Commentary (Breslin): Monoclonal Antibodies and Side Effect Management
Monoclonal antibodies are increasingly becoming a standard part of clinical cancer treatment. Eight monoclonal antibodies are approved by the Food and Drug Administration for the treatment of cancer in the United States. Oncology nurses are expected to be familiar with these agents, their indications, and their adverse effects, to provide appropriate care and symptom management to patients receiving these agents, and to adequately educate patients and families about these treatments and their specific and overlapping side effects. Monoclonal antibody mechanisms of action and indications, infusion guidelines, and symptom management are outlined in this article.
The use of monoclonal antibodies (MoAbs) is a novel targeted approach to therapy that has resulted in improved remission and survival rates for several types of cancer. Since the first MoAb received regulatory approval 2 decades ago, eight MoAbs have been approved by the US Food and Drug Administration (FDA) for cancer treatment in the United States. Monoclonal antibodies can be used alone as monotherapy, in combination with standard anticancer treatments, and as carriers for cytotoxins. In their article, Muehlbauer, Cusack, and Morris present an overview of six of the eight currently approved MoAbs, outlining their unique mechanisms of action, side effect profiles, and associated nursing implications.
Background and Mechanisms of Action
Monoclonal antibodies are immunoglobulin molecules in which the Fab or variable region has been tailored to target a specific antigen. The authors succinctly review several mechanisms involved in antibody-mediated cell killing, including ADCC, CDC, signal transduction pathway inhibition, and growth factor blockade. Monoclonal antibodies can be conjugated with cytotoxins and when used in this way act primarily as a carrier to deliver the cytotoxic substance directly to the targeted cell, inducing DNA damage or inhibiting protein synthesis. Originally produced by the hybridoma or cell fusion technique developed by Kohler and Milstein in the 1970s, most MoAbs are now produced using recombinant DNA technology.[1-5]
Knowing the derivation of the MoAb is important because it allows the nurse to assess which types have the most potential to cause both first-dose and delayed infusion reactions. The suffix associated with the generic name of the MoAb indicates whether it is murine (mouse), chimeric (variable region murine, constant region human), or humanized (only the CDR region of the variable region is murine). For example, rituximab and cetuximab (identified by the suffix "-ximab") are chimeric whereas bevacizumab, trastuzumab, and alemtuzumab (identified by the suffix "-zumab") are humanized. Murine monoclonal antibodies are denoted by the suffix "-momab," as in tositumomab.[4]
First-dose infusion reactions are thought to be due to cytokine release from tumor and effector cells as well as antigen-antibody complex deposition in the lung, liver, and spleen. Chimeric and humanized mono-clonal antibodies are associated with first-dose infusion reactions of varying degrees of severity, and therefore initial treatment is usually administered slowly and with premedication including histamine blockers and antipyretics. Patients with hematologic malignancies, especially if associated with high numbers of circulating malignant cells, appear to be at highest risk of developing potentially life-threatening infusion reactions.[6-9]
Murine monoclonal antibodies do not interact well with the human immune system, so the incidence of first-dose infusion reactions due to cytokine release is actually quite low. However, as early as 2 to 3 weeks after exposure, patients who receive murine monoclonal antibodies can develop human anti-mouse antibodies (HAMA), which can cause severe allergic-type reactions if the patient is rechallenged. Tositumomab is currently the only FDA-approved unconjugated murine anticancer MoAb and it is only authorized for use in conjunction with I131 tositumomab (Bexxar) administration. Patients must be tested for the presence of HAMA prior to readministration of this product and it should not be given again if they test positive. The rates of HACA (human anti-chimeric antibody) and HAHA (human anti-humanized antibody) are so low (< 1%) that routine testing is not done in patients receiving chimeric or humanized monoclonal antibodies.[2-6]
In Table 3, the authors provide a very useful summary of administration guidelines for each of the six monoclonal antibodies reviewed. Side-effect management strategies for bevacizumab and cetuximab are nicely outlined in Tables 4 and 5, respectively.
The other two FDA-approved conjugated monoclonal antibodies not reviewed in the article, I131 tositumomab and Y90 ibritumomab tiuxetan (Zevalin) warrant further discussion. Both are radiolabeled monoclonal antibodies that have received regulatory approval for the treatment of relapsed or refractory CD20+ indolent or transformed B-cell non-Hodgkin's lymphoma.
Radiolabeled Monoclonal Antibodies
Radiolabeled monoclonal antibodies, also known as radioimmunotherapy (RIT), act as carriers of a radionuclide, delivering a lethal dose of radiation directly to the targeted cells. In addition, cells in the vicinity are killed due to the "crossfire" or "bystander" effect that is a result of the ability of the radioisotope to penetrate 100 to 200 cell diameters beyond the targeted cell.[5] Although the nurse is not directly involved with administration of the radiolabeled product, which must be done by personnel licensed in the safe handling of radioisotopes, they are involved in administration of the unlabeled antibody, coordination of appointments, patient teaching, as well as monitoring for and management of side effects.
Patients receive an infusion of an unlabeled anti-CD20 MoAb (rituximab with Zevalin or tositumomab with Bexxar) 1 to 2 hours prior to infusion of the radiolabeled antibody. The purpose of this infusion is to clear circulating CD20+ cells in order to optimize biodistribution of the radiolabeled antibody to the tumor. The dose-limiting side effect of RIT is delayed pancytopenia with nadirs at 5 to 7 weeks posttreatment and recovery by week 12. Treatment is usually very well tolerated. Patients do not experience hair loss and the other common side effects associated with standard cytotoxic therapies such as nausea, vomiting, and mucositis. Radiation precautions must be observed by health-care personnel when handling the radioisotope and by the patient for several days post-treatment. Unlike Y90, which is a pure beta-emitter, I131 emits gamma as well as beta radiation and both the patient and the health-care team must observe stricter radiation precautions. Although both radiolabeled products are conjugated with small amounts of murine monoclonal antibodies, the incidence of HAMA is much higher with Bexxar due to the dose of murine MoAb patients receive with the unlabeled tositumomab infusion.[10,11]
Conclusion
Monoclonal antibodies have a unique mechanism of action and toxicity profile. Multiple products, both conjugated and unconjugated, are currently available for patients with hematologic malignancies as well as solid tumors. Many more products are in clinical trials as monotherapy or in combination with other anti-cancer agents. This review article will help nurses to provide safe care as well as optimal education to patients receiving these agents.
References:
1. Forero A, LoBuglio AF: History of antibody therapy for non-Hodgkin's lymphoma. Semin Oncol 30(suppl 17):1-5, 2003.
2. DiJulio JE: Monoclonal antibodies: Overview and use in hematologic malignancies, in Rieger PT (ed): Biotherapy: A Comprehensive Overview, 3rd ed, pp 283-316. Sudbury, Mass, Jones & Bartlett, 2001.
3. Karius D, Marriott MA: Immunologic advances in MoAb therapy: Implications for oncology nursing. Oncol Nurs Forum 24:483-494, 1997.
4. Schmidt KV, Wood BA: Trends in cancer therapy: Role of monoclonal antibodies. Semin Oncol Nurs 19:169-179, 2003.
5. Weiner LM: Monoclonal antibody therapy of cancer. Semin Oncol 26:43-51, 1999.
6. Dillman RO: Monoclonal antibody therapy, in Oldham RK (ed): Principles of Cancer Biotherapy, 4th ed, pp 329-390. Dordrecht, The Netherlands, Kluwer Academic, 2003.
7. Byrd JC, Waselenko JK, Maneatis TJ, et al: Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: Association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 17:791-795, 1999.
8. Winkler U, Jensen M, Manzke O, et al: Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti CD-20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 94:2217-2224, 1999.
9. Rieger PT: Monoclonal antibodies: Applications in solid tumors and other diseases, in. Rieger PT (ed): Biotherapy: A Comprehensive Overview, 3rd ed, pp 317-355. Sudbury, Mass, Jones & Bartlett, 2001.
10. Dillman RO: Radiolabeled anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoma. J Clin Oncol 20:3545-3557, 2002.
11. Riley MB, Byar K: The rationale for and background of radioimmunotherapy: An emerging therapy for B cell non-Hodgkin's lymphoma. Semin Oncol Nurs 20:1-7, 2004.
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