Real-World Evidence of FOLFIRI Combined with Anti-Angiogenesis Inhibitors or Anti-EGFR Antibodies for Patients with Early Recurrence Colorectal Cancer After Adjuvant FOLFOX/CAPOX Therapy: A Japanese Claims Database Study.

BACKGROUND: Oxaliplatin-containing adjuvant regimens (folinic acid, fluorouracil, and oxaliplatin/capecitabine and oxaliplatin [FOLFOX/CAPOX]) are used after curative resection of colorectal cancer (CRC). However, real-world evidence regarding treatment sequences and outcomes in patients with early recurrence CRC after adjuvant chemotherapy is limited. OBJECTIVE: We aimed to describe the patient characteristics, treatment sequence, and overall duration of second-line (2L) therapy in patients with early recurrence CRC who received adjuvant chemotherapy (FOLFOX/CAPOX) followed by folinic acid, fluorouracil, and irinotecan (FOLFIRI) + anti-angiogenesis drugs (AA) or FOLFIRI + anti-epidermal growth factor receptor (EGFR) antibodies. METHODS: This retrospective study analyzed Japanese administrative data from November 2014 to March 2023 of adult patients who underwent CRC resection surgery, started FOLFOX/CAPOX ≤3 months (mo) after surgery, and had early CRC recurrence. Early recurrence was defined as initiation of FOLFIRI+AA or FOLFIRI+anti-EGFR antibodies as 2L therapy, ≤12 mo of discontinuing adjuvant chemotherapy. Patient characteristics, treatment sequence, median time to treatment discontinuation (mTTD), i.e., duration between the start and end dates of 2L therapy (Kaplan-Meier method), and factors associated with 2L time to treatment discontinuation constituted the study outcomes (Cox regression model). Subgroup analyses were performed for timing of early CRC recurrence (≤6 mo and 6-12 mo) and tumor sidedness. RESULTS: Among the 832 selected patients (median age [minimum-maximum] 67 (24-86) years, 56.4% male), CAPOX (71.3%) was more commonly used than FOLFOX (28.7%) as adjuvant therapy. FOLFIRI+AA (72.5%) was used more commonly than FOLFIRI+anti-EGFR antibodies (27.5%) in 2L. AA and anti-EGFR antibodies groups had similar mTTD: 6.2 mo (95% confidence interval 5.8, 6.9) and 6.1 mo (95% confidence interval 5.2, 7.4). Age ≥70 years showed significant association with shorter 2L treatment duration (hazard ratio 1.2, 95% confidence interval 1.0, 1.4; p = 0.03). The AA cohort's mTTD was numerically shorter in the ≤6 mo recurrence subgroup compared with the 6-12 mo recurrence subgroup (6.1 mo vs 8.1 mo); the anti-EGFR antibodies cohort had similar mTTD (5.8 mo vs 6.2 mo). The AA and anti-EGFR antibodies cohorts also had similar mTTD in the left-sided CRC subgroup (6.5 mo vs 6.2 mo), but not in the right-sided subgroup (5.6 mo vs 3.9 mo). CONCLUSIONS: This is the first administrative data-based real-world evidence on treatment sequence and outcomes for patients with early recurrence CRC treated with FOLFIRI+AAs or FOLFIRI+ anti-EGFR antibodies after adjuvant FOLFOX/CAPOX therapy in Japan. Both regimens had similar TTD, but relapse timing and tumor sidedness may influence their efficacy.

Laparoscopic Colectomy for Cecal Cancer and Intestinal Malrotation: A Case Report.

Background/Aim: Intestinal malrotation (IM) often remains undetected until adulthood, being discovered during testing or surgery for other comorbidities. Preoperative understanding of this anatomical abnormality is crucial. Case Report: An 80-year-old woman presented with cecal cancer. Three-dimensional computed tomography (CT) revealed that the cecum was located at the midline of the abdominal cavity, the duodenum did not cross the midline, and the ileocolic vein ran to the left. Clinically diagnosed with stage IVc cecal cancer complicated by IM, the patient underwent laparoscopic surgery. The ascending colon and cecum were not fixed to the retroperitoneum. The duodenum lacked the second, third, and fourth portions and the small bowel was distributed on the left and right sides of the abdominal cavity. Adhesions had shortened the mesentery, which were released close to their normal positions. Conclusion: Although laparoscopic surgery is superior to open surgery in terms of securing the field of view in a narrow space, providing a magnifying effect, and minimal invasiveness, it has a limited field of view and is inferior in terms of grasping the overall anatomy, which may be disadvantageous in cases of anatomical abnormalities. Colorectal cancer with IM is rare; however, the rate of preoperative diagnosis seems to be increasing thanks to improvements in diagnostic imaging, such as three-dimensional CT scans. In this study, we also reviewed 49 cases of colorectal cancer associated with IM.

Risk factors of bleeding during rectal cancer surgery in obese patients in Japan.

BACKGROUND: According to several clinical trials for patients with rectal cancer, laparoscopic surgery significantly reduces intraoperative complications and bleeding compared with laparotomy and demonstrated comparable long-term results. However, obesity is considered one of the risk factors for increased surgical difficulty, including complication rate, prolonged operation time, and bleeding. METHODS: Patients with clinical pathological stage II/III rectal cancer and a body mass index of ≥25 kg/m2 who underwent laparotomy or laparoscopic surgery between January 2009 and December 2013 at 51 institutions participating in the Japan Society of Laparoscopic Colorectal Surgery were included. These patients were divided into major bleeding (>500 mL) group and minor bleeding (≤500 mL) group. The risk factors of major bleeding were evaluated by univariate and multivariate analyses. RESULTS: This study included 517 patients, of which 74 (19.9%) experienced major bleeding. Patient characteristics did not significantly differ between the two groups. The major bleeding group had a longer operative time (p < 0.001) and a larger tumor size than the minor bleeding group (p = 0.011). In the univariate analysis, age >65 years, laparotomy, operative time >300 min, and multivisceral resection were significantly associated with intraoperative massive bleeding. In the multivariate analysis, age >65 years (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.13-4.82), laparotomy (OR, 20.82; 95% CI, 11.56-39.75), operative time >300 min (OR, 5.39; 95% CI, 1.67-132), and multivisceral resection (OR, 10.72; 95% CI, 2.47-64.0) showed to be risk factors for massive bleeding. CONCLUSION: Age >65 years, laparotomy, operative time >300 min, and multivisceral resection were risk factors for massive bleeding during rectal cancer surgery in patients with obesity.

Curative resection via right hemicolectomy and regional lymph node dissection for colonic adenomatous polyposis of unknown etiology with adenocarcinomas localized in the right side of the colon: a case report.

BACKGROUND: APC and MUTYH are both well-known colorectal polyposis causative genes. However, 30-50% of colorectal adenomatous polyposis cases are classified as colonic adenomatous polyposis of unknown etiology and lack identifiable pathogenic variants. Although guidelines recommend total proctocolectomy for colonic adenomatous polyposis of unknown etiology with over 100 adenomas, evidence is lacking. This study presents a unique case of localized colonic adenomatous polyposis of unknown etiology with multiple adenocarcinomas, treated with hemicolectomy and regional lymph node dissection. CASE PRESENTATION: The patient was a 72-year-old woman whose colonoscopy revealed numerous polyps and two adenocarcinomas localized in the right side of the colon, with no lesions in the left side. The patient had no family history of polyposis or colorectal cancer. No extracolonic lesions, enlarged lymph nodes, or distant metastases were found. Considering the patient's age and lesion localization, laparoscopic right hemicolectomy with regional lymph node dissection was performed. Histopathological diagnosis revealed three adenocarcinoma lesions with no lymph node metastasis. The most advanced pathological stage was T2N0M0 Stage I (UICC 8th edition). The patient was alive 5 years postoperatively, without recurrence of cancer or polyposis in the remaining colon and rectum. To diagnose hereditary colorectal cancer/polyposis, a germline multigene panel testing for APC, EPCAM, MBD4, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, NTHL1, PMS2, POLD1, POLE, and TP53 was performed using DNA extracted from blood samples: however, no pathogenic variant was detected. Therefore, the patient was diagnosed with colonic adenomatous polyposis of unknown etiology. CONCLUSIONS: In this rare case, colonic adenomatous polyposis of unknown etiology, with numerous adenomatous polyps and multiple adenocarcinomas localized in the right side of the colon, was successfully treated with right hemicolectomy and regional lymph node dissection. Despite genetic analysis, no causative germline variants were identified. Segmental colectomy according to the distribution of polyps might be a curative approach.

Future direction of total neoadjuvant therapy for locally advanced rectal cancer.

Despite therapeutic advancements, disease-free survival and overall survival of patients with locally advanced rectal cancer have not improved in most trials as a result of distant metastases. For treatment decision-making, both long-term oncologic outcomes and impact on quality-of-life indices should be considered (for example, bowel function). Total neoadjuvant therapy (TNT), comprised of chemotherapy and radiotherapy or chemoradiotherapy, is now a standard treatment approach in patients with features of high-risk disease to prevent local recurrence and distant metastases. In selected patients who have a clinical complete response, subsequent surgery might be avoided through non-operative management, but patients who do not respond to TNT have a poor prognosis. Refined molecular characterization might help to predict which patients would benefit from TNT and non-operative management. Specifically, integrated analysis of spatiotemporal multi-omics using artificial intelligence and machine learning is promising. Three prospective trials of TNT and non-operative management in Japan, the USA and Germany are collaborating to better understand drivers of response to TNT. Here, we address the future direction for TNT.

Venous Thromboembolism Following Lateral Lymph Node Dissection for Rectal Cancer.

BACKGROUND/AIM: Postoperative venous thromboembolism (VTE) is a well-recognized complication that leads to morbidity and mortality. Lateral lymph node dissection (LLND) for rectal cancer is thought to potentially increase the risk of VTE due to its technical complexity. However, the relationship between LLND and VTE remains inadequately understood. The aim of this study was to elucidate the impact of LLND on the incidence of postoperative VTE. PATIENTS AND METHODS: This is a retrospective analysis of patients who underwent rectal cancer resection between 2010 and 2018 to identify the risk factors associated with postoperative VTE. Patients were divided into two groups: those who underwent surgery with LLND (LLND+ group) and those who underwent surgery without LLND (LLND- group). RESULTS: A total of 543 patients were enrolled in this study, and 113 patients underwent surgery for rectal cancer with LLND. VTE developed in 8 patients (1.47%), with the incidence rates being 4.42% in the LLND+ group and 0.69% in the LLND- group, respectively (p=0.012). Three of 8 patients had developed severe postoperative complications, and the other two patients needed intraoperative repair of the iliac vein during LLND procedure. Multivariate analysis identified the incidence of postoperative complications and LLND as the independent risk factors of VTE. CONCLUSION: Patients undergoing rectal cancer surgery with LLND should be closely monitored for signs of VTE.

Cardiac tamponade complicating esophagectomy and retrosternal gastric tube reconstitution in a patient with an abnormal ascending aorta position: a case report.

BACKGROUND: Cardiac tamponade is a rare postoperative complication of esophageal cancer surgery, which leads to rapid hemodynamic changes and can be fatal if not treated properly and promptly. Herein, we report a case of cardiac tamponade after thoracoscopic subtotal esophagectomy and retrosternal gastric tube reconstitution for esophageal cancer that was successfully treated with surgical drainage. CASE PRESENTATION: An 86-year-old man with lower thoracic esophageal cancer underwent thoracoscopic subtotal esophagectomy and retrosternal gastric tube reconstitution. No intra-operative complications were observed. On the first postoperative day, tachycardia and hypotension were observed, and pericardial effusion was identified on computed tomography images. The patient was diagnosed with obstructive shock secondary to cardiac tamponade. As percutaneous puncture drainage was not possible due to the presence of a retrosternal gastric tube, pericardiotomy with a small left anterior thoracotomy was performed, and a large amount of hematogenous fluid was drained, which instantly improved circulation. On the second postoperative day, the patient showed decreased pulse pressure, and computed tomography revealed a residual and enlarged hematoma around the right ventricle. The patient underwent surgical drainage and another pericardiotomy with a small right anterior thoracotomy was performed to drain the hematoma. At this time, multiple injuries to the fatty tissue, epicardium, and myocardium with active bleeding were observed on the anterior surface of the right ventricle near the root of the pulmonary artery. In this patient, the ascending aorta ran further to the right and dorsal sides than usual, causing the anterior wall of the right ventricle near the root of the pulmonary artery to be closer to the back of the sternum. This abnormality may have contributed to injury during the creation of the retrosternal pathway, leading to cardiac tamponade. CONCLUSIONS: Cardiac tamponade after esophagectomy can occur because of manipulation during creation of the retrosternal route, with an anomaly in the aortic position being present in this case. Gentle manipulation and selection of the reconstruction route according to the patient's condition are necessary in cases with such anatomical abnormalities.

Impact of the perioperative assessment of deglutition on postoperative respiratory complications in elderly patients undergoing gastrectomy for gastric cancer.

PURPOSE: To investigate the association between perioperative deglutition screening and postoperative respiratory complications (PRCs) in elderly patients undergoing gastrectomy for gastric cancer. METHODS: We analyzed data from 86 patients with gastric cancer (aged ≥ 70 years) who underwent gastrectomy between October, 2016 and November, 2018. Videofluoroscopic swallowing examinations (VFSEs) were performed before and after surgery. We examined the association of these results with postoperative respiratory complications, as well as the relationships between demographic, operative, and swallowing function assessment data. RESULTS: PRCs were identified in 16 patients. The results of pre- and postoperative VFSE showed abnormalities in 28 and 32 patients, respectively. Multivariate analysis revealed that abnormalities in the postoperative VFSEs were strongly associated with the development of PRCs (P = 0.002). The findings of this analysis suggests that ventilatory impairment, a Charlson comorbidity index score ≥ 3, and an open surgical approach are independent risk factors for PRCs. CONCLUSION: This is the first study to demonstrate the efficacy of perioperative assessment of swallowing function using VFSE for predicting PRCs in elderly patients undergoing gastrectomy for gastric cancer.

Short-term outcomes of a prospective multicenter phase II trial of total neoadjuvant therapy for locally advanced rectal cancer in Japan (ENSEMBLE-1).

Aim: To evaluate the feasibility and safety of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) in Japan. Methods: This prospective, multicenter, open-label, single-arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥ 20 years, LARC within 12 cm from the anal verge, and cT3-4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short-course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (six courses) followed by total mesorectum excision (TME) was the treatment protocol. Non-operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. Results: Thirty patients (male, n = 26; female, n = 4; median age, 62.5 [44-74] years; cT [T2, n = 1; T3, n = 25; T4, n = 4]; cN [N0, n = 13; N1, n = 13; N2, n = 4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%-50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients. There were no treatment-related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow-up period was 15.6 (10.5-22.8) months, with no recurrence or regrowth in NOM. Conclusions: ENSEMBLE-1 demonstrated satisfactory pCR and cCR, and well-tolerated safety of TNT for patients with LARC in Japan.

High Level Sacral Bone Resection for Locally Recurrent Rectal Cancer.

BACKGROUND/AIM: Locally recurrent rectal cancer (LRRC) involving the upper sacrum is generally considered a contraindication for curative surgery. In the surgical management of LRRC, sacrectomy is frequently performed to secure clear resection margins. Nonetheless, the indications for high sacrectomy remain controversial due to potential postoperative complications, questions about radicality, and the increased complexity of the operation. Furthermore, comprehensive studies addressing this issue are notably absent. This study aimed to assess the feasibility, safety, and surgical prognosis in high sacrectomy for LRRC. PATIENTS AND METHODS: All patients with LRRC who required concomitant sacrectomy, but did not include the inferior margin of the second sacral vertebra, between 2003 and 2014, were reviewed retrospectively. RESULTS: Eight patients with a median age of 59 years were included in this study. The proximal resection line for sacral bone resection was the central part of the S1 vertebra in one patient, lower edge of the S1 vertebra in six patients, and central part of the S2 vertebra in one patient. Negative margin resection was achieved in five out of the eight patients. The median operative time was 922 min, and the median operative blood loss volume was 6,370 ml. Major complications included pelvic abscess (n=5), ileus (n=1), and pulmonary vein embolism (n=1), none of which proved fatal during the postoperative period. Both the 5-year local re-recurrence-free survival rate and the 5-year distant metastasis-free survival rate were 50% (4/8). CONCLUSION: High sacrectomy is safe and feasible to achieve negative margins in patients with LRRC.

Treatment response prediction of neoadjuvant chemotherapy for rectal cancer by deep learning of colonoscopy images.

In current clinical practice, several treatment methods, including neoadjuvant therapy, are being developed to improve overall survival or local recurrence rates for locally advanced rectal cancer. The response to neoadjuvant therapy is usually evaluated using imaging data collected before and after preoperative treatment or postsurgical pathological diagnosis. However, there is a need to accurately predict the response to preoperative treatment before treatment is administered. The present study used a deep learning network to examine colonoscopy images and construct a model to predict the response of rectal cancer to neoadjuvant chemotherapy. A total of 53 patients who underwent preoperative chemotherapy followed by radical resection for advanced rectal cancer at the Osaka University Hospital between January 2011 and August 2019 were retrospectively analyzed. A convolutional neural network model was constructed using 403 images from 43 patients as the learning set. The diagnostic accuracy of the deep learning model was evaluated using 84 images from 10 patients as the validation set. The model demonstrated a sensitivity, specificity, accuracy, positive predictive value and area under the curve of 77.6% (38/49), 62.9% (22/33), 71.4% (60/84), 74.5% (38/51) and 0.713, respectively, in predicting a poor response to neoadjuvant therapy. Overall, deep learning of colonoscopy images may contribute to an accurate prediction of the response of rectal cancer to neoadjuvant chemotherapy.

Role of plasma angiogenesis factors in the efficacy of first-line chemotherapy combined with biologics in RAS wild-type metastatic colorectal cancer: Results from the GI-SCREEN CRC-Ukit study.

BACKGROUND: Several biomarkers have been established for metastatic colorectal cancer (mCRC). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemotherapy in first-line (1L) treatment in patients with RAS wild-type mCRC and the dynamics of plasma angiogenesis factors at progression during 1L treatment. METHODS: In this multicenter prospective observational study, serial plasma samples were prospectively collected at pretreatment and progression stages; 17 plasma angiogenesis factors were analyzed using the multiplex assay with Luminex® technology. Interactions between the pretreatment measurements and treatment groups on progression-free survival (PFS) and overall survival (OS) in patients with RAS wild-type were assessed using the propensity-score weighted Cox proportional hazards model. RESULTS: From February 2018 to September 2020, 202 patients were enrolled in the 1L cohort; 133 patients had RAS wild-type (chemotherapy plus bevacizumab [BEV group, n = 33] and plus anti-epidermal growth factor receptor monoclonal antibodies [aEGFR group, n = 100]). A trend of strong interaction on PFS was observed for interleukin-8 (IL-8) (p = 0.0752) and soluble vascular cell adhesion molecule-1 (sVCAM-1) (p = 0.0156). Regarding OS, IL-8 (p = 0.0283), soluble vascular endothelial growth factor-receptor-1 (sVEGFR-1) (p = 0.0777) and sVCAM-1 (p = 0.0011) tended to differentiate the treatment effect. In 112 patients, plasma samples were evaluable for dynamic analysis (57 and 55 from the BEV and aEGFR groups, respectively). In the BEV group, six factors significantly increased during progression, whereas two decreased. In the aEGFR group, three factors significantly increased, and six decreased. CONCLUSION: Pretreatment plasma IL-8 and sVCAM-1 levels could be predictive biomarkers to distinguish BEV and anti-EGFR mAbs when combined with chemotherapy in the 1L treatment of RAS wild-type mCRC. Several plasma angiogenesis factors showed significant change at progression in 1L chemotherapy plus biologics for RAS wild-type mCRC, which are potential biomarkers for selecting an optimal angiogenesis inhibitor in second-line treatment.

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases.

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial.

BACKGROUND: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC). METHODS: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33. RESULTS: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%). CONCLUSIONS: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. CLINICAL TRIAL REGISTRATION: JapicCTI-173618, jRCTs031180122.

Efficacy of Targeted Trials and Signaling Pathway Landscape in Advanced Gastrointestinal Cancers From SCRUM-Japan GI-SCREEN: A Nationwide Genomic Profiling Program.

PURPOSE: Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery. PATIENTS AND METHODS: Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results. RESULTS: A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies. CONCLUSION: Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.

[A Case of Rectal Cancer in Which Total Pelvic Organ Excision Could Be Avoided by TNT Therapy and Robotic Surgery].

The patient is a 50s year old man. He visited his local doctor with complaints of anal pain and bloody stools, and a rectal examination revealed a tumor on the anterior wall of the rectal canal. CT imaging showed tumors invading the prostate, urethra, and anorectal muscles, and a 3 mm-sized nodule was found in the lungs. The patient was diagnosed as cT4bN1M1a, Stage Ⅳ, and total neoadjuvant chemotherapy was planned as preoperative treatment. The 5 Gy×5 times radiation therapy followed by 5 courses of CAPOX plus BEV as preoperative chemotherapy and CAPOX. CAPOX was administered. After completion of treatment, the colonoscopy showed PR, and MRI showed clear boundary between the prostate and tumor but invasion into the anorectal muscles; CT showed no lung metastasis, and preoperative diagnosis was ycT4bN0M0, ycStage Ⅱ. Robotic-assisted rectal amputation and left lateral lymph node dissection were performed under general anesthesia. Pathologically, the patient was diagnosed as ycT4bN0M0, Stage Ⅱ, and the efficacy was determined as TRG 1(AJCC). Vertical dissection was negative and radical resection was possible.

[A Case of Locally Advanced Sigmoid Colon Cancer Invading the Urinary Bladder Treated with Neoadjuvant Chemotherapy and Robot Assisted Urinary Bladder-Conserving Surgery].

We report a case of 72s male with locally advanced sigmoid colon cancer. Colonoscopy revealed an advanced sigmoid colon cancer(AV 15 cm, type 2, semi-peripheral, deeper than T3). He was diagnosed as cT4bN2M0, cStage Ⅲc(Japanese Classification of Colorectal, appendiceal, and, Carcinoma, 9th edition), and was given chemotherapy as preoperative treatment. He was treated with CAPOX plus BEV as neoadjuvant chemotherapy. Preoperative diagnosis was ycT4bN0M0, ycStage Ⅱc. The robot assisted high anterior resection and partial bladder resection were performed. The bladder was sutured under robotic assistance. The residual bladder capacity was 100 mL. Postoperative diagnosis was ypT0N0M0, ypStage 0, TRG 0 (AJCC). We experienced a case of neoadjuvant chemotherapy for rectosigmoid colon cancer with bladder invasion, which resulted in pCR.

Phase II dose titration study of regorafenib in progressive unresectable metastatic colorectal cancer.

Regorafenib has shown significant survival benefit as a salvage therapy for colorectal cancer; however, its starting dose has been controversial in recent studies. Therefore, we conducted a prospective study on the efficacy and safety of the dose reduction of regorafenib to 120 mg. Patients received 120 mg regorafenib once per day for 3 weeks, followed by a 1-week off-treatment period. The primary endpoint was the investigator-assessed disease control rate (DCR). Sixty patients were registered, and the DCR was 38.3% with a median progression-free survival of 2.5 months (95% confidence interval [CI] 1.9-3.7) and median overall survival of 10.0 months (95% CI 6.9-15.2). Common grade 3-4 adverse events were hand-foot skin reaction and hypertension (20.0% each). The results of administration of 120 mg regorafenib as the starting dose are consistent with reports from prior phase III trials, which used starting doses of 160 mg. This lower initiating dose of regorafenib may be beneficial to certain patient populations. This clinical trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR number UMIN000018968, registration date: 10/09/2015).

A phase II study of neoadjuvant capecitabine, oxaliplatin, and irinotecan (XELOXIRI) in patients with locally advanced rectal cancer.

Purpose: Addition of perioperative multi-agent chemotherapy to the treatment strategy for locally advanced rectal cancer (LARC) may be a promising option. We conducted a phase II study to evaluate the safety and efficacy of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as triplet neoadjuvant chemotherapy in patients with LARC. Methods: Patients received neoadjuvant irinotecan and oxaliplatin and capecitabine and then underwent total mesorectal excision. The primary study endpoint was the pathological complete response (pCR) rate. Results: Between June 2013 and December 2016, 55 patients were enrolled in the study. Forty-two (77.8%) of 54 completed the study protocol. The pCR rate was 7.7% (95% CI 3.0% to 18.2%). The 3-year local recurrence rate was 3.9%, the 3-year disease-free survival (DFS) rate was 77.3, and the 3-year overall survival rate was 96.0%. Conclusion: XELOXIRI neoadjuvant chemotherapy appears to be feasible and efficacious for patients with LARC. Although neoadjuvant XELOXIRI alone did not yield our expected pCR rate, the local recurrence rate, 3-year DFS, and measures of safety met current standards.