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. 2021 Dec 17:12:774686.
doi: 10.3389/fendo.2021.774686. eCollection 2021.

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

Liza Das  1 , Nidhi Gupta  1 , Pinaki Dutta  1 , Rama Walia  1 , Kim Vaiphei  2 , Ashutosh Rai  1 , Bishan Dass Radotra  2 , Kirti Gupta  2 , Sreejesh Sreedharanunni  3 , Chirag Kamal Ahuja  4 , Anil Bhansali  1 , Manjul Tripathi  5 , Ridhi Sood  2 , Sivashanmugam Dhandapani  5
Affiliations

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

Liza Das et al. Front Endocrinol (Lausanne). .

Abstract

Introduction: 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.

Methods: This 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.

Results: 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 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.

Conclusion: Early initiation of TMZ therapy, functional tumors, and low MGMT h-score predict a favorable response to TMZ in APAs.

Keywords: MGMT; aggressive pituitary adenomas; controlled disease; early therapy; temozolomide.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A–E) Images depicting the baseline MRI of a patient presenting with headache and secondary amenorrhea due to an invasive macroprolactinoma (A) which was dopamine agonist resistant. She underwent transsphenoidal surgery elsewhere with significant tumor residue (B), necessitating redo surgery by the transfrontal route at our institute (right pterional craniotomy) (C). Due to persistent right temporal lobe residual mass (D), the patient was managed with intensity-modulated radiotherapy (50 Gy over 28#) along with initiation of temozolomide therapy at 150 mg/m2 dose for the first month followed by 200 mg/m2 dose in 5/28 day cycles, for a total of 9 cycles. This led to almost complete resolution of the tumor in the patient as well as normalization of serum prolactin (E) which was persistent even after 2 years of follow-up (F).
Figure 2
Figure 2
(A–D) Images depicting the bone marrow biopsy specimen of a patient who presented with acrogigantism due to an aggressive pituitary adenoma and subsequently developed bone marrow aplasia following temozolomide therapy, leading to discontinuation of the drug. (A) Peripheral blood film shows neutropenia and predominantly lymphocytes (May Grunwald–Giemsa stain/MGG; 20×); (B, C) paucicellular bone marrow aspirate and imprint smears show scattered myeloid and erythroid precursors (MGG; 40×); (D) trephine biopsy shows moderately to markedly hypocellular bone marrow spaces (hematoxylin and eosin stain; 10×). Later, the patient was reinitiated on long-acting octreotide therapy at a 30-mg monthly dose, leading to remission of disease activity, probably attributable to prior gamma knife radiosurgery.
Figure 3
Figure 3
(A–C) Images depicting the ROC cutoffs for the various parameters found significant in response to TMZ with (A) ROC cutoff depicting the optimal duration before initiation of TMZ therapy as 31 months (80% sensitivity, 70% specificity), (B) optimal MGMT percentage of cells as 40% for predicting response (86% sensitivity, 72% specificity), and (C) optimal MGMT h-score as 80 (86% sensitivity, 72% specificity) for predicting response.
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