Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial.

PURPOSE: The purpose of this study was to evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. METHODS AND MATERIALS: In this phase 3, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiation therapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiation therapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiation therapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea, ≥G1 and ≥G2 diarrhea lasting at least 3 days, and damage to the rectal mucosa due to radiation therapy measured by endoscopy. RESULTS: Two hundred and eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 142). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs 14.8 and 4.5 days, respectively; P < .001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs 55.7%, P < .001). Three patients felt intolerable or abdominal pain after rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P = .061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P < .001). CONCLUSIONS: The results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.

Improving the efficacy and safety of concurrent chemoradiotherapy by neoadjuvant chemotherapy: a randomized controlled study of locally advanced cervical cancer with a large tumor.

OBJECTIVE: To compare the efficacy and safety of neoadjuvant chemotherapy combined with concurrent chemoradiotherapy (NACT+CCRT) vs. concurrent chemoradiotherapy (CCRT) in locally advanced cervical cancer (LACC) patients with large tumor masses. METHODS: LACC patients with localized tumor diameter >4 cm, were randomly allocated in an unblinded 1:1 ratio to NACT+CCRT or CCRT groups. Patients in the NACT+CCRT group were given paclitaxel combined with cisplatin (TP) NACT every 3 weeks for 2 cycles, followed by CCRT, with the chemotherapy regimen the same as for NACT. CCRT group were given CCRT with the same as for NACT. RESULTS: From March 1, 2019, to June 30, 2021, 146 patients were included in the final analysis. Sixty-eight (93.2%) patients in the NACT+CCRT group and 66 (90.4%) patients in the CCRT group completed the expected treatment course. The complete response (CR) rate in the NACT+CCRT group was significantly higher than in the CCRT group (87.7% vs. 67.6%, χ²=54.540, p=0.000). In the NACT+CCRT group, the 1- and 2-year overall survival (OS) rates were significantly higher than those in the CCRT group (96% vs. 89% and 89% vs. 79%, χ²=5.737, p=0.017). Additionally, the rate of recurrences and distant metastases was significantly lower in the NACT+CCRT group than in the CCRT group (4.11% vs. 7.35%, χ²=4.059, p=0.021). Most treatment-related adverse events in both groups were grade 3. CONCLUSION: Compared to CCRT, NACT+CCRT might improve the treatment completion rate, increase CR rate and 1- and 2-year OS rates, and reduce distant metastases rate for LACC patients with large tumor masses.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A Comparison of Different Schemes of Neoadjuvant Chemotherapy Followed by Concurrent Chemotherapy and Radiotherapy for Locally Advanced Cervical Cancer: A Retrospective Study.

PURPOSE: To examine the clinical significance of unoperated cervical cancer patients treated with different neoadjuvant chemotherapy (NACT) schemes followed by concurrent chemotherapy and radiotherapy (CCRT). METHODS: This retrospective analysis included women with locally advanced cervical cancer treated with NACT-CCRT between September 2011 and September 2014. Neoadjuvant chemotherapy included paclitaxel plus cisplatin (TP group; 62 patients) or paclitaxel plus loplatin (TL group; 58 patients), which were administered three weekly, and cisplatin or loplatin, which were administered weekly for synchronous chemotherapy. External beam radiation therapy (50.4-56.35 Gy/28 f, 180-215 cGy/f, 5 f/w) was followed by intracavitary brachytherapy (5 Gy per fraction, mostly 5 fractions, Ir192 based). RESULTS: One hundred twenty women were included in the analysis. The complete/partial response rate was 99.2% after treatment. The one-year, three-year, and five-year survival rates were 99.2%, 82.5%, and 70.8%, respectively. In the TP and TL groups, the three-year and five-year survival rates were 85.5% vs 77.6% and 75.8% vs 65.5%, respectively, with no significant difference. The 5-year overall survival (OS) rates between patients with stage IIB and stage IIIB disease were not significantly different (69.2% vs 64.7%). In the TP group, grade 3 or 4 digestive reactions were more frequent than those in the TL group. Leukopenia, neutropenia, and thrombocytopenia were more common in the TL group. No significant difference was found in anemia, radiation enteritis, radiation proctitis, or radiation cystitis between the groups. CONCLUSION: Lobaplatin may be used as an alternative drug for patients with severe digestive system reactions or contraindications to cisplatin, but hematological toxicity must be considered, particularly in dose-intensive schemes. Neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy (NACT-CCRT) warrants further prospective study in cervical cancer patients with a wide range of tumor invasion (eg, mass size ≥5 cm or stage IIIB).

Neutrophil-to-Lymphocyte Ratio (NLR) and Monocyte-to-Lymphocyte Ratio (MLR) Predict Clinical Outcome in Patients with Stage IIB Cervical Cancer.

INTRODUCTION: Stage IIB cervical cancer (CC) is an advanced stage CC with poor prognosis. Inflammatory response plays a crucial role in the development of CC, and systemic inflammatory indexes were related to the prognosis in several cancers. The objective of the study was to determine the prognostic value of platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and systemic inflammation response index (SIRI) as inflammatory indexes in patients with stage IIB CC. MATERIALS AND METHODS: A retrospective study was performed in 260 patients with stage IIB CC. PLR, NLR, MLR, BLR, and SIRI were obtained from routine blood tests. Prognosis information of the patients was acquired from regular clinical follow-up. Recurrence and response to therapy were determined through electronic medical records (EMRs). Correlations of the inflammatory indexes with overall survival (OS), progression-free survival (PFS), recurrence, and response to therapy were analyzed using SPSS version 26.0 software. RESULTS: Receiver operating characteristic (ROC) curve analyses suggested that NLR, MLR, and SIRI had better predictive value than PLR as well as BLR in the prognosis and recurrence risk. Both univariate and multivariate survival analyses showed that higher NLR and MLR were significantly associated with shorter OS as well as PFS, whereas SIRI was not an independent predictive factor of PFS. Chi-square test results revealed that increased NLR was significantly correlated with higher recurrence rate (P=0.046), and increased MLR showed significant correlation with elevated recurrence risk (P=0.002). Univariate and binary logistic regression analyses for response to therapy indicated that elevated NLR was associated with decreased complete remission (CR) rate (P=0.031), and the P value lost statistical significance while being adjusted by tumor size (P=0.108). CONCLUSIONS: For patients with stage IIB CC, both NLR and MLR are independent prognostic factors as well as risk factors for recurrence; NLR serves as a potential marker for therapeutic response.

TOP2A Promotes Cell Migration, Invasion and Epithelial-Mesenchymal Transition in Cervical Cancer via Activating the PI3K/AKT Signaling.

BACKGROUND/OBJECTIVE: Topoisomerases type IIA (TOP2A) was identified to present with a high-expression pattern in cervical cancer. However, TOP2A role in the progression of cervical cancer remains unknown. Here, we aimed to explore the effect and reveal the underlying mechanism of TOP2A in the migration, invasion and epithelial-mesenchymal transition (EMT) of cervical cancer. MATERIALS AND METHODS: The expression profiles of TOP2A in 20 paired cervical cancer tissues and the paracancerous normal tissues were detected by using Western blotting assay. Transwell chambers were used to test cell migration and invasion abilities. Cell morphology and the expressions of E-cadherin and N-cadherin were detected to assess cell EMT. LY294002 was used to inhibit the activation of PI3K/AKT signaling. RESULTS: Compared with the paracancerous normal tissues, TOP2A was overexpressed in 85% (17/20) cervical cancer tissues. Repression of TOP2A expression in SiHa cells significantly weakened cell migration and invasion abilities, reduced cell numbers in shuttle shape and increased E-cadherin expression while decreased E-cadherin expression. To the opposite, overexpression of TOP2A in Hela cells induced opposite results. In addition, the expression of p-AKT was increased when TOP2A was overexpressed in Hela cells, and p-AKT expression was decreased when TOP2A was silenced in SiHa cells. Moreover, suppression of the PI3K/AKT signaling with LY294002 treatment apparently rescued TOP2A-mediated promotions in cell migration, invasion and EMT in Hela cells. CONCLUSION: This study reveals that TOP2A is abnormally overexpressed in cervical cancer tissues, and TOP2A overexpression leads to cell migration, invasion and EMT via activating PI3K/AKT signaling.

Pilot study of docetaxel combined with lobaplatin or gemcitabine for recurrent and metastatic breast cancer.

BACKGROUND: This study evaluated the efficacy and safety of docetaxel combined with lobaplatin, relative to docetaxel combined with gemcitabine, for treating patients with recurrent metastatic breast cancer (rMBC). METHODS: Patients with rMBC received ≥2 cycles (21 days each) of either docetaxel and lobaplatin (DL; n = 21), or docetaxel and gemcitabine (DG; n = 22). On day 1 of each cycle, all patients were given 75 mg/m intravenous docetaxel. Patients in DL and DG were also given, respectively, 35 mg/m intravenous lobaplatin (day 2) or 1000 mg/m intravenous gemcitabine (days 1, 8). RESULTS: Five (11.6%) and 16 (37.2%) patients achieved complete remission and partial response, respectively; rates of response and disease control were 48.8%. The response rates of the groups were comparable (47.6%, 50.0%). The median survival times after relapse and metastasis of the DL group (18 months) were significantly less than that of the DG group (25 months). Median progression-free survivals after relapse and metastasis were similar (12 cf. 14 months). The main toxic side reaction was grade 2, with no treatment-related deaths. Rates of the following were comparable between DG and DL: grade 3 or 4 white blood cells (23.8%, 31.8%) and digestive tract toxicity (4.8%, 4.5%); neutropenia (28.6%, 22.7%); anemia (4.8%, nil); and thrombocytopenia (19.0%, 13.6%). Other toxicities included hepatic toxicity, myalgia, infection, and fatigue. CONCLUSIONS: Both the DL and DG regimens were associated with encouraging benefits, while treatment-related toxicity was manageable. Therefore, these regimens are effective options for treatment of rMBC. TRIAL REGISTRATION: This clinical trial study was approved by the Ethics Committee of Guizhou Cancer Hospital, and has been registered in the China Clinical Trial Center (December 8, 2014, No. ChiCTR-IPR-14005633).

Anti-tumor effect of aloe-emodin on cervical cancer cells was associated with human papillomavirus E6/E7 and glucose metabolism.

Background：Aloe-emodin, an anthraquinone present in aloe latex, has been shown to have anti-proliferative properties in cervical cancer disease, all cases of which are almost caused by human papillomavirus (HPV), with the products of E6/E7. It is suggested that aloe-emodin may play an important role in HPV-induced cervical cancer cells. Methods：Hela and SiHa cells were treated with various concentrations of aloe-emodin. MTT assay and flow cytometry were used to identify the cell growth and apoptosis. The expressions of HPV E6, E7 and GLUT1 (glucose transporter-1) were detected by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot (WB). The glucose uptake, lactate production and ATP production in HeLa and SiHa cells were also investigated. Result：The results indicate that aloe-emodin promoted the apoptosis of HeLa and SiHa cells and decreased the expressions of HPV-related protein E6 and E7. Furthermore, aloe-emodin inhibited glucose metabolism by reducing GLUT1 expression. Overexpression of GLUT1 significantly weakened the apoptosis induced by aloe-emodin in HeLa cells. Conclusion：In this study, we found that aloe-emodin induce apoptosis of cervical cancer cells, which was associated with HPV E6 and E7 and glucose metabolism.

Expression of Long Noncoding RNA Urothelial Cancer Associated 1 Promotes Cisplatin Resistance in Cervical Cancer.

Cisplatin resistance is still one of the main reasons for failure of clinical therapy for cervical cancer. But the underlying molecular mechanisms involved in cisplatin resistance of cervical cancer have still remained unclear. Recent studies reported that long noncoding RNAs (lncRNAs) are novel nonprotein-coding transcripts, which might play a key role in cancer biogenesis and prognosis. One of the lncRNAs, urothelial cancer associated 1 (UCA1), has been shown to promote different types of cancer cell proliferation, migration, and invasion. This study showed that overexpression of UCA1 confers cisplatin resistance by promoting cancer cell proliferation and inhibiting apoptosis. In addition, knockdown of UCA1 remarkably decreased cisplatin resistance in cervical cancer cells. Moreover, results also indicated that UCA1 was involved in signaling pathways modulating cell apoptosis and proliferation. UCA1 suppressed apoptosis by downregulating caspase 3 and upregulating CDK2, whereas enhanced cell proliferation by increased level of survivin and decreased level of p21. This study reports for the first time that UCA1 might play an important role in the cisplatin resistance in cervical cancer, and also explain partially how UCA1 promotes cisplatin resistance in cancer cells. These results provide evidence to support that UCA1 can be used as a potential target for a novel therapeutic strategy for cervical cancer.