Dose escalation of an Evans blue-modified radiolabeled somatostatin analog 177Lu-DOTA-EB-TATE in the treatment of metastatic neuroendocrine tumors

Abstract

Purpose: To evaluate the safety and efficacy of 177Lu-DOTA-EB-TATE, a radiolabeled somatostatin analog modified by Evans blue, at escalating doses, was used to increase tumor retention in patients with progressive metastatic neuroendocrine tumors (NETs).

Methods: Thirty-three patients with metastatic NETs were prospectively enrolled into four groups: group A (n = 6, 43 ± 12 years) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTATATE as controls; group B (n = 7, 55 ± 7 years) administered approximately 1.11 GBq (30 mCi) 177Lu-DOTA-EB-TATE; group C (n = 6, 55 ± 10 years) administered approximately 1.85 GBq (50 mCi) 177Lu-DOTA-EB-TATE; group D (n = 14, 50 ± 10 years) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTA-EB-TATE. Treatment-related adverse events were graded according to the CTCAE v.5.0. 68Ga-DOTATATE PET/CT were performed at baseline and 2-3 months after treatment for response evaluation.

Results: Administration was well tolerated. No CTC 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity was observed during or after treatment in groups A-C. In group D, CTC-3 hematotoxicity was recorded in 2 patients with multicourse chemotherapy previously. After one-cycle treatment, the SUVmax decreased in group C (Δ% = - 17.4 ± 29.3%) and group D (Δ% = - 15.1 ± 39.1%), but greatly increased in group B (Δ% = 30.0 ± 68.0%) and mildly increased in group A (Δ% = 5.4 ± 45.9%). Referring to EORTC criteria, 16.7% (1/6), 0% (0/7), 50% (3/6), and 50% (7/14) were evaluated as partial response in groups A, B, C, and D, respectively. When selecting lesions with comparable baseline SUVmax ranging from 15 to 40, SUVmax showed no significant decrease in group B (Δ% = - 7.3 ± 24.5%) (P = 0.214), significant decrease in group C (Δ% = - 34.9 ± 12.4%) (P = 0.001), and in group D (Δ% = - 17.9 ± 19.7%) (P = 0.012) as compared with group A with increased SUVmax (Δ% = 8.4 ± 48.8%). SUVmax significantly decreased in the EBTATE groups (groups B-D combined) (Δ% = - 19.0 ± 21.5%) as compared with the TATE group (P = 0.045).

Conclusion: 177Lu-DOTA-EB-TATE is well tolerated and is more effective than 177Lu-DOTATATE. Both 1.85 GBq (50 mCi) and 3.7 GBq (100 mCi) doses appear to be more effective than 1.11 GBq (30 mCi) dose. Further investigation with more cycles of 177Lu-DOTA-EB-TATE treatment and longer follow-up is warranted.

Trial registration: Treatment Using 177Lu-DOTA-EB-TATE in Patients with Advanced Neuroendocrine Tumors (NCT03478358). URL: https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0001JRW&ts=13&sid=S0007RNX&cx=y3yqv4.

Keywords: 177Lu-DOTA-EB-TATE; 177Lu-DOTATATE; Neuroendocrine tumor; Peptide receptor radionuclide therapy (PRRT).

Conflict of interest statement

Conflicts of interest None

Figures

Fig.1

Participant flow chart of the four randomized groups.

Fig. 2

Changes of SUVmax between baseline and post-therapy in each group. (A-D) 50.0% (10/20), 50.0% (9/18), 75.0% (15/20) and 76.9% (30/39) tumor lesions had decreased SUVmax in group A-D, respectively

Fig. 3

Comparison of ΔSUVmax% between 177Lu-DOTATATE group and 177Lu-DOTA-EB-TATE groups (group B-D combined). (A) In all qualified lesions, ΔSUVmax% in 177Lu-DOTATATE group is 5.4 ± 45.9 and in 177Lu-DOTA-EB-TATE groups is −5.2 ± 49.0 (P=0.387); (B) Selecting comparable baseline SUVmax ranging from 15 to 40, mean ΔSUVmax% in 177Lu-DOTATATE group is 8.4 ± 48.8, in177Lu-DOTA-EB-TATE group is −19.0 ± 21.5 (P=0.045).

Fig. 4

When selecting lesions with comparable baseline SUVmax ranging from 15 to 40, SUVmax showed no significant decrease in group B (Δ%= −7.3 ± 24.5%, P=0.214), significant decrease in group C (Δ%= −34.9 ± 12.4%, P=0.001) and group D (Δ%= −17.9 ± 19.7%, P=0.012) as compared to group A with increased SUVmax (Δ%= 8.4 ± 48.8%).

Fig. 5

A 65-year-old woman with G2 duodenum NET, had extensive involvement of liver. (A-C) Baseline 68Ga-DOTATATE PET/CT before administration with 1.96 GBq 177Lu-DOTA-EB-TATE. (D-F) 2 months post-therapy 68Ga-DOTATATE PET/CT showed diffuse decreased uptake in primary tumor and liver metastases from 21.3 to 10.8 (lower arrow) and 38.3 to 22.2 (upper arrows), respectively.

Fig. 6

A 45-year-old man with pancreatic neuroendocrine tumor (G2, primary tumor removal), was accompanied with diarrhea, flushing and hyperglycemia. (A-C) Baseline 68Ga-DOTATATE PET/CT before administration with 4.14 GBq 177Lu-DOTA-EB-TATE. (D-F) 2 months post-therapy 68Ga-DOTATATE PET/CT showed volume reduction and decreased uptake of metastatic liver lesions(arrows) from 54.4 to 26.5.