Feasibility and Therapeutic Potential of Combined Peptide Receptor Radionuclide Therapy With Intensive Chemotherapy for Pediatric Patients With Relapsed or Refractory Metastatic Neuroblastoma

Abstract

Background Recent evidence has demonstrated high expression of somatostatin receptors in neuroblastoma (NB) cells. Because of this, we endeavored to evaluate the diagnostic performance and clinical efficacy of 68Ga-DOTATATE PET/CT and peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE combined with chemotherapy in pediatric NB patients. Patients and Methods In total, 14 pediatric patients with histopathologically confirmed NB underwent 68Ga-DOTATATE PET/CT. Among them, the patients who were refractory or relapsed after therapy with 131I-MIBG and had intensive uptake of 68Ga-DOTATATE were referred for PRRT using 177Lu-DOTATATE. Treatment response based on follow-up imaging was classified into complete response, partial response, stable disease, and progressive disease. After each cycle of PRRT, laboratory tests were performed for evaluation of hematological, renal, and hepatic toxicities. The CTCAE (Common Terminology Criteria for Adverse Events; version 4.03) was used for grading adverse event. Curie score and International Society of Pediatric Oncology Europe Neuroblastoma score were used for semiquantitative analysis of scans of patients who underwent PRRT. In addition, overall survival was calculated as the time interval between the date of the first cycle and the end of follow-up or death. Results Overall, 14 refractory NB children including 7 boys and 7 girls with a median age of 5.5 years (ranged from 4 to 9) underwent 68Ga-DOTATATE PET/CT. PET/CT was positive in 10/14 patients (71.4%), and the median number of detected lesions in positive patients was 2 (range, 1–13). Of 14 patients, 5 patients underwent PRRT, including 3 boys and 2 girls. A total of 19 PRRT cycles and 66.4 GBq 177Lu-DOTATATE were given. Among these 5 patients, 2 showed an initial complete response, which relapsed a few months later, 1 showed a partial response, and 2 showed progressive disease. According to the Kaplan-Meier test, the overall survival was estimated at 14.5 months (95% confidence interval, 8.9–20.1). In evaluation of PRRT-related toxicity according to the CTCAE, 4 patients showed grade 1, and 1 showed grade 2 leukopenia. Two patients showed grade 1, and 2 others showed grade 2 anemia. Two patients showed grade 1, and 3 patients showed grade 2 thrombocytopenia. Serum creatinine in 1 patient increased to grade 1. Conclusions Combination of 177Lu-DOTATATE with chemotherapeutic agents might achieve worthwhile responses with low toxicity, encouraging survival in NB patients who have relapsed or are refractory to conventional therapy, including 131I-MIBG therapy. Imaging with 68Ga-DOTATATE PET/CT in such patients has a relatively high detection efficacy, demonstrating its potential use as an alternative imaging tool to conventional modalities such as 123I/131I-MIBG. However, further well-designed trials are highly warranted.

Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy

“…(2,10,11,13,16,20,92,102,135,245,262). In studies on non-CNS tumors, PRRT has been successful both when used alone (4,11,20,21,42,73,74) and in combination with other cytotoxic therapies, including chemotherapy (284,(305)(306)(307)(308)(309). Third, the BnR ectopic expression/overexpression by these tumors can be used also for targeted delivery of cytotoxic non-radiolabeled compounds including chemotherapeutic agents, which is increasingly being studied in other malignant tumors (4,10,13,42,74,78,79).…”

Renal protection during 177lutetium DOTATATE molecular radiotherapy in children: a proposal for safe amino acid infusional volume during peptide receptor radionuclide therapy

“…Although there are a few published reports on the use of amino acid infusions in children for renal protection during PRRT, these describe significant variations in the infusional volume, the type of amino acids used, and the duration of the infusion [4,10,12,27,28]. While no immediate renal toxicity was reported in any of the publications, most of the reports did not include the cumulative radiation dose to the kidneys, which is predictive of late-onset renal disease [29].…”

“…Large randomised trials using PRRT in adults with neuroendocrine tumours have demonstrated survival and quality of life benefits [6][7][8][9]. There is increasing use of labelled SSTR analogues in paediatric neuroendocrine tumours including neuroblastomas [10][11][12].…”

Radiotheranostic Agents Targeting Neuroblastoma: State-of-the-Art and Emerging Perspectives

“…Another interesting research in the field was recently published by Fathpour et al, who evaluated the feasibility of PRRT with 177 Lu-DOTATATE in 14 children with histologically proven and therapy-refractory NB, some of whom had previously received chemotherapy [44]. All subjects were submitted to PET/CT with 68 Ga-DOTATATE, which resulted positive in 10 out of 14 cases and detected a median number of 2 lesions per patient.…”