european urology 53 (2008)

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1 european urology 53 (2008) available at journal homepage: Kidney Cancer High Frequency of Intracerebral Hemorrhage in Metastatic Renal Carcinoma Patients with Brain Metastases Treated with Tyrosine Kinase Inhibitors Targeting the Vascular Endothelial Growth Factor Receptor Damien Pouessel, Stéphane Culine * Department of Medical Oncology, C.R.L.C. Val d Aurelle, Montpellier, France Article info Article history: Accepted August 23, 2007 Published online ahead of print on September 4, 2007 Keywords: Intracerebral hemorrhage Renal cell carcinoma Sorafenib Sunitinib Vascular endothelial growth factor receptor Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Objectives: To report the high incidence of intracerebral hemorrhage (ICH) in patients with metastatic renal cell carcinoma (RCC) treated with the tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGFR). Methods and results: Between October 2005 and December 2006, 67 patients with metastatic RCC were treated with sorafenib or sunitinib at the Montpellier Cancer Center in compassionate access programs. The medical records of five (7%) patients who died of ICH during therapy were reviewed retrospectively. Four of them had known brain metastases. Previous radiation therapy had been indicated in two patients. Two patients had a history of hypertension. Death from ICH occurred in the first 2 wk following the onset of treatment. Three other patients with brain metastases who received sorafenib or sunitinib during the same period did not experience ICH. Conclusions: The frequency of fatal ICH in RCC patients with brain metastases treated with tyrosine kinase inhibitors targeting the VEGFR seems high. Prospective clinical trials will be necessary for assessing the true incidence and predictive factors related to this toxicity. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Medical Oncology, C.R.L.C. Val d Aurelle, Parc Euromédecine, Montpellier Cedex 5, France. Tel ; Fax: address: stculine@valdorel.fnclcc.fr (S. Culine). 1. Introduction The year 2006 will mark a turning point in the daily management of patients with metastatic renal cell carcinoma (RCC). Indeed, the growing understanding of molecular mechanisms involved in the pathogenesis of the disease, especially clear-cell carcinoma, has led to the development of targeted therapies with significant clinical benefits [1,2]. Two compounds that predominantly inhibit the /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 53 (2008) tyrosine kinase activity of the vascular endothelial growth factor receptor (VEGFR), sorafenib and sunitinib, improve the progression-free survival of patients in first-line (sunitinib vs. interferon-a)or second-line (sorafenib vs. placebo) treatment [3,4]. Additionally temsirolimus, an agent that inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics [5]. Therefore, molecularly targeted therapies are becoming the standard of care in metastatic RCC, but the extent of their benefit on overall survival remains to be refined [2,6]. The reported toxicities of these new drugs in phase 2 and 3 clinical trials appear moderate and manageable. Particularly, the incidence of intracerebral hemorrhage (ICH) was <1% [3 5,7 9]. However, we recently observed several fatal ICHs after VEGFR inhibitor treatment in RCC patients with brain metastases (BM). 2. Methods Between October 2005 and December 2006, 32 and 35 patients with metastatic RCC were treated with sorafenib and sunitinib, respectively, at the Montpellier Cancer Center in compassionate access programs. Patients received oral sorafenib as a continuous treatment at a dose of 400 mg twice daily. Sunitinib was administered orally at a dose of 50 mg once daily in 6-wk cycles consisting of 4 wk of treatment followed by 2 wk without treatment. Seven patients had BM at the onset of therapy. Five patients, four of whom had BM, developed ICH and died. We reviewed all of their medical records as well as the clinical outcome of other patients with BM who did not experience ICH. 3. Results 3.1. Patients who developed ICH (Table 1) Patient 1 A 71-yr-old woman with clear-cell RCC was initially treated by nephrectomy in February No history of hypertension (HT), stroke, transient ischemic attack, or cerebral hemorrhage was noted. Four years after surgery, she had a contralateral renal tumor along with lung, liver, and bone metastases. Because of progressive disease after immunotherapy, sunitinib (50 mg orally) was given daily for 4 wk followed by 2 wk without treatment. The pretreatment cerebral computed tomography (CT) scan was normal as well as blood pressure on the first day of therapy. Dysarthria developed 14 d after starting sunitinib. Confusion and troubles of consciousness appeared a few hours later with concomitant HT. A cerebral CT scan showed a massive ICH with Table 1 Characteristics of patients with intracerebral hemorrhage Patient no Sex Female Female Male Male Male Previous history No No Cerebral stroke Hypertension Hypertension Antiplatelet therapy Histology of primary renal tumor Clear cell Clear cell Papillary Clear cell Clear cell Age at diagnosis, yr Treatments before VEGFR inhibitor Nephrectomy Yes Yes Yes Yes Yes Immunotherapy Yes Yes Yes Yes Yes Chemotherapy No No Yes No No Bevacizumab No No No No No Cerebral metastases before VEGFR inhibitor No Yes Yes Yes Yes No. (maximal diameter in mm) Unique (36) Multiple (11) Unique (10) Unique (18) Radiotherapy No Yes Yes No Time interval between end of radiotherapy and initiation of VEGFR inhibitor, d 30 7 VEGFR inhibitor Sunitinib Sunitinib Sorafenib Sorafenib Sorafenib Blood pressure at initiation of VEGFR 160/ /60 150/85 160/ /55 inhibitor, mm Hg Time interval between VEGFR inhibitor and cerebral hemorrhage, d Hypertensive peak at diagnosis of ICH, mm Hg Yes, 190/100 No, 130/80 Yes, 200/100 Yes, 185/60 Yes, 210/100 Survival after ICH, d VEGFR = vascular endothelial growth factor receptor; ICH = intracerebral hemorrhage.

3 378 european urology 53 (2008) subarachnoid bleeding. The patient died of central neurologic failure 3 d later Patient 2 A 59-yr-old woman presented with clear cell RCC and concomitant mediastinal and retroperitoneal lymph nodes metastases in June She was initially treated by nephrectomy and immunotherapy. A few months later, her disease progressed with local and abdominal parietal recurrence. A cerebral CT scan showed a unique asymptomatic BM. No radiotherapy was delivered. She had no history of HT, stroke, transient ischemic attack, or cerebral hemorrhage. Sunitinib (50 mg orally) was given daily for 4 wk followed by 2 wk without treatment. Blood pressure was normal before therapy. Generalized convulsive crises and troubles of consciousness (Glasgow score 5) developed 4 d after the start of sunitinib. Blood pressure was normal (130/80 mm Hg) at hospital admission. The cerebral CT scan showed ICH around the frontal BM. Neurosurgery was decided for metastasectomy. After surgery, her neurologic state did not improve and she died 3 d later Patient 3 A 71-yr-old man with papillary RCC was initially treated by nephrectomy in May He had no history of HT. A stroke had occurred in 1995 and required antiplatelet therapy. Four months after surgery, his disease progressed with lung, mediastinal lymph node, and adrenal gland metastases. He received immunotherapy and chemotherapy as first- and second-line treatments, respectively. As disease progressed, treatment with a VEGFR inhibitor was considered. A systematic cerebral CT scan showed multiple asymptomatic BM, and wholebrain radiotherapy was performed (30 Gy in 10 fractions). Sorafenib (400 mg orally) twice daily was started 30 d after completion of irradiation. On the first day, blood pressure was normal. Hemiplegia developed 2 d later, associated with HT. Cerebral CT scan showed a massive ICH. He died on the same day Patient 4 A 62-yr-old man with clear-cell RCC was initially treated by nephrectomy in January Treatment for HT was ongoing. No history of stroke, transient ischemic attack, or cerebral hemorrhage was noted. In March 2006, his disease progressed with liver, retroperitoneal lymph node, and bone metastases. He received immunotherapy as firstline treatment. Because of progressive disease, an oral antiangiogenic tyrosine kinase inhibitor was considered. Because a pretreatment cerebral CT scan showed a unique asymptomatic BM, wholebrain radiotherapy was performed (30 Gy in 10 fractions). Sorafenib (400 mg orally) twice daily was started 7 d after completion of irradiation. Before treatment, systolic and diastolic blood pressures were, respectively, 160 and 100 mm Hg. Confusion developed 6 d after start of sorafenib, and troubles of consciousness appeared a few hours later. Cerebral CT scan showed a massive ICH with subarachnoid bleeding. He died 3 d later Patient 5 A 78-yr-old man with clear-cell RCC was diagnosed in March 2003 and initially treated by nephrectomy. He received treatment for HT, but no history of stroke, transient ischemic attack, or cerebral hemorrhage was noted. Two years after surgery, his disease recurred with lung and stomach metastases as well as mediastinal lymph nodes. Owing to progressive disease after immunotherapy, an orally antiangiogenic therapy was decided on. A pretreatment cerebral CT scan showed unique asymptomatic cerebral metastases and no radiotherapy was delivered. Sorafenib (400 mg orally) twice daily was given. Blood pressure was normal before therapy. Troubles of consciousness, then coma (Glasgow score 4) developed 5 d after the start of sorafenib. Clinical examination showed elevated blood pressure (210/100 mm Hg) and fever (40.5 8C). He died before a CT scan could be performed, but the clinical history highly suggests an ICH Patients with cerebral metastases without hemorrhage (Table 2) Patient 6 A 58-yr-old woman presented with RCC and lung metastases in July She was initially treated with nephrectomy and immunotherapy. A few months later, she presented left arm monoplegia and facial paralysis. Cerebral CT scan showed multiple cerebral metastases and whole-brain radiotherapy was performed (30 Gy in 10 fractions). Three months later, because of progressive disease with new lung and thyroid metastases, sunitinib (50 mg orally) once daily was given for 4 wk followed by 2 wk off. No history of HT, stroke, transient ischemic attack, or cerebral hemorrhage was noted. Blood pressure was normal before therapy. One cycle was delivered but disease progressed and she died 1 mo later without neurologic signs.

4 european urology 53 (2008) Table 2 Characteristics of patients with cerebral metastases who did not develop intracerebral hemorrhage Patient no Sex Female Male Female Previous history No No No Histology of primary renal tumor Clear cell Clear cell Clear cell Age at diagnosis, yr Treatments before VEGFR inhibitor Nephrectomy Yes Yes Yes Immunotherapy Yes Yes Yes Chemotherapy No No No Bevacizumab No Yes No Cerebral metastases before VEGFR inhibitor Yes Yes Yes No. (maximal diameter in mm) Multiple (15) Multiple (20) Unique (11) Radiotherapy Yes Yes Yes Time interval between radiotherapy and initiation of VEGFR inhibitor, d VEGFR inhibitor Sunitinib Sunitinib Sorafenib Blood pressure at initiation of VEGFR 120/70 130/90 120/80 inhibitor, mm Hg VEGFR = vascular endothelial growth factor receptor Patient 7 A 57-yr-old man with metastatic RCC was initially treated by nephrectomy in August He presented lung, pleura, mediastinal, and retroperitoneal lymph node metastases. He received immunotherapy and bevacizumab as first- and second-line treatments, respectively. As disease progressed, treatment with a VEGFR inhibitor was considered. As cerebral CT scan showed multiple asymptomatic BM; prior whole-brain radiotherapy was performed (30 Gy in 10 fractions). Then sunitinib (50 mg orally) was started, as previous described, 26 d after completion of irradiation. No history of HT, stroke, transient ischemic attack, or cerebral hemorrhage was noted. Blood pressure was normal before therapy. He died 3 mo later from progressive disease, without neurologic signs Patient 8 A 42-yr-old woman with clear-cell RCC was initially treated by nephrectomy in November Lung and mediastinal lymph node metastases were present at diagnosis. She received immunotherapy as first-line treatment. In September 2006, because of progressive disease, an oral antiangiogenic tyrosine kinase inhibitor was considered. A systematic pretreatment cerebral CT scan showed a unique asymptomatic metastasis, and prior stereotactic radiotherapy was performed (33 Gy in 3 fractions). Sorafenib (400 mg orally) twice daily was started 14 d after completion of irradiation. Before treatment, blood pressure was normal. No history of HT, stroke, transient ischemic attack, or cerebral hemorrhage was noted. At the present time, therapy is ongoing without any neurologic symptoms. 4. Discussion Four patients with BM from RCC, who were treated with sunitinib or sorafenib, died of ICH in our institution. Another patient with a pretreatment normal cerebral CT scan also died of ICH. The hemorrhages occurred between the days 2 and 14 after starting treatment, and all of them were acute, massive, and fatal. The rate of ICH during treatment with inhibitors of the VEGFR is very low in the literature reported so far. In recently published phase 3 trials of sorafenib or sunitinib conducted in metastatic RCC patients, no ICH was reported [3,4]. Similarly, no ICH was observed among > 200 patients with gastrointestinal stromal tumor who were treated with sunitinib as second-line treatment in a placebo-controlled phase 3 trial [10]. However, single cases of ICH were described in phase 2 studies with sunitinib in RCC and advanced non small-cell lung cancer or with sorafenib in hepatocellular carcinoma [11 13]. It is noteworthy that patients with BM were excluded from phase 3 trials. Similarly, neither life-threatening toxic effects nor ICHs were reported with bevacizumab, a humanized monoclonal antibody targeted against VEGF, in a randomized phase 2 study in RCC patients but brain metastasis was an exclusion criterion [14]. More recently were reported the results of preliminary assessment of toxicity in expanded access trials with sunitinib and sorafenib

5 380 european urology 53 (2008) [15,16]. One hundred and eighty-two patients and 65 patients were treated with sunitinib or sorafenib, respectively. Neither study reported a significant increase in risk of ICH. Because ICH occurred in four of seven patients who had known BM before therapy, BM should be considered as a major risk factor. There is no report suggesting an increased incidence of ICH in RCC patients with BM. No trend was detected concerning the number or the size of BM and the incidence of ICH. An elevated blood pressure was observed in two patients before treatment and four patients had an effective treatment for HT. HT is a well-known risk factor for cerebral bleeding [17,18]. In phase 3 trials, grade 3 4 HT has been observed with sunitinib and sorafenib in 8% and 4% of metastatic RCC patients, respectively [3,4]. At diagnosis of ICH, an increase in blood pressure was observed in most patients but was certainly secondary to ICH as reported before [19]. Another issue is related to the possible favoring role of antiplatelet or anticoagulant therapies. Indeed, bleeding complications observed during angiogenesis inhibition are most probably caused by disturbance of the tight endothelial cell platelet interaction that maintains vascular integrity [20]. Angiogenesis and coagulation are closely related biologic processes [21]. VEGF has a role in the coagulation cascade by inducing tissue factor expression on endothelial cells, which, in turn, activates platelets and converts fibrinogen into fibrin to cause clot formation. Therefore, antiplatelet or anticoagulant therapies are supposed to enhance the risk of bleeding complications. However, no relationships were identified between these treatments and the development of ICH in our patient population. Only one patient was treated with antiplatelet therapy because of a history of stroke 10 yr before. No definitive recommendations about the optimal use of these treatments along with VEGFR inhibitors have been published so far. Nevertheless sunitinib should be used cautiously in combination with anticoagulant therapies because of the risk of tumor necrosis reported in some trials. A lethal peritoneal hemorrhage has been described in a responding patient with peritoneal recurrence of gastrointestinal stromal tumor [22]. Finally, may radiotherapy have a role in preventing the development of ICH? Because two of the first three patients had not undergone irradiation before VEGFR inhibitor treatment, brain radiotherapy was delivered in subsequent patients. However, two additional deaths occurred despite previous radiotherapy. Conversely, ICH did not occur in two patients who received radiotherapy, respectively, 6 mo and 2 wk before starting on VEGFR inhibitor therapy. Because the two patients who died from ICH started VEGFR inhibitor therapy between 1 and 4 wk after the end of radiotherapy, a minimal time interval of 6 wk may be more appropriate. In the Cleveland Clinic Foundation experience, 23 patients who had received prior surgery or radiotherapy (or both) for BM received VEGFR inhibitors without significant toxicity [23]. 5. Conclusions The frequency of fatal ICH in RCC patients with BM treated with tyrosine kinase inhibitors targeting the VEGFR is high in our experience. Considering the small size of the cohort and the current recent data reported in the literature, it cannot be excluded that our cases are a random observation. Prospective clinical trials will be necessary to assess the true incidence and predictive factors related to this toxicity. Conflicts of interest The authors have nothing to disclose. References [1] Patard J-J, Rioux-Leclercq N, Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006;49: [2] Pouessel D, Culine S. Targeted therapies in metastatic renal cell carcinoma: the light at the end of the tunnel. Exp Rev Anticancer Ther 2006;6: [3] Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356: [4] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa (IFN-a) in metastatic renal-cell carcinoma. N Engl J Med 2007;356: [5] Hudes G, Carducci M, Tomczak P, et al. A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferonalpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol 2006;24:930s (abstract). [6] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51: [7] Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24: [8] Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebocontrolled randomized discontinuation trial of sorafenib

6 european urology 53 (2008) in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24: [9] Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295: [10] Demetri GD, Van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368: [11] Rini BI, George DJ, Michaelson MD, et al. Efficacy and safety of sunitinib malate (SU11248) in bevacizumabrefractory metastatic renal cell carcinoma (mrcc). Proc Am Soc Clin Oncol 2006;24:222s (abstract). [12] Socinski MA, Novello S, Sanchez JM, et al. Efficacy and safety of sunitinib in previously treated, advanced nonsmall cell lung cancer (NSCLC): preliminary results of a multicenter phase II trial. Proc Am Soc Clin Oncol 2006;24:364s (abstract). [13] Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24: [14] Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349: [15] Gore ME, Porta C, Oudard S, et al. Sunitinib in metastatic renal cell carcinoma: preliminary assessment of toxicity in an expanded access trial with subpopulation analysis. Proc Am Soc Clin Oncol 2007;25:237s (abstract). [16] Henderson CA, Bukowski R, Stadler WM, et al. The Advanced Renal Cell Carcinoma Sorafenib expanded access trial: subset analysis of patients with brain metastases. Proc Am Soc Clin Oncol 2007;25:650s (abstract). [17] Badjatia N, Rosand J. Intracerebral hemorrhage. Neurologist 2005;11: [18] Sutherland GR, Auer RN. Primary intracerebral hemorrhage. J Clin Neurosci 2006;13: [19] Rasool AH, Rahman AR, Choudhury SR, et al. Blood pressure in acute intracerebral haemorrhage. J Hum Hyperten 2004;18: [20] Verheul HMW, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Cancer Rev 2007;7: [21] Nash GF, Walsh DC, Kakkar AK. The role of the coagulation system in tumour angiogenesis. Lancet Oncol 2001;2: [22] Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24: [23] Unnithan JS, Choueri T, Garcia J, et al. Safety of VEGFtargeted tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma and central nervous system metastases. Proc Am Soc Clin Oncol 2007;25:246s (abstract).