The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R.
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.
Gross
David J
DJ
Endocrinology and Metabolism Service, Department of Medicine, Hadassah University Hospital, P.O.B 12000, Jerusalem, Israel 91120. gross@vms.huji.ac.il
Munter
Gabriel
G
Bitan
Menachem
M
Siegal
Tali
T
Gabizon
Alberto
A
Weitzen
Ronny
R
Merimsky
Ofer
O
Ackerstein
Aliza
A
Salmon
Asher
A
Sella
Avishai
A
Slavin
Shimon
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D001549:Benzamides; D004701:Endocrine Gland Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use* / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D011743:Pyrimidines / Q000627:therapeutic use* / Q000633:toxicity; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor