Abstract
Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding 131I-metaiodobenzylguanidine (131I-MIBG) to PRRT may be advantageous in this regard. Methods: A phase 1 clinical trial was initiated for patients with nonoperable progressive neuroendocrine tumors using a combination of 90Y-DOTATOC plus 131I-MIBG. Treatment cohorts were defined by radiation dose limits to the kidneys and the bone marrow. Subject-specific dosimetry was used to determine the administered activity levels. Results: The first cohort treated subjects to a dose limit of 1,900 cGy to the kidneys and 150 cGy to the marrow. No dose-limiting toxicities were observed. Tumor dosimetry estimates demonstrated an expected dose increase of 34%-83% using combination therapy as opposed to 90Y-DOTATOC PRRT alone. Conclusion: These findings demonstrate the feasibility of using organ dose for a phase 1 escalation design and suggest the safety of using 90Y-DOTATOC and 131I-MIBG.
Highlights
DOTATATE (Lutathera; Advanced Accelerator Applications) or as 90Y-DOTATOC, is well established as an effective form of treatment for patients with metastatic neuroendocrine tumors [1,2,3]
Delivering a tumor radiation dose sufficient to result in a high percentage of overall response rates remains challenging because of limits imposed on administered activity levels by radiation-induced normal-organ toxicity [4]
We have previously demonstrated that this difference enables the combination of large fractions of each agent into a single treatment regimen that results in higher total tumor radiation doses without exceeding dose limits for either the marrow or the kidneys [11]
Summary
DOTATATE (Lutathera; Advanced Accelerator Applications) or as 90Y-DOTATOC, is well established as an effective form of treatment for patients with metastatic neuroendocrine tumors [1,2,3]. Cancer trials on targeted radionuclide therapy have relied on a “one size fits all” approach to treating patients in terms of prescribed levels of administered activity. We initiated a phase 1 clinical trial in which the escalation design was based on increasing the radiation dose limits to critical organs between cohorts as opposed to using cohorts defined by specific escalated levels of administered activity. Within this trial framework, we applied the technique previously described for addition of 131I-MIBG to PRRT using patientspecific dosimetry [14]. We report here the results from this trial before a redesign wherein 90Y-DOTATOC is being replaced by 177Lu-DOTATATE and low-specific-activity 131I-MIBG is being replaced by high-specific-activity 131I-MIBG
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