Severe enteropathy among patients with stage II/III colon cancer treated on a randomized trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin: a prospective analysis

BACKGROUND: Cases of severe gastrointestinal toxicity were monitored prospectively during NSABP C-07, a randomized clinical trial of adjuvant therapy for patients with stage II/III colon cancer. METHODS: Patients were treated with weekly bolus 5-fluorouracil (5-FU) and leucovorin (FL; "Roswell Park Regimen") or the same regimen plus oxaliplatin (FLOX). RESULTS: Of 1857 patients, 79 (4.3%) developed a syndrome of bowel wall injury (BWI, small or large) characterized by hospitalization for the management of severe diarrhea or dehydration and radiographic or endoscopic evidence of bowel wall thickening or ulceration. Fifty-one (64.6%) of these adverse events occurred in patients treated with FLOX and 28 (35.4%) in those treated with FL (P < .01). Enteric sepsis (ES), characterized by grade 3 or greater diarrhea and grade 4 neutropenia with or without proven bacteremia occurred in 22 patients treated with FLOX, versus 8 in those treated with FL (P = .01). Patients >60 years were at higher risk for BWI after treatment with FLOX (6.7%) versus treatment with FL (2.9%, P < .01). Female patients had a higher incidence of BWI with FLOX (9.1%) than with FL (3.9%, P < .01). Severe gastrointestinal toxicity usually occurred during the third or fourth week on the first cycle of therapy, required hospitalization, and was managed with fluids, antidiarrheals, and antibiotics. There were 5 deaths (0.3%) due to enteropathy, 2 related to ES and 3 related to both BWI and ES. Seventy-one percent of patients resumed treatment with FL after recovery. CONCLUSIONS: Patients treated with adjuvant FL should be closely monitored for diarrhea and aggressively managed, especially if oxaliplatin has been added to the regimen. Society.     

miR-188-5p promotes oxaliplatin resistance by targeting RASA1 in colon cancer cells

The efficacy of chemotherapy for colon cancer is limited due to the development of chemoresistance. MicroRNA (miR)-188-5p is downregulated in various types of cancer. The aim of the present study was to explore the molecular role of miR-188 in oxaliplatin (OXA) resistance. An OXA-resistant colon cancer cell line, SW480/OXA, was used to examine the effects of miR-188-5p on the sensitivity of colon cancer cells to OXA. The target of miR-188-5p was identified using a luciferase assay. Cell cycle distribution was also assessed using flow cytometry. The measurement of p21 protein expression, Hoechst 33342 staining and Annexin V/propidium iodide staining was used to evaluate apoptosis. The expression of miR-188-5p significantly increased in SW480/OXA compared with wild-type SW480 cells. The luciferase assay demonstrated that miR-188-5p inhibited Ras GTPase-activating protein 1 (RASA1; also known as p120/RasGAP) luciferase activity by binding to the 3′-untranslated region of RASA1 mRNA, suggesting that miR-188-5p could target RASA1. In addition, miR-188-5p downregulation or RASA1 overexpression promoted the chemosensitivity of SW480/OXA, as evidenced by increased apoptosis and G₁/S cell cycle arrest. Moreover, RASA1 silencing abrogated the increase in cell apoptosis induced by the miR-188-5p inhibitor. The findings of the present study suggested that miR-188-5p could enhance colon cancer cell chemosensitivity by promoting the expression of RASA1.     

长链非编码RNA OR3A4 促进结直肠癌细胞奥沙利铂耐药

目的:探讨长链非编码RNA（long non-coding RNA,lncRNA）OR3A4在结直肠癌细胞奥沙利铂（L-OHP）耐药中的作用。方法:实时荧光定量（qPCR）检测结直肠癌组织和细胞中lncRNA OR3A4的表达。免疫印迹（Western blotting）检测OR3A4对耐药相关蛋白P-糖蛋白（P-GP）和多药耐药相关蛋白（MRP）表达的影响。利用细胞计数试剂盒（cell counting kit,CCK-8）检测半数抑制浓度（IC50）。结果:结直肠癌组织/细胞株中OR3A4的表达水平显著高于癌旁组织/正常结肠细胞株（P＜0.05）。L-OHP耐药组的结直肠癌细胞的IC50显著高于非耐药组,而且L-OHP耐药组中OR3A4的表达水平显著高于非耐药组（P＜0.05）。转染OR3A4 小干扰RNA的结直肠癌L-OHP耐药细胞中耐药蛋白表达水平以及IC50均显著低于未转染组（P＜0.05）。结论:lncRNA OR3A4促进结直肠癌细胞的奥沙利铂耐药性。     

单纯奥沙利铂-替吉奥化疗方案与化疗辅助西黄胶囊治疗晚期胃癌的疗效及对T细胞亚群、生存率及不良反应的影响

目的探讨单纯奥沙利铂-替吉奥化疗方案与化疗辅助西黄胶囊治疗晚期胃癌的疗效及对T细胞亚群、生存率及不良反应的影响。方法选取84例胃癌晚期患者,按照随机数字表法将所有患者分为对照组和试验组。对照组患者均给予替吉奥和奥沙利铂进行化疗,试验组患者则在对照组的治疗基础上加用西黄胶囊进行辅助治疗。比较2组患者的T细胞亚群和KPS评分、临床疗效、不良反应发生率以及生存率等指标。结果试验组患者的总有效率为59.5%,显著高于对照组患者的38.1%(P0.05);试验组患者的疾病控制率为78.6%,显著高于对照组患者的57.1%(P0.05)。2组患者治疗前以及治疗后的KPS评分组间比较,差异均无统计学意义(P0.05)。试验组患者治疗后4周的CD_3~+、CD_4~+、CD_4~+/CD_8~+显著高于治疗前1周(P0.05)。试验组患者中出现Ⅲ~Ⅳ度不良反应的例数(1例)显著低于对照组患者(5例)(P0.05)。试验组患者的1年半生存率和2年生存率分别为57.1%和40.5%,显著高于对照组患者的1年半生存率35.7%和2年生存率19.0%(P0.05)。结论在替吉奥和奥沙利铂化疗的同时加用西黄胶囊进行辅助治疗,能够有效提高患者的免疫力和生存率,临床疗效佳且不良反应较低,值得推广使用。     

Genetic determinants of chronic oxaliplatin‐induced peripheral neurotoxicity: a genome‐wide study replication and meta‐analysis

We aimed at validating the role of genetic variants identified by a recent genome‐wide association study (GWAS) as determinants of chronic oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin‐based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI‐CTC criteria and the clinical version of the Total Neuropathy Score^© (TNSc^©). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI‐CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc^© scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI‐CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI‐CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40–5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P‐value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta‐analysis for validation of GWAS findings.     

Palliative chemotherapy for patients 70 years of age and older with metastatic colorectal cancer: a single-centre experience

BackgroundMetastatic colorectal cancer (mcrc) commonly affects elderly people, an understudied subset of patients. We analyzed the survival impact of the first and subsequent lines of chemotherapy in eligible non-trial patients 70 years of age and older with mcrc treated between 2004 and 2012.MethodsThis single-centre retrospective analysis estimated overall survival (os) and progression-free survival (pfs) using the Kaplan–Meier method. Multivariate analysis was used to adjust for age, sex, Eastern Cooperative Oncology Group performance status, score on the Charlson comorbidity index, dependency in activities of daily living, and exposure to 1 or more chemotherapy doublets, capecitabine alone, or best supportive care (bsc).ResultsOf 109 patients identified, 29 elected bsc, and 80 received chemotherapy. In multivariate analysis, age was not associated with os [hazard ratio (hr): 0.99; 95% confidence interval (ci): 0.92 to 1.05], but a performance status of 2 or higher was associated with a decreased likelihood of survival (hr: 3.12; 95% ci: 1.87 to 5.76), and exposure to 1 or more doublets was associated with improved survival (hr: 0.33; 95% ci: 0.17 to 0.66). In univariate analysis, a trend toward improved os was observed for first-line doublet chemotherapy compared with capecitabine (hr: 0.66; 95% ci: 0.41 to 1.07), and pfs was superior (hr: 0.46; 95% ci: 0.26 to 0.84). Compared with exposure to 1 doublet, exposure to the 3 potential cytotoxic chemotherapies was not associated with improved os (hr: 0.77; 95% ci: 0.41 to 1.43). The incidence of neutropenia with first-line folfiri was 40%; the incidences of bevacizumab-related arterial and venous thrombosis were both 8%.ConclusionsExposure to 1 or more doublet chemotherapies for mcrc was associated with better outcomes in non-trial patients 70 years of age and older. Elderly patients treated with palliative chemotherapy and bevacizumab should be monitored carefully for arterial and venous thrombotic events.     

多西他赛联合奥沙利铂和替吉奥与DCF方案一线治疗晚期胃癌的对比研究

目的观察和比较多西他赛联合奥沙利铂和替吉奥与DCF方案一线治疗晚期胃癌的疗效及毒副作用。方法收集2009-08-01—2011-06-15深圳市人民医院符合入组条件的60例晚期胃癌患者,采用随机数字表法分为2组。DSOX组30例:多西他赛75mg/m2,持续静脉滴入1h,d1;奥沙利铂130mg/m2,持续静脉滴入3h,d1;替吉奥40mg/m2,口服,2次/d,d1~d14。DCF组30例:多西他赛75mg/m2,持续静脉滴入1h,d1;顺铂75mg/m2,静脉滴入,d1;氟尿嘧啶500mg/m2,静脉滴入,d1~d5。每例患者至少完成2个周期化疗。对疗效及不良反应进行对比观察。结果 DSOX和DCF组的近期有效(CR+PR)率分别为53.3%(16/30)和46.7%(14/30),差异无统计学意义,z=-0.427,P=0.669。中位疾病进展时间分别为7.0和6.8个月,差异无统计学意义,χ2=0.413,P=0.520。中位生存期分别为12.0和11.7个月,差异无统计学意义,χ2=0.048,P=0.826。2组的主要不良反应为骨髓抑制、脱发、神经毒性和胃肠道反应,不良反应发生率差异无统计学意义,P>0.05。DSOX组的骨髓抑制与胃肠道反应相对更轻。结论多西他赛联合奥沙利铂和替吉奥一线治疗晚期胃癌的疗效较好,不良反应可以耐受,值得临床进一步研究应用。     

PKC/MEK inhibitors suppress oxaliplatin‐induced neuropathy and potentiate the antitumor effects

Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose‐limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin‐induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin‐induced neuropathy via the PKC/extracellular signal‐regulated kinase (ERK)/c‐Fos pathway in lumbar spinal cords (lumbar segments 4–6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells‐implanted mice. Moreover, mitogen‐activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin‐induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin‐induced neuropathy is associated with PKC/ERK/c‐Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin‐induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin‐induced neuropathy and could aid in combination antitumor pharmacotherapy.     

A retrospective analysis of the risk factors for allergic reactions induced by the administration of oxaliplatin

This study retrospectively investigated the clinical features and risk factors of allergic reactions induced by oxaliplatin administration. This study investigated the incidence of allergic reactions and analysed the background and laboratory data in patients with colorectal cancer treated with oxaliplatin‐based chemotherapy at Kyushu Medical Center between April 2012 and September 2012. A total of 62 patients were included in this study. The number of patients in the allergic and non‐allergic groups was 7 and 55 respectively. The incidence of allergic reactions was 11.3%. We compared the patients' characteristics and laboratory data between the two groups and found that the average dose of dexamethasone in the allergic group was significantly lower than that observed in the non‐allergic group (P = 0.0111). Furthermore, the incidence of allergic reactions in the group that received prophylaxis of less than 12 mg of dexamethasone was significantly higher than that observed in the group that received more than 12 mg of dexamethasone (P = 0.0103). In conclusion, a lower dexamethasone dose is a possible risk factor for allergic reactions induced by the administration of oxaliplatin; however, given the retrospective design used in this study, further validation of this finding is warranted.     

Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure,increases intraperitoneal chemotherapy drug penetration,and impedes tumor growth in a mouse colorectal carcinomatosis model

Cytoreductive surgery combined with intraperitoneal chemotherapy (IPC) is currently the standard treatment for selected patients with peritoneal carcinomatosis of colorectal cancer. However, especially after incomplete cytoreduction, disease progression is common and this is likely due to limited tissue penetration and efficacy of intraperitoneal cytotoxic drugs. Tumor microenvironment-targeting drugs, such as VEGF(R) and PDGFR inhibitors, can lower the heightened interstitial fluid pressure in tumors, a barrier to drug delivery. Here, we investigated whether tumor microenvironment-targeting drugs enhance the effectiveness of intraperitoneal chemotherapy. A mouse xenograft model with two large peritoneal implants of colorectal cancer cells was developed to study drug distribution and tumor physiology during intraperitoneal Oxaliplatin perfusion. Mice were treated for six days with either Placebo, Imatinib (anti-PDGFR, daily), Bevacizumab (anti-VEGF, twice) or Pazopanib (anti-PDGFR, -VEGFR; daily) followed by intraperitoneal oxaliplatin chemotherapy. Bevacizumab and Pazopanib significantly lowered interstitial fluid pressure, increased Oxaliplatin penetration (assessed by laser ablation inductively coupled plasma mass spectrometry) and delayed tumor growth of peritoneal implants (assessed by MRI). Our findings suggest that VEGF(R)-inhibition may improve the efficacy of IPC, particularly for patients for whom a complete cytoreduction might not be feasible.