Monoclonal Antibodies: The Foundation of Therapy for Colorectal Cancer in the 21st Century?

The manuscript written by Drs. Hoff, Ellis, and Abbruzzese is an outstanding overview of the development, mechanism of action, and key clinical data for bevacizumab(Drug information on bevacizumab) (Avastin) and cetuximab(Drug information on cetuximab) (Erbitux). Over the past several years, the landscape for treating patients with colorectal cancer has changed dramatically with the inclusion of irinotecan (Camptosar), oxaliplatin (Eloxatin), and capecitabine(Drug information on capecitabine) (Xeloda). Then, before we can even catch our breath, along come cetuximab and bevacizumab. The next several years will be focused on testing these agents in a variety of clinical trial settings to optimize their use for patients with colorectal cancers. Three issues come to mind after reviewing the Hoff et al manuscript: (1) semantics, (2) awkward US Food and Drug Administration (FDA) indications, and (3) money. Terminology Concerns
The authors of this manuscript and many others refer to the novel agents as "targeted" therapies. I find this terminology somewhat problematic in that we have long been in the era of "targeted therapies" when one takes into account that the targets for chemotherapeutic agents have been known for several decades. While this might be a semantic splitting of hairs, what we have entered is not really an era of targeted therapy but an era of "better targets." Molecular biology research has identified a series of better targets distinguishing malignant cells from normal cells, widening our therapeutic advantage in treating patients with cancer. The agents bevacizumab and cetuximab are wonderful additions to our expanding list of agents directed against better targets. FDA Approvals: The Devil Is in the Details
The FDA granted approvals for both bevacizumab and cetuximab with relatively specific guidelines, which may have raised as many questions as were answered. Bevacizumab was approved for front-line metastatic colorectal cancer in combination with intravenous fluorouracil(Drug information on fluorouracil) (5-FU)-based regimens. The pivotal trial for bevacizumab was performed in combination with the bolus 5-FU/ leucovorin/irinotecan regimen developed by Len Saltz known as IFL. Since Dr. Saltz's landmark paper, however, several other events have altered the optimum treatment of metastatic colon cancer: (1) the development of oxaliplatin(Drug information on oxaliplatin), (2) the suggestion that infusion 5-FU is superior to bolus 5-FU, and (3) the inclusion of capecitabine as an option for patients with metastatic colon cancer. The wording of the FDA approval allows us as clinicians to incorporate bevacizumab into any regimen utilizing intravenous fluorouracil either alone, in combination with irinotecan(Drug information on irinotecan), or in combination with oxaliplatin, but excludes combinations with capecitabine. The available clinical trial data available support a benefit with the bolus IFL regimen, but this leaves us unsure of the clinical benefit of adding bevacizumab to infusion fluorouracil regimens such as FOLFIRI and FOLFOX, and also leaves us wondering whether we will ever give bevacizumab with capecitabine. In contrast to this relative freedom we have been given with bevacizumab, cetuximab has been approved only in those patients with metastatic colon cancers refractory to irinotecan that express the epidermal growth factor receptor. This is in the face of significant data that suggest that EGFR expression levels do not correlate with clinical outcomes. Given this restriction, it is important for oncologists to document epidermal growth factor receptor expression prior to the utilization of cetuximab. Hopefully, as mentioned in the manuscript, data in patients without EGFR expression will support a broadening of the utility of cetuximab. Also, as the indication reads today, we must first treat patients with irinotecan without cetuximab, have them progress, and then add cetuximab. This treatment pathway seems somewhat counterintuitive but we must wait on additional trial data to support an earlier use of cetuximab. Economic Factors
Finally, we as oncologists are under close scrutiny when it comes to the high cost of medical care, with the focal point being colon cancer therapies. First, our standard regimens are very expensive; second, bevacizumab and cetuximab will add further to these costs; and third, the finances of oncology are undergoing dramatic, difficult to predict changes. In this environment, it is unlikely that we will be able to maintain the same degree of therapeutic freedom we have enjoyed in the past. Clearly, both bevacizumab and cetuximab will play a significant role in the treatment of other cancer types, but the temptation to utilize these medicines off label must be balanced against our economic responsibilities. The risk is that the dramatic potential of these agents will be overshadowed by a public outrage over costs. One solution is to increase clinical trial participation. This would be a way to expand our understanding of the agents in other diseases, to expand access to other cancer types, and to expand FDA approvals, while meeting the expectations of third-party payers, the federal government, the media, and the public. Conclusions
In summary, we are delighted to enter the era of better targets for treatment against cancer. We are pleased by the rapid approval of these two new effective agents in the treatment of metastatic colon cancer, but must be highly cognizant of our economic responsibilities as shepherds of these new agents for our patients with this serious and common medical illness. Therefore, the data reviewed in the manuscript are vital for us to have at hand as we incorporate these medicines into our daily practices.