Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients

It has been reported that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have absorption characteristics of weakly basic drugs, suggesting that alkalization of the intestinal lumen might reduce reabsorption and its attendant side effects. Furthermore, stasis of stools containing these compounds is thought to induce damage to the intestinal mucosa. The prevention of CPT-11-induced side effects by oral alkalization (OA) combined with control of defecation (CD) was estimated in a case-control study of lung cancer patients. Coinciding with day 1 of CPT-11 infusion and for 4 days thereafter, OA and CD were practiced utilizing orally administered sodium bicarbonate, magnesium oxide, basic water and ursodeoxycholic acid. OA involved the daily use of all four therapeutics, and CD required doses of up to 4.0 g/day of magnesium oxide and 2 L/day of excess basic water. From three ongoing prospective phase I/II studies, we selected 37 consecutive patients who were treated with CPT-11 in combination with cisplatin in the presence of OA and CD (group B). Thirty-two control subjects who were matched to the background characteristics of the case patients were treated with the same regimen in the absence of OA and CD (group A). Toxicities induced by the CPT-11/cisplatin combination were evaluated and analyzed in group A and group B in a case-control format. The use of OA and CD resulted in significantly higher stool pH (p < 0.0001), while reducing the incidence of delayed diarrhea (> or = grade 2: group A 32.3% versus group B 9.4%; p = 0.005), nausea (p = 0.0001), vomiting (p = 0.001) and myelotoxicity, especially granulocytopenia (p = 0.03) and lymphocytopenia (p = 0.034). In addition, dose intensification was well tolerated in patients receiving OA and CD, allowing dose escalation from 35.6 +/- 6.0 to 39.9 +/- 5.6 mg/m(2)/week (p < 0.001). Tumor response rates for non-small cell lung cancer were 59.3% (16/27 patients) in group B compared with 38.5% (10/26 patients) in group A. Multivariate analysis revealed that the risk of CPT-11-induced delayed diarrhea greater than grade 2 was associated with OA and CD (odds ratio for delayed diarrhea, 0.14 with use of OA and CD; 95% confidence interval, 0.05 to 0.4; p = 0.0002) and age (odds ratio, 1.08 per increase in age; 95% confidence interval, 1.02 to 1.15; p = 0.009). OA and CD appear to be useful in preventing the dose-limiting side effects of CPT-11 noted in clinical practice, mainly nausea, vomiting, granulocytopenia and especially delayed diarrhea. Risk factors statistically associated with delayed diarrhea include advanced age and the use of CPT-11 without OA and CD.     

奥曲肽对伊立替康化疗后迟发性腹泻小鼠肠黏膜损伤的预防作用

目的:观察奥曲肽对伊立替康化疗引起的迟发性腹泻小鼠肠黏膜损伤的预防作用.方法:健康昆明小鼠20只,随即分成对照组,伊立替康组,奥曲肽组,伊立替康及奥曲肽预防组.观察迟发型腹泻发生情况,实验开始后第8天将小鼠处死,取小肠及结肠组织.光镜下根据Chiu标准对肠黏膜损伤程度进行分级.结果:与伊立替康组比较,伊立替康及奥曲肽预防组小鼠腹泻发生率和肠黏膜损伤程度显著降低.结论:奥曲肽可以对伊立替康引起的迟发型腹泻起到一定程度的预防作用.     

Gefitinib and celecoxib in advanced metastatic gastrointestinal tumors: a pilot feasibility study

Background

This pilot, open-label study examined the safety and tolerability (primary objective) and efficacy (secondary objective) of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, in patients with advanced or refractory gastrointestinal (GI) tumors of epithelial origin.

Methods

Patients were administered gefitinib (250 mg/day) plus celecoxib (400 mg twice daily). In the event of toxicity, dose interruptions were permitted and a single celecoxib dose reduction was allowed.

Results

Thirty patients (median age 60 years) with primary colorectal (25 patients), pancreatic (3 patients), esophageal (1 patient), or gall bladder (1 patient) tumors were recruited, 29 of whom had received prior chemotherapy. Adverse events (AEs) were generally mild and consisted mainly of acne, diarrhea, and nausea. Few severe AEs were noted. There were no withdrawals or deaths due to AEs. Dose reductions for celecoxib were reported for five patients, in three cases due to toxicity. Stable disease was confirmed in 12 patients (40%), with progressive disease in 18 patients (60%).

Conclusions

After study completion, safety issues relating to the long-term use of COX-2 inhibitors have been raised. However, in this pilot study, the combination of gefitinib and celecoxib was generally well tolerated in patients with advanced GI cancer.     

胃肠道恶性肿瘤t-PA、u-PA转录的临床研究

目的：研究胃肠道恶性肿瘤患者纤溶分子标志物血浆含量、mRNA水平的变化，初步探讨两者与肿瘤浸润、播散的关系及其临床检测意义。方法：采用逆转录、实时定量PCR技术检测23例胃癌、17例肠癌患者组织中组织型纤溶酶原激活剂(t—PA)、尿激酶型纤溶酶原激活剂(u—PA)mRNA水平；用ELISA法同步检测患者血浆纤溶分子标志物含量，包括t—PA、u—PA、尿激酶型纤溶酶原激活剂受体(u—PAR)、纤溶酶—抗纤溶酶复合物(PAP)等。结果：胃癌、肠癌组患者血浆u—PA、u—PAR、PAP蛋白含量均较正常对照明显升高，其中，有局部浸润、淋巴结转移、远处脏器转移者u一：PA升高更为显著；t—PA含量与正常对照无显著差异。u—PAmRNA在两种肿瘤细胞表达均显著增高，而t—PAmRNA则减少。结论：纤溶功能亢进是胃肠道恶性肿瘤细胞易播散、浸润的主要原因之一。t—PAmRNA水平的升高可能为组织分化较好的特征。     

胃肠道恶性肿瘤患者治疗前后血清CEA水平的动态分析

目的：探讨治疗前后不同时期胃肠道恶性肿瘤患者血清ＣＥＡ水平的变化规律及临床意义。方法：采用ＣＥＡ单克隆抗体酶联免疫检测试剂盒,检测患者血清ＣＥＡ水平,用统计学方法对检测结果进行比较分析。结果：胃肠道恶性肿瘤患者手术前ＣＥＡ水平显著高于健康人（Ｐ〈０．００５）,手术后ＣＥＡ普遍降低至较低水平。当患者再进行化疗时,化疗结束后６０天内８１．８％（１８／２２）的患者血清ＣＥＡ有升高现象;６１天～１８０天再     

Effect of immunochemotherapy on lymphocyte response of patients with gastrointestinal cancer

Patients with gastrointestinal cancer were treated with 5-fluorouracil (5-FU) in combination with a streptococcal preparation, OK-432, or without OK-432 before operation, and lymphocyte response to PHA was examined. Oral administration of 5-FU with or without intramuscular injection of OK-432 did not affect the response. However, treatment with cytostatic drugs in combination with OK-432 markedly augmented the lymphocyte response to PHA, but the cytotoxic activity of lymphocytes was not elevated.     

胃肠癌分子靶向治疗

Gastrointestinal cancer is one of the highly prevalent malignant diseases worldwide which is a major cause of morbidity and mortality. Gastric cancer is the second leading cause of cancer mortality in the world and its management, especially in advanced stages, has evolved relatively little [1]. Colorectal cancer (CRC) remains the third most common ma-lignancy and the third leading cause of cancer death worldwide [2]. The surgical treatment is still the most effective therapy for the gastrointestinal cancer...     

重组人血管内皮抑制素联合化疗治疗晚期消化道肿瘤的疗效观察

目的探讨重组人血管内皮抑制素联合化疗治疗晚期消化道肿瘤的疗效和安全性。方法经病理组织学或细胞学检查确诊的Ⅳ期患者65例,其中胃癌15例、结肠癌21例、直肠癌19例、食管癌10例。15例为初治,37例为二线治疗,13例为三线及三线以上治疗。治疗方案为：重组人血管内皮抑制素15mg加生理盐水500ml匀速缓慢滴注1—14天,间歇7天后重复给药;胃癌患者联合FOLFOX4方案,结直肠癌患者联合FOLFIRI方案,食管癌患者联合紫杉醇脂质体（135—175mg／m ^2）＋顺铂（75mg／m^2）方案。按照RECIST标准评价疗效,参照Kamofsky评分（KPS）标准评价生活质量（QOL）,按照NCICTC3．0标准评价毒性反应。结果全组65例患者共完成治疗周期160个,平均每例2．46个周期。用药1个周期后评价毒性,两周期后评价疗效。获得CR1例,PR20例,SD18例,PD26例,有效率（RR）为32．3％（21／65）,疾病控制率（DCR）为60％（39／65）。QOL改善率26．1％（17／65）,稳定率为63．0％（41／65）,下降率10．7％（7／65）。与重组人血管内皮抑制素相关的毒副反应主要为乏力、食欲减退、轻度心脏毒副反应,主要表现为胸闷、心悸,其他毒副反应与化疗药物相关。结论重组人血管内皮抑制素联合化疗治疗晚期消化道恶性肿瘤疗效较佳,且毒性低、安全性高、耐受性好,可以改善或稳定患者的QOL,特别对于老年患者也具有较好的安全性,具有进一步研究和应用的价值。     

Enteral and parenteral nutrition in anorectic patients with advanced gastrointestinal cancer

Seventeen patients with advanced, noncurable gastrointestinal cancer with symptoms of anorexia and malnutrition were treated with controlled enteral or total parenteral nutrition over a 3-week period. Eleven patients received enteral and six parenteral nutrition. The nutrition was given with 30-40 kcal/kg b.w. daily. No anticancer treatment was given. Before and after the treatment period, the patients were assessed regarding their nutritional, immunological, and performance status. None of the studied nutritional parameters changed significantly over the 3-week period and there was no clear indication of an improved lymphocyte reactivity. There was a tendency toward improvement in performance status for the patients on enteral nutrition, while the reverse seemed to be true for the parenteral group. It is concluded that nutritional support may halt the progressive malnutrition often seen in patients with cancer and serve as a palliative treatment in selected patients.     

A case-control study of prevention of irinotecan-induced diarrhea: the reducing side effects of irinotecan by oral alkalization combined with control of defecation

Irinotecan and its active metabolite, SN-38, were reported to have the absorption characteristics of weakly basic drugs. Moreover, stasis of these compounds is thought to induce damage to the intestinal mucous membrane. The purpose of this report was to examine whether oral alkalization (OA) combined with control of defecation (CD) might prevent irinotecan-induced side effects. From day one of irinotecan infusion to day four, OA & CD were practiced using orally administered sodium bicarbonate, magnesium oxide, basic water, and ursodeoxycholic acid. Thirty-two lung cancer patients were treated with irinotecan in combination with cisplatin in the absence of OA & CD (Group A). Thirty-seven patients matched for background characteristics were treated with the same regimen in the presence of OA & CD (Group B). Group B had a reduced incidence of delayed diarrhea (Grade 2 < or = Group A 32.3% vs. Group B 9.4%), nausea, vomiting, and myelotoxicity, especially granulocytopenia compared with Group A. In addition, dose intensification was well-tolerated in Group B. Tumor response rates for non-small cell lung cancer were 59.3% (16/27 patients) in Group B against 38.5% (10/26 patients) in Group A. OA & CD appears to reduce the irinotecan-induced side effects, especially delayed diarrhea. Risk factors statistically associated with delayed diarrhea include advanced age and the use of irinotecan without OA & CD.     

Alternative methods of interpreting quality of life data in advanced gastrointestinal cancer patients.

Understanding of how to analyse and interpret quality of life (QoL) data from clinical trials in patients with advanced cancer is limited. In order to increase the knowledge about the possibilities of drawing conclusions from QoL data of these patients, data from 2 trials were reanalysed. A total of 113 patients with pancreatic, biliary or gastric cancer were included in 2 randomised trials comparing chemotherapy and best supportive care (BSC) with BSC alone. Patient benefit was evaluated by the treating physician (subjective response) and by using selected scales and different summary measures of the EORTC QLQ-C30 questionnaire. An increasing number of drop-outs (mainly due to death) with time did not occur in a random fashion. Therefore, the mean scores in the different subscales of the QLQ-C30 obtained during the follow-up of interviewed patients did not reflect the outcome of the randomised population. The scores of the patient-provided summary measure, 'Global health status/QoL', were stable in a rather high proportion of the patients and could not discriminate between the 2 groups. 3 other summary measures revealed greater variability, and they all discriminated between the 2 groups. A high agreement was also seen between the changes in the summary measures and the subjective response. A categorisation of whether an individual patient had benefited or not from the intervention could overcome the problem with the selective attrition.     

Nutritional status in advanced upper gastrointestinal cancer

Fifty-four patients with advanced upper gastrointestinal cancer were assessed for their nutritional status prior to any form of therapy. Anthropometric parameters--weight loss, arm muscle circumference, skin-fold thickness--and biochemical parameters--serum albumin and delayed cutaneous hypersensitivity reactions to purified protein derivative (PPD) and phytohemagglutinin (PHA)--were used for nutritional assessment. Using standard values for comparison, about 80% of all patients were found to be nutritionally depleted. Immunocompetence did not show significant correlation with other nutritional parameters.     

肠内免疫营养对胃肠道恶性肿瘤化疗的影响

目的:评价肠内免疫营养对胃肠道恶性肿瘤化疗后免疫功能的影响。方法:86例胃肠道恶性肿瘤患者随机分为免疫营养组、普通营养组,化疗术前7d和化疗结束后14d分别检测多项营养指标和免疫指标。结果:化疗后免疫营养组免疫指标明显高于普通营养组,有显著性差异;营养指标变化差异无显著性。结论:肠内免疫营养可提高病人的免疫功能,改善病人预后。     

Adriamycin, CCNU, and 5-fluorouracil in patients with advanced gastrointestinal cancer

Forty-one patients with measurable advanced gastrointestinal malignancy were treated with a combination of Adriamycin (doxorubicin), 5-FU (5-fluorouracil), and CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea). The response to therapy was evaluated every eight weeks. In addition to standard clinical examinations and laboratory tests to evaluate toxicity, 31 patients were asked to rank both the expected and experienced negative effects of the treatment. Although both patients with hepatocellular cancer and the patient with a soft tissue sarcoma responded to the regimen, only 1 of 38 patients with adenocarcinoma had a favourable response. The clinically measurable toxicity, principally to the gastrointestinal tract and bone marrow, was relatively mild. However, the patients' subjective evaluation of their treatment made the side effects appear more significant. The results suggest that this regimen deserves further evaluation in patients with hepatocellular cancer and soft tissue sarcomas.     

Determination and validation of a predictive model for Clostridium difficile diarrhea in hospitalized oncology patients

Background: Clostridium difficile colitis in the cancer patient receiving chemotherapy is a frequent cause of morbidity which may prolong hospitalization. Techniques for identifying infection often delay the initiation of therapy.Patients and methods: In this retrospective case-control analysis, we identified predictors for C. difficile-associated diarrhea in 29 patients hospitalized from 1988 to 1993 on a hematologic malignancy/bone marrow transplant unit (hospital A). We then validated our model with 58 C. difficile cases and 74 controls admitted to an oncology unit from a different institution (hospital B).Results: We found that low intensity of chemotherapy (P < 0.001), lack of parenteral vancomycin use (P = 0.03) and hospitalization within the past two months (P = 0.05) were independently predictive of C. difficile colitis by multivariate analysis.These variables were weighted for predictive capability using a receiver operator characteristic score; low intensity chemotherapy was assigned two points, lack of parenteral vancomycin received one point and prior hospitalization one point (P < 0.00l by ² for trend).The receiver operating characteristic (ROC) curve areas were 0.78 for patients at hospital A and 0.70 at hospital B indicating moderate drop off in discrimination.Compared to hospital A patients, hospital B patients hospitalized between 1989 and 1994 were more often women (P = 0.04), received less systemic vancomycin (P = 0.01), were less frequently neutropenic (P < 0.05), and received less intense chemotherapy regimens (P < 0.05).Despite these differences in demographics in patients between these institutions, our predictive model was validated in hospital B patients (P = 0.02 by ² for trend).Conclusions: The results of this study may help clinicians predict the risk of C. difficile disease in the hospitalized immunocompromised oncology patient and may help guide empiric therapy while awaiting results of stool toxin assays.     

Aurora-A基因过表达与消化道肿瘤临床病理特征相关性Meta分析

目的 Aurora-A在消化道肿瘤组织中存在过表达,本研究通过Meta分析的方法综合评价Aurora-A基因过表达与消化道肿瘤患者临床病理特征的相关性,为消化道肿瘤的诊断和治疗寻求新的靶点.方法 计算机检索PubMed、Cochrane、Highwire Press、中国知网(CNKI)、维普中文科技期刊全文数据库(VIP)、万方和中国生物医学文献数据库(CBM)等,检索时间均为建库至2015-08-01.通过设置的纳入与排出标准筛选研究文献并提取资料,根据Newcastle-Ottowa Scale (NOS)评价纳入资料的质量,采用Review Manager 5.2软件进行系统分析.结果 符合条件的13篇(其中食管癌4篇,胃癌5篇,肠癌4篇)文献中样本量合计1 973例.Aurora-A蛋白表达与肿瘤浸润深度Meta分析共纳入9篇文献,样本量711例,Aurora-A在浅层浸润组(T1～T2)和深层浸润组(Ts～T4)表达差异有统计学意义,OR=2.90,95％CI为2.09～4.04,P＜0.001;Aurora-A蛋白表达与淋巴结转移Meta分析共纳入8篇文献,样本量758例,Aurora-A在淋巴结转移组和无淋巴结转移组表达差异有统计学意义,OR=1.47,95％CI为1.07～2.01,P=0.02;但Aurora-A过表达与肿瘤分化程度及临床分期无相关性.结论 Aurora-A基因过表达可以促进消化道肿瘤的侵袭和转移,与消化道肿瘤的恶性程度呈正相关,将这为消化道肿瘤的早期诊断、预后分析及靶向治疗提供重要的参考价值.     

A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies.

BACKGROUND: Oral eniluracil/5-fluorouracil (5-FU) was shown in early clinical studies to have promising activity against gastrointestinal malignancies. Oxaliplatin in combination with 5-FU also has activity against these tumour types. The primary objective of this study was to determine a tolerable dose for oral eniluracil/5-FU in combination with oxaliplatin. PATIENTS AND METHODS: Twenty-three patients with advanced gastrointestinal malignancies were recruited into this open-label study. Patients received a fixed dose of oxaliplatin (130 mg/m(2) on the first day of a 21-day cycle), and the dose intensity of oral eniluracil/5-FU was gradually increased by escalating the number of days of treatment per course. RESULTS: The maximum tolerated dose intensity was eniluracil/5-FU 10.0/1.0 mg/m(2) twice daily for 16 days in combination with oxaliplatin 130 mg/m(2) on the first day of a 21-day cycle. Dose-limiting toxicities included vomiting and diarrhoea. The objective tumour response rate was 26% with a median duration of response of 15.3 weeks (95% confidence interval 8.5-22.1). Twenty-two patients (96%) experienced neurotoxicity (sensory neuropathy or cold-related dysaesthesia), although only two events were severe (grade 3). CONCLUSIONS: The recommended dose for future study in patients with advanced gastrointestinal cancer is 10.0/1.0 mg/m(2) oral eniluracil/5-FU twice daily for 14 days in combination with oxaliplatin 130 mg/m(2) on the first day of each treatment cycle.