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Discerning between primary brain tumor progression and treatment-related effect is a significant issue and a major challenge in neuro-oncology. The difficulty in differentiating tumor progression from treatment-related effects has important implications for treatment decisions and prognosis, as well as for clinical trial design and results. Conventional MRI is widely used to assess disease status, but cannot reliably distinguish between tumor progression and treatment-related effects. Several advanced imaging techniques are promising, but have yet to be prospectively validated for this use. This review explores two treatment-related effects, pseudoprogression and radiation necrosis, as well as the concept of pseudoresponse, and highlights several advanced imaging modalities and the evidence supporting their use in differentiating tumor progression from treatment-related effect.

Treatment of brain tumors is increasingly informed by biomarkers that predict patient prognosis and response to therapy. While this progress represents a great opportunity for the field of neuro-oncology, it also presents significant challenges. Biomarkers are not straightforward to identify, and previously used clinical trial paradigms are poorly suited to the task of identifying treatments effective only in selected subsets of patients. Unless investigators adapt new tools and procedures that better account for the biological diversity of gliomas, future clinical trials run the dual risk of missing important treatment effects and exposing patients to interventions destined to prove ineffective for their tumors. In this article, we will review the progress made in the past decade with respect to biomarkers in neuro-oncology, address barriers to ongoing progress, and discuss clinical trial designs that may prove useful in moving neuro-oncology fully into the era of personalized medicine.

Imaging has become a central part of the evaluation of lesions of the central nervous system. Despite patterns of the appearances of several types of central nervous system malignancies and improving resolution of imaging techniques, there are other processes that can display similar characteristics. Time and again, vascular, inflammatory, and vascular lesions will mimic a neoplastic process, requiring tissue diagnosis. With the introduction of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging in the evaluation of the brain tumor, there has been improvement in determining whether a lesion is neoplastic, and further advances may lead to noninvasive pathological and molecular diagnoses.

Primary brain tumors and their treatment are associated with a significant impact on function and quality of life (QOL). Patient-reported outcomes (PROs) are measures that allow report of the impact directly from the patient. Instruments to measure both QOL and symptom burden have been developed for use in the primary brain tumor patient population. Use of these instruments coupled with tumor response assessment and other objective measures will allow for evaluation of the net clinical benefit for the patient.

Anaplastic oligodendrogliomas are rare primary brain tumors. However, they respond more effectively to treatment and have a better prognosis than commoner varieties. About 25 year ago, reports emerged that oligodendrogliomas can respond robustly and durably to chemotherapy with procarbazine, lomustine (CCNU), and vincristine (PCV). It was also discovered that co-deletion of chromosome arms 1p and 19q is more commonly observed in oligodendrogliomas (rather than astrocytomas). Early results of phase III trials confirmed that 1p/19q co-deletion was a favorable prognostic marker. Mature results now conclusively demonstrate that co-deletion also predicts longer survival from the addition of PCV chemotherapy to radiotherapy for newly diagnosed disease. However, changes in the treatment landscape, including a preference for deferred radiotherapy, the emergence of temozolomide as a better tolerated chemotherapy regimen, and the discovery of other biomarkers (e.g. IDH mutation and MGMT promoter methylation) that occurred in the interim emphasize the need for earlier, validated, and acceptable trial end points.

The treatment for most patients with primary brain tumors remains inadequate. Despite an overwhelming increase in our knowledge of the molecular and genomic changes in these cancers, translation of these findings to effective therapies remains the exception. As evidenced by the series of articles in this issue, the incorporation of molecular signatures and patient-reported outcome measures into clinical trials is becoming increasingly successful. These efforts recently yielded a treatment-determining predictive marker, but challenges remain in optimizing marker-based patient selection and systematic implementation of patient-reported outcomes to maximize the risk-to-benefit assessment, thereby achieving individualized treatment.

Histopathologic classification has been widely used to type and grade primary brain tumors. However, the diverse behavior of primary brain tumors has made prognostic determinations based purely on clinical and histopathologic variables difficult. Recent advances in the molecular genetics of brain tumors have helped to explain the witnessed heterogeneity regarding response to treatment, time to progression, and overall survival. Additionally, there has been interest in identifying predictive factors to help direct patients to therapeutic interventions specific to their tumor and patient biology. Further identification of both prognostic and predictive biomarkers will make possible better patient stratification and individualization of treatment.