Pharmacokinetics of heated intraperitoneal oxaliplatin

OBJECTIVE: To evaluate the pharmacokinetic inter-patient variability of 30-min hyperthermic intraperitoneal oxaliplatin chemotherapy. PATIENTS AND METHODS: Data were obtained from 24 patients who were treated according to two procedures of heated intra-operative intraperitoneal oxaliplatin. For the first procedure (12 patients), the solution instilled within the peritoneal cavity contained oxaliplatin, and a delay of 8-10 min was necessary to reach a temperature of 42-43 degrees C. For the second procedure (12 patients), the cavity was initially filled only with the dextrose solution, and oxaliplatin was added to the peritoneal instillate when temperature reached 42-43 degrees C. Plasma and peritoneal fluid oxaliplatin concentrations were analyzed according to a population pharmacokinetic approach using NONMEM. RESULTS: Peritoneal and total plasma data were simultaneously analyzed according to a three-compartment pharmacokinetic model. The peritoneal half-life ranged between 18 and 42 min. The mean peritoneal clearance was 5.47 L/h (+/-21%), and the mean plasma clearance was 3.71 L/h (+/-47%). The heated intra-operative procedure did not have any impact on oxaliplatin pharmacokinetics. CONCLUSION: The inter-individual variability was larger for plasma pharmacokinetic parameters than that for peritoneal parameters. However, the percentage of oxaliplatin dose absorbed during a 30-min hyperthermic intraperitoneal chemotherapy may vary from 40 to 68%. The present pharmacokinetic model will be useful to implement pharmacokinetic evaluation of further clinical trials of hyperthermic intraperitoneal chemotherapy based on platinum compounds' administration.     

Treatment of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: state of the art and future developments

Peritoneal carcinomatosis (PC) had long been regarded as a terminal disease, characterized by a very poor survival and worth treating with palliative therapy. A new strategy combining maximal surgery (cytoreductive surgery, CRS), with maximal regional chemotherapy (hyperthermic intraperitoneal chemotherapy, HIPEC), has been proposed to treat PC, resulting in long-term survival rates in selected patients. The emerging trend is to view localised peritoneal carcinomatosis, in the absence of other metastases, as a regional metastatic disease that is amenable to locoregional therapy. In spite of the need for more high quality studies, many international experts now agree that the use of this new strategy is a gold standard for treating selected patients with PC with the intent of curing. The best results are achieved in patients with limited disease who have completed macroscopic tumor removal. To offer a comprehensive review, we summarized the present status and possible future progress of this treatment modality, in particular outlining its rationale, current practice and general outcome.     

Hyperthermia modifies pharmacokinetics and tissue distribution of intraperitoneal melphalan in a rat model

Background and objectives Peritoneal surface malignancy is a common manifestation of failure of treatment for abdominal cancers. Best results of treatment have been achieved with complete cytoreduction followed by heated intraoperative chemotherapy. Melphalan is a chemotherapeutic agent that shows increased pharmacological activity with heat. But the combination of intraperitoneal administration and heat have never been tested for this drug. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics and tissue distribution of intraperitoneal melphalan in a rodent model.Methods Melphalan was given by the intraperitoneal route to 20 Sprague-Dawley rats at a dose of 12 mg/kg over 90 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (33.5°C) melphalan; group HT received hyperthermic (42°C) melphalan. During the course of intraperitoneal chemotherapy, peritoneal fluid and blood were sampled at 5, 15, 30, 60 and 90 min. At the end of procedure, the rats were killed and tissues samples (heart, liver, ileum, jejunum, colon, omentum, and abdominal wall) were collected. Concentrations of melphalan were determined in peritoneal fluid, plasma, and tissues by high-performance liquid chromatography.Results The area under the curve (AUC) of peritoneal fluid melphalan was significantly lower in the HT group than in the NT group (P=0.001), whereas no significant difference in plasma AUC was found. AUC ratios (AUC peritoneal fluid/AUC plasma) were 12.1 for the NT group and 12.3 for the HT group. The mean time to reach the plasma peak was shorter in the HT group than in the NT group (P=0.004). The HT group exhibited increased melphalan concentrations in all intraabdominal tissues. These differences were significant for the ileum (P=0.03) and jejunum (P=0.04).Conclusion Hyperthermia affected the pharmacokinetics of intraperitoneal melphalan by decreasing the AUC of peritoneal fluid melphalan without increasing the plasma AUC. It increased intraabdominal tissue concentrations.Olivier Glehen is supported by a grant from Fondation de France.     

Cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma: non-mucinous tumour associated with an improved survival

AIMS: Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy has been reported as a treatment option for patients with peritoneal carcinomatosis from colorectal carcinoma. METHODS: Thirty patients with colorectal peritoneal carcinomatosis underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy. All appendiceal cancers were excluded. All patients were followed until January 2006 or death. Univariate analysis was performed to evaluate significant prognostic factors for overall survival, defined from the time of surgery. RESULTS: There were 13 male patients. The mean age at the time of surgery was 54years. There was no hospital mortality. The mean duration of hospital stay was 27days. The overall median survival was 29months, with 1- and 2-year survival of 72% and 64%, respectively. Twenty-one patients had complete cytoreduction and their 1- and 2-year survival rates were 85% and 71%, respectively. Univariate analysis demonstrated that patients with non-mucinous colorectal adenocarcinoma, Peritoneal Cancer Index (PCI) < or =13, and complete cytoreduction were associated with an improved survival. CONCLUSIONS: This study reported on 30 patients who underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis. Patients with mucinous tumour had relatively more extensive intraperitoneal disease. Non-mucinous colorectal adenocarcinoma, PCI < or =13, and complete cytoreduction were associated with an improved survival.     

活性炭吸附丝裂霉素C腹腔化疗的药代动力学研究

目的探讨活性炭吸附丝裂霉素C（MMC—CH）腹腔化疗的药代动力学特征。方法建立人胃癌裸鼠模型,分别采取静脉注射MMC、腹腔注射水剂MMC及腹腔注射MMC—CH的给药方式,于给药后不同时间点,采用高效液相色谱法测定淋巴结、大网膜、血浆及腹腔液的MMC浓度,分析不同给药方法的药物代谢动力学特征。结果MMC—CH腹腔化疗可以在腹腔液、大网膜和淋巴结形成高药物浓度,并可维持24h以上,血浆药物浓度低。水剂MMC腹腔化疗可以形成短暂的腹腔液高药物浓度,但足不能在血浆、大网膜及淋巴结中形成高药物浓度。静脉MMC化疗可以在大网膜内形成短暂的高药物浓度,但是腹腔液和淋巴结药物浓度低,血浆药物浓度高。结论MMC—CH腹腔化疗可以在腹腔液、大网膜和淋巴结内形成持续24h以上的高药物浓度,同时血药浓度非常低。MMC—CH腹腔化疗是一种有效的辅助治疗方法,并可以达到淋巴化疗目的。     

Pharmacokinetic changes induced by the volume of chemotherapy solution in patients treated with hyperthermic intraperitoneal mitomycin C

Background: The rationale supporting the use of intraperitoneal chemotherapy in peritoneal surface malignancy relates to a large local–regional effect and low systemic toxicity. While optimizing the use of this treatment strategy, little information regarding the effect of volume of chemotherapy solution is available. Objective: The goal of this study was to provide data regarding the effect of volume of chemotherapy solution on the pharmacokinetics of intraperitoneal chemotherapy. Data by which to optimally adjust this parameter during intraperitoneal chemotherapy treatments were sought. Methods: Forty-eight patients with peritoneal surface malignancy were treated with hyperthermic intraperitoneal mitomycin C chemotherapy after a complete cytoreduction to remove all visible evidence of mucinous tumor. The dose of mitomycin C was always 12.5 mg/m² in males and 10 mg/m² in females. The first 12 patients were treated with 6 l of 1.5% dextrose peritoneal dialysis solution. The next 14 patients were treated with 4 l of fluid and then ten patients were treated with 2 l. In the last 12 patients the volume of fluid was 1.5 l/m² . Blood, peritoneal fluid, and urine samples were obtained every 15 min for 90 min; additional blood and urine samples were obtained at 120 min. Mitomycin C concentrations, urine volumes, and final intraperitoneal fluid volume were obtained. Results: The intraperitoneal and the plasma concentrations were highest in the 2-l group, less in the 4-l group, and least in the 6-l group. All differences were statistically significant. Also, the percent of mitomycin C absorbed decreased significantly from 2, to 4, to 6 l of fluid. The area under the curve (AUC) ratio of intraperitoneal concentration times time to intravenous concentration times time was 27.01±4.92 for 2 l, 22.22±7.95 for 4 l, and 24.01±8.46 for 6 l. These differences were not statistically significant. If both the volume of chemotherapy solution and the total dose of mitomycin C were determined from the body surface area, the pharmacokinetics of intraperitoneal mitomycin C were more consistent. Conclusions: In order to prescribe a uniform treatment for patients receiving hyperthermic intraperitoneal mitomycin C, the total dose of the drug and the total volume of chemotherapy solution should be determined from the body surface area. If the volume of chemotherapy solution is not based on patient body surface area, predictions regarding toxicity are less precise.     

The many faces of intraperitoneal chemotherapy

Cytoreductive surgery and intraperitoneal chemotherapy may offer chance for cure for patients with peritoneal metastasis. Many variations emerged, causing uncertainty when choosing the most suitable variant. By reviewing variability encountered in the management of peritoneal metastasis, we aim to raise awareness about this issue and hopefully initiate efforts to solve it.We review variance encountered in all aspects of this complex field of surgical oncology, indications, patient selection criteria, definition and extent of cytoreductive surgery and the numerous variables of intraperitoneal chemotherapy.Best benefit was achieved with pseudomyxoma peritonei, and to lesser extent in colorectal, ovarian and gastric cancer, but Indications keep expanding to include other tumors pathologies. Selection of patients depends on numerous prognostic indicators and criteria, according to tumor extent and pathology. The standard definition of cytoreductive surgery remains the same, but the boundaries of resection expand. Numerous chemotherapy regimens and administration methods are used, in search for best possible benefit.This variance must be reduced, to make the best use of, and further spread this treatment combination. Practical simple guidelines are needed for surgical oncologists willing to utilize this treatment for their patients, to be considered a true standard of care.     

Outcome following incomplete surgical cytoreduction combined with intraperitoneal chemotherapy for colorectal peritoneal metastases

Cytoreductive surgery combined with intraperitoneal chemotherapy can improve survival in appropriately selected patients with colorectal peritoneal metastases. Outcomes are best in those patients in whom a complete cytoreduction can be achieved. Unresectable disease is however encountered in approximately one-quarter of patients at laparotomy. The merits, or otherwise, of proceeding with an incomplete cytoreduction in this setting are unclear. We performed a review of published outcomes following incomplete cytoreduction for colorectal peritoneal metastases. Using the electronic databases, PubMed and MEDLINE, a systematic search of available literature published during the period January 1997 to September 2014 was conducted. Following application of exclusion criteria, 19 papers were identified and included in this review. These comprised fifteen case series, 3 case control studies and one randomised control trial. In the nineteen studies included in this review, 2790 patients underwent cytoreductive surgery with or without intraperitoneal chemotherapy for peritoneal metastases of colorectal origin. Of these, 1732 (62%) underwent a complete cytoreduction while 986 (35%) patients underwent an incomplete cytoreduction. Median survival in the complete cytoreduction group ranged from 11 to 62 mo while survival in the latter group ranged from 2.4 to 32 mo. Of the 986 patients with an incomplete cytoreduction, 331 patients received intraperitoneal chemotherapy and survival in this cohort ranged from 4.5 to 32 mo. An incomplete cytoreduction, with or without intraperitoneal chemotherapy, does not appear to confer a survival benefit. The limited available data points to a palliative benefit in a subset of patients. In the absence of high quality data, the decision as to whether or not to proceed with surgery should be made on an individual patient basis.     

Two-stage operative cytoreduction and intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma: Operative morbidity and mortality in phase I and II trials

Aims

The standard of care for diffuse malignant peritoneal mesothelioma involves operative cytoreduction and intraperitoneal chemotherapy. Most centers favor aggressive operative cytoreduction, accepting high morbidity and mortality. In our trials, patients underwent less extensive cytoreduction followed by prolonged intraperitoneal chemotherapy. Patients underwent a second cytoreduction with heated intraperitoneal chemotherapy. We hypothesized this would result in lower operative morbidity and mortality with similar survival.

Methods

Hospital records, discharge summaries, microbiology, radiography, and office records were retrospectively reviewed to supplement a prospective database. 30-day morbidity and mortality were categorized, and classified according to the Clavien methodology.

Results

47 first and 39 second operations were performed with 13% and 26% morbidity, respectively. Mortality was 2%. Infections comprised 59% of the morbidity. Inclusive of both operations, formal peritonectomy was performed in 16% of patients, resection of isolated lesions in less than half, and only 19% had a visceral organs other than the spleen resected. At the completion of the protocol, only 3% of patients had visible intraperitoneal disease. The mean total length of stay for both operations combined was 16 ± 23 days. Overall median survival was 54.9 months, and median survival for the epithelioid subtype was 70.2 months.

Conclusions

A two-stage cytoreduction with intraperitoneal chemotherapy offers median survival comparable to one-stage protocols, with relatively low morbidity, mortality, visceral resections and length of stay despite two operations. This series supports that our protocol is a feasible and safe approach.     

Cytoreductive surgery and intraperitoneal chemotherapy for peritoneal mesothelioma

Aims

Peritoneal mesothelioma is a rare disease and traditionally has been associated with a gloomy prognosis. The present study aimed to report the outcomes following surgery and intraperitoneal chemotherapy in selected patients with peritoneal mesothelioma.

Methods

Clinicopathological features, operative procedures, early outcomes and survival were analysed for 17 consecutive patients who underwent surgery for peritoneal mesothelioma between 1998 and 2007. Seventeen consecutive patients who underwent surgery for peritoneal mesothelioma between 1998 and 2007 were analysed for clinicopathological features, operative procedures, early outcomes and survival.

Results

Seventeen patients underwent 18 laparotomies. Most presented with abdominal distension (71%) and abdominal pain or discomfort (53%). Complete cytoreduction was achieved in 8 patients, major debulking in 8, and 1 patient had an exploratory laparotomy only due to extensive disease. One patient died on day 30 postoperatively due to a chest infection and pulmonary embolism. The median survival for 8 patients who underwent complete cytoreduction was 3.7 years (range, 0.7–6.9), whereas that for 8 patients with palliative debulking was 1.0 years year (range, 0.3–5.7). Among the 12 patients who had significant ascites as a presenting symptom, 10 reported good palliation of ascites.

Conclusions

Cytoreductive surgery combined with intraperitoneal chemotherapy appears to be the optimal treatment for selected patients with peritoneal mesothelioma. Increased familiarity with this condition's presentation and natural history, and knowledge of available treatment options, will hopefully facilitate treatment of these patients and expedite speedy referral to appropriate treatment centres.     

Postoperative adverse events and long-term survival after cytoreductive surgery and intraperitoneal chemotherapy

Background

Peritoneal carcinomatosis (PC) is fatal without special combined cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC). This study was designed to identify factors that may increase the risk of postoperative morbidity and mortality from combined CRS and IPC interventions for PC. Survival based on primary tumour type and extent of surgery is reported.

Methods

Between May 1991 and November 2004, 123 patients were treated with CRS and IPC for PC. Based on the National Cancer Institute Common Toxicity Criteria for grade 3 and 4, data on 30 days postoperative morbidity and 90 days mortality were analysed.

Results

Grade 3–4 adverse events were observed in 51 patients (41%) and were associated with stoma formation, duration of surgery, peroperative blood loss and peritoneal cancer index (PCI). Excision, or electrocautery evaporation, of tumour from small bowel surface was correlated to bowel morbidity. Five patients had treatment-related mortality (4%) within 90 days. Survival was associated with macroscopic radical surgery, prior surgical score, PCI and primary tumour type.

Conclusions

CRS and IPC for PC are associated with high morbidity and mortality. However, in light of the potential benefit indicated by long-term survival, the adverse event from this treatment is considered acceptable.     

A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin

Purpose  A pharmacologic analysis of intracavitary doxorubicin in the treatment of patients with intracavitary cancer dissemination was performed to further evaluate the possible benefits of this treatment modality. Methods  Twenty appendiceal malignancy patients with peritoneal carcinomatosis (PC), three appendiceal malignancy patients with direct extension into the pleural cavity, 20 patients with peritoneal mesothelioma and one patient with pleural mesothelioma were available for pharmacologic monitoring. After intraperitoneal or intrapleural administration of doxorubicin, plasma and peritoneal fluid samples were obtained at 15, 30, 45, 60 and 90 min in all patients. After intrapleural administration, plasma and pleural fluid samples were collected at similar intervals. Tumor and normal tissues were obtained when available. Doxorubicin concentrations were determined by high-performance liquid chromatography (HPLC). Results  Intraperitoneal doxorubicin showed a prolonged retention in the peritoneal cavity. Doxorubicin concentrations in tumor tissue were consistently elevated above intraperitoneal concentrations from 30 through 90 min. For appendiceal malignancy, the concentrations of doxorubicin were significantly higher in minimally aggressive mucinous tumors. Pleural chemotherapy solutions retained doxorubicin to a greater extent than peritoneal fluid. Conclusions  Doxorubicin shows characteristics favorable for intracavitary administration with sequestration of doxorubicin in cancer nodules.     

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。     

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.     

Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model

Background: The cytotoxic effect of several anticancer agents, including doxorubicin, can be enhanced by hyperthermia. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics, metabolism, and tissue distribution of intraperitoneal (i.p.) doxorubicin in a rodent model. Methods: Doxorubicin was given i.p. to 20 Sprague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (37 °C) i.p. doxorubicin; group HT received hyperthermic (43 °C) i.p. doxorubicin. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled every 10 min. At the end of the procedure, rats were sacrificed and tissue samples (liver, spleen, small bowel, omentum, bladder, diaphragm, abdominal wall, heart) were collected. Concentrations of doxorubicin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC. Results: No significant differences in areas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all intraabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in plasma aglycone AUC for group HT when compared with group NT. Group HT exhibited increased aglycone concentration for all tissues. This difference was significant for liver (P < 0.001) and bladder (P < 0.001). Conclusion: Hyperthermia did not affect significantly the pharmacokinetics of i.p. doxorubicin. Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, liver, and bladder. Received: 14 August 1996 / Accepted: 12 May 1997     

A pharmacological review on intraperitoneal chemotherapy for peritoneal malignancy

Perioperative intraperitoneal chemotherapy in combination with cytoreductive surgery has been shown to be of benefit for treating selected patients with peritoneal surface malignancy. It has become a new standard of care in the management of diffuse malignant peritoneal mesothelioma and peritoneal dissemination of appendiceal malignancy. Numerous recent publications on carcinomatosis from colorectal cancer and gastric cancer identify groups of patients that would benefit from this local-regional approach for prevention and treatment of carcinomatosis. This review focuses on pharmacological information regarding intraperitoneal chemotherapeutic agents commonly used in gastrointestinal oncology.     

Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous Vasopressin in non-resectable pancreas cancer

Background: Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity.Aim: To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer.Patients/methods: Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal5-FU instillation 750–1500 mg/m² and intravenous Leucovorin 100 mg/m² for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed.Results: The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8–54.1+), and median survival was 8.0 months (0.8–54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4 ± 2.5 and 6.1 ± 5.4 mol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment.Conclusion: Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.     

Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial

BackgroundFirst-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm).MethodsPatients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m²/d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity.ResultsThe study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27–0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5-year PFS. Grade III–IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities.ConclusionsCytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials.gov nr:NCT01524094).     

Pharmacokinetics and tissue distribution of intraperitoneal paclitaxel with different carrier solutions

Background For cancers that have disseminated to peritoneal surfaces, intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of paclitaxel infused intraperitoneally in two isotonic carrier solutions: 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution.Methods A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal paclitaxel (40 mg/m²) in 0.1 ml/g body weight of each carrier solution. Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded. Blood and tissues were sampled using a standardized protocol. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography.Results Fluid clearance from the peritoneal cavity was lower in the presence of hetastarch than in the presence of peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 18 h (P=0.0079). No excess peritoneal fluid remained with peritoneal dialysis solution at 24 h. Mean plasma paclitaxel concentrations were significantly lower with hetastarch at 3 h (P=0.0079), 12 h (P=0.0079), and 18 h (P=0.0317). The mean total quantity of drug remaining in the peritoneal cavity was significantly greater with hetastarch at 12 h (P=0.0079) and 18 h (P=0.0317). There was a 105% increase in the area under the curve ratio of peritoneal fluid to plasma paclitaxel concentrations with hetastarch (391) vs peritoneal dialysis solution (191). Paclitaxel concentrations were significantly greater with peritoneal dialysis solution at 6 h in colon, abdominal wall, and myocardium.Conclusions The use of intraperitoneal paclitaxel with hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual tumor cells with decreased systemic toxicity. Clinical investigations into the use of 6% hetastarch with high molecular weight chemotherapeutic agents are warranted.