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1.
J Hematol Oncol ; 13(1): 47, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393323

RESUMO

BACKGROUND: Association of immune-related adverse events with tumor response has been reported. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event related to camrelizumab, an immune checkpoint inhibitor, but lack of comprehensive analyses. In this study, we conducted comprehensive analyses on RCCEP in advanced hepatocellular carcinoma (HCC) patients treated with camrelizumab monotherapy. METHODS: Data were derived from a Chinese nationwide, multicenter phase 2 trial of camrelizumab in pre-treated advanced HCC. The occurrence, clinicopathological characteristics, and prognostic value of RCCEP were analyzed. RESULTS: With a median follow-up of 12.5 months, 145 of the 217 camrelizumab-treated patients (66.8%) experienced RCCEP (all grade 1 or 2). RCCEP occurred on the skin surface, mainly on the skin surface of head, face, and trunk. RCCEP could be divided into 5 types including "red-nevus-like," "pearl-like," "mulberry-like," "patch-like," and "tumor-like," according to the morphological features. RCCEP biopsy and pathology showed capillary endothelial hyperplasia and capillary hyperplasia in dermis. Significant association between RCCEP occurrence with higher objective response rate was observed (19.3% vs. 5.6%; one-sided p = 0.0044). Compared with those without RCCEP, patients with RCCEP had prolonged progression-free survival (median PFS; 3.2 months vs. 1.9 months; one-sided p < 0.0001) and overall survival (median OS; 17.0 months vs. 5.8 months; one-sided p < 0.0001). In multivariable analyses, the development of RCCEP was significantly associated with prolonged PFS and OS after adjusting for baseline covariates. In addition, the landmark analyses of PFS and OS were consistent with the unadjusted analysis. CONCLUSIONS: RCCEP occurred on the skin surface and was an immune response of skin capillary endothelial cells. RCCEP occurrence positively associated with outcomes of camrelizumab in advanced HCC.

2.
Lancet Oncol ; 21(4): 571-580, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112738

RESUMO

BACKGROUND: Blocking the interaction between PD-1 and its ligands is a promising treatment strategy for advanced hepatocellular carcinoma. This study aimed to assess the antitumour activity and safety of the anti-PD-1 inhibitor camrelizumab in pretreated patients with advanced hepatocellular carcinoma. METHODS: This is a multicentre, open-label, parallel-group, randomised, phase 2 trial done at 13 study sites in China. Eligible patients were aged 18 years and older with a histological or cytological diagnosis of advanced hepatocellular carcinoma, had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every 2 or 3 weeks, via a centralised interactive web-response system using block randomisation (block size of four). The primary endpoints were objective response (per blinded independent central review) and 6-month overall survival, in all randomly assigned patients who had at least one dose of study treatment. Safety was analysed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment is closed. FINDINGS: Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for eligibility, of whom 220 eligible patients were randomly assigned and among whom 217 received camrelizumab (109 patients were given treatment every 2 weeks and 108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7-15·5). Objective response was reported in 32 (14·7%; 95% CI 10·3-20·2) of 217 patients. The overall survival probability at 6 months was 74·4% (95% CI 68·0-79·7)]. Grade 3 or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the most common were increased aspartate aminotransferase (ten [5%]) and decreased neutrophil count (seven [3%]). Two deaths were judged by the investigators to be potentially treatment-related (one due to liver dysfunction and one due to multiple organ failure). INTERPRETATION: Camrelizumab showed antitumour activity in pretreated Chinese patients with advanced hepatocellular carcinoma, with manageable toxicities, and might represent a new treatment option for these patients. FUNDING: Jiangsu Hengrui Medicine.

3.
Lasers Med Sci ; 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32034563

RESUMO

To investigate whether the Warburg effect is a key modulator on the resistance mechanism of photodynamic therapy (PDT). Glycolysis was examined by the test of lactate product and glucose uptake at different post-PDT time points. Cell viability was detected by the CCK-8 assay and cell proliferation was detected by colony formation assay. The expression of glycolysis and related proteins were examined by western blotting. Target gene was silenced by RNAi. In the present study, we assessed the effect of PDT on cancer cell glycolysis. Our team has demonstrated that pyruvate kinase M2 (PKM2), a key speed-limiting enzyme of glycolysis, was significantly overexpressed in patients with esophageal cancer. Our results in the present study showed that PKM2 was downregulated, and lactate product and glucose uptake were inhibited in cells exposed to 5-aminolevulinic acid (5-ALA)-mediated PDT at 4 h after treatment. However, at 24 h after PDT, we observed a substantial increase in PKM2 expression, lactate product, and glucose uptake. Moreover, silencing of PKM2 gene abrogated the upregulatory effect of PDT on glycolysis at late post-PDT period. 2-Deoxy-D-glucose (2-DG) is a recognized chemical inhibitor of glycolysis. The combined treatment of 2-DG and PDT significantly inhibited tumor growth in vitro at 24 h. These results demonstrate that PDT drives the Warburg effect in a time-dependent manner, and PKM2 plays an important role in this progress, which indicated that PKM2 may be a potential molecular target to increase the sensitivity of esophageal cancer cells to PDT.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31900959

RESUMO

BACKGROUND AND AIM: In the phase 3 CONCUR trial (NCT01584830), regorafenib improved overall survival (OS) versus placebo in Asian patients with treatment-refractory metastatic colorectal cancer (mCRC). We conducted a post hoc subgroup analysis of Chinese patients in CONCUR. METHODS: Adults with mCRC progressing despite at least two prior treatment regimens and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:1 to regorafenib 160 mg once daily or placebo for the first 3 weeks of each 4-week cycle. Dose modifications were permitted. The primary endpoint was OS. Secondary endpoints included progression-free survival, objective overall response, disease control rate, and safety. RESULTS: A total of 172 Chinese patients were randomized and treated (regorafenib n = 112, placebo n = 60). OS was significantly improved with regorafenib versus placebo (8.4 vs 6.2 months, respectively; hazard ratio [HR] 0.56, 95% CI 0.39-0.80; one-sided P = 0.000632), as was progression-free survival (HR 0.32, 95% CI 0.22-0.47; one-sided P < 0.000001). The most common drug-related grade ≥ 3 treatment-emergent adverse events (TEAEs; regorafenib, placebo) were hand-foot skin reaction (19%, 0%), hypertension (13%, 3%), hypophosphatemia (7%, 0%), increased alanine aminotransferase (6%, 0%), and increased aspartate aminotransferase (5%, 0%). In patients receiving regorafenib and placebo, respectively, TEAEs led to treatment discontinuation in 14% and 7%, dose reduction in 39% and 0%, and dose interruption in 64% and 20%. CONCLUSIONS: This retrospective analysis showed that regorafenib provided an OS benefit over placebo for Chinese patients with previously treated mCRC. TEAEs were consistent with the regorafenib safety profile and manageable with treatment modifications.

5.
Oral Dis ; 26(2): 285-294, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31830347

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of dose-modified docetaxel plus cisplatin and 5-fluorouracil (TPF) in Chinese patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: This Phase III, open-label, multi-center study included Chinese adults with previously untreated TNM Stage III or IV SCCHN (NCT00995293). Patients were randomized (1:1) to induction chemotherapy with TPF (docetaxel 60 mg/m2 and cisplatin 60 mg/m2 on day 1 and 5-FU 750 mg/m2  per day continuous IV infusion on days 1-5) or PF (cisplatin 75 mg/m2 on day 1 and 5-FU 750 mg/m2  per day on days 1-5) every 3 weeks for 3-4 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS in the TPF (n = 108) and PF (n = 111) groups was 400 days and 342 days (HR = 0.75; 95% CI, 0.53─1.06; p = .227), respectively. Overall response rate was higher for TPF versus PF (76.3% vs. 52.9%; p = .001), although this equalized following radiotherapy (75.0% vs. 73.9%). In the TPF and PF groups, ≥1 treatment-emergent adverse event was experienced by 104 (94.5%) and 110 (93.2%) patients, respectively. CONCLUSION: Adding dose-modified docetaxel to PF did not significantly improve PFS but may increase anti-tumor activity in Chinese patients with locally advanced SCCHN.

6.
J Oncol ; 2019: 4035460, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31186633

RESUMO

Annexin A2 (ANXA2) has been well known to associate with the progress of malignant tumor. However, the biological behavior of ANXA2 in gastric cancer (GC) remains unclear. We made a hypothesis in transcriptome level from TCGA datasets. Then, we used immunohistochemical staining to quantify the expression level of ANXA2 protein in GC tissues compared with adjacent tissues. Quantitative real-time PCR and western blot were used for analyzing ANXA2 expression in human GC (SGC-7901, MKN-45, BGC-823, and AGS) cell lines. We investigated the effect of a lentivirus-mediated knock-down of ANXA2 on the proliferation, invasion and migration of gastric cancer AGS cells. Cell proliferation was examined by MTT and colony formation tests. Cell apoptosis and cycle were measured by flow cytometry. Migration and invasion were detected by transwell assay. We found that high expression of ANXA2 can increase the mobility of cancer cells from TCGA datasets. ANXA2 was upregulated in GC tissues compared with adjacent tissues. AGS cell line displayed significantly higher expression of ANXA2 among the four GC cell lines. In addition, ANXA2 silencing led to a weakened ability of proliferation, invasion, and migration in GC cells; targeting of ANXA2 may be a potential therapeutic strategy for GC patients.

7.
Eur J Pharmacol ; 857: 172470, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226250

RESUMO

Eukaryotic elongation factor 2 kinase (eEF-2K) is known as calcium/calmodulin-dependent protein kinase III and identified as a calcium/calmodulin (Ca2+/CaM)-dependent protein kinase (CaM-PK) that phosphorylates its only substrate eukaryotic elongation factor-2 (eEF-2) and blocks the ability of eEF-2 to bind the ribosome and translation elongation and inhibits global protein synthesis. The activators of eEF-2K include allosteric activator Ca/CaM, Ca/CaM-independent activator cAMP-dependent protein kinase (PKA) and H+. On the other hand, eEF-2K is inactivated by the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. However, the role of eEF-2K in cancer is not well understood. To provide opinion for the diagnosis and treatment of cancer, we summarized the role of eEF-2K in cancer. Based on the fundamental research on eEF-2K, scientists further investigated the role of eEF-2K in cancer and have reported its different effects in many kinds of cancer. eEF-2K involves in many signal pathways, including proliferation, apoptosis, autophagy, invasion and glycolysis, and promotes the development of cancer as an oncogene. Inhibition of eEF-2K by eEF-2K siRNA and little molecular inhibitors resulted in the suppression of proliferation, autophagy, invasion and glycolysis, and accelerate apoptosis to play an antitumor role. In this review, we summarize the regulation and role of eEF-2K in cancer as an oncogene and the exploitation of the inhibitor of eEF-2K. Combined treatment of eEF-2K inhibitor and chemotherapeutics should be a potential tool in cancer therapy.


Assuntos
Quinase do Fator 2 de Elongação/metabolismo , Neoplasias/enzimologia , Animais , Ativação Enzimática , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia
8.
Cancer Commun (Lond) ; 39(1): 38, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234927

RESUMO

BACKGROUND: The JACOB trial (NCT01774786) was a double-blinded, placebo-controlled, randomized, multicenter, international, phase III trial evaluating the efficacy and safety of adding pertuzumab to trastuzumab and chemotherapy in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer/gastroesophageal junction cancer (GEJC). The aim of this analysis was to investigate efficacy and safety outcomes in the Chinese subpopulation from the JACOB trial. METHODS: This post hoc subpopulation analysis included all patients recruited in mainland China (n = 163; 20.9%) between June 2013 and January 2016. The patients were randomly assigned in a 1:1 ratio to receive pertuzumab plus trastuzumab and chemotherapy (pertuzumab group; n = 82) or placebo plus trastuzumab and chemotherapy (control group; n = 81). Intravenous pertuzumab (840 mg) and trastuzumab (8 mg/kg loading and 6 mg/kg maintenance doses) were given every 3 weeks until disease progression or unacceptable toxicity. Chemotherapy was given as per standard regimens/doses of capecitabine or 5-fluorouracil plus cisplatin. The primary endpoint was overall survival (OS); secondary efficacy endpoints included progression-free survival (PFS), and overall objective response rate (ORR). RESULTS: The median OS was 18.7 months in the pertuzumab group and 16.1 months in the control group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.49 to 1.14). The median PFS was 10.5 and 8.6 months in the pertuzumab and control groups, respectively (HR 0.85; 95% CI 0.60 to 1.21), and the median ORRs were 68.9% and 55.7%, respectively. The treatment effect in this Chinese subpopulation showed consistency with that in the global ITT population with numerically lower HR for OS and PFS compared with the control group. The safety profiles of the pertuzumab and control groups in this Chinese subpopulation analysis were generally comparable. The most common grade 3-5 adverse events were neutropenia, anemia, and leukopenia. However, due to the nature of being a post hoc subgroup analysis, the results presented here are descriptive only and need to be interpreted with caution. CONCLUSIONS: OS and PFS were numerically improved by adding pertuzumab to trastuzumab and chemotherapy as first-line treatment in Chinese HER2-positive gastric cancer/GEJC patients, and this regimen demonstrated an acceptable safety profile. Trial registration ClinicalTrials.gov. NCT01774786. Registered on 24 January 2013, https://clinicaltrials.gov/ct2/show/NCT01774786.

9.
Cancer Commun (Lond) ; 39(1): 16, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940189

RESUMO

BACKGROUND: The benefit of systemic treatments in esophageal squamous cell carcinoma (ESCC) which has progressed after chemotherapy is still uncertain and optimal regimens based on randomized trials have not yet been established. We aimed to compare the efficacy of irinotecan plus S-1 with S-1 monotherapy in recurrent or metastatic ESCC patients who had resistance to platinum- or taxane-based chemotherapy. METHODS: We conducted a prospective randomized, multicenter, open-label, phase 3 trial in 15 centers across China. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC, and were randomly assigned (ratio, 1:1) to receive either irinotecan plus S-1 (intravenous infusion of irinotecan [160 mg/m2] on day 1 and oral S-1 [80-120 mg] on days 1-10, repeated every 14 days) or oral S-1 monotherapy (80-120 mg/day on days 1-14, repeated every 21 days) using a central computerized minimization procedure. The primary endpoint was progression-free survival (PFS). RESULTS: Between December 23, 2014 and July 25, 2016, we screened 148 patients and randomly assigned 123 patients to receive either irinotecan plus S-1 regimen (n = 61) or S-1 monotherapy (n = 62). After a median follow-up of 29.2 months (95% confidence interval [CI] 17.5-40.9 months), the median PFS was significantly longer in the irinotecan plus S-1 group than in the S-1 monotherapy group (3.8 months [95% CI 2.9-4.3 months] vs. 1.7 months [95% CI 1.4-2.7 months], hazard ratio = 0.58, 95% CI 0.38-0.86, P = 0.006). The objective response rates were 24.6% in the irinotecan plus S-1 group and 9.7% in the S-1 monotherapy group (P = 0.002). The patients in the irinotecan plus S-1 group presented with increased rates of grade 3-4 leukopenia (16.4% vs. 0%), neutropenia (14.8% vs. 1.6%), and nausea (4.9% vs. 0%). No significant difference in grade 3-4 diarrhea and no treatment-related deaths were observed in both groups. CONCLUSIONS: The combination of irinotecan with S-1 was similarly tolerable but significantly prolonged PFS compared to S-1 monotherapy as a second- or third-line treatment in patients with recurrent or metastatic ESCC. Clinical Trial Registration NCT02319187. Registered on December 9, 2014.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Irinotecano/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Inibidores da Topoisomerase I/uso terapêutico , Adulto , Idoso , Intervalo Livre de Doença , Combinação de Medicamentos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia
10.
Eur J Pharmacol ; 854: 232-239, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31004604

RESUMO

Esophageal cancer, especially esophageal squamous cell carcinoma (ESCC) threatens so many lives in China every year. Traditional treatment of ESCC has usually been disappointing. The development of novel therapy is worth investigation. We have previously demonstrated that dihydroartemisinin (DHA) has anticancer effect on esophageal cancer. However, the mechanism has not been completely known. In this present study, we explored the effect of DHA on cancer cell glycolysis, also known as Warburg effect. Pyruvate kinase M2 (PKM2) is a key regulatory factor of glycolysis, and our results showed that it is significantly overexpressed in patients with ESCC and ESCC cell lines. In DHA treatment cells, PKM2 was down-regulated and lactate product and glucose uptake were inhibited. Overexpression of PKM2 by lentiviral transfection abrogated the inhibition effect of DHA. These results suggested that DHA might repress esophageal cancer glycolysis partly by down-regulating PKM2 expression. We believe that DHA might be a prospective agent against esophageal cancer.


Assuntos
Artemisininas/farmacologia , Proteínas de Transporte/genética , Regulação para Baixo/efeitos dos fármacos , Neoplasias Esofágicas/patologia , Glicólise/efeitos dos fármacos , Proteínas de Membrana/genética , Hormônios Tireóideos/genética , Artemisininas/metabolismo , Transporte Biológico/efeitos dos fármacos , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Glucose/metabolismo , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Modelos Moleculares , Domínios Proteicos , Hormônios Tireóideos/química , Hormônios Tireóideos/metabolismo
11.
Per Med ; 16(4): 287-299, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30895868

RESUMO

Aim: To evaluate whether clinical genomic sequencing may benefit Chinese patients with stage IV cancer. Patients & methods: Chinese patients with cancer and their oncologists were provided with genomic sequencing results and corresponding clinical treatment recommendations based on evidence-based medicine, defined as CWES (clinical whole-exome sequencing) analysis. Chinese patients with stage IV cancer who failed the previous treatment upon receiving the CWES reports were included for analyzing the impact of CWES on clinical outcomes in 1-year follow-ups. Results: A total of 88.6% of 953 Chinese patients with cancer had clinically actionable somatic genomic alterations. Eleven patients followed the CWES reports, and 11 patients did not follow the CWES suggestions. The median progression-free survival of two groups were 12 and 4 months, and 45 and 91% of patients failed this round of therapy, respectively. Conclusion: The current study suggested that CWES has the potential to increase clinical benefits for Chinese patients with stage IV cancer.

12.
Oncologist ; 24(8): e702-e708, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30902918

RESUMO

BACKGROUND: Anlotinib is a tyrosine kinase inhibitor inhibiting angiogenesis. This multicenter, randomized phase II trial aimed to investigate the efficacy and safety of anlotinib in comparison with sunitinib as first-line treatment for patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Patients with mRCC from 13 clinical centers were randomly assigned in a 2:1 ratio to receive anlotinib (n = 90) or sunitinib (n = 43). Anlotinib was given orally at a dose of 12 mg once daily (2 weeks on/1 week off), and sunitinib was given orally at 50 mg once daily (4 weeks on/2 weeks off). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS: The median PFS was similar with anlotinib and sunitinib (17.5 vs. 16.6 months, p > .05). The median OS (30.9 vs. 30.5 months, p > .05), ORR (30.3% vs. 27.9%), and 6-week DCR (97.8% vs. 93.0%) were similar in the two groups. Adverse events (AEs) of grade 3 or 4 were significantly less frequent with anlotinib than with sunitinib (28.9% vs. 55.8%, p < .01), especially in terms of thrombocytopenia and neutropenia. AEs occurring at a lower frequency with anlotinib were hand-foot syndrome, eyelid edema, hair depigmentation, skin yellowing, neutropenia, thrombocytopenia, and anemia. The incidence of serious AEs was lower with anlotinib than with sunitinib. CONCLUSION: The clinical efficacy of anlotinib was similar to that of sunitinib as the first-line treatment for mRCC, but with a more favorable safety profile. IMPLICATIONS FOR PRACTICE: This study evaluated the efficacy and safety of anlotinib for the first-line treatment of metastatic renal cell carcinoma. Anlotinib, which was developed independently in China, is a new tyrosine kinase inhibitor inhibiting multiple kinases involved in angiogenesis and tumor proliferation. Results indicated that the efficacy of anlotinib is comparable to and the safety is better than that of sunitinib.

13.
J Clin Oncol ; 36(30): 3031-3039, 2018 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-30199311

RESUMO

PURPOSE: Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone. PATIENTS AND METHODS: TAILOR is an open-label, randomized (1:1), multicenter, phase III trial in patients from China comparing FOLFOX-4 with or without cetuximab in RAS wt (KRAS/NRAS, exons 2 to 4) mCRC. The primary end point of TAILOR was progression-free survival time; secondary end points included overall survival time, overall response rate, and safety and tolerability. RESULTS: In the modified intent-to-treat population of 393 patients with RAS wt mCRC, adding cetuximab to FOLFOX-4 significantly improved the primary end point of progression-free survival time compared with FOLFOX-4 alone (hazard ratio, 0.69; 95% CI, 0.54 to 0.89; P = .004; median, 9.2 v 7.4 months, respectively), as well as the secondary end points of overall survival time (current assessment after 300 events: hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = .02; median, 20.7 v 17.8 months, respectively) and overall response rate (odds ratio, 2.41; 95% CI, 1.61 to 3.61; P < .001; 61.1% v 39.5%, respectively). Treatment was well tolerated, and there were no new or unexpected safety findings. CONCLUSION: The TAILOR study met all of its objectives and relevant clinical end points, confirming cetuximab in combination with FOLFOX as an effective standard-of-care first-line treatment regimen for patients with RAS wt mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Cetuximab/efeitos adversos , China , Neoplasias Colorretais/mortalidade , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Intervalo Livre de Progressão , Adulto Jovem
14.
Future Oncol ; 14(20): 2031-2044, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30117334

RESUMO

AIM: To investigate whether the benefit of combining aflibercept with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) chemotherapy could be confirmed in patients from the Asia-Pacific region (ClinicalTrials.gov: NCT01661270). Patients & methods: Asian patients with oxaliplatin-pretreated metastatic colorectal cancer were randomized to receive aflibercept or placebo, followed by FOLFIRI. The primary end point was progression-free survival. RESULTS: The intention-to-treat population comprised 332 patients. A clinical supply misallocation resulted in 198/332 (60%) patients receiving at least one cycle of misallocated treatment. Nevertheless, the addition of aflibercept to FOLFIRI was shown to improve progression-free survival (hazard ratio: 0.629; 95% CI: 0.488-0.812). Adverse events were in line with expectations. CONCLUSION: The beneficial treatment effect associated with the addition of aflibercept to FOLFIRI was confirmed in Asian patients with pretreated metastatic colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Retratamento , Resultado do Tratamento
15.
Cell Physiol Biochem ; 48(5): 2035-2045, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30099443

RESUMO

BACKGROUND/AIMS: Although photodynamic therapy (PDT) can relieve esophageal obstruction and prolong survival time of patients with esophageal cancer, it can induce nuclear factor-kappa B (NF-κB) activation in many cancers, which plays a negative role in PDT. Dihydroartemisinin (DHA), the most potent artemisinin derivative, can enhance the effect of PDT on esophageal cancer cells. However, the mechanism is still unclear. METHODS: We generated stable cell lines expressing the super-repressor form of the NF-κB inhibitor IκBα and cell lines with lentivirus vector-mediated silencing of the HIF-1α gene. Esophageal xenograft tumors were created by subcutaneous injection of Eca109 cells into BALB/c nude mice. Four treatment groups were analyzed: a control group, photosensitizer alone group, light alone group, and PDT group. NF-κB expression was detected by an electrophoretic mobility shift assay, hypoxia-inducible factor α (HIF-1α) and vascular endothelial growth factor (VEGF) by real-time PCR, NF-κB, HIF-1α, and VEGF protein by western blot, and Ki-67, HIF-1α, VEGF, and NF-κB protein by immunohistochemistry. RESULTS: PDT increased NF-κB activity and the gene expression of HIF-1α and VEGF in vitro and in vivo. In contrast, the DHA groups, particularly the combined DHA and PDT treatment group, abolished the effect. The combined treatment significantly inhibited tumor growth in vitro and in vivo. NF-κB activity and HIF-1α expression were also reduced in the stable IκBα expression group, whereas the former showed no change in HIF-1α-silenced cells. CONCLUSION: DHA might increase the sensitivity of esophageal cancer cells to PDT by inhibiting the NF-κB/HIF-1α/VEGF pathway.


Assuntos
Artemisininas/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Crescimento do Endotélio Vascular/metabolismo , Ácido Aminolevulínico/uso terapêutico , Animais , Artemisininas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidor de NF-kappaB alfa/antagonistas & inibidores , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fatores de Crescimento do Endotélio Vascular/genética
16.
JAMA ; 319(24): 2486-2496, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29946728

RESUMO

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 (n = 278) or placebo (n = 138) 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; P < .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; P < .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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzofuranos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Quinazolinas/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzofuranos/efeitos adversos , China , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Quinazolinas/efeitos adversos , Análise de Sobrevida , Adulto Jovem
17.
Anal Cell Pathol (Amst) ; 2018: 8759745, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29888170

RESUMO

Despite recent advances in chemotherapy and surgical resection, the 5-year survival rate of esophageal cancer still remains at the low level. Therefore, it is very important to discover a new agent to improve the life expectancy of patients with esophageal cancer. Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has recently exhibited promising anticancer activity against various cancer cells. But so far, the specific mechanism remains unclear. We have previously demonstrated that DHA reduced viability of esophageal cancer cells in a dose-dependent manner in vitro and induced cell cycle arrest and apoptosis. Here, we extended our study to further observe the efficacy of DHA on esophageal cancer cells in vivo. In the present study, for the first time, we found that DHA significantly inhibits cell proliferation in xenografted tumor compared with the control. The mechanism was that DHA induced cell apoptosis in both human esophageal cancer cell lines Eca109 and Ec9706 in vivo in a dose-dependent manner. The results suggested that DHA was a promising agent against esophageal cancer in the clinical treatment.


Assuntos
Antineoplásicos/uso terapêutico , Artemisininas/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
18.
Gastric Cancer ; 21(5): 782-791, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29488121

RESUMO

BACKGROUND: We compared efficacy and safety of paclitaxel/capecitabine therapy followed by capecitabine for maintenance (PACX) versus cisplatin/capecitabine therapy (XP) in advanced gastric cancer. METHODS: Multicenter, randomized, phase III trial was conducted in China (December 2009-February 2014). Adults (n = 320) with histologically confirmed, untreated metastatic/unresectable gastric or gastroesophageal junction adenocarcinoma; with ≥ 1 measureable lesions according to Response Evaluation Criteria in Solid Tumors 1.0 criteria; Karnofsky performance score ≥ 70 and life expectancy ≥ 3 months were randomized (1:1) to PACX or XP. PACX group received paclitaxel 80 mg/m2 intravenous on days 1 and 8; capecitabine 1000 mg/m2 orally BD on days 1-14, followed by a 7-day rest interval for 4 cycles, followed by maintenance capecitabine at same dosage/schedule until disease progression, unendurable adverse events or death. XP group received cisplatin intravenous 80 mg/m2 on day 1 and capecitabine at same dosage/schedule as PACX group per cycle for 6 cycles. RESULTS: Median progression-free survival (5.0 versus 5.3 months; hazard ratio [95% CI]: 0.906; 0.706-1.164; p = 0.44) and overall survival (12.5 versus 11.8 months; hazard ratio: 0.878 [0.685-1.125]; p = 0.30) were not significantly different between PACX and XP groups. Objective response rate was significantly higher (43.1 versus 28.8%; p = 0.012) and disease control rate was similar (77.5 versus 72.5%; p = 0.75) in PACX versus XP, respectively. Quality of life was significantly improved in PACX versus XP after three treatment cycles. Many treatment-related adverse events were significantly lesser in PACX than XP. CONCLUSIONS: First-line chemotherapy with PACX is effective with milder toxicities in advanced gastric cancer, but could not replace XP.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Idoso , Capecitabina/administração & dosagem , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Qualidade de Vida , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Resultado do Tratamento
20.
J Clin Oncol ; 36(4): 350-358, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29215955

RESUMO

Purpose Trifluridine/tipiracil (TAS-102) was effective in patients with metastatic colorectal cancer (mCRC) in a phase II Japanese trial. This regional trial evaluated the efficacy and safety of trifluridine/tipiracil in Asian patients with mCRC with or without exposure to biologic therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase III trial was conducted at 30 sites in China, the Republic of Korea, and Thailand. Patients ≥ 18 years old with histologically or cytologically confirmed adenocarcinoma of the colon or rectum and known KRAS status who were refractory or intolerant to two or more prior chemotherapy regimens were enrolled. Eligible patients were randomly assigned (2:1 ratio; minimization method) to receive trifluridine/tipiracil (twice per day orally; 5 days on and 2 days off for 2 weeks, followed by 14 days off per cycle) or placebo. The primary end point was overall survival (intent-to-treat population). Results Between October 16, 2013, and June 15, 2015, 406 patients were randomly assigned to receive trifluridine/tipiracil (n = 271) or placebo (n = 135). Risk of death was significantly lower in the trifluridine/tipiracil arm than in the placebo arm (hazard ratio for death, 0.79; 95% CI, 0.62 to 0.99; log-rank P = .035). Median overall survival was significantly longer in the trifluridine/tipiracil than in the placebo arm (7.8 months [95% CI, 7.1 to 8.8 months] v 7.1 months [95% CI, 5.9 to 8.2 months], respectively), for a median survival follow-up time of 13.8 months (95% CI, 13.1 to 15.3 months) compared with 13.4 months (95% CI, 11.6 to 17.3 months), respectively. The incidence of serious adverse events was similar between the arms (trifluridine/tipiracil, n = 63 [23.2%]; placebo, n = 32 [23.7%]). No treatment-related deaths were reported. Conclusion Trifluridine/tipiracil has a statistically significant survival benefit compared with placebo in Asian patients with mCRC refractory or intolerant to standard chemotherapies, regardless of exposure to biologic therapy. The safety profile is similar to previous reports.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Trifluridina/administração & dosagem , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Ásia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirrolidinas , Fatores de Tempo , Trifluridina/efeitos adversos , Uracila/análogos & derivados , Adulto Jovem
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