Federica Franchino

Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study

BACKGROUND Few data are available on temozolomide (TMZ) in ependymomas.We investigated the response, survival, and correlation with MGMT promoter methylation in a cohort of patients with adult intracranial ependymoma receiving TMZ as salvage therapy after failure of surgery and radiotherapy. PATIENTS AND METHODS We retrieved clinical information from the institutional database and follow-up visits, and response to TMZ on MRI was evaluated according to the MacDonald criteria. RESULTS Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1-24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22-30.98) and 30.55 months (95% CI, 12.85-52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome. CONCLUSION TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma.

Treatment of brain metastasis: current status and future directions

Purpose of review The purpose of this review is to highlight the most recent advances in the management of brain metastases. Recent findings Role of local therapies (surgery and stereotactic radiosurgery), new approaches to minimize cognitive sequelae following whole-brain radiotherapy and advances in targeted therapies have been reviewed. Summary The implications for clinical trials and daily practice of the increasing use of stereotactic radiosurgery in multiple brain metastases and upfront targeted agents in asymptomatic brain metastases are discussed.

Molecularly based management of gliomas in clinical practice

Histological subtyping and grading of malignancy are the cornerstone of the present World Health Organization (WHO) Classification of CNS tumors. However, among diffuse gliomas of the adult, patients with histologically identical tumors may have different outcomes. As the genomic analysis of these tumors has progressed, it has become clear that specific molecular features transcend histologically defined variants, and may become markers of prognostic and/or predictive value. At the present time, the number of molecular biomarkers with confirmed clinical relevance (MGMT promoter methylation, 1p/19q codeletion, IDH1/2 mutations) remains limited, but new technologies will hopefully provide new candidates requiring rigorous validation in well-designed clinical trials.

Perspectives of Personalized Chemotherapy of Gliomas Based on Molecular Tumor Profiling

Histopathological typing and grading are the cornerstones of the World Health Organization classification of the central nervous system tumors. It provides clinicians with information on the natural course of the disease and thus guides therapeutic choices. Nonetheless, patients with histologically identical tumors may have different outcomes and response to therapy. In recent years, extensive research has been done on three molecular markers in adult gliomas, namely MGMT promoter methylation, 1p/19q co-deletion, and IDH1/IDH2 mutations. These markers may have either a prognostic or a predictive value, differentiation of which is often difficult as both can coexist. At present, MGMT promoter methylation is considered as a predictive marker for response of glioblastoma to chemotherapy with temozolomide, particularly in elderly patients, 1p/19q co-deletion is a molecular signature of oligodendroglial tumors and predictive marker for response of anaplastic gliomas to PCV chemotherapy, and IDH1/IDH2 mutations have a strong favorable prognostic value across all glioma histopathological grades.

Brain Metastasis as Complication of Systemic Cancers

Brain metastases occur in up to 40% of patients with cancer and their frequency has increased over time. Lung, breast and melanoma are the most common sources of brain metastases, and in 10–15% of patients the primary site remains unknown. Contrast-enhanced MRI is the gold standard for the diagnosis. Subgroups of patients with different prognosis have been identified (RPA and GPA classifications). Symptomatic therapy includes corticosteroids and anticonvulsants. Complete surgical resection allows for relief of intracranial hypertension, seizures and focal neurological deficits. Stereotatic radiosurgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT. WBRT after surgery or radiosurgery is increasingly omitted. The response rate of brain metastases to chemotherapy is similar to the response rate of the primary tumor and extracranial metastases. Targeted agents in specific molecular subgroups are emerging.

Mechanisms and therapy for cancer metastasis to the brain

Advances in chemotherapy and targeted therapies have improved survival in cancer patients with an increase of the incidence of newly diagnosed brain metastases (BMs). Intracranial metastases are symptomatic in 60–70% of patients. Magnetic resonance imaging (MRI) with gadolinium is more sensitive than computed tomography and advanced neuroimaging techniques have been increasingly used in the detection, treatment planning, and follow-up of BM. Apart from the morphological analysis, the most effective tool for characterizing BM is immunohistochemistry. Molecular alterations not always reflect those of the primary tumor. More sophisticated methods of tumor analysis detecting circulating biomarkers in fluids (liquid biopsy), including circulating DNA, circulating tumor cells, and extracellular vesicles, containing tumor DNA and macromolecules (microRNA), have shown promise regarding tumor treatment response and progression. The choice of therapeutic approaches is guided by prognostic scores (Recursive Partitioning Analysis and diagnostic-specific Graded Prognostic Assessment-DS-GPA). The survival benefit of surgical resection seems limited to the subgroup of patients with controlled systemic disease and good performance status. Leptomeningeal disease (LMD) can be a complication, especially in posterior fossa metastases undergoing a “piecemeal” resection. Radiosurgery of the resection cavity may offer comparable survival and local control as postoperative whole-brain radiotherapy (WBRT). WBRT alone is now the treatment of choice only for patients with single or multiple BMs not amenable to surgery or radiosurgery, or with poor prognostic factors. To reduce the neurocognitive sequelae of WBRT intensity modulated radiotherapy with hippocampal sparing, and pharmacological approaches (memantine and donepezil) have been investigated. In the last decade, a multitude of molecular abnormalities have been discovered. Approximately 33% of patients with non-small cell lung cancer (NSCLC) tumors and epidermal growth factor receptor mutations develop BMs, which are targetable with different generations of tyrosine kinase inhibitors (TKIs: gefitinib, erlotinib, afatinib, icotinib, and osimertinib). Other “druggable” alterations seen in up to 5% of NSCLC patients are the rearrangements of the “anaplastic lymphoma kinase” gene TKI (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib). In human epidermal growth factor receptor 2-positive, breast cancer targeted therapies have been widely used (trastuzumab, trastuzumab-emtansine, lapatinib-capecitabine, and neratinib). Novel targeted and immunotherapeutic agents have also revolutionized the systemic management of melanoma (ipilimumab, nivolumab, pembrolizumab, and BRAF inhibitors dabrafenib and vemurafenib).