Quality-adjusted survival in patients with metastatic colorectal cancer treated with fruquintinib in the FRESCO trial.

Aim: To assess whether the survival benefit of fruquintinib is quality-adjusted. Materials & methods: Data of 416 metastatic colorectal cancer patients from the Phase III FRESCO trial were used. The Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) analysis assessed the quality-adjusted survival benefit of fruquintinib versus placebo, accounting for freedom from symptomatic disease and from severe side effects of treatment. Results: Fruquintinib significantly improved patients' Q-TWiST (difference: 2.23 [1.41, 3.04] months) versus placebo. The Q-TWiST gain was 28.3% in the base case and ranged from 16.7 to 39.9% in the threshold analysis, favoring fruquintinib. The Q-TWiST benefit was observed in fruquintinib-treated patients regardless of prior targeted therapy. Conclusion: Fruquintinib provides a clinically meaningful quality-adjusted survival benefit versus placebo as a third-line treatment for metastatic colorectal cancer patients.

Lay abstract The objective of the study was to assess the benefit of fruqintinib, a chemotherapy drug for patients with metastatic colorectal cancer (mCRC) who do not respond well to previous chemotherapy. The study considered both the time of survival and the quality of life after patients received fruqintinib. In measuring patients' quality of life, the study assessed the time that was free from cancer symptoms and any severe side effects from treatment. The study used data obtained from a Phase III clinical trial, FRESCO, which included 416 mCRC patients receiving fruqintinib or placebo. The results showed that fruqintinib significantly extended patients' symptom-free and side effects-free survival time by approximately 2 months and 5 days. Fruqintinib was 16.7­39.9% more effective than placebo in extending mCRC patients' high-quality life, regardless of prior targeted therapy.

Disease characteristics and treatment patterns of Chinese patients with metastatic colorectal cancer: a retrospective study using medical records from China.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer in China but few large-scale studies were conducted to understand CRC patients. The current study is aimed to gain a real-world perspectives of CRC patients in China. METHODS: Using electronic medical records of sampled patients between 2011 and 2016 from 12 hospitals in China, a retrospective cohort study was conducted to describe demographics and disease prognosis of CRC patients, and examine treatment sequences among metastatic CRC (mCRC) patients. Descriptive, comparative and survival analyses were conducted. RESULTS: Among mCRC patients (3878/8136, 48%), the fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and other oxaliplatin-based regimens were the most widely-used first-line treatment (42%). Fluorouracil, leucovorin, irinotecan (FOLFIRI) and other irinotecan-based regimens dominated the second-line (40%). There was no a dominated regimen for the third-line. The proportion of patients receiving chemotherapy with targeted biologics increased from less than 20% for the first- and second- lines to 34% for the third-line (p < 0.001). The most common sequence from first- to second-line was from FOLFOX and other oxaliplatin-based regimens to FOLFIRI and other irinotecan-based regimens (286/1200, 24%). CONCLUSIONS: Our findings reflected a lack of consensus on the choice of third-line therapy and limited available options in China. It is evident o continue promoting early CRC diagnosis and to increase the accessibility of treatment options for mCRC patients. As the only nationwide large-scale study among CRC and mCRC patients before more biologics became available in China, our results can also be used as the baseline to assess treatment pattern changes before and after more third-line treatment were approved and covered into the National Health Insurance Plan in China between 2017 and 2018.

Circulating miRNAs with prognostic value in metastatic breast cancer and for early detection of metastasis.

Metastasis is the principal cause of high morbidity and mortality among breast cancer (BC) patients. Identification of markers that can be routinely monitored to predict onset of metastasis in BC patients and prognosis of metastatic breast cancer (MBC) patients would increase their median survival. In this study, plasma miRNAs of 40 MBC patients were profiled by TaqMan low density arrays and miRNAs with prognostic capacity were identified. The candidates were validated initially in the samples of 237 MBC patients and subsequently in 335 samples from an independent study cohort of BC patients. Sixteen miRNAs were established to be significantly associated with overall survival, and were termed as prognostic miRNA panel template (PROMPT). These included miR-141, miR-144, miR-193b, miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-215, miR-365, miR-375, miR-429, miR-486-5p, miR-801, miR-1260 and miR-1274a. Additionally, 11 of these miRNAs were also associated with progression-free survival. Their prognostic significance was further confirmed in samples from a second study cohort of BC patients. In addition, miR-200a, miR-200b, miR-200c, miR-210, miR-215 and miR-486-5p were found to be significantly associated with onset of metastasis up to 2 years prior to clinical diagnosis in BC patients. We have thus identified panels of miRNAs, which include metastasis promoting miR-200 family and miR-203, as well as oncogenic and tumor-suppressive miRNAs, that can serve as prognostic markers for MBC, and early detection markers of metastasis in BC.

Plasma hyaluronic acid level as a prognostic and monitoring marker of metastatic breast cancer.

Conventional tumor markers have limited value for prognostication and treatment monitoring in metastatic breast cancer (MBC) patients and novel circulating tumor markers therefore need to be explored. Hyaluronic acid (HA) is a major macropolysaccharide in the extracellular matrix and is reported to be associated with tumor progression. In our study, we investigated plasma HA level with respect to progression free survival (PFS) and overall survival (OS), as well as the treatment monitoring value in MBC patients. The prognostic value of plasma HA level was investigated in a discovery cohort of 212 MBC patients with 2.5-year follow-up and validated in an independent validation cohort of 334 patients with 5-year follow-up. The treatment monitoring value of plasma HA level was investigated in 61 MBC patients from discovery cohort who had been radiographically examined after first complete cycle of chemo therapy. We found a robust association between high plasma HA level and poor prognosis of MBC patients in both discovery (pPFS = 7.92 × 10(-6) and pOS = 5.27 × 10(-5)) and validation studies (pPFS = 3.66 × 10(-4) and pOS = 1.43 × 10(-4)). In the discovery cohort, the plasma HA level displayed independent prognostic value after adjusted for age and clinicopathological factors, with respect to PFS and OS. Further, the decrease of plasma HA level displayed good concordance with treatment response evaluated by radiographic examination (AUC = 0.79). Plasma HA level displays prognostic value, as well as treatment monitoring value for MBC patients.

Plasma S100P level as a novel prognostic marker of metastatic breast cancer.

UNLABELLED: Metastasis is the main cause of death in breast cancer patients. The development of reliable and cost-effective biomarker to evaluate the prognosis of metastatic breast cancer (MBC) patients is of great importance. S100P is a member of S100 family and has been proved to be associated with metastasis establishment. METHODS: We investigated the plasma S100P levels in 60 healthy controls, 48 primary and 273 metastatic breast cancer patients. The MBC patients were followed-up for disease progression and death up to 3.5 years after recruitment. Radiographic response of MBC patients were also analyzed for investigation on treatment monitoring value of plasma S100P level. We found a robust association between high plasma S100P level (>7 ng/mL) and poor prognosis of metastatic breast cancer (MBC) patients (median progression-free survival time: 5.0 vs. 8.7 months, log-rank test p < 0.001; median overall survival time: 22.5 vs. 31.6 months, log-rank test p < 0.001). The plasma S100P level added additional prognostic relevance to the conventional prognostication model with clinicopathological factors and CTC enumeration. The plasma S100P level decreased significantly after treatment, while the reduction correlated with the radiographic response of the MBC patients. This finding indicates the value of plasma S100P in dynamic evaluation of treatment outcome. We hereby suggest plasma S100P level as a simple and cost-effective marker for the prognosis of metastatic breast cancer.

S100P and HYAL2 as prognostic markers for patients with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a group of very aggressive breast tumours, characterised by lack of expression of oestrogen receptor (ER), progesterone receptor (PR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2). Nevertheless, TNBCs show different clinical characteristics and are very diverse regarding prognostic outcome. So far, only a few prognostic markers for TNBC have been reported that could be helpful for therapeutic stratification. Here we have analysed the expression of S100P and HYAL2 using immunohistochemistry (IHC) in a TNBC cohort of 98 patients with a follow-up for recurrence and death. TNBC patients with high expression of both proteins showed significantly shorter progression-free survival (PFS) (mean PFS=35.9months, P=0.001) compared to TNBC patients with high expression levels of only one of the proteins (mean PFS=69.4months) and to TNBC patients with low expression of both proteins (mean PFS=83.3months). Moreover, multivariate Cox-regression model showed the combined expression of S100P and HYAL2 as independent prognostic factor for PFS (P=0.001). The expression of S100P and HYAL2 indicated similar prognostic effect to the overall survival (OS) of TNBC patients. In addition, high expression levels of both S100P and HYAL2 showed significant association with different clinicopathological characteristics, such as more recurrence events (P=0.004), and higher occurrence of metastasis (P=0.002). Our study proposes S100P and HYAL2 as potential prognostic markers for TNBC.

Cost-effectiveness analysis of fruquintinib versus regorafenib as the third-line therapy for metastatic colorectal cancer in China.

OBJECTIVES: The aim of this study is to assess the cost-effectiveness of fruquintinib compared to regorafenib as third-line treatment for patients with metastatic colorectal cancer (mCRC) in China. METHODS: A three-state Markov model with monthly cycle was constructed to estimate lifetime incremental cost-effectiveness ratio (ICER) of fruquintinib versus regorafenib as third-line treatment for patients with mCRC from Chinese health care perspective. Survival analysis was applied to calculate transition probabilities using the data from the clinical trials FRESCO and CONCUR, which were also the data sources accessing probabilities of adverse events. Background mortality rate and drug costs were derived from government published data. Costs for medical services were obtained from real-world data and published literatures. Utilities applied to calculate the quality-adjusted life years (QALYs) were obtained from literature review. One-way sensitivity analysis and probabilistic sensitivity analysis were adopted to verify the robustness of the results. RESULTS: Fruquintinib provided 0.74 QALYs at a cost of CNY 151,058 (USD 22,888), whereas regorafenib provided 0.79 QALYs at a cost of CNY 226,657 (USD 32,224). Compared to fruquintinib, the ICER of regorafenib was CNY 1,529,197/QALY (USD 231,697/QALY) from Chinese health care perspective, which was above the triple GDP per capita of China in 2019 (CNY 212,676) (USD 32,224) as the threshold to define the cost-effectiveness. One-way sensitivity analysis showed the results were generally robust. Cost-effectiveness acceptability curves derived from probabilistic sensitivity analysis demonstrated the probability that fruquintinib was more cost-effective was 100% when the threshold was the triple GDP per capita of China. CONCLUSIONS: Compared to regorafenib, fruquintinib, which leads to forego about 0.05 QALYs and save about CNY 75,599 (USD 11,454), is a cost-effective choice as the third-line treatment for patients with mCRC in China.

Treatment patterns and direct medical costs of metastatic colorectal cancer patients: a retrospective study of electronic medical records from urban China.

Objectives: To describe direct medical costs associated with each line of treatment among metastatic colorectal cancer (mCRC) patients in China.Methods: Electronic medical records between 2011 and 2016 were extracted from 12 tertiary hospitals in China for adult patients who initiated third-line treatment at least nine months before the end of data collection. Direct medical costs included costs of wards, diagnostic tests, surgical procedures, special materials, drugs and others. Costs were assessed by line of treatment, and drug costs were further breakdown for patients receiving chemotherapy alone and those receiving chemo- and biologics-combined therapy.Results: Of the 404 mCRC patients, the mean age was 55 years old and 62% were male. Oxaliplatin- and irinotecan-based regimens dominated first- and second-line treatment, respectively (44 and 37%). From first- to second- to third-line, the proportion of patients receiving targeted biologics increased from 18% at first-line and 12% at second-line to 34% at third-line; median number of treatment cycles reduced from 6 to 4 and to 2. The corresponding mean direct medical costs per person per cycle increased from $2,514 to $2,678 to $5,121. Mean drug costs per cycle increased from $2,314 to $2,673 to $4,316 among patients receiving chemotherapy alone and from $3,245 to $2,717 to $6,533 among patients receiving chemo- and biologics-combined therapy.Conclusions: Before 2017, mCRC patients in China did not receive the maximum benefits of precision medicine breakthroughs. Reduced treatment cycles and increased costs per cycle from first- to third-line suggested poor healthcare resource utilization. With earlier initiation and more treatment cycles, targeted biologics may better demonstrate their effectiveness among Chinese patients. Our findings reflected the urgent need to increase drug accessibility in China before 2017 and underscore that including innovative biologics into Chinese health insurance plans can reduce patients' economic burden and improve the management of mCRC.

The effect of ethephon on immune system in male offspring of mice.

Ethephon can liberate ethylene which could interfere the plant growth process. The aim of the present study was to determine the effect of ethephon on developing immune system of male offspring. Ethephon could enhance NK cell activity in male mice. For 4-week-old male mice, lymphocytes of peripheral blood increased while the hemolytic plaque number decreased. Delayed type hypersensitivity(DTH) was inhibited in all groups. The expression of protein Bcl11b and p-p38 in thymus of treatment groups were lower than control group. Our results indicated that cellular immunity of male offspring is more sensitive to ethephon when exposed in pregnancy and lactation period. It should be emphasized that exposure to ethephon during the in utero stage and lactation stage still could damage the immune function of animal in the period before fully mature even in the dosage that could not influence the immune function of adult animal.

Let-7 g is involved in doxorubicin induced myocardial injury.

OBJECTIVES: To investigate whether let-7 g (miRNA) was involved in doxorubicin-induced cardiotoxicity. METHODS: Rats were treated with doxorubicin at increasing doses (0mg/kg, 6 mg/kg, 12 mg/kg, 18 mg/kg). Heart rate, pulse pressure and plasma cardiac troponin T concentrations were measured. Primary cultured myocardial cells were incubated with DOX at increasing concentrations (0 µmol/l, 0.004 µmol/l, 0.02 µmol/l, 0.1 µmol/l, 0.5 µmol/l) for 24h. Cellular viability and the beat frequency were measured. For both rats and cultured cells, miRNA content was measured by real-time reverse-transcription PCR. RESULTS: All DOX-treated rats had a decrease in heart rate, an increase in pulse pressure compared with control group after injections (p<0.05). Concentration of cTnT was increased significantly in 18 mg/kg group. Content of let-7 g decreased significantly (p<0.05) in 18 mg/kg group in vivo and all the doxorubicin treated group in vitro. CONCLUSIONS: The down regulation of let-7 g in the myocardial-injury model suggests that let-7 g may play an important role in the development of cardiac disease.