Commentary (Starling/Cunningham)-Cetuximab-Associated Infusion Reactions: Pathology and Management

The therapeutic landscape for colorectal cancer and, indeed, many solid tumors has evolved rapidly over the past decade, as several new biologic or so-called "targeted" agents have become incorporated into treatment pathways. The development and application of monoclonal antibodies against tumorigenic molecular targets represents a significant step forward in this shifting paradigm.

The list of available monoclonal antibodies continues to expand. Clinically useful agents include cetuximab (Erbitux) and most recently, panitumumab (Vectibix), which target the epidermal growth factor receptor (EGFR), and bevacizumab (Avastin), which targets the vascular endothelial growth factor receptor. Trastuzumab (Herceptin) targets HER2 in breast cancer patients, and rituximab (Rituxan) targets CD20 in lymphomas. With publication of the seminal paper by Hurwitz et al,[1] bevacizumab is now being used routinely in the United States and parts of Europe as first-line treatment of metastatic colorectal cancer. Cetuximab is licensed to treat irinotecan (Camptosar)-refractory colorectal cancer in this setting, on the basis of its activity alone and in combination with irinotecan.[2]

As the number of effective agents available to treat colorectal cancer has increased, so too has the median overall survival of treated patients. Therapy for pretreated patients, and therefore the issue of cetuximab usage, has become more pertinent. Several large, randomized studies evaluating cetuximab as part of the upfront combination treatment of metastatic colorectal cancer are due to report, and these upcoming findings may increase the indications for the drug. Furthermore, cetuximab was licensed to treat advanced head and neck cancer patients last year, after its combination with radiation therapy resulted in a significant improvement in survival.[3]

Confronting Toxicities

Biologic agents were originally developed to be more targeted, less toxic therapies that eventually would replace conventional cytotoxic agents. In practice, a combination therapy approach has often been required to demonstrate benefit, and these drugs are not entirely without side effects. Oncologists must now manage certain toxicities that are distinct from those of cytotoxic agents, and new guidance is required. Much has already been written on the management of bevacizumab-related toxicities and the identification of possible risk factors for toxicity.

By comparison, similar guidance for cetuximab has lagged behind. The issue of cetuximab-induced skin toxicity as a possible predictor of outcome is well documented. Only more recently have the characterization, etiology, and possible management of skin rash been addressed in peer-reviewed publications. This literature has highlighted the need for more research and controlled assessments of interventions to manage skin toxicity.[4,5]

This article by Patel and Goldberg is both relevant and timely in addressing the etiology and management of another important, but frequently overlooked, complication of cetuximab-infusion-related reactions. Severe infusion-related reactions may occur in up to 4% of patients treated with cetuximab; these may be life-threatening and, occasionally, fatal. Less serious infusion reactions are even more common. By comparison, bowel perforation, a frequently discussed bevacizumab-related toxicity, occurs in up to 2% of treated metastatic colorectal cancer patients and can also be fatal.

Activity and Toxicity

Understanding the mechanism of drug action and drug toxicity is imperative when instituting appropriate management guidelines. In this respect, Patel and Goldberg seek to elucidate the etiology of monoclonal antibody-induced hypersensitivity based on available data. In doing so, they highlight the lack of robust data in this area and draw an important distinction between possible cetuximab-associated anaphylactic and anaphylactoid reactions.

An understanding of immune-based mechanisms for infusion-related reactions provides a basis for instituting appropriate prophylaxis and assists in the use of rechallenge strategies (eg, desensitization and graded challenge). While acknowledging the dearth of available mechanistic data, Patel and Goldberg state clear and pragmatic guidelines for the management of infusion-related reactions, based on North American guidelines that clinicians in different parts of the world may adapt depending on their own national guidance. The authors quite rightly suggest that future studies assessing cetuximab should assess immunologic parameters that will aid in the formulation of rechallenge guidelines.

Predicting Toxicity

The article also touches on the important areas of predicting toxicity to cetuximab and delivering a more personalized approach-both key issues for cytotoxic and biologic therapy. A pharmacogenomic approach may be useful here, and there has certainly been an explosion of research in this area.

One better known example that validates this approach is the identification of the UGT1A1 gene polymorphism in predicting toxicity to irinotecan (Camptosar). Polymorphic variants that predict skin rash have been investigated in relation to cetuximab-induced skin rash (eg, the CA dinucleotide repeat in intron 1 of the EGFR gene[6]), but larger studies are required to validate potential candidate markers. In theory, a pharmacogenomic approach could be used to identify a predictor of infusion-related reactions, but this presumably would require a better understanding of the pathologic basis of the reactions. The role of clinical toxicity predictors should not be overlooked; the article mentions that potential risk factors include a history of atopy, antibiotic sensitivities, and use of certain concomitant medications.

A Look to the Future

In summary, Patel and Goldberg highlight and expound upon an important and infrequently discussed type of toxicity related to cetuximab. As the potential clinical applications for cetuximab increase, these toxicities and their etiology and management will become more important.

Many more anti-EGFR monoclonal antibodies have been developed, including the humanized monoclonal antibody matuzumab and the fully human monoclonal antibody panitumumab. The latter, by virtue of its lack of mouse protein, is reportedly less immunogenic than is cetuximab and causes fewer infusion reactions; it also may be given on a twice-weekly schedule as opposed to the weekly cetuximab schedule.[7] Having shown activity in pretreated metastatic colorectal cancer patients, panitumumab recently received regulatory approval and is being evaluated for first-line treatment of this population. Thus, clinicians may soon have even more therapeutic options for EGFR blockade, allowing choices based on both efficacy and toxicity considerations.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. 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.

2. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Eng J Med 351:337-345, 2004.

3. Bonner JA, Harari PM, Giralt J: Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab (abstract 5507). J Clin Oncol 22(suppl):488, 2004.

4. Perez-Soler, Saltz L: Cutaneous adverse effects with HER1/EGFR-targeted agents: Is there a silver lining? J Clin Oncol 23:5235-5246, 2005.

5. Segaert S, Van Cutsem E: Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 16:1425-1433, 2005.

6. Amador ML, Oppenheimer D, Perea S, et al: An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res 64:9139-9143, 2004.

7. Gibson TB, Ranganathan A, Grothey A: Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer 6:29-31, 2006.