Association between the antiadhesion membrane and small bowel obstruction after open gastrectomy: A supplemental analysis of the randomized controlled JCOG1001 trial.

Aim: Postoperative small bowel obstruction (SBO) is one of the major complications that is mainly caused by postoperative adhesion. Recently, the antiadhesion membrane has become popular for postoperative SBO prevention. However, its efficacy is yet to be confirmed in the gastric cancer surgery field. Here, we conducted the supplemental analysis of the randomized controlled trial JCOG1001 to investigate the efficacy of the antiadhesion membrane on SBO prevention in patients with open gastrectomy for gastric cancer. Methods: Of the 1204 patients enrolled in JCOG1001, 1200 patients were included. The development of SBO of Grade ≥ IIIa according to the Clavien-Dindo classification was recorded. Univariable and multivariable analyses were performed using the Fine and Gray model to determine the risk factors for SBO. Results: Fifty-one patients developed SBO (median follow-up duration: 5.6 years). Total gastrectomy, combined resection, and blood loss significantly increased the risk for SBO development in the univariable analysis. Large amount of blood loss was independently associated with SBO development in the multivariable analysis (hazard ratio [HR], 3.089; 95% confidence interval [CI], 1.562-6.109, p = 0.0012). Antiadhesion membrane did not reduce the risk for SBO (HR, 1.299; 95% CI 0.683-2.470; p = 0.4246). In the patients belonging to subgroup analyses who received distal and total gastrectomy, the antiadhesion membrane was not associated with the incidence of SBO. Conclusions: Antiadhesion membrane did not decrease SBO occurrence rate after open gastrectomy. Therefore, the use of antiadhesion membrane would not be effective for preventing SBO in gastric cancer surgery.

Role of reduction gastrectomy in patients with gastric cancer with a single non-curable factor: Supplementary analysis of REGATTA trial.

Background: REGATTA trial failed to demonstrate the survival benefit of reduction gastrectomy in patients with advanced gastric cancer with a single non-curable factor. However, a significant interaction was found between the treatment effect and tumor location in the subset analysis. Additionally, the treatment effect appeared to be different between Japan and Korea. This supplementary analysis aimed to elucidate the effect of reduction surgery based on tumor location and country. Methods: Multivariable Cox regression analyses in each subgroup were performed to estimate the hazard ratio (HRadj), including the following variables as explanatory variables: country, age, sex, incurable factor, cT, cN, primary tumor, performance status, histological type, and macroscopic type. Results: Patients (95 in Japan and 80 in Korea) were randomized to chemotherapy alone (86 patients) or gastrectomy plus chemotherapy (89 patients). The subgroup analysis according to the country revealed a worse overall survival in gastrectomy plus chemotherapy arm in Japan (hazard ratio: 1.32, 95% confidence interval: 0.85-2.05), but not in Korea (hazard ratio: 0.85.95% confidence interval: 0.52-1.40). Overall survival was better in distal gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 0.69, 95% confidence interval: 0.42-1.13), and worse in total gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 1.34, 95% CI: 0.93-1.94), which was more remarkable in Korea than in Japan. Conclusions: Primary chemotherapy is a standard of care for advanced gastric cancer; however, the survival benefits from reduction by distal gastrectomy remained controversial.

Quality of life comparison between esophagogastrostomy and double tract reconstruction for proximal gastrectomy assessed by Postgastrectomy Syndrome Assessment Scale (PGSAS)-45.

Aim: The current study compared the postoperative quality of life (QOL) between the esophagogastrostomy method (PGEG) and double tract method (PGDT) after proximal gastrectomy using the Postgastretomy Syndrome Assessment Scale (PGSAS)-45. Methods: Among the 2364 patients who received the PGSAS-45 questionnaire, 300 PGEG and 172 PGDT cases responded. The main outcomes measures (MOMs) consisted of seven subscales (SS) covering symptoms, meals (amount and quality), ability to work, dissatisfaction with daily life, physical and mental component summary of the 8-Item Short Form Health Survey (SF-8), and change in body weight, and were compared between PGEG and PGDT. Results: Overall, PGDT promoted significantly better constipation SS scores (p < 0.05), whereas PGEG tended to promote better body weight (BW) loss% (p < 0.10). A stratified analysis based on the remnant stomach size revealed that among those with a remnant stomach size of 1/2, PGDT had significantly better constipation and dumping SS scores (p < 0.05) and tended to have better working conditions (p < 0.10) compared to PGEG. Even among those with the remnant stomach size of 2/3, PGDT had significantly better diarrhea SS scores, lesser dissatisfaction with symptoms, and better dissatisfaction with daily life SS scores (p < 0.05) and tended to have better constipation SS scores and lesser dissatisfaction with work (p < 0.10) compared to PGEG. Conclusions: After comparing the QOLs of PGEG and PGDT, the stratified analysis according to remnant stomach sizes of 1/2 and 2/3 revealed that PGDT was relatively superior to PGEG for several MOMs.

Five-Year Survival Outcomes of Laparoscopy-Assisted vs Open Distal Gastrectomy for Advanced Gastric Cancer: The JLSSG0901 Randomized Clinical Trial.

Importance: Evidence of implementation of laparoscopic gastrectomy for locally advanced gastric cancer is currently insufficient, as the primary end point in previous prospective studies was evaluated at a median follow-up time of 3 years. More robust evidence is necessary to verify noninferiority of laparoscopic gastrectomy. Objective: To compare 5-year survival outcomes between laparoscopy-assisted distal gastrectomy (LADG) and open distal gastrectomy (ODG) with D2 lymph node dissection for locally advanced gastric cancer. Design, Setting, and Participants: This was a multicenter, open-label, noninferiority, prospective randomized clinical trial. Between November 26, 2009, and July 29, 2016, eligible patients with histologically proven gastric carcinoma from 37 institutes in Japan were enrolled. Two interim analyses and final analysis were performed in October 2014, May 2018, and November 2021, respectively. Interventions: Patients were randomly assigned (1:1) to either the ODG or LADG group. The procedures were performed exclusively by qualified surgeons. Main Outcomes and Measures: The primary end point was 5-year relapse-free survival, and the noninferiority margin for the hazard ratio (HR) was set at 1.31. The secondary end points were 5-year overall survival and safety. Results: A total of 502 patients were included in the full-analysis set: 254 (50.6%) in the ODG group and 248 (49.4%) in the LADG group. Patients in the ODG group had a median (IQR) age of 67 (33-80) years and included 168 males (66.1%). Patients in the LADG group had a median (IQR) age of 64 (34-80) years and included 169 males (68.1%). No significant differences were observed in severe postoperative complications between the 2 groups in the safety analysis (ODG, 4.7% [11 of 233] vs LADG, 3.5% [8 of 227]; P = .64). The median (IQR) follow-up for all patients after randomization was 67.9 (60.3-92.0) months. The 5-year relapse-free survival was 73.9% (95% CI, 68.7%-79.5%) and 75.7% (95% CI, 70.5%-81.2%) for the ODG and LADG groups, respectively, and the HR was 0.96 (90% CI, 0.72-1.26; noninferiority 1-sided P = .03). Further, no significant difference was observed in overall survival time between the 2 groups, and the HR was 0.83 (95% CI, 0.57-1.21; P = .34). The pattern of recurrence was similar between the 2 groups. Conclusions and Relevance: Results of this study show that on the basis of 5-year follow-up data, LADG with D2 lymph node dissection for locally advanced gastric cancer, when performed by qualified surgeons, was proved noninferior to ODG. This laparoscopic approach could become a standard treatment for locally advanced gastric cancer. Trial Registration: UMIN Clinical Trial Registry: UMIN000003420.

Gastric intramural metastasis caused by needle tract seeding after preoperative fine needle aspiration for pancreatic body cancer subsequently resected by total pancreatectomy: a case report and literature review.

BACKGROUND: Recently, there has been an increase in the number of reports of needle tract seeding (NTS) of tumor cells after a biopsy as one of the adverse events related to endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA). In most of the previously reported cases of NTS in pancreatic cancer, distal pancreatectomy was performed as the initial surgery, following which metachronous metastasis was discovered in the gastric wall, whose localization matched the puncture route of the EUS-FNA. We report a case of early metastasis from pancreatic cancer in the gastric wall, which was postulated to be caused by NTS. Our patient underwent a total pancreatectomy (TP), and the NTS was resected synchronously. CASE PRESENTATION: A 70-year-old woman with a diagnosis of pancreatic head-body-tail cancer presented to our department for surgery. Transgastric EUS-FNA and biopsy established the histological diagnosis in her case. We administered neoadjuvant chemotherapy (NAC) to the patient and performed a TP. Histopathological and immunohistochemical examination subsequently confirmed the diagnosis of pT3N1aM1 pancreatic adenocarcinoma and its gastric metastasis, which was caused by NTS. It is postulated that the tumor cells of NTS had progressed to develop the metastatic lesion in the gastric wall during the NAC period. This was also resected during the initial surgery. The patient developed an early postoperative recurrence in the peritoneum 8 months after the surgery. CONCLUSION: In pancreatic head cancer cases, the puncture route is often included in the resection area of radical surgery, and NTS is seldom considered as a potential clinical problem. However, NTS can progress rapidly and may be associated with early recurrence of malignancy. Therefore, when transgastrointestinal puncture is performed for the diagnosis of pancreatic cancer, the treatment strategy should be established considering the potential development of NTS.

Poor association between dihydropyrimidine dehydrogenase (DPYD) genotype and fluoropyrimidine-induced toxicity in an Asian population.

OBJECTIVE: Dihydropyrimidine dehydrogenase (DPYD) genotype is closely associated with fluoropyrimidine (FP)-induced toxicities in Caucasian population and European Medicines Agency now recommends DPYD genotype-based FP dosing strategy. PATIENTS AND METHODS: The current study aimed to investigate their impact on FP-related toxicities in an Asian population using genome-wide association study (GWAS) data set from 1364 patients with colon cancer. RESULTS: Among 82 variants registered in the Clinical Pharmacogenetics Implementation Consortium, 74 DPYD variants were directly genotyped in GWAS cohort; however, only 7 nonsynonymous DPYD variants (CPIC variants) were identified and none of the four recurrent DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A) were included. Seven CPIC variants were investigated for their association with the incidence of FP-related toxicities; however, none of these variants revealed a significant correlation with FP-related toxicities. CONCLUSION: These data suggested that the DPYD genotype registered in CPIC plays a minor role in FP-related toxicities in an Asian population.

Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial.

PURPOSE: The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety. PATIENTS AND METHODS: Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point. RESULTS: The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20; P = .51). Subgroup analysis of OS did not reveal a significant interaction between baseline characteristics and treatment duration. Peripheral sensory neuropathy lasting longer than 5 years was more common in the 6- compared with 3-month treatment group (16% v 8%, respectively), and in those receiving mFOLFOX6 compared with CAPOX (14% v 11%, respectively). CONCLUSION: In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.

Phase II Study of S-1 and Irinotecan Plus Bevacizumab as Second-line Treatment for Patients With Metastatic Colorectal Cancer Resistant to the Fluoropyrimidine-oxaliplatin-cetuximab Regimen.

BACKGROUND/AIM: The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC. PATIENTS AND METHODS: Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/m2 intravenously on day 1, whereas S-1 80 mg/m2 was administered orally twice daily until day 15, followed by a 7-day drug holiday period. The primary end point was 6-month progression-free survival (PFS) rate. RESULTS: In total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed. CONCLUSION: The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.

Treatment strategy for pancreatic head cancer with celiac axis stenosis in pancreaticoduodenectomy: A case report and review of literature.

BACKGROUND: During pancreaticoduodenectomy in patients with celiac axis (CA) stenosis due to compression by the median arcuate ligament (MAL), the MAL has to be divided to maintain hepatic blood flow in many cases. However, MAL division often fails, and success can only be determined intraoperatively. To overcome this problem, we performed endovascular CA stenting preoperatively, and thereafter safely performed pancreaticoduodenectomy. We present this case as a new preoperative treatment strategy that was successful. CASE SUMMARY: A 77-year-old man with a diagnosis of pancreatic head cancer presented to our department for surgery. Preoperative assessment revealed CA stenosis caused by MAL. We performed endovascular stenting in the CA preoperatively because we knew that going into the operation without a strategy could lead to ischemic complications. Double-antiplatelet therapy (DAPT) - which is needed when a stent is inserted - was then administered in parallel with neoadjuvant chemotherapy (NAC). This allowed us to administer DAPT for a sufficient period before the main pancreaticoduodenectomy procedure while obtaining therapeutic effects from NAC. Subtotal stomach-preserving pancreaticoduodenectomy was then performed. The operation did not require any unusual techniques and was performed safely. Postoperatively, the patient progressed well, without any ischemic complications. Histopathologically, curative resection was confirmed, and the patient had no recurrence or complications due to ischemia up to six months postoperatively. CONCLUSION: Preoperative endovascular stenting, with NAC and DAPT, is effective and safe prior to pancreaticoduodenectomy in potentially resectable pancreatic cancer.

Time limit to rescue intestine with viability at risk caused by blood flow disruption in patients presenting with acute abdomen.

PURPOSE: Early management is crucial for acute intestinal blood flow disorders; however, no published study has identified criteria for the time limit for blood flow resumption. This study specifically examines the time factors for avoiding intestinal resection. METHODS: The subjects of this retrospective cohort study were 125 consecutive patients who underwent emergency surgery for a confirmed diagnosis of intestinal strangulation (n = 86), incarceration (n = 27), or volvulus (n = 12), between January 2015 and March 2021. Intestinal resection was performed when intestinal irreversible changes had occurred even after ischemia was relieved surgically. We analyzed the relationship between the time from computed tomography (CT) imaging to the start of surgery (C-S time) and intestinal resection using the Kaplan-Meier method and calculated the estimated intestinal rescue rate. Patient background factors affecting intestinal resection were also examined. RESULTS: The time limit for achieving 80% intestinal rescue rate was 200 min in C-S time, and when this exceeded 300 min, the intestinal rescue rate dropped to less than 50%. Multivariate analysis identified the APACHE II score as a significant influencing factor. CONCLUSION: A rapid transition from early diagnosis to early surgery is critical for patients with acute abdomen originating from intestinal blood flow disorders. The times from presentation at the hospital to surgery should be reduced further, especially for severe cases.

18F-FDG-PET/CT as an imaging biomarker for regorafenib efficacy in metastatic colorectal cancer (JACCRO CC-12).

INTRODUCTION: Regorafenib is a multikinase inhibitor approved for the treatment of metastatic colorectal cancer (mCRC). Despite providing a statistically significant survival benefit, a substantial number of patients fail to respond to or continue with treatment, which has resulted in an unmet clinical need for a biomarker of regorafenib efficacy. METHODS: The JACCRO CC-12 study was a prospective, multicenter, single-arm phase II trial designed to evaluate the usefulness of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) as an imaging biomarker of regorafenib in patients with mCRC that progressed after standard chemotherapies. FDG-PET and contrast-enhanced computed tomography (CT) were performed before and after treatment with regorafenib 160 mg once daily 3 weeks on/1 week off. The primary end point was the change in the maximum standardized uptake value in the lesion with the highest uptake at pre-treatment FDG-PET. The secondary end points included overall survival (OS), progression-free survival (PFS), the objective response rate (ORR), safety, and the correlation between FDG-PET and CT. RESULTS: Twenty patients were enrolled from November 2014 to March 2016, 17 of whom were evaluated for metabolic and morphological changes. Metabolic response with FDG-PET was partial response (PR) in one case (5.9%), stable disease (SD) in four (23.5%), and progressive disease (PD) in 12 (70.6%). The metabolic response rate was 5.9%. On CT imaging, no complete response or PR was observed, and the ORR was 0%. Median PFS and OS were 1.7 and 9.8 months, respectively. The median PFS of patients who achieved PR or SD by FDG-PET was 3.7 months, whereas that of those assessed as PD was 1 month (p = 0.13). The median OS of patients who achieved PR or SD by FDG-PET was 13.0 months, whereas that of patients assessed as PD was 10.6 months (p = 0.43). Frequent adverse events were palmar-plantar erythrodysesthesia syndrome, hypertension, loss of appetite, and fatigue. CONCLUSIONS: In this study, FDG-PET failed to demonstrate usefulness as an early imaging biomarker of regorafenib in patients with mCRC.

Survival analysis of a prospective multicenter observational study on surgical palliation among patients receiving treatment for malignant gastric outlet obstruction caused by incurable advanced gastric cancer.

BACKGROUND: We had previously reported that surgical palliation could maintain quality of life (QOL) while improving solid food intake among patients with malignant gastric outlet obstruction (GOO) caused by advanced gastric cancer. The present study aimed to perform a survival analysis according to the patients' QOL to elucidate its impact on survival. METHODS: Patients with GOO who underwent either palliative gastrectomy or gastrojejunostomy were included in this study. A validated QOL instrument (EQ-5D) was used to assess QOL at baseline and 2 weeks, 1 month, and 3 months following surgical palliation. Postoperative improvement in oral intake was also evaluated using the GOO scoring system (GOOSS). Thereafter, univariate and multivariate survival analyses were performed to determine independent prognostic factors. RESULTS: The median survival time of the 104 patients included herein was 11.30 months. Patients who received postoperative chemotherapy, PS 0/1, baseline EQ-5D ≥ 0.75, improved or stable EQ-5D, and improved oral intake expressed as GOOSS = 3 had significantly better survival. Multivariate analysis identified postoperative chemotherapy, a better baseline PS, a better baseline EQ5D, improved or stable EQ5D scores, and improved oral intake 3 months after surgical palliation as independent prognostic factors. CONCLUSION: Apart from preoperative PS and postoperative chemotherapy, the present study identified better baseline QOL, improvement in postoperative QOL, and improvement in oral intake as prognostic factors among patients who underwent palliative surgery for advanced gastric cancer with GOO.

Gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer (JCOG0501): an open-label, phase 3, randomized controlled trial.

BACKGROUND: Specific treatment strategies are sorely needed for scirrhous-type gastric cancer still, which has poor prognosis. Based on the promising results of our previous phase II study (JCOG0210), we initiated a phase III study to confirm the efficacy of neoadjuvant chemotherapy (NAC) in type 4 or large type 3 gastric cancer. METHODS: Patients aged 20-75 years without a macroscopic unresectable factor as confirmed via staging laparoscopy were randomly assigned to surgery followed by adjuvant chemotherapy with S-1 (Arm A) or NAC (S-1plus cisplatin) followed by D2 gastrectomy plus adjuvant chemotherapy with S-1 (Arm B). The primary endpoint was overall survival (OS). RESULTS: Between October 2005 and July 2013, 316 patients were enrolled, allocating 158 patients to each arm. In Arm B, in which NAC was completed in 88% of patients. Significant downstaging based on tumor depth, lymph node metastasis, and peritoneal cytology was observed using NAC. Excluding the initial 16 patients randomized before the first revision of the protocol, 149 and 151 patients in arms A and B, respectively, were included in the primary analysis. The 3-year OS rates were 62.4% [95% confidence interval (CI) 54.1-69.6] in Arm A and 60.9% (95% CI 52.7-68.2) in Arm B. The hazard ratio of Arm B against Arm A was 0.916 (95% CI 0.679-1.236). CONCLUSIONS: For type 4 or large type 3 gastric cancer, NAC with S-1 plus cisplatin failed to demonstrate a survival benefit. D2 surgery followed by adjuvant chemotherapy remains the standard treatment.

Optimal Criteria for G3 (Poorly Differentiated) Stage II Colon Cancer: Prospective Validation in a Randomized Controlled Study (SACURA Trial).

Grade 3 (G3, poorly differentiated) is an important treatment-decision factor in stage II colon cancer, but no unified diagnostic criteria are established. According to previous studies, an intratumoural poorly differentiated area with no glandular formation (POR) that fills the microscopic field of a ×40 objective lens was an essential factor that defined G3. We aimed to prospectively validate this in a randomized controlled study of adjuvant chemotherapy (SACURA trial). We enrolled 991 patients with stage II colon cancer. POR was graded according to the ×40 objective lens rule and the intensity of poorly differentiated clusters (Grade), and its prognostic power was compared with that of the conventional tumor grade on the basis of predominant histology rule (Grade). According to Grade, 313, 526, and 152 tumors were classified as G1, G2, and G3, respectively, and the 5-year relapse-free survival (RFS) rates were 91.1%, 82.9%, and 74.7%, respectively (P<0.0001). When G3 and G3 were alternatively added to the prognostic model consisting of 8 conventional factors, only G3 was a significant factor for RFS (P=0.040, Wald test). The adverse impact of G3 on RFS was greater in the microsatellite stable/microsatellite instability-low subset than that in the full analysis set. In the microsatellite stable/microsatellite instability-low subset, the 5-year RFS rate of patients with G3 tumors in the chemotherapy group achieved greater improvement (9.1%) than the surgery-alone group. The least differentiation policy with the ×40 objective lens rule may be highlighted as the diagnostic criterion for G3 because of its validated prognostic value.

Phase 2 study of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type metastatic colorectal cancer: JACCRO CC-08.

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

Survival outcomes after laparoscopy-assisted distal gastrectomy versus open distal gastrectomy with nodal dissection for clinical stage IA or IB gastric cancer (JCOG0912): a multicentre, non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) is increasingly being used as an alternative to open distal gastrectomy (ODG) for gastric cancer treatment. Retrospective studies have shown equivalent survival with the two procedures, but these studies are limited by selection bias because LADG is more technically difficult than ODG. We aimed to evaluate whether LADG was non-inferior to ODG in terms of long-term survival outcomes. METHODS: We did an open-label, multicentre, non-inferiority, phase 3 randomised controlled trial at 33 institutions in Japan. Patients aged 20-80 years with histologically confirmed gastric adenocarcinoma (T1N0, T1N1, or T2[MP]N0), clinical stage I, in the middle or lower third of the stomach, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with a body-mass index of less than 30 kg/m2, were randomly assigned (1:1) to receive ODG or LADG. Randomisation was done by telephone, fax, or with a web-based system in the Japan Clinical Oncology Group Data Center; a minimisation method with a random component was used to adjust for institution and clinical stage (IA or IB). Only study-accredited surgeons performed ODG and LADG. The primary endpoint was relapse-free survival and was analysed according to the intention-to-treat principle. The non-inferiority margin (LADG vs ODG) was set at a hazard ratio (HR) of 1·54. The trial was registered with the UMIN Clinical Trials Registry, UMIN000003319. FINDINGS: Between March 15, 2010, and Nov 29, 2013, 921 patients were enrolled and randomly assigned to receive ODG (n=459) or LADG (n=462). 912 (99%) participants had the assigned surgery. 5-year relapse-free survival was 94·0% (95% CI 91·4-95·9) in the ODG group and 95·1% (92·7-96·8) in the LADG group. LADG was non-inferior to ODG for relapse-free survival (HR 0·84 [90% CI 0·56-1·27]), p=0·0075). The most common grade 3 or 4 adverse event was bowel obstruction, occurring in 11 (2%) of 455 patients in the ODG group and five (1%) of 457 patients in the LADG group. There were no treatment-related deaths. INTERPRETATION: This trial supports the non-inferiority of LADG compared with ODG for clinical stage I gastric cancer relapse-free survival, suggesting that LADG should be considered a standard treatment option when performed by experienced surgeons. FUNDING: Japan National Cancer Center, Ministry of Health, Labour and Welfare of Japan, Japan Agency for Medical Research and Development.

JOIN trial: treatment outcome and recovery status of peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer.

PURPOSE: Adjuvant FOLFOX therapy is an established standard-of-care for resected colon cancer. Peripheral sensory neuropathy (PSN) is regarded as the major toxicity issue related to FOLFOX therapy. There have been a few reports on the recovery status from PSN thereafter. JOIN trial investigated the tolerability and efficacy of adjuvant modified FOLFOX6 (mFOLFOX6) in Japanese patients with stage II/III colon cancer. METHODS: Twelve cycles of mFOLFOX6 were given to patients with stage II/III curatively resected colon cancer. Treatment outcomes, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery status of PSN during 3-year follow-up, were investigated. RESULTS: Of the 882 patients enrolled from 2010 to 2012, 864 were eligible for the efficacy analyses. Three-year DFS, RFS, and OS were favorable in 92.1, 92.8, and 97.4% of stage II patients; 76.4, 77.9, and 93.8% of stage IIIA/B; and 61.6, 62.7, and 85.9% of stage IIIC, respectively. The cumulative incidence of PSN during treatment was 47.8% in grade 1 (G1), 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% of patients at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 or G2 residual PSN after 3 years was observed in 21.0% (18.7%, G1; 2.3%, G2). CONCLUSIONS: Adjuvant mFOLFOX6 therapy was effective and well tolerated in patients with stage II/III colon cancer. Most patients recovered from G3 PSN related to oxaliplatin, but approximately 20% of patients had G1 or G2 PSN at 3-year follow-up.

Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial.

Importance: Oxaliplatin-based chemotherapy is associated with debilitating peripheral sensory neuropathy (PSN) for patients with stage III colon cancer. Objective: To assess disease-free survival (DFS) and long-lasting PSN in patients treated with 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. Design, Setting, and Participants: An open-label, multicenter, phase 3 randomized clinical trial of 1313 Asian patients with stage III colon cancer was conducted investigating the noninferiority of 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. From August 1, 2012, to June 30, 2014, participants were randomized to the 2 treatment groups. Data were analyzed from July 2017 to June 2018. Interventions: Patients were randomized to receive 3 or 6 months of adjuvant chemotherapy. The choice of chemotherapy regimen, with the drugs modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine plus oxaliplatin (CAPOX), was at the discretion of the treating physician. Main Outcomes and Measures: The primary outcome was DFS. Secondary end points included the evaluation of PSN for up to 3 years and overall survival. Results: Of the 1313 patients (651 were women and mean age was 66 [range, 28-85] years) enrolled and randomized, 22 were not treated because 10 were unable to begin treatment within 2 weeks of enrollment, 7 withdrew their consent, and 5 were not treated for various other reasons. Of 1291 patients treated (650 in the 3-month arm and 641 in the 6-month arm), 969 (75%) received the chemotherapy drug CAPOX. The hazard ratio (HR) for DFS of the 3-month arm compared with the 6-month arm was 0.95 (95% CI, 0.76-1.20). Hazard ratios were 1.07 (95% CI, 0.71-1.60) and 0.90 (95% CI, 0.68-1.20) for the drugs mFOLFOX6 and CAPOX, and 0.81 (95% CI, 0.53-1.24) and 1.07 (95% CI, 0.81-1.40) for patients with low-risk disease (TNM classification stages T1-3 and N1) and high-risk disease (stages T4 or N2), respectively. The rates of any grade of PSN lasting for 3 years in the 3-month vs 6-month treatment arms were 9.7% vs 24.3% (P < .001). Incidence of PSN lasting for 3 years was significantly lower for patients treated with CAPOX than for patients treated with mFOLFOX6 in both the 3-month (7.9% vs 15.7%; P = .04) and 6-month arms (21.0% vs 34.1%; P = .02). Conclusions and Relevance: The incidence of long-lasting PSN was significantly lower for 3 months than for 6 months of therapy, and significantly lower for treatment with the drug CAPOX than with mFOLFOX6. Since the shortened therapy duration did not compromise outcomes, a 3-month course of CAPOX may be the most appropriate treatment option, particularly for patients with low-risk disease. Trial Registration: UMIN Clinical Trials Registry: UMIN000008543.

Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial.

PURPOSE: S-1 is a standard postoperative adjuvant chemotherapy for patients with stage II or III gastric cancer in Asia. Neoadjuvant or perioperative strategies dominate in Western countries, and docetaxel has recently shown significant survival benefits when combined with other standard regimens in advanced cancer and perioperative settings. PATIENTS AND METHODS: This randomized phase III study was designed to prove the superiority of postoperative S-1 plus docetaxel over S-1 alone for R0 resection of pathologic stage III gastric cancer. The sample size of 1,100 patients was necessary to detect a 7% increase in 3-year relapse-free survival as the primary end point (hazard ratio, 0.78; 2-sided α = .05; ß = .2). RESULTS: The second interim analysis was conducted when the number of events reached 216 among 915 enrolled patients (median follow-up, 12.5 months). Analysis demonstrated the superiority of S-1 plus docetaxel (66%) to S-1 (50%) for 3-year relapse-free survival (hazard ratio, 0.632; 99.99% CI, 0.400 to 0.998; stratified log-rank test, P < .001), and enrollment was terminated as recommended by the independent data and safety monitoring committee. Incidences of grade 3 or greater adverse events, particularly neutropenia and leukopenia, were higher in the S-1 plus docetaxel group, but all events were manageable. CONCLUSION: Addition of docetaxel to S-1 is effective with few safety concerns in patients with stage III gastric cancer. The present findings may also be applicable in countries in which perioperative adjuvant chemotherapy or chemoradiation is not standard.

Updated 5-year survival and exploratory T x N subset analyses of ACTS-CC trial: a randomised controlled trial of S-1 versus tegafur-uracil/leucovorin as adjuvant chemotherapy for stage III colon cancer.

OBJECTIVE: Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC), a randomised phase III trial, demonstrated that adjuvant therapy with S-1 for stage III colon cancer was non-inferior in 3-year disease-free survival (DFS) to that of tegafur-uracil plus leucovorin (UFT/LV). We updated DFS and overall survival (OS) and performed T x N subset analysis. METHODS: A total of 1518 patients with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days, four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days, five courses). RESULTS: The 5-year DFS rates of the S-1 and UFT/LV group were 70.2 % and 66.9 %, respectively (HR 0.88; 95% CI 0.74 to 1.06; p=0.177), and non-inferiority of DFS was reconfirmed with a median of 63.5-month follow-up. The similarity of OS was also confirmed (HR 0.92; 95% CI 0.72 to 1.17; p=0.488); 5-year OS rates of the S-1 and UFT/LV group were 86.0 % and 84.4 %, respectively. No significant interactions were identified between the major baseline characteristics and DFS of the S-1 and UFT/LV groups, except for histological type; S-1 was more favourable in patients with poorly differentiated adenocarcinoma. Patient outcomes were well separated by TNM-substages (IIIA/IIIB/IIIC). With the patients divided into 20 subsets by T and N factors, the DFS and OS rates of T3 and N1 subset, which accounted for 62 % of stage IIIB patients and 44 % of all studied subjects, were significantly better than those of the other subsets in stage IIIB and similar to those of stage IIIA. CONCLUSIONS: Adjuvant therapy of S-1 for stage III colon cancer was reconfirmed to be non-inferior in DFS to those of UFT/LV after long follow-up. No difference in OS was also demonstrated. T3N1 patients might be considered separately from other patients included in stage IIIB because of its favourable outcome. TRIAL REGISTRATION NUMBER: NCT00660894.