Early clinical and neuroradiological worsening after radiotherapy and concomitant temozolomide in patients with glioblastoma: Tumour progression or radionecrosis?

Clinical Neurology and Neurosurgery 111 (2009) 331–334

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Early clinical and neuroradiological worsening after radiotherapy and concomitant temozolomide in patients with glioblastoma: Tumour progression or radionecrosis? C. Peca a , R. Pacelli c , A. Elefante b , M.L. Del Basso De Caro d , P. Vergara a , G. Mariniello a , A. Giamundo a , F. Maiuri a,∗ a

Department of Neurological Sciences, Neurosurgical Clinic, University Federico II, Naples, Italy Service of Neuroradiology, University Federico II, Naples, Italy c Department of Diagnostic Imaging, Service of Radiotherapy, University Federico II, Naples, Italy d Department of Biomorphological and Functional Sciences, Service of Pathology, University Federico II, Naples, Italy b

a r t i c l e

i n f o

Article history: Received 5 June 2008 Received in revised form 17 September 2008 Accepted 7 November 2008 Keywords: Glioblastoma Temozolomide Radionecrosis Recurrence

a b s t r a c t Objectives: This study investigates the diagnosis and management of patients with resected brain glioblastomas who presented early clinical and neuroradiological worsening after the completion of the Stupp protocol. Its aim is to discuss the occurrence of early radionecrosis. Methods: Fifty patients with brain glioblastoma treated by surgical resection and Stupp protocol were reviewed; 15 among them (30%) had early clinical and neuroradiological worsening at the 6-month follow-up. The MR spectroscopy and surgical findings of these patients are reviewed. Results: MR spectroscopy was in favour of tumour recurrence in 14 among 15 patients and showed radionecrosis in one. Among 10 patients who were reoperated on, 7 had histologically verified tumour recurrence or regrowth, whereas in 3 histopathology showed necrosis without evidence of tumour. The 7 patients with tumour progression had prevalence of focal neuroradiological signs (6/7) and a survival of 7.5–12 months (median survival 10 months). The 4 patients with early radionecrosis (including one patient who was not reoperated on) had clinical worsening with mental deterioration, confusion and ataxia, and MR spectroscopy positive for tumour recurrence in 3. Three were alive 24–30 months after the end of the radiotherapy, whereas one died at 40 months. Conclusion: Early radionecrosis after the Stupp protocol is not a rare event due to the radiosensitization effect of temozolomide. This phenomenon may predict a durable response to radiotherapy. MR spectroscopy may simulate tumour recurrence. A correct diagnosis is necessary to avoid useless reoperations and incorrect withdrawal of temozolomide. © 2008 Published by Elsevier B.V.

1. Introduction Radiation therapy for brain tumour may often result in several episodes of acute and chronic damage. The acute effects are related to oedema and necrosis [1]. A literature review [2] concluded that up to 27% of all patients receiving therapeutic cranial irradiation experienced some neurotoxicity, nearly half of them as dementia. The long-term effects of irradiation may involve several brain functions, especially intellect, visual deterioration and hypothalamic functions [3–5].

∗ Corresponding author at: Cattedra di Neurochirurgia Università Federico II, Via Pansini 5, 80131 Napoli, Italy. Tel.: +39 0817462581; fax: +39 0817462488. E-mail address: [email protected] (F. Maiuri). 0303-8467/$ – see front matter © 2008 Published by Elsevier B.V. doi:10.1016/j.clineuro.2008.11.003

Three distinct periods of radiation effect may be identified [3,5]: acute (during the radiation itself), early delayed (at around 1.5 months after radiation), and late delayed (between 4.7 and 7.6 months and for more than 2 years). More simply, radiation-induced effects are considered late effects if they occur after 90 days from the first day of radiotherapy. The actual standard protocol of treatment for patients with glioblastoma, as stated by the preliminary report of Stupp et al. [6] and the randomized European and Canadian trials [7], consists in radiotherapy and concomitant and adjuvant temozolomide. These studies have reported an improvement in median survival (14.6 months vs 12 months) and in the 2-year survival (27% vs 10%) with respect to patients not receiving temozolomide. However, a significant rate of patients treated according to this regimen shows early clinical and neuroradiological worsening shortly after the completion of radiotherapy. This group of patients

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Table 1 Summary of features of 4 GBM patients with early radionecrosis. N. of cases

Age, sex

Location

Surgical resection

Adjuvant therapy

Clinical symptoms after radiotherapy

MR spectroscopy

Reoperation

Histology

Outcome

1

72, M

R. temporal

Complete

Stupp protocol

Recurrence

Multiple biopsies

Radionecrosis

Alive 29 mo

2

28, F

R. frontoparietal

Partial

Stupp protocol

Recurrence

Partial removal

Radionecrosis

Dead 40 mo

3 4

64, F 68, F

L. frontal R. frontal

Subtotal Complete

Stupp protocol Stupp protocol

Mental deterioration, ataxia L. hemiparesis, confusion Ataxia, paraparesis Ataxia, confusion

Recurrence Radionecrosis

Partial removal –

Radionecrosis –

Alive 30 mo Alive 24 mo

is the object of the present study, because of the possible different diagnostic and therapeutic implications. 2. Patients and methods Fifty patients with glioblastoma, operated on at the Neurosurgical Clinic of the University Federico II of Naples between January 2004 and December 2006, were treated according to the Stupp protocol. Temozolomide was administered with conventional external beam therapy for 42 consecutive days (75 mg/(m2 day)) beginning with the first day of radiation. Radiotherapy was administered for a total dose of 60 Gy in 30 fractions (2 Gy per fraction). Temozolomide was administered for 5 days every 28 days at a dose of 200 mg/(m2 day) for at least six cycles. MRI was performed 4 weeks after the end of radiotherapy, and later at 6, 9 and 12 months. The actual follow-up ranges from 16 to 50 months.

b. The seven patients with early tumour recurrence or regrowth and histological verification were 4 males and 3 females (median age 50 years). Six among them had focal neurological signs at tumour recurrence, with confusion in 3. MR spectroscopy was positive for tumour recurrence in all cases. All patients underwent partial or subtotal removal, with histological verification of glioblastoma. The survival time ranged from 7.5 to 12 months (median survival 10 months).

3. Results Fifteen among 50 patients (30%) had clinical and radiological worsening at the 6-month follow-up. Magnetic Resonance (MR) spectroscopy was in favour of tumour recurrence in 14 among the 15 patients (increase of choline peak and decrease of Nacetylaspartate), whereas it showed radionecrosis in 1. Ten patients were reoperated on 10–12 months after the initial surgery; among them, 7 had tumour recurrence confirmed by histological examination; in 3 other patients histopathology was interpreted as necrosis without the evidence of tumour. Five other patients (where MR spectroscopy suggested tumour recurrence in 4 and radionecrosis in 1) were not reoperated on. The clinical findings and outcome of the two groups (tumour recurrence and radionecrosis) were as follows: a. The 4 patients with early radionecrosis (Table 1) (3 females and 1 male with an age range from 28 to 72 years, average 58 years) underwent seemingly complete (two cases) or subtotal (two cases) tumour resection at the first surgery. Clinical worsening after the radio-chemotherapy consisted in mental deterioration, confusion and ataxia, with recurrent focal deficit in 1. MR spectroscopy was in favour of tumour recurrence in three of the four cases (Figs. 1 and 2). The surgical findings and the management at reoperation in these 2 patients were as follows. In case 1 no evident tumour regrowth was found in the previous surgical bed; four biopsies (∼2–3 mm) were performed in different points of the tumour bed. Because intraoperative histology was negative for tumour, no further resection was performed. In cases 2 and 3, where a recurrent mass was found, a subtotal resection was performed (judged as 60% and 90%, respectively). In all three patients the regions of tissue resected or biopsied corresponded to the regions studied preoperatively by MR spectroscopy. Histological examination was in favour of radionecrosis; it did not evidence tumour cells in these three surgical specimens. At the actual follow-up, 3 patients are alive 24–30 months after the end of radiotherapy, whereas 1 died at 40 months.

Fig. 1. Case 1: MR spectroscopy suggesting recurrence of a right temporal glioblastoma (histological diagnosis:radionecrosis).

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4. Discussion

Fig. 2. Case 2: MR spectroscopy suggesting recurrence of a right fronto-parietal glioblastoma (histological diagnosis:radionecrosis).

Radionecrosis is a well-known effect of radiotherapy for malignant brain tumours. Before the introduction of the Stupp protocol, the incidence of radionecrosis in patients with glioblastoma after conventional external radiotherapy with doses of approximately 60 Gy was about 1% [8]; besides, the mean interval of appearance of necrosis in these patients was 12 months. In this series of patients with glioblastoma submitted to radiochemotherapy according to the Stupp protocol we have found an 8% incidence of radionecrosis (4 among 50 patients) and a mean interval of 6 months after the end of radiotherapy. Although our series is small, patients with early radionecrosis had the prevalence of nonfocal signs, such as confusion and ataxia, versus focal neurological signs. Early clinical and neuroradiological worsening after radiotherapy in malignant glioma, followed by improvement without surgical operation and other tumour-directed treatments, has been initially reported in an observation by de Wit et al. [9]. More recently, Chamberlain [10] found histologically verified radionecrosis in 7 among 15 patients reoperated upon for suspected early tumour recurrence in a series of 51 patients with glioblastoma treated according to the Stupp protocol (13.7%). Our experience is rather similar. In 3 patients with reappearance of clinical symptoms, good Karnofsky performance status (70%), enlargement of tumour image at MRI and MR spectroscopy in favour of tumour recurrence, the reoperation was considered appropriate; however, only radionecrosis was found histologically. The finding of MR spectroscopy positive for tumour recurrence in 3 among 4 patients with early radionecrosis is difficult to explain. Transient increase in choline and decrease in N-acetylaspartate have been reported after radiotherapy especially in areas exposed to lower doses [11,12]. Therefore, the results of MR spectroscopy should be interpreted on subsequent examinations. Other MR techniques, such as diffusion tensor imaging, may be more useful for differentiating radionecrosis versus tumour recurrence [13]. The etiology of early radionecrosis in patients with glioblastoma treated by the Stupp protocol is likely the radiosensitization effect of temozolomide [10,14]. An experimental study on glioblastoma cells [15] has shown that the cell line with a low level of O6-alkylguanine-DNA alkyltransferase (O6-AGT) and sensitivity to temozolomide had an additive growth inhibition (between 2- and 3-folds) after a single radiation exposure with respect to the more resistant cell line with high level of O6-AGT. Enhanced cytotoxicity, increased inhibition of glioblastoma cell growth and cell cycle arrest by combining temozolomide and radiation in vitro have been confirmed by experimental studies [16,17]. Several clinical studies have confirmed that temozolomide enhances radiation treatment efficacy both in malignant gliomas [7,10,18] and in brain metastases [19–21]. The finding of early necrosis in this study confirms the significant chemo-radiosensitization effect in patients treated with concomitant temozolomide and radiotherapy. The prognostic significance of early radionecrosis after Stupp protocol deserves some considerations. We agree that this phenomenon represents a favourable event that may predict a durable response. We have found in our series a median survival of 32 months in patients with radionecrosis versus 10 months in those with tumour progression. Thus, patients who develop radionecrosis seem to have glioblastomas more responsive to chemo-radiotherapy. Several implications in the patient management may arise from the occurrence of early radionecrosis after Stupp protocol. The neuroradiological progression with MR spectroscopy suggest-

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ing tumour recurrence advises an aggressive surgical approach. It carries the risk of a useless reoperation for patients with nontumoural lesions which resolve or improve only by observation, independently from new therapies (second surgery, second line chemotherapy). In doubtful cases a control MR after several weeks may clarify the diagnosis (no significant changes in patients with radionecrosis and enlargement of the enhancing mass in those with recurrence). Another therapeutic pitfall may be the inopportune suspension of temozolomide if these patients are considered early treatment failures and a tumour progression is erroneously suspected. We advise them to continue adjuvant temozolomide unless tumour progression is certainly established. 5. Conclusions Early clinical and neuroradiological worsening after radiotherapy and concomitant temozolomide according to the Stupp protocol may be due to radionecrosis. This phenomenon may predict a good and durable response to the radio- and chemotherapy, with a more prolonged survival. Further studies on a larger GBM population are required to better define this phenomenon. References [1] Watne K, Hager B, Heier M, Hirschberg H. Reversible oedema and necrosis after irradiation of the brain. Diagnostic procedures and clinical manifestations. Acta Oncol 1990;29:891–5. [2] Crossen JR, Garwood D, Glatstein E, Neuwelt EA. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 1994;12:627–42. [3] Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 1980;6:1215–28. [4] Al-Mefty O, Kersh JE, Routh A, Smith RR. The long-term side effects of radiation therapy for benign brain tumors in adults. J Neurosurg 1990;73:502–12. [5] Rottenberg D. Acute and chronic effects of radiation therapy on the nervous system. In: Rottenberg D, editor. Neurological Complications of Cancer Treatment. Boston: Butterworth-Heineman; 1991. pp. 3–18.

[6] Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, et al. Promising survival for patients with newly diagnosed glioblastoma multiform treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 2002;20:1375–82. [7] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96. [8] DeAngelis LM. Brain tumors. N Engl J Med 2001;344:114–23. [9] de Wit MC, de Bruin HG, Eijkenboom W, Sillevis Smitt PA, van den Bent MJ. Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 2004;63:535–7. [10] Chamberlain MC. Treatment options for glioblastoma. Neurosurg Focus 2006; 20:E2. [11] Esteve F, Rubin C, Grand S, Kolodie H, Le Bas JF. Transient metabolic changes observed with proton MR spectroscopy in normal human brain after radiation therapy. Int J Radiat Oncol Biol Phys 1998;40:279–86. [12] Nelson SJ, Graves E, Pirzkall A, Li X, Antiniw Chan A, Vigneron DB, et al. In vivo molecular imaging for planning radiation therapy of gliomas: an application of 1H MRSI. J Magn Reson Imaging 2002;16:464–76. [13] Kashimura H, Inoue T, Beppu T, Ogasawara K, Ogawa A. Diffusion tensor imaging for differentiation of recurrent brain tumor and radiation necrosis after radiotherapy—three case reports. Clin Neurol Neurosurg 2007;109:106–10. [14] Cross NE, Glantz MJ. Neurologic complications of radiation therapy. Neurol Clin 2003;21:249–77. [15] Wedge SR, Porteous JK, Glaser MG, Marcus K, Newlands ES. In vitro evaluation of temozolomide combined with X-irradiation. Anticancer Drugs 1997;8:92–7. [16] van Rijn J, Heimans JJ, van den Berg J, van der Valk P, Slotman BJ. Survival of human glioma cells treated with various combination of temozolomide and X-rays. Int J Radiat Oncol Biol Phys 2000;47:779–84. [17] Hirose Y, Berger MS, Pieper RO. p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res 2001;61:1957–63. [18] Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 2004;10:1871–4. [19] Antonadou D, Paraskevaidis M, Sarris G, Coliarakis N, Economou I, Karageorgis P, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 2002;20:3644–50. [20] Antonadou D. Temozolomide enhances radiation treatment efficacy in brain metastases: a randomized phase II study. In: 92th Annual Meeting of the American Association for Cancer Research. 2001. [21] Verger E, Gil M, Yaya R, Vinolas N, Villa S, Pujol T, et al. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat Oncol Biol Phys 2005;61:185–91.