Randomized phase II study of TX followed by XELOX versus the reverse sequence for chemo-naive patients with metastatic gastric cancer.

This research found that the clinical outcomes (PFS, ORR, OS) of the non-platinum-based doublet regimen (docetaxel capecitabine combination) were similar to those of the platinum-based (oxaliplatin capecitabine combination) when used as first line therapy for MGC patients. Background: Docetaxel, platinum and fluorouracil are the three most important drugs in the treatment of MGC. This study was to compare clinical outcomes of the docetaxel capecitabine combination and the oxaliplatin capecitabine combination as first-line therapy in MGC patients. Methods: In this phase II trial, MGC patients were randomly assigned and treated with either TX (capecitabine 1000 mg/m2/twice daily/1-14 days and docetaxel 60/75 mg/m2 on the 1st day) (because of toxicity, the dose of docetaxel was reduced to 60 mg/m2) or XELOX (capecitabine the same dose with TX and oxaliplatin 130 mg/m2 on the 1st day) as first-line therapy. After progression, patients were crossover to the other group as second-line treatment. Results: Total 134 MGC patients were randomized (69 in TX, 65 in XELOX). There was no significant difference between the PFS of the two groups (TX vs XELOX, 4.6 months vs 5.1 months, p=0.359), and the SFS (9.3 months vs 7.5 months, p=0.705), OS (13.1 months vs 9.6 months, p=0.261), and ORR (46.4% vs 46.2%) were also similar. Among patients with ascites, the TX group had significantly longer PFS and OS than the XELOX group. A total of 85 patients (48 in TX, 37 in XELOX) received second-line treatment, with overall survival of second-line chemotherapy (OS2) of 8.0 m and 5.3 m (p=0.046), respectively. Grade 3 to 4 treatment-related adverse events of first line treatment occurred more in TX group than that in XELOX group(60.6% vs 55.4%). Conclusion: TX regimen is an alternative choice of first-line treatment for MGC patients. We still need to explore the large number of cohort to confirm this results.

The Challenge to Deliver Oxaliplatin (l-OHP) to Solid Tumors: Development of Liposomal l-OHP Formulations.

Oxaliplatin (l-OHP) is a third-generation platinum (Pt) agent approved for the treatment of patients with advanced colorectal cancer. Despite the fact that l-OHP has shown clinical therapeutic efficacy and better tolerability compared with other Pt agents, the use of l-OHP has been limited to clinical settings because of dose-limiting side effects such as cumulative neurotoxicity and acute dysesthesias, which can be severe. In preclinical and clinical studies, our group and several others have attempted the delivery of l-OHP to solid tumors via encapsulation in PEGylated liposomes. Herein, we review these attempts.

PEA-OXA Mitigates Oxaliplatin-Induced Painful Neuropathy through NF-κB/Nrf-2 Axis.

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0-4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15-20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats; this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients.

Effect of intact oxaliplatin in plasma on a cold allodynia after multiple administrations in colorectal cancer model rats.

BACKGROUND: Oxaliplatin (L-OHP)-induced acute neuropathy is a major factor for influencing treatment compliance in patients receiving chemotherapy for colorectal cancer (CRC). Acute neuropathy is caused by the intact L-OHP affecting the function of transient receptor potential vanilloid 1 (TRPV1) channel. In this study, the effectiveness of the detection of the intact L-OHP and the association with the severity of L-OHP-induced acute neuropathy were investigated using a rat model of CRC. METHODS: Wistar male rats were prepared as models of CRC by using 1,2-dimethylhydrazine (DMH) and dextran sulfate. Intravenous L-OHP was administered (weekly) to CRC rats for 4 weeks, at doses of 3, 5, or 8 mg/kg, respectively. Pharmacokinetic and tumor distribution profiles of animals with intact L-OHP were observed on days 1 and 22. Cold allodynia was determined as a read-out of acute neuropathy using the acetone test over the 4 weeks. RESULTS: The mean AUC0-∞ values for the intact L-OHP were increased dose-dependently at the three doses. The accumulation of intact L-OHP was confirmed following an increase in L-OHP concentration on day 22. Acute neuropathy was observed from day 2 at all doses and the withdrawal response correlated with AUC (R2 =0.9816). CONCLUSIONS: To prevent the onset of L-OHP-induced acute neuropathy, the timely detection of the intact L-OHP is important. These findings could be a basis of the establishment a pharmacokinetic and toxicodynamic model to aid the planning of therapy cycle completion for CRC.

Assessment of Oxaliplatin-induced Chronic Neuropathy and Anticancer Efficacy Through Pharmacokinetic and Toxicodynamic Evaluation of a Rat Model of Colorectal Cancer.

BACKGROUND/AIM: Oxaliplatin-induced chronic neuropathy is a prominent factor for dose reduction and not completing all cycles of chemotherapy for patients with colorectal cancer (CRC). The aim of the study was to investigate the pharmacokinetics and toxicodynamics of oxaliplatin-induced chronic neuropathy in CRC rats to ensure effective management. MATERIALS AND METHODS: A rat model of CRC was developed using 1,2-Dimethylhydrazine and dextran sulfate. Oxaliplatin (L-OHP) was administered intravenously to CRC rats every week. The pharmacokinetic profiles and tumor distribution of L-OHP and chronic neuropathies were investigated for over four weeks. RESULTS: The mean values of the area under the concentration-time curve for L-OHP showed a dose-dependent increase. Chronic neuropathy occurred from Day 14 in the 8 mg/kg group and Day 19 in the 3 and 5 mg/kg groups. CONCLUSION: These results provide preliminary information for the development of a pharmacokinetic and toxicodynamic model of L-OHP for CRC therapy cycles.

Changes in upper extremity function, ADL, and HRQoL in colorectal cancer patients after the first chemotherapy cycle with oxaliplatin: a prospective single-center observational study.

PURPOSE: Oxaliplatin, an important chemotherapeutic agent in colorectal cancer, causes chemotherapy-induced peripheral neuropathy (CIPN), for which prophylactic or therapeutic interventions are lacking. We aimed to investigate changes in upper extremities, activities of daily living (ADL), and health-related quality of life (HRQoL) parameters after the first chemotherapy cycle. METHODS: Thirty-eight colorectal cancer patients scheduled to receive the leucovorin, 5'-fluorouracil, oxaliplatin (FOLFOX) therapy or the capecitabine, oxaliplatin (CAPOX) therapy, participated. Patients underwent objective assessment of sensory function, muscular strength, and manual dexterity and answered the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the Disabilities of the Arm, Shoulder, and Hand-Disability/Symptom (DASH-DS) questionnaires for subjective assessment. The CIPN was assessed at baseline and prior to the second drug cycle. RESULTS: Light touch sensation in both hands worsened significantly after the first drug cycle, though no significant changes were observed in muscular strength and manual dexterity. The QLQ-C30 analysis showed that Physical Functioning, Role Functioning, Nausea and Vomiting, and Dyspnea were significantly worse, whereas Emotional Functioning was improved. The DASH-DS analysis revealed significant worsening of dysfunction and subjective symptoms. CONCLUSIONS: Our results suggest that light touch sensation may worsen even in the absence of multiple chemotherapy cycles. Even if arm and hand function (muscular strength and manual dexterity) is apparently intact, patients may experience dysfunction and decreased HRQoL. For preserving or improving patients' ADL and HRQoL, it is imperative to provide support at chemotherapy initiation.

Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules.

Many therapeutic strategies have been applied in efforts to conquer the development and/or progression of cancer. The combination of chemotherapy and an RNAi-based approach has proven to be an efficient anticancer therapy. However, the feasibility of such a therapeutic strategy has been substantially restricted either by the failure to achieve the efficient delivery of RNAi molecules to tumor tissue or by the immunostimulatory response triggered by RNAi molecules. In this study, therefore, we intended to investigate the efficacy of using liposomal oxaliplatin (liposomal l-OHP) to guarantee the efficient delivery of RNAi molecules, namely shRNA against thymidylate synthase (TS shRNA) complexed with cationic liposome (TS shRNA-lipoplex), to solid tumors, and to suppress the immunostimulatory effect of RNAi molecules, TS shRNA, following intravenous administration. Herein, we describe how liposomal l-OHP enhanced the intra-tumor accumulation of TS shRNA-lipoplex and significantly reduced the immunostimulatory response triggered by TS shRNA. Consequently, such enhanced accumulation of TS shRNA-lipoplex along with the cytotoxic effect of liposomal l-OHP led to a remarkable tumor growth suppression (compared to mono-therapy) following systemic administration. Our results, therefore, may have important implications for the provision of a safer and more applicable combination therapy of RNAi molecules and anti-cancer agents that can produce a more reliable anti-tumor effect.

Oxaliplatin treatment changes the function of sensory nerves in rats.

Oxaliplatin (L-OHP) is a platinum-based chemotherapy drug, used in standard treatment of colorectal cancer. L-OHP frequently causes acute peripheral neuropathies. These adverse effects limit cancer therapy with L-OHP. The present study was designed to reveal the changes in sensory nerve function in L-OHP-injected rats. Mechanical static allodynia, dynamic allodynia, and cold allodynia were evaluated using the von Frey test, brush test, and acetone test, respectively. Sensory nerve fiber responsiveness was measured using a Neurometer. The fifth lumbar ventral root was sectioned to record multi-unit efferent discharges. Single intraperitoneal administration of L-OHP induced mechanical static allodynia, dynamic allodynia, and cold allodynia in Wistar/ST rats. The thresholds for paw withdrawal induced by 2000 Hz (Aß-fiber) and 5 Hz (C-fiber), but not 250 Hz (Aδ-fiber) sine-wave electrical stimulation were reduced in L-OHP-treated rats. Multi-unit efferent discharges were increased by mechanical stimulation using a von Frey filament applied to the plantar surface of the hindpaw. The discharges during and after stimulation were increased in the L-OHP-treated rats. Cold stimulation, but not brush stimulation, increased the discharges in L-OHP-treated rats. These results suggest that sensitization of Aß- and C-fibers, but not Aδ-fibers, contributes to the development of L-OHP-induced mechanical and cold allodynia.

Risk factors for oxaliplatin-induced hypersensitivity reactions in Japanese patients with advanced colorectal cancer.

OBJECTIVE: Previously, we suggested that oxaliplatin (L-OHP)-related grade 3/4 hypersensitivity reactions occurred immediately after the initiation, but grade 1/2 reactions did not. This study was conducted to clarify the risk factors for L-OHP-related hypersensitivity reactions. METHODS: Clinical data from 108 Japanese patients with colorectal cancer were analyzed, who were treated with L-OHP-containing regimens, FOLFOX4 and/or mFOLFOX6. The risk factors examined included demographic data, preexisting allergies, laboratory test data, treatment regimen, treatment line of therapy, pretreatment with steroids, total number of cycles and cumulative amount of L-OHP. RESULTS: The incidence of grade 1/2 and grade 3/4 hypersensitivity reactions were found at 13.0% (14/108) and 9.3% (10/108), respectively. Female (P = 0.037), preexisting allergies (P = 0.004) and lower level of lactate dehydrogenase (P = 0.003) were risk factors for grade 1/2 hypersensitivity reactions, and higher neutrophil count (P = 0.043) and lower monocyte count (P = 0.007) were for grade 3/4 reactions. Total number of cycles were larger in the patients with grade 3/4 reactions than those without reactions (P = 0.049). CONCLUSIONS: Further extensive examination with a large number of patients is needed to establish a patient management strategy.

Clinical effect of oxaliplatin-containing and cisplatin -containing regimen in TACE of advanced hepatocellular carcinoma / 肿瘤研究与临床

Objective To explore the clinical effect and side-effect of oxaliplatin(L-OHP)-containing regimen and cisplatin (DDP)-containing regimen in TACE of advanced hepatocellular carcinoma (HCC). Methods 108 patients with advanced HCC were randomly divided into experimental group(n=55) and control group (n =53). The experimental group were treated with TACE using L-OHP. After dilute with glucose solution, L-OHP(130 mg/m2) and FT207 (500-750 mg/m2) were injected into blood vessel respectively. ADM (40 mg/m2) and LP (10～30 ml) were emulsified and then used for vessel embolism according to the size of focus. The control group received TACE with DDP, DDP (40 mg/m2) and F]'207(500～750 mg,/m2) were diluted with glucose solution, and also according to the size of tumor' s focus, ADM(40 mg/m2) and LP(10～30 ml) were emulsified for vessel embolism, and then diuretic. Results The total effective rate of experimental group was 67.3 % (37/55), and that of control group was 47.2 % (25/53), and the difference was with statistical significance (P <0.05). The descent rate of AFP of experimental group was 73.1%(31/43), and that of control group was 44.7 % (17/38), and the difference was with statistical significance (P <0.05). The main side effects were gastrointestinal reactions, the incidence rate of nausea and vomiting in experimental group were lower than control group, and the difference was with statistical significance. The incidence rate of leucopenia, damage of hepatic function and peripheral neuritis were not significant. Damage of heart and kidney were not found in the two sets. Conclusion L-OHP -containing regimen in TACE of advanced HCC is an efficient method, with good security and good tolerance to patients.

Relationship between Chemosensitivity to L-OHP in vitro and Expressions of Multidrug Resistance Associated Factors in Lymph Node Metastases of Gastric Carcinoma / 中国肿瘤临床

Objective: To investigate the relationship between chemosensitivity to L-OHP and expressions of multidrug resistance (MDR) associated factors in lymph node metastases (LNMs) of gastric carcinoma. Methods: The chemosensitivity to L-OHP was measured by MIT assay, and the expressions of P-gp, GST-π, P53, Survivin and Bcl-2 were determined by immunohistochemistry in 54 paired primary tumor (PT) and LNMs of gastric carcinoma. Results: The inhibition rates of LNMs cells for L-OHP were lower than those of PT (P<0.05). The expressions of P-gp, GST-π and Bcl-2 were higher in LNMs than in PT (P<0.05), and no signifi-cant difference was found in the expression of P53 and Survivin between LNMs and PT (P>0.05). Positive cor-relations among P-gp, P53 and Bcl-2 were found in PT and LNMs (r=0.3424, 0.7123, 0.4548, P<0.05). There was no significant difference in the expression of GST-π and Survivin between PT and LNMs (P>0.05). There was statistically negative correlation between inhibition rates and expression of P-gp, GST-π, and Survivin in PT (P<0.05). In LNMs, only Survivin was negatively correlated with inhibition rates of L-OHP (P<0.05). Conclu-sion: The LNMs of gastric carcinoma are heterogeneous with PT in respect to chemosensitivity to L-OHP and expression of multidrug resistance associated factors. The main factors that affect chemosensitivity to L-OHP are also significantly different between PT and LNMs. Effective adjuvant chemotherapy after surgery and re-version to multidrug resistance (MDR) of gastric carcinoma depend on targeting the metastatic lesions of gas-tric carcinoma.

Effect of Astragalus Root Injection on hippocampal neuronal apoptosis induced by axaliplatin / 中华中医药杂志

Objective:To study the effects of Astragalus Root Injection(a traditional Chinese herb medicine) on oxaliplatin-induced apoptosis of hippocampal neurons. Motheds: The primary culture of hippocampus neurons from SD rats (aged within 24h) were treated with different concentrations of oxaliplatin( L-OHP) (0, 3, 5 and 10 ?g/mL) and Astragalus Root Injection (0.05, 0.2 and 0.5 g/mL). The apoptosis of the neurons and the nerve growth factor(NGF)level were analyzed. Results: Astragalus Root Injection dose-dependently decreased neuronal cell apoptosis induced by oxaliplatin (P