Shortening the infusion time of anticancer drugs: who will benefit?

In “Bevacizumab Can Be Infused Safely Over 10 Minutes,” Reidy et al already provide the conclusion in the title, making it unnecessary for someone to read the article, considering the role of the Journal as the voice of authority in clinical oncology practice. Although the objective of this editorial is not to encourage readers to accept the authors’ conclusions without a critical review of the data, the report itself is laudable. It describes a straightforward sequence of prospective, nonrandomized investigations of the serially shortened infusion time of bevacizumab in combination with cytotoxic chemotherapy. Shortening the length of infusion proved to be safe without an excessive risk of hypersensitivity reactions (HSRs). Although the role of the specific combination (namely, the cytotoxic agents and their routine premedication regimens) in declaring a particular infusion time to be safe was not addressed, the study design and large patient numbers appear adequate to support the authors’ conclusions. In this study, investigators from the Divisions of Solid Tumor Oncology and Pharmacy Services at Memorial Sloan-Kettering Cancer Center (New York, NY) began by identifying all patients treated with commercial bevacizumab at that institution in the first 2 years after its release. The recommended infusion times had been based historically on the observations of infusion reactions in patients treated with other humanized monoclonal antibodies that had structural similarity to bevacizumab. The package insert calls for the first dose to be administered over 90 minutes, the second over 60 minutes, and all subsequent infusions over 30 minutes. HSRs were classified as mild (syndrome not defined, but no medications required and no harm resulting), moderate (syndrome not defined, prescription medication required, but no harm resulting), and severe (defined as hypoxia, severe bronchospasm, hypotension, epinephrine requirement, or other life-threatening, disabling, or fatal event). More than 1,000 patients and more than 10,000 administered doses were reviewed, with the initial focus on patients receiving 5-mg/kg doses of bevacizumab administered every 2 weeks with fluorouracil-based combinations for colorectal cancer. After 202 patients were treated on the recommended schedule with no HSR, the authors treated 464 patients with all doses administered over 30 minutes and did not observe any HSR. With the advent of the 15-mg/kg dose in combinations for lung and other cancers, a fixed dose rate of 0.5 mg/kg/min (15 mg/kg over 30 minutes, a rate that was thus three-fold faster than used for the 5 mg/kg doses) was found to be safe, with no HSR in 89 patients. For 370 subsequent patients, the fixed rate of 0.5 mg/kg/ min was evaluated, resulting in a 10-minute infusion time for the 5-mg/kg doses. Half of these patients received the first dose over 30 minutes and all subsequent doses over 10 minutes and had no reported HSR. Among the remaining patients, who received all doses over 10 minutes, there were six events that met criteria for HSR. All of these events fell into the mild or moderate category (labeled by the authors in their discussion as “clinically minor”), consisting of nausea/emesis, hypoxia, flushing, urticaria, and rigors. All reactions were treated successfully with antihistamines (H2 and H1 blockers), oxygen, and slowing of the infusion. All patients were successfully re-treated after premedication with similar agents and, in most cases, without the need for prolonging the infusion time. In their discussion, the authors reviewed the historical reasons for prolonged infusions, including the early use of antibodies containing a greater amount of the more immunogenic murine sequences. There were also disease-related events such as severe rigors, hypotension or hypertension, hypoxia, and tumor pain when rituximab was introduced for the therapy of non-Hodgkin’s lymphoma, so for this antibody in particular, more rapid initial infusion times were not recommended, but patients served as their own controls to allow acceleration of the infusion rate. In the case of bevacizumab, disease factors do not appear to promote infusion reactions, and the incidence of these reactions is extremely rare, even when bevacizumab is given at higher total doses and in combination with drugs that are themselves associated with a substantial risk of HSR, such as paclitaxel/cremophor. It is possible that the aggressive dexamethasone and antihistamine premedication regimen for paclitaxel may also prevent such reactions from bevacizumab, though single-agent studies of bevacizumab alone and combination trials with fluorouracil-based regimens have not borne out any higher rate of HSR. Thus, there seems little reason to challenge the authors’ recommendation that infusion rates of 0.5 mg/kg/min, or 10 minutes for the 5 mg/kg dose, be widely adopted. Who will benefit from this observation and this practicealtering report? In the present era, bevacizumab infusions are increasingly included in regimens administered to patients with advanced solid tumors and may be continued as single-agent maintenance therapy for prolonged intervals. The agent is currently approved for firstand second-line chemotherapy combinations in colorectal cancer and for carboplatin plus paclitaxel JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 19 JULY 1 2007