Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma.
BACKGROUND
Doxorubicin exhibits high efficacy in malignant glioma cell cultures. Nonetheless, as a standard formulation, doxorubicin has not been used clinically, due to poor penetration of the blood-brain barrier. Furthermore, doxorubicin is known to induce tumor resistance genes. To address both of these issues, the authors investigated the use of pegylated liposomal doxorubicin (Caelyx; Essex Pharma, Munich, Germany) alone (Trial 1) and in combination with tamoxifen (Trial 2) in two sequentially performed nonrandomized prospective Phase II trials involving patients with recurrent high-grade glioma.


METHODS
Twenty patients were included in each trial. Progression-free survival at 6 months (PFS-6) and toxicity were the primary endpoints. Expression of the tumor resistance proteins multidrug resistance protein 1 (MDR-1) and multiple resistance protein (MRP) was evaluated by immunohistochemical methods and by sestamibi-single-photon emission computed tomography (SPECT).


RESULTS
The overall response rate (including cases of disease stabilization) was 40% in both Trial 1 and Trial 2. PFS-6 was 15%, and the median time to disease progression was 17 weeks. It is noteworthy that 40% of patients with Grade III tumors had long-term responses, which lasted for up to 3 years. There was no significant difference between Trial 1 and Trial 2 in terms of efficacy. Both regimens were well tolerated, with the main side effect being palmoplantar erythrodysesthesia. The authors found no correlation between clinical response and expression of tumor resistance genes or between clinical response and SPECT data.


CONCLUSIONS
Pegylated liposomal doxorubicin administered alone or in combination with tamoxifen is safe and moderately effective in patients with recurrent high-grade glioma. None of the putative predictors for response that were evaluated proved to be significant in this setting.
Hau
Peter
P
Klinik und Poliklinik für Neurologie der Universität Regensburg, Regensburg, Germany. peter.hau@medbo.de
Fabel
Klaus
K
Baumgart
Ulrike
U
Rümmele
Petra
P
Grauer
Oliver
O
Bock
Annekatrin
A
Dietmaier
Christopher
C
Dietmaier
Wolfgang
W
Dietrich
Jörg
J
Dudel
Christine
C
Hübner
Franz
F
Jauch
Tanya
T
Drechsel
Elisabeth
E
Kleiter
Ingo
I
Wismeth
Cäcile
C
Zellner
Anton
A
Brawanski
Alexander
A
Steinbrecher
Andreas
A
Marienhagen
Jörg
J
Bogdahn
Ulrich
U
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004337:Drug Carriers; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011788:Quality of Life; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; C063330:doxorubicin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer; D013629:Tamoxifen; D011092:Polyethylene Glycols; D004317:Doxorubicin