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Background: The aim was to determine the maximum tolerable dose of oxaliplatin added to (oral) 5FU in irresectable rectal cancer. Patients and Methods: Nineteen patients were treated; 13 patients received 5FU/LV and 6 patients capecitabine. Oxaliplatin was administered on days 1 and 29 at dose levels 85 and 130 mg/m(2). Four to seven weeks thereafter, surgery was performed. Results: In 6 patients treated with 85 mg/m(2) one grade 3 elevation of liver transaminases occurred. Of 7 patients who received 130 mg/m(2) 1 patient experienced a grade III thrombocytopenia and 1 patient died of neutropenic fever, probably due to an urosepsis. Six patients were treated with capecitabine, of whom 3 developed a grade III gastrointestinal toxicity. An R0 resection could be performed in 93%, a pT0-2N0 in 39%, with 2 pCR's. Conclusion: The addition of oxaliplatin at 85 mg/m(2) on days I and 29 to radiotherapy and 5FU/LV or capecitabine in irresectable rectal cancer is feasible.

PURPOSE: The aim of this study was to determine the relationship between survival and value of molecular markers in the primary tumour in a group of patients with irresectable rectal cancer, treated with preoperative chemo-radiotherapy. MATERIALS AND METHODS: Immunohistochemistry for p53, p21, bcl-2 and Ki-67 was performed on pre-treatment biopsy specimens of 34 patients with irresectable rectal cancer. Preoperative treatment consisted of pelvic irradiation of 45-56 Gy, combined with 5FU and leucovorin (350/20 mg/m2 x 5 d; in weeks 1 and 5 during radiotherapy). The median follow-up was 38 months. Endpoints were pathological T-stage and survival after surgery. RESULTS: Expression of p21 correlated significantly with survival (p=0.005). Survival and p21 expression also correlated significantly, when adjusted for tumour response (p=0.005, RR=4.8 (1.6-14.7)). CONCLUSION: Expression of p21 predicts a worse survival in irresectable rectal cancer treated with preoperative chemo-radiotherapy. No relationship was found between tumour response in chemo-radiotherapy and p53, bcl-2 or Ki-67.

Initial treatments of locally advanced rectal cancers focus on local control, as local relapse of a rectal cancer is correlated with a high morbidity and mortality. We studied the effect of neoadjuvant radiochemotherapy on advanced rectal cancer patients in relation to downstaging, local relapse and survival. Post-treatment pathological staging, local relapse and survival were analysed in 66 patients from a single institution. 43 patients had irresectable cancer as determined by laparatomy (n = 42) or rectal examination (n = 1). These 43 patients received 45-56 Gy preoperatively with 5-fluorouracil (5-FU) and leucovorin (350/20 mg/m(2) x 5 day (d)) in weeks I and 5 during the radiation therapy. 23 patients had primary resectable tumours with a T1-2 stage. Of the initially irresectable tumours 79% became macroscopically resectable, in 74% a R0 resection was performed. In 6 of 34 (18%) surgical specimens, no tumour was found (pT0), 7 patients had small tumour remnants (pT1-2). In these pT0-2 tumours, no local relapses occurred (observation period of median 4.5 years, range 18-87 months). In the 21 patients with pT3-4 tumours 3 local relapses were seen. In the 23 patients with primary resectable T1-2 tumours the relapse rate was 4%. Downstaging of an initially irresectable rectal tumour to pT2 or less results in a local relapse rate and overall survival that correspond with the rates in primary resectable cancer with the same T classification. (C) 2002 Elsevier Science Ltd. All rights reserved.

Radiation treatment of the liver for malignant disease has gained renewed interest due to newly developed treatment modalities. Still limited specific knowledge is available concerning liver damage following irradiation. Inconsistencies between reported animal experimental studies are largely due to differences in irradiation techniques and to varying Observation periods. Following the introduction of Megavoltage irradiation and the development of more sophisticated irradiation techniques, clinical reports concerning more reliable studies became available. The reaction of the fiver to irradiation depends specifically on parameters as type of irradiation, dose, dose rate, fractionation schedule, and irradiated volume. Also the use of cytotoxic agents and liver surgery are of importance for the ultimate therapeutic result. Radiation hepatitis in humans may develop following high-dose liver irradiation resulting in clinical and histopathological disorders resembling a veno-occlusive disease-like syndrome. These disorders may either totally or partially recover or be progressive in time resulting in hepatic failure. It is concluded that depending on the variables mentioned, ionizing radiation up to 35 Gy to the human liver, given to a limited volume, can be applied without major liver function disturbances.

Purpose: The histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT) were investigated in order to establish the tolerance of liver tissue to IORT, thus providing a framework for clinical IORT treatment of patients with metastatic disease to the liver. Materials and methods: Following partial resection of the liver, IORT in doses of 10, 20, 25, or 30Gy was applied to the resection plane and a non-surgically manipulated part of the liver of 25 beagles. Results: There were no postoperative complications, and no morbidity or mortality during a maximal follow-up of 5 years. Dogs were killed at. 3 months, and 1, 2, 3 and 5 years folloning IORT. Light microscopic examination revealed capsular thickening, severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1-2 years following IORT. At 3-5 years, however, only mild parenchymal changes were found that:consisted of slight periportal fibrosis, an incidental portal-central fibrous septum and vascular changes with endothelial proliferation and focal arteriolar hyalinosis. Conclusions: This study demonstrated that following partial hepatic resection, IORT to the liver in the canine model can be applied safely, without short- or long-term treatment morbidity. Although doses up to 30Gy resulted in severe local tissue damage 1-2 years following IORT, these changes were largely reversible due to hepatic regeneration.

Changes in TGF-beta plasma levels were observed 18 weeks after hemithoracic irradiation in rats. This coincides with an increase in the breathing frequency, being most pronounced between 22 and 28 weeks after irradiation. The correlation suggests a potential role of the circulating TGF-beta in the monitoring of localized radiation-induced lung injury. (C) 1997 Elsevier Science Ireland Ltd.

Background: The feasibility of concurrent chemotherapy and radiotherapy for advanced primary carcinoma of the cervix was evaluated and the results were compared to historical controls. Patients and methods: In a single institution study, patients (n = 74) with primary cervical carcinoma received 3 cycles carboplatin/5-fluorouracil concurrent with radiotherapy, followed by salvage hysterectomy (group I). Treatment results were compared with those of a historical control group (n = 39) (group II), treated similarly but without chemotherapy. Results: In group I median follow-up is 28 months (12-68+) and in group II 23 months (14-90+ months). The 5-year overall survival, progression-free survival and local recurrence free survival for group I and II are, respectively, 69% versus 38% (P

A phase I study was performed in 21 patients with previously untreated, locally inoperable, non-small-cell lung cancer (NSCLC) with ambulatory continuous carboplatin infusion together with continuous thoracic irradiation over 6 weeks. A dose range for carboplatin of 15 mg m(-2) day(-1) during the last 21 days (first level), during the last 31 days (second level), or during 6 weeks of the radiation period (third level) and thereafter 20 or 25 mg m(-2) day(-1) during 6 weeks of radiation (fourth and fifth level) was used. The total radiation dose was 60 Gy given as 2 Gy day(-1) for 5 days week(-1). The first three patients received radiotherapy without carboplatin. WHO grade III/IV leucopenia and thrombocytopenia occurred in the last two dose levels in two out of six and one out of six patients with 20 mg m(-2) day(-1) respectively, and in all three patients with 25 mg m(-2) day(-1) (dose-limiting toxicity). One local infection around the port and a subclavian vein thrombosis occurred. Radiation toxicity of the lung and oesophagus did not seem to be influenced by carboplatin treatment. Out of 21 patients one had a complete response (CR), ten partial response (PR), six stable disease (SD) and four progressive disease (PD). Total (TPt) and ultrafilterable plasma platinum (UPt) were measured in the last three dose levels with atomic absorption spectrophotometry with Zeeman correction. The mean (s.d.) level for TPt for 6 weeks at 15, 20 and 25 mg m(-2) day(-1) was 0.76 (0.15), 0.78 (0.19) and 0.90 (0.22) mg l(-1) for UPt 0.10 (0.03), 0.12 (0.02) and 0.20 (0.03) mg l(-1) respectively. TPt concentration levelled off after 3 weeks. The mean (s.d.) CL(TB) for UPt was 281 +/- 21 ml min(-1) and correlated with glomerular filtration rate (r = 0.61, P = 0.03). As estimated with the sigmoid E(max) model defined by the Hill equation the percentage reduction in platelets correlated with the area under the curve for UPt (r = 0.77). The maximum tolerable dose of carboplatin with concomitant continuous 60 Gy radiotherapy is 25 mg m(-2) day(-1); the recommended dose for phase II or III studies is 20 mg m(-2) day(-1) day for 6 weeks.