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

Published Online: September 14th 2012 US Endocrinology, 2012;8(2):112-117 DOI: http://doi.org/10.17925/USE.2012.08.02.112
Authors: Ann McCormack
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Abstract:
Overview

The management of aggressive pituitary tumors remains a challenge, however, the recent identification of temozolomide as a chemotherapeutic agent with significant efficacy against these tumors has heralded a new therapeutic era. There has been an exponential growth in the international experience with temozolomide over the past five years, now totaling 50 published cases. Overall, 67 % of cases demonstrated a response to temozolomide. Prolactin- and adrenocorticotrophic hormone (ACTH)-secreting tumors respond more frequently than non-functioning tumors. Response is typically evident in the first three months of treatment. Adverse effects occur in almost half of patients, although the majority are mild. The expression of a DNA repair enzyme, 06-methylguanine-DNA methyltransferase (MGMT), as determined by immunohistochemistry, appears to be the primary determinant of response to temozolomide in pituitary tumors. There is suggestion that MGMT may also play a role in pituitary tumorigenesis. Over the next few years we will see temozolomide used earlier in the treatment algorithm of aggressive pituitary tumors, making it imperative to collect global long-term data on its use.

Keywords

Pituitary tumor, pituitary carcinoma, temozolomide, MGMT

Article:

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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Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Ann McCormack, MBBS, FRACP, PhD, Department of Endocrinology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. E: a.mccormack@garvan.org.au

Received

2012-07-02T00:00:00

References

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  3. Fernandez A, Karavitaki N, Wass JA, Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK), Clin Endocrinol (Oxf), 2010;72:377–82.
  4. Kaltsas GA, Nomikos P, Kontogeorgos G, et al., Clinical review: Diagnosis and management of pituitary carcinomas, J Clin Endocrinol Metab, 2005;90:3089–99.
  5. Sautner D, Saeger W, Invasiveness of pituitary adenomas, Pathol Res Pract, 1991;187:632–6.
  6. Scheithauer BW, Kovacs KT, Laws ER Jr, Randall RV, Pathology of invasive pituitary tumors with special reference to functional classification, J Neurosurg, 1986;65:733–44.
  7. Lloyd RV, Kovacs K, Young WF, Pituitary Tumors, in: DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds), World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of Endocrine Organs, Lyon: IARC Press: 2004;10–47.
  8. Zada G, Woodmansee WW, Ramkissoon S, et al., Atypical pituitary adenomas: incidence, clinical characteristics, and implications, J Neurosurg, 2011;114:336–44.
  9. Pernicone PJ, Scheithauer BW, Sebo TJ, et al., Pituitary carcinoma: a clinicopathologic study of 15 cases, Cancer, 1997;79:804–12.
  10. Neyns B, Tosoni A, Hwu WJ, Reardon DA, Dose-dense temozolomide regimens: antitumor activity, toxicity, and immunomodulatory effects, Cancer, 2010;116:2868–77.
  11. Marchesi F, Turriziani M, Tortorelli G, et al., Triazene compounds: mechanism of action and related DNA repair systems, Pharmacol Res, 2007;56:275–87.
  12. Kaina B, Ziouta A, Ochs K, Coquerelle T, Chromosomal instability, reproductive cell death and apoptosis induced by O6-methylguanine in Mex-, Mex+ and methylation-tolerant mismatch repair compromised cells: facts and models, Mutat Res, 1997;381:227–41.
  13. Newlands ES, Blackledge GR, Slack JA, et al., Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856), Br J Cancer, 1992;65:287–91.
  14. Lashkari HP, Saso S, Moreno L, et al., Using different schedules of Temozolomide to treat low grade gliomas: systematic review of their efficacy and toxicity, J Neurooncol, 2011;105:135–47.
  15. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N Engl J Med, 2005;352:987–96.

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