Population pharmacokinetics and pharmacodynamics of mitomycin during intraoperative hyperthermic intraperitoneal chemotherapy

During recent years, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin has been used for various malignancies. To characterise the population pharmacokinetics and pharmacodynamics of mitomycin during HIPEC. Forty-seven patients received mitomycin 35 mg/m2 intraperitoneally as a perfusion over 90 minutes. Mitomycin concentrations were determined in both the peritoneal perfusate and plasma. The observed concentration-time profiles were used to develop a population pharmacokinetic model using nonlinear mixed-effect modelling (NONMEM). The area under the plasma concentration-time curve (AUC) was related to the haematological toxicity. Concentration-time profiles of mitomycin in perfusate and plasma were adequately described with one- and two-compartment models, respectively. The average volume of distribution of the perfusate compartment (V1) and rate constant from the perfusate to the systemic circulation (k12) were 4.5 +/- 1.1L and 0.014 +/- 0.003 min(-1), respectively (mean +/- SD, n = 47). The average volume of distribution of the central plasma compartment (V2), clearance from the central compartment (CL) and volume of distribution of the peripheral plasma compartment (V3) were 28 +/- 16L, 0.55 +/- 0.18 L/min and 36 +/- 8L, respectively. The relationship between the AUC in plasma and degree of leucopenia was described with a sigmoidal maximum-effect (Emax) model. The pharmacokinetics of mitomycin during HIPEC could be fitted successfully to a multicompartment model. Relationships between plasma exposure and haematological toxicity were quantified. The developed pharmacokinetic-pharmacodynamic model can be used to simulate different dosage schemes in order to optimise mitomycin administration during HIPE

Prognostic factors and evaluation of surgical management of hepatic metastases from colorectal origin: a 10-year single-institute experience

The aim of this study was to determine prognostic factors and outcome after liver resection for colorectal metastases in 102 patients over a period of 10 years. A stepwise procedure using proportional hazard regression analysis was used to identify prognostic factors. Estimated survival at 2 years was 71%, and at 5 years, 29% (Kaplan-Meier). Of 19 patients with isolated liver recurrence, 6 had a second metastasectomy; 4 of the 6 are still alive. We found that the number of hepatic lesions on computed tomography (P=0.012), the interval between resection of the primary colon tumor and the hepatic metastasectomy (P=0.012), and synchronicity of the primary and the hepatic metastasis (P=0.048) showed evidence of independent prognostic value regarding survival. Resection of hepatic colorectal metastases may result in long-term survival. Patients with recurrence after a first liver resection may benefit from a repeat metastasectomy. Our data suggest there is no strong predictor of survival. Survival seems to decrease with increasing number of metastases found on computed tomograph

Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma

STUDY OBJECTIVES: No established curative treatment is available for pleural thymoma metastases and malignant pleural mesothelioma (MPM). Recently, peritoneal malignancies have been treated by cytoreductive surgery and intraoperative hyperthermic intracavitary perfusion chemotherapy (HIPEC). We investigated the feasibility and safety of this multimodality treatment in the thoracic cavity. DESIGN: Patients with pleural thymoma metastases or early-stage MPM were enrolled in a feasibility study. Morbidity, recurrence, and survival rates were recorded. SETTING: The Netherlands Cancer Institute. PATIENTS: Three patients with pleural thymoma metastases and 11 patients with pleural mesothelioma were treated. INTERVENTIONS: Cytoreductive surgery and intraoperative hyperthermic intrathoracic perfusion chemotherapy (HITHOC) with cisplatin and adriamycin were performed. The mesothelioma patients received adjuvant radiotherapy on the thoracotomy wound and drainage tracts. MEASUREMENTS AND RESULTS: Morbidity and mortality rates were 47% and 0%, respectively. Reoperation was necessary in four cases. Severe chemotherapy-related complications were not observed. A solitary mediastinal and a contralateral pleural thymoma recurrence were successfully treated by radiotherapy and a contralateral HITHOC procedure. All thymoma patients were alive and free of disease after a mean follow-up period of 18 months. After a mean follow-up period of 7.4 months, nine mesothelioma patients are alive. Two mesothelioma patients died of contralateral pleural and peritoneal recurrent disease, while one patient is alive with locoregional recurrence. CONCLUSIONS: Cytoreductive surgery and HITHOC with cisplatin and adriamycin is feasible in patients with pleural thymoma metastases and early-stage MPM, and is associated with acceptable morbidity rates. Early data on locoregional disease control are encouraging, and a phase II study will be conducte

The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma

BACKGROUND: Patients with localized malignant pleural mesothelioma (MPM) can be considered for surgical resection with or without additional treatment. For this approach it is imperative to select patients without mediastinal lymph node involvement. In this study cervical mediastinoscopy (CM) is compared with computer tomography (CT) scanning for its diagnostic accuracy in assessing mediastinal lymph nodes during preoperative workup. METHODS: Computer tomography scans of the chest and CM were performed in 43 patients with proven unilateral MPM. The CT scans were reviewed by one radiologist and two chest physicians. At CM the lymph node samples were taken from stations Naruke 2, 3, 4, and 7. Computer tomography and CM results were compared with final histopathologic findings obtained at thoracotomy or, if this was not performed, at CM. RESULTS: Computer tomography scanning revealed pathologic enlarged lymph nodes with a shortest diameter of at least 10 mm in 17 of 43 patients (39%). There was histopathologic evidence of lymph node metastases at CM in 11 of these patients (26%). This resulted in a sensitivity of 60% and 80%, a specificity of 71% and 100%, and a diagnostic accuracy of 67% and 93% for CT and CM, respectively. CONCLUSIONS: Cervical mediastinoscopy is a valuable diagnostic procedure for patients with MPM who are considered candidates for surgical-based therapy. Results of CM are more reliable than those obtained by CT scanning. Our data confirm results of previous studies reporting that mediastinal lymph node involvement is a frequent event in MP

Survival Analysis of Pseudomyxoma Peritonei Patients Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

OBJECTIVE: To evaluate the survival of patients with pseudomyxoma peritonei (PMP) treated by cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC), and to identify factors with prognostic value. SUMMARY BACKGROUND DATA: PMP is a clinical syndrome characterized by progressive intraperitoneal accumulation of mucous and mucinous implants, usually derived from a ruptured mucinous neoplasm of the appendix. Survival is dominated by pathology. METHODS: A total of 103 patients (34 men and 69 women) treated at The Netherlands Cancer Institute between 1996 and 2004 were identified. Survival was calculated from date of initial treatment and corrected for a second procedure. PMP was pathologically categorized into disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and an intermediate subtype (PMCA-I). Clinical and pathologic factors were analyzed to identify their prognostic value for survival. RESULTS: Median follow-up was 51.5 months (range, 0.1–99.5 months). Recurrence developed in 44%. A second procedure for recurrence was performed in 11 patients. The median disease-free interval was 25.6 months (95% confidence interval [CI], 14.8–43.6 months). The 3-year and 5-year disease-free survival probability was 43.6% (95% CI, 34.4%–55.2%) and 37.4% (95% CI, 28.2%–49.5%), respectively. The disease-specific 3-year and 5-year survival probability was 70.9% (95% CI, 62.0%–81.2%) and 59.5% (95% CI 48.7%–72.5%), respectively. Factors associated with survival were pathological subtype, completeness of cytoreduction, and degree and location of tumor load (P < 0.05). The main prognostic factor, independently associated with survival, was the pathologic subtype (P < 0.01). CONCLUSION: Cytoreductive surgery in combination with intraoperative HIPEC is a feasible treatment strategy for PMP in terms of survival. The pathologic subtype remains the dominant factor in survival. Patients should be centralized to improve survival by a combination of surgical experience and adequate patient selection

Treatment of Malignancy Arising in Pilonidal Disease

Background: Malignant degeneration is a rare complication of pilonidal disease and is associated with a high recurrence rate and poor prognosis compared with regular nonmelanoma skin cancer. Treatment in our departments and in the international literature was evaluated.Methods: We analyzed the data from three patients with malignant degeneration who were treated in our departments and an additional 56 patients who were found after an extensive literature search.Results: A total of 47 males and 12 females, with a mean age of 52 years, were most frequently primarily treated with surgery. After a mean follow-up time of 28 months, 20% of all patients died with evidence of disease and an additional 10% died of unrelated causes. The overall recurrence rate was 39%, with a median time to recurrence of only 9 months. The local recurrence rate was lower when radiotherapy was added to surgical treatment alone (30% vs. 44%). Re-excision of local recurrence resulted in some long-term survivals.Conclusions: Early diagnosis and treatment may lead to improvement of the relative poor prognosis. Surgical treatment should be tailored according to the locoregional extent. The high recurrence rate after surgical treatment can be reduced by the addition of radiotherapy. Although repeat surgery for recurrent disease may involve extensive resection and morbidity, this may result in prolonged survival