Advances in the Management of Medullary Thyroid Carcinoma: Focus on Peptide Receptor Radionuclide Therapy

Effective treatment options in advanced/progressive/metastatic medullary thyroid carcinoma (MTC) are currently limited. As in other neuroendocrine neoplasms (NENs), peptide receptor radionuclide therapy (PRRT) has been used as a therapeutic option in MTC. To date, however, there are no published reviews dealing with PRRT approaches. We performed an in-depth narrative review on the studies published in this field and collected information on registered clinical trials related to this topic. We identified 19 published studies, collectively involving more than 200 patients with MTC, and four registered clinical trials. Most cases of MTC were treated with PRRT with somatostatin analogues (SSAs) radiolabelled with 90 yttrium (90Y) and 177 lutetium (177Lu). These radiopharmaceuticals show efficacy in the treatment of patients with MTC, with a favourable radiological response (stable disease, partial response or complete response) in more than 60% of cases, coupled with low toxicity. As MTC specifically also expresses cholecystokinin receptors (CCK2Rs), PRRT with this target has also been tried, and some randomised trials are ongoing. Overall, PRRT seems to have an effective role and might be considered in the therapeutic strategy of advanced/progressive/metastatic MTC.


Introduction
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine neoplasm (NEN). Surgery, with complete resection of the tumour, is, in most cases, curative [1]. However, in a subgroup of patients, the tumour shows an aggressive behaviour. In this setting (advanced/progressive/metastatic MTC), the management remains challenging [1,2]. Among systemic therapies, tyrosine kinase inhibitors (TKIs) have recently been shown to improve progression-free survival (PFS) in patients with advanced disease [3,4]. Two TKIs, namely vandetanib and cabozantinib, have been approved for the treatment of progressive or symptomatic MTC. Both drugs are effective, resulting in partial response (PR) or stable disease (SD), but tumour escape frequently occurs. On the other hand, both drugs may cause grade III or IV adverse events (classified according to the Common Terminology Criteria for Adverse Events of the National Cancer Institute) [3,4]. Therefore, other systemic options are needed. As in other advanced/progressive/metastatic NENs, radionuclide therapy may represent a therapeutic option, and indeed, it has been applied in MTC since the 1980s. Historically, the first radiopharmaceutical used in therapy was 131Iodine (131I)-metaiodobenzylguanidine (MIBG) [5,6], but its use has been limited in MTC, due to the low percentage of MTC that shows uptake on MIBG scintigraphy [7][8][9].
To date, there are no published reviews dealing with the different PRRT approaches in MTC comparing the outcomes in terms of efficacy and safety.

Aim of the Study
We aimed to perform an in-depth narrative review on the studies published on PRRT and MTC, in order to offer to the physician involved in the management of MTC an updated overview of the PRRT treatments.
Furthermore, we collected information on registered clinical trials (RCTs) related to this topic, in order to give the scientific community a glance about the future of PRRT in MTC.

Published Studies
A search on PubMed, Embase and Cochrane was made by using the terms "medullary thyroid carcinoma", medullary thyroid cancer", "radionuclide", lutetium", "yttrium", "indium", "peptide receptor radionuclide therapy", "radiolabelled somatostatin analogues", "gastrin-like peptides" and "cholecystokinin-like peptides". Additional studies were identified by reviewing the references of all selected articles. Only studies in the English language were included. We excluded from the analysis: (1) single-case reports, (2) abstracts from congresses and proceedings from workshops and (3) letters to the editor. The search was last updated 16 October 2020.

RCTs
By using the same terms used in the section describing published studies, we performed a search on the Registries Clinical Trials Gov and EudraCT. The search was last updated 16 October 2020.

Published Studies
We found 18 PRRT studies targeting SSRs involving patients with MTC: 14 with SSA labelled with the radionuclide(s) 90 yttrium (90Y) and/or 177 lutetium (177Lu) and four with SSA labelled with 111 indium (111In). Additionally, we found one study targeting cholecystokinin receptors (CCK2Rs), employing a gastrin analogue labelled with 90Y.
Symptomatic response and Quality of life (QoL). Data regarding the subjective response were nearly absent. The evaluation of the symptomatic response was available for 53 patients (28.5%) in two studies: the first one reported "no improvement" in all 10 patients (100%) [32]; the second one reported PD (new symptoms or symptoms increase > 30%) in 21 patients (49%), SD (symptoms reduction < 30%) in two patients (4%), PR (symptoms reduction 30-75%) in 12 patients (28%), and CR (symptoms reduction 100%) in eight patients (19%) [33]. Only one study specifically evaluated the QoL through the Short Form-36 Health Survey (SF-36) questionnaire on a small case series of six patients; all the responders (patients who had at least some tumour shrinkage) had an improvement in QoL six to 12 months after therapy [29].
Outcome. Data about time to progression (TTP) and/or PFS and/or overall survival (OS) were reported in five studies [22,26,[31][32][33]. A longer survival was reported in patients with disease control (PR + SD) in the study by Salavati et al. [31] and with biochemical response in the study by Iten et al. [27]. Finally, in the study by Parghane et al. [33], a longer OS was observed in patients with longer calcitonin doubling time.
Symptomatic response and QoL. The evaluation of the symptomatic response was available for five patients (50.0%) in the study of Valkema et al. [36]: only one patient (20.0%) showed symptomatic improvement, but the evaluation criteria were not specified. Only the study of Pasieka et al. specifically evaluated the QoL [38]: the single patient studied showed no improvement.
Disease data. In all cases, the disease status at baseline was represented by progressive and advanced disease.
Radiographic response. Since neither imaging procedures nor response criteria were specified, these data were not included in Table 3. However, patient responses were defined by the authors as follows: two PD (25.0%), four SD (50.0%), and two PR (25.0%).
Biochemical response, symptomatic response, QoL, and outcome. No data were available. Toxicity. Information about adverse reactions included no cases of treatment discontinuation, no cases of grade III-IV nephrotoxicity, and three cases of grade III-IV haemotoxicity (37.5%).

RCTs
We identified four RCTs on ClinicalTrials.gov, two on SSRs, and two on CCK2Rs. Details of the RCTs are reported in Table 4.

Discussion
The largest part of cases of MTC reported in our review were treated with PRRT with SSAs radiolabelled with 90Y and 177Lu. The radiographic response showed a significant disease control rate (DCR = CR + PR + SD) in 62.4% of cases (CR in 2.6%, PR in 5.1%, and SD in 54.7%), most of which were in progression at the baseline. PD was observed in 37.6% of cases [21][22][23][24][25][26]29,30,[32][33][34]. In two [22,30,32] of the three studies [22,30,32] in which the percentage of PD was higher, the population under study was of older age. This is in-line with the evidence that age is an important prognostic determinant in MTC [39].
The use of a concomitant radiosensitising agent, like low-dose oral capecitabine, could be even more beneficial, as suggested by a study from Satapathy et al. [40] in which the DCR was 86%. These results are in-line with similar observations made in gastroenteropancreatic NENs and malignant phaeocromocytomas about the combination of PRRT and chemotherapy [41][42][43].
In responsive patients, PRRT seems to stabilise the disease. However, the effects of the treatment on PFS and OS rates have yet to be determined. Indeed, only five studies evaluated these outcome endpoints. In particular, one study demonstrated longer survival in patients with a radiological disease control [31], and two studies [27,33] demonstrated longer survival in patients with a biochemical response, evaluated through calcitonin assessment, which, in MTC, can indicate tumour recurrence or progression [44] and indicate a treatment response with good sensitivity [45,46].
The TKI vandetanib and cabozantinib have been shown to improve PFS in patients with advanced MTC [3,4] and have been approved for the treatment of progressive or symptomatic MTC. However, both are associated in many patients with grade III-IV adverse events [3,4], which reduce the QoL of patients. Data from our review showed that a treatment discontinuation for toxicity was observed in only 1.3% of cases, grade III-IV haemotoxicity in 6.5% of cases, grade III-IV nephrotoxicity in 0.8%, and other grade III-IV side effects in no cases. The apparently higher rates of haemotoxicity compared with nephrotoxicity were derived from the high percentage of haemotoxicity found in a study from Bodei et al. [47], in which a transient lymphocytopenia was demonstrated in 88% of cases. These data could be explained by the fact that the series included patients who had received bone radiotherapy with the consequence of a potential reduction of bone marrow reserve [47]. On the contrary, the low nephrotoxicity that emerged from the data of the present review may be linked to the duration of follow-up. Indeed, it is unknown whether late renal damage may become evident four or five years after treatment administration [47].
PRRT has been used mainly in the treatment of gastroenteropancreatic NENs expressing SSRs, with promising results. Following the publication of the Neuroendocrine Tumors Therapy (NETTER-1) study [48], PRRT with 177Lu-oxodotreotide was approved by the Food and Drug Administration, European Medicines Agency, and National Institute for Health and Care Excellence in SSR-positive, well-differentiated (G1-G2) gastroenteropancreatic NENs. As for MTC, the guidelines of the European Society for Medical Oncology [49] and American Thyroid Association [50] agree that current experiences about PRRT with radiolabelled SSA in MTC are limited, and no randomised clinical trials have been carried out to compare the efficacies of PRRT versus TKIs. Consequently, at this time, PRRT should only be considered in selected patients in the context of clinical trials. However, its potential benefit when TKIs are contraindicated is recognised.
In order to establish the role of PRRT in the therapeutic algorithm of advanced/progressive/metastatic MTC, more solid data from randomised controlled studies with survival endpoints are needed. Nevertheless, the rarity and the long natural history of the disease have hindered the research in this field.
As with other NENs, 111In-diethylenetriaminepentacetic acid (DTPA)-octreotide was the first therapeutic radiopharmaceutical used as a PRRT in MTC. The contrasting results and the limited number of patients with MTC treated do not allow a judgment on this radiopharmaceutical, which was soon abandoned, due to the low rate of objective tumour responses and the significant haematologic toxicity in favour of SSAs labelled with the more efficient 90Y and 177Lu radionuclides. Moreover, the only RCT we found, namely NCT00002947, was terminated early (reason not stated).
The limitations of this review study about data on PRRT targeting SSRs in MTC are as follows: first, most analysed case series are small, and prospective studies are few. Second, most of the data-including treatment schedule, follow-up, response evaluation, and treatments before PRRT-are highly heterogeneous and sometimes incomplete. Finally, the outcome data are available only in a few studies, due to the small sample sizes and limited lengths of follow-up, which underpowered the evaluations of PFS and OS.
New data with the primary outcome of the tumour response are expected in 2022 (RCT NCT04106843).
As previously mentioned, a PRRT could also target CCK2Rs, which are overexpressed in more than 90% of MTCs [17][18][19][20]. In the past two decades, a variety of CCK2-related peptides radiolabelled with 90Y/177Lu have been synthesised and categorised based on the sequence of their parent peptide (CCK or gastrin). To date, most studies about PRRT targeting CCK2Rs were preclinical trials and investigated specific basic criteria of candidate radioligands such as nanomolar receptor affinity, rapid and efficient accumulation in the tumour, low uptake and rapid wash-out in/from normal tissues, and in vivo stability. Only a few pilot clinical studies have been carried out in small cohorts of patients. An important landmark study in this area was the study conducted in 2002 by Behr and Behe [17], which investigated 45 patients with metastatic MTC with 111In-DTPA-minigastrin scintigraphy (23 with known and 32 with occult diseases). The radiotracer physiological uptake was related to CCK2R-specific binding and to the route of excretion. As for the binding, the normal uptake mainly regarded the stomach and, to a lower extent, gallbladder and breasts. Regarding the route of excretion, the kidneys were identified as the only excretory organs. All tumour manifestations known by conventional imaging were visualised, and at least one lesion was detected in 29/32 patients with occult disease. Furthermore, eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a 90Y-labelled minigastrin derivative at four-six-weekly intervals ( Table 3, Results: section PRRT targeting CCK2Rs); haematologic and renal were identified as dose-limiting toxicities.
In general, although very promising in a theoretical context, the clinical translation of PRRT targeting CCK2Rs has been prevented by two major problems: high kidney uptake and/or fast in vivo degradation of the different radiopeptides developed. Radiopharmaceutical research has tried to overcome these limitations by introducing various modifications in the peptide sequence of gastrin or CCK-related peptides, with the aim of reducing kidney retention and improving metabolic stability. A co-injection of plasma expanders has been proposed to reduce kidney uptake and retention, consequently minimising radiation-induced nephrotoxicity [19,20,51]. In order to reduce in vivo radiopeptide degradation, a co-injection of neutral endopeptidase inhibitors is also under investigation, since endopeptidases are the major enzymes implicated in the catabolism of gastrin/CCK-based peptides, and they are widely distributed in the body [52,53]. Research in this field is actively ongoing, as evidenced by the two clinical trials pertaining to PRRT in CCK2Rs mentioned above (Table 4); this lesser-known but promising therapy is expected to establish a new and efficient strategy for the treatment of MTC, which is still a challenging entity.

Conclusions
On the basis of the reported efficacy and low toxicity, PRRT could represent a therapeutic option in the treatment of advanced/progressive/metastatic MTC. As in other NENs, most of the experience was obtained with PRRT targeting SSRs, but CCK2Rs might offer in the future an alternative PRRT option.
Author Contributions: E.G., G.F., L.P., F.S., C.D., and F.d.C. were responsible for the design, the methodology, the writing-original draft preparation, and the reviewing and editing. A.C. and A.F. were responsible for the supervision. All authors have read and agreed to the published version of the manuscript.