Cardiovascular Toxicity of Multi-Tyrosine Kinase Inhibitors in Advanced Solid Tumors: A Population-Based Observational Study
17
Citation
57
Reference
10
Related Paper
Citation Trend
Abstract:
Background Treatment with small molecule tyrosine kinase inhibitors (TKIs) has improved survival in many cancers, yet has been associated with an increased risk of adverse events. Warnings of cardiovascular events are common in drug labels of many TKIs. Despite these warnings, cardiovascular toxicity of patients treated with TKIs remains unclear. Here, we evaluate the cardiovascular outcomes of advanced cancer patients treated with small molecule tyrosine kinase inhibitors. Methods A population based cohort study was undertaken involving adults aged >18 years in Ontario, Canada, diagnosed with any advanced malignancy between 2006 and 2012. Data were extracted from linked administrative governmental databases. Adults with advanced cancer receiving TKIs were identified and followed throughout the time period. The main outcomes of interest were rates of hospitalization for ischemic heart disease (acute myocardial infarction and angina) or cerebrovascular accidents and death. Results 1642 patients with a mean age of 62.5 years were studied; 1046 were treated with erlotinib, 166 with sorafenib and 430 with sunitinib. Over the 380 day median follow-up period (range 6-1970 days), 1.1% of all patients had ischemic heart events, 0.7% had cerebrovascular accidents and 72.1% died. Rates of cardiovascular events were similar to age and gender-matched individuals without cancer. In a subgroup analysis of treatment patients with a prior history of ischemic heart disease, 3.3% had ischemic heart events while 1.2% had cerebrovascular accidents. Conclusions TKIs do not appear to increase the cause-specific hazard of ischemic heart disease and cerebrovascular accidents compared to age and gender-matched individuals without advanced cancer.Keywords:
Stroke
In recent years, targeted therapies have proven beneficial in terms of progression-free survival (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC). The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are included in international clinical guidelines as first-line and second-line therapy in mRCC. Hypertension is an adverse effect of these drugs and the degree of hypertension associates with the anti-tumour effect. Studies have compared newer targeted drugs to sorafenib and sunitinib in terms of PFS, OS, quality of life and safety profiles. Phase III studies presented promising response rates and acceptable safety profiles of axitinib and tivozanib compared to sorafenib, and a phase II study reported greater efficacy using a combination of bevacizumab and IFN-α compared to sunitinib. Treatment with nintedanib exhibited a notably low prevalence of hypertension compared to sunitinib. The use of sorafenib and sunitinib are challenged by new drugs, but do not appear likely to be substituted in the near future. To clarify whether newer targeted drugs should replace sorafenib and sunitinib, more research is needed. This manuscript reviews the current utility and adverse effects of sorafenib and sunitinib and newer targeted therapies in the treatment of mRCC.
Axitinib
Pazopanib
Targeted Therapy
Cite
Citations (75)
Cite
Citations (8)
The multi-kinase inhibitor sorafenib still remains the only approved agent for advanced HCC. Its benefits typically involve disease stabilisation, whereas an induction of response is rare. We report a series of five cases with extraordinary response to sorafenib. For two patients complete response to sorafenib was reported with a recurrence-free survival of 51 and 21 months. In another HCC patient pretreated with transarterial chemoembolisation (TACE) sorafenib treatment resulted in a complete response with no evidence of disease 18 months after first diagnosis. In patient 4 with unresectable HCC and sorafenib therapy secondary resectability and subsequent liver transplantation was achieved. Patient 5 had stabilised disease for 48 months after TACE and sorafenib treatment. Sorafenib may be very potent in individual patients. Excellent interdisciplinary strategies are required to achieve best results. There is an urgent need of predictive biomarkers to identify HCC patients that will benefit the most.
Complete response
Cite
Citations (3)
The up-regulation of P62 levels is associated with resistance of sorafenib in hepatocarcinoma cells.
Sorafenib is one of the most commonly used systemic therapies for hepatocellular carcinoma (HCC), but the acquired resistance towards sorafenib found in HCC patients usually led to failure of treatment and poor prognosis. Therefore, there is an urgent need to study the molecular mechanism caused by the acquired resistance. Previous studies demonstrated that P62 plays an important role in tumor cell resistance towards systemic therapies including chemotherapy and targeted therapy. However, the role of P62 in acquired resistance to sorafenib in HCC has not been clearly investigated.In this study we screened the most sensitive HCC cell lines towards sorafenib using CCK8. Then on this cell line, we analyzed the relationship between P62 expression level and the sensitivity towards sorafenib by western blot and CCK8. After knockdown and overexpression of P62 in HCC cells, cells were then treated with sorafenib. After that, we detect changes of sensitivity towards sorafenib. HCC samples were used to investigate the expression of P62 and their survival time.Among four HCC cell lines in our lab, HepG2 cell line with the highest sensitivity to sorafenib was screened and selected. After treatment with sorafenib, the expression of P62 was significantly increased. In HCC cells, we found that significant up-regulation of P62 was correlated with the reduction of sorafenib sensitivity. In HCC samples, we found that the expression of P62 was associated with sorafenib resistance and a shorter survival time.The up-regulation of P62 could reduce the sensitivity of HCC towards sorafenib. Thus, P62 could be therapeutic target to overcome sorafenib acquired resistance in the future.
Cite
Citations (9)
Temsirolimus
Cite
Citations (236)
The aim of our study was to evaluate the outcome of alternative sequences of sunitinib followed by sorafenib versus sorafenib followed by sunitinib therapies in patients with metastatic renal cell carcinoma (mRCC).This single-center study analyzed patients with mRCC on systemic therapy between January 2005 and August 2011. Patients were treated with the recommended first-line therapy (sunitinib, sorafenib, pazopanib, or immunotherapy) until progression or intolerable toxicity and afterward switched to another guideline-recommended systemic therapy. Only patients starting first-line therapy on either sorafenib or sunitinib and switching to the other of these drugs were included in this analysis.Out of 266 patients (females: 85, males: 181) with a median age of 57.1 years (30 - 76 years), 57 patients with a sequence of sunitinib and sorafenib were identified. First-line sorafenib therapy was followed by sunitinib (So-Su) in 32 patients; sunitinib was followed by sorafenib (Su-So) in 25 patients. Progression-free survival (PFS) for patients with first-line sorafenib was 11.6 months and was 8.7 months for sunitinib. Overall survival (OS) rates for Su-So was 118.8 months and 83.3 months with So-Su (p = 0.82). No new safety signals were detected.None of the therapeutic first-line approaches was superior to the other. Sequencing tyrosine kinase inhibitor (TKI) therapy seems to be effective in mRCC and superior to single-line therapy. Further studies should focus on the efficacy of single treatment lines rather than treatment sequences to estimate more potent drugs based on PFS rather than overall survival (OS).
Pazopanib
Combination therapy
Systemic therapy
Cite
Citations (2)
No AccessJournal of UrologyAdult Urology1 Jul 2009Sequential Sorafenib and Sunitinib for Renal Cell Carcinoma M.P. Sablin, S. Negrier, A. Ravaud, S. Oudard, C. Balleyguier, J. Gautier, C. Celier, J. Medioni, and B. Escudier M.P. SablinM.P. Sablin Institut Gustave Roussy, Villejuif, France , S. NegrierS. Negrier Centre Léon Bérard, Lyon, France , A. RavaudA. Ravaud Hôpital Saint-André, Bordeaux, France , S. OudardS. Oudard Hôpital Européen Georges Pompidou, Paris, France , C. BalleyguierC. Balleyguier Institut Gustave Roussy, Villejuif, France , J. GautierJ. Gautier Centre Léon Bérard, Lyon, France , C. CelierC. Celier Hôpital Saint-André, Bordeaux, France , J. MedioniJ. Medioni Hôpital Européen Georges Pompidou, Paris, France , and B. EscudierB. Escudier Institut Gustave Roussy, Villejuif, France View All Author Informationhttps://doi.org/10.1016/j.juro.2009.02.119AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Sorafenib and sunitinib are 2 tyrosine kinase inhibitors that were recently approved for renal cell carcinoma. In many patients sequential administration of the 2 drugs occurs because of the lack of sustained efficacy of the first agent. We determined the efficacy and safety of sequential administration. Materials and Methods: To determine whether cross-resistance occurs between these 2 drugs we analyzed the outcome in 90 consecutive patients with renal cell carcinoma from 4 sites in France who had received the 2 drugs sequentially. All patients received sorafenib followed by sunitinib or vice versa. From 2003 to 2006, 68 patients received sorafenib, while 22 received sunitinib first. Results: In the sorafenib-sunitinib group median progression-free survival was 26 weeks with sorafenib and 28 with sunitinib. In the sunitinib-sorafenib group median progression-free survival was 22 weeks with sunitinib and 17 with sorafenib. Median overall survival was 135 weeks in the sorafenib-sunitinib group and 82 weeks in the sunitinib-sorafenib group (HR 0.49, 95% CI 0.16 to 0.96, p = 0.04). The average duration of sequential administration was 61 and 49 weeks, respectively, in the sorafenib-sunitinib and sunitinib-sorafenib groups. Each sequence was well tolerated and no increase in grade 3-4 toxicity was observed. Conclusions: Overall this retrospective study supports the conclusion of the lack of absolute cross-resistance between tyrosine kinase inhibitors. In this renal cell carcinoma population sorafenib followed by sunitinib was associated with longer survival than sunitinib followed by sorafenib. However, this observation needs further confirmation. References 1 : Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med2007; 356: 125. Google Scholar 2 : Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med2007; 356: 115. Google Scholar 3 : Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med2007; 356: 2271. Google Scholar 4 : Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet2007; 370: 2103. Google Scholar 5 : Chemotherapy for advanced renal-cell carcinoma: 1983–1993. Semin Oncol1995; 22: 42. Google Scholar 6 : Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma: Groupe Francais d'Immunotherapie. N Engl J Med1998; 338: 1272. Google Scholar 7 : Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet1994; 7: 85. Google Scholar 8 : Overall survival with sunitinib versus interferon (IFN)-alfa as first line treatment of metastatic renal cell carcinoma (mRCC). J Clin Oncol2008; 26. abstract 5024. Google Scholar 9 Escudier B: Overvew of clinical trials in RCC. Presented at European Society for Medical Oncology Congress, Stockholm, Sweden, September 12–16, 2008. Google Scholar 10 : New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst2000; 92: 205. Google Scholar 11 : Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol1999; 17: 2530. Google Scholar 12 : In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res2003; 9: 327. Google Scholar 13 : BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res2004; 64: 7099. Google Scholar 14 : Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. J Clin Oncol2007; 25: 18S. abstract 5106. Google Scholar 15 : Evaluation of VEGF targeted therapy efficacy in mRCC after sorafenib failure or intolerance. J Clin Oncol2007; 25: 18S. abstract 15517. Google Scholar 16 : Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol2008; 179: 81. Link, Google Scholar 17 : Clinical activity of sorafenib and sunitinib in renal cell carcinoma refractory to previous vascular endothelial growth factor-targeted therapy: two case reports. Clin Genitourin Cancer2006; 5: 78. Google Scholar 18 : Use of von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (RCC). J Clin Oncol2009; 25: 18S. abstract 5012. Google Scholar 19 : Efficacy and safety of sunitinib malate in bevacizumab-refractory metastatic renal cell carcinoma (RCC). J Clin Oncol2006; 24: 18S. abstract 4522. Google Scholar 20 : Axitinib (AG013736; AG) in patients (pts) with metastatic clear cell renal cell cancer (RCC) refractory to sorafenib. J Clin Oncol2007; 25: 18S. abstract 5032. Google Scholar © 2009 by American Urological AssociationFiguresReferencesRelatedDetailsCited byLaguna M (2018) Re: Tivozanib versus Sorafenib as Initial Targeted Therapy for Patients with Metastatic Renal Cell Carcinoma: Results from a Phase III TrialJournal of Urology, VOL. 192, NO. 4, (1079-1079), Online publication date: 1-Oct-2014. Volume 182Issue 1July 2009Page: 29-34 Advertisement Copyright & Permissions© 2009 by American Urological AssociationKeywordsrenal cellsorafenibkidneysunitinibdrug resistancecarcinomaAcknowledgmentsJ. Balcaceres and L. Bouaita assisted with data collection, and S. Charnick assisted with manuscript preparation.MetricsAuthor Information M.P. Sablin Institut Gustave Roussy, Villejuif, France More articles by this author S. Negrier Centre Léon Bérard, Lyon, France More articles by this author A. Ravaud Hôpital Saint-André, Bordeaux, France More articles by this author S. Oudard Hôpital Européen Georges Pompidou, Paris, France More articles by this author C. Balleyguier Institut Gustave Roussy, Villejuif, France More articles by this author J. Gautier Centre Léon Bérard, Lyon, France More articles by this author C. Celier Hôpital Saint-André, Bordeaux, France More articles by this author J. Medioni Hôpital Européen Georges Pompidou, Paris, France More articles by this author B. Escudier Institut Gustave Roussy, Villejuif, France More articles by this author Expand All Advertisement PDF downloadLoading ...
Cite
Citations (156)
Cite
Citations (100)
the ideal sequence of targeted agents for advanced kidney cancer is still unknown. In the present study we assessed the clinical benefit of two different sequential approaches, namely sorafenib, an inhibitor of mammalian target of rapamycin (mTORi) and sunitinib, or sunitinib (an mTORi) and sorafenib.we retrospectively reviewed the outcome of 40 advanced kidney cancer patients treated with one of the two above sequences.a total of 26 patients were treated with the sequence sorafenib-mTORi-sunitinib and 14 with the sequence sunitinib-mTORi-sorafenib. The actuarial overall median progression-free survival (PFS) in the sorafenib-mTORi-sunitinib group and in the sunitinib-mTORi-sorafenib group were 21.9 and 22.8 months, respectively (log-rank test: p=0.928). In the sorafenib-mTORi-sunitinib group, patients in first-, second- and third-line therapy experienced PFS of 11.7, 5.1 and 9.1 months, respectively, while in the sunitinib-mTORi-sorafenib group PFS was 14.4, 4.3, and 3.9 months, respectively.Our results suggest there is no significant difference between the two sequence modalities.
Kidney cancer
Cite
Citations (3)
Το ήπαρ έχει τη μοναδική ικανότητα να αναγεννάται. Η ικανότητα αυτή θεωρείται ζωτικής σημασίας για την επιβίωση ασθενών που υποβάλλονται σε εκτεταμένη ηπατεκτομή για την αντιμετώπιση κακόηθων νεοπλασμάτων. Ο ηπατοκυτταρικός καρκίνος είναι η συχνότερη κακοήθεια του ήπατος, ο πέμπτος πιο συχνός καρκίνος παγκοσμίως και η τρίτη αιτία θανάτου από καρκίνο. Η μεταμόσχευση και η ηπατεκτομή αποτελούν δυνητικά θεραπευτικές προσεγγίσεις και είναι οι ενδεικνυόμενες θεραπευτικές προσεγγίσεις σε πρώιμα στάδια. Σε ασθενείς με προχωρημένο καρκίνο κατηγορίας Child-Pugh A, η θεραπεία με το Sorafenib, έναν αναστολέα κινασών, έδειξε θετικά αποτελέσματα. Οι σηματοδοτικές οδοί που επηρεάζονται από τη δράση του Sorafenib, σχετίζονται με την αγγειογένεση και τον κυτταρικό πολλαπλασιασμό, αναπόσπαστα κομμάτια της ηπατικής αναγέννησης. Στόχο της μελέτης αποτέλεσε η διερεύνηση της επίδρασης του Sorafenib στην ηπατική αναγέννηση, μετά από 2/3 μερική ηπατεκτομή. Χρησιμοποιήθηκε πειραματικό μοντέλο σε επίμυες. Η ουσία χορηγήθηκε σε δόση 30mg/kg/ημέρα για 14 ημέρες προεγχειρητικά per os. Τα πειραματόζωα διαχωρίστηκαν στην ομάδα ελέγχου που έλαβε Placebo και στην ομάδα που έλαβε Sorafenib. Θυσιάστηκαν στις 48, 96 και 168 ώρες μετά την ηπατεκτομή αντίστοιχα, ανάλογα με την υποομάδα στην οποία ανήκαν. Από τη σύγκριση και τη στατιστική ανάλυση των αποτελεσμάτων προκύπτει ότι η αναγέννηση του ηπατικού κολοβώματος επηρεάζεται από τη χορήγηση του Sorafenib σε όλες τις χρονικές στιγμές ελέγχου μετά τη 2/3 μερική ηπατεκτομή, ενώ η ανασταλτική του δράση γίνεται εμφανής και κατά τον υπολογισμό του μιτωτικού δείκτη, στις 48 και 96 ώρες. Από τη μελέτη των ιστοτεμαχίων στο οπτικό μικροσκόπιο για παρατήρηση των χαρακτηριστικών μεταβολών του ηπατικού παρεγχύματος κατά την ηπατική αναγέννηση, προκύπτει πως η ηπατική αναγέννηση στην ομάδα του Sorafenib ήταν επηρεασμένη. Η σύνθεση DNA των ηπατοκυττάρων που υπολογίστηκε ανοσοϊστοχημικώς με χρώση με το μονοκλωνικό αντίσωμα έναντι του πυρηνικού αντιγόνου Ki-67, φαίνεται ότι δεν επηρεάζεται στατιστικώς σημαντικά μετά τη 2/3 μερική ηπατεκτομή, όπως επίσης και η νεοαγγειογένεση, εκτιμούμενη με τον ενδοθηλιακό δείκτη σήμανσης για το CD34, δεν παρουσιάζει στατιστικώς σημαντική μεταβολή. Οι βιοχημικοί δείκτες εκφράζουν περισσότερο τη λειτουργική βλάβη του ήπατος και δεν μπορούν να εκτιμήσουν την ηπατική αναγέννηση και νεοαγγειογένεση. Είναι όμως πολύ καλός δείκτης παρακολούθησης τυχόν ηπατοτοξικότητας. Τα αποτελέσματα της παρούσας μελέτης, δηλαδή η επιλεκτική και παροδική μείωση της ηπατικής αναγέννησης και νεοαγγειογένεσης, δεν μπορούν να μεταφραστούν άμεσα σε κλινικό επίπεδο. Στην περίπτωση που τα αποτελέσματα και η ασφάλεια της παρούσας μελέτης επιβεβαιωθούν, τότε το Sorafenib θα μπορούσε να χρησιμοποιηθεί ως νεοεπικουρική θεραπεία σε ασθενείς που πάσχουν από HCC, πριν από την εκτέλεση ηπατεκτομών, προσδίδοντας τους μεγαλύτερο προσδόκιμο επιβίωσης, με καλύτερη ποιότητα ζωής. Η αντιμετώπιση ασθενών με HCC θα μπορεί να είναι πιο αποτελεσματική, με λιγότερες ανεπιθύμητες ενέργειες, καθώς φαίνεται το Sorafenib να είναι ευκολότερα ανεκτό στους ασθενείς. Επίσης με την απόδειξη ότι οι αντιαγγειογενετικοί παράγοντες μπορούν να περιορίσουν ή να καταπολεμήσουν καρκινικά κύτταρα και να μειώσουν τις πιθανότητες υποτροπής της νόσου, ένας νέος ορίζοντας ανοίγεται στην αντιμετώπιση του καρκίνου, όπου συνδυασμός θεραπευτικών μεθόδων θα είναι πιο αποτελεσματικός με λιγότερες υποτροπές της νόσου.
Cite
Citations (0)