[Efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer, mCRC].

OBJECTIVE: To assess the efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer (mCRC). METHODS: Seventy-seven mCRC patients received BEV plus 5-Fu type, oxaliplatin or irinotecan-based chemotherapy. The clinical efficacy and bevacizumab-related adverse reactions were observed. The efficacy assessment was conducted after at least 2 cycles of BEV therapy. The adverse reactions were recorded in each therapy cycle. Among the 77 cases, 64 patients had finished the efficacy assessment. The adverse reactions in all patients were assessed. RESULTS: The overall response rate (ORR) of BEV plus chemotherapy regimen was 18.75% (12/64), and the disease control rate (DCR) was 75.0% (48/64). In 27 patients who received the regimen as first-line treatment, the ORR reached 37.0% (10/27), while the DCR was 85.2%. Four patients with potentially resectable lesions became resectable after the regimen and received R0 resection of the liver metastases successfully. Twenty-five patients who received the regimen as second line therapy had poor result with ORR 8.0% and DCR 76.0%. Hypertension was observed in 12 cases, with 8 cases of grade 1, 3 cases of grade 2, 1 case of grade 3. Various bleedings occurred in 24/77 cases (31.2%), all were of grade 1-2, including 17 cases of epistaxis, grade 1 hemorrhoid bleeding in one case, hematuria in 3 case (2 of grade 1, 1 of grade 2), GI bleeding in 2 cases, hemoptysis in 1 case (grade 2), and proteinuria in 4 cases (grade 1). Intestinal perforation occurred in 1 case (0.3%). In two patients who had incomplete intestinal obstruction history appeared exacerbated intestinal obstruction symptoms after the application of BEV plus CPT11 regimen. CONCLUSIONS: BEV plus chemotherapy regimen as first-line treatment can improve the ORR and DCR of mCRC patients. When it was used as second- or later-line therapy, it may display satisfied DCR, although with a poor efficacy. The bevacizumab-related toxicity is mild and can be well tolerated.

Anlotinib plus Epirubicin Followed by Anlotinib Maintenance as First-line Treatment for Advanced Soft-tissue Sarcoma: An Open-label, Single-arm, Phase II Trial.

PURPOSE: The treatment outcome for locally advanced or metastatic soft-tissue sarcoma (STS) remains unsatisfactory. Anlotinib had demonstrated impressive activity in the subsequent-line treatment of STS. This study investigated the combination of anlotinib and epirubicin followed by anlotinib maintenance as first-line treatment for patients with advanced STS. PATIENTS AND METHODS: This prospective, open-label, single-arm, phase II trial was conducted in Zhongshan Hospital, Fudan University. Eligible patients were ages 18 years or older and had previously untreated, pathologically confirmed, unresectable locally advanced or metastatic STS. All patients received up to six cycles of anlotinib plus epirubicin followed by anlotinib maintenance until disease progression, unacceptable toxicity, or death. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The study was registered on chictr.org (identifier ChiCTR1900024928). RESULTS: From June 2019 to August 2020, 30 patients were enrolled. By December 2021, the median PFS was 11.5 months [95% confidence interval (CI): 8.6-14.4 months], while the median overall survival was not reached (95% CI: NE-NE). The objective response rate was 13.33% and the disease control rate was 80.0%. The most common adverse events (AE) included anemia (43.3%), nausea/vomiting (40.0%), fatigue (36.7%), leukopenia (30.0%), and proteinuria (10.0%), which were mainly of grade 1 or 2. The most frequent grade 3 or 4 AEs were anemia (10.0%), febrile neutropenia (33.3%), hypothyroidism (3.3%), and leukopenia (3.3%). No treatment-related death occurred. CONCLUSIONS: The combination of anlotinib and epirubicin followed by anlotinib maintenance demonstrated promising efficacy with a favorable safety profile.

Efficacy and safety of anlotinib, a multikinase angiogenesis inhibitor, in combination with epirubicin in preclinical models of soft tissue sarcoma.

BACKGROUND: Anlotinib is a novel, orally administered, multitarget receptor tyrosine kinase inhibitor. It functions by inhibiting tumor angiogenesis and proliferative signaling pathways. In this study, we aimed to investigate the efficacy and safety of anlotinib plus epirubicin in a sarcoma patient-derived xenografts (PDX) model. METHODS: We firstly established a PDX model using fresh tumor tissues that were surgically removed from a patient diagnosed with malignant fibrous histiocytoma. Thirty-six PDX models were divided into six groups and treated with anlotinib alone (low-dose, 1.5 or high-dose, 3.0 mg/kg/day, oral gavage), or with anlotinib plus epirubicin (3.0 mg/kg/once weekly, i.p.) when the tumors grew to 150-200 mm3 . After 5 weeks of treatment, the mice were sacrificed, and the tumors were measured by weight and processed for IHC and H&E staining. IHC staining was performed to detect CD31, EGFR, MVD, and Ki-67 on paraffin sections. H&E stainings were performed to examine the microcosmic changes that occurred in the tumor tissues and myocardium, respectively. RESULTS: After 5 weeks, treatment with anlotinib or epirubicin alone significantly inhibited tumor growth in the sarcoma PDX model compared with the vehicle control. Tumor volume in the high-dose anlotinib group was significantly smaller than the low-dose anlotinib group (P < .001). Combined high-dose anlotinib and epirubicin treatment resulted in the most pronounced tumor inhibition. In the groups treated with the anlotinib-containing regimen, the expression levels of CD31, EGFR, MVD, and Ki-67 were significantly low. The weight in each group had no statistical differences; the same applied to the hepatic function, cardiac function, and toxicity. CONCLUSIONS: High-dose anlotinib combined with epirubicin was an effective and safe therapy for STS.

No Association Between Calcium Channel Blockers and Survival in Patients with Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Any association between calcium channel blockers (CCBs) and survival in cancer patients remains unclear and the results of related studies are conflicting. The objective of the study was to investigate the association between calcium channel blocker (CCB) use and survival in cancer patients. MATERIALS AND METHODS: We searched PubMed, EMBASE, Web of Science and Cochrane Library for studies published before January 2016 with terms related to CCBs and survival in cancer patients. The information was reviewed and extracted by two evaluators independently. Data from publications were extracted and used to calculate hazard ratios (HRs) for overall survival (OS). Statistical analysis was performed by using Review Manager 5.3. RESULTS: There were 11 studies included in our meta-analysis. Analysis of all showed that CCBs use was not associated with survival in cancer patients (HR=1.07; 95% CI: 0.91-1.25; P=0.42). No association between CCB use and overall survival in cancer patients existed, whether in Asian (HR=1.18, 95% CI: 0.72-1.93; P=0.52) or Caucasian populations (HR=1.03, 95% CI: 0.89-1.20; P=0.66). CONCLUSIONS: There is no evidence that CCB use is associated with a better or worse survival in cancer patients.

Efficacy of preoperative chemotherapy regimens in patients with initially unresectable locally advanced gastric adenocarcinoma: capecitabine and oxaliplatin (XELOX) or with epirubicin (EOX).

Purpose We assessed the effectiveness of EOX (capecitabine, oxaliplatin and epirubicin) compared with XELOX (capecitabine and oxaliplatin) as preoperative chemotherapy for initially unresectable locally advanced gastric cancer.Methods This is a prospective observational study. Patients with unresectable locally advanced gastric cancer were performed EOX regimen or XELOX regimen at the discretion of the investigators. They were assessed for response every 2 cycles by CT (computed tomography) scan. A multidisciplinary team reassessed resectability after 4 cycles. The primary endpoint was the response rate. Secondary end points included the R0 resection rate, survival and adverse events.Results From November 2008 to May 2015, 242 patients were enrolled; 112 of them were assigned to EOX regimen and 130 to XELOX regimen. The response rates were 33.0% and 33.8% respectively in EOX group and XELOX group (P = 0.997). After 4 cycles of chemotherapy, 63 patients (56.3%) in EOX group and 81 patients (62.3%) in XELOX group received radical operation (P = 0.408). There was no significant difference in progress-free survival (PFS, 12.0m vs. 15.4m, P = 0.925) and overall survival (OS, 25.7m vs. 29.0m, P = 0.783) in two groups. In addition, more adverse effects occurred in EOX group, such as more leucopenia (22.3% vs. 10.0%, P = 0.014), neutropenia (23.2% vs. 11.5%, P = 0.025), fatigue (11.6% vs. 3.8%, P = 0.041) and vomiting (10.7% vs. 2.3%, P = 0.015).Conclusions For unresectable locally advanced gastric cancer patients, XELOX regimen showed similar effects in response rate, radical resection rate and survival benefits, but with less toxicity effects.

[A pilot study of chemotherapy combined with intraperitoneal perfusion of cytokine-induced killer cells for advanced gastric cancer patients with ascites].

OBJECTIVE: To investigate the efficacy and safety of chemotherapy combined with intraperitoneal perfusion of cytokine-induced killer (CIK) cells for advanced gastric cancer patients with ascites. METHODS: From January 2008 to December 2010, 42 advanced gastric cancer patients with ascites in Zhongshan Hospital of Fudan University were enrolled in the study. According to personal choice, patients were divided into 2 groups: XELOX chemotherapy alone (Capecitabine and Oxaliplatin) was applied in 22 patients (chemotherapy group) and XELOX combined with intraperitoneal perfusion of CIK cells in 20 patients (combination group). The efficacy, safety, and immunological function, including the time to progression (TTP), overall survival (OS), Karnofsky performance status (KPS) score, immunity index (CD4+/CD8+ ratio), volume of peritoneal fluid, were compared between two groups. RESULTS: Compared with the chemotherapy group after treatment, the combination group had a higher KPS score (78.0±9.8 vs. 70.0±8.9, P=0.009), less volume of 2-cycle peritoneal fluid drainage [(4500±1218) ml vs. (5527±1460) ml, P=0.018 ], longer median TTP (4.0 vs. 2.5 months, P=0.001) and OS (11.0 vs. 6.0 months, P=0.006), higher ratio of CD4+/CD8+ (1.34±0.36 vs. 0.96±0.26, P=0.001). While no significant significances were found between the two groups in disease response rate (35.0% vs. 22.7%, P=0.499) and disease control rate (75.0% vs. 54.5%, P=0.209). There were no serious adverse reactions in the combination group. CONCLUSIONS: As compared with XELOX chemotherapy alone, the combination immunological treatment of XELOX chemotherapy and intraperitoneal perfusion of CIK cells possesses better efficacy for the advanced gastric cancer patients with ascites, which can prolong the survival and enhance the immunological function with favorable safety.

[Efficacy of neoadjuvant chemotherpy in patients with locally advanced gastric cancer].

OBJECTIVE: To evaluate the efficacy and safety of neoadjuvant chemotherapy in patients with locally advanced gastric cancer, and to analyze the relevant factors of recurrent death of gastric cancer after adjuvant chemotherapy. METHODS: Clinical data of 49 patients who underwent neoadjuvant chemotherapy for locally advanced gastric cancer between July 2007 and June 2011 were reviewed. Preoperative staging was determined by endoscopic ultrasonography and abdominal computer tomography (CT) or magnetic resonance imaging (MRI). Chemotherapy was administered for regimen of two or three drugs. Prognostic factors were analyzed by univariate and multivariate analysis with Cox proportional hazard model. RESULTS: The response rate was 33.3% (16/48) and disease control rate was 93.8% (45/48). Forty-four (89.8%, 44/49) patients received curative resection after neoadjuvant chemotherapy, among whom 90.9% (40/44) underwent D2 lymphadenctomy. Thirty-two cases had pathological response and 2 patients had pathological complete response. The average hospital stay was 11.6 days and 2 patients had longer hospitalization because of postoperative pancreatic complications. The toxicities were most in grade 1-2. All the patients were followed up postoperatively and the median follow-up was 21.6 months. Median progression-free survival was 29.6 (95%CI:24.0-35.2) months and median overall survival was 34.6 months (95%CI:29.8-39.4). Imaging response (P=0.038, RR=0.168, 95%CI:0.031-0.904) and pathological response (P=0.007, RR=0.203, 95%CI:0.064-0.642) were identified as independent prognostic factors with COX multivariate analysis. CONCLUSIONS: Neoadjuvant chemotherapy has quite high disease control rate and R0 resecting rate for patients with locally advanced gastric cancer. Imaging response and pathological response are most important prognostic factors in those patients.

Polymorphism of thymidylate synthase gene and chemosensitivity of 5-fluorouracil regimen in metastatic gastrointestinal cancer.

OBJECTIVE: To explore the polymorphism of thymidylate synthase (TS) gene and chemosensitivity of a 5-fluorouracil (5-FU)-containing regimen in metastatic colorectal and gastric cancer. METHODS: Sixty-eight patients with metastatic gastric or colorectal cancer were included in this study. Doublets or triplets of 28 base pairs (bp) in the 5-untranslated region (UTR) of TS gene promoter were detected by polymerase chain reaction (PCR) analysis. Fragments of polymorphic products, 2R/2R, 2R/3R and 3R/3R were detected by the Agilent BioAnalyzer chip-lab system. All patients were followed up until the censoring date. A chi2 test was used to analyze the polymorphism. A Kaplan-Meier curve and a log-rank test were used to determine disease progression and overall survival. RESULTS: Among 68 patients, polymorphism expressions were 4.4% in 2R/2R, 29.4% in 2R/3R and 66.2% in 3R/3R, and clinical responses were 33.3%, 73.3% and 47.6%, respectively (2R/3R versus 3R/3R, P= 0.058). In the 64 evaluable cases, the median time to progression (TTP) was 4 months and the TTP were 3 months in 2R/2R, 6 months in 2R/3R and 4 months in 3R/3R, separately (log-rank test, P= 0.0316). Response rates to the 5-FU regimen were also better in the 2R/3R group than in the 3R/3R group both in metastatic colorectal cancer and advanced gastric cancer. CONCLUSION: Our study suggested that polymorphism of 3R/3R was more common in Chinese gastrointestinal cancer patients. Patients with a TS polymorphism expressed as 2R/3R might be more sensitive to 5-FU regimen than those with a polymorphism expressed as 3R/3R.