A novel strategy for predicting the efficacy of temozolomide treatment for metastatic pheochromocytomas/paragangliomas.

BACKGROUND: There are few studies on the efficacy of temozolomide (TMZ) in the treatment of Metastatic pheochromocytoma / paraganglioma (MPP) patients. And it remains unclear which MPP patients may benefit from TMZ treatment. METHODS: This was a prospective study. MPP patients were enrolled. Patients were treated with TMZ until disease progression or intolerable toxicities. The primary endpoints were disease control rate (DCR) and objective response rate (ORR). Secondary endpoints included biochemical response rate progression-free survival (PFS) and safety. We compared the difference between effective and ineffective groups, to explore which patients are more suitable for TMZ treatment. RESULTS: 62 patients with MPP were enrolled and tumor response were evaluated in 54 patients. The DCR was 83% (35/42), and the ORR was 24% (10/41) among the progressive patients. PFS was 25.2 ± 3.1 months. The most common adverse event was nausea (41/55). We found that 92.9% (13/14) of patients with MGMT methylation greater than 7% respond to treatment. For the patients with MGMT methylation less than 7%, Ki-67 index could be used to guide the use of TMZ in these patients. Among the patients with Ki-67 index less than 5%, 66% (8/12) patients showed respond to treatment, and only 33% (4/12) patients with Ki-67 index more than 5% showed respond to TMZ. CONCLUSIONS: This study indicated that TMZ is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. We recommended to MGMT methylation analysis test and Ki-67 index to guide TMZ application.

Metastatic pheochromocytoma and paraganglioma: Integrating tumor biology in clinical practice.

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors derived from chromaffin cells in the autonomic nervous system. Depending on their location, these tumors are capable of excessive catecholamine production, which may lead to uncontrolled hypertension and other life-threatening complications. They are associated with a significant risk of metastatic disease and are often caused by an inherited germline mutation. Although surgery can cure localized disease and lead to remission, treatments for metastatic PPGL (mPPGL)-including chemotherapy, radiopharmaceutical agents, multikinase inhibitors, and immunotherapy used alone or in combination- aim to control tumor growth and limit organ damage. Substantial advances have been made in understanding hereditary and somatic molecular signaling pathways that play a role in tumor growth and metastasis. Treatment options for metastatic disease are rapidly evolving, and this paper aims to provide a brief overview of the management of mPPGL with a focus on therapy options.

Multi-disciplinary surgery for simultaneous resection of multiple tumors in a patient with newly diagnosed metastatic pheochromocytoma/paraganglioma.

Metastatic pheochromocytoma/paraganglioma (MPP) is a rare endocrine tumor that originates from extra-adrenal chromaffin cells such as the paraganglia cells of sympathetic and parasympathetic nerves. It usually causes multiple solid tumors and exhibits strong aggressiveness with poor prognosis, with a reported 5-year survival rate of less than 50%. Cases of brain and retroperitoneal metastases at the initial diagnosis have not yet been reported. We report a 41-year-old male patient initially diagnosed with MPP in the brain and retroperitoneum who underwent multi-disciplinary collaborative surgery and simultaneous removal of two tumors at our center. Postoperative pathology revealed infiltrative growth of a skull base tumor. The patient chose to receive the tyrosine kinase inhibitor sunitinib as a targeted treatment. A 3-month follow-up after surgery showed that the patient recovered well without signs of metastasis or recurrence. We present multi-disciplinary surgery under similar circumstances for enhanced treatment and postoperative management. The patient demonstrates a favorable prognosis during postoperative follow-up, indicating that simultaneous multidisciplinary surgery may offer greater benefits for MPP patients.

Succinate Dehydrogenase Mutations as Familial Pheochromocytoma Syndromes.

It is recognized that a large portion of pheochromocytoma and paraganglioma cases will have an underlying germline mutation, supporting the recommendation for universal genetic testing in all patients with PPGLs. A mutation in succinate dehydrogenase subunit B is associated with increased rates of developing synchronous and/or metachronous metastatic disease. Patients identified with this mutation require meticulous preoperative evaluation, a personalized surgical plan to minimize the risk of recurrence and tumor spread, and lifelong surveillance.

Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.

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

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. Conclusions: 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.