First-line = treatment of malignant glioma with carmustine implants followed by = concomitant radiochemotherapy: a multicenter experience

Original Article

First-line treatment = of malignant=20 glioma with carmustine implants followed by concomitant = radiochemotherapy: a=20 multicenter experience

Hans Christoph Bock¹,=20 Maximilian Josef Anton Puchner²,=20 Frauke Lohmann², Michael Sch=FCtze³,=20 Simone Koll⁴, Ralf Ketter⁵,=20 Ruediger Buchalla⁶, Nikolai Rainov⁷,=20 Sven R. Kantelhardt¹, Veit Rohde¹ = and=20 Alf Giese^{1, 8}

(1)

Department of Neurosurgery, Center of=20 Neurological Medicine, University of G=F6ttingen, G=F6ttingen,=20 Germany

(2)

Department of Neurosurgery,=20 Bundesknappschafts-Krankenhaus Recklinghausen, Recklinghausen,=20 Germany

(3)

Department of Neurosurgery, Rostock=20 University, Rostock, Germany

(4)

Department of Neurosurgery, Klinikum = Fulda,=20 Saarbrucken, Germany

(5)

Department of Neurosurgery, Saarland=20 University, Saarbrucken, Germany

(6)

Department of Neurosurgery, Ev. Luth.=20 Diakonissenanstalt Flensburg, Flensburg,=20 Germany

(7)

Department of Neurosurgery, Klinikum = Augsburg,=20 Augsburg, Germany

(8)

Department of Neurosurgery, University = of=20 G=F6ttingen, Robert-Koch-Strasse 40, 37075 G=F6ttingen,=20 Germany

Alf Giese
= Email:=20 alf.giese@med.uni-goettin= gen.de

Received:=20 9 January 2009 Revised:=20 29 January 2010 Accepted:=20 26 May 2010 Published online:=20 13 August 2010

Abstract

Randomized phase III trials have shown significant = improvement=20 of survival 1, 2, and 3 years after implantation of 1,3-bis=20 (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly = diagnosed=20 malignant glioma. But these studies and subsequent non-phase III studies = have=20 also shown risks associated with local chemotherapy within the central = nervous=20 system. The introduction of concomitant radiochemotherapy with = temozolomide=20 (TMZ) has later demonstrated a survival benefit in a phase III trial and = has=20 become the current treatment standard for newly diagnosed malignant = glioma=20 patients. Lately, this has resulted in clinical protocols combining = local=20 chemotherapy with BCNU wafers and concomitant radiochemotherapy with TMZ = although this may carry the risk of increased toxicity. We have compiled = the=20 treatment experience of seven neurosurgical centers using implantation = of=20 carmustine wafers at primary surgery followed by 6 weeks of = radiation=20 therapy (59=9660 Gy) and 75 mg/m²/day TMZ in = patients with=20 newly diagnosed glioblastoma followed by TMZ monochemotherapy. We have=20 retrospectively analyzed the postoperative clinical course, occurrence = and=20 severity of adverse events, progression-free interval, and overall = survival in=20 44 patients with newly diagnosed glioblastoma multiforme. All patients = received=20 multimodal treatment including tumor resection, BCNU wafer implantation, = and=20 concomitant radiochemotherapy. Of 44 patients (mean age = 59 =B1 10.8 years)=20 with glioblastoma who received Gliadel wafer at primary surgery, 28 = patients=20 (64%) had died, 16 patients (36%) were alive, and 15 patients showed no = evidence=20 of clinical or radiographic progression after a median follow-up of=20 15.6 months. At time of analysis of adverse events in this patient=20 population, the median overall survival was 12.7 months and median=20 progression-free survival was 7.0 months. Surgical, neurological, = and=20 medical adverse events were analyzed. Twenty-three patients (52%) = experienced=20 adverse events of any kind including complications that did not require=20 treatment. Nineteen patients (43%) experienced grade 3 or grade 4 = adverse=20 events. Surgical complications included cerebral edema, healing = abnormalities,=20 cerebral spinal fluid leakage, meningitis, intracranial abscess, and=20 hydrocephalus. Neurological adverse events included newly diagnosed = seizures,=20 alteration of mental status, and new neurological deficits. Medical=20 complications were thromboembolic events (thrombosis, pulmonary = embolism) and=20 hematotoxicity. Combination of both treatment strategies, local = chemotherapy=20 with BCNU wafer and concomitant radiochemotherapy, appears attractive in = aggressive multimodal treatment schedules and may utilize the = sensitizing effect=20 of TMZ and carmustine on MGMT and AGT on their respective drug = resistance genes.=20 Our data demonstrate that combination of local chemotherapy and = concomitant=20 radiochemotherapy carries a significant risk of toxicity that currently = appears=20 underestimated. Adverse events observed in this study appear similar to=20 complication rates published in the phase III trials for BCNU wafer = implantation=20 followed by radiation therapy alone, but further add the toxicity of = concomitant=20 radiochemotherapy with systemic TMZ. Save use of a combined approach = will=20 require specific prevention strategies for multimodal treatments. =

Keywords Glioma - Loca= l=20 chemotherapy - BCNU - Carmustine - Gliadel&= nbsp;- Temozolomide - Radiochemotherapy=20

Introduction

Over the past years, few advances have been made = improving=20 progression-free survival (PFS) and overall survival (OAS) of patients = with=20 newly diagnosed malignant glioma. 1,3-bis (2-Chloroethyl)-1-nitrosourea = (BCNU)=20 wafer implantation directly into the resection cavity followed by = radiation=20 therapy has shown to significantly improve survival in patients with = newly=20 diagnosed malignant glioma [25],=20 and this survival benefit was maintained over the long term [26].=20 For the subgroup of glioblastoma, the treatment effect in this trail = failed to=20 reach statistical significance. However, a meta-analysis combining the = results=20 of the randomized phase III trial published by Westphal et al. [25]=20 and an earlier randomized phase III study by Valtonen et al. [24]=20 demonstrated that specifically for the subgroup of glioblastoma = treatment with=20 BCNU wafers resulted in a survival increase to 13.1 versus = 10.9 months for=20 placebo patients (p =3D 0.03). Representing class II = evidence, the results=20 of the two trials lead to Food and Drug Administration (FDA) approval of = Gliadel=20 in the treatment of newly diagnosed glioblastoma in March 2003.

Biodegradable BCNU wafers (Gliadel=AE) remain the only = approved=20 interstitial chemotherapy for treatment of newly diagnosed malignant = glioma and=20 recurrent glioblastoma today. More than 20,000 procedures of BCNU wafer=20 implantation into resection cavities have been performed worldwide since = the=20 initial release of the product and FDA approval in 1996. Surgically, = local=20 intracerebral chemotherapy using BCNU wafers is straightforward, and it = is not=20 associated with systemic toxicities [15,=20 16].=20 However, several complications have been associated with implantation of = BCNU=20 wafer, including cerebral edema, healing abnormalities, cerebral spinal = fluid=20 (CSF) leaks, intracranial infections, seizures, hydrocephalus, and cyst=20 formation. The rates for these adverse events (AE) were well established = in two=20 randomized phase III trials that tested BCNU wafers against placebo = wafers=20 [15,=20 16].=20 Since the completion of these studies, systemic chemotherapy for = malignant=20 gliomas has made significant progress and has greatly impacted current = treatment=20 standards. Stupp et al. demonstrated the efficacy of radiation therapy = and=20 concomitant temozolomide in newly diagnosed glioblastomas in a phase III = trial=20 [22].=20 After tumor resection, a 6-week protocol of concomitant = radiochemotherapy with=20 temozolomide followed by six cycles of temozolomide monochemotherapy can = now be=20 regarded as the treatment standard for patients with newly diagnosed=20 glioblastoma [22].=20 Generally, this treatment is well tolerated. In the pivotal phase III = study of=20 temozolomide in newly diagnosed malignant gliomas, 4.2% of patients = receiving=20 temozolomide plus radiotherapy experienced thromboembolic events. The=20 hematologic toxicities included pancytopenia, thrombocytopenia, and = neutropenia.=20 Grades 3 and 4 hematologic toxicity occurred in 16% of patients = receiving=20 chemoradiotherapy with temozolomide [22].=20

A combination of local BCNU wafer treatment and = concomitant=20 radiochemotherapy with temozolomide appears attractive not only because = it=20 merges successful treatment strategies for malignant gliomas but it may = also=20 take advantage of a sensitizing effect of temozolomide and carmustine on = their=20 respective resistance genes MGMT and AGT [18].=20 Only few data have become available on safety and efficiency of = combining local=20 BCNU wafer-based chemotherapy with systemic chemotherapy [10,=20 14,=20 17].=20 Temozolomide has been the most common treatment used with BCNU wafers = [1,=20 4,=20 7,=20 8,=20 10,=20 19].=20 Regimen in which temozolomide was administered concomitantly with = radiotherapy=20 2=964 weeks after surgery with BCNU wafer implantation and then = followed by=20 temozolomide monochemotherapy has been assessed in small retrospective = studies=20 [10,=20 11,=20 14,=20 19].=20 Further, Asher reported a protocol in which temozolomide was = administered for=20 5 days beginning on postoperative day 4 [1],=20 and a study by Heery et al. used chemoradiotherapy with concomitant = temozolomide=20 without additional cycles of a monochemotherapy [8].=20 These retrospective studies reported no notable increase in the toxicity = of BCNU=20 wafer implantation other than the known systemic effects of temozolomide = which=20 were mostly hematotoxic events. However, only a small number of patients = have=20 been studied, and those studies did not specifically focus on the = analysis of=20 adverse events associated with multimodal treatment approaches [10,=20 13,=20 17,=20 20,=20 21].=20 Our own experiences in contrast indicate an elevated risk of adverse = events than=20 reported in the above studies. In this multicenter toxicity data = collection, we=20 therefore have retrospectively analyzed adverse events and the treatment = experience of seven neurosurgical centers. Forty-four patients were = treated with=20 intraoperative BCNU wafer implantation followed by 6 weeks of daily = radiation therapy (59=9660 Gy) and concomitant temozolomide=20 (75 mg/m²/day) followed by a temozolomide = monochemotherapy=20 (150=96200 mg/m² on five consecutive days of a 28-day = cycle). All=20 patients had histologically confirmed newly diagnosed glioblastoma. This = analysis is focused on complication rates and risk profiles of BCNU = wafer=20 implantation. At time of data analysis, only preliminary survival data = were=20 available because of a relatively short follow-up.

Patients and methods

We have analyzed the clinical course of 44 patients = with newly=20 diagnosed glioblastoma WHO grade IV treated at seven neurosurgical = institutions.=20 Inclusion criteria for this study were written consent after careful = information=20 concerning potential risks and benefits of BCNU wafers, no previous = treatment=20 for malignant glioma (operations, chemotherapy, or radiation), and = confirmation=20 of a WHO grade IV glioblastoma in the frozen section during operation. = Inclusion=20 of the patients for data analysis of adverse events was based on the = treatment=20 decision of the individual center. No other formal inclusion criteria = applied.=20 All patients underwent initial microsurgical tumor resection (14% = planned=20 partial resection) and implantation of four to eight (mean = 7.3 =B1 1.3)=20 carmustine-containing wafers (Gliadel Wafers, Archimedes Pharma, = Reading, UK)=20 into the resection cavity. Within 4 weeks after surgery, patients = were=20 started on oral temozolomide (75 mg/m²/day) and = radiotherapy=20 1.8 Gy/day for 6 weeks (total dose ranged from 59 to = 60 Gy).=20 Within 2=964 weeks after completion of the concomitant = radiochemotherapy=20 protocol, patients received a temozolomide monochemotherapy=20 (150=96200 mg/m²) for the first 5 days of a 28-day = cycle.=20 Time period for data collection started at initial surgery and ranged = from=20 August 2005 to August 2008. Potential medical risk factors possibly = influencing=20 the clinical course such as diabetes, peripheral vascular disease, or=20 myelosuppression were documented as well as details in surgical = techniques for=20 wafer implantation. Clinical data were collected anonymously by = datasheet=20 evaluation and analyzed for the study endpoints. These were incidence = and grade=20 of adverse events, impact on scheduled oncological treatment, and = overall=20 survival and progression-free survival defined by Kaplan=96Meyer = survival=20 analysis. Adverse events were documented including time of occurrence, = severity,=20 necessity of hospitalization, and therapeutic measures taken. Reported = adverse=20 events were grouped into surgical, neurological, and medical adverse = events and=20 graded according to National Cancer Institute (NCI) guidelines [3].=20

This study was not undertaken or designed to = demonstrate=20 treatment efficacy but to analyze the risks associated with multimodal=20 treatments. However, for survival data analysis at time of data = collection=20 including OAS and PFS, Kaplan=96Maier analyses were performed; other = endpoints=20 were presented by descriptive statistics (WinStat, R. Fitch Software, = Bad=20 Krozingen, Germany).

The study cohort included 44 patients (16 females, = 28 males)=20 with a mean age of 57 =B1 10.9 years (range = 28=9674 years) and a mean=20 Karnofsky performance score (KPS) of 81 =B1 15.3% (range = 20=96100%) at the time of=20 hospital admission (Table 1).=20 Medical risk factors in this patient population included diabetes = mellitus in=20 six (14%) patients, peripheral vascular disease in two (5%) patients, = and=20 myelosuppression in two (5%) patients. Surgical risk factors included = opening of=20 the ventricular system in 13 patients (30%) and necessity of a dural = patch in 28=20 patients (64%). Thirty-seven patients (84%) received perioperative = prophylactic=20 antibiotic treatment (Table 1).=20

Table 1 Baseline=20 demographic characteristics

	Mean (SE)	N (%)	Range
Age	57 =B1 10.9		28=9674
Karnofsky performance score	81 =B1 15.3		20=96100
Medical risk factors
Diabetes mellitus		6 (14)
Peripheral vascular disease		2 (5)
Myelosuppression		2 (5)
Surgical risk factors
Opening of the ventricles		13 (30)
Dural patch required		28 (64)
Planned partial resection		6 (14)
Perioperative antibiotics		37 (84)

Results

At the time of data analysis, 28 patients (64%) had = died and=20 16 patients (36%) were alive with a median follow-up of 15.6 months = (Table 2).=20 Postoperative KPS at the time of discharge compared to hospital = admission had=20 improved in six patients (14%), remained unchanged in 29 patients (66%), = and=20 decreased in nine patients (20%). Ten patients (23%) were scheduled for=20 reoperation because of tumor progression during the evaluation period = (mean time=20 to reoperation 8.6 =B1 4.8 months).

Table 2 Follow-up=20 and outcome

Median follow-up (15.6 months)	Median OAS (months)	Median PFS (months)
Patients
Died 28 (64%)	10.7	6.0
Alive 16 (36%)	13.8	12.7
All 44	12.7	7.0

Adverse events

AE of any kind were reported for a total of 23 = patients (52%)=20 and resulted in therapy delays for concomitant radiochemotherapy in = eight=20 patients (18%) and a deferred start of subsequent temozolomide = monochemotherapy=20 in four patients (9%; Fig. 1).=20 Surgical adverse events included wound healing abnormalities and local = wound=20 infections (seven patients, 16%), CSF leakage (five patients, 11%), = meningitis=20 (three patients, 7%), intracranial abscess formation (two patients, 5%), = cerebral edema (11 patients, 25%), and hydrocephalus (three patients, = 7%).=20 Conservative treatment of surgical adverse events included lumbar = drainage for=20 CSF leaks, steroids for edema, and i.v. antibiotics for meningitis. = Unscheduled=20 readmission to the hospital was required for 19 patients (43%), and = surgical=20 intervention was necessary in seven patients (16%). Further details for=20 incidence, severity, and treatment of documented adverse events are = shown in=20 Table 3.=20

Fig. 1 Impact of AE=20 on treatment schedule

Table 3 Adverse=20 events

Type of AE	Overall incidence (%)^b	AE number of observations^c	AE requiring readmission [n = (%)]^d=20	AE conservative treatment alone [n = (%)]^d=20	AE requiring surgical intervention [n=20 (%)]^d
	52	23	19 (43)	16 (36)	7 (16)
Surgical/implantation site
Cerebral edema	25	11	7 (64)	11 (100)	=96
Healing abnormalities	16	7	6 (86)	3 (43)	4 (57)
CSF leak	11	5	5 (100)	3 (60)	2 (40)
Meningitis	7	3	2 (67)	3 (100)	=96
Intracranial abscess	5	2	2 (100)	=96	2 (100)
Hydrocephalus	7	3	2 (67)	2 (67)	1 (33)
Neurological
New seizures	16	7	7 (100)	7 (100)	=96
Alteration of mental status	18	8	6 (75)	8 (100)	=96
New neurological deficits	11	5	2 (40)	5 (100)	=96
Medical
Deep vein thrombosis	9	4	3 (75)	4 (100)	=96
Pulmonary embolism	7	3	3 (100)	3 (100)	=96
Leucopenia^a	2	1	=96	1 (2)	=96
Thrombocytopenia^a	5	2	1 (50)	2 (100)	=96
Anemia^a	=96	=96	=96	=96	=96

^aNCI grades 3 and 4

^b n =3D 44 patients = for the denominator=20

^cIn 44 patients

^dAE number of observations for the = denominator=20

Neurological AE included new onset seizures (seven = patients,=20 16%), mental alteration (eight patients, 18%), and new neurological = deficits=20 (five patients, 11%). Corresponding medical treatment was carried out in = all=20 cases.

Prophylactic subcutaneous low molecular weight heparin = or i.v.=20 heparin was administered in all patients. Medical adverse events were = reported=20 in seven patients (16%) including thrombosis (four patients, 9%) and = pulmonary=20 embolism (three patients, 11%). One patient suffered a grade 5 = thromboembolic=20 event and died because of pulmonary embolism following deep venous = thrombosis=20 during the course of postoperative radiation therapy.

NCI grade 4 leucopenia was observed in one patient = (2%) and=20 grade 3 thrombopenia in two patients (5%). One patient with preexisting=20 myelosuppressive disease required readmission for blood transfusion; = other=20 patients with low red or white blood counts did not require transfusion = or=20 readmission (Table 3).=20

With respect to time of occurrence of adverse = events, it was=20 of interest that complications occurred in 57% (13 patients) during the=20 postoperative concomitant radiochemotherapy course and in 39% later on = after=20 completion of radiochemotherapy. Only one patient (4%) was diagnosed = with a CSF=20 leak during the immediate postoperative period at day 6 = (Fig. 2).=20

Fig. 2 Time course=20 of AE occurrence in 44 patients

No significant difference in type or frequency of = adverse events=20 between the different centers was noted. No significant correlation of=20 preexisting risk factors like age, KPS, diabetes, vascular or = myelosuppressive=20 diseases, and the incidence of adverse events was observed. Further, no=20 significant impact of surgical techniques such as dural repair, = intraoperative=20 opening of the ventricular system, or perioperative administration of=20 antibiotics was noted.

Survival and progression

The median OAS in our patient population at time of = adverse=20 event analysis was 12.7 months (Fig. 3).=20 However, at the time of data summary, 16 patients (36%) were still alive = and 15=20 patients showed no evidence of clinical or radiographic progression. = Clinical=20 progression was documented for 30 patients (68%), and MRI follow-up = showed=20 radiographic progression in 18 patients (41%). The median follow-up for = all=20 patients alive was 15.6 months. The 12-month OS rate was 58% and = median PFS=20 was 7.0 months with a 6-month PFS/12-month PFS rate of 63% and 35%, = respectively.=20

Fig. 3 Survival and=20 progression in 44 glioblastoma patients treated with carmustine wafers = and=20 concomitant radiochemotherapy

Discussion

Recently, we have presented a review of the literature = from 1996=20 to February 2008 on the safety of BCNU wafer in newly diagnosed and = recurrent=20 malignant glioma patients. Three pivotal clinical phase III trials and = 26=20 non-phase III studies were analyzed. The treatment experience for = implantation=20 of BCNU wafers in patients with newly diagnosed malignant glioma and = patients=20 with recurrent disease were surveyed, and the overall incidence of = adverse=20 events was summarized [19].=20 BCNU wafer group AE rates from the pivotal phase III trials for newly = diagnosed=20 glioblastoma ranged from 4% to 23% for cerebral edema, 4% to 9% for = intracranial=20 hypertension, 14% to 16% for healing abnormalities, 5% for CSF leaks, 4% = to 5%=20 for intracranial infection, 19% to 33% for seizures, 10% for deep vein=20 thrombosis, and 8% for pulmonary embolus. For newly diagnosed disease,=20 statistically significant differences between BCNU wafer treatment and = the=20 placebo groups were observed only for intracranial hypertension which = occurred=20 at >6 months following implantation in nine of the 11 patients = in BCNU=20 wafer-treated patients. This was attributed to tumor recurrence and = subsequent=20 mass effect. CSF leak was more common in the BCNU wafer group than in = the=20 placebo wafer group, but did not reach statistical significance = [25].=20 However, for both BCNU wafer and placebo wafer treatment, wound healing=20 abnormalities and cerebral edema seemed higher than expected in a = general=20 population of brain tumor patients undergoing craniotomy. This may not = be=20 unexpected, as animal studies have reported an inflammatory response to = blank=20 polyanhydride copolymers [23].=20

In the phase III trial enrolling patients with = recurrent=20 malignant gliomas, the overall incidence of serious intracranial = infection was=20 more common with BCNU wafer treatment (four out of 110, 4%) compared = with=20 placebo (one out of 112, 1%), although the difference was not = statistically=20 significant [2].=20 However, there was a significant difference in the incidence of wound = healing=20 abnormalities (14% for the BCNU wafer group and 5% for the placebo wafer = group;=20 p < 0.05). While similar proportions of patients = had seizures=20 postoperatively, there was a difference in the proportion of patients=20 experiencing new or worsened postoperative seizures early = postoperatively. There=20 were no differences in AE rates between the three phase III studies and = 26=20 non-phase III studies. For the non-phase III studies, the overall = incidence of=20 AE was low, ranging from 0.2% for intracranial hypertension to 9.6% for = healing=20 abnormalities. Healing abnormalities, intracranial infection, and = seizures were=20 the most consistently reported AE [5,=20 14,=20 26].=20 Rates of healing abnormalities appeared higher in recurrent than in = newly=20 diagnosed disease [19].=20

While data from the Gliadel phase III studies = suggested that=20 BCNU wafer is generally well tolerated and effective, its use has = evolved in the=20 context of new treatment standards for malignant gliomas. Currently, = most=20 patients receiving BCNU wafer will also receive radiation and systemic=20 chemotherapy, as part of multimodal treatment strategies. This has led = to=20 combination of BCNU wafer with brachytherapy [4,=20 19,=20 27],=20 radiosurgery [1,=20 7,=20 10,=20 12,=20 19,=20 20],=20 and systemic therapies including irinotecan, lomustine, procarbazine,=20 carboplatin, interferon, and temozolomide [9,=20 11].=20 However, multimodal treatment strategies carry the potential of additive = toxicity and therefore have to be evaluated extremely carefully. = Temozolomide is=20 the most recent agent that has proven efficacy in the treatment of = malignant=20 gliomas. Temozolomide was shown to significantly prolong survival in = patients=20 with newly diagnosed malignant gliomas and is generally well tolerated, = with=20 hematologic toxicity being the most notable safety issue [22].=20 The combination of local BCNU wafer treatment and systemic temozolomide = has not=20 been assessed in phase III trials, but recently, some non-phase III = studies have=20 investigated the efficacy and safety of BCNU wafer and temozolomide = within=20 multimodal treatment strategies [1,=20 7,=20 10,=20 19].=20 There were no unexpected AE reported in the BCNU wafer and temozolomide = studies.=20 Compared to known AE associated with BCNU wafer treatment, the added=20 hematological toxicity at a median rate of 14.8% (7.1=9653.3%) was = comparable to=20 grade 3 or 4 hematologic toxic events reported in the phase III study = for=20 temozolomide alone [22].=20 Combining local and systemic treatment strategies is tempting. However, = elevated=20 complication rates may lead to delays in oncological treatment and may = even=20 result in early termination of treatment plans. The risk/benefit ratio = for these=20 intense multimodal treatments has therefore to be assessed very = carefully. In=20 contrast to the few other studies investigating intraoperative BCNU = wafer=20 treatment followed by postoperative radiation therapy and concomitant=20 temozolomide and subsequent temozolomide monochemotherapy, our = multicenter study=20 focused on the retrospective analysis of AE specifically and was not = designed=20 nor powered to demonstrate treatment efficacy. Inclusion of patients = with newly=20 diagnosed glioblastoma for analysis of treatment-related adverse events = was=20 based on the treatment decision of the individual center. No other = formal=20 inclusion criteria such as age, neurological performance score, or = feasibility=20 of a gross total resection applied. Therefore, this patient population = is likely=20 to represent a negative selection bias in terms of prognosis and = treatment risk=20 compared to phase III trials or other studies (compare material and = methods=20 section). However, this patient population is likely to reflect a cohort = requiring treatment in every day neuro-oncology practice. In this = patient=20 population, our analysis suggests a higher rate of AE compared to the = data=20 published for the BCNU wafer phase III trials [15,=20 16].=20 We found an elevated incidence of intracranial infections and CSF leaks=20 (Table 4)=20 compared to a recently published study [19]=20 that reported a comparatively low incidence of adverse events for BCNU = wafer=20 treatment and concurrent temozolomide. Only three of 21 patients = experienced=20 toxic side effects. A recent report on a similar phase II study = [10]=20 reported an overall high rate of adverse events (20 of 35 patients), but = did not=20 specifically report on wound healing abnormalities. One intracranial = abscess was=20 reported in the later analysis. However, there was an unexpected rate of = thromboembolic events (deep vein thrombosis in five and pulmonary = embolism in=20 four of 35 patients), respectively. A study designed to specifically = analyze=20 adverse events is likely to find an elevated rate of such events. The = non-phase=20 III studies cited above focused on treatment efficacy and did not = present clear=20 criteria for adverse event reporting. In this study, 23 patients (52%)=20 experienced adverse events of any kind which included complications that = did not=20 require specific treatment. Nineteen patients (43%) experienced grade 3 = or grade=20 4 adverse events including hematotoxic events. This compares to 16% = grade 3 or=20 grade 4 events for concomitant radiochemotherapy [22]=20 added to the adverse events reported in the phase three trials for local = BCNU=20 chemotherapy followed by radiation. These trails did not report how many = patients experienced grade 3 or grade 4 adverse events, but rather = presented=20 rates for specific events, for example, 16% wound healing, 5% = intracranial=20 infection, and 33% seizures [25].=20 Therefore, it is difficult to estimate the additional risk of the = multimodal=20 approach studied here. In our study for eight patients (18%), AE = resulted in the=20 delay of radiochemotherapy, and for four patients (9%), AE lead to delay = of=20 further oncological treatment. It is likely that surgical strategies or=20 preexisting medical conditions impact on the incidence of adverse = events.=20 Surprisingly, this was not observed in our study. Frequency and type of = adverse=20 events were independent of age, preoperative clinical condition, = surgical=20 strategy, or the institution at which patients were treated. = Interestingly, all=20 adverse events registered in this study occurred after scheduled = discharge from=20 hospital and during the first 2 to 3 months after BCNU wafer = implantation.=20 In 19 patients (43%), readmission in a neurosurgical center was = required, and=20 specific neurosurgical intervention was necessary in seven patients = (16%).=20 Because most adverse events occurred during concomitant = radiochemotherapy or=20 through the first cycles of temozolomide monochemotherapy, the = relatively short=20 follow-up of this study seems to be sufficient to evaluate the risk of = AE under=20 this treatment regimen. Our study suggests that the incidence of adverse = events=20 associated with BCNU wafer treatment in combination with concurrent = radiation=20 and temozolomide chemotherapy is currently underestimated. We have = therefore=20 recently conducted a comprehensive review of the literature on = individual=20 adverse events associated with carmustine wafer implantation reported in = the=20 literature and the proposed avoidance strategies [6].=20 Based on the reported incidence and the time course of adverse events, = we have=20 proposed a formal protocol for patient selection, surgical techniques, = and=20 follow-up schedules for patients scheduled for carmustine wafer = implantation at=20 our institution. Following introduction and strict adherence to this = risk=20 management protocol, specifically implantation site-related = complications=20 dropped significantly [6].=20 Our study further demonstrates that several adverse events occur late = after=20 initial surgery and wafer implantation (compare Fig. 2).=20 Most adverse events, including wound healing abnormalities and = intracranial=20 infections, occurred after patients had been discharged from = neurosurgical units=20 and manifested at a time when patients were not under direct care of = their=20 surgeons. Therefore, the neuro-oncological follow-up schedule was now = modified=20 to account for late wound healing complications [6].=20

Table 4 Incidence of=20 AE compared

Type of AE	Overall incidence (%)	Overall incidence (%)	Overall incidence (%)
Newly diagnosed GBM BCNU = wafer + radiation + TMZ=20 chemotherapy (n =3D 44 patients)	Newly diagnosed GBM pivotal phase III trial BCNU = wafer=20 reatment group (n =3D 120 patients)^a =	Selected non-phase III clinical studies of BCNU = wafer=20 treatment in newly diagnosed and recurrent malignant gliomas=20 (n =3D 887 patients)^b =
Healing abnormalities	16	16	9.6
CSF leak	11	5	2.1
Intracranial infection	9	5	2.4
Thromboembolic events
Deep vein thrombosis	9	10	1.6
Pulmonary embolism	7	8	1.0
Hematotoxic events
NCI grades 3 and 4	5	0	Not analyzed

^aWestphal et al. [25]=20

^bSabel and Giese [19]=20

GBM glioblastoma multiforme=20

Conclusion

The efficacy of BCNU wafer treatment followed by = radiation=20 chemotherapy within multimodal treatment strategies to day remains = unproven and=20 therefore has to be considered an experimental treatment strategy. The = safety=20 data provided here suggest that BCNU wafer treatment followed by = radiation=20 chemotherapy requires further validation of risk management strategies. = The use=20 of BCNU wafer with radiation and concurrent temozolomide followed by=20 temozolomide monochemotherapy does not appear to result in new types of = AE.=20 However, clinicians should be aware of the potential risks associated = with BCNU=20 wafer.

Conflict of=20 Interest =20

None.

Open=20 Access =20

This article is distributed under the terms of the = Creative=20 Commons Attribution Noncommercial License which permits any = noncommercial use,=20 distribution, and reproduction in any medium, provided the original = author(s)=20 and source are credited.

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Comments=20

Miguel A. Arraez, Malaga, = Spain

The article written by Bock and colleagues is = focusing on the=20 treatment of malignant gliomas by means of surgery, BCNU wafers in the = tumoral=20 bed, radiotherapy, and temozolomide. The addition of BCNU wafers as = local=20 therapy has been proven useful in malignant gliomas, although with = untoward side=20 effects. The Stupp scheme (radiation therapy and concomitant=20 temozolomide/6 weeks radiochemotherapy followed by six cycles of=20 temozolomide monochemotherapy) has also shown its potential to prolong = survival=20 in these patients. The current management of malignant gliomas varies = according=20 patients and centers, but it is important to notice that nowadays many = patients=20 undergo resection and receive BCNU wafers and after discharge from = hospital,=20 radiotherapy plus temozolomide is administered. In this paper, Bock et = al. do=20 state that the main aim of this study is not the survival analysis but = the=20 adverse effects of such a combination of treatments. This is a very = important=20 endpoint for the analysis. The results of Bock and colleagues show a=20 surprisingly high rate of complications and adverse effects, more than = probably=20 suspected, when the above-mentioned combination of treatments is used. = It calls=20 also the attention of the high number of thromboembolic events in this = subset of=20 patients. It is not known whether this series of patients did receive or = not=20 prophylaxis with heparin.

The results of this study suggest that a further = selection of=20 patients to follow this scheme should be regarded, as the risk/benefits = ratio=20 could not be the same for all patients. According to this consideration, = some=20 stratification could be made in the future taking into account survival = and=20 adverse events for obvious purposes of model prediction before = undertaking the=20 combination of surgery, BCNU wafers, radiation, and temozolomide. =

Oliver Heese, Hamburg, Germany

The currently available standard for the treatment = of=20 glioblastoma consists of gross total resection followed by concomitant = radiation=20 therapy/chemotherapy with temozolomide followed by cyclic temozolomide = for=20 6 months resulting in an overall survival of 14 to 15 months = with an=20 acceptable side effect spectrum. In theory, intensifying this regimen by = adding=20 a local chemotherapy may lead to a prolonged survival, in particular = since time=20 from surgery to the beginning of radiation therapy is without any = further=20 treatment so far. In this nicely written manuscript, a multicenter = approach was=20 taken to gain information regarding the number and severity of adverse = events of=20 a =93first-line treatment of malignant glioma with carmustine implants = followed by=20 concomitant radiochemotherapy=94. In 44 patients, the adverse events = were=20 collected retrospectively. Treatment efficacy data were not the = intention of the=20 study due to the retrospective and unrandomized trial design, but a = median=20 overall survival of 12.7 months and a median progression-free = survival of=20 7.0 months were seen.

Regarding the number of adverse events, 52% of = patients=20 experienced adverse events of any kind including complications not = needing=20 further treatment, and in 43% of patients=92 adverse events, grades 3 = and 4 were=20 seen. The authors summarize that a combination of local chemotherapy and = concomitant radiochemotherapy carries a significant risk of toxicity = that may=20 have been underestimated currently.

In conclusion, these data definitely lead to caution = when=20 planning new therapy protocols for malignant glioma treatment. It seems = that=20 1 + 1 is not always 2 and combining different therapy = regimens, in theory from a=20 pathophysiological perspective working synergistically, may lead to an = increased=20 and unacceptable side effects spectrum. Taking into account that all of = these=20 therapies are only performed in a palliative setting and so far the = overall=20 survival for glioblastoma multiforme (GBM) is still only approximately=20 14 month, severe side effects leading to hospitalization and = profound loss=20 of quality of life are unacceptable for patients and their families. For = further=20 study designs, focusing only on endpoints like overall survival and=20 progression-free survival may not be adequate, and adding quality of = life=20 assessments and other psycho-oncological criteria seems to be mandatory = in order=20 to do the best for GBM patients.