Case Report
Bevacizumab as First-Line Therapy for Patients With Brain Metastases From Renal Carcinoma: A Case Series Fable Zustovich, Alessandra Ferro, Patrizia Farina Clinical Practice Points Bevacizumab has been approved by the European
Medicines Agency and the US Food and Drug Administration for metastatic kidney carcinoma (mRCC) when used in combination with a-interferon (IFN). The efficacy of the protocol was proven in 2 large randomized phase III studies published in 2008: the AVOREN (Avastin for renal cell cancer) and Cancer and Leukemia Group B 90206 trials.
Bevacizumab can safely be administered to patients
with mRCC with cerebral lesions, and a-IFN can be reduced or discontinued to manage its toxicity. In our case series, bevacizumab was proven to reduce dimension and perilesional edema of cranial metastases, and provide relief of symptoms and prolongation of progression-free and overall survival.
Clinical Genitourinary Cancer, Vol. 12, No. 3, e107-10 ª 2014 Elsevier Inc. All rights reserved. Keywords: Antiangiogenic, Cerebral, Kidney, Target therapy, VEGF
Introduction Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). This protein is highly expressed in kidney cancer and it has been shown to be increased beginning with start of the disease.1 Most clear-cell kidney tumors are driven by dysfunction of the von Hippel-Lindau (VHL) gene: loss of VHL function causes upregulation of hypoxia-inducible factor, which results in increased VEGF.2 This dysfunction of the VHL gene is thought to be a very early event in clear-cell kidney tumor development.3 Because of the role of VHL gene dysfunction, VEGF is a primary disease driver in renal carcinoma. Bevacizumab has been approved since 2007 by the European Medicines Agency and 2009 by the US Food and Drug Administration for metastatic kidney carcinoma when used in combination with a-interferon (IFN).4,5 The efficacy of this protocol was proven in 2 large randomized phase III studies published in 2008: the AVOREN (Avastin for renal cell cancer) and Cancer and Leukemia Group B (CALGB) 90206 trials. The AVOREN study6 is a large, multicenter, randomized, double-blind, placebo-controlled Phase III trial study. Patients with previously untreated metastatic predominantly clear-cell kidney Istituto Oncologico Veneto e IRCCS, Padova, Italy Submitted: Nov 7, 2013; Revised: Dec 27, 2013; Accepted: Dec 27, 2013; Epub: Jan 2, 2014 Address for correspondence: Fable Zustovich, MD, Istituto Oncologico Veneto e IRCCS, Via Gattamelata, 64, 35127 Padova, Italy Fax: þ390498215904; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.12.005
carcinoma were randomized to receive bevacizumab at 10 mg/kg every 2 weeks with a-IFN starting at 9 million international units or placebo with a-IFN. The AVOREN protocol allowed for a-IFN dose escalation, reduction, or discontinuation to manage its toxicity, but bevacizumab was continued until disease progression or unacceptable toxicity. The progression-free survival (PFS) benefit of bevacizumab with a-IFN was observed as early as 2 months and was sustained throughout the duration of the study: bevacizumab with a-IFN improved median PFS by 89% over placebo with a-IFN (10.2 vs. 5.4 months; hazard ratio [HR], 0.60 [95% confidence interval (CI), 0.49-0.72]; P < .0001). Median overall survival (OS) with bevacizumab and a-IFN was 23 months, a nonsignificant increase versus placebo with a-IFN (21 months; HR, 0.86 [95% CI, 0.72-1.04]; P ¼ .1291). Bevacizumab with a-IFN more than doubled overall response rate (ORR) versus placebo with a-IFN (30% vs. 12%; P < .0001). Moreover, duration of response was longer with bevacizumab with a-IFN (13.5 months) compared with placebo with a-IFN (11.1 months). The open-label, phase III CALGB 90206 trial,7 which compared treatment using bevacizumab and a-IFN with a-IFN alone, also showed significant PFS and ORR benefits for bevacizumab with a-IFN (median PFS, 8.4 vs. 4.9 months, respectively; HR, 0.71; P < .001, stratified; ORR, 25.5% vs. 13.1%, respectively, stratified). OS was not statistically different in both groups (18.3 months for the combination vs. 17.4 months for a-IFN alone). With regard to the toxicity of the protocol, the most common adverse reactions observed for bevacizumab were: fatigue, proteinuria,
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Bevacizumab in the Therapy of Brain Metastases From Renal Carcinoma anorexia, nausea, fever, neutropenia, hypertension, rectal hemorrhage, epistaxis, headache, and taste alteration,6,7 and for a-IFN were: flu-like syndrome, fatigue, headache, arthralgia, myalgia, dysentery, and low blood counts.
Case Reports In our case report we included 4 patients with advanced clear-cell kidney carcinoma and brain metastases. They were first evaluated for a specific cerebral treatment, such as neurosurgery or radiosurgery: 1 patient was treated with stereotactic radiosurgery, another with whole brain radiation therapy, and the other 2 patients were not suitable for specific local treatment.
Case 1 This 56-year-old man, with a surgically treated clear-cell kidney carcinoma in 2008, came to our attention in March 2010 for metastatic lesions to the brain surrounded by significant edema, resulting in neurological symptoms (confusion, disorientation in time and space). A computed tomography scan of the body also showed bone metastases to the thigh bone and the jaw. A first-line therapy with bevacizumab at 10 mg/kg every 2 weeks and a-IFN at 3 million international unit (MUI) trice a week was soon started. The patient showed a dramatic improvement of neurological symptoms after a few days, so dexamethasone administration was reduced and soon stopped. After 3 months of therapy, a gadoliniumenhanced cerebral magnetic resonance imaging (MRI) scan showed an “almost complete” response (see Fig. 1). The same treatment had been administered for 25 cycles with no brain progression and stable disease of bone, resulting in a PFS of 20.3 months. In June 2011, multiorgan disease progression occurred, so the patient underwent whole brain radiotherapy (WBRT) and other lines of therapy such as sorafenib, everolimus, and sunitinib. The patient died in November 2012 with an OS of 33.2 months. Toxicity was mild: a Grade 2 hypertension and a delayed wound healing after the excision of a metastatic nodule on the gluteal area.
Case 2 In 2003 this patient was diagnosed with a clear-cell kidney carcinoma and he was surgically treated with a radical nephrectomy. In March 2011, when he was 72 years old, a spread of cancer to the brain occurred with a single lesion treated with stereotactic radiosurgery. In the following months, the patient became neurologically symptomatic with confusion and slowness of movement. In June 2011, bevacizumab treatment we started at 10 mg/kg every 2 weeks and a short course of a-IFN soon stopped because of poor tolerance. The patient rapidly improved, and returned to his normal active life, and a gadolinium-enhanced MRI scan after 3 months of therapy showed a partial response (see Fig. 2). The treatment had been continued for 44 courses, confirming the partial response until brain and multiorgan disease progression in March 2013 with a PFS of 26.3 months. After that, the patient received radiosurgery to the brain without benefit and started taking sunitinib; at present he is still receiving therapy with sorafenib. About this case we have to mention an episode of pulmonary embolism during the therapy treated with low-weight heparin. Then, considering the substantial efficacy of the therapy and the patient’s will, we restarted administration of bevacizumab without other adverse events.
Case 3 This 71-year-old man came to our observation in September 2011 with a metastatic renal carcinoma with concomitant spread to the lymph nodes and brain, with numerous lesions above and below the tentorium. The patient had few unspecific symptoms such as asthenia and mild anorexia. Treatment with bevacizumab at 10 mg/kg every 2 weeks and a-IFN 3 MUI trice a week was administered and after 3 months of therapy, a gadolinium-enhanced cerebral MRI scan showed disease stabilization of brain lesions but an important regression of their peripheral edema. The patient had undergone therapy for 14 courses, obtaining a stabilization of the disease for 6.5 months (see Fig. 3), then the patient received WBRT and started
Figure 1 Case 1. Cranial MRI of the Patient With Complete Response of Cerebral Disease. On the Left, the Imaging at the Time of the Diagnosis, and During the Bevacizumab-Based Therapy (on the Right), There is no Evidence of Brain Metastases
Abbreviation: MRI ¼ magnetic resonance image.
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Fable Zustovich et al Figure 2 Case 2. Cranial MRI of the Patient With Partial Response. Before (on the Left) and After (on the Right) the Treatment With Bevacizumab
Abbreviation: MRI ¼ magnetic resonance image.
to receive sunitinib, but he developed a fast decay of his general condition and died in September 2012 with an OS of 12.3 months. No relevant toxicity was observed.
Case 4 In 2007, this patient was diagnosed with a localized clear-cell kidney carcinoma which was surgically removed. This 76-year-old man came to our attention in February 2013 with a cerebral metastasis from renal cancer and he was treated with WBRT. Because of the progression of the unique cerebral edemigenous lesion, in July 2013 administration of bevacizumab was started at 10 mg/kg every 2 weeks and a-IFN 3 MUI trice a week. Soon after, the patient continued only with bevacizumab because of the poor tolerance of a-IFN. A gadolinium-enhanced cerebral MRI scan
showed edema and lesion decrease, indicating a partial response. The patient is still responding to therapy and continuing bevacizumab administrations. Toxicity was absent after the suspension of a-IFN.
Discussion After previous experience using bevacizumab for the therapy of relapsed glioblastoma, we noticed a short survival time but a high capability to provide clinical benefit, mostly reducing perilesional edema, sometimes with a long-lasting effect.8 These observations are confirmed and appear even better in our case series of brain metastases from renal carcinoma: indeed response rate, PFS, and OS data are encouraging in consideration of the prognostic features of this particular subset of patients (see Table 1). Moreover, we have
Figure 3 Case 3. Cranial MRI of the Patient With Stable Cerebral Disease but Significant Perilesional Edema Decrease. Before (on the Left) and During (on the Right) Bevacizumab Administration
Abbreviation: MRI ¼ magnetic resonance image.
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Bevacizumab in the Therapy of Brain Metastases From Renal Carcinoma Table 1 Patient Characteristics Characteristic
Patient 1
Patient 2
Sex Male Male Age, Years 56 73 ECOG PS 0 1 Site of Metastasis (in Addition to the Brain) Bone Adrenal gland Previous CNS Metastases Therapy None SRS Beva with a-IFN Treatment Beva with a-IFN CNS Response CR PR Extra-CNS Response PR PR PFS, Months 20.3 26.3 OS, Months 33.2 >31 Adverse Events Hypertension and delayed healing Vascular venous: DVT and PE
Patient 3
Patient 4
Male 71 1 Lymph nodes None Beva with a-IFN SD SD 6.5 12.3 None
Male 76 1 Lymph nodes WBRT Beva with a-IFN PR PR >4.5 >4.5 None
Abbreviations: Beva ¼ bevacizumab; CNS ¼ central nervous system; DVT ¼ deep vein thrombosis; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; IFN ¼ interferon; OS ¼ overall survival; PE ¼ pulmonary embolism; PFS ¼ progression-free survival; SRS ¼ stereotactic surgery; WBRT ¼ whole brain radiation therapy.
noticed, but not still measured, a considerable gain in quality of life, enabling the reduction, very early in the disease history of the patient, of high-dose dexamethasone administration. This early suspension of dexamethasone administration is possible solely because of the antiedemigenous effect of bevacizumab. Soon after starting the treatment, patients have a rapid relief of their neurological symptoms and can reduce dexamethasone administration, even completely suspending it. Patients treated with bevacizumab as firstline therapy for brain metastatic disease are also able to delay, as much as possible, the administration of WBRT, avoiding all of the associated detrimental effects on cognitive function in case of longterm survival. In our experience with this subset of patients with brain metastasis, the contribution of a-IFN is minimal and the side effects of the combination of bevacizumab with a-IFN are substantially due to the a-IFN. That is the reason we did not hesitate to suspend a-IFN administration soon after the first quality of life-impairing symptoms such as fever, myalgia, and arthralgia. Some data regarding the role of target therapies in the treatment of patients with brain metastasis from renal cell carcinoma are available from the expanded access studies of sunitinib and sorafenib. Data are limited by the fact that there is no mention about previous or subsequent brain-specific therapies such as surgery, radiotherapy, and so on.9-11 Regarding sunitinib, in 213 patients with brain metastasis a partial response rate of 12% was observed compared with the 16% obtained in the overall patient population. In the same report, 320 patients were those evaluable for PFS and OS, which were respectively, 5.6 and 9.2 months, compared with 10.9 and 18.4 months of the overall patient population.9 The role of sorafenib was explored by the North American and European expanded access studies in which 50 and 28 patients respectively had brain metastasis from renal cell carcinoma. Data are fragmentary with partial response
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rate of 4% and median PFS of 7.0 months, and no data on OS are available.10,11 In our knowledge, there are no reported cases of patients with cerebral metastases from renal cancer treated with bevacizumab with IFN-a as first-line therapy, so we share our experience on bevacizumab which appears feasible, safe, and can lead to very promising efficacy data.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Audenet F, Yates DR, Cancel-Tassin G, et al. Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine. BJU Int 2012; 109:1864-70. 2. Vanharanta S, Shu W, Brenet F, et al. Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Nat Med 2013; 19:50-6. 3. Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008; 14:4726-34. 4. Rini BI. Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions. Clin Cancer Res 2007; 13:1098-106. 5. FDA Gives Roche’s Avastin the Go-Ahead for Metastatic Renal Carcinoma. Available at: http://www.genengnews.com/gen-news-highlights/fda-gives-roche-s-avastin-thego-ahead-for-metastatic-renal-carcinoma/59562374/. Accessed: August 3, 2009. 6. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370:2103-11. 7. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008; 26:5422-8. 8. Zustovich F, Lombardi G, Pastorelli D, et al. Bevacizumab and glioblastomas, a single-centre experience: how disease history and characteristics may affect clinical outcome. Anticancer Res 2010; 30:5213-6. 9. Gore ME, Szcylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 2009; 10:757-63. 10. Stadler WM, Figlin RA, McDermott DF, et al. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer 2010; 116:1272-80. 11. Beck J, Procopio G, Bajetta E, et al. Final results of the European advanced renal cell carcinoma sorafenib (EU-ARCCS) expanded access study: a large open-label study in diverse community settings. Ann Oncol 2011; 22:1812-23.
Bevacizumab as First-Line Therapy for Patients With Brain Metastases From Renal Carcinoma: A Case Series Fable Zustovich, Alessandra Ferro, Patrizia Farina Clinical Practice Points Bevacizumab has been approved by the European
Medicines Agency and the US Food and Drug Administration for metastatic kidney carcinoma (mRCC) when used in combination with a-interferon (IFN). The efficacy of the protocol was proven in 2 large randomized phase III studies published in 2008: the AVOREN (Avastin for renal cell cancer) and Cancer and Leukemia Group B 90206 trials.
Bevacizumab can safely be administered to patients
with mRCC with cerebral lesions, and a-IFN can be reduced or discontinued to manage its toxicity. In our case series, bevacizumab was proven to reduce dimension and perilesional edema of cranial metastases, and provide relief of symptoms and prolongation of progression-free and overall survival.
Clinical Genitourinary Cancer, Vol. 12, No. 3, e107-10 ª 2014 Elsevier Inc. All rights reserved. Keywords: Antiangiogenic, Cerebral, Kidney, Target therapy, VEGF
Introduction Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). This protein is highly expressed in kidney cancer and it has been shown to be increased beginning with start of the disease.1 Most clear-cell kidney tumors are driven by dysfunction of the von Hippel-Lindau (VHL) gene: loss of VHL function causes upregulation of hypoxia-inducible factor, which results in increased VEGF.2 This dysfunction of the VHL gene is thought to be a very early event in clear-cell kidney tumor development.3 Because of the role of VHL gene dysfunction, VEGF is a primary disease driver in renal carcinoma. Bevacizumab has been approved since 2007 by the European Medicines Agency and 2009 by the US Food and Drug Administration for metastatic kidney carcinoma when used in combination with a-interferon (IFN).4,5 The efficacy of this protocol was proven in 2 large randomized phase III studies published in 2008: the AVOREN (Avastin for renal cell cancer) and Cancer and Leukemia Group B (CALGB) 90206 trials. The AVOREN study6 is a large, multicenter, randomized, double-blind, placebo-controlled Phase III trial study. Patients with previously untreated metastatic predominantly clear-cell kidney Istituto Oncologico Veneto e IRCCS, Padova, Italy Submitted: Nov 7, 2013; Revised: Dec 27, 2013; Accepted: Dec 27, 2013; Epub: Jan 2, 2014 Address for correspondence: Fable Zustovich, MD, Istituto Oncologico Veneto e IRCCS, Via Gattamelata, 64, 35127 Padova, Italy Fax: þ390498215904; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.12.005
carcinoma were randomized to receive bevacizumab at 10 mg/kg every 2 weeks with a-IFN starting at 9 million international units or placebo with a-IFN. The AVOREN protocol allowed for a-IFN dose escalation, reduction, or discontinuation to manage its toxicity, but bevacizumab was continued until disease progression or unacceptable toxicity. The progression-free survival (PFS) benefit of bevacizumab with a-IFN was observed as early as 2 months and was sustained throughout the duration of the study: bevacizumab with a-IFN improved median PFS by 89% over placebo with a-IFN (10.2 vs. 5.4 months; hazard ratio [HR], 0.60 [95% confidence interval (CI), 0.49-0.72]; P < .0001). Median overall survival (OS) with bevacizumab and a-IFN was 23 months, a nonsignificant increase versus placebo with a-IFN (21 months; HR, 0.86 [95% CI, 0.72-1.04]; P ¼ .1291). Bevacizumab with a-IFN more than doubled overall response rate (ORR) versus placebo with a-IFN (30% vs. 12%; P < .0001). Moreover, duration of response was longer with bevacizumab with a-IFN (13.5 months) compared with placebo with a-IFN (11.1 months). The open-label, phase III CALGB 90206 trial,7 which compared treatment using bevacizumab and a-IFN with a-IFN alone, also showed significant PFS and ORR benefits for bevacizumab with a-IFN (median PFS, 8.4 vs. 4.9 months, respectively; HR, 0.71; P < .001, stratified; ORR, 25.5% vs. 13.1%, respectively, stratified). OS was not statistically different in both groups (18.3 months for the combination vs. 17.4 months for a-IFN alone). With regard to the toxicity of the protocol, the most common adverse reactions observed for bevacizumab were: fatigue, proteinuria,
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Bevacizumab in the Therapy of Brain Metastases From Renal Carcinoma anorexia, nausea, fever, neutropenia, hypertension, rectal hemorrhage, epistaxis, headache, and taste alteration,6,7 and for a-IFN were: flu-like syndrome, fatigue, headache, arthralgia, myalgia, dysentery, and low blood counts.
Case Reports In our case report we included 4 patients with advanced clear-cell kidney carcinoma and brain metastases. They were first evaluated for a specific cerebral treatment, such as neurosurgery or radiosurgery: 1 patient was treated with stereotactic radiosurgery, another with whole brain radiation therapy, and the other 2 patients were not suitable for specific local treatment.
Case 1 This 56-year-old man, with a surgically treated clear-cell kidney carcinoma in 2008, came to our attention in March 2010 for metastatic lesions to the brain surrounded by significant edema, resulting in neurological symptoms (confusion, disorientation in time and space). A computed tomography scan of the body also showed bone metastases to the thigh bone and the jaw. A first-line therapy with bevacizumab at 10 mg/kg every 2 weeks and a-IFN at 3 million international unit (MUI) trice a week was soon started. The patient showed a dramatic improvement of neurological symptoms after a few days, so dexamethasone administration was reduced and soon stopped. After 3 months of therapy, a gadoliniumenhanced cerebral magnetic resonance imaging (MRI) scan showed an “almost complete” response (see Fig. 1). The same treatment had been administered for 25 cycles with no brain progression and stable disease of bone, resulting in a PFS of 20.3 months. In June 2011, multiorgan disease progression occurred, so the patient underwent whole brain radiotherapy (WBRT) and other lines of therapy such as sorafenib, everolimus, and sunitinib. The patient died in November 2012 with an OS of 33.2 months. Toxicity was mild: a Grade 2 hypertension and a delayed wound healing after the excision of a metastatic nodule on the gluteal area.
Case 2 In 2003 this patient was diagnosed with a clear-cell kidney carcinoma and he was surgically treated with a radical nephrectomy. In March 2011, when he was 72 years old, a spread of cancer to the brain occurred with a single lesion treated with stereotactic radiosurgery. In the following months, the patient became neurologically symptomatic with confusion and slowness of movement. In June 2011, bevacizumab treatment we started at 10 mg/kg every 2 weeks and a short course of a-IFN soon stopped because of poor tolerance. The patient rapidly improved, and returned to his normal active life, and a gadolinium-enhanced MRI scan after 3 months of therapy showed a partial response (see Fig. 2). The treatment had been continued for 44 courses, confirming the partial response until brain and multiorgan disease progression in March 2013 with a PFS of 26.3 months. After that, the patient received radiosurgery to the brain without benefit and started taking sunitinib; at present he is still receiving therapy with sorafenib. About this case we have to mention an episode of pulmonary embolism during the therapy treated with low-weight heparin. Then, considering the substantial efficacy of the therapy and the patient’s will, we restarted administration of bevacizumab without other adverse events.
Case 3 This 71-year-old man came to our observation in September 2011 with a metastatic renal carcinoma with concomitant spread to the lymph nodes and brain, with numerous lesions above and below the tentorium. The patient had few unspecific symptoms such as asthenia and mild anorexia. Treatment with bevacizumab at 10 mg/kg every 2 weeks and a-IFN 3 MUI trice a week was administered and after 3 months of therapy, a gadolinium-enhanced cerebral MRI scan showed disease stabilization of brain lesions but an important regression of their peripheral edema. The patient had undergone therapy for 14 courses, obtaining a stabilization of the disease for 6.5 months (see Fig. 3), then the patient received WBRT and started
Figure 1 Case 1. Cranial MRI of the Patient With Complete Response of Cerebral Disease. On the Left, the Imaging at the Time of the Diagnosis, and During the Bevacizumab-Based Therapy (on the Right), There is no Evidence of Brain Metastases
Abbreviation: MRI ¼ magnetic resonance image.
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Fable Zustovich et al Figure 2 Case 2. Cranial MRI of the Patient With Partial Response. Before (on the Left) and After (on the Right) the Treatment With Bevacizumab
Abbreviation: MRI ¼ magnetic resonance image.
to receive sunitinib, but he developed a fast decay of his general condition and died in September 2012 with an OS of 12.3 months. No relevant toxicity was observed.
Case 4 In 2007, this patient was diagnosed with a localized clear-cell kidney carcinoma which was surgically removed. This 76-year-old man came to our attention in February 2013 with a cerebral metastasis from renal cancer and he was treated with WBRT. Because of the progression of the unique cerebral edemigenous lesion, in July 2013 administration of bevacizumab was started at 10 mg/kg every 2 weeks and a-IFN 3 MUI trice a week. Soon after, the patient continued only with bevacizumab because of the poor tolerance of a-IFN. A gadolinium-enhanced cerebral MRI scan
showed edema and lesion decrease, indicating a partial response. The patient is still responding to therapy and continuing bevacizumab administrations. Toxicity was absent after the suspension of a-IFN.
Discussion After previous experience using bevacizumab for the therapy of relapsed glioblastoma, we noticed a short survival time but a high capability to provide clinical benefit, mostly reducing perilesional edema, sometimes with a long-lasting effect.8 These observations are confirmed and appear even better in our case series of brain metastases from renal carcinoma: indeed response rate, PFS, and OS data are encouraging in consideration of the prognostic features of this particular subset of patients (see Table 1). Moreover, we have
Figure 3 Case 3. Cranial MRI of the Patient With Stable Cerebral Disease but Significant Perilesional Edema Decrease. Before (on the Left) and During (on the Right) Bevacizumab Administration
Abbreviation: MRI ¼ magnetic resonance image.
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Bevacizumab in the Therapy of Brain Metastases From Renal Carcinoma Table 1 Patient Characteristics Characteristic
Patient 1
Patient 2
Sex Male Male Age, Years 56 73 ECOG PS 0 1 Site of Metastasis (in Addition to the Brain) Bone Adrenal gland Previous CNS Metastases Therapy None SRS Beva with a-IFN Treatment Beva with a-IFN CNS Response CR PR Extra-CNS Response PR PR PFS, Months 20.3 26.3 OS, Months 33.2 >31 Adverse Events Hypertension and delayed healing Vascular venous: DVT and PE
Patient 3
Patient 4
Male 71 1 Lymph nodes None Beva with a-IFN SD SD 6.5 12.3 None
Male 76 1 Lymph nodes WBRT Beva with a-IFN PR PR >4.5 >4.5 None
Abbreviations: Beva ¼ bevacizumab; CNS ¼ central nervous system; DVT ¼ deep vein thrombosis; ECOG PS ¼ Eastern Cooperative Oncology Group performance status; IFN ¼ interferon; OS ¼ overall survival; PE ¼ pulmonary embolism; PFS ¼ progression-free survival; SRS ¼ stereotactic surgery; WBRT ¼ whole brain radiation therapy.
noticed, but not still measured, a considerable gain in quality of life, enabling the reduction, very early in the disease history of the patient, of high-dose dexamethasone administration. This early suspension of dexamethasone administration is possible solely because of the antiedemigenous effect of bevacizumab. Soon after starting the treatment, patients have a rapid relief of their neurological symptoms and can reduce dexamethasone administration, even completely suspending it. Patients treated with bevacizumab as firstline therapy for brain metastatic disease are also able to delay, as much as possible, the administration of WBRT, avoiding all of the associated detrimental effects on cognitive function in case of longterm survival. In our experience with this subset of patients with brain metastasis, the contribution of a-IFN is minimal and the side effects of the combination of bevacizumab with a-IFN are substantially due to the a-IFN. That is the reason we did not hesitate to suspend a-IFN administration soon after the first quality of life-impairing symptoms such as fever, myalgia, and arthralgia. Some data regarding the role of target therapies in the treatment of patients with brain metastasis from renal cell carcinoma are available from the expanded access studies of sunitinib and sorafenib. Data are limited by the fact that there is no mention about previous or subsequent brain-specific therapies such as surgery, radiotherapy, and so on.9-11 Regarding sunitinib, in 213 patients with brain metastasis a partial response rate of 12% was observed compared with the 16% obtained in the overall patient population. In the same report, 320 patients were those evaluable for PFS and OS, which were respectively, 5.6 and 9.2 months, compared with 10.9 and 18.4 months of the overall patient population.9 The role of sorafenib was explored by the North American and European expanded access studies in which 50 and 28 patients respectively had brain metastasis from renal cell carcinoma. Data are fragmentary with partial response
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rate of 4% and median PFS of 7.0 months, and no data on OS are available.10,11 In our knowledge, there are no reported cases of patients with cerebral metastases from renal cancer treated with bevacizumab with IFN-a as first-line therapy, so we share our experience on bevacizumab which appears feasible, safe, and can lead to very promising efficacy data.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Audenet F, Yates DR, Cancel-Tassin G, et al. Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine. BJU Int 2012; 109:1864-70. 2. Vanharanta S, Shu W, Brenet F, et al. Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Nat Med 2013; 19:50-6. 3. Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008; 14:4726-34. 4. Rini BI. Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions. Clin Cancer Res 2007; 13:1098-106. 5. FDA Gives Roche’s Avastin the Go-Ahead for Metastatic Renal Carcinoma. Available at: http://www.genengnews.com/gen-news-highlights/fda-gives-roche-s-avastin-thego-ahead-for-metastatic-renal-carcinoma/59562374/. Accessed: August 3, 2009. 6. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370:2103-11. 7. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008; 26:5422-8. 8. Zustovich F, Lombardi G, Pastorelli D, et al. Bevacizumab and glioblastomas, a single-centre experience: how disease history and characteristics may affect clinical outcome. Anticancer Res 2010; 30:5213-6. 9. Gore ME, Szcylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 2009; 10:757-63. 10. Stadler WM, Figlin RA, McDermott DF, et al. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer 2010; 116:1272-80. 11. Beck J, Procopio G, Bajetta E, et al. Final results of the European advanced renal cell carcinoma sorafenib (EU-ARCCS) expanded access study: a large open-label study in diverse community settings. Ann Oncol 2011; 22:1812-23.
