BACKGROUND.: Radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ) is now the standard of care for patients with newly diagnosed glioblastoma. The occurrence of pseudo‐progression directly after RT is a recognized phenomenon, but to the authors' knowledge its incidence after combined RT/TMZ is unknown. The occurrence of early pseudo‐progression was retrospectively assessed in a cohort of malignant glioma patients treated with RT/TMZ.METHODS.: The pre‐RT and post‐RT brain scans from patients treated with RT/TMZ for a malignant glioma were reviewed. Scans were made before the start of RT, 4 weeks after the end of RT, and every 3 months thereafter. In addition, information was collected regarding clinical signs and symptoms, dexamethasone dose, histology, and survival.RESULTS.: Eighty‐five patients were identified. In 36 patients (42%) the first follow‐up scan 4 weeks after the end of RT indicated disease progression. Of these 36 patients, 18 (50%) were diagnosed with pseudo‐progression. None of the patients received additional treatment other than TMZ. Six of 18 patients with pseudo‐progression and 12 of the 18 patients with real tumor progression developed new clinical signs and symptoms during RT or in the first 4 weeks thereafter.CONCLUSIONS.: Up to 50% of malignant glioma patients treated with RT/TMZ and progression immediately after RT develop pseudo‐progression. The current study data support the idea to continue TMZ in the case of progressive lesions immediately after RT/TMZ. Surgery should be considered in symptomatic cases. The inclusion of patients with progressive lesions developing directly after chemoradiation in studies regarding recurrent gliomas will lead to an overestimation of the results. Cancer 2008. © 2008 American Cancer Society.

The treatment of glial brain tumors begins with surgery, and standard adjuvant treatment at the end of the past millennium for high-grade glioma and high-risk low-grade glioma was radiotherapy and chemotherapy was given at recurrence. However, over the past 10 years much has changed regarding the role of chemotherapy in gliomas and it is now clear that chemotherapy has a role in the treatment of almost all newly diagnosed diffuse gliomas (WHO grade II-IV). This is the result of several prospective studies that showed survival benefit after combined chemoradiotherapy with temozolomide in glioblastoma (WHO grade IV) or after procarbazine, CCNU (lomustine) and vincristine chemotherapy in diffuse low-grade (WHO grade II) and anaplastic (WHO grade III) glioma. The current standard of treatment for diffuse gliomas is described in this overview and in addition some attention is given to targeted therapies.

Purpose: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61–1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.

Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1-5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.

Background. As the incidence of pseudo-progressive disease (psPD), or pseudoprogression, in low-grade glioma (LGG) is unknown, we retrospectively investigated this phenomenon in a cohort of LGG patients given radiotherapy (RT). Methods. All MRI scans and clinical data from patients with histologically proven LGG treated with radiation between 2000 and 2011 were reviewed. PsPD was scored when a new enhancing lesion occurred after RT and subsequently disappeared or remained stable for at least a year without therapy, including dexamethasone. Results. Sixty-three out of 71 patients who received RT for LGG were deemed eligible for evaluation of psPD. The median follow-up was 5 years (range 1‒10 y). PsPD was seen in 13 patients (20.6%). PsPD occurred after a median of 12 months with a range of 3–78 months. The median duration of psPD was 6 months, with a range of 2–26 months and always occurred within the RT high dose fields of at least 45 Gy. The area of the enhancement at the time of psPD was significantly smaller compared with the area of enhancement during “true” progression (median size 54mm² [range 12–340mm²] vs 270mm² [range 30–3420mm²], respectively; P = .009). Conclusions. PsPD occurs frequently in LGG patients receiving RT. This supports the policy to postpone a new line of treatment until progression is evident, especially when patients have small contrast enhancing lesions within the RT field. Importance of the Study The phenomenon of progressive enhancing MRI lesions in high-grade gliomas (HGGs) after chemoradiation with spontaneous improvement was termed pseudoprogression (psPD). PsPD and its incidence in HGG are now firmly established. As little is known about (the incidence of) psPD in LGG, we investigated this in a cohort of 71 LGG patients receiving a relatively low dose of RT (median 50.4 Gy) and found a remarkably high incidence of psPD in 20.6% of these patients. The area of the enhancement at the time of psPD was significantly smaller compared with the area of enhancement during “true” progression and notably almost 50% of the psPD enhancing lesions were located subependymally in the ventricular wall. We therefore propose not to change the therapeutic strategy in LGG patients after RT in case of an asymptomatic small (bidirectional diameter <10mm) enhancing lesion within the RT field, especially when this lesion is located subependymally.