¹⁷⁷Lu-DOTATATE Therapy of Advanced Pancreatic Neuroendocrine Tumors Heavily Pretreated with Chemotherapy: Analysis of Outcome, Safety, and Their Determinants

Abstract

Objective: To retrospectively analyze toxicity, progressionfree survival (PFS), overall survival (OS), and their determinants in patients with advanced pancreatic neuroendocrine tumors (PanNETs), previously pretreated with chemothe rapy, undergoing peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE. Methods: A total of 102 patients with advanced PanNETs, previously pretreated with one (67%) or several (33%) lines of chemotherapy, were included, of whom 90% had progressive disease and the majority (74.5%) had grade 2 tumors. 177 Lu-DOTATATE, 7.4 GBq per cycle, was administered with 6-to 8-week intervals in 88% of patients utilizing a dosimetry-guided protocol until an absorbed dose of 23 Gy to the kidneys was reached. Results: A mean dose of 32 ± 10.9 GBq per patient was administered in 1-10 cycles starting a median of 36 months after PanNET diagnosis. The median follow-up was 34 months, the median PFS was 24 months, and the median OS was 42 months from start of PRRT. Independent risk factors for both progression and death were liver tumor burden > 50%, more than one line of previous chemotherapy, and elevated alkaline phosphatase. Resection of the primary tumor was linked to longer survival. Bone marrow toxicity grade 3-4 occurred in 10.8%. One patient (1.0%) developed acute myeloid leukemia. Bone marrow toxicity was unrelated to type and length of previous chemotherapy, amount of administered activity, and absorbed dose to the bone marrow. Conclusion: 177 Lu-DOTATATE therapy was feasible, highly effective, and safe in patients with advanced PanNETs heavily pretreated with chemotherapy. More than one line of chemotherapy was a therapy-related independent risk factor for shorter PFS and OS.

Tumor growth rate in pancreatic neuroendocrine tumor patients undergoing PRRT with 177Lu-DOTATATE

“…As the number of patients with G1 and G3 tumors was fairly low, a subgroup analysis based on the WHO grading was not applicable in our material. Therefore, patients were dichotomized based on a Ki-67 index at 10% ( 15 , 29 ). This turned out to be useful both in the univariable (HR 0.39; 95% CI 0.17–0.91, P = 0.029, n = 53) and in the multivariable (HR 0.38; 95% CI 0.16–0.93, P = 0.033, n = 53) analysis.…”

“…In therapy monitoring of PanNET patients undergoing PRRT with 177 Lu-DOTATATE, the RECIST 1.1 criteria are used to measure changes in the sum of tumor diameters by CECT/MRI ( 10 ). As changes in tumor size tend to appear in late stages of the therapy, or even after finishing PRRT, there is a need for more precise methods to differentiate responders from non-responders earlier ( 13 , 15 , 30 ). Such methods could be a complement to the RECIST 1.1 criteria to identify the patients with a less favorable prognosis who need to be followed more closely vs those for whom these intervals may be longer.…”

“…Therapy monitoring based on tumor size changes is associated with several problems as well-differentiated NETs tend to stabilize or initially increase in size even when responding to the treatment ( 13 , 14 ). Tumor shrinkage in patients during PRRT is usually a late event, as illustrated in a recent study on PanNET patients showing best response (RECIST 1.1) at median 14.8 months after start of 177 Lu-DOTATATE therapy ( 15 ).…”

Shuttling of Peptide‐Drug Conjugates by G Protein‐Coupled Receptors Is Significantly Improved by Pulsed Application

“…The effectiveness of current PRRT is promising but applications are still limited owing to the lack of suitable conjugates. Until now, two diverse peptide–drug conjugates ( 177 Lu‐DOTATATE, 90 Y‐DOTATOC), both addressing the somatostatin receptor are typically used to treat neuroendocrine tumors (NETs) with great potential [25,26] …”

Currently available treatment options for neuroendocrine liver metastases

“…Although in most studies assessment of the treatment response occurred at all sites, many patients had undergone resection of the primary and the liver was the dominant site of metastases assessed by RECIST criteria. Although no randomized PRRT trial has been conducted in pancreatic and lung NENs as yet, the efficacy of PRRT in these subsets of NENs has been confirmed in retrospective studies with real-world data, also in the setting of patients heavily pretreated with chemotherapy [ 109 - 111 ].…”