Infection risk in breast cancer patients treated with trastuzumab: a systematic review and meta-analysis.

Infections related to anti-HER2 monoclonal antibodies (mAbs), trastuzumab and pertuzumab, have been reported in clinical trials. It is not yet clear whether these drugs increase an infection risk or not. We performed a systematic review and meta-analysis to assess the risk of infections associated with anti-HER2 mAbs. We searched PubMed and the ASCO online database of meeting abstracts up to January 2014 for relevant clinical trials. Eligible studies included randomized controlled trials of trastuzumab or pertuzumab for breast cancer patients that reported adequate safety data for grade 3-4 infection, febrile neutropenia, neutropenia, or leukopenia. The summary incidence, relative risk (RR), and 95 % confidence intervals (CIs) were calculated. A total of 10,094 patients from 13 trials were included. The use of trastuzumab was associated with an increased risk of high-grade infection (RR 1.21, 95 % CI 1.07-1.37, P = 0.002) and febrile neutropenia (RR 1.28, 95 % CI 1.08-1.52, P = 0.004). The incidence of high-grade infection and febrile neutropenia due to trastuzumab was 8.5 % (95 % CI 4.5-15.4 %) and 12.0 % (95 % CI 8.1-17.4 %), respectively. There was no significant increase in a risk of high-grade neutropenia or leukopenia in patients receiving trastuzumab. Treatment with trastuzumab is associated with a significantly higher risk of high-grade infection and febrile neutropenia. Our findings suggest an importance of close monitoring for any signs of infections in patients treated with trastuzumab.

Infectious complications in cancer patients treated with anti-EGFR monoclonal antibodies cetuximab and panitumumab: a systematic review and meta-analysis.

BACKGROUND: Clinical trials have reported a substantial variation in the risk of infection related to anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab. We performed a systematic review and meta-analysis to assess the infection risk in cancer patients treated with anti-EGFR mAbs. PATIENTS AND METHODS: We searched PubMed and the ASCO online database of meeting abstracts up to January 2014 for relevant clinical trials. Eligible studies included randomized controlled trials (RCTs) of cetuximab and panitumumab that reported adequate safety data for grade 3-4 infection or febrile neutropenia (FN). The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 14,957 patients from 28 trials were included. Treatment with anti-EGFR mAbs was associated with an increased risk of high-grade infection (RR, 1.49; 95% CI, 1.33-1.66; P<0.001) and FN (RR, 1.27; 95% CI, 1.09-1.48; P=0.002). The incidence of high-grade infection and FN due to anti-EGFR mAbs was 9.3% (95% CI, 7.2-12.0%) and 5.3% (95% CI, 3.3-8.3%), respectively. A significantly increased risk of high-grade infection was observed in all subgroups analyses (type of anti-EGFR mAb, therapy of control arm and duration of treatment) except for tumor type (only colorectal cancer and non-small cell lung cancer (NSCLC) groups had the increased risk). Subgroup analyses revealed a significantly increased risk of FN in the following subgroups: cetuximab, NSCLC and treatment duration longer than the median of all trials (3.1months). CONCLUSIONS: The use of anti-EGFR mAbs is associated with a significantly higher risk of high-grade infection and febrile neutropenia.

Impact of Prescription Patterns on Compliance With Follow-Up Visits at an Urban Teaching Primary Care Continuity Clinic.

BACKGROUND: Although limiting prescription refills is considered as a strategy to increase compliance with the treatment regimen and follow-up, no literature exists to support its effectiveness. We sought to investigate whether decreasing the number of prescription refills affects no-show rate at an urban teaching primary care continuity clinic in New York. METHODS: Eight teaching attending physicians and 19 residents implemented a "new prescribing strategy" from February 9 to 22, 2012, which limited the number of refills only to cover until the next intended clinic visit. All adult patient visits were included if follow-up visits were requested to be scheduled within 3 months and prescriptions were given through an electronic prescription system. No-show rates for the first follow-up visits up to 120 days from the initial visits during the interventional period were compared with those during the baseline period (December 15-28, 2011). RESULTS: Two hundred twenty-one patients in the baseline period and 278 in the interventional period were included in the analysis. Median total supply of prescription was 6 and 3 months, respectively (P < .001). The no-show rates were not significantly different between the 2 periods (19.0% [42/221] vs 16.6% [46/278], P = .5). In multivariate regression analysis, the no-show rate did not change significantly during the interventional period compared with the baseline period (odds ratio [OR] 1.0; 95% confidence interval, 0.6-1.5; P = .8). Younger age (OR 1.03 per year, P = .008), male gender (OR 2.0, P = .003), Medicaid or Medicare insurance (OR 3.7, P = .01; OR 4.2, P = .02), and diagnosis of diabetes (OR 1.8, P = .04) or asthma (OR 2.0, P = .03) were associated with higher no-show rates. CONCLUSIONS: Reducing the number of refills did not significantly affect no-show rates in the immediate follow-up. Alternative strategies should be considered to minimize no-shows.

Safety and efficacy of addition of VEGFR and EGFR-family oral small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The approach of combining cytotoxic chemotherapy with oral small molecule tyrosine kinase inhibitors (TKIs) has been explored in a large number of randomized trials, in a variety of tumor. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of this therapeutic approach. PATIENTS AND METHODS: PubMed and the ASCO databases were searched up to March 2013. We included randomized trials in which the FDA approved vascular endothelial growth factor receptor (VEGFR) or epidermal growth factor receptor-family (EGFR)-targeted TKI in combination with chemotherapy was compared with chemotherapy alone in patients with any type of solid cancer. The endpoints included safety [fatal adverse events (FAEs), treatment discontinuation, any severe (grade 3 or 4) adverse events (AEs), and individual severe AEs] and efficacy [progression-free survival (PFS), and overall survival (OS)]. The pooled relative risk (RR) or hazard ratio (HR) were calculated. RESULTS: A total of 16,011 patients from 43 trials were included. Compared with chemotherapy alone, the addition of a TKI significantly increased the risk of FAEs (RR, 1.63; 95% CI, 1.32-2.01), treatment discontinuation (RR, 1.80; 95% CI, 1.58-2.06), and any severe AE (RR, 1.25; 95% CI, 1.16-1.36). The addition of a TKI was associated with a significant improvement in PFS (HR, 0.82; 95% CI, 0.76-0.89), but not OS (HR, 0.99; 95% CI, 0.95-1.03). CONCLUSIONS: It is important for physicians to weigh the risk of toxicity versus the modest PFS benefit associated with chemotherapy plus TKI in patients with solid cancers.

A systematic review of predictive and prognostic biomarkers for VEGF-targeted therapy in renal cell carcinoma.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy is the currently standard treatment for advanced and metastatic renal cell carcinoma (RCC). Multiple candidate predictive and prognostic biomarkers have been evaluated. We performed a systematic review and graded the available evidence on the biomarkers for VEGF-targeted therapy in RCC. METHODS: We conducted an independent review of PubMed and ASCO databases up to August 2013. Studies were included if biomarkers obtained from metastatic clear-cell RCC patients treated with the FDA-approved VEGF-targeted therapy were assessed for their correlation with clinical outcomes. We graded the studies and determined the Level-of-evidence for each biomarker using a previously published framework. RESULTS: A total of 50 articles were selected for this review. Seven studies assessed the predictive value of biomarkers using the archived specimens from randomized controlled trials. Five predictive biomarkers, such as VEGF, interleukin (IL)-6, hepatocyte growth factor (HGF), osteopontin, single nucleotide polymorphisms in IL-8, satisfied Level II evidence. IL-6 is the most corroborated predictive biomarker based on its consistent predictive value in two different trials. The prognostic value of biomarkers was assessed in 48 studies using the archived specimens from clinical trials, prospective and retrospective observational registries. Three biomarkers, including IL-8, HGF and osteopontin, satisfied Level I evidence for PFS. CONCLUSION: Though several promising predictive biomarkers for VEGF-targeted therapy have been found, none of them has satisfied the determination of Level I evidence. A more focused development of biomarkers with prospective assessment in clinical trials and clear intent of use in clinical practice is needed.

Risk of hematologic toxicities in patients with solid tumors treated with everolimus: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis of hematologic toxicities associated with everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor. Eligible studies included phase II and III trials of patients with solid tumors on 10mg of everolimus daily describing events of neutropenia, thrombocytopenia, anemia or lymphopenia. The incidence of everolimus-associated all-grade and high-grade (Grade 3-4) hematologic toxicities were, respectively: neutropenia: 21.7% and 3.6%; thrombocytopenia: 36.0% and 4.7%; anemia: 61.2% and 8.4% and lymphopenia: 40.9% and 14.9%. Everolimus was associated with an 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, all-grade (RR=1.58, [95% CI 1.25-1.99]) and high-grade (RR=3.92, [95% CI 1.46-10.52]) anemia and all-grade (RR=1.72, [95% CI 1.50-1.97]) and high-grade (RR=2.70, [95% CI 1.86-3.93]) lymphopenia.

Risk of hematologic toxicities in cancer patients treated with sunitinib: a systematic review and meta-analysis.

BACKGROUND: The incidence and risk of unique toxicities associated with a multi-targeted tyrosine kinase inhibitor sunitinib, such as hypertension and thromboembolic events, have been previously reported. However, the incidence and risk of hematologic toxicities have been less well characterized. We performed an up-to-date meta-analysis of trials to evaluate the risk of sunitinib-related hematologic toxicities. 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 of sunitinib that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia. The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) 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 (Grades 3 and 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 (2667 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). 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.

Risk of hypothyroidism in patients with cancer treated with sunitinib: a systematic review and meta-analysis.

BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib is used in various cancers. Clinical studies have reported a substantial variation in the incidence of hypothyroidism associated with sunitinib, without a systemic attempt to synthesize these data. METHODS: We searched Medline databases for relevant clinical trials published up to May 2012. Phase II and III trials and expanded access programs of sunitinib in patients with any type of cancer that reported occurrence of hypothyroidism were eligible. The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models based on the heterogeneity of included studies. RESULTS: Incidence analysis was performed using 6678 sunitinib-treated patients from all 24 eligible trials. The incidence of all- and high-grade hypothyroidism was 9.8% (95% CI 7.3-12.4%) and 0.4% (95% CI 0.3-0.5%), respectively. A meta-analysis of seven randomized trials with 2787 subjects revealed a RR of all- and high-grade hypothyroidism of 13.95 (95% CI 6.91-28.15; p < 0.00001) and 4.78 (95% CI 1.09-20.84; p = 0.04), respectively. Subgroup analysis revealed a significantly higher incidence of all-grade hypothyroidism in patients receiving sunitinib for longer duration than in patients receiving sunitinib for shorter duration (p = 0.02). CONCLUSIONS: This meta-analysis of data available from clinical trials demonstrates that sunitinib is associated with a significant risk of developing all- and high-grade hypothyroidism. These data provide further evidence to recommend monitoring for hypothyroidism in patients receiving sunitinib.