Nomogram to predict cycle-one serious drug-related toxicity in phase I oncology trials

Abstract

Purpose: All patients in phase I trials do not have equivalent susceptibility to serious drug-related toxicity (SDRT). Our goal was to develop a nomogram to predict the risk of cycle-one SDRT to better select appropriate patients for phase I trials.

Patients and methods: The prospectively maintained database of patients with solid tumor enrolled onto Cancer Therapeutics Evaluation Program-sponsored phase I trials activated between 2000 and 2010 was used. SDRT was defined as a grade ≥ 4 hematologic or grade ≥ 3 nonhematologic toxicity attributed, at least possibly, to study drug(s). Logistic regression was used to test the association of candidate factors to cycle-one SDRT. A final model, or nomogram, was chosen based on both clinical and statistical significance and validated internally using a bootstrapping technique and externally in an independent data set.

Results: Data from 3,104 patients enrolled onto 127 trials were analyzed to build the nomogram. In a model with multiple covariates, Eastern Cooperative Oncology Group performance status, WBC count, creatinine clearance, albumin, AST, number of study drugs, biologic study drug (yes v no), and dose (relative to maximum administered) were significant predictors of cycle-one SDRT. All significant factors except dose were included in the final nomogram. The model was validated both internally (bootstrap-adjusted concordance index, 0.60) and externally (concordance index, 0.64).

Conclusion: This nomogram can be used to accurately predict a patient's risk for SDRT at the time of enrollment. Excluding patients at high risk for SDRT should improve the safety and efficiency of phase I trials.

Fig 1.

Nomogram for predicting cycle-one serious drug-related toxicity (SDRT) in phase I trials. To calculate probability of SDRT, first determine value for each factor by drawing vertical line from that factor to points scale. Then sum all individual values and draw vertical line from total points scale to risk of SDRT. An electronic tool for calculating risk of SDRT using this nomogram is available online. ECOG, Eastern Cooperative Oncology Group.

Fig 2.

Nomogram model calibration curves. Gold line represents ideal fit, where nomogram-predicted probability (x-axis) matches observed probability (y-axis). Dashed blue line represents unadjusted calibration accuracy in derivation set and is estimated using LOWESS smoother, relating predicted probabilities to observed binary outcomes. Dashed gray line represents adjusted (bootstrap-corrected) calibration accuracy of derivation set.

Fig A1.

Distribution of model-estimated risk. Histogram of model-estimated risk of cycle-one serious drug-related toxicity in derivation cohort. Line represents proportion of patients with estimated risk at or below given risk (x-axis).