Temozolomide responsiveness in aggressive corticotroph tumours: a case report and review of the literature

Abstract

Pituitary carcinoma occurs in ~0.2% of resected pituitary tumours and carries a poor prognosis (mean survival <4 years), with standard chemotherapy regimens showing limited efficacy. Recent evidence suggests that temozolomide (TMZ), an orally-active alkylating agent used principally in the management of glioblastoma, may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas. A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) predicts TMZ responsiveness in glioblastomas, and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date. Here, we report a case of a silent pituitary corticotroph adenoma, which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases. The tumour exhibited low immunohistochemical MGMT expression in both primary (pituitary) and secondary (hepatic) lesions. Initial TMZ therapy (200 mg/m² for 5 days every 28 days-seven cycles) resulted in marked clinical, biochemical [>50% fall in adrenocorticotrophic hormone (ACTH)] and radiological [partial RECIST (response evaluation criteria in solid tumors) response] improvements. The patient then underwent bilateral adrenalectomy. However, despite reintroduction of TMZ therapy (further eight cycles) ACTH levels plateaued and no further radiological regression was observed. We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours, and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma. Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered.

The role of temozolomide in the treatment of aggressive pituitary tumors

“…Temozolomide therapy was suspended for 6 weeks to allow bilateral adrenalectomy and plasma ACTH levels rose to 3519 ng/L. At the conclusion of cycle 15, plasma ACTH fell to preoperative levels [2].…”

“…The clinical response in temozolomide-sensitive tumors has been rapid with decreased optic chiasm compression and relief of local mass effect [2,4,5,[10][11][12][13]27,29,38,[45][46][47]. A favorable response can be seen as early as 2 months after initiation of treatment with evidence of tumor shrinkage, tumor necrosis and hemorrhage, and cystic degeneration.…”

“…Although the majority of pituitary tumors are benign, a subset of these tumors can exhibit more aggressive clinical behavior with high rates of recurrences and resistance to conventional treatments [1][2][3][4][5][6]. These aggressive pituitary adenomas can sometimes be characterized by markers of high cell proliferation such as a Ki-67 index P3%, mitotic activity >2 per 10 high power field, and p53 expression on immunohistochemistry [1,6].…”

“…More recently, the use of temozolomide appears to have potential benefits in the treatment of aggressive pituitary adenomas and carcinomas with favorable results [2,4,[8][9][10][11][12][13]. Temozolomide has been used successfully in aggressive prolactinomas, adrenocorticotrophic hormone (ACTH) producing tumors, Nelson's syndrome and nonfunctional adenomas that exhibit continued growth despite surgery, radiotherapy and medical therapy.…”

Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin-Secreting Pituitary Tumors

“…Although conventional chemotherapies are largely ineffective (2,3), recent case reports using temozolomide, an oral alkylating agent used in the management of glioblastoma, have given some hope, especially at early stages (4)(5)(6). However, about 60% of the published cases demonstrated only an initial response to temozolomide therapy (5, 7) with up to 25% of these patients becoming resistant to temozolomide during follow-up (5,(7)(8)(9). Because temozolomide treatment is not effective for all pituitary carcinomas or aggressive tumors, the development of new therapeutic options is necessary.…”