Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Reinduction of Bevacizumab in Combination with Pegylated Liposomal Doxorubicin in a Patient with Recurrent Glioblastoma Multiforme Who Progressed on Bevacizumab/Irinotecan

Reinduction of Bevacizumab in Combination with Pegylated Liposomal Doxorubicin in a Patient with... 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, raltaha@hsc.wvu.edu 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 [4]. 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- [1]. 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. [2] 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 [5]. 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- [6]. A cross-resistance between irinotecan and PLD to ized tumor with a high expression of VEGF [3]. 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 [7]. He had a temozolomide [8]. 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 [7]. 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 [4]. 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 [12]. The significant response noted when option in recurrent GBM [9]. 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 [10]. This might lead to by bevacizumab [13]. 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 [14]. 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 [15] and is subject to resistance due to P- reduction in tumors size, a reduction in edema was noted [3]. 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 [18]. 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 [19]. 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 [20]. were treated with bevacizumab [11]. 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 [7] 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 [8] 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. [9] http://www.nccn.org/professionals/physician gls/PDF/cns.pdf. Significant partial response for 8 [10] 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 [11] 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. [12] 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 [21]. Similarly, Hau et al. observed [13] R. K. Jain, “Normalizing tumor vasculature with anti- 40% (out of 20 patients) overall response rate and 15% six angiogenic therapy: a new paradigm for combination ther- months progression-free survival using PLD 20 mg/m every apy,” Nature Medicine, vol. 7, no. 9, pp. 987–989, 2001. 2 weeks, either alone or with tamoxifen [22]. [14] J. E. A. Wolff,T.Trilling,G.Molenkamp ¨ , R. M. Egeler, and In summary, previous studies demonstrated that pegy- H. Jurgens, ¨ “Chemosensitivity of glioma cells in vitro: a meta lated liposomal doxorubicin penetrates BBB and achieves analysis,” Journal of Cancer Research and Clinical Oncology, vol. high-level concentration in tumor tissue. The recently 125, no. 8-9, pp. 481–486, 1999. described response to bevacizumab containing regimens [15] E. A. Neuwelt, M. Pagel, P. Barnett, M. Glassberg, and opens the door for combining bevacizumab with other E. P. Frenkel, “Pharmacology and toxicity of intracarotid cytotoxic chemotherapeutic agents. The addition of pegy- adriamycin administration following osmotic blood-brain barrier modification,” Cancer Research, vol. 41, no. 11, part 1, lated liposomal doxorubicin to bevacizumab seems to be a pp. 4466–4470, 1981. reasonable alternative in recurrent GBM, as illustrated by [16] A. C. Stan, S. Casares, D. Radu, G. F. Walter, and T.- the dramatic response observed in our patient despite heavy D. Brumeanu, “Doxorubicin-induced cell death in highly pretreatment. Further studies are needed to evaluate this invasive human gliomas,” Anticancer Research, vol. 19, no. 2A, regimen as a therapeutic option for treatment of recurrent pp. 941–950, 1999. or refractory GBM. [17] B. Schott, S. Bennis, P. Pourquier, C. Ries, D. Londos- Gagliardi, and J. Robert, “Differential over-expression of mdr1 genes in multidrug-resistant rat glioblastoma cell lines selected References with doxorubicin or vincristine,” International Journal of [1] D. A. Reardon and P. Y. Wen, “Therapeutic advances in the Cancer, vol. 55, no. 1, pp. 115–121, 1993. treatment of glioblastoma: rationale and potential role of [18] M. I. Koukourakis, S. Koukouraki, I. Fezoulidis, et al., targeted agents,” Oncologist, vol. 11, no. 2, pp. 152–164, 2006. “High intratumoural accumulation of stealth→ liposomal →) in glioblastomas and in metastatic [2] R.Stupp,W.P.Mason,M.J.van denBent, et al., “Radio- doxorubicin (Caelyx therapy plus concomitant and adjuvant temozolomide for brain tumours,” British Journal of Cancer, vol. 83, no. 10, pp. 1281–1286, 2000. glioblastoma,” The New England Journal of Medicine, vol. 352, no. 10, pp. 987–996, 2005. [19] L. Warren, J.-C. Jardillier, A. Malarska, and M.-G. Akeli, [3] W. B. Pope, A. Lai, P. Nghiemphu, P. Mischel, and T. F. “Increased accumulation of drugs in multidrug-resistant cells Cloughesy, “MRI in patients with high-grade gliomas treated induced by liposomes,” Cancer Research, vol. 52, no. 11, pp. with bevacizumab and chemotherapy,” Neurology, vol. 66, no. 3241–3245, 1992. 8, pp. 1258–1260, 2006. [20] T. Siegal, A. Horowitz, and A. Gabizon, “Doxorubicin encap- [4] J. J. Vredenburgh, A. Desjardins, J. E. Herndon II, et al., sulated in sterically stabilized liposomes for the treatment of a “Bevacizumab plus irinotecan in recurrent glioblastoma mul- brain tumor model: biodistribution and therapeutic efficacy,” tiforme,” Journal of Clinical Oncology, vol. 25, no. 30, pp. 4722– Journal of Neurosurgery, vol. 83, no. 6, pp. 1029–1037, 1995. 4729, 2007. [21] K. Fabel, J. Dietrich, P. Hau, et al., “Long-term stabilization in [5] A. A. Gabizon, “Liposomal anthracyclines,” Hematology/On- patients with malignant glioma after treatment with liposomal cology Clinics of North America, vol. 8, no. 2, pp. 431–450, doxorubicin,” Cancer, vol. 92, no. 7, pp. 1936–1942, 2001. 1994. [22] P. Hau, K. Fabel, U. Baumgart, et al., “Pegylated liposomal [6] A. M. Rahman, S. W. Yusuf, and M. S. Ewer, “Anthracycline- doxorubicin-efficacy in patients with recurrent high-grade induced cardiotoxicity and the cardiac-sparing effect of lipo- glioma,” Cancer, vol. 100, no. 6, pp. 1199–1207, 2004. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Oncology Hindawi Publishing Corporation

Reinduction of Bevacizumab in Combination with Pegylated Liposomal Doxorubicin in a Patient with Recurrent Glioblastoma Multiforme Who Progressed on Bevacizumab/Irinotecan

Download PDF
5 pages

Loading next page...
 
/lp/hindawi-publishing-corporation/reinduction-of-bevacizumab-in-combination-with-pegylated-liposomal-fqHtIpaaXS

References (24)

Publisher
Hindawi Publishing Corporation
Copyright
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.
ISSN
1687-8450
eISSN
1687-8469
DOI
10.1155/2008/942618
Publisher site
See Article on Publisher Site

Abstract

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, raltaha@hsc.wvu.edu 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 [4]. 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- [1]. 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. [2] 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 [5]. 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- [6]. A cross-resistance between irinotecan and PLD to ized tumor with a high expression of VEGF [3]. 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 [7]. He had a temozolomide [8]. 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 [7]. 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 [4]. 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 [12]. The significant response noted when option in recurrent GBM [9]. 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 [10]. This might lead to by bevacizumab [13]. 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 [14]. 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 [15] and is subject to resistance due to P- reduction in tumors size, a reduction in edema was noted [3]. 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 [18]. 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 [19]. 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 [20]. were treated with bevacizumab [11]. 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 [7] 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 [8] 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. [9] http://www.nccn.org/professionals/physician gls/PDF/cns.pdf. Significant partial response for 8 [10] 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 [11] 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. [12] 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 [21]. Similarly, Hau et al. observed [13] R. K. Jain, “Normalizing tumor vasculature with anti- 40% (out of 20 patients) overall response rate and 15% six angiogenic therapy: a new paradigm for combination ther- months progression-free survival using PLD 20 mg/m every apy,” Nature Medicine, vol. 7, no. 9, pp. 987–989, 2001. 2 weeks, either alone or with tamoxifen [22]. [14] J. E. A. Wolff,T.Trilling,G.Molenkamp ¨ , R. M. Egeler, and In summary, previous studies demonstrated that pegy- H. Jurgens, ¨ “Chemosensitivity of glioma cells in vitro: a meta lated liposomal doxorubicin penetrates BBB and achieves analysis,” Journal of Cancer Research and Clinical Oncology, vol. high-level concentration in tumor tissue. The recently 125, no. 8-9, pp. 481–486, 1999. described response to bevacizumab containing regimens [15] E. A. Neuwelt, M. Pagel, P. Barnett, M. Glassberg, and opens the door for combining bevacizumab with other E. P. Frenkel, “Pharmacology and toxicity of intracarotid cytotoxic chemotherapeutic agents. The addition of pegy- adriamycin administration following osmotic blood-brain barrier modification,” Cancer Research, vol. 41, no. 11, part 1, lated liposomal doxorubicin to bevacizumab seems to be a pp. 4466–4470, 1981. reasonable alternative in recurrent GBM, as illustrated by [16] A. C. Stan, S. Casares, D. Radu, G. F. Walter, and T.- the dramatic response observed in our patient despite heavy D. Brumeanu, “Doxorubicin-induced cell death in highly pretreatment. Further studies are needed to evaluate this invasive human gliomas,” Anticancer Research, vol. 19, no. 2A, regimen as a therapeutic option for treatment of recurrent pp. 941–950, 1999. or refractory GBM. [17] B. Schott, S. Bennis, P. Pourquier, C. Ries, D. Londos- Gagliardi, and J. Robert, “Differential over-expression of mdr1 genes in multidrug-resistant rat glioblastoma cell lines selected References with doxorubicin or vincristine,” International Journal of [1] D. A. Reardon and P. Y. Wen, “Therapeutic advances in the Cancer, vol. 55, no. 1, pp. 115–121, 1993. treatment of glioblastoma: rationale and potential role of [18] M. I. Koukourakis, S. Koukouraki, I. Fezoulidis, et al., targeted agents,” Oncologist, vol. 11, no. 2, pp. 152–164, 2006. “High intratumoural accumulation of stealth→ liposomal →) in glioblastomas and in metastatic [2] R.Stupp,W.P.Mason,M.J.van denBent, et al., “Radio- doxorubicin (Caelyx therapy plus concomitant and adjuvant temozolomide for brain tumours,” British Journal of Cancer, vol. 83, no. 10, pp. 1281–1286, 2000. glioblastoma,” The New England Journal of Medicine, vol. 352, no. 10, pp. 987–996, 2005. [19] L. Warren, J.-C. Jardillier, A. Malarska, and M.-G. Akeli, [3] W. B. Pope, A. Lai, P. Nghiemphu, P. Mischel, and T. F. “Increased accumulation of drugs in multidrug-resistant cells Cloughesy, “MRI in patients with high-grade gliomas treated induced by liposomes,” Cancer Research, vol. 52, no. 11, pp. with bevacizumab and chemotherapy,” Neurology, vol. 66, no. 3241–3245, 1992. 8, pp. 1258–1260, 2006. [20] T. Siegal, A. Horowitz, and A. Gabizon, “Doxorubicin encap- [4] J. J. Vredenburgh, A. Desjardins, J. E. Herndon II, et al., sulated in sterically stabilized liposomes for the treatment of a “Bevacizumab plus irinotecan in recurrent glioblastoma mul- brain tumor model: biodistribution and therapeutic efficacy,” tiforme,” Journal of Clinical Oncology, vol. 25, no. 30, pp. 4722– Journal of Neurosurgery, vol. 83, no. 6, pp. 1029–1037, 1995. 4729, 2007. [21] K. Fabel, J. Dietrich, P. Hau, et al., “Long-term stabilization in [5] A. A. Gabizon, “Liposomal anthracyclines,” Hematology/On- patients with malignant glioma after treatment with liposomal cology Clinics of North America, vol. 8, no. 2, pp. 431–450, doxorubicin,” Cancer, vol. 92, no. 7, pp. 1936–1942, 2001. 1994. [22] P. Hau, K. Fabel, U. Baumgart, et al., “Pegylated liposomal [6] A. M. Rahman, S. W. Yusuf, and M. S. Ewer, “Anthracycline- doxorubicin-efficacy in patients with recurrent high-grade induced cardiotoxicity and the cardiac-sparing effect of lipo- glioma,” Cancer, vol. 100, no. 6, pp. 1199–1207, 2004. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal

Journal of Oncology – Hindawi Publishing Corporation

Published: Sep 2, 2008

There are no references for this article.