Abstract
Simple SummaryIt is known that drug transport barriers in the tumor determine drug concentration at the tumor site, causing disparity from the systemic (plasma) drug concentration. However, current clinical standard of care still bases dosage and treatment optimization on the systemic concentration of drugs. Here, we present a proof of concept observational cohort study to accurately estimate drug concentration at the tumor site from mathematical modeling using biologic, clinical, and imaging/perfusion data, and correlate it with outcome in colorectal cancer liver metastases. We demonstrate that drug concentration at the tumor site, not in systemic circulation, can be used as a credible biomarker for predicting chemotherapy outcome, and thus our mathematical modeling approach can be applied prospectively in the clinic to personalize treatment design to optimize outcome.Chemotherapy remains a primary treatment for metastatic cancer, with tumor response being the benchmark outcome marker. However, therapeutic response in cancer is unpredictable due to heterogeneity in drug delivery from systemic circulation to solid tumors. In this proof-of-concept study, we evaluated chemotherapy concentration at the tumor-site and its association with therapy response by applying a mathematical model. By using pre-treatment imaging, clinical and biologic variables, and chemotherapy regimen to inform the model, we estimated tumor-site chemotherapy concentration in patients with colorectal cancer liver metastases, who received treatment prior to surgical hepatic resection with curative-intent. The differential response to therapy in resected specimens, measured with the gold-standard Tumor Regression Grade (TRG; from 1, complete response to 5, no response) was examined, relative to the model predicted systemic and tumor-site chemotherapy concentrations. We found that the average calculated plasma concentration of the cytotoxic drug was essentially equivalent across patients exhibiting different TRGs, while the estimated tumor-site chemotherapeutic concentration (eTSCC) showed a quadratic decline from TRG = 1 to TRG = 5 (p < 0.001). The eTSCC was significantly lower than the observed plasma concentration and dropped by a factor of ~5 between patients with complete response (TRG = 1) and those with no response (TRG = 5), while the plasma concentration remained stable across TRG groups. TRG variations were driven and predicted by differences in tumor perfusion and eTSCC. If confirmed in carefully planned prospective studies, these findings will form the basis of a paradigm shift in the care of patients with potentially curable colorectal cancer and liver metastases.
Highlights
Systemic cytotoxic chemotherapy is still the primary treatment for many cancer patients with solid tumors who present with de novo metastatic disease
With a validated tissue perfusion model and incorporating relevant treatment and tumor-related variables, here we report the development of a mathematical model to estimate chemotherapy drug concentration at the tumor-site, and its association with response to treatment
We examined the estimated tumor-site chemotherapeutic concentration (eTSCC) and response to therapy in a cohort of patients with colorectal cancer liver metastases treated with standard preoperative chemotherapy regimens prior to curative-intent surgery
Summary
Systemic cytotoxic chemotherapy is still the primary treatment for many cancer patients with solid tumors who present with de novo metastatic disease. There is substantial heterogeneity in the overall response to treatment within and across cancer types, suggesting a puzzling differential chemotherapy effect even among patients with apparently similar clinical features of the disease [8,9,10,11]. Such variability in response to chemotherapy in patients remains poorly understood. Previous works have reported on the heterogeneity of chemotherapy delivery to tumor cells as a plausible explanation for the observed differences in response to chemotherapy
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