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Bibliography for Chemotherapy Solutions
1. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer
patients.
Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH.
James P. Wilmot Cancer Center and Department of Medicine, University of Rochester,
Rochester, New York 14642, USA.
Cancer. 2006 May 15;106(10):2258-66. PMID: 16575919
Hospitalization for febrile neutropenia (FN) in cancer patients is associated with
considerable morbidity, mortality, and cost. The study was undertaken to better define
mortality, length of stay (LOS), cost, and risk factors associated with mortality and
prolonged hospitalization in cancer patients with FN. METHODS: The longitudinal
discharge database derived from 115 US medical centers was used to study all adult
cancer patients hospitalized with FN between 1995 and 2000, comprising a total of
41,779 patients. Primary outcomes included mortality, LOS, and cost per episode.
RESULTS: Overall, in-hospital mortality was 9.5%. Patients without any major
comorbidities had a 2.6% risk of mortality, whereas 1 major comorbidity was associated
with a 10.3% and more than 1 major comorbidity with a > or = 21.4% risk of mortality,
respectively. Mean (median) length of stay was 11.5 (6) days, and the mean (median)
cost was ,110 (,376) per episode of FN. Patients hospitalized for > or = 10 days
(35% of all patients) accounted for 78% of overall cost. Independent major risk factors
for inpatient mortality included invasive fungal infections, Gram-negative sepsis,
pneumonia and other lung disease, cerebrovascular, renal, and liver disease. Main
predictors for LOS > or = 10 days included leukemia, invasive fungal infections, other
types of infection, and several comorbid conditions. CONCLUSION: Factors associated
with increased mortality, LOS, and cost in hospitalized adult cancer patients with FN
include patient characteristics, type of malignancy, comorbidities, and infectious
complications. These factors may be useful in identifying patients at increased risk of
serious medical complications and mortality for more aggressive supportive care
measures.
Copyright 2006 American Cancer Society
2. Chemotherapy-induced neutropenia: risks, consequences, and new directions for
its management.
Crawford J, Dale DC, Lyman GH.
Divisions of Oncology and Hematology, Duke University Medical Center, PO Box
25178 Morris Building, Durham, NC 27710-0001, USA.
Cancer. 2004 Jan 15;100(2):228-37. Erratum in: Cancer. 2004 May 1;100(9):1993-4.
PMID: 14716755.
Cytotoxic chemotherapy suppresses the hematopoietic system, impairing host protective
mechanisms and limiting the doses of chemotherapy that can be tolerated. Neutropenia,
the most serious hematologic toxicity, is associated with the risk of life-threatening
infections as well as chemotherapy dose reductions and delays that may compromise
treatment outcomes. The authors reviewed the recent literature to provide an update on
research in chemotherapy-induced neutropenia and its complications and impact, and
they discuss the implications of this work for improving the management of patients with
cancer who are treated with myelosuppressive chemotherapy. Despite its importance as
the primary dose-limiting toxicity of chemotherapy, much concerning neutropenia and its
consequences and impact remains unknown. Recent surveys indicate that neutropenia
remains a prevalent problem associated with substantial morbidity, mortality, and costs.
Much research has sought to identify risk factors that may predispose patients to
neutropenic complications, including febrile neutropenia, in an effort to predict better
which patients are at risk and to use preventive strategies, such as prophylactic colonystimulating
factors, more cost-effectively. Neutropenic complications associated with
myelosuppressive chemotherapy are a significant cause of morbidity and mortality,
possibly compromised treatment outcomes, and excess healthcare costs. Research in
quantifying the risk of neutropenic complications may make it possible in the near future
to target patients at greater risk with appropriate preventive strategies, thereby
maximizing the benefits and minimizing the costs. Copyright 2003 American Cancer
Society.
3. Myeloid Growth Factors Clinical Practice Guidelines in Oncology
Crawford J, Althaus B, Armitage J, Blayney DW, Cataland S, Dale DC, Demetri GD,
Foran J, Heaney ML, Htoy S, Kloth DD, Lyman GH, Michaud L, Motl S, Vadhan-Raj S,
Wong MK; National Comprehensive Cancer Network.
Duke Comprehensive Cancer Center, Duke University, Durham, NC, USA.
J Natl Compr Canc Netw. 2005 Jul;3(4):540-55. PMID: 16038645
Chemotherapy-induced neutropenia is the major dose-limiting toxicity of systemic
cancer chemotherapy, associated with substantial morbidity, mortality, and cost.
Although prophylactic colony-stimulating factors (CSFs), can reduce this complication,
their routine use in all patients on myelosuppressive chemotherapy is prohibitively
costly. Selective use in patients most at risk for neutropenia may enhance
costeffectiveness, but determining the actual risk is complicated by issues in reporting
myelosuppression and dose intensity, among other factors. For this reason, NCCN
experts developed these guidelines to assist practitioners in the appropriate
prophylactic use of CSFs.
4. Risk models for predicting chemotherapy-induced neutropenia.
Lyman GH, Lyman CH, Agboola O.
Health Services and Outcomes Research Program, James P. Wilmot Cancer Center,
University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Oncologist. 2005 Jun-Jul;10(6):427-37. PMID: 15967836
Neutropenia and its complications, including febrile neutropenia, are major dose-limiting
toxicities of systemic cancer chemotherapy. A number of studies have attempted to
identify risk factors for neutropenia and its consequences to develop predictive models
capable of identifying patients at greater risk for such complications and to guide more
effective and cost-effective applications of the colony-stimulating factors. A systematic review of the literature showed that age, performance status, nutritional status,
chemotherapy dose intensity, and low baseline blood cell counts were associated with the
risk of severe and febrile neutropenia or reduced chemotherapy dose intensity in
multivariate analysis in two or more studies. Similarly, age, diagnosis of leukemia or
lymphoma, high temperature or low blood pressure at admission, and i.v. site infection
along with low blood cell counts and organ dysfunction were associated with serious
medical complications of febrile neutropenia, including bacteremia and death. The
available risk model studies, however, had several limitations, including retrospective
analyses of small study populations lacking independent validation, frequent missing
values, and differences in the predictive factors considered. To overcome the limitations
of previous studies, efforts are under way to develop and validate risk models based on
large prospective studies in representative populations of patients receiving systemic
chemotherapy.
5. Prospective validation of a risk model for first cycle neutropenic complications in
patients receiving cancer chemotherapy.
G. H. Lyman, N. M. Kuderer, J. Crawford, D. A. Wolff, E. Culakova, M. S.
Poniewierski, D. C. Dale for the ANC Study Group
2006 ASCO Annual Meeting
Category: Patient and Survivor Care Sub-category: Cancer-Related Complications
Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I.
Vol 24, No. 18S (June 20 Supplement), 2006: Abstract No: 8561
A nationwide, prospective cohort study was undertaken to develop and validate a risk
model for neutropenic complications (NC) in cancer patients receiving chemotherapy.
Methods: 3,596 patients initiating a new chemotherapy regimen with solid tumors or
lymphoma were registered at 115 randomly selected sites. Data on at least 1 cycle of
chemotherapy were available on 3,468. A logistic regression model for cycle 1 NC was
derived and then validated using a split sample random selection process. Results: The
risk of cycle 1 NC ranged from 5.5%-30.2%, averaging 18.5% across tumor types. No
significant differences in distribution of NC or predictive factors were observed between
the derivation dataset (n=2,592) or the validation dataset (n=876). Major independent
baseline clinical risk factors for cycle 1 NC in the derivation model include: prior
chemotherapy (P=.044), number of myelosuppressive agents (P<.0001), anthracyclinebased
regimens (P<.0001), planned delivery >85% of standard (P<.0001), cancer type
(P<.0001), concurrent antibiotics (P=.023) or phenothiazines (P=.006), abnormal alkaline
phosphatase (P=.002), elevated bilirubin (P=.031), low platelets (P=.004), elevated
glucose (P=.023) and reduced glomerular filtration rate (P=.013). Reduced risk of cycle 1
NC was associated with primary prophylaxis with a myeloid growth factor (P<.0001).
Model R2 was 0.273 and c-statistic 0.80 [95% CI: 0.78-0.82; P<.0001]. At the median
predicted risk of cycle 1 NC of 11%, model test performance consisted of: sensitivity
84%; specificity 57% and diagnostic odds ratio (DOR) 7.2 while cycle 1 NC risk was
31% and 6% among high risk and low risk half, respectively. The model performed well
in the smaller validation dataset with a model R2 of 0.354 and c-statistic of 0.84 [95% CI: 0.81-0.87, P<.0001]. Test performance of the model in the validation sample included:
sensitivity 90%; specificity 62%; DOR 14.1 and risks of 35% and 4% in high risk and
low risk patients, respectively. Conclusions: Validation in a randomly selected patient
sample suggests that this model has general applicability in identifying patients at
increased risk for NC. Further validation in other independent cancer patient populations
receiving chemotherapy is planned.
6. Economic analysis of prophylactic granulocyte colony-stimulating factor (G-CSF)
use based on a risk model for neutropenic complications in breast cancer patients
receiving adjuvant chemotherapy.
D. C. Dale, L. E. Cosler, D. A. Wolff, E. Culakova, M. S. Poniewierski, J. Crawford, G.
H. Lyman for the ANC Study Group
2006 ASCO Annual Meeting
Category: Health Services Research Sub-category: Outcomes Research
Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I.
Vol 24, No. 18S (June 20 Supplement), 2006: Abstract No: 6107
Although recent economic analyses of prophylactic G-CSF provide cost saving febrile
neutropenia (FN) risk estimates of approximately 20%, many regimens have reported
rates <20%. A prospective nationwide cohort study was undertaken to develop risk
models for neutropenic complications (NC) including severe and febrile neutropenia in
patients receiving cancer chemotherapy (Lyman ASCO 2005). A cost-effectiveness
model is presented to evaluate the economic impact of G-CSF prophylaxis based on the
model. Methods: Data on 974 consecutive breast cancer patients receiving adjuvant
chemotherapy at 115 randomly selected practice sites were analyzed. The clinical and
cost impact of G-CSF prophylaxis in high-risk patients based on the model was compared
with: 1) no G-CSF; 2) primary prophylaxis; and 3) secondary prophylaxis. Pegfilgrastim
costs were based on Medicare pricing while hospitalization costs and mortality on
national hospitalization data. Results: Independent predictors of first cycle NC included:
type and schedule of chemotherapy, diabetes, elevated bilirubin, planned RDI >85%, low
glomerular filtration rate and low neutrophil count. Prophylactic G-CSF was associated
with a decreased risk. Model R2=0.327 and c-statistic=0.80 [95% CI: 0.78-0.83; P<.001].
At a baseline FN risk of 8.4% per cycle, the expected costs over four cycles of
chemotherapy were: no pegfilgrastim: ,285; primary prophylaxis: ,573; secondary
prophylaxis: ,040 and model-targeted G-CSF: ,527. Expected cost varied with FN
risk and model performance. Primary prophylaxis was associated with lower cost than no
prophylaxis at FN risk >18%, while the model outperformed both strategies at an FN risk
>10%. At a baseline cycle risk of FN of 8.4%, model-guided G-CSF was associated with
an expected cost of ,980 per life saved. Cost savings increased as model
discrimination increased. The model was consistently associated with lower cost
compared to secondary prophylaxis. Conclusions: A risk model for NC has been
developed in breast cancer patients receiving adjuvant chemotherapy. Use of the model to
guide G-CSF support appears to be cost-effective at an overall FN risk of 10%.
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