Final analyses of the prospective controlled trial on the efficacy of uracil and tegafur/leucovorin as an adjuvant treatment for stage II colon cancer with risk factors for recurrence using propensity score-based methods (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. Using propensity score matching, we previously reported that the 3-year disease-free survival (DFS) rate was significantly higher in patients treated with uracil and tegafur plus leucovorin (UFT/LV) against surgery alone. We report the final results, including updated 5-year overall survival (OS) rates and risk factor analysis outcomes. METHODS: In total, 1902 high-risk stage II CC patients with T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and/or < 12 dissected lymph nodes were enrolled in this prospective, non-randomized controlled study based on their self-selected treatment. Oral UFT/LV therapy was administered for six months after surgery. RESULTS: Of the 1880 eligible patients, 402 in Group A (surgery alone) and 804 in Group B (UFT/LV) were propensity score-matched. The 5-year DFS rate was significantly higher in Group B than in Group A (P = 0.0008). The 5-year OS rates were not significantly different between groups. The inverse probability of treatment weighting revealed significantly higher 5-year DFS (P = 0.0006) and 5-year OS (P = 0.0122) rates in group B than in group A. Multivariate analyses revealed that male sex, age ≥ 70 years, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for DFS and/or OS. CONCLUSION: The follow-up data from our prospective non-randomized controlled study revealed a considerable survival advantage in DFS offered by adjuvant chemotherapy with UFT/LV administered for six months over surgery alone in individuals with high-risk stage II CC. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019), UMIN Clinical Trials Registry: UMIN000007783 (date of registration: 18/04/2012).

Exacerbated prognostic impact of multiple intramural metastasis versus single intramural metastasis of thoracic esophageal squamous cell carcinoma: evidence from an Uzbekistan cohort.

PURPOSE: Intramural metastasis (IM) is a poor prognostic factor for patients with esophageal squamous cell carcinoma (ESCC). We conducted this study to assess the prognostic impact of IM in an Uzbekistan cohort and to identify the factors associated with the poor prognosis of patients with ESCC and IM. METHODS: The subjects of this retrospective analysis were 1083 patients with thoracic ESCC, who underwent curative esophagectomy between 2001 and 2021 at the National Cancer Center of Uzbekistan. We compared the clinicopathological characteristics and survival outcomes of patients with versus those without IM and evaluated the factors associated with the poor prognosis of patients with IM. RESULTS: Patients with pathological IM (n = 59, 5.4%) were significantly older, had a higher percentage of lymphatic invasion and worse pathological N stage, and had shorter overall survival (OS) than patients without IM. Multivariable analysis of OS identified multiple IMs as the only independent prognostic factor in patients with IM (hazard ratio, 6.04; 95% confidence interval, 2.77-13.18; P < 0.001). Patients with multiple IMs had shorter OS and recurrence-free survival than those with a single IM. CONCLUSION: IM was a poor prognostic factor for patients with ESCC in this Uzbekistan cohort and multiple IMs were associated with worse outcomes.

Time required for indocyanine green fluorescence emission for evaluating bowel perfusion in left-sided colon and rectal cancer surgery.

BACKGROUND: Indocyanine green fluorescence imaging (ICG-FI) has been reported to be useful in reducing the incidence of anastomotic leakage (AL) in colectomy. This study aimed to investigate the correlation between the required time for ICG fluorescence emission and AL in left-sided colon and rectal cancer surgery using the double-stapling technique (DST) anastomosis. METHODS: This retrospective study included 217 patients with colorectal cancer who underwent left-sided colon and rectal surgery using ICG-FI-based perfusion assessment at our department between November 2018 and July 2022. We recorded the time required to achieve maximum fluorescence emission after ICG systemic injection and assessed its correlation with the occurrence of AL. RESULTS: Among 217 patients, AL occurred in 21 patients (9.7%). The median time from ICG administration to maximum fluorescence emission was 32 s (range 25-58 s) in the AL group and 28 s (range 10-45 s) in the non-AL group (p < 0.001). The cut-off value for the presence of AL obtained from the ROC curve was 31 s. In 58 patients with a required time for ICG fluorescence of 31 s or longer, the following risk factors for AL were identified: low preoperative albumin [3.4 mg/dl (range 2.6-4.4) vs. 3.9 mg/dl (range 2.6-4.9), p = 0.016], absence of preoperative mechanical bowel preparation (53.8% vs. 91.1%, p = 0.005), obstructive tumor (61.5% vs. 17.8%, p = 0.004), and larger tumor diameter [65 mm (range 40-90) vs. 35 mm (range 4.0-100), p < 0.001]. CONCLUSION: The time required for ICG fluorescence emission was associated with AL.

The clinical impacts of postoperative complications after colon cancer surgery for the clinical course of adjuvant treatment and survival.

AIM: We investigated whether or not postoperative complications (POCs) themselves have a negative survival impact or indirectly worsen the survival due to insufficient adjuvant chemotherapy in a pooled analysis of two large phase III studies performed in Japan PATIENTS AND METHODS: The study examined the patients who enrolled in 1304, phase III study comparing the efficacy of 6 and 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer patients and in 882, a phase III study to confirm the tolerability of oxaliplatin, fluorouracil, and l-leucovorin in Japanese stage II/III colon cancer patients. In our study, POCs were defined as the following major surgical complications: anastomotic leakage, pneumonia, bowel obstruction/ileus, surgical site infection, postoperative bleeding, urinary tract infection, and fistula. Patients were classified as those with POCs (C group) and those without POCs (NC group). RESULTS: A total of 2095 patients were examined in the present study. POCs were observed in 169 patients (8.1%). The overall survival (OS) rates at 5 years after surgery were 75.3% in the C group and 86.5% in the NC group (p = 0.0017). The hazard ratio of POCs for the OS in multivariate analysis was 1.70 (95% confidence interval, 1.19 to 2.45; p = 0.0040). The time to adjuvant treatment failure (TTF) of adjuvant chemotherapy was similar between the groups, being 68.6% in the C group and 67.1% in the NC group for the 6-month continuation rate of adjuvant chemotherapy. The dose reduction rate of adjuvant chemotherapy and adjuvant treatment suspension rate were also similar between the groups (C vs. NC groups: 45.0% vs. 48.7%, p = 0.3520; and 52.7% vs. 55.0%, p = 0.5522, respectively). CONCLUSION: POCs were associated with a poor prognosis but did not affect the intensity of adjuvant chemotherapy. These results suggested that POCs themselves negatively influence the survival.

Meta-analysis of three randomized trials of capecitabine plus cisplatin (XP) versus S-1 plus cisplatin (SP) as first-line treatment for advanced gastric cancer.

BACKGROUND: S-1 plus cisplatin (SP) and capecitabine plus cisplatin (XP) are standard first-line regimens for advanced gastric cancer (AGC) worldwide. We conducted a meta-analysis using individual participant data (IPD) to investigate which is more suitable. METHODS: IPD from three randomized trials were collected. In these trials, patients with AGC were randomly allocated to SP (S-1 80-120 mg for 21 days plus cisplatin 60 mg/m2 (q5w)) or XP (capecitabine 2000 mg/m2 for 14 days plus cisplatin 80 mg/m2 (q3w)). RESULTS: In 211 eligible patients, median overall survival (OS) for SP versus XP was 13.5 and 11.7 months (hazard ratio [HR], 0.787; p = 0.114), progression-free survival (PFS) was 6.2 and 5.1 months (HR, 0.767; P = 0.076), and TTF was 5.1 and 4.0 months (HR, 0.611; P = 0.001). The most common grade ≥ 3 adverse events with SP or XP were neutropenia (18% vs. 29%) and anorexia (16% vs.18%). Subgroup analysis demonstrated significant interaction between treatment effect and performance status > 1 (HR, 0.685; P = 0.036), measurable lesion (HR, 0.709; P = 0.049), primary upper third tumor (HR, 0.539; P = 0.040), and differentiated type (HR, 0.549; interaction, 0.236; P = 0.019). For the differentiated type, OS was significantly longer in the SP group (13.2 months) than in the XP group (11.1 months) (HR, 0.549; P = 0.019). For the undifferentiated type, OS was similar in the SP group (14.2 months) and in the XP group (12.4 months) (HR, 0.868; P = 0.476). CONCLUSIONS: SP and XP were both effective and well tolerated. SP might be suitable for the pathological differentiated subtype of AGC. CLINICAL TRIAL REGISTRATION: The HERBIS-2, HERBIS-4A, and XParTS II trials were registered with UMIN-CTR as UMIN000006105, UMIN000006755, and UMIN000006045, respectively.

Mid-term outcomes of intracorporeal versus extracorporeal anastomosis after laparoscopic colectomy: a propensity score-matched cohort study from a single institution.

PURPOSE: There is still insufficient discussion of the mid- to long-term safety of the intracorporeal anastomosis (IA) method of reconstruction after laparoscopic colectomy (LAC) for colon cancer. The present study clarified the postoperative mid-term results of IA based on recurrence and the incidence of incision hernia. METHODS: This single-institution observational retrospective study included 268 patients with colon cancer who underwent IA or extracorporeal anastomosis (EA) after LAC at our institution between 2018 and 2021. The mid-term results of the IA group were compared with those of the EA group using a propensity score matching method. RESULTS: The median follow-up periods were 36 and 25 months in the EA and IA groups, respectively (p < 0.0001). In this matched cohort study, the recurrence-free survival (RFS) rates were comparable between the IA and EA groups (each group, n = 72; 3-year RFS: IA, 92.1%; EA, 88.2%; hazard ratio, 0.78; 95% confidence interval, 0.25-2.40; p = 0.66). The cumulative incisional hernia rates were 9.8% and 9.9% (p = 0.99) for the IA and EA groups, respectively. CONCLUSION: The safety of IA after LAC was demonstrated in this study, as IA after LAC showed good mid-term results, including with regard to the rates of recurrence and incisional hernia.

Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

OBJECTIVE: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. DESIGN: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. RESULTS: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). CONCLUSION: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).

Multicenter, single-arm, phase II study of the continuous use of panitumumab in combination with FOLFIRI after FOLFOX for RAS wild-type metastatic colorectal cancer: Exploratory sequential examination of acquired mutations in circulating cell-free DNA.

This multicenter single-arm, phase II study evaluated the efficacy and safety of uninterrupted panitumumab usage combined with cytotoxic doublets for unresectable/metastatic colorectal cancer (mCRC). Additionally, clinical value of the RAS/BRAF mutation status in circulating cell-free DNA (ccfDNA) was evaluated; this evaluation was measured independently of the protocol treatment. Eligible patients with RAS wild-type mCRC who had received the first-line panitumumab plus FOLFOX treatment were recruited and administered continuous panitumumab combined with FOLFIRI. Progression-free survival (PFS) at 6 months was the primary endpoint, with threshold and expected values of 35% and 50%, respectively. In total, 54 patients were enrolled between October 2017 and October 2019. The crude 6-month PFS rate was 37.0%, with a 4.8-month median PFS. The response rate and disease control rate were 16.7% and 50.0%, respectively. Notably, of the 54 participants, 17 showed RAS/BRAF mutations until the end of the protocol treatment and of the 22 patients with progressive disease as their best response, 10 possessed RAS/BRAF mutations in their plasma ccfDNA at baseline. The median PFS significantly differed among patients harboring tumors with BRAF and RAS mutations and those with wild-type tumors. In conclusion, our study failed to show the expected efficacy of the continuous panitumumab use in the second-line treatment. Liquid biopsy discriminated the duration of PFS according to the mutation status. The effectiveness of continuous treatment with panitumumab should be evaluated in patients with RAS/BRAF wild-type mCRC determined by liquid biopsy at the start of the second-line treatment.

Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. METHODS: We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. RESULTS: Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW. CONCLUSIONS: Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).

Impact of early tumor shrinkage on quality of life in patients treated with first-line cetuximab plus chemotherapy for unresectable metastatic colorectal cancer: results of Phase II QUACK trial.

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.

Usefulness of Carcinoembryonic Antigen Doubling Time in Prognosis Prediction after Curative Resection of Locally Recurrent Rectal Cancer: A Retrospective Study.

INTRODUCTION: Given that doubling time is an indicator of tumor growth, we assessed the usefulness of carcinoembryonic antigen doubling time (CEA-DT) in prognosis prediction after curative resection for locally recurrent rectal cancer. METHODS: During January 1986-December 2016, 33 patients with locally recurrent rectal cancer who underwent curative resection at our hospital were retrospectively reviewed. The primary endpoint was the 3-year recurrence-free survival (RFS) rate. The Kaplan-Meier method was used to compare RFS rates and evaluate univariate and multivariate analyses for factors associated with oncologic outcomes, including CEA-DT. CEA-DT was classified into 2 groups: the short and long CEA-DT groups. RESULTS: The 3-year overall survival and RFS rates were 62.6% and 42.4%, respectively. In multivariate analyses, CEA-DT was an independent risk factor for poor RFS. The 3-year RFS rate was significantly better in the long CEA-DT group than in the short CEA-DT group (58.8% vs. 25.0%, p = 0.0063). CONCLUSION: CEA-DT is a useful prognostic factor that can be assessed before surgery for locally recurrent rectal cancer. Long CEA-DT may indicate a favorable prognosis. Contrarily, short CEA-DT is associated with poor prognosis; therefore, further treatment intervention is necessary for patients with short CEA-DT.

Short-term outcomes of intracorporeal versus extracorporeal anastomosis after laparoscopic colectomy: a propensity score-matched cohort study from a single institution.

PURPOSE: To compare the postoperative short-term results of intracorporeal anastomosis (IA) using overlap anastomosis (OLA), with those of extracorporeal anastomosis (EA) using functional end-to-end anastomosis (FEEA) or hand-sewn anastomosis (HSA), after laparoscopic colectomy (LAC). METHODS: The subjects of this retrospective study were 208 patients with colon cancer who underwent OLA, FEEA, or HSA after LAC at our institution, between 2018 and 2021. The short-term results of the OLA group were compared with those of the FEEA and HSA groups, respectively, using a propensity score-matching method. RESULTS: The mean operative time for anastomosis was longer in the OLA group than in the FEEA and HSA groups (p < 0.0001). The mean blood loss volume was less in the OLA group than in the FEEA and HSA groups (p = 0.0344 and p = 0.0002, respectively). The mean skin incision size was smaller in the OLA group than in the FEEA and HSA groups (p < 0.0001 and p = 0.0031, respectively). None of the patients in the OLA group had surgical site infections. Three to five patients were required for the surgeon to plateau on the learning curve. CONCLUSION: Although IA required more time than EA, the skills appeared to improve with experience and the short-term results were superior to those of EA.

[Retrospective Analysis of Adjuvant Chemotherapy for Elderly Patients with Stage â ¢ Colorectal Cancer].

OBJECTIVE: To investigate the efficacy and toxicity of adjuvant chemotherapy(AC)in elderly patients with Stage Ⅲ colorectal cancer(CRC). METHODS: We performed a single-institutional retrospective analysis of 84 patients aged≥75 years with Stage Ⅲ CRC who underwent curative resection from August 2009 to February 2018. RESULTS: Thirty-seven(44.0%) patients received AC. Eleven(29.7%)patients required dose reduction at the start of AC. Twenty-three(62.2%)patients accomplished AC, and 13(35.1%)needed dose reduction during AC. Although toxicities of Grade 3 or higher occurred in 56.8% of patients, they were controllable. The 3-year recurrence-free survival rate was significantly better in the AC group than in the non-AC group(70.3% versus 50.5%, respectively; p=0.011). The prognosis tended to be worse in the group that started AC with dose reduction than in the group with the normal dose. CONCLUSION: AC is effective and well tolerated in elderly patients with Stage Ⅲ CRC. When reducing the initial dose, the need for dose reduction should be carefully considered.

[Usefulness of Nutritional Evaluation in Adjuvant Chemotherapy for Colorectal Cancer in Older Patients].

OBJECTIVE: To clarify the usefulness of Onodera's prognostic nutritional index(OPNI)in adjuvant chemotherapy(AC)for older patients with colorectal cancer. MATERIALS AND METHODS: This study included 39 patients aged over 70 years who underwent AC for colorectal cancer from August 2009 to February 2018. We evaluated the association of OPNI with AC toxicities and prognosis. RESULTS: OPNI was an independent predictor of toxicities of Grade 3 or higher(OR: 0.18, 95%CI: 0.043-0.75, p=0.019). The 3-year recurrence-free survival rate was significantly better in the higher OPNI group than in the lower OPNI group(89.9% and 66.7%, respectively; HR: 0.19, 95%CI: 0.04-0.92, p=0.038). There was a positive correlation with Spearman's rank correlation coefficient of 0.66 in OPNI before and after AC(p<0.001). CONCLUSION: OPNI could be one of the valuable predictors of AC toxicities and the prognosis. There was a high correlation between OPNI before and after AC. These findings suggest the importance of early nutritional support for patients with lower OPNI.

Impact of UGT1A1 genotype on the efficacy and safety of irinotecan-based chemotherapy in metastatic colorectal cancer.

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events-caused by irinotecan-and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype.

Proton Pump Inhibitor Use and the Efficacy of Chemotherapy in Metastatic Colorectal Cancer: A Post Hoc Analysis of a Randomized Phase III Trial (AXEPT).

BACKGROUND: Concomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the data set from the AXEPT trial, a phase III randomized trial that demonstrated the noninferiority of mXELIRI (modified XELIRI: capecitabine plus irinotecan) to FOLFIRI (leucovorin, fluorouracil, and irinotecan), either with or without bevacizumab in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Out of the per-protocol set (n = 620), patients with information on concomitant medications (n = 482) were included in this post hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment-by-PPI-use interaction was examined after adjusting for stratification factors. RESULTS: Of the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the nonusers, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression-free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in nonusers. Treatment-by-PPI-use interaction was significant for overall survival and progression-free survival. CONCLUSION: The significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression-free survival suggests that fluorouracil could be a more favorable option than capecitabine for patients with metastatic colorectal cancer using PPIs. IMPLICATIONS FOR PRACTICE: This study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug-drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer.

Randomized phase II study of daily and alternate-day administration of S-1 for adjuvant chemotherapy in completely-resected stage I non-small cell lung cancer: results of the Setouchi Lung Cancer Group Study 1301.

BACKGROUND: The aim of this multicenter, randomized phase II study was to analyze the feasibility and safety of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological stage I (tumor diameter > 2 cm) non-small cell lung cancer (NSCLC). METHODS: Patients were randomly assigned to receive adjuvant chemotherapy for 1 year comprising either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Group A) or a 2-week oral administration of S-1 (80 mg/m2/day) followed by 1 week of rest (Group B). The primary endpoint was feasibility, which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: Ninety-three patients were enrolled of whom 90 patients received S-1 treatment. Median follow-up was 66.9 months. The treatment completion rate based on an RDI of 70% or more for 6 months was 84.4% (95%CI; 70.5-93.5%) in group A and 64.4% (95%CI; 48.8-78.1%) in group B. There were no grade 4 adverse events in either group. Moderate or severe adverse events (grade 2 or grade 3) were significantly more frequent in group B (67%) compared with group A (29%, P = 0.001). The 5-year relapse-free survival rate was 87.0 and 80.9% for group A and B, respectively (P = 0.451). The 5-year overall survival rate for all patients (n = 93) was 100 and 89.4% for group A and B, respectively (P = 0.136). CONCLUSION: Alternate-day oral administration of S-1 for 1 year as adjuvant chemotherapy was demonstrated to be feasible with low toxicity in completely resected stage I (tumor diameter > 2 cm) NSCLC. TRIAL REGISTRATION: Trial registration number: UMIN000011994 . Date of registration: 10/8/2013.

Clinical biomarkers in adjuvant chemotherapy for gastric cancer after D2 dissection by a pooled analysis of individual patient data from large randomized controlled trials.

BACKGROUND: Adjuvant therapy for gastric cancer is a standard among the world with no regimen selection criteria. Also, prognostic factors except for tumor staging have not been established. We aimed to identify prognostic and predictive markers for gastric cancer adjuvant therapy from large randomized controlled trials with standard lymph node dissection. METHODS: Three studies: ACTS-GC, CLASSIC, and SAMIT were found and selected for a pooled analysis, following PRISMA guideline. The integrity of individual participant data (IPD) was verified in the eligible 3527 patients registered, and fixed-effect model was used. The primary endpoint was relapse-free survival (RFS) and the secondary endpoint was overall survival (OS). RESULTS: Age was a significant prognostic factor in addition to tumor stages both in "surgery alone" and "adjuvant" groups. Adjuvant therapy was effective for every TN stage; however, it tended to be more effective in T1-2 than in T3-4. Also, it was more effective in low- or middle-BMI than in high-BMI group with Hazard ratio [HR]s: 0.58, 0.58, and 1.05, respectively. Capecitabine plus oxaliplatin (CAPOX) was more effective than S-1 for T1-2, N2-3, and differentiated type with HRs between 0.59 and 0.70, but with no difference among TNM stages. Combining histology to TN; the HRs in differentiated T1-2 N1-3 groups were between 0.29 and 0.45. For T3-4 N0-1 group, S-1 was likely to be effective, not significant. CONCLUSIONS: Age is a significant prognostic factor both in surgery alone and adjuvant group. CAPOX is more effective for differentiated T1-2 tumors with lymph node metastasis.

A multicenter non-randomized phase III study of sentinel node navigation surgery for early gastric cancer.

This prospective multicenter non-randomized phase III study aims to evaluate the long-term outcome of sentinel node navigation surgery for early gastric cancer compared with conventional distal or total gastrectomy. Clinically diagnosed primary T1N0M0 gastric cancer patients with a single lesion (≤40 mm) and without previous endoscopic treatment will be enrolled in this study. Sentinel nodes are identified by dye and radioisotope tracers and are subjected to intraoperative rapid pathology. For patients with negative sentinel node metastasis, individualized surgery consisting of limited stomach resection and sentinel node basin dissection is performed, while standard gastrectomy with D2 lymph node dissection is employed for the positive sentinel node patients. A total of 225 patients will be accrued from 13 hospitals that have experience in sentinel node mapping. The primary endpoint is 5-year relapse-free survival. The secondary endpoints are overall survival, sentinel node detection rate, diagnostic accuracy for sentinel node, distribution of sentinel nodes and metastatic sentinel node/non-sentinel node, and postoperative quality of life.

Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment-free remission.

This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D-STOP, after a 3-year follow-up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Estimated treatment-free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7-74.3] and 59.3% (95% CI: 45.0-71.0), respectively. CD3- CD56+ NK, CD16+ CD56+ NK, and CD57+ CD56+ NK large granular lymphocyte (NK-LGL), CD8+ CD4- cytotoxic T cell, and CD57+ CD3+ T-LGL cell numbers were relatively elevated throughout the 24-month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients, these subsets elevated transiently after 12 months, but returned to basal levels after 24-month consolidation. Therefore, smaller changes in NK/T, particularly the NK subset throughout consolidation, reflected higher TFR rates. TFR rates of those patients exhibiting elevation in CD3- CD56+ NK >376 cells/µL, CD16+ CD56+ NK > 241 cells/µL, or CD57+ CD56+ NK-LGL >242 cells/µL during consolidation compared with others were 26.7% (8.3%-49.6%) vs 78.3% (55.4%-90.3%), HR 0.032 (0.0027-0.38; P = .0064), 31.2% (11.4%-53.6%) vs 85.0% (60.4%-94.9%), HR 0.039 (0.0031-0.48; P = .011), or 36.8% (16.5%-57.5%) vs 77.3% (53.7%-89.8%), HR 0.21 (0.065-0.69; P = .010), respectively. Therefore, silent responses of T/NK subsets to dasatinib throughout consolidation were significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, may be immunologically insufficient to maintain TFR. Their decline, subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR, might be immunologically significant. (D-STOP, NCT01627132).