A Mathematical Model to Estimate Chemotherapy Concentration at the Tumor-Site and Predict Therapy Response in Colorectal Cancer Patients with Liver Metastases

Cancers

卷:13

Marija Plodinec¹  DanielK. Jeong²  GregoryY. Lauwers²  Kerry Thomas²  Masoumeh Ghayouri²  DanielA. Anaya³  Richard Kim³  Jasmina Ehab³  JasonB. Fleming³  Mintallah Haider³  RichardL. Sidman⁴  WebsterK. Cavenee⁵  Prashant Dogra⁶  Sara Nizzero⁶  Vittorio Cristini⁶  Zhihui Wang⁶  JavierRuiz Ramírez⁶  JosephD. Butner⁶  Renata Pasqualini⁷  Wadih Arap⁸ 

[1] Biozentrum and the Swiss Nanoscience Institute, University of Basel, 4001 Basel, Switzerland;

[2] Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;

[3] Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;

[4] Department of Neurology, Harvard Medical School, Boston, MA 02115, USA;

[5] Ludwig Institute for Cancer Research, University of California-San Diego, La Jolla, CA 92093, USA;

[6] Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA;

[7] Rutgers Cancer Institute of New Jersey & Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;

[8] Rutgers Cancer Institute of New Jersey & Division of Hematology/Oncology, Department of Medicine Rutgers New Jersey Medical School, Newark, NJ 07103, USA;

关键词: chemotherapy;    colorectal cancer;    FOLFOX;    liver metastases;    mathematical model;   

DOI  :  10.3390/cancers13030444

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown