The validation sample included 153 chemotherapy-naive patients with stage I, II, IIIa, or IIIb breast cancer who had been treated with adjuvant chemotherapy during 1986–92 as part of the MD Anderson Cancer Center (MDACC) 86–12 trial. Patients aged more than 75 years, those with inflammatory breast cancer, those with a previous history of contralateral breast cancer with higher stage of disease, and those with second primary other than basal cell carcinoma of skin or in situ carcinoma of cervix were excluded from the original MDACC 86–12 study.
Of the 153 patients participating in the trial, 10 were excluded from analysis. Four patients had no complete blood cell count data recorded, three had incomplete chemotherapy delivery information, and three had received filgrastim. Results are reported for the remaining 143 patients. Therefore, as in the study by Silber and colleagues , this validation sample describes the natural history of neutropenia.
Primary surgical treatment consisted of a modified radical mastectomy or segmental mastectomy. If indicated, the patient was treated with preoperative or postoperative local radiotherapy. All patients were treated with the FAC (fluorouracil, doxorubicin, cyclophosphamide) regimen that consisted of 50 mg/m2 doxorubicin given as a continuous infusion over 72 hours starting on day 1, 500 mg/m2 cyclophosphamide intravenously on day 1, and 500 mg/m2 fluorouracil intravenously on days 1 and 4. Treatment was given every 3 or 4 weeks for a total of six cycles. Complete blood counts with differential counts were usually obtained on days 1, 8, and 15 of each cycle. Chemotherapy was usually delayed if the ANC was less than 1.5 × 109/liter on the planned first day of the cycle. Dose delays were usually for 1 week. The chemotherapy dose was reduced if, on the previous cycle, the nadir ANC was less than 0.5 × 109/liter or if the patient experienced an episode of febrile neutropenia, defined as an ANC of less than 1.0 × 109/liter with a temperature of more than 100.6°F. Dose reductions usually consisted of a 20% reduction in dosage of all chemotherapy drugs.
A neutropenia-related event was defined similarly to that in the study by Silber and colleagues : a nadir ANC of 0.5 × 109/liter or less, a neutropenia-related dose reduction of 15% or more of the planned dose of any agent, a neutropenia-related dose delay of 7 days or more, or a febrile–neutropenic episode. Delays and reductions were related to neutropenia, and the reasons for the dose modifications were documented. A response group for the risk model consists of all patients who experienced at least one neutropenia-related event after the first cycle of chemotherapy. The ANC cutoff point to define an event was 0.5 × 109/liter, rather than 0.25 × 109/liter used in the Silber model to accommodate the physician practice style associated with patients in the validation sample.
The originally estimated Silber risk model was cross-validated with the MDACC sample. We used the same definitions as in the original model for the predictor variables. The distribution of these predictor variables was compared across the original Silber and validation MDACC study samples. The outcome variable in the validation sample differs in that an ANC cutoff point of 0.5 × 109/liter is used in the compound outcome definition. Given this difference in ANC cutoff point and the difference in chemotherapy regimens used in the two samples, the absolute predicted probabilities of events resulting from the cross-validation might not be interpretable, but their relative magnitude (or ranking of patients by predicted probability of an event) is valid. To assess the cross-validation results, we divided the patients into predicted positive and predicted negative groups by using varying probability cut points. This process is equivalent to ranking the patients by their predicted event probability and dividing the ranked list in all possible ways, declaring the higher-ranked patients predicted positive and the lower-ranked patients predicted negative.
The sensitivity and specificity of each possible resulting classification are summarized in a receiver-operating-characteristic curve plot. The C-statistic (area under the receiver-operating-characteristic curve) , which summarized the sensitivity and specificity across the entire (0 to 1) range of probability cut points, is reported together with the sensitivity and specificity rates for the optimal classification table. This validation process does not address the effect of concurrent radiotherapy because none of the patients in the validation sample were treated with this modality. As a result, the indicator variable for concurrent radiotherapy present in the original model is set to 0, effectively applying the model to patients with no concurrent radiotherapy.
For the model-specification test, the same variables used to predict neutropenic complications in the Silber model were fitted with a logistic regression to our data and the significance was reported. Furthermore, we explored other potential predictors to examine whether new significant risk factors would emerge. The discrimination and calibration of the model fitted to our data and original models were compared by using the C-statistic and the Hosmer–Lemeshow statistic . The receiver-operating-characteristic curves for the two models were plotted and compared. The magnitudes of the risk factors' effects were compared across the validation and original models. Regression coefficient differences were tested with an asymptotic normal test and the estimated probability of event curves derived from the original and validation models were plotted for comparison. Finally, we assessed the importance of first-cycle nadir ANC as a predictor of subsequent episodes of febrile neutropenia and of reduced dose intensity (not more than 85% of planned dose intensity) by comparing the proportion of observed events in patients grouped by first-cycle nadir ANC ranges. Statistical analyses were performed by using SAS 8.00 for Windows (SAS Institute Inc, Cary, NC). All reported P values are two-sided.