Continued Tumor Reduction of Metastatic Pheochromocytoma/Paraganglioma Harboring Succinate Dehydrogenase Subunit B Mutations with Cyclical Chemotherapy

Jawed, Irfan; Velarde, Margarita; Därr, Roland; Wolf, Katherine I.; Adams, Karen T.; Venkatesan, Aradhana M.; Balasubramaniam, Sanjeeve; Poruchynsky, Marianne S.; Reynolds, James C.; Pacák, Karel; Fojo, Tito

doi:10.1007/s10571-018-0579-4

Cited by 31 publications

(28 citation statements)

References 41 publications

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“…154 Very recently Jawed et al studied 12 patients with a metastatic PGL/PCC, all with SDHB mutation, who received CVD; a marked efficacy was noted. 155 Two out of 12 patients had a complete remission and eight patients a partial response. The median duration of response was 478 days, with a median progression-free survival of 930 days.…”

Section: Heat Shock Protein 90 Inhibitorsmentioning

confidence: 93%

“…Both patients showed hypermethylation of the MGMT promotor region, suggesting that monotherapy of temozolomide may benefit patients with metastatic SDHB‐ related PGL/PCC . Very recently Jawed et al studied 12 patients with a metastatic PGL/PCC, all with SDHB mutation, who received CVD; a marked efficacy was noted . Two out of 12 patients had a complete remission and eight patients a partial response.…”

Section: Implications For Treatment Of Metastatic Pgl/pccmentioning

confidence: 99%

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Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro-intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α-ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations. K E Y W O R D S oncometabolites, paraganglioma, pheochromocytoma, SDH mutation, succinate 1 | INTRODUCTION Mutations of genes encoding for the succinate dehydrogenase (SDH) complex, associated with familial paraganglioma (PGL) and pheochromocytoma (PCC), lead to accumulation of succinate, which disturbs the metabolic regulation of the cell. Nowadays metabolic dysregulation is recognized as one of the eight hallmarks of cancer. 1 Although germline mutations in SDHx genes are predominantly linked to PGL and PCC, these mutations also predispose to renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs) and, possibly, pituitary adenomas. PCC, PGL and head and neck PGL (HNPGL) are rare neuroendocrine tumors arising from chromaffin cells that can synthesize and release catecholamines. Sympathetic PGLs are derived from sympathetic paraganglia in the chest, abdomen or pelvis. PCC are PGLs located in the adrenal medulla. 2 HNPGLs are derived from parasympathetic paraganglia. Common locations for HNPGLs include the carotid body and the middle ear, as well as the vagus nerve and internal jugular vein. While parasympathetic PGLs are most often non-functional tumors, PCC and sympathetic PGL release catecholamines into the circulation and can

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Section: Heat Shock Protein 90 Inhibitorsmentioning

confidence: 93%

Section: Implications For Treatment Of Metastatic Pgl/pccmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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“…A meta-analysis involving 50 MPP patients showed that the effective rate of CVD, in terms of tumor volume, was 55% (7). A recent retrospective study showed that, in 12 MPP patients with SDHB gene mutation, all patients had tumor reduction (12-100% by RECIST) upon CVD (6), which suggests CVD therapy probably works better in patients with SDHB mutation. However, CVD is not effective in all patients with SDHB mutation (patient 1 and patient 2 in Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…Molecular targeted therapy, such as sunitinib, has shown great potential in the treatment of MPP, but needs to be further investigated (4). Chemotherapy mainly includes CVD regimen (cyclophosphamide, vincristine, and dacarbazine) and temozolomide (TMZ) (5,6). CVD is the most commonly used chemotherapeutic regimen for MPP (7), and TMZ, an oral alkylation chemotherapeutic agent, was first reported to be used for the treatment of MPP in 2006 (8).…”

Section: Introductionmentioning

confidence: 99%

Temozolomide Is a Potential Therapeutic Tool for Patients With Metastatic Pheochromocytoma/Paraganglioma—Case Report and Review of the Literature

Tong

Cui

et al. 2020

Front. Endocrinol.

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Context: Metastatic pheochromocytoma/paraganglioma (MPP) therapy mainly involves radionuclide therapy, chemotherapy, and targeted therapy. In recent years, temozolomide (TMZ) showed great promise in some MMP patients, especially those with SDHB germline mutation. We reported a patient with MPP who did not have any known germline genetic change and responded remarkably well to TMZ monotherapy.Case presentation: The patient was a 41-year-old woman with local and distant recurrence (soft tissues and bone metastases) of retroperitoneal paraganglioma. She suffered from dizziness, palpitation, sweating, weight loss and constipation, with the blood pressure fluctuating substantially from 130/100 mmHg to 190/120 mmHg, although she was on phenoxybenzamine and metoprolol medication. The patient showed clinical and radiological response after 3-cycle TMZ therapy. Upon 15 cycles of TMZ therapy, her symptoms were dramatically alleviated, urinary norepinephrine excretion decreased from 1,840 µg/24 h to 206 µg/24 h, and CT showed that the lesions further shrank. Molecular profiling of the tumor tissue of the patient revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter and a negative immunostaining for MGMT. Globally, only 26 cases of MPP treated with TMZ have been described so far. TMZ is effective, especially in patients with SDHB mutation, which can be explained by the silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumors. Although, in general, patients with SDHB mutation or MGMT promoter hypermethylation have better response to TMZ, there are also exceptions. Severe side effects are uncommon, with only 17.4% patients experiencing Grade 3 toxicities, including lymphopenia, and hypertension. Tong et al. Temozolomide Is Effective for MPPConclusions: TMZ is effective and safe in MPP patients, and, it may work better on patients with SDHB-related MPP. Measurement of MGMT expression might help assess the tumor sensitivity to TMZ but this needs further systematic investigation.

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“…However, compared to I-131-MIBG therapy, peptide receptor radionuclide therapy had logistic and radiation-safety advantages [43] . As for the chemotherapy, the combination chemotherapy cyclophosphamide, vincristine, and dacarbazine (CVD) was recommended to be considered part of the initial management in patients with metastatic succinate dehydrogenase complex subunit B (SDHB)-related PPGL, because cyclical CVD chemotherapy lead to continued tumor reduction of metastatic PPGL harboring SDHB mutations [44] . Meanwhile, in our results, adjuvant therapy, radiotherapy, and chemotherapy can improve the CSS of the patients with PPGL.…”

Section: Discussionmentioning

confidence: 99%

Summary of clinical characteristics of common primary adrenal malignancies in adults

zhang¹,

wang²,

Li³

et al. 2020

Preprint

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Background To summary the clinical characteristics of common primary adrenal malignancies in adults, the survival time of the patients, and the prognostic factors associated with these rare malignancies. Methods The Surveillance, Epidemiology, and End Results database (1975–2016) was queried for all patients who were diagnosed with primary adrenal malignancies, including adrenocortical carcinoma(ACC), pheochromocytoma and paraganglioma (PPGL), lymphoma, and sarcoma (SA). The clinical characteristics, overall survival (OS) and cancer-specific survival (CSS) were analyzed, in which propensity score methodology, logistic regression modeling and Kaplan-Meier survival curves were used. The Multivariate Cox proportional hazard model was used to identify factors affecting the prognosis of patients with ACC. Results 3204 patients with primary adrenal malignancies were identified, including 2180 with ACC, 593 with PPGL, 307 with lymphoma, and 124 with SA. Generally, PPGL had a better prognosis than others. For ACC and PPGL, the non-metastatic group had better OS and CSS than the metastatic group; for SA, the non-metastatic group had better OS, however, there was no significant difference in CSS between the two groups. Furthermore, For ACC, the single metastasis group had a better OS than the multiple metastasis group. After tumors metastasis, the surgery group, surgery of primary adrenal lesions, had better OS and CSS than the non-surgery group for ACC and PPGL. For lymphoma, the chemotherapy group had better OS and CSS; for ACC and PPGL, the chemotherapy group had better CSS and worse OS; for SA, the survival showed no significant difference between the two groups. Radiotherapy had the same effect on patients' survival as chemotherapy, except for the lymphoma and the ACC. As for lymphoma, the radiotherapy group had better CSS, whereas the survival showed no significant difference in OS between the two groups. For ACC, the non- radiotherapy group had better CSS and OS. More importantly, for lymphoma, under the condition that both cohorts were the same basically, the surgical group had a better prognosis. The prognosis of ACC was related to sex, age, seer historic stage, surgery, chemotherapy. Conclusion Understanding the clinical characteristics of these tumors and factors affecting prognosis can facilitate the selection of more appropriate clinical treatment options.

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Continued Tumor Reduction of Metastatic Pheochromocytoma/Paraganglioma Harboring Succinate Dehydrogenase Subunit B Mutations with Cyclical Chemotherapy

Cited by 31 publications

References 41 publications

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Temozolomide Is a Potential Therapeutic Tool for Patients With Metastatic Pheochromocytoma/Paraganglioma—Case Report and Review of the Literature

Summary of clinical characteristics of common primary adrenal malignancies in adults

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