Asma Latif

Adverse Event Reporting in Cancer Clinical Trial Publications

PURPOSE Reporting adverse events is a critical element of a clinical trial publication. In 2003, the Consolidated Standards of Reporting Trials (CONSORT) group generated recommendations regarding the appropriate reporting of adverse events. The degree to which these recommendations are followed in oncology publications has not been comprehensively evaluated. METHODS A review of citations from PubMed, Medline, and Embase published between Jan 1, 2009 and December 31, 2011, identified eligible randomized, controlled phase III trials in metastatic solid malignancies. Publications were assessed for 14 adverse event-reporting elements derived from the CONSORT harms extension statement; a completeness score (range, 0 to 14) was calculated by adding the number of elements reported. Linear regression analysis identified which publication characteristics associated with reporting completeness. RESULTS A total of 175 publications, with data for 96,125 patients, were included in the analysis. The median completeness score was eight (range, three to 12). Most publications (96%) reported only adverse events occurring above a threshold rate or severity, 37% did not specify the criteria used to select which adverse events were reported, and 88% grouped together adverse events of varying severity. Regression analysis revealed that trials without a stated funding source and with an earlier year of publication had significantly lower completeness scores. CONCLUSION Reporting of adverse events in oncology publications of randomized trials is suboptimal and characterized by substantial selectivity and heterogeneity. The development of oncology-specific standards for adverse event reporting should be established to ensure consistency and provide critical information required for medical decision-making.

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.

Adult Cancer Clinical Trials That Fail to Complete: An Epidemic?

The number and diversity of cancer therapeutics in the pipeline has increased over the past decade due to an enhanced understanding of cancer biology and the identification of novel therapeutic targets. At the same time, the cost of bringing new drugs to market and the regulatory burdens associated with clinical drug development have progressively increased. The finite number of eligible patients and limited financial resources available to evaluate promising new therapeutics represent rate-limiting factors in the effort to translate preclinical discoveries into the next generation of standard therapeutic approaches. Optimal use of resources requires understanding and ultimately addressing inefficiencies in the cancer clinical trials system. Prior analyses have demonstrated that a large proportion of trials initiated by the National Cancer Institute (NCI) Cooperative Group system are never completed. While NCI Cooperative Group trials are important, they represent only a small proportion of all cancer clinical trials performed. Herein, we explore the problem of cancer clinical trials that fail to complete within the broader cancer clinical trials enterprise. Among 7776 phase II-III adult cancer clinical trials initiated between 2005-2011, we found a seven-year cumulative incidence of failure to complete of approximately 20% (95% confidence interval = 18% to 22%). Nearly 48000 patients were enrolled in trials that failed to complete. These trials likely contribute little to the scientific knowledge base, divert resources and patients from answering other critical questions, and represent a barrier to progress.

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 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.

Geographic accessibility to clinical trials for advanced cancer in the United States.

Geographic Accessibility to Clinical Trials for Advanced Cancer in the United States Clinical trials yield critical evidence to guide the care of patients with cancer. According to commonly used practice guidelines, “...the best management of any cancer patient is in a clinical trial.”1 Nonetheless, only about 2% to 7% of US adult patients with cancer participate in clinical trials.2 Poor accrual to clinical trials has far-reaching implications in the way it affects the pace of progress, cost of drug development, and generalizability of study findings. Prior studies exploring trial enrollment have identified several barriers.3 However, geographic barriers to participation in clinical trials remain underexplored. A survey of patients with cancer revealed that most were not willing to travel for trial participation.4 We sought to estimate the geographic accessibility of clinical trials for advanced cancer in the United States.

Safety and efficacy of addition of VEGFR and EGFR-family small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: A meta-analysis.

415 Background: The approach of combining cytotoxic chemotherapy with small molecule tyrosine kinase inhibitors (TKIs) has been explored in a large number of randomized trials, in a diverse range of tumor. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of this therapeutic approach. Methods: PubMed and the ASCO databases were searched up to March 2013. Eligible studies included randomized trials in which the FDA approved 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), with corresponding 95% confidence intervals (CI) were calculated. Results: A total of 16,011 patients from 43 trials were included. Among the 43 trial...

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.