Annals of Oncology Advance Access published June 10, 2014
1 History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in cancer patients not receiving G-CSF prophylaxis
C. Chao1, J. H. Page2, S-J. Yang1, R. Rodriguez3, J. Huynh4, V. M. Chia2 1
Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena,
USA Center for Observational Research, Amgen Inc., Thousand Oaks, USA
3
Department of Oncology, Los Angeles Medical Center, Kaiser Permanente Southern California,
Los Angeles, USA 4
Department of Hematology and Oncology, Harbor-UCLA Medical Center, Los Angeles, USA
Corresponding and Reprints author: Dr. Chun Chao, Department of Research and Evaluation, Kaiser Permanente Southern California, 100 S Los Robles Ave, 2nd Floor, Pasadena, 91101, USA, Tel: 1 626-564-3797, Email: [email protected]
Key Message: "This cohort study of 19,160 patients with six types of cancers found that chronic obstructive pulmonary disease, congestive heart failure, HIV infection, autoimmune disease, peptic ulcer disease, renal disease, thyroid disorder and bone marrow suppression prior to chemotherapy were associated with increased risk of chemotherapy induced febrile neutropenia. If confirmed, these comorbidities should be taken into consideration when making treatment decisions." Key words: febrile neutropenia, neutropenia, chemotherapy, toxicity, comorbidities, cancer
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Maastricht University on June 24, 2014
2
2 ABSTRACT Background: Chemotherapy-induced febrile neutropenia (FN) is a clinically important complication that impacts patient outcome by delaying chemotherapy doses or reducing dose intensity. Risk of FN depends on chemotherapy- and patient-level factors. We sought to determine the effects of chronic comorbidities on risk of FN. Design: We conducted a cohort study to examine the association between a variety of chronic
lymphoma and breast, colorectal, lung, ovary, and gastric cancer) from 2000-2009 who were treated with chemotherapy at Kaiser Permanente Southern California, a large managed care organization. We excluded those patients who received primary prophylactic granulocyte colony-stimulating factor. History of comorbidities and FN events were identified using electronic medical records. Cox models adjusting for propensity score, stratified by cancer type, were used to determine the association between comorbid conditions and FN. Models that additionally adjusted for cancer stage, baseline neutrophil count, chemotherapy regimen, and dose reduction were also evaluated. Results: A total of 19,160 patients with mean age of 60 years were included; 963 (5.0%) developed FN in the first chemotherapy cycle. Chronic obstructive pulmonary disease [HR=1.30 (1.07-1.57)], congestive heart failure [HR=1.43 (1.00-1.98)], HIV infection [HR=3.40 (1.905.63)], autoimmune disease [HR=2.01 (1.10-3.33)], peptic ulcer disease [HR=1.57 (1.05-2.26)], renal disease [HR=1.60 (1.21-2.09)], and thyroid disorder [HR=1.32 (1.06-1.64)] were all associated with a significantly increased FN risk. Conclusions: These results provide evidence that history of several chronic comorbidities increase risk of FN, which should be considered when managing patients during chemotherapy.
Downloaded from http://annonc.oxfordjournals.org/ at Maastricht University on June 24, 2014
comorbidities and risk of FN in patients diagnosed with six types of cancer (non-Hodgkin
3 INTRODUCTION Chemotherapy-induced febrile neutropenia (FN) is a clinically important complication that can impact patient treatment outcomes and often incur a significant health care cost.[1] Previous studies have found that prophylactic granulocyte colony-stimulating factor (G-CSF) was costeffective when used among patients at high risk for FN.[2] In the past decade, risk stratification for FN has progressed from a chemotherapy regimen-based algorithm to one that incorporates
influence the risk of FN. Specifically, a history of heart and renal disease has been linked to increased risk of FN in NHL patients.[4]_ENREF_10 However, there are limited data regarding the effects of other chronic comorbidities on the risk of FN or severe neutropenia. To understand the effects of chronic comorbidities on risk of chemotherapy-induced neutropenia, we conducted a retrospective cohort study of patients diagnosed with six types of cancer in Kaiser Permanente Southern California (KPSC) to examine the association between a wide variety of chronic comorbidities and the risk of neutropenia and FN in the first cycle of chemotherapy among patients who are not already receiving prophylactic G-CSF.
METHODS Study setting and population KPSC is an integrated managed care organization that provides comprehensive health services for 3.5 million racial/ethnically and socioeconomically diverse enrollees who are broadly representative of residents in southern California.[5] KPSC maintains a number of electronic clinical records for virtually all aspects of care delivered, including diagnoses in the form of ICD-9 codes, medical procedures, pharmacy dispensing, laboratory test results and disease
Downloaded from http://annonc.oxfordjournals.org/ at Maastricht University on June 24, 2014
patient characteristics.[3] A few studies have suggested that chronic comorbidities can also
4 registries, all linkable through a unique member identifier. Incident cancer cases were identified using KPSC’s Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry. KPSC’s cancer registry routinely collects information on age at diagnosis, sex, race/ethnicity, cancer histology, site, stage, and initial cancer treatment. The quality of the cancer registry data is assured by the SEER standard.
diagnosed with incident non-Hodgkin lymphoma (NHL), breast cancer, colorectal cancer, lung cancer, ovarian cancer or gastric cancer at KPSC between 2000 and 2009; (2) aged 18 years and older at cancer diagnosis; (3) received chemotherapy within 12 months of cancer diagnosis and (4) had at least 12 months of KPSC membership prior to cancer diagnosis (to ensure sufficient medical records exist to allow assessment of comorbidities of interest). Of those who met the inclusion criteria, we further excluded subjects who met the following criteria: (1) unknown cancer stage or for whom chemotherapy agents could not be identified; (2) received prophylactic G-CSF defined as use within 4 days after the first chemotherapy administration, including those on dose-dense chemotherapy regimens; (4) had bone marrow or stem cell transplantation (as identified by CPT 38204-38242); or (5) were patients of Orange County Medical Center if their cancer was diagnosed before 2007. This last criterion was used because laboratory data on absolute neutrophil count could not be readily extracted electronically for this medical center before 2007.
Downloaded from http://annonc.oxfordjournals.org/ at Maastricht University on June 24, 2014
The study cohort was composed of patients who met the following inclusion criteria: (1)
5 Exposure of interest The main exposure of interest in this study was the history of chronic comorbidities at the time of cancer diagnosis. Comorbidities of interest included diabetes mellitus, diabetes mellitus with end organ damage, hypertension, obesity, myocardial infarction, congestive heart failure (CHF), peripheral vascular disease, cerebrovascular disease, thromboembolic events, chronic obstructive pulmonary disease (COPD), previous cancer, liver disease (hepatitis, cirrhosis), renal failure,
osteoarthritis, connective tissue disease, HIV infection and acquired immunodeficiency syndrome (AIDS). We also considered a person’s total number of comorbidities (those listed above). A bone marrow suppression score (BMSS) was also created based on the presence of the following conditions at study baseline: anemia (1 point if prior diagnosis of anemia or hemoglobin
1 History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in cancer patients not receiving G-CSF prophylaxis
C. Chao1, J. H. Page2, S-J. Yang1, R. Rodriguez3, J. Huynh4, V. M. Chia2 1
Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena,
USA Center for Observational Research, Amgen Inc., Thousand Oaks, USA
3
Department of Oncology, Los Angeles Medical Center, Kaiser Permanente Southern California,
Los Angeles, USA 4
Department of Hematology and Oncology, Harbor-UCLA Medical Center, Los Angeles, USA
Corresponding and Reprints author: Dr. Chun Chao, Department of Research and Evaluation, Kaiser Permanente Southern California, 100 S Los Robles Ave, 2nd Floor, Pasadena, 91101, USA, Tel: 1 626-564-3797, Email: [email protected]
Key Message: "This cohort study of 19,160 patients with six types of cancers found that chronic obstructive pulmonary disease, congestive heart failure, HIV infection, autoimmune disease, peptic ulcer disease, renal disease, thyroid disorder and bone marrow suppression prior to chemotherapy were associated with increased risk of chemotherapy induced febrile neutropenia. If confirmed, these comorbidities should be taken into consideration when making treatment decisions." Key words: febrile neutropenia, neutropenia, chemotherapy, toxicity, comorbidities, cancer
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Maastricht University on June 24, 2014
2
2 ABSTRACT Background: Chemotherapy-induced febrile neutropenia (FN) is a clinically important complication that impacts patient outcome by delaying chemotherapy doses or reducing dose intensity. Risk of FN depends on chemotherapy- and patient-level factors. We sought to determine the effects of chronic comorbidities on risk of FN. Design: We conducted a cohort study to examine the association between a variety of chronic
lymphoma and breast, colorectal, lung, ovary, and gastric cancer) from 2000-2009 who were treated with chemotherapy at Kaiser Permanente Southern California, a large managed care organization. We excluded those patients who received primary prophylactic granulocyte colony-stimulating factor. History of comorbidities and FN events were identified using electronic medical records. Cox models adjusting for propensity score, stratified by cancer type, were used to determine the association between comorbid conditions and FN. Models that additionally adjusted for cancer stage, baseline neutrophil count, chemotherapy regimen, and dose reduction were also evaluated. Results: A total of 19,160 patients with mean age of 60 years were included; 963 (5.0%) developed FN in the first chemotherapy cycle. Chronic obstructive pulmonary disease [HR=1.30 (1.07-1.57)], congestive heart failure [HR=1.43 (1.00-1.98)], HIV infection [HR=3.40 (1.905.63)], autoimmune disease [HR=2.01 (1.10-3.33)], peptic ulcer disease [HR=1.57 (1.05-2.26)], renal disease [HR=1.60 (1.21-2.09)], and thyroid disorder [HR=1.32 (1.06-1.64)] were all associated with a significantly increased FN risk. Conclusions: These results provide evidence that history of several chronic comorbidities increase risk of FN, which should be considered when managing patients during chemotherapy.
Downloaded from http://annonc.oxfordjournals.org/ at Maastricht University on June 24, 2014
comorbidities and risk of FN in patients diagnosed with six types of cancer (non-Hodgkin
3 INTRODUCTION Chemotherapy-induced febrile neutropenia (FN) is a clinically important complication that can impact patient treatment outcomes and often incur a significant health care cost.[1] Previous studies have found that prophylactic granulocyte colony-stimulating factor (G-CSF) was costeffective when used among patients at high risk for FN.[2] In the past decade, risk stratification for FN has progressed from a chemotherapy regimen-based algorithm to one that incorporates
influence the risk of FN. Specifically, a history of heart and renal disease has been linked to increased risk of FN in NHL patients.[4]_ENREF_10 However, there are limited data regarding the effects of other chronic comorbidities on the risk of FN or severe neutropenia. To understand the effects of chronic comorbidities on risk of chemotherapy-induced neutropenia, we conducted a retrospective cohort study of patients diagnosed with six types of cancer in Kaiser Permanente Southern California (KPSC) to examine the association between a wide variety of chronic comorbidities and the risk of neutropenia and FN in the first cycle of chemotherapy among patients who are not already receiving prophylactic G-CSF.
METHODS Study setting and population KPSC is an integrated managed care organization that provides comprehensive health services for 3.5 million racial/ethnically and socioeconomically diverse enrollees who are broadly representative of residents in southern California.[5] KPSC maintains a number of electronic clinical records for virtually all aspects of care delivered, including diagnoses in the form of ICD-9 codes, medical procedures, pharmacy dispensing, laboratory test results and disease
Downloaded from http://annonc.oxfordjournals.org/ at Maastricht University on June 24, 2014
patient characteristics.[3] A few studies have suggested that chronic comorbidities can also
4 registries, all linkable through a unique member identifier. Incident cancer cases were identified using KPSC’s Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry. KPSC’s cancer registry routinely collects information on age at diagnosis, sex, race/ethnicity, cancer histology, site, stage, and initial cancer treatment. The quality of the cancer registry data is assured by the SEER standard.
diagnosed with incident non-Hodgkin lymphoma (NHL), breast cancer, colorectal cancer, lung cancer, ovarian cancer or gastric cancer at KPSC between 2000 and 2009; (2) aged 18 years and older at cancer diagnosis; (3) received chemotherapy within 12 months of cancer diagnosis and (4) had at least 12 months of KPSC membership prior to cancer diagnosis (to ensure sufficient medical records exist to allow assessment of comorbidities of interest). Of those who met the inclusion criteria, we further excluded subjects who met the following criteria: (1) unknown cancer stage or for whom chemotherapy agents could not be identified; (2) received prophylactic G-CSF defined as use within 4 days after the first chemotherapy administration, including those on dose-dense chemotherapy regimens; (4) had bone marrow or stem cell transplantation (as identified by CPT 38204-38242); or (5) were patients of Orange County Medical Center if their cancer was diagnosed before 2007. This last criterion was used because laboratory data on absolute neutrophil count could not be readily extracted electronically for this medical center before 2007.
Downloaded from http://annonc.oxfordjournals.org/ at Maastricht University on June 24, 2014
The study cohort was composed of patients who met the following inclusion criteria: (1)
5 Exposure of interest The main exposure of interest in this study was the history of chronic comorbidities at the time of cancer diagnosis. Comorbidities of interest included diabetes mellitus, diabetes mellitus with end organ damage, hypertension, obesity, myocardial infarction, congestive heart failure (CHF), peripheral vascular disease, cerebrovascular disease, thromboembolic events, chronic obstructive pulmonary disease (COPD), previous cancer, liver disease (hepatitis, cirrhosis), renal failure,
osteoarthritis, connective tissue disease, HIV infection and acquired immunodeficiency syndrome (AIDS). We also considered a person’s total number of comorbidities (those listed above). A bone marrow suppression score (BMSS) was also created based on the presence of the following conditions at study baseline: anemia (1 point if prior diagnosis of anemia or hemoglobin
