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PURPOSE To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node–positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group ( P < .001). CONCLUSION Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

Supplemental Methods S1 contained the complete inclusion and exclusion criteria.

Correlation between the percentage changes in calcitonin levels and in the sum of longest diameters of target lesions from baseline to week 6

Best calcitonin biochemical response

Detailed assay method for calcitonin

Kaplan-Meier curves for progression-free survival (A) and overall survival (B) of the initial 43 patients and the subsequent 123 patients enrolled.

Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies.Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks).Results: A total of 166 patients were included in the final analysis. Overall, the PFR12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%–18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months for UPS (n = 19); 63%, 5.6 and 13 months for LPS (n = 13); 75%, 11 and 15 months for LMS (n = 26); 75%, 7.7 and 12 months for SS (n = 47); 81%, 5.6 and 12 months for FS (n = 18); 77%, 21 and not reached for ASPS (n = 13); 54%, 11 and 16 months for CCS (n = 7); and 44%, 2.8 and 8.8 months for other sarcoma (n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred.Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233–8. ©2018 AACR.

Purpose:Medullary thyroid cancer (MTC) accounts for about 2% of all thyroid cancer, but has a relatively poor prognosis compared with differentiated thyroid cancer. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This multicenter, randomized, double-blind, placebo-controlled phase IIB study (ALTER 01031 and NCT02586350) was conducted to investigate the efficacy and safety of anlotinib in MTC.Patients and Methods:Patients with histopathologically confirmed, unresectable locally advanced or metastatic MTC were enrolled and randomly assigned in a 2:1 ratio to receive anlotinib (12 mg once daily from day 1 to 14 every 3 weeks) or placebo. Patients in placebo group were allowed to receive open-label anlotinib after disease progression. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS).Results:Ninety-one patients were enrolled. At data cutoff date, the median PFS was significantly prolonged in the anlotinib group than in the placebo group (20.7 months vs. 11.1 months, P = 0.029; HR, 0.53; 95% confidence interval, 0.30–0.95). The ORR of anlotinib treatment was 48.4%. The incidence of treatment-related adverse events (TRAE) was 100% and 89.7% in the anlotinib and placebo groups, respectively. The most common TRAEs of all grades in the anlotinib group were palmar–plantar erythrodysesthesia syndrome (62.9%), proteinuria (61.3%), and hypertriglyceridemia (48.4%).Conclusions:Anlotinib demonstrates its efficacy and safety in this phase IIB trial for the treatment of MTC and may become a new choice for this rare disease, especially for Chinese patients.

BACKGROUND Adjuvant chemoradiotherapy (ACRT) with oral capecitabine and intensity-modulated radiotherapy (IMRT) were well tolerated in a phase I study in patients who had undergone partial or total gastrectomy for locally advanced gastric cancer (GC). This phase II study aimed to further determine the efficacy and toxicity of this combination after radical resection and D1/D2 lymph node dissection (LND) for patients with locally advanced GC. AIM To further determine the efficacy and toxicity of this combination after radical resection and D1/D2 LND for patients with locally advanced GC. METHODS Forty patients (median age, 53 years; range, 24-71 years) with pathologically confirmed adenocarcinoma who underwent D1/D2 LND were included in this study. The patients received ACRT comprising IMRT (total irradiation dose: 45 Gy delivered in daily 1.8-Gy fractions on 5 d a week over 5 wk) and capecitabine chemotherapy (dose: 800 mg/m² twice daily throughout the duration of radiotherapy). The primary study endpoint was disease-free survival (DFS), and the secondary endpoints were overall survival (OS), toxic effects, and treatment compliance. RESULTS The 3-year DFS and OS were 66.2% and 75%, respectively. The median time to recurrence was 19.5 mo (range, 6.1-68 mo). Peritoneal implantation (n = 10) was the most common recurrence pattern, and the lung was the most common site of extra-abdominal metastases (n = 5). Nine patients developed grade 3 or 4 toxicities during ACRT. Two patients discontinued ACRT, while eleven underwent ACRT without receiving the entire course of capecitabine. There were no treatment-related deaths. CONCLUSION The ACRT protocol described herein showed acceptable safety and efficacy for patients with locally advanced GC who received radical gastrectomy and D1/2 LND.

Yan Song, Tao Qu, Honggang Zhang, Yongkun Sun, Chengxu Cui, Yihebali Chi, Wen Zhang, Xingyuan Wang, Lin Yang Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaCorrespondence: Lin Yang; Tao QuDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaEmail linyang@cicams.ac.cn; thomasqu1972@hotmail.comBackground: In FRESCO trial, a phase III study of fruquintinib demonstrated a significant improvement on the overall survival (OS) of patients with metastatic colorectal cancer (mCRC) who failed to response to available standard treatments. The aim of the current study was to evaluate the safety and effectiveness of fruquintinib in Chinese mCRC patients in the real-world setting.Methods: Patients with mCRC treated with fruquintinib at our hospital were retrospectively reviewed. Patient demographics, treatment, adverse events and survival data were collected. OS and progression-free survival (PFS) were estimated using the Kaplan–Meier method.Results: In total, 76 patients were evaluated from December 2018 to January 2020. The median (range) age was 59.5 (34– 86) years, ECOG PS 0-1/2 was 86.8%/13.2%, and 38 (50%)/30 (39.5%) patients had experienced more than two prior therapies for mCRC. The median treatment duration was 3.6 cycles. Treatment-related adverse events (TRAEs) resulted in dose reduction were 17.1% of the patients without any treatment discontinuation. The most common grade 3 or 4 TRAEs were hypertension (9.2%), hand-foot skin reaction (7.9%), thrombocytopenia (3.9%), anaemia (2.6%), increased ALT (1.3%), oral mucositis (1.3%), proteinuria (1.3%) and neutropenia (1.3%). The median PFS was 5.1 months (95% CI 3.8– 6.4 months), and the median OS was 12.0 months (95% CI 8.0– 16.1 months). In patients with hypertension or hypothyroidism, a survival extension approximate to 6 months was observed, but the difference is not yet statistically significant. CEA decreased after fruquintinib treatment could be considered as a potential predictor for better OS.Conclusion: The outcome of this real-life study was consistent with that of the randomised controlled trial. There were no new safety concerns. Future studies of fruquintinib should be conducted to identify patients who tend to obtain more benefits from fruquintinib alone or in combination with other agents.Keywords: fruquintinib, metastatic colorectal cancer, real-world settings, toxicities

For advanced tumors that lack specific oncogenic alteration and are resistant to chemotherapy, anti-angiogenesis therapy or immunotherapy or a combination of the two are the most important treatments. Anlotinib is a newly developed oral small molecule receptor tyrosine kinases inhibitor with the potency of inhibiting tumor angiogenesis. This was an open-label, single-arm, phase 2 study to validate the efficacy and safety of anlotinib in patients with various cancer types. Patients with advanced malignancy who have failed previous therapies or lack effective treatment choices received daily oral administration of 12 mg anlotinib on days 1–14 every 3 weeks until disease progression, intolerable toxicity or physician decision. The primary endpoint was objective response rate (ORR). A total of 93 eligible patients with 26 different cancer types were enrolled. The overall ORR was 21.5%. The median PFS was 5.7 months and median OS was 12.0 months. The most common treatment-related AE of all grades and of grade 3 was both hypertriglyceridemia at an incidence of 40.9% and 5.4%, respectively. Anlotinib exhibits objective efficacy and safety in advanced malignancy and might be a possible treatment option for many types of cancer patients who have failed prior treatment and with no optimal therapy regimen.

Background Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC. Materials and Methods This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1–14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety. Results A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4–4.5) over placebo group (1.5 months; 95% CI, 1.4–1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27–0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8–9.7 vs. 7.2 months; 95% CI, 6.2–8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%). Conclusion Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients. Implications for Practice In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

Objective The predictive effect of preoperative chemoradiotherapy (CRT) is low and difficult in guiding individualized treatment. We examined a surrogate endpoint for long-term outcomes in locally advanced gastric cancer patients after preoperative CRT. Methods From April 2012 to April 2019, 95 patients with locally advanced gastric cancer who received preoperative concurrent CRT and who were enrolled in three prospective studies were included. All patients were stage T3/4N+. Local control, distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were evaluated. Clinicopathological factors related to long-term prognosis were analyzed using univariate and multivariate analyses. The down-staging depth score (DDS), which is a novel method of evaluating CRT response, was used to predict long-term outcomes. Results The median follow-up period for survivors was 30 months. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve predicted by the DDS was 0.728, which was better than the pathological complete response (pCR), histological response and ypN0. Decision curve analysis further affirmed that DDS had the largest net benefit. The DDS cut-off value was 4. pCR and ypN0 were associated with OS (P=0.026 and 0.049). Surgery and DDS are correlated with DMFS, DFS and OS (surgery: P=0.001

Summary Background Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs. Methods SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov , NCT02588170 . Follow-up is ongoing. Findings Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1–16·7) in the surufatinib group and 16·6 months (9·2–not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4–11·1) in the surufatinib group versus 3·8 months (3·7–5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22–0·50; p Interpretation Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. Funding Hutchison MediPharma.

High‐grade myofibroblastic sarcoma (HGMS) is a rare cancer that has high recurrence and metastatic rates. Here, we report the first case of HGMS originating from the pleura. Based on the findings of pleural biopsy, pathological examination and immunohistochemical staining, grade III myofibroblastic sarcoma (MS) was diagnosed. The patient underwent eight cycles of chemotherapy (epirubicin and ifosfamide), followed by radiotherapy. As of May 2020, the patient had been followed for six months and no tumor progression had occurred. Key points This is the first report of high‐grade myofibroblastic sarcoma originating from the pleura. The patient was treated via nonsurgical strategies, including chemotherapy and radiotherapy., High‐grade myofibroblastic sarcoma (HGMS) is a rare disease. This is the first case diagnosed with HGMS originating from the pleura that was nonsurgically treated.

Huijing Tan,1 Lijie Zuo,1,2 Shutao Ma,1 Dingyuan Wang,3 Rui Li,1,2 Yiqi Yang,1,2 Weili Liu,1,2 Yihebali Chi1 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Beijing Chaoyang Sanhuan Cancer Hospital, Beijing, 100021, People’s Republic of China; 3Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaCorrespondence: Yihebali ChiDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 South Panjiayuan Lane, Chaoyang District, Beijing, 100021, People’s Republic of ChinaTel +8613911075626Email yihebalichi@hotmail.comBackground: Leiomyosarcoma (LMS) accounts for 24% of all soft tissue sarcomas (STSs) and this STS subtype has high metastatic potential. Previous studies indicated the best median progression-free survival (mPFS) time was 9.2 months and the best overall response rate (ORR) was 30.9%. We evaluated the efficacy and safety of epirubicin combined with temozolomide (EPI-TMZ) for treatment of advanced LMS.Methods: This was a retrospective review of the records of patients with advanced LMS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All patients initiated EPI-TMZ treatment between January 2018 and December 2020.Results: We examined 15 patients who received EPI-TMZ for LMS. This was a first-line treatment in 6 patients, a second- or third-line treatment in 7 patients, and a fourth-line treatment in 2 patients. At the time of data cutoff (April 25, 2021), the median PFS was 10 months, 1 patient had clinical complete response (cCR), 7 had partial response (PR), and 7 had stable disease (SD). The overall response rate (ORR) was 53.3% (8/15) and the disease control rate (DCR) was 100.0% (15/15). The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. One patient had severe adverse effect (febrile neutropenia), but there were no treatment-related deaths.Conclusion: EPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ provided better outcomes than reported in previous studies of other treatments for advanced LMS.Keywords: epirubicin, temozolomide, advanced leiomyosarcoma, chemotherapy

To investigate the health-related quality of life (HRQoL) of patients who had neuroendocrine tumors (NETs) from SANET trials.Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo. HRQoL questionnaires, including the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-G.I.NET21, were collected. The prespecified HRQoL outcome was the mean change of scores from baseline to the last available visit for each domain. Time until definitive deterioration (TUDD) was defined as the time from randomization to deterioration of ≥10 points from baseline in domain score, disease progression, or death.370 patients were enrolled and randomly assigned to surufatinib (n = 242) or placebo (n = 128). No significant difference in mean scores change from baseline to the last available visit was observed for QLQ-C30 and QLQ- G.I.NET21 domains, with the exception of diarrhea. The mean score of diarrhea increased 11.7 points from baseline in the surufatinib arm and decreased 1.2 points in the placebo arm, and the between-group difference was 12.9 points. Compared with placebo, surufatinib treated patients had a significantly longer TUDD for dyspnea (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.39-0.86; P = 0.0058) and a significantly shorter TUDD for diarrhea (HR 2.91; 95% CI, 1.66-5.10; P 0.0001). There were no significant differences in TUDD for the remaining domains of QLQ-C30 and G.I.NET-21.HRQoL was similar in patients treated with surufatinib and placebo except for diarrhea. The preservation of HRQoL supports surufatinib as a treatment option for NETs.ClinicalTrials.gov: NCT02589821, NCT02588170.

Background and Aim In the phase 3 CONCUR trial (NCT01584830), regorafenib improved overall survival (OS) versus placebo in Asian patients with treatment‐refractory metastatic colorectal cancer (mCRC). We conducted a post hoc subgroup analysis of Chinese patients in CONCUR. Methods Adults with mCRC progressing despite at least two prior treatment regimens and Eastern Cooperative Oncology Group performance status 0–1 were randomized 2:1 to regorafenib 160 mg once daily or placebo for the first 3 weeks of each 4‐week cycle. Dose modifications were permitted. The primary endpoint was OS. Secondary endpoints included progression‐free survival, objective overall response, disease control rate, and safety. Results A total of 172 Chinese patients were randomized and treated (regorafenib n = 112, placebo n = 60). OS was significantly improved with regorafenib versus placebo (8.4 vs 6.2 months, respectively; hazard ratio [HR] 0.56, 95% CI 0.39–0.80; one‐sided P = 0.000632), as was progression‐free survival (HR 0.32, 95% CI 0.22–0.47; one‐sided P

Background: The benefit of repeat lumpectomy for ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) is currently inconclusive. This issue has become even more important as small and isolated recurrent tumors were frequently diagnosed. Methods: IBTR patients with definitive surgery were identified in the Surveillance, Epidemiology, and End Results registry between 1973 and 2013. The effect of different IBTR surgeries on overall and cancer-specific mortality was assessed using risk-adjusted Cox proportional hazard regression modeling and stratified propensity score matching analysis (PSMA). Results: Based on the selection criteria, 5098 patients were recruited. Of those, 4048 (79.4%) women underwent mastectomy and 1050 (20.1%) underwent repeat lumpectomy after IBTR. Patients who received repeat lumpectomy had lower grade (23.7% vs 15% for well-differentiated) and smaller recurrent tumor (47% vs 36.2% for ≤ 1 cm) but earlier recurrence (23.9% vs 11.2% for interval times < 48 months) than those who underwent mastectomy. A minority of each group (24.7% of those undergoing repeat lumpectomy and 3% of the mastectomy group) underwent RT after surgery. In multivariable Cox regression analysis, repeat lumpectomy was associated with increased overall mortality (Hazard ratio (HR) = 1.58, 95% CI = 1.353 to 1.844, P < 0.001) and cancer-specific mortality (HR = 1.721, 95% CI = 1.345 to 2.202, P< 0.001). Similar HRs were derived from the PSMA cohort. However, we found no significant difference in overall mortality for women who underwent repeat lumpectomy followed by RT compared with that for those who underwent mastectomy (P= 0.411). Moreover, IBTR patients with small tumors (≤ 1 cm) who underwent repeat lumpectomy with RT rather than without had similar overall and cancer-specific survival rates to those who underwent mastectomy (P= 0.189 and P= 0.604, respectively). Conclusions: Our investigation suggests that compared with mastectomy, repeat lumpectomy for IBTR is associated with higher overall and cancer-specific mortality under real-world observational conditions. Furthermore, repeat lumpectomy with RT is equivalent to mastectomy with respect to overall mortality and may influence treatment decision making for patients with small IBTR. Citation Format: Su Y, Guo R, Xue J, Chi Y, Wu J. Increased mortality with repeat lumpectomy alone after ipsilateral breast tumor recurrence: A propensity-adjusted, population-based SEER analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-13-09.

For the patients with breast cancer, the pathological status of axillary lymph nodes is one of the most important predictor of prognosis. In recent years, the application of sentinel lymph node biopsy has provided us with an opportunity for the further study on the mechanism of lymph node metastasis in breast cancer. Through detailed pathological examination of sentinel lymph nodes, we can easily find patients who are in the early stage of lymph node metastasis - that is, the tumor cells from the primary tumor, invading the lymph nodes and successfully colonized, but not yet break through the lymph node microenvironment defense to the subsequent lymph node. It is the most important stage during lymph node metastasis. In the present study, we selected the pairing samples from breast cancer patients with early stage lymph node metastasis to carry out differential genomics research. A total of 182 genes with significant function and involved in significant signal transduction pathways were obtained. Bioinformatics method was used to screen out the mRNA, microRNA and transcription factor in the process of lymph node metastasis of breast cancer. We investigated the role of activated T cells c2 (NFATC2) in the core transcription factors as a target for further clinical and basic research. The expression of NFATC2 was detected in the tissue microarray prepared from 200 patients with primary breast cancer. After the median follow-up period of 89.5 months, it showed that the prognosis of patients with NFATC2 overexpression was significantly better than that of the control group (p = 0.022). We also measured the expression of NFATC2 in 50 pairs of breast cancer patients with lymph node metastasis. The results showed that the expression of NFATC2 in the primary tumor was significantly higher than that in the matched lymph node, suggesting that in patients with breast cancer, the down-regulate or deficiency of NFATC2 expression may be related with lymph node metastasis. We also attempted to add the expression of NFATC2 as a new parameter in the prediction model of lymph node metastasis based on preoperative clinical and pathological parameters. The area under the ROC curve obtained in the newly established model was 0.767, the expression state of NFATC2 had impact on the performance of the prediction model. Furthermore, when we removed the NFATC2 parameter, it could reduce the area under the ROC curve in the validation group, suggesting that the expression of NFATC2 in the primary tumor may be used as a predictor of the pathological state of axillary lymph nodes. In vitro and in vivo experiments, we demonstrated that NFATC2 has a significant suppression effect on the proliferation, migration and invasion of breast cancer cells. The potential NFATC2-target genes were determined by RNAseq and Chipseq. Nine differentially expressed genes were found to be regulated by NFATC2 in the Chip-seq analysis and bound to the promoter region of the gene, whereas GRAMD3 and SRGAP2 in the subsequent validation showed a positive correlation with the expression of NFATC2, suggesting that the two genes are likely to have a positive regulatory relationship with NFATC2. This study clarifies that NFATC2 may represent a therapeutic target for early metastasis breast cancer. Citation Format: Xue J, Chi Y, Chen J, Wu J. NFATC2 suppresses the metastatic cascade in breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-11.

Background: peri-operative chemo-radiotherapy played important role in locally advanced gastric cancer. Whether preoperative strategy can improve the long-term prognosis compared with postoperative treatment is unclear. The study purpose to compare long-term oncologic outcomes in locally advanced gastric cancer patients treated with preoperative chemo-radiotherapy (pre-CRT) and postoperative chemo-radiotherapy (post-CRT). Methods: From January 2009 to April 2019, 222 patients from 2 centers with stage T3/4 and/or N positive gastric cancer who received pre-CRT and post-CRT were included. After propensity score matching (PSM), comparisons of local regional control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were performed using Kaplan-Meier analysis and log-rank test between pre- and post-CRT groups.Results: The median follow-up period was 30 months. 120 matched cases were generated for analysis. Three-year LC, DMFS, DFS and OS for pre- vs. post-CRT groups were 93.8% vs. 97.2% (p=0.244), 78.7% vs. 65.7% (p=0.017), 74.9% vs. 65.3% (p=0.042) and 74.4% vs. 61.2% (p=0.055), respectively. Pre-CRT were significantly associated with DFS in uni- and multi-variate analysis. Conclusion: Preoperative CRT showed advantages of long-term outcome compared with postoperative CRT. Trial registration: ClinicalTrial.gov NCT01291407, NCT03427684 and NCT04062058, date of registration: Feb 8, 2011

4126 Background: Surufatinib is a small-molecule inhibitor of VEGFR1, 2, & 3, FGFR1, and CSF-1R. Surufatinib demonstrated prolonged PFS and tolerable safety in two phase 3 studies in advanced neuroendocrine tumors (NETs) of pancreatic (SANET-p; NCT02589821) and extrapancreatic (SANET-ep; NCT02588170) origin (Xu, 2020 Lancet Oncology). Detailed outcomes on safety from these 2 studies are reported here as a pooled analysis. Methods: Data is pooled from SANET-p and SANET-ep studies which have similar designs including a 2:1 randomization of surufatinib to placebo in patients ≥18 years with advanced, well differentiated NETs, progressing on or after ≤2 prior therapies. Surufatinib 300 mg or placebo, was administered once daily until disease progression or unacceptable toxicity. Safety outcomes for each pooled treatment group are reported as treatment-emergent adverse events (TEAE) assessed by NCI-CTC 4.03. Patients were included if they had received study treatment during the double-blinded phase of the studies. Results: As of 30th June 2020, 396 patients were assigned to the surufatinib (n = 263) and placebo (n = 133) groups. Median treatment duration was longer with surufatinib 7.4 months (range 0.1–41.4) compared with placebo 4.6 months (range 0.1–39.9). 29% of patients reached more than 12 months of treatment with surufatinib group compared to 11% with placebo. The mean relative dose intensity was 87.56% in the surufatinib group and 97.01% in the placebo group. Most common TEAEs (surufatinib vs placebo) were proteinuria 68.8% vs 54.9%, hypertension 68.4% vs 27.1%, and diarrhea 49% vs 22.6%. Most common grade ≥3 TEAE were hypertension 38.8% vs 13.5%, proteinuria 14.8% vs 0.8% and hypertriglyceridaemia 5.3% vs 0%. Deaths due to TEAEs were comparable between groups 2.7% vs 2.3%. TEAEs led to dose reductions in 43.0% vs 6.8% of patients and dose interruptions in 47.1% vs 29.3% of patients. The majority of patients (83.3% vs 93.2%) were managed without discontinuation because of TEAE. Median onset of proteinuria and hypertension were < 1 month in both groups. Median (range) onset was 0.95 months (0.16–30.36) vs 0.95 months (0.23–16.95) for proteinuria and 0.49 months (0.03–31.18) vs 0.89 months (0.03–14.75) for hypertension. Among patients with hypertension, 59% (n = 111) vs 28% (n = 11) received antihypertensive medication. Conclusions: Surufatinib was generally well tolerated in this pooled analysis and the safety profile was consistent with its previously reported data. The monitoring and management of hypertension and proteinuria are important for patients receiving surufatinib. Clinical trial information: NCT02589821; NCT02588170. [Table: see text]

Background: Adjuvant chemoradiotherapy (ACRT) with oral capecitabine and intensity-modulated radiotherapy (IMRT) was well tolerated in a phase I study in patients who had undergone partial or total gastrectomy for locally advanced gastric cancer. This phase II study aimed to further determine the efficacy and toxicity of this combination after radical resection and D1/D2 lymph node dissection (LND) for local advanced gastric patients.Methods: Forty patients (median age, 53 years; range, 24–71 years) with pathologically confirmed adenocarcinoma who underwent D1/D2 LND were included in this study. The patients received ACRT comprising IMRT (total irradiation dose: 45 Gy delivered in daily 1.8-Gy fractions on 5 days a week over 5 weeks) and capecitabine chemotherapy (dose: 800 mg/m² twice daily throughout the duration of RT). The primary study endpoint was disease-free survival (DFS) and the secondary endpoints were overall survival (OS), toxic effects, and treatment compliance.Results: The 3-year DFS and OS were 66.2% and 75%, respectively. The median time to recurrence was 19.5 months (range, 6.1–68 months). Peritoneal implantation (n = 10) was the most common recurrence pattern, and the lung was the most common site of extra-abdominal metastases (n = 5). Nine patients developed grade 3 or 4 toxicities during ACRT. Two patients discontinued ACRT, while 11 underwent ACRT without receiving the entire course of capecitabine. There were no treatment-related deaths.Conclusion: The ACRT protocol described herein showed acceptable safety and efficacy for local advanced gastric cancer received radical gastrectomy and D1/2 LND.Trial registration: ClinicalTrials.gov, NCT01674959. Registered August 2012 - Retrospectively registered, http://www.isrctn.com/ISRCTN12345678

Purpose: Medullary thyroid cancer (MTC) accounts for about 2% of all thyroid cancer, but has a relatively poor prognosis compared with differentiated thyroid cancer. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This multicenter, randomized, double-blind, placebo-controlled phase IIB study (ALTER 01031 and NCT02586350) was conducted to investigate the efficacy and safety of anlotinib in MTC. Patients and Methods: Patients with histopathologically confirmed, unresectable locally advanced or metastatic MTC were enrolled and randomly assigned in a 2:1 ratio to receive anlotinib (12 mg once daily from day 1 to 14 every 3 weeks) or placebo. Patients in placebo group were allowed to receive open-label anlotinib after disease progression. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: Ninety-one patients were enrolled. At data cutoff date, the median PFS was significantly prolonged in the anlotinib group than in the placebo group (20.7 months vs. 11.1 months, P = 0.029; HR, 0.53; 95% confidence interval, 0.30–0.95). The ORR of anlotinib treatment was 48.4%. The incidence of treatment-related adverse events (TRAE) was 100% and 89.7% in the anlotinib and placebo groups, respectively. The most common TRAEs of all grades in the anlotinib group were palmar–plantar erythrodysesthesia syndrome (62.9%), proteinuria (61.3%), and hypertriglyceridemia (48.4%). Conclusions: Anlotinib demonstrates its efficacy and safety in this phase IIB trial for the treatment of MTC and may become a new choice for this rare disease, especially for Chinese patients.

Summary Background Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. Methods SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov , NCT02589821 . Findings Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3–19·4) in the surufatinib group and 11·1 months (5·7–35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5–13·8) for surufatinib versus 3·7 months (2·8–5·6) for placebo (hazard ratio 0·49, 95% CI 0·32–0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. Interpretation Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. Funding Hutchison MediPharma.

Background: The prediction effect of preoperative chemo-radiotherapy(CRT) is not high and difficult to guide individualized treatment. We explored a surrogate endpoint for long-term outcomes in locally advanced gastric cancer patients after preoperative CRT. Methods: From April 2012 to April 2019, 95 patients enrolled in 4 prospective studies with locally advanced gastric cancer who received preoperative concurrent radio-chemotherapy were included. All patients were stage T3/4, N+. Local control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were evaluated. The clinicopathological factors related to the long-term prognosis were analysed by uni- and multivariant analyses. The downstaging depth score (DDS), a novel method of evaluating the CRT response, was used to predict long-term outcomes. Results: The median follow-up period for survivors was 30 months. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve predicted by the DDS was 0.728, which was better than that of pathological complete response (pCR), histological response and ypN0 (AUC= 0.634, 0.640 and 0.643, respectively). The DDS cut-off value was 4. pCR and ypN0 were associated with OS (p = 0.026, 0.049). Surgery and the DDS were correlated with DMFS, DFS and OS (p = 0.001, 0.000, and 0.000 and 0.009, 0.013, and 0.032, respectively). The multivariate analysis showed that the DDS was an independent prognostic factor of DFS (p = 0.021). Conclusion: The DDS, a simple, short-term indicator, seems to be a better surrogate endpoint than pCR, histological response and ypN0 for DFS.

Background To assess the safety profile, pharmacokinetics, pharmacodynamics and preliminary antitumour activity of fixed-dose SHR-1210, a novel anti-PD-1 antibody, in advanced solid tumours. Methods A total of 36 patients with advanced solid tumours received intravenous SHR-1210 at 60 mg, 200 mg and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The concentration of SHR-1210 was detected for pharmacokinetics, and receptor occupancy on circulating T lymphocytes was assessed for pharmacodynamics. Results No dose-limiting toxicities were observed. Maximum administered dose was not reached. Most adverse events were grade 1 or 2. Treatment-related severe adverse events were found in two patients. No treatment-related death was reported. Two complete responses (gastric cancer, bladder carcinoma) and seven partial responses were seen. In responders, the median follow-up time was 16.0 months (range 8.3–19.5), and the median duration of response was not reached (range 2.7–17.5+ months). The half-life of SHR-1210 was 2.94 d, 5.61 d and 11.0 d for 3 dose levels, respectively. Conclusions Our results demonstrated a promising antitumour activity and a manageable safety profile of SHR-1210, displayed an explicit PK evidence of the feasibility of fixed dose, and established the foundation for further exploration.