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Merola, E.; Grana, C.M. Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements. Encyclopedia. Available online: https://encyclopedia.pub/entry/56578 (accessed on 25 May 2024).
Merola E, Grana CM. Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements. Encyclopedia. Available at: https://encyclopedia.pub/entry/56578. Accessed May 25, 2024.
Merola, Elettra, Chiara Maria Grana. "Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements" Encyclopedia, https://encyclopedia.pub/entry/56578 (accessed May 25, 2024).
Merola, E., & Grana, C.M. (2024, April 10). Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements. In Encyclopedia. https://encyclopedia.pub/entry/56578
Merola, Elettra and Chiara Maria Grana. "Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements." Encyclopedia. Web. 10 April, 2024.
Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements
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Neuroendocrine neoplasms (NENs) are tumors originating from neuroendocrine cells distributed throughout the human body. With an increasing incidence over the past few decades, they represent a highly heterogeneous group of neoplasms, mostly expressing somatostatin receptors (SSTRs) on their cell surface. Peptide receptor radionuclide therapy (PRRT) has emerged as a crucial strategy for treating advanced, unresectable neuroendocrine tumors by administering radiolabeled somatostatin analogs intravenously to target SSTRs. This article will focus on the multidisciplinary theranostic approach, treatment effectiveness (such as response rates and symptom relief), patient outcomes, toxicity profile of PRRT for NEN patients and results of the most significant studies.

peptide receptor radionuclide therapy neuroendocrine neoplasms somatostatin receptor

1. Introduction: Neuroendocrine Neoplasms

Neuroendocrine neoplasms (NENs) represent a highly heterogeneous group of neoplasms with varying biological behavior. In fact, some cases have a very malignant behavior, whereas in other patients, disease may be stable for a long time even without any treatment. NENs are characterized by a gap between the low incidence (3–5 cases per 100,000 people annually) and the prevalence, as they are frequently slowly growing, and behave as chronic oncological diseases with a relatively long survival [1][2]. Several prognostic factors impact their survival, including the proliferative index (Ki-67), TNM stage and the World Health Organization (WHO) 2019 classification [3][4]. According to this classification, the definition of NENs includes all neoplasms with a neuroendocrine differentiation, characterized by immunolabeling for chromogranin A and synaptophysin. However, two different subgroups can be distinguished in terms of cell morphology, genetics, and prognosis: neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NETs are well-differentiated neuroendocrine neoplasms, with cells presenting uniform nuclear features, “salt and pepper” chromatin, and only minimal necrosis. NETs are classified according to the proliferation index in G1 (Ki-67 index < 3%), G2 (Ki-67 index 3–20%), and G3 (Ki-67 index > 20%). Instead, NECs are high-grade, poorly differentiated neoplasms, with aggressive behavior, and presenting with abundant necrosis. They are further distinguished into small-cell NECs or large-cell NECs, based on the cell morphology.
Somatostatin receptor (SSTR) expression characterizes approximately 90% of NENs. Among the five subtypes of SSTRs, NETs usually express SSTR2 and SSTR5, though different tumor types present considerable variability in expression [5]. SSTRs are primarily identified through functional imaging tests, which are usually performed at diagnosis both for disease staging and for choosing a therapeutic strategy. Among these techniques, which represent a standard procedure for whole-body imaging of NENs, octreotide scintigraphy with radiolabeled somatostatin analogs (SSAs) ([111In]In-DTPA-Octreotide) is limited by a low accuracy in detecting lesions with size < 1 cm and by a difficult semiquantitative analysis. The subsequent development of different radiolabeled DOTA-conjugated peptides (DOTA-NOC, DOTA-TOC, DOTA-TATE) for positron emission tomography/computed tomography (PET/CT) has represented a relevant innovation, progressively showing the ability to detect at least 30% more lesions than [111In]In-DTPA-Octreotide and conventional CT [6][7].
Despite international guidelines proposing therapeutic algorithms, NEN patients require personalized treatments based on disease characteristics [8]. Surgery with curative intent is always the option to prefer when feasible, but up to 80% of cases are metastatic at diagnosis and are not candidates for this approach. Moreover, data on adjuvant treatments are still insufficient for NENs. Thus, medical treatments represent the best approach for these patients, with somatostatin analogs (SSAs) frequently representing the first-line option when lesions express SSTRs. Other medical treatments, providing the possibility of multiple therapy lines, include chemotherapy, targeted drugs (such as everolimus and sunitinib), and peptide receptor radionuclide therapy (PRRT) [9].

2. Peptide Receptor Radionuclide Therapy (PRRT): Mechanisms of Action

Peptide receptor radionuclide therapy (PRRT) is a type of targeted radionuclide therapy which involves the systemic administration of therapeutic peptides labeled with radionuclides that selectively target cancer cells. Radiolabeled SSAs are the preferred choice for PRRT, as the receptor-peptide complex is internalized via endocytosis and the radionuclide is preferentially retained by the receptor-expressing tumor cells [10]. This process can lead to cell death, as the beta-particles released by lutetium-177 or yttrium-90 primarily cause DNA single-strand breaks. Furthermore, in addition to the direct effects of the radiation on treated cells, beta-particles can also impact neighboring cells by means of the cross-fire effect and bystander effect, enhancing PRRT efficacy. The former effect is attributed to the greater range of beta-particles compared to the cell diameter [11], while the latter refers to the induction of biological effects in cells near the targeted cells as if they were directly hit [12].

3. PRRT in Clinical Practice

Before initiating PRRT, a baseline [111In]In-DTPA-Octreotide or [68Ga]Ga-DOTA-TOC (SomaKit TOC®, Advanced Accelerator Applications, Saint-Genis-Pouilly, France) is mandatory with the aim of obtaining a mapping of all SSTR-positive lesions. Candidates for PRRT should exhibit a strong SSTR expression, while diffuse hepatic and/or bone disease, as well as impaired renal function, may represent a limit to its indication. According to the ENETS Consensus Guidelines, “PRRT is a therapeutic option in progressive SSTR-positive NET with homogenous SSTR expression (all lesions are positive)” [13].
Several radiolabeled DOTA-derivatized are available. [90Y]Y-DOTA-TOC is currently used for locoregional treatments of liver metastases, due to its higher renal toxicity, or in some clinical trials. [177Lu]Lu-DOTA-TOC and [177Lu]Lu-DOTA-TATE are also used in PRRT, with the latter approved for gastro-entero-pancreatic (GEP-) NETs by the United States Food and Drug Administration (FDA) in 2018. The standard schedule for PRRT comprises four infusions of 7.4 GBq (200 mCi) [177Lu]Lu-DOTA-TATE every eight weeks, which may be extended up to 16 weeks if dose-modifying toxicity occurs [14].
Toxicity includes myelotoxicity, which can be mitigated through extracorporeal affinity adsorption treatment and is typically mild and reversible. However, up to 10% of patients may develop WHO Grade 3/4 hematotoxicity, and rarely myelodysplastic syndrome or leukemia [15][16]. Since radiopeptides accumulate in the renal interstitium, nephrotoxicity may also arise; nonetheless, it can be reduced by administering a positively charged amino acid infusion (L-lysine and L-arginine) before, during, and after the radiopharmaceutical administration, decreasing kidney radiation dose by up to 60%. This infusion may induce nausea and vomiting, and hence the concomitant administration of antiemetic drugs is recommended. Nevertheless, prior to each dose of [177Lu]Lu-DOTA-TATE, liver and kidney function, as well as blood-related measures, should be assessed as signs of toxicity may necessitate a longer treatment interval, reduced dosage, or even permanent cessation of the treatment [15].
Caution should be adopted in the case of GEP-NENs with peritoneal carcinomatosis, as this therapy has relevant limitations in controlling peritoneal disease. Furthermore, inflammation induced by PRRT may cause bowel obstruction and/or ascites in up to 22% of treated patients presenting with diffuse peritoneal disease (especially in the case of large tumor nodules) [17]. These complications may be caused by the occurrence of radiation-induced peritonitis or paralytic ileus. Similar events have been reported in the literature for other neoplasms, such as ovarian carcinomas treated with external irradiation, and may be prevented by administering a low-dose steroid starting on the day of PRRT and continuing for 2–4 weeks after therapy. The correlation between PRRT and these clinical complications, as well as the ineffective peritoneal disease control, suggest that this therapy might not be the treatment of choice in cases with diffuse carcinomatosis, and that should be reserved only for strictly selected cases with minor peritoneal involvement.

4. Data from the Literature

PRRT has been studied in numerous retrospective studies and single-arm clinical trials in heterogeneous patient populations that have demonstrated that radiolabeled SSAs deliver targeted radiation with a high therapeutic index to tumors that express SSTRs, thus inhibiting tumor growth in 50–70% of GEP-NETs [18]. However, the true turning point for the widespread adoption of PRRT for advanced, progressive GEP-NETs was the phase III randomized controlled trial (RCT) NETTER-1 [14]. The study demonstrated that in 229 patients affected by progressive, unresectable, midgut NETs G1–G2, the combination of [177Lu]Lu-DOTA-TATE and best supportive care (including Octreotide 30 mg) outperformed the monthly administration of Octreotide 60 mg alone. The progression-free survival (PFS) rates after 20 months of treatment were 65.2% and 10.8%, respectively. Following the publication of the preliminary results of NETTER-1 in the New England Journal of Medicine, the international scientific community began to recognize the potential of PRRT. Consequently, PRRT with [177Lu]Lu-DOTA-TATE has been approved by both the US FDA and the European Medicines Agency (EMA).
The final overall survival (OS) analysis was carried out five years after the last patient was randomized, with a median follow-up of 76 months for both groups [19]. The PRRT arm exhibited a median OS of 48.0 months, compared to 36.3 months in the control group. It is important to note that the adjusted median OS for control group patients who switched to receive PRRT was 30.9 months.
Regarding safety, the trial demonstrated that PRRT with [177Lu]Lu-DOTA-TATE was well-tolerated, safe, and provided significant quality-of-life benefits compared to high-dose octreotide [20]. The concurrent administration of amino acids as renal-protective agents played a crucial role in preventing radiation damage to the kidneys. PRRT was associated with low incidences of Grade 3 or 4 hematologic toxic effects, indicating that the doses to the red marrow were not dangerously high.
These successful results were reinforced by a meta-analysis of 22 studies investigating the efficacy of [177Lu]Lu-DOTA-TATE/DOTATOC in 1758 advanced/inoperable NETs [9]. The pooled disease partial response accounted for 25.0–35.0%, while the pooled disease control rate (DCR) reached 80.0%. These results proved the efficacy of PRRT as an antineoplastic therapy for GEP-NETs.
An international consensus has then confirmed the indication for PRRT as a second-line approach for the patients with [68Ga]Ga-DOTA-SSA-uptake in all lesions, in NET G1–G2 at disease progression, and in selected cases of NETs G3 with all lesions being positive at [68Ga]Ga-DOTA-PET/CT [21].

5. Novel Biomarkers and Potential Role of 18F-FDG-PET/CT

Disease progression during PRRT has been reported in 15–30% of cases, and reliable predictive biomarkers of response to therapy are still lacking. Proposed tests include the “PRRT prediction quotient” (PPQ), which is a blood-based assay for eight genes, capable of predicting PRRT efficacy with a 97% accuracy, and the “NETest”, which boasts a 98% accuracy rate in assessing response to PRRT. Trends in NETest results correlate with PPQ predictions. However, neither test can predict toxicity [22][23].
The 18Fluorine-fluorodeoxyglucose ([18F]F-FDG) PET/CT may also aid in selecting patients for PRRT. As it documents the metabolic activity of tumoral lesions, and as many NENs present a low Ki-67, it has been initially reserved only for selected cases, mainly with poorly differentiated diseases. Recently, the International Consensus on the role of theranostics in NENs has expanded its application also to NECs, NETs G3, and even NETs G1–G2, with the goal of identifying the mismatched lesions ([18F]F-FDG-PET/CT-positive/[68Ga]Ga-DOTA-SSA-negative) [21]. Indeed, as up to 45% of patients referred to PRRT may exhibit heterogeneous SSTR expression, ([18F]F-FDG-PET/CT could differentiate GEP-NETs G1–G2 into low- and high-risk categories for poor response [24]. Chan et al. have proposed a grading system of the combined reading of SSTR-PET/CT and ([18F]F-FDG-PET/CT, defined as the “NETPET” score [25]. Although requiring validation in larger prospective studies, this score may represent a useful tool to apply in clinical practice for both lung and GEP-NENs [26].
Further trials aimed at assessing potential biomarkers for PRRT are currently ongoing (NCT05513469).

6. PRRT for G3 Patients

As for the application of PRRT in GEP-NENs G3, available data stem from retrospective series, suggesting a potentially active role of this therapy for highly proliferating diseases. Median PFS with PRRT reached 19 months for NETs G3 compared to 11 months for NECs with Ki-67 < 55%, and a mere 4 months for NECs with higher Ki-67 [27]. PRRT may thus be considered for GEP-NENs G3 with the following features: increased uptake on somatostatin-based imaging tests, Ki-67 < 55%, unresectable disease, reasonable performance status (Karnofski Score > 50%), and a life expectancy of at least 3–6 months [28][29][30]. At the moment, two RCTs are exploring PRRT in G2 and G3 GEP-NENs: the NETTER-2 and the COMPOSE trials, with results expected in approximately two years.
PRRT for NEC should be limited to highly selected patients, also with the support of dual tracer use involving somatostatin-based imaging tests and ([18F]F-FDG-PET/CT, while excluding cases with discordant ([18F]F-FDG-positive/SSTR-negative) lesions [29].

7. Conclusions

In summary, NENs represent a highly heterogeneous disease treated with therapeutic protocols that are not fully standardized. Based on this observation, a multidisciplinary
approach is recommended for their management. Based on the available data in the literature, PRRT represents a valid and effective therapeutic option for advanced NETs,
especially G1–G2 cases after SSA failure. Significant progress has been made in the past decade regarding treatments. Ongoing trials will help address the unresolved questions concerning PRRT for these patients, presenting new insights in terms of novel radiopeptides, therapy sequence and therapy combination. These findings, in conjunction with molecular profiling and the application of radiomics to understand tumor characteristics and behavior, will play a critical role in advancing precision medicine within this oncological domain
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