Long-term outcome of regional cooperation pathway after endoscopic submucosal dissection for early detection of new gastric cancer.

OBJECTIVES: The Cancer Control Act requires the maintenance of regional cooperation pathways (RCP) for cancer treatment. In 2008, we started RCP for early detection of new gastric cancer after endoscopic submucosal dissection (ESD). In gastric cancer treatment, RCP after surgical resection had been widely used, but little is known about RCP after ESD. This study aimed to evaluate the effectiveness of RCP after ESD. METHODS: This study included 465 patients on whom our RCP was implemented from 2008 to 2018. A regional family physician performed surveillance endoscopy at 3 months and 1 year after ESD and annually thereafter. We retrospectively evaluated the cumulative incidence and treatment outcomes of new gastric cancer and compared them with previous reports. RESULTS: During a median follow-up period of 70.5 months (3-120 months), 58 patients developed new gastric cancers, and metachronous gastric cancer was detected in 55 patients more than 1 year after ESD. The 5-year cumulative incidence rate was 9.8%. Three patients did not want treatment. Among the remaining 55 patients, the initial treatment was ESD in 51 and surgical resection in 4. Eventually, 50 patients (48 in the ESD group and 2 in the surgical resection group) fulfilled the pathologic criteria for curative ESD. There were no deaths due to gastric cancer. CONCLUSION: Our study was the first to reveal the incidence of new gastric cancer after ESD using RCP. Most lesions were cured with ESD, and no patients died of gastric cancer. Therefore, we consider RCPs to be an option for surveillance after ESD.

Derivation of pancreatic acinar cell carcinoma cell line HS-1 as a patient-derived tumor organoid.

Acinar cell carcinoma (ACC) of the pancreas is a malignant tumor of the exocrine cell lineage with a poor prognosis. Due to its rare incidence and technical difficulties, few authentic human cell lines are currently available, hampering detailed investigations of ACC. Therefore, we applied the organoid culture technique to various types of specimens, such as bile, biopsy, and resected tumor, obtained from a single ACC patient. Despite the initial propagation, none of these organoids achieved long-term proliferation or tolerated cryopreservation, confirming the challenging nature of establishing ACC cell lines. Nevertheless, the biopsy-derived early passage organoid developed subcutaneous tumors in immunodeficient mice. The xenograft tumor histologically resembled the original tumor and gave rise to infinitely propagating organoids with solid features and high levels of trypsin secretion. Moreover, the organoid stained positive for carboxylic ester hydrolase, a specific ACC marker, but negative for the duct cell marker CD133 and the endocrine lineage marker synaptophysin. Hence, we concluded the derivation of a novel ACC cell line of the pure exocrine lineage, designated HS-1. Genomic analysis revealed extensive copy number alterations and mutations in EP400 in the original tumor, which were enriched in primary organoids. HS-1 displayed homozygous deletion of CDKN2A, which might underlie xenograft formation from organoids. Although resistant to standard cytotoxic agents, the cell line was highly sensitive to the proteasome inhibitor bortezomib, as revealed by an in vitro drug screen and in vivo validation. In summary, we document a novel ACC cell line, which could be useful for ACC studies in the future.

Enzymatically modified isoquercitrin in soy protein temporarily enhanced the plasma amino-acid concentrations, antioxidant index, and plasma hormone levels: a randomized, double-blind cross-over trial.

This study investigated the effects of a dietary protein supplement containing enzymatically modified isoquercitrin (EMIQ) on plasma amino-acid levels in healthy people. A randomized double-blind cross-over trial (UMIN000044791) was conducted with a sample of nine healthy individuals. These participants ingested soy protein with or without 42 mg EMIQ for 7 days after performing mild exercise. Plasma amino-acid levels were measured before ingestion and at 15, 30, 45, 60, 90, 120, 180, and 240 min after ingestion on the last day. The concentrations of total amino acids at 0 and 120 min and easily oxidized amino acids at 120 min were significantly higher in the plasma of individuals who consumed 42 mg EMIQ. Oxidative stress levels were lower and plasma testosterone levels were higher in participants who ingested soy protein with 42 mg EMIQ than in those who did not. These results suggest that daily ingestion of soy protein with 42 mg EMIQ can be useful for effective protein absorption.

Second-generation narrow-band imaging to detect colorectal adenomas: A prospective study including community hospitals.

BACKGROUND AND AIM: It is unclear whether second-generation narrow-band imaging (NBI) improves colorectal adenoma detection in clinical practice. We aimed to evaluate the ability of NBI to detect adenomas in academic and community hospitals. METHODS: This observational, multicenter study was conducted in four academic and four community hospitals between July 2018 and April 2019. We enrolled patients aged ≥ 20 years who underwent colonoscopy for screening, polyp surveillance, or diagnostic workup. The primary endpoint was the adenoma detection rate (ADR) between NBI (NBI group) and white-light imaging colonoscopies (WLI group) after propensity score (PS) matching. RESULTS: Of 1831 patients analyzed before PS matching, the NBI and WLI groups included 742 and 1089 patients, respectively. After PS matching, 711 pairs from both groups were analyzed. ADR and the mean number of adenomas per patient did not differ significantly between the NBI and WLI groups (43.5% vs 44.4%, P = 0.71; 0.90 ± 1.38 vs 0.91 ± 1.40, P = 0.95, respectively). Academic hospitals showed higher ADR in the NBI group (60.5% vs 53.8%), whereas community hospitals showed higher ADR in the WLI group (35.8% vs 40.5%). In the NBI group, ADR was significantly higher among NBI-screening-experienced endoscopists than among NBI-screening-inexperienced endoscopists (63.2% vs 39.2%, P < 0.001). The mean number of flat and depressed lesions detected per patient was significantly higher with NBI than with WLI (0.62 ± 1.34 vs 0.44 ± 1.01, P = 0.035). CONCLUSIONS: Second-generation NBI could not surpass WLI in terms of ADR based on patient recruitment from both academic and community hospitals but improved the detection of easily overlooked flat and depressed lesions.

Randomized phase II study of chemoradiotherapy with versus without induction chemotherapy for locally advanced pancreatic cancer: Japan Clinical Oncology Group trial, JCOG1106.

BACKGROUND: Chemoradiotherapy is a treatment option for locally advanced pancreatic cancer. However, the efficacy of induction chemotherapy prior to chemoradiotherapy is uncertain. The aim of this randomized, multicentre phase II study is to evaluate the efficacy and safety of chemoradiotherapy with and without induction chemotherapy to determine the significance of induction chemotherapy. METHODS: Patients with locally advanced pancreatic cancer were randomly assigned to the chemoradiotherapy arm (Arm A) or induction chemotherapy followed by the chemoradiotherapy arm (Arm B). Patients in Arm A underwent radiotherapy with concurrent S-1. Patients in Arm B received induction gemcitabine for 12 weeks, and thereafter, only patients with controlled disease underwent the same chemoradiotherapy as Arm A. After chemoradiotherapy, gemcitabine was continued until disease progression or unacceptable toxicity in both arms. The primary endpoint was overall survival. RESULTS: Amongst 102 patients enrolled, 100 were eligible for efficacy assessment. The probability of survival was greater in Arm B in the first 12 months, but the trend was reversed in the following periods (1-year survival 66.7 vs. 69.3%, 2-year survival 36.9 vs. 18.9%). The hazard ratio was 1.255 (95% confidence interval 0.816-1.930) in favour of Arm A. Gastrointestinal toxicity was slightly more frequent and three treatment-related deaths occurred in Arm A. CONCLUSIONS: This study suggested that the chemoradiotherapy using S-1 alone had more promising efficacy with longer-term survival, compared with induction gemcitabine followed by chemoradiotherapy for locally advanced pancreatic cancer. CLINICAL TRIAL REGISTRATION: The study was registered at the UMIN Clinical Trials Registry as UMIN000006811.

Comparison of endoscopic visibility and miss rate for early gastric cancers after Helicobacter pylori eradication with white-light imaging versus linked color imaging.

BACKGROUND AND AIM: We aimed to investigate whether linked color imaging (LCI) improves endoscopic visibility of early gastric cancers (EGC) after Helicobacter pylori eradication, which are often difficult to detect, and reduces the miss rate when compared with white-light imaging (WLI). METHODS: The visibility study used two images, one each with WLI and LCI, from 84 consecutive EGC after H. pylori eradication. Endoscopic visibility was evaluated using a visibility score and color difference (CD) value. To analyze miss rates, we studied a library of recorded videos using both WLI and LCI for 70 other consecutive patients after H. pylori eradication, among whom 19 had EGC. Endoscopic screening was done using the same protocol to map the entire stomach. Six endoscopists reviewed the videos in a randomized order. Miss rates of EGC were compared among the modalities. RESULTS: Mean [(±standard deviation) visibility scores with LCI were significantly higher than those with WLI (3.19 ± 0.84 vs 2.52 ± 0.98, P < 0.001), as were mean CD values (26.3 ± 9.1 vs 13.6 ± 6.3, P < 0.001). Miss rates of the six endoscopists were significantly lower with LCI than with WLI (30.7% vs 64.9%, P < 0.001). Both expert and trainee endoscopists had significantly better results with LCI than with WLI. CONCLUSIONS: Linked color imaging significantly improved the visibility of EGC after H. pylori eradication compared with WLI using both subjective and objective criteria. Furthermore, LCI significantly reduced miss rates of these lesions compared with WLI.

Skill-up study of systemic endoscopic examination technique using narrow band imaging of the head and neck region of patients with esophageal squamous cell carcinoma: Prospective multicenter study.

OBJECTIVE: To evaluate the usefulness of a training program on endoscopic head and neck surveillance for beginner endoscopists. METHODS: This prospective multicenter study included 13 beginner endoscopists from 10 institutions who received training in systematic observation techniques and diagnostic criteria, and the training involved hands-on learning. Between May 2016 and February 2017, enrolled patients with current or previously diagnosed esophageal squamous cell carcinomas underwent head and neck surveillance using narrow band imaging (NBI) endoscopy, and histologically confirmed head and neck squamous cell carcinoma (HNSCC) detection rates, endoscopic image quality, and examination times were compared before (group A) and after (group B) the training program. Maximum possible score for the endoscopic images was 30 points. RESULTS: A total of 330 patients, comprising 181 in group A and 149 in group B, were enrolled. Three patients with HNSCC were detected in group A (1.7%) and in group B (2.0%; P = 1.000). Mean ± standard deviation (SD) examination times were 157 ± 71 s and 174 ± 109 s in groups A and B, respectively, (P = 0.073). Mean ± SD scores of the endoscopic images were 25.04 ± 5.47 points and 27.01 ± 4.35 points in groups A and B, respectively, (P < 0.001). CONCLUSION: The HNSCC detection rate based on the use of NBI on patients with ESCC did not improve after the training program for beginner endoscopists; however, endoscopic image quality improved significantly after the training program.

Magnified endoscopic observation of small depressed gastric lesions using linked color imaging with indigo carmine dye.

BACKGROUND AND STUDY AIMS: Magnifying linked color imaging with indigo carmine dye (M-Chromo-LCI) enables sterically enhanced and color image-magnified observation of the superficial gastric mucosa. This study investigated the usefulness of M-Chromo-LCI for the differential diagnosis of gastric lesions. PATIENTS AND METHODS: 100 consecutive small depressed lesions were examined with conventional white-light imaging (C-WLI), magnifying blue-laser imaging (M-BLI), and M-Chromo-LCI. Endoscopic images were reviewed by three experts and three non-experts. Diagnostic accuracy and interobserver agreement were compared among the modalities. RESULTS: For experts, M-BLI showed a significantly higher diagnostic accuracy than C-WLI (82.7 % vs. 67.0 %; P < 0.001). The diagnostic accuracy of M-Chromo-LCI was not different from M-BLI (87.7 % vs. 82.7 %; P = 0.31). For non-experts, M-BLI showed a significantly higher diagnostic accuracy than C-WLI (69.3 % vs. 52.3 %; P < 0.001). M-Chromo-LCI additionally showed a significantly higher diagnostic accuracy than M-BLI (79.7 % vs. 69.3 %; P = 0.005). M-Chromo-LCI had the highest interobserver agreement for each group. CONCLUSIONS: M-Chromo-LCI is expected to become a useful modality for the accurate diagnosis of gastric lesions.

Usefulness of close observation with non-magnified blue laser imaging for determining cold polypectomy indications.

PURPOSE: To examine the usefulness of non-magnified close observation with blue laser imaging (BLI) using a colonoscope with close observation capability in determining indications for cold polypectomy. METHODS: We conducted an image evaluation study on 100 consecutive colorectal lesions of 10 mm or less which were observed endoscopically without magnification using BLI mode prior to treatment. Two experts and two non-experts reviewed the images using the Japan NBI expert team (JNET) classification and the diagnostic accuracy was analyzed. RESULTS: The final pathological diagnoses of the 100 lesions were hyperplastic/sessile serrated polyp (HP/SSP), low grade dysplasia (LGD), high grade dysplasia (HGD) and deep submucosal invasive cancer (dSM), respectively, in 12, 79, 9 and 0 lesions. When JNET classification type 1 corresponds to HP/SSP; 2A to LGD; 2B to HGD; and 3 to dSM; the overall diagnostic accuracy was 84.3%. Accuracy was 90.5% for experts and 78.0% for non-experts. High confidence rate was 67.5% for experts and 48.0% for non-experts. In diagnostic accuracy for HGD, the sensitivity, specificity, PPV and NPV were, respectively, 77.8%, 98.9%, 87.5% and 97.8% for experts; and 66.6%, 92.3%, 46.2% and 96.6% for non-experts. CONCLUSIONS: The diagnostic accuracy of unmagnified close observation with BLI using a colonoscope with close observation capability is similar to that reported for magnifying endoscopy and is useful in predicting the histological diagnosis of colorectal polyps of 10 mm or less although the effectiveness may be limited for non-experts. This modality is a potentially useful tool in deciding indications for cold polypectomy.

Feasibility of endoscopic submucosal dissection for cecal lesions.

BACKGROUND: The treatment results of endoscopic submucosal dissection (ESD) for colorectal lesions have improved markedly, but some lesions remain difficult to treat. Hence the cecum is considered a technically challenging site for ESD. We examined the feasibility of ESD for cecal lesions. METHODS: Among a total of 708 colorectal ESD performed in our hospital between March 2006 and December 2016, 549 procedures performed after April 2012 were studied, at a time when the techniques of ESD had stabilized and the procedure was covered by health insurance in Japan. Among 549 cases, 61 were cecal lesions and 488 were noncecal lesions. The treatment outcomes were analyzed. RESULTS: For cecal lesions, the en bloc resection rate was 95.1%, R0 resection rate was 91.8%, perforation rate was 0%, delayed bleeding rate was 6.6%, median diameter of resected specimen was 32 mm (16-65 mm), median time of the procedure was 44 minutes (8-140 min). The corresponding results for noncecal lesions were 97.3%, 95.5%, 0.4%, 2.7%, 30 mm (10-109 mm), and 37 min (7-225 min). No significant differences were observed and the good treatment results were seen. When the outcomes were analyzed for cecal sites considered to be particularly challenging; proximity to appendiceal orifice, the ileocecal valve, and the bottom of cecum, the treatment results were not inferior to other sites. CONCLUSIONS: ESD is safe and effective even for cecal lesions considered challenging to treat. ESD is feasible for cecal lesions.

Safety and efficacy of endoscopic submucosal dissection using IT knife nano with clip traction method for early esophageal squamous cell carcinoma.

BACKGROUND: Although endoscopic submucosal dissection (ESD) is an accepted and established treatment for early esophageal squamous cell carcinoma (EESCC), it is technically difficult, time consuming, and less safe than endoscopic mucosal resection. To perform ESD safely and more efficiently, we proposed a new technique of esophageal ESD using an IT knife nano with the clip traction method. This study aimed to evaluate the efficacy and safety of ESD using this new technique. METHODS: We retrospectively reviewed all consecutive cases of esophageal ESD performed using an IT knife nano with the clip traction method at our hospital between March 2013 and January 2017. Therapeutic efficacy and safety were also assessed. RESULTS: A total of 103 patients underwent esophageal ESD using the IT knife nano with the clip traction method. In all cases, we performed en bloc resection. Complete resection was achieved in 100 cases (97.1%). The median operating time was 40 (range 13-230) min. No cases of perforation or delayed bleeding occurred. Although two cases (2.0%) of mediastinal emphysema occurred without visible perforation at endoscopy, all were successfully managed conservatively. CONCLUSIONS: The new technique of esophageal ESD using the IT knife nano with the clip traction method appears to be feasible, effective, and safe for EESCC treatment.

Linked-color imaging improves endoscopic visibility of colorectal nongranular flat lesions.

BACKGROUND AND AIMS: As a newly developed image-enhanced endoscopy (IEE) technique, linked-color imaging (LCI) provides very bright images with enhanced color tones. With the objective of improving the detection rate of colorectal flat tumor lesions, which are difficult to detect, we examined the usefulness of LCI from the viewpoint of visibility. METHODS: Fifty-three consecutive nongranular flat tumors were used in this study. Endoscopic images were acquired by white-light imaging (WLI), blue-laser imaging (BLI)-bright, and LCI modes. For each lesion, we selected 1 image each acquired by WLI, BLI-bright, and LCI modes. Six endoscopists interpreted the images. By using a previously reported visibility scale, we scored the visibility level on a scale of 1 to 4. RESULTS: The mean (± standard deviation) visibility scores were 2.74 ± 1.08 for WLI, 2.94 ± 0.97 for BLI-bright, and 3.36 ± 0.72 for LCI. The score was significantly higher for BLI-bright compared with WLI (P < .001) and again higher for LCI compared with BLI-bright (P < .001). When we compared between experts and trainees, the corresponding scores of experts were 2.83 ± 1.06, 3.17 ± 0.88, and 3.40 ± 0.74, with a tendency similar to the scores of all endoscopists. For the trainees, there was no difference between the scores for WLI (2.65 ± 1.10) and BLI-bright (2.71 ± 1.00), but the score for LCI (3.31 ± 0.69) was significantly higher than that for WLI or BLI-bright (P < .001). When only sessile serrated adenoma/polyp lesions were analyzed, LCI remained significantly higher than the other 2. CONCLUSIONS: The present findings suggest that LCI increases the visibility of colorectal flat lesions and contributes to improvement of the detection rate for these lesions.

A case report of prostate cancer metastasis to the stomach resembling undifferentiated-type early gastric cancer.

BACKGROUND: Occurrence of metastatic cancer to the stomach is rare, particularly in patients with prostate cancer. Gastric metastasis generally presents as a solitary and submucosal lesion with a central depression. CASE PRESENTATION: We describe a case of gastric metastasis arising from prostate cancer, which is almost indistinguishable from the undifferentiated-type gastric cancer. A definitive diagnosis was not made until endoscopic resection. On performing both conventional and magnifying endoscopies, the lesion appeared to be slightly depressed and discolored area and it could not be distinguished from undifferentiated early gastric cancer. Biopsy from the lesion was negative for immunohistochemical staining of prostate-specific antigen, a sensitive and specific marker for prostate cancer. Thus, false initial diagnosis of an early primary gastric cancer was made and endoscopic submucosal dissection was performed. Pathological findings from the resected specimen aroused suspicion of a metastatic lesion. Consequently, immunostaining was performed. The lesion was positive for prostate-specific acid phosphatase and negative for prostate-specific antigen, cytokeratin 7, and cytokeratin 20. Accordingly, the final diagnosis was a metastatic gastric lesion originating from prostate cancer. CONCLUSION: In this patient, the definitive diagnosis as a metastatic lesion was difficult due to its unusual endoscopic appearance and the negative stain for prostate-specific antigen. We postulate that both of these are consequences of hormonal therapy against prostate cancer.

Cumulative incidence, risk factors and prognostic impact of venous thromboembolism in Japanese patients with advanced gastric cancer.

BACKGROUND: Advanced gastric cancer (AGC) and systemic chemotherapy are some of the risk factors for venous thromboembolism (VTE). However, the cumulative incidence, risk factors and prognostic impact of VTE have not been evaluated in Japanese patients with AGC. METHODS: This retrospective study included patients who received fluoropyrimidine-based first-line chemotherapy for AGC between September 2009 and July 2015 at our institution. VTE was diagnosed by computed tomography scan and was managed by anticoagulant therapy. The cumulative incidence of VTE was estimated by the Kaplan-Meier method. Multivariate analysis was performed to identify the risk factors and prognostic impact of VTE. RESULTS: Of 283 patients, 37 (13.1%) developed VTE before or during chemotherapy. The cumulative incidence of VTE was 8.7% at 6 months and 13.6% at 1 year. The independent risk factors for VTE were body mass index (BMI) of ≥25 kg/m2 (HR 3.38, 95% CI 1.72-6.65, P < 0.01) and presence of peritoneal metastasis (HR 2.01, 95% CI 1.00-4.00, P < 0.05). The median overall survival (OS) was 13.4 months for patients with VTE and 11.7 months for those without VTE (P = 0.58). After adjusting for other prognostic factors, the number of metastatic sites and metastases to the peritoneum and bone were independent prognostic factors for OS, but not for VTE (HR 0.89, 95% CI 0.62-1.28, P = 0.53). CONCLUSIONS: BMI ≥ 25 kg/m2 and peritoneal metastasis could be the risk factors for VTE in Japanese AGC patients. VTE might have no negative impact on OS in AGC patients treated with chemotherapy.

Frequent Presence of Lymphovascular Invasion in Small Rectal Neuroendocrine Tumors on Immunohistochemical Analysis.

Rectal neuroendocrine tumors (RNETs) have become common in recent years and are good candidates for endoscopic resection (ER). To achieve clear resection margins, more advanced techniques such as endoscopic submucosal dissection, endoscopic submucosal resection with a ligation device, and cap-assisted endoscopic mucosal resection are available for ER. After ER, lymphovascular invasion (LVI) is regarded as an important predictor of nodal metastasis. Previous studies have shown that small RNETs with LVI were uncommon (0-8.3%). However, using immunohistochemical analysis, a recent study revealed the frequent occurrence of LVI in small RNETs in a systematic manner (46.7%). There is a possibility that the actual detection rate of LVI in small RNETs is not always evaluated accurately because of the limited detection sensitivity of conventional hematoxylin-eosin staining. In addition, the correlation between LVI detected using immunohistochemical analysis and the development of metastasis remains unclear. Further prospective studies are required to clarify the role of LVI detected using immunohistochemical analysis.

Magnified endoscopic observation of early colorectal cancer by linked color imaging with crystal violet staining (with video).

BACKGROUND AND AIMS: Many reports have shown the usefulness of magnification endoscopy with crystal violet (CV) staining for delineating the pit pattern in the diagnosis of colorectal carcinoma. However, the diagnostic accuracy of this method is not adequate for assessing the depth of invasion of early stage cancers. The novel technology of linked color imaging (LCI) combined with CV staining is expected to improve the accuracy of determining the depth of invasion. METHODS: We studied 3 patients with early stage colorectal cancer who were referred to our hospital. After CV spraying, high-magnification endoscopy was conducted by using the LCI mode. Efficacy of this modality was evaluated by comparing the preoperative diagnostic endoscopic images with posttreatment histopathologic findings. RESULTS: In 2 cases of rectal cancer, although conventional endoscopic examination could not exclude the possibility of submucosal cancer, use of the LCI mode with CV staining confirmed mucosal cancer. Eventually, EMR was conducted and achieved curative resection. In 1 case of sigmoid colon cancer, both conventional and CV magnification endoscopy suggested submucosal cancer. However, mucosal cancer was diagnosed by the novel method, and EMR achieved curative resection. CONCLUSIONS: LCI high-magnification endoscopy combined with CV staining provides images close to histopathologic findings and is expected to improve the accuracy of endoscopic diagnosis of the depth of invasion for early stage colorectal cancer.

A randomized phase II study comparing S-1 plus weekly split-dose cisplatin with S-1 plus standard-dose cisplatin as first-line chemotherapy for advanced gastric cancer.

BACKGROUND: S-1 plus weekly split-dose cisplatin demonstrated promising results in previous phase I and II studies for advanced gastric cancer (AGC) patients. METHODS: In this randomized phase II study, the efficacy and safety of S-1 plus weekly split-dose cisplatin (SWP, S-1 daily oral dose of 80-120 mg according to body surface area on days 1-14, and cisplatin 20 mg/m(2) i.v. on days 1 and 8 every 3 weeks) were compared with those of S-1 plus standard-dose cisplatin (SP) as first-line chemotherapy for AGC patients. The primary endpoint was 1-year survival rate. RESULTS: Patients were randomized into two groups: 18 in the SWP arm and 19 in the SP arm. This trial was terminated early because of low patient enrollment. The 1-year survival rate was 61 % [95 % confidence interval (CI), 36-86 %] and 53 % (95 % CI, 30-75 %) in the SWP and SP arms, respectively. However, the median survival time was 12.3 months (9.9-14.6 months) and 15.7 months (4.0-27.4 months), respectively (P = 0.064). Progression-free survival was significantly shorter in the SWP arm than in the SP arm (P = 0.047). Toxicity tended to be milder in the SWP arm than in the SP arm. For approximately 40 % of patients in the SWP arm, cisplatin was omitted on day 8 and treatment delayed because of prolonged myelosuppression. CONCLUSIONS: No clear benefits of adding cisplatin to S-1 in the SWP arm were demonstrated in this study. At this point, split-dose cisplatin combined with S-1 cannot be recommended for use in clinical practice.