Comparison of UGT1A1 Polymorphism as Guidance of Irinotecan Dose Escalation in RAS Wild-Type Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab Plus FOLFIRI as the First-Line Therapy

Abstract

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORR), disease control rates (DCR), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.0–32.5 months), no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months versus 14.0 months; 95% confidence interval (CI), 0.517– 1.027; hazard ratio (HR), 0.729; P = 0.071], OS (40.0 months versus 30.0 months; 95% CI, 0.410–1.008; HR, 0.643; P = 0.054), ORR (65.3% versus 62.7%; P = 0.720), DCR (92.8% versus 86.7%; P = 0.175), metastatectomy (36.7% versus 29.3%; P = 0.307), and SAEs (P = 0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all P > 0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.

Effects of the number of neoadjuvant therapy cycles on clinical outcomes, safety, and survival in patients with metastatic colorectal cancer undergoing metastasectomy

“…Neoadjuvant chemotherapy/targeted therapy is already being practiced in many institutions in patients with CRC undergoing metastasectomy, although the principle of the cycles of chemotherapy/targeted therapy has not yet been formally validated [9]. In recent years, a multidisciplinary treatment approach, including neoadjuvant chemotherapy and targeted therapy, has emerged for mCRC, resulting in increased curability and improved survival [6,11,12,15]. We determined the effects of increasing the number of cycles of neoadjuvant chemotherapy/targeted therapy on survival and clinical outcomes of patients with mCRC undergoing major metastasectomy.…”

“…PFS was defined as the interval between the start of neoadjuvant chemotherapy/targeted therapy and the first record of progression, regardless of the patient's treatment status or final follow-up. OS was defined as the interval from the beginning of neoadjuvant chemotherapy/targeted therapy to the date of death or last visit [11,19]. Adverse events were monitored and graded in each cycle according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCT-CTCAE) Version 4.3 (https://ctep.cancer.gov/ protocoldevelopment/electronic_applications/ctc.htm).…”

“…The only potentially curative treatment is complete resection of metastatic lesions, but the outcomes remain poor. Accordingly, multimodality treatment approaches, including adjuvant or neoadjuvant chemotherapy, are implemented to improve outcomes and survival [8][9][10][11]. Some studies revealed the mCRC patients who received primary tumor resection and targeted therapy combination chemotherapy had better clinical outcomes than patients who did not receive primary tumor resection [12][13][14].…”

Gut microbiota composition in chemotherapy and targeted therapy of patients with metastatic colorectal cancer

“…State-of-the-art therapies for mCRC have been widely researched to improve treatment outcomes (13). The human gut microbiota plays a crucial role in human health and CRC treatment (14)(15)(16).…”

MicroRNA-148a induces apoptosis and prevents angiogenesis with bevacizumab in colon cancer through direct inhibition of ROCK1/c-Met via HIF-1α under hypoxia

“…The more progressive screening techniques and treatment modalities were used to decline the mortality rate of CRC. The metastatic colorectal cancer (mCRC) patients are used with various combinations of chemotherapeutic drugs and biologics, including vascular endothelial growth factors inhibitors (VEGF inhibitors; e.g., bevacizumab) and epidermal growth factor receptors inhibitors (EGFR inhibitors; e.g., cetuximab) [ 4 ]. The current standard treatment improves outcomes in most patients with mCRC but fails to provide prominent benefits in a notable proportion of individuals who experience drug-associated toxicities.…”