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PURPOSE Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer. PATIENTS AND METHODS We conducted this randomized, open-label, multicenter, phase III trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomly allocated to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28, followed by irinotecan and capecitabine. The primary end point was pCR. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02605265). RESULTS Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). Surgery was performed in 87% and 88% of patients in the control and experimental groups, respectively. The pCR rates were 15% (n = 27 of 178) and 30% (n = 53 of 178) in the control and experimental groups (risk ratio, 1.96; 95% CI, 1.30 to 2.97; P = .001). Four and 6 patients achieved complete clinical response in the control and experimental groups, respectively. Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups, respectively ( P < .001). The commonest grade 3-4 toxicities were leukopenia, neutropenia, and diarrhea. The overall surgical complication rate was not significantly different between the two groups (11% v 15%; P < .001). CONCLUSION Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.

Ying Jiang, Shan Jin, Shisheng Tan, Qi Shen, Yingbo XueDepartment of Oncology, Guizhou Provincial People‘s Hospital, Guiyang, Guizhou, People’s Republic of ChinaObjective: Gastric cancer (GC) is a common tumor malignancy with high incidence and poor prognosis. Radiotherapy is one of the main strategies for GC treatment, while development of radioresistance limits the effectiveness. microRNA-203 (miR-203) has been reported to participate in progression of GC, whereas its interaction with radiosensitivity of GC and the related mechanism remain largely unclear.Methods: The expressions of miR-203 and zinc finger E-box binding homeobox 1 (ZEB1) were measured in GC tissues and cells by quantitative real-time polymerase chain reaction or western blot. Survival fraction, cell viability and apoptosis were measured in GC cells after treatment of radiation by colony formation, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay or flow cytometry, respectively. Tumor volume and weight were detected in murine xenograft model after radiation treatment. The interaction between miR-203 and ZEB1 was explored by bioinformatics analysis and luciferase activity assay.Results: miR-203 expression was down-regulated and ZEB1 mRNA level was up-regulated in GC. The expression of miR-203 was associated with radiosensitivity of GC cells. Moreover, overexpression of miR-203 decreased survival fraction, cell viability and tumor growth but promoted cell apoptosis in radiation-treated GC cells. However, knockdown of miR-203 played an opposite effect. ZEB1 was validated as a target of miR-203, and it was involved in miR-203-mediated radiosensitivity of GC cells in vitro and in vivo.Conclusion: miR-203 promoted radiosensitivity of GC cells by targeting ZEB1, indicating miR-203 as a promising radiosensitizer for GC treatment.Keywords: gastric cancer, miR-203, ZEB1, radiosensitizer, radiosensitivity

Background This survey aims to investigate the incidence of chemotherapy-induced nausea and vomiting (CINV) in Chinese real clinical setting and evaluate the effect of guideline-consistent CINV prophylaxis (GCCP) and guideline-inconsistent CINV prophylaxis (GICP) on incidence of complete response (CR) of CINV.Materials and Methods A cross-sectional nationwide multicenter study assessing the guideline consistency and CINV incidence of patients was conducted at a total of 32 large medical centers from 26 provinces across the west,east༌northeast and middle part of China between April and May 2021.Result Data for 2964 patients were analyzed. Patients treated with moderately emetogenic chemotherapy (MEC) were more prone to experience CINV during the acute phase compared to those receiving highly emetogenic chemotherapy (HEC); patients receiving low or minimally emetogenic chemotherapy (L/mEC) were least likely to experience CINV during the overall phase among the whole study population. The prevalence of GCCP was 29.2% in the whole study population, and 13.6%, 35.7% and 45.1% for the patients receiving HEC, MEC and L/mEC, respectively. For patients receiving HEC and MEC, GCCP increased incidence of CR during both delayed and overall phases. For those receiving L/mEC and GICP, incidence of CR was not higher than that of patients receiving L/mEC and GCCP.Conclusion This study revealed Chinese CINV status, the prevalence of GCCP in the real clinical setting and the association between GCCP and CR rate for the first time. The findings indicate that prescribing antiemetics in compliance with guidelines for all patients receiving chemotherapy is strongly suggested.

e17524 Background: Approximately 30%-65% of patients have residual disease or subsequent recurrence after completion of chemoradiotherapy (CRT) treatment. The treatment of residual/recurrent cervical cancer in previously irradiated field is challenging and generally associated with a poor prognosis. Local treatments such as salvage surgery and re-irradiation are usually traumatic and have limited efficacy. High intensity focused ultrasound (HIFU) treatment can directly ablate solid tumors without damaging neighboring healthy tissue. However, the HIFU studies for these patients are limited. Over 10 years of experience gained with the management of HIFU in cervical cancer patients with residual disease or recurrence after CRT is reported here. Methods: 153 patients with residual or recurrent cervical cancer in previously irradiated field who received HIFU treatment between 2010 and 2021 were retrospectively analyzed. Adverse effects, survival benefit, and factors affecting prognosis were given particular attention. Results: A total of 36 patients (23.5%) achieved a partial response following HIFU treatment and 107 patients (69.9%) had stable disease. The objective response and disease control rates were 23.5% and 93.5%, respectively. The median progression-free survival (mPFS) and median overall survival (mOS) were 17.0 months and 24.5 months, respectively. Moreover, patients with lesions ≥ 1.40 cm before HIFU treatment and a shrinkage rate ≥ 30% after treatment had a higher mPFS and mOS, and patients with lesions ≤ 1.00 cm after HIFU treatment had a higher mPFS (P < 0.05). All of the treatment-related adverse events were limited to minor complications, which included skin burns, abdominal pain and vaginal discharge. Conclusions: Many cervical cancer patients have few efficacious treatment options following chemoradiotherapy. This study demonstrates that HIFU treatment is likely a preferred option that can safely improve the local control rate and extend survival.

Interleukin-2 (IL-2) benefits some cancer patients by promoting the proliferation of cytotoxic effector T cells, but this process is limited by the expansion of regulatory T cells (Tregs). Low-dose cyclophosphamide (CTX) can inhibit the number and function of Tregs. We treated carcinoma-bearing mice with Vehicle, CTX, IL-2 and CTX + IL-2 to investigate the effects of low-dose CTX combined with IL-2 in antitumor treatment. In comparison to monotherapy, CTX + IL-2 significantly limited tumor growth, via tumor cell proliferation inhibition and increased apoptosis. The infiltration of CD8

Background: Our previous study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant chemoradiotherapy and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a randomized, open-label, multicenter, phase 3 trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to the control arm (CapRT arm): pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT; or the experimental arm (CapIriRT arm): radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Findings: Of the 360 patients initial enrolled, 356 were evaluated in mITT dataset (both 178 in two arms). Surgery was performed in 87% and 88% of patients in two arms, with 39% and 31% of patients got abdominoperineal resection respectively. The pCR rates were 18% (27/154) in CapRT arm and 34% (53/157) in CapIriRT arm (risk ratio 1.93; 95% CI 1.28–2.89, p=0.001), additional 4 and 6 patients were marked as complete clinical response (cCR). therefore, the overall CR rates were 17% and 33%, respectively. The most common grade 3-4 toxicities during CRT were leukopenia (3% vs. 25%), neutropenia (2% vs. 20%), and diarrhoea (2% vs. 13%). The overall rate of surgical complications were not significantly different between arms (11% vs. 15%). Interpretation: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. Trial Registration: ClinicalTrials.gov, number NCT02605265 Funding Information: This study was funded by grants from Fudan University Shanghai Cancer Center (YJLC201601) and National Natural Science Foundation of China (81773357). We thank the patients, investigators, and institutions involved in this study. Competing Interest Declaration: I/We declare no competing interests. Ethical Approval Statement: The study was approved by the central ethics committee of Fudan University Shanghai Cancer Center (Shanghai, China)

Additional file 1. PRISMA 2009 Flow Diagram

Additional file 1: Table S1 shRNA, miRNA mimic and miRNA inhibitor sequences.

Supplemental material, Figure_legends for Synergistic antitumor effect of 5-fluorouracil with the novel LSD1 inhibitor ZY0511 in colorectal cancer by Wen Peng, Huaqing Zhang, Shisheng Tan, Yan Li, Yang Zhou, Liang Wang, Chunqi Liu, Qiu Li, Xiaobo Cen, Shengyong Yang and Yinglan Zhao in Therapeutic Advances in Medical Oncology

3603 Background: Adding UGT1A1-guided irinotecan to capecitabine-based neoadjuvant chemoradiotherapy (CRT) significantly increased the pathological complete response (pCR) rate nearly doubling [J Clin Oncol. 2020 Dec 20;38(36):4231-4239]. Here, results of long-term outcome are reported. Methods: Eligible patients with clinical stage II/III rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomized to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by a cycle of oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with *1*1 or 65 mg/m2 for patients with *1*28, followed by a cycle of irinotecan and capecitabine. Surgery was scheduled for 8 weeks after completion of CRT. Five cycles of adjuvant XELOX chemotherapy were administered regardless of the pathologic result. Patients were stratified by UGT1A1 genotype (*1*1 vs. *1*28) clinical T stage (cT3 vs. cT4) and tumor distance from the anal verge (≤5 cm vs. > 5 cm). The primary end point of pCR was reached. Survival time was calculated from the date of randomization to the date of event or the last follow-up. Secondary endpoints were defined as local failure for local control (LC), tumor recurrence or death from any cause for disease-free survival (DFS), and death from any cause for overall survival (OS). Results: Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). A total of 311 patients underwent surgery and pCR was achieved in 80 patients, another 10 patients undergo a watch-and-wait approach after achieving cCR. With a median follow-up time of 48 months (Q25-Q75, 41-55 months), 57 deaths (33 and 24), 17 local failures (11 and 6) and 69 distant metastases (37 and 32) were observed, respectively. Overall, the 4y LC rate were 93% and 96% in control and experimental groups, with estimated LC HR of 0.53 (95% confidence interval [CI], 0.20-1.43), the 4y DFS rates were 69% and 74% (HR = 0.74, 95% CI 0.49-1.10), and the 4y OS were 80% and 85%, (HR = 0.70, 95% CI 0.42-1.19), respectively. In the subgroup analysis, irinotecan showed a significant improvement in DFS (HR = 0.77, 95% CI 0.61-0.98) and OS (HR = 0.71, 95% CI 0.51-0.98) in UGT1A1 *1*1 patients. Conclusions: The addition of irinotecan to standard capecitabine-based CRT had a tendency towards improving LC, DFS, and OS, but without reaching statistical significance. UGT1A1 *1*1 patients seem to benefit the most from irinotecan. Molecular studies and subsequent therapies should be considered. Clinical trial information: NCT02605265.

The DNA mismatch repair (MMR) system plays an important role in the initiation, diagnosis and treatments of colorectal cancer (CRC). Compared to CRC patients deficient in DNA MMR (dMMR), CRC patients proficient in DNA MMR (pMMR) have higher metastasis, short survival and poor response to chemotherapy and immunotherapy. It is well‑known that a high‑fat diet can cause CRC, and lipid metabolism is closely related to the development and metastasis of CRC. However, there have been few studies that address the difference in lipid metabolism between dMMR and pMMR CRC. Liquid chromatography‑tandem mass spectrometry (LC/MS) is an advanced technique that can perform the analysis of lipid metabolites and the roles of lipids present in low abundance in cell signaling and membrane stability. In the present study, we used the LC/MS technique to analyze the difference in the lipid metabolic profiles between dMMR cell lines (HCT116, DLD1, LoVo and HCT15) and pMMR cell lines (SW480, SW620, HT29 and NCM460). The results revealed that, among the 19 classes and 157 intact lipid species identified by the LC/MS analysis, the levels of most phospholipids were lower in dMMR cells than pMMR cells. Higher levels of phosphatidylcholine (PC; 16:0/18:1) and phosphatidic acid (PA; 18:0/18:0) were observed in pMMR cells than in dMMR cells. Furthermore, our results revealed that SCD1 and PLD1, the key enzymes involved in lipid metabolism associated with metastasis, are higher in pMMR cells than dMMR cells. To the best of our knowledge, we are the first to reveal that the levels of metastasis‑associated lipids and key enzymes in lipid metabolism were higher in the CRC patients with pMMR compared with the CRC patients with dMMR. This study identified potential anti‑metastatic targets in the therapy of patients with pMMR, and also personalized therapy for the patients with pMMR.

3510 Background: Our phase I/II study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant CRT and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a prospective, randomized, open-label, multicenter, phase 3 trial in China from Nov.2015 to Dec.2017. Eligible patients with clinical stage T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to two arms. The approach in control arm (Arm A, n = 180) was pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT. The experimental arm (Arm B, n = 180) was pelvic radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Results: Surgery was performed in 86.5% and 88.2% of patients in two groups, with 38.9% and 30.5% of patients got abdominoperineal resection respectively. The pCR rate was 17.5% in Arm A and 33.8% in Arm B (P = 0.001). Four and 6 patients maintained a complete clinical response status at least 12 months and were marked as cCR. The CR rate, including pCR and cCR, was 17.4% in Arm A and 33.1% in Arm B (P = 0.001). The most common grade 3-4 adverse events during preoperative treatment were leucopenia (3.4% vs. 25.3%), neutropenia (1.7% vs. 19.7%) and diarrhea (1.7% vs. 13.5%) in two arms. The overall rate of surgical complications were not significantly different between arms (11.0% vs. 14.6%). Conclusions: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. This treatment can be as an option for ‘watch and wait’ approach. Clinical trial information: NCT02605265.

Oxaliplatin (OX) has been widely used in adjuvant and palliative treatments of advanced colon cancer; however, cancer cells ultimately become resistant in the majority of cases. Therefore, the development of a novel strategy to overcome this resistance is important for the effective treatment of colon cancer. Cell autophagy reduces the sensitivity of cancer cells to therapeutic reagents in various types of human cancer; therefore, the present study used murine CT26 colon carcinoma cells to explore whether inhibition of autophagy by 3-methyladenine (3-MA) is able to enhance OX-induced apoptosis in vitro and OX-suppressed tumor growth in vivo. CT26 cells were treated with 3-MA, OX, or 3-MA plus OX, and the autophagy, apoptosis and proliferation of the CT26 cells was investigated. Additionally, the therapeutic efficiency of the combination of 3-MA and OX treatment was evaluated in vivo by determining the survival time of the tumor-bearing mice and, thus, tumor growth rate. The treatment of CT26 cells in vitro with OX alone increased autophagy as well as apoptosis, whereas treatment with 3-MA plus OX markedly inhibited OX-induced autophagy, but increased OX-induced cell apoptosis. Furthermore, the combination of OX and 3-MA treatment significantly suppressed tumor growth in vivo and prolonged mouse survival time when compared with OX treatment alone. Similarly, 3-MA increased OX-induced cell apoptosis and decreased autophagy in xenograft tumor tissues. Thus, the administration of 3-MA may increase tumor cell sensitivity to OX by reducing its autophagic effects and enhancing its apoptotic effects. Data obtained in the present study indicates that the clinical combination of an autophagy inhibitor with OX may increase the therapeutic effect of OX and improve the clinical outcome of patients with colon cancer.

TPS3632 Background: Irinotecan is an effective drug for rectal cancer. Early small sample size trials have assessed the addition of irinotecan to standard CRT with fluoropyrimidines in neoadjuvant phase of locally advanced rectal cancer, in which pCR rates varied from 13.7 to 37%. ARISTOTLE trial, a multicentre UK-based phase III trial, will complete recruitment in autumn 2016. However, all patients in case group were prescribed with weekly irinotecan dose of 60mg/m2 guided by UGT1A1*28 6/6 and 6/7 genetypes in neoadjuvant chemoradiation. Therefore, this phase III trial was designed to confirm the potential improvement in outcomes seen with the addition of irinotecan to CRT. Methods: Eligible patients are randomly allocated to either radiotherapy 50 Gy with concurrent capecitabine, followed by a cycle of capecitabine and oxaliplatin two weeks after the end of CRT (Control arm) or radiotherapy 50 Gy with concurrent capecitabine and irinotecan, followed by a cycle of capecitabine and irinotecan (Case arm). Capecitabine is prescribed with 825mg/m2 The primary end point is ypCR. The hypothesis is to increase ypCR from 12% in the control group to 25% in the case group. To detect such a difference, with alpha = 0.05 (two-tailed) and belta = 0.15, 360 randomly assigned patients are required. Secondary end points are toxicities, surgical complications, local control, progression-free survival and overall survival. Clinical trial information: NCT02605265.