First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study.

Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m-2 on day 1 plus 5-fluorouracil 800 mg m-2 day-1 on days 1-4) every 3 weeks for up to six cycles. At the prespecified interim analysis this study had met dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival was statistically significant with sugemalimab plus chemotherapy compared with placebo plus chemotherapy (median 6.2 versus 5.4 months, hazard ratio 0.67 (95% confidence interval 0.54-0.82), P = 0.0002) as assessed by blinded independent central review. Overall survival was also superior with sugemalimab chemotherapy (median 15.3 versus 11.5 months, hazard ratio 0.70 (95% confidence interval 0.55-0.90, P = 0.0076). A significantly higher objective response rate (60.1 versus 45.2%) as assessed by blinded independent central review was observed with sugemalimab chemotherapy. The incidence of grade 3 or above treatment-related adverse events (51.3 versus 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. The ClinicalTrials.gov identifier is NCT04187352 .

Multicenter phase I dose escalation and expansion study of pyrotinib in combination with camrelizumab and chemotherapy as first-line treatment for HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma.

Background: Pembrolizumab plus trastuzumab and chemotherapy showed remarkable efficacy as first-line therapy for advanced HER2-positive gastric cancer. Pyrotinib is an irreversible pan-HER inhibitor. This single-arm, open-label phase 1 dose-escalation (1a) and expansion (1b) study investigated camrelizumab, an anti-PD-1 antibody, plus pyrotinib and chemotherapy as first-line treatment for advanced HER2-positive gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. Methods: Between June 2020 and June 2022, 41 patients with previously untreated HER2-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma were enrolled. In phase 1a, patients underwent a 3 + 3 escalating dose design, receiving oral pyrotinib (240 mg, 320 mg, or 400 mg daily), intravenous camrelizumab (200 mg), and CapeOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily for two weeks) every 3 weeks until progression, intolerable toxicity or consent withdrawal. The recommended phase 2 dose (RP2D) of pyrotinib was determined and used in the phase 1b. The primary endpoints were the safety, maximum tolerated dose (MTD), RP2D, and confirmed objective response rate (ORR). This trial was registered with chictr.org, number ChiCTR2000029717. Findings: Among 41 patients, 10 were in phase 1a (3 at 240 mg, 3 at 400 mg, and 4 at 320 mg due to one patient withdrawing consent), and 31 were in phase 1b. In phase 1a, the MTD of pyrotinib was 320 mg daily due to dose-limiting toxicities (diarrhea [n = 3] and vomiting [n = 1]) observed at 400 mg. Based on all available data, the RP2D of pyrotinib was set at 320 mg. Among 41 patients, 20 patients (48.8%) developed grade ≥3 treatment-emergent adverse events (TEAEs), and four patients (9.8%) had any grade serious adverse events. No deaths occurred due to TEAEs. Among 27 patients who received the RP2D of pyrotinib and had a post-baseline tumor assessment, two patients (7.4%) achieved a confirmed complete response, and 19 patients (70.4%) achieved a confirmed partial response, resulting in a confirmed ORR of 77.8% (95% CI: 57.7-91.4). Interpretation: Pyrotinib plus camrelizumab and chemotherapy showed promising efficacy in the first-line treatment of advanced HER2-positive G/GEJ cancer. The safety profile was consistent with known toxicities of the agents, and no new or unexpected safety signals were identified. Funding: This study was funded by the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0377).

Analysis of the efficacy and safety of paclitaxel (albumin-bound) combined with S-1 and oxaliplatin combined with S-1 in the first-line treatment of advanced gastric cancer: a cohort study.

Background: Single-drug albumin-bound paclitaxel is one of the standard second-line treatments for advanced gastric cancer. Some clinical studies suggest that albumin-bound paclitaxel combined with S-1 can be used in the first-line treatment of gastric cancer. Both the two regimens have been commonly used in the past few years. Which is more effective? What's the safety? Methods: From 2016 to 2021, a total of 70 untreated patients with advanced gastric cancer were included in our study. They all received at least two cycles of chemotherapy. Among them, 37 cases received standard S-1 and oxaliplatin (SOX) regimen, and 33 cases received albumin-bound paclitaxel combined with S-1 (aTS) regimen. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events (AEs) were analyzed. The OS and PFS curves were estimated using the Kaplan-Meier method. Results: The PFS of the aTS group was higher than that of the SOX group (9.27 vs. 7.03 months; P=0.046), but there was no significant difference in the OS between the two groups (19.2 vs. 12.5 months; P=0.131). The ORR of the aTS group was higher than that of the SOX group, and the side effects were tolerable. Conclusions: Both regimens can be applied to advanced gastric cancer patients. Albumin-bound paclitaxel showed a higher ORR and could effectively prolong PFS.

Cholinesterase is Associated With Prognosis and Response to Chemotherapy in Advanced Gastric Cancer.

Background: Cholinesterase (CHE) is a routine serum biomarker in gastric cancer (GC). However, little research has been done on its clinical value in advanced GC. In addition, it is not clear whether it can be used as biomarker for the response and prognosis of advanced GC patients. Methods: Between Jan. 2013 and Dec. 2016, a total of 150 patients with advanced GC treated with first-line chemotherapy were admitted to Changzhou Tumor Hospital Affiliated to Soochow University. We retrospectively identified serum CHE level on the day before chemotherapy and at the end of chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between serum CHE levels and progression-free survival (PFS) and overall survival (OS). Results: A total of 150 advanced GC patients were included and divided into serum level ≥5,000 IU/L and serum level <5,000 IU/L. CHE level lower than 5,000 IU/L was associated with poorer PFS (HR, 1.60; 95% CI, 1.141-2.243; p = 0.006), poorer OS (HR, 1.76; 95% CI, 1.228-2.515; p = 0.002) and trend of poorer response (HR, 0.56; 95% CI, 0.272-1.129; p = 0.104). In univariate and multivariate logistic regression analysis, only liver metastasis and PS score were significantly associated with objective response (p < 0.05). The medium PFS was 8.0 months in patients with post-treatment CHE increased vs. 3.8 months in patients with CHE decreased after chemotherapy (HR, 1.82; 95% CI 1.28-2.57; p = 0.0002). The medium OS was 13.1 months in patients with increased post-treatment CHE vs. 8.1 months in patients with decreased post-treatment CHE (HR, 1.87; 95% CI 1.29-2.71; p = 0.0002). Conclusion: Advanced GC with CHE levels below 5,000 IU/L was significantly associated with poor PFS and OS. The results suggested that CHE analysis before chemotherapy was a promising prognostic marker for advanced GC.

Improved efficacy and safety of low-dose oxaliplatin/pegylated liposomal doxorubicin/S-1 regimen in advanced gastric cancer: a cohort study.

BACKGROUND: Dose-limiting neurotoxicity is the major side effect caused by oxaliplatin treatment. Optimization of oxaliplatin-containing chemotherapeutic regimens may potentially benefit advanced gastric cancer (AGC) patients. We tried to reduce the dose of oxaliplatin and add a drug to compensate for the efficacy. This cohort study evaluated the efficacy and side effects of low-dose oxaliplatin combined with pegylated liposomal doxorubicin and S-1 (D-SOX) as first-line treatment for AGC. METHODS: 64 AGC patients treated in our hospital between January 2015 and December 2018 were included in this study. Among them, 29 cases received standard S-1 and oxaliplatin (SOX) regimen, and 35 cases received D-SOX. Progression-free survival (PFS), overall survival (OS), response rate (RR), and safety were analyzed. DISCUSSION: The median PFS was 7.0 months [95% confidence interval (CI): 5.77 to 8.23 months] in the SOX group and 9.3 months (95% CI: 8.145 to 10.45 months) in the D-SOX group (P=0.021). The median OS was 12.5 months (95% CI: 7.00 to 17.97 months) in the SOX group and 18.7 months (95% CI: 14.485 to 22.9 months) in the D-SOX group (P=0.027). The incidence of treatment-related grade III-IV adverse events (AEs) was less than 10%. The RRs to these 2 regimens were similar (P=0.609). The incidence of neurotoxicity was significantly reduced in the D-SOX group (62.8% vs. 82.7%). CONCLUSIONS: Low-dose oxaliplatin combined with S-1 and pegylated liposomal doxorubicin (PLD) regimen improved OS and PFS, while exhibiting better toxicity profile as compared with standard SOX regimen for AGC.

A retrospective analysis of plasma concentration monitoring of fluorouracil in patients with advanced colorectal cancer.

Objectives: To analyse the results of fluorouracil (5-FU) plasma concentration monitoring in patients with advanced colorectal cancer after 5-FU treatment, and to provide a reference for the application prospect of 5-FU plasma concentration monitoring technology. Methods: A retrospective analysis was performed with advanced colorectal cancer patients treated with 5-FU from March 2015 to August 2018. The results of plasma concentration monitoring of 5-FU, severe adverse reactions, and anti-tumour efficacy were analysed. Results: Among 47 patients, 5-FU plasma concentration monitoring was carried out a total of 289 times. The area under the receiver operating characteristic (ROC) curve (AUC) reflecting 5-FU exposure in vivo was 2.8-158 mg*h/L (41±94.6 mg*h/L). Mean AUC range within the target range (20-30 mg*h/L) for each patient was observed in 28.8% of patients. The overall incidence of related severe adverse reactions in the AUC ≤30 mg*h/L group was lower than that in the >30 mg*h/L group (24.0% and 50.0%, respectively) (p=0.06), and the incidence of severe neutropenia was 12.0% and 40.9%, respectively (p=0.05). The disease control rate and overall response rate of the AUC <20 mg*h/L group was lower than that of the ≥20 mg*h/L group: 83.3% vs 97.1% (p=0.19) and 25.0% vs 51.4% (p = 0.10), respectively. Conclusions: The 5-FU plasma concentration monitoring technique can improve the safety and efficacy of 5-FU administration to advanced colorectal cancer patients. It is expected to become an important means to individualise 5-FU use in the Chinese population.

LncRNA-H19 regulates cell proliferation and invasion of ectopic endometrium by targeting ITGB3 via modulating miR-124-3p.

Endometriosis, a common gynecological disease, is associated with pelvic pain and infertility. Endometriosis affects approximately 10% of women, but that number increases to 30-50% in symptomatic premenopausal women. Despite the prevalence of endometriosis, the cause has yet to be fully elucidated. Recent study of the molecular pathways of endometrial cancer has brought the long non-coding RNA (lncRNA) H19 to our attention. In this paper, we explored the role of lncRNA-H19 in endometrial tissue proliferation. We found that ectopic endometrial cells taken from women with endometriosis showed elevated levels of lncRNA-H19, with expression levels correlating to disease progression. Knockdown of H19 in ectopic endometrial cells inhibited cell proliferation and invasion. Coinciding with this change was an increase in microRNA-124-3p (miR-124-3p) and a decrease in integrin beta-3 (ITGB3) levels. The addition of a miR-124-3p inhibitor mitigated this decrease in ITGB3. Up-regulation of miR-124-3p markedly suppressed ITGB3 expression by binding to the 3' untranslated region (3' UTR), while inhibition of miR-124-3p had the opposite effect. ITGB3 overexpression potently counteracted the effects of miR-124-3p mimics on ectopic endometrial cells. From these results, we can infer that in endometriosis both miR-124-3p and ITGB3 operate as downstream effector proteins in the H19-signaling pathway. Down-regulation of lncRNA-H19 could inhibit ectopic endometrial cell proliferation and invasion by modulating miR-124-3p and ITGB3, offering a novel target for treatment.

Rechallenge and maintenance therapy using cetuximab and chemotherapy administered to a patient with metastatic colorectal cancer.

BACKGROUND: Cetuximab combined with chemotherapy is one of the first-line treatments of metastatic colorectal cancer. Although disease progression inevitably occurs, rechallenge and maintenance therapies using cetuximab-based regimens may be beneficial, particularly for patients with wild-type (WT) KRAS. CASE PRESENTATION: A 47-year-old female patient who underwent right hemicolectomy presented with an ulcerative adenocarcinoma (grade 2) revealed by histopathological analysis. The patient received three cycles of adjuvant chemotherapy, but disease recurred 15 months later. Cetuximab and a FOLFOX-4 regimen were administered, followed by surgery and adjuvant chemotherapy that was administered for approximately one year. Three years after completing adjuvant therapy, her serum carcinoembryonic antigen levels rapidly increased, and enhanced computed tomography showed widespread metastases. Rechallenge with cetuximab and the FOLFIRI regimen was then initiated, and after 12 cycles, lesions in the lung and liver shrank significantly, and serum CEA levels dramatically declined. Maintenance therapy with cetuximab and capecitabine was then administered for 10 months until the metastatic lesions in the lung and liver enlarged. CONCLUSION: Rechallenge and maintenance therapy with cetuximab-based chemotherapy were relatively effective for managing a female patient with WT KRAS. Optimization of this strategy requires further in-depth investigations of more patients.

Changes in serum thymidine kinase 1 levels during chemotherapy correlate with objective response in patients with advanced gastric cancer.

Serum thymidine kinase 1 (STK1) is a reliable proliferation marker in most solid tumors, including gastric cancer. The aim of this study was to evaluate whether STK1 levels are related to the tumor response to chemotherapy and survival in advanced gastric cancer. The results showed that the average STK1 level in patients with gastric cancer (5.57±3.07 pM) was significantly higher than that in the healthy controls (1.12±0.57) (P<0.001). Among the 84 patients, the average STK1 level (6.02±3.12) in the 56 patients who did not undergo surgery was higher than the level (4.68±2.78) in the 28 patients who received surgery (P=0.049). The STK1 value correlated with clinical stage, ECOG PS and serum CEA levels (P<0.001, P=0.001 and P=0.004, respectively), but not with age and gender. The average STK1 levels after 1,2 and 4 cycles of chemotherapy did not significantly decrease in the total patients, when compared to the levels prior to chemotherapy. Yet, after 2 cycles of chemotherapy, the average level of STK1 was significantly decreased in patients who achieved an objective response (OR) (CR, PR or no recurrence). Particularly after 1 cycle of chemotherapy, the average level of STK1 in patients who achieved OR started to decline, while in most of the patients with disease progression or recurrence, the STK1 level started to increase. In patients receiving palliative chemotherapy or receiving adjuvant chemotherapy, a significant difference in the median PFS (median PFS, not defined vs. 4 months, P<0.001) or RFS (median RFS, not defined vs. 5 months, P<0.001) was noted between patients with decreased STK1 levels and patients with increased STK1 levels during the first 2 months of chemotherapy. The log-rank test showed that patients with decreased STK1 levels had a trend of a longer OS in the palliative chemotherapy group. Our results suggest that serum TK1 levels correlate with clinical stage, ECOG PS and serum CEA levels in patients with gastric cancer, and changes in STK1 levels during the first 2 months of chemotherapy may be more important for evaluating chemotherapy response, predicting PFS and RFS than baseline values of STK1 in patients with advanced gastric cancer.