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Hindawi Publishing Corporation Journal of Oncology Volume 2008, Article ID 942618, 4 pages doi:10.1155/2008/942618 Case Report Reinduction of Bevacizumab in Combination with Pegylated Liposomal Doxorubicin in a Patient with Recurrent Glioblastoma Multiforme Who Progressed on Bevacizumab/Irinotecan 1 2 1 Mohammed Almubarak, Michael Newton, and Ramin Altaha Section of Hematology/Oncology, Mary Babb Randolph Cancer Center, West Virginia University Hospital, Morgantown, WV 26506, USA School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA Correspondence should be addressed to Ramin Altaha, email@example.com Received 5 June 2008; Accepted 5 August 2008 Recommended by Minesh Mehta Glioblastoma multiforme (GBM) carries a dismal prognosis despite the current standard of multimodality treatments. Recent studies showed promising results to a regimen consisting of a VEGF inhibitor, (bevacizumab) and a topoisomerase I inhibitor (irinotecan) [BI] in recurrent GBM. However, those patients with GBM who progress on BI will succumb to their disease generally in a very short period of time. We report a case of a 56-year-old male patient with GBM who declined surgical resection and received chemoradiation with temozolomide. This treatment was withheld secondary to signiﬁcant thrombocytopenia. Subsequently, he achieved stable disease for 10 months with a regimen consisting of thalidomide and tamoxifen before progressing. This was followed by bevacizumab with irinotecan [BI], for which he had a signiﬁcant partial response for 8 months with subsequent progression. Reinducing the patient with bevacizumab in combination with a pegylated liposomal doxorubicin [PLD] (a topoisomerase II inhibitor) demonstrated antitumor activity with signiﬁcant shrinkage of contrast enhancing mass and peritumoral edema. Copyright © 2008 Mohammed Almubarak et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1. Introduction for the treatment of recurrent GBM . The antitumor activity of bevacizumab containing regimens could be due Glioblastoma multiforme (GBM) is the most common to enhanced permeability of the tumor vasculature which primary brain tumor in adults. Despite advancement in areas leads to improved penetration of the cytotoxic chemother- of clinical detection and treatment, GBM continues to have apy agents. We hypothesized that replacing irinotecan an ominous prognosis with median survival less than a year with another cytotoxic chemotherapy agent with a diﬀer- . Historically, GBM was treated with resection followed by enet resistance proﬁle may overcome the resistance to BI radiation. The addition of nitrosourea-based chemotherapy regimen. added a small survival beneﬁt. The standard of treatment was PLD is a liposome-encapsulated dosage form of doxoru- changedafter Stuppetal.  demonstrated an improvement bicin which works by intercalating into DNA resulting in in survival by 2 months using temozolomide in combination inhibition of DNA synthesis. It also inhibits topoisomerase with radiation compared to radiation alone. II . PLD has several potential advantages over standard Bevacizumab is a recombinant humanized monoclonal doxorubicin including longer circulatory half-life, more antibody that inhibits the biologic activity of vascular speciﬁc delivery to tumor tissue and reduced cardiac toxicity endothelial growth factor (VEGF). GBM is a highly vascular- . A cross-resistance between irinotecan and PLD to ized tumor with a high expression of VEGF . Bevacizumab our knowledge has not been described. Combining PLD has shown promising results in a recent phase II clinical trial with bevacizumab might prove to be eﬀective in treating when combined with a topoisomerase I inhibitor, irinotecan, GBM. 2 Journal of Oncology [D] Study Study [A] mm mm Magnetic [F] W [D] (a) (b) Figure 1: MRI brain T1 with gadolinium after stopping bevacizumab with irinotecan. 2. Case Report of disease (Figure 2). He was not considered a candidate for additional alkylating agent-based chemotherapy such A 56-year-old healthy man presented in October 2004 with as carmustine (BCNU) or the PCV regimen (procarbazine, short-term memory deﬁcit and a left-sided visual ﬁeld lomustine, vincristine) due to dose limiting hematologic defect. A magnetic resonance image (MRI) of the brain toxicity experienced with temozolomide. showed a large (5.7 cm × 3.5 cm) right occipitoparietal The patient was reinduced with bevacizumab 10 mg/kg enhancing mass with extension into the ventricular system with the addition of pegylated liposomal doxorubicin and satellite metastases with associated edema and mass (Doxil, Ortho Biotech Products, LP, Bridgewater, NJ, USA) eﬀect.He underwent a stereotactic biopsy of the lesion 20 mg/m every 2 weeks. His brain MRI (T1 with gadolin- that revealed a diagnosis of GBM. The patient declined ium, FLAIR and T2 weighted images) after 4 treatments surgical resection. He received steroids and was placed on showed substantial decrease in bulk of the large mass in the levetiracetam (Keppra, UCB Inc., Smyrna, Ga, USA) for right posterior cerebral hemisphere with associated decrease seizure prophylaxis. in edema (Figure 3). The patient was started on concomitant chemoradio- Despite achieving the dramatic imaging response and therapy per Stupp regimen consisting of temozolomide initial improvement in performance status, the patient (Temodar, Schering Corporation, Kenilworth, NJ, USA) declined further chemotherapy and imaging modalities. He 75 mg/m daily as well as radiation therapy (a total of 59.4 developed decubitus ulcer and died 2 months after he Gy). He had signiﬁcant improvement in his neurological received his last dose of PLD/bevacizumab. function with evidence of partial response on brain MRI. Table 1 summarizes the treatment regimens and duration However, temozolomide had to be discontinued after of response for this patient. 2 months secondary to severe thrombocytopenia. After completion of the radiation therapy, he was then started 3. Discussion on thalidomide 300 mg and tamoxifen 200 mg daily for maintenance. His disease was stable on this regimen GBM is a highly vascularized tumor and thus target- for approximately 10 months. Subsequently, a brain ing angiogenesis could represent a major new treatment MRI showed progression of disease. This regimen was approach. Ahmed et al. demonstrated 64% (or 9 out of discontinued and he was started on bevacizumab (Avastin, 14 patients) response/disease stabilization lasting anywhere Genentech Inc., South San Francisco, Calif, USA) 10 mg/kg from 8 to 135 weeks using an outpatient oral regimen of with irinotecan 125 mg/m every 2 weeks based on an the angiogenesis inhibitor, thalidomide, plus tamoxifen, and abstract published by Stark-Vance in 2005 . He had a temozolomide . 90 percent decrease in the tumor size after two cycles on VEGF inhibitors are currently being investigated in this regimen. However, after seven cycles on this regimen several clinical trials. An abstract published by Stark-Vance a brain MRI showed increased mass eﬀect and interval at the sixth meeting of the European Association of Neuro- development of abnormal contrast enhancement in the oncology showed 43% response (9 out of 21 patients) to a medial hemispheric aspect of the right occipital and parietal regimen consisting of bevacizumab and irinotecan every 2 lobe area, compatible with progression of disease (Figure 1). weeks . Vredenburgh et al. further conﬁrmed the eﬃcacy Subsequently, he was restarted on temozolomide of irinotecan and bevacizumab in patients with recurrent 150 mg/m on days 1–5 every month. He developed grade III-IV gliomas. In this phase II trial, 57% out of the neutropenia requiring growth factor support as well as 35 patients had radiographic response and the 6-month thrombocytopenia requiring oprelvekin (Neumega, Wyeth overall survival was 77%. Of note, four patients developed Pharmaceuticals Inc., Philadelphia, Pa). After 2 cycles on thomboembolic complications and one had a CNS bleed this regimen, his follow-up brain MRI showed progression . Based on this data, the National Cancer Comprehensive Journal of Oncology 3 99.58 mm 66.77 mm (a) (b) Figure 2: Brain T1 with gadolinium prior to reinduction with bevacizumab with PLD. 95.19 mm 56.25 mm (a) (b) Figure 3: Brain T1 with gadolinium after treatment with bevacizumab with PLD. Network (NCCN) has updated their guidelines recently to enzyme. Irinotecan as a single agent has very low response include bevacizumab-based regimens as a salvage treatment rate in GBM . The signiﬁcant response noted when option in recurrent GBM . combined with bevacizumab could be due to improved Since VEGF inhibitors aﬀect the vascular permeability drug delivery resulting from a reduction in interstitial of the tumor, this may result in decrease in contrast ﬂuid pressure and normalization of the tumor vasculature enhancement in MRI images . This might lead to by bevacizumab . This introduces the possibility of questioning the true validity of using MRI to assess response enhanced blood brain barrier (BBB) penetration of other to treatment. Pope et al. evaluated MRI response in high- cytotoxic agents when combined with bevacizumab. grade gliomas treated with bevacizumab in addition to Doxorubicin has shown signiﬁcant in vitro cytotoxicity diﬀerent chemotherapeutic agents. They noted reduction in in cell lines derived from malignant glioma cells . contrast enhancing tumor in 7 out of 14 patients in as little as Unfortunately, doxorubicin does not adequately penetrate 2 weeks. Of interest, even in those patients who did not have the BBB  and is subject to resistance due to P- reduction in tumors size, a reduction in edema was noted . glycoprotein mediated eﬄux [16, 17]. However, pegylated Nonetheless, response to such bevacizumab containing liposomal doxorubicin selectively overcomes the BBB in the regimen in high-grade gliomas was proved using positron tumor areas, with accumulation more than 10 fold higher in emission tomography (PET) by Chen et al. In this study, a the tumor than in normal brain tissue . Pegylated lipo- 47% response rate (9 out of 19) was reported with 65% 6- somal doxorubicin also appears to overcome P-glycoprotein month survival. Metabolic responders survived three times mediated resistance . Moreover, there seems to be an as long as nonresponders (10.8 versus 3.4 months). This was enhanced drug exposure and improvement in therapeutic the ﬁrst study to describe the ability to use PET scan as activity when comparing pegylated liposomal doxorubicin to an imaging modality for predicting survival in patients who conventional doxorubicin in brain tumors in rats . were treated with bevacizumab . A single agent regimen with pegylated liposomal dox- Irinotecan is a water soluble camptothecin (CPT) analog orubicin has proven moderate eﬃcacy in GBM patients that interferes with the catalytic cycle of topoisomerase I as demonstrated by Fabel et al. who observed disease 4 Journal of Oncology Table 1: Summary of treatment regimens and duration of response. somal formulation,” International Journal of Nanomedicine, vol. 2, no. 4, pp. 567–583, 2007. Chemotherapy/treatment Response  V. Stark-Vance, “Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma,” Neuro-Oncology,vol. 7, no.3,p. Partial response after two 369, 2005. months, but discontinued (1) Temozolomide and  T. Ahmed, B. Chen, and G. Rabbani, “Phase II trial of secondary to signiﬁcant radiation thalidomide (TD), tamoxifen (TX), and temozolomide (T) thrombocytopenia. for patients with advanced malignant gliomas (MG),” in Disease stabilization for 10 Proceedings of the 41st Annual Meeting of the American Society (2) Thalidomide and months with subsequent of Clinical Oncology (ASCO ’05), Orlando, Fla, USA, May 2005. tamoxifen progression.  http://www.nccn.org/professionals/physician gls/PDF/cns.pdf. Signiﬁcant partial response for 8  E. R. Gerstner,D.G.Duda,E.diTomaso, G. Sorensen,R. (3) Bevacizumab with months with subsequent K. Jain, and T. T. Batchelor, “Antiangiogenic agents for the irinotecan progression. treatment of glioblastoma,” Expert Opinion on Investigational Drugs, vol. 16, no. 12, pp. 1895–1908, 2007. Disease progression after 2 (4) Temozolomide  W. Chen, S. Delaloye, D. H. S. Silverman, et al., “Predicting months. reinduction treatment response of malignant gliomas to bevacizumab and (5) Bevacizumab Partial response (approximately irinotecan by imaging proliferation with [18F] ﬂuorothymi- reinduction and pegylated 60%) after 2 months. Treatment dine positron emission tomography: a pilot study,” Journal of liposomal doxorubicin stopped at the patient’s request. Clinical Oncology, vol. 25, no. 30, pp. 4714–4721, 2007.  M. D. Prados,K.Lamborn,W.K.A.Yung,etal., “A phase2 trial of irinotecan (CPT-11) in patients with recurrent malig- nant glioma: a North American Brain Tumor Consortium stabilization in 7 of 13 patients (54%) treated with PLD 2 study,” Neuro-Oncology, vol. 8, no. 2, pp. 189–193, 2006. 20 mg/m every 2 weeks . Similarly, Hau et al. observed  R. K. 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