Abstract
IntroductionAggressive pituitary adenomas (APAs) are, by definition, resistant to optimal multimodality therapy. The challenge lies in their early recognition and timely management. Temozolomide is increasingly being used in patients with APAs, but evidence supporting a favorable response with early initiation is lacking.MethodsThis was a single-center study of all patients with APAs who received at least 3 cycles of temozolomide (150–200 mg/m2). Their baseline clinico-biochemical and radiological profiles were recorded. Immunohistochemical evaluation for cell-cycle markers O6-methylguanine-DNA methyltransferase (MGMT), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutL homolog 1 (MLH1), and postmeiotic segregation increased 2 (PMS2) was performed, and h-scores (product of the number of positive cells and staining intensity) were calculated. Response was assessed in terms of radiological response using the RECIST criteria. Patients with controlled disease (≥30% reduction in tumor volume) were classified as responders.ResultsThe study comprised 35 patients (48.6% acromegaly, 37.1% prolactinomas, and 14.3% non-functioning pituitary adenomas). The median number of temozolomide (TMZ) cycles was 9 (IQR 6–14). Responders constituted 68.6% of the cohort and were more likely to have functional tumors, a lower percentage of MGMT-positive staining cells, and lower MGMT h-scores. There was a significantly longer lag period in the initiation of TMZ therapy in non-responders as compared with responders (median 36 vs. 15 months, p = 0.01). ROC-derived cutoffs of 31 months for the duration between diagnosis and TMZ initiation, low-to-intermediate MGMT positivity (40% tumor cells), and MGMT h-score of 80 all had a sensitivity exceeding 80% and a specificity exceeding 70% to predict response.ConclusionEarly initiation of TMZ therapy, functional tumors, and low MGMT h-score predict a favorable response to TMZ in APAs.
Highlights
Aggressive pituitary adenomas (APAs) are, by definition, resistant to optimal multimodality therapy
Early initiation of TMZ therapy, functional tumors, and low methylguanine-DNA methyltransferase (MGMT) h-score predict a favorable response to TMZ in APAs
The current study enabled the evaluation of the efficacy and safety of early initiation of TMZ in both functional and non-functional APAs, and we found that early initiation of TMZ was associated with good response
Summary
Aggressive pituitary adenomas (APAs) are, by definition, resistant to optimal multimodality therapy. In neuroendocrine oncology especially pituitary oncology, locally invasive pituitary adenomas are not considered malignant neoplasms, unlike in general oncology [2]. Aggressive pituitary adenoma (APA) refers to a tumor that is both invasive and proliferative or displays clinically meaningful tumor growth/recurrence despite optimal standard therapy [3, 4]. The clinical behavior, proliferative markers, resilience to multimodality therapy, and outcomes of APAs and PCs are very similar [6]. Unlike other neuroendocrine neoplasms which are stratified by the WHO grade and TNM stage, pituitary adenomas have been classified by the recent clinicopathological grade which incorporates both invasion (basis of the stage) and proliferation (basis of grade) [7]
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