Efficacy and Long-Term Safety of Everolimus in Pancreatic Neuroendocrine Tumor Associated with Multiple Endocrine Neoplasia Type I: Case Report

Maia, Manuel Caitano; Lourenço, Delmar M.; Riechelmann, Rachel P.

doi:10.1159/000448699

Cited by 9 publications

(5 citation statements)

References 14 publications

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“…The 5-year survival rate of these patients is 30% to 40%, with median survival up to 44 months (17)(18)(19)(20). One of the few case reports in the literature described a patient with pNET and genetically confirmed MEN1 syndrome who achieved 3 years of disease control with everolimus (21). Our cohort showed a numerically, albeit not statistically significant, superior mPFS and mTTF in the germline mutated group treated with everolimus, achieving a mPFS of 33 months, which seems longer than the mPFS of 12 months reported in the phase III placebo-controlled trials of everolimus (22).…”

Section: Discussionmentioning

confidence: 99%

The efficacy of everolimus and sunitinib in patients with sporadic or germline mutated metastatic pancreatic neuroendocrine tumors

Nuñez¹,

Donadio²,

Filho³

et al. 2019

J. Gastrointest. Oncol

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Background: Hyperactivation of mTOR pathway and angiogenesis have been implicated in the pathogenesis of neuroendocrine tumors (NETs). Everolimus, an oral inhibitor of mTOR, and sunitinib, an antiangiogenic drug, are effective targeted therapies approved to treat locally advanced/metastatic pancreatic neuroendocrine tumors (pNETs). Most pNETs are sporadic and mutations in genes involved directly or indirectly in mTOR pathway regulation have been implicated, including somatic mutation in MEN1 in 44% of cases. About 10% of pNETs can be part of hereditary syndromes, e.g., multiple endocrine neoplasia type 1 (MEN1) and Von-Hippel Lindau (VHL), and these patients are underrepresented in pivotal phase III trials.We hypothesized that everolimus would be particularly effective in patients with MEN1-associated pNETs. Likewise, we inferred that sunitinib would also be beneficial to patients with VHL-associated pNETs. Methods:We conducted a multicenter retrospective and comparative study to assess the efficacy of everolimus and/or sunitinib in a cohort of patients with advanced pNETs with or without known MEN1 or VHL syndrome. The evaluation of the germline mutational status of VHL and MEN1 genes was retrospectively collected from the medical records. The primary endpoints were progression free survival (PFS) and time to treatment failure (TTF) of patients who received at least one month of sunitinib or everolimus in monotherapy. Results: Thirty-three patients were identified from September 2009 to April 2018. Most were male 60.6%.Median Ki67 was 9%, liver metastases were present in 97%. The majority of tumors were non-functioning. Thirty-one patients received everolimus, of them 8 patients had germline mutations (6 in MEN1 and 2 in VHL genes). Nine patients received sunitinib, of them 3 had germline mutation (2 in MEN1 and 1 in VHL genes). In a median follow up of 26 months, among everolimus-treated patients, mTTF and mPFS were numerically superior in patients with germline mutations compared with those with sporadic pNETs (mTTF: 16.1 vs. 9.9 months, P=0.888; mPFS: 33.1 vs. 12.3 months, P=0.383). The disease control rate with everolimus was numerically higher in favor of germline mutated tumors compared to sporadic ones (87.5% vs. 68.4%). Sunitinib was used by 1 patient with VHL syndrome, achieving a PFS of 17.6 months.In the subgroup of sporadic pNETs, sunitinib was used by 6 patients reaching a mPFS of 18 months (range, 5-25 months), predominantly in second line. Conclusions: Our study suggests that everolimus may offer a prolonged tumor control in pNETS with germline mutations (MEN1 or VHL) compared to sporadic ones. The small number of patients and the retrospective nature of this study precludes any definitive conclusions.

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Section: Discussionmentioning

confidence: 99%

The efficacy of everolimus and sunitinib in patients with sporadic or germline mutated metastatic pancreatic neuroendocrine tumors

Nuñez¹,

Donadio²,

Filho³

et al. 2019

J. Gastrointest. Oncol

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“…For patients with MEN-1-associated metastatic pancreatic NET, we prefer everolimus as the first option [ 119 ] [VC].…”

Section: Common Hereditary Syndromes Associated With Gep Nets: Multipmentioning

confidence: 99%

“…We prefer sunitinib as the first choice in pancreatic NET associated with VHL syndrome [VC] and everolimus as the first choice in MEN-1-associated pancreatic NET [ 119 ][VC]…”

Section: Common Hereditary Syndromes Associated With Gep Nets: Multipmentioning

confidence: 99%

Guidelines for the management of neuroendocrine tumours by the Brazilian gastrointestinal tumour group

Riechelmann¹,

Weschenfelder

Costa

et al. 2017

ecancer

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Neuroendocrine tumours are a heterogeneous group of diseases with a significant variety of diagnostic tests and treatment modalities. Guidelines were developed by North American and European groups to recommend their best management. However, local particularities and relativisms found worldwide led us to create Brazilian guidelines. Our consensus considered the best feasible strategies in an environment involving more limited resources. We believe that our recommendations may be extended to other countries with similar economic standards.

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“…Because of the sparsity of these syndromes, it is challenging to establish evidence-based guidelines, especially in terms of treatment. Patients with PNETs associated with germline mutations are underrepresented in phase III trials of drugs used in sporadic PNETs (21,22). We have data on pharmacotherapy in patients with PNETs and MEN1 or VHL, but mostly from case reports or trials that assessed very small groups of patients (21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

“…Patients with PNETs associated with germline mutations are underrepresented in phase III trials of drugs used in sporadic PNETs (21,22). We have data on pharmacotherapy in patients with PNETs and MEN1 or VHL, but mostly from case reports or trials that assessed very small groups of patients (21)(22)(23)(24)(25)(26)(27). Despite the great interest in the topic, still, the surgical treatment of PNETs in MEN1/VHL remains controversial (9,14,(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

A Direct Comparison of Patients With Hereditary and Sporadic Pancreatic Neuroendocrine Tumors: Evaluation of Clinical Course, Prognostic Factors and Genotype–Phenotype Correlations

et al. 2021

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IntroductionPancreatic neuroendocrine tumors (PNETs) in hereditary syndromes pose a significant challenge to clinicians. The rarity of these syndromes and PNETs itself make it difficult to directly compare them with sporadic PNETs. Despite research suggesting differences between these two entities, the same approach is used in hereditary and sporadic PNETs.MethodsWe included 63 patients with hereditary PNET (GpNET) and 145 with sporadic PNET (SpNET) in a retrospective observational study. Clinical and genetic data were collected in two Polish endocrine departments from January 2004 to February 2020. Only patients with confirmed germline mutations were included in the GpNET cohort. We attempted to establish prognostic factors of metastases and overall survival in both groups and genotype–phenotype correlations in the GpNET group.ResultsPatients with GpNET were younger and diagnosed earlier, whereas their tumors were smaller and more frequently multifocal compared with patients with SpNET. Metastases occurred more frequently in the SpNET group, and their appearance was associated with tumor size in both groups. GpNET patients had longer overall survival (OS). OS was affected by age, age at diagnosis, sex, grade, stage, tumor diameter, occurrence and localization of metastases, type of treatment, and comorbidities. In the MEN1 group, carriers of frameshift with STOP codon, splice site, and missense mutations tended to have less advanced disease, while patients with mutations in exon 2 tended to have metastases more frequently.ConclusionsDirect comparisons of GpNET and SpNET demonstrate significant differences in the clinical courses of both entities, which should force different approaches. A larger group of patients with GpNET should be assessed to confirm genotype–phenotype correlations.

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Efficacy and Long-Term Safety of Everolimus in Pancreatic Neuroendocrine Tumor Associated with Multiple Endocrine Neoplasia Type I: Case Report

Cited by 9 publications

References 14 publications

The efficacy of everolimus and sunitinib in patients with sporadic or germline mutated metastatic pancreatic neuroendocrine tumors

The efficacy of everolimus and sunitinib in patients with sporadic or germline mutated metastatic pancreatic neuroendocrine tumors

Guidelines for the management of neuroendocrine tumours by the Brazilian gastrointestinal tumour group

A Direct Comparison of Patients With Hereditary and Sporadic Pancreatic Neuroendocrine Tumors: Evaluation of Clinical Course, Prognostic Factors and Genotype–Phenotype Correlations

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