Quantifying Renal And Tumor Doses with Individualized Dosimetry In 177Lu DOTATATE Therapy – What Difference Does It Make?

Abstract

The 177Lu DOTATATE (Lu) therapy can potentially improve progression free and overall survival in patients (pts) with progressive metastatic neuroendocrine tumors. We hypothesized that individualized dosimetry is effective in enabling normal tissue adapted prescription of Lu. A multi-institution prospective single arm study of Lu (4 cycles) with individualized dosimetry, in pts with 68Ga DOTATATE positive, progressive metastatic disease is ongoing in Ontario (NCT02743741). Dosimetry calculations are based on quantitative SPECT/CT images acquired at 4, 24, and 72 hours post Lu therapy. A 2cm spherical region of interest (ROI) is placed over normal kidneys and a vertebral body to estimate renal and bone marrow (BM) absorbed dose after each cycle. All pts received 7.4GBq for cycle (C) 1 (with modifications based on creatinine clearance and hematology for all cycles). Subsequent injected activities were varied based on renal absorbed dose (tolerance dose of 23Gy). Dose escalation was permitted to a max. of 11.1GBq/cycle. To quantify tumor absorbed dose, a ROI was placed over representative (highest SUV uptake) intra and extrahepatic areas. In addition, the liver was segmented and a threshold of >41%Max SUV was used to auto-segment liver tumors. To explore if tumor dose changed during treatment, we calculated the actual and normalized (using 7.4GBq) absorbed dose change. Between August 2016 and December 2018, 100 pts were accrued from the four consortium sites, 62 pts have completed the therapeutic phase, 53 pts have received all four cycles and were the basis of the current analysis. Using 29.6GBq (±10%) as the conventional total dose (when no Individualized dosimetry is used), 36 (68%) pts had dose escalation (>32.56GBq), 9 (17%) pts no change, and 8 (15%) pts had dose de-escalation (<26.64GBqi). The median (med) total renal dose absorbed was 18 (SD4, range 7 – 24) Gy. Only 1 pt received renal dose above tolerance. The med BM dose was 0.79 (SD1.3; range 0.15– 9.69) Gy. In 4 pts, the BM dose was >2Gy, attributable to multiple bone metastases and difficulty identifying a tumor free ROI. Using the threshold method, the med % liver containing tumor was 5% (SD 5; range 1-31%). The med liver tumor dose was 69 (SD 48; range 12 – 227) Gy. The med uninvolved liver dose was 10 (SD 8, range 5-33) Gy. Using the ROI method, the med liver tumor dose was 93Gy (SD64; range 20-291) Gy. The C1 med liver tumor dose was 21 (SD19 range: 4 – 112) Gy. In contrast, the C4 dose was 16 (SD 16; range 2 – 67) Gy. The normalized med difference was -4 (SD 15; range -45 to 38) Gy. Individualized dosimetry allowed dose escalation in 68% and de-escalation in 15% of pts while maintaining the renal dose within tolerance. Dose absorbed by tumor (ROI method) showed a >10-fold variation across patients. Longer follow-up is required to understand the impact of individualized dosimetry on outcomes.