Long-term response of pituitary carcinoma to temozolomide

Abstract

Pituitary carcinoma is a rare tumor characterized by poor responsiveness to therapy, leading to early death. Reported responses to standard chemotherapy have only been anecdotal, with no single agent or combination demonstrating consistent efficacy in the treatment of patients with this disease. The authors report rare examples of a persistent response to cytotoxic chemotherapy in two patients with pituitary carcinoma. One patient was a 38-year-old man with visual field loss caused by a luteinizing hormone-secreting pituitary carcinoma that had recurred despite multiple surgeries and radiation therapy. Intradural metastases to the spine that had failed to respond to radiation therapy were pathologically confirmed. The second patient was a 26-year-old man with hyperprolactinemia from a prolactin-secreting pituitary tumor. Spine magnetic resonance images obtained to search for causes of neck pain showed a vertebral tumor, which was later confirmed through pathological analysis to be a metastatic pituitary carcinoma. His disease progressed despite radiation therapy, high-dose bromocriptine, and chemotherapy. Both patients were treated monthly with temozolomide, which was administered orally on the first 5 days of a 28-day cycle. The patient in the first case underwent all 12 treatment cycles without serious side effects, and his visual field deficits improved. The patient in the second case had undergone only 10 cycles when the drug was stopped because of his severe fatigue. Nonetheless, his pain disappeared and his serum prolactin concentration decreased. Both patients continue to have partial responses and have been employed full-time for more than 1 year after discontinuing temozolomide therapy. These two examples demonstrate that temozolomide may be effective in treating pituitary carcinomas and thus should be considered in the treatment algorithm for these difficult cases.

Treatment of pituitary neoplasms with temozolomide

“…19 Of the reported cases, 4 of 11 pituitary adenomas 11,14-16,23 and 4 of 6 pituitary carcinomas 10,13,14,25 that were responsive to temozolomide were the PRL-producing type (Tables 1 and 2), in keeping with the finding by McCormack et al that prolactinomas had a propensity for low-level MGMT expression compared with other tumors. 19 Also noteworthy is the study by Takeshita et al 24 of 7 invasive Crooke cell adenomas, a morphologic variant of corticotrophic adenomas; of these, 5 had low MGMT expression compared with 1 of 17 conventional ACTH-producing adenomas.…”

“…49,50 Various combinations, such as cisplatinum, etoposide, and/or paclitaxel, have not achieved sustained responses. 8 Fadul et al 12,13 first reported the successful use of temozolomide in pituitary carcinomas in 2004. Their 2 patients, 1 patient who had systemic metastases of a luteinizing hormone (LH)-producing (gonadotropic) pituitary carcinoma and 1 patient who had a prolactin (PRL)-producing (lactotrophic) carcinoma with spinal dissemination, were treated, and both achieved a sustained response.…”

“…To date, 6 patients with pituitary carcinomas have received treatment with temozolomide 10,[12][13][14]17,19,[23][24][25] (Table 1). These included 4 men and 2 women ages 26 to 77 years (mean, 49.8 years).…”

Nelson's Syndrome

“…We have shown recently that even higher than licensed doses of rosiglitazone (12 mg/day) are not effective in reducing plasma ACTH levels, and by inference tumour growth (45) (figure 1). The orally active alkylating agent temozolomide has been shown to be highly effective in a few aggressive pituitary tumours and in lowering prolactin and controlling tumour growth in highly aggressive prolactinomas (46)(47)(48). Although there are no reports of its use in Nelson's syndrome, temozolomide could be considered in patients with Nelson's syndrome not responding to other modalities of therapy.…”

Effect of temozolomide on cell viability in gonadotroph adenoma cell lines

“…In addition, TMZ clinical trials have been performed to test its activity against brain metastatic solid tumors, leukemia (8), pancreatic neuro endocrine tumors (9) and refractory pituitary adenomas (10)(11)(12)(13)(14). Two case studies related to gonadotroph adenoma patients report that their lesions decreased after TMZ therapy (15,16), and studies of TMZ on MMQ, GH3, and AtT20 cell lines suggested that this drug may have efficacy in pituitary adenoma cells (17 to attain biochemical control in a severe case of acromegaly (18). These conflicting data prompted us to further study the effectiveness and mechanism of TMZ on pituitary adenoma cell death in detail.…”