AUTHOR=Das Liza , Gupta Nidhi , Dutta Pinaki , Walia Rama , Vaiphei Kim , Rai Ashutosh , Radotra Bishan Dass , Gupta Kirti , Sreedharanunni Sreejesh , Ahuja Chirag Kamal , Bhansali Anil , Tripathi Manjul , Sood Ridhi , Dhandapani Sivashanmugam 

TITLE=Early Initiation of Temozolomide Therapy May Improve Response in Aggressive Pituitary Adenomas

JOURNAL=Frontiers in Endocrinology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.774686

DOI=10.3389/fendo.2021.774686

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>Aggressive 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.</p></sec><sec><title>Methods</title><p>This was a single-center study of all patients with APAs who received at least 3 cycles of temozolomide (150–200 mg/m<sup>2</sup>). Their baseline clinico-biochemical and radiological profiles were recorded. Immunohistochemical evaluation for cell-cycle markers O<sup>6</sup>-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 <italic>h</italic>-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.</p></sec><sec><title>Results</title><p>The 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 <italic>h</italic>-scores. There was a significantly longer lag period in the initiation of TMZ therapy in non-responders as compared with responders (median 36 <italic>vs</italic>. 15 months, <italic>p</italic> = 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 <italic>h</italic>-score of 80 all had a sensitivity exceeding 80% and a specificity exceeding 70% to predict response.</p></sec><sec><title>Conclusion</title><p>Early initiation of TMZ therapy, functional tumors, and low MGMT <italic>h</italic>-score predict a favorable response to TMZ in APAs.</p></sec>