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A phase I study of nintedanib combined with cisplatin/gemcitabine as first-line therapy for advanced squamous non-small cell lung cancer (LUME-Lung 3).
Forster, M, Hackshaw, A, De Pas, T, Cobo, M, Garrido, P, Summers, Y, Dingemans, AC, Flynn, M, Schnell, D, von Wangenheim, U, et al
Lung cancer (Amsterdam, Netherlands). 2018;:27-33
Abstract
BACKGROUND There are limited treatment options for squamous non-small cell lung cancer (sqNSCLC) and prognosis remains poor. The safety and pharmacokinetics (PK) of nintedanib, a triple angiokinase inhibitor, plus cisplatin/gemcitabine as first-line treatment for advanced sqNSCLC patients, were evaluated. MATERIALS AND METHODS A phase I, dose-escalation study administering drugs in a 21-day cycle: cisplatin (75 mg/m2, Day 1), gemcitabine (1250 mg/m2, Days 1 and 8) and nintedanib (Days 2-7, 9-21) were given for 4-6 cycles, followed by monotherapy until disease progression or adverse events (AEs). Two nintedanib doses were tested, 150 mg twice daily (bid) and 200 mg bid, to determine maximum tolerated dose (MTD) based on occurrence of dose-limiting toxicities (DLTs) during Cycle 1. DLTs were primarily defined as drug-related non-hematologic (Grade ≥3) or hematologic (Grade 4) AEs. RESULTS Sixteen patients were treated with nintedanib; n = 4 for 150 mg bid, n = 12 for 200 mg bid. No DLTs were observed in Cycle 1; therefore, the MTD was 200 mg bid. In subsequent cycles, two patients had DLTs: renal failure and reduced blood magnesium levels. The most common AEs were gastrointestinal. Three patients discontinued last study medication due to AEs and one had a nintedanib dose reduction. No relevant PK interactions were observed. Five patients had partial responses (31.3%) and eight had stable disease (50.0%); disease control rate was 81.3%. There were three long-term survivors (17-35 months). CONCLUSIONS The safety profile of nintedanib 200 mg bid plus cisplatin/gemcitabine was manageable, with AEs consistent with previous observations. PK data demonstrated no interaction, and preliminary antitumor activity was observed.
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BK channels blockage inhibits hypoxia-induced migration and chemoresistance to cisplatin in human glioblastoma cells.
Rosa, P, Catacuzzeno, L, Sforna, L, Mangino, G, Carlomagno, S, Mincione, G, Petrozza, V, Ragona, G, Franciolini, F, Calogero, A
Journal of cellular physiology. 2018;(9):6866-6877
Abstract
Glioblastoma (GBM) cells express large-conductance, calcium-activated potassium (BK) channels, whose activity is important for several critical aspects of the tumor, such as migration/invasion and cell death. GBMs are also characterized by a heavy hypoxic microenvironment that exacerbates tumor aggressiveness. Since hypoxia modulates the activity of BK channels in many tissues, we hypothesized that a hypoxia-induced modulation of these channels may contribute to the hypoxia-induced GBM aggressiveness. In U87-MG cells, hypoxia induced a functional upregulation of BK channel activity, without interfering with their plasma membrane expression. Wound healing and transwell migration assays showed that hypoxia increased the migratory ability of U87-MG cells, an effect that could be prevented by BK channel inhibition. Toxicological experiments showed that hypoxia was able to induce chemoresistance to cisplatin in U87-MG cells and that the inhibition of BK channels prevented the hypoxia-induced chemoresistance. Clonogenic assays showed that BK channels are also used to increase the clonogenic ability of U87-MG GBM cells in presence, but not in absence, of cisplatin. BK channels were also found to be essential for the hypoxia-induced de-differentiation of GBM cells. Finally, using immunohistochemical analysis, we highlighted the presence of BK channels in hypoxic areas of human GBM tissues, suggesting that our findings may have physiopathological relevance in vivo. In conclusion, our data show that BK channels promote several aspects of the aggressive potential of GBM cells induced by hypoxia, such as migration and chemoresistance to cisplatin, suggesting it as a potential therapeutic target in the treatment of GBM.
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Effects of Reduction in Tumor Burden on Survival in Epithelioid Malignant Pleural Mesothelioma.
Mansfield, AS, Peikert, T, Vogelzang, NJ, Symanowski, JT
Mayo Clinic proceedings. 2018;(8):1026-1033
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OBJECTIVE To understand the relationship between response and survival in malignant pleural mesothelioma (MPM). PATIENTS AND METHODS The original clinical trial was conducted from April 1999 through March 2001. Patients with epithelioid MPM (n=305) were categorized using modified pleural Response Evaluation Criteria in Solid Tumors by whether they responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were estimated and hazard ratios for responders and nonresponders were estimated and compared using the log-rank test. Multivariable Cox proportional hazards models were used to adjust for baseline prognostic factors. RESULTS Patients who responded to frontline therapy had a significantly longer OS (hazard ratio, 0.34; 95% CI, 0.24-0.49; median, 20.6 months; 95% CI, 15.3 months to not reached) than did those who did not respond (median, 9.4 months; 95% CI, 8.1-11.0 months) (P<.001). Similarly, responders had a significantly longer PFS (hazard ratio, 0.50; 95% CI, 0.39-0.64; median, 7.8 months; 95% CI, 6.5-8.5 months) than did nonresponders (median, 3.7 months; 95% CI, 2.9-4.3 months) (P<.001). These results were confirmed when adjusting for baseline prognostic factors. We also observed a survival benefit associated with disease stabilization in MPM. CONCLUSION Our findings indicate that reduction in tumor burden or disease stabilization determined using modified pleural Response Evaluation Criteria in Solid Tumors is strongly associated with OS and PFS in epithelioid MPM.
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Which neoadjuvant chemotherapy regimen should be recommended for patients with advanced nasopharyngeal carcinoma?: A network meta-analysis.
Yuan, C, Xu, XH, Luo, SW, Wang, L, Sun, M, Ni, LH, Xu, L, Wang, XL, Zeng, G
Medicine. 2018;(34):e11978
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BACKGROUND The clinical application has widespread disagreement on the different regimens of neoadjuvant chemotherapy (NCT) in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). We conducted a network meta-analysis (NMA) to evaluate the efficacy of the different NCT regimens in the treatment of NPC. METHODS A systematic literature search was performed using PubMed, Embase, and Cochran Library. Totally, 31 randomized controlled trials (RCTs) (n = 4062) met study selection criteria and were incorporated in this NMA study. RESULTS Our study showed that certain NCT regimens improved the prognosis of patients, and found out the relative best solution for each endpoint, such as paclitaxel, carboplatin, and gemcitabine for 1-year overall survival (OS) rate, cisplatin, calcium folinate, and 5-fluorouracil for 2-year OS rate, vinorelbine and cisplatin (NP) for 3-year OS rate, cyclophosphamide, cisplatin, and 5-fluorouracil for 5-year OS rate, NP for complete remission rate, cisplatin and gemcitabine for overall remission rate of the primary tumor. In addition, for certain grade 3 and above toxicity, the results of the NMA reflected certain NCT regimens can reduce toxicity of chemoradiotherapy (CRT) to a minimum, such as NP for anemia, mucositis, and thrombocytopenia, paclitaxel, epirubicin, and cisplatin for neutropenia and skin toxicity. CONCLUSION Our NMA showed that certain cisplatin-based NCT regimens improved the prognosis of patients with NPC and reduced the toxicity of CRT. However, in view of survival rate and response rate, the best NCT regimen is not entirely consistent. Therefore, which NCT regimen will benefit most patients will need further explored.
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Randomized Phase II Study Comparing Mannitol with Furosemide for the Prevention of Renal Toxicity Induced by Cisplatin-based Chemotherapy with Short-term Low-volume Hydration in Advanced Non-small Cell Lung Cancer: The OLCSG1406 Study Protocol.
Makimoto, G, Ichihara, E, Hotta, K, Ninomiya, K, Oze, I, Minami, D, Ninomiya, T, Kubo, T, Ohashi, K, Tabata, M, et al
Acta medica Okayama. 2018;(3):319-323
Abstract
Although cisplatin-based chemotherapy shows a survival advantage compared to carboplatin for treating advanced non-small cell lung cancer, high-volume hydration and a long infusion time are necessary to avoid nephrotoxicity, and cisplatin-based chemotherapy has been difficult to administer in outpatient settings. A low-volume hydration method using mannitol or furosemide as forced diuresis was recently introduced, but there are no clear conclusions regarding which agent should be used. We describe our ongoing randomized phase II trial (the OLCSG1406 Study) evaluating the efficacy of forced diuresis. This study will clarify whether mannitol or furosemide is more suitable in cisplatin-based chemotherapy with low-volume hydration.
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Renal toxicity and chemotherapy in children with cancer.
Ruggiero, A, Ferrara, P, Attinà, G, Rizzo, D, Riccardi, R
British journal of clinical pharmacology. 2017;(12):2605-2614
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The clinical use of antineoplastic drugs can be limited by different drug-induced toxicities. Of these, renal dysfunction may be one of the most troublesome in that it can be cumulative and in general is only partially reversible with the discontinuation of the treatment. Renal toxicity may be manifested as a reduction of the glomerular filtration rate, electrolyte imbalances, or acute renal failure. Careful assessment of renal function has to be performed taking into account that the impairment of renal function is initially silent and only later may be clinically dramatic. When clinically indicated, the reduction or, in cases of severe nephrotoxicity, the suspension of chemotherapy should be considered to avoid the progressive deterioration of the compromised glomerular and/or tubular function.
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Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer.
Kritsch, D, Hoffmann, F, Steinbach, D, Jansen, L, Mary Photini, S, Gajda, M, Mosig, AS, Sonnemann, J, Peters, S, Melnikova, M, et al
International journal of cancer. 2017;(8):1600-1614
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Aim was to identify methylated genes with functional involvement in cisplatin-resistance development of epithelial ovarian cancer (EOC). Genome-wide analyses of hypermethylated CpG-islands in resistant cell lines in combination with qRT-PCR analyses were used to identify epigenetically silenced genes. EOC-Type-II tumors were analyzed for gene methylation and expression and TCGA data were interrogated in-silico. Experiments revealed 37 commonly hypermethylated genes in resistant cells of which Tribbles 2 (TRIB2) showed the most pronounced downregulation on mRNA level and was characterized further. TRIB2 showed a reactivation after 5'-Aza-Cytidine treatment in resistant cells but a cisplatin-dependent, prominent upregulation on mRNA level in sensitive cells, only. Re-expression in resistant A2780 cells increased the sensitivity to cisplatin and other DNA-damaging agents, but not taxanes. Contrary, knockdown of TRIB2 increased resistance to cisplatin in sensitive cells. TRIB2 was involved in the induction of a cisplatin-dependent cell cycle arrest and apoptosis by influencing p21 and survivin expression. An increased Pt-DNA-adduct formation in TRIB2 re-expressing cells did not translate in higher levels of dsDNA damage (yH2AX-foci). Thus, TRIB2 is potentially involved in the signal transduction from nucleotide excision repair of intrastrand cross links. Importantly, patient stratification of two homogenous cohorts of EOC-Type-II patients from Jena (n = 38) and the TCGA (n = 149) by TRIB2 mRNA expression consistently revealed a significantly decreased PFS for patients with low TRIB2 levels (log-rank p < 0.05). Tumors from resistant patients expressed the lowest levels of TRIB2. Downregulation of TRIB2 contributes to platin-resistance and TRIB2 expression should be validated as prognostic and predictive marker for EOC.
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The efficacy of the Kampo medicine rikkunshito for chemotherapy-induced anorexia (RICH trial): study protocol for a randomized controlled trial.
Inoue, T, Takagi, H, Owada, Y, Watanabe, Y, Yamaura, T, Fukuhara, M, Muto, S, Okabe, N, Matsumura, Y, Hasegawa, T, et al
Trials. 2017;(1):485
Abstract
BACKGROUND Cisplatin is a key drug in lung cancer therapy. However, cisplatin is also well known to induce gastrointestinal disorders, such as chemotherapy-induced nausea and vomiting, anorexia, and weight loss. These symptoms sometimes affect patients' quality of life and make continuation of chemotherapy difficult. Anorexia is a cause of concern for patients with cancer because a persistent loss of appetite progresses to cancer cachexia. Although evidence-based management for chemotherapy has recently been established, there is room for improvement. METHODS/DESIGN This placebo-controlled, double-blind, randomized trial will aim to determine the efficacy of the traditional Japanese Kampo medicine rikkunshito (TJ-43) for preventing anorexia caused by cisplatin-including chemotherapy in patients with lung cancer. Patients with lung cancer who plan to receive cisplatin-including chemotherapy will be recruited. Patients who provide written consent will be randomly allocated to receive either TJ-43 (arm A) or placebo (arm B) for one course of chemotherapy (21 or 28 consecutive days). Investigators and patients will be masked to the treatment assignment throughout the trial. The primary endpoint will be evaluated as the change in dietary intake from day 0 (the day before the start of chemotherapy) to day 7 of cisplatin-including chemotherapy. The two arms of the trial will comprise 30 patients each. From November 2014, a total of 60 patients will be recruited, and recruitment for the study is planned to be complete by October 2017. DISCUSSION This trial is designed to examine the efficacy of rikkunshito (TJ-43) for reducing anorexia and maintaining food intake caused by cisplatin-including chemotherapy in patients with lung cancer. TRIAL REGISTRATION Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC CTI), trial registration: JAPIC CTI-142747 . Registered on 15 December 2014; the RICH trial.
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Proliferation inhibition of cisplatin-resistant ovarian cancer cells using drugs screened by integrating a metabolic model and transcriptomic data.
Motamedian, E, Taheri, E, Bagheri, F
Cell proliferation. 2017;(6)
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OBJECTIVES If screening to find effective drugs is possible, the inhibition of proliferation using existing drugs can be a practical strategy to control the drug resistance of cancer. Development of a system-oriented strategy to find effective drugs was the main aim of this research. MATERIALS AND METHODS An algorithm (transcriptional regulated flux balance analysis [TRFBA]) integrating a generic human metabolic model with transcriptomic data was used to identify genes affecting the growth of drug-resistant cancer cells. Drugs that inhibit activation of the target genes were found and their effect on the proliferation was experimentally evaluated. RESULTS Experimental assessments demonstrated that TRFBA improves the prediction of cancer cell growth in comparison with previous algorithms. The algorithm was then used to propose the system-oriented strategy to search drugs effective in limiting the growth rate of the cisplatin-resistant A2780 epithelial ovarian cancer cell. Experimental evaluations resulted in the selection of azathioprine, terbinafine, hydralazine and sodium valproate that appropriately inhibit the proliferation of resistant cancer cells while minimally affecting normal cells. Furthermore, experimental data indicate that the selected drugs are synergistic and can be used in combination therapies. CONCLUSIONS The proposed strategy was successful to identify drugs effective on the viability of resistant cancer cells. This strategy can enhance the potency of treatments for drug-resistant cancer cells and provides the possibility of using existing drugs.
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Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.
Dósa, E, Heltai, K, Radovits, T, Molnár, G, Kapocsi, J, Merkely, B, Fu, R, Doolittle, ND, Tóth, GB, Urdang, Z, et al
Fluids and barriers of the CNS. 2017;(1):26
Abstract
BACKGROUND Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. METHODS Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200 mg/kg NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 ± 6.8 years) received NAC IV (N = 13) or IA (N = 15). RESULTS The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p < 0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3 mM concentration which seemed to be nephroprotective in previous preclinical studies. CONCLUSIONS In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450 mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: https://eudract.ema.europa.eu . Unique identifier: 2011-000887-92.