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Li L, Bai J, Wen X, Zeng X. Adverse reactions of four multi-targeted tyrosine kinase inhibitors: a descriptive analysis of the WHO-VigiAccess database. Front Pharmacol 2025; 16:1585862. [PMID: 40331199 PMCID: PMC12052882 DOI: 10.3389/fphar.2025.1585862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Accepted: 04/04/2025] [Indexed: 05/08/2025] Open
Abstract
Background The introduction of multi-targeted tyrosine kinase inhibitors (MTKIs) such as axitinib, lenvatinib, sorafenib, and sunitinib has greatly broadened the available treatment options for Renal Cell Carcinoma (RCC). The study aims to compare the nature of the adverse reactions associated with these four MTKIs to identify which medication poses the least risk for personalized patient management, thus enabling more accurate clinical drug oversight. Methods Employing a retrospective descriptive analysis methodology, this research concentrated on four commercially available MTKIs. Reports pertaining to these medications were sourced from the WHO-VigiAccess database. The data gathering process involved collecting comprehensive information on various parameters, such as age demographics, gender, and the geographical distribution of patients associated with the ADR reports. Furthermore, the study explored disease systems and symptoms that were documented alongside the adverse reactions, as outlined in the annual ADR reports produced by the WHO. To assess the relationship between these four MTKIs and the linked AEs, both the Proportional Reporting Ratio (PRR) and the Reported Odds Ratio (ROR) were utilized. Results At the time of the search, a total of 123,818 AEs associated with the four MTKIs had been documented in the VigiAccess database. The common ADRs for these four MTKIs include diarrhoea, fatigue, death, hypertension, nausea, asthenia, weight decreased, and vomiting. Gastrointestinal disorders and general disorders and administration site conditions emerged as the SOCs with the highest number of adverse signals, both ranking first in terms of frequency. The elevated ROR (1.08) and PRR (1.06) values associated with gastrointestinal disorders in patients treated with sorafenib suggest a higher incidence of such adverse events compared to those observed with axitinib, lenvatinib, and sunitinib. Conclusion Recent comparative observational research suggests that the ADR reports submitted to the WHO and the FDA for these medications highlight both common and specific ADRs. It is essential for clinical practitioners to develop personalized treatment strategies that consider the adverse effects linked to different medications, alongside the unique circumstances of their patients, thus encouraging the responsible use of these MTKIs.
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Affiliation(s)
- Lijun Li
- Department of Pharmacy, The Second Affiliated Hospital, University of South China, Hengyang, Hunan, China
- Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Hunan Provincial Key Clinical Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, the Second Affiliated Hospital, University of South China, Hengyang, Hunan, China
| | - Jiayu Bai
- Department of rehabilitation medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xuelong Wen
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Xuefan Zeng
- Chongqing Medical University, Chongqing, China
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Catalano F, Rebuzzi SE, Murianni V, Damassi A, Martelli V, Borea R, Rollandi GA, Fornarini G. Rare anti-VEGFR therapy-induced toxicity and long-term response to immunotherapy in a rare non-clear cell renal cell carcinoma patient. Anticancer Drugs 2022; 33:e724-e729. [PMID: 34261919 DOI: 10.1097/cad.0000000000001152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Advanced non-clear cell renal cell carcinoma (nccRCC) has a poor prognosis and clinical data on the therapeutic options currently available, including immunotherapy, are generally limited highlighting an unmet clinical need. Moreover, the onset of rare adverse events raises the need of a better therapeutic management of limited treatment options. We report the clinical case of a 63-year-old man with the diagnosis of metastatic mucinous tubular and spindle cell carcinoma, a rare nccRCC, with sarcomatoid differentiation who developed two episodes of posterior reversible encephalopathy syndrome (PRES) to first-line sunitinib. It appeared after 5 months the start of the targeted therapy and reappeared at the reintroduction of the therapy. PRES is a rare and unusual adverse event to anti-vascular endothelial growth factor receptor (VEGFR) therapies, which is characterized by acute neurological disorders along with typical changes on neurological imaging, especially MRI. Moreover, this rare histotype of RCC experienced a long-term response to immunotherapy which is lasting more than 2 years. This clinical case is interesting for its rarity as a rare neurological adverse event developed twice in a rare type of RCC which also experienced an unusual long-term benefit to immunotherapy.
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Affiliation(s)
| | | | | | - Alessandra Damassi
- Academic Unit of Medical Oncology, IRCCS Ospedale Policlinico San Martino IST
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Lv B, Chen J, Liu XL. Anlotinib-Induced Hypertension: Current Concepts and Future Prospects. Curr Pharm Des 2021; 28:216-224. [PMID: 34620054 DOI: 10.2174/1381612827666211006145141] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/27/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Anlotinib is a new tyrosine kinase inhibitor developed in China that targets the receptors for vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and stem cell factor. Therefore, anlotinib inhibits tumor angiogenesis, representing a new therapeutic alternative for lung cancer. Hypertension is one of its most common adverse effects, leading to discontinuation of the drug and limited clinical usefulness. OBJECTIVE The present review aims to summarize the evidence on the prevalence, physiopathology, and management of anlotinib-induced hypertension, as well as its effect on the cancer prognosis. METHOD Searches in Medline, Cochrane Central Library, and Embase were performed using the following terms: anlotinib, adverse effect, hypertension, clinical trial, vascular endothelial growth factor, and antiangiogenic drugs. Citations were also identified by checking the reference sections of selected papers. RESULTS Except for a phase I clinical trial with a small sample size (n = 6), almost all the clinical trials on anlotinib have reported the development of anlotinib-induced hypertension. In these trials, the incidence of hypertension ranged from 13% to 67.7%, and that of grade 3/4 hypertension ranged from4.8% to 16%. Alterations in nitric oxide, endothelin-1, microvascular rarefaction, selective vasoconstrictions, and renal injury have been cited as potential mechanisms leading to anlotinib-induced hypertension. When needed, treatment may include general hygienic measures and pharmacotherapy in some cases. CONCLUSIONS To effectively manage anlotinib-induced hypertension, early prevention, a reasonable dosage regimen, and appropriate treatment are critical to effectively manage anlotinib-induced hypertension. Additionally, anlotinib-induced hypertension may be considered a marker for predicting efficacy.
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Affiliation(s)
- Bing Lv
- Emergency Department, First Hospital of Jilin University, Changchun, Jilin Province. China
| | - Jing Chen
- Department of Endocrinology and Nephrology, Central Hospital of Tonghua, Tonghua, Jilin Province. China
| | - Xiao-Liang Liu
- Emergency Department, First Hospital of Jilin University, Changchun, Jilin Province. China
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Dong M, Wang R, Sun P, Zhang D, Zhang Z, Zhang J, Tse G, Zhong L. Clinical significance of hypertension in patients with different types of cancer treated with antiangiogenic drugs. Oncol Lett 2021; 21:315. [PMID: 33692847 PMCID: PMC7933774 DOI: 10.3892/ol.2021.12576] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 01/13/2021] [Indexed: 12/13/2022] Open
Abstract
Hypertension is a common comorbidity in patients receiving antiangiogenic therapy. Prior studies have reported worsening or new-onset hypertension as an adverse event of antiangiogenetic therapy, which can be managed by dose reduction or discontinuation of the culprit medication. By contrast, other studies have found that the occurrence of hypertension is a potential biomarker associated with greater efficacy of antiangiogenic therapy and predicts improved survival. At present, there is no consensus on the effects of hypertension in patients treated with antiangiogenic drugs. The present study reviewed the relationship between antiangiogenic drugs and hypertension in different types of cancer. It was demonstrated that the use of antiangiogenic drugs was associated with an increased risk of hypertension in most types of solid cancers. There was no significant difference in the incidence of hypertension between monoclonal antibody and small-molecule tyrosine kinase inhibitor treatments. Hypertension was more likely to occur in patients younger than 75 years old, female, and those with no history of bevacizumab use. Discontinuation or death caused by hypertension was rare, although previous studies have reported that hypertension was a risk factor for acute and chronic cardiovascular diseases and ischemic stroke. Of note, the early development of hypertension may serve as a potential biomarker associated with greater efficacy of antiangiogenic therapy.
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Affiliation(s)
- Mei Dong
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Rujian Wang
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Ping Sun
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Dongxia Zhang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Zhenzhen Zhang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Jing Zhang
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Lin Zhong
- Department of Cardiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
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Winters AC, Bedier F, Saab S. Management of Side Effects of Systemic Therapies for Hepatocellular Carcinoma: Guide for the Hepatologist. Clin Liver Dis 2020; 24:755-769. [PMID: 33012457 DOI: 10.1016/j.cld.2020.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Historically, systemic treatment of advanced hepatocellular carcinoma was limited to the tyrosine kinase inhibitor sorafenib. With the recent approval of several new agents the armamentarium of treatment options available to providers and patients has expanded. Although these promising advances offer hope for patients with advanced hepatocellular carcinoma, they also present new and challenging adverse effects that threaten to limit their efficacy. Immunotherapy with checkpoint inhibitors introduce immune-related adverse events, which may affect a wide array of organ systems. With prompt recognition, however, common side effects of systemic therapies for hepatocellular carcinoma are predictable, manageable, and many improve with appropriate intervention.
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Affiliation(s)
- Adam C Winters
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA
| | - Fatima Bedier
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA
| | - Sammy Saab
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA.
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Castellano D, Maroto JP, Espinosa E, Grande E, Bolós MV, Llinares J, Esteban E, González Del Alba A, Climent MA, Arranz JA, Méndez MJ, Fernández Parra E, Antón-Aparicio L, Bayona C, Gallegos I, Gallardo E, Samaniego L, García Donas J. Experience with Sunitinib in metastatic renal cell carcinoma (mRCC) patients: pooled analysis from 3 Spanish observational prospective studies. Expert Opin Drug Saf 2018; 17:573-579. [PMID: 28535693 DOI: 10.1080/14740338.2017.1330410] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 05/10/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients. OBJECTIVE To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice. METHODS Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered. RESULTS 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02-12.25), median OS 21.9 months (95% CI: 17.2-26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8-50.7). Median time to PR was 3.8 months (95% CI: 3.86-5.99) and to CR 8.2 months (95% CI: 4.75-9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05) Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.
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Affiliation(s)
| | - José Pablo Maroto
- b Medical Oncology , Hospital de la Santa Creu i Sant Pau , Barcelona , Spain
| | | | | | | | | | - Emilio Esteban
- f General University Hospital of Asturias , Asturias , Spain
| | | | | | | | - Mª José Méndez
- j Medical Oncology , Hospital Universitario Reina Sofia , Córdoba , Spain
| | | | | | | | | | | | | | - Jesús García Donas
- q 17HM Hospitales, Centro Integral Oncológico HM Clara Campal , Madrid , Spain
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Mizuno R, Mikami S, Takamatsu K, Shinojima T, Kikuchi E, Oya M. Baseline risk stratification or duration of prior therapy predicts prognosis in patients with metastatic renal cell carcinoma treated with axitinib. Jpn J Clin Oncol 2017; 47:1170-1174. [PMID: 28977627 DOI: 10.1093/jjco/hyx134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 08/30/2017] [Indexed: 01/05/2023] Open
Abstract
Background To elucidate the clinical prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with axitinib. Methods A total of 58 patients were retrospectively analyzed. All patients received axitinib treatment for mRCC at Keio University hospital in Japan. Baseline clinical factors and on treatment adverse events were assessed to predict survival. Results The median progression free survival (PFS) for axitinib treatment was 10.9 months (95% CI 5.8-13.5), and the median overall survival (OS) from the start of axitinib treatment was 39.8 months (95% CI 25.9-NR), respectively. The PFS (P < 0.0001) and OS (P = 0.0022) were significantly correlated with the International mRCC Database Consortium (IMDC) classification, respectively. The PFS and OS were significantly longer in patients who received longer prior treatment (P = 0.0424 and 0.0067, respectively). On-treatment hypertension, hand foot syndrome and hypothyroidism were associated with longer PFS (P = 0.0002, 0.0055 and 0.0290, respectively). On-treatment hypertension, diarrhea, and hand foot syndrome were associated with longer OS (P = 0.0004, 0.0036 and 0.0115, respectively). Conclusions Baseline and on treatment factors are identified as prognostic markers in mRCC patients treated with axitinib. Our findings might be helpful for clinicians to select the best treatment to individual patients.
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Boursiquot BC, Zabor EC, Glezerman IG, Jaimes EA. Hypertension and VEGF (Vascular Endothelial Growth Factor) Receptor Tyrosine Kinase Inhibition: Effects on Renal Function. Hypertension 2017; 70:HYPERTENSIONAHA.117.09275. [PMID: 28739979 PMCID: PMC5783791 DOI: 10.1161/hypertensionaha.117.09275] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 03/12/2017] [Accepted: 06/24/2017] [Indexed: 12/26/2022]
Abstract
VEGF (vascular endothelial growth factor) receptor tyrosine kinase inhibitors have become first-line therapy for metastatic renal cell carcinoma. Their use commonly leads to hypertension, but their effects on long-term renal function are not known. In addition, it has been suggested that the development of hypertension is linked to treatment efficacy. The objective of this study was to determine the effects of these drugs on long-term renal function, especially in those with renal dysfunction at baseline, and to examine the role of hypertension on these effects. Serum creatinine measurements were used to calculate the estimated glomerular filtration rate for 130 renal cell carcinoma patients who were treated with this class of tyrosine kinase inhibitors. New or worsening hypertension was defined by documented start or addition of antihypertensive medications. Overall, the use of tyrosine kinase inhibitors in patients with estimated glomerular filtration <60 or ≥60 mL/min per 1.73 m2 was not associated with a decline in long-term renal function. During follow-up, 41 patients developed new or worsening hypertension within 30 days from first drug administration, and this was not linked to further reductions in glomerular filtration. These patients seemed to survive longer than those who did not develop hypertension within 30 days, although this was not statistically significant (P=0.07). Our findings suggest that the use of VEGF tyrosine kinase inhibitors does not adversely affect long-term renal function even in the setting of new-onset hypertension or reduced renal function at baseline.
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Affiliation(s)
- Brian C Boursiquot
- From the Stanford University School of Medicine, CA (B.C.B.); Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY (E.C.Z.); Department of Medicine, Division of Nephrology & Hypertension, Weill-Cornell Medical College, New York, NY (I.G.G., E.A.J.); and Department of Medicine, Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (I.G.G., E.A.J.)
| | - Emily C Zabor
- From the Stanford University School of Medicine, CA (B.C.B.); Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY (E.C.Z.); Department of Medicine, Division of Nephrology & Hypertension, Weill-Cornell Medical College, New York, NY (I.G.G., E.A.J.); and Department of Medicine, Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (I.G.G., E.A.J.)
| | - Ilya G Glezerman
- From the Stanford University School of Medicine, CA (B.C.B.); Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY (E.C.Z.); Department of Medicine, Division of Nephrology & Hypertension, Weill-Cornell Medical College, New York, NY (I.G.G., E.A.J.); and Department of Medicine, Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (I.G.G., E.A.J.)
| | - Edgar A Jaimes
- From the Stanford University School of Medicine, CA (B.C.B.); Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY (E.C.Z.); Department of Medicine, Division of Nephrology & Hypertension, Weill-Cornell Medical College, New York, NY (I.G.G., E.A.J.); and Department of Medicine, Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (I.G.G., E.A.J.).
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Granito A, Marinelli S, Negrini G, Menetti S, Benevento F, Bolondi L. Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib. Therap Adv Gastroenterol 2016; 9:240-249. [PMID: 26929785 PMCID: PMC4749854 DOI: 10.1177/1756283x15618129] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Sorafenib is the standard treatment for patients with hepatocellular carcinoma (HCC) with advanced stage disease. Although its effectiveness has been demonstrated by randomized clinical trials and confirmed by field practice studies, reliable markers predicting therapeutic response have not yet been identified. Like other tyrosine kinase inhibitors, treatment with sorafenib is burdened by the development of adverse effects, the most frequent being cutaneous toxicity, diarrhoea, arterial hypertension and fatigue. In recent years, several studies have analysed the correlation between off-target effects and sorafenib efficacy in patients with HCC. In this review, an overview of the studies assessing the prognostic significance of sorafenib-related adverse events is provided.
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Affiliation(s)
- Alessandro Granito
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Via Albertoni 15, 40138, Bologna, Italy
| | - Sara Marinelli
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Giulia Negrini
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Saverio Menetti
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Luigi Bolondi
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
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Lainez N, García-Donas J, Esteban E, Puente J, Sáez MI, Gallardo E, Pinto-Marín Á, Vázquez-Estévez S, León L, García-Carbonero I, Suárez-Rodríguez C, Molins C, Climent-Duran MA, Lázaro-Quintela M, González Del Alba A, Méndez-Vidal MJ, Chirivella I, Afonso FJ, López-Brea M, Sala-González N, Domenech M, Basterretxea L, Santander-Lobera C, Gil-Arnáiz I, Fernández O, Caballero-Díaz C, Mellado B, Marrupe D, García-Sánchez J, Sánchez-Escribano R, Fernández Parra E, Villa Guzmán JC, Martínez-Ortega E, Belén González M, Morán M, Suarez-Paniagua B, Lecumberri MJ, Castellano D. Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study. BMC Cancer 2016; 16:135. [PMID: 26906039 PMCID: PMC4763443 DOI: 10.1186/s12885-016-2084-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 01/25/2016] [Indexed: 12/21/2022] Open
Abstract
Background The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. Methods Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. Results Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7 % out of 966 post-implementation cycles compared with 23.1 % out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33 % pre-implementation vs. 44.5 % post-implementation cycles; p < 0.0001), diarrhea (74.0 % vs. 80.5 %; p = 0.011) and dyslipemia (25.0 % vs. 44.6 %; p < 0.001). Conclusions Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction.
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Affiliation(s)
- Nuria Lainez
- Department of oncology, Complejo Hospitalario de Navarra, Servicio Oncología Médica. Pabellón B 2ª planta. Hospital de día, C/ Irunlarrea, 3, 31008, Pamplona, Navarra, Spain.
| | - Jesús García-Donas
- Department of oncology, Hospital Sanchinarro, C/ Oña, 10, 28050, Madrid, Spain.
| | - Emilio Esteban
- Department of oncology, Hospital Universitario Central de Asturias, Julián Clavería s/n, 33006, Oviedo, Spain.
| | - Javier Puente
- Department of oncology, Hospital Clínico de Madrid, C/ Doctor Martín Lagos s/n, 28040, Madrid, Spain.
| | - M Isabel Sáez
- Department of oncology, Hospital Universitario Clínico Virgen de la Victoria, Campus Universitario de Teatinos, s/n, 29010, Málaga, Spain.
| | - Enrique Gallardo
- Department of oncology, Parc Taulí Sabadell Hospital Universitari, Parc Taulí 1, 08208, Sabadell, Spain.
| | - Álvaro Pinto-Marín
- Department of oncology, Hospital Universitario La Paz, P de la Castellana 261, 28046, Madrid, Spain.
| | - Sergio Vázquez-Estévez
- Department of oncology, Hospital Universitario Lucus Augusti, Lugar San Cibrao, S/N, 27003, Lugo, Spain.
| | - Luis León
- Department of oncology, Hospital Santiago de Compostela, Travesía da Choupana, s/n, 15706, Santiago de Compostela, Spain.
| | - Icíar García-Carbonero
- Department of oncology, Hospital Virgen de la Salud, Adva. De Barber, 30, 45004, Toledo, Spain.
| | | | - Carmen Molins
- Department of oncology, Hospital Universitario Dr. Peset, Avda. Gaspar Aguilar 90, 46017, Valencia, Spain.
| | - Miguel A Climent-Duran
- Department of oncology, Instituto Valenciano de Oncología, Gregorio Gea, 31-1° Planta, 46009, Valencia, Spain.
| | - Martín Lázaro-Quintela
- Department of oncology, Complexo Hospitalario Universitario de Vigo, Pizarro 22, 36204, Vigo, Spain.
| | - Aranzazu González Del Alba
- Department of oncology, Hospital Universitario Son Espases, Ctra Valldemossa, 79, 07010, Palma de Mallorca, Spain.
| | - María José Méndez-Vidal
- Department of oncology, Hospital Universitario Reina Sofía, Avda. Menéndez Pidal, s/n, 14004, Córdoba, Spain.
| | - Isabel Chirivella
- Department of oncology, Hospital Clínico de Valencia, Avda Blasco Ibáñez, 17, 46010, Valencia, Spain.
| | - Francisco J Afonso
- Department of oncology, Complejo Hospitalario Arquitecto Marcide, Rúa da residencia s/n. San pedro de Leixa, 15405, Ferrol, Spain.
| | - Marta López-Brea
- Department of oncology, Hospital Marqués de Valdecilla, Avda. Valdecila s/n, 39008, Santander, Spain.
| | | | - Montserrat Domenech
- Department of oncology, Hospital de Althaia Xarxa Asistencial Manresa, Dr. Joan Soler, 1-3, 08243, Barcelona, Spain.
| | - Laura Basterretxea
- Department of oncology, Hospital de Donostia, P° Dr. Beguiristain 109, 20014, San Sebastian, Spain.
| | - Carmen Santander-Lobera
- Department of oncology, Hospital Miguel Servet, Avda Gómez Laguna 25, 50009, Zaragoza, Spain.
| | - Irene Gil-Arnáiz
- Department of oncology, Hospital Reina Sofía, Carretera Tarazona, KM 3, 31500, Tudela, Spain.
| | - Ovidio Fernández
- Department of oncology, Complejo Hospitalario Ourense. Hospital Santa María Nai, Ramón Puga, 52-54, 32005, Orense, Spain.
| | - Cristina Caballero-Díaz
- Department of oncology, Hospital General Universitario de Valencia, Avda Tres Cruces, s/n, 46014, Valencia, Spain.
| | - Begoña Mellado
- Department of oncology, IDIBAPS, Hospital Clinic i Provincial de Barcelona, Villarroel, 170, 08036, Barcelona, Spain.
| | - David Marrupe
- Department of oncology, Hospital Universitario de Móstoles, Río Júcar s/n, 28935, Móstoles, Madrid, Spain.
| | - José García-Sánchez
- Department of oncology, Hospital Arnau de Vilanova, C/ San Clemente n 12, 46015, Valencia, Spain.
| | - Ricardo Sánchez-Escribano
- Department of oncology, Hospital Universitario de Burgos, Avenida Cid Campeador, 96, 09005, Burgos, Spain.
| | - Eva Fernández Parra
- Department of oncology, H.U. Hospital de Valme, Ctra. de Cádiz Km. 548.9, 41014, Sevilla, Spain.
| | - José C Villa Guzmán
- Department of oncology, Hospital de Ciudad Real, Obispo Rafael Torija, 13005, Ciudad Real, Spain.
| | - Esther Martínez-Ortega
- Department of oncology, Hospital Ciudad de Jaén, Avenida Ejercito Español 10, 23007, Jaén, Spain.
| | - María Belén González
- Department of oncology, Hospital Son Llatzer, Ctra. Manacor, km.4, Sont Frriol, 07198, Palma de Mallorca, Spain.
| | - Marina Morán
- Pfizer Madrid, Avda. de Europa, 20B, 28108, Alcobendas, Madrid, Spain.
| | | | - María J Lecumberri
- Department of oncology, Complejo Hospitalario de Navarra, Servicio Oncología Médica. Pabellón B 2ª planta. Hospital de día, C/ Irunlarrea, 3, 31008, Pamplona, Navarra, Spain.
| | - Daniel Castellano
- Department of oncology, Hospital 12 de Octubre, Av. de Córdoba s/n, 28041, Madrid, Spain.
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Chen Y, Rini BI, Bair AH, Mugundu GM, Pithavala YK. Population pharmacokinetic-pharmacodynamic modelling of 24-h diastolic ambulatory blood pressure changes mediated by axitinib in patients with metastatic renal cell carcinoma. Clin Pharmacokinet 2015; 54:397-407. [PMID: 25343945 DOI: 10.1007/s40262-014-0207-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Increased blood pressure (BP) is commonly observed in patients treated with vascular endothelial growth factor pathway inhibitors, including axitinib. Ambulatory BP monitoring (ABPM) and pharmacokinetic data were collected in a randomised, double-blind phase II study of axitinib with or without dose titration in previously untreated patients with metastatic renal cell carcinoma. OBJECTIVE Aims of these analyses were to (1) develop a population pharmacokinetic-pharmacodynamic model for describing the relationship between axitinib exposure and changes in diastolic BP (dBP) and (2) simulate changes in dBP with different axitinib dosing regimens. METHODS We employed a three-stage modelling approach, which included development of (1) a baseline 24-h ABPM model, (2) a pharmacokinetic model from serial and sparse pharmacokinetic data, and (3) an indirect-response, maximum-effect (Emax) model to evaluate the exposure-driven effect of axitinib on dBP. Simulations (N = 1,000) were performed using the final pharmacokinetic-pharmacodynamic model to evaluate dBP changes on days 4 and 15 of treatment with different axitinib doses. RESULTS Baseline ABPM data from 62 patients were best described by 24-h mean dBP and two cosine terms. The final indirect-response Emax model showed good agreement between observed 24-h ABPM data and population and individual predictions. The maximum increase in dBP was 20.8 %, and the axitinib concentration at which 50 % of the maximal increase in dBP was reached was 12.4 ng/mL. CONCLUSION Our model adequately describes the relationship between axitinib exposure and dBP increases. Results from these analyses may potentially be applied to infer dBP changes in patients administered axitinib at nonstandard doses.
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Affiliation(s)
- Ying Chen
- Pfizer Oncology, Clinical Pharmacology, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA,
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12
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Bouattour M, Payancé A, Wassermann J. Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging. World J Hepatol 2015; 7:2245-2263. [PMID: 26380650 PMCID: PMC4568486 DOI: 10.4254/wjh.v7.i20.2245] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 05/16/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimizing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.
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Affiliation(s)
- Mohamed Bouattour
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Audrey Payancé
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Johanna Wassermann
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
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Bronte G, Bronte E, Novo G, Pernice G, Lo Vullo F, Musso E, Bronte F, Gulotta E, Rizzo S, Rolfo C, Silvestris N, Bazan V, Novo S, Russo A. Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy. Expert Opin Drug Saf 2014; 14:253-67. [PMID: 25494575 DOI: 10.1517/14740338.2015.986092] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach. AREAS COVERED This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs individually. A literature search was conducted on PubMed selecting review articles, original studies and clinical trials, with a focus on Phase III studies. EXPERT OPINION Side-effects on the cardiovascular system could lead both to the worsening of general health status of cancer patients and to the discontinuation of the cancer treatment affecting its efficacy. Cardiologists often have to face new triggers of heart disease in these patients. They need a specific approach, which must be carried out in cooperation with oncologists. It must start before cancer treatment, continue during it and extend after its completion.
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Affiliation(s)
- Giuseppe Bronte
- University of Palermo, Department of Surgical, Oncological and Oral Sciences , Palermo , Italy
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Li Y, Li S, Zhu Y, Liang X, Meng H, Chen J, Zhang D, Guo H, Shi B. Incidence and risk of sorafenib-induced hypertension: a systematic review and meta-analysis. J Clin Hypertens (Greenwich) 2014; 16:177-85. [PMID: 24621095 DOI: 10.1111/jch.12273] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 11/30/2013] [Accepted: 12/08/2013] [Indexed: 01/10/2023]
Abstract
Hypertension is one of the major side effects of sorafenib, and reported incidences vary substantially among clinical trials. A systematic review was conducted using Medline, PubMed, Embase, and the Cochrane Library for all longitudinal studies to investigate the incidence and risk of hypertension events in cancer patients treated with sorafenib. A total of 14 randomized controlled trials and 39 prospective single-arm trials involving 13,555 patients were selected for the meta-analysis. The relative risk of all-grade and high-grade hypertension associated with sorafenib were 3.07 (95% confidence interval [CI], 2.05–4.60; P<.01) and 3.31 (95% CI, 2.21–4.95; P<.01), respectively. The overall incidence of sorafenib-induced all-grade and high-grade hypertension were 19.1% (95% CI, 15.8%–22.4%) and 4.3% (95% CI, 3.0%–5.5%), respectively. A significantly higher incidence of hypertension was noted in patients with renal cell carcinoma (RCC) compared with those with non-RCC malignancies (all-grade: 24.9% [95% CI, 19.7%–30.1%] vs 15.7%[95% CI, 12.1%–19.3%]; P<.05; high-grade:8.6% [95% CI, 6.0%–11.2%] vs 1.8% [95% CI, 0.9%–2.6%]; P<.05). The trials with median progression-free survival (PFS) longer than 5.3 months (mean PFS) demonstrated a significantly higher incidence of high-grade hypertension than trials with shorter PFS (6.3% [95% CI, 4.1%–8.5%] vs 2.6% [95% CI, 1.4%– 3.8%]; P<.05). Findings of the meta-analysis indicated a significantly high risk of sorafenib-induced hypertension. Patients with RCC have a significantly higher incidence of hypertension and the occurrence of hypertension may be associated with improved prognosis.
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15
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Izzedine H. Anti-VEGF Cancer Therapy in Nephrology Practice. Int J Nephrol 2014; 2014:143426. [PMID: 25210627 PMCID: PMC4158308 DOI: 10.1155/2014/143426] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 08/11/2014] [Indexed: 01/26/2023] Open
Abstract
Expanded clinical experience with the antivascular endothelial growth factor (VEGF) agents has come with increasing recognition of their renal adverse effects. Although renal histology is rarely sought in antiangiogenic-treated cancer patients, kidney damage related to anti-VEGF is now established. Its manifestations include hypertension, proteinuria, and mainly glomerular thrombotic microangiopathy. Then, in nephrology practice, should we continue to perform kidney biopsy, and what should be done with the anti-VEGF agents in case of renal toxicity?
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Affiliation(s)
- Hassan Izzedine
- Department of Nephrology, Pitie-Salpetriere Hospital, 75013 Paris, France
- Department of Nephrology, Monceau Park International Clinic, 75017 Paris, France
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16
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Révision de l’index thérapeutique des thérapies ciblées dans le cancer du rein : le mieux peut-il être l’ennemi du bien ? La toxicité peut-elle prédire l’efficacité ? Bull Cancer 2014; 101:608-18. [DOI: 10.1684/bdc.2014.1935] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Sunitinib combined with angiotensin-2 type-1 receptor antagonists induces more necrosis: a murine xenograft model of renal cell carcinoma. BIOMED RESEARCH INTERNATIONAL 2014; 2014:901371. [PMID: 24967411 PMCID: PMC4054801 DOI: 10.1155/2014/901371] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 04/25/2014] [Indexed: 12/28/2022]
Abstract
Background. Angiotensin-2 type-1 receptor antagonists not are only antihypertensive drugs but also can inhibit VEGF production. We hypothesised that adding telmisartan to sunitinib could potentiate the antiangiogenic effects. Material and Methods. 786-O cell lines were injected in nude mice. After tumor development, mice were divided into 4 groups: the first was the control group (DMSO), the second group was treated with sunitinib alone, the third group was treated with telmisartan alone, and the fourth group was treated with the combination. Drugs were orally administered every day for four weeks. Animals were sacrificed after treatment. Blood and tumor tissues were collected for analysis by immunohistochemistry, Western Blot, and ELISA methods. Results. All animals developed a ccRCC and ten in each group were treated. Using a kinetic model, tumors tended to grow slower in the combination group compared to others (P = 0.06). Compared to sunitinib alone, the addition of telmisartan significantly increased tissue necrosis (P = 0.038). Central microvascular density decreased (P = 0.0038) as well as circulating VEGF (P = 0.003). There was no significant variation in proliferation or apoptosis markers. Conclusion. The combination of sunitinib and telmisartan revealed an enhancement of the blockage of the VEGF pathway on renal tumor resulting in a decrease in neoangiogenesis and an increase in necrosis.
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Miyahara K, Nouso K, Yamamoto K. Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age. World J Gastroenterol 2014; 20:4151-9. [PMID: 24764653 PMCID: PMC3989951 DOI: 10.3748/wjg.v20.i15.4151] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 01/02/2014] [Accepted: 02/26/2014] [Indexed: 02/06/2023] Open
Abstract
The kinase inhibitor sorafenib is the only systemic therapy proven to have a positive effect on survival of patients with advanced hepatocellular carcinoma (HCC). After development of sorafenib and its introduction as a therapeutic agent used in the clinic, several critical questions have been raised. Clinical parameters and biomarkers predicting sorafenib efficacy are the most important issues that need to be elucidated. Although it is difficult to know the responders in advance using conventional characteristics of patients, there are specific serum cytokines and/or gene amplification in tumor tissues that have been reported to predict efficacy of sorafenib. Risk and benefits of continuation of sorafenib beyond radiological progression is another issue to consider because no other standard therapy for advanced HCC as yet exists. In addition, effectiveness of the expanded application of sorafenib is still controversial, although a few studies have shed some light on combinational treatment with sorafenib for intermediate-stage HCC. Recently, over 50 relevant drugs have been developed and are currently under investigation. The efficacy of some of these drugs has been extensively examined, but none have demonstrated any superiority over sorafenib, so far. However, there are several drugs that have shown efficacy for treatment after sorafenib failure, and these are proceeding to further studies. To address these issues and questions, we have done extensive literature review and summarize the most current status of therapeutic application of sorafenib.
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19
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Ravaud A, Schmidinger M. Clinical biomarkers of response in advanced renal cell carcinoma. Ann Oncol 2013; 24:2935-42. [PMID: 23925998 DOI: 10.1093/annonc/mdt288] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
There are now a range of effective targeted agents available for the first- and second-line treatment of advanced renal cell carcinoma (RCC). However, patients with advanced RCC have varied responses to therapy; some experience long-term responses while others may not respond, or even progress rapidly. Characteristics or markers that could be used to determine which patients will benefit most from which agent may enable us to select the optimal treatment of each individual patient, thereby improving efficacy and avoiding unnecessary toxic effects. These characteristics may be at the cellular or genetic level. Alternatively, the occurrence of adverse events may act as surrogate markers of a drug's on treatment activity, enabling prediction of outcomes during treatment. Recently, it has been suggested that during some targeted therapy for advanced RCC, the occurrence of specific adverse events, such as hypertension, hypothyroidism, hand-foot syndrome or fatigue/asthenia, may be associated with improved efficacy. This article reviews the evidence supporting clinical biomarkers in patients with advanced RCC receiving targeted agents. We also consider how these clinical biomarkers may affect the future management of patients with advanced RCC.
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Affiliation(s)
- A Ravaud
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital, Bordeaux
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20
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Abstract
Axitinib is a new inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, with greater inhibition potency than existing VEGF receptor inhibitors sunitinib, sorafenib and pazopanib. In a pivotal phase III trial in patients with advanced renal cell carcinoma that had progressed despite first-line therapy, axitinib 5 mg twice daily significantly prolonged median progression-free survival (primary endpoint) compared with sorafenib 400 mg twice daily. A significant between-group difference favouring axitinib over sorafenib in terms of progression-free survival was maintained in the subgroups of patients who had previously received cytokine or sunitinib therapy. However, median overall survival was not significantly different between the treatment groups. Significantly more axitinib than sorafenib recipients achieved an objective response, and axitinib therapy significantly prolonged time to deterioration (a composite endpoint of death, disease progression and symptom worsening) relative to sorafenib therapy. While its tolerability profile was generally consistent with that of other VEGF receptor inhibitors, axitinib was associated with a numerically lower incidence of palmar-plantar erythrodysaesthesia, cutaneous toxicity and anaemia than sorafenib in the phase III trial.
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Foerster R, Welzel T, Debus J, Gruellich C, Jaeger D, Potthoff K. Posterior reversible leukoencephalopathy syndrome associated with pazopanib. Case Rep Oncol 2013; 6:204-8. [PMID: 23626562 PMCID: PMC3636956 DOI: 10.1159/000350742] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
A 62-year-old female patient with metastatic renal cell carcinoma under third-line treatment with pazopanib for 8 weeks suddenly developed severe headaches, grand mal seizures and paresis of the left arm in combination with gait instability as well as nausea and vomiting during her vacation abroad. The emergency physician measured systolic blood pressure values over 300 mm Hg and suspected a stroke. The CT imaging without contrast agent in a local hospital did not show any pathologic findings despite bone metastases. The colleagues suspected cerebral metastases or meningeosis carcinomatosa and referred the patient to our department for further diagnostics and treatment planning. An MRI scan ruled out the suspected cerebral metastases or meningeosis carcinomatosa, but showed signs of reversible posterior leukoencephalopathy syndrome (RPLS) in the form of band-like hyperintensities as a sign of cytotoxic edema in the gray and white matter of the left parietal lobe. The patient then reported that similar blood pressure values had been measured shortly after the start of a first-line therapy with sunitinib, so that we discontinued the current treatment with pazopanib. Within 6 days the neurologic symptoms vanished and the patient was discharged. An intermittent hypertension persisted. A follow-up MRI 3 weeks later showed an RPLS-typical cortical infarction in the affected area. RPLS should be considered as the actual reason for neurologic findings in hypertensive patients with known metastatic cancers under tyrosine kinase inhibitor therapy.
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Affiliation(s)
- Robert Foerster
- Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany
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22
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Abstract
For a few years, new targeted therapies have been used for metastatic cancers, targeting VEGF and its receptors and improving patients' survival for metastatic carcinoma (kidney, GIST, breast, colorectal). The objective of these treatments is to block either circulating VEGF (bevacizumab; VEGF-Trap), or tyrosine kinase receptors (especially the VEGF receptor) (sorafenib, sunitinib, brivanib, imatinib, etc.). Indeed, VEGF stimulates endothelial cell proliferation and then tumour growth and metastasis. However, all these antiangiogenic drugs share similar side effects, most frequently gastrointestinal disturbance, skin toxicity and hypertension. Hypertension seems to be especially frequent in case of good response. Renal side effects have probably been underestimated in the first place and their exact frequency is not known, needing some specific trials and registries. Proteinuria, thrombotic microangiopathies and acute renal failures have been reported: renal biopsies might be necessary for precise evaluation of renal damages. Physiopathology seems very close to preeclampsia. Good collaboration between oncologists, nephrologists and cardiologists is therefore crucial in order to continue these targeted therapies safely for the patients.
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Affiliation(s)
- Cécile Vigneau
- Service de Néphrologie, Centre Hospitalier Universitaire Pontchaillou, 2, rue Henri-Le-Guilloux, 35033 Rennes cedex 9, France.
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Qi WX, Lin F, Sun YJ, Tang LN, He AN, Yao Y, Shen Z. Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis. Cancer Chemother Pharmacol 2012. [PMID: 23178953 DOI: 10.1007/s00280-012-2025-5] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
PURPOSES To gain a better understanding of the overall incidence and risk of hypertension in cancer patients who receive pazopanib and to compare the differences in incidence among sorafenib, sunitinib, and pazopanib. METHODS Several databases were searched, including PubMed, Embase, and Cochrane databases. Eligible studies were phase II and III prospective clinical trials of patients with cancer assigned single drug pazopanib 800 mg/day with data on hypertension available. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included trials. RESULTS A total of 1,651 patients with a variety of solid tumors from 13 clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hypertension in cancer patients were 35.9 % (95 % CI 31.5-40.6 %) and 6.5 % (95 % CI 5.2-8.0 %), respectively. The use of pazopanib was associated with an increased risk of developing all-grade (RR 4.97, 95 % CI 3.38-7.30, p < 0.001) and high-grade hypertension (RR 2.87, 95 % CI 1.16-7.12, p = 0.023). Additionally, there was no significant difference in the incidence of all-grade (RR 1.21, 95 % CI 0.96-1.53, p = 0.11) and high-grade hypertension (RR 1.29, 95 % CI 0.80-2.07, p = 0.30) between RCC and non-RCC patients. Interestingly, the risk of all-grade hypertension with pazopanib was substantially higher than sorafenib (RR 1.99; 95 % CI 1.73-2.29, p = 0.00) and sunitinib (RR 2.20; 95 % CI 1.92-2.52, p = 0.00), while the risk of pazopanib-induced high-grade hypertension was similar to sorafenib (RR 0.98; 95 % CI 0.75-1.30, p = 0.90) and sunitinib (RR 0.81; 95 % CI 0.62-1.06, p = 0.12). CONCLUSIONS The use of pazopanib is associated with a significantly increased risk of developing hypertension. Close monitoring and appropriate managements are recommended during the therapy. Future studies are still needed to investigate the risk reduction and possible use of pazopanib in selected patients.
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Affiliation(s)
- Wei-Xiang Qi
- Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, No 600, yishan road, Shanghai 200233, China
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Edeline J, Vauléon E, Rioux-Leclercq N, Perrin C, Bensalah CVK, Laguerre B. Safety and Efficacy of Sorafenib in Renal Cell Carcinoma. CANCER GROWTH AND METASTASIS 2012. [DOI: 10.4137/cgm.s7526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
This article reviews data on sorafenib use in renal cell carcinoma. Mechanisms of actions and pharmacokinetics are briefly described. Major clinical trials are presented, summarizing efficacy and safety of sorafenib. Its place in current treatment of renal cell carcinoma is discussed. Sorafenib is likely to remain one of the mainstays of RCC treatment in coming years.
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Affiliation(s)
- Julien Edeline
- Eugene Marquis Comprehensive Cancer Center, Medical Oncology Department, Rennes, France
- CNRS/UMR 6061, IFR140, Rennes1 University, France
| | - Elodie Vauléon
- Eugene Marquis Comprehensive Cancer Center, Medical Oncology Department, Rennes, France
| | - Nathalie Rioux-Leclercq
- CHU Pontchaillou, Pathology Department, Rennes, France
- CNRS/UMR 6061, IFR140, Rennes1 University, France
| | - Christophe Perrin
- Eugene Marquis Comprehensive Cancer Center, Medical Oncology Department, Rennes, France
- CNRS/UMR 6061, IFR140, Rennes1 University, France
| | | | - Brigitte Laguerre
- Eugene Marquis Comprehensive Cancer Center, Medical Oncology Department, Rennes, France
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Yang L, Jiang YQ, Mei Q, Chen Y. Bevacizumab-induced hypertension in patients with metastatic colorectal cancer: Its incidence and clinical significance. Shijie Huaren Xiaohua Zazhi 2012; 20:2525-2528. [DOI: 10.11569/wcjd.v20.i26.2525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the incidence and management of bevacizumab-induced hypertension in patients with metastatic colorectal cancer (MCC), and to evaluate its relationship with response to bevacizumab.
METHODS: MCC patients treated with bevacizumab and chemotherapy were retrospectively enrolled in this study. Focus was placed on the patients' blood pressure, corresponding management and clinical outcome. Patients were divided into two groups according to the occurrence of bevacizumab-induced hypertension or not. The disease control rate (DCR) and progression-free survival (PFS) were compared between the two groups.
RESULTS: In total, 40 MCC patients were treated with bevacizumab and chemotherapy. The median time from the initiation of bevacizumab to the beginning of hypertension was 38 days. The incidence of treatment-induced hypertension was 17.5% (7/40). Two patients (5.0%) were classified to have grade 3 hypertension. No grades 4-5 hypertension occurred. Blood pressure was controlled well in 7 patients after corresponding treatment. Patients with bevacizumab-induced hypertension had better DCR (85.8% vs 60.1%, P = 0.439) and PFS (13 mo vs 8 mo, P = 0.191), but there were no statistical differences between the two groups.
CONCLUSION: In MCC patients treated with bevacizumab and chemotherapy, the incidence of treatment-induced hypertension is high. But most of cases are mild to moderate and respond well to proper treatment. Bevacizumab-induced hypertension is not predictive factor of response to bevacizumab.
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Polymorphisms in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) predict sunitinib-induced hypertension. Clin Pharmacol Ther 2012; 92:503-10. [PMID: 22948895 DOI: 10.1038/clpt.2012.136] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.
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Otsuka T, Eguchi Y, Kawazoe S, Yanagita K, Ario K, Kitahara K, Kawasoe H, Kato H, Mizuta T. Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib. Hepatol Res 2012; 42:879-86. [PMID: 22469363 DOI: 10.1111/j.1872-034x.2012.00991.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIM Sorafenib is the first small molecule with significant clinical activity for advanced hepatocellular carcinoma (HCC). However, intolerable adverse events are sometimes observed. On the other hand, it has been reported that some toxicities of molecular targeted drugs, such as skin toxicities and arterial hypertension, are correlated with good clinical outcomes in other cancers. METHODS We identified the correlations between adverse events and prognosis for sorafenib therapy in all patients with HCC treated at the institutions of the Saga Liver Cancer Study Group. The toxicities were assessed using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS Ninety-four patients received sorafenib until August 2010. The overall incidence of treatment-related adverse events was 98% of patients. Skin toxicities, including palmar-plantar erythrodysesthesia syndrome, rash, pruritus and alopecia, were the most common adverse events and were observed in 58 patients (62%). Hypertension was observed in 23 patients (24%). The median survival time was 12.5 months among the total patients. The patients with skin toxicities showed significantly longer survival than the patients without these toxicities (hazard ratio, 0.449; 95% confidence interval, 0.256-0.786; P = 0.005). Hypertension had no correlation with survival. Skin toxicities were also significant prognostic factors in a multivariate analysis (hazard ratio, 0.522; 95% confidence interval, 0.274-0.997; P = 0.049), along with Child-Pugh class and α-fetoprotein level. The median development time for skin toxicities was 21 days. CONCLUSION Skin toxicities occur commonly at the early phase in patients treated with sorafenib, and could be a promising surrogate marker for the treatment outcome.
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Affiliation(s)
- Taiga Otsuka
- Department of Internal Medicine, Hepatobiliary and Pancreatology Division, Saga Prefectural Hospital, Ureshino, Japan
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Abstract
The use of anti-angiogenic agents as part of the therapeutic armamentarium for advanced stage solid tumors has become the standard of care in several instances, particularly for renal cell carcinoma, non-small cell lung carcinoma, colorectal carcinoma, and gastrointestinal stromal tumors. These agents primarily target vascular endothelial growth factor (VEGF) and/or its receptors, and include bevacizumab, a humanized monoclonal antibody against VEGF, as well as tyrosine kinase inhibitors that target several receptor tyrosine kinases (RTK), including VEGF receptors. These therapies, as a general class of anti-angiogenic medications, have been shown to have common adverse vascular effects attributable directly or indirectly to their anti-VEGF effects, including hypertension, renal vascular injury, often manifested by proteinuria and thrombotic microangiopathy, and congestive heart failure. Knowledge of these common side effects and their underlying mechanisms may allow for more accurate and prompt diagnoses, timely clinical interventions, and the development of rational and standard treatments. These measures may minimize patient morbidity and mortality, not only by the treatment of side effects, but also by minimizing the disruption of treatment of the underlying malignancy, as well as improving patient quality of life.
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Affiliation(s)
- Suzanne R Hayman
- Department of Internal Medicine, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
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29
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Novel antiangiogenic therapies against advanced hepatocellular carcinoma (HCC). Clin Transl Oncol 2012; 14:564-74. [PMID: 22855137 DOI: 10.1007/s12094-012-0842-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Accepted: 04/13/2012] [Indexed: 12/12/2022]
Abstract
Angiogenesis is a cornerstone in the process of hepatocarcinogenesis. In the sorafenib era, other antiangiogenic targeted drugs, such as monoclonal antibodies and a new generation of tyrosine kinase inhibitors, have been shown in phase II trials to be safe and effective in the treatment of advanced hepatocellular carcinoma. Several currently active phase III trials are testing these drugs, both in first- and second-line settings. Strategies to overcome primary and acquired resistance to antiangiogenic therapy are urgently needed. Novel biomarkers may help in improving the efficacy of drugs targeting angiogenesis.
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Rutkowski P, Bylina E, Klimczak A, Switaj T, Falkowski S, Kroc J, Lugowska I, Brzeskwiniewicz M, Melerowicz W, Osuch C, Mierzejewska E, Wasielewski K, Woźniak A, Grzesiakowska U, Nowecki ZI, Siedlecki JA, Limon J. The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study. BMC Cancer 2012; 12:107. [PMID: 22439647 PMCID: PMC3361487 DOI: 10.1186/1471-2407-12-107] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2011] [Accepted: 03/22/2012] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure. METHODS We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes. RESULTS One year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively). CONCLUSIONS We confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.
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Affiliation(s)
- Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.
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Cohen RB, Oudard S. Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities. Invest New Drugs 2012; 30:2066-79. [PMID: 22327313 PMCID: PMC3432793 DOI: 10.1007/s10637-012-9796-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Accepted: 01/20/2012] [Indexed: 12/21/2022]
Abstract
Treatment of metastatic renal cell carcinoma (mRCC) has evolved rapidly over the last two decades as major pathways involved in pathogenesis have been elucidated. These include the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR). Therapies targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel therapies—VEGF and mTOR inhibitors—are associated with a variety of unique toxicities, some of which may necessitate expert medical management, treatment interruption, or dose reduction. Common adverse events with newer drugs include hypertension, skin reactions, gastrointestinal disturbances, thyroid dysfunction, and fatigue. Skilled management of these toxicities is vital to ensure optimal therapeutic dosing and maximize patient outcomes, including improved survival and quality of life. This review describes and compares the toxicity profiles of novel molecularly targeted agents used in the treatment of mRCC and presents guidance on how best to prevent and manage treatment-related toxicities. Particular attention is given to axitinib, the newest agent to enter the armamentarium. Axitinib is a second-generation receptor tyrosine kinase inhibitor with potent VEGF receptor inhibition that provides durable responses and superior progression-free survival in advanced RCC compared with sorafenib.
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Affiliation(s)
- Roger B Cohen
- Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Tonini G, Fratto ME, Imperatori M, Pantano F, Vincenzi B, Santini D. Predictive factors of response to treatment in patients with metastatic renal cell carcinoma: new evidence. Expert Rev Anticancer Ther 2011; 11:921-30. [PMID: 21707289 DOI: 10.1586/era.11.63] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Renal cell carcinoma represents approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. Many agents that target angiogenesis (e.g., sunitinib, sorafenib, bevacizumab and pazopanib) and mTOR-targeted therapy (e.g., temsirolimus and everolimus) have been approved as first-line agents. The choice of the most suitable treatment for advanced renal cell carcinoma depends on the definition of risk. In this article, we reviewed the scientific literature identifying predictive factors on the activity/efficacy of a specific therapy.
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Affiliation(s)
- Giuseppe Tonini
- Department of Medical Oncology, University Campus Bio-Medico, Via Alvaro del Portillo, 200 00128 Rome, Italy.
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Webber K, Cooper A, Kleiven H, Yip D, Goldstein D. Management of metastatic renal cell carcinoma in the era of targeted therapies. Intern Med J 2011; 41:594-605. [PMID: 21627746 DOI: 10.1111/j.1445-5994.2011.02540.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Metastatic renal cell cancer is associated with poor prognosis and survival and is resistant to conventional chemotherapy. Therapeutic targeting of molecular pathways for tumour angiogenesis and other specific activation mechanisms offers improved tumour response and prolonged survival. AIMS To conduct a retrospective audit of metastatic renal cell carcinoma patients treated with targeted therapies. METHODS Data were extracted from clinical records of patients undergoing targeted treatment between 2005 and 2009 at two hospital sites. Data collected included pathology, systemic therapy class, toxicity and survival. Univariate and multivariate survival analyses were performed. RESULTS Sixty-one patients were treated with 102 lines of therapy with a median overall survival (OS) of 23 months, median time to failure of first-line treatment (TTF1) of 10 months and median time to failure of second-line treatment (TTF2) of 5.2 months. Time from first diagnosis to treatment >12 months was significantly associated with improved OS, longer TTF1, TTF2 and response to first-line anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGF TKI) therapy. Variables associated with tumour biology, natural history and the systemic inflammatory response were associated with improved OS and TTF1. Development of hypertension was predictive of anti-VEGF TKI outcome. Toxicities were as expected for each drug class. CONCLUSIONS Survival and toxicity outcomes from two Australian sites are comparable to published data. The adverse event profile differs to conventional chemotherapy. Clinicians caring for patients with metastatic renal cancer will need to become familiar with these toxicities and their management as these agents enter widespread use.
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Affiliation(s)
- K Webber
- Department of Medical Oncology, Prince of Wales Hospital, University of New South Wales, Sydney, Australia.
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Ravaud A. Treatment-associated adverse event management in the advanced renal cell carcinoma patient treated with targeted therapies. Oncologist 2011; 16 Suppl 2:32-44. [PMID: 21346038 DOI: 10.1634/theoncologist.2011-s2-32] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Targeted therapy for advanced renal cell carcinoma (RCC) has recently expanded the available treatment options for patients with these malignancies. The rapid introduction of novel treatment options into clinical practice within a relatively short time frame has created some new challenges pertaining to adverse event (AE) management in patients with advanced RCC. Accumulating safety data from the pivotal phase III clinical trials of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab plus interferon, VEGF receptor tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have served to characterize the toxicity profiles of these novel agents. Overall, it is evident that RCC-directed targeted therapy differs from immunotherapy and cytotoxic chemotherapy in terms of a number of unique nonhematologic AEs (some of which have not been traditionally encountered in oncology practice) and that there are distinctions within and across the various classes of agents with respect to the most prominent AEs and the risk for less common but serious complications. Although treatment-associated AEs are common, the majority of AEs reported during clinical trial experiences were grade 1 or 2 in severity and manageable with intervention in the form of supportive measures and/or dosage modification. Therefore, despite the relatively complex AE profiles of RCC-directed targeted therapy, patient education, consistent monitoring with a focus on early detection by health care providers (oncologists, general physicians, nurses), and the application of emerging AE management strategies may allow for prolonged treatment in most patients with advanced RCC.
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Affiliation(s)
- Alain Ravaud
- Bordeaux University Victor Se´galen, Bordeaux University Hospital, Hôpital Saint André, Bordeaux, France
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35
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Bamias A, Manios E, Karadimou A, Michas F, Lainakis G, Constantinidis C, Deliveliotis C, Zakopoulos N, Dimopoulos MA. The use of 24-h ambulatory blood pressure monitoring (ABPM) during the first cycle of sunitinib improves the diagnostic accuracy and management of hypertension in patients with advanced renal cancer. Eur J Cancer 2011; 47:1660-8. [PMID: 21549588 DOI: 10.1016/j.ejca.2011.03.033] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 03/24/2011] [Accepted: 03/29/2011] [Indexed: 12/31/2022]
Abstract
AIM Hypertension (HT) complicates treatment with antiangiogenic agents, including the tyrosine kinase inhibitor (TKI) sunitinib. To prospectively evaluate the prevalence and management of HT in patients with advanced renal cell carcinoma (RCC) receiving sunitinib we used 24-h ABPM and we treated HT according to guidelines of the Joint National Committee on Prevention, Detection and Evaluation and the Treatment of High Blood Pressure (JNC7). PATIENTS AND METHODS Normal 24-h ABPM at the baseline and at 2, 4 and 6 weeks of the first cycle was ensured with the successive use of hydrochlorothiazide+irbesartan, nebivolol and amlodipine. Office BP measurements were used in subsequent cycles to monitor HT. Sunitinib dose was modified only if BP was not controlled with four anti-hypertensive agents. RESULTS Forty patients were included in this analysis. Twenty-one patients (53%) had baseline HT, while 12 of 14 (84%) normotensive patients required anti-HT treatment during the 1st cycle of sunitinib. HT was infrequent in subsequent cycles and increase of anti-HT medication was required in only 2 cases. Two patients permanently discontinued sunitinib due to HT. The remaining 34 (94%) required no dose modifications for HT. One cardiac event (2.8%) was observed. There was no correlation of HT with sunitinib efficacy. CONCLUSION Sunitinib-associated HT is more frequent than previously reported. The use of 24-h ABPM for diagnosis and tailoring of HT according to JNC7 guidelines may achieve uninterrupted, full dose therapy in most patients. The substitution of such protocols for currently used Toxicity Criteria may be warranted.
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Affiliation(s)
- A Bamias
- Department of Clinical Therapeutics, University of Athens, Medical School, Greece.
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36
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Bono P, Rautiola J, Utriainen T, Joensuu H. Hypertension as predictor of sunitinib treatment outcome in metastatic renal cell carcinoma. Acta Oncol 2011; 50:569-73. [PMID: 21208033 DOI: 10.3109/0284186x.2010.543696] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
UNLABELLED Hypertension and hypothyreoidism are frequent side effects of VEGFR-inhibitors. We investigated whether hypertension or hypothyreoidism diagnosed during sunitinib treatment is associated with treatment efficacy. MATERIAL AND METHODS Sixty-four consecutive patients with metastatic renal cell cancer (RCC) were treated with sunitinib in a single center. Hypertension was defined as persistent blood pressure >150/100 mmHg or blood pressure requiring intensification of pre-existing anti-hypertensive medication. Hypothyreoidism was defined as elevation of TSH levels and clinical symptoms requiring hormone replacement therapy (≥Gr. II hypothyreoidim). RESULTS Twenty-four (38%) patients developed hypertension and 12 (19%) hypothyreoidism. The dose of sunitinib administered was not significantly associated with hypertension or hypothyreoidism. There was no correlation between hypertension and hypothyreoidism. Hypertension was associated with frequent tumor response to sunitinib, a long time to disease progression and long overall survival (p= 0.001, 0.0003 and 0.001, respectively). In a multivariate analysis, hypertension was an independent predictor of progression-free survival (hazard ratio, 0.21; 95% CI 0.076 to 0.59, p=0.0030). There were no statistically significant differences in the frequency of ≥ grade 3 adverse events between patients with or without hypertension. CONCLUSION Sunitinib-associated hypertension may be a strong predictive marker for treatment efficacy in metastatic RCC.
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Affiliation(s)
- Petri Bono
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
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Rini BI, Schiller JH, Fruehauf JP, Cohen EE, Tarazi JC, Rosbrook B, Bair AH, Ricart AD, Olszanski AJ, Letrent KJ, Kim S, Rixe O. Diastolic Blood Pressure as a Biomarker of Axitinib Efficacy in Solid Tumors. Clin Cancer Res 2011; 17:3841-9. [DOI: 10.1158/1078-0432.ccr-10-2806] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Robinson ES, Khankin EV, Choueiri TK, Dhawan MS, Rogers MJ, Karumanchi SA, Humphreys BD. Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors. Hypertension 2010; 56:1131-6. [PMID: 20956731 PMCID: PMC3078049 DOI: 10.1161/hypertensionaha.110.160481] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Accepted: 09/29/2010] [Indexed: 12/11/2022]
Abstract
Therapies that target the vascular endothelial growth factor (VEGF) pathway cause hypertension, but the mechanism remains unknown. This cross-sectional study tested the hypothesis that VEGF inhibition causes hypertension by suppressing VEGF-mediated vasodilatory pathways. Urine was collected from 80 patients with metastatic renal cell carcinoma from 2002 to 2009, 40 at baseline and 40 while on VEGF inhibitors. Measured urinary biomarkers include albumin, metabolites of the nitric oxide (NO) pathway and its downstream effector cGMP, and prostaglandin pathway biomarkers prostaglandin E2, 6-keto prostaglandin F1α, and cAMP, all normalized to urinary creatinine. The mean age in both groups was 61.8 years, 76% were men, and urinary albumin was higher in patients receiving VEGF inhibitors (median: 18.4 versus 4.6 mg/g; P = 0.009). cGMP/creatinine was suppressed in patients on VEGF inhibitors (0.28 versus 0.39 pmol/μg; P = 0.01), with a trend toward suppression of nitrate/creatinine (0.46 versus 0.62 μmol/mg; P = 0.09). Both comparisons were strengthened when patients on bevacizumab were excluded, and only those receiving small molecule tyrosine kinase inhibitors were analyzed (cGMP/creatinine: P = 0.003; nitrate/creatinine: P = 0.01). Prostaglandin E2, 6-keto prostaglandin F1α, and cAMP did not differ between groups. These results suggest that hypertension induced by VEGF inhibitors is mediated by suppression of NO production. Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF-targeted therapies.
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Affiliation(s)
- Emily S Robinson
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Robinson ES, Khankin EV, Karumanchi SA, Humphreys BD. Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker. Semin Nephrol 2010; 30:591-601. [PMID: 21146124 PMCID: PMC3058726 DOI: 10.1016/j.semnephrol.2010.09.007] [Citation(s) in RCA: 143] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway are a rapidly growing chemotherapy class for treatment of solid tumors. This targeted therapy is more specific than traditional chemotherapy, causing fewer side effects. However, VEGF-targeted therapies cause hypertension in 30% to 80% of patients. Unlike traditional off-target side effects, hypertension is a mechanism-dependent, on-target toxicity, reflecting effective inhibition of the VEGF signaling pathway rather than nonspecific effects on unrelated signaling pathways. In this article, we review current understanding of the mechanisms of VEGF-targeted therapy-induced hypertension, discuss similarities with preeclampsia, review implications for therapy of this increasingly common clinical problem, and discuss the potential use of blood pressure increase as a biomarker for proper drug dosing and effective VEGF pathway inhibition.
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Affiliation(s)
| | | | - S. Ananth Karumanchi
- Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Benjamin D. Humphreys
- Brigham and Women’s Hospital, Boston, Massachusetts
- Dana Farber Cancer Institute, Boston, Massachusetts
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40
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Desar IME, van Herpen CML, van Asten JJA, Fiedler W, Marreaud S, Timmer-Bonte JNH, ter Voert EGW, Lambiase A, Bordignon C, Heerschap A, van Laarhoven HWM. Factors affecting the unexpected failure of DCE-MRI to determine the optimal biological dose of the vascular targeting agent NGR-hTNF in solid cancer patients. Eur J Radiol 2010; 80:655-61. [PMID: 20863638 DOI: 10.1016/j.ejrad.2010.08.045] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Accepted: 08/30/2010] [Indexed: 01/18/2023]
Abstract
INTRODUCTION To understand which factors could affect the assessment of anti-vascular treatment by DCE-MRI, we investigated possible causes that could have hampered the selection of an optimal biological dose in humans of the vascular targeted agent NGR-hTNF by DCE-MRI: (1) insufficient reproducibility of DCE-MRI; (2) less specific targeting of NGR-hTNF; (3) interference of vessel characteristics with NGR-hTNF efficacy; (4) interfering pharmacodynamic effects. EXPERIMENTAL In a phase I study NGR-hTNF, DCE-MRI was performed at baseline and 2 h after NGR-hTNF administration in 31 patients with advanced solid cancer. Reproducibility measurements were performed in 5 other non-treated patients with metastatic disease. Mean kep, Ktrans values and their histogram distribution were determined in metastases and healthy liver tissue. The correlation between tumour size and DCE-MRI parameters was determined. Kinetics of soluble TNF receptors and the development of anti-TNF antibodies were assessed. RESULTS Reproducibility of the DCE-MRI technique was adequate. Mean DCE-MRI parameters did not significantly change after NGR-hTNF administration, but histogram analyses showed significant changes in metastases and healthy liver tissue in some patients. The anti-vascular effects of NGR-hTNF were larger in smaller tumours, which have less mature neovasculature. Soluble TNF receptors were released. CONCLUSIONS The difficulty to find an optimal biological dose of NGR-TNF by DCE-MRI is likely caused by a combination of factors: (i) different profiles of early anti-vascular effects in tumours and healthy liver tissue, (ii) dependence of the magnitude of the anti-vascular effect of NGR-hTNF on tumour size and (iii) shedding kinetics of soluble TNFα receptors.
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Affiliation(s)
- Ingrid M E Desar
- Department of Medical Oncology, Radboud University Nijmegen Medical Centre, The Netherlands.
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Abstract
Antiangiogenic cancer therapy is based on agents that target blood vessels of the tumor to inhibit its growth. However, experience from the clinic demonstrates that survival benefits following antiangiogenic therapy do not always correlate with tumor size and growth inhibition. Emerging evidence shows that delivery of antiangiogenic drugs might induce systemic alterations of the vasculature that modulate the function of various tissues and organs. Normalization of tissues and organs by antiangiogenic therapy may be an important mechanism underlying the survival benefits seen in patients with cancer who suffer cancer-associated systemic syndromes. This new concept has been validated in preclinical tumor models, and responses in patients have positively correlated with clinical benefits.
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Reduction in skin microvascular density and changes in vessel morphology in patients treated with sunitinib. Anticancer Drugs 2010; 21:439-46. [PMID: 20051825 DOI: 10.1097/cad.0b013e3283359c79] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Hypertension is a common side effect in cancer patients treated with inhibitors of vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling and may represent a marker of clinical benefit. Functional rarefaction (a decrease in perfused microvessels) or structural rarefaction (a reduction in anatomic capillary density) may play an important role in the development of hypertension. We investigated whether sunitinib caused impairment of microvascular function and/or reduction of capillary density in patients with metastatic renal cell cancer (mRCC). Sixteen mRCC patients were treated with sunitinib (50 mg/day). Assessments of 24-h ambulatory blood pressure, microvascular endothelial function by laser Doppler fluxmetry, and capillary density by capillary microscopy were performed at baseline and days 14 and 28. Median blood pressure had increased on day 14 (systolic 10 mmHg, P<0.01 and diastolic blood pressure 8 mmHg, P<0.01). Capillary density had decreased from 69 to 61 capillaries/mm (P<0.01). This decrease was related to the increase in systolic and diastolic blood pressure (r=-0.57, P<0.05 and r=-0.68, P<0.01, respectively). A more pronounced decrease in capillary density was associated with increased visibility of the subpapillary plexus (P=0.041). Preliminary findings indicated that median progression-free survival was significantly prolonged in patients with a greater than 6 capillaries/mm decrease in density as compared with patients with a less pronounced decrease (P=0.044). In conclusion, reduction in skin capillary density is associated with a rise in blood pressure during sunitinib therapy and, by itself, might be useful as a predictive marker of clinical outcome.
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Lindauer A, Di Gion P, Kanefendt F, Tomalik-Scharte D, Kinzig M, Rodamer M, Dodos F, Sörgel F, Fuhr U, Jaehde U. Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. Clin Pharmacol Ther 2010; 87:601-8. [PMID: 20376000 DOI: 10.1038/clpt.2010.20] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
A pharmacokinetic/pharmacodynamic (PK/PD) study of the tyrosine kinase inhibitor sunitinib was conducted in 12 healthy volunteers using blood pressure and circulating biomarker levels as PD markers. Blood pressure was measured, and plasma concentration-time courses of sunitinib, its major metabolite SU12662, vascular endothelial growth factors VEGF-A and VEGF-C, and soluble VEGF receptor-2 (sVEGFR-2) were studied in healthy subjects receiving 50 mg of sunitinib orally for 3-5 consecutive days. Using NONMEM, PK/PD models were established that predicted changes (expressed as multiples relative to baseline values) in systolic blood pressure, diastolic blood pressure, VEGF-A level, and sVEGFR-2 level, of 1.10, 1.18, 2.24, and 0.76, respectively, for a typical subject after 4 weeks of treatment with 50 mg/day. Simulated blood pressure-time courses compare excellently with published data in patients, whereas changes in circulating biomarkers were greater in patients than simulations suggest for healthy subjects. In conclusion, the tumor-independent pharmacological response to sunitinib could be described by PK/PD models, thereby facilitating model-based investigations with antiangiogenic drugs, using blood pressure and circulating proteins as biomarkers.
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Affiliation(s)
- A Lindauer
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
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Vincenzi B, Santini D, Russo A, Addeo R, Giuliani F, Montella L, Rizzo S, Venditti O, Frezza AM, Caraglia M, Colucci G, Del Prete S, Tonini G. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist 2010; 15:85-92. [PMID: 20051477 PMCID: PMC3227883 DOI: 10.1634/theoncologist.2009-0143] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2009] [Accepted: 12/07/2009] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Sorafenib is an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases and has led to a longer median overall survival (OS) time and time to progression (TTP) in patients with advanced hepatocellular carcinoma (HCC). This study was conducted to assess the link between the antitumor efficacy of sorafenib and its early cutaneous side effects in advanced HCC patients. MATERIALS AND METHODS All patients received 800 mg daily of sorafenib until progression or unacceptable toxicities. We retrospectively analyzed the incidence of rash and hand-foot skin reactions (HFSR) during the first month of treatment, comparing tumor control (partial response plus stable disease) and TTP. RESULTS Sixty-five HCC patients treated with sorafenib were included in this analysis: 47 (73.3%) received sorafenib after failure of some local treatment, whereas 18 (27.7%) received it as first-line treatment. Twenty-nine patients developed at least grade 1 skin toxicity (rash, 13; HFSR, 16). In patients who developed skin toxicity, the tumor control rate was 48.3%, versus 19.4% in patients without cutaneous side effects. The median TTP was 8.1 months in the group of patients with skin toxicity versus 4.0 months in those without skin toxicity. This difference was also statistically significant on multivariate analysis. A borderline statistically significant difference was also observed in terms of OS in patients with early skin toxicity. CONCLUSIONS Skin toxicity should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy.
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Affiliation(s)
- Bruno Vincenzi
- Medical Oncology, University Campus Bio-Medico, Rome, Italy
| | | | - Antonio Russo
- Section of Medical Oncology, Department of Surgical and Oncological Sciences, Università di Palermo, Palermo, Italy
| | - Raffaele Addeo
- Oncology Unit, S. Giovanni di Dio Hospital, Naples, Italy
| | | | | | - Sergio Rizzo
- Section of Medical Oncology, Department of Surgical and Oncological Sciences, Università di Palermo, Palermo, Italy
| | - Olga Venditti
- Medical Oncology, University Campus Bio-Medico, Rome, Italy
| | | | - Michele Caraglia
- Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy
| | - Giuseppe Colucci
- Medical and Experimental Oncology Unit, Oncology Institute, Bari, Italy
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Bono P, Joensuu H. Reply to Arterial hypertension and clinical benefit of sunitinib, sorafenib and bevacizumab in first and second-line treatment of metastatic renal cell cancer. Ann Oncol 2009; 20:967. [PMID: 32560016 DOI: 10.1093/annonc/mdp204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- P Bono
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
| | - H Joensuu
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
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