Gliadel wafers in the treatment of malignant glioma: = a systematic review

Journal=20 List > Curr=20 Oncol > v.1= 4(5);=20 Oct 2007

PubMed=20 articles by:

Perry, J.

Chambers, A.

Spithoff, K.

Laperriere, = N.

Curr Oncol. 2007 October; 14(5): 189=E2=80=93194.

Gliadel wafers in the treatment of malignant = glioma: a=20 systematic review

J. Perry, = MD,^*=20 A. Chambers, MA,^=E2=80=A0 K. Spithoff, = BHSc,^=E2=80=A0 and N.=20 Laperriere, MD^=E2=80=A1, on behalf of the = Neuro-oncology Disease=20 Site Group of Cancer Care Ontario=E2=80=99s Program in = Evidence-Based=20 Care^=C2=A7

^* Toronto=E2=80=93Sunnybrook = Regional Cancer Centre,=20 Toronto, Ontario

^=E2=80=A0 Cancer Care Ontario, = Program in=20 Evidence-Based Care, McMaster University, Hamilton, Ontario.

^=E2=80=A1 Princess Margaret = Hospital, Toronto,=20 Ontario

Correspondence to: = James Perry,=20 c/o Ms. Karen Spithoff, Cancer Care Ontario, Program in = Evidence-Based=20 Care, McMaster University, Courthouse T-27, 3rd Floor, Room 319, = 1280 Main=20 Street West, Hamilton, Ontario L8S 4L8. E-mail: spithokd/at/mcmaster.ca

^=C2=A7Please see the Web=20 site of the Cancer Care Ontario Program in Evidence-Based Care = (http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;reftype=3Dextlink&artid=3D2002480&iid=3D150973&jid=3D481&= ;FROM=3DArticle%7CFront%20Matter&TO=3DExternal%7CLink%7CURI&artic= le-id=3D2002480&journal-id=3D481&rendering-type=3Dnormal&&= ;www.cancercare.on.ca/index_AboutthePEBC.htm#dsg)=20 for a complete list of current members of the Neuro-oncology = Disease Site=20 Group.

This is an open-access article distributed under the terms of = the=20 Creative Commons Attribution License, which permits unrestricted = use,=20 distribution, and reproduction in any medium, provided the = original work=20 is properly cited.

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"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Abstract

1. = QUESTION

2. CHOICE OF TOPIC AND=20 RATIONALE

3. = METHODS

4. = RESULTS

5. = DISCUSSION

6. = CONCLUSIONS

7. = REFERENCES

Abstract

Question

What is the = safety and=20 efficacy of interstitial chemotherapy with carmustine-loaded = polymers=20 (Gliadel wafers: MGI Pharma, Bloomington, MN, U.S.A.) in the = treatment of=20 newly diagnosed or recurrent malignant glioma (that is, = glioblastoma=20 multiforme, anaplastic astrocytoma, anaplastic oligoastrocytoma, = and=20 anaplastic oligodendroglioma)?

Perspectives

Malignant = glioma is=20 the most common type of primary brain tumour in adults. In = general,=20 efficacy of systemic therapy in this patient population has been=20 disappointing, and novel treatment approaches are needed. Because = several=20 randomized controlled trials (rcts)=20 investigating the safety and efficacy of Gliadel are available, = the=20 Neuro-oncology Disease Site Group of Cancer Care Ontario=E2=80=99s = Program in=20 Evidence-Based Care decided that a systematic review of the = evidence was=20 necessary.

Outcomes

The outcomes = of=20 interest for this review were overall survival, adverse events, = and=20 quality of life.

Methodology

Systematic = searches=20 of the medline, embase, and Cochrane Library databases = were=20 conducted for relevant evidence. Fully-published reports of rcts comparing treatment with Gliadel = wafers to=20 placebo or alternative treatment were selected for inclusion. = Prospective=20 cohort studies were also included.

Results

Two rcts that compared Gliadel to placebo in = patients=20 with newly diagnosed malignant glioma were obtained. Both rcts reported a significant survival = benefit for=20 patients who received Gliadel as compared with patients in the = control=20 group. One rct and one prospective = cohort=20 study were obtained that examined the role of Gliadel in patients = with=20 recurrent malignant glioma. The rct=20 demonstrated a significant survival benefit for Gliadel only after = adjustment for prognostic factors, and the prospective cohort = study=20 reported no survival benefit for Gliadel as compared with a = historical=20 control group. All three rcts = reported=20 similar rates of adverse events in the treatment and control = groups. The=20 most frequently reported adverse events were convulsions, = confusion, brain=20 edema, infection, hemiparesis, aphasia, and visual field defects.

Conclusions

Gliadel is = an option=20 for selected patients with newly diagnosed malignant glioma where = a near=20 gross total resection is possible. No evidence is available = comparing=20 Gliadel with systemic therapy, and a decision to combine Gliadel = with=20 systemic therapy should be made for patients individually. The = patient=20 population that would benefit from Gliadel (age, histology, and=20 performance status) is unclear; further investigation is needed. = Gliadel=20 is also an option for patients with surgically resectable = recurrent=20 malignant glioma.

Keywords: Gliadel, interstitial chemotherapy, carmustine, = malignant=20 glioma, glioblastoma, systematic = review

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1. QUESTION

What is the safety and efficacy of interstitial chemotherapy = with=20 carmustine-loaded polymers (Gliadel wafers: MGI Pharma, = Bloomington, MN,=20 U.S.A.) in the treatment of newly diagnosed or recurrent malignant = glioma=20 [that is, glioblastoma multiforme (gbm),=20 anaplastic astrocytoma, anaplastic oligoastrocytoma, and = anaplastic=20 oligodendroglioma]?

Outcomes of interest for this guideline were overall survival, = adverse=20 events, and quality of life.

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Abstract

1. = QUESTION

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>2. CHOICE OF TOPIC AND=20 RATIONALE

3. = METHODS

4. = RESULTS

5. = DISCUSSION

6. = CONCLUSIONS

7. = REFERENCES

2. CHOICE OF TOPIC AND = RATIONALE

Malignant glioma is the most common type of primary brain = tumour in=20 adults. Approximately 5 new cases per 100,000 population are = diagnosed=20 each year.

The current standard treatment for malignant glioma consists of = surgical resection followed by radiation therapy. On recurrence, = regimens=20 of systemic chemotherapy delivered by the intravenous or oral = route are=20 used. Median survival remains poor despite refinement in surgical=20 techniques and radiation therapy delivery.

Nitrosoureas, especially carmustine (bcnu) and, more recently, temozolomide, = are the=20 agents most frequently used in systemic chemotherapy. Temozolomide = concurrently with radiotherapy and as adjuvant therapy has shown = promising=20 survival benefits with low toxicity, but the clinical = effectiveness of=20 systemic therapy in general has been disappointing. Systemic = toxicities,=20 short half-life, and limitations in traversing the = blood=E2=80=93brain barrier are=20 common problems limiting the clinical effectiveness of systemic = agents.=20 Novel methods for treating malignant gliomas are needed and should = be=20 evaluated to assess their role in this devastating disease.

Gliadel wafers represent a novel approach to the delivery of=20 chemotherapy in malignant glioma. Recurrence of malignant glioma = is often=20 local, suggesting a role for a regional therapy. Gliadel wafers = contain=20 carmustine and are designed to release this agent over a 2- to = 3-week=20 period. Gliadel wafers are placed on the surface of the resected = tumour=20 beds in recurrent tumours and after initial resection. Data from = phase=20 i trials have demonstrated that = Gliadel is=20 safe and active in selected subgroups of patients with newly = diagnosed and=20 recurrent disease ¹^=E2=80=933,=20 and randomized data are now available. The Neuro-oncology Disease = Site=20 Group (dsg) felt that a systematic = review of=20 the evidence to provide an interpretation of the available = clinical trials=20 with respect to survival advantage, adverse events, and quality of = life=20 was warranted.

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Abstract

1. = QUESTION

2. CHOICE OF TOPIC AND=20 RATIONALE

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>3.=20 METHODS

4. = RESULTS

5. = DISCUSSION

6. = CONCLUSIONS

7. = REFERENCES

3. METHODS

3.1 Guideline = Development

The=20 present systematic review was originally completed in the context = of=20 developing an evidence-based series, including a clinical practice = guideline, for Cancer Care Ontario=E2=80=99s Program in = Evidence-Based Care (pebc), using the methodology of the = practice=20 guidelines development cycle ⁴.=20 The evidence was selected and reviewed by members of the = Neuro-oncology=20 dsg and by methodologists. The = pebc is editorially independent of = Cancer Care=20 Ontario and the Ontario Ministry of Health and Long-Term Care.=20 Evidence-based series produced by the pebc=20 undergo periodic review and evaluation of the literature, and new = evidence=20 is incorporated into the original reports as appropriate. The most = recent=20 versions of the reports can be found on the pebc Web site: http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;reftype=3Dextlink&artid=3D2002480&iid=3D150973&jid=3D481&= ;FROM=3DArticle%7CBody&TO=3DExternal%7CLink%7CURI&article-id=3D20= 02480&journal-id=3D481&rendering-type=3Dnormal&&www.cance= rcare.on.ca/index_practiceGuidelines.htm.

3.2 Literature Search = Strategy

A=20 systematic search of the medline = (1990 to=20 March 2006, week 3), embase (1990 = to 2006,=20 week 11), cancerlit (1990 to = October 2002),=20 and Cochrane Library (2006, Issue 1) databases was conducted. The = terms=20 =E2=80=9Cglioma=E2=80=9D (Medical Subject Heading) and = =E2=80=9Cbrain neoplasms=E2=80=9D were combined=20 with the text words =E2=80=9CGliadel,=E2=80=9D = =E2=80=9Ccarmustine,=E2=80=9D and =E2=80=9Cbcnu.=E2=80=9D In addition, the = Physician Data Query=20 clinical trials database (http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;reftype=3Dextlink&artid=3D2002480&iid=3D150973&jid=3D481&= ;FROM=3DArticle%7CBody&TO=3DExternal%7CLink%7CURI&article-id=3D20= 02480&journal-id=3D481&rendering-type=3Dnormal&&www.cance= r.gov/clinical_trials/)=20 and the proceedings of the 1997=E2=80=932005 meetings of the = American Society of=20 Clinical Oncology were searched for reports of new or ongoing = trials.=20 Relevant articles and abstracts were selected and reviewed, and = the=20 reference lists from these sources were searched for additional = trials.

3.3 Study Selection=20 Criteria

Articles were selected for inclusion if they

were fully published reports of rcts or systematic reviews of rcts comparing treatment with Gliadel = wafers to=20 placebo or alternative treatment in patients with malignant = glioma.=20 Prospective cohort studies were also included.
included results regarding the safety or efficacy of = Gliadel=20 for patients with malignant glioma.

Articles were excluded from this systematic review of the = evidence if=20 they were

letters and editorials.
papers published in a language other than=20 English.

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Abstract

1. = QUESTION

2. CHOICE OF TOPIC AND=20 RATIONALE

3. = METHODS

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>4.=20 RESULTS

5. = DISCUSSION

6. = CONCLUSIONS

7. = REFERENCES

4. RESULTS

4.1 Literature Search = Results

In=20 2000, Engelhard published a review describing the role of = interstitial=20 bcnu chemotherapy in patients with = malignant=20 glioma ⁵.=20 The Engelhard review included five studies, including two phase = i studies¹^,²,=20 one prospective cohort study with historical controls ⁶,=20 and two rcts ⁷^,⁸.=20 Since the publication of the Engelhard review, one large rct evaluating the role of Gliadel in = patients=20 with malignant glioma has been published ⁹.

Three rcts ⁷^=E2=80=939=20 and one prospective cohort study with historical controls ⁶=20 were eligible for inclusion in this systematic review (Table=20 I). A long-term follow-up study ¹⁰=20 for one of the rcts ⁹=20 was also included.

TABLE=20 I

Overview = of studies=20 included in this systematic=20 review

The rcts compared patients = treated with=20 Gliadel with patients treated with placebo, and all were supported = by=20 pharmaceutical funding. Two of the rcts=20 studied patients with newly diagnosed malignant glioma ⁸^,⁹.=20 The third rct ⁷=20 and the prospective study⁶=20 investigated patients with recurrent malignant glioma. No studies=20 comparing Gliadel with alternative treatment were identified.

4.2 Outcomes

4.2.1 Efficacy.

Newly Diagnosed Malignant Glioma. = Two rcts compared Gliadel with placebo in = patients=20 with newly diagnosed malignant glioma ⁸^,⁹.=20 Westphal et al. ⁹=20 conducted a multicentre, double-blind phase iii=20 rct that compared 120 patients in each study arm at the = time of=20 surgery. The sample size was specified in advance and based on a=20 two-tailed log-rank test with an alpha level of 0.05 and a power = of 0.90=20 to detect an 18% difference in 1-year survival between Gliadel and = placebo=20 (68% vs. 50%). The original course of the trial was 30 months, but = a=20 long-term follow-up study was later published, extending the = follow-up to=20 56 months ¹⁰.=20 Survival data for 58 patients who were known to be alive at the = end of the=20 original trial period were obtained retrospectively and were = combined with=20 data from the original study period for analysis. Over the = 56-month=20 period, only 1 patient was lost to follow-up.

Westphal et al ⁹^,¹⁰=20 reported that overall survival at 1 year was 59.2% for the Gliadel = patients and 49.2% for the placebo patients ¹⁰.=20 Survival for the Gliadel and placebo groups was 15.8% and 8.3%=20 respectively at 2 years and 9.2% and 1.7% respectively at 3 years. = The=20 difference between the survival curves was statistically = significant=20 [hazard ratio (hr): 0.73; 95% = confidence=20 interval (ci): 0.56 to 0.95; = p =3D=20 0.018], with a 27% reduction in risk of death for patients = receiving=20 Gliadel as compared with those receiving placebo. Median survival = was 13.8=20 months in the Gliadel arm and 11.6 months in the placebo arm = (p =3D=20 0.017).

Because the high number of patients undergoing re-operation = could have=20 confounded the results (29% in the Gliadel arm and 25% in the = placebo arm=20 at 30 months), an analysis of the intent-to-treat population was=20 performed, in which patients undergoing re-operation were censored = at the=20 time of surgery. That analysis was performed at the end of the = 30-month=20 study period, because no data for re-operation were available for = the 58=20 patients who were followed long-term after that time point. In the = resulting analysis, patients in the Gliadel group survived longer = than did=20 those in the placebo group (hr: = 0.64; 95%=20 ci: 0.45 to 0.92; p =3D = 0.01), with a=20 median survival of 64.1 weeks as compared with 49.4 weeks ⁹.

Westphal et al. ⁹^,¹⁰=20 also analyzed their results in histologic subgroups. In the = Gliadel arm,=20 101 patients had gbm, and in the = placebo=20 arm, 106 patients had gbm. For = that=20 subgroup, median survival was 13.1 months in the Gliadel arm and = 11.4=20 months in the placebo arm. No significant difference in survival = between=20 the two gbm subgroups was detected = (hr: 0.78; 95% ci:=20 0.595 to 1.03, p =3D 0.08) ¹⁰.=20 When Westphal et al. corrected for the possible imbalance = in=20 prognostic factors (because the groups had not originally been = randomized=20 according to histologic subgroup), no significant survival = advantage was=20 detected for the patients with gbm = in the=20 Gliadel arm as compared with equivalent patients in the placebo = arm (hr: 0.78; 95% ci:=20 0.58 to 1.05; p =3D 0.10). However, the trial was not = designed to=20 detect differences between histologic subgroups.

Valtonen et al. ⁸=20 reported the results of a small double-blind randomized trial in = which 32=20 patients with newly diagnosed malignant glioma were randomized to = receive=20 either Gliadel or a placebo. Initially, the trial was designed to = recruit=20 100 patients; however, because of difficulty obtaining Gliadel, = the trial=20 was terminated early. An imbalance was noted in the histologies in = the two=20 arms: 16 patients in the placebo arm had gbm=20 (100%) as compared with 11 patients in the Gliadel arm (69%). = Valtonen=20 et al. ⁸=20 reported a statistically significant overall survival benefit = (hr: 0.27; 95% ci:=20 0.11 to 0.68; p =3D 0.006) and increased median survival = (58.1=20 weeks vs. 39.9 weeks, p =3D 0.012) in the Gliadel arm. A = subgroup=20 analysis of the 27 patients with grade iv=20 tumours revealed a similar benefit for Gliadel in overall survival = (hr: 0.27; 95% ci:=20 0.10 to 0.71; p =3D 0.008). Median survival for that = subgroup of=20 patients was 53.3 weeks in the treatment arm and 39.9 weeks in the = placebo=20 arm (p < 0.05). Those results need to be interpreted = with=20 caution because of the small number of patients and the small = variances in=20 prognostic factors, both of which could have significantly = influenced=20 outcome.

Recurrent Malignant Glioma. One = rct examined the role of Gliadel in = recurrent=20 malignant glioma ⁷.=20 Brem et al. compared 110 patients receiving Gliadel to = 112=20 patients receiving a placebo. Each trial arm had a similar = proportion of=20 gbm patients: 65.5% in the Gliadel = arm and=20 65.2% in the placebo arm. The analysis of overall treatment effect = showed=20 no significant benefit for Gliadel (hr:=20 0.83; 95% ci: 0.63 to 01.10; = p =3D=20 0.19). However, once adjustment was made for the effects of = prognostic=20 factors, the overall treatment effect favoured Gliadel (hr: 0.67; 95% ci:=20 0.51 to 0.90; p =3D 0.006). The median survival was 31 = weeks for=20 the Gliadel arm and 23 weeks for the placebo arm. Overall patient = survival=20 at 6 months was 60% in the Gliadel arm and 47% in the placebo arm. = That=20 difference was nonsignificant (p =3D 0.061).

As in the rct by Westphal = et al.=20 ⁹,=20 Brem et al. ⁷=20 compared histologic subgroups in the Gliadel and placebo arms. = However,=20 the results of these subgroup analyses need to be interpreted with = caution, because the study was not designed to detect survival = differences=20 between subgroups. The authors reported that 6-month overall = survival for=20 gbm patients was 56% in the = Gliadel arm and=20 36% in the placebo arm (p =3D 0.020). The estimated hr showed no significant difference = between=20 treatment arms (0.81, p =3D 0.22), but a benefit for = Gliadel was=20 observed after an adjustment for treatment group and prognostic = factors=20 (hr: 0.67; 95% ci: 0.48 to 0.95; p =3D = 0.02).

One prospective cohort study with a historical control examined = the=20 role of Gliadel in patients with recurrent malignant glioma = ⁶.=20 In that study, 17 patients underwent surgery for recurrent = malignant=20 glioma and received Gliadel wafers. A cohort of 45 patients who = had=20 undergone surgery for recurrent malignant glioma during the same = time=20 period was retrospectively identified as a control group. The = authors=20 reported median survival from diagnosis as 58 weeks for the = Gliadel group=20 and 97 weeks for the control group. Although the authors reported = no=20 significant difference in prognostic factors between groups, a = possible=20 selection bias was suggested, because the patients offered Gliadel = had no=20 remaining treatment options. Patients in the control cohort = received=20 established adjuvant treatment. The potential for bias in = nonrandomized=20 studies with historical controls prevents any conclusions being = drawn from=20 the results of the study.

4.2.2 Safety. Westphal et = al. ⁹=20 reported that the number of deaths, adverse events, and laboratory = abnormalities were high, as expected in this particular patient=20 population. The Gliadel arm and the placebo arm both experienced = similar=20 adverse events. The most frequently reported adverse events among = the=20 patients receiving Gliadel were hemiplegia, convulsions, = confusion, and=20 brain edema. The most commonly reported adverse events among the = patients=20 in the placebo arm were convulsions, confusion, brain edema, and = aphasia.=20 The only difference between the groups in the Westphal et = al.=20 study ⁴=20 was that more patients in the Gliadel arm experienced intracranial = hypertension (11 patients vs. 2 patients in the placebo arm, = p =3D=20 0.019).

Valtonen et al. ⁸=20 reported results similar to those of Westphal et al. = ⁹.=20 They found that 12 patients in the treatment group and 9 patients = in the=20 placebo group reported adverse events. The most common adverse = events=20 among the patients in the Gliadel group were hemiparesis, = convulsion,=20 visual field defect, and aphasia.

Brem et al. ⁷=20 also found that both groups had similar occurrences of adverse = events.=20 They found that 2% of the patients in each group developed=20 thrombocytopenia, and that 1% of the patients in the Gliadel group = developed leukopenia. Brem et al. ⁷=20 also compared seizures between the groups. They found that 41 = patients in=20 the Gliadel group and 32 patients in the placebo group experienced = seizures (p =3D 0.199). The overall incidence of serious=20 intracranial infection was 2.2%, but this complication was more = common in=20 the Gliadel arm than in the placebo arm (3.6% and 0.89% = respectively).=20 This difference was statistically nonsignificant.

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Abstract

1. = QUESTION

2. CHOICE OF TOPIC AND=20 RATIONALE

3. = METHODS

4. = RESULTS

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>5.=20 DISCUSSION

6. = CONCLUSIONS

7. = REFERENCES

5. DISCUSSION

5.1 Newly Diagnosed Malignant=20 Glioma

Two rcts compared the = efficacy=20 of Gliadel with placebo in patients with newly diagnosed gliomas = ⁸^,⁹.=20 In the largest rct to date, = patients who=20 received Gliadel for newly diagnosed malignant glioma were = reported to=20 have experienced a 2-month improvement in median survival as = compared with=20 patients who received placebo (p =3D 0.017) ¹⁰.=20 In addition, analysis of the survival curves revealed a = significant 27%=20 reduction in risk of mortality for patients who received Gliadel=20 (p =3D 0.018). A survival advantage with Gliadel in = patients with=20 gbm was not detected, but the = trial was not=20 designed to make comparisons between histologic subgroups. Because = the=20 researchers in another randomized trial were unable to obtain = sufficient=20 Gliadel, that trial included only 32 patients newly diagnosed with = malignant glioma instead of the anticipated 100 ⁸.=20 Although a survival benefit was reported for Gliadel in the = overall=20 patient population and in patients with gbm,=20 no conclusions could be reached based on the small number of = patients=20 enrolled.

Both studies reported similar adverse events in the treatment = and=20 control arms. The most common adverse events associated with = Gliadel were=20 hemiplegia, convulsions, confusion, and brain edema. The most = commonly=20 reported adverse events among patients who received placebo were=20 convulsions, confusion, brain edema, and aphasia. A significantly = higher=20 number of patients experienced intracranial hypertension in the = Gliadel=20 arm of the Westphal trial ⁹.=20 Because neither trial included a comparison with systemic therapy, = the=20 possible contrast between the adverse event rates associated with=20 interstitial chemotherapy wafers and the rates expected with = systemic=20 chemotherapy is unclear.

Given that the largest trial demonstrated a survival advantage = in the=20 Gliadel treatment arm, Gliadel may be considered an option in the = subgroup=20 of patients with newly diagnosed resectable malignant gliomas. = However,=20 the exact patient population (based on age, histology, performance = status,=20 and so on) that may benefit from Gliadel is unclear; further = investigation=20 is needed. In addition, no comparison has been performed between = the=20 efficacy of interstitial and systemic chemotherapy; clinicians = should=20 therefore review the latest evidence for the benefit of systemic=20 chemotherapy in patients with newly diagnosed malignant = glioma.

5.2 Recurrent Malignant = Glioma

One=20 rct compared the efficacy of = Gliadel with=20 that of placebo in patients with recurrent glioma ⁷.=20 The overall result of that trial was negative, with no significant = survival advantage seen in the primary analysis. However, a = survival=20 advantage for Gliadel was observed in the overall patient = population and=20 in patients with gbm after = adjustment for=20 prognostic factors. Given that no subgroups had been identified = a=20 priori, the results of the subgroup analysis of gbm patients in that trial should be = interpreted=20 with caution.

No survival advantage for Gliadel was detected in the cohort = study with=20 historical controls ²,=20 but no conclusions can be reached because of the heterogeneity = between=20 patients and the potential for bias in studies of this nature.

The positive results of the rct = ⁷=20 after adjustment for prognostic factors suggest that Gliadel may = increase=20 overall survival in some patients with recurrent resectable = malignant=20 glioma. Because such patients generally have a poor outlook, any = treatment=20 that has the potential for prolonging life without significant = adverse=20 events should be considered an option.

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Abstract

1. = QUESTION

2. CHOICE OF TOPIC AND=20 RATIONALE

3. = METHODS

4. = RESULTS

5. = DISCUSSION

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>6.=20 CONCLUSIONS

7. = REFERENCES

6. CONCLUSIONS

Evidence from rcts suggests a = significant=20 survival benefit for Gliadel as compared with placebo. Gliadel = followed by=20 standard radiotherapy is an option for selected patients with = newly=20 diagnosed malignant glioma where a near gross total resection is = possible;=20 however, most patients with malignant glioma will be ineligible = for=20 various reasons (non-resectable tumours or contact with the = ventricular=20 system). Similarly, Gliadel is an option in patients with = surgically=20 resectable recurrent malignant gliomas. The specific patient = population=20 (based on age, histology, performance status, and so on) that = would=20 benefit from Gliadel is unclear; further investigation is = needed.

A direct comparison between Gliadel and systemic chemotherapy = has not=20 been undertaken; such a study would be helpful in defining the = relative=20 roles of this local therapy and systemic therapy. The current = standard of=20 care for patients with newly diagnosed gbm=20 is radiotherapy with concurrent and adjuvant temozolomide. No = evidence is=20 currently available to support the sequential combination of = Gliadel with=20 temozolomide, and therefore a decision to use Gliadel with = subsequent=20 temozolomide should be made for patients individually, recognizing = that=20 little clinical experience with this combined treatment has = accrued and=20 that patients should be made aware of the possibility of increased = toxicity. Clinical trials investigating the combination of Gliadel = wafers=20 with systemic therapy are required to further clarify this=20 issue.

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Abstract

1. = QUESTION

2. CHOICE OF TOPIC AND=20 RATIONALE

3. = METHODS

4. = RESULTS

5. = DISCUSSION

6. = CONCLUSIONS

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>7.=20 REFERENCES

7. REFERENCES

Brem H, Mahaley MS Jr, Vick NA, et al. = Interstitial=20 chemotherapy with drug polymer implants for the treatment of = recurrent=20 gliomas. J=20 Neurosurg. 1991;74:441=E2=80=936. [PubMed]

Brem H, Ewend MG, Piantadosi S, Greenhoot J, = Burger PC,=20 Sisti M. The safety of interstitial chemotherapy with bcnu-loaded = polymer=20 followed by radiation therapy in the treatment of newly diagnosed=20 malignant gliomas: phase i trial. J Neuro-oncol. 1995;26:111=E2=80=9323.

Olivi A, Grossman SA, Tatter S, et al. Dose = escalation=20 of carmustine in surgically implanted polymers in patients with = recurrent=20 malignant glioma: a New Approaches to Brain Tumor Therapy CNS = Consortium=20 Trial. J Clin=20 Oncol. 2003;21:1845=E2=80=939. [PubMed]

Browman GP, Levine MN, Mohide EA, et al. The = practice=20 guidelines development cycle: a conceptual tool for practice = guidelines=20 development and implementation. J Clin Oncol. 1995;13:502=E2=80=9312. [PubMed]

Engelhard HH. The role of interstitial bcnu=20 chemotherapy in the treatment of malignant glioma. Surg = Neurol.=20 2000;53:458=E2=80=9364. = [PubMed]

Subach BR, Witham TF, Kondziolka D, Lunsford = LD, Bozik=20 M, Schiff D. Morbidity and survival after 1,3-bis=20 (2-chloroethyl)-1-nitrosourea wafer implantation for recurrent=20 glioblastoma: a retrospective case-matched cohort series. Neurosurgery.=20 1999;45:17=E2=80=9322. = [PubMed]

Brem H, Piantadosi S, Burger PC, et al.=20 Placebo-controlled trial of safety and efficacy of intraoperative=20 controlled delivery by biodegradable polymers of chemotherapy for=20 recurrent gliomas. Lancet. 1995;345:1008=E2=80=9312. [PubMed]

Valtonen S, Timonen U, Toivanen P, et al. = Interstitial=20 chemotherapy with carmustine-loaded polymers for high-grade = gliomas: a=20 randomized double-blind study. Neurosurgery. 1997;41:44=E2=80=939. [PubMed]

Westphal M, Hilt DC, Bortey E, et al. A phase = 3 trial=20 of local chemotherapy with biodegradable carmustine (bcnu) wafers = (Gliadel=20 wafers) in patients with primary malignant glioma. Neuro-oncol.=20 2003;5:79=E2=80=9388. = [PubMed]

10.

Westphal M, Ram Z, Riddle V, Hilt D, Bortey = E. on=20 behalf of the Executive Committee of the Gliadel Study Group. = Gliadel=20 wafer in initial surgery for malignant glioma: long-term follow-up = of a=20 multicenter controlled trial. Acta Neurochir (Wien). 2006;148:269=E2=80=9375. [PubMed]

Articles=20 from Current = Oncology are=20 provided here courtesy of
Multimed Inc.

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