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Introduction: Regorafenib is a multi-kinase inhibitor approved for patients with metastatic colorectal cancer (mCRC) who were previously treated with standard therapies. A few reports showed the impact of KRAS mutation on therapeutic efficacy of regorafenib. Only one study reported poor prognoses for patients treated with regorafenib who had large amounts of circulating cell-free DNA (cfDNA). In the present study, we evaluated the impact of KRAS mutations in tissue or plasma and amounts of cfDNA on prognoses of mCRC patients treated with regorafenib. Method: This is a biomarker investigation of the RECC study, which evaluated efficacy of regorafenib dose-escalation therapy. Plasma samples were obtained just before initiation of treatment with regorafenib. KRAS mutations were evaluated using tissue and plasma samples. cfDNA was extracted from plasma samples and quantified. Results: Forty-five patients were enrolled in this biomarker study. Median progression-free survival (PFS) and overall survival (OS) of patients without KRAS mutations in tissues were 1.9 months (95% confidence interval [CI] 1.7–2.0) and 8.9 months (95% CI: 6.5–11.2), and those of patients with KRAS mutations were 1.4 months (95% CI: 1.3–1.5) and 6.8 months (95% CI: 5.0–8.5). Median PFS and OS of patients with plasma KRAS mutations were 1.9 months (95% CI: 1.8–1.9) and 7.0 months (95% CI: 5.3–8.7), respectively. Median PFS and OS of patients without plasma KRAS mutations were 1.7 months (95% CI: 1.1–2.3) and 8.9 months (95% CI: 6.7–11.2), respectively. Prior to administration of regorafenib, KRAS mutations were detected in 6 of 16 (37.5%) patients who had no tissue KRAS mutations. Median OS of patients with high cfDNA concentration (>median) was significantly poorer than that of patients with low cfDNA. Conclusion:KRAS mutations in the tissue or plasma have no impact on efficacy of regorafenib. KRAS emerging mutations were observed in quite a few patients. Large amounts of cfDNA may indicate poorer prognoses for patients receiving late-line regorafenib chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The detection of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) by liquid biopsy may have prognostic information. In this perioperative study, we evaluate if there is a relationship between mutant allele frequency (MAF) of Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor recurrence and how that could be useful in the early detection of recurrence. Methods: Among 304 cases of colorectal cancer surgery, ctDNA was sampled from the perioperative blood of 84 patients with CRC with KRAS mutation (exon 4 p.A146T, exon 4 p.A146V, exon 2 p.G12A, exon 2 p.G12C, exon 2 p.G12D, exon 2 p.G12S, exon 2 p.G12V, exon 2 p.G13D, exon 3 p.Q61H) and analyzed using the digital polymerase chain reaction system. The median observation period was 26 months. Results: Although the relationship between the perioperative MAF of KRAS and recurrence was not proved, tumor diameter, tumor depth, and stage were correlated with the preoperative MAF of KRAS (p = 0.034, p = 0.002, p = 0.008). However, tumor diameter, tumor depth, and stage did not correlate with MAF of KRAS at postoperative day 30. Conclusions: In this study, pathological tumor size, tumor depth, and stage were correlated with preoperative MAF of KRAS, but it was unreliable to predict recurrence by detection of ctDNA with KRAS mutation in the perioperative period of colorectal surgery. [ABSTRACT FROM AUTHOR]

Abstract Background The start of chemotherapy usually requires a delay of about 4 weeks after surgical resection of colorectal cancer. However, there is no evidence for the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. We therefore conducted a pilot study to determine the safety and feasibility of an early start of chemotherapy after the resection of colorectal cancer with distant metastases. Methods Five patients were enrolled. They received XELOX therapy (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1 to 14) on the 7th postoperative day and XELOX + bevacizumab (7.5 mg/kg of bevacizumab on day 1) after the 2nd cycle of chemotherapy. Results Five patients underwent open surgery. The procedures included right hemicolectomy in 1 patient, sigmoidectomy in 2 patients, high anterior resection in 1 patient, and Hartmann procedure in 1 patient. All patients started chemotherapy on postoperative day 7. The median number of cycles of chemotherapy was 11 (8 to 22). No postoperative complications were observed. The tumor reduction rate was 44.3% (32.0 to 66.6%). Progression-free survival was 10.3 months. Conclusions An early start of chemotherapy after surgery is feasible and safe. These findings suggest possible changes in the start time of chemotherapy after surgery in the future. We have already started a new phase II trial to confirm the effects of the early start of chemotherapy after surgery. Trial registration UMIN000004361.

The detection of circulating cell-free DNA (cfDNA) by liquid biopsy is reported to provide prognostic information in colorectal cancer (CRC). Although the frequency of BRAF V600E mutation in CRC is less than 10%, it is associated with poor responses to conventional chemotherapy. We conducted a prospective study to investigate the relationship between the perioperative mutant allele frequency (MAF) of BRAF V600E and tumor recurrence, and to evaluate the possibility of early detection of recurrence. Among 362 patients who underwent radical resection, cfDNA was extracted from the perioperative blood of 11 CRC patients with BRAF V600E mutation and analyzed using the digital polymerase chain reaction (dPCR) system. The median follow-up time was 22 months, and there were four cases of recurrence. Although there was no correlation between recurrence and the perioperative MAF of BRAF V600E, tumor diameter was correlated with the MAF (p = 0.024), and the MAF increased with time in two patients from whom additional samples were obtained prior to recurrence. In this study, we identified a correlation between the pathological tumor diameter and the MAF, but it was difficult to predict recurrence by measuring cfDNA with BRAF V600E mutation in the perioperative period of radical resection of CRC. [ABSTRACT FROM AUTHOR]

Background: TAS-102 improved the overall survival of metastatic colorectal cancer (CRC) patients with a median progression-free survival (PFS) in the RECOURSE trial. Subsequently, the combination of TAS-102 and bevacizumab was shown to extend the median PFS (C-TASK FORCE study). However, the study included patients who received second- and third-line treatment. Our study exclusively examined patients receiving this combination as a third-line treatment to investigate the clinical impact beyond cytotoxic doublets. Methods: This investigator-initiated, open-label, single-arm, multi-centered phase II study was conducted in Japan. Eligible CRC patients were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin in first- and second-line therapy. TAS-102 (35 mg/m2) was given orally twice daily on days 1–5 and 8–12 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion every 2 weeks. The primary endpoint was PFS and the secondary endpoints were time-to-treatment failure, response rate, overall survival (OS), and safety. Results: Between June 2016 and August 2017, 32 patients were enrolled. All patients previously received bevacizumab. The median PFS was 4.5 months; the median overall survival was 9.3 months. Partial response was observed in two patients. The most common adverse events above grade 3 were neutropenia followed by thrombocytopenia. There were no non-hematological adverse events above grade 3 and no treatment-related deaths occurred. Conclusions: This study met its primary endpoint of PFS, which is comparable to the results of the C-TASK FORCE study. The TAS-102 and bevacizumab combination has the potential to be a therapeutic option for third-line treatment of metastatic CRC. [ABSTRACT FROM AUTHOR]

TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The incidence of neutropenia is high, and there is no known effective prevention method. Furthermore, the administration method of TAS-102 is complicated. We reported that neutropenia could be avoided by changing to a simple administration method of TAS-102. [ABSTRACT FROM AUTHOR]

Background: During oxaliplatin chemotherapy administration via a peripheral vein, vascular pain requires changing of the intravenous infusion route on occasion. Vascular pain induced by anticancer drugs reduces the rate of patient continuation and completion of chemotherapy. Pain is presently appraised using subjective methods, such as the visual analog scale (VAS). However, because pain evaluation can vary depending on the physical state and mood of the patient at the time of assessment, it is desirable to evaluate pain objectively. PainVision PS-2100 (PV) is a medical device that was designed to objectively and quantitatively assess patient nociception and perception. Methods: The present study examined the correlation of subjective and objective assessment of oxaliplatin-induced vascular pain using VAS and PV, respectively. Results: Vascular pain was assessed using both PV and VAS a total of 173 times for 58 colorectal cancer patients. Partial correlation analysis was performed to evaluate the relationship between PV and VAS. The mean PV and VAS scores were 44.5 (range: 0-596) and 24.8 (range: 0-100), respectively. The partial correlation coefficient was 0.408 (p < 0.0001). Conclusions: A strong correlation was not observed between the results, and a weak correlation was observed between VAS and PV scores. Objective evaluation of oxaliplatin-induced vascular pain will be required to help patients overcome vascular pain. [ABSTRACT FROM AUTHOR]