Title : Temozolomide treatment in refractory pituitary adenomas and pituitary carcinomas
Abstract:
Refractory pituitary adenomas (RPAs) and pituitary carcinomas (PCs) present significant therapeutic challenges, as they often do not respond to conventional treatment modalities such as surgery, radiation, and traditional medical therapies. Temozolomide (TMZ), an alkylating chemotherapy agent, has emerged as a first-line treatment for these aggressive tumours due to its ability to cross the blood-brain barrier and its relatively mild side effect profile. TMZ, a non-classical agent, has shown promising efficacy in clinical trials, with a radiological response rate of approximately 41% and a hormonal response rate of 53%. Functional tumours, which secrete hormones, tend to show a higher response rate compared to non-functional tumours. This makes TMZ an especially valuable treatment option for patients with hormonally active tumours that are resistant to other therapies. When combined with radiotherapy, TMZ has been shown to further improve treatment outcomes, offering tumor shrinkage and hormonal normalization. However, there is still debate about the optimal duration of TMZ therapy, as the results from various studies suggest that longer treatment durations may correlate with better survival outcomes. Importantly, pre-treatment evaluation using immunohistochemistry (IHC) to assess markers such as O6-methylguanine-DNA methyltransferase (MGMT), MSH2, MSH6, MLH1, PMS2, and N-methylpurine DNA glycosylase (MPG) is recommended. These markers help predict the likelihood of TMZ efficacy, as DNA repair mechanisms such as direct repair (DR), mismatch repair (MMR), and base excision repair (BER) play a crucial role in determining tumour response to TMZ. Despite its success, TMZ resistance remains a major concern in the treatment of RPAs and PCs. Resistance mechanisms include the overexpression of MGMT, which can repair the damage caused by TMZ and reduce its effectiveness. To improve patient outcomes, researchers are exploring combination therapies, including TMZ with capecitabine, PARP inhibitors, and immune checkpoint inhibitors, which may help overcome resistance and enhance TMZ's effectiveness. This presentation will provide an overview of TMZ’s clinical application, including its efficacy, response rates, and the challenges of TMZ resistance. It will also discuss the role of biomarkers in predicting treatment success and explore emerging combination therapy strategies to optimize outcomes for patients with refractory pituitary tumours. By understanding the mechanisms of resistance and utilizing personalized approaches, TMZ has the potential to improve prognosis and quality of life for patients with these challenging tumours.
