Pharmacokinetics of recombinant human erythropoietin in children treated with continuous ambulatory peritoneal dialysis

In children treated by continuous ambulatory peritoneal dialysis (CAPD) renal anaemia is preferably treated by intraperitoneal administration of erythropoietin, since subcutaneous administration is painful and frightening for the child. Pharmacokinetics of erythropoietin were studied in three groups of children treated by CAPD. In group subcutaneous (SC) (n=5) erythropoietin was administered subcutaneously, whereas in group intraperitoneal 1 (IP1) (n=8) and intraperitoneal 2 (IP2) (n=8) erythropoietin was given intraperitoneally during a 12-h dwell. Group IP1 received erythropoietin in 20 ml/kg of dialysis fluid, while in group IP2 the hormone was added to only 50 ml of dialysate, irrespective of body weight. The median area under the curve (AUC) was 4064 mU·h/ml (range 2647–24357) in group SC, 1698 (570–5514) in group IP1 and 3577 (1225–6555) in group IP2. In comparison to group SC the AUC was significantly lower in group IP1 (Wilcoxon;P=0.02). The difference between group SC and group IP2 was not statistically significant.In children on CAPD the resorption of erythropoietin after intraperitoneal administration, measured as AUC, is similar to subcutaneous administration, when erythropoietin is administered in 50 ml of dialysate. The dose needed to treat renal anaemia with erythropoietin administered intraperitoneally this way will have to be established in a therapeutic study.     

Granulocyte Macrophage-Colony Stimulating Factor Improves Impaired Anastomotic Wound Healing in Rats Treated with Intraperitoneal Mitomycin-C

Purpose Intraperitoneal chemotherapy (IPCT) delivers higher local concentrations of cytotoxic drugs than intravenous (IV) chemotherapy, but it can adversely affect the healing of intestinal anastomoses if given in the early postoperative period. Intestinal anastomotic leakage is a serious surgical complication. Experimental and clinical studies have shown that the local administration of granulocyte macrophage-colony stimulating factor (GM-CSF) improves would healing. Therefore, we evaluated the effects of locally applied GM-CSF on anastomotic wound healing in rats treated with intraperitoneal mitomycin-C immediately after surgery.Methods We performed colon anastomoses in albino rats, which were then divided into three treatment groups. Group A was a control group that received no treatment, Group B was given intraperitoneal mitomycin-C postoperatively, and Group C was given intraperitoneal mitomycin-C with a local injection of GM-CSF postoperatively. We measured bursting pressures and hydroxyproline content, and histologically examined the resected anastomoses on postoperative day (POD) 3.Results Anastomotic healing was impaired after intraperitoneal mitomycin-C, but this was overcome by the injection of GM-CSF into the perianastomotic area.Conclusion Local GM-CSF administration counteracts the detrimental effects of intraperitoneal mitomycin-C treatment on intestinal anastomoses in rats.     

Peritoneal surface oncology: review of a personal experience with colorectal and appendiceal malignancy

Peritoneal surface malignancy usually results from implantation of gastrointestinal cancer. In the past, this clinical situation was treated with palliative intent. A definitive approach to peritoneal surface malignancy involves peritonectomy procedures, visceral resections, perioperative intraperitoneal chemotherapy and knowledgeable patient selection. The quantitative prognostic indicators necessary for valid clinical judgements include the cancer histopathology (invasive vs. expansive progression), the preoperative abdominal and pelvic CT, the peritoneal cancer index and the completeness of cytoreduction score. Proper patient selection is mandatory for optimizing the results of treatment. In a series of phase II studies, appendiceal tumors with peritoneal seeding became the paradigm for success with an 85% long–term survival in selected patients. Carcinomatosis from colon cancer had an overall 5–year survival of 45% with selected patients. In all malignancies, early aggressive treatment of minimal peritoneal surface dissemination showed the greatest benefit. The definitive prognostic indicator was the complete cytoreduction. Oncologists must seek new knowledge regarding the management of peritoneal surface dissemination of cancer because a curative approach has been demonstrated in large phase II studies; in contrast all historical controls show 0% long–term survival. Additional adjuvant phase III studies with perioperative intraperitoneal chemotherapy in diseases where peritoneal surface spread occurs are indicated.     

Recurrences after Peritoneal Carcinomatosis of Colorectal Origin Treated by Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy: Location,Treatment, and Outcome

Background: After treatment of peritoneal carcinomatosis of colorectal cancer origin by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC), recurrences develop in approximately 80% of patients. This study evaluates the outcome of such recurrences after initial treatment by cytoreduction and HIPEC.Methods: Between November 1995 and May 2003, 106 patients underwent cytoreduction and HIPEC. The progression-free interval, the location of the recurrence, and its treatment were recorded. Factors potentially related to survival after recurrences were studied.Results: Sixty-nine patients had a recurrence within the study period. For patients who had undergone a gross incomplete initial cytoreduction, the median duration of survival after recurrence was 3.7 months (standard error of the mean [SE], .3). If a complete cytoreduction had been accomplished initially, the median duration of survival after the recurrence was 11.1 months (SE, .9). A shorter interval between HIPEC and recurrence was associated with shorter survival after treatment of recurrence (hazard ratio, .94; SE, .02). After effective initial treatment, a second surgical debulking for recurrent disease resulted in a median survival duration of 10.3 months (SE, 1.9), and after treatment with chemotherapy it was 8.5 months (SE, 1.6). The survival was 11.2 months (SE, .5) for patients who received radiotherapy for recurrent disease. Patients who did not receive further treatment survived 1.9 months (SE, .3).Conclusions: Treatment of recurrence after cytoreduction and HIPEC is often feasible and seems worthwhile in selected patients. Selection should be based mainly on the completeness of initial cytoreduction and the interval between HIPEC and recurrence.     

A novel model of pneumonia from intraperitoneal injection of bacteria

BACKGROUND: Pneumonia remains a major clinical problem in the surgical patient. Experimental modeling by intratracheal injection of bacteria is not consistently reproducible. In an attempt to produce peritonitis by Klebsiella, we found evidence of pneumonia on autopsy and further developed this approach as a new experimental model. METHODS: Male Swiss Webster mice were given intraperitoneal (IP) injections of Klebsiella pneumoniae serotype 2 in different doses and this was compared with similar doses given intravenously (IV). A dose dependent survival curve was generated. Subsequently, 10(3) colony forming units (CFU) of bacteria were used in further experiments. Blood, peritoneal fluid and lung tissue were collected at time points up to 72 hours after injection and were cultured for levels of bacteria. Lung weights and myeloperoxidase levels were also measured. RESULTS: Intraperitoneal administration of Klebsiella was uniformly lethal with as few as 10(2) bacteria. Lung weight increased after IP Klebsiella, and all animals became bacteremic within 24 hours correlating with high bacterial levels in the lung. Conversely, most animals (72%) survived IV injection of bacteria, and were able to clear bacteria from the blood and lung. CONCLUSIONS: We found that this model produced no clinically apparent peritonitis after 48 hours, but uniformly resulted in histopathologic changes of pneumonia by 24 hours. Survival time was related to initial dose of Klebsiella and there was a linear correlation between bacterial levels in the blood and lung. This model is reproducible, simple to perform, and the severity is easy to manipulate.     

Long-Term Survivorship and Quality of Life After Cytoreductive Surgery Plus Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Carcinomatosis

Background:Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy with mitomycin C for peritoneal carcinomatosis is used as a palliative treatment for a variety of malignancies. The purpose of this study was to measure the quality of life (QOL) of survivors (>3 years) after treatment.Methods:Patients were interviewed by telephone with the following tools: (1) the Functional Assessment of Cancer Therapy–Colon (FACT-C), (2) the Short Form of the Medical Outcomes Study Questionnaire, (3) the Center for Epidemiologic Studies–Depression scale, (4) the Life Appreciation scale, (5) the Psychosocial Concerns Questionnaire, and (6) performance status rating.Results:Seventeen (10 appendix, 5 large intestine, 1 ovarian, and 1 peritoneum) of 109 patients were interviewed from 3.1 to 8.0 years after treatment. Ten patients (62.5%) described their health as excellent or very good. No limitations on moderate activity were reported in 94% of cases. Paired t-tests were used to compare 10 patients who had baseline QOL data. FACT mean difference scores and P values (positive difference scores indicate improved QOL) were functional well-being: 4.9, P = .01; physical well-being: 3.3, P = .05; and FACT total: 14.3, P = .02.Conclusions:Long-term survival with good QOL is possible for selected patients with peritoneal carcinomatosis after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy.     

Fluid dynamics in man of an intraperitoneal drug delivery solution: 4% icodextrin

Interest in targeting drugs into the peritoneal cavity for intra-abdominal cancers or infections is undergoing a revival as recent clinical trials have demonstrated, not only a regional advantage in concentration of the active agent, but also improved long-term outcomes. Solutions currently used for intraperitoneal (IP) drug delivery have short residence times, however, which can limit the exposure of all areas of the peritoneum to the active agent. Icodextrin 4% solution was compared with saline and a glucose-based peritoneal dialysis solution in a clinical study of IP residence time. The study was carried out during the fortnightly rest phase in 9 patients undergoing 5-fluorouracil (5-Fu) IP treatment for colorectal cancer. The volume remaining in the peritoneal cavity was measured at 0, 12, 24, 48, 72, and 96 hr after an instillation of 2 liters of each fluid. Saline (n = 3 dwells) and glucose (n = 3 dwells) peritoneal dialysis solutions were almost fully absorbed by 24 hr, and the patients experienced discomfort when using these solutions. In contrast, icodextrin 4% solution (n = 188 dwells) maintained its instilled volume for up to 48 hr, and half the instilled volume remained after 72 and 96 hr. This result would allow extensive and prolonged coverage of the peritoneal surface. Icodextrin 4% solution may be an effective vehicle to deliver therapeutic agents into the peritoneal cavity.     

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.     

胃肠道癌术后腹腔静脉双途径化疗临床研究

目的 探讨腹腔内温热淋巴化疗联合静脉双途径化疗对提高生存率及防治腹膜复发和淋巴转移的作用。方法 38例侵及浆膜或有腹腔淋巴结转移的胃肠癌患者术后行温热腹腔淋巴化疗（腹腔化疗同时静脉点滴垂体后叶素）联合全身化疗（治疗组）；42例仅予温热腹腔内化疗＋全身化疗（对照组）而未行腹腔淋巴化疗。结果 治疗组患者1，2，3年生存率分别为97．4％，86．7％，78．9％；对照组为83．3％，73．8％，64．2％。治疗组患者1，2，3年生存率明显优于对照组，2组差异有统计学意义（P〈0．05）。治疗组患者3年内腹膜复发率15．3％，淋巴结转移率为18．4％，明显低于对照组42．1％，38．1％，2组差异有统计学意义（P〈0．05）。结论 温热腹腔淋巴化疗联合静脉双途径化疗可降低胃肠道肿瘤术后腹腔内及腹膜后淋巴转移率。提高术后生存率。     

胃肠肿瘤术后早期腹腔并全身化疗30例

 目的 研究术后早期腹腔内化疗与胃肠肿瘤术后生存率的关系。方法 用术后早期腹腔内化疗并MF全身化疗的方法治疗了30 例经病理确诊的胃肠癌中, Ⅲ～Ⅳ期占83 %.结果 在30 例病人中, 1、2 、5 年生存率分别为86-6 % , 63-3 % , 6-6 % , 其中2 例胃癌病人生存了6年。结论 术后早期腹腔内化疗并MF方案全身化疗对胃肠癌术后腹腔复发和肝转移有预防作用。