Dosing 225Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumors: 5-year follow-up of hematological and renal toxicity

Abstract

Purpose: The aim of this retrospective analysis is to estimate the most appropriate single cycle and cumulative doses of ²²⁵Ac-DOTATOC in patients treated for somatostatin-receptor-expressing cancers.

Methods: ²²⁵Ac-DOTATOC was administered to thirty-nine patients with various somatostatin-receptor-positive tumors. Baseline and follow-up ⁶⁸Ga-DOTATOC PET/CT, lab tests, and renal scintigraphy were obtained. Patients received long-term follow-up either at the local cancer center or in close collaboration with external oncologists. Acute and chronic hematological toxicity was evaluated quantitatively over time. Long-term follow-up of creatinine was used to approximate the annual loss of estimated GFR (eGFR).

Results: Dose-dependent acute hematological toxicity was seen at single doses above 40 MBq or repeated doses greater than approximately 20 MBq ²²⁵Ac-DOTATOC at 4 month intervals. Treatment-related kidney failure occurred in 2 patients after a delay of >4 years but was independent of administered radioactivity, and other clinical risk factors were important contributors to renal decline. In general, the annual decline of eGFR among patients did not follow a clear dose-effect relationship even in patients with previous β-therapy. An average eGFR-loss of 8.4ml/min (9.9%) per year was observed which is similar to the experience with β-therapy studies.

Conclusion: Treatment activities of approx. 20 MBq per cycle (4 monthly repetition) and cumulative doses up to 60-80 MBq generally avoided both acute and chronic grade 3/4 hematotoxicity in patients with advanced stage malignancies. Chronic renal toxicity was observed at these doses, but pre-existing renal risk factors were important co-factors. These data represent a starting point for additional research to more precisely define safety thresholds of ²²⁵Ac-DOTATOC.

Keywords: Ac-225; Neuroendocrine tumor; PRRT; TAT; Targeted α therapy.

Fig. 1

Follow-up of platelet count over time. If repeated treatments were conducted with 30–44 MBq activities, i.e., close to the maximum single dose of 45 MBq, additive toxicity occurred (a). In 3–4 monthly intervals, treatment activities < 25 MBq were tolerated without additive effect on thrombocytopenia (b). In 2 monthly interval, additive effects could even be observed for treatment activities of < 25 MBq (c)

Fig. 2

Course of serum creatinine over time of the 24 patients with the longest follow-up (patient numbers according to Supplement Table 1)

Fig. 3

Distributions of patients to the respective extend of annual GFR-loss, following PRRT based on different radiopharmaceuticals (data for ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-Dotatate are based on Ref.-17)

Fig. 4

Scatter plot presenting annual GFR-loss as a function of either (lower x-axis) β-radiation absorbed dose (adopted from Ref.-18,19), overlaid with a scatter plot presenting annual GFR-loss as a function of (upper x-axis) administered activity ²²⁵Ac (actual data)

Fig. 5

A patient who presented with progression of disease (size and novel lesions) during only 3 months of somatostatin analog therapy (orange time-frame), demonstrated enduring tumor response to ²²⁵Ac-DOTATOC for nearly 6 years (green). Next progression was treated with external-beam radiotherapy of painful bone lesions and temozolomide/capecitabine, however again with only short benefit to conventional therapy (red)