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

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.

Temozolomide Nonresponsiveness in Aggressive Prolactinomas and Carcinomas: Management and Outcomes

“…The fact that earlier administration of the drug in her case could have yielded better results is plausible. In view of the recent proposition to classify invasive and highly proliferative (Ki67 > 10%) tumors as having malignant potential [ 37 ], our patient could have, in retrospect, been initiated with TMZ earlier without discontinuation of the DA [ 38 ].…”

The biological behavior and clinical outcome of pituitary adenoma are affected by the microenvironment

“…18,88,89 In addition to surgery and radiation therapy, temozolomide is currently the only oral chemotherapeutic drug considered to be effective for pituitary adenomas, and some studies have suggested that early treatment with temozolomide may also have positive effects in patients with functional invasive pituitary adenomas. 17,90 Immunotherapy is a promising treatment that has shown clinical activity in many cancer types. 91,92 Previous studies have explored pituitary adenomas and invasive pituitary adenomas at the molecular level, and have summarized the therapeutic targets and clinical experience.…”

“…Surgical treatment is currently the first choice of treatment for pituitary adenomas and refractory pituitary adenomas; however, the postoperative recurrence rate of some tumors remains high 18,88,89 . In addition to surgery and radiation therapy, temozolomide is currently the only oral chemotherapeutic drug considered to be effective for pituitary adenomas, and some studies have suggested that early treatment with temozolomide may also have positive effects in patients with functional invasive pituitary adenomas 17,90 …”

“… 18 , 88 , 89 In addition to surgery and radiation therapy, temozolomide is currently the only oral chemotherapeutic drug considered to be effective for pituitary adenomas, and some studies have suggested that early treatment with temozolomide may also have positive effects in patients with functional invasive pituitary adenomas. 17 , 90 …”

Aggressive and Metastatic Pituitary Neuroendocrine Tumors: Therapeutic Management and Off-Label Drug Use

“…While it appears that the assessment of MGMT status is critical in predicting a therapeutic response in other tumors (e.g., glioblastomas), it is still controversial in pituitary tumors. In a recent cohort study of 35 AgPitNET patients, all TMZ responders had <15% MGMT expression, whereas non-responders had an average of 50% MGMT expression [ 35 ]. A recent meta-analysis study showed that the radiologic response rate was significantly lower in patients with AgPitNET and MetPitNETs with high MGMT expression compared to that obtained in the patients with minimal and intermediate MGMT expression, with no significant difference between the latter two groups [ 32 ].…”