Temozolomide in the Treatment of Aggressive Pituitary Tumours – An Overview of Existing Knowledge and Future Perspectives

Pituitary tumours are common, with an estimated prevalence of 16.7 % in the general population based on imaging and autopsy studies.¹ Clinically significant pituitary tumours are more prevalent than previously recognised, with one case per 1,000–1,300 people.^2,3 The majority of pituitary tumours are indolent, slow-growing neoplasms. However, 40–50 % of pituitary tumours are locally invasive and commonly unable to be completely surgically excised.^4,5 An ‘aggressive pituitary tumour’ typically refers to an invasive pituitary tumour that demonstrates progressive growth despite multimodal therapy, including surgery and radiotherapy. Whilst these tumours have malignant potential, the term pituitary carcinoma is strictly reserved for those tumours with demonstrated craniospinal or systemic metastases.⁶ As there is a lack of formal criterion used to define an aggressive pituitary tumour, epidemiological 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 tumour with the potential for more aggressive behaviour.⁷ A recent study, conducted in a tertiary referral centre, identified 15 % of atypical adenomas amongst their surgical cohort.⁸ Pituitary carcinoma is rare, accounting for 0.2 % of pituitary tumours.⁹

The management of aggressive pituitary tumours is challenging, and there is substantial morbidity and mortality associated with both the tumour and treatment. Patients often undergo multiple surgeries and radiotherapy in an attempt to control tumour growth. These tumours 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 tumours. International experience with temozolomide, as used in the management of an aggressive pituitary tumour, has grown exponentially, with 50 published cases now reported. This review will summarise and examine the existing knowledge base, but also speculate on the future possibilities regarding the use of temozolomide in pituitary tumours. 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 tumour biology will be discussed.

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