Temozolomide in the Treatment of Aggressive Pituitary Tumors— An Overview of Existing Knowledge and Future Perspectives

Pituitary tumors are common, with an estimated prevalence of 16.7 % in the general population based on imaging and autopsy studies.¹ Clinically significant pituitary tumors are more prevalent than previously recognized, with one case per 1,000–1,300 people.^2,3 The majority of pituitary tumors are indolent, slow-growing neoplasms.

Pituitary tumors are common, with an estimated prevalence of 16.7 % in the general population based on imaging and autopsy studies.¹ Clinically significant pituitary tumors are more prevalent than previously recognized, with one case per 1,000–1,300 people.^2,3 The majority of pituitary tumors are indolent, slow-growing neoplasms. However, 40–50 % of pituitary tumors are locally invasive and commonly unable to be completely surgically excised.^4,5 An ‘aggressive pituitary tumor’ typically refers to an invasive pituitary tumor that demonstrates progressive growth despite multimodal therapy, including surgery, and radiotherapy. Whilst these tumors have malignant potential, the term pituitary carcinoma is strictly reserved for those tumors with demonstrated craniospinal or systemic metastases.⁶ As there is a lack of formal criterion used to define an aggressive pituitary tumor, epidemiologic data with respect to this group is lacking. The World Health Organization pathological classification of an ‘atypical pituitary adenoma’ (Ki67 >3 %, excessive p53 immunoreactivity and increased mitotic activity) was coined in an attempt to identify a tumor with the potential for more aggressive behaviour.⁷ A recent study, conducted in a tertiary referral center, identified 15 % of atypical adenomas amongst their surgical cohort.⁸ Pituitary carcinoma is rare, accounting for 0.2 % of pituitary tumors.⁹

The management of aggressive pituitary tumors is challenging, and there is substantial morbidity and mortality associated with both the tumor and treatment. Patients often undergo multiple surgeries and radiotherapy in an attempt to control tumor growth. These tumors are often also resistant to medical therapies, such as dopamine agonists. Historically, systemic chemotherapy was reserved as a ‘last resort’ therapy, principally due to the lack of identification of a consistently effective chemotherapeutic agent. However, over the past five years temozolomide, an oral alkylating agent commonly used in the management of glioblastoma, has emerged as the first chemotherapeutic with substantial efficacy in the treatment of aggressive pituitary tumors. International experience with temozolomide, as used in the management of an aggressive pituitary tumor, has grown exponentially, with 50 published cases now reported. This review will summarize and examine the existing knowledge base, but also speculate on the future possibilities regarding the use of temozolomide in pituitary tumors. The role of 06-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, as a biomarker of response to temozolomide and its possible role in pituitary tumor biology will be discussed.

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