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Supplements Clinical Advance in the Management of Febrile Neutropenia

Perspectives in Febrile Neutropenia: Q&A With Gary Lyman, MD, MPH

AJMC®: What is the importance of febrile neutropenia (FN) in oncology?

Lyman: Fundamentally, those who work in the field consider febrile neutropenia to be either one of the most, if not the most important dose-limiting toxicity of conventional cancer chemotherapy. It not only greatly increases the risk of sepsis and life-threatening infection, but also often leads to reductions in chemotherapy intensity through early termination or reductions in dose or delays that can have a direct impact on the effectiveness of chemotherapy in patients with cancer. It has a dual impact: first, in terms of the risk of infection, which increases as neutrophil counts go down, and second, in terms of the delivery of chemotherapy at safe, effective, or even curative levels. Before the availability of the myeloid growth factors [granulocyte colony-stimulating factors; G-CSFs] for prevention and aggressive treatment strategies, FN was often fatal and severely limited effective cancer chemotherapy. Even now, the risk of life-threatening infection and delivery of full-dose chemotherapy remains a challenge in cancer patients who are often older with other serious medical conditions. There continues to be a lot of research in this area, particularly looking at adherence to guidelines, and what can be done to improve on quality of cancer care by ensuring that the patients who are at risk for these complications get the right supportive care, as well as prompt, effective treatment for infection if they develop FN.

AJMC®: In 55% to 95% of cases, G-CSFs as primary prophylaxis are used inconsistently with guidelines. What, in your opinion, accounts for the inconsistency in use of G-CSFs as primary prophylaxis?

Lyman: There are probably multiple factors, and part of our ongoing Pragmatic Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER) study is to identify the main drivers. There is clearly both underuse and overuse of G-CSFs. Certainly, from a cost perspective, the overuse is of high concern because these are expensive drugs, and if they are not needed, it drives up healthcare costs.

From a clinician standpoint, we may be even more concerned about underuse: that is, not providing prophylaxis or prevention of these life-threatening complications leading to costly hospitalizations in patients getting high-risk chemotherapy. These patients may end up with serious infections and hospitalizations that could be avoided with the appropriate use of these agents that are costly in their own right. In terms of why there is both underuse and overuse, I think it is complicated and multifactorial. We have seen in our survey data that a lot of growth factor use is either automatic, meaning some practices administer growth factors to almost everyone getting chemotherapy, and other practices give very little if any growth factor, and that may stem out of how individuals are trained or constraints in terms of costs that have been imposed on them. 

The 3 major guidelines from ASCO, NCCN, and EORTC are consistent, and they recommend G-CSF use based on the level of risk. The guidelines are all in sync, and recommend the routine use of myeloid growth factor support if the risk is in the range of 20% or more. If the risk is less than 10%, the benefits and risks may not favor using these drugs routinely, unless the patient has other high-risk conditions. A remaining big challenge, however, is that there are a large proportion of chemotherapy regimens that fall in a gray zone that we call “intermediate risk,” where the risk of FN is somewhere between 10% and 20%. That may account for upwards of half to two-thirds of chemotherapy regimens. Of course, those risks are generally estimated from clinical trials that led to the approval of those drugs or regimens. It is complicated because the clinical trials are often very selective of which patients they allow to participate. These trials do not allow patients with important comorbid medical conditions to participate. Often the trials are conducted in younger patient populations. The patients in those trials are a more favorable risk population that may not be representative of patients in a real-world setting where patients are often older or have other health problems, where complications like FN can be much more serious or life-threatening. For that reason, this gray area where the regimens are associated with a 10% to 20% risk of FN based on clinical trials, the guidelines are somewhat ambiguous. However, the guidelines recommend that if, in addition to the chemotherapy, a patient has other risk factors either for developing FN or having a bad outcome if they were to get FN, then one should consider using G-CSF support. This represents more personalized supportive care that goes beyond the guidelines based on patients eligible for clinical trials.

Our own data suggest that approximately half of patients receiving chemotherapy who are considered intermediate risk for FN are actually at high risk for FN because of other medical conditions, such as heart disease, lung disease, liver disease, and so forth. Presence of these comorbidities, in addition to the cancer, progressively increases the risk of FN, and the potential for complicated hospitalizations or even dying from febrile neutropenia. Although the guidelines do not give strict prescription of when to give growth factor support and when not to give growth factor support, treating clinicians should consider other risk factors in addition to the chemotherapy regimen when making a decision whether to utilize G-CSF support. 

In the TrACER trial that’s under way, we’re just being run through SWOG and through the community oncology sites affiliated with SWOG. We are randomizing sites, not patients. Some practices have agreed to embed the guidelines into their computer order entry system. This means that for patients getting high-risk chemotherapy, G-CSF support would be automatically given, even if, in the past, the physician might not have made that call. Of course, the physician can always opt out of that, but the default position is, if the patient is high risk they receive the support, if the patient is low risk they do not receive it, and these are built into the order systems for various chemotherapy regimens. The comparison groups at the other sites receive usual care. The physician selects the chemotherapy and they make the decision, presumably, how they always have, on whether to give growth factor support or not. Our hypothesis is, by having this built in automatically, and to somewhat enforce guideline adherence, we will see better outcomes. Again, patients who do not need growth factor are not getting it, and those who should get the support are getting it. We will follow and see if the rates of FN and complications from FN are altered and improved by building this into electronic order systems. 

There is another element to this study. Again, there are not much data on G-CSF support in patients getting intermediate-risk chemotherapy, which accounts for half to two-thirds of chemotherapy regimens. The guidelines are ambiguous on this and simply call for the physicians to use their best judgment. So, in our trial, at the sites where growth factor support is built into the treatment regimen, if the patients receiving chemotherapy are at intermediate risk, the protocol calls for a second randomization, to either automatically give growth factor support or not, depending on the trial site. The purpose of this second randomization is to see if we can improve our understanding of the effectiveness and safety of G-CSF support in patients getting intermediate-risk chemotherapy, because data on this are limited. This is a 5-year study, and, so far, we have great engagement from the sites; the accrual is going well, but it’s still going to be a couple of years before we begin to see results coming out of this, to see whether we can improve adherence to guidelines and how effective growth factor support is in intermediate-risk chemotherapy groups. 

AJMC®: In many of your previous publications, you have mentioned financial toxicity as an important challenge in oncology care. How are the costs of G-CSFs affecting prescribing decisions, and how might those decisions be affected by lower-cost agents, such as biosimilars? What is the experience with these agents in Europe, and what could that mean for the United States? 

Lyman: One of the reasons we do not give G-CSF to every patient, if they don’t need it, is to avoid the burden of injections, which are administered as frequently as once daily. The other reason to limit the use of G-CSF when the risk of FN is low is cost. These are very expensive drugs. Like with all of healthcare, the prices on these drugs have gone up over time, and certainly that has been true in the last 5 to 10 years. We have done economic analyses to suggest that, for high-risk patients, you either break even or save money by using these agents, based on their ability to prevent serious infections leading to hospitalization, and sometimes even death. The cost of hospitalization, like healthcare costs in general, has gone up greatly, and has exceeded the overall increase in healthcare costs. The cost of hospitalization with FN, if it is not prevented, is thousands of dollars a day in many institutions. It is true that the drug may be expensive, but comparing that cost with the preventable cost of hospitalization and intensive care unit stay and any other complication that may come with it, the net effect can be cost saving. So, all of these considerations are important. 

Another concern that has gained considerable attention in recent years is that cost increasingly has become a barrier to a patient either getting appropriate and potentially curative treatment at all, or safely administered treatment. Patients who should be getting a chemotherapy regimen where growth factor support is necessary, or indicated, may simply be unable to afford treatment because they have no insurance, or because the associated out-of-pocket cost, which has also gone up, has become a barrier to access to care and appropriate treatment. And even when patients can and do get treated, they may be left with insurmountable bills, which we refer to as the “financial burden” or “financial toxicity” of treatment. We have shown that financial toxicity can double the rate of bankruptcies when a patient is diagnosed with cancer and goes through treatment. Financial toxicity may even increase mortality just by virtue of dealing with the cost associated with cancer care. 

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