High-grade Anemia Research Articles

Veliparib‑Induced Toxicity in Cancer Patients: A Systematic Review and Meta‑Analysis

In this study, we investigate the veliparib‑induced toxicity in cancer patients. Databases were searched for RCTs treated with veliparib. We found veliparib could increase the risk of hematologic and gastrointestinal toxicities. Anemia, neutropenia, thrombocytopenia, and nausea were the most common toxicities. Patients diagnosed with gastrointestinal tumors tend to have a higher risk of high-grade neutropenia; patients in the first-line setting tend to have a higher risk of high-grade anemia and neutropenia than those in the ≥ second line setting. Patients receiving higher dosage of veliparib tend to have a higher risk of all-grade anemia. Veliparib could also increase the risk of insomnia, myalgia, pneumonia, dyspnea, hyponatremia, and fatigue.

Hematological Toxicities with PARP Inhibitors in Prostate Cancer: A Systematic Review and Meta-Analysis of Phase II/III Randomized Controlled Trials.

Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events. To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer. A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews-Cochrane were queried from inception to 9 June 2023. The Mantel-Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities. The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37-4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97-10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60-6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06-11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80-10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77-17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities. PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient-physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs.

Weekly versus tri-weekly paclitaxel with carboplatin for first-line treatment in women with epithelial ovarian cancer.

Epithelial ovarian cancer is the sixth most common cancer worldwide: 295,414 new cases were diagnosed in 2018, with 184,799 deaths. The lack of an effective screening strategy has led to the majority of women being diagnosed at an advanced stage. For these women, intravenous carboplatin combined with paclitaxel for six cycles is widely accepted as the standard first-line treatment for epithelial ovarian cancer, in combination with debulking surgery. However, there is conflicting evidence regarding the optimal dosing schedule of paclitaxel when combined with carboplatin in this setting. To compare the efficacy and tolerability of intravenous weekly paclitaxel with that of tri-weekly paclitaxel, in combination with intravenous carboplatin, as first-line treatment for epithelial ovarian cancer (defined as epithelial ovarian, primary peritoneal and fallopian tube cancer). We searched CENTRAL, MEDLINE, and Embase databases for relevant studies up to 15 November 2021, using keywords and MeSH terms. We additionally handsearched conference libraries, online clinical trial databases and screened through lists of retrieved references. We Included randomised controlled trials (RCTs) comparing weekly paclitaxel in combination with carboplatin versus tri-weekly paclitaxel in combination with carboplatin, for treatment of newly-diagnosed epithelial ovarian cancer. We used the hazard ratio (HR) to estimate the primary efficacy outcomes progression-free (PFS) and overall survival (OS). We used the risk ratio (RR) to estimate the primary toxicity outcome of severe neutropenia and secondary outcomes of quality of life (QoL) and treatment-related adverse events. Two review authors independently selected studies, extracted data, and assessed risk of bias, using standard Cochrane methodological procedures. We included individual participant data (IPD) from one of the included studies, ICON-8, provided by the study team. We analysed data using a random-effects model in Review Manager 5.4 software. Additionally, we reconstructed IPD for PFS and OS data from published Kaplan-Meier curves from all studies and subsequently pooled these to analyse the two primary efficacy outcomes. From 2469 records, we identified four eligible RCTs with data for 3699 participants. All eligible studies were included in the main meta-analysis and reported on PFS and OS. There was likely a slight improvement in PFS when paclitaxel was dosed weekly compared to tri-weekly (HR 0.89, 95% confidence interval (CI) 0.81 to 0.98; 4 studies, 3699 participants; moderate-certainty evidence). We found little to no improvement in OS when paclitaxel was dosed weekly compared to tri-weekly (HR 0.92, 95% CI 0.79 to 1.06; 4 studies, 3699 participants; high-certainty evidence). There was likely little to no difference in high-grade (grade 3 or 4) neutropenia when paclitaxel was dosed weekly compared to tri-weekly (RR 1.11, 95% CI 0.86 to 1.43; 4 studies, 3639 participants; moderate-certainty evidence). However, weekly paclitaxel increased high-grade (grade 3 or 4) anaemia when compared to tri-weekly dosing (RR 1.57, 95% CI 1.12 to 2.20; 4 studies, 3639 participants; high-certainty evidence). There may be little to no difference in high-grade neuropathy when paclitaxel was dosed weekly compared to tri-weekly (RR 1.12, 95% CI 0.64 to 1.94; 4 studies, 3639 participants; low-certainty evidence). The overall risk of detection bias and performance bias was low for OS, but was unclear for other outcomes, as treatments were not blinded. The risk of bias in other domains was low or unclear. We note that OS data were immature for three of the included studies (GOG-0262, ICON-8 and MITO-7). Weekly paclitaxel combined with carboplatin for first-line treatment of epithelial ovarian cancer likely improves PFS slightly (moderate-certainty evidence) but not OS (high-certainty evidence), compared to tri-weekly paclitaxel combined with carboplatin. However, this was associated with increased risk for high-grade anaemia, treatment discontinuation, dose delays and dose omissions (high- to low-certainty evidence). Our findings may not apply to women receiving bevacizumab in first-line therapy, those receiving treatment in the neo-adjuvant setting, or those with rare subtypes of clear cell or mucinous ovarian cancer.

Risk of Fatigue and Anemia in Patients With Prostate Cancer Treated With Novel Oral Anti-androgens: A Meta-Analysis of Randomized Controlled Trials.

Novel oral anti-androgens (NOAAs) represent a new class of drugs that are being approved for prostate cancer. However, fatigue and anemia are among the most common treatment-related symptoms. Hence, we conducted a meta-analysis of randomized controlled trials (RCTs) to investigate the relative risks (RRs) of fatigue and anemia associated with NOAAs. PubMed, Cochrane, EMBASE, and abstracts presented at the annual meeting of the American Society of Clinical Oncology and European Society of Clinical Oncology were searched for phase III and V RCTs of NOAAs from January 2000 to March 2020. Safety profile from each selected study was evaluated for all-grade and high-grade fatigue and anemia adverse events. The RRs with 95% confidence intervals (95% CIs) were calculated using random-effects for all-grade and high-grade events.Our analysis involved 15 RCTs, including 16,795 patients. Overall, 9,177 patients were treated with NOAAs in the experimental arm, whereas 7,095 received a standard of care in the control arm. The RR of all-grade and high-grade fatigue was 1.26 (95% CI 1.15-1.38) and 1.24 (95% CI 0.83-1.84), and that of all-grade and high-grade anemia was 0.81 (95% CI 0.77-1.19) and 0.81 (95% CI 0.61-1.06), respectively. Our findings suggest that NOAAs are associated with an increased risk of fatigue but decreased risk of anemia. Patients should be frequently monitored to identify adverse events to improve oncological outcomes and optimize the overall treatment efficacy and safety. Not all the RCTs addressed fatigue and anemia simultaneously as side effects of NOAA treatment.

Haematologic toxicities with PARP inhibitors in cancer patients: an up-to-date meta-analysis of 29 randomized controlled trials.

Poly ADP-ribose polymerase (PARP) inhibitors have emerged as one of the most exciting new treatments for patients with certain types of cancer. Haematologic toxicities are common adverse events (AEs) for all PARP inhibitors. We conducted a meta-analysis to fully investigate the haematologic toxicities of PARP inhibitors in cancer patients. PubMed/Medline and Embase were searched for articles published till September 2020. The relevant randomized controlled trials (RCTs) in cancer patients treated with PARP inhibitors were retrieved, and the systematic evaluation was performed. Twenty-nine RCTs and 9247 patients were included. The current meta-analysis suggests that the use of PARP inhibitors significantly increases the risk of all-grade anaemia (RR, 2.32; 95% CI, 1.78-3.01; p<0.00001), neutropenia (RR, 1.69; 95% CI, 1.38-2.07; p<0.00001) and thrombocytopenia (RR, 2.54; 95% CI, 1.87-3.45; p<0.00001). The use of these agents also significantly increased the risk of high-grade anaemia (RR, 3.06; 95% CI, 2.11-4.43; p<0.00001), neutropenia (RR, 1.66; 95% CI, 1.33-2.07; p<0.00001) and thrombocytopenia (RR, 2.76; 95% CI, 1.83-4.16; p<0.00001). Anaemia was the most common haematologic toxicity, and all the five included PARP inhibitors were associated with a significant increased risk of anaemia. Combination treatment may reduce the risk of anaemia and thrombocytopenia compared to those receiving PARP inhibitor monotherapy. The available data suggested that the use of PARP inhibitors was associated with a significantly increased risk of haematologic toxicities.

Effect of Body Mass Index on 5-FU-Based Chemotherapy Toxicity and Efficacy Among Patients With Metastatic Colorectal Cancer; A Pooled Analysis of 5 Randomized Trials

IntroductionWe conducted this study to assess the effect of baseline body mass index (BMI) on the toxicity and efficacy of systemic chemotherapy among patients with metastatic colorectal cancer (CRC). Patients and MethodsThis was a pooled analysis of 5 clinical trials (NCT00115765, NCT00364013, NCT00272051, NCT00305188, and NCT00384176), which were accessed from the Project Data Sphere (www.projectdatasphere.org) platform. Multivariable logistic regression analysis was used to assess the relationship between BMI and the probability of different toxicities. Kaplan–Meier survival estimates were used to assess the effect of BMI on overall and progression-free survival. Multivariable Cox regression analysis was additionally conducted to evaluate the effect of BMI on overall and progression-free survival. ResultsA total of 3155 patients were included in the current analysis. Within multivariable logistic regression analysis, higher BMI was associated with higher probability of all-grade nausea and vomiting (odds ratio [OR], 1.025; 95% confidence interval [CI], 1.009-1.042; P = .002) and peripheral neuropathy (OR, 1.018; 95% CI, 1.001-1.034; P = .036; analysis restricted to oxaliplatin-treated patients). Lower BMI was associated with a higher probability of all-grade anemia (OR, 0.975; 95% CI, 0.956-0.995; P = .015), high-grade anemia (OR, 0.941; 95% CI, 0.890-0.994; P = .030), all-grade neutropenia (OR, 0.983; 95% CI, 0.968-0.999; P = .034), and high-grade neutropenia (OR, 0.962; 95% CI, 0.945-0.979; P < .001). Higher BMI also seemed to correlate with better overall survival in a multivariable Cox regression model (hazard ratio as a continuous variable: 0.977; 95% CI, 0.967-0.988; P < .001). ConclusionLower BMI was associated with a higher risk of hematological toxicities (anemia and neutropenia) whereas higher BMI might be associated with a higher risk of nausea, vomiting, and peripheral neuropathy. Higher BMI also seemed to be associated with better overall survival among patients with metastatic CRC.

Risk of fatigue and anemia in patients with advanced cancer treated with olaparib: A meta-analysis of randomized controlled trials.

PARP inhibitors are a new class of drugs that are currently being studied in several malignancies. Olaparib is FDA-approved for advanced breast cancer and advanced ovarian cancer patients. Fatigue and anemia are among the most common cancer and treatment-related symptoms. Therefore, we conducted a meta-analysis of randomized controlled trials (RCT) to characterize the incidence and relative risks (RRs) of fatigue and anemia associated with olaparib. PubMed, Cohrane, Embase and abstracts presented at the annual meeting of the American Society of Clinical Oncology (ASCO) were searched for articles published from 2000 to June 2018. The eligible studies were phase II and III RCT of olaparib. Safety profile from each selected study was evaluated for all-grade and high-grade fatigue and anemia adverse events. Summary incidences and the RR, with 95% confidence intervals, of all-grade and high-grade events were calculated using random-effects or fixed-effects model based on the heterogeneity of selected studies. A total of 9 trials were selected, and included 2074 patients with advanced ovarian, gastric, prostate, lung or breast cancer. 908 patients received placebo/control treatments and 1166 received olaparib alone or combination with other active cancer treatments. The RR of all-grade and high fatigue was 1.24 (95% CI, 1.10-1.39) and 1.71 (95% CI, 1.06-2.77), respectively. The RR of all-grade and high-grade anemia was 2.10 (95% CI, 1.48-2.98) and 3.15 (95% CI, 1.73-5.71), respectively. Our findings suggest that the olaparib treatment is associated with an increased risk of fatigue and anemia. Since fatigue and anemia are very common treatment related adverse events, and both can impair the quality of life of patients, it is important to identify them early and manage it accordingly in order to optimize the overall treatment.

Toxicity patterns associated with chemotherapy/immune checkpoint inhibitor combinations: a meta-analysis.

Aim: This study aims to clarify toxicity patterns associated with chemotherapy/immune checkpoint inhibitor combinations. Methods: Eligible studies included randomized studies evaluating chemotherapy with or without an immune checkpoint inhibitor (including pembrolizumab, nivolumab, atezolizumab, durvalumab or avelumab). The primary summary statistic was the relative risk (RR). Results: A total of 11 studies were finally included into this meta-analysis. RRs of high-grade anemia, thrombocytopenia and neutropenia were 0.98 (95% CI: 0.83-1.16; p =0.84), 1.10 (95% CI: 0.83-1.47; p =0.51) and 0.96 (0.78-1.17; p =0.66), respectively. RR of high-grade nausea, vomiting and diarrhea was 1.19 (95% CI: 0.78-1.82; p =0.42), 1.09 (95% CI: 0.69-1.72; p =0.71) and 2.61 (1.42-4.79; p =0.002), respectively. Conclusion: Addition of immune checkpoint inhibitors to chemotherapy backbone does not increase the risk of high-grade hematological or gastrointestinal toxicities (except for high-grade diarrhea).

EPR19-071: Risk of Hematologic Toxicities and Health-Related Quality of Life Events in Patients With Hematologic Malignancies Treated With Ibrutinib: A Combined Analysis of 6 Phase III Trials

Background: Bruton’s tyrosine kinase (BTK) is essential for signaling of B-cell and chemokine receptors. Ibrutinib targets BTK and has become frontier in many hematologic malignancies. We undertook systematic review and pooled analysis of randomized controlled trials (RCTs) to determine the risk of hematologic toxicities and health-related quality of life (HRQOL) events associated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase III RCTs that mention hematologic toxicities and HRQOL events as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% CI. Random effects model was applied. Results: 6 phase III RCTs with a total of 1,811 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle-cell lymphoma, and Waldenstrom’s macroglobulinemia were eligible. Studies compared Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B) + rituximab (R) vs placebo + B+ R, I vs temsirolimus and I vs R were included in the analysis. The relative risks (RR) of all-grade side effects were as follows: anemia, 0.812 (95% CI: 0.565–1.168; P=.261); neutropenia, 0.956 (95% CI: 0.720–1.268; P=.754); thrombocytopenia, 1.054 (95% CI: 0.450–2.470; P=.904); fatigue, 0.896 (95% CI: 0.761–1.056; P=.192); pyrexia, 1.123 (95% CI: 0.893–1.413; P=.322); and arthralgia, 1.863 (95% CI: 1.101–3.152; P=.020). The RR of high-grade adverse effects were as follows: anemia, 0.522 (95% CI: 0.371–0.733; P&lt;.0001); neutropenia, 0.969 (95% CI: 0.751–1.249; P=.807); thrombocytopenia, 0.608 (95% CI: 0.252–1.470; P=.270); fatigue, 0.618 (95% CI: 0.396–0.964; P=.034); pyrexia, 1.165 (95% CI: 0.534–2.542; P=.701); and arthralgia, 3.623 (95% CI: 0.743–17.663; P=.111). Conclusion: Ibrutinib increased the risk of all-grade arthralgia whereas the risks of high-grade anemia and fatigue were significantly lower in the study arm, favoring ibrutinib.

Incidence and risk of hematologic toxicities with hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukopenia: A systematic review and meta-analysis.

Hypomethylating agents (HMAs) are believed to have reliable efficacy in treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Meanwhile, the adverse events of HMAs have become an increasing concern. There is, however, no systematic meta-analysis available to evaluate overall hematologic toxicities for HMAs. In this meta-analysis, we aim to determine the risk of hematologic toxicities in patients treated with HMAs. Relevant studies were identified from PubMed, Embase, Cochrane Library, and the Clinical Trials. gov databases incepted to February 2018. All phase II and III trials meeting the inclusion criteria included adequate safety data. We calculated the relative risk (RR) of high-grade hematologic toxicities (HTEs) with corresponding 95% CI using Review Manager. The incidences of HTEs were also evaluated by R. Heterogeneity was calculated and reported mainly via I analyses. A total of 2337 MDS or AML patients from 14 studies were identified in this meta-analysis. The overall incidences of high-grade hematologic toxicities in patients who received HMAs were: 27% of the patients with anemia, 45% with neutropenia, 38% with thrombocytopenia, and 25% with febrile neutropenia, respectively. There was a significantly increased RR of neutropenia and thrombocytopenia using HMAs, in comparison with conventional care regimens (CCR) based on the drug type (decitabine vs azacitidine). We conclude that the use of HMAs are associated with an increased risk of neutropenia and thrombocytopenia in MDS or AML patients, and our results also demonstrate that HMAs exposure does not significantly increase the risk of high-grade anemia, leukopenia, or febrile neutropenia compared with CCR.

Efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer

ABSTRACTImmune checkpoint inhibitors (ICIs) are new therapeutic strategies for non-small cell lung cancer (NSCLC). We aimed to quantitatively evaluate the efficacy and safety of ICIs in NSCLC. Pubmed, Embase, Cochrane Library, and Web of Science were searched for randomized clinical trials comparing ICIs with control therapies in NSCLC. Data were pooled according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 12 trails comprising 6,919 NSCLC patients were included in this meta-analysis. ICIs therapies significantly improved progression-free survival (PFS) (HR, 0.838; P < 0.001), overall survival (OS) (HR, 0.747; P < 0.001) and objective response rates (ORR) (RR, 1.311; P < 0.001) in NSCLC. Prognostic benefit was observed irrespective of age, sex, treatment line, performance status and histology. Survival improvement of ICIs was limited for NSCLC patients with non-smoker (PFS, P = 0.468; OS, P = 0.317) or central nervous system (CNS) metastasis (PFS, P = 0.209; OS, P = 0.090), or positive EGFR mutation (PFS, P = 0.083; OS, P = 0.522) or PD-L1 expression level less than 5% (PFS, P = 0.370; OS, P = 0.047). The relative risks of all-grade and high-grade (≥3) anemia, neutropenia, leukopenia, thrombocytopenia, stomatitis, nausea, pyrexia, asthenia and neuropathy were all decreased in patients received ICIs compared with control therapies. This meta-analysis provides clinical evidence that ICIs improve PFS, OS, and ORR in NSCLC with fewer adverse effects. Our data establish ICIs as a prefer treatment option for NSCLC patients with smoker, no CNS metastasis, wild type EGFR, and high PD-L1 expression.

A systematic review of the safety profile of the different combinations of fluoropyrimidines and oxaliplatin in the treatment of colorectal cancer patients.

The available fluoropyrimidines and oxaliplatin combinations for colorectal cancer patients have different safety profiles. The aim of this systematic review was to compare their toxicities. The eligible studies were classified as: no bolus; 5-FU single bolus; 5-FU double bolus; capecitabine. We calculated the incidence of "any-grade" and "severe" toxicity for haematological and non-haematological adverse events of each group. We identified 184 treatment groups; compared to 5-FU double bolus, except for high-grade anaemia, all the groups showed reduced risk of haematological toxicities, with the most relevant advantages for single bolus regimens. Concerning non-haematological toxicities, compared to double bolus, the single bolus group showed a statistically significant reduced risk for many gastrointestinal toxicities and for pheripheral neuropathy. This is the first systematic review of the toxicity profile of different 5-FU or capecitabine and oxaliplatin regimens. Single 5-FU bolus is associated with a definitely favourable toxicity profile, both for haematological and non-haematological toxicity.

Incidence and risk of hematologic toxicities in cancer patients treated with regorafenib.

Regorafenib, an oral vascular endothelial growth factor receptor tyrosine-kinase inhibitor, has been approved for the treatment of several malignancies. As a non-traditional cytotoxic chemotherapeutic agent, regorafenib is often associated with hematologic toxicities. Here we searched PubMed and Embase up to June 2017 for relevant clinical trials. Eligible studies include trials in which subjects treated with 160 mg of regorafenib daily during the first 21 days of each 28-day cycle, and adequate safety data profile reporting thrombocytopenia, anemia, neutropenia and leucopenia. Statistical analyses were conducted to calculate the overall incidences, relative risks (RRs) and their 95% confidence intervals (CIs). A total of 2,341 subjects from 16 trials were included in the present studies. The incidences of regorafenib associated all-grade and high-grade hematologic toxicities were: thrombocytopenia, 22% and 3%; anemia, 20% and 3%; neutropenia, 10% and 2%, and leucopenia, 13% and 2%, respectively. Regorafenib-treated subjects had a significant increased risk of all-grade (RR=6.35; 95% CI, 3.19-12.64) and high-grade (RR=6.27; 95% CI, 1.69-23.26) thrombocytopenia, all-grade (RR=2.76; 95% CI, 1.63-4.68) and high-grade (RR=5.38; 95% CI, 1.60-18.06) anemia. Our results suggested that regorafenib therapy was associated with significantly increased risks of hematological toxicities, and hematologic monitoring at regular intervals should be advised to clinician.

Risk of infectious, hematological, and gastrointestinal side effects in patients treatedwith ibrutinib: A systematic review and meta-analysis of randomized controlled trials.

e18265 Background: Bruton’s tyrosine kinase (BTK) is essential for signaling of B-cell and chemokine receptors. Ibrutinib targets BTK and has become frontier in many hematologic malignancies. We undertook systematic review and pooled analysis of randomized controlled trials (RCTs) to determine infectious, hematological and gastrointestinal risks associated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through December 31, 2016. The RCTs that mention infectious, hematological and gastrointestinal side effects as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% confidence interval (CI). Results: Four RCTs with a total of 1505 patients were eligible for the analysis. Studies compared Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B)+ rituximab (R) vs placebo + B+ R and I vs temsirolimus were included in the analysis. The relative risks (RR) of all-grade side effects were as follows: infection, 1.34 (95% CI: 1.04 – 1.74; p = 0.02); pneumonia, 1.16 (95% CI: 0.82–1.66; p = 0.38); anemia, 0.77 (95% CI: 0.64 – 0.93; p = 0.007); neutropenia, 0.99 (95% CI: 0.87 – 1.14; p = 0.98); thrombocytopenia, 0.86 (95% CI: 0.71 – 1.04; p = 0.12); diarrhea, 1.74 (95% CI: 1.48 – 2.05; p &lt; 0.0001); nausea, 0.94 (95% CI: 0.80 – 1.10; p = 0.45); and vomiting, 0.98 (95% CI 0.74 – 1.30; p = 0.93). The RR of high-grade adverse effects were as follows: febrile neutropenia, 1.32 (95% CI: 0.84 – 2.08; p = 0.21); infection, 1.20 (95% CI: 0.73 – 1.98; p = 0.45); pneumonia, 1.22 (95% CI: 0.76–1.95; p = 0.39); anemia, 0.48 (95% CI: 0.33 – 0.71; p &lt; 0.0001); neutropenia, 0.99 (95% CI: 0.86 – 1.15; p = 0.94); thrombocytopenia, 0.61 (95% CI: 0.47 – 0.81; p = 0.001); diarrhea, 1.72 (95% CI: 0.88 – 3.34;p = 0.10); nausea, 2.56 (95% CI: 0.59 – 10.99; p = 0.20); and vomiting, 0.42 (95% CI 0.11 – 1.63; p = 0.21). Conclusions: Ibrutinib increased the risk of all-grade diarrhea and infection whereas the risks of all-grade anemia, high-grade anemia and thrombocytopenia were significantly lower in the study arm, favoring ibrutinib.

Evaluation of the health-related quality of life using the 36-item short form health survey in patients with chronic hepatitis C receiving pegylated interferon/ribavirin/telaprevir triple treatment.

The rate of sustained virologic response (SVR) has increased in patients with chronic hepatitis C (CHC; genotype 1) since triple treatment with pegylated interferon (PEG-IFN), ribavirin (RBV) and telaprevir (TVR) was included in Japanese health insurance. However, side effects such as high-grade anemia and skin disorders means it is important to investigate the extent to which quality of life (QOL) is maintained during treatment. The impact on health-related (HR) QOL, as a result of TVR-based triple treatment was investigated long-term (48 weeks) in 34 patients (18 men, 16 women) following TVR-based triple treatment, using the 36-item short form health survey (SF-36). While scores for physical health were significantly lower during treatment, an improvement was seen in patients who showed complete response to treatment from 12 weeks following treatment (P<0.05). HRQOL improved significantly following completion of TVR-based triple treatment in these complete-responders, with higher scores compared with those prior to treatment. Anemia and skin symptoms appeared frequently during treatment and scores for physical health dropped. Particular care needs to be taken in regards to the management of side effects during TVR treatment. Further evaluations using the SF-36 may help in controlling doses to achieve SVR.

Bevacizumab did not reduce the risk of anemia associated with chemotherapy: an up-to-date meta-analysis.

The risk of anemia due to bevacizumab-based chemotherapy has not been well described, and new randomized controlled trials (RCTs) have been reported in recent years. We therefore conducted an up-to-date meta-analysis of RCTs to fully characterize the risk of anemia with bevacizumab. We carried out an electronic search of Medline, Embase, and The Cochrane Central Register of Controlled Trials to investigate the effects of RCTs on bevacizumab treatment on cancer patients up to October 2014, and random or fixed-effect meta-analytical models were used to assess the risk ratio (RR) of anemia due to the use of bevacizumab according to the heterogeneity of included studies. A total of 13,173 patients were included in this analysis from 18 RCTs. Among those patients receiving bevacizumab and chemotherapy, the incidences of all-grade and high-grade (grade 3 and above) anemia were 24% (95% confidence interval (CI) 13-41%) and 4.0% (95% CI 3.0-6.0%), respectively. Bevacizumab-containing therapy did not significantly decreased the risk of developing all-grade anemia (RR 0.872, 95% CI 0.739-1.029, P = 0.104) and high-grade anemia (RR 0.850, 95% CI 0.720-1.002, P = 0.053), which is not in agreement with previous meta-analysis. On subgroup analysis, we did not find significant risk differences based on bevacizumab dosage, tumor types, and concomitant drugs. When stratified by dose level, a significantly decreased risk of high-grade anemia with bevacizumab was obtained in a lower dose level (2.5 mg/kg/week, RR 0.773, 95% CI 0.611-0.978, P = 0.031) compared to control group. Bevacizumab did not significantly reduce the risk of anemia with chemotherapy in cancer patients.

Hematologic toxicities associated with mTOR inhibitors temsirolimus and everolimus in cancer patients: a systematic review and meta-analysis

Background:Mammalian target of rapamycin (mTOR) inhibitors, temsirolimus and everolimus, are currently approved for the treatment of several malignancies. Hematological toxicities have been reported with these drugs, but overall incidence and relative risk remains undefined. We perform an up-to-date meta-analysis to determine the incidence and risk of hematologic toxicities associated with mTOR inhibitors.Methods:Several databases were searched, including PubMed, Embase and Cochrane databases. Eligible studies included prospective phase II and III trials of temsirolimus and everolimus with adequate safety data profile reporting anemia, leucopenia, neutropenia or thrombocytopenia. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated by using either random effects or fixed effects models according to the heterogeneity of included studies.Results:A total of 5436 patients with a variety of solid tumors from 26 clinical trials were included for the meta-analysis. The overall incidences of mTOR inhibitor associated all-grade and high-grade hematologic toxicities were, respectively: anemia – 38.8% and 7.5%; leucopenia – 19.6% and 1.8%; neutropenia – 14.9% and 5.6%; thrombocytopenia – 33.1% and 3.6%. Compared to placebo/control arms, mTOR inhibitors were associated with a significantly increased risk of all-grade (RR 2.05, 95% CI: 1.52–2.77; p < 0.001) and high-grade anemia (RR 1.57, 95% CI: 1.20–2.05; p = 0.001), all-grade (RR 6.03, 95% CI: 2.76–13.14; p < 0.001) and high-grade thrombocytopenia (RR 2.73, 95% CI: 1.87–3.99; p < 0.001). Additionally, a non-significantly increased risk of all-grade leucopenia (RR 1.46, 95% CI: 0.66–3.23; p = 0.34) and neutropenia (RR 1.77, 95% CI: 0.80–3.93; p = 0.16) was observed in the mTOR inhibitor group, while the risk of high-grade leucopenia (RR 0.53, 95% CI: 0.31–0.90, p = 0.019) and neutropenia (RR 0.96, 95% CI: 0.62–1.51; p = 0.87) did not increase. Similar results were also observed in sub-group analysis according to mTOR inhibitor based regimens.Conclusions:The use of mTOR inhibitors is associated with a significant increase in the risk of developing all-grade and high-grade anemia and thrombocytopenia compared with placebo/control arms.

Meta-analysis of hematologic toxicities in patients with solid tumors treated with everolimus.

e15580 Background: Everolimus is an orally administered targeted agent that inhibits mammalian target of rapamycin (mTOR) signaling involved in tumor growth and proliferation. Hematologic toxicities associated with everolimus have been reported with a substantial variation in the incidences among clinical studies without a systematic attempt to synthesize these data. We performed a systemic review and meta-analysis of published clinical trials to evaluate the overall risk of everolimus-related hematologic toxicities. Methods: We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to December 2012 for relevant clinical trials. Eligible studies included phase II and III trials in patients with solid tumors treated with everolimus that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia based on the CTCAE of the NCI. The relative risk (RR), summary incidence and 95% confidence intervals (CI) were calculated. Results: For the incidence analysis, we included a total of 1,090 patients from 14 studies (three phase III and 11phase II trials) considering only arms with everolimus as a single agent. The incidence of everolimus -associated all-grade and high-grade (Grade 3-4) hematologic toxicities were, respectively: neutropenia: 21.7% and 3.7%; thrombocytopenia: 36.0% and 4.7% and anemia: 61.2% and 4.4%. For the RR calculation, seven randomized trials with everolimus in only one of the arms in addition to similar therapy in both arms were available (five phase III and two phase II trials, representing 2,462 patients). Everolimus -treated patients had a significantly increased risk of all-grade neutropenia (RR = 2.24; 95% CI, 1.51–3.32), all-grade (RR = 9.19; 95% CI, 4.51–18.70) and high-grade (RR = 7.46; 95% CI, 2.58–21.61) thrombocytopenia and all-grade (RR = 1.58; 95% CI, 1.25–1.99) and high-grade (RR = 3.92; 95% CI, 1.46–10.52) anemia. RR of high-grade neutropenia was 1.40 (95% CI: 0.70-2.78; p=0.34). Conclusions: Everolimus is associated with a significant increase in the risk of developing all-grade and high-grade thrombocytopenia and anemia and all-grade neutropenia compared with control.

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

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.

Haematologic toxicities associated with the addition of bevacizumab in cancer patients

BackgroundBevacizumab is currently approved for the treatment of several malignancies. Haematologic toxicities are not among the main concerns associated with bevacizumab, but they have been occasionally reported. We performed a meta-analysis to determine the incidence and risk of haematologic toxicities associated with bevacizumab. MethodsPubmed databases from 1966 to September 2010 were searched for studies reported, as well as American Society of Clinical Oncology meetings. Bevacizumab randomised clinical trials with adequate safety data profile were included. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR) and 95% confidence intervals (CI). Results15,263 patients were included. The incidence of bevacizumab-associated all-grade and high-grade haematologic toxicities were, respectively: anaemia: 18.7% and 3.9%; neutropenia: 25.0% and 18.5%; and thrombocytopenia: 13.9% and 3.4%. Febrile neutropenia incidence was 3.8%. Compared to placebo/control arms, bevacizumab was associated with a decreased risk of all-grade (RR=0.81; 95%CI 0.68–0.96; p=.016) and high-grade (RR=0.73; 95%CI 0.60–0.89; p=.002) anaemia, and increased risks of all-grade (RR=1.15; 95%CI 1.01–1.30; p=.033) and high-grade (RR=1.08; 95%CI 1.02–1.13; p=.005) neutropenia, all-grade thrombocytopenia (RR=1.22; 95%CI 1.00–1.48; p=.047) and febrile neutropenia (RR=1.31; 95%CI 1.08–1.58; p=.006). ConclusionsBevacizumab is associated with a lower risk of anaemia and increased risks of neutropenia, thrombocytopenia and febrile neutropenia.