Tolerance of the Novel Chemosensitizer Dexverapamil in Combination with Anthracycline Chemotherapy: a Prospective Toxicity Analysis in Advanced Gastrointestinal Cancer

Abstract

Background: A prospective clinical study was performed to determine the incidence and severity of cardiovascular and other systemic toxicities associated with the novel chemosensitizer dexverapamil (DVPM) combined with anthracycline chemotherapy. Patients and Methods: Sixteen patients with advanced colorectal cancer and 20 patients with pancreatic cancer were analyzed in this study. Treatment consisted of oral DVPM 1,000-1,400 mg/day for 3 days and intravenous doxorubicin 75 mg/m² on day 2 (colorectal cancer) or epirubicin 90-120 mg/m² on day 2 plus Gm-CSF support from day 5-15 (pancreatic cancer). Treatment cycles were repeated every 3-4 weeks. Toxicity was monitored clinically, radiologically, with laboratory tests, ECG, and serial echocardiographic determinations of the left ventricular ejection fraction (LVEF). Results: The most common DVPM-related cardiovascular side effect was transient hypotension (mean arterial BP < 70 mm Hg), which occurred in 24/36 patients (67%). It was rarely symptomatic, however, and never required pressure support. Sinus bradycardia (heart rate < 50 beats/min) was noted in 9 patients (25%), and 9 patients experienced transient heart block with only one exceeding grade I. All cardiovascular reactions either resolved spontaneously or within 2-3 h following temporary discontinuation of DVPM. As opposed to racemic verapamil, the mean LVEF was not decreased during subsequent measurements, and PR interval was the only cardiovascular parameter which demonstrated a significant correlation with the cumulative dose of DVPM (p = 0.0035). Other DVPM-related side effects were uncommon and mild, and there appeared to be no potentiation of organic toxicities known to occur with anthracyclines except for myelosuppression. Conclusions: Because of the mild and reversible toxicity patterns, both cardiovascular and noncardiovascular, we conclude that DVPM can be safely coadministered with anthracyclines at this dose and schedule, making it a promising candidate for in vivo reversal of multidrug resistance.