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RNOP-09: pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma--a phase II study.

Beier CP, Schmid C, Gorlia T, Kleinletzenberger C, Beier D, Grauer O, Steinbrecher A, Hirschmann B, Brawanski A, Dietmaier C, Jauch-Worley T, Kölbl O, Pietsch T, Proescholdt M, Rümmele P, Muigg A, Stockhammer G, Hegi M, Bogdahn U, Hau P - BMC Cancer (2009)

Bottom Line: The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I.None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison.Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany. christoph.beier@gmx.de

ABSTRACT

Background: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for.

Methods: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression.

Results: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison.

Conclusion: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.

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Overall survival of RNOP-09 patients as compared to historical control. Kaplan-Meier estimates of overall survival according to treatment group. The unadjusted hazard ratio for death among patients treated with PEG-Dox and prolonged administration of TMZ as compared with those treated in the EORTC26981/NCIC-CE.3 trial was 0.83 (CI: 0.60-1.16; p = 0.28).
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Figure 2: Overall survival of RNOP-09 patients as compared to historical control. Kaplan-Meier estimates of overall survival according to treatment group. The unadjusted hazard ratio for death among patients treated with PEG-Dox and prolonged administration of TMZ as compared with those treated in the EORTC26981/NCIC-CE.3 trial was 0.83 (CI: 0.60-1.16; p = 0.28).

Mentions: All patients were observed until progression after treatment initiation. One patient was lost to follow-up, and his data were included in the statistical analysis using the last date of observation. PFS-12 as primary endpoint was 30.2% as compared to 26.9% for patients treated with combined radio-chemotherapy in the EORTC26981/NCIC-CE.3 study (adjusted HR for progression free survival: 0.91; CI: 0.67-1.26; p = 0.58). The OS-24 was 35.3% (EORTC26981/NCIC-CE.3: 27.2%), the mOS was 17.6 months (EORTC26981/NCIC-CE.3: 14.6 months), and the adjusted HR for overall survival was 0.79 (CI: 0.55-1.14; p = 0.21, Figure 2). Complete response during the protocol therapy including radiotherapy and chemotherapy (CR, n = 2), partial response (PR, n = 3) or stable disease (SD, n = 41) were observed in 73% of patients 8 weeks after initial diagnosis. 8 weeks after initiation of the maintenance therapy (i.e. 20 weeks after tumor resection), 34 patients (53%) were free of progression [18]. There was no significant difference between patients that received less than 20 mg/m2 PEG-Dox in the phase I part of the study and the patients treated with 20 mg/m2 [see Additional File 1]. All other endpoints are summarized in Table 3. Of note, the combination of PEG-Dox, prolonged TMZ, and radiotherapy was significantly superior to radiotherapy alone with respect to overall survival and PFS-12 (30.2% vs. 9.1%; p < 0.002) confirming previous results [2] (data not shown).


RNOP-09: pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma--a phase II study.

Beier CP, Schmid C, Gorlia T, Kleinletzenberger C, Beier D, Grauer O, Steinbrecher A, Hirschmann B, Brawanski A, Dietmaier C, Jauch-Worley T, Kölbl O, Pietsch T, Proescholdt M, Rümmele P, Muigg A, Stockhammer G, Hegi M, Bogdahn U, Hau P - BMC Cancer (2009)

Overall survival of RNOP-09 patients as compared to historical control. Kaplan-Meier estimates of overall survival according to treatment group. The unadjusted hazard ratio for death among patients treated with PEG-Dox and prolonged administration of TMZ as compared with those treated in the EORTC26981/NCIC-CE.3 trial was 0.83 (CI: 0.60-1.16; p = 0.28).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2749868&req=5

Figure 2: Overall survival of RNOP-09 patients as compared to historical control. Kaplan-Meier estimates of overall survival according to treatment group. The unadjusted hazard ratio for death among patients treated with PEG-Dox and prolonged administration of TMZ as compared with those treated in the EORTC26981/NCIC-CE.3 trial was 0.83 (CI: 0.60-1.16; p = 0.28).
Mentions: All patients were observed until progression after treatment initiation. One patient was lost to follow-up, and his data were included in the statistical analysis using the last date of observation. PFS-12 as primary endpoint was 30.2% as compared to 26.9% for patients treated with combined radio-chemotherapy in the EORTC26981/NCIC-CE.3 study (adjusted HR for progression free survival: 0.91; CI: 0.67-1.26; p = 0.58). The OS-24 was 35.3% (EORTC26981/NCIC-CE.3: 27.2%), the mOS was 17.6 months (EORTC26981/NCIC-CE.3: 14.6 months), and the adjusted HR for overall survival was 0.79 (CI: 0.55-1.14; p = 0.21, Figure 2). Complete response during the protocol therapy including radiotherapy and chemotherapy (CR, n = 2), partial response (PR, n = 3) or stable disease (SD, n = 41) were observed in 73% of patients 8 weeks after initial diagnosis. 8 weeks after initiation of the maintenance therapy (i.e. 20 weeks after tumor resection), 34 patients (53%) were free of progression [18]. There was no significant difference between patients that received less than 20 mg/m2 PEG-Dox in the phase I part of the study and the patients treated with 20 mg/m2 [see Additional File 1]. All other endpoints are summarized in Table 3. Of note, the combination of PEG-Dox, prolonged TMZ, and radiotherapy was significantly superior to radiotherapy alone with respect to overall survival and PFS-12 (30.2% vs. 9.1%; p < 0.002) confirming previous results [2] (data not shown).

Bottom Line: The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I.None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison.Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany. christoph.beier@gmx.de

ABSTRACT

Background: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for.

Methods: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression.

Results: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison.

Conclusion: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.

Show MeSH
Related in: MedlinePlus