Radioligand therapy (RLT) as neoadjuvant treatment for inoperable pancreatic neuroendocrine tumors: a literature review

In the last 10 years, several literature reports supported radioligand therapy (RLT) in neoadjuvant settings for pancreatic neuroendocrine tumors (PanNETs). Indeed, primary tumor shrinkage has been frequently reported following RLT in unresectable or borderline resectable PanNETs. Moreover, RLT-induced intratumoral modifications facilitate surgery, both on primary tumor and metastasis, having a great impact on progression free survival (PFS), overall survival (OS) and quality of life (QoL). However, prospective controlled investigations are necessary to confirm preliminary data and to define the best RLT scheme and the ideal patient that, in a multidisciplinary approach, should be referred to neoadjuvant RLT.


Introduction
Pancreatic neuroendocrine tumors (PanNETs) account for 10% of all neuroendocrine tumors (NETs). Approximately 70% of these neoplasms are non-functioning and frequently present as relatively indolent and slow-growing masses. Therefore, diagnosis is frequently delayed, occurring when the disease has already spread to lymph nodes, liver, or bone [1][2][3].
PanNETs are currently classified according to the 2017 WHO classification. Grading has a strong impact on both clinical behavior and prognosis of patients affected by PanNETs, being a crucial parameter to take into consideration in the global therapeutic strategy [4].
Currently, surgery is potentially the only curative treatment for PanNETs [5]. Conversely, chemotherapy and molecular targeted agents are indicated in patients with advanced, recurrent or metastatic tumors not suitable for surgery (unresectable or borderline resectable), particularly in higher grade forms, while the role of external beam radiotherapy is limited [5][6][7].
Since 2017, after the encouraging results from the NETTER-1 phase III clinical trial, RLT has been established as an effective and safe therapy for advanced, metastatic or inoperable gastro-entero pancreatic (GEP) NETs [10][11][12]. RLT is usually proposed as a delayed treatment, when other lines of therapy have already failed [13]. Nevertheless, before NETTER-1 several studies reported a greater efficacy of RLT if offered at a relatively earlier stage of disease, when the tumor burden is lower and patients have a better performance status [14,15]. Therefore, based on literature evidences, RLT has been proposed as a neoadjuvant treatment, in order to obtain a tumor size decrease or downstaging, allowing a surgical approach and increasing the likelihood of a radical resection [3,[16][17][18][19][20].
The present mini-review explores the emerging role of RLT as a potential neoadjuvant treatment for PanNETs.

Methods
We performed a literature search using MEDLINE (PubMed database) on April 30 th 2022 to identify articles in English on neoadjuvant RLT. We used Keywords chosen according to Medical Subject Heading (MeSH) terms "neoadjuvant" OR "preoperative" AND "radioligand therapy" OR "Peptide Receptor Radionuclide Therapy". We included original articles and case reports. Editorials, Letters, and abstracts from conference proceedings were excluded. The full articles of selected studies were examined, and additional searches of their reference lists performed to identify other potentially eligible articles. Moreover, research of active ongoing trials was performed on clinicaltrials.gov.

Results
We found 11 papers including 148 patients as reported in Table 1. Literature evidence is heterogeneous considering sample size, patient characteristics, RLT schemes and outcome assessment. Our analysis and considerations were focused on the following issues: a) tumor response: primary shrinkage, downstaging and downgrading; b) histological and tumor microenvironment modifications; c) influence on tumor burden; d) safety and reproducibility of neoadjuvant RLT.
Moreover, consulting clinicaltrials.gov we found 1 active prospective multicentre trial concerning neoadjuvant RLT for PanNETs.
Tumor response: primary shrinkage, downstaging and downgrading Overall 148 patients with locally advanced PanNETs undergoing neoadjuvant RLT are described in literature. Seventytwo became eligible for surgery [16,[21][22][23][24][25][26][27][28][29]. Of note, we found 2 cases of extremely large primary tumors who became eligible for surgery following a significant tumor shrinkage and reduction in vascular involvement [24,25]. Indeed, RLT acts as a cytoreductive agent in well-differentiated NETs, leading to a volumetric reduction of target lesions (Fig. 1). The possibility of performing curative or debulking surgery, in this subset of patients, is associated with an improvement in survival rates and quality of life (QoL), even in advanced or metastatic disease [25]. Moreover, Partelli et al. [16] reported that, among patients with a curative resection (i.e. R0), those treated with neoadjuvant RLT showed a significantly longer progression free survival (PFS) than those who performed surgery up-front. Similarly, Minczeles et al. [29] reported that patients with neoadjuvant RLT followed by surgery had a longer PFS and OS than those who performed RLT only.
The same authors also demonstrated a downstaging in 38% of patients with baseline tumor-vessel involvement.
Grading is a key parameter to assess NETs aggressiveness and, consequently, prognosis [4]. A few papers reported downgrading after RLT [21,25,28], mostly from G2 to G1. The reduction in Ki-67 index may be due to the greater radiosensitivity of tumor cells characterized by a higher proliferating cell population [16,30]. Therefore, we can speculate that neoadjuvant RLT in PanNETs might act by preserving low-grade cell clones compared to the highgrade ones, which are more radiosensitive and selectively killed. The resulting global downgrading obtained could potentially have a significant impact on long surviving patients' outcomes, both in terms of PFS, OS and QoL [25]. Nevertheless, further studies with larger number of cases are required to validate this hypothesis.

Histological and tumor microenvironment modifications
As reported by Schiavo Lena et al. [31], neoadjuvant RLT can induce intratumoral microenvironment modifications and changes in stroma/cellularity ratio, inducing a progressive scarring process and fibrotic involution. Of note, stromal percentage was higher in patients treated with neoadjuvant RLT in comparison with those who underwent surgery up-front, particularly in patients in which a remarkable reduction in tumor diameter was achieved. Such tissue modifications, together with tumor size decrease can simplify surgery, reducing both operative time and major complications, particularly pancreatic fistula [16]. As a consequence, patients treated with neoadjuvant PRRT could benefit of a faster post-operative recovery, with a concomitant cost reduction for the Healthcare System.

Influence on tumor burden
RLT is a systemic therapy targeting tumor cells expressing SSTRs. In patients with oligometastatic NETs, neoadjuvant RLT could therefore potentially target both primary tumor and metastases. Particularly, liver tumor burden is well known as a main prognostic factor in NETs [12,30,32]. Recently, the North American Neuroendocrine Tumor Society suggested several potential advantages of neoadjuvant RLT in reducing liver tumor burden in metastatic PanNETs [33]. In this subset of patients RLT might allow subsequent locoregional hepatic therapies with a potential curative outcome and a consequent increase in PFS, OS and time to recurrence [26,33]. This recommendation is supported by the positive results obtained with neoadjuvant RLT in reducing liver disease burden, as previously reported [26][27][28]34]. Moreover, RLT-induced biological modifications can cause liver metastases necrotic involution, avoiding the need of a subsequent therapeutic approach [31]. Theoretically, a similar outcome could be pursued with neoadjuvant chemotherapy, as described by Squires et al. [35], who reported promising results combining neoadjuvant capecitabine and temozolomide in PanNET. Moreover, recent evidence suggests that capecitabine may act as a radiosensitizer in synergy with RLT, increasing the efficacy of this approach in aggressive or radioresistant NETs [36]. Therefore, these results suggest that a combined approach with RLT and chemotherapy in neoadjuvant settings could be effective. Indeed, Barber et al. [28] achieved functional/radiological and symptomatic response over 12-42 month combining neoadjuvant RLT and chemotherapy (5-Fluorouracil). However, further prospective studies, comparing and combining neoadjuvant RLT and neoadjuvant chemotherapy approaches in patients with systemic disease at diagnosis are needed to explore this therapeutic option. A multidisciplinary approach is always preferable for selecting the best treatment and the correct timing.

Safety and reproducibility of neoadjuvant RLT
Among available studies, only one reported that a single patient was withdraw from neoadjuvant RLT before completing the treatment, due to severe hematologic toxicity [16]. Mild and transient hematologic toxicity was reported in other studies [21,23,24,27,29], in line with the most updated clinical and dosimetric evidence [37][38][39]. The available results derive from studies with heterogeneous neoadjuvant RLT schemes. Indeed, different isotopes have been employed: 90 Y in 3 studies [21,25,34], 177 Lu in 6 [22-24, 26, 28, 29] and both radioisotopes in 2 [16,27], always as mono-therapy. It should be noted that, overall, most of the patients (141/148) were treated with [ 177 Lu]-labeled radiopeptides. On the other hand, very different schemes were employed concerning cycles number and injected activity. Therefore, a better standardization of neoadjuvant RLT is desirable and should be investigated in future trials. Although RLT is currently mainly performed with [ 177 Lu]-based radiopharmaceuticals, [ 90 Y]-radiolabeled peptides might still play an important role. Indeed, the greater tissue penetrance of the beta radiations emitted by 90 Y, compared to 177 Lu, enhances the cross-fire effect that damages even those cellular clones with lower SSTR expression and potentially more undifferentiated. This feature, combined with the higher linear energy transfer (LET), candidates [ 90 Y]-radiopeptides as potentially more effective in the treatment of large and biologically aggressive lesions [8,40]. On the other hand, [ 177 Lu]-based RLT has proven to be safer than 90 Y. 177 Lu could be more effective on small lesions, also in relation to its longer half-life, allowing a prolonged dose delivery [41]. Baum et al. [8] reported greater benefits in terms of objective response and survival in a large series of patients affected by NET (including PanNETs) who received combination treatments with [ 177 Lu]-DOTATOC and [ 90 Y]-DOTATOC, but not in neoadjuvant settings. A dual-isotope approach could allow a better risk-benefit ratio in neoadjuvant setting in PanNETs, representing a challenge for planning future multicentre randomized trials in this subset of patients.

Ongoing trials
On the basis of available evidence, a phase II single-arm multicentric trial on neoadjuvant RLT with [ 177 Lu]-DOTA-TATE, followed by surgery for PanNETs, (NEOLUPANET, EUDRACT 20019-002196-34 -Clinical Trials Identifier NCT04385992) is ongoing [42]. The main purposes of the study are to evaluate safety and efficacy of neoadjuvant RLT followed by surgery in resectable PanNETs at high-risk of recurrence. The secondary endpoints are to investigate the rate of objective radiological response to RLT according to modified RECIST criteria (mRECIST) and patients QoL. The results of this study are not available, yet.
Further ongoing trials proposing neoadjuvant RLT for PanNETS or for NETs of different primary origin are not available at present. Likewise, other trials aiming to compare the efficacy of different RLT schemes in this subset of patients are lacking.

Limits of the study
The present mini-review summarizes the available data in the literature. However, most of the studies on neoadjuvant RLT are single case reports or small sample size studies [16,[21][22][23][24][25][26][27][28][29]34]. Therefore, the quality of the evidence is quite low. On the other hand, prospective randomized clinical trials are difficult to plan for these patients.

Conclusions
RLT could represent a safe and effective neoadjuvant therapy in unresectable or border line resectable PanNETs. Further prospective controlled investigations are necessary to confirm these preliminary data and to define the ideal therapeutic scheme. In addition, the multidisciplinary approach is preferable to identify patients who could benefit from neoadjuvant RLT to become eligible for second-line surgery.
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