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Objectives: Breast carcinoma is related to the increase of lipid peroxidation in plasma with concomitant decrease of antioxidant (AO) defense capacity in blood cells, which becomes more pronounced during aging of the patients. This work evaluated the potential age-related effect of chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) on the level of lipid hydroperoxides (LP), glutathione (GSH), AO enzyme activities of copper, zinc superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in breast cancer patients. The level of CuZnSOD protein was assessed after the FAC therapy and radiotherapy of breast cancer. Design and methods: AO parameters were measured in the blood of 58 breast cancer patients and 60 healthy age-matched healthy subjects by biochemical and Western blot analyses. Results: Increased oxidative stress (LP: p LT 0.05) and decreased AO enzyme activities (CuZnSOD: p LT 0.01, GPx: p LT 0.05, GR: p LT 0.01) and GSH level (p LT 0.01) in the blood of breast cancer patients in response to FAC chemotherapy seem not to be age-dependent. CuZnSOD enzyme expression decreased after the FAC chemotherapy (p LT 0.05), while it increased after the radiotherapy of breast cancer (p LT 0.05). Conclusion: FAC chemotherapy and radiotherapy promote further oxidative shift, which potentiate already existing chronic oxidative stress linked to breast cancer. In these effects, impaired capacity for H2O2 detoxification (CAT. GPX and GSH) seems to have major contribution. (C) 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Introduction. Although radical radiotherapy has proved to be a successful method in prostate cancer treatment, the conventional (box) technique can result in significant adverse events. Objective. The objective of our study was to estimate the frequency, type and severity of acute and late toxicity in radical radiotherapy of prostate cancer. Methods. In a clinical retrospective study, we included 283 patients with histologically confirmed prostate cancer. All our patients received radical, conventional radiotherapy using the four-field technique. The study was performed at the Radiotherapy Department of the Institute for Oncology and Radiology of Serbia between January 1991 and December 2005. During regular follow-up, we analyzed the frequency, type and severity of acute and late toxicity. Results. Two thirds (71%) of our patients had acute toxicity of at least one organ within the radiation field. Most frequent complication was radiation dermatitis (10.5%), and enteritis (9%), cystitis (6%) and proctitis (2.5%). Acute adverse events were mostly low grade (I and II, 28-61%). Late complications were registered in 20.5% of patients. Skin fibrosis was most frequent (12%). Chronic proctitis was detected in 4% and urethral stricture in 4.5% of our patients. All late complications were low grade. Conclusion. Treatment tolerance of radical radiotherapy is relatively good. Although most patients develop acute toxicity, it is commonly low grade and requires the interruption of radiotherapy treatment in 20% of patients only. Late toxicity is rarer than acute and, in most cases, it does not affect the quality of life.

In this study we investigated the effects of breast cancer radiotherapy on the antioxidant (AO) enzyme activities of copper, zinc superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR), as well as on the concentration of reduced glutathione (GSH) and lipid peroxides (LP) in blood of patients aged 45-58 years and older than 60 years. The results show that in blood of patients aged 45-58 years, radiotherapy increased the activities of CuZnSOD, CAT, and GR, as well as the concentration of GSH, without affecting the activity of GPx and concentration of LP. In patients older than 60 years, radiotherapy increased the activities of CuZnSOD and CAT, lowered the activity of GPx and concentration of GSH, and increased the concentration of LP. Our results indicate that the response to radiotherapy involves age-related impairment of AO capacity for elimination of H2O2, causing oxidative damage to blood cells. This suggests that cytotoxic effects of radiation on healthy tissues might be more pronounced during the aging of breast cancer patients, and should be considered in the further development of individualization protocols in cancer radiotherapy.

Numerous questions regarding combined hormono-radiotherapy in the treatment of locally advanced prostate cancer still remain open. We present results of combined treatment in 133 our patients with locally advanced prostate cancer. All patients received hormonotherapy as neoadjuvant, concomitant with radiotherapy (tumor dose range 65-72Gy), and adjuvant. In six months follow-up time, complete regression (CR) was noted in 120 patients (90%), partial regression (PR) in 6 (4,5%), stabile disease (SD) in 2 (1,5%) and progression of disease (PD) in 5 patients (4%). In mean follow up time of 17 months (6-77), 13 patients relapsed. Five-year time to progression was 70%. Five-year disease-free interval for CR patients was 70%. At the date of last control CR was noted in 116 patients (87%), PR in 2 patients (2%), SD in 7 patients (5%), and 8 patients (6%) had progressive disease. Second malignancy was noted in 4 patients. Multidisciplinary studies directed towards the optimisation of combined treatment are ongoing. There are no definitive conclusions.

INTRODUCTION Although there is no consensus on which is the best option in prostate cancer treatment, these patients could be successfully treated with radiotherapy. Regarding some prognostic factors, it is possible today to classify prostate cancer patients into several risk groups for clinical and biochemical relapse, and therefore to choose the right treatment modality. OBJECTIVE The objective in our study was to analyze the impact of tumor stage and grade, previous transurethral resection of the prostate (TUR), initial prostate specific antigen (PSA) level and age on disease relapse after radical radiotherapy of the prostate cancer. METHOD Between January 1991 and December 2005, a clinical, retrospective study was performed at the Radiotherapy Department of the Institute for Oncology and Radiology of Serbia, which included 283 patients with prostate cancer treated only with radical radiotherapy. During regular follow-up we analyzed response to treatment and disease relapse. RESULTS After radical radiotherapy disease relapse more often occurred (with statistical significance) in patients with locally advanced tumor (stage C 35% vs. A 13% vs. B 19%), low tumor grade (grade III 38% vs. grade II 23% vs. grade I 17%), initial PSA level over 10 ng/ml (29%) and over 20 ng/ml (37%) compared to 11% in the patients with initial PSA level below10 ng/ml, and patients of lower age (less than 55 years 50% vs. 16% in patients over 70 years). CONCLUSION Tumor stage C, low tumor grade (grade II-III), initial PSA level over 10 ng/ml (over 20 ng/ml) and younger age are poor prognostic factors for disease relapse. In this case, radiotherapy as monotherapy is not an adequate approach, and it needs to be combined with other therapeutic modalities.

Background: Bevacizumab is an anti-VEGF, humanized mAb that is the most advanced agent of its class in clinical development. Several studies have examined bevacizumab in combination with chemotherapy in the first- and second-line settings in patients with metastatic CRC. Despite of that, there is lack of information concerning the extent to which bevacizumab can be used to treat metastatic CRC. We still need more evidence related to efficacy and safety of bevacizumab in different settings, or sequential treatments. The aim of this study was to investigate efficacy and safety of bevacizumab added to different chemotherapy in patients with metastatic CRC. Methods: This was a controlled, prospective, multicentre, cohort study. Thirty patients with advanced colorectal cancer were enrolled into this study. Bevacizumab was applied with oxaliplatin-, irinotecan-, 5FU- or capecitabine -based chemotherapy in the first-, second- or third-therapy lines. Totally 261 cycles were applied. The median number of applied cycles per patient was 8 (range 2-16). Results: Objective tumor response (RR) was seen in 11 patients 37% (95%CI 19-69%) calculated on an intention-to-treat basis. The median duration of response was 12 months. Three of 11 patients (27%) with PR had secondary surgery. RR was seen in 9 of 16 patients (56%) who received bevacizumab in the first-line treatment and in 2 of 14 patients (14%) who received therapy in the second+ lines (p=0.02). Clinical benefit (PR+SD) was seen in 22 (74%) patients. 75% of patients achieved clinical benefit in the first-line and 74% in the second+ chemotherapy lines. The median time to progression (TTP) of the patients is was 9 + months (95%CI 7 - + ?) at the moment of this analysis. The median TTP of patients who received bevacizumab in the first line was 11 months (95%CI 8 - + ?). The median TTP of patients who received bevacizumab in the second+ lines was 5.5 months (95%CI 4 - + ?) (p=0.015). The median survival time (OS) for all patients was 9 + months (95%CI 7 - + ?). The median OS at the moment of analysis was 11 months (95%CI 9 - + ?) for patients receiving bevacizumab in the first line, and 7 months for patients receiving the drug in the second+ lines (95%CI 6 - + ?) (p=0.024). The incidence of any toxicity grade 3-4 was less than 10%. Bevacizumab associated incidence of grade 3-4 side effects did not exceed 5%. Hypertension 5% and thromboembolism 5% were the most frequent events. Gastrointestinal perforation did not occur. There was one toxic death due to sepsis and not directly associated with bevacizumab toxicity. Conclusion: Bevacizumab can safely be added to different chemotherapeutic regimens in first- and second+ line. The conferred benefit in overall survival, TTP and response rate obviously requires randomized trials.

Prostate cancer is a complex disease, with many controversial aspects of management in almost all stages of disease. The natural history of this tumor is variable and is influenced by multiple prognostic factors. Radical prostatectomy and radiotherapy are standard treatment options for disease limited to the prostate. The data in literature does not provide clear- cut evidence for the superiority of any treatment. Neo- adjuvant or adjuvant hormonal therapy improves local control and survival in locally advanced disease. The patients treated with radiotherapy would have a relatively long life expectancy, not great risk factors for radiation toxicity and a preference for radiotherapy. The advantages of radiotherapy are that it has a significant potential for cure, it is well tolerated in the majority of men especially when the modern techniques of conformal radiotherapy and intensity modulated therapy are used and it is non-invasive therapeutic options with no anesthesia risk. Expected complications like radiation cystitis, impotence and proctitis are registered in about 1% of patients.

Treatment of inoperable (locally advanced) esophagus cancer, even today, has been a subject of numerous clinical researches. Combination of several clinical modalities is needed, of radiotherapy and chemotherapy the most frequently. This combination applied as neoadjuvant or concomitant brought to improvement of treatment results of these patients. Local control is still a big problem, since majority of these patients die of local treatment "failure". Because of that, estimation of the local control is very important, ie. assessment of the tumor response the treatment. For those reasons, a study has been conducted on 52 patients with locally advanced esophagus tumor, who in the first group of 25 patients, were treated only by radiotherapy, and in the second group of 27 patients, by combined radio-chemotherapy. Pretherapy evaluation, evaluation of esophagus stenosis as well as the tumor regression to conducted treatment, were done in all patients by radiography and endoscopy and the findings were compared: there was no statistically significant difference between investigated methods (p>0.05). although bigger number of the tumor complete regressions was verified by radiography (6 in the first group and 5 in the second group of patients) in relation to endoscopic finding (3 in the first group and 2 in the second group of patients), which had no microscopical evidence of remaining disease. Partial tumor regression made greater differences between investigated methods (10:4 in the first group and 6:3 in the second group of patients).

From February 1995 to August 2001, 34 pts with squamous cell carcinoma of the anal canal (stage T2-35,3%, stage T3-44,1%, stage T4-20,6%, stage N1-29,4%) were treated prospectively by definitive radiotherapy only, delivered with megavoltage linear accelerator, combined with intracavitary brachytherapy in some patients, at the Institute for Oncology and Radiology of Serbia. Total tumor dose was range 55-75Gy. Median follow-up time was 24,7 months (range 6-66 months). Overall survival and disease free survival at 5 years were 65,44% and 68,44%. Local control was 82,3% (28/34 pts). Eight pts had local or distant failure. Early and late complication rates were acceptable. In majority of patients the anal sphincter function was preserved.

The most optimal dosimetry model for the application of large photon fields (dimensions larger than 40x40 cm) at extended focus-phantom/patient distances has not been adopted yet. A method based on a "classical" approach, that helps establishing a database (PDD, output and OF, PSF, Sc and TMR parameters) is discussed. Large photon fields produced by a CLINAC 2100C, Varian, in the low energy mode (6 MV) were analyzed by application of absolute and relative radiation dosimetry, as well as, by comparison with calculated data. A good agreement between measured and calculated values of radiation parameters examined, at FFD=180 and 300 cm, was observed Slight increase in discrepancy (about 10 percent) of the TMR at FFD=300 cm for fields larger than 50x50 cm and at larger depths was observed by comparison of calculated and measured values. Discrepancies of outputs between measured and calculated values (calculated by the inverse square law) were less than 2 percent. Most of the dosimetric data obtained points out the possibility of application of radiotherapy unit CLINAC 2100C (Varian) for therapies with large fields in given conditions.

Objective: The aim of the study was to assess the efficacy and safety of concomitant radiotherapy (CRT) and carboplatin. Patients and Methods: From 1992 until 1997, 67 patients with T3 invasive bladder cancer (IBC) were treated using CRT and carboplatin. X-Ray radiotherapy (10 MeV) was applied using LINAC in a locoregional technique, with a total tumor dose of 65 Gy in 32 fractions. Carboplatin was administered as a bolus infusion once a week, on day 5, up to a total dose of 900 mg. Results: The most frequent toxicity was hematological. Of the 67 treated patients, 92.5% achieved a clinically complete response, and 7.5% developed progressive disease during therapy. The 5-year overall survival was 55% and disease-free survival was 35%. Conclusion: CRT and carboplatin appear to be safe and extremely active in the treatment of T3 IBC, but the results should be confirmed in a randomized study.

BACKGROUND AND PURPOSE: To assess the efficacy and safety of gefitinib given concomitantly and/or as maintenance therapy to standard cisplatin/radiotherapy for previously untreated, unresected, stage III/IV non-metastatic SCCHN. MATERIALS AND METHODS: In this phase II, double-blind, study, 226 patients were randomized to gefitinib 250mg/day, 500mg/day or placebo in two phases: a concomitant phase (gefitinib or placebo with chemoradiotherapy), followed by a maintenance phase (gefitinib or placebo alone). Primary endpoint was local disease control rate (LDCR) at 2years; secondary endpoints were LDCR at 1year, objective response rate, progression-free survival, overall survival, and safety and tolerability. RESULTS: Gefitinib (250 and 500mg/day) did not improve 2-year LDCR compared with placebo either when given concomitantly with chemoradiotherapy (32.7% vs. 33.6%, respectively; OR 0.921, 95% CI 0.508, 1.670 [1-sided p=0.607]) or as maintenance therapy (28.8% vs. 37.4%, respectively; OR 0.684, 95% CI 0.377, 1.241 [1-sided p=0.894]). Secondary efficacy outcomes were broadly consistent with the 2-year LDCR results. In both doses, gefitinib was well-tolerated and did not adversely affect the safety and tolerability of concomitant chemoradiotherapy. CONCLUSION: Gefitinib was well-tolerated, but did not improve efficacy compared with placebo when given concomitantly with chemoradiotherapy, or as maintenance therapy alone.

To evaluate the efficacy and safety of preoperative radiotherapy with capecitabine and mitomycin C in patients with locally advanced rectal cancer.A prospective, open-label, non-randomized, phase II study was performed on 49 patients with locally advanced rectal cancer. Preoperative radiotherapy was conducted on linear accelerators (15 or 18 MV) with a tumor dose of 45 Gy in 25 fractions over 5 weeks, combined with mitomycin C 7 mg/m(2) on days 1 and 29 and oral capecitabine 825 mg/m(2) twice daily on days 1-35. Surgery was performed 5-6 weeks after the end of chemoradiation. The primary study endpoint was histopathological complete regression rate (pCR; Dworak grade 4).Disease stage at diagnosis was T3 in 34 patients (69%) and T4 in 15 patients (31%). Positive lymph nodes were diagnosed in 28 patients (57%). Toxicity (all grades) was documented in 35 patients (71%). Grade 3 toxicities were radiation dermatitis (25%), diarrhea (2%), neutropenia (2%), and granulocytopenia (2%). No patient experienced grade 4 toxicity. A pCR was seen in 8 (16%, 95% CI 9-29%) patients, a major response was noted in 24 (49%) patients and a minor response in 14 (29%) patients. R0 resection was performed in 46 patients (93.9%) and R1 in 3 patients (6.1%). Histopathological tumor downstaging was documented in 26 patients (53%). One-year disease-free survival was 93.3% and 1-year survival was 97.7%.Preoperative chemoradiation with capecitabine and mitomycin C appeared to be effective with low toxicity in patients with locally advanced rectal cancer.

Preoperative or definitive chemoradiotherapy defines today the standard treatment of patients with localized or locally advanced esophageal cancer. Preliminary results of our study are presented. 46 patients with locally advanced squamous cell esophageal cancer (T3-4, N0-1, M0) were enrolled. All patients recieved concomitant chemotherapy (Cisplatin/ 5FU/LV) and radiotherapy (45-50,4Gy). Clinical response rate was 59% (3 patients (7%) complete response, 24 patients (52%) partial regression, 13 (28%) stabile disease, 6 patients (13%) disease progression). Out of 46 patients, 12 were operated (26%), all with R0 resection. Complete patohistolgical regression (TRG 1) was noted in 5 patients (42%). TRG 2 i TRG 3 in one (8%) and 3 patients (25%), and TRG 4 in 3 patients (25%). Mean survival time in operated group of patients was 9,3 months, and in nonoperated group 5,5 months. Studies show improved survival rate in patients with complete response to chemoradiotherapy and R0 resection. Individualy tailored therapy is essential.

Introduction and potentials of classical radiotherapy After purchase of radiotherapy equipment in 2003, classic radiation therapy in Serbia will reach the highest world level. In order to define the highest standards in radiation technology, we analyzed the current status and potential perspectives of radiation therapy. Technological levels of radiotherapy in developed countries An analysis of present situation in the USA, assumed as the most developed in the world, was done. Available data, collected in the last 3 years (equipment assortment, therapy modalities, workload and manpower) for 284 radiotherapy centers, out of potential 2050, were analyzed. Results were presented as crude percentage and mached to point current status. Results of analysis and discussion The analysis showed that CLINAC accelerators are the most popular (82.7%), as well as, ADAC (43.7%) and Focus (CMS) (27.4%) systems for therapy planning. Movement towards virtual simulation is evident (59.3%), although classic ?simulation? is not fully eliminated from the radiotherapy chain. The most popular brachytherapy afterloader is Microselectron HDR (71%). About 64.4% centers use IMPAC communication/verification/record system that seems more open than Varis. All centers practice modern radiotherapy modalities and techniques (CFRT, IMRT, SRS/SRT, TBI, IORT, IVBHRT, HDR BHRT, etc.). CT and MRI availability is out of question, but PET is available in 3% of centers, however this percentage is rapidly growing. Up to 350 new patients per year are treated by one accelerator (about 35 pts. a day). Centers are relatively small and utilize 2-3 accelerators on average. Average FTE staffing norm is 4 radiation oncologists, 2-3 medical radiotherapy physicists, about 3 certified medical dosimetrists and about 6 radiotherapy technologists. Technological aspects and conclusion In the past 5 years relative stagnation in classic radiotherapy has been observed. In spite of substantial investments in technology and consequent improvements, as well as wide introduction of computers in radiotherapy, radiotherapy results have not changed significantly. Vendor development strategies do not point that this trend will change in the next 5 years. On the other hand, wide introduction of the PET in each radiotherapy chain ring (diagnostics, planning, follow-up), could improve results (local and regional control, as well as quality of patients' life).

Background: The goal of this study was to introduce a new predictive biomarker assay that might improve a clinical irradiation treatment of malignant diseases. Methods: Thirty-two peripheral blood samples obtained from breast cancer patients were analyzed for superoxide dismutase (SOD) after irradiation with gamma rays (60 Co). SOD was measured in subcellular fractions prepared from unirradiated and irradiated blood samples (McCord and Fridovich). The activity of SOD was measured by the method of Misra and Fridovich and protein concentration by the method of Lowry et al. Results Antioxidant radiation response of patients' blood cells was very variable and specific for each individual. The results indicated that the radiation response during radiotherapy directly depends on the initial state of antioxidant activity in the blood of cancer patients. In the blood samples with high level of SOD activity the irradiation decreased enzymatic activity while in the samples with medium or low level of SOD, the SOD activity was preserved or increased by irradiation with 2 Gy of gamma rays. Conclusion We showed that the modulation of SOD activity in blood cells after irradiation in vitro might be used as predictive biomarker in individualization of therapy protocols.

Background: The aim was to investigate the application of radiopotentiation which was initiated by the fact that in patients with locally advanced non-small cell lung cancer there is a high risk of relapse due to failure in local control of the disease and the risk of systemic micrometastases. The other aim was the evaluation of quality of life. Methods: A study group consisted of 67 patients. Patients were first treated with TD30 Gy in 10 fractions during 2 weeks (5 fractions per week) with a potentiation by 20 mg/m 2 of carboplatinol intravenous bolus infusion just prior to each radiotherapy fraction. After a 2-week pause, additional radiation of 25 Gy in 10 fractions was applied during 2 weeks (5 fractions/week) with a potentiation by 20 mg/m 2 of carboplatinol. Total tumor dose (TTD) was 55 Gy (30+25 Gy) in 20 fractions, total duration of the therapy was 6 weeks, and total dose of carboplatinol was 600 mg. A control group consisted of 70 patients and they were treated with a radical radiotherapy with a conventional fractionation (60 Gy in 30 fractions, 2 Gy per day, 5 fractions per week). Quality of life was evaluated by Karnofsky performance scale (KI), at the beginning of the treatment, after the completion of the whole course of treatment, and during follow-up at regular check-ups. Results After the completion of the whole course of treatment most of patients had KI 80%. Analysis made during the last check-up showed statistically significant low KI. In both study and control groups KI was significantly higher at the beginning of the treatment than KI after the completion of the whole course of treatment (p=0.001). However, the analysis of KI at the time of the completion of the whole course of treatment showed significantly better KI in study group (p=0.036) than in control group. Conclusion: These results showed that the combined radiochemotherapy treatment is well tolerated.