Anaya Daniel A, Dogra Prashant, Wang Zhihui, Haider Mintallah, Ehab Jasmina, Jeong Daniel K, Ghayouri Masoumeh, Lauwers Gregory Y, Thomas Kerry, Kim Richard, Butner Joseph D, Nizzero Sara, Ramírez Javier Ruiz, Plodinec Marija, Sidman Richard L, Cavenee Webster K, Pasqualini Renata, Arap Wadih, Fleming Jason B, Cristini Vittorio
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA.
Cancers (Basel). 2021 Jan 25;13(3):444. doi: 10.3390/cancers13030444.
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 ( < 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.
化疗仍然是转移性癌症的主要治疗方法，肿瘤反应是衡量治疗效果的基准指标。然而，由于从体循环到实体瘤的药物递送存在异质性，癌症的治疗反应难以预测。在这项概念验证研究中，我们通过应用数学模型评估了肿瘤部位的化疗浓度及其与治疗反应的关联。通过使用治疗前成像、临床和生物学变量以及化疗方案来构建模型，我们估计了接受根治性肝切除术前治疗的结直肠癌肝转移患者肿瘤部位的化疗浓度。相对于模型预测的全身和肿瘤部位化疗浓度，我们检查了切除标本中用金标准肿瘤消退分级（TRG；从1级完全缓解到5级无反应）测量的治疗差异反应。我们发现，在表现出不同TRG的患者中，细胞毒性药物的平均计算血浆浓度基本相当，而估计的肿瘤部位化疗浓度（eTSCC）从TRG = 1到TRG = 5呈二次下降（<0.001）。eTSCC显著低于观察到的血浆浓度，在完全缓解（TRG = 1）和无反应（TRG = 5）的患者之间下降了约5倍，而血浆浓度在各TRG组中保持稳定。TRG的变化由肿瘤灌注和eTSCC的差异驱动并可由其预测。如果在精心设计的前瞻性研究中得到证实，这些发现将成为潜在可治愈的结直肠癌和肝转移患者护理模式转变的基础。
