This review describes the definition, incidence, clinical implications, and magnetic resonance imaging (MRI) findings of pseudoprogression of brain tumors, in particular, but not limited to, high‐grade glioma. Pseudoprogression is an important clinical problem after brain tumor treatment, interfering not only with day‐to‐day patient care but also the execution and interpretation of clinical trials. Radiologically, pseudoprogression is defined as a new or enlarging area(s) of contrast agent enhancement, in the absence of true tumor growth, which subsides or stabilizes without a change in therapy. The clinical definitions of pseudoprogression have been quite variable, which may explain some of the differences in reported incidences, which range from 9–30%. Conventional structural MRI is insufficient for distinguishing pseudoprogression from true progressive disease, and advanced imaging is needed to obtain higher levels of diagnostic certainty. Perfusion MRI is the most widely used imaging technique to diagnose pseudoprogression and has high reported diagnostic accuracy. Diagnostic performance of MR spectroscopy (MRS) appears to be somewhat higher, but MRS is less suitable for the routine and universal application in brain tumor follow‐up. The combination of MRS and diffusion‐weighted imaging and/or perfusion MRI seems to be particularly powerful, with diagnostic accuracy reaching up to or even greater than 90%. While diagnostic performance can be high with appropriate implementation and interpretation, even a combination of techniques, however, does not provide 100% accuracy. It should also be noted that most studies to date are small, heterogeneous, and retrospective in nature. Future improvements in diagnostic accuracy can be expected with harmonization of acquisition and postprocessing, quantitative MRI and computer‐aided diagnostic technology, and meticulous evaluation with clinical and pathological data.

Level of Evidence: 3

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2018;48:571–589.

/pdf/pseudoprogression-of-brain-tumors-2cl4gg3hf2.pdf

Pseudoprogression of brain tumors

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients.

/pdf/recurrent-glioblastoma-from-molecular-landscape-to-new-4sgyigvh61.pdf

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives.

Immunotherapy has achieved unprecedented clinical efficacy in patients with various types of advanced tumors; however, some patients experience delayed tumor shrinkage following an increase in tumor burden after such a therapeutic method. This phenomenon is called pseudoprogression and can lead to premature cessation of efficacious immunotherapeutic agents. Consequently, we summarized the available data on methods to differentiate pseudoprogression from true progression in patients who have been treated with immunotherapy including biomarkers, medical imaging techniques and biopsy. We also introduce hyperprogression and special pseudoprogression for improved evaluation of immunotherapy.

How to differentiate pseudoprogression from true progression in cancer patients treated with immunotherapy.

There are currently seven approved immune checkpoint inhibitors (ICIs) for the treatment of various cancers. These drugs are associated with profound, durable responses in a subset of patients with advanced cancers. Unfortunately, in addition to individuals whose tumors show resistance, there is a minority subgroup treated with ICIs who demonstrate a paradoxical acceleration in the rate of growth or their tumors-hyperprogressive disease. Hyperprogressive disease is associated with significantly worse outcomes in these patients. This phenomenon, though still a matter of dispute, has been recognized by multiple groups of investigators across the globe and in diverse types of cancers. There are not yet consensus standardized criteria for defining hyperprogressive disease, but most commonly time to treatment failure less than 2 months and an increase in pace of progression of at least twofold between pre-immunotherapy and on-treatment imaging has been used. In some patients, the change in rate of progression can be especially dramatic-up to 35- to 40-fold. MDM2 amplification and EGFR mutations have been suggested as genomic correlates of increased risk of hyperprogression, but these correlates require validation. The underlying mechanism for hyperprogression is not known but warrants urgent investigation.

/pdf/hyperprogression-and-immune-checkpoint-inhibitors-hype-or-4ubzv9wfg1.pdf

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

The imaging of primary and metastatic brain tumours is very complex and relies heavily on advanced magnetic resonance imaging (MRI). Utilisation of these advanced imaging techniques is essential in helping clinicians determine tumour response after initiation of treatment. Many options are currently available to treat brain tumours, and each can significantly alter the brain tumour appearance on post-treatment imaging. In addition, there are several common and uncommon treatment-related complications that are important to identify on standard post-treatment imaging. This article provides a review of the various post-treatment-related imaging appearances of brain neoplasms, including a discussion of advanced MR imaging techniques available and treatment response criteria most commonly used in clinical practice. This article also provides a review of the multitude of treatment-related complications that can be identified on routine post-treatment imaging, with an emphasis on radiation-induced, chemotherapy-induced, and post-surgical entities. Although radiological evaluation of brain tumours after treatment can be quite challenging, knowledge of the various imaging techniques available can help the radiologist distinguish treatment response from tumour progression and has the potential to save patients from inappropriate alterations in treatment. In addition, knowledge of common post-treatment-related complications that can be identified on imaging can help the radiologist play a key role in preventing significant patient morbidity/mortality. • Contrast enhancement does not reliably define tumour extent in many low-grade or infiltrative gliomas. • Focal regions of elevated cerebral blood volume (rCBV) on dynamic susceptibility contrast (DSC) perfusion-weighted imaging are suggestive of tumour growth/recurrence. • Brain tumour treatment response criteria rely on both imaging and clinical parameters. • Chemotherapeutic agents can potentiate many forms of radiation-induced injury. • Ipilimumab-induced hypophysitis results in transient diffuse enlargement of the pituitary gland.

/pdf/brain-tumour-post-treatment-imaging-and-treatment-related-5bcrig8rpt.pdf

Brain tumour post-treatment imaging and treatment-related complications

We explored predictive factors of pseudoprogression (PsP) and its impact on prognosis in a retrospective series of uniformly treated glioblastoma patients. Patients were classified as having PsP, early progression (eP) or neither (nP). We examined potential associations with clinical, molecular, and basal imaging characteristics and compared overall survival (OS), progression-free survival (PFS), post-progression survival (PPS) as well as the relationship between PFS and PPS in the three groups. Of the 256 patients studied, 56 (21.9%) were classified as PsP, 70 (27.3%) as eP, and 130 (50.8%) as nP. Only MGMT methylation status was associated to PsP. MGMT methylated patients had a 3.5-fold greater possibility of having PsP than eP (OR: 3.48; 95% CI: 1.606–7.564; P = 0.002). OS was longer for PsP than eP patients (18.9 vs. 12.3 months; P = 0.0001) but was similar for PsP and nP patients (P = 0.91). OS was shorter–though not significantly so—for PsP than nP patients (OS: 19.5 vs. 27.9 months; P = 0.63) in methylated patients. PPS was similar for patients having PsP, eP or nP (PPS: 7.2 vs. 5.4 vs. 6.7; P = 0.43). Neurological deterioration occurred in 64.3% of cases at the time they were classified as PsP and in 72.8% of cases of eP (P = 0.14). PsP confounds the evaluation of disease and does not confer a survival advantage in glioblastoma.

/pdf/pseudoprogression-as-an-adverse-event-of-glioblastoma-18yfpxshhr.pdf

Pseudoprogression as an adverse event of glioblastoma therapy

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Pseudoprogression as an adverse event of glioblastoma therapy