Search

Few data of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (RAM) obtained in bevacizumab-naive patients in clinical trials or routine clinical practice are available. The purpose of this retrospective study was to report the results of FOLFIRI plus RAM treatment as second-line chemotherapy for metastatic colorectal cancer (mCRC). Seventy-four patients with mCRC who received second-line FOLFIRI + RAM mCRC therapy were stratified by previous first-line therapy to groups that had (PB) or had not (NPB) been given bevacizumab. The overall survival (OS), progression-free survival (PFS), and objective response were evaluated. The overall median PFS was 6.2 months (95% CI 4.6–9.3) and median OS was 17.0 months (95% CI 11.6–NA). Median PFS was 8.0 months (95% CI 4.9–11.2) in NPB patients and 5.0 months (95% CI 3.1–7.3) in PB patients (hazard ratio = 0.72, 95% CI 0.40–1.30, p = 0.28). The response rates were 23% and 3% in NPB and PB patients, respectively. The disease control rates were 85% and 69% in NPB and PB patients, respectively. The effectiveness of FOLFIRI + RAM as a second-line chemotherapy in patients with mCRC was in line with that reported in the previous RAISE phase III trial. The response was better in bevacizumab-naive patients than those with first-line treatment that had included bevacizumab.

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

TPS4161 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. DESTINY-Gastric01 study showed significantly higher objective response rate with T-DXd than physician's choice of chemotherapy (51.3%, vs. 14.3%, Shitara K, et al. NEJM 2020) as well as prolonged overall survival (median 12.5 vs. 8.4 months, hazard ratio 0.59). Considering that high response rate or major pathological response (MPR), which is defined as the proportion of subjects with < 10% residual tumor may be associated with favorable survival outcomes after preoperative chemotherapy, T-DXd could be a promising neoadjuvant treatment for patients with gastric and gastroesophageal junction (GEJ) cancer. However, to our knowledge, there is no currently ongoing study of T-DXd as a neoadjuvant setting for patients with gastric and GEJ cancers. Methods: This is an open-label, single-arm, multicenter, investigator initiated phase 2 trial to evaluate antitumor activity of T-DXd as the neoadjuvant treatment for patients with HER2 positive gastric and GEJ adenocarcinoma. Eligible patients should have previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort will enroll patients with HER2 overexpression defined as immunohistochemistry （IHC）3+ or IHC2+/ in situ hybridization（ISH）+ by local assessment. According to the results of exploratory biomarker analysis of DESTINY-Gastric01 study (Shitara K, et al. ESMO-GI2021), patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with HER2-extra cellular domein (ECD) higher than 11.6 ng/ml also will be enrolled into the exploratory cohort. Patients will receive 3 cycles of T-DXd (6.4mg/kg) by intravenous infusion every 3 weeks followed by surgery at 3 to 8 weeks after last T-DXd infusion.The primary endpoint is MPR rate. The threshold in the main cohort is defined as 20%, and the expected MPR rate was set at 45%. The minimum sample size of this trial is 23 patients in the main cohort (α- and β-error probabilities, 0.1 and 0.15, respectively). Total number of patients will be increased up to 27 patients depending on the enrollment. In addition, 10 patients will be recruited into the exploratory cohort. Secondary endpoints are pathologic complete response (pCR) rate, curative resection rate, and adverse event rate. Biomarker analyses including whole exome sequencing, RNA sequencing, proteomics, and ctDNA changes will also be conducted using pre- and post-treatment tumor and blood samples. Enrollment is ongoing at six sites in Japan from November 2021. Clinical trial information: NCT05034887.

3528 Background: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer. However, there is a lack of consensus of CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. Previously, we reported that genome-wide DNAmethylation statuscould predict the effect of epidermal growth factor receptor (EGFR) inhibitors more accurately than previously reported methylation classifications (Ouchi et al. Cancer Sci 2015). Moreover, we had developed a DNA methylation assay based on MethyLight to reflect genome-wide DNA methylation status and reported its usefulness in predicting prognosis in patients with metastatic colorectal cancer (mCRC) treated with EGFR inhibitors as a third-line chemotherapy (Ouchi et al. Cancer Sci 2022). This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with mCRC treated with first-line EGFR inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment, and analyzed the associations between genome-wide DNA methylation status using a novel comprehensive methylation marker panel and clinical outcomes and evaluated the predictive power and value of the methylation status. Results: Total 169 patients were included in the final analyses. The frequency of highly methylated CRC (HMCC) was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAFV600E mutation (P < 0.001). Patients with HMCC showed worse clinical outcomes than those with low methylated CRC in terms of response rate (P = 0.017), progression-free survival (PFS; P = 0.004), and overall survival (P = 0.019). In the multivariate analysis, peritoneal metastasis (Hazard ratio (HR): 2.24, P = 0.017), methylation status (HR: 3.04, P = 0.037), and BRAFV600E mutations (HR: 5.83, P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status may be an independent predictor of first-line EGFR inhibitors in patients with mCRC.

Trifluridine (FTD)/tipiracil (TPI) plus bevacizumab (Bev) is a promising late-line treatment in metastatic colorectal cancer (mCRC). Although chemotherapy-induced neutropenia (CIN) is a well-known predictor of FTD/TPI efficacy, whether CIN is a predictive marker of efficacy for FTD/TPI + Bev remains unclear. Thus, the present study aimed to investigate the clinical outcomes of FTD/TPI + Bev and the predictive markers of its efficacy. Clinical data of patients with mCRC who received FTD/TPI + Bev at the Cancer Institute Hospital between January 2017 and August 2020 were retrospectively collected. Disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety were assessed. In addition, subgroup analyses of prognostic and predictive efficacy markers were performed. In total, 94 patients (median age, 60.0 years; age range, 32-82 years; 37 men and 57 women) were included in the present study. The DCR was 44.7%, the median PFS time was 2.9 months (2.3-4.1 months) and the median OS time was 10.0 months (7.3-11.1 months). Grade 3 or 4 CIN within the first cycle of treatment occurred in 27.7% of patients, which was significantly associated with a longer PFS time than those who did not develop CIN [3.8 months (2.3-8.4 months) vs. 2.7 months (1.8-4.0 months); P=0.008]. Furthermore, the DCR was higher in patients with grade 3 or 4 CIN within the first cycle of treatment than those without CIN (61.5 vs. 38.2%; P=0.07). Multivariate Cox regression analysis revealed that grade 3 or 4 CIN within the first cycle of treatment are independent predictors for a longer PFS time (P=0.01). Taken together, the results of the present study suggest that grade 3 or 4 CIN within the first cycle of treatment are early predictors of the efficacy of FTD/TPI + Bev.

178 Background: Colorectal cancer with liver metastases (CLM) has high post operative recurrence rates, and optimizing the perioperative treatment is imperative. Post operative carcinoembryonic antigen (CEA) can help detecting minimal residual disease in colon cancer after curative resection. Methods: The aim of this study was to identify the potential role of serum CEA after liver resection in patients with CLM. This study was conducted at the Cancer Institute Hospital, Japanese Foundation for Cancer Research from 2004 to 2018. Patients with CLM who underwent complete resection of primary tumors and liver metastases were enrolled in this study. We studied the associations between the perioperative CEA levels and characteristics of recurrence. Results: Recurrence was detected during the median follow-up time of 50.9 months in 343 (54.1%) of the total 633 patients analyzed. Patients with postoperative CEA (>5) group had a significantly higher recurrence rate (75.7% vs 50.0%, p < 0.01), with a shorter time until recurrence (4.4 months vs 36.9 months, p < 0.01) than those with a postoperative CEA level (≤5) group. In multivariate analysis, a postoperative CEA level >5 ng/ ml was an independent predictor, with the highest hazard ratio for both recurrence free survival (RFS) and overall survival (OS) (RFS: 2.77, 95% confidence interval [CI] 2.14–3.60, p 5) group who did not have normalized CEA levels after adjuvant chemotherapy compared to normalized CEA group (3.3 months vs 18.5 months, p = 0.008). Conclusions: The postoperative CEA and postadjuvant chemotherapy CEA level in the CEA level (>5) group after surgery may be a predictor of RFS and OS.

276 Background: Addition of an anti-PD-1 antibody to trastuzumab reportedly enhances ADCC activity of trastuzumab, leading to an additive antitumor effect. In the KEYNOTE-811 study, pembrolizumab in combination with trastuzumab plus chemotherapy resulted in a durable response. We investigated the safety and tolerability of nivolumab plus trastuzumab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for patients (pts) with HER2-positive advanced gastric cancer (AGC). The safety parts of this study have already shown that there are no safety concerns (Takahari, et al. ASCO-GI 2021). Methods: This study is an open-label, non-randomized phase 1b study conducted at four centers in Japan to confirm the tolerability of addition of nivolumab to chemotherapies with trastuzumab in safety part (n = 12) followed by assessing their efficacy in expansion part (n = 30). Chemotherapy-naïve adult pts with histologically confirmed HER2-positive AGC who had measurable lesions were eligible. Pts received nivolumab (360 mg/body, day 1) and trastuzumab (cycle 1: 8 mg/kg; cycle 2–: 6 mg/kg, day 1), Ox (130 mg/m2, day 1) in combination with either S-1 (40 mg/m2 bid, days 1–14; cohort 1) or Cape (1000 mg/m2 bid, days 1–14; cohort 2) every 3 weeks until disease progression or unacceptable toxicity. Initial eligible 12 pts for safety part were enrolled alternatively to cohort 1 or 2, and patients for expansion part were allocated to either cohort by investigators’ choice up to 21 patients in each cohort. Safety and short-term efficacy data during 8 cycles (6 months) were assessed for this presentation. Results: Between November 2018 and January 2021, a total of 42 pts with HER2-positive AGC were enrolled (21 pts in each cohort). As of July 31, 2021, 29 pts discontinued protocol treatment and the rest 13 pts are still on treatment. Of the 29 pts, only 3 pts (10.3%)discontinued the treatment due to adverse event (AE). AE (≥ G3) occurred in 25 pts (59.5%) including neutropenia in 8 pts (19.0%) and diarrhea in 4 pts (9.5%). Immune-related AEs (≥ G3) occurred in 7 pts (16.6%) including diarrhea/colitis in 4 pts (9.5%). Median relative dose intensity was 100%, 78%, 73%, 75%, and 75% for nivolumab, trastuzumab, Ox, S-1, and Cape, and the percentage of dose reduction or discontinuation within initial 8 cycles were 33%, 33%, 79%, 81%, and 81%, respectively. The ORR was 76.2% (95% CI 60.6-86.9, CR 4.8%, PR 71.4%), and the DCR was 97.6%. Conversion surgery was performed in 2 pts (4.8%). 6-month PFS rate was 68.7% (95% CI 51.7-81.3). Subset results by the cohorts will be presented at the conference. Conclusions: Nivolumab, trastuzumab and either S-1 or Cape plus Ox was tolerable and showed acceptable safety and promising early efficacy results in pts with HER2-positive AGC. Clinical trial information: UMIN000034222.

The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (CThe CWe analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the CThis study showed that the C

Patients who receive trastuzumab (T-mab) plus chemotherapy for stage IV HER2-positive gastric or gastroesophageal junction cancer sometimes respond remarkably well and can undergo radical surgery. However, the clinical outcomes of preoperative T-mab combined chemotherapy with radical gastrectomy remain unclear. We conducted this study to investigate the clinical outcomes of this multimodal treatment. From among a total of 199 patients who received T-mab-based chemotherapy for stage IV HER2-positive gastric or gastroesophageal junction cancer between 2011 and 2018, the subjects of this retrospective analysis were 20 patients who subsequently underwent radical gastrectomy. Seven patients had gastroesophageal junction cancer and 13 had gastric cancer. Eleven patients had unresectable stage IV cancer and 9 had resectable metastatic disease. Chemotherapy regimens included capecitabine, cisplatin + T-mab (11 patients), and S-1, oxaliplatin + T-mab (nine patients). The median number of chemotherapy cycles before surgery was three (range, 2–62). During preoperative chemotherapy, grade 3/4 adverse events developed in six patients. None suffered grade ≥ 3b postoperative complications. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 58.9% and 89.5%, respectively. Combined preoperative T-mab-based chemotherapy and surgery appears to be safe and effective for stage IV HER2-positive gastric or gastroesophageal junction cancer, with a clinically meaningful impact on RFS and OS.

This is a phase 2 study aimed at evaluating the efficacy and safety of TAS-114, a novel deoxyuridine triphosphatase inhibitor, combined with S-1 in patients with advanced gastric cancer (AGC). Eligible patients had AGC with measurable lesions, according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1), with two or more previous chemotherapy regimens including fluoropyrimidines, platinum agents, and taxanes or irinotecan. The primary endpoint was objective response rate (ORR) according to the RECIST, v1.1. Twenty-nine patients were required according to Simon’s optimal two-stage design, with one-sided a = 5% and power = 80%. Threshold and expected ORRs were 5% and 25%. Patients received TAS-114 (400 mg/body, twice a day) and S-1 (30 mg/m2, twice a day) for 14 days, followed by 7 days of rest in one 3-week cycle. Protein expression levels of dUTPase and BRCA1 in tumor samples were determined by immunohistochemistry. Accrual was terminated in June 2018 because meeting the predefined efficacy criteria was considered difficult. ORR and disease control rate were 5.0% [95% confidence interval (CI), 0.1–24.9%] and 70.0% (95% CI, 45.7–88.1%), respectively, for all 20 patients enrolled. Median progression-free survival (PFS) and overall survival were 2.4 months (95% CI, 1.2–3.3 months) and 7.1 months (95% CI, 5.2–9.4 months), respectively. Median PFS in the groups with high and low dUTPase protein expression in the cytoplasm was 2.8 months (95% CI, 1.4–3.9) and 1.6 months (95% CI, 0.6–2.4), respectively [hazard ratio, 0.40 (95% CI, 0.16–1.04), log-rank test two-sided p = 0.047]. Grade 3 or higher treatment-related adverse events included anemia (20%), leucopenia (15%), neutropenia (10%), rash (10%), thrombocytopenia (5%), and lymphopenia (5%) TAS-114 with S-1 showed only modest antitumor activity with acceptable safety profiles for patients heavily pretreated with AGC.

Background This study aimed to evaluate the efficacy and the safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev) in clinical practice. Methods We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF as preventing or treating grade 3 or 4 neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0. Results A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2–16.9), and the median OS was 24.2 months (13.6–NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients, and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or 4 neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.8%), no dose adjustment was required. Conclusions PEG-G-CSF is useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

Background Ramucirumab monotherapy as a second-line treatment for advanced gastric cancer (AGC) prolongs survival compared to the best supportive care. However, in clinical practice, ramucirumab monotherapy is sometimes used as third- or later-line treatment for AGC refractory to fluoropyrimidine and taxanes. This study evaluated the efficacy and safety of salvage-line ramucirumab monotherapy for treating AGC. Methods The subjects of this retrospective study were advanced gastric or gastro-esophageal junction adenocarcinoma patients who received ramucirumab monotherapy after failure of 2 or more prior regimens containing fluoropyrimidine and taxanes but not ramucirumab. Results From June 2015 to April 2017, 51 patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 1.8 (95% confidence interval [CI] = 1.6–2.2) and 5.1 (95% CI = 4.0–6.8) months, respectively. The objective response and disease control rates were 2 and 17%, respectively. Grade 3 adverse events (AEs; e.g., anemia, fatigue, hypertension, proteinuria, intestinal bleeding) occurred in seven (13%) patients, but no grade 4 AEs and treatment-related deaths were observed. A neutrophil–lymphocyte ratio (NLR) of Conclusions Salvage-line ramucirumab monotherapy has acceptable toxicity and comparable efficacy to second-line treatment; therefore, we consider physicians might choose this therapy as a salvage-line treatment option for AGC refractory to the standard therapies.

Background: This study aimed to evaluate the efficacy and safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev) in clinical practice. Methods: We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF as preventing or treating grade 3/4 neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0. Results A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2–16.9), and the median OS was 24.2 months (13.6–NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients, and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or higher neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.8%), no dose adjustment was required. Conclusions PEG-G-CSF is useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

We recently reported the clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using surgical specimens; patients with homogeneously HER2 positive gastric cancer benefitted more from trastuzumab. However, the majority of patients are diagnosed by endoscopic biopsy, and surgical specimens are not available in these patients. The aim of this study is to verify clinical significance of HER2 heterogeneity on trastuzumab efficacy using biopsy specimens.Eighty-seven patients, who received trastuzumab-based chemotherapy and whose endoscopic biopsy specimens were available for HER2 assessment, were consecutively enrolled. When all tumor cells in all biopsy specimens overexpressed HER2 protein, it was defined as homogeneously HER2 (homo-HER2) positive group, and the others were defined as heterogeneously HER2 (hetero-HER2) positive group. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were evaluated.Thirty-four patients (39%) were diagnosed as the homo-HER2 group and 53 patients (61%) were the hetero-HER2 group. After the median follow-up period of 17.8 months, the median PFS and OS were 7.6 and 17.8 months, respectively. Significant survival differences were shown between the two groups; the homo-HER2 group showed significantly longer PFS (10.8 vs. 6.1 months, HR 0.469 95% CI 0.29-0.77, p = 0.003) and OS (29.3 vs. 14.4 months, HR 0.352 95% CI 0.20-0.61, p 0.001). ORR was 68.6% in this cohort. Higher response rate (85.2% vs 58.1%, p = 0.020) and deeper response (- 49.0% vs - 40.0%, p = 0.018) were also found in the homo-HER2 group.Similar to surgical specimens, we verified clinical significance of HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens.

Background: Colorectal cancer (CRC) with lung metastases has an unfavorable prognosis. However, nowadays, even advanced CRC can have a favorable outcome in certain cases. A complete response (CR) is a rare event in advanced CRC with lung metastases. Herein, we report 2 rare cases of advanced CRC attaining a CR. Case Presentation: Case 1 was a 58-year-old man who underwent laparoscopic ileocecal resection for cecum cancer with multiple metastases to the lungs in 2011. We performed treatment with mFOLFOX6 and bevacizumab chemotherapy in August 2011. After 11 courses, computed tomography (CT) revealed a CR to chemotherapy in February 2012. He has remained disease-free for 5 years and 3 months. Case 2 was a 70-year-old woman who underwent laparoscopic ileocecal resection for cecum cancer in August 2010. Recurrence of multiple metastases to both lungs was detected in November 2010. We started treatment with XELOX and bevacizumab chemotherapy in January 2011. In January 2011, CT after 14 courses revealed disappearance of the lung lesions, thereby indicating a CR. She has remained disease-free for 5 years and 4 months. Conclusion: We encountered 2 patients with CRC with lung metastases who were treated with chemotherapy leading to a CR. Cases resulting in such a desirable outcome are extremely rare.

Efficacy and safety of biweekly cetuximab plus irinotecan were evaluated to provide guidance for its use in Japan as third‐line treatment for pretreated metastatic colorectal cancer (mCRC) patients harboring wild‐type KRAS exon 2. Objective response rate (ORR) was used as primary endpoint based on an expected proportion of 0.23 with confidence width of 0.298 (95% CI, 0.105‐0.403), which showed 35 to be the minimal participant number. Forty patients, refractory to first‐ and second‐line chemotherapy containing irinotecan, oxaliplatin, and fluoropyrimidine, were enrolled. ORR and disease control rate were 25.0% (95% CI: 11.5‐38.4) and 72.5% (95% CI: 56.8‐86.4), respectively. Median progression‐free survival (PFS), overall survival (OS), and number of courses were 5.70 months (95% CI: 2.7‐7.9), 15.1 months (95% CI: 11.8‐19.0), and 10.5 (range: 3.0‐31.0), respectively. Grade 3 adverse events were skin toxicity (12.5%), diarrhea (10.0%), neutropenia (5.0%), febrile neutropenia (5.0%), nausea (5.0%), anorexia (5.0%), and fatigue (2.5%). C max mean was 723.2 μg/mL after first dose. High area under the curve (AUC)last variance was associated with t1/2 range of 131.2‐1209.6 hours (median, 174.4 hours). Early tumor shrinkage (ETS) and median depth of response were 25.0% and 13.0%, respectively. Mutation frequencies in KRAS exon 3 or 4, NRAS,BRAF, and PIK3CA were 5.5%, 2.7%, 8.3%, and 5.5%, respectively. Multivariate Cox regression analysis assessed whether any gene mutations and ETS are predictors for PFS, and whether performance status, synchronous metastasis, and ETS are predictors for OS. Importantly, the data provide guidance for a biweekly cetuximab plus irinotecan regimen in mCRC patients.

One-year adjuvant S-1 monotherapy following D2 gastrectomy has been the Japanese treatment standard for pathological stage II or III gastric cancer since the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) was concluded in 2007. Trial patients were selected according to the 13th edition of the Japanese classification (JC-13). The JC-13 and the TNM classification underwent major revisions in 2010 (JC-14/TNM-7). However, neither the recent therapeutic results for patients with stage II/III disease defined by the current system nor comparisons with the ACTS-GC-results have been reported.The 390 study patients had pathological stage II/III gastric cancer defined by the JC-14/TNM-7 and treated with S-1 following D2 gastrectomy between 2008 and 2012. The completion rate of 1-year S-1, first relapse site, and stage-specific survival according to the JC-14/TNM-7, JC-13, and TNM-6 were examined and the results compared with those of the ACTS-GC.The completion rate for 1-year S-1 (69.5%) was slightly higher than in the ACTS-GC. The recurrence pattern was almost identical. The 5-year overall survival rates of pathological IIA, IIB, IIIA, IIIB, and IIIC in the JC-14/TNM-7 were 96.0, 85.5, 81.8, 72.0, and 51.1%, respectively. Their 5-year overall and relapse-free survival rates by the JC-13 and TNM-6 systems were favorable as compared to those of ACTS-GC patients for all substages.Survival outcome shown in this study of patients treated with 1-year adjuvant S-1 after D2 gastrectomy at a high-volume cancer hospital will provide a reference for future adjuvant trials targeting JC-14/TNM-7 stage II/III disease.

Background The Japan Clinical Oncology Group (JCOG) prognostic index, consisting of performance status, primary tumor resected, number of metastases, and serum alkaline phosphatase, has been one of the robust prognostic indices for patients with advanced gastric cancer on the basis of which clinical trials have stratified prognosis. Only a few studies, however, have utilized the JCOG prognostic index in daily practice. Methods We conducted a retrospective study on patients with advanced gastric cancer who received first-line platinum-containing chemotherapy at a single institute between 2011 and 2017. Prognostic factors were evaluated using a Cox proportional regression model. Results A total of 608 patients were enrolled. Multivariate analysis showed that performance status ≥1, presence or absence of primary tumor, serum alkaline phosphatase, neutrophil-to-lymphocyte ratio ≥4, and diffuse-type histology were significantly associated with worse prognosis, whereas the number of metastases was not. Although the original prognostic index could not adequately stratify patients into three risk groups, the modified index (good: 0 and 1, moderate: 2 and 3, poor: 4-6), which was established by incorporating diffuse-type histology and high neutrophil-to-lymphocyte ratio, demonstrated excellent stratification. The median overall survival of the good (n = 315), moderate (n = 243), and poor (n = 54) risk groups was 20.5, 13.5, and 10.2 months, respectively. Hazard ratios (HRs) were 1.69 [95% confidence interval (CI), 1.40-2.04; good versus moderate] and 1.52 (95% CI, 1.11-2.08; moderate versus poor). This novel index also demonstrated a statistically significant stratification of survival after progression following first-line chemotherapy (good versus moderate: HR, 1.41; 95% CI, 1.16-1.70; moderate versus poor: HR, 2.00; 95% CI, 1.45-2.74). Conclusions The modified JCOG prognostic index showed excellent stratification of overall survival in real-world patients, which could also help determine the need for treatment changes throughout the continuum of chemotherapy., Highlights • The applicability of the JCOG prognostic index in daily practice was investigated for advanced gastric cancer (AGC). • The JCOG prognostic index could not adequately stratify patients into three risk groups. • The modified JCOG prognostic index incorporates diffuse-type histology and high NLR (≥4) into the JCOG prognostic index. • The modified JCOG prognostic index showed excellent stratification in terms of overall survival and progression. • The modified JCOG prognostic index may help determine the need for treatment changes during first-line chemotherapy in AGC.

The REGARD trial demonstrated that ramucirumab monotherapy improved both overall survival (OS) and progression-free survival (PFS) compared with best supportive care plus placebo as second-line treatment for patients with advanced gastric cancer. However, the efficacy and safety of ramucirumab monotherapy for previously treated Japanese patients with advanced gastric cancer remains unknown. Previously treated Japanese patients with advanced gastric cancer who received ramucirumab monotherapy between June 2015 and March 2016 at the Cancer Institute Hospital were enrolled in the study. OS, PFS, best overall response, and safety profiles were retrospectively evaluated. Nineteen patients were enrolled in this study. Ramucirumab monotherapy was generally administered as third-line therapy. After a median follow-up period of 7.4 months, the median PFS was 2.1 months (95% CI 1.0–3.5), and median OS was 12.9 months (95% CI 2.3, not reached). In 13 patients who had measurable lesions on radiologic examination, partial response was observed in one patient (7.7%) and stable disease was observed in five patients (38.5%). A total of 12 patients (63.2%) had adverse events (AEs). Common AEs included hypertension (8 patients, 42.1%), fatigue (6 patients, 31.6%), and bleeding (5 patients, 26.3%). Grade 3 AEs included gastrointestinal bleeding and aspiration pneumonia (1 patient each, 5.3%). Our data suggest that ramucirumab monotherapy in Japanese patients with previously treated advanced gastric cancer has comparable efficacy and safety profiles as reported in the REGARD trial.

Taxane monotherapy is widely used for advanced gastric cancer (AGC) after failure of standard first-line chemotherapy with fluoropyrimidine and cisplatin. Triplet chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is a promising regimen for first-line chemotherapy of AGC. The aim of this study was to evaluate the efficacy of taxane monotherapy in patients refractory to DCS. We retrospectively evaluated the efficacy and safety of taxane monotherapy in patients with AGC refractory to first-line therapy with DCS between January 2010 and April 2015. Selection criteria were as follows: ECOG PS of 0–2, treatment with taxane monotherapy in second-line or third-line therapy after failure of second-line irinotecan, absence of massive ascites, and adequate organ function. A total of 30 patients were included in this study. Of these, 15 patients received paclitaxel while another 15 received nanoparticle albumin-bound paclitaxel in either second- or third-line treatment. Median age for the second/third-line group was 64.0/62.0 (range 27–75/42–75); 14/13 (93.3/86.7%) had ECOG PS of 0 or 1. No patients achieved complete or partial response and stable disease was observed in 37.5/35.7% of the patients in the second/third line. Median progression-free survival and overall survival were 3.4 and 5.8 months in the second-line group, and 2.0 and 4.5 months in the third-line group, respectively. The incidences of any grade ≥3 adverse events in the second-line group and the third-line group were 60.0 and 33.3%, respectively. There was no treatment-related death. Taxane monotherapy after DCS failure had acceptable toxicities but was ineffective in AGC patients.

There is currently no clinical data regarding the efficacy of trastuzumab treatment for the progression of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) occurring during trastuzumab-based chemotherapy. The aim of this study was to retrospectively examine the clinical benefits of trastuzumab for HER2-positive AGC patients who progressed during first-line trastuzumab-based chemotherapy. Among the 108 patients treated with trastuzumab combined with fluoropyrimidine and cisplatin as first-line therapy, 46 HER2-positive AGC patients who received cytotoxic agents with or without trastuzumab subsequent to disease progression were included. Of these, the efficacy and safety outcomes of 26 patients who continued trastuzumab were compared with those of the 20 patients who discontinued trastuzumab. No difference in response rate (18.2 vs. 15.8%, P=1.00) was observed between the two groups. Progression-free survival (PFS) time was numerically longer in the chemotherapy combination with trastuzumab group than in the chemotherapy combination without trastuzumab group (median, 4.0 vs. 2.3 months), with no significance [hazard ratio (HR), 0.63; P=0.14]. In the subset analysis, continuation of trastuzumab significantly improved PFS time in selected subgroups of patients with tumors exhibiting HER2 expression scores of 3+ (HR, 0.41; P=0.04), intestinal-type histology (HR, 0.32; P6 months (HR, 0.44; P=0.04). The survival times for the trastuzumab beyond progression (TBP) and non-TBP groups were similar (HR, 1.06; P=0.88), with equivalent overall survival times in the subgroups with immunohistochemistry scores of 3+ (HR, 0.97; P=0.94), intestinal-type histology (HR, 0.53; P=0.19), and a first PFS time of >6 months (HR, 0.62; P=0.31). There were no differences in the incidence rates of toxicity, including cardiac dysfunction, between the two groups. The study results suggest that selected HER2-positive AGC patients may benefit from trastuzumab continuation during first progression, and further prospective studies are warranted.

Although early tumor shrinkage (ETS) predictions of the efficacy and depth of response (DpR) reflects clinical outcomes in chemotherapy with epidermal growth factor receptor inhibitor regimens to treat metastatic colorectal cancer, their value in assessing treatments for advanced gastric cancer (AGC) is unclear. Here we evaluated relationships between ETS and DpR and clinical outcomes in AGC patients treated with first-line chemotherapy. We retrospectively enrolled 612 consecutive patients treated with first-line chemotherapy for AGC between January 2010 and June 2016. ETS and DpR were defined as changes from baseline in summed longest diameters in target lesions at 8 (±4) weeks for ETS and at the smallest observed volume for DpR. Eligible patients were sorted into HER2+ (n = 100) and HER2− (n = 186) groups. Median follow-up was 14.8 months. The overall response rate and disease control rates were 64 and 87% in the HER2+ group and 53.2 and 86.0% in the HER2− group. Respective median PFS and OS were HER2+: 7.9 and 20.8 months and HER2−: 6.6 and 13.8 months. The respective ETS rate and median DpR were HER2+: 70 and 44% and HER2−: 57.5 and 24%. Clinical outcomes and ETS/DpR were correlated, especially in the HER2+ group (OS: P

The purpose of this study was to assess hepatic arterial infusion (HAI) of oxaliplatin combined with intravenous 5-fluorouracil (5-FU) and l-leucovorin (l-LV) in colorectal cancer (CRC) patients with systemic chemotherapy failure in a phase I/II trial. CRC patients with unresectable liver metastases following standard systemic chemotherapy failure were eligible. A catheter-port system for HAI was placed using interventional radiology. In phase I, escalating doses of oxaliplatin for levels 1 and 2 were set at 50 and 100 mg/m2, respectively, and were combined with fixed doses of intravenous 5-FU (200 mg/m2 bolus and 2400 mg/m2/46-h continuous infusion) and l-LV (200 mg/m2). The dose-limiting toxicity (DLT) was assessed, and the recommended dose (RD) was estimated. In phase II, patients receiving RD were included to assess the 6-month survival rate (the expected rate 80%), overall survival time, tumor response, and toxicity. In phase I, none of the six enrolled patients exhibited DLT. RD for oxaliplatin by HAI was estimated as 100 mg/m2. In phase II, seven additional patients were enrolled. In patients receiving RD (n = 10), the disease control rates for total lesions and liver lesions were 30 and 70%, respectively. The 6-month survival rate and the overall survival time were 53.3% and 6.9 months, respectively. There were no adverse reactions equivalent to DLT in any of the patients. The estimated RD for oxaliplatin by HAI in combination with intravenous 5-FU and l-LV was 100 mg/m2. This combination therapy was feasible and safe, but the expected efficacy was not achieved.

Background Carcinoembryonic antigen (CEA) is the most widespread tumour marker of colorectal cancer, however, it is not helpful to judge for recurrence of the disease because of low sensitivity and specificity. It is recommended for patients who were diagnosed with pStage III colorectal cancer to receive adjuvant chemotherapy after curative resection and to measure CEA every 3 months. Moreover, It is reported that postoperative CEA level is more informative than preoperative CEA level about the impact for prognosis but the association between postoperative, post adjuvant CEA level and the prognosis is still unclear. This study aimed to evaluate whether perioperative and post adjuvant CEA level was useful for estimation of the prognosis in stage III CRC. Methods This retrospective study was conducted at the Cancer Institute Hospital of JFCR. A total of 567 consecutive patients who underwent curative resection for stage III colon adenocarcinoma and adjuvant chemotherapy in our hospital from March 2005 to December 2013 were identified. The patients who received bevacizumab as adjuvant chemotherapy and didn’t measure CEA were excluded. Results The 3-year DFS rate in patients with normal preoperative CEA is superior to patients with high preoperative CEA (HR:1.59;95%CI:1.10-2.31, p = 0.014). There was no significant difference in the 5-year OD between the two groups (HR1.17;95%CI:0.62–2.20, p = 0.63). The 3-year DFS rate and 5-year OS rate in patients with normal postoperative CEA were superior to patients with high postoperative CEA (HR:2.18;95%CI:1.23–3.88, p = 0.0079, and HR:2.40;95%CI:1.02–5.69, p = 0.046). The 3-year DFS in patients with normal postadjuvant CEA was superior to patients with high postadjuvant CEA(HR1.79;95%CI:1.23–3.88, p = 0.022), whereas regarding the 5-year OS there was no significant difference between the two groups (HR2.10;95%CI:0.98–4.53, p = 0.057).In the multivariate analysis, the histological type and N-stage were predictive factors of OS. Conclusions High postoperative and post adjuvant CEA level may be negative prognosis factors for OS in patients who underwent curative resection for stage III CRC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background: This study aimed to evaluate in clinical practice the efficacy and safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev). Methods: We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF for treating neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0. Results: A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2–16.9), and the median OS was 24.2 months (13.6–NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or higher neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.7%), no dose adjustment was required.Conclusions: PEG-G-CSF was useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

Background Different approaches are used to treat resectable tumours in patients having adenocarcinoma at the oesophagogastrointestinal junction (EGJ) or in the stomach. However, there is limited information about treatment efficacy for patients at metastatic stage. A recent molecular analysis of upper gastrointestinal tract adenocarcinoma revealed that the anatomical location can influence the molecular backgrounds of tumours. This study sought to elucidate whether different therapeutic approaches should be used for EGJ tumours relative to those in the stomach. Methods This retrospective cohort study was conducted at a single institute in Japan. Patients having metastatic or recurrent adenocarcinoma in the EGJ or stomach who underwent platinum doublet chemotherapy between January 2007 and August 2014 were enrolled. Patients in the EGJ tumour group had tumours having an epicentre within 2 cm proximal or 5 cm distal to the estimated anatomical EGJ and cardia. Results Among 378 consecutively enrolled patients, 61 were grouped into the EGJ group and the remainder comprised the stomach group. The EGJ group had more men and lower incidence of diffuse type and Borrmann type IV tumours and peritoneum metastasis compared with the stomach group. The median overall survival of patients in the EGJ and stomach groups was similar (17.3 months (95% CI 13.5 to 23.2) vs 14.5 months (95% CI 13.3 to 16.4)). No statistically significant difference was observed in progression-free survival. Although the overall postprogression survival differed significantly between the EGJ and stomach groups (8.2 months (95% CI 5.7 to 12.7) vs 7.1 months (95% CI 6.1 to 7.8)), on grouping patients by histological type, the two groups exhibited similar postprogression survival. Multivariate analysis demonstrated that diffuse-type histology, higher serum CA19-9 levels and neutrophil to lymphocyte ratios were independent poor prognostic factors. Conclusions Different clinicopathological features of EGJ adenocarcinoma were not associated with clinical outcomes of platinum doublet chemotherapy. Histological subtype rather than anatomical location has more significance for treatment decisions for advanced gastric cancers.

In the ATTRACTION-2 trial, nivolumab significantly improved the survival of advanced gastric cancer patients. The pretreatment neutrophil-to-lymphocyte ratio (NLR) is prognostic in patients receiving immune checkpoint inhibitors (ICIs) to treat various cancers. However, a few reports have explored the relationships between NLR changes during ICI treatment and patient survival. Here, we evaluated factors (including NLR changes in patients on nivolumab monotherapy) prognostic for gastric cancer patients. We retrospectively analyzed 98 gastric cancer patients who received nivolumab (3 mg/kg or 240 mg/body bi-weekly) at our institution between December 2014 and September 2018. We evaluated pretreatment data, and those obtained 30 and 60 days after treatment commenced. We explored the prognostic utility of relative NLR changes in terms of the overall survival (OS) of patients on nivolumab monotherapy. Over a median of 4.9 months of follow-up, 98 gastric cancer patients received a median of four treatment courses. The overall response and disease-control rates were 25% and 52%, respectively. The median OS was 6.4 months (95% confidence interval [CI] 4.6–9.1). On multivariate analysis, factors poorly prognostic in terms of OS were an ECOG performance status of 0–1, a pretreatment NLR > 3, and an NLR difference ≧ 2 over the 60 days before and after nivolumab administration (∆NLR60). Patients with ∆NLR60 values

Yusuke Kitagawa, Hiroki Osumi, Eiji Shinozaki, Yumiko Ota, Izuma Nakayama, Takeshi Suzuki, Takeru Wakatsuki, Takashi Ichimura, Mariko Ogura, Akira Ooki, Daisuke Takahari, Mitsukuni Suenaga, Keisho Chin, Kensei YamaguchiDepartment of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JapanPurpose: Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line treatment, the benefit of amrubicin (AMR) and salvage chemotherapy in those who develop platinum-refractory GI-NEC remains unknown. This study aimed to evaluate the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC.Patients and methods: Platinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 were retrospectively analyzed. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. PFS and OS were estimated using Kaplan-Meier methods and compared using log-rank tests.Results: In total, 16 patients were enrolled. Of them, 13 (81.3%), 1 (6.2%), and 2 (12.5%) received cisplatin plus irinotecan, cisplatin plus etoposide, and fluoropyrimidine plus platinum, respectively, before AMR monotherapy. The primary sites of NEC included the esophagus (N=3, 18.8%), stomach (N=10, 62.5%), duodenum (N=1, 6.2%) and colorectum (N=2, 12.5%). Patients were administered a median of 3 (range, 1–15) cycles of AMR. The ORR was 6.3%, and the median PFS and OS were 2.9months (95% CI: 1.7–7.4) and 13.8months (95% CI: 7.9–23.5), respectively. Neutropenia was the most serious adverse event. Grade 3 or higher neutropenia and febrile neutropenia occurred in 50.0% and 6.2% of patients, respectively. Other nonhematological toxicities were not severe, and no treatment-related deaths occurred. The 10 patients who received subsequent chemotherapy after AMR had significantly longer OS than those who did not (17.3months vs 8.9months; p=0.018). The median PFS of those who received organ-specific subsequent chemotherapy after AMR was 3.8months, which was longer than that of those who received prior AMR.Conclusion: AMR is feasible with minimal side effects for platinum-refractory GI-NEC. Organ-specific subsequent chemotherapy after AMR may improve patient survival.Keywords: amrubicin monotherapy, platinum refractory, gastrointestinal neuroendocrine carcinoma

Trastuzumab with cisplatin and fluoropyrimidines improves overall survival (OS) in patients with HER2-positive advanced gastric cancer (AGC). S-1 plus oxaliplatin (SOX) is one of the standard regimens for HER2-negative AGC in Japan. However, few studies have evaluated trastuzumab combined with SOX in patients with HER2-positive AGC. This was a multicenter, phase II study conducted at 10 institutions in Japan. Patients with HER2-positive AGC received S-1 twice a day on days 1–14 and oxaliplatin and trastuzumab on day 1 of a 21-day cycle. The primary endpoint was the confirmed overall response rate (ORR), and the secondary endpoints were OS, progression-free survival (PFS), and safety. The sample size was 75 to have 90% power with an alpha error of 0.1 (one-sided), expecting an ORR of 65% and threshold of 50%. From June 2015 to January 2018, 75 patients were enrolled. The ORR was 70.7% [95% confidence interval (CI) 59.0–80.6]. The median OS and PFS were estimated as 18.1 months (95% CI 15.6–26.5) and 8.8 months (95% CI 7.4–12.2), respectively. The major grade 3 or 4 adverse events were sensory neuropathy (16.0%) and neutropenia (10.7%). Trastuzumab with SOX had promising activity with well-tolerated toxicities for patients with HER2-positive AGC. UMIN000017602.

S-1 monotherapy is one of the standard adjuvant treatments for patients with stage II and III gastric cancers. Early recurrence after S-1 adjuvant therapy has a poor prognosis. This study aimed to clarify the treatment outcomes of systemic chemotherapy and explore encouraging regimens. This was a multicenter retrospective study. Among gastric cancer patients who underwent curative gastrectomy followed by adjuvant S-1 monotherapy, patients who experienced a recurrence while receiving adjuvant therapy or within 6 months after completion and started systemic chemotherapy at four institutions between 2005 and 2015 were eligible. A total of 112 patients were included. The main treatment regimens were weekly paclitaxel (n = 38, 34%), irinotecan plus cisplatin (n = 31, 28%), capecitabine plus cisplatin (n = 7, 6%), and irinotecan monotherapy (n = 6, 5%). For all patients, median progression-free survival and overall survival were 3.7 and 11.4 months, respectively. Among 77 patients with measurable lesions, the overall response and disease control rates were 24.7% and 62.3%, respectively. Multivariate analyses for overall survival showed that Eastern Cooperative Oncology Group performance status 2 [hazard ratio (HR) 3.71; 95% confidence interval (CI) 1.78–7.73] and undifferentiated histological type (HR 2.04; 95% CI 1.35–3.44) were independent prognostic factors, and treatment regimens were not prognostic. Exploratory comparisons did not show statistically significant differences between treatment regimens. This study of the largest number of patients with early recurrence after S-1 adjuvant monotherapy demonstrated that the prognosis for patients treated by all regimens was similar and poor.

Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m2) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m2 twice daily (bid) on days 1–5 and 15–19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m2 bid on days 1–5 and 15–19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC.

Hiroki Osumi, Daisuke Takahari, Keisho Chin, Mariko Ogura, Takashi Ichimura, Takeru Wakatsuki, Takeshi Suzuki, Yumiko Ota, Izuma Nakayama, Akira Ooki, Mitsukuni Suenaga, Eiji Shinozaki, Kensei Yamaguchi Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Background: Oral fluoropyrimidine plus platinum is a standard first-line treatment for advanced gastric cancer (AGC). However, this treatment is problematic for AGC patients with massive ascites or inadequate oral intake. This study aimed at evaluating the efficacy and safety of modified oxaliplatin (L-OHP) with l-leucovorin (l-LV) and bolus/continuous infusion of 5-fluorouracil (5-FU) (mFOLFOX6) regimen for patients with massive ascites or inadequate oral intake.Methods: This retrospective study was conducted at a single Japanese institute from November 2015 to May 2018. The mFOLFOX6 regimen consisted of 85mg/m2 L-OHP, 400mg/m2 bolus of 5-FU, and 400mg/m2 1-LV on the first day, followed by 2,400mg/m2 of 5-FU as a continuous infusion in 46 hours for first-line treatment. The definition of inadequate oral intake was the need for total parenteral nutrition (TPN). Massive ascites was defined as continuous ascites from the pelvic cavity to the upper abdomen. Improvement in oral intake was defined as no TPN for more than 7 days, and improvement in ascites was defined as a decrease in ascites of more than one grade defined by the Japan Clinical Oncology Study Group trial (JCOG0106).Results: Among the 364 patients with AGC who received first-line chemotherapy, 17 patients (13 [76.5%] had inadequate oral intake, and four [23.5%] had massive ascites) were enrolled in this study. Median time to treatment failure and overall survival were 4.8 (95% CI=1.5–7.5) and 8.8 months (95% CI=2.3–not available), respectively. Objective improvements in oral intake and ascites were seen in 11 of 13 patients (84.6%) and 6 of 12 patients (50%), respectively. The major grade 3 or 4 adverse events were neutropenia (35.3%), febrile neutropenia (5.9%), fatigue (5.9%), anorexia (5.9%), and infection (5.9%). No treatment-related deaths occurred.Conclusion: We found that mFOLFOX6 can be a novel treatment option as the first-line treatment for AGC patients with massive ascites or inadequate oral intake. Keywords: advanced gastric cancer, FOLFOX, massive ascites, inadequate oral intake&nbsp

Background We recently reported the clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using surgical specimens; patients with homogeneously HER2 positive gastric cancer benefitted more from trastuzumab. However, the majority of patients are diagnosed by endoscopic biopsy, and surgical specimens are not available in these patients. The aim of this study is to verify clinical significance of HER2 heterogeneity on trastuzumab efficacy using biopsy specimens. Methods Eighty-seven patients, who received trastuzumab-based chemotherapy and whose endoscopic biopsy specimens were available for HER2 assessment, were consecutively enrolled. When all tumor cells in all biopsy specimens overexpressed HER2 protein, it was defined as homogeneously HER2 (homo-HER2) positive group, and the others were defined as heterogeneously HER2 (hetero-HER2) positive group. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were evaluated. Results Thirty-four patients (39%) were diagnosed as the homo-HER2 group and 53 patients (61%) were the hetero-HER2 group. After the median follow-up period of 17.8 months, the median PFS and OS were 7.6 and 17.8 months, respectively. Significant survival differences were shown between the two groups; the homo-HER2 group showed significantly longer PFS (10.8 vs. 6.1 months, HR 0.469 95% CI 0.29–0.77, p = 0.003) and OS (29.3 vs. 14.4 months, HR 0.352 95% CI 0.20–0.61, p

The Raf murine sarcoma viral oncogene homolog B (BRAFV600E ) mutation (MT) in metastatic colorectal cancer (CRC) is a well-known prognostic indicator and a negative predictive biomarker for antiepidermal growth factor receptor (EGFR) treatment. However, the clinical characteristics and significance of BRAFnon-V600E MTs remain unclear. Here, we evaluated the clinical characteristics of BRAFnon-V600E MTs vs. those of other MTs in the EGFR signaling pathway, including BRAFV600E . Consecutive CRC patients in our institute from June 2012 to November 2013 were enrolled in our study. Multiplex genotyping of the EGFR pathway was performed with archival samples using a Luminex Assay for BRAFV600E /BRAFnon-V600E , KRAS/NRAS exons 2-4, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA). We analyzed correlations among the MT profiles, clinical data and primary tumor locations in CRC. All statistical analyses were performed using R software. CRC samples (824) from 374 (45.4%) male and 450 (54.6%) female patients were analyzed, of which 154 (18.7%), 202 (24.5%), 270 (32.8%) or 198 (24.0%) had Stages I, II, III or IV or recurrent CRC, respectively. The frequencies of BRAFV600E /BRAFnon-V600E , KRAS (including exons 2-4), NRAS and PIK3CA MTs were 5.3/1.7, 41.4, 3.3 and 9.6%, respectively. The characteristics of patients with the BRAFV600E MT were an age of ≥65 years old, a right-sided primary tumor location, poorly differentiated histology and an advanced disease stage. In contrast, the characteristics of patients with BRAFnon-V600E MTs were a left-sided primary tumor location and well-differentiated histology. BRAFnon-V600E MTs were relatively rare and showed different characteristics compared to the BRAFV600E MT. These results may contribute to future precision medicine.

Izuma Nakayama, Keisho Chin, Daisuke Takahari, Mariko Ogura, Takashi Ichimura, Takeru Wakatsuki, Hiroki Osumi, Yumiko Ota, Takeshi Suzuki, Mitsukuni Suenaga, Eiji Shinozaki, Kensei Yamaguchi Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Purpose: Gastric cancer in young adults (GCYA) is known to have distinct clinicopathological features, including a female predominance and diffuse-type histology. Previous reports have focused on patients who had undergone gastrectomy with curative intent. Information concerning the treatment of unresectable advanced- or recurrent-stage GCYA is lacking. Therefore, we aimed to investigate whether the distinct clinicopathological features of GCYA affect the outcome of systemic chemotherapy.Patients and methods: We conducted a retrospective cohort study at a single institution in Japan. GCYA was classified as a disease in individuals who were

205 Background:TAS-118 (S-1 and leucovorin) + oxaliplatin (L-OHP) improved overall survival (OS) compared to S-1 + cisplatin for patients (pts) with advanced gastric cancer (GC) (Kang, Lancet Oncol. 2020). This study investigated the feasibility of peri (pre and post)-operative (op) chemotherapy (chemo) with TAS-118 ± L-OHP in pts with locally advanced resectable GC. While it was reported that pre-op TAS-118 + L-OHP followed by D2 gastrectomy was well tolerated and showed promising efficay (Takahari, ASCO-GI. 2020), the recommended post-op chemo regimen, TAS-118 or TAS-118 + L-OHP, has yet to be determined. Methods:Eligible pts with GC of clinical T3-4N1-3M0 were enrolled. The protocol treatment consisted of pre-op chemo with 4 courses of TAS-118 (40-60 mg/body, orally, twice daily, 7 days) + L-OHP (85 mg/m2, intravenously, day 1) in a 2-week cycle, and gastrectomy with D2 lymphadenectomy, followed by post-op chemo with 12 courses of TAS-118 (step 1) and 8 courses of TAS-118 + L-OHP (step 2). Step 2 was started if the dose-limiting toxicity (DLT) occurred in < 6 of 10 pts in step 1. Up to 20 pts were included in the analysis of feasibility after a recommended regimen was determined. Results:Between December 2016 and February 2019, 45 pts were enrolled. The numbers of pts with cT3/4a and cN1/2/3 were 13/32 and 25/17/3, respectively. Excluding 14 pts (4 achieving pathological complete response, 4 not satisfying the criteria for post-op chemo, 3 physician judgement or pt withdrawal, 2 progressive disease, 1 adverse event [AE]), 31 pts (11/20 in step 1/2) received the post-op chemo. No DLT was observed in either step. The post-op chemo completion rate was 90.9% (95% CI, 63.6-99.5) in step 1 and 80.0% (95% CI, 59.9-92.9) in step 2. The median relative dose intensity of TAS-118 in step 1 was 83.3%, and those of TAS-118 and L-OHP in step 2 were 69.9% and 74.3%, respectively. One pt in step 2 discontinued post-op chemo due to AE. Grade ³ 3 AEs observed in ≥ 10% of pts were weight loss in both step 1 and step 2 (2 in each), and hypokalemia (n = 3) and neutropenia (n = 2) in step 2. At 1-year follow-up after the last pt was enrolled, recurrence-free survival and OS rates were 91.1% (95% CI, 78.0-96.6) and 100%, respectively at 12 months, and 69.1% (95% CI, 49.6-82.3) and 95.5% (95% CI, 71.9-99.3), respectively at 24 months. Conclusions:Taken together with the feasibility and efficacy of pre-op chemo, peri-op chemo with TAS-118 + L-OHP with D2 gastrectomy was well tolerated and showed promising efficacy. Clinical trial information: UMIN000024688.

Gastric cancer with extensive lymph node metastasis is commonly considered unresectable, with a poor prognosis. We previously reported the results of the use of cisplatin and S-1 as preoperative chemotherapy for gastric cancer with extensive lymph node metastasis; docetaxel, cisplatin, and S-1 (DCS) have now been investigated for the same purpose.Patients received two or three 28-day cycles of DCS therapy (docetaxel at 40 mg/mBetween July 2011 and May 2013, 53 patients were enrolled, of whom 52 were eligible. The clinical RR was 57.7 % [30/52, 80 % confidence interval 47.9-67.1 %, p = 0.89], and R0 resection was achieved in 84.6 % of patients (44/52). Common grade 3 or grade 4 adverse events during DCS therapy were leukocytopenia (18.9 %), neutropenia (39.6 %), and hyponatremia (15.1 %). The common grade 3 or grade 4 surgical morbidity was abdominal infection (10.2 %). The pathological RR was 50.0 % (26/52).Preoperative DCS therapy was feasible but did not show a sufficient RR. Preoperative cisplatin and S-1 therapy is still considered the tentative standard treatment for this population until survival results are known.

A germ cell tumor is the most common form of malignancy in early male life, and can be classified as either seminomatous or nonseminomatous. Choriocarcinoma, comprised of nonseminomatous germ cells, is the most aggressive type of germ cell tumor and characteristically metastasizes to the retroperitoneal lymph nodes and less frequently to the lungs, liver, bone or brain [Shibuya et al., 2009;48: 551–554]. A 56-year-old man was admitted to another hospital complaining of abdominal distension. Symptoms included anorexia, vomiting, and diarrhea. The patient was diagnosed with an extragonadal germ cell tumor and referred to our hospital to receive chemotherapy. The day after admission, the patient’s abdominal distension gradually worsened. An emergency operation revealed venous hemorrhage from the surface of a metastatic extragonadal germ cell tumor between the ligament of Treitz and the inferior mesenteric vein in a horizontal position. Hemostatic treatment was performed with 4-0 proline thread attached to a medicated cotton sponge, rather than using a simple proline thread, and the closure area was manually compressed. Chemotherapy was initiated on postoperative day 10. A metastatic extragonadal germ cell tumor that causes massive hemorrhage and gastrointestinal hemorrhage is very rare, and represents a life-threatening emergency. If the patient’s condition carries a substantial risk of bleeding to death, it may be worthwhile to attempt abdominal operations.

4525 Background: Addition of an anti-PD-1 antibody to trastuzumab (Tmab) reportedly enhances ADCC activity of Tmab, leading to an additive antitumor effect. We investigated the safety and tolerability of nivolumab (Nivo) plus Tmab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for pts with HER2-positive (+) advanced gastric cancer (AGC). Here, we report the safety evaluation results. Methods: This open-label, phase 1b study was conducted at four centers in Japan. The study consisted of safety (n = 12) and expansion (n = 24–30) parts. Chemotherapy-naïve pts aged ≥ 20 years with histopathologically confirmed HER2+ AGC and measurable lesions were eligible. In the safety evaluation, pts were assigned to cohort 1 or 2 in sequence. Pts received Nivo (360 mg, day 1), Tmab (course 1: 8 mg/kg; course 2–: 6 mg/kg, day 1), Ox (130 mg/m2, day 1) and either S-1 (40 mg/m2 bid, days 1–14; cohort 1) or Cape (1000 mg/m2 bid, days 1–14; cohort 2) every 3 weeks until disease progression or unacceptable toxicity. The primary purpose of the safety evaluation was to determine the toxicity and tolerability of this combination therapy. An independent data and safety monitoring committee assessed the tolerability of the study treatments before starting the second treatment course. A preliminary evaluation of tumor response on the cut-off date (December 16, 2019) was also performed. Results: From November 2018 to August 2019, 12 pts with HER2+ AGC were enrolled in the safety part (six pts each in cohorts 1 and 2). During the 1st course, all 12 pts experienced at least one adverse event (AE). The most common AEs were peripheral sensory neuropathy (PSN) (n = 4) and leukocytopenia (n = 3) in cohort 1 and PSN (n = 5) and anorexia (n = 4) in cohort 2. AEs of grade ≥ 3 were observed in only one pt in cohort 1 (grade 3 neutropenia). No pt suspended or discontinued study treatments due to AEs. One pt in cohort 1 reduced dose of S-1 due to grade 2 erythema and continued the subsequent courses with the dose. After a median follow-up of 6.1 (range, 3.1–13.3) months, one pt from cohort 1 achieved a complete response, eight pts (four in each cohort) achieved a partial response, and three pts (one in cohort 1 and two in cohort 2) showed stable disease. No progressive disease was observed. Conclusions: Both Nivo plus Tmab and either S-1 or Cape plus Ox are tolerable in pts with HER2+ AGC. Both cohorts 1 and 2 have progressed to the expansion part of the study. Clinical trial information: 000034222 .

351 Background: TAS-118 is a novel oral agent, containing S-1 and leucovorin. In the SOLAR study (NCT02322593), TAS-118 + oxaliplatin (OHP) significantly improved overall survival compared to S-1 + cisplatin for patients (pts) with advanced gastric cancer (GC). We conducted this open-label study to assess feasibility of perioperative adjuvant chemotherapy with TAS-118 + OHP in pts with locally advanced resectable GC with lymph node metastasis. (Clinical trial information: UMIN000024688). Methods: Eligible pts who had histopathologically confirmed GC with clinical T3-4N1-3M0 on image findings (14th Japanese classification of gastric carcinoma), age 20 to 79 years, were enrolled in this study. The protocol treatment consisted of preoperative 4 courses of TAS-118 (80-120 mg/body, days 1-7) + OHP (85 mg/m2, day 1) every 2 weeks, and gastrectomy with D2 lymphadenectomy, followed by postoperative 12 courses of TAS-118 alone (step1) or 8 cycles of TAS-118 + OHP (step2). The primary endpoints were tolerability of preoperative chemotherapy, gastrectomy and postoperative chemotherapy with TAS-118 plus OHP. Here, we report the feasibility of preoperative chemotherapy and gastrectomy, and pathological response. Results: Between December 2016 and April 2018, 45 pts with a median age of 61 years were enrolled. The numbers of pts with T stage (cT3/4a) and those with N stage (cN1/2/3) were 13/32 and 25/17/3, respectively. The completion rate of preoperative chemotherapy and gastrectomy was 88.9% ( 95% CI 78.0-95.5) and 95.6% (95% CI 86.7-99.2). The relative dose intensity of TAS-118 and OHP was 86.0% and 90.6%. During the 4 cycles of preoperative TAS-118 + OHP, 2 pts discontinued the treatment due to adverse event (AE). Major grade 3-4 AEs were diarrhea (17.8%) and neutropenia (8.9%). R0 resection rate was as high as 95.6%. One pts experienced grade 4 postoperative bleeding, but no treatment-related death was reported. pCR was achieved in 6/45 pts (13.3%) and other 7 pts (28.9%) showed near complete regression (

389 Background: AFPGC is an aggressive subgroup of gastric cancer and is associated with a worsened survival because of a high incidence of liver metastasis. Ramucirumab-based chemotherapy is the standard treatment as a second line in advanced gastric cancer. Recently ramucirumab has showed survival benefit in hepatocellular carcinoma, but only those with higher AFP levels. However, the efficacy of ramucirumab in AFPGC is unknown. Methods: We retrospectively assessed 283 patients who received paclitaxel or nab-paclitaxel combined with ramucirumab between July 2015 and December 2018. AFPGC was defined when serum AFP levels were elevated and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal when diagnosed. Other patients were excluded. Patients’ demographics, progression-free survival (PFS), overall survival (OS) and objective response rates (ORR) were compared between the two groups. Results: Among the 283 patients, 24 patients were AFPGC and 189 patients were non-AFPGC. AFPGC was associated with high incidences of intestinal histology (46%) and liver metastasis (63%), while AFPGC was associated with a low incidence of peritoneal metastasis (21%), compared with non-AFPGC. There was no significant difference in PFS and OS between the two groups. Median PFS were 5.4 (95%CI 3.6-6.7) months in AFPGC and 4.1 (3.7-5.1) months in non-AFPGC (HR 0.93 95%CI 0.60-1.46, p = 0.788), respectively. Median OS were 19.0 (95%CI 13.2-NA) months in AFPGC and 19.3 (17.9-20.1) months in non-AFPGC (HR 1.21 95%CI 0.70-2.10, p = 0.494), respectively. Regarding with ORR, AFPGC showed higher ORR with 52.6% (95%CI 30.2-75.1), while 37.3% (95%CI 26.4-48.3) in non-AFPGC (p = 0.296), although this was not statistically significant. Conclusions: Ramucirumab showed comparable survival and higher ORR in AFPGC than in non-AFPGC. Considering the generally poor prognosis of AFPGC, it is speculated that ramucirumab may have compensated for disadvantage in survival.

413 Background: Nivolumab (Nivo) plus ramucirumab (Ram) showed promising efficacy in the second-line chemotherapy for advanced gastric cancer (AGC) in NIVORAM study with the 44% of objective response rate (ORR) and 38.6% of 6-month progression free survival (PFS) rate. We investigated the correlation of tumor mutation load and efficacy. Methods: Patients received Nivo (3mg/kg, Q2W) in combination with Ram (8mg/kg, Q2W) until unacceptable toxicity or disease progression. Tissue samples were collected before the treatment, and analyzed for tumor mutation load using Oncomine Tumor Mutation Load Assay. Efficacy included ORR, overall survival (OS), PFS and duration of response. OS and PFS curves were estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazards model. Results: By the data cut off of December 15, 2018, the median follow duration on therapy was 13.7 month. Thirty AGC pts who obtained tissue sample were analyzed. Median tumor mutation load (TML) was 6.755 mutation/Mb (range 0.84-19.67). Higher TML (cut-off median) related to better tendency of efficacy with ORR (40.0% vs 20.0%), PFS (5.32 vs 2.33 months) and OS (18.1 vs 10.6 months). 6-month PFS rate was better in TML higher group (48%) compared to TML lower group (18%). In multivariate analysis, higher TML showed 2.030 of hazard ratio (95% CI; 0.849-4.855, p-0.112) for PFS, and 1.915 (95% CI; 0.578-6.343, p=0.287) for OS. Conclusions: The patients with higher tumor mutation load have a better tendency for OS and PFS, among AGC patients who received Nivo and Ram combination therapy. Clinical trial information: NCT02999295.

Background There is no standard first-line chemotherapy for advanced gastric cancer with severe peritoneal metastasis. Although fluoropyrimidine is often used, its efficacy is limited, and it remains unclear whether combination therapy with platinum improves clinical outcomes. Methods This retrospective study involved patients at six Japanese academic hospitals between 2010 and 2016. Patients with advanced gastric cancer and severe peritoneal metastasis were included if they had massive ascites and/or inadequate oral intake requiring intravenous nutritional support. We then compared the efficacy and safety of fluoropyrimidine monotherapy with those of fluoropyrimidine/platinum combination therapy. Results Compared with the combination therapy group (n = 64), the monotherapy group (n = 65) had worse general health (more patients with elderly age, performance status > 2, and having both massive ascites and inadequate oral intake). Both overall survival (9.0 vs 5.0 months, p