Next Article in Journal
Urethral Injuries: Diagnostic and Management Strategies for Critical Care and Trauma Clinicians
Previous Article in Journal
Treatment of Skull Base Diseases: A Multidisciplinary Challenge
Previous Article in Special Issue
Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 12
Issue 4
10.3390/jcm12041494
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Response to Peptide Receptor Radionuclide Therapy in Pheocromocytomas and Paragangliomas: A Systematic Review and Meta-Analysis

by
Antonella Lucia Marretta
1,†,
Alessandro Ottaiano
2,†,
Domenico Iervolino
3,
Alessandra Bracigliano
4,
Ottavia Clemente
5,*,
Francesca Di Gennaro
4,
Roberto Tafuto
6,
Mariachiara Santorsola
2,
Secondo Lastoria
4 and
Salvatore Tafuto
5
1
Department of Clinical and Surgery Oncology Unit, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy
2
SSD Innovative Therapies for Abdominal Metastases, Department of Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
3
Pathology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
4
Nuclear Medicine Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
5
Sarcomas and Rare Tumours Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
6
Department of Neuroscience and Reproductive and Dental Sciences, Division of Neurosurgery, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2023, 12(4), 1494; https://doi.org/10.3390/jcm12041494
Submission received: 11 November 2022 / Revised: 3 January 2023 / Accepted: 8 February 2023 / Published: 13 February 2023
(This article belongs to the Special Issue Neuroendocrine Tumors: Challenges and Future Perspectives)
Browse Figures
Versions Notes

Abstract

:
Introduction. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE and 90Y-DOTATOC showed efficacy in the metastatic setting of pheocromocytomas (PCCs) and paragangliomas (PGLs) where no standard therapies have been established. Background. A search of peer-reviewed and English articles reporting on 177Lu-DOTATATE and 90Y-DOTATOC efficacy was performed through Medline and Scopus. A subsequent meta-analysis was performed to evaluate the pooled effect size on disease control rate (DCR) with PRRT. Secondary endpoints were description of patients’ genetic characteristics, hematologic toxicity, and time-to-outcome. The pooled effect was estimated with both a mixed-effects model and a random-effects model. Results. Twelve studies met the criteria for this meta-analysis: ten with 177Lu- and two with 90Y-PRRTs (213 patients). The largest one included 46 patients. Median ages ranged from 32.5 to 60.4 years. When reported, mutations of SDHB were the most frequent genetic alterations. The pooled DCRs were 0.83 (95% CI: 0.75–0.88) and 0.76 (95% CI: 0.56–0.89) for 177Lu- and 90Y-PRRT, respectively. The pooled DCR for PRRT was 0.81 (95% CI: 0.74–0.87). Conclusions. We report an updated and solid estimate of DCR achieved with 177Lu- and 90Y-PRRT in PCCs and PGLs, showing that these therapies can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy.

1. Introduction

Pheocromocytomas (PCCs) and paragangliomas (PGLs) are tumors derived from adrenal medulla and extra-adrenal paraganglia, respectively, developing in relationship with parasympathetic and sympathetic components of the autonomic nervous system [1]. Their incidence is about 0.6 cases per 100,000 person-years, and the most common symptoms guiding diagnosis are palpitations, hypertension, profuse sweating, and headaches. They are more common in females than males, and have a higher incidence in people over the age of 40 [2]. Hereditary syndromes linked to PCCs and PGLs are von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF-1), and multiple endocrine neoplasia, especially type 2 (MEN 2); however, a non-negligible number of PCCs and PGLs are non-functioning, and most of them are sporadic [3]. These features contribute to diagnosis delay. Geographically, PCCs and PGLs have a higher incidence in North America, Europe, and Australia compared to Asia. The tumors are also more commonly found in individuals of northern European descent. Association of clinical, biochemical, and histological findings is the best way to determine PCC and/or PGL malignant potential [4].
Imaging approaches used to identify PCCs and PGLs are based on CT and MRI with a sensibility of 77–98% and 90–100%, and specificity of 29–92% and 50–100%, respectively [5]. The most important functional imaging is PET/CT 68Ga-DOTATATE (DOTA-Tyr3-octreotate), which shows superiority over I131-MIBG SPECT/CT [6], and has an excellent diagnostic power for extra-adrenal sympathetic PGLs and metastatic and multifocal PGLs and PCCs, according to European Association of Nuclear Medicine and Society of Nuclear Medicine and Molecular Imaging (EANM/SNMMI) guidelines [7]. The current diagnostic role of the 131I-MIBG appears to be limited to abdominal paragangliomas and theranostic purposes [6]. Somatostatin receptor imaging is performed with different DOTA-coupled somatostatin agonists, namely DOTA-Tyr3-octreotate (DOTATATE), DOTA-Tyr3-octreotide (DOTATOC), and DOTA-Nal3-octreotide (DOTANOC) [6,7].
There are no widely accepted, standard sequential treatments for PCCs and PGLs. According to international guidelines [4,5,6,7], somatostatin receptor positivity allows the treatment of metastatic PCCs or PGLs with peptide receptor radionuclide therapy, or PRRT (theranostic) [8]. Briefly, PRRT is a treatment modality that has gained great relevance in the management of various neuroendocrine tumors (NETs). The concept of PRRT is based on the selective targeting of somatostatin receptors (SSTRs) that are highly expressed on the surface of NET cells. PRRT leverages the capability of radiolabeled somatostatin analogues to deliver high doses of ionizing radiation directly to the site of the tumor mass. In this way, PRRT effectively targets and destroys the malignant cells while minimizing exposure to normal surrounding tissues. The mechanism of action of PRRT can be divided into two phases. The first phase involves the localization and internalization of the radiolabeled somatostatin analogue in the NET cells. This is achieved through the high-affinity binding of the analogue to the SSTRs on the cell surface. The internalization of the analogue initiates a cascade of intracellular events that culminate in the formation of endocytic vesicles. In the second phase, the radionuclide is delivered to the target tumor cells, releasing a high dose of ionizing radiation. This radiation causes cellular damage by inducing double-stranded DNA breaks and oxidative stress, leading to the death of the cancer cells. Most importantly, the high specificity of the SSTR-targeting mechanism ensures that normal cells with low SSTR expression are spared, minimizing the risk of side effects.
In conclusion, PRRT may offer a highly targeted and effective treatment option for patients with NETs. By leveraging the SSTR-targeting mechanism, PRRT delivers high doses of ionizing radiation directly to the site of the tumor, reducing the risk of systemic toxicity and maximizing therapeutic efficacy. The mechanism of action of PRRT demonstrates the potential of targeted radionuclide therapy as a safe and effective modality in the management of NETs.
In this context, 177Lu-DOTATATE and 90Y-DOTATOC PRRTs have shown good results, particularly in terms of disease control improvement.
This meta-analysis comprised studies focusing on treatment with 177Lu- and 90Y-PRRTs; our principal aim is to provide the scientific community with an updated and solid estimate of DCR (disease-control rate) achievable with these therapeutic options.

2. Materials and Methods

The present systematic review and meta-analysis was performed to investigate the role of 177Lu-DOTATATE and 90Y-DOTATOC in the treatment of metastatic PCCs and PGLs. It was conducted according to the recommendations of the Preferred Reporting Item For Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement [9]. The primary outcome was the disease control rate (DCR: percent of complete responses plus partial responses plus stable disease) of patients treated with 177Lu-DOTATATE and 90Y-DOTATOC. According to our internal policies, the institutional review board approval and PROSPERO (International Prospective Register of Systematic Reviews) registration were not required for the systematic literature review. Trial search strategy is described below.

2.1. Search Strategy and Trial Identification Criteria

A search was performed on September 2022 through Medline (PubMed: www.ncbi.nlm.nih.gov/PubMed, accessed on 12 September 2022) and Scopus. Keywords used for searching were “pheochromocytoma” AND/OR “paraganglioma” AND/OR “therapy”. A large time range (2006–2022) was applied. In addition to computer browsing, manuscripts were also checked in the reference section to select further reports. A flow-chart reporting the criteria for study selection and exclusion is depicted in Figure 1. Only peer-reviewed and English papers on 177Lu-DOTATATE and 90Y-DOTATOC efficacy were considered. Manuscripts reporting on fewer than 5 patients were excluded. To avoid spurious and heterogeneous results, studies reporting on multiple PRRT agents and/or plus concomitant chemotherapy or radiosensitizers were excluded.

2.2. Data Extraction

The following data were extracted for each study: first author; year of publication; type of study; clinic-pathological and genetic characteristics of patients; type of PRRT agent; treatment characteristics; number of patients enrolled; no. of PRRT cycles; response criteria; best response; hematological toxicities; previous treatments. All data were reviewed and separately computed by three investigators (ALM, DI and AO). Criticisms and discordances were discussed with all authors.

2.3. Studies Quality Rating

The quality rating of the methodologies and results of the selected studies was managed by three authors (A.L.M., M.S., and O.C.) to provide a formal quality evaluation as well as a risk-of-bias assessment. To this end, MINORS (Methodological Index for Non-Randomized Studies) criteria [10] and Newcastle–Ottawa Scale [11] were used. Final scores were independently rated by A.O. and D.I., who were blinded to the previous results. Discordances were resolved in consensus discussion involving A.L.M., M.S., O.C., A.O., and D.I. The impact factors (Ifs) of the scientific journals reporting the analyzed articles are publicly available at https://jcr.clarivate.com/jcr/home (accessed on 28 December 2022). They were taken into account after a final evaluation of the studies’ quality. However, as our policy, possible associations between Ifs and quality scores were neither explored nor shown.

2.4. Statistical Methods

A meta-analysis was performed in order to evaluate the pooled effect size in response to PRRT agents in pheocromocytomas and paragangliomas. The primary endpoint of the meta-analysis was the disease-control rate (DCR). The description of clinic-pathological and genetic characteristics was a secondary endpoint.
The pooled effect of the various studies was estimated with both fixed- and a random-effects models. The fixed-effects model assumes that all studies being analyzed have the same underlying effect size. This means that any differences in results between studies are solely due to random error or chance, rather than differences in the underlying population or treatment effect. The fixed-effects model uses a weighted average of the study-specific effect sizes to estimate the overall effect size. The random-effects model assumes that the true effect size varies between studies. This may be due to differences in the population, treatment, or study design. The random-effects model uses a more complex model to account for this variability, by estimating the between-study variance and using it to calculate the overall effect size. It provides a more conservative estimate of the average effect size. To assess the degree of heterogeneity between studies, the I2 statistic and the relative p value were taken into consideration, considering as significant the heterogeneity between studies in case of p < 0.10. The presence of possible publication bias was assessed by funnel plot [12].
The selected studies were divided into two groups, namely 177Lu- and 90Y-PRRT. The analysis of the pooled proportions was carried out on the DCR. The pooled descriptors of time-to-events (progression-free and overall survivals) in the various studies was determined by the algorithm suggested by Xiang Wan et al. [13] [sample-size weighted means ± standard deviation (SD)]. Descriptive statistics (means) with 95% confidence intervals (95% CI) were performed to pool and describe ages from different studies. Statistical analyzes were carried out using the R studio software version 4.1.1. (R studio Inc. Company, 250 Northern Avenue # 420 Boston, MA 02210, USA).

3. Results

Twelve studies met the criteria for this meta-analysis (from an initial identification of 5919 records) [14,15,16,17,18,19,20,21,22,23,24,25]: 10 with 177Lu-, 2 90Y- PRRT studies. The selection flow-chart and study characteristics are reported in Figure 1 and in Table 1 and Table 2, respectively.
In detail, we report pooled data on 149 177Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with 177Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy (Table 1).
Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias (Figure 2). The MINORS and Newcastle–Ottawa Scale scoring for the selected articles are reported in Table 3.
A forest plot of the treatments’ effect on DCR is shown in Figure 3. There was no statistically significant heterogeneity among the 177Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75–0.88) and 0.76 (95% CI: 0.56–0.89) for 177Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74–0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between 177Lu- and 90Y-PRRT treatments.
Funnel and forest plots for response rate (complete plus partial responses) in the selected studies are reported in Figures S1 and S2, respectively. Table S1 synthetized patients’ age and time-to-event outcomes in the analyzed articles.

4. Discussion

PCCs and PGLs are rare neoplasms. For this reason, it is useful and legitimate to pool the effects from different studies in order to provide a more solid estimate of treatment efficacy. In the present meta-analysis, we show the efficacy of PRRT treatment based on 177Lu- DOTATATE and 90Y- DOTATOC in 213 patients affected by PCCs and PGLs. The primary endpoint was the correct quantification of DCR. We report a pooled DCR of 83% and 76% for 177Lu- DOTATATE and 90Y- DOTATOC treatments, respectively, and a good toxicity profile. Pooled estimates on response rates, age of enrolled patients and time-to-event are reported in a Supplementary File.
To our knowledge, this is the largest and first study reporting on the pooled effect of these specific treatments without radiosensitiziser administration. Radiosensitizers are agents that enhance the effectiveness of radiation therapy in the treatment of cancers. In the context of PRRT for pheochromocytomas and paragangliomas, radiosensitizers may be used to increase the uptake of radionuclides by tumor cells, to synergize with the anti-neoplastic effects, and to enhance the therapeutic efficacy of PRRT. However, the use of radiosensitizers in PRRT for PCCs and PGLs is still an area of ongoing research, and its role in clinical practice is unclear. A previous meta-analysis reported the pooled efficacy of PRRT in 201 patients with advanced PPCs and PGLs [26]. The authors included in their analysis clinical series treated with concomitant radiosensitizers (capecitabine/temozolomide/fluorouracil) and PRRT (concomitant 177Lu-DOTATATE and 90Y-DOTATOC). The use of different radiosensitizers can also produce spurious and scarcely comparable results.
The PRRT treatment achieved a DCR of 84% (95% CI: 77–89%), with similar responses among 90 Y- and 177 Lu-based agents. Non-hematologic toxicity was negligible. For this reason, we focused on hematologic toxic events. Another meta-analysis on PRRT (131I-MIBG) has been previously published [27]. It showed a high DCR (70%) but a high risk of publication bias, with inadequate clinical sample description and inadequate reporting of intervention and response criteria in 12 out 17 analyzed studies. Furthermore, a high rate of hematologic toxicity was evidenced (grade 3/4 neutropenia and trombocitopenia in 87% and 83% of patients, respectively).
Notably, there are no widely accepted guidelines for PCC and PGL therapy. In this context, a multidisciplinary approach is desired and pursued in most centers [8]. Surgery is applied in localized disease, while chemotherapy, radiotherapy, and PRRT are administered as palliative treatments in metastatic disease, where the goals are quality of life and survival improvement [28]. The role of chemotherapy is still controversial and debated. A meta-analysis on the role of cyclophosphamide, vincristine, and dacarbazine (CVD) as first-line treatments for metastatic disease in PCCs and PGLs evidenced a high pooled DCR (57%) assessed with RECIST 1.1, but a poor toxicity profile with a clinically significant discontinuation rate due to grade 3/4 episodes of hematological and non-hematological toxicities (neuropathy and gastro-intestinal symptoms) [29] highlighting the importance of patient selection. Unfortunately, there are neither large phase II nor randomized phase III trials validating the role of alternative chemotherapy schedules in this clinical setting.
To understand the therapeutic panorama of PCCs and PGLs, it is important to discuss that genetic assessments are gaining a crucial role in their diagnosis and management. These tumors are caused by mutations in specific genes, which can be inherited or occur sporadically. The characterization of the genetic background of these tumors will become increasingly important for diagnosis, prognosis, and treatment. The most common mutations associated with PCCs and PGLs are in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, and SDHD [30]. These mutations result in alterations in the regulation of cell growth and division, leading to the development of the tumors. On a genetic point of view, PCCs and PGLs can be classified into two types: hereditary and sporadic. Hereditary forms are caused by mutations that are inherited from a parent and occur in multiple family members. The most common hereditary form is associated with mutations in the RET gene. Sporadic forms are caused by mutations that arise spontaneously and are not inherited from a parent. The majority of PCCs and PGLs are sporadic; in this case, SDHB is the most frequently mutated gene [31]. In the future, this characteristic could be exploited to target and cure these neoplasms. However, very few data are available on the role of targeted therapies. A phase II study analyzed the effect of sunitinib in patients with progressive PCCs or PGLs (SNIPP trial), reporting a promising DCR of 83% in 25 enrolled patients. Grade 3/4 toxicities were represented by fatigue (16%), thrombocytopenia (16%), cardiac events (8%), and hypertension (4%) [32]. Clinical studies on cabozantinib, axitinib, lenvatinib, and everolimus are ongoing, and available results are too few to provide definitive indications on the role of TKIs (tyrosin-kinases inhibitors) in PCCs and PGLs [33,34,35].
The PRRT treatment, with its manageable and low toxicity, represents a “less intensive” treatment. This finding is gaining great attention and re-evaluation in oncology, as these treatments refer to less aggressive therapeutic approaches in patients with high disease burdens not eligible for curative treatments (due to factors such as poor performance status, advanced age, or the presence of comorbid conditions). In this context, PRRT based on 177Lu-DOTATATE and 90-YDOTATOC without radiosensitizer is a highly valuable option.
The goal of this meta-analysis was the reporting of a solid and updated estimate of DCR achieved with 177Lu- and 90Y-PRRT in PCCs and PGLs. In this regard, the main limitations were the heterogeneity in response criteria (even if 10/12 studies use the RECIST) and the small sample size related to the rarity of the selected neoplasms. Another limitation of our study was the lack of registration in PROSPERO (an international database dedicated to the prospective registration of systematic reviews). There are two main consequences: a possible future work “duplication” and a potential bias related to the absence of comparison between what was methodologically planned in the protocol (at inception) and what was actually made and reported. These risks exist at any phase, including the review and post-publication periods. Even if, at present, there are no equivalent systematic reviews in the literature, registration in PROSPERO would have helped to avoid any effects of scientific redundancy of the researchers’ work.

5. Conclusions

We showed that PRRT based on 177Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm12041494/s1. Figure S1: Funnel plot for response rate (complete plus partial responses) in the selected studies; Figure S2: Forest plot for response rate (complete plus partial responses) in the selected articles; Table S1: Pooled age and time-to-event in the analyzed articles.

Author Contributions

Conceptualization, A.L.M., A.O., D.I. and S.T.; Methodology, D.I., M.S. and O.C.; Software, D.I. and R.T.; Validation, S.L., S.T.; Formal analysis, A.O., M.S., O.C. and D.I.; Investigation, A.L.M., A.B., O.C., R.T., S.L., F.D.G. and S.T.; Resources, S.L., S.T.; Data curation, A.O., D.I., M.S., O.C. and A.B.; Writing/original draft preparation, A.L.M., A.O., D.I. and M.S.; Writing/review and editing, F.D.G. and S.T.; Supervision, S.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

R studio software analysis for making Forest Plots is reported in https://zenodo.org/record/7621656#.Y-Os5i-ZO3A (accessed on 10 November 2022).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lam, A.K.-Y. Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours. Endocr. Pathol. 2017, 28, 213–227. [Google Scholar] [CrossRef] [PubMed]
  2. Lenders, J.W.; Eisenhofer, G.; Mannelli, M.; Pacak, K. Phaeochromocytoma. Lancet 2005, 366, 665–675. [Google Scholar] [CrossRef] [PubMed]
  3. Chrisoulidou, A.; Kaltsas, G.; Ilias, I.; Grossman, A.B. The diagnosis and management of malignant phaeochromocytoma and paraganglioma. Endocrine-Related Cancer 2007, 14, 569–585. [Google Scholar] [CrossRef] [PubMed]
  4. Korevaar, T.I.M.; Grossman, A.B. Pheochromocytomas and paragangliomas: Assessment of malignant potential. Endocrine 2011, 40, 354–365. [Google Scholar] [CrossRef] [PubMed]
  5. Ilias, I.; Sahdev, A.; Reznek, R.H.; Grossman, A.B.; Pacak, K. The optimal imaging of adrenal tumours: A comparison of different methods. Endocrine-Related Cancer 2007, 14, 587–599. [Google Scholar] [CrossRef]
  6. Jing, H.; Li, F.; Wang, L.; Wang, Z.; Li, W.; Huo, L.; Zhang, J. Comparison of the 68Ga-DOTATATA PET/CT, FDG PET/CT, and MIBG SPECT/CT in the Evaluation of Suspected Primary Pheochromocytomas and Paragangliomas. Clin. Nucl. Med. 2017, 42, 525–529. [Google Scholar] [CrossRef]
  7. Taïeb, D.; Hicks, R.J.; Hindié, E.; Guillet, B.A.; Avram, A.; Ghedini, P.; Timmers, H.J.; Scott, A.T.; Elojeimy, S.; Rubello, D.; et al. European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur. J. Nucl. Med. 2019, 46, 2112–2137. [Google Scholar] [CrossRef]
  8. Neumann, H.P.H.; Young, W.F., Jr.; Eng, C. Pheochromocytoma and Paraganglioma. N. Engl. J. Med. 2019, 381, 552–565. [Google Scholar] [CrossRef]
  9. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef]
  10. Slim, K.; Nini, E.; Forestier, D.; Kwiatkowski, F.; Panis, Y.; Chipponi, J. Methodological index for non-randomized studies (MINORS): Development and validation of a new instrument. ANZ J. Surg. 2003, 73, 712–716. [Google Scholar] [CrossRef]
  11. Stang, A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur. J. Epidemiol. 2010, 25, 603–605. [Google Scholar] [CrossRef]
  12. Egger, M.; Smith, G.D.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315, 629–634. [Google Scholar] [CrossRef]
  13. Wan, X.; Wang, W.; Liu, J.; Tong, T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. 2014, 14, 135. [Google Scholar] [CrossRef]
  14. van Essen, M.; Krenning, E.P.; Kooij, P.P.; Bakker, W.H.; Feelders, R.A.; de Herder, W.W.; Wolbers, J.G.; Kwekkeboom, D.J. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J. Nucl. Med. 2006, 47, 1599–1606. [Google Scholar]
  15. Imhof, A.; Brunner, P.; Marincek, N.; Briel, M.; Schindler, C.; Rasch, H.; Mäcke, H.R.; Rochlitz, C.; Müller-Brand, J.; Walter, M.A. Response, Survival, and Long-Term Toxicity After Therapy With the Radiolabeled Somatostatin Analogue [90Y-DOTA]-TOC in Metastasized Neuroendocrine Cancers. J. Clin. Oncol. 2011, 29, 2416–2423. [Google Scholar] [CrossRef]
  16. Pinato, D.J.; Black, J.R.M.; Ramaswami, R.; Tan, T.M.; Adjogatse, D.; Sharma, R. Peptide receptor radionuclide therapy for metastatic paragangliomas. Med. Oncol. 2016, 33, 47. [Google Scholar] [CrossRef]
  17. Hamiditabar, M.; Ali, M.; Roys, J.; Wolin, E.M.; O’Dorisio, T.; Ranganathan, D.; Tworowska, I.; Strosberg, J.R.; Delpassand, E.S. Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors. Six years assesment. Clin. Nucl. Med. 2017, 42, 436–443. [Google Scholar] [CrossRef]
  18. Demirci, E.; Kabasakal, L.; Toklu, T.; Ocak, M.; Şahin, O.E.; Alan-Selcuk, N.; Araman, A. 177Lu-DOTATATE therapy in patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours. Nucl. Med. Commun. 2018, 39, 789–796. [Google Scholar] [CrossRef]
  19. Garske-Román, U.; Sandström, M.; Baron, K.F.; Lundin, L.; Hellman, P.; Welin, S.; Johansson, S.; Khan, T.; Lundqvist, H.; Eriksson, B.; et al. Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): Feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity. Eur. J. Nucl. Med. 2018, 45, 970–988. [Google Scholar] [CrossRef]
  20. Zandee, W.T.; Brabander, T.; Blažević, A.; Kam, B.L.R.; Teunissen, J.J.M.; Feelders, R.A.; Hofland, J.; De Herder, W.W. Symptomatic and Radiological Response to 177Lu-DOTATATE for the Treatment of Functioning Pancreatic Neuroendocrine Tumors. J. Clin. Endocrinol. Metab. 2019, 104, 1336–1344. [Google Scholar] [CrossRef]
  21. Vyakaranam, A.R.; Crona, J.; Norlén, O.; Granberg, D.; Garske-Román, U.; Sandström, M.; Fröss-Baron, K.; Thiis-Evensen, E.; Hellman, P.; Sundin, A. Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE. Cancers 2019, 11, 909. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Kolasinska-Ćwikła, A.; Pęczkowska, M.; Ćwikła, J.B.; Michałowska, I.; Pałucki, J.M.; Bodei, L.; Lewczuk-Myślicka, A.; Januszewicz, A. A Clinical Efficacy of PRRT in Patients with Advanced, Nonresectable, Paraganglioma-Pheochromocytoma, Related to SDHx Gene Mutation. J. Clin. Med. 2019, 8, 952. [Google Scholar] [CrossRef] [PubMed]
  23. Jaiswal, S.K.; Sarathi, V.; Memon, S.S.; Garg, R.; Malhotra, G.; Verma, P.; Shah, R.; Sehemby, M.K.; Patil, V.A.; Jadhav, S.; et al. 177Lu-DOTATATE therapy in metastatic/inoperable pheochromocytoma-paraganglioma. Endocr. Connect. 2020, 9, 864–873. [Google Scholar] [CrossRef] [PubMed]
  24. Severi, S.; Bongiovanni, A.; Ferrara, M.; Nicolini, S.; Di Mauro, F.; Sansovini, M.; Lolli, I.; Tardelli, E.; Cittanti, C.; Di Iorio, V.; et al. Peptide receptor radionuclide therapy in patients with metastatic progressive pheochromocytoma and paraganglioma: Long-term toxicity, efficacy and prognostic biomarker data of phase II clinical trials. ESMO Open 2021, 6, 100171. [Google Scholar] [CrossRef]
  25. Prado-Wohlwend, S.; Bernal-Vergara, J.; Utrera-Costero, A.; Cañón-Sánchez, J.; Agudelo-Cifuentes, M.; Bello-Arques, P. Peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE. Rev. Española De Med. Nucl. E Imagen Mol. 2021, 41, 55–65. [Google Scholar] [CrossRef]
  26. Satapathy, S.; Mittal, B.R.; Bhansali, A. ‘Peptide receptor radionuclide therapy in the management of advanced pheochromocytoma and paraganglioma: A systematic review and meta-analysis’. Clin. Endocrinol. 2019, 91, 718–727. [Google Scholar] [CrossRef]
  27. van Hulsteijn, L.T.; Niemeijer, N.D.; Dekkers, O.M.; Corssmit, E.P.M. 131I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: Systematic review and meta-analysis. Clin. Endocrinol. 2013, 80, 487–501. [Google Scholar] [CrossRef]
  28. Lenders, J.W.M.; Eisenhofer, G. Update on Modern Management of Pheochromocytoma and Paraganglioma. Endocrinol. Metab. 2017, 32, 152–161. [Google Scholar] [CrossRef]
  29. Niemeijer, N.D.; Alblas, G.; Van Hulsteijn, L.T.; Dekkers, O.M.; Corssmit, E.P.M. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: Systematic review and meta-analysis. Clin. Endocrinol. 2014, 81, 642–651. [Google Scholar] [CrossRef]
  30. Jhawar, S.; Arakawa, Y.; Kumar, S.; Varghese, D.; Kim, Y.S.; Roper, N.; Elloumi, F.; Pommier, Y.; Pacak, K.; Del Rivero, J. New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications. Cancers 2022, 14, 594. [Google Scholar] [CrossRef]
  31. Amar, L.; Baudin, E.; Burnichon, N.; Peyrard, S.; Silvera, S.; Bertherat, J.; Bertagna, X.; Schlumberger, M.; Jeunemaitre, X.; Gimenez-Roqueplo, A.-P.; et al. Succinate Dehydrogenase B Gene Mutations Predict Survival in Patients with Malignant Pheochromocytomas or Paragangliomas. J. Clin. Endocrinol. Metab. 2007, 92, 3822–3828. [Google Scholar] [CrossRef]
  32. O’Kane, G.M.; Ezzat, S.; Joshua, A.; Bourdeau, I.; Leibowitz-Amit, R.; Olney, H.J.; Krzyzanowska, M.; Reuther, D.; Chin, S.; Wang, L.; et al. A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: The SNIPP trial. Br. J. Cancer 2019, 120, 1113–1119. [Google Scholar] [CrossRef]
  33. Prinzi, N.; Corti, F.; Torchio, M.; Niger, M.; Antista, M.; Pagani, F.; Beninato, T.; Pulice, I.; Rossi, R.E.; Coppa, J.; et al. Metastatic pheochromocytomas and paragangliomas: Where are we? Tumori J. 2022, 108, 526–540. [Google Scholar] [CrossRef]
  34. Granberg, D.; Juhlin, C.C.; Falhammar, H. Metastatic Pheochromocytomas and Abdominal Paragangliomas. J. Clin. Endocrinol. Metab. 2021, 106, e1937–e1952. [Google Scholar] [CrossRef]
  35. Oh, D.Y.; Kim, T.W.; Park, Y.S.; Shin, S.J.; Shin, S.H.; Song, E.-K.; Lee, H.J.; Lee, K.-W.; Bang, Y.-J. Phase 2 study of everolimus monotherapy in patients with non-functioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer 2012, 118, 6162–6170. [Google Scholar] [CrossRef]
Jcm 12 01494 g001 550
Figure 1. Selection flow-chart of studies included in the meta-analysis.
Figure 1. Selection flow-chart of studies included in the meta-analysis.
Jcm 12 01494 g001
Jcm 12 01494 g002 550
Figure 2. Funnel plot for DCR (disease-control rate) in the selected articles.
Figure 2. Funnel plot for DCR (disease-control rate) in the selected articles.
Jcm 12 01494 g002
Jcm 12 01494 g003 550
Figure 3. Forest plot for DCR according to 177Lu- and 90Y- PRRT treatments.
Figure 3. Forest plot for DCR according to 177Lu- and 90Y- PRRT treatments.
Jcm 12 01494 g003
Table
Table 1. Baseline characteristics of included studies.
Table 1. Baseline characteristics of included studies.
AuthorYearType of StudyNo. of PatientsAge, Years
Median (Range)		SexSites of Metastases
(No. of Patients)		Genetic Characteristics
(No. of Patients)		Previous Treatments
(No. of Patients)
van Essen M. [14]2006retrospective12 (1 PCC, 11 PGL)39.7 (22–55)6 male, 6 femaleliver (4), bone (7)NAsurgery (9), CHT (4), RT (7), naive (2)
Imhof A. [15]2011prospective39 (11 PCC, 28 PGL)39NSNSNANS
Pinato DJ. [16]2016retrospective5 (5 PGL)34 (16–47)4 male, 1 femalenodes (1), bone (5), lung (1)SDHB (5)surgery (4), CHT (1), RT (1), 131I-MIBG (1)
Hamiditabar M. [17]2017prospective5 (1PCC, 4 PGL)NSNSNSNANS
Demirci E. [18]2018retrospective12 (NS)NSNSNSNANS
Garske-Román U. [19]2018prospective5 (2 PCC, 3 PGL)60.4 (25–71)2 male, 3 femalenodes (2), liver (2), bone (5)NAsurgery (5)
Zandee WT. [20]2019retrospective30 (3 PCC, 27 PGL)47 (29–74)10 male, 20 femalenodes (10), liver (7), bone (13), lung (6)SDHB (5), SDHD (11), familiar (2), sporadic (5), unknown (7)surgery (19), CHT (5), RT (6), 131I-MIBG (3), SSA (2)
Vyakaranam AR. [21]2019retrospective22 (9 PCC + 13 PGL)60 (24–80)13 male, 9 femalenodes (7), liver (9), bone (17), lung (4)sporadic (4), SDHB (4), SDHD (2), SDHA (1), NF1 (2), unknown (9)surgery (16), CHT (1), RT (14), 131I-MIBG (6), naive (1)
Kolasinska-Ćwikła A. [22]2019prospective13 (4 PCC + 9 PGL)41.8 (27–62)8 male, 5 femaleliver (6), bone (9)SDHB (5),
SDHD (8)		surgery (13), SSA (8)
Jaiswal SK. [23]2020retrospective15 (5 PCC + 10 PGL)32.57 male, 8 femalenodes (3), liver (4), bone (6), lung (3)VHL (2), SDHB (1), SDHD (1), negative (1), unknown (10)surgery (10), RT (3)
Severi S. [24]2021retrospective46 (NS)5220 male, 26 femaleliver (8), bone (19)wildtype (10), SDHD or SDHB (20)NS
Prado-Wohlwend S. [25]2022retrospective9 (3 PCC + 6 PGL)45.8 (20–72)4 male, 5 femalenodes (6), liver (3), bone (8), lung (3)SDHD (1)—SDHB (3)—NF1 (1)—sporadic (4)CHT (3), RT (3), 131I-MIBG (2), SSA (8), naive (1)
CHT: chemotherapy; NF1: neurofibromatosis type 1; NS: not specified; PCC: pheochromocytoma; PGL: paraganglioma; RT: radiotherapy; SDHA: succinate dehydrogenase subunit A; SDHB: succinate dehydrogenase subunit B; SDHD: succinate dehydrogenase subunit D; SSA: somatostatin analogues; VHL: von Hippel-Lindau.
Table
Table 2. Efficacy and toxicity profile of PRRT in the included studies.
Table 2. Efficacy and toxicity profile of PRRT in the included studies.
Author
(First Name)		YearPRRT AgentTreatment CharacteristicsNo. of CyclesResponse CriteriaBest Response to PRRT (Radiologically Assessed Patients)Haematological Toxicity Grades 3/4
(No. of Patients)
van Essen M. [14]2006177Lu7.4 GBq per cycleNSSWOGPR (2), SD (6)thrombocytopenia and anemia (2)
Imhof A. [15]201190Y3.7 GBq/mq per cycle2 (1–10)RECIST 1.0PR (7) *NS
Pinato DJ. [16]2016177Lu6.6–7.6 GBq per cycle3NSPR (1), SD (3)none
Hamiditabar M. [17]2017177Lu7.4 GBq per cycleNSRECIST 1.1SD (4)NS
Demirci E. [18]2018177Lu3.7–8.1 GBq per cycleat least 3 cyclesRECIST 1.1PR (4), SD (2)NS
Garske-Román U. [19]2018177Lu7.4 GBq per cycleNSRECIST 1.1SD (5)NS
Zandee WT. [20]2019177Lu7.4 GBq per cycle73% of patients received 4 cyclesRECIST 1.1PR (7), SD (20)anemia (2), thrombocytopenia (5), leukopenia (3)
Vyakaranam AR. [21]2019177Lu7.4 GBq per cycle4.9RECIST 1.1PR (2), SD (20)no
Kolasinska-Ćwikła A. [22]201990Y3.4 GBq per cycleNS (61% of patients received 2 cycles)RECIST 1.0PR (1), SD (9)anemia (2)
Jaiswal SK. [23]2020177LuNS4.13RECIST 1.1PR (1), SD (11)none
Severi S. [24]2021177Lu (34) and 90Y- (12)177Lu: 3.7–5.5 GBq per cycle
90Y: 1.1–1.85 GBq per cycle		5RECIST 1.1177Lu: PR (3), SD (25) 90Y: PR (1), SD (8)none
Prado-Wohlwend S. [25]2022177Lu8.01 (7.4–8.4)
GBq per cycle		3.11RECIST 1.1PR (2), SD (6)NS
GBq: Gigabecquerel; NS: not specified; PR: partial response; SD: stable disease. * In this study, the DCR is not evaluable.
Table
Table 3. MINORS and Newcastle-Ottawa Scale scores of selected articles.
Table 3. MINORS and Newcastle-Ottawa Scale scores of selected articles.
AuthorYearAccrual TimeMINORS ScoreNewcastle Ottawa Scale Score
SelectionComparabilityOutcomeTotal
van Essen M. [14]2006NS73036
Imhof A. [15]20111997–2010103137
Pinato DJ. [16]20162008–201493036
Hamiditabar M. [17]20172010–201683036
Demirci E. [18]20182010–201583036
Garske-Román U. [19]20182010–201483137
Zandee WT. [20]20192000–NS103137
Vyakaranam AR. [21]20192005–2018103137
Kolasinska-Ćwikła A. [22]20192006–2018113238
Jaiswal SK. [23]20202010–201983137
Severi S. [24]20212008–2018103238
Prado-Wohlwend S. [25]20222014–202193137
NS: Not Specified.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Marretta, A.L.; Ottaiano, A.; Iervolino, D.; Bracigliano, A.; Clemente, O.; Di Gennaro, F.; Tafuto, R.; Santorsola, M.; Lastoria, S.; Tafuto, S. Response to Peptide Receptor Radionuclide Therapy in Pheocromocytomas and Paragangliomas: A Systematic Review and Meta-Analysis. J. Clin. Med. 2023, 12, 1494. https://doi.org/10.3390/jcm12041494

AMA Style

Marretta AL, Ottaiano A, Iervolino D, Bracigliano A, Clemente O, Di Gennaro F, Tafuto R, Santorsola M, Lastoria S, Tafuto S. Response to Peptide Receptor Radionuclide Therapy in Pheocromocytomas and Paragangliomas: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. 2023; 12(4):1494. https://doi.org/10.3390/jcm12041494

Chicago/Turabian Style

Marretta, Antonella Lucia, Alessandro Ottaiano, Domenico Iervolino, Alessandra Bracigliano, Ottavia Clemente, Francesca Di Gennaro, Roberto Tafuto, Mariachiara Santorsola, Secondo Lastoria, and Salvatore Tafuto. 2023. "Response to Peptide Receptor Radionuclide Therapy in Pheocromocytomas and Paragangliomas: A Systematic Review and Meta-Analysis" Journal of Clinical Medicine 12, no. 4: 1494. https://doi.org/10.3390/jcm12041494

APA Style

Marretta, A. L., Ottaiano, A., Iervolino, D., Bracigliano, A., Clemente, O., Di Gennaro, F., Tafuto, R., Santorsola, M., Lastoria, S., & Tafuto, S. (2023). Response to Peptide Receptor Radionuclide Therapy in Pheocromocytomas and Paragangliomas: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine, 12(4), 1494. https://doi.org/10.3390/jcm12041494

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop