partial-volume correction. Linear mixed-effect models were used to analyze changes in tumor ADs over cycles, absorbed-dose rates and activity concentrations on day 1, effective half-times, and tumor volumes. Tumors smaller than 8 cm³ were excluded from analyses. Results: Tumor ADs ranged between 2 and 77 Gy per cycle. On average, the AD decreased over the cycles, with significantly different rates (P < 0.05) of 6% and 14% per cycle for grade 1 and 2 NETs, respectively. The absorbed-dose rates and activity concentrations on day 1 decreased by similar amounts. The effective half-times were less variable but shorter for grade 2 than for grade 1 (P < 0.001). For grade 2 NETs, the tumor volumes decreased, with a similar tendency in grade 1. Conclusion: The tumor AD, absorbed-dose rate, and activity uptake decrease, in parallel with tumor volumes, between ¹⁷⁷Lu-DOTATATE treatment cycles, particularly for grade 2 NETs. The effective half-times vary less but are lower for grade 2 than grade 1 NETs. These results may indicate the development of radiation-induced fibrosis and could have implications for the design of future treatment and dosimetry protocols.

Keywords: 177Lu-DOTATATE; absorbed dose; fractionation; neuroendocrine tumors.

Graphical abstract

FIGURE 1.

VOIs for cycle 1 (A and C) and cycle 4 (B and D) for 1 G1 NET patient (A and B) and 1 G2 NET patient (C and D). SPECT images are shown as maximum-intensity projections overlaid on high-pass-filtered maximum-intensity projections of CT.

FIGURE 2.

Measured RCs and fitted curve.

FIGURE 3.

Dispersion of AD per 7.4 GBq to tumors over cycles (left), within patients (middle), and between patients (right) for G1 NETs (red) and G2 NETs (blue). In tumor graph, dots represent median AD over cycles for each tumor, and whiskers are minimum and maximum AD. In patient graph, dots represent median AD of medians for tumors, and whiskers are minimum and maximum median AD. All-patients graph is box plot of median, first and third quartiles, and minimum and maximum of median ADs for patients.

FIGURE 4.

AD as function of cycle for G1 NETs (left) and G2 NETs (right) across all patients and all tumors. Whiskers indicate 5th and 95th percentiles. At bottom, numbers of tumors and patients are indicated beneath each box.

FIGURE 5.

AD as function of cycle number (circles) for 2 patients, with G1 NET (3 tumors, A) and G2 NET (2 tumors, B). Solid curves show fixed effects combined with patient-specific random effects, each including intercept and rate constant (Eq. 1). Dashed curves are tumor-specific curves, obtained as sum of fixed effects and patient- and tumor-specific random effects.

FIGURE 6.

Activity concentration (A) and effective half-time (B) as functions of cycle number for G1 and G2 NETs across all patients and all tumors. At bottom, numbers of tumors and patients are indicated beneath each box. For activity concentration in G1, 2 outliers at cycle 1 (6.8 and 7.5 MBq/mL) are excluded.

FIGURE 7.

Ratio of AD to tumor and kidneys (mean left and right) for G1 and G2 NETs.