Cetuximab for the treatment of colorectal cancer.

BACKGROUND: Cetuximab, an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor (EGFR), has activity against colorectal cancers that express EGFR. METHODS: From December 2003 to August 2005, 572 patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin or had contraindications to treatment with these drugs underwent randomization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care (287 patients) or best supportive care alone (285 patients). The primary end point was overall survival. RESULTS: In comparison with best supportive care alone, cetuximab treatment was associated with a significant improvement in overall survival (hazard ratio for death, 0.77; 95% confidence interval [CI], 0.64 to 0.92; P=0.005) and in progression-free survival (hazard ratio for disease progression or death, 0.68; 95% CI, 0.57 to 0.80; P<0.001). These benefits were robust after adjustment in a multivariable Cox proportional-hazards model. The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone. Partial responses occurred in 23 patients (8.0%) in the cetuximab group but in none in the group assigned to supportive care alone (P<0.001); the disease was stable in an additional 31.4% of patients assigned to cetuximab and in 10.9% of patients assigned to supportive care alone (P<0.001). Quality of life was better preserved in the cetuximab group, with less deterioration in physical function and global health status scores (both P<0.05). Cetuximab treatment was associated with a characteristic rash; a rash of grade 2 or higher was strongly associated with improved survival (hazard ratio for death, 0.33; 95% CI, 0.22 to 0.50; P<0.001). The incidence of any adverse event of grade 3 or higher was 78.5% in the cetuximab group and 59.1% in the group assigned to supportive care alone (P<0.001). CONCLUSIONS: Cetuximab improves overall survival and progression-free survival and preserves quality-of-life measures in patients with colorectal cancer in whom other treatments have failed. (ClinicalTrials.gov number, NCT00079066 [ClinicalTrials.gov].).

Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study.

Background The incidence and management of trastuzumab-mediated cardiotoxicity outside of clinical trials has not been well described. Objective and methods The aim of the study was to retrospectively evaluate the incidence of cardiac dysfunction, characterize its natural history, and identify the degree of reversibility using cardiac MRI, in a population of HER-2 positive breast cancer patients receiving trastuzumab in the adjuvant setting. Results Out of 152 patients (mean age 52 +/- 10 years), 36 (24%) developed trastuzumab mediated cardiomyopathy, the majority asymptomatic. Factors that predicted the development of trastuzumab mediated cardiac dysfunction were a pre-existing history of hypertension, smoking history, and a family history of coronary artery disease. Within 3 months of treatment with trastuzumab, there was a difference in LVEF between the normal cohort and those patients who developed LV systolic dysfunction (61 +/- 5% vs. 51 +/- 8%, P < 0.01). During the 6-month-followup, 34/36 patients demonstrated subepicardial linear delayed enhancement of the lateral wall of the left ventricle on cardiac MRI, suggesting trastuzumab induced myocarditis. Conclusion Approximately 1 in 4 women may develop LV systolic dysfunction after treatment with adjuvant trastuzumab, necessitating careful patient selection and close serial monitoring using noninvasive cardiac imaging.

The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy.

OBJECTIVES: The aim of this study was to evaluate whether cardiac biomarkers, tissue velocity (TVI) and strain imaging, and cardiac magnetic resonance imaging can predict early left ventricular (LV) dysfunction in human epidermal growth factor receptor II-positive breast cancer patients treated with trastuzumab in the adjuvant setting. BACKGROUND: Early indexes of LV systolic dysfunction with noninvasive cardiac imaging would be useful for addressing the cardiac safety profile of trastuzumab, potentially avoiding the detrimental effects of heart failure. METHODS: We used cardiac biomarkers, TVI and strain imaging, and cardiac magnetic resonance imaging to detect pre-clinical changes in LV systolic function, before conventional changes in left ventricular ejection fraction (LVEF) in human epidermal growth factor receptor II-positive breast cancer patients treated with trastuzumab in the adjuvant setting. RESULTS: Of 42 patients (mean age 47 ± 9 years) prospectively followed between 2007 and 2009, 10 (25%) developed trastuzumab-mediated cardiomyopathy (CM). Troponin T, C-reactive protein, and brain natriuretic peptide did not change over time. Within 3 months of adjuvant therapy with trastuzumab, there was a significant difference in the lateral S' between the normal cohort and the CM group (9.1 ± 1.6 cm/s and 6.4 ± 0.6 cm/s, respectively, p < 0.05). Similarly, the peak global longitudinal and radial strain decreased as early as 3 months in the trastuzumab-mediated cardiotoxicity group. As compared with both global longitudinal and radial strain, only S' was able to identify all 10 patients who developed trastuzumab-mediated CM. The LVEF subsequently decreased at 6 months of follow-up in all 10 patients, necessitating discontinuation of the drug. All 10 patients demonstrated delayed enhancement of the lateral wall of the LV within the mid-myocardial portion, consistent with trastuzumab-induced CM. CONCLUSIONS: Both TVI and strain imaging were able to detect pre-clinical changes in LV systolic function, before conventional changes in LVEF, in patients receiving trastuzumab in the adjuvant setting.