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

Authors: Mohammed Almubarak; Michael Newton; Ramin Altaha
Journal: Journal of Oncology
 (2008)

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## Abstract

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.


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## Body

## 1. Introduction

Glioblastoma
multiforme (GBM) is the most common primary brain tumor in adults. Despite advancement in areas of clinical detection
and treatment, GBM continues to have an ominous prognosis with median survival
less than a year [1].  Historically,
GBM was treated with resection followed by radiation. The addition of
nitrosourea-based chemotherapy added a small survival benefit. The standard of
treatment was changed after Stupp et al. [2] demonstrated an
improvement in survival by 2 months using temozolomide in combination with
radiation compared to radiation alone.Bevacizumab
is a recombinant humanized monoclonal antibody that inhibits the biologic
activity of vascular endothelial growth factor (VEGF). GBM is a highly
vascularized tumor with a high expression of VEGF [3].
Bevacizumab
has shown promising results in a recent phase II clinical trial when combined
with a topoisomerase I inhibitor, irinotecan, for the treatment of recurrent
GBM  [4]. The antitumor
activity of bevacizumab containing regimens could be due to enhanced
permeability of the tumor vasculature which leads to improved penetration of
the cytotoxic chemotherapy agents.
We hypothesized that replacing
irinotecan with another  cytotoxic
chemotherapy agent with a differenet resistance profile may overcome the
resistance to BI regimen.PLD is a
liposome-encapsulated dosage form of doxorubicin which works by intercalating
into DNA resulting in inhibition of DNA synthesis. It also inhibits
topoisomerase II [5]. PLD has several potential advantages over
standard doxorubicin including longer circulatory half-life, more specific
delivery to tumor tissue and reduced cardiac toxicity [6]. A
cross-resistance between irinotecan and PLD to our knowledge has not been
described. Combining PLD
with bevacizumab might prove to be effective in
treating GBM.


## 2. Case Report

A 56-year-old healthy man presented in October 2004 with short-term memory
deficit and a left-sided visual field defect. A magnetic resonance image (MRI) of
the brain showed a large (5.7 cm× 3.5 cm)
right occipitoparietal enhancing mass
with extension into the ventricular system and satellite metastases with associated
edema and mass effect.He underwent a stereotactic biopsy of the lesion that revealed
a diagnosis of GBM. The patient declined surgical resection. He received steroids and
was placed on levetiracetam (Keppra, UCB Inc., Smyrna, Ga, USA) for
seizure prophylaxis.The patient was started on concomitant chemoradiotherapy per Stupp regimen
consisting of temozolomide (Temodar, Schering Corporation, Kenilworth, NJ, USA)
75 mg/m2 daily as well as radiation therapy (a total of 59.4 Gy).
He had significant improvement in his neurological function with evidence of partial
response on brain MRI. However, temozolomide had to be discontinued after 2 months secondary
to severe thrombocytopenia. After completion of the radiation therapy, he was then started on
thalidomide 300 mg and tamoxifen 200 mg daily for maintenance. His disease was stable
on this regimen for approximately 10 months. Subsequently, a brain MRI showed progression
of disease. This regimen was discontinued and he was started on bevacizumab
(Avastin, Genentech Inc., South San Francisco, Calif, USA) 10 mg/kg with
irinotecan 125 mg/m2 every 2 weeks based on an abstract published
by Stark-Vance in 2005 [7].  He had a 90 percent decrease in the
tumor size after two cycles on this regimen. However, after seven cycles on this
regimen a brain MRI showed increased mass effect and interval development of abnormal
contrast enhancement in the medial hemispheric aspect of the right occipital and parietal
lobe area, compatible with progression of disease
(Figure 1).MRI brain T1 with gadolinium
after stopping bevacizumab with irinotecan.
(a)(b)Subsequently, he was restarted on temozolomide 150 mg/m2
on days 1–5 every month. He developed neutropenia requiring growth factor
support as well as thrombocytopenia requiring oprelvekin (Neumega, Wyeth Pharmaceuticals
Inc., Philadelphia , Pa). After 2 cycles on this regimen, his follow-up brain MRI showed
progression of disease (Figure 2). He was not considered a candidate for additional
alkylating agent-based chemotherapy such as carmustine (BCNU) or the PCV regimen
(procarbazine, lomustine, vincristine) due to dose limiting hematologic toxicity
experienced with temozolomide.Brain T1 with gadolinium
prior to reinduction with bevacizumab with PLD.
(a)(b)The patient was reinduced with bevacizumab
10 mg/kg with the addition of pegylated liposomal doxorubicin (Doxil, Ortho Biotech
Products, LP, Bridgewater, NJ, USA) 20 mg/m2 every 2 weeks.  His brain MRI
(T1 with gadolinium, FLAIR and T2 weighted images) after 4 treatments showed substantial
decrease in bulk of the large mass in the right posterior cerebral hemisphere with
associated decrease in edema (Figure 3).Brain T1 with gadolinium
after treatment with bevacizumab with PLD.
(a)(b)Despite achieving the dramatic imaging response and initial improvement
in performance status, the patient declined further chemotherapy and imaging modalities.
He developed decubitus ulcer and died 2 months after he received his last dose
of PLD/bevacizumab.Table summarizes the treatment regimens and duration of response for this patient.Table 1
Summary of treatment regimens and duration of response.
Chemotherapy/treatmentResponse(1)  Temozolomide and radiationPartial response after two
months, but discontinued secondary to significant thrombocytopenia.(2) Thalidomide and tamoxifenDisease stabilization for 10
months with subsequent progression.(3)  Bevacizumab with irinotecanSignificant partial response
for 8 months with subsequent progression.(4) Temozolomide reinductionDisease progression after 2
months.(5)  Bevacizumab reinduction and pegylated liposomal doxorubicinPartial response
(approximately 60%) after 2 months. Treatment stopped at the patient’s
request.


## 3. Discussion

GBM is a highly
vascularized tumor and thus targeting angiogenesis could represent a major new
treatment approach. Ahmed et al. demonstrated 64% (or 9 out of 14 patients)
response/disease stabilization lasting anywhere from
8 to 135 weeks using an outpatient oral regimen of the angiogenesis inhibitor,
thalidomide, plus tamoxifen, and temozolomide [8].VEGF inhibitors are
currently being investigated in several clinical trials.  An abstract
published by Stark-Vance at the
sixth meeting of the European Association of Neuro-oncology showed 43% response
(9 out of 21 patients) to a regimen consisting of bevacizumab and irinotecan
every 2 weeks [7]. Vredenburgh et al. further confirmed the efficacy
of irinotecan and
bevacizumab in patients with recurrent grade III-IV gliomas. In this phase II
trial, 57% out of the 35 patients had radiographic response and the 6-month overall
survival was 77%. Of note, four patients developed thomboembolic complications
and one had a CNS bleed [4]. Based
on this data, the National Cancer Comprehensive Network (NCCN) has updated
their guidelines recently to include bevacizumab-based regimens as a salvage
treatment option in recurrent GBM [9].Since VEGF
inhibitors affect the vascular permeability of the tumor, this may result in
decrease in contrast enhancement in MRI images [10].
This might lead
to questioning the true
validity of using MRI to assess response to treatment.  Pope et al. evaluated
MRI response in high-grade
gliomas treated with bevacizumab in addition to different chemotherapeutic
agents. They noted reduction in contrast enhancing tumor in 7 out of 14
patients in as little as 2 weeks. Of interest, even in those patients who did
not have reduction in tumors size, a reduction in edema was noted
[3].Nonetheless,
response to such bevacizumab containing regimen in high-grade gliomas was
proved using positron emission tomography (PET) by Chen et al. In this study, a
47% response rate (9 out of 19) was reported with 65% 6-month survival.
Metabolic responders survived three times as long as nonresponders (10.8 versus
3.4 months). This was the first study to describe the ability to use PET scan
as an imaging modality for predicting survival in patients who were treated
with bevacizumab [11].Irinotecan is a
water soluble camptothecin (CPT) analog that interferes with the catalytic
cycle of topoisomerase I enzyme. Irinotecan
as a single agent has very low response rate in GBM [12]. The
significant response noted when combined with bevacizumab could be due to
improved drug delivery resulting from a reduction in interstitial fluid
pressure and normalization of the tumor vasculature
by bevacizumab [13].
This introduces the possibility of enhanced
blood brain barrier (BBB) penetration of other cytotoxic agents when combined
with bevacizumab.Doxorubicin has
shown significant in vitro cytotoxicity in cell lines derived from
malignant glioma cells [14]. Unfortunately, doxorubicin does not
adequately penetrate the BBB [15] and is subject to resistance due
to P-glycoprotein mediated efflux [16, 17]. However, pegylated liposomal doxorubicin
selectively overcomes the BBB in the tumor areas, with accumulation more than
10 fold higher in the tumor than in normal brain tissue [18]. Pegylated liposomal doxorubicin also
appears to overcome P-glycoprotein mediated resistance [19].
Moreover, there seems to be an enhanced
drug exposure and improvement in therapeutic activity when comparing pegylated
liposomal doxorubicin to conventional doxorubicin in brain tumors in rats
[20].A single agent
regimen with pegylated liposomal doxorubicin has proven moderate efficacy in
GBM patients as demonstrated by Fabel et al. who observed disease stabilization
in 7 of 13 patients (54%) treated with PLD 20 mg/m2
every 2 weeks [21]. Similarly,
Hau et al. observed 40% (out of 20 patients) overall response
rate and 15% six months progression-free survival using PLD 20 mg/m2 every 2
weeks, either alone or with tamoxifen [22].In summary,
previous studies demonstrated that pegylated liposomal doxorubicin penetrates
BBB and achieves high-level concentration in tumor tissue. The recently
described response to bevacizumab containing regimens opens the door for
combining bevacizumab with other cytotoxic chemotherapeutic agents. The
addition of pegylated liposomal doxorubicin to bevacizumab seems to be a
reasonable alternative in recurrent GBM, as illustrated by the dramatic
response observed in our patient despite heavy pretreatment. Further studies
are needed to evaluate this regimen as a therapeutic option for treatment of
recurrent or refractory GBM.



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*Source: 942618-2008-09-02.xml*