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Risk Assessment in Oncology Clinical Practice
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Risk Assessment in Oncology Clinical Practice
Review Article [1] | November 01, 2003
By Gary H. Lyman, MD, MPH, FRCP (EDIN) [2]
Myelosuppression and neutropenia represent the major dose-limiting toxicity of cancer
chemotherapy. Chemotherapy-induced neutropenia may be accompanied by fever, presumably due
to life-threatening infection, which generally requires hospitalization for evaluation and treatment
with empiric broad-spectrum antibiotics. The resulting febrile neutropenia is a major cause of the
morbidity, mortality, and costs associated with the treatment of patients with cancer. Furthermore,
the threat of febrile neutropenia often results in chemotherapy dose reductions and delays, which
can compromise long-term clinical outcomes. Prophylactic colony-stimulating factor (CSF) has been
shown to reduce the incidence, severity, and duration of neutropenia and its complications.
Guidelines from the American Society of Clinical Oncology recommend the use of CSF on the basis of
the myelosuppressive potential of the chemotherapy regimen. The challenge in ensuring the
appropriate and cost-effective use of prophylactic CSF is to determine which patients would be most
likely to benefit from it. A number of patient-, disease-, and treatment-related factors are associated
with an increased risk of neutropenia and its complications. A number of clinical predictive models
have been developed from retrospective datasets to identify patients at greater risk for neutropenia
and its complications. Early studies have demonstrated the potential of such models to guide the
targeted use of CSF to those patients who are most likely to benefit from the early use of these
supportive agents. Additional prospective research is needed to develop more accurate and valid
risk models and to evaluate the efficacy and cost-effectiveness of modeltargeted use of CSF in
high-risk patients.
Despite the recent introduction of a number of new agents for cancer treatment, chemotherapy
remains the principal method of systemic treatment in many of the nearly 1.3 million cancer patients
in the United States each year.[1,2] Along with surgery and radiotherapy, chemotherapy plays a
major role in the treatment of many common malignancies- including lung, breast, colon, and
ovarian cancer-as well as the hematologic malignancies. The importance of the dose-response
relation of chemotherapy agents has long been recognized.[3] Long-term studies have shown the
importance of maintaining chemotherapy dose to patient survival, especially in responsive and
potentially curable malignancies.[4-8] Myelosuppression, specifically neutropenia, is the major
dose-limiting toxicity of cancer chemotherapy, constraining the regimens, doses, and schedules that
can be used. Consequently, avoiding or reducing the risk of chemotherapy-induced neutropenia
continues to be an important consideration in the treatment of patients with cancer.
Chemotherapy-Induced Neutropenia Because neutrophils represent a major defense against
infection, neutropenia can create a favorable environment for bacterial invasion and multiplication,
with the potential for rapidly spreading life-threatening infection.[ 9] The relative absence of
neutrophils also reduces the symptoms and signs of infection, with fever often being the only
indication of infection in a patient with neutropenia. Because of the risk of life-threatening infection
and sepsis, patients with febrile neutropenia must be treated aggressively.[ 9,10] Hospitalization for
rapid evaluation and treatment with intravenous antibiotics remains the standard of care for the
majority of these patients.[11] Hospitalization for febrile neutropenia represents a considerable
financial burden in the care of patients with cancer. The current costs of cancer care are estimated
to be more than $150 billion per year, with the financial consequences of hospitalization accounting
for the largest single component of these costs. Two economic analyses have placed the mean
length of hospitalization for febrile neutropenia at 10 days and the average cost of hospitalization at
more than $20,000.[12,13] Substantial indirect and out-of-pocket costs have also been reported in
association with neutropenia and its complications.[14] Neutropenia also has negative effects on
patients' quality of life. When patients are hospitalized for febrile neutropenia their well-being suffers
from being separated from family.[15] Patients hospitalized with febrile neutropenia may be anxious
about infection, invasive medical procedures, ineffective treatments, and death.[15] Further,
preliminary research suggests an association between the depth of the absolute neutrophil count
(ANC) nadir and a decline in quality of life.[16,17] A neutropenia-specific quality-of-life instrument
developed to study how neutropenia can affect specific quality-of-life domains such as fatigue and
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worry is undergoing further validation.[18] Perhaps of greatest importance, the complications of
neutropenia can lead to reductions in chemotherapy dose intensity, adversely affecting longterm
patient outcomes. The occurrence of neutropenia often leads physicians to reduce the chemotherapy
dose or delay subsequent cycles of treatment. The net result is the delivery of lower relative dose
intensity.[19-21] In potentially curable cancers, such as earlystage breast cancer and non-Hodgkin's
lymphoma, there is considerable evidence that such chemotherapy dose alterations are associated
with lower disease- free and overall survival.[4-6,8] The extent to which chemotherapy dose
intensity was modified in major randomized clinical trials has been explored in a systematic review
of the literature on chemotherapy in patients with early-stage breast cancer and non-Hodgkin's
lymphoma. Data on relative dose intensity delivered were reported inconsistently and in various
ways in the trials analyzed in this study, with 40% of the trials not reporting dose intensity
information at all.[22] Studies of practice patterns have also shown the extent to which
chemotherapy dose reductions and delays occur in practice. A survey of practice patterns in more
than 20,000 patients treated with chemotherapy in the adjuvant setting for breast cancer found that
56% of patients were treated with a relative dose intensity less than 85% of the reference standard,
increasing to 67% of patients aged 65 years and older.[20] Several factors may influence the relative
dose intensity delivered, including both planned and unplanned dose reductions and treatment
delays (Table 1). The Role of Colony-Stimulating Factor Prophylactic colony-stimulating factor
(CSF) is associated with a reduced risk of febrile neutropenia, documented infection, and the need
for dose reduction or treatment delay, often enabling the delivery of full dose intensity.[23-25]
Clinical practice guidelines for the use of the CSF have been developed by the American Society of
Clinical Oncology (ASCO).[26] These guidelines currently support the routine use of prophylactic CSF
in patients treated with a chemotherapy regimen with an average risk of febrile neutropenia of 40%
or greater. These guidelines were supported by early economic analyses based on a limited
assessment of the direct medical costs of hospitalization for febrile neutropenia at a single
institution.[ 27] This model found that CSF use is associated with a reduction in cost when the risk of
febrile neutropenia is above the 40% threshold. The risk threshold is the breakeven point at which
the added cost of the CSF is offset by the reduction in the costs of hospitalization for febrile
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neutropenia. The costs of hospitaliza-
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tion for febrile
neutropenia have been further studied both within single-institution and in multi-institution studies.
Incorporating updated cost estimates into this economic model provides threshold risk estimates
closer to 20% (Figure 1). The ASCO CSF guidelines are currently being revised in consideration of this
and other additional clinical and economic information. Risk thresholds for the cost-saving use of CSF
have been further evaluated in sensitivity analyses and are seen to depend on the assumed baseline
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risk of febrile neutropenia. It is clear that some chemotherapy regimens are more likely to cause
serious myelosuppression than others, but much about the patterns and incidence of
chemotherapy-induced neutropenia with the regimens remains unknown. A survey of the literature
for the rates of neutropenia in randomized clinical trials of chemotherapy found that the rates of
myelosuppression and its complications often were not reported.[ 22] When they were reported, the
rates of hematologic toxicity with the same and similar regimens varied greatly, making it difficult to
assess the actual risk. The actual risk has been shown to vary with a large number of treatment-,
disease-, and patient-related characteristics. The use of a specified risk threshold for a given
regimen to select patients for first-cycle CSF use assumes an average population risk profile. There
clearly is a need to "individualize" the risk by considering a specific patient's risk factors. This can be
most reliably and reproducibly done by using a risk model to select patients for CSF prophylaxis.
Whether to use CSF in accordance with a costminimization model with a specified risk threshold is an
economic decision that is based on population risk, and it does not take into account the possible
clinical benefits in individual patients in whom neutropenic complications could be avoided.[27] The
optimal cost-effective use of CSF hinges on using it in those patients who are most likely to benefit
from it, and being able to predict who those patients are. In the absence of reliable values for
chemotherapy regimen- specific risks, clinicians often use various patient characteristics to get an
idea of a patient's risk for neutropenia and its complications. The ASCO guidelines define "special
circumstances" as patient populations in whom the risk is high and primary prophylaxis with CSF is
recommended. These include extensive prior treatment, prior radiation therapy to considerable
marrow-producing bone, and risk factors for infection, includ-
ing open
wounds, low performance status, and reduced immune function. However, the list of these special
circumstances is not comprehensive, nor is the list routinely used in selecting patients for first-cycle
CSF management. The lack of uniform standards can leave oncologists uncertain about which
patients are at greatest risk for neutropenic complications. A "watch and wait" approach is often
used, in which patients who experienced severe or febrile neutropenia in the first cycle are given CSF
after chemotherapy in later cycles. Such "secondary prophylaxis," while reasonable in lower-risk
settings, is not a desirable option in those at greater risk, given the life-threatening nature of febrile
neutropenia and demonstration with several chemotherapy regimens that the greatest risk of the
initial episode of febrile neutropenia occurs early in the treatment course.[29- 31] Initiating CSF later
in the treatment course forces most patients to experience the very complication they are intended
to prevent. Clearly, a new strategy is needed to better select patients for early CSF management.
Risk Models for Neutropenia Considerable research has been directed toward identifying patient-,
disease-, and treatment-related factors associated with the risk of neutropenia and its complications.
The focus has moved from the uncertainty of reported risk associated with various regimens in
highly selected populations to a more focused assessment of risk in the individual patient based on
his or her clinical condition and treatment history.[28] The purpose of clinical predictive models is to
define the independent contributions of the various risk factors for neutropenic complications and
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reduced dose intensity. By identifying patients at greater risk, such models can be used to target the
CSFs more efficiently and cost-effectively to those most likely to benefit from such supportive care.
Predictive risk models more closely reflect the situation in clinical practice, in which patients are
selected for treatment on the basis of their individual prognostic and predictive factors, while basing
such decisions on explicit, objective, and reproducible measures that can be systematically applied
and validated[ 28] (Figure 2). Risk models for neutropenic events have been studied most
extensively in chemosensitive, potentially curable malignancies with full-dose chemotherapy,
namely early-stage breast cancer and non-Hodgkin's lymphoma.[ 32-35] Those risk factors found to
be statistically significant in multivariate models in two or more studies are indicated in Figure 3.
Clinical prediction models evaluate relations between risk factors and clinical outcomes, such as
hospitalization for febrile neutropenia or reduced chemotherapy dose intensity. Risk models can be
based on pretreatment characteristics alone (unconditional) or include the initial results with
treatment (conditional). Some obvious pretreatment factors are advanced age, low performance
status, comorbidities, and prior treatment. Additional risk factors found to be useful in risk models in
patients with non- Hodgkin's lymphoma include serum albumin levels, lactate dehydrogenase levels,
bone marrow involvement, and soluble tumor necrosis factor receptor levels.[33-35] The most
common type of conditional model for predicting later neutropenic complications incorporates the
patient's early hematologic response to chemotherapy, which can identify patients at increased risk
for subsequent neutropenic events who are likely to benefit from CSF support.[32,37] Conditional
models are most useful with regimens that are associated with a relatively low average risk in the
early cycles of treatment, while unconditional models are more useful when the early risk of
neutropenic events is relatively high. An example of an unconditional risk model has recently been
presented that identified five independent factors associated with an increased risk of hospitalization
for febrile neutropenia: age 65 years or greater, serum albumin levels 3.5 g/dL or less, planned
average reduced dose intensity 80% or more, pretreatment ANC 1.5 109/L or less, and hepatic
disease.[36] This model was then used to classify patients as being at low, medium, or high risk
according to how many risk factors were present.[36] Economic evaluations have shown the ability
of clinical prediction models to increase cost savings and the cost-effective application of CSF by
enabling targeted use in patients at greatest risk and most likely to benefit.[ 29,38] For instance,
using a validated conditional model for identifying patients treated with adjuvant chemotherapy for
early-stage breast cancer who are at increased risk for future neutropenic events that are likely to
compromise dose intensity, Silber and colleagues showed that a strategy of targeting G-CSF in the
50% of patients at greatest risk was associated with an average cost-effectiveness of approximately
$34,000 per life-year gained.[38] Evaluating Risk Models Most of the risk models for
chemotherapy- induced neutropenia that have been developed to date have been retrospective in
design, fail to provide clearly defined hypotheses, and lack important data elements for adequate
analysis. Clinical predictive models should be developed from studies that minimize bias by stating
the hypothesis in advance and providing clear inclusion and exclusion criteria. Any subgroup
analyses that are to be performed should be stated in advance, and any differences in the outcomes
between subgroups should be assessed by testing the interaction between the prognostic factor and
the variable that defined the subgroups rather than by separate analyses within the subgroups.
Studies should be designed to limit the potential for missing data, ideally to less than 10%. The
issues of multiple comparisons should be considered when several prognostic factors or cut points
are evaluated, and tests of significance should be adjusted accordingly. The pitfalls of stepwise
multiple regression models, including model instability, and exaggeration of coefficient estimates
(and P values) should be acknowledged. The majority of the studies to date have not been
independently validated in a similar but separate patient population. The issue of multiple testing or
small sample sizes within subgroups must be properly addressed when apparent differences
between subgroups are observed. A risk model should ideally be developed from a prospective,
hypothesis- driven study in a large representative patient population. For this purpose, a prospective
registry in different tumor types in a large communitybased oncology setting has been created. The
registry will make it possible to collect comprehensive patient data, including cycle-by-cycle
information on hematologic function. The purpose of the registry is to develop a powerful risk model
for neutropenia that is reliable in routine clinical practice.[ 22,39] Conclusions Neutropenia and its
complications remain a major challenge in the management of patients with cancer treated with
cytotoxic chemotherapy. Colonystimulating factor is effective in reducing neutropenia and its
complications across a broad range of disease categories and treatment regimens. The American
Society of Clinical Oncology has developed clinical practice guidelines for the use of CSF that were
supported by early economic models based on the average risk of febrile neutropenia with various
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chemotherapy regimens. While updated cost studies support lower cost-savings risk thresholds in
the average setting, current efforts have shifted the focus to treatment-, disease-, and
patient-specific risk factors for neutropenia and its complications. Early studies of predictive models
for identifying patients at increased risk for neutropenic complications show promise for clinical
decision making and the effective targeting of CSF use toward those most likely to benefit. Such
models have been shown to further reduce the cost associated with CSF support in patients treated
with chemotherapy for cancer and to be cost-effective in responsive and potentially curable
malignancies by enabling the delivery of full-dose-intensity therapy on time. A multi-institution effort
is currently under way to establish a large prospective registry of patients treated with cytotoxic
therapy in order to develop accurate and valid risk models to guide clinicians in the optimal use of
CSF.[39,40]
Disclosures: The author(s) have no significant financial interest or other relationship with the
manufacturers of any products or providers of any service mentioned in this article.
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