Zhendong Chen

Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

BACKGROUNDnMost cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma.nnnMETHODSnBetween Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752.nnnFINDINGSn271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation.nnnINTERPRETATIONnSorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III Sorafenib Asia–Pacific trial☆

BACKGROUNDnThe phase III Sorafenib Asia-Pacific (AP) trial-conducted in China, Taiwan and South Korea - confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib.nnnMETHODSnIn the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1-2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety.nnnFINDINGSnSorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32-0.87 and 0.31-0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups.nnnINTERPRETATIONnThe efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status.

Fulvestrant 250 mg versus anastrozole for Chinese patients with advanced breast cancer: Results of a multicentre, double-blind, randomised phase III trial

Background and purposeFulvestrant, an oestrogen receptor (ER) antagonist with no known agonist effects, has shown activity in postmenopausal patients with ER-positive advanced breast cancer recurring or progressing following prior endocrine therapy. This double-blind, double-dummy, randomised phase III study (NCT00327769) was designed to compare the efficacy and safety of fulvestrant versus anastrozole in advanced breast cancer of Chinese postmenopausal women whose disease has progressed following prior endocrine treatment.Materials and methodsA total of 234 patients were randomised to fulvestrant 250xa0mg/month (nxa0=xa0121) or 1xa0mg/day anastrozole (nxa0=xa0113), together with matching placebo. The primary endpoint was time to progression (TTP). Secondary endpoints included objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR) and time to treatment failure (TTF).ResultsBaseline characteristics were similar, with the possible exception that a higher number of fulvestrant patients had received two prior chemotherapy regimens. Median TTP was 110xa0days in the fulvestrant group versus 159xa0days in the anastrozole group (hazard ratio [HR], 1.314; 95% confidence intervals [CI], 0.948, 1.822; Pxa0=xa00.101). ORR was 10% in the fulvestrant group and 14% in the anastrozole group. Median DoR from randomisation to progression was 436xa0days versus 432xa0days for the fulvestrant and anastrozole groups, respectively. CBR for fulvestrant (36.1%) versus anastrozole (48.2%) was not statistically different between the groups. TTF (110xa0days versus 147xa0days for the fulvestrant and anastrozole groups, respectively) was not statistically different between the treatments (HR, 1.307; 95% CI, 0.961, 1.778; Pxa0=xa00.088). Both treatments were well tolerated, with only two patients treated with fulvestrant and four patients treated with anastrozole withdrawn from study treatment due to adverse events.ConclusionsThese data demonstrate that fulvestrant 250xa0mg and anastrozole were similarly effective and well tolerated in the treatment of postmenopausal Chinese women with advanced breast cancer whose disease had progressed or recurred on prior endocrine treatment.

Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial

Importance Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. Objective To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. Design, Setting, and Participants FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Interventions Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (nu2009=u2009278) or placebo (nu2009=u2009138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. Main Outcomes and Measures The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Results Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; Pu2009<u2009.001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; Pu2009<u2009.001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Conclusions and Relevance Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. Trial Registration ClinicalTrials.gov Identifier: NCT02314819

Transdermal granisetron for the prevention of nausea and vomiting following moderately or highly emetogenic chemotherapy in Chinese patients: a randomized, double-blind, phase III study

BACKGROUNDnThe granisetron transdermal delivery system (GTDS) has been demonstrated effectiveness in the control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of GTDS in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in China.nnnMETHODSnA total of 313 patients were randomized into the GTDS group (one transdermal granisetron patch, 7 days) or the oral granisetron group (granisetron oral 2 mg/day, ≥2 days). The primary endpoint was the percentage of patients achieving complete control (CC) from chemotherapy initiation until 24 h after final administration (PEEP). Chi-square test and Fishers exact test were used for statistical analysis.nnnRESULTSnTwo hundred eighty-one patients were included in the per protocol analysis. During PEEP, CC was achieved by 67 (47.52%) patients in the GTDS group and 83 (59.29%) patients in the oral granisetron group. There was no statistical significance between the groups (P=0.0559). However, the difference of the CC percentage mainly occurred on the first day of chemotherapy between the groups. The CC was 70.13% on day 1 in the GTDS group, which was significantly lower than that of 91.03% in the oral granisetron group in the full analysis set. In the following days of chemotherapy, the CC was similar between the groups. In terms of cisplatin-contained regimen and female, there was statistical significance between the groups. Both treatments were well tolerated and safe. The most common adverse event was constipation.nnnCONCLUSIONSnGTDS provided effective and well-tolerated control of CINV in Chinese patients, especially to non-cisplatin-contained regimen.

Efficacy and safety of fosaprepitant in the prevention of nausea and vomiting following highly emetogenic chemotherapy in Chinese people: A randomized, double-blind, phase III study.

&NA; The prevention of chemotherapy‐induced nausea and vomiting was one of the most challenging supportive care issues in oncology, especially to highly emetogenic chemotherapy (HEC). A total of 645 patients were randomized into fosaprepitant group (fosaprepitant/placebo 150 mg d1 in combination with granisetron and dexamethasone) or aprepitant group (aprepitant/placebo 125 mg d1; 80 mg d2‐d3 plus granisetron and dexamethasone).The primary endpoint was the percentage of patients who had a complete response (CR) over the entire treatment course (0‐120 hr, overall phase [OP]). It was assessed by using a non‐inferiority model, with a non‐inferiority margin of 10%. The difference of the CR rate was compared between two groups with chi‐square analysis. Six hundred and twenty‐six patients were included in the per protocol analysis. The percentage of patients with a CR in the fosaprepitant group was not inferior to that in the aprepitant group (90.85% versus 94.17%, p = .1302) during OP. Whether the cisplatin‐based chemotherapy or not, the CR rate of the fosaprepitant group was not inferior to that of the aprepitant group. Both regimens were well tolerated. The most common adverse event was constipation. Fosaprepitant provided effective and well‐tolerated control of nausea and vomiting associated with HEC in Chinese patients.

Differential expression of small ubiquitin-like modifier family of proteins in patients with colorectal adenocarcinoma.

420 Background: The cytotoxic effects of radiation and chemotherapy are mediated in part by DNA damage. The small ubiquitin-like modifier (SUMO) family of proteins regulates DNA repair pathways by activating factors involved in homologous recombination (HR) or non- homologous end joining (NHEJ). Our objective was to determine the potential role of SUMO proteins in patients with colorectal cancer.nnnMETHODSnWe first assessed two established colorectal cancer cell lines (HCT116 and HT29) and two normal colonic mucosa cell populations utilizing ultra high-throughput expression analysis (Solexa) to examine differential expression of genes involved in SUMOylation (SAE1, SAE2, PIAS-1, and DNAPKcs). To verify the clinical relevance of SUMOylation in colorectal cancer, we obtained archived specimens from patients with colorectal cancer (n=51) and examined the expression of these proteins in both benign and malignant tissue by immunohistochemistry (IHC).nnnRESULTSnUltra high-throughput expression analysis of cancer and normal cells revealed a 10 to 15-fold upregulation of SAE2 (heterodimer of the E1 activation enzyme in SUMOylation), a 10 to 11-fold upregulation of DNAPKcs (catalytic subunit in NHEJ repair pathway), and a 6-fold upregulation of SAE1 in cancer cells. In contrast, PIAS-1 showed similar expression levels between cancer and normal colonic cells. By IHC, SAE1 and SAE2 were highly expressed in 65% and 53% of tumor specimens, respectively; but only in 7% and 0% of normal tissues, respectively. DNAPKcs was also highly expressed in tumor tissues (63%) with corresponding low expression (0%) in normal tissues. Corroborating the cell line results, PIAS-1 was infrequently expressed in both tumor (10%) and normal tissues (0%).nnnCONCLUSIONSnWe are the first to demonstrate the differential expression of SUMO proteins in colorectal cancer cell lines and in clinical specimens. SUMO proteins have a role in DNA repair and their expression in colorectal cancer may modify tumor response to chemoradiotherapy. No significant financial relationships to disclose.