Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life

Abstract

Peptide receptor radionuclide therapy (PRRT), developed over the last two decades, is carried out using radiopharmaceuticals such as 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotate (177Lu-Dotatate). These radiocompounds are obtained by labeling a synthetic somatostatin analog with a β-emitting radioisotope. The compounds differ from each other in terms of their energetic features (due to the radionuclide) and peptide receptor affinity (due to the analog) but share the common characteristic of binding specific membrane somatostatin receptors that are (generally) overexpressed in neuroendocrine neoplasms (NENs) and their metastases. NENs are tumors arising from diffuse neuroendocrine system cells that are classified according to grading based on Ki67 percentage values (Grades 1 and 2 are classed as neuroendocrine tumors [NETs]) and to the anatomical site of occurrence (in this paper, we only deal with gastroenteropancreatic [GEP]-NETs, which account for 60%–70% of all NENs). They are also characterized by specific symptoms such as diarrhea and flushing (30% of cases). Despite substantial experience gained in the area of PRRT and its demonstrable effects in terms of efficacy, safety, and improvement in quality of life, these compounds are still not registered (registration of 177Lu-Dotatate for the treatment of midgut NETs is expected soon). Thus, PRRT can only be used in experimental protocols. We provide an overview of the work of leading groups with wide-ranging experience and continuity in data publication in the area of GEP-NET PRRT and report our own personal experience of using different dosage schedules based on the presence of kidney and bone marrow risk factors. Our results on the retreatment of patients previously administered 90Y-DOTA-Tyr3-octreotide with a low dosage of 177Lu-Dotatate are also included. A comment on potential future developments of PRRT in GEP-NETs is provided.

Theranostics of Neuroendocrine Tumors

“…The initial studies on Y-90-DOTA-Tyr3-octreotide (Y-90 DOTATOC) had reported objective response rates in 6-37% of patients, and response to Y-90 DOTATOC was associated with a longer survival. SSTR imaging was predictive for both survival after Y-90 DOTATOC therapy and the occurrence of renal toxicity [3,11]. Whilst Lu-177-DOTA-Tyr3-octreotate (Lu-177 DOTATATE) utilized the lower tissue penetration of Lu-177 coupled with the longer half-life of the radionuclide, DOTATATE has up to 9-fold higher peptide receptor affinity for SSTR2 compared to DOTATOC [12], the latter having higher affinity to SSTR 3 and SSTR5 [13].…”

“…Lu-177 DOTATATE might have more favorable characteristics for PRRT due to a lower whole-body dose, resulting in potentially lower bone marrow toxicity [15]. Dosimetry studies have also confirmed the high specificity of PRRT against tumors, whilst being able to spare healthy tissue [3]. Current administration schedules comprise the most appropriate number of cycles (generally four or five) and the best delivery frequency (10 ± 2 weeks apart).…”

“…In some situations, the efficacy of PRRT in high-risk patients can be raised by increasing the total administered activity or the number or frequency of PRRT cycles, or by administering radiosensitizer agents such as capecitabine or capecitabine plus temozolomide [20]. These new therapeutic options may provide a further personalization of treatment by increasing the dose intensity only when required [3]. …”

“…These tumors are characterized by high expression of somatostatin receptors (SSTRs) and specific markers, including chromogranin A, CD53 protein, and neuron-specific enolase [3]. Currently, NET is classified based on the grading (Ki67 and mitotic index (MI)) and location of the neoplasms.…”

Compartment Biokinetic Model for 90y-Dotatoc

“…21 90 Y-DOTATOC has a high affinity to tumor tissue expressing somatostatin receptors, but this therapy can damage kidneys and red bone marrow. [22][23][24][25][26][27] Clinical studies show that this therapy can delivery very large doses, up to 200 Gy in the tumor tissue, but doses in kidneys, 28,29 liver, 30,31 and red bone marrow 32,33 are also relatively large.…”