Pheochromocytoma originated from the ectodermal chromatin tissue is a rare and potentially dangerous tumor that continuously or intermittently releases catecholamines to act on adrenergic receptors. The released catecholamine causes persistent or paroxysmal hypertension with headache, hyperhidrosis, palpitations, multiple organ functions and metabolic disorders. Depending on whether the tumor is from the sympathetic or parasympathetic, we can divide it into parasympathetic paraganglioma (including chemoreceptor tumor, carotid body tumor, etc.) and sympathetic paraganglioma (including retroperitoneal, pelvic and mediastinal paraganglioma after mediastinum). Some cases can be life-threatening because of severe heart, brain, kidney damage or sudden high blood pressure caused by long-term high blood pressure. However, if it can be diagnosed and treated promptly and early, it is a curable secondary hypertension.
The prevalence of pheochromocytoma in hypertensive patients is 0.05% to 0.2%, and the peak incidence is 20 to 50 years old. About 80% to 90% of pheochromocytoma is located in the adrenal gland, and mostly on one side; incidence of women is slightly higher than men. The main site of occurrence is the adrenal medulla, and the extra-adrenal tumors are mainly located in the extraperitoneal and para-aortic aorta. These tumors are mostly benign, but about 10% is malignant. As with most tumors, the etiology of sporadic pheochromocytoma remains unclear. Familial pheochromocytoma is genetically related.
Case Study
Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors with an incidence of between two and eight cases per million per year. Most PPGLs hyper-secrete catecholamines, which can cause hypertension, arrhythmias, and headaches, leading to considerable morbidity and mortality. Due to lacking therapies approved by the FDA for the treatment of their diseases, patients with advanced PPGL have few treatment options. Current treatment paradigms include the use of cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) and conventional l-131 meta-iodobenzylguanidine (l-131 MIBG). HAS l-131 MIBG with high specific activity is a targeted therapeutic that entirely consists of l-131 labeled MIBG. HAS l-131 MIBG showed antitumor activity in patients with metastatic or unresectable PPGL in a phase 1 trial and has received breakthrough therapy designation for the treatment of patients with this ultra-orphan disease. In this multicenter, phase 2 trial, we evaluated the efficacy and safety of HAS l-131 MIBG in patients with advanced PPGL. Collectively, our findings provide substantial evidence of the efficacy and safety of HAS l-131 MIBG therapy.
Regarding statistical analysis of data, OS duration, calculated from the date of first therapeutic dose to death, or censored at the date the patient was known to be alive, was estimated using the Kaplan-Meier product-limit method; 1-through 5-year OS rates were presented as medians and respective two-sided 95% confidence intervals (CLs). All statistical analyses, data listing, tables, and figures (excluding dosimetry analyses), were produced using SA software (version 9.4; SA Institute, Cary, NC).
Design:
This multicenter, open-label, single-arm trial, which was conducted under a Special Protocol Assessment (SPA) agreement with the FDA, consisted of a 1-year efficacy phase followed by a 4-year long-term follow-up phase.
Participants:
Patients were screened for enrollment at ten centers in the United States between June 2009 and February 2016. Eligible patients were ≥ 12 years of age; had a documented PPGL diagnostic confirmed by histology or by a physician using other data (e.g., abnormal MIBG diagnostic study, elevated tumor marker levels); were ineligible for curative surgery; had no progress on prior therapy for PPGL or were not candidates for chemotherapy or other therapy; had hypertension secondary to a catecholamine excess; and had been on a stable antihypertensive medication regimen for at least 30 days before the first therapeutic dose of HAS l-131 MIBG. Eligibility criteria required patients’ tumors to have definitive iobenguane avidity; at least one metastatic or not resectable tumor site identified by computed tomography (CT), magnetic resonance imaging (MRI), or iobenguane l-131 scan; karnofsky performance status ≥ 60; and absence of active central nervous system lesions.
Patients were excluded if they had received any previous systemic radiotherapy resulting in bone marrow toxicity before 3 months of study entry; had a malignancy other than PPGL that required treatment during the present trial; had a platelet count of < 8000/µl, absolute neutrophil count of < 1200 cell/µl, or creatinine clearance of < 30 ml/min.
Length of Enrollment Period:
12 months.
Interventions:
Eligible patients received an intravenous treatment-planning dose of HAS l-131 MIBG (~0.185 GBq [5 mCi]) and then underwent serial whole-body scans for assessing MIBG avidity, biodistribution and performing dosimetry calculation to determine normal organs’ absorbed radiation does. Patients with MIBG-avid tumors (Figure 1) following the treatment-planning dose received one or two therapeutic doses of HAS l-131 MIBG (~18.5 GBq [500 mCi], for patients ≤ 62.5 kg, 0.296 GBq/kg [8 mCi/kg]), administered intravenously approximately 90 days apart. The dosing regimen was based on the previous dose-ranging study of HAS l-131 MIBG by Noto et al. To ensure that critical organs’ absorbed radiation doses would not exceed established toxicity limits after two therapeutic doses, we performed individualized dose reduction as described preciously. Patients underwent electrocardiography before, during, and after each therapeutic dose. Whole body scans were acquired within 7 days after each therapeutic dose to assess the biodistribution and tumor uptake of HAS l-131 MIBG. Patients whose hematologic values returned to baseline levels or were within the normal range within 24 weeks following the first therapeutic dose were eligible for the second therapeutic dose.
Figure 1. Flowchart of patient disposition. 81 patients were enrolled in the study. 74 patients received a dosimetric dose of which 68 received one therapeutic dose and 50 received two therapeutic doses.
LTFU, long term follow up; MIBG, meta-iodobenzylguanidine
1Analysis cutoff: Dec 11, 2017
Main outcomes:
- Overall survival (OS)
- Radiographic tumor response
- Biochemical tumor marker response
- Baseline tumor lengths
- Reduction in antihypertensive medication use
Results:
Of 81 PPGL patients who were screened for enrollment, 74 (safety population) received a treatment-planning dose of HAS l-131 MIBG. These patients’ demographic and clinical characteristic are given in Table 1. Objective tumor responses among patients who received at least one therapeutic dose of HSA I‐131 MIBG are presented in Table 2. Of the 68 patients who received at least one therapeutic dose of HSA I‐131 MIBG, four did not have evaluable target lesions at baseline. Overall, of the 64 patients with evaluable disease, 59 (92%) had partial responses (PRs) (15 patients) or stable disease (44 patients); no patients had a complete response (CR). Of the 50 patients who received two therapeutic doses and had evaluable disease, 15 (30%) had PRs (Figure 1). Among the 17 patients who did and the 47 patients who did not have a reduction in antihypertensive medication, 7 (41%) and 8 (17%) ad PRs, respectively.
Of the 56 patients who had measurable target lesions, all 16 patients (100%) who had a reduction in baseline antihypertensive medication use also had PRs or stable disease (Figure 2). Among the 40 patients who did not achieve the primary endpoint and had measurable target lesions, 36 (90%) had PRs or stable disease, three (7.5%) had progressive disease, and one (2.5%) had unevaluable disease (Figure 2). Our finding shows that HAS l-131 MIBG conferred sustained control of catecholamine-associated hypertension in 25% of patients and had persistent anti-tumor effects in 22% of patients with advanced PPGL. All patients who had a sustained reduction in antihypertensive medication use also had partial response (PR) or stable disease as their best objective tumor response, which suggests that HAS l-131 MIBG has broad anti-tumor effects.
Table 1. Demographics and baseline characteristic of 74 patients with advanced pheochromocytoma or paraganglioma who received any dose HAS l-131 MIBG.
SD, standard deviation; CVD, cyclophosphamide, vincristine, and dacarbazine.
Note: all data are no. of patients (%) unless otherwise indicated.
1Data provided for 64 patients with evaluable target lesions at baseline.
2Abdominal cavity, adrenal gland, kidney, neck soft tissue, pancreas, pelvic soft tissue, pericardial effusion, peritoneal cavity, peritoneal cavity, peritoneum, pleural cavity, retroperitoneum, or small bowel.
Table 2. Antihypertensive medication uses reductions and objective tumor responses among 68 patients with advanced pheochromocytoma or paraganglioma
CI, confidence interval; RECIST 1.0, Response Evaluation Criteria in Solid Tumors version 1.0.
Note: All data are no. of patients (%) unless otherwise indicated.
Figure 2. Maximum reductions in baseline tumor lengths of 56 patients with advanced pheochromocytoma or paraganglioma who had measurable target lesions.
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References:
1. Al-Sharefi Ahmed, Perros Petros, James Robert Andrew. (2018) ‘Phaeochromocytoma/ paraganglioma and adverse clinical outcomes in patients with neurofibromatosis-1’, Endocr Connect, 2018.
2. Pryma Daniel A, Chin Bennett B, Noto Richard B et al. (2018) ‘Efficacy and Safety of High-Specific-Activity I-131 MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma’. J. Nucl. Med.