Response to Single Low-dose 177Lu-DOTA-EB-TATE Treatment in Patients with Advanced Neuroendocrine Neoplasm: A Prospective Pilot Study

Abstract

Objective:¹⁷⁷Lu-DOTA-EB-TATE is a theranostic agent based on octreotate that uses an Evans blue structure to bind albumin to improve the pharmacokinetics and pharmacodynamics. This pilot study aims to evaluate the efficacy of a single low-dose treatment using ¹⁷⁷Lu-DOTA-EB-TATE in patients with advanced neuroendocrine neoplasm (NEN). Methods: With IRB approval and informed consent, 4 NEN patients were enrolled to undergo ¹⁷⁷Lu-DOTA-EB-TATE treatment with a single low dose of 0.66 ± 0.06 GBq (17.8 ± 1.7 mCi); 3 other NEN patients were enrolled as controls to undergo ¹⁷⁷Lu-DOTA-TATE treatment with administered activity of 3.98 ± 0.17 GBq (107.6 ± 4.6 mCi). One primary tumor and 62 metastatic lesions in the 7 patients were evaluated by ⁶⁸Ga-DOTA-TATE PET/CT immediately before and one or three months after the treatment. Maximum SUV (SUV_max) of the tumors ≥2.0 cm in diameter were measured and percentage of change (ΔSUV) after treatment were calculated. Results: All 4 patients subjected to ¹⁷⁷Lu-DOTA-EB-TATE treatment tolerated the administered activity without significant adverse effects and showed symptomatic remission. Among the patients, 40 tumors were found with diameter ≥2.0 cm, with the baseline SUV_max varied from 1.5-82.9 (35.9 ± 21.0) and the ΔSUVs before and three months after the treatment from -75.1-26.3% (-38.9 ± 25.5%). Twenty-nine (72.5%) of the tumors showed >15% decrease of SUV_max (ΔSUV = -75.1%--17.1%). There was a significant negative correlation between the baseline SUV_max and the ΔSUV after treatment (r = -0.852, P < 0.001). Compared with the control ¹⁷⁷Lu-DOTA-TATE therapy, the ¹⁷⁷Lu-DOTA-EB-TATE treatment using approximately 1/6 the dose showed no significant difference in ΔSUV (-7.9 ± 5.4% vs. -5.8 ± 3.9%, P = 0.189) as demonstrated by the tumors with comparable baseline SUV_max from 10.0-35.0. Conclusion: A single low-dose ¹⁷⁷Lu-DOTA-EB-TATE treatment appears to be safe and effective in the treatment of NENs with high ⁶⁸Ga-DOTA-TATE uptake. This pilot study merits further investigation with increased dose and frequency of ¹⁷⁷Lu-DOTA-EB-TATE administration with potential advantages over ¹⁷⁷Lu-DOTA-TATE.

Keywords: 177Lu-DOTA-EB-TATE; 68Ga-DOTA-TATE; PET/CT; neuroendocrine neoplasm; treatment.

Figure 1

The changes of indicators of hemotoxicity (A-D), hepatotoxicity (E-H) and nephrotoxicity (I, J) at baseline, 1 month and 3 months after the ¹⁷⁷Lu-DOTA-EB-TATE treatment. The two dotted lines on each graph represent the upper and lower limits of the reference range. The P values were from one-way ANOVA of repeated-measures. No significant change was observed in hematology parameters, kidney and liver function. WBC, white blood counts; NE, neutrophils counts; PLT, platelet counts; Hb, hemoglobin; ALT, alanine aminotransferase; AST, aspartate transferase; GGT, glutamyl transpeptidase; TBIL, total bilirubin; Scr, serum creatinine.

Figure 2

Molecular response demonstrated by changes of ⁶⁸Ga-DOTA-TATE uptake in the patients. A: Changes of tumor SUV_max in 40 NEN lesions with diameter ≥2.0 cm in 4 patients underwent a dose of 0.65 ± 0.06 GBq (17.8 ± 1.7 mCi) ¹⁷⁷Lu-DOTA-EB-TATE treatment. B: Changes of tumor SUV_max in 23 NEN lesions in 3 control patients after ¹⁷⁷Lu-DOTA-TATE treatment in a dose of 2.91 ± 0.12 GBq (107.6 ± 4.6 mCi). C: There was a significant negative correlation between baseline SUV_max and ΔSUV among the 40 NEN lesions underwent ¹⁷⁷Lu-DOTA-EB-TATE treatment (r = -0.852, P < 0.001). The P value was from Spearman rank correlation test. D: In the tumors with comparable baseline SUV_max from 10.0-35.0, ¹⁷⁷Lu-DOTA-EB-TATE treatment using approximately 1/6 the doses and ¹⁷⁷Lu-DOTA-TATE therapy showed similar molecular response as revealed by ΔSUV (-7.9 ± 5.4% vs. -5.8 ± 3.9%, P = 0.189). The P value was from Student's t-test.

Figure 3

Comparison of ⁶⁸Ga-DOTA-TATE PET/CT images immediately before (A-C) and 3 months after (D-F) a single low-dose (19.5 mCi) treatment of ¹⁷⁷Lu-DOTA-EB-TATE in a patient (patient 2) with pancreatic neuroendocrine tumor and liver metastases. The SUV_max of the primary tumor in pancreas decreased from 26.7 to 13.0 (arrow), and the SUV_max of the highest-uptake liver metastasis decreased from 50.6 to 28.6 (triangle). The tumor-to-muscle uptake ratio changed from 29.0 and 55.0 to 13.7 and 30.1 for the primary tumor and liver metastasis, respectively.

Figure 4

Comparison of ⁶⁸Ga-DOTA-TATE PET/CT images immediately before (A-C) and 3 months after (D-F) a single low-dose (18.5 mCi) treatment of ¹⁷⁷Lu-DOTA-EB-TATE in a patient (patient 4) with G3 neuroendocrine tumor originated from mediastinum (primary tumor removed). The SUV_max of the highest-uptake mediastinal lymph node metastasis increased from 4.0 to 4.2 (arrow), the SUV_max of the highest-uptake axillary lymph node metastasis increased from 3.8 to 4.8 (triangle). The tumor-to-muscle uptake ratio increased from 5.0 and 4.8 to 6.1 and 7.0 for mediastinal lymph node metastasis and axillary lymph node metastasis, respectively.

Figure 5

Comparison of ⁶⁸Ga-DOTA-TATE PET/CT images immediately before (A-C) and 1 month after (D-F) 105 mCi treatment of ¹⁷⁷Lu-DOTA-TATE in a patient (patient 5) with G2 neuroendocrine tumor. The SUV_max of the highest-uptake liver metastasis decreased from 29.4 to 23.1 (arrow), the SUV_max of the highest-uptake abdominal lymph node metastasis decreased from 33.7 to 19.7 (triangle). The tumor-to-muscle uptake ratio decreased from 56.5 and 64.8 to 42.0 and 35.8 for liver metastasis and abdominal lymph node metastasis, respectively.