Preventing Dose-Limiting Febrile Neutropenia in Early-Stage Breast Cancer

Febrile neutropenia can be a dose-limiting complication of treatment with myelosuppressive chemotherapy for early-stage breast cancer.

Gary H. Lyman, MD, MPH

Febrile neutropenia can be a dose-limiting complication of treatment with myelosuppressive chemotherapy for early-stage breast cancer. Although lowering the dose makes the patient feel better, Gary H. Lyman, MD, MPH, advises against changing the recommended dose, for it may result in poorer outcomes and a higher risk of disease recurrence further down the road. Instead, researchers suggest using substances such as myeloid growth factor to prevent febrile neutropenia in patients identified at high risk for this treatment-related adverse event.

Lyman directs the Hutchinson Institute for Cancer Outcomes Research at the Fred Hutchinson Cancer Research Center and is a medical oncologist in the Breast Cancer Program at the Seattle Cancer Care Alliance. He sat down with Oncology Nursing News at the recent annual meeting of the American Society of Clinical Oncology where he presented a talk on risk factors and neutropenic complications in patients receiving chemotherapy.

What are some of the issues surrounding clinical understanding of febrile neutropenia risk as a result of chemotherapy for breast cancer?

If you look at the randomized controlled trials of patients receiving chemotherapy for early-stage breast cancer, the reported rates of febrile neutropenia and other toxicities are all over the board. The toxicity rates for febrile neutropenia range from 25% to 50%. The problem with these randomized trials is that toxicities such as febrile neutropenia are considered secondary outcomes; they’re not the main reason they’re conducting the study. Instead, researchers focus on survival and long-term results. There’s less diligence in terms of capturing these outcomes.

Additionally, the patients are selected for those trials to provide the best chance of showing the chemotherapy works. As a result, researchers exclude patients who have comorbidities [and thus, a higher risk of febrile neutropenia], including liver disease, lung disease, diabetes, and hypertension.

Therefore, not only are toxicities of secondary importance, the trials enroll a lower-risk population than that seen in the real-world setting. In practice, many patients with cancer have other medical problems. Those conjoined medical problems, along with the chemotherapy and the cancer, raise the risk for febrile neutropenia.

A systematic review and meta-analysis examined research involving both a randomized trial and an observational study from a real-world setting using the same chemotherapy regimen. The researchers found that when they compared these—consistently and regimen by regimen in the breast cancer setting—the observational experience reported significantly higher rates of febrile neutropenia than the original randomized trial did where febrile neutropenia outcomes are underreported.

Research we recently conducted offers additional validation that data should be gathered on patients in the real-world setting. The data often come from insurance claims. We had an advantage because our data were melded with pharmacy data, so we knew the drugs the patient was getting, including the chemotherapy. We then studied these patients in the long-term. This is an unselected group of patients who aren’t in clinical trials. They all came from hundreds of practices throughout the United States. Once again, we found higher rates of febrile neutropenia with the common chemotherapy regimens for early-stage breast cancer.

What are the risks associated with febrile neutropenia?

Febrile neutropenia puts patients at increased risk for infection and has a mortality rate around 8%. Febrile neutropenia causes morbidity and mortality in patients who end up in the hospital as a complication of chemotherapy. Most patients survive and get treated as an outpatient or they leave the hospital and continue treatment. Doctors will then modify the chemotherapy and reduce the dose intensity of the chemotherapy, making patients feel better and less likely to be in the hospital, but it has a dramatic impact on the cure rate.

Early-stage breast cancer is considered a curable disease, but if doctors don’t give the chemotherapy as it was originally designed in the clinical trials, we have evidence that the cure rates goes down due to a higher rate of disease recurrence.

We collected data from over 100,000 patients with cancer hospitalized with febrile neutropenia throughout the United States over a 20-year period. Although the mortality rate has come down, going from 8% to 9% of patients to 6% or 7%, it’s still a significant number. The length of stay in the hospital, on average, is about the same, and a subgroup of patients requires very long complicated hospitalizations. Many end up in the intensive care unit. In addition, there is the issue of costs. The cost of treating patients with febrile neutropenia in the hospital has risen 30% percent over the same period of time. Institutions are constantly balancing the risk-benefit equation as well as costs.

What are the recommendations to prevent febrile neutropenia?

The use of prophylactic approaches like the myeloid growth factor G-CSF, when given to patients during chemotherapy, significantly reduces the risk of febrile neutropenia, and related hospitalization and enables the delivery of full-dose chemotherapy, resulting in long-term survival rates.

Right now the guideline recommendations for the use of the myeloid growth factors are to use it routinely when the risk of febrile neutropenia is 20% or greater. The risk from most chemotherapy regimens for early-stage breast cancer is not that high. Most of the time, they’re in the 10% to 20% risk range. We’ve developed risk models that are, perhaps, upwards of about half of those patients getting lower-risk chemotherapy, who, because of their age, comorbidities, previous anticancer therapies, and performance status, for example, are personally at increased risk.

It’s important that physicians perform personalized supportive care for their patients and identify those patients who are most at risk for febrile neutropenia, target them with these more expensive agents to prevent the febrile neutropenia, but don’t treat patients whose risk is very low. We actually mention the risk factors in the guidelines that help the clinician to stratify patients who are at high risk and those at low risk. Even if the chemotherapy isn’t high risk but the patient has a lot of comorbidities, doctors should consider treating the patient with growth factor from the beginning. If the patient is otherwise very healthy and not too old (under 65), there’s probably little indication to use these agents, unless a patient develops a problem.