Gross DJ, Munter G, Bitan M, et al. The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R

Shaare Zedek Medical Center, Yerushalayim, Jerusalem, Israel
Endocrine Related Cancer (Impact Factor: 4.81). 07/2006; 13(2):535-40. DOI: 10.1677/erc.1.01124
Source: PubMed


Imatinib mesylate (IM), a small molecule that is a selective inhibitor of the ABL, platelet derived growth factor receptor (PDGFR-R) and stem cell ligand receptor (c-kit) tyrosine kinases (TK). IM was also found to inhibit the TK activity of BCR/ABL fusion protein produced in chronic myelogenous leukemia, with marked clinical activity against the disease. Since both PDGF-R and c-kit both having a putative role in tumorigenesis, we investigated the efficacy and safety of the use of IM in patients with endocrine tumors unresponsive to conventional therapies that expressed c-kit and/or PDGF-R (within the framework of a comprehensive phase II multi-center study of IM in patients with solid tumors). IM was initiated at a dose of 400 mg/day, with possible dose escalation within 1 week to 600 mg/day and an option to raise the dose to 800 mg/day in the event of progression and in the absence of safety concerns for a period of up to 12 months. Between September 2002 and July 2003, 15 adult patients with disseminated endocrine tumors were recruited as follows: medullary thyroid carcinoma (MTC, n = 6); adrenocortical carcinoma (ACC, n = 4); malignant pheochromocytoma (pheo, n = 2); carcinoid (non-secreting, n = 2), neuroendocrine tumor (NET, n = 1). No objective responses were observed. MTC--disease progression in 4 patients, and treatment discontinuation in 2 patients due to adverse events; ACC--disease progression in 3 patients, and treatment discontinuation in 1 patient due to severe psychiatric adverse event; Pheo--disease progression in 2 patients; Carcinoid--stable disease in 1 patient (6.5 months), and disease progression in 1 patient; NET--disease progression in 1 patient. IM does not appear to be useful for treatment of malignant endocrine tumors, also causing significant toxicity in this patient population.


Available from: Gabriel Munter
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    • "Early studies of the in vitro effects demonstrated RET inhibition and death of oncogene-addicted MTC cells [14, 33], but these studies demonstrated successful RET inhibition only at serum concentrations that could not be achieved with tolerable doses of imatinib, and subsequent clinical trials of imatinib monotherapy revealed no responses in MTC [32, 34]. In one of these trials of imatinib monotherapy, patients with ACC were included as well, without evidence of clinical response [32]. Additional investigation of this agent in ACC, alone or in combination with cytotoxic chemotherapy has otherwise been lacking, making our combination entirely novel. "
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    ABSTRACT: Patients with advanced endocrine cancers, such as adrenocortical carcinoma and medullary thyroid carcinoma, have few well-validated therapeutic options. Pre-clinical studies have suggested potential activity of imatinib in these tumors. We therefore sought to establish a safe, novel treatment regimen combining imatinib with cytotoxic chemotherapy for future study in endocrine cancers. A standard 3 + 3 dose-escalation design was used with a 21-day cycle, including imatinib on days 1–21, dacarbazine on days 1–3, and capecitabine on days 1–14. Twenty patients were treated. The most frequent toxicities were edema and fatigue, with dose-limiting fatigue and dyspnea. The recommended phase II regimen is dacarbazine 250 mg/m2 daily on day 1–3, capecitabine 500 mg/m2 twice daily on days 1–14, and imatinib 300 mg daily on days 1–21 of a 21-day cycle. Interestingly, responses were seen in patients with adrenocortical carcinoma, with 1 of 6 patients experiencing a partial response and a second experiencing a minor response, with progression-free survival of 8.8 and 6.4 months, respectively. The regimen of imatinib, dacarbazine, and capecitabine is well-tolerated. It may have some activity in adrenocortical carcinoma, and further study of this combination or its components may be beneficial for this disease with limited treatment options. Trial registration identifier NCT00354523, registered July 18, 2006.
    BMC Cancer 08/2014; 14(1):561. DOI:10.1186/1471-2407-14-561 · 3.36 Impact Factor
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    • "EGFR is overexpressed in most ACCs, making it a useful target for treatment;61 however, targeted treatment with the tyrosine kinase inhibitor erlotinib plus gemcitabine showed a limited response as a salvage treatment, with a response only seen in one out of ten patients.62 Poor response was also seen with the use of imatinib.63 Sunitinib, which targets several tyrosine kinase inhibitors, has been shown to have a modest response, with some patients achieving stable disease in a phase-II trial.64 "
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    ABSTRACT: Adrenal cortical carcinoma (ACC) is a rare cancer that poses a number of management challenges due to the limited number of effective systemic treatments. Complete surgical resection offers the best chance of long-term survival. However, despite complete resection, ACC is associated with high recurrence rates. This review will discuss the management of recurrent ACC in adults following complete surgical resection. Management should take place in a specialist center and treatment decisions must consider the individual tumor biology of each case of recurrence. Given the fact that ACC commonly recurs, management to prevent recurrence should be considered from initial diagnosis with the use of adjuvant mitotane. Close follow up with clinical examination and imaging is important for early detection of recurrent disease. Locoregional recurrence may be isolated, and repeat surgical resection should be considered along with mitotane. The use of radiotherapy in ACC remains controversial. Systemic recurrence most often involves liver, pulmonary, and bone metastasis and is usually managed with mitotane, with or without combination chemotherapy. There is a limited role for surgical resection in systemic recurrence in selected patients. In all patients with recurrent disease, control of excessive hormone production is an important part of management. Despite intensive management of recurrent ACC, treatment failure is common and the use of clinical trials and novel treatment is an important part of management.
    OncoTargets and Therapy 06/2013; 6:635-43. DOI:10.2147/OTT.S34956 · 2.31 Impact Factor
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    • "Consistently with that, a phase II study involving 4 patients with advanced ACC treated with oral imatinib mesylate, a PDGFR inhibitor, reported disease progression in three cases. In one case the side effects were so severe that treatment was suspended [106]. "
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    ABSTRACT: Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. The overall survival is five years from detection. Radical surgery is considered the therapy of choice in the first stages of ACC. However postoperative disease-free survival at 5 years is only around 30% and recurrence rates are frequent. o,p'DDD (ortho-, para'-, dichloro-, diphenyl-, dichloroethane, or mitotane), an adrenolytic drug with significant toxicity and unpredictable therapeutic response, is used in the treatment of ACC. Unfortunately, treatment for this aggressive cancer is still ineffective. Over the past years, the growing interest in ACC has contributed to the development of therapeutic strategies in order to contrast the neoplastic spread. In this paper we discuss the most promising therapies which can be used in this endocrine neoplasia.
    Journal of Oncology 08/2012; 2012(2):408131. DOI:10.1155/2012/408131
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