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Meta-analysis of FOLFIRINOX-based neoadjuvant therapy for locally advanced pancreatic cancer.
Chen, Z, Lv, Y, Li, H, Diao, R, Zhou, J, Yu, T
Medicine. 2021;(3):e24068
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Abstract
Currently, the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is the standard therapy for metastatic pancreatic cancer. In recent years, FOLFIRINOX-based neoadjuvant therapy for locally advanced pancreatic cancer (LAPC) has been gaining an increasing amount of attention, owing to its ability to reduce disease stage and transform LAPC to borderline resectable or even resectable pancreatic cancer. Accordingly, we aimed to evaluate the efficacy of first-line FOLFIRINOX chemotherapy in patients with LAPC.We searched PubMed, Embase, and Cochrane Library from the time of establishment till January 1, 2020 and included studies focusing on LAPC patients who received FOLFIRINOX as first-line neoadjuvant treatment. The primary outcomes were: resection rate and radical (R0) resection rate while the secondary outcomes were: objective response rate, overall survival, progression-free survival, and rate of grade 3 to 4 adverse events. The meta package for R 3.6.2 was used for heterogeneity and publication bias testing.Twenty-one studies, including 653 patients with LAPC, were selected. After treatment with FOLFIRINOX, the resection rate was 26% (95% confidence interval [CI] = 20%-32%, I2 = 61%) and R0 resection rate was 88% (95% CI = 78%-95%, I2 = 62%). The response rate was 34% (95% CI = 25%-43%, I2 = 56%). The median overall survival and progression-free survival durations ranged from 10.0 to 32.7 months and 3.0 to 25.3 months, respectively. The observed grade 3 to 4 adverse events were neutropenia (20.0 per 100 patients, 95% CI = 14%-27%, I2 = 75%), febrile neutropenia (7.0 per 100 patients, 95% CI = 5%-9%, I2 = 42%), thrombocytopenia (6.0 per 100 patients, 95% CI = 5%-8%, I2 = 27%), nausea/vomiting (7.0 per 100 patients, 95% CI = 7%-12%, I2 = 76%), diarrhea (10.0 per 100 patients, 95% CI = 8%-12%, I2 = 38%), and fatigue (9.0 per 100 patients, 95% CI = 7%-11%, I2 = 43%).FOLFIRINOX-based neoadjuvant chemotherapy has the potential to improve the rates of resection, R0 resection, and median OS in LAPC. Our results require further validation in large, high-quality randomized controlled trials.
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NRF2 activation induced by PML-RARα promotes microRNA 125b-1 expression and confers resistance to chemotherapy in acute promyelocytic leukemia.
Yu, X, Mansouri, A, Liu, Z, Gao, R, Li, K, Chen, C, Huang, Y, Chen, Z, Chen, S, Lu, Y, et al
Clinical and translational medicine. 2021;(5):e418
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Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)-Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study.
Cho, BC, Obermannova, R, Bearz, A, McKeage, M, Kim, DW, Batra, U, Borra, G, Orlov, S, Kim, SW, Geater, SL, et al
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019;(7):1255-1265
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Abstract
INTRODUCTION In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted. METHODS Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1. RESULTS In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%). CONCLUSION Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.
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A Pilot Study of Amino Acids in Unresectable Non-Small-Cell Lung Cancer Patients During Chemotherapy: A Randomized Serial N-of-1 Trials Design.
Liu, L, Zhang, Y, Wei, J, Chen, Z, Yu, J
Nutrition and cancer. 2019;(3):399-408
Abstract
The aim of this study was to evaluate the effect of amino acids (AAs) on immune function and inflammation level in patients with NSCLC receiving chemotherapy. We conducted a series of randomized, multiple-crossover, double-blind, placebo-controlled N-of-1 trials comparing AAs with isocaloric glucose in unresectable NSCLC patients and combined the individual results using Bayesian statistical modeling. 25 patients completed two cycles of chemotherapy. The baseline total blood albumin (ALB) level in all patients was 28 ± 3.3 g/l, and the mean total ALB level in patients receiving AAs supplementation and isocaloric glucose was 29.2 ± 2.2 and 28.1 ± 3.7 g/l, respectively (P = 0.028). Patients' baseline C-reactive protein (CRP) level was 4 ± 1.2 mg/l, the mean total CRP level in patients receiving AAs supplementation and isocaloric glucose was 11 ± 2.8 and 13 ± 3.2 mg/l, respectively (P = 0.028). The baseline total blood CD4+ T cells level was 36 ± 7.8%. The percentage of CD4+ T cells in patients receiving AAs supplementation and isocaloric glucose was 42 ± 6.4 and 33.7 ± 17.3, respectively (P = 0.034). Our preliminary results indicated that AAs improve immune status and suppress inflammation in unresectable NSCLC patients receiving chemotherapy.
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Maintenance of Sorafenib following combined therapy of three-dimensional conformal radiation therapy/intensity-modulated radiation therapy and transcatheter arterial chemoembolization in patients with locally advanced hepatocellular carcinoma: a phase I/II study.
Zhao, JD, Liu, J, Ren, ZG, Gu, K, Zhou, ZH, Li, WT, Chen, Z, Xu, ZY, Liu, LM, Jiang, GL
Radiation oncology (London, England). 2010;:12
Abstract
BACKGROUND Three-dimensional conformal radiation therapy (3DCRT)/intensity-modulated radiation therapy (IMRT) combined with or without transcatheter arterial chemoembolization (TACE) for locally advanced hepatocellular carcinoma (HCC) has shown favorable outcomes in local control and survival of locally advanced HCC. However, intra-hepatic spreading and metastasis are still the predominant treatment failure patterns. Sorafenib is a multikinase inhibitor with effects against tumor proliferation and angiogenesis. Maintenance Sorafenib would probably prevent or delay the intrahepatic and extrahepatic spread of HCC after radiotherapy, which provides the rationale for the combination of these treatment modalities. METHODS AND DESIGN Patients with solitary lesion (bigger than 5 cm in diameter) histologically or cytologically confirmed HCC receive TACE (1-3 cycles) plus 3DCRT/IMRT 4-6 weeks later. Maintenance Sorafenib will be administered only for the patients with non-progression disease 4 to 6 weeks after the completion of radiotherapy. The dose will be 400 mg, p.o., twice a day. Sorafenib will be continuously given for 12 months unless intolerable toxicities and/or tumor progression. If no more than 3 patients discontinue Sorafenib treatment who experience dose-limiting toxicity after necessary dose modification and delay and/or radiation-induced liver disease in the first 15 enrolled patients, the study will recruit second fifteen patients for further evaluating safety and efficacy of treatment. Hypothesis of the current study is that Sorafenib as a maintenance therapy after combined therapy of 3DCRT/IMRT and TACE is safe and superior to radiotherapy combined with TACE alone in terms of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) in comparison to historical data. DISCUSSION A recent meta-analysis showed TACE in combination with radiotherapy, improved the survival and the tumor response of patients, and was thus more therapeutically beneficial. In this study, local therapy for HCC is the combination of TACE and radiotherapy. Radiation exposure as a kind of stress might induce the compensatory activations of multiple intracellular signaling pathway mediators, such as PI3K, MAPK, JNK and NF-kB. Vascular endothelial growth factor (VEGF) was identified as one factor that was increased in a time- and dose-dependent manner after sublethal irradiation of HCC cells in vitro, translating to enhanced intratumor angiogenesis in vivo. Therefore, Sorafenib-mediated blockade of the Raf/MAPK and VEGFR pathways might enhance the efficacy of radiation, when Sorafenib is followed sequentially as a maintenance modality. (ClinicalTrials.gov number, NCT00999843.).
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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.
Cheng, AL, Kang, YK, Chen, Z, Tsao, CJ, Qin, S, Kim, JS, Luo, R, Feng, J, Ye, S, Yang, TS, et al
The Lancet. Oncology. 2009;(1):25-34
Abstract
BACKGROUND Most 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. METHODS Between 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. FINDINGS 271 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. INTERPRETATION Sorafenib 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.
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Mutant transcription factors and tyrosine kinases as therapeutic targets for leukemias: from acute promyelocytic leukemia to chronic myeloid leukemia and beyond.
Hu, J, Zhou, GB, Wang, ZY, Chen, SJ, Chen, Z
Advances in cancer research. 2007;:191-220
Abstract
Mutations in transcription factors (TFs) and protein tyrosine kinases (PTKs), which result in inhibition of differentiation/apoptosis or enhanced proliferative/survival advantage of hematopoietic stem/progenitor cells, are two classes of the most frequently detected genetic abnormalities in leukemias. The critical roles for mutant TFs and/or PTKs to play in leukemogenesis, and the absence of mutant TFs/PTKs in normal hematopoietic cells, suggest that the two types of aberrant molecules may serve as ideal therapeutic targets. The great success of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in treating acute promyelocytic leukemia through modulation of the causative PML-RARalpha oncoprotein represents the first two paradigms of mutant TFs-targeting therapeutic strategies for leukemia. More recently, tyrosine kinase inhibitor STI-571/Imatinib mesylate/Gleevec in the treatment of Breakpoint Cluster Region-Abelson (BCR-ABL) positive leukemia elicits paradigm of mutant PTKs as ideal antileukemia targets. Thus to further improve clinical outcome of leukemia patients, elucidation of pathogenesis of leukemia, screening for oncoprotein-targeting small molecules, as well as rationally designed combination of drugs with potential synergy are of importance.
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Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy.
Zhou, GB, Zhang, J, Wang, ZY, Chen, SJ, Chen, Z
Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2007;(1482):959-71
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Abstract
To turn a disease from highly fatal to highly curable is extremely difficult, especially when the disease is a type of cancer. However, we can gain some insight into how this can be done by looking back over the 50-year history of taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute myeloid leukaemia characterized by an accumulation of abnormal promyelocytes in bone marrow, a severe bleeding tendency and the presence of the chromosomal translocation t(15;17) or variants. APL was considered the most fatal type of acute leukaemia five decades ago and the treatment of APL was a nightmare for physicians. Great efforts have been made by scientists worldwide to conquer this disease. The first use of chemotherapy (CT) was unsuccessful due to lack of supportive care and cytotoxic-agent-related exacerbated coagulopathy. The first breakthrough came from the use of anthracyclines which improved the complete remission (CR) rate, though the 5-year overall survival could only be attained in a small proportion of patients. A rational and intriguing hypothesis, to induce differentiation of APL cells rather than killing them, was raised in the 1970s. Laudably, the use of all-trans retinoic acid (ATRA) in treating APL resulted in terminal differentiation of APL cells and a 90-95% CR rate of patients, turning differentiation therapy in cancer treatment from hypothesis to practice. The combination of ATRA with CT further improved the 5-year overall survival. When arsenic trioxide (ATO) was used to treat relapsed APL not only the patients but also the ancient drug were revived. ATO exerts dose-dependent dual effects on APL cells: at low concentration, ATO induces partial differentiation, while at relatively high concentration, it triggers apoptosis. Of note, both ATRA and ATO trigger catabolism of the PML-RARalpha fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARalpha (retinoic acid receptor alpha) or promyelocytic leukaemia (PML) moieties, respectively. Hence, in treating APL both ATRA and ATO represent paradigms for molecularly targeted therapy. At molecular level, ATRA and ATO synergistically modulate multiple downstream pathways/cascades. Strikingly, a clearance of PML-RARalpha transcript in an earlier and more thorough manner, and a higher quality remission and survival in newly diagnosed APL are achieved when ATRA is combined with ATO, as compared to either monotherapy, making APL a curable disease. Thus, the story of APL can serve as a model for the development of curative approaches for disease; it suggests that molecularly synergistic targeted therapies are powerful tools in cancer, and dissection of disease pathogenesis or anatomy of the cancer genome is critical in developing molecular target-based therapies.
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[Experimental study of low dose arsenic trioxide in treatment of patients with acute promyelocytic leukemia].
Jia, PM, Zhu, Q, Yu, Y, Chen, GQ, Chen, SJ, Chen, Z, Wang, ZY, Tong, JH
Ai zheng = Aizheng = Chinese journal of cancer. 2002;(4):337-40
Abstract
BACKGROUND & OBJECTIVE Low dose arsenic trioxide(As2O3) is one of the effective treatments for patients with acute promyelocytic leukemia (APL). As2O3 could induce complete remission in de novo APL patients as well as in relapsed APL patients who have been resistant to all-trans retinoic acid (ATRA). However, the underlying mechanisms of As2O3-induced remission remain obscure. Therefore, we designed this study to explore the possible mechanism of low dose As2O3 in treatment of the patients with APL. METHODS The APL cell line NB4 and primary malignant cells isolated from APL patients were used as in vitro models. Cell differentiation was determined by cell morphology, NBT reduction test and cytometry assay of cell differentiation antigens. The change of PML-RAR alpha fusion protein was analyzed by immunofluorescence and Western blot. RESULTS The 0.25 mumol/L As2O3 combined with cyclic adenosine monophosphate(cAMP) analogue, 8-(4-chlorophenylthio) adenosine 3', 5'-cyclic monophosphate (8-CPT-cAMP), had induced differentiation in NB4 cell line and primary cells. It was also found that this effect could be attenuated by H89, a specific PKA inhibitor. Moreover, 8-CPT-cAMP was able to facilitate the As2O3-mediated degradation of PML-RAR alpha. CONCLUSIONS The 8-CPT-cAMP could enhance As2O3-induced differentiation in APL cells.
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Expanding the use of arsenic trioxide: leukemias and beyond.
Chen, Z, Chen, GQ, Shen, ZX, Sun, GL, Tong, JH, Wang, ZY, Chen, SJ
Seminars in hematology. 2002;(2 Suppl 1):22-6
Abstract
Arsenic has a long history of use in Chinese and Western medicine but fell out of use in the mid-20th century because of the unacceptable side effects that occurred at the doses that were thought to be necessary. The re-emergence of arsenic trioxide (ATO) in clinical use is due largely to purification of this compound from traditional mixtures, and the definition of effective, low-dose regimens for the treatment of acute promyelocytic leukemia (APL). ATO was first purified and used in controlled studies in patients with APL in China in the 1970s. Studies have subsequently also been performed in the United States. Complete response (CR) rates reported in patients with relapsed or refractory APL have varied from 52% to 92%, with similar rates reported in patients with newly diagnosed disease. The mechanism of action of ATO suggests it may be active against other malignancies, and ATO has shown some activity in patients with accelerated phase chronic myelogenous leukemia (CML) and multiple myeloma (MM). Clinical trials are ongoing and planned to define the optimal use of this compound in hematologic malignancies. Preliminary results from studies in patients with primary hepatocellular and gallbladder tumors indicate that ATO may also prove active against some solid tumors.