Hematologic toxicities in renal cell carcinoma and other malignancies treated with bevacizumab: A meta-analysis of clinical trials.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 336-336
Author(s):  
D. L. Fontes Jardim ◽  
Y. Je ◽  
F. A. Schutz ◽  
T. K. Choueiri
Keyword(s):  
Clinical Trials ◽  
Febrile Neutropenia ◽  
Renal Cell ◽  
Meta Analysis ◽  
Cell Cancer ◽  
Safety Data ◽  
High Grade ◽  
Concurrent Use ◽  
Increased Risk ◽  
American Society

336 Background: Bevacizumab is a humanized monoclonal antibody directed against the VEGF ligand. Clinical trials with this drug mainly included patients with renal cell cancer (in combination with interferon-alpha) and several other solid tumors (in combination with cytotoxic chemotherapy). Although hematologic toxicities are not among the main concerns associated with the addition of bevacizumab, discontinuation of therapy or dose reductions due to these toxicities have been reported. We performed a meta-analysis to determine the incidence and risk of hematologic toxicities associated with bevacizumab use. Methods: The databases of Medline were searched for articles from 1966 to September 2010. Abstracts presented at the American Society of Clinical Oncology meetings were also searched. Eligible studies include randomized trials with bevacizumab, and adequate safety data profile reporting anemia, neutropenia, febrile neutropenia, or thrombocytopenia. Statistical analyses were conducted to calculate the summary incidence, RR, and 95% confidence intervals (CI). Results: A total of 15,239 patients were included in the analysis. The incidence of bevacizumab-associated all-grade anemia, neutropenia and thrombocytopenia were 19.4%, 22.3%, and 14.5%, respectively. The incidences of high-grade events were 3.94%, 18.4% and 3.38%, respectively. Febrile neutropenia was present in 3.75% of patients. Bevacizumab was associated with a decreased risk of high-grade anemia (RR=0.73; 95% CI 0.60-0.89; p=0.002), and increased risks of high-grade neutropenia (RR=1.08; 95% CI 1.02-1.13; p=0.005) and febrile neutropenia (RR=1.31; 95% CI 1.08-1.58; p=0.006), as compared to the non-bevacizumab containing arms. Stratified analysis by the dose of bevacizumab (2.5mg/wk vs. 5mg/wk) demonstrated similar risks. Conclusions: Concurrent use of bevacizumab with chemotherapy or immunotherapy is associated with a lower risk of high-grade anemia and an increased risk of high-grade neutropenia and febrile neutropenia. [Table: see text]

Meta-analysis of hematologic toxicities in patients with cancer treated with sunitinib.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 373-373
Author(s):  
Tomohiro Funakoshi ◽  
Asma Latif ◽  
Kamyar Arasteh ◽  
Matt D. Galsky
Keyword(s):  
Relative Risk ◽  
Tyrosine Kinases ◽  
Meta Analysis ◽  
Cell Cancer ◽  
Single Agent ◽  
Safety Data ◽  
High Grade ◽  
Increased Risk ◽  
Significant Difference ◽  
American Society

373 Background: Sunitinib is a small molecule which inhibits receptor tyrosine kinases involved in cell proliferation and angiogenesis. Though the incidence and risk of unique toxicities associated with sunitinib, such as hypertension and thromboembolic events, have been previously reported, the incidence and risk of hematologic toxicities have been less well characterized. Methods: We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to July 2012 for relevant clinical trials. Eligible studies included phase II and III trials and expanded access programs with sunitinib that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia. The relative risk (RR), summary incidence and 95% confidence intervals (CI) were calculated. Results: A total of 8,526 patients from 60 trials of sunitinib as a single agent revealed that the incidence of sunitinib-associated all-grade and high-grade (grade 3-4) hematologic toxicities were, respectively: neutropenia: 42.1% and 12.8%; thrombocytopenia: 44.7% and 10.7% and anemia: 50.4% and 6.2%. Sunitinib-treated patients (2,667 subjects from 10 randomized trials) had a significantly increased risk of all-grade (RR = 3.58; 95% CI, 1.71–7.49) and high-grade (RR = 3.32; 95% CI, 1.60–6.90) neutropenia, all-grade (RR = 4.59; 95% CI, 2.76–7.63) and high-grade (RR = 5.84; 95% CI, 2.22–15.41) thrombocytopenia and all-grade anemia (RR = 1.15; 95% CI, 1.00–1.31). Subgroup analysis revealed the significantly higher relative risk of high-grade neutropenia in patients receiving sunitinib monotherapy than in patients receiving concomitant therapy (p = 0.026). There was no statistically significant difference in the incidence of hematologic toxicities between subgroups; renal cell cancer (RCC) versus non-RCC or continuous daily sunitinib dosing versus intermittent dosing. Conclusions: Sunitinib is associated with a significant increase in the risk of developing all-grade and high-grade neutropenia and thrombocytopenia and all-grade anemia compared with control.

Hematologic toxicities in cancer patients treated with the multityrosine kinase sorafenib: A meta-analysis of clinical trials.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 352-352
Author(s):  
F. A. Schutz ◽  
Y. Je ◽  
T. K. Choueiri
Keyword(s):  
Kinase Inhibitor ◽  
Meta Analysis ◽  
Safety Data ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
High Grade ◽  
Increased Risk ◽  
American Society ◽  
Stratified Analysis ◽  
Endothelial Growth Factor

352 Background: Sorafenib is a vascular endothelial growth factor receptor tyrosine-kinase inhibitor currently used in several malignancies. While not a traditional cytotoxic chemotherapeutic agent, hematological toxicities have been reported with this drug but the incidence and risk have not been formerly assessed. We performed a meta-analysis to determine the incidence and risk of hematologic toxicities associated with sorafenib use. Methods: The databases of Medline were searched for articles from 1966 to May 2010. Abstracts presented at the American Society of Clinical Oncology meetings were also searched. Eligible studies include randomized trials with sorafenib, and adequate safety data profile reporting anemia, neutropenia, lymphopenia or thrombocytopenia. Statistical analyses were conducted to calculate the summary incidence, RR and 95% confidence intervals (CI). Results: A total of 3,221 patients were included. The incidence of sorafenib-associated all- grade anemia, neutropenia, thrombocytopenia and lymphopenia were 43.9%, 18.0%, 25.3% and 34.1%, respectively. The incidences of high-grade events were 2.0%, 5.1%, 4.0% and 13.1%, respectively. Sorafenib was associated with a decreased risk of high-grade anemia (RR=0.62; 95% CI 0.39-0.98), an increased risk of all-grade (RR=1.69; 95% CI 1.33-2.17) and high-grade (RR=1.61; 95% CI 1.02-2.57) neutropenia, all-grade (RR=2.56; 95% CI 1.37-4.80) and high-grade (RR=3.63; 95% CI 1.98-6.66) thrombocytopenia, and high-grade lymphopenia (RR=1.84; 95% CI 1.22-2.78). Stratified analysis by the presence or not of concomitant chemotherapy demonstrated similar risks. Conclusions: Independent of cytotoxic chemotherapy, sorafenib has significant hematologic toxicities, with a decreased risk of anemia and increased risk of neutropenia, thrombocytopenia and lymphopenia. [Table: see text]

Risk of Skin Rash in Proteasome Inhibitor Bortezomib: A Systematic Literature Review and Meta-Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5120-5120
Author(s):  
Emily C Case ◽  
Shenhong Wu ◽  
John Gerecitano ◽  
Mario E Lacouture
Keyword(s):  
Literature Review ◽  
Skin Rash ◽  
Systematic Literature Review ◽  
Proteasome Inhibitor ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Phase Iii ◽  
High Grade ◽  
Increased Risk ◽  
American Society

Abstract Abstract 5120 Background: Bortezomib (VELCADE) is the first proteasome inhibitor to be approved by regulatory agencies for treatment of multiple myeloma and mantle cell lymphoma. Maculopapular rash is a common, adverse event to bortezomib. Because the summary incidence of bortezomib-induced skin rash is not well known, we performed a systematic literature review and meta-analysis to determine the incidence and overall risk. Methods: We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology and The American Society of Hematology annual meetings from 1998 to July 2011, to identify relevant clinical studies. Eligible studies included prospective clinical phase II and phase III trials, with data on the incidence of rash in patients taking 1.3mg/m2, 1.5mg/m2, or 1.6 mg/m2 of bortezomib twice weekly for two weeks followed by one week off, in a 21-day cycle. The incidence of rash and relative risk (RR) were calculated using random-effects or fixed-effects model, depending on the heterogeneity of included studies. Results: A total of 2,469 patients with various hematologic and solid malignancies from 32 clinical trials were included for analysis. Among patients receiving bortezomib, the summary incidences of all-grade and high-grade rash were 18.8 % (95% CI: 14.9% to 23.5%) and 3.6 % (95% CI: 2.3% to 5.7%), respectively. We found no significant increase in rash incidence with higher doses of bortezomib. In addition, bortezomib was associated with an increased risk in both all grade (RR:19.703, 95% CI: 8.734 to 44.446, p<0.001) and high-grade rash (RR: 5.354, 95% CI: 2.158 to 13.285, p<0.001), in comparison with controls. Conclusion: Bortezomib is associated with a significant risk of developing rash. Management of bortezomib-induced rash is critical to prevent a negative effect on quality of life and dose modifications, both of which may affect clinical outcome. Disclosures: Wu: Onyx: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Speakers Bureau. Gerecitano:Millenium: Research Funding.

High-grade proteinuria associated with bevacizumab in patients with renal cell cancer and non-renal cell cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16089-e16089
Author(s):  
C. Y. Kim ◽  
D. Chu ◽  
L. Baer ◽  
S. Wu
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Significant Risk ◽  
Close Monitoring ◽  
Tumor Type ◽  
High Grade ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Significant Difference

e16089 Background: Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor. It is a widely used angiogenesis inhibitor in the treatment of renal cell cancer (RCC) and other solid tumors. Proteinuria is associated with significant morbidity and treatment interruptions. The overall risk for proteinuria is unclear. This study was conducted to determine the risk of developing proteinuria among RCC and non-RCC patients receiving bevacizumab. Methods: Databases from PUBMED and Web Science from January 1966 until July 2008 and abstracts presented at ASCO from January 2000 to July 2008 were searched to identify relevant studies. Studies included randomized controlled clinical trials in which standard anti-neoplastic therapy was administered with and without bevacizumab with available data for proteinuria. Summary incidence rate, relative risk (RR), and 95% confidence interval (CI) were calculated employing fixed or random effect models based upon the heterogeneity of included studies. Results: A total of 6,702 patients from 14 randomized controlled studies were included for analysis. The incidence of all-grade proteinuria in patients receiving bevacizumab was 19.3% (95% CI: 11.9–29.6%) with 2.3% (95% CI: 1.2–4.1%) being high-grade (grade 3 or 4). Patients treated with bevacizumab had an increased risk of developing high-grade proteinuria with RR of 6.3 (95% CI: 4.0–9.9) compared with controls. Risk may vary with dose of bevacizumab; significant difference may exist in patients receiving bevacizumab at 5 mg/kg/week (RR 9.1, 95% CI: 4.3–19.6, p < 0.001) and 2.5 mg/kg/week (RR = 5.1, 95%CI: 3.0–8.8, p < 0.001). The risk of high-grade proteinuria may also depend on tumor type; the incidence of high-grade proteinuria was 10.0% (95% CI: 4.3–22.4%) with a RR 48.7 (95% CI: 9.7–244.3) among 703 RCC patients compared with an incidence of 1.7% (95% CI: 0.09–3.2%) and RR of 5.2 (95% CI: 3.3–8.4) among 5,999 non-RCC patients. Conclusions: There is a significant risk for high-grade proteinuria in patients receiving bevacizumab. The risk may vary with bevacizumab dose and tumor type. RCC patients may have higher risk than non-RCC patients. Close monitoring and management are recommended for patients at high risk. No significant financial relationships to disclose.

Incidence and risk of congestive heart failure risk in renal cell cancer (RCC) and non-RCC patients treated with sunitinib.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 316-316 ◽  
Author(s):  
C. J. Richards ◽  
Y. Je ◽  
F. A. Schutz ◽  
S. M. Dallabrida ◽  
J. J. Moslehi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Cancer Patients ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Cell Cancer ◽  
Tumor Type ◽  
High Grade ◽  
Increased Risk

316 Background: Sunitinib is a multitargeted receptor tyrosine kinase inhibitor that is widely used in the treatment of renal cell cancer (RCC) and several other malignancies. Congestive heart failure (CHF) has been reported with sunitinib, but the overall incidence and relative risk (RR) remain undefined. We preformed an up-to-date comprehensive meta-analysis to determine the risk of developing serious CHF in patients with both RCC and non-RCC tumors treated with sunitinib. Methods: Medline databases were searched for articles from January 1966 to September 2010. Eligible studies were limited to phase II and III trials of sunitinib in cancer patients with any primary tumor type and adequate safety profile reporting. Statistical analyses were conducted to calculate the summary incidence, RR and 95% confidence intervals (CI), using random-effects models. Results: A total of 5,497 patients were included. Overall incidence for all-grade and high-grade CHF in sunitinib-treated patients was 4.9% (95% CI, 1.6–14.1%) and 1.8% (95% CI, 0.8–3.9%), respectively. The RR of all-grade and high-grade CHF in sunitinib-treated patients compared to placebo-treated ones was 1.81 (95% CI, 1.30–2.50; p<0.0001) and 3.17 (95% CI, 1.12–8.97; p=0.030), respectively. On subgroup analysis there was no difference observed in the CHF incidence for RCC vs. non-RCC patients. No evidence of publication bias was observed. Conclusions: This is the first comprehensive report to demonstrate that sunitinib use is associated with an increased risk of significant heart failure in cancer patients. [Table: see text]

Incidence and risk of treatment-related mortality in patients with renal cell cancer (RCC) and non-RCC treated with mammalian target of rapamycin (mTOR) inhibitors.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 347-347
Author(s):  
Toni K. Choueiri ◽  
Youjin Je ◽  
Guru Sonpavde ◽  
Matt D. Galsky ◽  
Marina Kaymakcalan ◽  
...  
Keyword(s):  
Adverse Events ◽  
Renal Cell ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Cell Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Therapeutic Modality ◽  
Increased Risk

347 Background: Inhibition of the mammalian target of rapamycin (mTOR) is an established therapeutic modality for multiple malignancies including renal cell carcinoma (RCC). Agents that target mTOR have been sporadically associated with an increased risk of potentially life-threatening adverse events. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors, including RCC. Methods: MEDLINE/PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to trials of US Food and Drug Administration—approved mTOR inhibitors (everolimus and temsirolimus) that reported on patients with cancer, randomized design, and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% Confidence Intervals (CIs) by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all 2,990 patients from 8 randomized controlled trials (RCTs) were included, 2033 from everolimus trials and 957 from temsirolimus trials. The incidence of FAEs related to mTOR inhibitors use was 3.4% (95% CI, 1.9-6.0) with a RR of 2.33 (95% CI, 1.32 to 4.10; P = .003) compared to control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types (RCC vs. non-RCC). No evidence of publication bias was observed. Conclusions: The use of mTOR inhibitors is associated with an increased risk of FAEs in RCC and non-RCC patients, compared with control patients.

Rash to mTOR inhibitor everolimus: Systematic review and meta-analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19624-e19624 ◽  
Author(s):  
Marigdalia K. Ramirez-Fort ◽  
Emily Christine Case ◽  
Alyx C. Rosen ◽  
Shenhong Wu ◽  
Mario E. Lacouture
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Fixed Effects ◽  
Mtor Inhibitor ◽  
Meta Analysis ◽  
Significant Risk ◽  
Phase Iii ◽  
Subependymal Giant Cell Astrocytoma ◽  
High Grade ◽  
Increased Risk

e19624 Background: Everolimus is an mTOR inhibitor approved for treatment of renal cell carcinoma, subependymal giant cell astrocytoma, and progressive neuroendocrine tumors of pancreatic origin. Its use may be hindered due to adverse events, including rash. The reported incidence and risk of rash to everolimus varies widely and has not been closely investigated. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing rash. Methods: We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology from 1998 to July 2011 using the keyword “everolimus” to identify relevant clinical trials. Eligible studies included prospective phase II and phase III clinical trials of cancer patients on 10 mg of everolimus daily with available data on incidence of rash. The summary incidence and relative risk (RR) of rash were calculated using either the random-effects or fixed-effects model, depending on the heterogeneity of the constituent studies. Results: A total of 2,242 patients with various malignancies from 13 clinical trials were included in the analysis. The summary incidences of all-grade and high-grade rash in patients on everolimus were28.6% (95% CI: 20.8 – 38.0) and 1.0% (95% CI: 0.6 – 1.7), respectively. Everolimus was associated with a statistically significant increased risk of all-grade rash (RR=3.853, 95% CI: 2.470 – 6.013, p=0.000), but the RR for high-grade rash (RR= 2.997, 95% CI: 0.633 – 14.185) was not statistically significant, with a p value of 0.166. Conclusions: Everolimus is associated with a significant risk of developing rash. Management of rash to everolimus is critical to prevent dose modifications and decreased quality of life, both of which can negatively affect clinical outcomes.

Erythropoiesis Stimulating Agent (ESA) Use for Anemic Cancer and Chronic Kidney Disease (CKD) Patients in 2008: Advocacy for Conservative Use

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4680-4680
Author(s):  
Charles L. Bennett ◽  
Benjamin Kim ◽  
Athena T Samaras ◽  
Allen R Nissenson ◽  
A. Oliver Sartor ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Cancer Patients ◽  
Basic Science ◽  
Meta Analysis ◽  
Cardiovascular Risks ◽  
Increased Risk ◽  
American Society ◽  
Meta Analyses ◽  
Patient At Risk

Abstract The ESAs epoetin and darbepoetin were approved for treatment of chemotherapy-associated anemia in 1993 and 2002 and CKD-associated anemia in 1989 and 2001, respectively. In 2006, ESAs were the largest single pharmaceutical expenditure by the Center for Medicare and Medicaid Studies (CMS). Recently, a series of preclinical experiments, clinical trials, and meta-analyses of ESAs have been reported. The Food and Drug Administration (FDA), National Comprehensive Cancer Network (NCCN), American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO), and Kidney Disease Outcomes Quality Improvement (KDOQI) have issued guideline statements for ESAs, and CMS has implemented an ESA Monitoring Policy (EMP) to help ensure appropriate ESA claims. Herein, we analyze these actions and usage trends of ESAs for anemic cancer and CKD patients. Data sources included basic science studies, clinical trials, meta-analyses, notifications from CMS, ESA manufacturers, and the FDA, guidelines from the NCCN, ASH/ASCO, and KDOQI, and published reports regarding ESA usage reported between 2006 and 2008. Search terms included erythropoietin, darbepoetin, anemia, neoplasm, and CKD. Results from eight recent clinical trials and one 2008 meta-analysis for anemic cancer patients identified tumor progression and mortality risks with ESA versus placebo/control use. Analyses from one clinical trial and one 2008 meta-analysis for CKD patients identified mortality and cardiovascular risks when high hemoglobin levels were targeted. Guidelines, manufacturer notifications, and reimbursement policies have become increasingly conservative. ESA administration to anemic cancer and CKD patients has decreased. Among anemic cancer patients, red blood cell transfusions are increasing and ESA use is decreasing. Among anemic CKD patients, target and achieved hemoglobin levels and ESA doses have decreased. Regulatory, clinical and professional communities now advocate for conservative use of ESAs for anemic patients with cancer or CKD. Chemotherapy-associated anemia CKD-associated anemia Basic Science ESAs may be harmful: Erythropoietin receptors have been identified in tumor cells and have demonstrated downstream cellular effects including proliferation, anti-apoptosis, invasion, and chemotherapy resistance. ESAs may be beneficial: Studies have identified neurotrophic and neuroprotective effects of erythropoietin. Also, erythropoietin protects against hypoxia-induced apoptosis, ischemia-reperfusion injury, and promotes ventricular modeling. Clinical Trials and Meta-analyses Eight clinical trials and one meta-analysis have identified increased risk of mortality and/or tumor progression associated with ESA use. Two meta-analyses have identified significantly increased risk of VTE and seven trials reported four-fold or greater increased risk of VTE. One trial and one meta-analysis have identified mortality and cardiovascular risks when ESAs were targeted to higher versus lower hemoglobin levels. A second trial did not identify clinical benefits with ESA administration targeted to normal versus lower hemoglobin levels. Guidelines NCCN and ASH/ASCO guidelines support ESA administration targeted to between 10 and 12 g/dl and a trigger hemoglobin level to initiate ESA use at 10 g/dl. KDOQI supports hemoglobin levels targeted to between 11 and 12 g/dl and avoiding levels &gt; 13 g/dl. Recent Manufacturer Notifications The FDA mandated that product labels state that ESAs are not indicated for patients receiving myelosuppressive therapy with curative intent, the trigger hemoglobin should be &lt;10 g/dl, and ESAs should be withheld if the hemoglobin exceeds a level necessary to avoid transfusion. Revised labels indicated hemoglobin levels should be targeted to between 10 and 12 g/dl and that high ESA doses should be avoided. Reimbursement Policies Target and trigger hemoglobin levels of &lt; 10 g/dl and a maximum duration of 8 weeks of treatment are supported by CMS. Target hemoglobin levels &lt; 13 g/dl are supported by CMS. Reimbursement is reduced when hemoglobin levels &gt; 13 g/dl are recorded for 3 or more consecutive billing cycles. Usage Trend Between November 2006 and October 2007, usage of ESAs declined from 42% to 15% per patient at risk while transfusions increased from 24% to 28% per patient at risk. ESA use among CKD patients not on hemodialysis decreased from 54% to 42% from 2007 to 2008.

Risk of skin rash with the proteasome inhibitor bortezomib: Updated systematic review and meta-analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9092-9092
Author(s):  
Emily Christine Case ◽  
Shenhong Wu ◽  
John F. Gerecitano ◽  
Mario E. Lacouture
Keyword(s):  
Skin Rash ◽  
Proteasome Inhibitor ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Significant Risk ◽  
Phase Iii ◽  
High Grade ◽  
Fixed Effects Model ◽  
Increased Risk ◽  
American Society

9092 Background: Rash is a common, adverse event to the novel proteasome inhibitor bortezomib (Velcade). Indicated for the treatment of multiple myeloma and mantle cell lymphoma, bortezomib is the first proteasome inhibitor approved by regulatory agencies. Because the incidence of bortezomib-induced skin rash varies widely in published manuscripts, we performed a systematic literature review and meta-analysis to determine the incidence and overall risk. Methods: We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology and The American Society of Hematology annual meetings (1998 to July 2011) to identify relevant clinical studies. Eligible studies included prospective clinical phase II and phase III trials, with data on the incidence of rash in patients taking 1.3mg/m2, 1.5mg/m2, or 1.6 mg/m2 of bortezomib intravenously either weekly or twice weekly. The incidence of rash and relative risk (RR) were calculated using random-effects or fixed-effects model, depending on the heterogeneity of included studies. Results: A total of 2,616 patients with various hematologic and solid malignancies from 35 clinical trials were included for analysis. Among patients receiving twice weekly bortezomib, the summary incidence of all-grade and high-grade rash were 18.8 % (95% CI: 14.9% to 23.5%) and 3.6 % (95% CI: 2.3% to 5.7%), respectively. We found no significant increase in all grade rash incidence with higher doses of bortezomib: 19.3 % (95% CI: 15% to 24.5%) and 20.8% (95% CI: 11.6% to 34.4%) for doses of 1.3 mg/m2 and 1.5 mg/m2, respectively. In addition, bortezomib was associated with an increased risk in both all grade (RR: 19.70, 95% CI: 8.73 to 44.44, p<0.001) and high-grade rash (RR: 5.35, 95% CI: 2.16 to 13.29, p<0.001), compared to controls. Weekly bortezomib is associated with lower risk of rash compared to twice weekly dosing (incidence 3.9% versus 18.8%, p=0.001). Conclusions: Bortezomib is associated with a significant risk of developing rash with a higher risk among patients receiving twice weekly dosage. Management of rash to bortezomib is critical to prevent a negative effect on quality of life and dose modifications, both of which affect clinical outcome.

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