Experimental and clinical studies on the intraperitoneal administration of cis-diamminedichloroplatinum (II) for peritoneal carcinomatosis caused by gastric cancers

The effectiveness of the intraperitoneal administration of cis-diamminedichloroplatinum (II) (DDP) on peritoneal carcinomatosis caused by gastric cancers was evaluated. Seventeen patients were treated with one of three protocols, consisting of the intraperitoneal injection (ip) of DDP at doses of 70 and 110 mg/m2, with or without sodium thiosulfate (STS) rescue. The area under the curve (AUC) of DDP for sufficient anticancer activities against cultured human cell lines in vitro was estimated at 240 micrograms h/ml, which was equivalent to the AUC gained by 110 mg/m2 ip DDP in the clinical studies. The cytotoxic activity of DDP was reduced by approximately 50% with 100-fold STS in the AUC in the experimental studies. However, this was achieved only in urine, and not in either the peritoneal cavity or in plasma in the clinical studies. Three cases of a partial response against peritoneal carcinomatosis were seen from a total of four evaluable cases treated with 110 mg/m2 DDP, and no renal toxicities were observed in those treated with the STS rescue. The results of this study led us to conclude that high-dose ip DDP treatment combined with the STS rescue would be useful chemotherapy against peritoneal carcinomatosis caused by gastric cancers.     

Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene

BACKGROUND: Metastatic pancreatic cancer is uniformly fatal because no effective chemotherapy is available. Mutations in the p53 tumor suppressor gene are found in up to 70% of pancreatic adenocarcinomas. We examined the efficacy of a retroviral vector containing the wild-type p53 gene on metastatic pancreatic cancer in a nude mouse model. METHODS: Bxpc3 human pancreatic cancer cells were transduced with either a retroviral p53 vector or an LXSN empty vector. Cells were examined for incorporation of tritiated thymidine to determine the effect of p53 retroviral transduction on DNA synthesis, and a TACS2 assay for apoptosis was performed. The functional activity of p53 in transduced cells was assessed by Western blot analysis with an antibody to WAF1/p21. In vivo effects of intraperitoneal injections of the p53 vector were examined in a nude mouse model of peritoneal carcinomatosis. RESULTS: Cells treated with the p53 vector exhibited a 59% to 85.5% reduction in cell number compared with the control cells (P < .05). p53-treated cells demonstrated decreased incorporation of tritiated thymidine (12.7% +/- 0.7% vs 17.5% +/- 1.4%; P = .002), increased staining for apoptosis, and increased expression of the WAF1/p21 protein. Treatment of nude mice with the retroviral p53 vector resulted in a significant inhibition of growth of the primary pancreatic tumor, as well as the peritoneal tumor deposits, compared with the LXSN control vector. CONCLUSIONS: Intraperitoneal delivery of a retroviral p53 vector may provide a novel treatment approach for peritoneal carcinomatosis from pancreatic cancer.     

Forgetting in the workplace: attributions and recommendations for young and older employees

A novel method of prophylaxis and treatment for peritoneal carcinomatosis--mitomycin C bound to activated carbon particles (MMC-CH)--was tested in patients with advanced gastric cancer in a prospective randomized study. Activated carbon particles are taken up selectively by lymphatic tissues, which seem to be a primary site of peritoneal carcinomatosis in the peritoneal cavity, and adsorb a large amount of anticancer agent mitomycin C, which is subsequently released slowly and for a protracted period. A group of 113 patients who underwent radical resection for gastric cancer with definite serosal involvement were entered in this trial. Those in the control group received no intraperitoneal anticancer drugs. Patients in the MMC-CH group were given 50 mg mitomycin C as MMC-CH, which was dispersed throughout the peritoneal cavity just before surgical closure. No other anticancer drugs were given to these patients after surgery. The 2- and 3-year survival rates for the MMC-CH group were 42% and 38%, respectively; and the rates for the control group were 28% and 20%, respectively. The difference in survival between the two groups was significant at 2 and 3 years (p < 0.05). For the survival of patients with macroscopic peritoneal carcinomatosis, there was no difference between these two groups. For the survival of patients who underwent histologically curative resection, 2- and 3-year survivals for the MMC-CH group were 66% and 66%, respectively and for the control group 35% and 20%, respectively. The difference between the two groups was statistically significant (p < 0.01) at both 2 and 3 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

The approach to the patient with single and multiple liver metastases, pulmonary metastases, and intra-abdominal metastases from colorectal carcinoma

Recurrent colorectal carcinoma constitutes a major health care problem, with 90,000 patients diagnosed annually with metastatic disease. Recent advances have offered treatment to selected patients with liver, lung, and intra-abdominal metastases. Resection of liver secondary tumors improves 5-year survival from 0% to approximately 30% and offers the only possibility for cure. As experience mounts, hepatic surgery can be performed with quite acceptable morbidity and mortality. Adjuvant therapies are being developed that may improve results with surgery alone. Cryoablation is a new technique that appears to effectively eradicate liver tumors, but its role remains to be defined. In patients with unresectable disease, the benefit of hepatic artery infusion of chemotherapy is unproven. Resection of pulmonary metastases significantly improves survival in patients with solitary nodules. Consistent data regarding the benefit of pulmonary metastatectomy in patients with multiple nodules are not available. Combined cytoreductive surgery and intraperitoneal hyperthermic chemotherapy is being investigated as a treatment for peritoneal carcinomatosis from colorectal cancer. Although selected patients may benefit, this combined treatment modality appears to be less effective in patients with colorectal cancer than with other types of cancer.     

Limitations in medicine. Challenge and threat

Intraoperative chemohyperthermia is a new method in the treatment of peritoneal seedings from digestive cancers, which combines surgery, intraperitoneal chemotherapy (mitomycin C and/or cisplatyl) and peritoneal hyperthermia. After a brief reminder on the general principles concerning high temperature action, a review of literature is made: 5 teams have performed this technique. We differentiate the indications, design features and results of each team. The results show a mean survival after 2 years of 35% (in peritoneal carcinomatosis) up to 78% (in gastric serosal invasion, peritoneal seeding free). The best result of the method is the drying up of cancerous ascites, allowing a more comfortable survival.     

Intestinal obstruction caused by peritoneal carcinomatosis due to signet ring cell carcinoma of the breast

The signet ring variant of lobular mammary carcinoma is aggressive and metastasis to serosal surfaces. We report a 46 years old woman presenting with an intestinal obstruction due to a peritoneal carcinomatosis secondary to a signet ring cell carcinoma of the breast. After surgery, the patient received chemotherapy (5-fluorouracil, adriamycin, cyclophosphamide and tamoxifen). A satisfactory response, with regression of peritoneal carcinomatosis and a good quality of life, was achieved. The patient is alive after 2 years of diagnosis.     

Intraperitoneal chemotherapy: a prolonged infusion of 5-fluorouracil using a novel carrier solution

A novel carrier solution, icodextrin 20 (7.5%) has allowed exploration of prolonged intraperitoneal (IP) infusion of the cytotoxic drug, 5-fluorouracil. Eighteen patients with intraperitoneal carcinomatosis were entered into a feasibility and pharmacokinetic study of prolonged regional (IP) chemotherapy.. Specialist nurses trained the patients to self-administer their own treatment via a permanent i.p. catheter. A twin bag delivery system was used to perform one exchange daily. It proved possible to deliver continuous (5 days per week) i.p. 5-fluorouracil at doses of 200 mg/m2 and 300 mg/m2 for up to 12 weeks. The toxicities seen were infective peritonitis, nausea and vomiting, lethargy and anorexia. This was a nurse-led study and the home-based therapy holds promise for patients with malignant peritoneal disease.     

Prolonged intraperitoneal infusion of 5-fluorouracil using a novel carrier solution

A novel peritoneal carrier solution, Icodextrin 20 (7.5%), has allowed exploration of prolonged, intraperitoneal (i.p.) infusion of the cytotoxic drug 5-fluorouracil (5-FU). A phase I and pharmacokinetic study was performed to determine the toxicities and maximum tolerated dose of prolonged and continuous intraperitoneal 5-FU in patients with peritoneal carcinomatosis. Seventeen patients were entered into this study. Each patient had a Tenckhoff catheter placed into the peritoneal cavity under general anaesthetic. After initial flushing and gradual increase in exchange volumes with Icodextrin 20, 5-FU was administered daily from Monday to Friday, 50% as a bolus in the exchange bag and 50% in an elastomeric infusor device delivering continuous 5-FU to the peritoneal cavity at 2 ml h-1. Treatment was continued for 12 weeks or until intolerable toxicity developed. Abdominal pain and infective peritonitis proved to be the main dose-limiting toxicities. Initial problems with infective peritonitis were overcome by redesign of the delivery system, and it proved possible to deliver 300 mg m-2 5-FU daily (5 days per week) for 12 weeks. Pharmacokinetic studies showed i.p. steady-state 5-FU concentrations (mean 47 500 ng ml-1) that were > 1000-fold higher than systemic venous levels (mean 30 ng ml-1).     

Appendiceal mucocele. Contraindication to laparoscopic appendectomy

Indications and contraindications to laparoscopic surgery continue to be refined. Laparoscopic appendectomy for acute appendicitis is frequently selected by patients and surgeons, and clinical studies show it to be a reasonable alternative. In this case study, laparoscopic surgery was used to resect an appendiceal mucocele caused by a nonperforated mucinous adenocarcinoma. Implants of mucinous tumor were found widely disseminated on peritoneal surfaces at laparotomy 9 months later. As a result of this case study, the authors suggest that when an appendiceal mucinous tumor is encountered at laparoscopy, a special situation requiring totally atraumatic appendectomy is indicated. This clinical situation should be considered an indication for conversion to open appendectomy. All appendiceal tumors, including the most benign-appearing adenomas, can result in diffuse peritoneal implantation. This is the first report of an appendiceal mucinous tumor resected by laparoscopy associated with subsequent diffuse peritoneal carcinomatosis. This patient presentation reaffirms that dissemination of cancer may be associated with laparoscopic resection of structures containing a malignancy.     

Pseudomyxoma peritonei

BACKGROUND: Pseudomyxoma peritonei is an unusual condition in which gelatinous fluid collections are associated with mucinous implants on the peritoneal surfaces and omentum. The pathological origin and ideal treatment of the condition are subjects of debate. METHODS: An unrestricted Medline search over 1986-1997 was performed for pseudomyxoma peritonei. RESULTS AND CONCLUSIONS: There is increasing evidence that pseudomyxoma peritonei is a neoplastic condition which usually arises from a primary adenoma or adenocarcinoma of the appendix. Reported series include a spectrum of pathological lesions, from entirely benign ruptured mucocele to advanced carcinoma. This, and the rarity of the condition, limit the conclusions that can be drawn regarding its treatment and prognosis. Most authorities agree that a thorough surgical debulking should be made. In most cases this will be a difficult and time-consuming undertaking, possibly requiring cooperation between two or more specialists and consideration of delivering intraperitoneal adjuvant therapy during or immediately after surgery. Treatment therefore requires a planned approach with accurate preoperative assessment of the diagnosis and the extent of the condition. There is some largely anecdotal evidence in favour of intraperitoneal chemotherapy and radioisotope treatment. Ultraradical surgery, with heated intraoperative and further postoperative chemotherapy, is strongly advocated by one group but remains contentious. The majority of patients will eventually suffer recurrence. The 5-year survival rate ranges from 53 to 75 per cent, but outcomes vary widely between relatively benign and malignant subgroups.     

Four long-surviving cases of gastric cancer with peritoneal dissemination treated by intraperitoneal administration of mitomycin C adsorbed on activated carbon particles

A new dosage format (MMC-CH) of mitomycin C, which is composed of mitomycin C on activated carbon particles, was efficacious for prevention of peritoneal recurrence of gastric cancer. However, it had no such excellent therapeutic effect on the survival of patients with peritoneal dissemination. Out of 50 patients with peritoneal dissemination of gastric cancer treated by intraperitoneal administration of MMC-CH, 4 patients have survived for long periods of time (39-80 months). However, all of the other 50 patients, who did not receive intraperitoneally administered MMC-CH, died of peritoneal carcinomatosis within two years.     

Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure

Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or recurrent disease following systemic therapy, and has produced a survival advantage in a recent phase III trial. Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration by the drug and incomplete irrigation of serosal surfaces by the drug-containing solution. We have examined these problems in the context of a very simple, spatially distributed model. If D is the diffusivity of the drug in a tissue adjacent to the peritoneal cavity and k is the rate constant for removal of the drug from the tissue by capillary blood, the model predicts that (for slowly reacting drugs) the characteristic penetration distance is (D/k)1/2 and the apparent permeability of the surface of a peritoneal structure is (Dk)1/2. The permeability-area product used in classical pharmacokinetic calculations for the peritoneal cavity as a whole is the sum of the products of the tissue-specific permeabilities and the relevant superficial surface areas. Since the model is mechanistic, it provides insight into the expected effect of procedures such as pharmacologic manipulation or physical mixing. We observe that large changes in tissue penetration may be difficult to achieve but that we have very little information on the transport characteristics within tumors in this setting or their response to vasoactive drugs. Enhanced mixing is likely to offer significant potential for improved therapy; however, procedures easily applicable to the clinical setting have not been adequately investigated and should be given high priority. Clinical studies indicate that an increase in irrigated area may be achieved in many patients by individualizing the dialysate volume and consideration of patient position.     

Pharmacokinetics and bactericidal activity of a single daily dose of netilmicin in the treatment of CAPD-associated peritonitis

Single daily dosage of netilmicin is generally accepted in systemic infections, due to biphasic bactericidal activity and prolonged postantibiotic effect of aminoglycosides. Since little is known about the efficacy of single daily intraperitoneal application of netilmicin in the treatment of CAPD-associated peritonitis, we conducted this prospective study. Seven patients with CAPD-associated peritonitis were treated with a single daily dose of netilmicin (loading dose 1.5 mg/kg, followed by 40 mg/21 bag/day). Serum and intraperitoneal levels as well as bactericidal activity of netilmicin against Acinetobacter baumanii, E. coli and Pseudomonas aeruginosa were measured for 48 hours. Serum and peritoneal levels widely varied among the patients due to different interindividual plasma clearance of netilmicin. The intraperitoneal antibacterial action of netilmicin was decreased, more over, substantial differences in the bactericidal activity were found among the patients. However, with high initial netilmicin levels sufficient bactericidal activity was found for Acinetobacter and E. coli, but not for Pseudomonas aeruginosa. Hence, a single daily dosage of netilmicin can be a suitable treatment of CAPD-associated peritonitis, only if the dose is adapted according to the first serum and peritoneal levels. In infections with Pseudomonas aeruginosa higher peritoneal levels of netilmicin and the combination with other antibiotics will be needed for a sufficient peritoneal bactericidal activity.     

Bispecific antibody targeted T cell therapy of ovarian cancer: clinical results and future directions

The high frequency of relapse after induction chemotherapy in advanced ovarian carcinoma patients calls for new therapeutic modalities. Retargeted T cell-mediated lysis can be achieved using the bispecific antibody (BsmAb) OCTR, directed to CD3 on T cells and to the folate receptor on ovarian carcinoma cells. Twenty-eight patients with limited intraperitoneal disease after first-line therapy entered a phase II study. They received two i.p. 5 day cycles of activated PBMC retargeted with OCTR. Despite unfavorable tumor characteristics, 7 of 26 patients (27%) showed complete or partial intraperitoneal responses with strict surgicopathologic evaluation. In most cases, the disease relapsed outside the peritoneal cavity, and in 1 case complete intraperitoneal response was accompanied by progression in retroperitoneal lymph nodes. The morbidity was mild to moderate and transient. Combination of i.v. and i.p. administration of OCTR-retargeted lymphocytes will possibly lead to extraperitoneal cure. Ongoing clinical studies indicate that the i.v. infusion of up to 8 x 10(8) OCTR-retargeted T lymphocytes does not induce a higher toxicity than the i.p. treatment. To avoid PBMC preactivation, new approaches for delivering accessory signals are under investigation. Preliminary results indicate that nonactivated PBMC retargeted by OCTR in the presence of an anti-CD28 monoclonal antibody (mAb) are able to significantly inhibit tumor growth.     

Cisplatin/5-fluorouracil intraperitoneal administration superior to intravenous administration for liver metastases of colonic carcinoma]

A 28-year-old female underwent sigmoidectomy for sigmoid colon cancer with peritoneal seeding. One month later, a solitary metastasis was found in S3 of the liver. After CDDP/5-FU intravenous chemotherapy, another metastasis appeared in S7. Intravenous administration showed PD. But the metastatic tumors shrank and became inobservable by CT after the 1st round of CDDP/5-FU intraperitoneal chemotherapy, and S7 tumor could not be identified after the 2nd round. Many previous reports demonstrated the concentration of cytotoxic drug in intraperitoneal administration was much higher than in intravenous administration. Theoretically, intraperitoneal chemotherapy is superior to intravenous chemotherapy for the prevention and treatment of liver metastases. This case demonstrated this hypothesis was right. We think adjuvant intraperitoneal chemotherapy should be re-considered for the prevention of the liver metastases of gastrointestinal cancers.     

Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization

Ovarian cancer is characterized by the rapid growth of solid intraperitoneal tumors and large volumes of ascitic fluid. Vascular endothelial growth factor (VEGF) augments tumor growth by inducing neovascularization and may stimulate ascites formation by increasing vascular permeability. We examined the role of VEGF in ovarian carcinoma using in vivo models in which intraperitoneal or subcutaneous tumors were induced in immunodeficient mice using the human ovarian carcinoma cell line SKOV-3. After tumor engraftment (7 to 10 days), some mice were treated with a function-blocking VEGF antibody (A4.6.1) specific for human VEGF. A4.6.1 significantly (P < 0.05) inhibited subcutaneous SKOV-3 tumor growth compared with controls. However, tumor growth resumed when A4.6.1 treatment was discontinued. In mice bearing intraperitoneal tumors (IP mice), ascites production and intraperitoneal carcinomatosis were detected 3 to 7 weeks after SKOV-3 inoculation. Importantly, A4.6.1 completely inhibited ascites production in IP mice, although it only partially inhibited intraperitoneal tumor growth. Tumor burden was variable in A4.6.1-treated IP mice; some had minimal tumor, whereas in others tumor burden was similar to that of controls. When A4.6.1 treatment was stopped, IP mice rapidly (within 2 weeks) developed ascites and became cachectic. These data suggest that in ovarian cancer, tumor-derived VEGF is obligatory for ascites formation but not for intraperitoneal tumor growth. Neutralization of VEGF activity may have clinical application in inhibiting malignant ascites formation in ovarian cancer.     

Promyelocytic blast crisis of chronic myelogenous leukaemia with translocations (9;22) and (15;17)

The murine monoclonal antibody A7 (MAb A7) is reactive against most human gastric cancer cell lines. Using a nude mouse peritoneal dissemination model of human gastric cancer, we investigated targeted chemotherapy using a conjugate of neocarzinostatin (NCS) with MAb A7 (A7-NCS). After demonstrating cytotoxicity of the complex against the human gastric cancer cell line MKN45 in vitro, we intraperitoneally injected A7-NCS, NCS or saline into nude mice bearing peritoneally disseminated human gastric cancer. A7-NCS inhibited peritoneal dissemination significantly more effectively than NCS. MAb A7 may prove to be an effective carrier for antineoplastic drugs in patients with peritoneal dissemination of gastric cancer.     

Strategies to decrease the incidence of intra-abdominal recurrence in resectable gastric cancer

Two main approaches are suggested to improve treatment results in resectable gastric cancer: extended lymphadenectomy and adjuvant antitumour therapy. Progress is to some extent stalled by the perception of gastric cancer as a pathophysiologically uniform disease; it has been demonstrated, however, that there are variants of gastric cancer associated with predominantly intra-abdominal spread or with haematogenous metastases. Recent clinicopathological studies have provided information about the mechanisms of this metastatic diversity. A review of clinical trials suggests that no single method of treatment can efficiently address all variants of gastric cancer spread, but new treatment strategies may be based on defining the pathophysiological variant of gastric cancer and selecting adjuvant therapy according to the most probable mode of tumour spread. Treatment should start with surgery which includes a 'reasonably' extended lymphadenectomy aimed at achieving an increased rate of curative resection and more accurate staging. Risk factors for peritoneal spread of tumour require the perioperative use of intraperitoneal chemotherapy. Subsequent adjuvant therapy may be indicated in patients at high risk of further cancer spread or occult metastases, as determined by pathological examination of the resected specimen.     

Assignment of the 1H, 15N and 13C resonances of the calcium-free and calcium-bound forms of the first C2-domain of synaptotagmin I

Two cases of sigmoid perforation and fistula occurred as late complications after insertion of a nonresorbable prosthesis by the open preperitoneal inguinal route. These infrequent complications are favoured by peritoneal defects and use of materials which can cause extensive sclerous reactions. Indications for this type of mesh are increasingly common with the intraperitoneal laparoscopic approach, so that careful peritoneal dissection and closure are required.     

Evaluation of peritoneal lavage smears and intraperitoneal administration of anti-neoplastic agents in stage III and IV gastric cancer

Examinations of peritoneal lavage smears (cy) in gastric cancer surgical stages III and IV are very important for determining the disease stage. We have been carrying out these examinations for 8 years. One hundred sixty patients with gastric cancer were examined. The incidence of cy positivity was higher in T4 than in T3, and higher in P1,2,3 than in P0. We performed intraperitoneal administration of CDDP in 10 patients with gastric cancer using a reservoir (Infuse-A-Port) implanted in the abdominal wall once a week. No difference in survival was observed between patients who received chemotherapy via i.p. and those who received it i.v.