Severe Electrolyte Disturbances After Hyperthermic Intraperitoneal Chemotherapy: Oxaliplatin Versus Mitomycin C

Division of Surgical Oncology, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
Annals of Surgical Oncology (Impact Factor: 3.93). 01/2011; 18(1):174-80. DOI: 10.1245/s10434-010-1210-1
Source: PubMed


Oxaliplatin (OX) is increasingly used for hyperthermic intraperitoneal chemotherapy (HIPC) for patients with peritoneal metastases. Our aim was to review electrolyte disturbances and complications after HIPC with oxaliplatin (OX) versus mitomycin C (MMC).
We included patients enrolled in single-institution prospective clinical trials who underwent cytoreductive surgery and HIPC with MMC or OX. We reviewed patient demographics, pathology, perioperative course, HIPC administration, and postoperative electrolyte disturbances. Measured postoperative sodium values were corrected for systemic hyperglycemia using the formula: (measured Na(+)) × [(glucose - 100/100) × 1.6].
From January 2002 to April 2009 we performed 80 HIPC procedures. A total of 60 patients (75%) received MMC (dose range 12.5-50 mg/m(2)) carried in lactated ringers solution. There were 20 patients (25%) who received OX (dose range 300 × 400 mg/m(2)) carried in 5% dextrose solution. For patients receiving HIPC with OX, electrolyte disturbances were the most common complication. Compared with MMC, patients receiving OX had significant 24-h postoperative uncorrected hyponatremia (P < 0.001), corrected hyponatremia (P < 0.001), hyperglycemia (P < 0.001), and metabolic acidosis (P < 0.001). In the OX group, corrected (mean 130.5) and uncorrected (mean 127.4) sodium levels were significantly lower than preoperatively (mean 139.9, P < 0.001). The overall nonelectrolyte complication rate was 56.2%. (MMC n = 33, 55.0%; OX n = 12, 60%); the 30-day mortality rate was 0% in both groups.
Compared with MMC, HIPC with OX was associated with significant but predictable electrolyte disturbances; however, these electrolyte disturbances were not associated with higher overall complication rates. Close monitoring with early correction is imperative to maximize perioperative care. Further studies are needed to provide mechanistic insight.

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    • "The use of large intraperitoneal volumes of 5% dextrose is associated with serious hyperglycemias and electrolyte disturbances, resulting in significant postoperative morbidity and mortality (Ceelen et al., 2008; De Somer et al., 2008; Rueth et al., 2011). These metabolic disturbances have not been observed in patients treated with mitomycin C, in which more physiological chloride-containing carrier solutions have been used (Rueth et al., 2011). It is surmised that the chloride ions in these solutions could potentially limit oxaliplatin stability and therefore its oncolytic capacity during CRS–HIPEC. "
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    ABSTRACT: Purpose: Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30 min to 90 min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS-HIPEC procedures. Methods: 5 mg of oxaliplatin was added to 50 mL of various carrier solutions at 42 °C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal(®) PD4 glucose 1.36% solution for peritoneal dialysis and 0.14 M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC-UV); oxaliplatin degradation products were identified using HPLC-mass spectometry. Results: In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30 min (the standard peritoneal perfusion time in most clinical CRS-HIPEC protocols) and <20% degradation after 120 min at 42 °C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2]. Conclusions: The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS-HIPEC procedures.
    International Journal of Pharmaceutics 12/2014; 479(1). DOI:10.1016/j.ijpharm.2014.12.025 · 3.65 Impact Factor
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    • "To our knowledge, this is the first study to specifically compare the hematologic toxicity profiles of MMC and oxaliplatin use as HIPEC agents as a function of splenectomy. Rueth et al [30] compared the electrolyte disturbances profiles of MMC and oxaliplatin following hyperthermic intraperitoneal chemotherapy. We hypothesized that as a secondary lymphoid organ, the spleen has a role in the hematologic response after HIPEC. "
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    ABSTRACT: BACKGROUND: Although peritoneal carcinomatosis (PC) from colorectal and appendiceal tumors is consistent with metastatic disease, complete cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) using mitomycin C (MMC) can improve survival. A recent phase I study by our group using hyperthermic intraperitoneal oxaliplatin has demonstrated its safety and appropriate dose. Our goal in this study is to present a single institution's experience with the hematologic toxicities of the two agents. METHODS: We performed a retrospective review of 187 patients with PC of colorectal or appendiceal origin who underwent HIPEC with MMC or oxaliplatin between October 2006 and September 2009. Hematologic toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.0. RESULTS: Of the 187 patients, 55 had oxaliplatin-based HIPEC while 132 patients received MMC. Splenectomy was performed in 95 patients (50.8%) due to disease involvement. When comparing hematologic toxicity for MMC and oxaliplatin among the cohort of patients who underwent splenectomy, a statistically significant difference was noted in the incidence of platelet (P = .02) and neutrophil (P = .05) toxicity, with oxaliplatin having a higher incidence of grade 3 and grade 4 platelet and neutrophil toxicity respectively. However, no statistically significant difference in hematologic toxicity was noted between the two agents in patients who did not undergo splenectomy during cytoreductive surgery. CONCLUSIONS: Oxaliplatin-based HIPEC for PC of colorectal and appendiceal origin is associated with similar white blood cell toxicity and higher platelet and neutrophil toxicity compared to MMC-based HIPEC.
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