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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2642-2643 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.7334
Shortening the Infusion Time of Anticancer Drugs: Who Will Benefit?1 City of Hope National Medical Center, Duarte, CA
2 Premiere Oncology of Arizona, Scottsdale, AZ 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.1 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,2 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 alone3,4 and combination trials with fluorouracil-based regimens5 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 practice-altering 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 first- and second-line chemotherapy combinations in colorectal cancer and for carboplatin plus paclitaxel combinations in non–small-cell lung cancer. It has shown similar benefits in combination with taxanes in breast cancer.6 The authors of this report did not provide a cost analysis or a time-utilization analysis of the impact of shortened infusions of bevacizumab. At the City of Hope National Medical Center (Duarte, CA), chemotherapy and other infusions for solid tumor patients are administered in a 14-room infusion center that handles an average of 50 chemotherapy infusions per day, 5 days per week, with an abbreviated service on weekends. Use of the chemotherapy rooms is scheduled and billed in 1-hour units, so a 90-minute infusion requires two units, while 60, 30 or 10 minutes all require only a 1-hour unit. Patients with colorectal cancer receive an average of 20 infusions at 5 mg/kg, whereas those with lung cancer receive an average of six infusions at 15 mg/kg. As only the first infusion requires 90 minutes, the difference in billing for room use is only a single hour over 10 months for the average colorectal cancer patient and only a single hour over 4 months for the average lung cancer patient (in each case a savings of only $460). Also, there is likely only a small increase in the number of patients who could be treated per day in a clinic in which the majority of patients are scheduled to receive bevacizumab-containing regimens. What about the potential benefit in terms of Q-TWiST, the quality of life measured as time without symptoms of cancer or treatment?7 Patients who receive bevacizumab-containing regimens as first-line therapy for metastatic colorectal or lung cancer are likely to be asymptomatic or minimally symptomatic from their cancer, so the possibility of restoring to the patient some of the precious time spent receiving chemotherapy infusions is appealing. Unfortunately, for the average patient in these two categories, the time savings is only approximately 5 hours for the colorectal cancer patient, who gains a median of 5 months with the addition of bevacizumab to the regimen,8 and only 90 minutes for the lung cancer patient, whose survival is prolonged by only 2 months.9 How can the observations from this study be turned to future benefit for patients with advanced solid tumors? Having shown that short infusion times for bevacizumab added to the most commonly used combinations for metastatic solid tumors are safe, but add little to patient's quality of life, infusion center efficiency, or cost savings to the third party payer, it is inevitable that this discussion be directed toward the bigger picture of the role for agents like bevacizumab in the therapeutic armamentarium. The value of these agents must be considered in terms of health care expenditures, particularly with regard to the limited access to costly drugs in developing countries.10 Thus, for example, the incremental charge for the addition of bevacizumab at 5 mg/kg every 2 weeks to the standard regimen of modified infusional fluorouracil, leucovorin, and oxaliplatin is $9,600 per month in addition to the chemotherapy alone, which costs $12,000 per month. To date, no small-molecule tyrosine kinase inhibitor of the receptors for vascular endothelial growth factor has shown activity as promising as the antibody when combined with chemotherapy, but it is likely that one or more such agents will be developed in the near future. Unfortunately, if currently available small molecules approved for use as single agents in diseases such as chronic myelogenous leukemia and renal cell cancer are any example, the overall cost savings is likely to be minimal, as these drugs are also extremely expensive and likely to be administered orally over prolonged periods of time. But cost and charges are only a small part of the bigger picture, which is really about how to pick the best therapy for each patient based on sound scientific evidence of factors that predict benefit in subsets of patients. In the case of bevacizumab, which is presumed to act via one or both of two important mechanisms involving the tumor and its vascular supply (neoangiogenesis and dynamic characteristics of tumor vasculature),11 it is likely that there are subsets of individuals for whom the chemotherapy combinations are not augmented by the antibody and others for whom the antibody adds substantially to the benefits of chemotherapy. Furthermore, complex actions of vascular endothelial growth factor on immune and inflammatory pathways also may contribute to the benefit of bevacizumab added to cytotoxic therapy, adding another layer of complexity to the elucidation of predictive markers for benefit. When we better understand how to answer those questions and apply the answers to therapeutic decision making, we will have overcome a far greater hurdle than that which is posed by the safe reduction of infusion time. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Kim A. Margolin, Michael Gordon ACKNOWLEDGMENTS We thank Cecilia Lau, RPh, BCOP, for providing the City of Hope infusion center data. REFERENCES
1. Reidy DL, Chung KY, Timoney JP, et al: Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol 25:2691-2695, 2007 2. Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998 3. Cobleigh MA, Langmuir VK, Sledge GW, et al: A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30:117-124, 2003 (suppl 16)[CrossRef][Medline] 4. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003 5. Hurwitz H, Fehrenbacher L, Hainsworth J, et al: Bevacizumab in combination with fluorouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502-3508, 2005 6. Miller KD, Wang M, Gralow J, et al: E2100: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005. 7. Cole BF, Gelber RD, Gelber S, et al: A quality-adjusted survival (Q-TWiST) model for evaluating treatments for advanced stage cancer. J Biopharm Stat 14:111-124, 2004[CrossRef][Medline] 8. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 9. Sandler A, Gray R, Perry M, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2549, 2006 10. Berenson A: A cancer drug shows promise, at a price that many can't pay. New York Times, Feb 15, 2006 11. Jain R, Duda D, Clark J, et al: Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3:24-40, 2006[CrossRef][Medline] Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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