Advanced Pheochromocytoma Research Articles

High-specific-activity iodine-131-meta-iodo-benzylguanidine for the treatment of advanced pheochromocytoma and paraganglioma: a real-world study

High-specific-activity iodine-131-meta-iodo-benzylguanidine for the treatment of advanced pheochromocytoma and paraganglioma: a real-world study

Efficacy and Safety of 124I-MIBG Dosimetry-Guided High-Activity 131I-MIBG Therapy of Advanced Pheochromocytoma or Neuroblastoma.

We aim to evaluate the efficacy and safety of 124I-metaiodobenzylguanidine (MIBG) dosimetry-guided high-activity 131I-MIBG therapy of advanced pheochromocytoma or neuroblastoma. Methods: Fourteen patients with advanced pheochromocytoma or neuroblastoma, age 9-69 y, underwent 124I-MIBG PET scans and whole-body retention measurements to assess the whole-body dose as a surrogate of bone marrow toxicity and tumor (absorbed) dose per unit of administered activity. Dosimetry results together with individual patient characteristics were combined to guide a single therapeutic activity to achieve a high tumor dose without exceeding toxicity threshold. Toxicity was assessed for hematologic, hepatic, and renal function. Response was evaluated by RECIST, International Society of Pediatric Oncology Europe Neuroblastoma-like score, change in PET uptake, and quantitative PET parameters (SUVmax, SUVpeak, metabolic tumor volume, total lesion glycolysis), as well as visual decrease in number or in visual intensity of lesions on baseline to follow-up 124I-MIBG PET/CT. Results: The average therapeutic activity was 14 GBq. Eleven of 14 patients (79%) received each more than 10 GBq. One male patient was treated with a single activity of 50 GBq. Three patients were treated with lower activities between 3.5 and 7.0 GBq. Median overall survival was 85 mo (95% CI), and median progression-free survival was 25 mo (95% CI). Four (29%) and 5 (36%) patients demonstrated response (complete response or partial response) by RECIST and functional imaging, respectively. One patient exceeded whole-body dose of 2 Gy and demonstrated grade 3 hematologic toxicity, which resolved spontaneously within 12 mo after the therapy without the need for further treatment. Three patients (21%) demonstrated transient grade 1 renal toxicity. Conclusion: 124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy in patients with advanced pheochromocytoma or neuroblastoma resulted in durable responses with a low rate of manageable adverse events. Efficacy of 124I-MIBG-guided activity escalation should further be assessed in a prospective setting.

Biomarker response to high-specific-activity I-131 meta-iodobenzylguanidine in pheochromocytoma/paraganglioma.

The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6-12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.

Quality of Life Assessments for Advanced Pheochromocytoma and Paraganglioma Patients that Received High-Specific-Activity I-131 MIBG: Results from a Pivotal Phase 2 Clinical Trial

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

OR29-3 High-specific-activity Iodine 131 Metaiodobenzylguanidine for the Treatment of Advanced Pheochromocytoma and Paraganglioma: A Real-world Study

Abstract Introduction Metastatic pheochromocytomas/paragangliomas (mPPGLs) are rare tumors with limited treatment options. High-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) is the only approved therapy for mPPGLs. We summarized the efficacy and safety profile of HSA 131I-MIBG in patients with mPPGL. Methods This is a retrospective cohort study in patients with mPPGL treated with HSA 131I-MIBG on label at a tertiary cancer center. The primary endpoint was radiographic treatment response determined with CT/MRI according to RECIST v1.1 and 123 I-MIBG scan. Secondary endpoints were blood pressure changes and HSA 131I-MIBG related adverse events. We correlated responses with the genetic background as an exploratory endpoint. Results Twenty-four patients were treated including 15 men (62%). Median age at the time of treatment was 44 years (range 18–82). Twenty-three patients had distant metastases and one patient had an unresectable primary tumor. Seventeen patients (70%) had hormonally active tumors and 17 patients (70%) were on antihypertensive medications before HSA 131I-MIBG therapy [7 patients on alpha-blockers only and 10 on combination antihypertensive therapy]. Thirteen patients (54%) previously received antineoplastic treatment. Eleven patients (46%) received one dose of HSA 131−I-MIBG, the remaining received two doses. Median duration of follow-up was 15 months (range 2–52). In 23 evaluable patients, radiographic responses included: 2 complete responses (CR), 10 partial responses (PR), 8 stable diseases (SD), 2 mixed responses (MR), and 1 progressive disease (PD) yielding disease control rate (DCR) of 87%. Median time to response was 12.5 months (95% CI, 4.6 to 25.1). Radiographic responses in patients with sporadic disease were [6/11 SD, 3/11 PR, 1/11 MR, 1/11 PR], while the response in patients with a genetic mutation (SDHB, VHL, RET) was [2/12 CR, 7/12 PR, 2/12 SD, 1/12 MR]. In 17 hormonally active tumors, plasma metanephrines normalized in 3(18%), improved by 50% in 5(29%), increased in 4(24%), 4 patients (24%) had no repeat levels and one had stable levels. Blood pressure was evaluable in 22 (92%) patients. Blood pressure normalized in 9 patients (41%) leading to discontinuation of antihypertensive therapy. One patient had an improvement in the blood pressure leading to a reduction of antihypertensive medications. The most common adverse events were grade I/II nausea/vomiting and transient bone marrow suppression. One patient developed premature ovarian failure. Grade III/IV myelosuppression was seen in 3/24 (12%) patients. One patient had fatal pneumonitis, and one patient developed fatal gastrointestinal bleeding a month after treatment with unclear attribution to HSA 131 −I-MIBG. Conclusions In mPPGL, HSA 131I-MIBG is associated with high DCR regardless of underlying genetic mutation. Severe adverse events are infrequent but can be fatal. Presentation: Tuesday, June 14, 2022 10:15 a.m. - 10:30 a.m.

Favorable outcome in advanced pheochromocytoma and paraganglioma after hypofractionated intensity modulated radiotherapy.

The purpose of this study was to review outcomes of patients with advanced/metastatic pheochromocytoma/paraganglioma (PPGL) treated at our institution with Intensity-modulated radiotherapy (IMRT), describe the treatment outcomes, and determine predictors. A retrospective study on patients with advanced/metastatic PPGL who received IMRT at Peking Union Medical College Hospital between 2014 and 2019. A total of 14 patients with 17 lesions were included in this study. Ultra-hypofractionated radiation therapy was used for 7 lesions in 5 patients, while hypofractionated radiation therapy was used for 8 lesions in 7 patients. 2 patients got conventional fractionated radiotherapy. Patients who received external beam radiation therapy were given a median total radiation dose of 74.4/130Gy (BED10/3) in a median of 13 fractions. OS at 2years was 78% for all patients. For lesions evaluated by RECIST response, at least stable disease of the target lesion was achieved in 94% and distant progression in 28.5%, with an average time to progression of 5.2months. Patients with locally advanced primary tumors or recurred in situ (n = 8) achieved 100% local control, and none of them got recurrence or distant metastasis after radiotherapy at last follow-up (median 29months). Of patients with catecholamine-related syndromes (n = 12), 91% of symptomatic lesions improved following radiation therapy and a more than 50% decline in catecholamines. We have found hypofractionated IMRT effective as an additional therapy for patients with advanced primary tumors or recurrence in situ and not amenable to complete surgical resection.

Biochemical Tumor Marker Status and Its Role in Treatment Response in Patients Who Received High-Specific-Activity I-131 MIBG in Advanced Pheochromocytoma and Paraganglioma (PPGL): Results From a Pivotal Phase 2 Clinical Trial

Background: High-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131 MIBG; AZEDRA®) has been approved for the treatment of adult and pediatric patients (pts) 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. We have previously presented data showing improved biomarker responses in pts treated with HSA I-131 MIBG. Here we report the impact of biomarker status on the study primary endpoint and objective tumor response. Methods: Pts with iobenguane-avid PPGL who were ineligible for surgery, failed prior therapy or not candidates for chemotherapy, and on a stable antihypertensive medication regimen were treated. Pts received up to two therapeutic doses, each at ~18.5 GBq (or 296 MBq/kg for pts ≤62.5 kg), administered ~90 days apart. Biomarkers were analyzed at baseline and over a 12-month efficacy period. Confirmed biochemical responses (at least ≥ 50% decrease in abnormal tumor marker value for all hypersecreted biomarkers) required subsequent responses to be identical to or better compared with the previous assessment. The primary endpoint was clinical benefit, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) for ≥6 months beginning during the efficacy period. The secondary endpoint, confirmed objective tumor response by RECIST, was also evaluated. Results: 68 pts received at least one therapeutic dose of HSA I-131 MIBG. For all pts with hypersecretory tumors (with a baseline biochemical marker level of ≥1.5× ULN) (n=60), a comparison of biomarker response with antihypertensive therapy yielded a correlation coefficient of 0.35 (P = 0.006; Fisher exact P = 0.012). For pts with norepinephrine only-hypersecreting tumors (n=31), a correlation coefficient of 0.47 (P = 0.008; Fisher exact P = 0.015) was observed. The overall biomarker response also correlated with objective tumor response (n=55) yielding a correlation coefficient of 0.36 (P = 0.007; Fisher exact P = 0.012) for all pts with hypersecreted biomarkers. Pts who were not biochemical hypersecretors for any biomarker (n=6) had only one responder for the primary endpoint and no objective tumor responses. Conclusions: The biomarker data from this study establish a moderate but statistically significant correlation between biomarker response following treatment with HSA I-131 MIBG and objective tumor response and durable reduction of antihypertensive therapy. This correlation was improved with norepinephrine only-hypersecreting tumors in pts with unresectable, locally advanced or metastatic PPGL.

Recurrence-Free Survival Analysis in Locally Advanced Pheochromocytoma: First Appraisal.

The behavior of locally advanced pheochromocytoma (LAP) remains unknown. We characterized the population with LAP and recurrence-free survival (RFS). This retrospective multicentric study was run within the ENDOCAN-COMETE network and French Group of Endocrine Tumors (GTE) from 2003 to 2018, including patients from 11 French referral centers with LAP as defined by capsular invasion, vascular invasion, adipose tissue invasion, and/or positive locoregional lymph nodes at diagnosis without evidence of distant metastasis. The main outcome measure was recurrence, defined as tumor reappearance, including local site and/or distant metastasis. The primary endpoint was RFS analysis; secondary endpoints were characterization, overall survival (OS), and prognostic factors of recurrence. Among 950 patients, 90 (9%) exhibited LAP criteria and 55 met inclusion criteria (median age, 53 years; 61% males; 14% with germline mutation; 84% with catecholamine excess). LAP was defined by 31 (56%) capsular invasions, 27 (49%) fat invasions, 6 (11%) positive lymph nodes, and 22 (40%) vascular invasions. After median follow-up of 54 months (range, 6-180), 12 patients (22%) had recurrences and 3 (5%) died of metastatic disease. Median RFS was 115 months (range, 6-168). Recurrences were local in 2 patients, distant in 2, and both local and distant in 8 patients. Median OS of patients was not reached. Size above 6.5 cm (P = 0.019) and Ki-67 > 2% (P = 0.028) were identified as independent significant prognostic factors in multivariate analysis. LAP represents 9% of pheochromocytoma's population and has a metastatic behavior. This study paves the way for future pathological TNM classification.

'Peptide receptor radionuclide therapy in the management of advanced pheochromocytoma and paraganglioma: A systematic review and meta-analysis'.

Inoperable and metastatic pheochromocytomas and paragangliomas (PPGLs) present a therapeutic challenge with current treatment options being limited to radiolabelled meta-iodo-benzyl-guanidine (MIBG) and systemic chemotherapy. Peptide receptor radionuclide therapy (PRRT) seems to be a promising option for these patients with few studies reporting favourable response. This systematic review was conducted to evaluate the efficacy and safety of PRRT in patients with advanced PPGLs. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in PubMed, Scopus and Embase were made using relevant keywords and articles up to May 2019 were included. Data on efficacy and toxicity were extracted from the individual articles, and pooled estimates were generated using meta-analysis. Twelve articles consisting of 201 patients with advanced PPGLs were included. Overall, treatment with PRRT achieved an objective response rate of 25% (95% CI: 19%-32%) and a disease control rate of 84% (95% CI: 77%-89%). Clinical and biochemical responses were seen in 61% and 64% of the patients, respectively. Among the PRRTs, similar tumour response rates were noted for 90 Y-yttrium- and 177 Lu-lutetium-based agents. Treatment-related adverse effects were minimal with grade 3/4 neutropenia, thrombocytopenia, lymphopenia and nephrotoxicity observed in 3%, 9%, 11% and 4% of the patients, respectively. Treatment discontinuation was noted in five out of 102 patients. Peptide receptor radionuclide therapy is a safe and efficacious treatment option for advanced PPGLs and may be considered a viable alternative to chemotherapy and I-131 MIBG.

Current Consensus on I-131 MIBG Therapy.

Metaiodobenzylguanidine (MIBG) is structurally similar to the neurotransmitter norepinephrine and specifically targets neuroendocrine cells including some neuroendocrine tumors. Iodine-131 (I-131)-labeled MIBG (I-131 MIBG) therapy for neuroendocrine tumors has been performed for more than a quarter-century. The indications of I-131 MIBG therapy include treatment-resistant neuroblastoma (NB), unresectable or metastatic pheochromocytoma (PC) and paraganglioma (PG), unresectable or metastatic carcinoid tumors, and unresectable or metastatic medullary thyroid cancer (MTC). I-131 MIBG therapy is one of the considerable effective treatments in patients with advanced NB, PC, and PG. On the other hand, I-131 MIBG therapy is an alternative method after more effective novel therapies are used such as radiolabeled somatostatin analogs and tyrosine kinase inhibitors in patients with advanced carcinoid tumors and MTC. No-carrier-aided (NCA) I-131 MIBG has more favorable potential compared to the conventional I-131 MIBG. Astatine-211-labeled meta-astatobenzylguanidine (At-211 MABG) has massive potential in patients with neuroendocrine tumors. Further studies about the therapeutic protocols of I-131 MIBG including NCA I-131 MIBG in the clinical setting and At-211 MABG in both the preclinical and clinical settings are needed.

Clinical presentation and outcomes in patients with advanced pheochromcytoma/paraganglioma: Evidence of temozolomide efficacy.

e15157 Background: The clinical course and treatment options for patients with advanced pheochromocytoma (PCC) and paraganglioma (PGL) remain poorly defined. Few antitumor therapies have been developed for patients with this condition. Currently available regimens include radiolabeled metaiodobenzylguanidine (131I-MIBG), or treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Methods: We identified patients with locally unresectable or advanced PCC/PGL enrolled in a prospective clinical outcomes study of neuroendocrine tumor patients at Dana-Farber Cancer Institute between 2003 and 2010. We reviewed patient demographics, clinical symptoms, and treatment outcomes. Results: We identified 28 patients who presented to the institution with PCC/PGL, of whom 25 had recurrent or metastatic disease. Among these 25 patients, the most common signs and symptoms at presentation with metastatic disease were local pain, hypertension, and headache. Hypertension and headache were the dominant sy...

Targeting Heat Shock Protein 90 for the Treatment of Malignant Pheochromocytoma

Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma.

Pheochromocytoma (PC)/paraganglioma (PG) and sunitinib: Review of reported cases and literature and case report contribution.

406 Background: Pheochromocytomas/paragangliomas (PC/PG) are rare diseases, but may be responsible for lower quality of life to patients,if progressive or metastatic when malignant. Recently, some benefit has been reported with the use of palliative tyrosine-kinase inhibitors (TKI),such as sunitinib, already approved for kidney cancer. Methods: Review of litearure with a Medline search for PC/PG and suninitib, due to the need to treat a patient with progressive advanced malignant PC, refractory to chemotherapy (CT). Our plan is to contribute reporting safety and efficacy in an additional PC patient. Results: We expose the data found in a table below,with most relevant features related to PC/PG treatments and TKI. Conclusions: Sunitinib as a treatment option to refractory PC/PG may be active and should be further evaluated in this context. A phase II trial is under way (SNIPP; NTC00843037). Other therapies may be evaluated, such as sorafenib, bevacizumab, temozolomide, temsirolimus, thalidomide, and other potential molecular strategies, also with other small molecules, target therapies, and antiangiogenic factors. We plan to follow the reported PC patient and show additional data in the near future. [Table: see text] No significant financial relationships to disclose.

Efficacy of Octreotide in combination with MIBG-radiotherapy in patients with advanced pheochromocytoma

Efficacy of Octreotide in combination with MIBG-radiotherapy in patients with advanced pheochromocytoma