Study setting and source population
Data for this study were obtained from a large combined retrospective/prospective observational evaluation of supportive care among NHL patients receiving CHOP-14 or CHOP-21 chemotherapy in geographically diverse centers primarily across Western and Southern Europe (97% of patients) and in Australia (3% of patients). The design of this study, termed the “IMPACT NHL Study” (ClinicalTrials.gov: NCT00903812), is described in detail elsewhere in the literature [10
]. In countries where it was required, ethical approval of the IMPACT NHL Study was obtained and patients provided written informed consent.
Briefly, approximately 1800 adult patients with NHL who were planned to receive at least three cycles of CHOP-14 or CHOP-21 chemotherapy--with or without rituximab--were recruited (about 600 retrospectively, 1200 prospectively) from 128 geographically diverse study centers. Study patients may have received a prior course of chemotherapy (~9% of study population). Patients enrolled retrospectively included those who completed all cycles of chemotherapy--regardless of actual number of cycles or outcomes thereof--after January 1, 2005 and prior to site participation in the study. Patients enrolled prospectively included all patients for whom CHOP-14 or CHOP-21 chemotherapy was planned for administration between January 2006 and December 2008; no additional interventions were required as a result of participation in the study. All patients enrolled in the IMPACT NHL Study (n
1,864) who met protocol-defined eligibility criteria and received at least one cycle of chemotherapy (n
1,829) were included in the source population for the current analysis.
For each patient, baseline data were collected on patient demographics (e.g., age, sex, race, height, weight), medical history (e.g., comorbid conditions), Eastern Cooperative Oncology Group Performance Status (ECOG PS), cancer characteristics (e.g., bulky disease, bone marrow involvement), International Prognostic Index (IPI) score (non-follicular patients only)/Follicular Lymphoma International Prognostic Index (FLIPI) score (follicular patients only), prior antineoplastic therapy, planned chemotherapy (i.e., CHOP-14 or CHOP-21, with or without rituximab [“-R”], doses, number of cycles), and predicted risk of FN (i.e., <20% vs ≥20%). Cycle-specific data collected during the chemotherapy course included actual chemotherapy regimen (i.e., drug, dose, date of administration), use of selected drugs/services (e.g., granulocyte colony-stimulating factor [G-CSF] for prophylaxis [primary or secondary] or treatment, erythropoiesis-stimulating agent [ESA], transfusions, anti-infective agents), performance status, and occurrence of FN--as well as selected other adverse outcomes--and associated setting of care (i.e., hospital, outpatient setting, home). Hospitalizations for reasons other than FN were also captured.
The study population, consisting of patients who experienced FN and matched comparison patients, was selected from the source population as follows. For each patient in the source population, all chemotherapy cycles in which FN occurred were identified. FN was defined as a single oral temperature of ≥38.30C or a temperature of ≥38.0°C for ≥1 hour, and a neutrophil count of <0.5 x 109/L or a neutrophil count of <1.0 x 109/L that is predicted to fall below 0.5 x 109/L. Patients with FN in more than one cycle were classified according to the cycle number in which FN first occurred.
Patients in the source population who developed FN during their first cycle of chemotherapy (“FN patients”) were matched on selected covariates--hypothesized to be possibly associated with FN and healthcare costs--to patients who did not develop FN during their first cycle of chemotherapy (“comparison patients”), whether or not they developed FN in any subsequent cycles. Matched cycle-one FN patients and comparison patients were then removed from their respective pools. From remaining patients in the source population (i.e., those not previously matched), those who first developed FN in their second cycle of chemotherapy were matched to those who did not develop FN in that cycle. Matched cycle-two FN patients and comparison patients were then removed from their respective pools. FN patients and comparison patients were similarly matched in the third and all subsequent cycles. The cycle in which patients were matched was designated the “index cycle”.
Matching was implemented--sequentially, on a cycle-specific basis--for each FN patient by identifying all candidate comparison patients matching that FN patient in terms of age (±5 years), tumor stage, and chemotherapy regimen. The candidate with the closest propensity score (“nearest neighbor”) to the FN patient was selected as the matched comparison patient. Matching was conducted for FN patients randomly, and without replacement of comparison patients (i.e., comparison patients were matched to one FN patient only). Propensity scores were estimated using multivariate logistic regression; independent variables included all demographic and disease-specific characteristics (e.g., age, sex, IPI/FLIPI score, bone marrow involvement), predicted risk of FN, presence of (current/continuing) comorbidities, chemotherapy regimen, supportive care, ECOG PS, absolute neutrophil count (ANC), and presence of anemia symptoms (e.g., fatigue/tiredness, pallor/pale skin, headache, dyspnea). All of the above-listed variables--with the exception of ANC, presence of anemia symptoms, and supportive care--were characterised using data collected at baseline in the IMPACT NHL Study; the exceptions were characterised using data collected during the pre-index cycles and index cycle, as appropriate.
An alternative, more restrictive matching procedure--including age (±5 years), country of residence, tumor stage, bone marrow involvement, IPI/FLIPI score, and chemotherapy regimen when identifying candidate comparison patients--was first employed, but was ultimately deemed by study investigators to be inadequate due to small sample size (n
118). The characteristics of FN patients and comparison patients matched using this more restrictive procedure is described in Additional file 1
: Table S1 of the online supplement.
FN-related healthcare utilization was tallied for each FN patient and matched comparison patient from the cycle in which FN first occurred (for the former) through the last cycle of chemotherapy. Healthcare utilisation was examined in terms of: the number of FN events requiring inpatient care, outpatient care, home care, and other/unknown care, respectively; the total number of hospital days for all FN-related admissions that occurred from the index cycle through the end of the last chemotherapy cycle; and use--and reason for use--of G-CSF (pegfilgrastim, filgrastim, and other G-CSF [presumably lenograstim]) and IV antimicrobial agents by setting of care. Use of G-CSF and antimicrobial agents as prophylaxis was considered in post-index cycles only, while use of these agents as treatment was considered beginning with the index cycle.
FN-related healthcare costs were calculated for FN patients and comparison patients by combining estimates of FN-related healthcare utilization--as described above--with unit-cost data from the United Kingdom (UK). UK-specific unit costs were estimated from the perspective of the National Health Service using data from readily-available secondary sources and published literature, where available, as well as expert opinion, where needed. Principal sources of cost data were the 2009–2010 National Health Service (NHS) Schedule of Reference Costs (hospital costs), the 2010 Unit Costs of Health and Social Care Report from the Personal Social Services Research Unit (outpatient, home care, and other setting costs), and the British National Formulary (BNF), 60th Edition (pharmacotherapy costs) [14
]. Unit costs are set forth in Table ; a full description of methods employed to estimate unit costs is provided in Additional file 1
: Table S2 of the online supplement.
UK-specific unit costs of FN-related care
The adequacy of the matching procedure was evaluated based on the similarity of matched FN and comparison patients in terms of their baseline characteristics. Categorical variables were compared using the McNemar or Bowker test, and continuous variables were compared using the paired-samples t-test. The similarity of matched patients and unmatched patients--in terms of their characteristics--also was examined.
FN-related healthcare utilization and costs from the index cycle through the end of the last cycle of chemotherapy were examined on a cumulative basis for each patient in the FN and comparison groups. Mean values were estimated for the two groups, as well as for differences between groups, on an overall basis during the index cycle and during post-index cycles. Hospital days for FN patients and comparison patients with missing data on admission/discharge dates were imputed based on corresponding subgroup-specific mean values. FN-related healthcare costs also were evaluated among subgroups of patients defined on the basis of key characteristics, including index cycle, chemotherapy regimen, and predicted FN risk. Ninety-five percent confidence intervals (95% CIs) were generated using techniques of nonparametric bootstrapping.
The appropriateness of combining FN-related healthcare utilization data from different countries with unit cost information from the UK was evaluated based on a comparison of country-specific mean numbers of patients developing FN by setting of care, and for patients requiring inpatient care, country-specific mean numbers of hospital days. These analyses were based on data from FN patients and comparison patients who were matched on the basis of the criteria set forth above (i.e., age, tumor stage, chemotherapy regimen, and propensity score) as well as country of residence. Results were summarized using means and 95% CIs; formal statistical tests for heterogeneity between patients in different countries were not undertaken due to small country-specific sample sizes.