NEWS

NCCN Guidelines Advocate Wider Use of Colony-Stimulating Factor

Caroline McNeil

Citing data from a recent major clinical trial, the National Comprehensive Cancer Network (NCCN) has issued guidelines advocating the use of colony-stimulating factor (CSF) to prevent febrile neutropenia in patients with a 20% risk of developing the condition. Up to now, guidelines from the American Society of Clinical Oncology (ASCO) and others have recommended CSFs only for patients at a 40% or higher risk.

The new guidelines have the potential to affect supportive care for hundreds of thousands of chemotherapy patients. Amgen, which makes the two most commonly used CSFs in the United States, filgrastim (Neupogen) and pegfilgrastim (Neulasta), estimates that about 300,000 patients now take the drugs annually.

The trial that played a major role in the NCCN panel's decision involved 928 breast cancer patients who received single-agent docetaxel, which is associated with a 20% risk of febrile neutropenia. Led by Charles L. Vogel, M.D., of Cancer Research Networks Inc., in Plantation, Fla., and sponsored by Amgen, the trial randomly assigned patients to either pegfilgrastim or a placebo. Only 1% of those taking pegfilgrastim developed febrile neutropenia, compared with 17% of those on placebo. Likewise, just 1% of the pegfilgrastim patients were hospitalized, compared with 14% in the control group.

"We thought that benefit would go down as risk decreased. But actually [CSF] almost eliminated febrile neutropenia when there was just a modest risk," said Jeffrey Crawford, M.D., of Duke University in Durham, N.C., who chaired the NCCN expert panel and helped present the new guidelines at the organization's annual meeting in Hollywood, Fla., in March.



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Jeffrey Crawford

 
Like single-agent docetaxel, many commonly used chemotherapy regimens are associated with a 10%–20% risk of febrile neutropenia, and many others fall in the 20%–40% range. (Risk is based on incidence of febrile neutropenia associated with the each regimen in large clinical trials.) Standard practice is to treat the condition with hospitalization and intravenous antibiotics, which are costly and carry their own risk of complications.

In addition, febrile neutropenia may result in delays in chemotherapy or dose reductions. However, there are no data on response rate or mortality from large, randomized trials. The NCCN's guideline is based only on CSF's effectiveness in reducing the incidence of febrile neutropenia.

The 20% guideline was given a Category 1 designation, meaning that it was supported by the full consensus of the panel and high-level evidence. "We clearly have that now. I'm very comfortable with the 20% level, certainly based on efficacy," Crawford said.

The panel also recommended that physicians consider CSFs when the risk of febrile neutropenia is between 10% and 20%. The guidelines do not recommend the drugs for patients at a less than 10% risk.

If ASCO, which is currently updating its own CSF guidelines, also lowers the 40% risk threshold, it would likely prompt clinicians to prescribe the drugs more widely. That could be welcomed by some practicing oncologists. "The 40% bar was just too high to be clinically useful," Crawford said in an interview. "It was not a viable clinical threshold."

The common practice for patients who had less than a 40% risk had been to wait and see if febrile neutropenia occurred during the first cycle of chemotherapy. If it did, CSFs were given with later cycles. The problem with this approach, Crawford said, is that febrile neutropenia is most common during the first cycle of chemotherapy, so by waiting, physicians are missing their best opportunity to prevent it.

Another problem with the 40% risk threshold, Crawford argues, is that it emerged from clinical trials with a narrowly defined patient population. In the community, clinicians see patients who tend to be older and have more comorbidities than those in trials and thus have risks for febrile neutropenia on top of those associated with a particular chemotherapy regimen. But even with accumulated clinical experience, the new evidence, and the unanimity of the NCCN panel, it is not likely the ASCO panel will have an easy time deciding whether to lower its risk threshold for use of CSFs. ASCO's evidence-based guidelines, first developed in 1993 and updated in 1996 and 2000, have emphasized data—or rather, the lack of data—on patient outcomes, as well as cost-effectiveness for CSFs. These are issues that the NCCN panel was not asked to address but that ASCO presumably will consider again.

ASCO's evidence-based guidelines emerge through a long systematic review of all available literature on a specific topic. In contrast, NCCN's consensus-based guidelines are based on both evidence and clinical experience. The NCCN's aim is to provide clinicians with practical tools for day-to-day decision making, even when there is insufficient evidence.

The two systems are complementary, and many of the same people serve on both panels, said Deborah Schrag, M.D., of Memorial Sloan Kettering Cancer Center in New York, who is the chair of ASCO's Health Services Research Committee. But with ASCO's strong, primary emphasis on evidence, "we tend to be a little more conservative," she said.

And although the recent trial of pegfilgrastim showed a drop in incidence of febrile neutropenia, it provides no evidence of improved patient outcome.

The issue of cost-effectiveness has also figured prominently in ASCO's guidelines. CSFs are among the most expensive cancer drugs. Pegfilgrastim, for instance, given once in each cycle of chemotherapy, costs from $1,900 to $2,800 a dose.

ASCO's 40% risk threshold for CSFs results in an overall cost savings from reduced costs for hospitalization and intravenous antibiotics. Over the past decade, rising hospital costs may have changed this hospitalization/CSF ratio, according to some analyses. The Vogel study cites a 1998 economic modeling study, also supported by Amgen, suggesting that the cost of filgrastim could be offset when the risk of febrile neutropenia is 20%–25%. However, there are still no hard data on cost-effectiveness, and ASCO's 2000 guidelines state unequivocally that, for almost all newly diagnosed patients, "CSF use for primary treatment cannot be recommended on either clinical or economic grounds."

More studies of CSF are under way and are sure to provide fuel for subsequent rounds of guideline revisions. The Awareness of Neutropenia in Chemotherapy Study Group, led by Gary Lyman, M.D., of the University of Rochester Medical Center in New York, and supported by Amgen, is conducting the FIRST trial, which is examining first-cycle use of CSF and incidence of febrile neutropenia in more than 2,000 patients. The study group is also developing risk models to help quantify patient characteristics, such as age and comorbidities, that increase risk.

No study is currently looking at patient outcomes with CSFs. With the old 40% threshold, that was hard to do, said Crawford, but now it may be more feasible. For instance, a randomized trial of CSFs in patients who are in the 10%–20% risk category could be mounted, he said.

"We still have to look at CSFs as primarily supportive care," Crawford said. "Hopefully, we will get data on outcomes."


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