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。     

间苯三酚治疗伊立替康所致重度迟发性腹泻的临床观察

目的　观察间苯三酚治疗伊立替康所致重度迟发性腹泻应用易蒙停无效患者的疗效。方法　回顾性分析３例间苯三酚治疗伊立替康致重度迟发性腹泻但服用易蒙停无效病例。结果　间苯三酚治疗第１天,３例患者的大便次数均明显减少,其中１例患者大便恢复正常;治疗第２天另２例患者大便亦恢复正常。３例患者均于１周内康复出院。结论　对伊立替康化疗致重度迟发性腹泻用易蒙停无效患者可尝试间苯三酚静脉滴注治疗,但其安全性需临床进一步大样本研究。     

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.     

奥曲肽联合丙氨酰谷氨酰胺预防伊立替康迟发性腹泻的临床观察

目的 伊立替康的主要剂量依赖性毒副反应是骨髓抑制和胃肠道不良反应,特别是不可预测的严重腹泻。本研究 的目的在于评价奥曲肽联合丙氨酰谷氨酰胺预防伊立替康导致大肠癌患者迟发性腹泻的临床作用。方法 选取本院 2015 年 1 月至 12 月期间接受 FOLFIRI 方案化疗的晚期结直肠癌患者 60 例,分为预防组（n=30）及对照组（n=30）。预防组于化 疗当日开始给予奥曲肽 0.1mg tid 皮下注射及丙氨酰谷氨酰胺 10g qd ivgtt,连续应用 6 天,对比两组患者迟发性腹泻发生率 及严重程度。两组患者出现稀便或便次增多时,均开始给予大剂量洛哌丁胺治疗,必要时给予蒙脱石散、双歧杆菌胶囊止 泻并给予对症补液治疗。结果 对照组患者 12 例发生迟发性腹泻,发生率为 40%,其中 2 级腹泻 6 例（20%）,3 级腹 泻 4 例（13.3%）,4 级腹泻 2 例（6.7%）。预防组患者 4 例发生迟发性腹泻,发生率为 13.3%（P<0.05）,且均为 2 级腹泻, 无 3~4 级腹泻发生。结论 奥曲肽联合丙氨酰谷氨酰胺对伊立替康导致的迟发性腹泻有良好的预防作用,可以提高伊立替康 使用的安全性。     

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...     

替吉奥改善老年晚期胃肠道肿瘤患者生存质量的临床观察

目的:观察替吉奥对老年晚期胃肠道肿瘤患者生存质量的影响及不良反应。方法:65例老年晚期胃肠道肿瘤患者分为治疗组（34例）和对照组（31例）,治疗组口服替吉奥胶囊单药（40mg/m2,早晚餐后口服）,连续服用4周,休息2周为1个周期,至少完成2个周期治疗后进行生存质量评价;对照组给予最佳支持治疗。结果:治疗组角色功能、情绪功能、认知功能、疲乏、恶心呕吐、疼痛、失眠、食欲不振、便秘、总体健康（生存质量）评分均显著性优于对照组(P<0.05);治疗组药物不良反应较轻,无因不良反应需停药者。结论:替吉奥胶囊能够改善近期老年晚期胃肠道恶性肿瘤患者的生存质量,不良反应较轻,耐受性较好。     

China special issue on gastrointestinal tumors-Improved survival after multidisciplinary team decision for patients with advanced gastrointestinal cancer: A multicenter,noninterventional, controlled study

Formal multidisciplinary team (MDT) discussions in clinical practice require time and space but have unclear survival benefits for advanced gastrointestinal cancer patients. Our study aimed to investigate the long-term survival of patients with advanced gastrointestinal cancer after MDT decision. From June 2017 to June 2019, continuous MDT discussions on advanced gastrointestinal cancer were conducted in 13 medical centers in China. MDT decisions and actual treatment received by patients were prospectively recorded. The primary endpoint was the difference in overall survival (OS) between patients in the MDT decision implementation and nonimplementation groups. The secondary endpoints included the implementation rate of MDT decisions and subgroup survival analysis. A total of 461 MDT decisions of 455 patients were included in our study. The implementation rate of MDT decisions was 85.7%. Previous treatment had an impact on MDT decision-making. The OS was 24.0 months and 17.0 months in the implementation and nonimplementation groups, respectively. The implementation of MDT decisions significantly reduced the risk of death in multivariate analyses (hazard ratio = 0.518; 95% confidence interval: 0.304-0.884, P = .016). Subgroup analysis showed a significant difference in survival of patients with colorectal cancer, but not in survival of patients with gastric cancer. The rate of secondary MDT discussion was only 5.6% among patients who the MDT decisions were discontinued due to changes in their condition. MDT discussion can prolong the OS of patients with advanced gastrointestinal cancer, especially those with colorectal cancer. Timely scheduling of the subsequent MDT discussion is necessary when the disease condition changes.     

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.     

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。     

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.     

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.     

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.     

肠道微生态与消化道肿瘤的研究进展

人体微生态系统存在于胃肠道、口腔、泌尿生殖道、呼吸道和皮肤等多个部位,其中以肠道中的微生态系统最为主要和复杂。肠道微生态参与机体的生长发育、免疫调节、内分泌代谢等各种功能,并受到年龄、饮食、抗菌药物及心理压力、应激等因素的影响。肠道微生态的失调可能会引起许多疾病,包括皮肤病、肥胖、感染性疾病、心脑血管疾病和自身免疫病。随着肠道微生态与消化道疾病研究的不断深入,越来越多的学者发现,消化道肿瘤的发生、发展与肠道菌群失调有显著的相关性。肠道菌群失调通过微生物直接与肿瘤接触,调节机体免疫,产生细菌代谢物等机制直接或者间接作用影响肿瘤的发生、发展。此外,近年来研究还发现,肠道微生态与各类免疫检测点抑制剂如抗程序性死亡蛋白1抗体、抗程序性死亡蛋白配体1抗体及抗细胞毒性T淋巴细胞相关抗原4抗体的疗效密切相关,肠道微生态有可能是一个潜在的可预测肿瘤免疫治疗效果的生物标志物。本文归纳了肠道微生态的功能及其在消化道肿瘤发生、发展中的作用等,希望为今后的研究重点和发展方向提供参考。