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Background: Recently, pleural mesothelioma has been treated by cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin and cisplatin. The well-established cardiotoxicity of doxorubicin and distressing data from an animal study raised concern about its impact on cardiac function. In the present study, early cardiotoxicity of this treatment modality was prospectively analyzed., Patients and Methods: In 13 pleural mesothelioma patients, cardiotoxicity was monitored by clinical examination, electrocardiography, Troponin levels, cardiac ultrasonography, and estimation of left ventricular ejection fraction (LVEF) by radionuclide ventriculography before and during the first 6 months after cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin (25-54 mg/m(2)) and cisplatin (65-120 mg/m(2))., Results: No clinical cardiac failure or treatment-related death was observed. In two patients transient atrial fibrillation was noted; one associated with pulmonary emboli. Early posttreatment Troponin release was not of predictive value. Ultrasonography did not reveal significant alterations. LVEF decreased significantly (mean 0.07 or 11%, P = .001) during the first 3 months and remained stable thereafter. In univariate analysis, the degree of LVEF reduction was statistically related to maximal intrathoracic doxorubicin concentration (P = .031) and total cisplatin dose (P = .029). Direct exposure of the heart to the drugs as a result of partial pericardectomy was not associated with greater LVEF decrease. On the contrary, partial pericardectomy seemed to be associated with a smaller LVEF decline than when the pericardium remained intact (P = .045). In this small series, no statistically significant correlation between other treatment or pharmacokinetic parameters and LVEF decline was found. Notably, higher doxorubicin plasma concentrations and exposure were not associated with increased LVEF reduction., Conclusions: Early cardiotoxicity is limited after this treatment modality using substantial doses of doxorubicin and cisplatin. Hence, this study suggests that intrathoracic chemotherapy with doxorubicin and/or cisplatin may be used for primary and secondary pleural malignancies, even immediately after extensive thoracic surgery, without concern of severe early cardiotoxicity.

Background: Peritoneal carcinomatosis in the absence of distant metastasis occurs in approximately 8 per cent of patients with colorectal cancer. Cytoreduction followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a new treatment option. Patient selection is crucial to outcome., Methods: Cytoreduction followed by HIPEC was performed in 102 patients with peritoneal carcinomatosis. The following factors were studied for association with survival: perforation and obstruction of the primary lesion, location of the primary lesion, obstruction associated with carcinomatosis, presentation, tumour differentiation and histological type. Extent of disease and completeness of cytoreduction were also studied. Hazard ratios (HRs) were used to study these factors., Results: Location of the primary tumour in rectum (HR 3.14 (95 per cent confidence interval (c.i.) 1.11 to 8.91); P = 0.069), poor differentiation (HR 1.73 (95 per cent c.i. 1.04 to 2.88); P = 0.031) and signet cell histological type (HR 2.24 (95 per cent c.i. 1.21 to 4.16); P = 0.008) were associated with shorter survival. Important factors predicting survival were the number of affected regions (HR 1.38 (95 per cent c.i. 1.20 to 1.59); P < 0.001), the simplified peritoneal cancer score (HR 1.19 (95 per cent c.i. 1.12 to 1.26); P < 0.001) and completeness of cytoreduction (HR 8.54 (95 per cent c.i. 4.01 to 18.18); P < 0.001). No other factor correlated with survival., Conclusion: The survival of patients with peritoneal carcinomatosis of colorectal origin is dominated by the extent of disease and the amount of residual tumour after cytoreduction., (Copyright 2004 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background and Objectives: Cytoreduction with hyperthermic intra-peritoneal chemotherapy (HIPEC) is a treatment with a high morbidity. Optimal patients selection can possible reduce toxicity and complications., Patients and Methods: Complications and toxicity of 102 patients were studied. Toxicity was graded according National Cancer Institute Common Toxicity Criteria (NCI CTC) classification. A complication was defined as any post-operative event that needed re-intervention. Potential patients, tumor, and treatment factors were studied on their relation to complications., Results: Grade 3, 4, or 5 toxicity was observed in 66 patients (65%). Eight patients died of treatment-related causes. Surgical complications occurred in 36 patients (35%). Fistulae were frequently encountered (18 patients). The risk of a complicated recovery was higher in carcinomatosis with recurrent colorectal cancer (P = 0.009) and in the case of more than five regions affected (P = 0.044), who had a Simplified Peritoneal Cancer (SPC) score of 13 (P = 0.012) and with an incomplete initial cytoreduction (P = 0.035). Patients with blood loss exceeding 6 L (P = 0.028) and those with three or more anastomoses also had an increased post-operative complication rate (P = 0.018)., Conclusions: Toxicity of cytoreduction followed by HIPEC was 65% (Grade 3-5 NCI CTC), with a surgical complication rate of 35%. Patients with six or seven regions involved and those in whom complete cytoreduction cannot be reached are probably better off without this treatment., (Copyright 2004 Wiley-Liss, Inc.)

Background: Malignant pleural mesothelioma (MPM) is a disease mostly confined to the thoracic cavity. Untreated, the median survival is <1 year. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy is used to kill residual tumor cells on the surface of the thoracic cavity while having limited systemic side effects., Methods: From August 1998 to August 2001, 22 patients with stage I MPM were included in this study. Two patients were irresectable at operation because of extrathoracic tumor growth. Twenty procedures were performed. After cytoreduction, a perfusion was performed with cisplatin and doxorubicin at 40 degrees C to 41 degrees C for 90 minutes. Adjuvant radiotherapy was given to surgical scars and drainage tracts., Results: There was no perioperative mortality, but significant morbidity was seen in 13 patients (65%), including bronchopleural fistula, diaphragm rupture, wound dehiscence, persistent air leakage, and chylous effusion. No hair loss or leucopenia was noticed. The median follow-up was 14 months. The median survival (Kaplan-Meier) was 11 months, with a 1-year survival of 42%. A favorable pharmacokinetic ratio was observed for both cisplatin and doxorubicin., Conclusions: Cytoreductive surgery combined with hyperthermic intrathoracic chemotherapy for stage I MPM is feasible. However, this treatment is accompanied by considerable morbidity. Survival data were less encouraging.

Based on the first favourable results of adjuvant therapy of 5FU plus levamisole in Dukes C colonic cancer in 1990, we conducted a prospective trial. 1029 patients were randomised to receive one year 5FU plus levamisole or no further treatment following curative surgery for stage II or III colon (n = 730) or rectal cancer (n = 299). 45% were in stage II and 55% in stage III. With a median follow-up of 4 years and 9 months a significant reduction in odds of death (25%, SD 9%, P = 0.007) was observed for those with adjuvant treatment (65% at 5 year) compared to the observation group (55%). Improved relative survival was present in stage III (56% vs 44%), and in stage II patients (78% vs 70%). In rectal cancer a non-significant difference in disease-free or overall survival was observed. Distant metastases developed in 76%, while local recurrence alone occurred in 14%. An early start of adjuvant treatment (< 4 weeks) did not affect results. Compliance to 5FU plus levamisole was 69%. Severe toxicity did not occur. In conclusion, one year 5FU plus levamisole was of benefit in stage II and III colonic cancer; in rectal cancer a significant positive effect could not be demonstrated.

Peritoneal seeding from colorectal cancer has a very poor prognosis and is relatively resistant to systemic chemotherapy. We performed a phase I/II trial to investigate the feasibility and effectiveness of extensive cytoreductive surgery in combination with intra-operative hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. 29 patients with peritoneal carcinomatosis of colorectal origin without evidence of distant metastases underwent cytoreductive surgery and intra-operative HIPEC with mitomycin-C (MMC), followed by systemic chemotherapy with 5-fluorouracil (5-FU)/leucovorin. Surgical complications occurred in 11 patients (38%). One patient died directly related to the treatment, resulting in a mortality rate of 3%. MMC toxicity existed mainly of leucocytopenia (in 15 patients; 52%). After a median follow-up of 38 months (range 26-52 months) we found a 2- and 3-year survival rate (Kaplan-Meier) of 45 and 23%, respectively. Extensive cytoreductive surgery and HIPEC is feasible in patients with peritoneal seeding of colorectal cancer. First results suggest that a higher median survival could be achieved compared with conventional palliative surgery and systemic chemotherapy, therefore a randomised phase III study is now being conducted.

Background: Pseudomyxoma peritonei remains a fatal disease. However, extensive surgical cytoreduction combined with intraoperative heated intraperitoneal chemotherapy (HIPEC) has recently emerged as a new treatment modality, which might improve survival., Methods: Patients underwent treatment if the tumour appeared to be technically resectable on preoperative abdominal computed tomography and there were no distant metastases. After aggressive surgical cytoreduction, HIPEC with the administration of mitomycin C was performed for 90 min. Depending on histological grading, patients received adjuvant 5-fluorouracil and leucovorin therapy., Results: Forty-six patients were treated. Optimal surgical cytoreduction was obtained in 40 patients. Postoperative surgical complications occurred in 18 patients. Four patients died as a direct result of the treatment. Bone marrow suppression due to mitomycin C toxicity occurred in 22 patients. There was no other major toxicity related to the HIPEC procedure. After a median follow-up of 12 months, 40 patients are alive, eight of whom have proven recurrence. The actuarial survival rate (Kaplan-Meier) at 3 years was 81 per cent., Conclusion: These results confirm that extensive surgery combined with HIPEC is feasible in patients with pseudomyxoma peritonei and that improved long-term survival might be achieved.