A British study on antibacterial prophylaxis is giving additional information about defining the line between protecting chemotherapy patients from dangerous infections and needlessly promoting drug-resistant bacteria. Researchers from University Hospital Birmingham Cancer Centre found that levofloxacin given after the first chemotherapy cycle can be used both to ward off infections when patients are most vulnerable and to distinguish patients who will benefit from continued prophylaxis from those who will not (JCO 2007;25:4821–4828).
“[Infections are] an expensive undertaking and there's concern with the morbidity in patients who already have enough to cope with,” said lead researcher Michael H. Cullen, MD, a clinical oncologist.
In the United States, the National Comprehensive Cancer Network (NCCN) estimates that the combination of fever and neutropenia sends 60,000 cancer patients to the hospital every year. The average cost per hospitalization is $13,372 and the mortality rate is nearly 10%.
Less serious infections could still necessitate delays or changes to chemotherapy regimens, compromising the effectiveness of treatment, Dr. Cullen noted. “The most successful chemotherapy is given on schedule and at full dosage.”
Follow-up to Study Published in 2005
His recent study is a follow-up to the trial named SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy Plus/Minus Antibiotic in a Number of Tumors), published in 2005 in the New England Journal of Medicine [2005:353:988–998]).
In that original study, he and his colleagues conducted a randomized, double-blind, placebo-controlled trial of 1,565 patients to evaluate the effectiveness of antibacterial prophylaxis in preventing febrile episodes. All patients were undergoing cyclic, myelosuppressive chemotherapy. Eighty-six percent of patients had solid tumors, and the rest had lymphoma.
The study demonstrated that antibacterial prophylaxis works. Patients given 500 milligrams of levofloxacin daily for seven days following a chemotherapy cycle had fewer febrile incidents than those given placebo. Febrile incidents were defined as fevers above 38°C (100.4°F).
The authors were prompted to reevaluate their data amid growing concern that prophylaxis antibiotics could promote bacterial resistance, Dr. Cullen explained. As far back as 1996, researchers have reported evidence of resistance in cancer patients treated with antibacterial prophylaxis (Antimicrobial Agents and Chemotherapy 1996;40:503–505).
“There's a reluctance to use prophylaxis due to the fear of creating drug-resistant bacteria,” he said.
Because infection risk is highest following the first chemotherapy cycle, the Birmingham researchers decided to compare the rate of febrile episodes between patients treated with levofloxacin only after the first cycle and those treated after every cycle. Patients underwent an average of 4.4 cycles.
Levofloxacin cut the rate of febrile episodes following the first cycle from 15.2 in the placebo group to 10.8 in the treated group. The data suggest that patients who escape febrile episodes in the first cycle can safely forego prophylaxis afterward.
Only 2.6% of patients who were taken off prophylaxis after a fever-free first cycle developed fevers later. Patients with febrile episodes during the first cycle, on the other hand, remained susceptible throughout chemotherapy. Those who did not have prophylaxis after a first-cycle fever had a 15.5% fever incidence in later cycles, and others who continued taking levofloxacin following febrile episodes in the first cycle reduced their risk in later cycles to just 9.5%.
Based on the data, Dr. Cullen recommends having antibacterial prophylaxis during the first cycle for any patient getting myelosuppressive chemotherapy. He suggests continuing prophylaxis through subsequent cycles only for patients who had a first-cycle fever.
“If the treatment works, you stop giving it,” he explained. “If it doesn't work, you continue doing it. That sounds counterintuitive, but it works because you're selecting high-risk patients.”
Asked for his opinion for this article, Brahm Segal, MD, Chief of the Division of Infectious Disease at Roswell Park Cancer Institute, noted that the NCCN guidelines do not support antibacterial prophylaxis in patients with solid tumors. “We're very concerned about the benefit versus the risk of resistance,” said Dr. Segal, who was a co-presenter (with Alison G. Freifeld, MD) at the NCCN's most recent Annual Conference of the organization's update of guidelines for the prevention and treatment of infections in cancer patients.
Those guidelines recommend antibacterial prophylaxis only for high-risk patients, which include leukemia and transplant patients. Antibiotics are advised only for patients who have had fevers or a neutrophil count of less than 100/mm3 for at least seven days.
Dr. Segal did, however, commend the Birmingham group for trying to identify patients at greatest risk for infection: “This is a step in the right direction in trying to stratify patients and target those at risk,” he said.
Researcher Corey Casper, MD, MPH, agreed: “I like the concept of trying to identify people,” said Dr. Casper, of the Program in Infectious Diseases at Fred Hutchinson Cancer Research Center. “That's a major step forward.”
Dr. Cullen said his group's next step is to help answer the question critics are posing—whether antibacterial prophylaxis does indeed promote resistant bacteria. “We're going to look at patients who've had prophylaxis to see if resistant organisms are developing,” he said. “We want to confirm this isn't a serious risk.”
FDA Priority Review of Bendamustine for CLL
Bendamustine (Treanda) has been granted priority review by the FDA for the first-line treatment of patients with chronic lymphocytic leukemia (CLL).
The purine analog/alkylator hybrid, which was granted orphan drug status in the United States in August, kills cancer cells by damaging the DNA within them, leading to apoptosis, and by stopping cancer cells from dividing to create new cancer cells.
When compared with chlorambucil, FDA approved as first-line therapy for patients with CLL, in a multicenter Phase III clinical trial that evaluated the safety and efficacy of bendamustine in patients who were not previously treated for CLL, bendamustine met both primary endpoints of overall response rate and progression-free survival and demonstrated a manageable tolerability profile. da) has been granted priority review by the FDA for the first-line treatment of patients with CLL.