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Patients' characteristics of JACCRO CC-05/06 and 05/06AR trials

Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cut-off point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assessable for gene expression data. Overexpression of BECN1 [log2(CPM) ≥ 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log2(CPM) ≥ 7.5] predicted significantly longer progression-free survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P = 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P = 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors.

Consort flow diagram of the study

The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC.Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/mIn total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed.The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.

Introduction: Gastric cancer is divided into four subtypes by their molecular features linked with genetic alterations, e.g., Epstein-Barr virus (EBV), microsatellite instability-high (MSI-high), chromosomal instability (CIN), and genomically stable (GS), called as TCGA classification. In this study, we tried to clarify the epigenetic features of the four GC subtypes according to aberrant methylation status in 23 loci. Methods: A total of 98 gastric cancers and their normal gastric mucosa samples were included in this study. We divided gastric cancers into TCGA subtypes which were determined in line with MSI-high, EBV, CIN, to GS by their molecular features. The 13 loci of polymorphic microsatellite sequences were used to determine loss of heterogeneity for the detection of CIN. The MSI status was determined by three mononucleotide repeat markers. Infection of EBV was determined by recovering EBV BNRF1 sequence from genomic DNA collected from gastric cancers. Methylation status of 23 loci was investigated by the combined bisulfite restriction analysis. Status of other findings, e.g., KRAS mutations, HER2 expression status, and infection of helicobacter pylori were confirmed. Results: Gastric cancers were divided into MSI (13%), EBV (7%), CIN (53%), and GS (27%). By histological classification, poorly differentiated adenocarcinoma was more in tumors categorized in MSI-high, and GS and signet-ring cell carcinoma (sig) were more in GS. Among the 23 loci investigated their methylation status, 18 loci were significantly hypermethylated in caner tissues. An unsupervised clustering divided gastric cancers into two clusters and revealed that most GS tumors clustered together in a cluster that exhibited lower methylation levels, distinct from the other subtypes. The inter-variable clustering revealed that a cluster contained the three loci (SFRP2-region 1/2 and APC) belonging to the Wnt signal cascade (Wnt-associated loci). The mean methylation score of Wnt-associated loci was the lowest in GS tumors (MSI-high: 2.7 [95% confidence interval, 2.3–2.9]; EBV: 2.1 [1.2–3.1]; CIN: 2.4 [2.2–2.7]; GS: 1.3 [0.8–0.7]). In contrast, the mean methylation score of the other 15 loci was significantly higher in MSI-high, while that in GS was as same as that in EBV or CIN (MSI-high: 10.4 [8.3–12.4]; EBV: 5.7 [1.7–9.7]; CIN: 4.4 [3.6–5.1]; GS: 3.4 [2.2–4.6]). Additionally, the lower methylation score of Wnt-associated loci was observed only in sig tumors. Conclusions: GS subtype tumors have the potential to possess distinct signatures in DNA hypomethylation profiles in Wnt signaling pathway, especially in sig.

Lessons Learned Background The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM. Methods Patients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence-free survival (RFS), overall survival (OS), dose intensity, and safety. Results Twenty-eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%–89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five-year recurrence-free survival and overall survival were 65.2% and 87.2%, respectively. Conclusion Three-month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.

In this work, we propose design parameters for optimized high-density optical cables to control the spatial-mode dispersion (SMD) of randomly coupled multi-core fibers (MCF). The analytical results of our proposed cable demonstrated the controllability of the bending and twisting of the implemented optical fibers by means of tension that is applied for a bundled fiber while keeping the sufficient reliability. An optical characterization showed that appropriate cabling parameters resulted in SMD controllability and a 47% reduction of the SMD coefficient while avoiding undesired loss increase. C-L band transmission experiments using our optical cable showed no degradation of the Q-factor or mode-dependent loss (MDL). Our proposed cable design is beneficial for achieving an SMD-managed large-capacity and long-haul transmission link.

The status and prognostic value of the disagreement between physician and patient assessments of symptomatic adverse events (AEs) remain unclear for patients with metastatic colorectal cancer treated with first‐line cetuximab plus chemotherapy. Paired data on patient‐reported outcomes using the EORTC QLQ‐C30 and physician‐reported outcomes using the NCI‐CTCAE for eight symptomatic AEs (fatigue, pain, insomnia, dyspnea, constipation, appetite loss, nausea/vomiting, and diarrhea) were collected from a prospective trial assessing the relationships between treatment efficacy, AEs, and quality of life. The overall agreement rates between patient and physician reporting at 4 weeks ranged from 40.2% to 76.5% for 129 patients. The level of agreement based on Cohen's κ statistics was slight to poor for dyspnea, pain, fatigue, and insomnia, while it was moderate to fair for the remaining AEs. No clinicopathological characteristics of disagreement were found. The underreporting by physicians ranged from 12.5% (nausea/vomiting) to 56.7% (fatigue). The 2‐year overall survival (OS) rate was more favorable for patients with high agreement than for those with low agreement (71.2% vs. 46.5%, p = .016), and the agreement status was an independent factor of OS (HR, 2.31; 95% CI, 1.13–4.71; p = .022). For patients who were reported as asymptomatic by the physician, the presence of patient‐reported symptoms resulted in a trend toward poor prognostic outcomes for appetite loss, dyspnea, diarrhea, and constipation. These findings provide the clinical importance of the monitoring of patient‐reported symptoms that can be complementary to physician‐reported data to ensure more accurate clinical outcomes., The routine use of PROs could be complementary to physician‐reported outcomes to ensure the accurate assessment of symptomatic AEs and facilitate patient‐centered healthcare in clinical practice.

Purpose FOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes. Methods Twelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR). Results Of the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8–77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively. Conclusions FOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia.

Background Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC). Methods This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses. Results Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4–60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group. Conclusions Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial. Clinical trial registration UMIN000010638

The preoperative prognostic nutritional index (PNI) calculated based on the serum albumin concentration and peripheral blood lymphocyte count has been reported to correlate with the prognosis in patients undergoing cancer surgery. However, in case of very old patients over 85 years old, the value of preoperative PNI in colorectal cancer has not been studied in any detail. The aim of this study was to assess the PNI as a predictor of postoperative outcome in elderly patients over 85 years old with colorectal cancer. We performed a retrospective review in forty-five patients over 85 years old who underwent colorectal tumor resection at our hospital from April 2013 to March 2018. The correlations between preoperative PNI and postoperative complications were examined. The incidence rate of postoperative complications was 31.1% (14/45). All of cases with postoperative complications were improved conservatively. The median preoperative PNI was 43.20 (range 24.05–57.05) in the validation study. According to the receiver operating characteristic (ROC) curve, cutoff value of PNI was set at 45.0 in the validation study. An univariate analysis demonstrated that PNI (p = 0.0006), operation style (elective/emergency) (p = 0.03), operation approach (open/laparoscopy) (p = 0.03), and T factor (p = 0.04). A multivariate analysis showed that PNI was independent predictive factor of postoperative complications. Moreover 3-year overall survival rates of patients in the PNI ≧ 45 and PNI p = 0.009). This study suggested that PNI is a pivotal independent predictor of the postoperative outcome among elderly patients over 85 years old after colorectal cancer surgery.

Background It remains unclear whether patients’ self‐perceptions of symptoms at baseline clinically impact the prognostic relevance, treatment efficacy, or toxicity profiles in metastatic colorectal cancer (mCRC) patients treated with the first‐line cetuximab and standard chemotherapy. Methods The data were collected from a prospective trial that assessed the relationships between quality of life (QOL), treatment efficacy, and adverse events (AEs). Results The analysis of 137 mCRC patients revealed a significant association between the presence of baseline tumor‐related symptoms and a lower overall survival (OS) compared to the absence of symptoms (HR, 2.49; 95% CI, 1.37‐4.62; P = .003). The asymptomatic responders had favorable outcomes compared to the symptomatic nonresponders (2‐year OS rates: 83.6% and 35.9%, respectively), while the symptomatic responders had similar outcomes to the asymptomatic nonresponders. The median postprogression survival differed significantly: 10.2 months for the symptomatic patients and 15.9 months for the asymptomatic patients (HR, 2.29; 95% CI, 1.25‐4.29, P = .008). The objective response rates and patient toxicity profiles were similar irrespective of the severity of baseline symptoms. Conclusion Baseline symptoms were associated with worse OS but not with impaired treatment efficacy or more frequent AEs in mCRC patients treated with cetuximab in addition to chemotherapy., This study provides that the baseline patient‐reported symptoms are associated with worse OS, but not with impaired treatment efficacy or deteriorated AEs, for patients treated with cetuximab plus chemotherapy.

An optimal treatment strategy using oxaliplatin and bevacizumab for metastatic colorectal cancer has not been defined. We investigated whether the sequential treatment using fluoropyrimidines with bevacizumab followed by the addition of oxaliplatin at first progression was better than a combination treatment using fluoropyrimidines and oxaliplatin with bevacizumab.In the sequential treatment, the escalation from fluoropyrimidines plus bevacizumab to fluoropyrimidines plus oxaliplatin with bevacizumab was recommended in case of progressive disease. Time to failure of strategy was the primary end-point, whereas the secondary end-points were overall survival, progression-free survival, overall response rate and safety.Three hundred patients with previously untreated metastatic colorectal cancer were randomised to receive either the sequential treatment (n = 151) or the combination treatment (n = 149). The sequential treatment was superior to the combination treatment about time to failure of strategy (15.2 months; 95% CI, 12.5-17.2 months vs. 7.8 months: 95% CI, 6.3-9.5 months; P 0.001). However, the median overall survival was 27.5 (95% CI, 24.4 to 32.7) months in the sequential treatment and 27.0 (95% CI, 22.8 to 36.0) months in the combination treatment (hazard ratio, 0.92; 95% CI, 0.66 to 1.28; P = 0.61). The overall response rate was 33.1% in the sequential treatment arm and 51.7% in the combination treatment.The findings support the extension of the sequential treatment starting from fluoropyrimidine plus bevacizumab to selected patients who do not need an objective response to the threatening disease.

Background: The neutrophil-to-lymphocyte ratio (NLR) is a well-known prognostic marker for gastric cancer (GC) patients. However, for GC patients treated with palliative chemotherapy, the prognostic value of NLR remains obscure. Therefore, we evaluated the clinical impact of NLR in GC patients treated with multiple lines of chemotherapy.Methods: We retrospectively evaluated 83 unresectable GC patients who received a series of chemotherapy treatments. NLR in the blood was calculated before the initiation of each line of chemotherapy (before 1st-, 2nd-, and 3rd-line, respectively).Results: Of the 83 patients enrolled, 56 (67%) received 2nd-line chemotherapy and 34 (41%) received 3rd-line treatment. NLR at 1st-line treatment ranged from 0.72 to 48.9 (the median NLR was 3.00). Thus, we used this median NLR value (3.00) as the cut-off for NLR throughout this study. All patients were divided into a NLR-high (> 3.00) or NLR-low group (< 3.00) by NLR values determined at before each line of chemotherapy. The median overall survival (OS) of the NLR-low group was better than that of the NLR-high group throughout 1st- to 3rd-line treatment (1st-line: 18.1 vs. 8.0 months, p = 0.06; 2nd-line: 10.7 vs. 4.5 months, p = 0.0001; 3rd-line: 8.7 vs. 4.7 months, p = 0.003), respectively. Of the 34 patients who received 3rd-line chemotherapy, 24 were treated with nivolumab. Of the 24 patients treated with nivolumab, patients in the NLR-low group showed better OS compared with those in the NLR-high group (8.3 months in NLR-low and 6.6 months in NLR-high, p = 0.06).Conclusions: Estimates of NLR prior to each chemotherapy line may be readily performed in a clinical setting and are useful for predicting outcome in unresectable GC patients, including in patients treated with nivolumab.

Purpose Although early tumor shrinkage (ETS) is a predictor of improved overall survival (OS), the association between ETS and health-related quality of life (HRQOL) remains unclear for patients with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus chemotherapy. Methods The data were collected from a prospective trial that assessed HRQOL using the EORTC QLQ-C30. The impact of ETS on HRQOL was estimated using a linear mixed-effects model for repeated measures. Results ETS was achieved in 82 (64.1%) of 128 mCRC patients treated with first-line cetuximab plus chemotherapy, and these patients had a significantly longer OS than those without ETS (HR, 0.38; 95% CI, 0.20–0.72; P = .002). Asymptomatic patients with ETS had a favorable OS, while symptomatic patients without ETS had a worse OS (2-year OS rates, 77.8% vs. 42.5%). Symptomatic patients with ETS had similar outcomes as asymptomatic patients without ETS (2-year OS rates, 64.1% vs. 67.0%). For symptomatic patients, ETS was associated with improved HRQOL scores between baseline and 8 weeks: the mean changes for patients with and without ETS were 5.86 and -4.94 for global health status (GHS)/QOL, 26.73 and 3.79 for physical functioning, and 13.58 and -3.10 for social functioning, respectively. The improved HRQOL was comparable to that of asymptomatic patients without ETS. For asymptomatic patients, ETS showed a decreased deterioration in HRQOL. Conclusion Our findings highlight the importance of ETS for HRQOL and prognostic estimates, and assessing ETS may provide clinically useful information for physicians and patients to make more informed decisions.

Aim: To evaluate whether PCR-reverse sequence-specific oligonucleotide can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Materials & methods: We examined acquired mutations in chemoresistant lesions and blood obtained from four patients with RAS wild-type metastatic colorectal cancer who underwent treatment with anti-epidermal growth factor receptor antibodies. Results: In one patient, metastatic lesions harbored diverse acquired mutations in KRAS in all seven metastases; the two acquired mutations were detectable in blood collected after the patient acquired resistance. None of the other patients exhibited liquid biopsy mutations, except one, with a BRAF mutation confirmed in primary tumor and peritoneal dissemination. Conclusion: Liquid biopsy based on PCR-reverse sequence-specific oligonucleotide is a successful procedure for capturing acquired mutations with precise information on the RAS mutational spectrum.

Background Mutations in the POLE gene result in an ultra-hypermutated phenotype in colorectal cancer (CRC); however, the molecular characterisation of epigenetic alterations remains unclear. We examined the genetic and epigenetic profiles of POLE-mutant CRC to elucidate the clinicopathological features of the associated genetic and epigenetic alterations. Results Tumour tissues (1,013) obtained from a cohort of patients with CRC were analysed to determine associations between the proofreading domain mutations of POLE with various clinicopathological variables, microsatellite instability (MSI) status, BRAF and KRAS mutations, and the methylation status of key regions of MLH1, MGMT, and SFRP2 promoters by calculating the methylation scores (range 0–6). Only four cases (0.4%) exhibited pathogenic POLE hotspot mutations (two p.P286R [c.857C > G], one p.V411L [c.1231G > C], and p.S459F [c.1376C > T] each), which were mutually exclusive to BRAF and KRAS mutations and MSI. CRC patients were divided into four subgroups: patients with POLE mutations (POLE, 0.4%, n = 4), patients with both MSI and extensive methylation in MLH1 (MSI-M, 2.9%, n = 29), patients with MSI but no extensive methylation in MLH1 (MSI-U, 3.6%, n = 36), and patients without MSI (non-MSI, 93.2%, n = 944). The POLE group was younger at diagnosis (median 52 years, P P P POLE-mutant tumours was small, the number of CD8-positive cells increased in tumours with partial methylation in the MLH1 gene. Conclusions CRC patients with POLE proofreading mutations are rare. Such mutations are observed in younger individuals, and tumours are primarily located in the right colon. Diagnosis occurs at an earlier stage, and distinct epigenetic alterations may be associated with CD8 cell infiltration.

Background Triweekly capecitabine plus irinotecan (CAPIRI) was not a replacement for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the treatment of metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. Recently, it has reported that mCAPIRI is well tolerated and non-inferior to FOLFIRI. In this study, we conducted a multicenter phase II trial to assess the efficacy and safety of biweekly CAPIRI plus bevacizumab as second-line chemotherapy for mCRC with reduced toxicity and preserved efficacy. Methods Patients with mCRC who had received prior chemotherapy, including oxaliplatin-based regimens, were eligible for this study. The treatment protocol administered capecitabine at 1000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan at 150 mg/m2 on day 1, and bevacizumab at 10 mg/kg on day 1 every 2 weeks. Primary endpoints for this study were progression-free survival (PFS) and safety. Secondary endpoints were overall survival (OS), time to treatment failure, response rate (RR), and disease control rate (DCR). Results Fifty-one patients were enrolled in this study. Median PFS was 5.5 months [95% confidence interval (CI) 4.23–7.40 months], and median OS was 13.5 months (95% CI 11.57–20.23 months). The RR was 14.6% (95% CI 6.5–28.4%), and the DCR was 66.7% (95% CI 51.5–79.2%). Hypertension was the most common Grade 3 adverse event (27.5%), followed by neutropenia (17.6%). Only two patients suffered from grade 3 hand–foot syndrome. Conclusions In mCRC patients, biweekly CAPIRI + bevacizumab appears effective and feasible as a second-line chemotherapy with relatively low toxicities, and has potential as a useful substitute for FOLFIRI + bevacizumab.

Background: Acquired mutations are detected in plasma. However, still few reports examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Herein we evaluated whether a polymerase chain reaction-reverse sequence-specific oligonucleotide (PCR-rSSO) method can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance.Methods: Firstly, we examined the presence of acquired mutations in 7 chemoresistant metastatic lesions and blood samples obtained from a metastatic colorectal cancer (mCRC) patient without RAS activating mutations treated with anti-EGFR treatment. The patient (patient 1) displayed initial early tumor shrinkage and finally progressed to disease (PD). Blood samples were collected before the development of PD and after acquiring resistance. Next, we evaluated RAS and BRAF mutational status among blood samples, primary tumors, and metastatic lesions obtained from three additional mCRC patients without RAS activating mutations. Acquired mutations were examined using Sanger sequencing and the PCR-rSSO approach.Results: Of patient 1, metastatic tumor specimens harbored diverse acquired mutations in the KRAS gene in all of the 7 (100%) metastases, and the three acquired mutations were detected in blood specimens collected after acquiring resistance. Next, we analyzed primary tumors, metastatic lesions after chemotherapy, and blood samples from three additional mCRC patients but noted that none of the patients exhibited mutations in liquid biopsy except for one case with BRAF V600E mutation, which was confirmed in both primary tumor and peritoneal dissemination. Of the four cases, acquired mutations of RAS, as well as BRAF V600E mutation, was detected in the blood obtained only after confirmation of acquiring resistance by radiological examinations.Conclusions: Our results suggest liquid biopsy based on the PCR-rSSO is a successful procedure for capturing acquired mutations with precise information of mutational spectrum that may lend us to reach selective target agents for RAS mutations.

257 Background: NIVO therapy is a standard care treatment for heavily pretreated patients with AGC. Improvement in objective response rate (ORR) to CTx after NIVO therapy for various cancer types has been reported. However, the efficacy and safety of CTx for AGC after progression on NIVO remains unclear. Methods: The REVIVE trial was a prospective, multicenter, observational study that evaluated the efficacy and safety of CTx in NIVO-refractory or NIVO-intolerant patients (pts) with AGC (UMIN000032182). The primary endpoint was overall survival (OS) of CTx following NIVO therapy. The median threshold and expected survival times were set as 4.0 and 7.0 months (M). The secondary endpoints are ORR, disease control rate (DCR), progression-free survival (PFS), and incidence of adverse events (AEs), including immune-related adverse events (irAEs). CTx consisted of irinotecan alone (IRI), trifluridine/tipiracil alone (FT), and oxaliplatin-containing regimens (OX). Results: Of 395 pts treated with NIVO who met the eligibility at formal registration from Jun 2018 to Sep 2020, 199 pts who received CTx after NIVO were evaluated. Pt characteristics were as follows: median age, 69 years; male, 70%; ECOG PS 0/1/2, 38/51/12%; histology (diffuse/intestinal), 39/59%; metastatic lesions (peritoneum/liver/lung), 38/34/15%; number of metastatic organ sites (0–1/≥2), 40/60%; measurable lesions, 83%; and CTx regimens (IRI/FT/OX), 64/31/5%. Median OS and PFS were 7.5 M (95%CI, 6.7–9.7) at 145 events for OS and 2.9 M (95%CI, 2.2–3.5) at 184 events for PFS. The ORR and DCR were 17.0% (95%CI, 11.6–23.6) and 46.7% (95%CI, 38.9–54.6). Median OS, median PFS, ORR, and DCR according to CTx regimens (IRI/FT/OX) were 8.1/7.1/6.2 M, 3.3/2.8/2.4 M, 18.9/10.9/25.0%, and 47.8/43.5/50.0%, respectively. At the start of CTx, 42 pts had irAEs due to prior NIVO therapy. The most common any-grade and grade ≥3 AEs during CTx included decreased appetite (46% and 7.5%), fatigue (26% and 2.5%), nausea (24% and 1.5%), constipation (16% and 0%), and diarrhea (28% and 4.0%). No treatment-related deaths were observed. Conclusions: Prior NIVO therapy may lead to improved prognosis after CTx without unexpected AEs in pts with AGC, warranting further investigations after NIVO is approved as first-line treatment.[Table: see text]

Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

PURPOSE This study evaluated the continuous use of trastuzumab beyond progression (TBP) in human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer. PATIENTS AND METHODS Patients with HER2-positive advanced G/GEJ cancer refractory to first-line chemotherapy with trastuzumab in combination with fluoropyrimidine and platinum were eligible. Patients were randomly assigned to the paclitaxel (80 mg/m2, days 1, 8, and 15, every 4 weeks) or paclitaxel with trastuzumab (PT; initially 8 mg/kg followed by 6 mg/kg, every 3 weeks) arms. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate, and safety. Biomarkers such as HER2 expression status in tumor tissue after first-line treatment, HER2 amplification evaluated in serum cell-free DNA, and soluble HER2 levels were analyzed. RESULTS Overall, 91 patients were allocated to the paclitaxel (n = 46) and PT (n = 45) arms. The median PFS in the paclitaxel and PT arms was 3.2 and 3.7 months, respectively (hazard ratio [HR], 0.91; 80% CI, 0.67 to 1.22; P = .33), and the median OS in both arms was 10 months (HR, 1.2; 95% CI, 0.75 to 2.0; P = .20). The overall response rates in the paclitaxel and PT arms were 32% and 33%, respectively ( P = 1.00), and safety was comparable between the 2 arms. On exploratory analyses, HER2 positivity of tumor tissues was lost after first-line chemotherapy in 11 (69%) of 16 patients whose tumor tissues were available, and circulating HER2 DNA amplification was detected in 41 (60%) of 68 patients. However, no biomarkers associated with efficacy of TBP were found. CONCLUSION The TBP strategy failed to improve PFS in patients with HER2-positive advanced G/GEJ cancer, and no beneficial biomarkers were found.

Most patients with unresectable advanced digestive cancers require placement of a fully implantable venous access port to facilitate safe delivery of anti-cancer drugs. Anti-VEGF therapies are commonly used even though they increase the risk of thrombosis. The objective of this study was to assess the incidence of radiologically confirmed catheter-related thrombosis(CRT)in patients with advanced digestive cancers.We retrospectively reviewed 88 patients with advanced digestive cancers who had adapted implantable ports placed in our institution for chemotherapy.Thirty-nine patients were diagnosed with colorectal cancer, 26 with gastric cancer, 12 with pancreatic cancer, 8 with esophageal cancer, and 3 with other cancers. During follow-up, 22 patients(25%)received anti-VEGF therapies, while 66 patients(75%)did not. Four out of 88 patients(4.5%)had asymptomatic CRT. The incidence of CRT was the same(4.5%)regardless of whether the patient received anti-VEGF therapy.In patients with digestive cancers who had implantable venous access ports, the incidence of the CRT was 4.5% with no association with anti-VEGF therapies.

This case was observed in a man in his 70s. Although symptomatic treatment was performed for epigastralgia, endoscopic examination revealed a type 3 tumor on the fornix of the stomach to the lesser curvature of the body just above the esophagogastric junction, and the patient was diagnosed with moderately differentiated tubular adenocarcinoma(cT4bN3aM0, cStage ⅣA). As esophageal and diaphragmatic invasion was suspected based on CT findings, S-1 plus CDDP was started as preoperative chemotherapy. Although the primary lesion and lymph node metastasis decreased in size, chemotherapy was discontinued after one course due to stenosis symptoms, and total gastrectomy and D2 dissection were performed. Postoperative adjuvant chemotherapy with S-1 was started. However, 6 months after starting the treatment, para-aortic lymph node recurrence was observed, and the treatment strategy was changed to weekly PTX. After 5 courses of weekly PTX, the lymph nodes continued to increase in size, and chemotherapy was discontinued per the patient's request. The patient was followed up with CT and PET-CT; however, no new recurrent lesions were found in other sites for approximately 1 year. Therefore, para-aortic lymph node dissection was performed as the salvage surgery. Pathological findings showed that gastric cancer metastasis was present in 1 swollen lymph node only, as confirmed by PET. At present, 6 years have passed since the first operation, and there has been no recurrence. In general, para-aortic lymph node metastasis is considered to result in poor prognosis in gastric cancer. However, in the absence of other noncurative factors, a good prognosis may be obtained with combined therapeutic modalities.

Colorectal cancer (CRC) manifests after the accumulation of genetic and epigenetic alterations along with tumor microenvironments. MicroRNA (miRNA/miR) molecules have been revealed to serve in critical roles in the progression various types of cancer, and their expression level is often an important diagnostic, predictive or prognostic biomarker. The aim of the present study was to evaluate the potential of miRNAs as prognostic biomarkers for patients with advanced CRC. miRNA arrays were performed on CRC specimens obtained from tumors with various molecular statuses [e.g. KRAS proto-oncogene, GTPase (KRAS)/B-Raf proto-oncogene, serine/threonine kinase (BRAF)/microsatellite instability (MSI)], and their paired normal mucosal specimens. The miRNA array revealed that miR-31-5p (miR-31) was specifically upregulated in CRCs with the BRAF V600E mutation, the results of which were supported by subsequent analysis of a dataset retrieved from The Cancer Genome Atlas (TCGA) database, which contained information regarding 170 patients with CRC including 51 BRAF-mutant CRCs. Of our cohort of 67 patients with stage IV CRC, 15 (22%) and 4 (6%) showed KRAS and BRAF V600E mutations, respectively. Since the median miR-31 expression was 3.45 (range, 0.004–6330.531), the cut-off value was chosen as 3.5, and all tumors were categorized into two groups accordingly (high-/low-miR-31 expression). The high miR-31 expression group (n=33) was significantly associated with a poorer mortality (univariate hazard ratio=2.12; 95% confidence interval, 0.23–0.95; P=0.03) and exhibited a shorter median survival time (MST; 20.1 months) compared with the low miR-31 expression group (n=34) (MST, 38.3 months; P=0.03), indicating that miR-31 is a promising prognostic biomarker for patients with advanced CRC. Thus, performing a functional analysis of miR-31 expression may lead to the development of new targeted therapies for the various genetic subtypes of CRC.

The decrease in carcinoembryonic antigen (CEA) level is faster and greater during cetuximab treatment than bevacizumab treatment and correlates with prolonged survival in patients with metastatic colorectal cancer (mCRC) who receive cetuximab. We investigated if the degree of change in the CEA value can serve as a diagnostic tool for predicting survival, as well as tumor regression in mCRC patients treated with cetuximab combined regimen as first-line treatment. Associations among the CEA decrease, depth of response (DpR), and clinical outcomes were evaluated in 113 patients with mCRC from two phase II trials of first-line therapy: the JACCRO CC-05 trial of cetuximab plus FOLFOX and the CC-06 trial of cetuximab plus SOX. Analysis was performed using Spearman’s rank correlation coefficient. A 75% decrease in the CEA was used as the cut-off value to define the CEA response and discriminate CEA responders on the basis of the results of a previous study. Ninety-two patients were eligible for analyses of both CEA and DpR. The median CEA decrease was 67.4%, and the median time to CEA nadir was 2.8 months, which was similar to the median time to DpR of 3.0 months. The DpR was associated with PFS and OS (rs = 0.56, P

Primary tumor location is a critical prognostic factor in metastatic colorectal cancer (mCRC); however, it remains unclear whether tumor location is a predictor of the response to cetuximab treatment. It is also uncertain if BRAF mutation contributes to the impact of tumor location on survival. We assessed the prognostic impact of tumor location on clinical outcomes in mCRC patients treated with first-line cetuximab chemotherapy.The associations of tumor location with overall survival and progression-free survival were evaluated in mCRC patients with KRAS exon 2 wild-type tumors who were enrolled onto 2 clinical trials: JACCRO CC-05 of cetuximab plus FOLFOX (n = 57, UMIN000004197) and CC-06 of cetuximab plus SOX (n = 61, UMIN000007022). Tumors proximal or from splenic flexure to rectum were defined as right-sided or left-sided, respectively. In addition, exploratory RAS and BRAF mutation analyses were performed.A total of 110 patients were assessable for tumor location; 90 had left-sided tumors. Left-sided tumors were significantly associated with longer overall survival (36.2 vs. 12.6 months, hazard ratio = 0.28, P .0001) and progression-free survival (11.1 vs. 5.6 months, hazard ratio = 0.47, P = .0041) than right-sided tumors; similar results were obtained in multivariate analysis. A subanalysis showed that the association was evident in the FOLFOX group and that tumor location was an independent prognostic factor irrespective of BRAF status in RAS wild-type patients.Primary tumor location might be a predictor of survival independent of BRAF status in mCRC patients who receive first-line cetuximab combined with oxaliplatin-based chemotherapy.

Predictive factors of cetuximab efficacy for metastatic colorectal cancer (mCRC) have not been sufficiently revealed. The present study aimed to explore new predictors. A total of 30 patients with KRAS exon 2 wild-type unresectable mCRC, who had been treated with cetuximab-based regimen as first-line therapy, were retrospectively analyzed. We assessed whether gender, age, primary tumor site, RAS genotype, the Eastern Cooperative Oncology Group Performance Status (ECOG PS), metastatic status, histological grade, carcinoembryonic antigen (CEA), treatment regimen, and oxaliplatin-based adjuvant chemotherapy at baseline were associated with cetuximab efficacy. Progression-free survival (PFS) and objective response rate (ORR) were evaluated and statistically analyzed. Analysis of PFS revealed that left-sided tumor and good PS had relevance to good results. PFS among patients with left-sided CRC was longer than that among those with right-sided CRC (median, 10.6 and 3.5 months, respectively). Patients with a PS of 0 - 1 experienced significantly longer PFS than those with a PS of 2 - 3 (median, 8.6 versus 1.3 months, respectively). In analysis of ORR, high histological grade and serum CEA level showed interaction with good effect. Patients with histological grade I/II cancer experienced better ORR than those with histological grade III/IV cancer (76% versus 20%, respectively). ORR among patients with serum CEA level higher than 5.0 ng/ml was significantly higher than that among those with lower serum levels (88% versus 38%, respectively). ECOG PS, tumor location, histological grade, and serum CEA level at baseline might be useful predictors of cetuximab efficacy in the first-line treatment of mCRC.

Background Paclitaxel is used in second-line conventional chemotherapies to manage patients with unresectable advanced gastric cancer (GC). Paclitaxel-induced peripheral neuropathy is a known adverse event leading to treatment discontinuation. Additionally, oxaliplatin which causes irreversible peripheral neuropathy is now commonly used in first-line chemotherapy for advanced GC in Japan. Thus, examining the incidence of peripheral neuropathy with paclitaxel after oxaliplatin is necessary to improve the quality of life and outcomes of patients with advanced GC in the second-line treatment setting. Methods This prospective observational multicenter study, (which we named IVY study), will evaluate the degree of chemotherapy-induced peripheral neuropathy (CIPN) and the efficacy of second-line chemotherapy for unresectable advanced GC. A patient neurotoxicity questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) will be used to assess CIPN during the second-line treatment. The key eligibility criteria are as follows: 1) unresectable or recurrent GC histologically confirmed to be primary adenocarcinoma of the stomach, 2) age over 20 years, 3) Eastern Cooperative Oncology Group performance status score of 0–2, 4) written informed consent following full study information is provided to the patient, 5) progression or intolerance for first-line chemotherapy comprising fluorinated pyrimidine and platinum anticancer drugs (cisplatin or oxaliplatin) for advanced GC. 6) presence of evaluable lesions as confirmed using a computed tomography (CT) or magnetic resonance imaging. A total of 200 patients is considered to be appropriate for inclusion in this study. Discussion The results of this study will provide some information on CIPN with the sequential usage of oxaliplatin as first-line chemotherapy to paclitaxel as second-line chemotherapy in clinical practice. Trial registration This trial is registered in the University Hospital Medical Information Network’s Clinical Trials Registry with the registration number UMIN000033376 (Registered 11 July 2018).

The reintroduction of oxaliplatin as a third-or-later-line regimen has been a promising option for patients with metastatic colorectal cancer (mCRC) who previously received chemotherapy including oxaliplatin. In this single-arm phase II study, we evaluated the efficacy of biweekly SOX, which is the combination of oxaliplatin reintroduction and S-1, as a third-or-later-line treatment. Patients with mCRC who had previously received prior chemotherapy including oxaliplatin and irinotecan and were planned to receive the reintroduction of oxaliplatin were enrolled. Oxaliplatin (85 mg/m2) with/without bevacizumab (5 mg/kg) was given intravenously on day 1. Oral S-1 was administered on day 2–8 at a dose of 40–60 mg (calculated according to the body surface area) twice a day. Cycles were repeated every 2 weeks. The primary endpoint was the progression-free survival (PFS); our hypothesis was that the median PFS would be 3.5 months with a minimum threshold above 2.0 months. The secondary endpoints included the adverse events (AEs), response rate and overall survival (OS). A total of 41 patients from 12 institutes were enrolled. The median PFS and OS survival were 3.3 months (95% confidence interval [CI] 2.7–4.2) and 10.1 months (8.3–14.6), and response rate and disease control rate were 10.0% and 65.0%, respectively. Grade 3 AEs included thrombocytopenia (5.0%), anorexia (5.0%), pneumonia (5.0%) and fatigue (5.0%). There were no cases of grade 4 AEs or treatment-related death. Biweekly SOX regimen with reintroduction of oxaliplatin could be exploitable as the third- and/or later-line treatments for patients with mCRC.

Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC.Patients with mCRC who were previously treated with oxaliplatin-containing regimens were enrolled. Oral S-1 at a dose of 40 mg/m(2) was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150 mg/m(2) and bevacizumab at a dose of 7.5 mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS).Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6 % (95 % confidence interval [CI] 8.7-37.9), and the disease control rate was 76.5 % (95 % CI 58.8-89.3). The median PFS was 5.6 months (95 % CI 3.8-7.0). The median overall survival was 16.4 months (95 % CI 8.1-20.0). The most common grade 3/4 adverse events included neutropenia (25.0 %), anorexia (22.2 %), anemia (16.7 %), and fatigue/malaise (16.7 %). The most common grade 3/4 adverse event of special interest for bevacizumab was hypertension (30.6 %). One treatment-related death caused by gastrointestinal bleeding occurred.The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin-refractory mCRC.

For several years, adoptive immunotherapy (AIT) has been performed using autologous zoledronate-activated killer (ZAK) cells to develop a novel modality for cancer treatment. In the current study, data from 50 patients with incurable gastric cancer were analyzed. Patients were treated with AIT using intravenous ZAK cells every 3-4 weeks in combination with chemotherapy of the physician’s choice. The possible clinical benefits were subsequently examined. The median overall survival (OS) time of all patients was 7.5 months. In patients that received 5 or more rounds of treatment, the OS was 13.5 months. Additionally, the OS times of 1st, 2nd or later line chemotherapy with ZAK cell AIT were 27.3 months and 13.3 months, respectively. No objective response was observed and the disease control rate was 67.9%. No severe adverse event was recorded. Functional Assessment of Cancer Therapy-Biologic Response Modifier analysis revealed possible improvement of quality of life after ZAK cell AIT. Univariate analysis revealed a significant positive association between longer survival times and baseline lymphocyte percentages in white blood cell counts (P

399 Background: Prognosis for locally advanced gastric cancer (LAGC), such as clinical T4 disease, bulky nodal metastases, type 4 and large type 3 gastric cancer, was not satisfactory even by D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach, therefore, we have conducted a phase II study to evaluate the efficacy and safety of the neoadjuvant chemotherapy of S-1 and oxaliplatin (G-SOX) followed by gastrectomy with D2/3 lymph node dissection for LAGC, and the primary endpoint of curative resection rate was met [Miki A, ESMO 2019]. We show longer follow-up data from this study. Methods: Patients with adenocarcinoma of the stomach; clinical T4; clinically resectable gastric cancer of type 4 or large type 3; bulky nodal involvement around major branched arteries to the stomach were enrolled. Patients receive two cycles of neoadjuvant chemotherapy with S-1 (80 mg/m2, p.o., days 1-14 followed by 1 week rest) and oxaliplatin (130 mg/m2 at day 1), followed by D2 or higher surgery with no residual disease. Patients with pathological R0/1 resection received S-1 (80 mg/m2, p.o., days 1-28 followed by 2 week rest) for 1 year as adjuvant chemotherapy. Primary endpoint was curative resection rate. Results: Between August 2015 and March 2017, forty-one patients were in enrolled. Of the patients, 39 patients (95%) completed the two courses of neoadjuvant chemotherapy of G-SOX, 37 (90%) received gastrectomy, and 36 (87.8%) received curative resection (R0/1). Grade 3 or higher toxicities during neoadjuvant chemotherapy of G-SOX were neutropenia (7%), fatigue (7%), diarrhea (5%) and thrombocytopenia (2%). No treatment related deaths were observed. Surgical complications including postoperative complications were observed in 13 patients (35%). Pathological response rate after neoadjuvant G-SOX was 40%. With a median follow-up period of 33.8 months, 3year-relapse free survival and 3year-ovearll survival was 54.3% and 73.1%, respectively. Conclusions: An update analysis confirmed that neoadjuvant chemotherapy of G-SOX is a feasible and might be one of the promising strategies for patients with LAGC. Clinical trial information: UMIN000018661.

134 Background: FOLFOXIRI-Bmab has been recognized as one of the standard first-line treatments for mCRC. We conducted a single arm, multicenter, phase II study to assess the efficacy and safety of FOLFOXIRI-Bmab in pts with untreated mCRC harboring UGT1A1(*6 and *28) wild or single hetero genotype. Methods: Pts received FOLFOXIRI-Bmab (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin 200mg/m2, fluorouracil 3200 mg/m2 and Bmab 5mg/kg repeated biweekly) up to a maximum of 12 cycles, followed by the sequential therapy which consisted of the remaining drugs if any of the individual drugs were discontinued at the investigator’s discretion. Protocol therapy was continued until progressive disease, an unacceptable adverse event, tumor resection or consent withdrawal. The primary endpoint was ORR evaluated by central reviewers. Secondary endpoints include TTF, PFS, OS, R0 resection rate, relative dose intensity (RDI) and safety. The exploratory objectives were early tumor shrinkage (ETS), depth of response (DoR). Results: 47 pts were enrolled from 16 centers between April 2015 and May 2017, of whom 1 was excluded for not meeting the inclusion criteria. The full analysis set consisted of 44 pts because 2 had no target lesions that were considered measurable lesion by central reviewers. 46 pts had the following characteristics: median age 58 (29-68), 57% male, 76% PS0, 22% right-sided tumors and 52% UGT1A1 wild. RAS status was 37% wild, 52% mutant, 11% unknown. Primary endpoint was met. The ORR was 63.6% (95% CI, 47.8-77.6). ETS and DoR was 70.5%, 43.9%, respectively. R0 resection rate was 23%. Median PFS was 15.5mo (95% CI, 11.5-23.4). Median TTF was 8.1mo (95% CI, 5.3-10.1). Median OS was 34.4mo (95% CI, 26.4-not reached). The mean RDI of fluorouracil, irinotecan and oxaliplatin were 71%, 67%, and 64%, respectively. Grade 3 or higher adverse events (≥10%) were neutropenia (65.2%), febrile neutropenia (FN) (26.1%), anorexia (10.9%), nausea (10.9%), and diarrhea (10.9%). No treatment-related deaths were observed. Conclusions: Our results of FOLFOXIRI-Bmab in Japanese pts showed to be beneficial and manageable although caution to FN is required. Clinical trial information: NCT02497157.

Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cut-off point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assessable for gene expression data. Overexpression of BECN1 [log2(CPM) ≥ 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log2(CPM) ≥ 7.5] predicted significantly longer progression-free survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P = 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P = 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors.

Time has come when oncology has met immunology. Immune checkpoint inhibitors(ICIs)are being approved as standard cancer treatments, day by day. ICIs, however, have serious immune-related adverse events(irAEs)in a diverse manner, requiring the establishment of team-approach system to manage irAEs. Here, irAEs are summarized and their managements are discussed.