Safety and preliminary efficacy of electrostatic precipitation during pressurized intraperitoneal aerosol chemotherapy (PIPAC) for unresectable carcinomatosis

IntroductionPressurized intraperitoneal aerosol chemotherapy (PIPAC) was recently introduced to treat unresectable peritoneal metastases. Adding an electrostatic field may enhance charged droplet precipitation and tissue penetration, resulting in improved anticancer efficacy. We report for the first time its safety and preliminary efficacy.Materials and methodsPatients underwent PIPAC combined with an electrostatic field, using the Ultravision™ apparatus. Adverse events were scored with the Common Terminology Criteria. Treatment response was assessed after more than one PIPAC, using clinical symptoms, tumor markers, CT imaging and histological regression.ResultsForty-eight patients (median age, 61 y) with diverse primary tumors underwent 135 procedures (median per patient, 3). Most (65.2%) were treated as outpatient. Twenty-eight (58.3%) patients received concomitant chemotherapy. The most frequent treatment-related toxicities were anemia (grade 1 to 3, 13 [9.6%]), ileus (grade 1 to 3, 5 [3.7%]), anorexia (grade 1 to 3, 6 [4.4%]), nausea (grade 1 to 3, 5 [3.7%]) and vomiting (grade 1 to 3, 7 [5.2%]). There was no grade 4 or 5 morbidity. Twenty (41.7%) patients did not complete three treatments, mainly because of disease progression (n = 13). After two procedures, there were one responder and 8 non-responders. After three treatments, we observed 11 responders, two patients with stable disease, and 15 non-responders. All but one patient with therapy response received simultaneous chemotherapy.ConclusionElectrostatic precipitation during PIPAC is well tolerated and safe. After three procedures and concomitant chemotherapy, response or stable disease is achieved in approximately half of cases. These findings warrant prospective trials in homogeneous patient cohorts.     

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent

Purpose The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide.Methods Etoposide plasma levels were determined by HPLC.Results The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses.Conclusions The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.Abbreviations AUC_0– Area under the curve from time zero to infinity - C_max Maximum plasma concentration of drug - Cl_tot Total plasma clearance - HPLC High-pressure liquid chromatography - P_oct Octanol-water partition coefficient - t_1/2 Beta phase plasma elimination half-time - t_r Retention time Patricia Schroeder and Kenneth Hofland contributed equally to this work.     

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.     

Hypotonic intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in mice.

The intraperitoneal (i.p.) administration of cisplatin (CDDP) is one of the most effective therapies for cancers that are confined to the abdominal cavity. However, the effect of fluid osmolarity on the therapeutic efficacy of i.p. administration of CDDP has not been well established. In the current study, hypotonic (154 mosmol 1-1), isotonic (308 mosmol 1-1) and hypertonic (616 mosmol 1-1) solutions of CDDP were prepared for an evaluation of their therapeutic efficacy in an experimental system. After i.p. administration, uptake of CDDP in vivo by tumor cells in hypotonic solution was significantly greater than in isotonic or hypertonic solution. The 50% lethal dose (LD50) value of CDDP in hypotonic solution (12.1 mg kg(-1)) was lower than that in isotonic solution (16.9 mg kg(-1)) and than that in hypertonic solution (28.6 mg kg(-1)). However, when a dose equal to one-half of the LD50 was administered in each solution to mice with i.p. tumours, survival of mice given the CDDP in hypotonic solution was significantly prolonged as compared with the survival of the other mice. These results demonstrate that the therapeutic efficacy of i.p. CDDP in mice is augmented when the drug is administered in hypotonic solution.     

Toxic reduction and superior therapeutic effects on peritoneal carcinomatosis of etoposide particles suspended in oil in mice]

Two dosage forms of etoposide diluted by saline solution (Etp-sol) and etoposide particles suspended in oil (Etp-oil) were examined for the toxicity and therapeutic effects when injected intraperitoneally (ip) in mice. The 50% lethal dose (LD50) values for two weeks observation were 135 mg/kg in Etp-oil and 108 mg/kg in Etp-sol. Two days after intraperitoneal transplantation of 10(6) cells/mouse of P388 leukemia to CDF1 male mice, etoposide was injected intraperitoneally in the form of Etp-oil or Etp-sol. In the mice receiving 20mg/kg of etoposide, 11 of 19 mice given Etp-oil and 3 of 20 given Etp-sol survived to day 60. In the mice receiving 80 mg/kg of etoposide, 1 in 20 treated with Etp-oil and 8 of 20 treated with Etp-sol died from by the toxicity.     

Impact of surgical and clinical factors on the pharmacology of intraperitoneal doxorubicin in 145 patients with peritoneal carcinomatosis

Background

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are a combined treatment modality considered for selected patients with peritoneal carcinomatosis from colorectal and appendiceal cancer. Doxorubicin is a drug consistently used by our group in this clinical setting. The surgical and clinical factors that modify the pharmacokinetics of HIPEC may be important for the design of future perioperative chemotherapy regimens.

Materials and methods

The patients included were 145 who had colorectal or appendiceal carcinomatosis resected using CRS prior to treatment with HIPEC with doxorubicin as part of a multidrug regimen. The effect of clinical and surgical factors on drug distribution after a single intraperitoneal bolus administration with doxorubicin was determined.

Results

The pharmacokinetics of 145 patients treated with intraperitoneal doxorubicin showed a 78 times greater exposure to peritoneal surfaces as compared to plasma. At 90 min 12% of the drug remained in the chemotherapy solution and 88% was retained in the body. The extent of visceral resection and peritonectomy increased the clearance of doxorubicin from the peritoneal space. A major resection of visceral peritoneal surface, a contracted peritoneal space, and an incomplete cytoreduction reduced drug clearance.

Conclusions

Surgical and clinical factors may require modifications of chemotherapy administration. A large visceral resection and a contracted peritoneal space caused a reduced doxorubicin clearance. Total diffusion surface is an important determinant of doxorubicin pharmacokinetics.     

Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis: Prognosis and treatment of recurrences in a cohort study

Background

Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) treatment of colorectal peritoneal carcinomatosis (PC) is gaining acceptance, but controversy remains. The primary aims were to analyse the outcome and prognostic variables of colorectal PC patients treated with CRS and IPC, and to report on the outcome of additional surgical treatments of subsequent recurrences.

Methods

Patients referred for treatment of colorectal PC between 1996 and 2010 were included in a cohort. The following data was collected: clinicopathological parameters, survival, recurrences, perioperative chemotherapy and type of IPC (hyperthermic intraperitoneal chemotherapy, HIPEC; or sequential postoperative intraperitoneal chemotherapy, SPIC). Multivariable analyses were conducted on potential prognostic factors for overall survival (OS).

Results

In the 151-patient cohort, the median OS was 34 months (range: 2–77) for CRS and HIPEC with five-year survival predicted at 40% (five-year disease-free survival 32%). For CRS and SPIC, the OS was 25 months (range: 2–188) with five-year survival at 18%. Open-and-close patients survived 6 months (range: 0–14) with no five-year survival (HIPEC vs. SPIC p = 0.047, SPIC vs. open-and-close p < 0.001). Adjuvant systemic chemotherapy was a noteworthy independent prognostic factor in the multivariable analysis. OS for patients undergoing additional surgical treatment of recurrences was 25 months vs. 10 months with best supportive care or palliative chemotherapy (p = 0.01).

Conclusion

Substantial long-term survival is possible in patients with colorectal PC. HIPEC was associated with better OS than SPIC and adjuvant systemic chemotherapy may improve the outcome in patients. Good OS is achievable in selected patients undergoing additional surgical treatment of isolated liver or peritoneal recurrences after prior complete CRS.     

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.     

Curative cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis and synchronous resectable liver metastases arising from colorectal cancer

Objectives

This study describes the outcomes of patients with colorectal peritoneal carcinomatosis (PC) with or without liver metastases (LMs) after curative surgery combined with hyperthermic intraperitoneal chemotherapy, in order to assess prognostic factors.

Safety of intraperitoneal Mitomycin C versus intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis of colorectal cancer undergoing cytoreductive surgery and HIPEC

Background

Colorectal peritoneal carcinomatosis (PC) is commonly treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). There is an ongoing international debate about which intraperitoneal chemotherapeutic agent is preferred, Mitomycin C (MMC) or oxaliplatin. We questioned whether the type of chemotherapeutic agent influenced postoperative complication rates or short-term survival.

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.     

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.     

Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas

Background The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin’s lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions. Patients and methods We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n = 7; female, n = 3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m² given intravenously on day 1, and 200 mg/m² orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program. Results Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3 ± 3.7 vs. 12.0 ± 4.2 μg/ml; P = 0.015). The mean bioavailability of oral etoposide was 58 ± 15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m² intravenous and a 200 mg/m² oral dose of etoposide were 74.0 ± 18.3 and 84.9 ± 29.6 μg h/ml (P = 0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4 ± 10.6% after intravenous infusion versus 35.4 ± 9.4% after oral intake (P = 0.422). Renal clearance was also very similar with intravenous and oral route (18.5 ± 7.4 vs. 16.7 ± 6.6 ml/min; P = 0.546). Conclusion The equivalency of AUC after 200 mg/m² of oral and 100 mg/m² of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.     

腹腔转移肿瘤腹腔温热灌注化疗的临床疗效

目的探讨腹腔温热灌注化疗治疗腹膜腔转移肿瘤的临床疗效和不良反应。方法选取2011年1月至2012年1月间收治的腹膜腔转移肿瘤患者82例,随机分为对照组和观察组,对照组患者单纯采用静脉化疗,观察组患者采用腹腔温热灌注化疗,比较两组患者临床疗效和不良反应发生情况。结果观察组患者有效率为65.9%,明显高于对照组的43.9%,两组差异有统计学意义(P<0.05);观察组患者不良反应发生率均明显低于对照组,两组差异有统计学意义(P<0.05)。结论腹腔温热灌注化疗治疗腹膜腔转移肿瘤疗效显著,可杀灭腹腔游离癌细胞,改善患者预后,且不良反应少,安全有效,值得临床推广和应用。     

Adjuvant intraperitoneal chemotherapy for the treatment of colorectal cancer at risk for peritoneal carcinomatosis: a systematic review

Background: The peritoneal surface is the second most common site of disease recurrence, after the liver, following definitive surgery for colorectal cancer. Adjuvant intraperitoneal (IP) chemotherapy delivered at time of surgical resection has the potential to delay or prevent future spread to the peritoneal surface and improve clinical outcome. The exact role of adjuvant IP chemotherapy in colorectal cancer, including its associated morbidity and mortality, is not well defined.

Study design: Systematic review and pooled random effect analysis of comparative trials examining the addition of adjuvant IP chemotherapy compared to surgery alone in colorectal cancer. The primary outcome was overall survival, and the secondary outcomes were of post-operative morbidity and mortality.

Results: In nine colorectal cancer studies identified, seven were two-arm trials comparing adjuvant IP chemotherapy to surgery alone. Of these, four trials had outcome reporting and met criteria that allowed inclusion into a random effects model. Heterogeneity was measured by Cochran’s Q-test (Q?=?13.9; p?=?0.01) and random effect models were utilised. Pooling eligible trials together revealed a 0.55 odds ratio of death associated with the administration of IP chemotherapy compared to surgery alone (CI?=?0.31, 0.98; p?=?0.04). Trials selecting patients at elevated risk for the development of peritoneal carcinomatosis by clinicopathological biomarkers for administration of adjuvant IP chemotherapy reported more favourable overall outcomes. There was no increase in mortalities or IP chemotherapy-related abdominal complication rates among patients undergoing IP chemotherapy (OR?=?1.4; CI?=?0.52, 3.8; p?=?0.5).

Conclusions: This systematic review supports the use of adjuvant IP chemotherapy in resectable colorectal cancer at risk for peritoneal spread. Future trials should seek to standardise inclusion criteria and IP chemotherapy modalities to better define the role of this treatment in patients with resectable colorectal cancer.     

Heterogeneous activity of cytotoxic drugs in patient samples of peritoneal carcinomatosis

Aims

To investigate if the pattern of cytotoxic drug sensitivity in vitro in patient samples of peritoneal carcinomatosis (PC) is supportive to the current standardized approach for drug selection for perioperative intraperitoneal chemotherapy (IPC).

Methods

The cytotoxic effect of cisplatin, oxaliplatin, irinotecan, 5-fluorouracil, mitomycin-C, doxorubicin and melphalan was investigated in vitro on tumour cells from 223 patient tumour samples of different PC origins.

Results

Considerable differences in cytotoxic drug sensitivity between tumour types of the PC entity and within each tumour type were observed. Cisplatin showed high cross-resistance with oxaliplatin but low cross-resistance with doxorubicin and irinotecan. No cross-resistance was found between irinotecan and doxorubicin. The dose-response relationships for melphalan and irinotecan in individual samples showed great variability.

Conclusions

The activity in vitro of cytotoxic drugs commonly used in IPC for PC is very heterogeneous. Efforts for individualizing drug selection for PC patients undergoing IPC seem justified.     

CA 19-9 to peritoneal carcinomatosis index (PCI) ratio is prognostic in patients with epithelial appendiceal mucinous neoplasms and peritoneal dissemination undergoing cytoreduction surgery and intraperitoneal chemotherapy: A retrospective cohort study

Background

Serum tumour levels have been shown to be prognostic in patients with epithelial appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei (PMP)). A singular index which incorporates both tumour activity (as depicted by serum tumour marker levels) and tumour volume (as depicted by peritoneal carcinomatosis index (PCI)), may give a more precise surrogate of tumour biological behaviour. The prognostic implication of this index has not yet been reported.

Safety and efficacy of hypotonic CDDP intraperitoneal administration for gastric cancer with peritoneal dissemination

We examined safety and efficacy of hypotonic CDDP intraperitoneal administration followed by systemic chemotherapy using MTX/5-FU and UFT. Between 1998 and 2004, seven patients who had histologically proven gastric adenocarcinoma with peritoneal metastases underwent palliative gastrectomy at Niigata University Medical Hospital. For residual peritoneal tumors, 100 mg/body of CDDP diluted with distilled water was intraperitoneally administered to the patients before closure of abdominal wall and was drained 30 to 60 minutes after administration. During the postoperative period, a patient suffered from intraperitoneal abscess and another patient had a renal dysfunction with an increasing level of serum Cr (2.1 mg/dl). As adverse effects of the following systemic chemotherapy, three patients had grade 3 anemia and one had grade 3 leukopenia. The median time to progression was 109 days and the median survival time was 248 days. Although intraperitoneal CDDP administration is safe to be carried out intraoperatively, the effect on survival is not better than new anticancer drugs, such as TS-1 and paclitaxel.