Glioblastoma multiforme with oligodendroglial = component (GBMO): favorable outcome after post-operative radiotherapy = and chemotherapy with nimustine (ACNU) and teniposide (VM26)

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Journal = List >=20 BMC=20 Cancer > v.6= ;=20 2006

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PubMed articles by:

Vordermark, D.

Ruprecht, K.

Rieckmann, P.

Flentje, M.

BMC Cancer. 2006; 6: 247.

Published online 2006 October = 18. doi: = 10.1186/1471-2407-6-247.

Glioblastoma multiforme with = oligodendroglial=20 component (GBMO): favorable outcome after post-operative = radiotherapy and=20 chemotherapy with nimustine (ACNU) and teniposide (VM26)

Dirk Vordermark,¹=20 Klemens Ruprecht,² Peter Rieckmann,² = Wolfgang=20 Roggendorf,³ Giles H Vince,⁴ Monika=20 Warmuth-Metz,⁵ Oliver K=C3=B6lbl,¹ and = Michael=20 Flentje¹

¹Dept. of Radiation Oncology, = University of=20 W=C3=BCrzburg, W=C3=BCrzburg, Germany

²Dept. of Neurology, University of = W=C3=BCrzburg,=20 W=C3=BCrzburg, Germany

³Dept. of Neuropathology, = University of=20 W=C3=BCrzburg, W=C3=BCrzburg, Germany

⁴Dept. of Radiosurgery, University = of=20 W=C3=BCrzburg, W=C3=BCrzburg, Germany

⁵Dept. of Neuroradiology, = University of=20 W=C3=BCrzburg, W=C3=BCrzburg, Germany

Corresponding=20 author.

Dirk Vordermark: = vordermark_d@klinik.= uni-wuerzburg.de;=20 Klemens = Ruprecht: klemens.ruprecht@m= ail.uni-wuerzburg.de;=20 Peter Rieckmann: p.rieckmann@mail.uni-wu= erzburg.de;=20 Wolfgang Roggendorf: path060@mail.uni-wuerzburg.= de;=20 Giles H Vince: gvince@gmx.de; Monika = Warmuth-Metz: warmuth@neurorad= iologie.uni-wuerzburg.de;=20 Oliver = K=C3=B6lbl: oliver.koelbl@klin= ik.uni-regensburg.de;=20 Michael Flentje: flentje_m@klinik.uni-wu= erzburg.de

Received March 16, 2006; Accepted October 18, 2006.

This is an Open Access article distributed under the terms of = the=20 Creative Commons Attribution License (http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;reftype=3Dextlink&artid=3D1621074&iid=3D125940&jid=3D16&= FROM=3DArticle|Front%20Matter&TO=3DExternal|Link|URI&article-id=3D= 1621074&journal-id=3D16&&http://creativecommons.org/licenses/= by/2.0),=20 which permits unrestricted use, distribution, and reproduction in = any=20 medium, provided the original work is properly=20 cited.

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

Background

Methods

Results

Discussion

Conclusion

Competing=20 interests

Authors'=20 contributions

Pre-publication history

References

Abstract

Background

The = presence of an=20 oligodendroglial component within a glioblastoma multiforme (GBM) = is=20 considered a prognostically favorable factor, but the clinical = outcome of=20 patients with glioblastoma multiforme with oligodendroglial = component=20 (GBMO) after combined post-operative radiotherapy and chemotherapy = has=20 rarely been reported.

Methods

We analyzed = overall and=20 progression-free survival in a group of ten consecutive patients = initially=20 diagnosed with GBMO between 1996 and 2004 (4.2% of all GBM = patients).=20 Median (range) age was 54 (34=E2=80=9373) years, 90% were resected = and median=20 radiotherapy dose was 54 (45=E2=80=9360.6) Gy. 80% of patients = received=20 post-operative chemotherapy with nimustine (ACNU) and VM26 = (teniposide)=20 for a median of 3.5 (1=E2=80=936) cycles, the remainder were = treated with=20 post-operative radiotherapy alone. All specimens were reviewed by = an=20 experienced neuropathologist.

Results

Neuropathological=20 re-evaluation revealed GBM with an oligodendroglial component of = 30% or=20 less in five cases, predominant oligoastrocytic tumors with focal = areas of=20 GBM in four patients and WHO grade III oligoastrocytoma with = questionable=20 transition to GBM in one patient. Four of ten patients were alive = at at=20 40, 41, 41 and 82 months. The median overall survival = (Kaplan-Meier) was=20 26 months, the 2-year survival rate was 60% (progression-free = survival:=20 9.8 months and 40%, respectively).

Conclusion

In = conclusion,=20 patients with GBMO treated with post-operative radiotherapy and=20 chemotherapy with ACNU/VM26 had a better prognosis than reported = for GBM=20 in modern chemoradiation series.

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Abstract

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

Methods

Results

Discussion

Conclusion

Competing=20 interests

Authors'=20 contributions

Pre-publication history

References

Background

Although glioblastoma multiforme with oligodendroglial = component (GBMO)=20 is not considered as a distinct disease entity in the most recent = World=20 Health Organization (WHO) classification of central nervous system = tumors=20 [1],=20 the increased chemosensitivity and radiosensitivity of WHO grade = III=20 anaplastic oligodendrogliomas [2,3]=20 has led to the assumption that patients with GBMO might similarly = have a=20 better prognosis than patients with classic glioblastoma = multiforme (GBM).=20 To the authors' knowldedge, data from phase III clinical trials on = the=20 outcome of the subgroup of patients with GBMO have not been = published. In=20 trial 83-02 of the Radiation Therapy Oncology Group (RTOG), a = four-arm=20 randomized phase I/II trial assessing different radiotherapy = fractionation=20 schedules with carmustine (BCNU) chemotherapy in all arms, the = median=20 survival of 14.3 months in GBMO was significantly longer than the = 10.4=20 months observed in classic GBM [4].=20 The 2-year survival rates were 35% and 4%, respectively.

Until the recent establishment of combined chemoradiation with=20 temozolomide as a new treatment standard [5],=20 the use of chemotherapy in GBM patients was not generally = recommended. A=20 meta-analysis of randomized controlled trials of mostly = nitrosurea-based=20 chemotherapy in malignant glioma found an absolute increase in = overall=20 survival of 6% at one year and of 4% at two years in glioblastoma = patients=20 treated with chemotherapy [6].=20 In Germany, combination chemotherapy with nimustine (ACNU) and = teniposide=20 (VM26) was a preferred protocol in glioblastoma patients in whom=20 chemotherapy was indicated, leading to a median overall survival = of 17.3=20 months in glioblastoma in the NOA-01 trial [7].=20 It has been the policy in the authors' institution to recommend=20 post-operative chemotherapy with ACNU and VM26, in addition to=20 radiotherapy, if patients with GBMO were in sufficiently good = general=20 general condition (Karnofsky index of at least 70). We report here = the=20 clinical outcome of a series of ten consecutive patients with GBMO = treated=20 between 1996 and 2004.

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Abstract

Background

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

Results

Discussion

Conclusion

Competing=20 interests

Authors'=20 contributions

Pre-publication history

References

Methods

Patients and treatment

The = charts of=20 all patients with a diagnosis of GBM referred to the Dept. of = Radiation=20 Oncology, University of W=C3=BCrzburg, were reviewed regarding a=20 histopathological diagnosis of GBMO. For initial histopathological = evaluation, immunohistochemistry for the markers glial fibirillary = acidic=20 protein (GFAP), Ki-67, p53 or CD68 was routinely performed by = standard=20 techniques. Although there is no uniform definition of GBMO, all = patients=20 in whom the initial histopathological report =E2=80=93 on which = treatment=20 decisions were based =E2=80=93 described a population of cells = with=20 oligodendroglial features next to a population of astrocytic and=20 anaplastic glioma cells, with obvious features of highest = malignancy=20 typically found in GBM, were included in the study cohort, = regardless of=20 the extent of the oligodendroglial component [8].=20 Of 240 patients with GBM treated during the period studied, n =3D = 10 (4.2%)=20 were found to have an oligodendroglial component described in the = initial=20 pathology report. Histopathological slides of these ten patients = were=20 reviewed by an experienced neuropathologist (W. R.), who was = blinded to=20 the clinical outcome of the patients, on the basis of the WHO=20 classification of 2000 [1].=20 The results of this re-evaluation did not affect inclusion of = patients in=20 the present analysis. The 1p/19q status was not determined as part = of the=20 present study.

A summary of patient and treatment characteristics for this = group of=20 GBMO patients is given in Table 1.=20 Characteristics of individual patients are shown in Table 2.=20 Patients were assigned to defined prognostic groups based on the = RTOG=20 recursive-partioning analysis data for malignant glioma [9].=20 Treatment details are listed in Tables 1=20 and 2.=20 Radiotherapy was administered as a 3-D conformal treatment, the = target=20 volume being based on contrast-enhanced planning computed = tomogrophy (CT)=20 and pre-operative imaging. Chemotherapy with ACNU (90 mg/m^{2 =}iv,=20 day1) and VM26 (60 mg/m², days 1 to 3; both drugs given = in=20 six-week intervals) was usually initiated after completion of=20 radiotherapy. In general, it was aimed to administer six cycles of = chemotherapy. In three patients, one or two cycles were given=20 post-operatively before radiotherapy (Table 2).

Statistics

Overall = survival was=20 studied as the main end point. Overall survival status was = obtained from=20 local resident's registration offices. Progression-free survival = was used=20 as a secondary endpoint. The dates of diagnostic imaging studies = were=20 considered in the calculation of progression-free survival. = Progression=20 was defined as an unequivocal increase in the size of the=20 contrast-enhancing lesion on CT or magnetic resonance imaging = (MRI),=20 typically performed in three-month intervals, leading to a = consideration=20 of salvage treatment options in the interdisciplinary tumor board. = Actuarial survival rates were calculated from the time of = histological=20 diagnosis using the Kaplan-Meier method. Patients consented to = anonymous=20 data analysis as part of the treatment contract with the = university=20 hospital.

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Abstract

Background

Methods

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

Discussion

Conclusion

Competing=20 interests

Authors'=20 contributions

Pre-publication history

References

Results

The clinical course of individual patients is shown in Table 2.=20 Eight of ten patients with GBMO received a median of 3.5 (range 1 = to 6)=20 cycles of chemotherapy with ACNU/VM26 as part of their adjuvant = treatment.=20 At the time of analysis, 4 of 10 patients were alive at 40, 41, 41 = and 82=20 months. The Kaplan-Meier curves of overall survival and = progression-free=20 survival are shown in Fig. 1.=20 The median overall survival of GBMO patients was 26 months. = Overall=20 survival at two years and at four years was 60% and 25%, = respectively. The=20 median progression-free survival was 9.8 months. At two and four = years,=20 40% and 26.7% of patients, respectively, were free of = progression.

Histopathological re-evaluation of all specimens by an = experienced=20 neuropathologist revealed different degrees of oligodendroglial = component=20 within the tumor tissue. The grading of results of = immunohistochemistry=20 for GFAP, Ki-67, p53 and CD68 in individual patients is given in = Table 3.=20 Whereas five tumors were classified as GBM with an = oligodendroglial=20 component of 30% or less, the others were diagnosed as containing = a=20 predominant WHO grade III oligodendroglial or oligoastrocytic = component.=20 In four of the latter group, features of WHO grade IV GBM were = seen. In=20 one case, for which only very limited biopsy material was = available,=20 anaplastic oligodendroglioma was diagnosed upon review without=20 confirmation of GBM. The overall survival times for patients with = GBM and=20 oligodendroglial component of 30% or less were 10, 10, 13, 26 and = 40+=20 months as compared to 7, 41+, 41+, 47, and 82+ months for patients = with a=20 predominant WHO grade III oligodendroglial or oligoastrocytic=20 component.

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Abstract

Background

Methods

Results

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

Conclusion

Competing=20 interests

Authors'=20 contributions

Pre-publication history

References

Discussion

Before the recent introduction of combined radiochemotherapy = with=20 temozolomide [5],=20 the use of chemotherapy in GBM was not universally recommended. = The=20 presence of an oligodendroglial component within an astrocytic = tumor with=20 features of a WHO grade IV glioblastoma, however, has been = regarded by=20 some authors as an indicator of increased chemosensitivity of such = tumors.=20 This assumption was based on the high response rates of WHO grade = III=20 anaplastic oligodendroglioma, as compared to grade III anaplastic=20 astrocytoma, established in phase II trials in the 1990s [2].=20 Two recent randomized phase III trials of adjuvant PCV in = anaplastic=20 oligodendroglioma and anaplastic oligoastrocytoma, RTOG 94-02 and = EORTC=20 26951, found a significant improvement in progression-free = survival (2.6=20 vs. 1.9 years and 2.0 vs. 1.1 years, respectively) after addition = of PCV=20 chemotherapy, but so far no effect on overall survival [10,11].=20 The clinical outcome of patients with WHO grade IV GBMO has rarely = been=20 reported. Median survival rates in the small series available in = the=20 literature (Table 4)=20 ranged between 14 and 26 months, 2-year survival rates between 20% = and=20 58%. The overall survival of 10 consecutive patients with GBMO in = the=20 present series (median 26 months, 60% at two years) compares = favorably to=20 these GBMO series and to the outcome of all GBM patients in large = clinical=20 trials, including the temozolomide radiochemotherapy arm in EORTC = 26981=20 and the ACNU/VM26 arm in the NOA-01 trial [5,7].

The favorable survival rates in the present series of patients = with=20 GBMO may be a result of a good response of these tumors to initial = multi-modality management with surgery, post-operative irradiation = and=20 chemotherapy with ACNU/VM26 (where feasible), but may also be = influenced=20 by the criteria for patient selection and the response to salvage = therapy.=20 Although the patients now analyzed were retrieved from the = database of the=20 radiation oncology department it appears unlikely that this = introduced a=20 relevant selection bias. Post-operative radiotherapy is a standard = treatment in GBM and the reported median survival rate of all = patients=20 with GBM treated with radiotherapy in this department between 1990 = and=20 1999 was 11.5 months [12].=20 The term GBMO has not been uniformly defined and especially the=20 distinction of GBMO from anaplastic oligoastrocytoma is generally=20 considered difficult [1,8,13].=20 However, nine of ten patients included clearly had tumors with = components=20 of highest malignancy, as found in grade IV GBM. In one patient = with very=20 limited biopsy material, the GBM component within a grade III=20 oligoastrocytoma was judged as uncertain upon review. The fact = that the=20 patients now analyzed were actually considered to have GBM at the = time of=20 adjuvant treatment planning is underscored by the use of = accelerated=20 radiotherapy schedules, limiting the treatment duration to = approximately=20 three weeks, in 8 of 10 patients =E2=80=93 an approach reserved = for grade IV=20 tumors at the authors' institution.

Within the limited patient cohort studied, the extent of the=20 oligodendroglial component appeared to be linked to prognosis. = Whereas=20 only one of five patients with 30% or less oligodendroglial cells = survived=20 for more than two years, this was true for four of five patients = with a=20 predominant oligodendroglial component. Obviously, such = quantifications=20 must be regarded with caution as percentages for particular cell = types on=20 sectioned material need not be representative of the overall = tumors.

GBMO tumors have been reported to frequently contain molecular = genetic=20 alterations associated with increased chemosensitivity in = oligodendroglial=20 tumors such as a loss of heterozygosity (LOH) on chromosome arms = 1p and=20 19q [8,13].=20 Microarray analysis of gene expression has been suggested as a = method to=20 distinguish "classic GBM" tumors from a group termed "non-classic" = GBM=20 with a better prognosis [14].=20 In the present series, identification of an oligodendroglial = component on=20 routine histopathological evaluation of tumor sections was = apparently able=20 to select a patient group with a better prognosis than in classic = GBM.

In some of the previous series of patients with GBMO, patients = were=20 mostly treated with surgery and post-operative radiotherapy, but = without=20 chemotherapy. This may in part explain the favorable results of = the=20 present analysis. The low rate of patients surgically treated with = biopsy=20 only (1/10 in the present series) is comparable to the series of = Kraus et=20 al. [8]=20 (Table 3)=20 where all patients were resected such that a particularly = aggressive=20 surgical approach in the present patient group appears to be an = unlikely=20 explanation of the high survival rates.

The progression-free survival observed may be regarded as a = better=20 indicator of the efficacy of the initial treatment regimen. The = median=20 progression-free survival of 9.8 months is also longer than that = seen in=20 large trials of GBM, e. g. 6.9 months in the temozolomide arm of = EORTC=20 26981 [5].=20 This suggests that the response of GBMO to ACNU/VM26 might be = better than=20 that of GBM in general to temozolomide. Clearly, the use of = salvage=20 treatments including surgery, stereotactic hypofractionated = reirradiation=20 [15]=20 and temozolomide chemotherapy has led to prolonged survival in = individual=20 patients failing early after initial post-operative chemotherapy = with=20 ACNU/VM26 (Table 2).=20 The efficacy of temozolomide as an initial treatment or as salvage = therapy=20 for GBMO has not been published to our knowledge.

The information gained by the present study is limited by the = small=20 number of patients who, nevertheless, represent the total number = of this=20 entitity from an eight-year period at a university center. A = similar=20 analysis focussing on specific effects of the addition of = chemotherapy in=20 patients with GBMO would be possible in subsets of patients from = recently=20 completed randomized trials in glioblastoma. It would, therefore, = be of=20 interest to analyze specifically the clinical course of GBM = patients with=20 an oligodendroglial component treated with temozolomide in EORTC = 26981. It=20 is also unknown whether patients with GBMO might benefit from an=20 escalation of radiation dose, an approach currently considered not = benefitial in GBM [16],=20 or from high-dose chemotherapy protocols as investigated in = anaplastic=20 oligodendroglioma [17].

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Conclusion

In summary, the prognosis of patients with GBMO treated with=20 post-operative radiotherapy and chemotherapy with ACNU/VM26 was = favorable=20 compared to published data for GBMO treated mostly with = post-operative=20 radiotherapy alone and compared to GBM treated with post-operative = radiotherapy and different regimens of chemotherapy. The outcome = of GBMO=20 after radiotherapy with concomitant and adjuvant temozolomide, the = current=20 standard for GBM, is not known. A superiority of ACNU/VM26 over=20 temozolomide in GBMO can not be advocated. From our experience,=20 post-operative chemotherapy should be offered to patients with GBM = whenever possible in the presence of an oligodendroglial = component.

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Competing interests

The author(s) declare that they have no competing = interests.

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Abstract

Background

Methods

Results

Discussion

Conclusion

Competing=20 interests

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

Pre-publication history

References

Authors' contributions

DV designed the analysis, reviewed patient data, performed = statistical=20 analysis and drafted the manuscript.

KR treated the patients, reviewed patient data and revised the=20 manuscript.

PR treated the patients, reviewed patient data and revised the=20 manuscript.

WR performed neuropathological evaluation and revised the=20 manuscript.

GHV treated the patients, reviewed patient data and revised the = manuscript.

MWM performed imaging studies on the patients, reviewed patient = data=20 and revised the manuscript.

OK treated the patients, reviewed patient data and revised the=20 manuscript.

MF treated the patients, reviewed patient data and revised the=20 manuscript.

All authors read and approved the final manuscript.

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Pre-publication history

The pre-publication history for this paper can be accessed = here:

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Abstract

Background

Methods

Results

Discussion

Conclusion

Competing=20 interests

Authors'=20 contributions

Pre-publication history

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References

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Figures and Tables

Figure=20 1

Overall = survival (A) and=20 progression-free survival (B) of n =3D 10 consecutive = patients with=20 glioblastoma multiforme with oligodendroglial component=20 (GBMO).

Table=20 1

Overview of = patient and=20 treatment characteristics

Table=20 2

Characteristics,=20 treatment and clinical course of individual=20 patients

Table=20 3

Results of=20 immunohistochemistry in individual patients with=20 GBMO

Table=20 4

Treatment = results of=20 selected series of GBM and=20 GBMO

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