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Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: Efficacy and toxicity
Clinical Neurology and Neurosurgery 114 (2012) 1222–1225
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: Efficacy and toxicity Petra Miglierini a,∗ , Mohamed Bouchekoua a , Benoit Rousseau b , Phong Dam Hieu b,c , Jean-Pierre Malhaire a , Olivier Pradier a a
Department of Radiotherapy, Institute of Oncology and Haematology, University Hospital Morvan, 2 Avenue Foch, 29 200 Brest, France Department of Neurosurgery, University Hospital, Brest, France c Research group EA 4586 LNB, Brest, France b
a r t i c l e
i n f o
Article history: Received 4 April 2011 Received in revised form 24 January 2012 Accepted 29 February 2012 Available online 31 March 2012 Keywords: Gliadel wafers Glioblastoma multiforme Temozolomide Radiotherapy Toxicity Survival
a b s t r a c t Purpose: For the last few years wafers of Gliadel have been inserted into the operation cavity in patients with glioblastoma multiforme. This is followed by concurrent radio-chemotherapy with temozolomide (TMZ) according to the Stupp protocol. Only a few studies have investigated this kind of treatment regimen and the impact in terms of survival and toxicity of the combination of Gliadel with TMZ and radiotherapy. Methods and materials: From November 2006 to January 2010, 24 patients with a newly diagnosed glioblastoma have undergone a tumour resection which was considered to be macroscopically complete in 12 cases and with tumour residue in another 12 cases. The mean age at the moment of diagnosis was 60.25 years and the median age 63. Twenty-three patients underwent subsequently concurrent radio-chemotherapy with TMZ followed by cycles of elevated doses of TMZ as an adjuvant treatment. One patient had adjuvant radiotherapy alone followed by adjuvant chemotherapy. Thirteen were able to receive 6 or more cycles of adjuvant TMZ. Seven patients had received less than 6 cycles of TMZ as an adjuvant therapy. Two patients did not receive adjuvant TMZ at all. Results: The median overall survival of our group was 19.2 months and the median progression free survival was 12.3 months. Overall survival for the macroscopically complete-resection patients was 14 months, and 12.85 months in subtotal-resection patients. The median OS was 14.25 months for patients PS 0 – 1 at the moment of diagnosis and 12.65 for PS 2 patients. Chemotherapy with TMZ had to be stopped prematurely in 10 cases due to haematotoxicity, digestive toxicity or early relapse. Conclusions: The concomitant use of surgery with implantation of BCNU wafers and radio-chemotherapy seems to be well tolerated. Despite the small number of patients treated in our group, particular attention should be paid to the potential haematological consequences of this multimodal treatment regimen. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Glioblastoma multiforme is the most frequent primary cerebral disease in adults [1]. Despite the progress in such disciplines like surgery, radiotherapy and chemotherapy, overall survival rates remain generally less than 2 years following diagnosis. The present and standard treatment consists in the largest possible surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ, Temodal) followed by 6 cycles of TMZ alone, according to the Stupp protocol [2]. Since 1998, the
∗ Corresponding author. Tel.: +33 2 98 22 33 98; fax: +33 2 98 22 30 87. E-mail address: [email protected] (P. Miglierini). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2012.02.056
implantation of biodegradable carmustine wafers as a local chemotherapy into the tumour resection cavity in recurrent malignant glioblastomas has been performed in various French centres. According to the 1995 study of Brem [3] the overall survival in patients with intraoperatively placed BCNU wafers for recurrent glioblastomas was 31 weeks compared with 23 weeks in the placebo group. Each implant of GLIADEL (wafer) contains 7.7 mg of carmustine [1,3-bis (2-chloroethyl)-1-nitroso-urea] integrated into a biodegradable copolymer. It delivers carmustine directly to the cavity formed after the tumour resection. More than 70% of the copolymer is degraded within three weeks. Since 2005, in France, the indication of Gliadel implantation was also extended to the adjuvant treatment, together with surgery and radiotherapy in patients with newly diagnosed malignant gliomas.
P. Miglierini et al. / Clinical Neurology and Neurosurgery 114 (2012) 1222–1225
In the study by Westphal et al. [4,5], the use of Gliadel Implants was found to significantly increase the median survival of patients with malignant gliomas (p = 0.03). In patients treated with BCNU wafers the median survival was 13.8 months compared to 11.6 months in the placebo-group patients. The estimated advantage of this combination therapy is to try to overlap the gap between surgery and radiotherapy and to modulate the DNA repair enzyme O6 -methylguanine methyltransferase, which is the major cause of chemoresistance to alkylating agents such as TMZ [6]. Only a few studies have evaluated the safety of BCNU wafer implantation in patients with newly diagnosed glioblastomas receiving standard multimodal therapy. The aim of this retrospective study was to analyse the impact of Gliadel wafers added to the radio-chemotherapy with TMZ protocol based on toxicity and median survival rates. 2. Methods and materials 2.1. Patients From November 2006 to January 2010, 24 patients with newly diagnosed glioblastoma underwent a tumour resection which was considered to be macroscopically complete in 12 cases and with tumour residue in another 12 cases. Surgical resection of the tumours was performed followed by the implantation of Gliadel wafers in the Department of neurosurgery at the Regional University Hospital in Brest. In all of these patients, 8 BCNU wafers were inserted on average into the tumour resection cavity. Twenty-three patients underwent subsequently concurrent radio-chemotherapy. One patient did not receive concurrent chemotherapy but he had 9 cycles of TMZ as adjuvant chemotherapy. This decision was taken because of an unsatisfactory clinical status and age of the patient (71 years old). All other patients received concurrent radiotherapy with TMZ and were then followed up in the Institute of Oncology and Haematology at the Regional University Hospital in Brest. This concomitant treatment modality was initiated generally within 4 weeks after operation. Characteristics and composition of the studied group is to be seen in Table 1. The mean age at the moment of diagnosis was 60.25 years and the median age was 63. Nineteen patients were less than 70 years old and 5 were 70 years or more. External 3-D conformational radiotherapy was used delivering a total dose of 60 Gy with 2 Gy per fraction during 6 weeks, concurrently with oral TMZ at the daily dose of 75 mg/m2 (42 total doses). Four weeks after completion of chemo-radiotherapy, patients received TMZ at the dose of 150 mg/m2 during five days Table 1 Characteristics and composition of the studied group. Sex
Male, n (%) Female, n (%)
17 (70.8%) 7 (29.2%)
Age
Median (years) Mean (years)
63 60.25
Performance status
PS 0 – 1, n (%) PS 2, n (%)
18 (75%) 6 (25%)
Histology
Glioblastoma Glioblastoma + Oligodendroglial component Anaplasic oligodendroglioma
18 4 2
Type of resection
Complete Incomplete
12 12
Tumor localisation
Frontal Parietal Temporal
8 4 12
Lateralisation
Right Left
16 8
1223
Fig. 1. Kaplan–Meier estimate of the probability of survival (n = 24).
followed by a 21-day interval and the re-administration of TMZ at the dose of 200 mg/m2 daily for five days for a 28-day cycle for a total of 6 cycles on average. Thirteen patients were able to receive 6 or more cycles of TMZ. More than 6 cycles were administered in case of relapse and only under condition of good tolerance of the preliminary TMZ treatment. Seven patients had received less than 6 cycles of TMZ. For 5 of them this was due to the premature relapse (another sort of second therapy regime was chosen for these patients, i.e. reoperation, second line chemotherapy, best supportive care) tumour residue progression, one due to the thrombocytopenia of grade 3 and one due to short follow up time of data. Two patients did not receive adjuvant TMZ at all because of an important haematological intolerance of TMZ during radiotherapy in one case and digestive intolerance in another one. Number of adjuvant TMZ cycles could not be found in the documentation of two patients. 2.2. Safety and outcomes Adverse effects were defined according to the guidelines of the Common Terminology for Adverse Events [7]. Clinical status was evaluated during a medical visit every 4 weeks and tumour progression was diagnosed on MRI performed, at the end of every third cycle of adjuvant TMZ. 2.3. Statistics Overall survival (OS) and progression free survival (PFS) from the date of diagnosis (equal to the date of surgery) were assessed using the Kaplan–Meier method [8]. OS was defined as the time from the initial surgery until the date of the last medical visit or the
Fig. 2. Kaplan–Meier estimate of the probability of time to progression (n = 18).
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P. Miglierini et al. / Clinical Neurology and Neurosurgery 114 (2012) 1222–1225
date of death, PFS as the time from the surgery to the radiologically proved relapse. Statistics were computed using MedCalc Software® version 11.4.3.
[10,11]. These show that it should appear mostly in long surviving patients and lead to important and acute clinical manifestations.
3. Results
4. Discussion
The mean follow up time in this study was 14 months with the range of 5–45.3 months. Of the 24 patients included in the study, 13 had died and 11 were still alive at the time of the data summary. Three of the eleven patients alive do not present any signs of relapse. Radiological progression was documented in 18 patients 11 of whom had died. In our group median overall survival was 19.2 months (6.6–46 months) and median progression free survival was 12.3 months (1–18 months). The overall survival at 12 months was 78% and was 24% at 24 months (Fig. 1). Six-month progression free survival was 81.5% and 12-month PFS represented 52% (Fig. 2). There has been no case of pseudo-progression noticed within our group of patients. All radiologically detected progressions corresponded to the real progressions of the disease. Regarding the causes of the deaths, these have not been always detailed in the patient’s documentations. Only in two of thirteen patients the exact cause of the death was mentioned. These were due to the respiratory infections leading to a complete respiratory failure and later on to death. In other patients a general clinical aggravation with a deterioration of their neurological status due to their disease progression was only noted. Menei et al. [9] demonstrated that total or subtotal resection has a great impact on the survival rates (581 days versus 275 days). In our study, the median OS for the macroscopically completeresection patients was 14 months, and was 12.85 months in the subtotal-resection patients. The difference was not significant, with a p-value of 0.42. Surprisingly, progression free survival was found to be longer in the R 2 (macroscopically incomplete) resection group with 9.5 months of median PFS, in comparison with 4.5 months when complete tumour resection was achieved. This is probably the result of the relatively small number of patients. No statistical significance has been shown when comparing the survival rates in patients with performance status at the moment of diagnosis equal to 0 or 1, with those of patients with PS at 2. The median OS were 14.25 months and 12.65 respectively (p = 0.54). When evaluating the impact of the number of cycles of adjuvant TMZ on the OS rates, these seemed to be better if the number of cycles was over 6. OS have been found to be 14.6 months in the case of 6 or more cycles and 13.9 months when less than 6 courses were performed (p = 0.14). No difference was found in PFS rates, p = 0.36. Regarding the safety and tolerance of concurrent chemoradiotherapy and per-operatory implanted BCNU wafers, only grade 3 or less toxicity was experienced. Three cases of haematological toxicity (thrombocytopenia of grade 3) were seen. This caused that adjuvant TMZ could not be administered at all in one case and had to be interrupted in two other cases. Intensive digestive problems of type nausea and vomiting of grade 2 led to total abstention of adjuvant TMZ in one patient. Two cases of post-operative meningitis were seen. Up to this day, one of these two patients is still alive. One case of cerebral abscess has to be mentioned. Nevertheless, the patient is still alive. We can mention also the case of a nephrotic syndrome which appeared during the follow up period in one patient. This was described to be associated with the temozolomide treatment. Concerning the eventual cerebrospinal fluid (CSF) dissemination of the primary intracranial disease, we did not experience any case in our group of patients. Even though this seems to be a rare problem, few case reports have been already published in the literature
The results achieved in this study are able to confirm a relatively good tolerance and a mild occurrence of side effects of BCNU wafers and subsequent radio-chemotherapy. Preliminary results of a phase II multicentre clinical trial [12,13] that assessed the safety and efficacy of Gliadel plus the Stupp protocol in patients with newly diagnosed gliomas reported a median survival of 18.5 months, and retrospective analysis showed that the use of a combination of carmustine wafers followed by radiotherapy and concurrent TMZ plus rotational multiagent chemotherapy increased survival compared with the same regimen without carmustine wafers. In Westphal’s study [4] the risk of death was reduced by nearly 30% in the BCNU wafer-treated group as compared to the placebo group. Comparing concurrent radio-chemotherapy alone and radiochemotherapy after implantation of the Gliadel wafers our results look promising. It was demonstrated by Stupp et al. [2] that the overall survival was 14.6 months in the group radiotherapy plus temozolomide, and 12.1 months for radiotherapy alone. Our results show an improvement in terms of OS with an OS of 19.2 months. With regard to the safety and side effects of this multimodal treatment regimen, we could have experienced such common effects as haematotoxicity, which is mostly associated with the radio-chemotherapy in the Stupp protocol, and some effects due to the insertion of BCNU wafers. Multiple studies demonstrated that there were no unexpected adverse effects reported in the cases where the combination of BCNU wafers and temozolomide was used [12,14–16]. Compared to the known effects associated with BCNU wafer treatment, a quite high haematological toxicity (grade 3–4) with a median rate of 14.8% (7.1–53.3%) was reported in a phase III study for temozolomide alone [2]. On the contrary, Affronti et al. [17] noted in their study a higher toxicity with 17% grade 3–4 thrombocytopenia and 14% grade 3–4 leucopenia. Three patients in their cohort experienced grade 2–4 anaemia. Several studies have demonstrated an elevated incidence of intracranial infections and cerebrospinal fluid leaks as well as a risk of brain abscess. This latter adverse event may be due to the local delivery of cytotoxic drug that suppresses the patient’s local defences, meaning that a small amount of bacteria that would normally be dealt with by the patient’s immune system may rapidly proliferate [18]. In the Menei’s group [9], aseptic meningitis occurred in 4.8% of newly diagnosed patients. These adverse events were probably a mix of bacterial meningitis and chemically induced meningitis. As mentioned in a German study [19] it is likely that surgical strategies or pre-existing medical conditions impact on the incidence of adverse events. Apart from all these effects, other side effects have been noted in the cases of BCNU wafer implantations such as headache, cerebral oedema, drowsiness, nausea and seizures [20]. However all these effects cannot be described as specific for this kind of surgical technique. They could equally be due to radiotherapy, as well as to chemotherapy alone. The question of eventual efficiency of the BCNU wafers in CSF dissemination of the disease has not been yet described particularly. On contrary, one of the main indications against of the application of these wafers into the operation cavity is the direct communication of the cavity with the ventricles during the surgery. This is in order to prevent from a wafer migration and following fluid obstruction or other form of toxicity.
P. Miglierini et al. / Clinical Neurology and Neurosurgery 114 (2012) 1222–1225
5. Conclusions The multimodal treatment strategy including surgery, BCNU wafer implantation and radio-chemotherapy seems to be an interesting and perspective way to fight against poor prognosis malignant gliomas. Its use and indications should of course be carefully evaluated according to the patient’s performance status, age, associated medical conditions and surgical possibilities. Thus, this combination of local and systemic treatment seems to offer some clinical benefit with a good tolerance of the treatment. More prospective studies are needed to prove the significant improvement of survival by this combined approach. Conflict of interest None. References [1] Surawicz TS, McCarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG. Descriptive epidemiology of primary brain and CNS tumours: results from the Central Brain Tumour Registry of the United States, 1990–1994. Neuro-oncol 1999;1:14–25. [2] 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. [3] Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al. Placebocontrolled trail of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 1995;345(8956):1008–12. [4] Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU wafers) in patients with primary malignant glioma. Neuro Oncol 2003;5(2):79–88. [5] Westphal M, Ram Z, Riddle V, Hilt D, Bortey E, Exclusive Commitee of the Gliadel Study Group. Gliadel® wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 2006;148:269–75. [6] Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, et al. Mechanisms of chemo resistance to alkylating agents in malignant glioma. Clinic Cancer Res 2008;14(10): 2900–8. [7] National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, published May 28, 2009 (v4.03: June 14, 2010). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 5x7.pdf.
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[8] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Statt Assn 1958;53:457–81. [9] Menei P, Metellus P, Parot-Schinke E, Loiseau H, Capelle L, Jacquet G, et al. Biodegradable carmustine wafers (Gliadel) alone or in combination with chemoradiotherapy: the French experience. Ann Surg Oncol 2010;17(7):1740–6. [10] Stark AM, Hugo HH, Mehdorn HM, Knerlich – Lukoschus F. Acute hydrocephalus due to secondary leptomeningeal dissemination of an anaplastic oligodendroglioma. Case Rep Med 2009;2009:370901. Epub 2009 December 20. [11] Oshiro S, Komatsu F, Tsugu H, Nabeshima K, Abe H, Ohkawa M, et al. A case of intramedullary cervical metastasis from cerebellar anaplastic oligodendroglioma without typical MR appearance for CSF dissemination. No Shinkei Geka 2010;38(3):279–85. [12] LaRocca RV, Hodes J, Villanueva WG, Vitaz TW, Morassutti DJ, Doyle MJ, et al. A phase II study of radiation with concomitant and then sequential temozolomide (TMZ) in patients with newly diagnosed supratentorial high-grade malignant glioma who have undergone surgery with carmustine (BCNU) wafer insertion [Abstract]. Neuro Oncol 2006;8(4):445. [13] Rich JN. Overall survival of primary glioblastoma (GBM) patients receiving carmustine (BCNU) wafer followed by radiation (RT) and concurrent temozolomide (TMZ) plus rotational multi-agent chemotherapy [Abstract]. J Clin Oncol 2007;25:2070. [14] Asher A. Prospective analysis of temozolomide as adjuvant to Gliadel and radiation in newly diagnosed malignant glioma [Abstract]. In: The Annual Meeting of the American Association of Neurological Surgeons. 2007. [15] Gururangan S, Cokgor I, Rich JN, Edwards S, Affronti ML, Quinn JA, et al. Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas. Neuro Oncol 2001;3:246–50. [16] Sabel M, Giese A. Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience. Curr Med Res Opin 2008;24(11):3239–57. [17] Affronti ML, Heery CR, Herndon 2nd JE, Rich JN, Reardon DA, Desjardins A, et al. Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. Cancer 2009;115(15):3501–11. [18] McGovern PC, Lautenbach E, Brennan PJ, Lustiq RA, Fishman NO. Risk factors for pastcraniotomy surgical site infection after 1,3-bis (2-chloroethyl)1-nitrosourea (Gliadel) wafer placement. Clin Infect Dis 2003;36(6): 759–65. [19] Bock HC, Puchner MJ, Lohmann F, Shütze M, Koll S, Ketter R, et al. Firstline treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience. Neurosurg Rev 2010;33(4):441–9. [20] Weber EL, Goebel EA. Cerebral oedema associated with Gliadel wafers: two case studies. Neuro-oncol 2005;7(1):84–9.
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: Efficacy and toxicity Petra Miglierini a,∗ , Mohamed Bouchekoua a , Benoit Rousseau b , Phong Dam Hieu b,c , Jean-Pierre Malhaire a , Olivier Pradier a a
Department of Radiotherapy, Institute of Oncology and Haematology, University Hospital Morvan, 2 Avenue Foch, 29 200 Brest, France Department of Neurosurgery, University Hospital, Brest, France c Research group EA 4586 LNB, Brest, France b
a r t i c l e
i n f o
Article history: Received 4 April 2011 Received in revised form 24 January 2012 Accepted 29 February 2012 Available online 31 March 2012 Keywords: Gliadel wafers Glioblastoma multiforme Temozolomide Radiotherapy Toxicity Survival
a b s t r a c t Purpose: For the last few years wafers of Gliadel have been inserted into the operation cavity in patients with glioblastoma multiforme. This is followed by concurrent radio-chemotherapy with temozolomide (TMZ) according to the Stupp protocol. Only a few studies have investigated this kind of treatment regimen and the impact in terms of survival and toxicity of the combination of Gliadel with TMZ and radiotherapy. Methods and materials: From November 2006 to January 2010, 24 patients with a newly diagnosed glioblastoma have undergone a tumour resection which was considered to be macroscopically complete in 12 cases and with tumour residue in another 12 cases. The mean age at the moment of diagnosis was 60.25 years and the median age 63. Twenty-three patients underwent subsequently concurrent radio-chemotherapy with TMZ followed by cycles of elevated doses of TMZ as an adjuvant treatment. One patient had adjuvant radiotherapy alone followed by adjuvant chemotherapy. Thirteen were able to receive 6 or more cycles of adjuvant TMZ. Seven patients had received less than 6 cycles of TMZ as an adjuvant therapy. Two patients did not receive adjuvant TMZ at all. Results: The median overall survival of our group was 19.2 months and the median progression free survival was 12.3 months. Overall survival for the macroscopically complete-resection patients was 14 months, and 12.85 months in subtotal-resection patients. The median OS was 14.25 months for patients PS 0 – 1 at the moment of diagnosis and 12.65 for PS 2 patients. Chemotherapy with TMZ had to be stopped prematurely in 10 cases due to haematotoxicity, digestive toxicity or early relapse. Conclusions: The concomitant use of surgery with implantation of BCNU wafers and radio-chemotherapy seems to be well tolerated. Despite the small number of patients treated in our group, particular attention should be paid to the potential haematological consequences of this multimodal treatment regimen. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Glioblastoma multiforme is the most frequent primary cerebral disease in adults [1]. Despite the progress in such disciplines like surgery, radiotherapy and chemotherapy, overall survival rates remain generally less than 2 years following diagnosis. The present and standard treatment consists in the largest possible surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ, Temodal) followed by 6 cycles of TMZ alone, according to the Stupp protocol [2]. Since 1998, the
∗ Corresponding author. Tel.: +33 2 98 22 33 98; fax: +33 2 98 22 30 87. E-mail address: [email protected] (P. Miglierini). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2012.02.056
implantation of biodegradable carmustine wafers as a local chemotherapy into the tumour resection cavity in recurrent malignant glioblastomas has been performed in various French centres. According to the 1995 study of Brem [3] the overall survival in patients with intraoperatively placed BCNU wafers for recurrent glioblastomas was 31 weeks compared with 23 weeks in the placebo group. Each implant of GLIADEL (wafer) contains 7.7 mg of carmustine [1,3-bis (2-chloroethyl)-1-nitroso-urea] integrated into a biodegradable copolymer. It delivers carmustine directly to the cavity formed after the tumour resection. More than 70% of the copolymer is degraded within three weeks. Since 2005, in France, the indication of Gliadel implantation was also extended to the adjuvant treatment, together with surgery and radiotherapy in patients with newly diagnosed malignant gliomas.
P. Miglierini et al. / Clinical Neurology and Neurosurgery 114 (2012) 1222–1225
In the study by Westphal et al. [4,5], the use of Gliadel Implants was found to significantly increase the median survival of patients with malignant gliomas (p = 0.03). In patients treated with BCNU wafers the median survival was 13.8 months compared to 11.6 months in the placebo-group patients. The estimated advantage of this combination therapy is to try to overlap the gap between surgery and radiotherapy and to modulate the DNA repair enzyme O6 -methylguanine methyltransferase, which is the major cause of chemoresistance to alkylating agents such as TMZ [6]. Only a few studies have evaluated the safety of BCNU wafer implantation in patients with newly diagnosed glioblastomas receiving standard multimodal therapy. The aim of this retrospective study was to analyse the impact of Gliadel wafers added to the radio-chemotherapy with TMZ protocol based on toxicity and median survival rates. 2. Methods and materials 2.1. Patients From November 2006 to January 2010, 24 patients with newly diagnosed glioblastoma underwent a tumour resection which was considered to be macroscopically complete in 12 cases and with tumour residue in another 12 cases. Surgical resection of the tumours was performed followed by the implantation of Gliadel wafers in the Department of neurosurgery at the Regional University Hospital in Brest. In all of these patients, 8 BCNU wafers were inserted on average into the tumour resection cavity. Twenty-three patients underwent subsequently concurrent radio-chemotherapy. One patient did not receive concurrent chemotherapy but he had 9 cycles of TMZ as adjuvant chemotherapy. This decision was taken because of an unsatisfactory clinical status and age of the patient (71 years old). All other patients received concurrent radiotherapy with TMZ and were then followed up in the Institute of Oncology and Haematology at the Regional University Hospital in Brest. This concomitant treatment modality was initiated generally within 4 weeks after operation. Characteristics and composition of the studied group is to be seen in Table 1. The mean age at the moment of diagnosis was 60.25 years and the median age was 63. Nineteen patients were less than 70 years old and 5 were 70 years or more. External 3-D conformational radiotherapy was used delivering a total dose of 60 Gy with 2 Gy per fraction during 6 weeks, concurrently with oral TMZ at the daily dose of 75 mg/m2 (42 total doses). Four weeks after completion of chemo-radiotherapy, patients received TMZ at the dose of 150 mg/m2 during five days Table 1 Characteristics and composition of the studied group. Sex
Male, n (%) Female, n (%)
17 (70.8%) 7 (29.2%)
Age
Median (years) Mean (years)
63 60.25
Performance status
PS 0 – 1, n (%) PS 2, n (%)
18 (75%) 6 (25%)
Histology
Glioblastoma Glioblastoma + Oligodendroglial component Anaplasic oligodendroglioma
18 4 2
Type of resection
Complete Incomplete
12 12
Tumor localisation
Frontal Parietal Temporal
8 4 12
Lateralisation
Right Left
16 8
1223
Fig. 1. Kaplan–Meier estimate of the probability of survival (n = 24).
followed by a 21-day interval and the re-administration of TMZ at the dose of 200 mg/m2 daily for five days for a 28-day cycle for a total of 6 cycles on average. Thirteen patients were able to receive 6 or more cycles of TMZ. More than 6 cycles were administered in case of relapse and only under condition of good tolerance of the preliminary TMZ treatment. Seven patients had received less than 6 cycles of TMZ. For 5 of them this was due to the premature relapse (another sort of second therapy regime was chosen for these patients, i.e. reoperation, second line chemotherapy, best supportive care) tumour residue progression, one due to the thrombocytopenia of grade 3 and one due to short follow up time of data. Two patients did not receive adjuvant TMZ at all because of an important haematological intolerance of TMZ during radiotherapy in one case and digestive intolerance in another one. Number of adjuvant TMZ cycles could not be found in the documentation of two patients. 2.2. Safety and outcomes Adverse effects were defined according to the guidelines of the Common Terminology for Adverse Events [7]. Clinical status was evaluated during a medical visit every 4 weeks and tumour progression was diagnosed on MRI performed, at the end of every third cycle of adjuvant TMZ. 2.3. Statistics Overall survival (OS) and progression free survival (PFS) from the date of diagnosis (equal to the date of surgery) were assessed using the Kaplan–Meier method [8]. OS was defined as the time from the initial surgery until the date of the last medical visit or the
Fig. 2. Kaplan–Meier estimate of the probability of time to progression (n = 18).
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P. Miglierini et al. / Clinical Neurology and Neurosurgery 114 (2012) 1222–1225
date of death, PFS as the time from the surgery to the radiologically proved relapse. Statistics were computed using MedCalc Software® version 11.4.3.
[10,11]. These show that it should appear mostly in long surviving patients and lead to important and acute clinical manifestations.
3. Results
4. Discussion
The mean follow up time in this study was 14 months with the range of 5–45.3 months. Of the 24 patients included in the study, 13 had died and 11 were still alive at the time of the data summary. Three of the eleven patients alive do not present any signs of relapse. Radiological progression was documented in 18 patients 11 of whom had died. In our group median overall survival was 19.2 months (6.6–46 months) and median progression free survival was 12.3 months (1–18 months). The overall survival at 12 months was 78% and was 24% at 24 months (Fig. 1). Six-month progression free survival was 81.5% and 12-month PFS represented 52% (Fig. 2). There has been no case of pseudo-progression noticed within our group of patients. All radiologically detected progressions corresponded to the real progressions of the disease. Regarding the causes of the deaths, these have not been always detailed in the patient’s documentations. Only in two of thirteen patients the exact cause of the death was mentioned. These were due to the respiratory infections leading to a complete respiratory failure and later on to death. In other patients a general clinical aggravation with a deterioration of their neurological status due to their disease progression was only noted. Menei et al. [9] demonstrated that total or subtotal resection has a great impact on the survival rates (581 days versus 275 days). In our study, the median OS for the macroscopically completeresection patients was 14 months, and was 12.85 months in the subtotal-resection patients. The difference was not significant, with a p-value of 0.42. Surprisingly, progression free survival was found to be longer in the R 2 (macroscopically incomplete) resection group with 9.5 months of median PFS, in comparison with 4.5 months when complete tumour resection was achieved. This is probably the result of the relatively small number of patients. No statistical significance has been shown when comparing the survival rates in patients with performance status at the moment of diagnosis equal to 0 or 1, with those of patients with PS at 2. The median OS were 14.25 months and 12.65 respectively (p = 0.54). When evaluating the impact of the number of cycles of adjuvant TMZ on the OS rates, these seemed to be better if the number of cycles was over 6. OS have been found to be 14.6 months in the case of 6 or more cycles and 13.9 months when less than 6 courses were performed (p = 0.14). No difference was found in PFS rates, p = 0.36. Regarding the safety and tolerance of concurrent chemoradiotherapy and per-operatory implanted BCNU wafers, only grade 3 or less toxicity was experienced. Three cases of haematological toxicity (thrombocytopenia of grade 3) were seen. This caused that adjuvant TMZ could not be administered at all in one case and had to be interrupted in two other cases. Intensive digestive problems of type nausea and vomiting of grade 2 led to total abstention of adjuvant TMZ in one patient. Two cases of post-operative meningitis were seen. Up to this day, one of these two patients is still alive. One case of cerebral abscess has to be mentioned. Nevertheless, the patient is still alive. We can mention also the case of a nephrotic syndrome which appeared during the follow up period in one patient. This was described to be associated with the temozolomide treatment. Concerning the eventual cerebrospinal fluid (CSF) dissemination of the primary intracranial disease, we did not experience any case in our group of patients. Even though this seems to be a rare problem, few case reports have been already published in the literature
The results achieved in this study are able to confirm a relatively good tolerance and a mild occurrence of side effects of BCNU wafers and subsequent radio-chemotherapy. Preliminary results of a phase II multicentre clinical trial [12,13] that assessed the safety and efficacy of Gliadel plus the Stupp protocol in patients with newly diagnosed gliomas reported a median survival of 18.5 months, and retrospective analysis showed that the use of a combination of carmustine wafers followed by radiotherapy and concurrent TMZ plus rotational multiagent chemotherapy increased survival compared with the same regimen without carmustine wafers. In Westphal’s study [4] the risk of death was reduced by nearly 30% in the BCNU wafer-treated group as compared to the placebo group. Comparing concurrent radio-chemotherapy alone and radiochemotherapy after implantation of the Gliadel wafers our results look promising. It was demonstrated by Stupp et al. [2] that the overall survival was 14.6 months in the group radiotherapy plus temozolomide, and 12.1 months for radiotherapy alone. Our results show an improvement in terms of OS with an OS of 19.2 months. With regard to the safety and side effects of this multimodal treatment regimen, we could have experienced such common effects as haematotoxicity, which is mostly associated with the radio-chemotherapy in the Stupp protocol, and some effects due to the insertion of BCNU wafers. Multiple studies demonstrated that there were no unexpected adverse effects reported in the cases where the combination of BCNU wafers and temozolomide was used [12,14–16]. Compared to the known effects associated with BCNU wafer treatment, a quite high haematological toxicity (grade 3–4) with a median rate of 14.8% (7.1–53.3%) was reported in a phase III study for temozolomide alone [2]. On the contrary, Affronti et al. [17] noted in their study a higher toxicity with 17% grade 3–4 thrombocytopenia and 14% grade 3–4 leucopenia. Three patients in their cohort experienced grade 2–4 anaemia. Several studies have demonstrated an elevated incidence of intracranial infections and cerebrospinal fluid leaks as well as a risk of brain abscess. This latter adverse event may be due to the local delivery of cytotoxic drug that suppresses the patient’s local defences, meaning that a small amount of bacteria that would normally be dealt with by the patient’s immune system may rapidly proliferate [18]. In the Menei’s group [9], aseptic meningitis occurred in 4.8% of newly diagnosed patients. These adverse events were probably a mix of bacterial meningitis and chemically induced meningitis. As mentioned in a German study [19] it is likely that surgical strategies or pre-existing medical conditions impact on the incidence of adverse events. Apart from all these effects, other side effects have been noted in the cases of BCNU wafer implantations such as headache, cerebral oedema, drowsiness, nausea and seizures [20]. However all these effects cannot be described as specific for this kind of surgical technique. They could equally be due to radiotherapy, as well as to chemotherapy alone. The question of eventual efficiency of the BCNU wafers in CSF dissemination of the disease has not been yet described particularly. On contrary, one of the main indications against of the application of these wafers into the operation cavity is the direct communication of the cavity with the ventricles during the surgery. This is in order to prevent from a wafer migration and following fluid obstruction or other form of toxicity.
P. Miglierini et al. / Clinical Neurology and Neurosurgery 114 (2012) 1222–1225
5. Conclusions The multimodal treatment strategy including surgery, BCNU wafer implantation and radio-chemotherapy seems to be an interesting and perspective way to fight against poor prognosis malignant gliomas. Its use and indications should of course be carefully evaluated according to the patient’s performance status, age, associated medical conditions and surgical possibilities. Thus, this combination of local and systemic treatment seems to offer some clinical benefit with a good tolerance of the treatment. More prospective studies are needed to prove the significant improvement of survival by this combined approach. Conflict of interest None. References [1] Surawicz TS, McCarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG. Descriptive epidemiology of primary brain and CNS tumours: results from the Central Brain Tumour Registry of the United States, 1990–1994. Neuro-oncol 1999;1:14–25. [2] 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. [3] Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al. Placebocontrolled trail of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 1995;345(8956):1008–12. [4] Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU wafers) in patients with primary malignant glioma. Neuro Oncol 2003;5(2):79–88. [5] Westphal M, Ram Z, Riddle V, Hilt D, Bortey E, Exclusive Commitee of the Gliadel Study Group. Gliadel® wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 2006;148:269–75. [6] Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, et al. Mechanisms of chemo resistance to alkylating agents in malignant glioma. Clinic Cancer Res 2008;14(10): 2900–8. [7] National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, published May 28, 2009 (v4.03: June 14, 2010). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 5x7.pdf.
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[8] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Statt Assn 1958;53:457–81. [9] Menei P, Metellus P, Parot-Schinke E, Loiseau H, Capelle L, Jacquet G, et al. Biodegradable carmustine wafers (Gliadel) alone or in combination with chemoradiotherapy: the French experience. Ann Surg Oncol 2010;17(7):1740–6. [10] Stark AM, Hugo HH, Mehdorn HM, Knerlich – Lukoschus F. Acute hydrocephalus due to secondary leptomeningeal dissemination of an anaplastic oligodendroglioma. Case Rep Med 2009;2009:370901. Epub 2009 December 20. [11] Oshiro S, Komatsu F, Tsugu H, Nabeshima K, Abe H, Ohkawa M, et al. A case of intramedullary cervical metastasis from cerebellar anaplastic oligodendroglioma without typical MR appearance for CSF dissemination. No Shinkei Geka 2010;38(3):279–85. [12] LaRocca RV, Hodes J, Villanueva WG, Vitaz TW, Morassutti DJ, Doyle MJ, et al. A phase II study of radiation with concomitant and then sequential temozolomide (TMZ) in patients with newly diagnosed supratentorial high-grade malignant glioma who have undergone surgery with carmustine (BCNU) wafer insertion [Abstract]. Neuro Oncol 2006;8(4):445. [13] Rich JN. Overall survival of primary glioblastoma (GBM) patients receiving carmustine (BCNU) wafer followed by radiation (RT) and concurrent temozolomide (TMZ) plus rotational multi-agent chemotherapy [Abstract]. J Clin Oncol 2007;25:2070. [14] Asher A. Prospective analysis of temozolomide as adjuvant to Gliadel and radiation in newly diagnosed malignant glioma [Abstract]. In: The Annual Meeting of the American Association of Neurological Surgeons. 2007. [15] Gururangan S, Cokgor I, Rich JN, Edwards S, Affronti ML, Quinn JA, et al. Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas. Neuro Oncol 2001;3:246–50. [16] Sabel M, Giese A. Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience. Curr Med Res Opin 2008;24(11):3239–57. [17] Affronti ML, Heery CR, Herndon 2nd JE, Rich JN, Reardon DA, Desjardins A, et al. Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. Cancer 2009;115(15):3501–11. [18] McGovern PC, Lautenbach E, Brennan PJ, Lustiq RA, Fishman NO. Risk factors for pastcraniotomy surgical site infection after 1,3-bis (2-chloroethyl)1-nitrosourea (Gliadel) wafer placement. Clin Infect Dis 2003;36(6): 759–65. [19] Bock HC, Puchner MJ, Lohmann F, Shütze M, Koll S, Ketter R, et al. Firstline treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience. Neurosurg Rev 2010;33(4):441–9. [20] Weber EL, Goebel EA. Cerebral oedema associated with Gliadel wafers: two case studies. Neuro-oncol 2005;7(1):84–9.