Treatment Of Malignant Pheochromocytoma Research Articles

Organic cation transporter 3 mediates the non-norepinephrine transporter driven uptake of meta-[211At]astato-benzylguanidine

IntroductionMeta-[211At]astato-benzylguanidine ([211At]MABG) accumulates in pheochromocytoma via norepinephrine transporter (NET) and leads to a strong antitumor effect, but it also distributed in normal tissues non-specifically. Meta-[131I]iodo-benzylguanidine ([131I]MIBG), an iodine-labeled analog of [211At]MABG, is known to be transported by not only NET but also organic cation transporter (OCT). The involvement of OCT in [211At]MABG uptake is still largely unknown. We investigated the involvement of OCT in the non-NET-driven uptake of [211At]MABG both in vitro and in vivo. Methods[123I]MIBG and [211At]MABG uptake was investigated in PC-12 (rat pheochromocytoma cell line), NIH/3T3 (mouse fibroblasts cell line), ACHN (human renal cancer cell line), and BxPC-3 (human pancreatic cancer cell line). Herein, we used desipramine and dl-norepinephrine to inhibit NET, and we used steroids (hydrocortisone and prednisolone) to inhibit OCT3. The [211At]MABG uptake in OCT3-knockdown cells established with OCT3-selective siRNA was also investigated. We investigated the biodistribution of [211At]MABG in PC-12 tumor-bearing mice after a preloading of phosphate-buffered saline (PBS) or hydrocortisone solution. ResultsThe uptake of both [123I]MIBG and [211At]MABG was significantly inhibited by desipramine in PC-12 cells but not the other cell lines. The expression of OCT3 was relatively higher than those of the other OCT subtypes in ACHN and BxPC-3 cells. The expression of OCTs was not observed in NIH/3T3 cells. The uptake of both [123I]MIBG and [211At]MABG in ACHN and BxPC-3 cells was significantly inhibited by the steroid treatments. The [211At]MABG uptake was also reduced in OCT3-knockdown cells (p < 0.001). The radioactivity of [211At]MABG was significantly reduced in normal tissues by the preloading of hydrocortisone. In contrast, there was an increasing trend of [211At]MABG uptake in the PC-12 tumors. The tumor-to-normal tissue ratio was significantly increased by the preloading of hydrocortisone compared to that of PBS. ConclusionOur results suggest that OCT3 is involved in non-NET-driven [211At]MABG uptake. The preloading of hydrocortisone selectively reduced [211At]MABG accumulation in normal organs in vivo. OCT3 inhibition may therefore be beneficial for a reduction of the radiation risk in healthy organs in the treatment of malignant pheochromocytomas.

Epic battles in endocrinology — malignant pheochromocytoma: a case report

The rarity of malignant pheochromocytoma coupled with the lack of definitive predictors of malignancy and the variability of clinical course, poses a significant diagnostic and therapeutic challenge. Since data on treatment is so scarce, case reports are a valuable source of knowledge for clinicians. This case report describes the medical history of a woman, aged 51 at the time of initial diagnosis and adrenalectomy. Within over 5 years she presented with recurrent relapse of tumour in adrenal gland bed and multiple distant metastases to descending colon, abdominal wall, postoperative scars, and the peritoneum. Neither before diagnosis nor during the whole follow-up were symptoms associated with pheochromocytoma present. The treatment administered to our patient consisted of numerous debulking surgeries along with administration of both hot and cold somatostatin analogues. We believe that debulking surgeries played a substantial role in enabling the patient to survive nearly 6 years despite aggressive clinical course of pheochromocytoma. She passed away in 2012 as a result of postlaparotomy complications. We stress the role of debulking surgery in the treatment of malignant pheochromocytoma and summarise current literature.

Complete remission of metastatic pheochromocytoma in 123I-metaiodobenzylguanidine scintigraphy after a single session of 131I-metaiodobenzylguanidine therapy: a case report

BackgroundPheochromocytomas are rare neuroendocrine tumors, with a malignancy frequency of approximately 10%. The treatment of malignant pheochromocytoma is palliative, and the traditional management strategy has limited efficacy. Furthermore, no clear criteria exist for the treatment of metastatic pheochromocytoma, especially for unresectable lesions. We report a case of complete remission of metastatic pheochromocytoma in 123I-metaiodobenzylguanidine (MIBG) scintigraphy after a single session of 131I-MIBG therapy.Case presentationA 61-year-old woman had a right adrenal grand tumor and lymph node metastasis on the hilum of the right kidney, both of which incorporated MIBG. After surgery, immunostaining of a tumor specimen showed expression of the tumor makers chromogranin and synaptophysin. One year postoperatively, abdominal computed tomography revealed a local recurrence and retroperitoneal lymph node swelling. The local recurrence was positive for MIBG uptake, whereas the swollen retroperitoneal lymph nodes were negative. She underwent surgery again, but the local recurrence was unresectable because of rigid adhesion to the surrounding tissue. Immunostaining of an intraoperatively extracted swollen retroperitoneal lymph node showed expression of tumor markers. The patient then underwent a single session of 131I-MIBG therapy (7.4 GBq, 200 mCi), after which the residual lesions no longer incorporated MIBG, and a complete response in 123I- metaiodobenzylguanidine (MIBG) scintigraphy was achieved. The 131I-MIBG treatment was repeated 6 months later. None of the lesions were positive for MIBG uptake.Conclusions131I-MIBG therapy efficaciously treats unresectable lesions that are positive for MIBG uptake.

Large Malignant Pheochromocytoma: About Three Cases

Introduction : Malignant pheochromocytomas are rare tumors which carry a poor prognosis and their clinical presentation is variable. Malignancy is defined by the presence of local invasion and/or metastases. In this report, we describe three cases of large malignant pheochromocytomas. Cases Presentation : The three cases have presented abdominal masses. Two patients complained of hypochondrium pain, and the third one was asymptomatic. One of the patients experienced sweating for 2 years, while the two others had no symptoms suggesting the hyper secretion of catecholamines. Urinalysis revealed elevation of daily urinary excretion of catecholamine metabolites in two cases and the computed tomography (CT) revealed large adrenal masses in the three cases. The malignancy was confirmed by the presence of multiple liver, lung and bone metastases. Surgery was performed in one case, but the tumor resection was impossible because the mass was adherent to great vessels. Calcitonin, intact parathormone (PTH) and calcium were normal in the 3 cases, which ruled out multiple endocrine neoplasia syndrome type 2. Otherwise, there was no sign suggesting phacomatosis. Two patients died before starting therapy, while in the third case the treatment considered was surgery and chemotherapy regimen of cyclophosphamide, dacarbazine and vincristine (CVD). Follow-up, showed a progression of tumor size with no significant improvement of metastatic disease. Conclusion : Malignant pheochromocytomas are particularly rare and aggressive tumors. Despite advances in diagnosis and treatment of malignant pheochromocytomas, their management is still a real dilemma, especially in our context because of the lack of diagnostic tools such as genetic analysis and the cost of therapy.

Targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant pheochromocytoma.

Recent studies have found that mammalian target of rapamycin complex 2 (mTORC2) is emerging as a potential therapeutic target in the treatment of many human cancers. However, the effects of targeting of mTORC2 on malignant pheochromocytomas (PCC) and paragangliomas (PGL) have not been reported. The aim of the study was to investigate the effects of targeting of mTORC2 on malignant PCC/PGL by comparing the inhibitory effects of targeting of mTORC2 with mTORC1 on pheochromocytoma PC12 cell in vitro and vivo. The expressions of regulatory-associated protein of mTOR (raptor) and rapamycin-insensitive companion of mTOR (rictor) were detected by immunohistochemistry in human tissues of malignant PCC. Targeting of mTORC1, mTORC2, and mTORC1/2 (mTORC1 and mTORC2) were performed by transfected with raptor, rictor, and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) in pheochromocytoma PC12 cell, respectively. MTT assay, apoptosis analysis, wound healing, and Transwell approach were performed. A tumor model in nude mice bearing PC12 cell xenografts, which were dosed with rapamycin or PP242, was established. The expression of raptor was frequently moderate positive, but the expression of rictor was frequently strong positive in malignant PCC. In vitro, although inhibition of mTORC1 was able to suppress PC12 cell proliferation, inhibition of mTORC2 more effectively suppressed cell proliferation. Inhibition of mTORC2 or mTORC1/2 more effectively prevented cell migration and invasion, and promoted cell apoptosis, while inhibition of mTORC1 only slightly prevented cell migration and invasion, and was not able to promoted apoptosis. Also, we found that mTOR downstream kinases were deregulated by targeting of mTORC2, but not mTORC1. In vivo, we found that PP242 was more potent than rapamycin in inhibiting tumor growth in tumor model. Our data suggest that targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant PCC/PGL. However, more clinical trials are needed to prove our findings.

External beam radiation therapy in treatment of malignant pheochromocytoma and paraganglioma.

Purpose: Pheochromocytomas (PCCs) are neuroendocrine tumors arising from the adrenal medulla or as paraganglioma (PGL) from extra-adrenal sites. While usually benign, a small fraction is malignant. Multi-modality therapy is used in treating malignant disease; however, little data exist on the role of external beam radiation therapy (EBRT). In this retrospective review, we assessed response to EBRT in malignant PCCs or PGLs.Methods and Materials: Records of patients treated at the National Institutes of Health who received EBRT between 1990 and 2012 were studied. Patients were assessed for symptomatic control, biochemical response, local and distant control by response evaluation criteria in solid tumors v1.1 or stable disease on imaging reports, toxicity by radiation therapy oncology group (RTOG) criteria, and survival.Results: There were 24 patients treated who received EBRT to lesions of the abdomen (n = 3), central nervous system (n = 4), and bone (n = 40). Lesions were treated with 3D conformal EBRT to a mean dose of 31.8 Gy in 3.3 Gy fractions, or fractionated stereotactic radiosurgery to 21.9 Gy in 13.6 Gy fractions. Patients experienced acute (n = 15) and late (n = 2) RTOG toxicities; no patient experienced acute toxicity ≥4 or late toxicity ≥2. Symptomatic control was achieved in 81.1% of lesions. Stable radiographic response was achieved in 86.7% of lesions with progression in 13%. Distant progression was observed overall in 75% of patients and average survival was 52.4 months.Conclusion: Malignant PCC and PGL often do not respond well to current systemic therapies. In these cases, EBRT can be considered in patients with symptomatic, localized disease progression.

Therapy of endocrine disease: treatment of malignant pheochromocytoma and paraganglioma.

Metastatic pheochromocytomas and paragangliomas (MPPs) present clinicians with three major challenges: scarcity, complexity of characterization, and heterogeneous behavior and prognosis. As with the treatment for all neuroendocrine tumors, the control of hormonal symptoms and tumor growth is the main therapeutic objective in MPP patients. A significant number of MPP patients still die from uncontrolled hormone secretion. In addition, the management of MPPs remains palliative. Steps forward include proper characterization of MPP patients at large cancer referral centers with multidisciplinary teams; improved strategies to stratify patients prognostically; and implementation of trials within national and international networks. Progress in the molecular characterization and staging of MPPs constitutes the basis for significant treatment breakthroughs.

Sunitinib for refractory malignant pheochromocytoma: two case reports

Sunitinib, a molecular-targeted therapy, is a potential new treatment strategy for malignant pheochromocytoma. However, because of the rarity of malignant pheochromocytoma and the consequent limited number of patients available for clinical study, there is no good evidence of the efficacy of sunitinib for malignant pheochromocytoma. The present report describes our experience with sunitinib for refractory malignant pheochromocytoma. Two patients were treated with sunitinib at a standard dose (50 mg daily; 4 weeks on, 2 weeks off) after cyclophosphamide/vinblastine/dacarbazine chemotherapy, because vascular endothelial growth factor (VEGF)-positive cells were partly observed by immunohistochemical staining. Both patients were assessed as having stable disease according to the Response Evaluation Criteria in Solid Tumors 1.1. The duration of overall survival from the time sunitinib was initiated was 13 and 8 months, respectively, and the progression-free survival was 5 and 4 months, respectively. Adverse events were evaluated according to the Common Terminology Criteria for adverse events of the US Department of Health and Human Services version 4.0. One patient experienced hypothyroidism (Grade 2) and thrombocytopenia (Grade 2). The other patient experienced anorexia (Grade 3) and general malaise (Grade 3). In conclusion, sunitinib was effective in the treatment of malignant pheochromocytoma when VEGF-positive cells were observed in the tumor specimens.

Diagnosis and Treatment of Malignant Pheochromocytoma

Diagnosis and Treatment of Malignant Pheochromocytoma

Changing Paradigms in the Treatment of Malignant Pheochromocytoma

Pheochromocytomas and paragangliomas are intra- and extra-adrenal neoplasms that are rarely malignant. The treatment of those that are malignant has remained a challenge because little was known about the molecular pathways involved in its malignant transformation. Recently, however, the genetic and molecular changes involved in malignant pheochromocytoma have come to be understood. The authors review the recent literature about the changing treatment options for malignant pheochromocytomas and paragangliomas. Traditional treatments for malignant pheochromocytoma remain unsuccessful. With the advances made in genomics and proteomics, novel pathways in pheochromocytoma carcinogenesis are becoming the targets of new treatment strategies and show promising results. Although several studies and clinical trials show great promise for improving the treatment of pheochromocytomas and paragangliomas, the hope is that future collaborative efforts will allow for prospective clinical trials using an evidenced-based approach.

Tumor markers in the diagnosis and treatment of malignant pheochromocytomas

HER2,VEGF,hTERT,HSP90 and Ki-67 are tumor markers closely related to pheochromocytomas.Gene amplification and protein overexpression of these markers may be associated with the malignancy of pheochromocytomas.Recent studies have revealed that patients with aggressive malignant pheochromocytomas may benefit by VEGF-targeted therapy with Sunitinib.Trastuzumab,Gamitrinibs and tumor marker-targeted gene therapy may also be a therapeutic choice for malignant pheochromocytomas. Key words: Malignant pheochromocytomas; Tumor markers; Target therapy

Phase II Study of High-Dose [131I]Metaiodobenzylguanidine Therapy for Patients With Metastatic Pheochromocytoma and Paraganglioma

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). 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. 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). 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.

Current Treatment of Malignant Pheochromocytoma

Pheochromocytomas are rare tumors of predominantly adrenal origin that often produce and secrete catecholamines. Malignancy occurs in a variable percentage of cases depending on genetic background and tumor location. Definitive diagnosis relies on the detection of distant metastases. Treatments for malignant pheochromocytoma include surgical debulking, pharmacological control of hormone-mediated symptoms, targeted methods such as external irradiation, and systemic antineoplastic therapy. Different agents and protocols for this purpose are reviewed, and their therapeutic potential is discussed. Literature on antineoplastic therapies for malignant pheochromocytoma was identified by searching the PubMed database with restriction to articles published in English during the past 30 yr. Because of the rarity of the condition, no randomized clinical trials concerning the treatment of malignant pheochromocytoma have been performed. The strategy established best is [131I]meta-iodobenzylguanidine (MIBG) therapy, which is well tolerated. Similar to cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine, MIBG can induce remission for a limited period in a significant proportion of patients. Octreotide as a single agent seems to be largely ineffective. MIBG radiotherapy and cyclophosphamide, vincristine, and dacarbazine chemotherapy are comparable with respect to response rate and toxicity. It is unclear whether combining both can improve the outcome. Future developments may include new multimodal concepts with focus on inhibition of angiogenetic factors and heat shock protein 90. Any present or new therapeutic approach must take into account the highly variable natural course of the disease.

Systemische Therapie maligner Nebennierentumoren

Systemic treatment of advanced-stage adrenal malignancies is most often only palliative. Mitotane alone or in combination with other chemotherapeutic agents such as cisplatin, etoposide, and vincristine are established therapeutic concepts for the treatment of metastatic adrenal cancer. Suramin and gossypol are rarely employed. New therapeutic options are tumor vaccination and treatment with antiangiogenic drugs. Metaiodobenzylguanidine as a radiotherapeutic drug or chemotherapeutic combination therapies that include cyclophosphamide, vincristine, and dacarbazine are applied for systemic treatment of malignant pheochromocytomas.. However, the clinical efficacy of the latter regimen needs further evaluation.

Malignant pheochromocytoma: current status and initiatives for future progress.

Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors that are usually benign, but which may also present as or develop into a malignancy. Predicting such behavior is notoriously difficult and there are currently no curative treatments for malignant tumors. This report follows from a workshop at the Banbury Conference Center, Cold Spring Harbor, New York, on the 16th-18th November 2003, held to review the state of science and to facilitate future progress in the diagnosis and treatment of malignant pheochromocytoma. The rarity of the tumor and the resulting fragmented nature of studies, typically involving small numbers of patients, represent limiting factors to the development of effective treatments and diagnostic or prognostic markers for malignant disease. Such development is being facilitated by the availability of new genomics-based tools, but for such approaches to succeed ultimately requires comprehensive clinical studies involving large numbers of patients, stringently collected clinical data and tumor samples, and interdisciplinary collaborations among multiple specialist centers. Nevertheless, the well-characterized hereditary basis and the unique functional nature of these neuroendocrine tumors provide a useful framework that offers advantages for establishing the pathways of tumorigenesis and malignancy. Such findings may have relevance for understanding the basis of other more common malignancies where similar frameworks are not available. As the relevant pathways leading to pheochromocytoma are established it should be possible to take advantage of the new generation of drugs being developed to target specific pathways in other malignancies. Again the success of this will require well-designed and coordinated multi-center studies.

Feocromocitoma maligno tratado con MIBG I131: una larga supervivencia

131I-metaiodobenzylguanidine (131I-MIBG) is a structural analogue of adrenal hormone norepinephrine employed to localise tumours derived of neural crest and in the treatment of malignant pheochromocytomas. Although the number of patients is low, in the revised literature there are objective remissions and reduction of hormonal activity, with symptomatic answers. However, the reduction of size of tumour only has been described in some times and hardly ever in the presence of osseous metastasis. We present one patient diagnoses of malignant pheochromocytoma with osseous metastasis, who was treated with 131I-MIBG. It was administrated a total dose of 1,800 mCu, with an excellent tolerance and short adverse symptoms. There were a partial tumour response and a complete hormonal response, with a survival of 30 years after the diagnoses.

The management of benign and malignant pheochromocytoma and abdominal paraganglioma

Aims: To report treatment and outcome in patients with malignant and benign pheochromocytoma and abdominal paraganglioma.Methods: Review of clinical and therapeutic features in 85 patients with pheochromocytoma or abdominal paraganglioma between 1976 and 1999.Results: Thirty-nine of 85 patients presented with symptoms other than classical paroxysmal attacks. Paragangliomas were more often malignant (7/15) than pheochromocytomas (7/70). No recurrences have occurred in 71 patients with tumours initially classified as benign after a median follow-up time of 144 months (range 7–287). Nine of 14 patients with tumours classified as malignant have developed metastasis and/or local recurrence. Treatment of malignant tumours with cyclophosphamide, vincristine and dacarbazine (CVD) improved or stabilised the disease in three of four patients.Conclusion: Life long follow-up of patients with benign pheochromocytoma is not necessary. Combination chemotherapy (CVD) is a valid option in the treatment of malignant pheochromocytomas and abdominal paragangliomas.

Diagnosis and treatment of malignant pheochromocytoma with 131I-meta-iodobenzylguanidine: a case report

The case of a 67-year-old male patient with metastatic malignant pheochromocytoma is described to illustrate the significant improvement of the diagnosis and treatment of pheochromocytoma since the recent introduction of 131I-meta-iodobenzylguanidine ( 131I-MIBG). Because of the generally observed tumor heterogeneity as to 131I-MIBG uptake and radiosensitivity in advanced disease, treatment results may be improved further, if 131I-MIBG therapy is initiated when tumor load is still small.

Applications of [ 131I] m-iodobenzylguanidine ([ 131I]MIBG)

The development of the aralkylguanidine [ 131I] m-iodobenzylguanidine ([ 131I]MIBG) in the University of Michigan Nuclear Medicine Division has led to diagnostic and therapeutic evaluations of all the neuroendocrine tumors. These tumors share the property of uptake, storage and release of [ 131I]MIBG uptake in chromaffin granules. This property has allowed the detection of pheochromocytomas, the detection of metastases in 46% of such patients, the treatment of malignant pheochromocytomas, the detection of neuroblastoma metastases, the treatment of neuroblastomas and the detection of a percent of apudomas. We have learned how to improve our results and this is discussed.