腹腔化疗对胃癌细胞腹腔种植的影响

目的以人胃癌细胞株裸鼠腹腔种植模型，比较术后早期和延期腹腔内化疗对胃癌细胞腹腔种植生长的影响程度。方法３４只雄性裸鼠腹腔内接种ＭＫＮ┐４５细胞（３×１０６细胞数／只）后，随机分成对照组和４个不同剂量、不同时间表阿霉素腹腔内化疗组。结果对照组裸鼠致瘤率为６／６（１００％），０．４ｍｇ·ｋｇ－１·ｄ－１和０．８ｍｇ·ｋｇ－１·ｄ－１表阿霉素早期腹腔内化疗（接种后１～３天）的致瘤率分别为２／７和１／７；前两种不同剂量表阿霉素的延期腹腔内化疗（接种后５～７天）的致瘤率均为６／７。早期腹腔内化疗的抑瘤作用明显高于延期腹腔内化疗（Ｐ＜０．０５）。结论在预防胃癌术后腹腔内种植复发时，术后早期腹腔内化疗优于术后延期腹腔内化疗。     

高剂量大容积5－Fu腹腔化疗药代动力学和疗效实验观察

高剂量大容积５－Ｆｕ腹腔给药后２４０分钟内腹腔液浓度是股静脉血浓度的２８８倍，门静脉血浓度是股静脉血浓度的１３．８倍，肝静脉血浓度是股静脉血浓度的３．７倍，组织中肝浓度最高，胃、结肠次之，肺、肾最低。经腹腔化疗后的腹腔荷人结肠癌移植瘤裸鼠对照组全部产生腹腔移植瘤，５－Ｆｕ１０和２０ｍｇ／ｋｇ组均有２／５产生腹腔移植瘤，３０ｍｇ／ｋｇ组无腹腔移植瘤产生。结果表明高剂量大容积５－Ｆｕ腹腔化疗有利于胃肠恶性肿瘤术后腹腔复发和肝转移的防治。     

卡铂腹腔化疗药代动力学实验研究

应用高效液相色谱法（ＨＰＬＣ）对６只犬体内卡铂腹腔内给药药代动力学进行研究。卡铂３０ｍｇ／ｋｇ加生理盐水５００ｍｌ，快速腹腔给药，不同时间取腹腔液、门静脉及股静脉血测定总铂浓度。结果表明：大剂量、大容量卡铂经腹腔给药后，２４０分钟内腹腔液浓度最高，峰值浓度和平均浓度分别为股静脉浓度的１３９倍和６４倍；门静脉次之，分别为股静脉浓度的１３．３倍和６．５倍。卡铂腹腔给药可为腹腔、门静脉和肝脏提供恒定持久的高药物浓度，大大提高抗癌药对肿瘤细胞的杀伤作用，减少其到达体循环量，从而减轻全身毒副作用，对胃肠道恶性肿瘤术后腹腔复发和肝转移的预防和治疗颇有意义。     

进展期胃癌术前卡铂腹腔、静脉化疗肿瘤组织聚积浓度的比较及药代动力学研究

目的探讨不同给药途径抗癌药在肿瘤组织内药物浓度的聚积性。方法对２０例可切除进展期胃癌比较研究了术前卡铂腹腔、静脉化疗药代动力学。术前卡铂３００ｍｇ／ｍ２加生理盐水７５０ｍｌ分别腹腔（ｉｐ）、静脉（ｉｖ）给药，注射后１６０～１８０分钟取腹腔液、门静脉及外周血，２４０～２７０分钟取癌组织、癌旁正常组织、大网膜、腹膜及转移阴性淋巴结，应用高效液相色谱法（ＨＰＬＣ）测定总铂浓度。结果腹腔给药各组织内聚积较高的药物浓度，其中腹膜浓度最高，超出静脉给药组近４倍，癌组织内含量高于正常组织。腹腔液、门静脉、外周血超出静脉给药组１３，３，１．５倍。结论术前腹腔化疗不仅提高了腹膜、肿瘤组织内浓度，延长药物作用时间，而且大大降低癌细胞生物活性，使对药物敏感的细胞得到控制，对消灭亚临床灶，改善临床病期，提高手术切除率，控制医源性转移颇为重要。     

进展期胃癌术前卡铂腹腔,静脉化疗肿瘤组织聚积浓度的比较及药…

探讨不同给药途径抗癌药在肿瘤组织内药物浓度的聚积性。方法：对２０例可切除进展期胃癌比较研究了术前卡铂腹腔,静脉化疗化代动力学。术前卡铂３００ｍｇ／ｍ＾２加生理盐水７５０ｍｌ分别腹腔、静脉给药,注射后１６０－１８０取腹腔液、门静脉及外周血,２４０－２７０取癌组织,癌旁正常组织大网膜,腹膜及转移阴性淋巴结,应用高效液相色谱法（ＨＰＬＣ）测定总铂浓度。结果腹腔给药各组织内聚积较高的药物浓度,其中腹膜浓度     

高剂量大容积5—Fu腹腔化疗药代动力学和疗效实验观察

高剂量大容积５－Ｆｕ腹腔给药后２４０分钟内腹腔液浓度是股静脉血浓度的２８８倍，门静脉血浓度是股静脉血浓度的１３．８倍，肝静脉血浓度是股静脉血浓度的３．７倍，组织中肝浓度最高，胃，结肠次之，肺，肾最低，经腹腔化疗后的腹腔荷人结肠癌移植瘤裸鼠对是照组全部产生腹腔移植瘤，５Ｆｕ１０和２０ｍｇ／ｋｇ组均有２／５产生腹腔移植瘤，３０ｍｇ／ｋｇ组无腹腔移植瘤产生。结果表明高剂量大容积５－Ｆｕ腹腔化疗有利于胃肠     

进展期胃肠道癌术后早期腹腔灌注化疗(附56例报告)

我院自 1994年底开始对进展期胃肠道癌术后早期行腹腔内灌注化疗预防腹腔内复发和肝转移 ,效果良好 ,现报告如下。临床资料　 1994～ 1999年经手术探查及病理证实侵及浆膜的进展期胃癌 65例 ,结肠癌 2 3例、直肠癌 17例。男性 86例 ,女性 19例。年龄 2 1～ 80岁 ,平均 46.8岁。 10 5例随机分成腹腔灌注化疗组 5 6例 ,静脉化疗组 49例。两组均行根治性切除 ,其中病期及病理类型两组均相似。治疗方法　腹腔化疗组在肿瘤切除后于盆腔置小号硅胶双导管引至腹外固定。用 43～ 45℃蒸馏水 15 0 0ｍｌ加 5 Ｆｕ1.0 ,ＭＭＣ8ｍｇ从注药孔灌注腹腔 ,…     

胃癌术前卡铂腹腔化疗肿瘤组织浓度测定及药代动力学研究

作者采用高效液相色谱法对１０例可切除进展期胃癌进行腹腔卡铂术前化疗药代动力学研究。卡铂３００ｍｇ／ｍ２加生理盐水７５０ｍｌ快速腹腔注射，１６０～１８０ｍｉｎ取腹腔液、门静脉及外周血，２４０～２７０ｍｉｎ取癌组织、癌旁正常组织、腹膜、大网膜、阴性淋巴结，测定总铂浓度。结果表明，腹腔液浓度最高，平均４８．１４μｌ／ｍｌ，门静脉次之为１０．１μｌ／ｍｌ，分别是外周血的８、１．６倍。被测组织中，腹膜浓度超出其它组织浓度（Ρ＜０．０５），癌组织含量高于正常组织。研究证明，卡铂术前腹腔化疗不仅提高腹腔、门静脉药物浓度，而且，在腹膜、癌组织内有一定聚积性，对于杀灭腹腔亚临床病灶，改善临床分期，控制医源性转移，提高治愈性手术切除率发挥重要作用。     

进展期大肠癌术后早期腹腔灌洗化疗

目的了解进展期大肠癌术后早期腹腔灌洗化疗对防治腹腔内复发和肝脏转移的价值。方法选择１９９０年～１９９７年经手术及病理证实的１０２例侵及浆膜或腹腔癌胚抗原增高的大肠癌,随机分成腹腔灌洗化疗组５４例,静脉化疗组４８例。腹腔灌洗化疗组于手术当日开始用４３～４５℃的双蒸馏水１５００～２０００ｍｌ加５Ｆｕ１ｇ、ＭＭＣ１０ｍｇ行腹腔灌洗,连续应用６次;静脉化疗组用５Ｆｕ１ｇ、ＭＭＣ８ｍｇ每日静滴１次,连续６次;两组各用６次后改为口服呋喃氟脲嘧啶,总量为４０ｇ。结果静脉化疗组腹腔内复发１２例,肝脏转移６例;腹腔灌洗化疗组腹腔内复发２例,肝脏转移２例。两组未见并发症。结论术后早期腹腔灌洗化疗对防治进展期大肠癌腹腔内复发和肝脏转移有明显疗效,而且方法简单,安全、实用     

消化道恶性肿瘤术后腹腔化疗的临床观察

收集１９９４年１月至２０００年１１月消化道恶性肿瘤术后病例共１２７例 ,以是否行术后腹腔化疗分为腹腔静脉综合化疗组和静脉化疗组。分别比较逐年生存率 ,并对术后２年、５年生存率行统计学分析。１材料与方法１．１一般资料全组病例１２７例 ,分组及分期情况 ,见表１。１．２治疗方法１．２．１腹腔组术后３月内行腹腔化疗１～２次 ,化疗前尽量抽尽腹水。胃癌用５ 氟脲嘧啶（５ ＦＵ）５００ｍｇ～７５０ｍｇ,顺铂（ＤＤＰ）２０ｍｇ～３０ｍｇ,生理盐水１０００ｍｌ～１５００ｍｌ腹腔灌注 ,第１～５天 ,１月１次 ;或５ ＦＵ１０００…     

Neoadjuvant treatment of gastric cancer with peritoneal dissemination.

AIMS: To report our experience of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) for patients having a complete resection of the primary gastric cancer and peritoneal carcinomatosis (PC). PATIENTS AND METHODS: Patients with advanced peritoneal dissemination of primary gastric cancer had the placement of a peritoneal port system. For intraperitoneal chemotherapy, 40 mg of docetaxel and 150 mg of carboplatin were introduced in 1000 ml of saline on a weekly basis. Simultaneously, 100 mg/m2 of methotrexate and 600 mg/m2 of 5-fluorouracil were infused via a peripheral vein. A minimum of two cycles and up to six cycles of NIPS were used prior to cancer resection. At surgery a complete removal of the primary gastric cancer and the peritoneal implants by peritonectomy was attempted. RESULTS: Sixty-one patients were enrolled in the study. Thirty-nine had positive intraperitoneal cytology which reverted to negative cytology after treatment in 22. Thirty-eight showed a partial response. Thirty patients came to resection and 14 patients could be made disease-free. Median survival time of all patients was 14.4 months. Patients who received a complete resection had a median survival time of 20.4 months. Grade III/IV toxicities were not found after two courses of NIPS, but did develop in seven patients after more than three courses of NIPS. CONCLUSION: NIPS can downstage large volume peritoneal dissemination of gastric cancer. When combined with gastrectomy including peritonectomy a complete surgical resection was possible in one-quarter of the patients and resulted in a prolonged survival. This combined intraperitoneal and systemic chemotherapy for PC from gastric cancer is worthy of consideration for phase III clinical investigations.     

Docetaxel: pharmacokinetics and tissue levels after intraperitoneal and intravenous administration in a rat model

PURPOSE: Docetaxel (Taxotere) has been shown to possess a broad spectrum of antitumor activity against various malignancies such as breast and lung cancers, but also against intraabdominal malignancies such as mesothelioma and ovarian cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the prolonged high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue distribution of intraperitoneal versus intravenous docetaxel. METHODS: The study animals were comprised of 15 Sprague Dawley rats. They were randomized into three groups according to dose and route of administration (15 mg/kg intravenously, 15 mg/kg intraperitoneally, or 150 mg/kg intraperitoneally) and then given a single dose of docetaxel. Blood and peritoneal fluid were sampled using a standardized protocol for 90 min. At the end of the procedure the rats were killed and docetaxel concentrations in peritoneal fluid, plasma and selected tissue samples were determined by high-performance liquid chromatography (HPLC). RESULTS: When docetaxel was delivered at 15 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (110.6 microg/ml.min) as compared to intravenous administration (0.043 microg/ml.min; P=0.0079). This represents more than a 2500-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. Conversely, at the same dose the AUC of the plasma was significantly lower with intraperitoneal administration (0.11 microg/ml.min) as compared to intravenous administration (4.25 microg/ml.min; P=0.0079). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 976 for intraperitoneal administration as opposed to 0.01 for intravenous delivery. The AUC ratio for intraperitoneal docetaxel at 150 mg/kg was 3004. There were significantly different concentrations in the heart and the abdominal wall ( P=0.0079) and in the stomach and colon ( P=0.0159) when intraperitoneal versus intravenous docetaxel were compared. CONCLUSIONS: The exposure of the peritoneal surface to docetaxel is significantly increased and the systemic exposure decreased with intraperitoneal docetaxel administration. Also, high concentrations of drug were observed in the abdominal wall and in the colon after intraperitoneal delivery. This experiment suggests the need for clinical studies to evaluate intraperitoneal administration of docetaxel in humans.     

Pharmacokinetics of the intraperitoneal nanoparticle pegylated liposomal doxorubicin in patients with peritoneal metastases

BackgroundPeritoneal surfaces are a common site for the dissemination of gastrointestinal and gynecologic malignancy. Often, the surgeon can achieve a complete response. Unfortunately, current perioperative chemotherapy regimens fail to maintain control of cancer nodules within the abdomen and pelvis. More effective perioperative chemotherapy is needed.Materials and methodsThe nanoparticle pegylated liposomal doxorubicin (PLD) was instilled directly into the peritoneal space in peritoneal metastases patients following maximal efforts of cytoreductive surgery to resect abdominal and pelvic disease. Pharmacokinetics were determined intraoperatively during hyperthermic intraperitoneal chemotherapy (HIPEC) conditions and postoperatively during early postoperative intraperitoneal chemotherapy (EPIC) at normothermic conditions.ResultsThe retention of PLD within the peritoneal tissues over a 90-min HIPEC was only approximately 20% and 180 min of HIPEC 40%. The median area under the curve ratio of peritoneal fluid concentration times time as compared to plasma concentration times was over 1000 and increased with dose escalation from 50 to 100 mg/m2. When PLD was instilled for EPIC, the area under the curve ratios were very similar to the HIPEC but retention of drug within the peritoneal tissues with access to cancer nodules was maintained for 24 h with approximately 80% drug utilization. Adverse events were tabulated and found to be absent. No evidence of peritoneal dysfunction from sclerosis was evident with a 1 year of follow-up.ConclusionsThe nanoparticle PLD is slowly absorbed into the intraperitoneal tissues and not appropriate for HIPEC. EPIC is the preferred methodology for administration.     

Pharmacokinetics of intraperitoneal oxaliplatin: experimental studies

BACKGROUND AND OBJECTIVES: Oxaliplatin is an antineoplastic platinum-based compound which has shown significant activity against advanced colon cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue absorption of intraperitoneal versus intravenous oxaliplatin. METHODS: In the first phase of this study, fifteen Sprague Dawley rats were given a single dose of oxaliplatin then randomized into three groups according to dose and route of delivery (5 mg/kg intravenously, 5 mg/kg intraperitoneally, or 25 mg/kg intraperitoneally). In the second phase, 10 Sprague Dawley rats were given a continuous intraperitoneal perfusion of oxaliplatin (15 mg/kg) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic vs. hyperthermic). In both phases, peritoneal fluid and blood were sampled using a standardized protocol. At the end of each procedure the animals were sacrificed. Selected tissue samples were taken in the second phase only. For all samples, platinum levels were measured by direct current (d-c) plasma emission spectroscopy. RESULTS: When oxaliplatin was delivered at 5 mg/kg the area under the curve (AUC) of the peritoneal fluid was 15-fold higher with intraperitoneal administration as compared to intravenous administration (P < 0.0001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 16 (+/- 5):1 for intraperitoneal delivery as opposed to 1:5 (+/- 2) for intravenous delivery (P = 0.0059). The AUC ratio for intraperitoneal oxaliplatin at 25 mg/kg was 17 (+/- 8):1. With the exception of the kidneys and the mesenteric nodes, tissue samples in the hyperthermic group exhibited increased oxaliplatin concentrations. These differences were not significant. For both groups colon tissues had the highest oxaliplatin concentrations. CONCLUSIONS: These experiments demonstrated that the exposure of peritoneal surfaces to oxaliplatin was significantly increased with intraperitoneal administration. Although the differences were not statistically significant, hyperthermia did show a trend toward the enhancement of tissue absorption of oxaliplatin. The high concentration of drug observed in colonic tissues suggests the need for clinical studies to evaluate intraperitoneal oxaliplatin for microscopic residual tumor after surgical resection of colon malignancies.     

腹膜播散型胃癌术后腹腔化疗21例报道

目的探讨腹膜播散型胃癌姑息性胃切除后腹腔化疗的价值。方法２１例腹膜播散型胃癌姑息性胃切除后腹腔内５ＦＵ１ｇ化疗,每天一次连用５天为１疗程,每月重复,６个疗程后结束化疗。并与１５例腹膜播散型胃癌姑息性胃切除后静脉化疗相比较。结果腹腔化疗组无明显毒副反应,术后一年、二年的生存率分别为８０７％、４７１％,对照组生存率为５６５％、１４３％。治疗组的一年、二年生存率明显高于对照组（Ｐ＜００１）。结论腹腔化疗毒副反应少,是腹膜播散胃癌姑息性胃切除后较好的辅助治疗措施。     

腹腔灌注顺铂射频热疗联合EF方案治疗晚期胃癌临床观察

目的:观察腹腔灌注顺铂(DDP)射频热疗联合静脉注射表阿霉素(EPI)、5氟尿嘧啶(5FU)治疗晚期胃癌的疗效及安全性。方法:共入组晚期胃癌56例,其中管状腺癌5例,低分化腺癌26例,黏液腺癌16例,印戒细胞癌9例,治疗方案为DDP40mg/m2加入44℃生理盐水1500～2000mL中,行腹腔灌注。然后腹腔射频热疗1.5h,温度42℃～43℃,d1、d8;EPI50mg/m2,静脉冲入,d1;5FU500mg/m2,静脉滴入6～8h,d1～d5。21d为1个周期,至少应用4～6个周期。结果:可评价疗效51例中,CR4例,PR25例,SD16例,PD6例,总有效率为56.9%(29/51),中位肿瘤进展时间5.3个月,中位生存期12.4个月,主要不良反应为骨髓抑制、恶心、呕吐。结论:腹腔灌注DDP射频热疗联合静脉注射EPI、5FU治疗晚期胃癌疗效较好,毒性可耐受。     

Local and systemic effects of repeated intraperitoneal epirubicin treatment

The local toxicity, general morbidity and mortality of repeated intraperitoneal administration of epirubicin (0.5 mg/kg in 100 ml isotonic saline) was investigated using a rat model. This dose is equivalent to that which would be used in the human. After six perfusions, the incidence of peritoneal inflammation was similar in the epirubicin group and saline controls. The vesicant properties of the drug were reflected in a significantly higher incidence of peritoneal fibrosis (P = 0.0015) but adhesions were more common in the controls (29%) than in the epirubicin perfused animals (4%). Animals from both groups showed inflammatory collections within the liver. There were no chronic hepatic lesions such as fibrosis/cirrhosis. This may be owing to portal bacteraemia caused by repeated cannulation of the peritoneal cavity. Evidence of microabscess formation in the hepatic parenchyma was observed in both animals. No histologically demonstrable toxicity was observed in the heart or gastrointestinal tract of the animals included in this study. The mortality of the epirubicin treated rats (2/146 perfusions) was similar to that of the saline controls (2/84 perfusions). These findings indicate that repeated intraperitoneal perfusion with epirubicin is not associated with significant toxicity. This anthracycline is therefore suitable for prolonged cyclical intraperitoneal chemotherapy.     

Multi-targeted antifolate (MTA): pharmacokinetics of intraperitoneal administration in a rat model.

AIMS: LY 231514 or MTA is a multi-targeted antifolate which has been used as an anticancer drug. It is an analogue of folic acid which has shown antitumour activity against various malignancies, particularly mesothelioma and colon cancer. For cancers with peritoneal surfaces extension, the advantage of intraperitoneal chemotherapy over intravenous chemotherapy administration is the high drug concentration that can be achieved locally. Using a rat model, this study was designed to compare the pharmacokinetics and tissue adsorption of intraperitoneal vs intravenous MTA. METHODS: Sprague-Dawley rats were randomized into three groups according to dose and route of delivery of chemotherapy (10 mg/kg: intravenous; 10 mg/kg: intraperitoneal; 100 mg/kg: intraperitoneal). During the course of the experiment, peritoneal fluid and blood were sampled using a standardized protocol. At the end of the 3 hour procedure the rats were sacrificed, all urine was extracted and selected tissue samples were taken. One additional rat was studied over a 6 hour period for each group. The concentration of MTA in all samples was determined by high performance liquid chromatography (HPLC). RESULTS: When MTA was delivered at 10 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (10 778 microg/mlxmin) compared to intravenous administration (454 microg/mlxmin) (P<0.0001). This represents a 24-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. The AUC ratio (AUC peritoneal fluid/AUC plasma) was 40.8 for intraperitoneal delivery as opposed to 0.014 for intravenous delivery (P=0.0063). The AUC ratio for intraperitoneal MTA at 100 mg/kg was 19.2. The half-life of MTA in the peritoneal fluid after intraperitoneal infusion was approximately 2 hours. There was a significant difference in MTA concentration in the mesenteric nodes and the abdominal wall (P=0. 0036 and 0.0017) and in the kidneys (P=0.0122) when intraperitoneal and intravenous administration were compared. Other tissue samples did not demonstrate any difference in drug concentration. CONCLUSION: These experiments demonstrated that the exposure of peritoneal surfaces to MTA is significantly increased with intraperitoneal MTA administration. Due to the high likelihood of microscopic residual disease after resection of intra-abdominal malignancies, clinical studies to evaluate intraperitoneal MTA may be indicated.     

A case of gastric cancer with multiple liver metastasis treated with transarterial and transportal chemoembolization of tegafur/lipiodol and epirubicin]

A 56-year-old woman was admitted for advanced gastric cancer (S3H3N3P2 Stage IV). She underwent subtotal gastrectomy, left ovariectomy, and catheterization of the hepatic artery. Pre- and postoperative adjuvant chemotherapies consisting of tegafur, epirubicin, mitomycin C and cisplatin were performed. Two months after surgery, combination of transhepatic arterial and transportal chemoembolization with tegafur 400 mg/lipiodol 3 ml and epirubicin 20 mg was especially effective for this patient. The metastatic lesions of the liver regressed by 85% on computed tomography and the CEA level in the plasma decreased from 51.3 to 5.1 ng/ml. The response was judged partial response (PR), and the patient is now in good general condition.