Chemo-Related Febrile Neutropenia Rates Higher in Elderly

BOSTON—Researchers from the Awareness of Neutropenia in Chemotherapy (ANC) Study Group report that older cancer patients are at greater risk of death due to chemotherapy-related febrile neutropenia. They recommend that the elderly receive prophylactic colony-stimulating factors (CSFs) as adjuncts to CHOP and CHOP-like chemotherapy regimens.

The group’s findings, presented at the third meeting of the International Society of Geriatric Oncology (SIOG), were based on two studies: a retrospective analysis of more than 55,000 episodes of febrile neutropenia (abstract P-25) and a review of 11 randomized CHOP trials from which data could be extracted for older patients (abstract O-7B-02).

The ANC Study Group receives support from Amgen Inc. of Thousand Oaks, California, which manufactures the CSFs filgrastim (Neupogen) and pegfilgrastim (Neulasta).

The first study reviewed discharge information for adult, nontransplant patients admitted with febrile neutropenia from 1995 to 2000 at 115 teaching hospitals in the University HealthSystem Consortium (UHC) database. Jeffrey Crawford, MD, director of clinical research, Duke University Comprehensive Cancer Center, and his colleagues reported that patients age 65 and older accounted for 27% of admissions for febrile neutropenia but 36% of inpatient deaths.

The researchers found 55,276 episodes of febrile neutropenia in 41,779 patients during this 6-year period. More than 14,000 episodes occurred in patients age 65 or older.

The large number surprised the investigators, Dr. Crawford said. "I think this has to do with the lack of appreciation of the magnitude of this problem," he told ONI, suggesting that many oncologists don’t recognize how frequently neutropenia occurs or how much it interferes with treatment.

"Unfortunately, our strategy for altering chemotherapy doses or adding CSF support is more reactive than proactive," he added. "The data speak to that. We’re getting thousands of admissions per year in these 115 institutions of patients over 65. We’re clearly not identifying these patients well enough prospectively."

Excluding transplant patients, the analysis found that risk of inpatient mortality was significantly associated with diagnosis of secondary febrile neutropenia, diagnosis of leukemia, older age, and male sex. Older patients had a higher risk of death than younger patients at all lengths of stay, and the risk increased with increasing age.

The total cost was more than $1 billion for 619,837 patient days, according to the investigators. While average hospital stay declined slightly from 11.2 days in 1995 to 10.7 days in 2000, average charges increased 41%, from $1,275 per day to $1,797. As a result, the cost per episode went up 28%, from $14,685 to $18,810.

Patients Receiving CHOP Regimens

Lodovico Balducci, MD, of the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, presented the literature review, which plumbed 11 randomized trials from which data could be extracted on the incidence and severity of neutropenic complications in older patients given CHOP or CHOP-like regimens for non-Hodgkin’s lymphoma.

American Society for Clinical Oncology (ASCO) guidelines, updated in 2000, do not recommend prophylactic use of CSF on the basis of age, but allow it for patients in special circumstances who are at high risk for chemotherapy-induced infectious complications. Typically, these are patients who had a previous episode or can be expected to have a 40% incidence of infection, Dr. Balducci said.

"I think the 40% threshold is much too high for older people," he told ONI, citing higher instances of febrile neutropenia in older patients in many of the studies reviewed by the ANC group. In six studies that reported on grade 4 neutropenia, the rate ranged from 4% to 91% in elderly patients. Four studies reported febrile events; these ranged from 10% to 47% in the elderly. Among seven studies reporting on treatment-related mortality, these deaths ranged from 0% to 19% in elderly patients.

Incidence is not the only issue, Dr. Balducci said. The 40% cut-off was based on an estimated hospitalization of 5 days, but older patients typically stay 12 days, driving up costs. "I think the threshold for routinely starting CSFs with the first chemotherapy cycle is much closer to 18% to 20% for older patients," he said. "Even if you are not interested in preventing death—which you should be—from the pure cost-effectiveness viewpoint, I think it would be cost-effective to use growth factors prophylactically in these patients."

Giving prophylactic CSF significantly reduced myelosuppression, according to four randomized trials in the sample. The rate of grade 3-4 neutropenia was reduced by 32% to 83%, and neutropenic infection rates declined by 32% to 100%. In one study, patients given prophylactic CSF had fewer treatment delays, shorter delays when they occurred, and shorter hospitalizations for treatment-related complications.

The National Comprehensive Cancer Network (NCCN) has recommended prophylactic CSF use in cancer patients age 70 and older, and Dr. Balducci said he expects that ASCO will review its guidelines.