http://oncology.thelancet.com Vol 9 May 2008 453 Review Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas Dieta Brandsma, Lukas Stalpers, Walter Taal, Peter Sminia, Martin J van den Bent Since the introduction of chemoradiotherapy with temozolomide as the new standard of care for patients with glioblastoma, there has been an increasing awareness of progressive and enhancing lesions on MRI, noted immediately after the end of treatment, which are not related to tumour progression, but which are a treatment effect. This so-called pseudoprogression can occur in up to 20% of patients who have been treated with temozolomide chemoradiotherapy, and can explain about half of all cases of increasing lesions after the end of this treatment. These lesions decrease in size or stabilise without additional treatments and often remain clinically asymptomatic. Additionally, there is evidence that treatment-related necrosis occurs more frequently and earlier after temozolomide chemotherapy than after radiotherapy alone. The mechanisms behind these events have not yet been fully elucidated, but the likelihood is that chemoradiotherapy causes a higher degree of (desired) tumour-cell and endothelial-cell killing. This increased cell kill might lead to secondary reactions, such as oedema and abnormal vessel permeability in the tumour area, mimicking tumour progression, in addition to subsequent early treatment-related necrosis in some patients and milder subacute radiotherapy reactions in others. In patients managed with temozolomide chemoradiotherapy who have clinically asymptomatic progressive lesions at the end of treatment, adjuvant temozolomide should be continued; in clinically symptomatic patients, surgery should be considered. If mainly necrosis is noted during surgery, continuation of adjuvant temozolomide is logical. Trials on the treatment of recurrent malignant glioma should exclude patients with progression within the first 3 months after temozolomide chemoradiotherapy unless histological confirmation of tumour recurrence is available. Further research is needed to establish reliable imaging parameters that distinguish between true tumour progression and pseudoprogression or treatment-related necrosis. Introduction Since randomised trials in the 1970s showed a survival benefit for postoperative 60-Gy whole-brain radiotherapy (WBRT), radiotherapy has been the cornerstone in the management of high-grade gliomas. 1 The introduction of the CT scan in the 1980s and MRI in the 1990s improved tumour delineation and consequently radiotherapy precision. This precision has allowed the use of involved- field radiotherapy for glioma, during which only the tumour area and a 2–3-cm margin (involved fields) are irradiated (figure 1). This technique has resulted in a decrease of radiotherapy-induced neurotoxicity in patients with glioma. 2 Unfortunately, attempts to further improve survival by increasing the radiation dose or by alternative (ie, hyperfractionated and hypofractionated) radiotherapy schedules have failed. 3 By contrast, the addition of concurrent and adjuvant temozolomide to radiotherapy has been shown to further improve survival of newly diagnosed patients with glioblastoma. 4 Now- adays, chemoradiotherapy with temozolomide is the standard of care for patients with glioblastoma and is routinely followed by MR scans to monitor treatment outcome. This monitoring has led to an increased awareness that many patients with progressive lesions shortly after treatment, with or without progressive clinical signs and symptoms, do not suffer from tumour recurrence (figure 2). An early study 5 noted that patients with malignant glioma had an increase in the size of contrast-enhancing lesions, or new areas with contrast enhancement, immediately after radiotherapy, with subsequent improvement without any further treatment. This occurrence, which mimics tumour progression, has been labelled pseudoprogression. Moreover, a high incidence of radionecrosis (ie, treatment-related necrosis) has been noted in patients who underwent surgery for progressive brain lesions within the first 6 months after combined chemoradiotherapy with temozolomide. 6 Both findings Lancet Oncol 2008; 9: 453–61 Department of Neuro- oncology, Daniel den Hoed Cancer Centre, Erasmus Medical Centre, Rotterdam, Netherlands (D Brandsma MD, W Taal MD, Prof M J van den Bent MD); Department of Neuro- oncology, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D Brandsma); Department of Radiotherapy, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands (L Stalpers MD); and Department of Radiotherapy, VU University Medical Centre, Amsterdam, Netherlands (P Sminia PhD) Correspondence to: Prof M J van den Bent, Department of Neuro-Oncology, Daniel den Hoed Cancer Centre, 3008AE Rotterdam, Netherlands m.vandenbent@erasmusmc.nl Figure 1: Radiotherapy planning and radiation fields in a patient with glioma T2-weighted MRI of a low-grade glioma (left) and isodose distribution after radiotherapy planning with three beams (right). Yellow line=gross target volume (ie, area with abnormal signal intensity on T2-weighted MRI). Blue line=gross clinical target volume (ie, T2 abnormal area plus 1·5 cm margin to cover microscopic disease). Red line=planning target volume (to control for changes in patient position). The dark red area receives 100% of the prescribed dose.