The Advantage of Bevacizumab in Treating Colorectal Brain Metastasis

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1 台灣癌症醫誌 (J. Cancer Res. Pract.) 1(2), , 2014 DOI: /JCRP Case Report journal homepage: The Advantage of Bevacizumab in Treating Colorectal Brain Metastasis Hung-Ming Chen 1 *, Hao-Wei Teng 2 1 Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan 2 Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Abstract. Bevacizumab is known to be a humanized monoclonal antibody that inhibits vascular endothelial growth factor. It is used to treat varied kinds of cancers, such as breast cancer, colorectal cancer, non-small cell lung cancer, high grade glioma and etc. While it do appear to delay cancer progression, it is not a curative approach. Because of its high molecular weight, bevacizumab would be believed to be not cross the blood- brain barrier. However, this theory is to be challenged by series of studies proving the efficacy of bevacizumab in brain tumor. On account of lack of vital information about safety events and increasing risk of intra-cranial hemorrhage, Food and Drug Administration (FDA) lifted the ban on use of bevacizumab in colorectal cancer with brain metastasis since several years ago. Therefore, the reports of use of bevacizumab in colorectal cancer with brain metastasis are limited. Here, we presented a case of colorectal cancer with brain metastasis, and the brain lesion got shrinkage after starting bevacizumab in combination with chemotherapy. 病例報告 Keywords : biochemotherapy, bevacizumab, avastin, colorectal cancer, brain metastasis Bevacizumab 對於結腸直腸癌合併腦轉移的治療成效 陳鴻明 1 * 鄧豪偉 1 國軍桃園總醫院內科部 2 台北榮民總醫院內科部 2 中文摘要 Bevacizumab 是一種人工合成單株性抗體主要可抑制血管內皮細胞生長因子, 目前被廣泛運用在許多癌症, 例如乳癌 結腸直腸癌, 非小細胞肺癌以及高度膠質瘤等等, 主要目的在於延緩疾病的惡化, 而非讓疾病獲得治癒 因為高分子量,bevacizumab 在以往都被視無法穿透血腦屏障, 然而根據一些關於其對腦瘤的療效的研究,bevacizumab 目前被相信仍會有部分穿透血腦屏障的能力, 但儘管如此由於其缺乏全盤安全性資料以及會增加顱內出血的機率, 在多年前美國食品藥物管理局已經將 bevacizumab 對於大腸直腸癌合併腦轉移的適應症撤銷, 因此目前關於其對於大腸致腸癌合併腦轉移治療相關的研究極少 在這篇文章中, 我們呈現一位結腸直腸癌合併腦轉移病患在接受 bevacizumab 合併化學治療後腦病灶明顯縮小的案例 關鍵字 : 生物化學治療 bevacizumab 癌思停 結腸直腸癌 腦轉移 Open access under CC BY-NC-ND license.

2 H. M. Chen et al./jcrp 1(2014) INTRODUCTION Colorectal cancer is a major cause of death throughout the world, and the frequency of this kind of cancer has increased two to four fold in Asian countries during the past few decases [1,2]. In 2008, a new kind of colorectal cancer occurred in 1.2 million people, and it accounted for 9.7% of all cancers [3,4]. In Taiwan, its proportion was up to 14.3% [5]. Although the incidence of the colorectal cancer is commonly higher than those of other malignancies, brain metastasis occurs rather infrequently in colorectal cancer. With the advances in treatment of colorectal cancer, the overall survival has been prolongd over the past decades. However, for unresectable disease, the five-year overall survival rate has remained low, been estimated to be less than 10% [6]. The cumulative incidence of brain metastasis originating from colorectal cancer 5 years after initial treatment is estimated to be 1-2% [7-9]. We believe that the rate of brain metastasis in colorectal cancer will rise continuously as the survival of patients is prolonged. The mechanism of brain metastasis remains unclear, but the affinity between cancerous cells and neuronal tissues may be involved in the process [10]. In one study, its authors restrospectively identified 17 patients with brain metastasis and concluded that higher neural cell adhesion molecule (NCAM) expression in primary colorectal cancer was in association with a higher incidence rate of brain metastasis [11]. Overexpression of the vascular endothelial growth factor that increases vascular permeability and interstitial fluid pressure is critical for vascular proliferation and tumor survival. Therefore, it is reasonable to *Corresponding author: Hung-Ming Chen M.D. * 通訊作者 : 陳鴻明醫師 Tel: Fax: mpttkimo@yahoo.com.tw support that bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, can suppress new blood vessel growth and existence. It was provided in first-line and second-line bevacizumabnaïve settings in combination with 5-fluorouracil (5-FU) based therapy to metastatic colorectal cancer [12,13]. Because of its efficacy and manageable toxicity, it was approved by the FDA for patients with metastatic colorectal cancer on February 26, However, the role of bevacizumab in the treatment of brain metastases is still unclear. In the past, bevacizumab was believed to be useless in brain metastasis because of its limited ability to cross the blood-brain barrier. But in animal models, bevacizumab was shown to be effective in brain tumor [14]. In some case reports [15-17] and also in a phase II study [18], the clinical benefit of bevacizumab in patients with colorectal, breast and non-small cell lung cancers with brain metastases was proven. Although the mechanism is not completely clarified, we believe, at least in part, it is due to blood-brain barrier reconstitution and vascular normalization. This is probably why penetration of the blood-brain barrier is not required for intratumoral penetration. In this article, we present a clinical course of a complicated case with colorectal cancer with brain metastasis, and the patient s condition improved after use of bevacizumab. CASE REPORT In May 2010, a 57-year-old female presented with bloody stools for two weeks. Colonoscopy was then performed at an outside institution and showed an ulcerative tumor six to fifteen centimeters from the anal verge. To seek a second medical opinion, the patient was transferred to our hospital. After the second colonoscopy, the patient was diagnosed to have adenocarcinoma of the rectum on the basis of the biopsy. Baseline computed tomography (CT) of the chest and abdomen showed multiple small nodules in lung fields bilaterally and in both hepatic lobes. Increased soft tissue density in the right lower quadrant of the abdo-

3 148 H. M. Chen et al./jcrp 1(2014) A B Figure 1. Contrast enhanced CT of brain showing. (A) A heterogenous enhancing soft tissue nodule 15 millimeters in dimension with prominent perifocal edema, in left parasagital high parietal region; (B) An enhancing nodule 7 mm in dimension with mild perifocal edema, at right occipital pole men was also noted on the CT. Therefore, the final parasagital high parietal region and the other, seven diagnosis was adenocarcinoma of the rectum with per- millimeters in dimension in the right occipital lobe itoneal seeding, liver and lung metastases, and ac- (Figure 1). We performed the magnetic resonance im- cording to the American Joint Committee on Cancer aging (MRI) of the brain (Figure 2) and its result was (AJCC), clinical stage T3N2M1. The baseline carci- compatible with the findings of CT. Under the diagno- noembryonic antigen (CEA) level was 980 ng/ml, sis of brain metastasis, the patient received whole- Subsequently, the patient underwent a radical proctec- brain radiotherapy with 3600 cgy in 12 fractions dur- tomy with low anterior resection plus lymph node ing the hospitalization. Xeloda was concurrently used dissection and bilateral salpingo oophorectomy in with radiotherapy following three cycles of XELIRI June, And the surgical stage of the tumor was (Xeloda, leucovorin and irinotecan). After therapy, the compatible with the clinical one which was mentioned brain lesions were in stable condition, and the pa- above. Adjuvant chemotherapy with FOLFOX (5-FU, tient s neurological symptoms improved gradually. leucovorin and oxaliplatin) was administered in 6 However, the pulmonary lesions remained progressing, cycles. We changed the chemotherapy regimen to and we added cetuximab to XELIRI subsequently. FOLFIRI (5-FU, leucovorin and irinotecan) in Octo- After five cycles of cetuximab plus XELIRI and sub- ber, 2010 because of increased size of pulmonary sequent three cycles of XELIRI, a follow-up chest CT nodular lesions. In October 2010, the patient was taken in May, 2011 and it revealed that the pulmonary found to have nausea, intermittent headache and diz- lesions seemed to be still progressive. The patient s ziness. Subsequent CT of the brain revealed two het- nausea and dizziness became worse, and she devel- erogenous enhancing nodules with perifocal edema. oped unstable gait in June, 2011, while brain lesions One was fifteen millimeters in dimension in the left remained stationary on the CT (Figure 2A, 2B).

4 H. M. Chen et al./jcrp 1(2014) A B C D 149 Figure 2. Comparison of contrast-enhanced CT of brain before bevacizumab (A, B) and the one after bevacizumab (C, D) showing shrinkage of brain lesions Therefore, the patient started on Bevacizumab plus patient presented with vomiting with massive coffee XELIRI in July, Dramatically, the following ground material and severe dyspnea. After receiving brain CT in August showed shrinkage of the brain le- medical treatment, the patient was eventually referred sions (Figure 2C, 2D). In spite of the improvement of to a hospice. the brain lesions and neurological symptoms, the systemic lesions (lung, liver, and peritoneal carcinomatosis) progressed after our therapy. In October, 2011, the DISCUSSION Since last decades, bevacizumab combined with

5 150 H. M. Chen et al./jcrp 1(2014) intravenous 5-FU based drugs have become the first line therapy for patients with metastatic colorectal cancer. However, its role in the metastatic brain lesions originating from the colorectal cancer is still unclear because of the limited number of cases in clinical trials. A case report [15] similar to ours published in 2008 first presented the therapeutic effect of bevacizumab in a patient with colorectal cancer with brain metastasis. Here, we have presented a case of adenocarcinoma of the rectum with multiple metastases. Even at the begining, the patient already had extensive metastatic disease to the liver, lung, and peritoneum. Metastatic brain lesions, however developed during her therapeutic course. According to the previous analytic data, one year median survival was less than 1% for the patients with brain metastasis [19]. For our patient, the duration of her survival period was 14 months after the confirmed diagnosis. We believe that the patient s longer survival period was attributed to the progressive and aggressive treatment. Tracing our patient s treatment and clinical presentation, we find that the brain lesions remained stable under series of treatments started in October, During this period, the treatments included XE- LIRI and cetuximab. After addition of bevacizumab, the brain lesions began to show regressive change on the image study, and the patient s neurological symptoms improved subsequently. In a retrospective study [20], the authors reviewed 14 patients with recurrent glioma who have been treated with bevacizumab and chemotherapy. Seven patients (50%) showed partial response on MRI. The effect of bevacizumab was presumed not only to reduce peri-focal edema but also to directly inhibit glioma cells. Notablely, the response occurred in as few as 18 days after the initiation of therapy. For our case, the response was noted 45 days after the beginning of bevacizumab by the evidence of brain CT. In fact, the response was noted earlier clinically. In a case report which was published in 2010 [21], the authors presented a 54-year-old woman with metastatic infiltrating ductal breast carcinoma which developed brain metastasis. After microsurgical resection followed by stereotactic radiosurgery, bevacizumab was administered for six months. After the six months therapy of bevacizumab, a newly enhanced nodular lesion was noted on the brain MRI. By histopathologic examination, the new lesion was still the metastatic breast cancer. After discontinuation of bevacizumab, the enhanced nodular lesions developed again. Thus, the authors concluded bevacizumab would alter neuroimaging characteristics. Compared with this case, our patient did not have resection and continued to be placed on bevacizumab for three months. Because of improvement of neurologic deficits, we believe that the shrinkage of brain lesions on the brain CT reflected tumor in regression instead of showing a masking effect of the bevacizumab. CONCLUSIONS The therapeutic advantage seemed to be obvious and impressive in our case hereby presented. However, large scale clinical trials are necessary for a complete understanding of the exact therapeutic mechanisms of bevacizumab. REFERENCES 1. Sung JJ, Lau JY, Goh KL, et al. Increasing incidence of colorectal cancer in Asia: Implications for screening. Lancet Oncol 6: , Coleman MP, Quaresma M, Berrino F, et al. Cancer survival in five continents: A worldwide population-based study (CONCORD). Lancet Oncol 9: , Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No Lyon, France: International Agency for Research on Cancer, Available from: iarc.fr. Accessed May Health and National Health Insurance Annual Statistics Information Service. Department of Health,

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