Abstract Purpose: Mathematical models combined with new imaging technologies could improve clinical oncology studies. To improve detection of therapeutic effect in patients with cancer, we assessed volumetric measurement of target lesions to estimate the rates of exponential tumor growth and regression as treatment is administered. Experimental Design: Two completed phase III trials were studied (988 patients) of aflibercept or panitumumab added to standard chemotherapy for advanced colorectal cancer. Retrospectively, radiologists performed semiautomated measurements of all metastatic lesions on CT images. Using exponential growth modeling, tumor regression (d) and growth (g) rates were estimated for each patient's unidimensional and volumetric measurements. Results: Exponential growth modeling of volumetric measurements detected different empiric mechanisms of effect for each drug: panitumumab marginally augmented the decay rate [tumor half-life; d [IQR]: 36.5 days (56.3, 29.0)] of chemotherapy [d: 44.5 days (67.2, 32.1), two-sided Wilcoxon P = 0.016], whereas aflibercept more significantly slowed the growth rate [doubling time; g = 300.8 days (154.0, 572.3)] compared with chemotherapy alone [g = 155.9 days (82.2, 347.0), P ≤ 0.0001]. An association of g with overall survival (OS) was observed. Simulating clinical trials using volumetric or unidimensional tumor measurements, fewer patients were required to detect a treatment effect using a volumetric measurement-based strategy (32–60 patients) than for unidimensional measurement-based strategies (124–184 patients). Conclusions: Combined tumor volume measurement and estimation of tumor regression and growth rate has potential to enhance assessment of treatment effects in clinical studies of colorectal cancer that would not be achieved with conventional, RECIST-based unidimensional measurements.