Tailoring Radionuclide Therapy of Neuroendocrine Tumors - Bridging the Gaps

Abstract: Background and Aims: Radionuclide therapy is systemic, targeted radiotherapy. As such, we can apply the basic principles of radiobiology used in everyday practice in radiation oncology, as a means of tailoring the treatment to each patient and optimizing the balance between efficacy and toxicity. The most common type of radionuclide therapy used for the treatment of neuroendocrine tumors, is 177Lu-DOTATATE. It has proven to be safe and effective, even without any tailoring. The aim of the work presented in this thesis is to systematically explore how we can further improve results for patients by tailoring the treatment. Methods and Results: The thesis is based on two clinical trials – Iluminet and Gapetto – which were both designed to address different aspects of the overall aim. The Iluminet trial is a phase II trial in which patients, instead of receiving the standard four cycles of 7.4 GBq of 177Lu-DOTATATE, are treated to the maximum number of cycles within the predefined limits for radiation dose to the kidneys. Safety and efficacy data are collected during treatment and follow-up. The Gapetto trial was a prospective observational study looking at the effect of somatostatin analog treatment on the uptake of 68Ga-DOTATATE in PET/CT. Papers I and II are based on the first 51 patients included in the Iluminet trial. Paper I presents data from an interim analysis of renal function, and also describes the effects that tailoring has on treatment planning. The mean number of treatment cycles the patients received was 5, but there were large interindividual variations. No serious renal toxicity was detected during the 24-month median follow-up. Paper II describes the consequences of simplifying the dosimetric protocol in order to make dosimetry more feasible in clinical practice. The results show that basing dosimetry on just one SPECT-image taken att 96h is as accurate as doing full hybrid dosimetry, which is the reference in the trial protocol. Paper III describes the pituitary function in 68 evaluable patients during long-term follow-up in the Iluminet trial. A significant decrease in IGF1 was detected, which could be secondary to the radiation received by the pituitary gland during treatment with 177Lu-DOTATATE, but other possible explanations are also discussed. Paper IV is based on the Gapetto trial. The SUV values in 68Ga-DOTATATE PET/CT were compared before and after initiating treatment with long-acting somatostatin analogs. The effect of the time from the last injection to the PET/CT was also analyzed. Results showed that the use of somatostatin analogs decreased the SUV in normal tissues, but not in tumor. The time since last injection did not affect the SUV-values. Conclusions: Tailoring radionuclide treatment based on individual dosimetry is feasible and safe, and leads to considerable interindividual variations in the number of treament cycles received. No signs of serious renal or pituitary toxicity have been detected. Dosimetry can be substantially simplified without compromising accuracy. Treatment with long-acting somatostatin analogs improves the tumor-to-normal ratio in 68Ga-DOTATATE PET/CT, and possibly also in the therapeutic setting, i.e. when using 177Lu-DOTATATE to treat neuroendocrine tumors.