Variants of carboxylesterase 1 have no impact on capecitabine pharmacokinetics and toxicity in capecitabine plus oxaliplatin treated-colorectal cancer patients.

PURPOSE: Capecitabine is a prodrug that undergoes metabolism in three steps to form an active 5-fluorouracil (5-FU). The first step is primarily catalyzed by liver carboxylesterases (CES) 1. Here, we examined the effects of CES1 variants on pharmacokinetics and toxicity of capecitabine. METHODS: We enrolled postoperative colorectal cancer (CRC) patients administered with adjuvant capecitabine plus oxaliplatin (CapeOX) and metastatic CRC patients receiving CapeOX. The pharmacokinetic analysis of the first capecitabine dose (1000 mg/m2) was done on day 1, and oxaliplatin administration was shifted to day 2. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (5'-DFUR), and 5-FU were analyzed by high-performance liquid chromatography. CES1 polymorphisms (rs3217164, rs2244614, rs2244613, rs7187684, and rs11861118) and the functional CES1 genes (1A1, var1A1, 1A2, and pseudo 1A3) in their diplotype configurations were analyzed by direct sequencing. RESULTS: Thirty-seven patients were enrolled from September 2017 to February 2020. Patients with a higher area under the plasma concentration-time curve to capecitabine dose ratio (AUC/dose) of 5'-DFUR than its mean showed a higher frequency of overall ≥ grade 3 toxicity and lower relative dose intensity (RDI) of capecitabine than those with a lower ratio. Higher CES1 activity expressed as a metabolic ratio (AUC of capecitabine/sum of three AUCs of each metabolite) lower than its mean was associated with higher 5'-DFUR AUC/dose and lower RDI, indicating essential roles of CES1 in capecitabine activation to produce 5'-DFUR. However, the association between CES1 variants and capecitabine pharmacokinetics and toxicity was not significant. CONCLUSION: CES1 variants are not associated with capecitabine pharmacokinetics and toxicity.

VEGF Inhibitors Do Not Increase D-dimer Levels in Colorectal Cancer Patients Without Venous Thromboembolism: A Retrospective Non-inferiority Analysis

BACKGROUND/AIM: If VEGF inhibitors contribute to an increase in D-dimer levels, they may adversely affect the diagnosis of venous thromboembolism (VTE). Consequently, this retrospective study examined the effects of VEGF inhibitors on D-dimer levels in colorectal cancer patients. PATIENTS AND METHODS: A total of 104 colorectal cancer patients who received chemotherapy, were included in this study. To perform D-dimer analysis, patients were divided into two analysis targets: patients with VTE and without VTE. Statistical analysis included a natural logarithmic transformation of D-dimer data. RESULTS: In the D-dimer analysis of non-VTE patients, the natural logarithm D-dimer mean difference was -0.186, with a 95% CI of -0.525 to 0.154. The upper limit of the 95%CI (0.154) did not exceed the non-inferiority margin (Δ) of 0.199, and therefore met the non-inferiority criteria. CONCLUSION: VEGF inhibitors don't contribute to increased D-dimer levels in colorectal cancer patients without VTE.

Two cases of lymphangitic carcinomatosis as the primary symptom of colorectal carcinoma that achieved complete remission using combination anti-EGFR antibody therapy.

Clinicians often encounter cases of pulmonary lymphangitic carcinomatosis when treating patients with cancer. When such a condition develops before the diagnosis of cancer, its diagnosis is often challenging. Herein, we report about two patients with colorectal carcinoma diagnosed after the identification of lymphangitic carcinomatosis, which achieved complete remission with combination anti-epidermal growth factor receptor (anti-EGFR) antibody therapy. In case 1, a 74-year-old woman presented with cough and dyspnea that had persisted for 1 month. She had unresectable advanced carcinoma of the sigmoid colon with lymphangitic carcinomatosis. Her respiratory status gradually deteriorated due to the disease. Thus, FOLFIRI plus cetuximab therapy was initiated. Her dyspnea rapidly resolved with the treatment, and complete remission of lymphangitic carcinomatosis was achieved. In case 2, a 46-year-old man presented with fever and dyspnea that had persisted for 1 month. He had unresectable advanced carcinoma of the transverse colon with lymphangitic carcinomatosis. FOLFOXIRI therapy was then initiated. However, his respiratory status did not improve. Therefore, his treatment was immediately switched to FOLFIRI plus panitumumab. His dyspnea rapidly resolved with the treatment, and complete remission of lymphangitic carcinomatosis was achieved. In oncologic emergencies, such as lymphangitic carcinomatosis, requiring an early response to treatment, the administration of anti-EGFR antibodies may be a highly effective treatment option.

Early tumor shrinkage as a predictor of favorable outcomes in patients with advanced pancreatic cancer treated with FOLFIRINOX.

There are several reports on the correlation between early tumor shrinkage (ETS) or depth of response (DpR) and survival in chemotherapies for colorectal cancer; however, few studies have investigated it in pancreatic cancer. We therefore investigated whether the ETS will predict outcomes in 59 patients with advanced pancreatic cancer treated with FOLFIRINOX therapy. The association of ETS with progression-free survival (PFS) and overall survival (OS) was evaluated but also we addressed to the correlation between outcomes and DpR. ETS was defined as a reduction ≥ 20% of target lesions' diameters measured at 6 to 8 weeks from treatment start. DpR was percentage of maximal tumor shrinkage observed at the nadir diameter compared with baseline. Among 47 evaluable patients for the ETS, 12 (25.5%) patients experienced ETS. The ETS was significantly associated with better PFS (9.0 vs. 4.2 months) as well as OS (24.0 vs. 9.1 months); moreover, the association had a statistically significance for PFS but a strong trend for OS in multivariate analysis. The DpR was statistically significantly but weakly associated with OS. In conclusion, this is the first report that the early response to chemotherapy may predict favorable outcomes in patients with advanced pancreatic cancer treated with FOLFIRINOX therapy.

Acute appendicitis with a neuroendocrine tumor G1 (carcinoid): pitfalls of conservative treatment.

A man in his early thirties presented to our clinic with right lower abdominal pain. Computed tomography (CT) and ultrasonography (US) revealed a swollen appendix and an appendicolith. Abscess formation was not observed but ongoing appendiceal rupture was not ruled out. Three months after successful conservative therapy, the lumen of the apical portion was kept dilated and laparoscopic interval appendectomy was performed. No tumorous findings were observed macroscopically. However, histology revealed many tiny nests infiltrating the submucosa, muscular layer, and subserosa at the root of the appendix. An appendiceal neuroendocrine tumor G1 (NET G1; carcinoid) was diagnosed immunohistologically. Neither CT nor US visualized the tumor because of its non-tumor-forming but infiltrative growth. In conclusion, after successful conservative treatment, interval appendectomy should be considered to uncover a possible appendiceal NET G1 (carcinoid), particularly when dilatation of the distal lumen is kept under observation.