羟基喜树碱两种不同给药途径的药动学研究

目的:比较羟基喜树碱(10-hydroxycamptothecin,HCPT)腹腔内和外周静脉两种不同给药途径的药动学特点。方法:比格犬12只,随机分为两组,每组6只。2 mg/kg HCPT溶于生理盐水10 mL中,腹腔内给药组先腹腔内注入生理盐水290 mL,随后用恒速泵快速注入HCPT;外周静脉给药组腹腔内注入生理盐水300 mL,于股静脉中用恒速泵快速注入HCPT。随后按不同时间点抽取血液和腹腔液,各样本用高效液相色谱分析药物浓度,并用3P87软件包计算药动学参数。结果:HCPT给药1 h后,腹腔给药组的门静脉浓度和外周静脉浓度持续超过外周静脉给药组,两组间门静脉浓度和外周静脉浓度的AUC比分别为为1.08∶1和1.45∶1。腹腔内给药组的腹腔液HCPT浓度明显高于外周静脉给药组的腹腔液浓度,峰值为60.4倍,AUC为21倍,P值均小于0.001。结论:腹腔内给药组其药动学具有明显优越性,能维持腹腔液和门静脉血更高更持久的血药浓度,因而有利于化疗药物发挥更大的生物学效应,值得临床应用。     

Use of hyperthermia versus normothermia during intraperitoneal chemoperfusion with oxaliplatin for colorectal peritoneal carcinomatosis: A propensity score matched analysis

BackgroundHyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is increasingly used in the treatment of colorectal peritoneal carcinomatosis (PC). However, the additional benefit of hyperthermia remains clinically unproven, while it may aggravate postoperative morbidity. Here, we report the correlation of perfusion temperature with postoperative morbidity during clinical HIPEC with OX.Patients and methodsPatients who underwent hyperthermic (41 °C, HT) or normothermic (37 °C, NT) chemoperfusion with OX for colorectal PC were identified from a prospectively kept database of HIPEC cases and matched for baseline characteristics using propensity score (PS) analysis. The groups were compared to assess the impact of perfusion temperature on morbidity. Morbidity was graded using the Clavien-Dindo (CD) classification and the Comprehensive Complication Index (CCI).ResultsOut of 612 patients, 146 patients met the inclusion criteria and from these patients, 45 HT patients were matched with 45 NT patients. Baseline variables were comparable between the PS matched groups. Overall mortality was 0.7% and major morbidity (CD ≥ 3) occurred in 35,6% of patients. There were no significant differences between the HT and NT cohorts in mortality, major morbidity (RR 1.33, 95% CI 0.71 to 2.49, p = 0.36), anastomotic leakage (13.8% versus 11.1%, p = 1.0), hemorrhagic complications, or systemic toxicity. A trend of increased wound infections was observed in the hyperthermia group (13.3% versus 4.4%, P = 0.27).ConclusionsCompared to NT, the use of HT during HIPEC with OX does not aggravate postoperative mortality or morbidity in a high-volume center.     

Oxaliplatin use in pressurized intraperitoneal aerosol chemotherapy (PIPAC) is safe and effective: A multicenter study

IntroductionPressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method used in patients with peritoneal cancer (PC) of primary or secondary origin. Intraperitoneal use of oxaliplatin raises concerns about toxicity, especially abdominal pain. The objective of this study was to assess the tolerance of PIPAC with oxaliplatin (PIPAC-Ox) in a large cohort of patients and to identify the risk factors for high grade toxicity, discontinuation of treatment and impaired survival.Material and methodsThis retrospective cohort study included all consecutive patients treated with PIPAC-Ox (92 mg/m²) in five centers specialized in the treatment of PC. The procedure was repeated every 6 weeks. Outcomes of interest were Common Terminology Criteria for Adverse Events (CTCAE), symptoms and survival (Kaplan-Meier). Univariate risk factors were included in a multinominal regression model to control for bias.ResultsOverall, 251 PIPAC-Ox treatments were performed in 101 patients (45 female) having unresectable PC of various origins: 66 colorectal, 15 gastric, 5 ovarian, 3 mesothelioma, 2 pseudomyxoma, 10 other malignancies (biliary, pancreatic, endocrine) respectively. The median PCI was 19 (IQR: 10–28). Postoperative abdominal pain was present in 23 patients. Out of the 9 patients with grade 3 abdominal pain, only 3 needed a change of PIPAC drug. CTCAE 4.0 toxicity grade 4 or higher was encountered in 16(15.9%) patients. The patients had a mean of 2.5 procedures/patient (SD = 1.5). 50 subjects presented with symptom improvement.ConclusionsOxaliplatin-based PIPAC appears to be a safe treatment that offers good symptom control and promising survival for patients with advanced peritoneal disease.     

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.     

T_3、T_4型胃癌根治术后早期腹腔内化疗36例

（目的）探讨T3、T4型胃癌根治术后早期腹腔内化疗的疗效。（方法）对36例T3、T4型胃癌病人在根治术后早期行腹腔内化疗，并与同期16例T3、T4胃癌根治术后行传统的静脉化疗相比较。（结果）腹腔内化疗用无明显血毒性反应，对肝肾功能无明显影响，未发生严重并发症，能显著报高胃癌根治术后病人的1年、2年、3年生存率，疗效满意。（结论〕腹腔内化疗简便易行，无严重责副反应和并发症，是T3、T4型胃癌病人术后一项颇有前途的辅助化疗措施。     

Effect of carcinomatosis and intraperitoneal 5-fluorouracil on peritoneal blood flow modulated by vasopressin in the rat as measured with the <Superscript>133</Superscript>Xe-clearance technique

Purpose Intraperitoneal administration of 5-fluorouracil for the treatment of gastrointestinal malignancies results in a greater total drug exposure in the peritoneal fluid than in plasma. Drugs are eliminated from the peritoneal cavity mainly by capillaries leading to the portal venous system and to a lesser extent by lymphatics. The drug itself and the presence of peritoneal carcinomatosis may affect elimination of the drug. The ¹³³Xe-clearance technique allows the influence of a vasoactive agent on the peritoneal blood flow to be estimated with minimal invasiveness. The aim of the present study was to explore whether intraperitoneal 5-FU or peritoneal carcinomatosis affects the peritoneal blood flow and its reactivity to intravenous vasopressin, as measured indirectly with the ¹³³Xe-clearance technique.Methods The animals used in this study were 63 Wistar-Fu (W-Fu) rats and 67 Lister-Hooded (LH) rats. On day 0, either 5-FU at 25 mg/kg body weight in 25 ml/kg isotonic saline was instilled intraperitoneally, or 1×10⁵ syngeneic tumour cells were inoculated intraperitoneally. On days 1, 2 and 3 in the 5-FU-treated rats, and on days 12–16 in rats inoculated with tumour cells, peritoneal blood flow was analysed with the ¹³³Xe-clearance technique, before and during intravenous infusion of vasopressin at 0.07 IU/min/kg body weight.Results The basal ¹³³Xe-clearance before administration of vasopressin was similar in all groups except in the LH rats treated with 5-FU in which it was significantly lower. Infusion of vasopressin induced a significant decrease in ¹³³Xe-clearance of the same magnitude in controls and in tumour-bearing rats. In the rats given intraperitoneal 5-FU, vasopressin did not reduce the ¹³³Xe-clearance the first day after administration of 5-FU.Conclusions Intravenous vasopressin at 0.07 IU/min/kg decreased peritoneal blood flow as measured indirectly with the ¹³³Xe-clearance method. Intraperitoneal 5-FU abrogated the reduction in peritoneal blood flow with intravenous vasopressin the first day after treatment. In contrast, the presence of peritoneal carcinomatosis did not influence peritoneal blood flow, nor the effect of vasopressin     

Results of Treatment of 385 Patients With Peritoneal Surface Spread of Appendiceal Malignancy

Introduction: In the past, peritoneal carcinomatosis, regardless of primary tumor type, has always been a lethal condition. Recently, special treatments using cytoreductive surgery with peritonectomy procedures combined with perioperative intraperitoneal chemotherapy have resulted in long-term survival. Appendiceal malignancy with a low incidence of liver and lymph node metastases may be especially appropriate for these aggressive local regional treatments.Methods: All patients treated with surgery before January 1999 are included. Patients left with gross residual disease after surgery were not given intraperitoneal chemotherapy, but were later treated with intravenous chemotherapy. The intraperitoneal chemotherapy was given in the perioperative period, starting with mitomycin C at 12.5 mg/m² for males and 10 mg/m² for females. For patients whose pathology showed adenomucinosis, intraperitoneal chemotherapy was limited to treatment in the operating theater with heated mitomycin C. Patients with mucinous adenocarcinoma or pseudomyxoma/adenocarcinoma hybrid had, in addition to mitomycin C, five consecutive days of intraperitoneal 5-fluorouracil at 650 mg/m2 instilled in 1–1.5 liters of 1.5% dextrose peritoneal dialysis solution. A complete cytoreduction was defined as tumor nodules <2.5 mm in diameter remaining after surgery. The histopathology categorized the patients as having adenomucinosis, adenomucinosis/carcinomatosis hybrid, or mucinous carcinomatosis. A previous surgical score was used to estimate the extent of previous surgical procedures.Results: The morbidity of treated patients was 27% and the mortality was 2.7%. In a multivariate analysis, prognostic factors for survival included the completeness of cytoreduction (P < .0001), the histopathological character of the appendix malignancy (P < .0001), and the extent of previous surgical interventions (P = .001). Patients with a complete cytoreduction and adenomucinosis by pathology had a 5-year survival of 86%; with hybrid pathology, survival at 5 years was 50%. Incomplete cytoreduction had a 5-year survival of 20% and 0% at 10 years.Conclusions: Cytoreductive surgery and perioperative intraperitoneal chemotherapy can be used to salvage selected patients with peritoneal surface spread of appendiceal primary tumors. Similar strategies for other patients with peritoneal surface malignancy such as peritoneal carcinomatosis from colon or gastric cancer, peritoneal sarcomatosis, or peritoneal mesothelioma should be pursued.Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999     

Surgical Debulking and Intraperitoneal Chemotherapy for Established Peritoneal Metastases From Colon and Appendix Cancer

Background: Aggressive treatment of peritoneal metastases from colon cancer by surgical cytoreduction and infusional intraperitoneal (IP) chemotherapy may benefit selected patients. We reviewed our institutional experience to assess patient selection, complications, and outcome.Methods: Patients having surgical debulking and IP 5-fluoro-2-deoxyuridine (FUDR) plus leucovorin (LV) for peritoneal metastases from 1987 to 1999 were evaluated retrospectively.Results: There were 64 patients with a mean age of 50 years. Primary tumor sites were 47 in the colon and 17 in the appendix. Peritoneal metastases were synchronous in 48 patients and metachronous in 16 patients. Patients received IP FUDR (1000 mg/m² daily for 3 days) and IP leucovorin (240 mg/m²) with a median cycle number of 4 (range, 1–28). The median number of complications was 1 (range, 0–5), with no treatment related mortality. Only six patients (9%) required termination of IP chemotherapy because of complications. The median follow-up was 17 months (range, 0–132 months). The median survival was 34 months (range, 2–132); 5-year survival was 28%. Lymph node status, tumor grade, and interval to peritoneal metastasis were not statistically significant prognostic factors for survival. Complete tumor resection was significant on multivariate analysis (P = .04), with a 5-year survival of 54% for complete (n = 19) and 16% for incomplete (n = 45) resection.Conclusions: Surgical debulking and IP FUDR for peritoneal metastases from colon cancer can be accomplished safely and has yielded an overall 5-year survival of 28%. Complete resection is associated with improved survival (54% at 5 years) and is the most important prognostic indicator.Presented in part at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.     

A comparison of primary intraperitoneal chemotherapy to consolidation intraperitoneal chemotherapy in optimally resected advanced ovarian cancer

Objective

To compare survival outcomes for patients with advanced epithelial ovarian cancer (EOC) who received primary intravenous/intraperitoneal (IV/IP) chemotherapy to those who received IV followed by consolidation (treatment given to patients in remission) IP chemotherapy.

Methods

Data were analyzed and compared for all patients with stage III–IV EOC who underwent optimal primary cytoreduction (residual disease ≤ 1 cm) followed by cisplatin-based consolidation IP chemotherapy (1/2001–12/2005) or primary IV/IP chemotherapy (1/2005–7/2011).

Results

We identified 224 patients; 62 (28%) received IV followed by consolidation IP chemotherapy and 162 (72%) received primary IV/IP chemotherapy. The primary IP group had significantly more patients with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites. There were no differences in residual disease at the end of cytoreduction between both groups. The median progression-free survival (PFS) was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57–1.06; p = 0.11). The median overall survival (OS) was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38–0.83; p = 0.004). On multivariate analysis, after adjusting for confounders, the difference in PFS was not significant (HR 0.78; 95% CI, 0.56–1.11; p = 0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39–0.89; p = 0.01).

Conclusions

In our study, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP chemotherapy in patients with optimally cytoreduced advanced EOC.     

腹腔热化疗治疗癌性腹水的临床研究

目的：探讨腹腔热化疗治疗癌性腹腔积液的临床疗效和毒副作用，方法：将60例癌性腹水病人随机分成两组：腹腔热化疗组和腹腔化疗组，每组30例，化疗方案为FP方案（5－FU和DDP）。结果：腹腔热化疗组有效率为83．3％，腹腔化疗有效率为56．7％，两组统计学上有明显差异（P＜0．05）。结论：腹腔化疗是治疗癌性腹腔积液较有效的方法之一，值得临床推广。