Experimental study on intraperitoneal versus intravenous CPT-11 for peritoneal seeding and liver metastasis

Paclitaxel is an effective antitumor agent that shows ideal pharmacological characteristics for intraperitoneal chemotherapy. Intraperitoneal administration of this agent was compared with intravenous administration in mouse models of peritoneal seeding and liver metastasis. The peritoneal seeding model and liver metastasis model were established by inoculation of Colon 26 tumor cells into the peritoneal cavity and spleen of female BALB/c mice, respectively. Paclitaxel (20 mg/kg) was injected into the peritoneal seeding model intraperitoneally or intravenously on day 2 and 4 after inoculation of tumor cells. Paclitaxel (30 mg/kg) was injected into the liver metastasis model intraperitoneally and intravenously on days 4 and 8 after inoculation of tumor cells. Median survival time for intraperitoneal administration (17.50 +/- 0.86 days) was longer than that for intravenous administration (13.70 +/- 0.47 days) in the peritoneal seeding model experiment. Median survival time for intraperitoneal administration (19.78 +/- 0.74 days) was longer than that for intravenous administration (17.50 +/- 0.54 days) in the liver metastasis model experiment. Intraperitoneal administration of paclitaxel may be a more efficient form of adjuvant chemotherapy for prevention of both peritoneal seeding and liver metastasis in patients with gastrointestinal cancer.     

Experimental study on CPT-11 intraperitoneal chemotherapy--metabolism of CPT-11 in malignant ascites

The metabolism of CPT-11 in malignant ascites of gastric cancer patients with peritoneal seedings was studied in advance of the intraperitoneal chemotherapy of CPT-11 in humans. Malignant ascites and blood were drawn from gastric cancer patients. CPT-11 solution (20 mg/ml; 0.2 ml) was added into 3.8 ml ascites or plasma under 37 degrees C and CPT-11, SN-38 and SN-38GLU concentrations were measured with HPLC at times of 5, 30 and 60 minutes after addition of CPT-11. The change from CPT-11 to SN-38 was minimal not only in plasma, but also in malignant ascites. SN-38 GLU concentration was below the limit of measurement. This study showed that in malignant ascites, the enzymes such as carboxyesterase that convert CPT-11 to SN-38 were not present or minimal.     

Experimental study on intraperitoneal and intravenous administration of anti-tumor agents for liver metastasis

Intraperitoneal chemotherapy has been the treatment for peritoneal seedings. Most of the anti-tumor agent administered intraperitoneally is absorbed from visceral peritoneum, gets into the portal vein system and reaches the liver. Theoretically, intraperitoneal administration of anti-tumor agents must show equivalent effects on the liver metastasis to portal vein infusion. We compared the efficacy of intraperitoneal and intravenous administration of 5-FU, CDDP and CPT-11, using colon 26 mouse liver metastasis model. Intraperitoneal administration of 5-FU or CPT-11 was statistically superior to intravenous administration to diminish the liver metastatic deposits. CDDP experiment did not show a statistical difference, but the superiority intraperitoneal administration was recognized. Intraperitoneal administration of anti-tumor agents is more effective for not only peritoneal seedings but also liver metastases than intravenous administration. Intraperitoneal chemotherapy might be an effective adjuvant chemotherapy for gastrointestinal malignancies.     

Experimental study on intraperitoneal administration of 5-fluorouracil for liver metastasis in comparison with intravenous administration

We studied the effects of 5-fluorouracil intraperitoneal administration using mouse liver metastasis model. We inoculated 50 microliters Colon26 cell suspension into the spleen and resected it 15 min after cell inoculation under general anesthesia with Ketamine. Control group (n = 7) had no treatment. The intraperitoneal (i.p.) group (n = 8) and intravenous (i.v.) group (n = 7) underwent the treatment on the 2nd and 4th day after the operation. Experimental chemotherapies consisted of 1.5 ml 5-fluorouracil solution (50 mg/kg) for i.p. group and 0.2 ml 5-fluorouracil solution (50 mg/kg) for i.v. group. On the 14th day after the cell implantation, necropsies were performed. Deposits on mouse livers were counted and the mouse livers weighted. Counting of metastatic liver deposits revealed the number of deposits in the control group was 25.6 +/- 12.9, against 2.9 +/- 1.9 and 16.0 +/- 15.6, in the i.p. and i.v. group, respectively. Significant differences in the number of liver deposits were obtained between the control group and i.p. group, and between i.p. group and i.v. group (p < 0.05). The mean liver weight (mg)/mouse body weight (g) were 76.3 +/- 24.7 in the control group, 54.3 +/- 4.7 in the i.p. group and 60.0 +/- 12.7 in the i.v. group. A significant difference was observed only between the control group and the i.p. group (p < 0.05). I.p. administration of 5-fluorouracil was superior to i.v. administration for control of the liver metastasis. Moreover, the side effect by 5-fluorouracil i.p. treatment was milder than by i.v. therapy. We confirmed the effectiveness of 5-fluorouracil intraperitoneal chemotherapy for the potential liver metastasis and liver micrometastasis. Intraperitoneal chemotherapy is also useful for peritoneal seeding. We think intraperitoneal chemotherapy is a recommendable administration route for gastrointestinal malignancies.     

Liver concentration of CPT-11, SN-38 and SN-38 GLU in intraperitoneal and intravenous administration of CPT-11

Our previous mouse experiment showed intraperitoneal administration of CPT-11 was more effective not only for peritoneal seeding but for liver metastases than intravenous administration of CPT-11. We studied tissue concentrations of the liver when CPT-11 was administered intraperitoneally or intravenously for ICR mice. Mice liver was resected at 15 min, 1, 2, 4, 8 and 26 hours after intraperitoneal or intravenous administration of 40 mg/kg CPT-11. CPT-11, SN-38 and SN-38 GLU were measured with HPLC. The liver concentration of CPT-11 at 15 min after intravenous administration was higher than after intraperitoneal administration. A higher liver CPT-11 concentration was prolonged in the intraperitoneal administration group. No differences were demonstrated in the concentrations of SN-38 and SN-38 GLU between i.p. and i.v. groups.     

Pharmacokinetic study of the intraperitoneal administration of CPT-11 for patients with peritoneal seedings of gastric and colonic cancers]

We studied the pharmacokinetics of the intraperitoneal administration of CPT-11 for four patients with peritoneal metastasis (2 gastric cancer cases, 2 colon cancer cases). CPT-11 was administrated in a dose of 40-60 mg and the intraperitoneal and serum levels of CPT-11, SN-38 and SN-38 glucuronized (SN-38 Glu) were measured periodically. Intraperitoneal therapy with CPT-11 was effective for the control of malignant ascites. No serious side effects were observed. The levels of CPT-11, SN-38 were no different 30 min afterwards the administration of CPT-11 either intraperitoneally or intravenously. The high concentration of CPT-11 was achieved with intraperitoneal therapy and a small fraction of CPT-11 changed into SN-38 in the abdominal cavity.     

Cisplatin and irinotecan (CPT-11) for peritoneal mesothelioma

Peritoneal mesothelioma is a rare malignancy that is seen in patients exposed to asbestos or in young women with no known exposure to asbestos. The clinical features of the disease are similar in these two groups, and include peritoneal carcinomatosis, ascites, thrombocytemia, systemic symptoms (fever and night sweats), and hypercoagulability. There is no known curative therapy for this disease. Cisplatin has activity in 25% of patients. Mesothelial cells are known to contain high levels of carboxylesterase, a key enzyme in the activation of Irinotecan (CPT-11) to SN-38. This retrospective review of our experience in combining cisplatin 50 or 60 mg/m² IV or i.p. on day 1 with CPT-11 50 or 60 mg/m² IV on day 1, 8, and 15. Courses were repeated every 4 weeks×6. If i.p. administration of cisplatin were feasible, it was the preferred route. Response to treatment was based on RECIST criteria.

Fourteen men and 3 women, median age 62 years (35-76 years) and median PS 1 (0-2) were treated. Median number of courses was two for nonresponders and six for responders. The overall response rate was 24%, but 76% of patients improved on treatment. Median survival is not reached. Grade ≥2 side effects included anemia (n=6), neutropenia (n=3), nausea/vomiting (n=4), and constipation (n=2). Grade 1 side effects were fatigue, anorexia, weight loss, alopecia, diarrhea, neuropathy, and gastric reflux. There were no grade ≥3 hematologic toxicities.

The combination of cisplatin and CPT-11 is well tolerated and has clinical benefits in patients with peritoneal mesothelioma.     

Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis

BackgroundA phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis.Patients and methodsGastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m² and i.p. at 20 mg/m² on days 1 and 8. S-1 was administered at 80 mg/m²/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety.ResultsForty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1–23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%).ConclusionCombination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.     

Pharmacokinetic study of CPT-11, SN-38 and SN-38 glucuronide in the ascites,plasma and bile after intraperitoneal administration of CPT-11

We studied the pharmacokinetics of CPT-11 with intraperitoneal administration in a patient with a PTCD tube. The patient had advanced gastric cancer with peritoneal metastasis. CPT-11 was administrated in a dose of 40 mg and the intraperitoneal, plasma and bile levels of CPT-11, SN-38 and SN-38 glucuronide (SN-38 GLU) were measured periodically. The results showed that the periodical concentration pattern of CPT-11, SN-38 and SN-38 GLU in the bile was closely related to that of CPT-11 in the abdominal cavity.     

Phase I study of intraperitoneal irinotecan in patients with gastric adenocarcinoma with peritoneal seeding

Purpose

The objectives of this phase I study were to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of intraperitoneally administered irinotecan (CPT-11) in gastric cancer patients with peritoneal seeding.

Experimental design

Gastric adenocarcinoma patients with surgical biopsy proven peritoneal seeding were enrolled at the time of surgery. Prior to IP chemotherapy, patients underwent palliative gastrectomy and CAPD catheter insertion in which CPT-11 was administered on postoperative day 1. The IP CPT-11 was initiated at 50?mg/m², which was escalated to 100, 150, 200, 250, and 300?mg/m². IP CPT-11 chemotherapy was repeated every 3?weeks.

Results

Seventeen patients received a total of 56?cycles at five different CPT-11 dose levels. The DLTs were neutropenic fever, neutropenia, and diarrhea. At the dose level 2 (100?mg/m²), there were one DLTs in one of the first cohort of three patients, but no DLTs at the second cohort of this level. At the dose level 5 (250?mg/m²), two DLTs were detected in the first two patients; thus, the accrual was stopped resulting in the recommended dose of IP CPT-11 of 200?mg/m². Median progression-free survival was 8.6?months (95% CI, 5.9,11.2), and median overall survival was 15.6?months (95% CI, 8.4,22.8). Pharmacokinetic results of the study showed that the C _max of peritoneal SN-38 was achieved earlier than that of plasma SN-38.

Conclusions

Intraperitoneally administered CPT-11 was feasible and tolerable. Further, phase II study of IP CPT-11 in gastric cancer patients with peritoneal seeding is warranted.     

开普拓+希罗达方案介入及全身化疗治疗大肠癌肝转移的临床疗效

目的：评价开普拓＋希罗达方案（XELILI方案）介入及全身化疗治疗大肠癌肝转移的疗效及毒副作用。方法：病理确诊的大肠癌患者50例,其中45例为根治术后FOLFOX4方案化疗后出现肝转移,5例为初治者。术前常规检查除外治疗禁忌症并CT扫描测量肝转移灶大小,予以开普拓＋希罗达方案介入栓塞化疗序贯全身化疗,开普拓用量：180mg/m^2,碘化油10ml～20ml,希罗达2000mg/m^2,分两次口服,连服14天,休息7天,21天一周期。2周期后复查血常规、肝肾功能、腹部CT,判断疗效及是否进一步介入治疗,若肝转移灶及原发灶CR,继续静脉点滴开普拓,口服希罗达化疗至6个周期;PR者经皮肝穿瘤内注射盐酸;PD者改含贝伐单抗方案化疗。结果：CR8例,PR25例,SD10例,PD7例,总有效率为66%（34/50）,主要毒副反应为栓塞后综合征、急性胆碱能综合症及骨髓抑制,5例出现轻中度肝功能损害,4例迟发性腹泻。随访3年,疾病进展时间为7个月,中位生存期为25个月。结论：开普拓＋希罗达方案介入结合全身治疗大肠癌肝转移是安全、有效的,但两者配合的标准方案尚待研究。     

Comparison of intravenous versus intraperitoneal administration of oncolytic herpes simplex virus 1 for peritoneal carcinomatosis in mice

hrR3 is an oncolytic herpes simplex virus 1 (HSV-1) mutant that replicates preferentially in tumors compared with normal tissues. Portal venous administration of hrR3 in mice bearing diffuse colorectal carcinoma liver metastases significantly reduces tumor burden and prolongs animal survival. In this study, we compared survival benefit and biodistribution of hrR3 following intravenous (i.v.) administration versus intraperitoneal (i.p.) administration in immunocompetent mice bearing colon carcinoma peritoneal metastases. Mice bearing peritoneal metastases received 1 x 10(8) plaque-forming units hrR3 or mock-infected media every other day for three doses and were randomized to have the viruses administered by either an i.p. or i.v. route. Biodistribution was assessed by PCR amplification of HSV-1-specific sequences from tumor and normal tissues including the small bowel, liver, spleen, kidney, lung, heart and brain. LD(50) for i.p. administration was compared with the LD(50) for i.v. administration. In subsequent experiments, animals were monitored for survival. The frequency of HSV-1 detection in peritoneal tumors was similar in mice randomized to either i.p. or i.v. administration. However, i.p. administration resulted in a more restricted systemic biodistribution, with a reduced frequency of virus detected in the kidney, lung and heart. The LD(50) associated with i.p. administration was higher than that with i.v. administration. Tumor burden was more effectively reduced with i.p. compared with i.v. administration. Median survival following i.p. administration was approximately twice that observed with i.v. administration. I.p. administration of an HSV-1 oncolytic mutant is associated with a more restricted biodistribution, less toxicity and greater efficacy against peritoneal metastases compared with i.v. administration.     

Successful treatment of liver metastasis and extrahepatic metastasis with hepatic arterial infusion of CDDP, CPT-11, and 5-FU

A 63-year-old man, who had been operated with right hemicolectomy 1 year and 3 months ago, had giant liver metastasis, lung metastasis, and local dissemination tumor due to ascending colon cancer. He was treated by systemic chemotherapy with 5-FU and the treatment evaluation was PD on CT. After admission to our hospital, he was treated by hepatic arterial infusion chemotherapy with CDDP, CPT-11, and 5-FU. After 3 courses of the treatment, each recurrent lesion decreased on CT and the CEA level decreased. There were no side effects except mild diarrhea. We believe hepatic arterial infusion chemotherapy with CDDP, CPT-11, and 5-FU may be an effective strategy against liver metastasis and extrahepatic metastsis due to colon cancer.     

CPT-11 hepatic arterial injection plus oral UFT administration for liver metastasis of rectal cancer--report of two cases

The first patient was a 51-year-old male who had 5-fluorouracil-resistant recurrent rectal cancer with multiple liver metastases. He was given our new combination chemotherapy consisting of hepatic arterial injection of CPT-11 (20 mg/body) on day 1 and day 2 and oral administration of UFT (300 mg/day) on days 3 to 6 of a 7 day cycle starting in January 2001. Six weeks after the beginning of chemotherapy, the liver metastatic lesions were reduced. He is now living with outpatient treatment. The second patient was a 76-year-old male who had initial recurrent rectal cancer with multiple liver metastases. Thirty-two weeks after the same chemotherapy, the metastatic lesions had completely disappeared. Twelve months have passed since this chemotherapy, and we have not found any recurrent tumor. While significant antitumor effects were observed, there were few adverse events in either patient. These results suggest that combined chemotherapy of CPT-11 by hepatic arterial injection and oral administration of UFT is an effective treatment for liver metastases of rectal cancer.     

Feasibility study of postoperative intraperitoneal hyperthermochemotherapy by radiofrequency capacitive heating system for advanced gastric cancer with peritoneal seeding

Background: Gastric carcinoma patients with peritoneal dissemination have an extremely poor prognosis. Attempting to improve regional control and decrease the risk of complications related to hyperthermic chemotherapy, we applied a new treatment modality using a combination of gastrectomy with postoperative intraperitoneal hyperthermo-chemotherapy (PIHC) using Thermotron RF-8. The purpose of this study was to evaluate the feasibility of PIHC in advanced gastric carcinoma patients with peritoneal seeding.

Patients and methods: Between March 2002 and April 2006, 20 gastric carcinoma patients with peritoneal dissemination were allocated to two groups in the patient's selection. The PIHC group (10 patients) received a 60-min PIHC with a cisplatin dose of 80?mg/m² two weeks after surgery, and the control group (10 patients) received surgery alone. Thermotron RF-8 is a heating device that can raise temperatures in both superficial and deep-seated tumours using 8?MHz radiofrequency electromagnetic waves as a source of heat.

Results: No patients in either group had life-threatening complications. The most frequent nonhaematologic toxicity (grade 3) was nausea. The one-, two-, and three-year cumulative survival rates for the PIHC group were 60%, 48%, and 36%, respectively, whereas those for the control group were 40%, 10%, and 0%, respectively. The survival rates for the PIHC group were significantly higher than those for the control group.

Conclusion: Although this study was conducted non-randomly with a small number of patients, the PIHC group had a higher survival rate and better prognosis compared with the control group.     

Three cases of liver metastasis of colon cancer responding to systemic combination chemotherapy utilizing CPT-11

Though the first choice of treatment for liver metastasis in colon cancer is surgical resection of liver, 30-60% of such patients experience a recurrence of liver metastasis. Even if reoperation is done optimally, the surgical resection of liver metastasis may not be a definitely curative treatment. For cases of liver metastasis from colon cancer that are non-resectable due to multiple liver metastases, other organ metastases (lung, bone, brain etc.), the advanced age of the patient, or other complications (cerebrovascular disease, diabetes mellitus, heart disease etc.), hepatic arterial infusion or systemic combination chemotherapies are selected. In the present paper, we report 3 cases of effective systemic chemotherapy utilizing CPT-11 for liver metastases from colon cancers. The method was UFT + irinotecan (CPT-11), cisplatin (CDDP) + tegafur + CPT-11, UFT + CPT-11 + etoposide (ETP) + pirarubicin (THP). The result obtained was a partial response (PR) in each case. As there were few adverse effects, we could provide treatment during a short-term admission or an outpatient basis. We thus obtained good post-chemotherapeutic QOL, and these regimens may be effective forms of chemotherapies in the future.     

Hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A multicenter propensity score-matched cohort study

ObjectiveSystemic chemotherapy has limited efficacy in the treatment of peritoneal metastasis (PM) in gastric cancer (GC). Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with complete cytoreductive surgery (CRS) has shown promising outcomes but remains controversial. The present study aimed to evaluate the safety and efficacy of HIPEC without CRS in GC patients with PM.MethodsThis retrospective propensity score-matched multicenter cohort study included GC patients with PM treated with either chemotherapy alone (Cx group) or with HIPEC combined with chemotherapy (HIPEC-Cx group) in four Chinese high-volume gastric medical centers between 2010 and 2017. The primary outcomes were median survival time (MST) and 3-year overall survival (OS). Propensity score matching was performed to compensate for controlling potential confounding effects and selection bias.ResultsOf 663 eligible patients, 498 were matched. The MST in the Cx and HIPEC-Cx groups was 10.8 and 15.9 months, respectively [hazard ratio (HR)=0.71, 95% confidence interval (95% CI), 0.58−0.88; P=0.002]. The 3-year OS rate was 10.1% (95% CI, 5.4%−14.8%) and 18.4% (95% CI, 12.3%−24.5%) in the Cx and HIPEC-Cx groups, respectively (P=0.017). The complication rates were comparable. The time to first flatus and length of hospital stay for patients undergoing HIPEC combined with chemotherapy was longer than that of chemotherapy alone (4.6±2.4 dvs. 2.7±1.8 d, P<0.001; 14.2±5.8 dvs. 11.4±7.7 d, P<0.001), respectively. The median follow-up period was 33.2 months. ConclusionsCompared with standard systemic chemotherapy, HIPEC combined with chemotherapy revealed a statistically significant survival benefit for GC patients with PM, without compromising patient safety.     

Surgery after intraperitoneal and systemic chemotherapy for gastric cancer with peritoneal metastasis or positive peritoneal cytology findings

Background

Despite recent progress in systemic chemotherapy, the prognosis of gastric cancer patients with peritoneal metastasis (P1) or positive peritoneal cytology findings (CY1) is still poor. We developed a regimen combining intraperitoneal (IP) paclitaxel (PTX) with S-1 and PTX, which can produce notable efficacy with regard to peritoneal lesions. Surgery after response to combination chemotherapy is a promising option for P1 or CY1 gastric cancer. A retrospective study was performed to evaluate the safety and efficacy.

Methods

This study enrolled 100 primary P1 or CY1 gastric cancer patients treated with IP PTX plus S-1 and PTX at the University of Tokyo Hospital between 2005 and 2011. Radical gastrectomy was performed when peritoneal cytology findings became negative, and the disappearance or obvious shrinkage of peritoneal metastasis was confirmed by laparoscopy. The same chemotherapy regimen was restarted after surgery and repeated with appropriate dose reduction.

Results

Gastrectomy was performed in 64 (P1 56, P0CY1 8) of 100 (P1 90, P0CY1 10) patients. R0 resection was achieved in 44 patients (69%). The median survival time was 30.5 months [95% confidence interval (CI) 23.6–37.7 months] from the initiation of intraperitoneal chemotherapy and 34.6 months (95% CI 26.8–39.4 months) from the diagnosis of gastric cancer. Postoperative complications included anastomotic leakage and pancreatic fistula, each in two patients, which were cured conservatively. There were no treatment-related deaths. The median survival time of the 36 patients who did not undergo surgery was 14.3 months (95% CI 10.0–17.8 months).

Conclusions

Surgery after response to intraperitoneal and systemic chemotherapy is safe and may prolong the survival of P1 and CY1 gastric cancer patients.