High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

Long-Term Outcomes of 125 Patients With Metastatic Pheochromocytoma or Paraganglioma Treated With 131-I MIBG.

CONTEXT: Prognosis of metastatic pheochromocytoma/paraganglioma following 131-Iodine metaiodobenzylguanidine (MIBG) is incompletely characterized due to small samples and shorter follow-up in these rare, often indolent tumors. OBJECTIVE: To describe long-term survival, frequency, and prognostic impact of imaging, biochemical, and symptomatic response to 131-I MIBG. DESIGN: Retrospective chart and imaging review at a tertiary referral center. PATIENTS: Six hundred sixty-eight person-years of follow-up in 125 patients with metastatic pheochromocytoma/paraganglioma with progression through prior multimodal treatment. INTERVENTION: Median 18 800 MBq 131-I MIBG. MAIN OUTCOME MEASURES: Overall survival, Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) imaging response, symptomatic response per chart review, and biochemical response (20% change over 2 consecutive assays of catecholamines, vanillylmandelic acid, metanephrines, or chromogranin A). RESULTS: Median survival standard deviation [SD] from diagnosis was 11.5 years [2.4]; following metastasis, 6.5 years [0.8]; post treatment, 4.3 years [0.7]. Among 88 participants with follow-up imaging, 1% experienced complete response, 33% partial response, 53% stability, and 13% progression. Fifty-one percent showed subsequent progression, median progression-free survival [SD] of 2.0 years [0.6]. Stability/response vs progression at first imaging follow-up (3-6 months) predicted improved survival, 6.3 vs 2.4 years (P = 0.021). Fifty-nine percent of 54 patients demonstrated biochemical response. Fifty percent of these relapsed, with median time to laboratory progression [SD] of 2.8 years [0.7]. Biochemical response did not predict extended survival. Seventy-five percent of 83 patients reported improvement in pretreatment symptoms, consisting primarily of pain (42%), fatigue (27%), and hypertension (14%). Sixty-one percent of these patients experienced subsequent symptomatic progression at median [SD] 1.8 years [0.4]. Symptomatic response did not predict extended survival. CONCLUSIONS: Imaging, symptomatic, and laboratory response to multimodal treatment including high-dose 131-I MIBG were achieved on long-term follow-up in metastatic pheochromocytoma or paraganglioma. Imaging response at 3 to 6 months was prognostic.

Radioiodinated metaiodobenzylguanidine treatment of neuroendocrine tumors in adults.

Metaiodobenzylguanidine (MIBG), radioiodinated with (131)I, has been available for 25 years. Its role in the United States is limited to diagnostic imaging, whereas its therapeutic application in patients with neuroendocrine tumors for whom surgical treatment would not lead to a cure, has been approved in Europe. (131)I-MIBG treatments can be a valuable addition to the current gamut of treatment options for patients with metastatic neuroendocrine tumors, especially given the limited role for other systemic treatments, such as chemotherapy. There are basically two treatment strategies: one or two high-dose treatments or continuous low-dose treatments. (131)I-MIBG could induce symptomatic relief in the vast majority of patients treated, both following high-dose treatment and low-dose maintenance treatment. Biochemical responses can be observed in about half of the patients, whereas radiographic responses are described in roughly one third of the patients. Several articles suggested a survival benefit to patients treated with (131)I-MIBG. Side-effects of the treatment mainly consist of myelotoxicity, nausea, and hypothyroidism. Future developments are focused on the use of high-specific-activity (131)I-MIBG in high doses. The role of (131)I-MIBG in relation to other treatments remains to be established, although treatment (131)I-MIBG seems to be at least as effective as other systemic treatments, with limited side-effects.

Radiation dosimetry, pharmacokinetics, and safety of ultratrace Iobenguane I-131 in patients with malignant pheochromocytoma/paraganglioma or metastatic carcinoid.

This is a first of many phase 1 study of Ultratrace Iobenguane I-131 (Ultratrace 131I-MIBG; Molecular Insight Pharmaceuticals, Inc., Cambridge, MA). High-specific-activity Ultratrace 131I-MIBG may provide improved efficacy and tolerability over carrier-added 131I-MIBG. We investigated the pharmacokinetics (PK), radiation dosimetry, and clinical safety in 11 patients with confirmed pheochromocytoma/paraganglioma (Pheo) or carcinoid tumors. A single 5.0-mCi (185 MBq) injection of Ultratrace 131I-MIBG, supplemented with 185 microg of unlabeled MIBG to simulate the amount of MIBG anticipated in a therapeutic dose, was administered. Over 120 hours postdose, blood and urine were collected for PK, and sequential whole-body planar imaging was performed. Patients were followed for adverse events for 2 weeks. Ultratrace 131I-MIBG is rapidly cleared from the blood and excreted in urine (80.3% +/- 2.8% of dose at 120 hours). For a therapeutic administration of 500 mCi (18.5 GBq), our estimate of the projected dose is 1.4 Gy for marrow and 10.4 Gy for kidneys. Safety results showed 12 mild adverse events, all considered unrelated to study drug, in 8 of 11 patients. These findings support the further development of Ultratrace 131I-MIBG for the treatment of neuroendocrine tumors, such as metastatic Pheo and carcinoid.

Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma.

PURPOSE: To evaluate the safety and efficacy of high-dose [(131)I]metaiodobenzylguanidine ([(131)I]MIBG) in the treatment of malignant pheochromocytoma (PHEO) and paraganglioma (PGL). METHODS: Fifty patients with metastatic PHEO or PGL, age 10 to 64 years, were treated with [(131)I]MIBG doses ranging from 492 to 1,160 mCi (median, 12 mCi/kg). Cumulative [(131)I]MIBG administered ranged from 492 to 3,191 mCi. Autologous hematopoietic stem cells were collected and cryopreserved before treatment with [(131)I]MIBG greater than 12 mCi/kg or with a total dose greater than 500 mCi. Sixty-nine [(131)I]MIBG infusions were given, which included infusions to 35 patients treated once and infusions to 15 patients who received two or three treatments. Response was evaluated by [(123)I]MIBG scans, computed tomography/magnetic resonance imaging, urinary catecholamines/metanephrines, and chromogranin A. RESULTS: The overall complete response (CR) plus partial response (PR) rate in 49 evaluable patients was 22%. Additionally, 35% of patients achieved a CR or PR in at least one measure of response without progressive disease, and 8% of patients maintained stable disease for greater than 12 months. Thirty-five percent of patients experienced progressive disease within 1 year after therapy. The estimated 5-year overall survival rate was 64%. Toxicities included grades 3 to 4 neutropenia (87%) and thrombocytopenia (83%). Grades 3 to 4 nonhematologic toxicity included acute respiratory distress syndrome (n = 2), bronchiolitis obliterans organizing pneumonia (n = 2), pulmonary embolism (n = 1), fever with neutropenia (n = 7), acute hypertension (n = 10), infection (n = 2), myelodysplastic syndrome (n = 2), and hypogonadism (n = 4). CONCLUSION: Although serious toxicity may occur, the survival and response rates achieved with high-dose [(131)I]MIBG suggest its utility in the management of selected patients with metastatic PHEO and PGL.

[Other therapeutic alternatives: radiotherapy and chemotherapy]. / Otras alternativas terapéuticas: radioterapia y quimioterapia.

Paragangliomas are rare tumors and most are benign: less than 10% show criteria for malignancy. In the head and neck, the main locations are carotid, jugulo-tympanic and vagal. Surgery continues to be the mainstay of treatment but both external beam radiotherapy (EBRT) and stereotactic radiosurgery (SRS) have been shown to be effective therapeutic alternatives. EBRT requires large volumes to cover the lesion, while radiosurgery allows administration of a high dose in a smaller volume, with high precision, which should reduce the number of long-term complications. The results in terms of local control with both treatment modalities are good, as reflected in published series. The role of chemotherapy is restricted to malignant paragangliomas. The treatment used includes the combination of chemotherapy, which provides short-lasting responses, and the role of new molecular targets is currently being investigated. The present article reviews the indications and results of the non-surgical treatment of paragangliomas.

Otras alternativas terapéuticas: radioterapia y quimioterapia / Other therapeutic alternatives: radiotherapy and chemotherapy

Los paragangliomas (Pg) son tumores poco frecuentes, la mayoría benignos; menos del 10% presenta criterios de malignidad. En la cabeza y el cuello las principales localizaciones son carotídeos, yúgulo-timpánicos y vagales. La cirugía sigue siendo la principal modalidad de tratamiento, pero tanto la radioterapia externa (EBRT) como la radiocirugía(SRS) han demostrado su eficacia como alternativa terapéutica. La EBRT precisa volúmenes amplios para cubrir la lesión, en tanto que la radiocirugía permite la administración de una dosis elevada en un volumen más restringido, con alta precisión, lo que en principio produciría menos tasa de complicaciones a largo plazo. Los resultados en cuanto a control local con ambas modalidades de tratamiento son elevados, como se refleja en las series publicadas. El papel de la quimioterapia está limitado a los Pg malignos. El tratamiento utilizado incluye la combinación de quimioterapia, que ofrece respuestas de corta duración, y en la actualidad se está investigando el papel de nuevas “moléculas dianas”. En este capítulo se revisarán las indicaciones y los resultados del tratamiento no quirúrgico de los Pg (AU)

Paragangliomas are rare tumors and most are benign: less than 10% show criteria for malignancy. In the head and neck, the main locations are carotid, jugulo-tympanic and vagal. Surgery continues to be the mainstay of treatment but both external beam radiotherapy (EBRT) and stereotactic radiosurgery (SRS) have been shown to be effective therapeutic alternatives. EBRT requires large volumes to cover the lesion, while radiosurgery allows administration of a high dose in a smaller volume, with high precision,which should reduce the number of long-term complications. The results in terms of local control with both treatment modalities are good, as reflected in published series. The role of chemotherapy is restricted to malignant paragangliomas. The treatment used includes the combination of chemotherapy, which provides short-lasting responses, and the role of new “molecular targets” is currently being investigated. The present article reviews the indications and results of the non-surgical treatment of paragangliomas (AU)

Whole-body iodine-131 metaiodobenzylguanidine imaging for detection of bone metastases in patients with paraganglioma: comparison with bone scintigraphy.

Iodine-131 metaiodobenzylguanidine ((131)I-MIBG) therapy is an effective treatment for patients with malignant paraganglioma for which surgical resection is not indicated. We performed high-dose (131)I-MIBG therapy on two patients with malignant paraganglioma and multiple bone metastases. The bone metastases were diagnosed by magnetic resonance imaging (MRI). Metastatic bone lesions were evaluated by whole-body (131)I-MIBG imaging and bone scintigraphy. Whole-body (131)I-MIBG imaging showed extensive metastatic bone lesions, whereas conventional bone scintigraphy did not. There was a remarkable discrepancy between (131)I-MIBG imaging and bone scintigraphy in the diagnosis of metastatic bone lesions of malignant paraganglioma in our two patients. High-dose (131)I-MIBG imaging may detect early stages of bone metastases, compared with bone scintigraphy, in patients with malignant paraganglioma.

Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG).

Thirty patients with malignant pheochromocytoma (PHEO) or paraganglioma (PGL) were treated with high-dose 131I-MIBG. Patients were 11-62 (mean 39) years old: 19 patients males and 11 females. Nineteen patients had PGL, three of which were multifocal. Six PGLs were nonsecretory. Eleven patients had PHEO. All 30 patients had prior surgery. Fourteen patients were refractory to prior radiation or chemotherapy before 131I-MIBG. Peripheral blood stem cells (PBSCs) were collected and cryopreserved. 131I-MIBG was synthesized on-site, by exchange-labeling 131I with 127I-MIBG in a solid-phase Cu2+-catalyzed exchange reaction. 131I-MIBG was infused over 2 h via a peripheral IV. Doses ranged from 557 mCi to 1185 mCi (7.4 mCi/kg to 18.75 mCi/kg). Median dose was 833 mCi (12.55 mCi/kg). Marrow hypoplasia commenced 3 weeks after 131I-MIBG therapy. After the first 131I-MIBG therapy, 19 patients required platelet transfusions; 19 received GCSF; 12 received epoeitin or RBCs. Four patients received a PBSC infusion. High-dose 131I-MIBG resulted in the following overall tumor responses in 30 patients: 4 sustained complete remissions (CRs); 15 sustained partial remissions (PRs); 1 sustained stable disease (SD); 5 progressive disease (PD); 5 initial PRs or SD but relapsed to PD. Twenty-three of the 30 patients remain alive; deaths were from PD (5), myelodysplasia (1), and unrelated cause (1). Overall predicted survival at 5 years is 75% (Kaplan Meier estimate). For patients with metastatic PHEO or PGL, who have good *I-MIBG uptake on diagnostic scanning, high-dose 131I-MIBG therapy was effective in producing a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.

[Paraganglioma of the head and neck--tumor control, functional results and quality of life]. / Paragangliome des Kopf-Hals-Bereiches--Tumorkontrolle, funktionelle Ergebnisse und Lebensqualität nach Operation.

BACKGROUND: Surgical therapy for paragangliomas (PG) of the head and neck is, due to the alternatives of radiation therapy and wait-and-scan strategy and because of postoperative morbidity, under ongoing discussion. MATERIAL AND METHODS: Between 1981 and 2004, 79 patients with 94 PG of the head and neck were treated at our department. These patients had follow-up examination within a clinical trial considering tumor control, functional results and for the first time neuropsychologically evaluated postoperative quality of life. Mean follow-up time was 65 months (1 to 228 months). RESULTS: Among the 94 PG there were 19 carotid body (GCP), 12 vagal nerve (GVP) and 63 jugular-tympanal paragangliomas (JTP). Of these, 87 tumors underwent surgery. In 68 patients (78.1 %), the tumor could be removed completely. In particular, complete resection of GCP was achieved in 100 %, of GVP in 90.9 %, of JTP type A in 100 %, of JTP type B in 83.3 %, of JTP type C in 66.6 % and of JTP type D in 61.5 %. During the follow-up period, residual or recurrent tumors were diagnosed in 17 patients (19.5 %). Six of the seven residual PG were observed by magnetic resonance tomography and did not show growth. One residual PG and 6 recurrencies were resected completely. One recurrent tumor was radiated and 3 others are under observation without showing growth tendencies. Two patients died postoperatively due to borderline operations of extended tumors. The quality of life after PG surgery showed a SIP of 4.8, which is comparably much better than after acoustic neuroma surgery (SIP 10.3). CONCLUSION: Whereas complete tumor resection of GCP and JTP types A and B is almost ever possible without cranial nerve palsies, surgery of GVP and advanced JTP causes often severe functional deficits. However, postoperative quality of life is mostly good. Nevertheless, advanced PG require an individualized therapeutic regime also including radiation and observation of tumor growth.

Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma.

INTRODUCTION: Iodine 131-meta-iodobenzylguanidine ((131)I-MIBG) has been applied to the palliative treatment of metastatic pheochromocytoma in small studies. We report our institutional experience for the treatment of metastatic pheochromocytoma and paraganglioma. METHODS: We performed a retrospective review of 33 patients with metastatic pheochromocytoma (n=22) and paraganglioma (n=11) treated at our institution with (131)I-MIBG over a 10-year period. RESULTS: Patients received a mean dose of 388+/-131 mCi (131)I-MIBG. Median survival after treatment was 4.7 years. Most patients experienced a symptomatic response leading to an improved survival (4.7 years vs 1.8 years, P<.01). Patients with a measurable hormone response demonstrated an increased survival in comparison to those with no response (4.7 years vs 2.6 years, P=.01). Patients who received a high dose (>500 mCi) as their initial therapy also had improved survival (3.8 years vs 2.8 years, P=.02). CONCLUSION: These data support (131)I-MIBG treatment for select patients with metastatic pheochromocytoma. In our experience, prolonged survival was best predicted by symptomatic and hormone response to (131)I-MIBG treatment. An initial dose of 500 mCi may be optimal. The benefit of (131)I-MIBG treatment for metastatic pheochromocytoma must also be weighed against its side effects.

[Secreting paraganglioma of the organ of Zuckerkandl. A case report]. / Paragangliome sécrétant de l'organe de Zuckerkandl. A propos d'un cas.

We report a case of a secreting retroperitoneal paraganglioma which developed on the organ of Zuckerkandl. Paraganglioma is a rare tumor of the paraganglioma system arising from undifferentiated cells of the neural crest. The originality of our observation comes from the secreting character of the tumor and the malignity proved by the local spreading to the wall of the inferior vena cava and the metastasis. The probable existence of a double primary localisation is also exceptional.