Health Economic Analysis of the Burden of Infusion Reactions on Patients, Caregivers, and Providers

In recent years, both the cost and efficiency of medical care have emerged as important considerations and areas of research. These considerations are of particular importance in the outpatient community oncology setting, where the demands for clinical productivity and evidence for quality and effectiveness are increasing amidst an evolving reimbursement system.

Early evidence suggests that the management of the side effects of outpatient cancer treatment is associated with an increased burden on patients, caregivers, clinical staff, and the overall practice.[1-3] Beyond the inherent negative experience of the toxicity itself, the additional burden of chemotherapy-induced toxicities on the patient includes direct expenses stemming from copays, medication, and travel, along with indirect expenses, such as increased time away from work.[1,4-6] Chemotherapy-induced side effects also impose a significant burden on health-care providers, particularly nurses, by increasing time spent attending to the patient.[7,8]

Such events ultimately have an impact on the overall pattern of human resources required to sustain highquality, efficient, and cost-effective care. Health economic models provide information to potentially improve management and the decision-making process of treating cancer to maximize effectiveness, while reducing or minimizing the economic impact on the patient and the health-care system.[9]

The use of monoclonal antibodies (MoAbs) in the treatment of cancer has increased in the past 10 years. These therapies are generally associated with relatively fewer and milder side effects than traditional cytotoxic agents. However, MoAbs have been shown to induce specific side effects associated with inhibition of the therapeutic target (cardiovascular events with vascular endothelial growth factor [VEGF] and skin toxicity with epidermal growth factor receptor [EGFR]) and immunologic recognition of foreign protein (Erbitux package insert, 2008; Avastin package insert, 2008; Vectibix package insert, 2008).

The immunologic response, generally characterized as an infusion reaction (IR) or hypersensitivity reaction, can range from mild (itching, rash) to severe (anaphylaxis).[10,11] The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grades hypersensitivity reactions on a scale of 1 (mild) to 5 (death).[12] Grade 1/2 reactions are generally considered mild and are associated with rash, fl ushing, or fever. Grade 3 reactions are associated with bronchospasm, urticaria, or hypotension, while grade 4 IRs are associated with anaphylaxis.[12]

The overall incidence of severe IRs to monoclonal antibodies used in the treatment of solid tumors varies from 0.1% for the fully human monoclonal antibody panitumumab (Vectibix) to 3% for the chimeric antibody cetuximab(Drug information on cetuximab) (Erbitux).[10] The humanized monoclonal antibodies trastuzumab(Drug information on trastuzumab) (Herceptin) and bevacizumab(Drug information on bevacizumab) (Avastin) have reported an incidence of severe infusion reactions of less than 1% (Herceptin package insert, 2008; Avastin package insert, 2008). An increased incidence of severe IRs to cetuximab of 22% has been observed among patients from the midsoutheastern region of the United States.[13]

Despite the relative low rate of severe IRs observed in the clinic, the occurrence of these and of less severe adverse events can be burdensome to patients and health-care providers. Initial studies examining the impact of IRs on patients, caregivers, and providers illustrate the need for effective preparedness and management of IRs to decrease the overall burden of care.[14,15]

Impact on Human Resource Costs

In addition to the direct physical, functional, and psychological impact of adverse events such as infusion reactions on patients, there is also an increased burden on the health-care provider. The NCI CTC guidelines recommend therapeutic intervention and/or infusion interruption for grade 2–4 IRs.[12] However, even with grade 1/2 reactions, staff must engage in careful monitoring of the patient’s status to guard against the escalation of symptoms.

A study involving 416 health professionals and staff from 21 community oncology clinics systematically described the clinical tasks involved in the management of both mild and severe infusion reactions and enumerated the associated human resource costs.[14] Data were collected from a modified time and motion survey that identified tasks involved in the management of IRs and the associated human resource costs.

Findings suggested that human resource tasks required to manage patients experiencing IRs fell into three categories[14]:
1. Mild IR not requiring discontinuation of infusion therapy
2. Severe IR requiring discontinuation of infusion therapy but managed in the outpatient setting
3. Severe IR resulting in hospitalization
For mild IRs, a total of 13 tasks were required, an average of 4,320 seconds (72 minutes) of time was spent, and a mean increased cost of $51 was incurred per patient with a mild IR. For severe IRs managed in the outpatient clinic, a total of 20 tasks were needed to manage the IR, resulting in an average total human resource time expenditure of 8,340 seconds (139 min) and an increased human resource cost of $102 per patient. For severe IRs requiring hospitalization, 22 tasks were needed to manage the IRs, resulting in an average of 6,320 seconds (106 min) of human resource time and an increased human resource cost of $134 per patient. (See Table 1 and Figure 1.)

Overall, severe infusion reactions resulted in increased estimates of time spent by staff to manage the IR, which resulted in increased human resource costs. The findings were presented at the 2006 Multinational Association of Supportive Care in Cancer International Symposium.