Tumor growth rate is an early indicator of antitumor drug activity in phase I clinical trials

Abstract

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) evaluation does not take into account the pretreatment tumor kinetics and may provide incomplete information about experimental drug activity. Tumor growth rate (TGR) allows for a dynamic and quantitative assessment of the tumor kinetics. How TGR varies along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown.

Experimental design: Medical records from all patients (N = 253) prospectively treated in 20 phase I trials were analyzed. TGR was computed during the pretreatment period (reference) and the experimental period. Associations between TGR, standard prognostic scores [Royal Marsden Hospital (RMH) score], and outcome [progression-free survival (PFS) and overall survival (OS)] were computed (multivariate analysis).

Results: We observed a reduction of TGR between the reference versus experimental periods (38% vs. 4.4%; P < 0.00001). Although most patients were classified as stable disease (65%) or progressive disease (25%) by RECIST at the first evaluation, 82% and 65% of them exhibited a decrease in TGR, respectively. In a multivariate analysis, only the decrease of TGR was associated with PFS (P = 0.004), whereas the RMH score was the only variable associated with OS (P = 0.0008). Only the investigated regimens delivered were associated with a decrease of TGR (P < 0.00001, multivariate analysis). Computing TGR profiles across different clinical trials reveals specific patterns of antitumor activity.

Conclusions: Exploring TGR in phase I patients is simple and provides clinically relevant information: (i) an early and subtle assessment of signs of antitumor activity; (ii) independent association with PFS; and (iii) it reveals drug-specific profiles, suggesting potential utility for guiding the further development of the investigational drugs.

Figure 1

Distribution of TGR across the REFENCE and the EXPERIMENTAL periods.

Figure 2

Pairwise comparisons of TGR between the REFERENCE and THE EXPERIMENTAL periods in 201 patients treated in 20 phase I clinical trials (P values are computed from wilcoxon pairwise tests, n represent the number of samples with pairwise TGR information). Red, grey and green colors indicate progressive disease, stable disease and partial response as per RECIST criteria, respectively.

Figure 3

TGR profiling reveals specific patterns of antitumor activity across twelve phase 1 clinical trials (P values are computed from wilcoxon pairwise tests; n represent the number of samples with pairwise TGR information; only clinical trials with more than 7 patients were analyzed). Red, grey and green colors indicate progressive disease, stable disease and partial response as per RECIST criteria, respectively.