RNOP-09: Pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma - a phase II study
- Christoph P Beier1,
- Christina Schmid1,
- Thierry Gorlia2,
- Christine Kleinletzenberger1,
- Dagmar Beier1,
- Oliver Grauer1,
- Andreas Steinbrecher1,
- Birgit Hirschmann1,
- Alexander Brawanski3,
- Christopher Dietmaier4,
- Tanja Jauch-Worley1,
- Oliver Kölbl5,
- Torsten Pietsch6,
- Martin Proescholdt3,
- Petra Rümmele7,
- Armin Muigg8,
- Günther Stockhammer8,
- Monika Hegi9,
- Ulrich Bogdahn1 and
- Peter Hau1Email author
© Beier et al; licensee BioMed Central Ltd. 2009
Received: 29 May 2009
Accepted: 2 September 2009
Published: 2 September 2009
Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for.
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.
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.
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
Glioblastomas represent 40% of all tumors of the central nervous system (CNS) and are among the most lethal tumors. Therapy comprising debulking surgery and radiotherapy prolongs the median overall survival after initial diagnosis to only 8-12 months [1, 2]. Temozolomide (Temodar™, TMZ) combined with radiotherapy was the first substance to significantly improve the overall survival (to 14.6 months) as compared to surgery and radiotherapy alone and increased the proportion of patients surviving more than 2 years to 26%. TMZ showed the best efficacy in patients with a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter by eliminating more sensitive differentiated tumor cells and in part stem cell-like tumor cells [3, 4]. Among patients with a methylated MGMT promoter, the median survival after treatment with combined radio-chemotherapy was 21.7 months, as compared to 15.3 months among those who were assigned to radiotherapy only. In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups .
Doxorubicin is one of the most effective substances in vitro against cells derived from glioblastoma . However, it has no significant effect in vivo due to poor blood-brain-barrier penetration . In a tumor model, tissue and CSF-concentrations of doxorubicin were substantially increased when sterically stabilized liposomes were used  resulting in a comparable clinical response using approximately half of the dose of stabilized liposomes compared to conventional doxorubicin . A pegylated formulation (PEG-liposomal Doxorubicin, Caelyx™, PEG-Dox) even further improved the penetration of the blood-brain barrier . Case series and two phase II-studies in patients with recurrent glioblastoma have shown modestly promising results for PEG-Dox [10–13]. In our cohort, we treated 27 patients with recurrent glioblastoma with 20 mg/m2 PEG-Dox on days 1 and 15 of each 28-day cycle. The overall response rate was 39%. The progression free survival at 6 and 12 months after initiation of therapy was 15% and 7.5%, and median time to tumor progression for responders was 14 weeks, respectively. Median overall survival was 68 weeks after initial diagnosis and 26 weeks after initiation of the relapse regimen .
Based on these results, we combined PEG-Dox, TMZ, and radiotherapy in the study presented here, adapting the standard of care EORTC26981/NCIC-CE.3 protocol. Because long-term administration of TMZ for more than 6 cycles (as used in the EORTC26981/NCIC-CE.3 trial) is feasible and well tolerated , we decided to administer TMZ for at least 12 cycles or until disease progression. To determine the dose limiting toxicity of PEG-Dox combined with prolonged administration of TMZ, we performed a phase I part ahead of the phase II study. To investigate, by means of a historical control analysis, if the addition of PEG-Dox to TMZ and radiotherapy improves the survival of patients, we chose similar inclusion criteria and identical TMZ and radiotherapeutic regimes as in the EORTC26981/NCIC-CE.3 study.
Patients and Selection Criteria
Study Design and Treatment
Within 4 weeks after the histological diagnosis of glioblastoma, all patients received standard radiotherapy (total dose 60 Gy; fractions of 2 Gy Monday to Friday) plus concomitant daily TMZ 75 mg/m2 orally daily (including weekends). Radiotherapy was planned with dedicated computed tomography and three-dimensional planning systems and delivered to the gross tumor volume with a 2 to 3 cm margin for the clinical target volume. After a 4-week break, patients received adjuvant TMZ 150 to 200 mg/m2 day 1 to 5 in 28 days until tumor progression or up to at least 12 cycles . In the dose escalation phase of the study, PEG-Dox was raised in steps of 5 mg/m2 in a 3-by-3 design, starting with 5 mg/m2 (group 1) up to 20 mg/m2 (group 4). In the phase II part of the study, the targeted dose of 20 mg/m2 was administered up to a cumulative dose of 550 mg/m2 or until tumor progression.
The following events were defined as dose limiting toxicity (DLT) occurring within the first cycle of adjuvant treatment and graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (NCI-CTC 3.0): myelosuppression, palmoplantar erythrodysesthesia (PPED), cardiac, hepatic or renal toxicity grade 3 or 4; and every severe adverse event (SAE) as long as a correlation to the study medication was at least "possible" using standard SAE grading criteria. Each dose level was evaluated for DLTs using the criteria detailed above before advancing to the next level. In both parts of the study, the dosing of TMZ and PEG-Dox was modified as follows: If myelotoxicity of grade 3 or 4 occurred, the next cycle of chemotherapy was delayed, and the dose was reduced to 75% in the next cycle. If grade 4 myelotoxicity recurred after dose reduction or persisted for more than four weeks, treatment was terminated. All patients received trimethoprim-sulfamethoxazole as prophylaxis against Pneumocystis jiroveci pneumonia during concomitant treatment with radiotherapy plus TMZ.
Surveillance and follow-up
The baseline examination included magnetic resonance imaging (MRI, minimum T1, T1 plus gadolinium and FLAIR), full blood counts and blood chemistry tests, and a physical examination. During radiotherapy, patients were seen weekly. Transthoracic echocardiography was performed before the first application of PEG-Dox and at every 4th cycle of the maintenance chemotherapy. During and after radiotherapy, full blood counts were drawn every week until termination of the regimen. 28 days after the completion of radiotherapy and every 8 weeks thereafter, clinical data and KPS were raised prior to every cycle throughout the study, until the tumor progressed. Patients in whom toxicity precluded further treatment were closely followed up until resolution or stabilization of the respective condition. Standard supportive care measures were thoroughly applied in addition to chemotherapy. At tumor progression, patients were treated at the investigator's discretion. The therapeutic modalities used in recurrent disease included re-resections, re-radiotherapy, and salvage chemotherapy (e.g. CCNU, and Imatinib Mesylate based chemotherapies).
Evaluation of Toxicity and Activity
Tumor progression was defined according to Macdonald criteria . Toxicity (dose limiting toxicity, DLT, and targeted dose) graded according to NCI-CTC 3.0 in phase I and progression free survival at 12 months (PFS-12) after initiation of therapy in phase I and II were defined as the primary endpoints of the study; PFS-24, median overall survival (mOS), overall survival after 1 and 2 years (OS-12, OS-24), median time to progression (mTTP), response rate (RR, complete responses plus partial responses), rate of stabilizations (SD, stable disease), and the toxicity profile were secondary endpoints.
The MGMT methylation status was determined by the classic gel based methylation specific PCR (MSP) assay  and a high throughput quantitative MSP technique (qMSP) as part of a validation study .
The study was planned on an adapted intent-to-treat-design. An interim analysis was performed after phase I (termination criterion: unacceptable toxicity) of the study and after treating 10 patients in phase II (termination criterion: tumor progression within 10 weeks in more than 8 patients). The primary endpoint of the study was progression free survival probability at 12 months starting at the time of diagnosis. The trial was designed to accrue 60 patients (plus 5% drop-out reserve) with glioblastoma and to detect an improvement of the PFS-12 of 15.6% as compared to the data of the EORTC26981/NCIC-CE.3 (radiotherapy plus concomitant and adjuvant TMZ) arm (PFS-12: 26.9%) with an α error of 0.10 and β error of 10%. The exact patient number was determined during study accrual after publication of the EORTC26981/NCIC-CE.3 trial in 2005. Based on a Fleming design, the hypothesis tested was H0:PFS-12 ≤ 26.9% and H1: PFS-12 ≥ 42.5% The minimum PFS-12 to consider the study as "positive" was 36.7%.
As this trial was not randomized, the EORTC26981/NCIC-CE.3 data were used as historical controls and the Cox proportional hazard model was fit to directly assess the effect of the new treatment measured by their Hazard Ratios (HR) in presence of known prognostic factors (age, KPS, extent of surgical resection, corticosteroids at beginning of therapy) in order to correct for selection biases. HR, median PFS and OS, PFS-12, OS-12, and OS-24 were assessed in all patients and in subsets split by MGMT methylation status. The Cox proportional hazard model was fit to assess the prognostic value of the methylation status of the MGMT promoter in combination with the protocol treatment modalities.
Baseline characteristics of the RNOP-09 cohort as compared to the patients enrolled into the EORTC 26981/NCIC-CE.3 trial.
(N = 63)
(N = 287)
Performance status (KPS)
Extent of surgery
Corticosteroids at study entry
Survival at evaluation
Progression free survival at evaluation
Not progressive and alive
Progressive or dead
51 patients (81%) had undergone open surgery at primary diagnosis, aiming at maximum tumor removal. All patients received conventional involved-field radiotherapy with a total dose of 60 Gy and concomitant TMZ (75 mg/m2 daily, every day including weekends) during radiotherapy. Three of the patients did not complete the combined radio-chemotherapy due to progressive disease or were lost for follow-up but were included in the analysis due to the intent-to-treat design.
The most important prognostic risk factors (age, KPS, extent of resection, corticosteroids at entry) did only moderately differ between this study and the EORTC26981/NCIC-CE.3 trial (Table 1). Based on sufficient patient numbers, we concluded that a comparison of our data to the EORTC26981/NCIC-CE.3 trial was feasible.
Toxicity of the combination regimen
During phase I, the escalation groups consisted of 7 (5 mg/m2 PEG-Dox), 4 (10 mg/m2), 3 (15 mg/m2) and 4 (20 mg/m2) patients. One grade 4 leukopenia and neutropenia occurred in the first group within 3 months after diagnosis which was therefore expanded from 4 to 7 patients in accordance to the treatment plan. In the 2nd, 3rd and 4th treatment groups, the regimen was tolerated without DLT. As no DLT was observed in dose group 4, the targeted dose was reached and we proceeded to the efficacy phase of the trial with PEG-Dox in a dose of 20 mg/m2.
Side effects of the combined radio-chemotherapy with TMZ and PEG-Dox.
Treatment related toxicity **
Common toxicity criteria (NCI CTC Version 3.0)
Herpes simplex infection
Cardiac and vascular toxicity
Deep vein thrombosis
Activity of the combination regimen
Primary and secondary endpoints of the RNOP-09 study as compared to the EORTC26981/NCIC-CE.3 trial.
(N = 287)
(N = 63)
Progression Free Survival
Median duration (mo)
Rate at 1 yr (%) †
Rate at 2 yrs (%)
Hazard Ratio ‡
P = 0.58
Median duration (mo)
Rate at 1 yr (%)
Rate at 2 yrs (%)
Hazard Ratio ‡
P = 0.21
MGMT methylation status
(N = 106)
(46 meth., 60 unmeth.)
(N = 33)
(16 meth., 17 unmeth.)
Methylated MGMT Promoter
Progression Free Survival
Rate at 1 yr (%)
Hazard Ratio ‡
P = 0.52
Rate at 1 yr (%)
Rate at 2 yrs (%)
Hazard Ratio ‡
P = 0.97
Unmethylated MGMT Promoter
Progression Free Survival
Rate at 1 yr (%)
Hazard Ratio ‡
P = 0.94
Rate at 1 yr (%)
Rate at 2 yrs (%)
Hazard Ratio ‡
P = 0.84
MGMT methylation status and correlation with tumor progression and survival
The MGMT methylation status could be determined in 33 patients (52%). The samples with assignable MGMT promoter status were representative of the overall treatment population with respect to prognostic factors and outcomes except for a slight imbalance in the resection status (patients with determined MGMT promoter status had less biopsies, data not shown). Of the evaluated tumors, 16 (48%) had detectable MGMT promoter methylation, whereas 17 (52%) did not. The proportion of MGMT methylated and unmethylated tumors is similar to previous studies . With respect to all analyzed endpoints, there were no statistically significant differences between both groups. However, the statistical power of this study was too low to allow final conclusions (Table 3).
This is the first phase II-trial to evaluate the activity of PEG-Dox and prolonged administration of TMZ in addition to standard radio-chemotherapy in the first-line treatment of patients with glioblastoma. Our data were compared to the standard-of-care established in the EORTC26981/NCIC-CE.3 trial by means of a historical control analysis to disclose superiority of our combined approach. In this multi-institutional trial, we could show that neither the addition of PEG-Dox (20 mg/m2 day 1 and 15 of 28 days) nor the prolonged administration of TMZ to standard therapy comprising TMZ and radiotherapy meaningfully improves PFS-12 in comparison to the EORTC study. However, the study was not formally powered to evaluate long-term survival. Although the combined therapy slightly increased the median overall survival of the total study population to 17.6 months as compared to 14.6 in the EORTC26981/NCIC-CE.3 study , this difference did not reach statistical significance. Agreed confidence intervals of medians were largely overlapping (RNOP-09: median 14.6; CI: [13.2-16.8] - EORTC26981/NCIC-CE.3: median: 17.6; CI: [12.2-22.7]). In addition, 73% of all patients had objective responses or stabilizations according to Macdonald's criteria .
The overall toxicity pattern was acceptable over the study course. As expected, the most common adverse effect clearly attributable to PEG-Dox was palmaroplantar erythrodysesthesia (PPED). The relatively high incidence of PPED under therapy with PEG-Dox may be explained by accumulation of liposomes in the small capillaries of the skin [19, 20]. Higher grade toxicity was rare due to extensive supportive care measures  and in line with previous studies suggesting that skin toxicity occurs more frequently if the dose exceeds 60 mg/m2 per month [20, 21]. Hematological side effects were pronounced as compared to the EORTC26981/NCIC-CE.3 study and possibly caused more infectious complications. Although the data cannot be compared directly as they were evaluated in different study populations, they suggest that the addition of PEG-Dox and/or prolonged administration of TMZ increased the myelotoxicity of TMZ moderately. Still, the overall toxicity profile remained favorable. In line with previous reports, cardiotoxicity did not occur .
Although unknown biasing factors cannot be excluded due to the lack of randomization, our data allow final conclusions because of the large patient population (63 patients), the statistical design (power of 90% to detect a meaningful improvement of PFS-12), and the well balanced patient populations of RNOP-09 and the EORTC26981/NCIC-CE.3 study. The slight increase of long term survivors is low as compared to other phase II studies  but may also reflect minor differences in the patients characteristics (e.g. low proportion of patients on steroids at entry). Thus, it is unlikely that a larger patient population, e.g. in a Phase III-setting, would unveil a clinically meaningful improvement of the PFS-12 or the proportion of long term survivors by PEG-Dox. In addition, our data does not support prolonged TMZ based chemotherapy schedule in non-progressive patients. Although non-progressive patients were treated in the RNOP-09 trial up to at least 12 cycles of maintenance chemotherapy with TMZ, this neither translated into a meaningful improvement of PFS nor mOS, at least summarized over all patients. The slightly increased toxicity of the combined therapy did not translate into a relevant PEG-Dox related mortality. Thus it appears unlikely that PEG-Dox induced toxicity masked the positive effects of prolonged TMZ administration. With the comparable activity, the common cutaneous side effects, and the increased rate of infections this combined therapy did not show sufficient signs of activity in addition to the EORTC26981/NCIC-CE.3 protocol to be recommended.
Based on in vitro results, PEG-Dox was among the promising substances of a large panel of "classical" chemotherapeutic substances tested in glioblastoma during the last decades . None of these substances, except TMZ, could improve the prognosis of glioblastoma in a first-line setting, and the improvement is largely limited to patients with a methylated MGMT promoter. Recent trials that tested dose intensifications of TMZ [25, 26] or combinations of different agents with TMZ [23, 27] failed to improve the prognosis of patients with an unmethylated MGMT promoter. Thus, we suggest that combinations of classic cytostatic drugs may not be effective to improve the outcome of these patients. New targeted therapies combined with cytotoxic drugs might be better suitable to delay progression and improve survival in patients with an unmethylated MGMT promoter. This hypothesis will have to be tested in randomized phase II trials, as even large non-randomized trials might miss clinically meaningful results due to the inappropriate control for unknown biasing factors beyond the known prognostic factors. Such studies are in development or started accrual recently and hopefully will produce relevant improvements for these patients.
The study was supported by Essex Pharma (Schering-Plough Germany) with an unrestricted educational grant. Essex Pharma had no influence on the design, the evaluation, and the publication. MGMT-testing was supported by Oncomethylome Sciences (Liège, Belgium).
- Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999, 17: 2572-2578.PubMedGoogle Scholar
- Stupp R, Mason WP, Bent van den MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005, 352: 987-996. 10.1056/NEJMoa043330.View ArticlePubMedGoogle Scholar
- Beier D, Rohrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P, Proescholdt M, Brawanski A, Bogdahn U, Trampe-Kieslich A, et al: Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res. 2008, 68: 5706-5715. 10.1158/0008-5472.CAN-07-6878.View ArticlePubMedGoogle Scholar
- Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005, 352: 997-1003. 10.1056/NEJMoa043331.View ArticlePubMedGoogle Scholar
- Wolff JE, Trilling T, Molenkamp G, Egeler RM, Jurgens H: Chemosensitivity of glioma cells in vitro: a meta analysis. J Cancer Res Clin Oncol. 1999, 125: 481-486. 10.1007/s004320050305.View ArticlePubMedGoogle Scholar
- Neuwelt EA, Pagel M, Barnett P, Glassberg M, Frenkel EP: Pharmacology and toxicity of intracarotid adriamycin administration following osmotic blood-brain barrier modification. Cancer Res. 1981, 41: 4466-4470.PubMedGoogle Scholar
- Siegal T, Horowitz A, Gabizon A: Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg. 1995, 83: 1029-1037. 10.3171/jns.19220.127.116.119.View ArticlePubMedGoogle Scholar
- Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E: Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer. 2002, 94: 25-36. 10.1002/cncr.10201.View ArticlePubMedGoogle Scholar
- Cabanes A, Tzemach D, Goren D, Horowitz AT, Gabizon A: Comparative study of the antitumor activity of free doxorubicin and polyethylene glycol-coated liposomal doxorubicin in a mouse lymphoma model. Clin Cancer Res. 1998, 4: 499-505.PubMedGoogle Scholar
- Fabel K, Dietrich J, Hau P, Wismeth C, Winner B, Przywara S, Steinbrecher A, Ullrich W, Bogdahn U: Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin. Cancer. 2001, 92: 1936-1942. 10.1002/1097-0142(20011001)92:7<1936::AID-CNCR1712>3.0.CO;2-H.View ArticlePubMedGoogle Scholar
- Hau P, Fabel K, Baumgart U, Rummele P, Grauer O, Bock A, Dietmaier C, Dietmaier W, Dietrich J, Dudel C, et al: Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Cancer. 2004, 100: 1199-1207. 10.1002/cncr.20073.View ArticlePubMedGoogle Scholar
- Chua SL, Rosenthal MA, Wong SS, Ashley DM, Woods AM, Dowling A, Cher LM: Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme. Neuro Oncol. 2004, 6: 38-43. 10.1215/S1152851703000188.View ArticlePubMedPubMed CentralGoogle Scholar
- Glas M, Koch H, Hirschmann B, Jauch T, Steinbrecher A, Herrlinger U, Bogdahn U, Hau P: Pegylated liposomal doxorubicin in recurrent malignant glioma: analysis of a case series. Oncology. 2007, 72: 302-307. 10.1159/000113052.View ArticlePubMedGoogle Scholar
- Hau P, Koch D, Hundsberger T, Marg E, Bauer B, Rudolph R, Rauch M, Brenner A, Rieckmann P, Schuth J, et al: Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology. 2007, 68: 688-690. 10.1212/01.wnl.0000255937.27012.ee.View ArticlePubMedGoogle Scholar
- Macdonald DR, Cascino TL, Schold SC, Cairncross JG: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990, 8: 1277-1280.PubMedGoogle Scholar
- Vlassenbroeck I, Califice S, Diserens AC, Migliavacca E, Straub J, Di Stefano I, Moreau F, Hamou MF, Renard I, Delorenzi M, et al: Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J Mol Diagn. 2008, 10: 332-337. 10.2353/jmoldx.2008.070169.View ArticlePubMedPubMed CentralGoogle Scholar
- Vail DM, Chun R, Thamm DH, Garrett LD, Cooley AJ, Obradovich JE: Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: a randomized, double-blind clinical trial using a canine model. Clin Cancer Res. 1998, 4: 1567-1571.PubMedGoogle Scholar
- Grant R, Liang BC, Slattery J, Greenberg HS, Junck L: Chemotherapy response criteria in malignant glioma. Neurology. 1997, 48: 1336-1340.View ArticlePubMedGoogle Scholar
- Remlinger KA: Cutaneous reactions to chemotherapy drugs: the art of consultation. Arch Dermatol. 2003, 139: 77-81. 10.1001/archderm.139.1.77.View ArticlePubMedGoogle Scholar
- Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G, Gabizon A: Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer. 2000, 89: 1037-1047. 10.1002/1097-0142(20000901)89:5<1037::AID-CNCR13>3.0.CO;2-Z.View ArticlePubMedGoogle Scholar
- Koukourakis MI, Koukouraki S, Fezoulidis I, Kelekis N, Kyrias G, Archimandritis S, Karkavitsas N: High intratumoural accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic brain tumours. Br J Cancer. 2000, 83: 1281-1286. 10.1054/bjoc.2000.1459.View ArticlePubMedPubMed CentralGoogle Scholar
- Gabizon A, Martin F: Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs. 1997, 54 (Suppl 4): 15-21. 10.2165/00003495-199700544-00005.View ArticlePubMedGoogle Scholar
- Herrlinger U, Rieger J, Koch D, Loeser S, Blaschke B, Kortmann RD, Steinbach JP, Hundsberger T, Wick W, Meyermann R, et al: Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. J Clin Oncol. 2006, 24: 4412-4417. 10.1200/JCO.2006.06.9104.View ArticlePubMedGoogle Scholar
- ClinicalTrials.gov - a service of the U.S. National Institutes of Health. [http://www.clinicaltrials.gov]
- Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten M, Blaschke B, Meyermann R, Reifenberger G, Weller M, Wick W: Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol. 2007, 25: 3357-3361. 10.1200/JCO.2007.10.7722.View ArticlePubMedGoogle Scholar
- Chinot OL, Barrie M, Fuentes S, Eudes N, Lancelot S, Metellus P, Muracciole X, Braguer D, Ouafik L, Martin PM, et al: Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol. 2007, 25: 1470-1475. 10.1200/JCO.2006.07.4807.View ArticlePubMedGoogle Scholar
- Reardon DA, Nabors LB, Stupp R, Mikkelsen T: Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin Investig Drugs. 2008, 17: 1225-1235. 10.1517/13543718.104.22.1685.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/9/308/prepub
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