A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of olanzapine plus triple antiemetic regimen for the prevention of multiday highly emetogenic chemotherapy-induced nausea and vomiting (OFFER study).

Background: Evidence supports prophylactic use of olanzapine for the treatment of chemotherapy-induced nausea and vomiting (CINV). However, most studies to date have focused on patients with single-day highly emetogenic chemotherapy (HEC). Currently, administration of antiemetic therapies for nausea and vomiting induced by multiday chemotherapy regimens remains a challenge. In this study, we evaluated the efficacy of olanzapine combined with triple antiemetic therapy for the prevention of CINV in patients receiving multiday chemotherapy. Methods: We performed a randomized, double-blind, placebo-controlled phase 3 trial in 22 hospitals. Eligible patients were between 18 and 75 years old, were diagnosed with malignant solid tumors, and they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. All the study participants were scheduled to be treated with chemotherapy regimens containing 3-day cisplatin (3-day total dose ≥75 mg/m2). Randomization was computer generated and stratified by gender and chemotherapy treatment history. Allocation was done via an interactive web response system. Enrolled patients were randomly assigned 1:1 to receive either 5 mg olanzapine or placebo orally before bedtime for 5 days combined with intravenous fosaprepitant (150 mg) 1 h before the administration of cisplatin on day 1, ondansetron hydrochloride intravenously, and dexamethasone orally 30 min before cisplatin from days 1 to 3. Dexamethasone was also administered at the same time on days 4 and 5. The primary endpoint was the proportion of subjects with complete response (no vomiting and no rescue therapy) within the overall phase (days 1-8) after starting chemotherapy. Baseline plasma concentrations of P-substance and 5-HT were measured for exploratory analysis. This study was registered at ClinicalTrials.gov, number NCT04536558. Findings: Between December 2020 and September 2021, 349 patients with malignant solid tumors were enrolled in the study, with 175 participants randomly assigned to receive olanzapine and 174 participants assigned to receive placebo. The proportion of patients who achieved a complete response in the overall phase was significantly higher in the olanzapine group than in the placebo group (69% vs. 58%, P = 0.031). A complete response benefit was observed in the olanzapine group versus the placebo group in almost all the subgroups. Four factors were considered significantly associated with complete response in multivariable analysis: treatment group, gender, baseline plasma concentration of 5-HT, and prior radiotherapy. All the reported adverse events associated with olanzapine administration were grades 1 and 2. Interpretation: Olanzapine (5 mg) combined with fosaprepitant, ondansetron, and dexamethasone was better than triple antiemetic therapy alone for patients receiving multiday chemotherapy regimens. Based on these results, the four-drug combination should be recommended as the best antiemetic regimen given to patients receiving multiday cisplatin-based chemotherapy and baseline plasma concentration of 5-HT may be used to identify individuals who are prone to CINV. However, all these findings need to be further validated in future studies. Funding: Jiangsu Hansoh Pharmaceutical Group Co., Ltd. provided research grant and study drugs for this investigator-initiated study.

Treatment patterns and outcomes change in early-stage non-small cell lung cancer in octogenarians and older: a SEER database analysis.

BACKGROUND: Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death in the world. AIMS: We used the Surveillance, Epidemiology, and End Results (SEER) database to investigate the changes in the incidence, treatment patterns, and outcomes of early-stage non-small cell lung cancer (NSCLC) in octogenarians and older from 1995 to 2015. METHODS: Using the SEER database, we identified patients ≥ 80 years stage I-IIa NSCLC diagnosed from 1995 to 2015. Changes in the treatment patterns, incidence and proportion, and survival were assessed by years of diagnosis. RESULTS: In total, 25,394 patients were identified. The incidence number sharply increased from 260 in 1995 to 2120 in 2015. There was a tremendous increase in the proportion who underwent radiotherapy from 22.7% in 1995 to 50% in 2015 (P < 0.0001), with a corresponding decrease in surgical treatment, from 50 to 28.6% (P < 0.0001). The 2-year cancer-specific survival (CSS) and overall survival (OS) improved for patients treated with radiation alone and relatively subtly for those who received surgery alone. CONCLUSION: At present, RT has replaced surgery as the most commonly used modality in early-stage NSCLC in patients ≥ 80 years in the United States. An improvement was observed in CSS and OS for patients treated with definitive RT and surgery.

c-Myc maintains the self-renewal and chemoresistance properties of colon cancer stem cells.

Cancer stem cells (CSCs) are responsible for cancer formation, recurrence and drug resistance. c-Myc, one of the core markers for stem cells, has recently been considered to serve as a link between malignancy and 'stemness'. However, the precise function of c-Myc in colon CSCs is still unclear. In the present study, a subpopulation of colon CSCs expressing a CD133 surface phenotype was isolated from the human HT-29 cell line, which possess greater tumor sphere-forming efficiency and have higher expression of 'stemness'-associated genes compared with CD133-negative cells. Furthermore, it was demonstrated that c-Myc was highly expressed in CD133+ colon CSCs. Knockdown of c-Myc expression with small interfering RNA in colon CSCs can significantly inhibit tumor sphere formation, reduce the invasive and migratory capacity of CD133+ cells in vitro, and suppress the tumorigenicity of colon CSCs in vivo. In addition, it was suggested that c-Myc silencing may sensitize colon CSCs to chemotherapy-induced cytotoxicity via the downregulation of ABCG2 and ABCB5. These findings support a central role for c-Myc in maintaining the self-renewing and chemoresistant properties of colon CSCs.

Prognostic Impact of Different Histological Types on Gastric Adenocarcinoma: a Surveillance, Epidemiology, and End Results Database Analysis.

The clinicopathological characteristics and prognosis of gastric mucinous adenocarcinoma (MAC) and signet ring cell carcinoma (SRC) are still controversial. We designed our study to evaluate the clinicopathologic features and prognosis of MAC, SRC and ordinary gastric adenocarcinoma (OGAC) by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. The 5-year overall survival (OS) of patients with SRC was significantly lower than that of patients with MAC (P = 0.001) and OGAC (P < 0.001), and there was no significant difference in 5-year OS between MAC and OGAC (P = 0.804). Furthermore, there were no significant differences of 5-years OS among these three groups at stage I, II and III (all P > 0.05) and no significant difference between MAC and OGAC at stage IV (P = 0.110). Patients in SRC group had significantly worse survival than those in MAC and OGAC at stage IV (both P = 0.008), with 5-year OS of 3.3%, 5.8%, and 5.8%, respectively. However, the histological type was not found to be an independent prognostic factor of gastric cancer according to the multivariate analysis with Cox regression.

The recommended treatment strategy for locally advanced gastric cancer in elderly patients aged 75 years and older: a Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: As patients aged 75 years and older are often underrepresented in randomized clinical trials, the external validity of clinical trials-based recommendations in older gastric patients was still controversial. The aim of this study is to explore the recommended treatment strategy for locally advanced gastric cancer in elderly patients. METHODS: We designed our study to specifically evaluate the cancer-specific survival (CSS) of four subgroups of patients according to four different treatment modalities: adjuvant radiation (RT), surgery only, RT only and no surgery/no RT by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of survival outcomes and risk factors. RESULTS: The 5-year CSS was 43.8 % in adjuvant RT, 28.5 % in surgery only, 14.9 % in RT only and 1.4 % in no surgery/no RT, which had significant difference in univariate log-rank test (P < 0.001) and multivariate Cox regression (P < 0.001). Moreover, we observed significant survival benefits in adjuvant RT group in all age categories, including age 75-79 years, age 80-84 years and age ≥85 years (all P < 0.001). CONCLUSIONS: Surgery and adjuvant RT may be the recommended treatment strategy in elderly patients with locally advanced gastric cancer, especially for patients medically fit for the combined modality therapy.

[c-Myc regulation of ATP-binding cassette transporter reverses chemoresistance in CD133(+) colon cancer stem cells].

The present study was aimed to explore the role of c-Myc gene regulation in maintaining the self-renewal and drug-resistant properties of colon cancer stem cells (CSCs) and the underlying mechanism. CD133(+) cells were isolated by flow cytometry cell sorting from human HT29 cancer cells. A small interfering RNA (siRNA) against c-Myc was used, and the mRNA and protein expressions of c-Myc were investigated by real-time PCR and Western blotting, respectively. To evaluate the effect of c-Myc on the drug resistance of colon CSCs, CD133(+) cells transfected with c-Myc-siRNA were exposed to 5-FU, oxaliplatin, or their combination. The expressions of ATP-binding cassette (ABC) transporters, including ABCG2, ABCB5 and MDR-1, were detected by Western blotting. The results showed that c-Myc was highly expressed in CD133(+) colon CSCs, and the protein and mRNA expressions of c-Myc were effectively blocked by c-Myc siRNA. Furthermore, CD133(+) cells showed significantly increased survival rate in chemotherapy treatment, compared with CD133(-) cells. c-Myc silencing sensitized CD133(+) cells to chemotherapy-induced cytotoxicity and down-regulated the protein expression levels of ABCG2, MDR-1 and ABCB5. These results suggest c-Myc silencing may regulate the expressions of ABC transporters in colon CSCs, and enhance the sensitivity of CSCs to the chemotherapy.