Phase I trial of 90Y-DOTATOC therapy in children and young adults with refractory solid tumors that express somatostatin receptors

Abstract

The purpose of this study was to conduct a phase I trial of (90)Y-DOTATOC to determine the dose-toxicity profile in children and young adults with somatostatin receptor-positive tumors.

Methods: A 3 × 3 design was used to determine the highest tolerable dose of (90)Y-DOTATOC, with administered activities of 1.11, 1.48, and 1.85 GBq/m(2)/cycle given in 3 cycles at 6-wk intervals. An amino acid infusion was coadministered with the radiopharmaceutical for renal protection. Eligibility criteria included an age of 2-25 y, progressive disease, a positive lesion on (111)In-diethylenetriaminepentaacetic acid-D-Phe(1)-octreotide scanning, a glomerular filtration rate of 80 mL/min/1.73 m(2) or more, bone marrow cellularity of 40% or more or stored autologous hematopoietic stem cells, 60% or more on the Lansky Play Scale, and informed consent.

Results: Seventeen subjects (age, 2-24 y) received at least 1 dose of (90)Y-DOTATOC; diagnoses included neuroblastoma, embryonal and astrocytic brain tumors, paraganglioma, multiple endocrine neoplasia IIB, and neuroendocrine tumors. No dose-limiting toxicities and no individual dose reductions due to renal or hematologic toxicity were noted. No complete responses were observed; 2 subjects experienced partial response, 5 had minor responses, 6 experienced stable disease, 2 had progressive disease, and 2 withdrew.

Conclusion: Peptide receptor radionuclide therapy with (90)Y-DOTATOC is safe in children and young adults and demonstrated a 12% partial response plus 29% minor response rate in patients with somatostatin receptor-positive tumors. No dose-limiting toxicities were observed. The recommended phase II dosing is 3 cycles of 1.85 GBq/m(2)/dose of (90)Y-DOTATOC coadministered with amino acids.

Figures

Figure 1

Baseline and posttherapy imaging of Subject #3 with anaplastic astrocytoma. This subject had surgery and chemotherapy followed by cranial-spinal radiation as initial treatment of disease with further chemotherapy after recurrence. Baseline OctreoScan (A) shows intense uptake in the left parietal tumor seen on MRI (B). Posttherapy images show decrease in uptake (C) with partial response on MRI with reduction of tumor size and decrease in enhancement around the lesion (D). This patient was able to return to school and participate in sports for 2 years following therapy, but ultimately experienced tumor recurrence and died of the disease 23 months after the last dose of 90Y-DOTA0-Tyr3-octreotide.

Figure 2

Baseline (A1–A3) and posttherapy (B1–B3) coronal OctreoScan and CT scan images of Subject #5 with pancreatic gastrinoma and extensive liver metastases. The pancreatic primary tumor (A2; arrow) and an adjacent liver lesion (A3; arrow) show intense uptake of 111In-DTPA-D-Phe1-octreotide (A1; arrow). This patient was treated for gastric ulcers until liver metastases were observed on CT scan. After treatment with 90Y-DOTA0-Tyr3-octreotide, there is significant decrease in tumor burden on OctreoScan (B1) and partial response in target lesions on the CT scan (B2 and B3; arrows). The serum gastrin levels decreased from 5440 pg/ml to 824 pg/ml. The pancreatic tumor was subsequently resected along with a partial hepatectomy. A subsequent increase in gastrin level coincided with regrowth of a liver lesion at the resection margin. A second surgery was performed to extricate this lesion and achieve clear margins; this subject remains free of disease, maintained on octreotide, 68 months post 90Y-DOTA0-Tyr3-octreotide.

Figure 3

Baseline (A1–A5) and posttherapy (B1–B5) coronal OctreoScan and CT scan images of a patient with liver metastases from poorly differentiated bronchial carcinoid (Subject #14). The primary bronchial carcinoid had not been removed due to extensive liver disease at the time of initial diagnosis. Baseline OctreoScan images show multiple hepatic metastases (A1–A2), a left lung lesion and a thoracic spine metastasis (A4; arrows) with corresponding liver and lung lesions seen on CT (A5; arrow). The standard 111In activity (S) is seen on pretherapy OctreoScan. Posttherapy images (B1–B5) show improvement in the liver lesions as well as the thoracic spine and lung lesions on OctreoScan, although this only qualified for minimal response based on the assessment of target lesions on CT. The serum chromogranin level in this patient dropped from 69404 ng/ml to 11160 ng/ml. This was followed by resection of primary lung lesion and stabilization of disease for 19 months.

Figure 4

The mean blood concentration of 111In-DTPA-D-Phe1-octreotide and 90Y-DOTA0-Tyr3-octreotide normalized to the amount of administered activity for 8 administrations in 5 patients.