Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Cilengitide is a selective αvß3 and αvß5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany.

Tumor topoisomerase II alpha status and response to anthracycline-based neoadjuvant chemotherapy in breast cancer.

OBJECTIVES: Individualized chemotherapy for breast cancer improves the outcome. Anthracyclines target the enzyme topoisomerase IIα (TOP2A). We set out to perform a retrospective study of the presence of gene abnormalities and the expression of TOP2A in a cohort of breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. METHODS: Forty-three patients with 45 breast cancers were treated with neoadjuvant docetaxel-epirubicin with/without capecitabine chemotherapy. The TOP2A status of the cancers, determined retrospectively by fluorescent in situ hybridization and immunohistochemistry, was analyzed in relation to the standard clinical and pathological data. RESULTS: Clinically and pathologically complete remission (pCR) was achieved in 15 (33.3%) and 9 (20%) cases, respectively. The TOP2A gene was amplified in 2 human epidermal growth factor receptor 2 (HER2)-positive cancers (8%), and 32 (84.2%) overall exhibited TOP2A expression in >15% of the cells. The expression of TOP2A exhibited a strong correlation with the expression of Ki67 (R = 0.743, p < 0.001), and was negatively correlated with estrogen receptors (ER; R = 0.404, p = 0.012) and progesterone receptors (R = 0.430, p = 0.007). The expression of TOP2A was not related to the amplification of the TOP2A gene or the HER2 status of the tumor. The proportions of Ki67- and TOP2A-positive tumor cells were significantly reduced after chemotherapy (56.1 ± 23.6 vs. 19.0 ± 27.7%, p = 0.004, and 41.0 ± 27.9 vs. 12.7 ± 24.8%, p < 0.001, respectively). The development of pCR was related to a high grade (p = 0.054), ER negativity (p = 0.027) and high TOP2A expression (p = 0.037). The expression of TOP2A was an independent predictor of pCR (OR = 1.460, for every 10% increase, 95% CI: 1.016-2.096, p = 0.041). After a median follow-up time of 31.0 months, neither relapse-free survival nor overall survival was related to the tumor response. CONCLUSIONS: TOP2A expression is a marker of the tumor's proliferation rate and sensitivity to anthracycline-based chemotherapy, and does not depend on the amplification of its gene.

Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer.

OBJECTIVES: To perform a protocol-specified analysis of the dose-dense adriamycin-paclitaxel-cyclophosphamide (ddATC) study. METHODS: Survival and late toxicity were analyzed in 55 patients enrolled to receive 4 x adriamycin 60 mg/m(2), 4 x paclitaxel 200 mg/m(2), 4 x cyclophosphamide 800 mg/m(2), every 2 weeks, with cardioxane and filgrastim support. Kaplan-Meier curves were used to analyze relapse-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). Survival analyses were performed according to the presence of casting-type calcifications on the mammogram. RESULTS: After a median follow-up time of 78.5 (64.3-100.0) months, 29 (52.7%) patients were free of relapse (local, regional, distant or contralateral breast cancer), 34 (61.8%) patients were free of distant metastases, and 36 patients (65.5%) survived. The median times of RFS, DDFS and OS were not yet reached at 100.0 months. The median RFS, DDFS and OS times among breast cancer patients with tumors not associated with casting-type calcifications were >100.0 months, the corresponding parameters among patients with tumors accompanied by casting calcifications were 11.5 (p < 0.001), 11.5 (p < 0.001) and 29.6 months (p = 0.035), respectively. None of the patients developed myelodysplastic syndrome or leukemia. No cardiac failure occurred during the follow-up period. CONCLUSIONS: Our results indicate that adjuvant sequential ddATC is an efficient and less toxic chemotherapy regimen in high-risk breast cancer. The presence of casting-type calcifications on the mammogram points to a special biologic nature with very poor prognosis.

[Effect of lifestyle counseling given by health personnel on the changes in dietary habits of Hungarian women treated for cancer]. / Az egészségügyi személyzet életmód-tanácsadó tevékenységének szerepe daganatos betegséggel kezelt nôk táplálkozási szokásainak megváltoztatásában.

The aim of this study was to investigate the changes in dietary habits in women with gynecological or breast cancer, and to analyze the role of some demographic factors, type of the malignant tumor, and the role of medical staff's advice in dietary behavior change of these women, after the diagnosis of cancer. A self-administered questionnaire-based retrospective study was performed, and 155 randomly selected patients, treated for gynecological or breast cancer, were involved. A self-developed questionnaire was used to measure the socio-demographic characteristics, the circumstances of visiting the physician, therapy, present health status and lifestyle before and after the diagnosis of neoplasm. More than three-fourths of the women reported changes in nutrition after the diagnosis of cancer. The consumption of fruits and vegetables increased in the highest proportion (70.3%). Women with higher education changed their diet in higher proportion (p=0.031) compared to women with lower education. Women who were advised to change their lifestyle by their therapists were about four times more likely (OR: 3.87; CI: 1.40-10.69 ) to change their nutrition. Patients with breast cancer changed three times more likely (OR: 3.21; CI: 1.05-9.84) their dietary habits than patients with gynecological cancer. The most influential proven factor to make cancer patients alter their diet was being advised for this by physicians. Thus, our study proved that physicians and nurses have a very important role in changing their cancer patients' nutritional habits into a healthier one.

[Neoadjuvant systemic therapy in breast cancer]. / Neoadjuváns szisztémás terápia emlorákban.

Neoadjuvant (preoperative) systemic therapy is a good possibility for the treatment of symptomatic breast cancers of the locoregional stage. Chemotherapy or hormone therapy chosen according to the characteristics of the primary tumor, result in the regression of the tumor in the majority of the cases, favoring breast conserving surgery thereafter. The long-term effects of neoadjuvant systemic therapy are equivalent to that of adjuvant therapy, and the in vivo observed efficiency of the treatment reflects prognosis. Finally, systemic therapy introduced prior to surgery is not delayed by the possible adverse effects of the surgery. Detailed examination of the tumor and the patient is mandatory before starting systemic therapy. Besides breast imaging and histological examinations, staging is necessary. Pathological characterization of the tumor will enhance treatment choice based on the features of chemo- or hormone-sensitivity. For the treatment of chemosensitive tumors, taxane- and anthracycline-based polychemotherapy is the most efficacious. Data on neoadjuvant hormone therapy have been provided by studies on postmenopausal patients. Since the aromatase inhibitors are more efficient than tamoxifen, their use is the first option in this patient population. Among the molecular targeted agents, trastuzumab combined with chemotherapy produces extending therapeutic response rate. Following the completion of the neoadjuvant systemic therapy, breast imaging is required once more before performing breast and lymph node surgery. Postoperative radiotherapy is generally needed. The use of a common language and professional guidelines by the members of the multidisciplinary breast team is a condition for neoadjuvant systemic therapy.

Seasonal variation of childhood acute lymphoblastic leukaemia is different between girls and boys.

The aim of this study was to investigate seasonal trends in the incidence of acute lymphoblastic leukaemia (ALL) around the times of birth and diagnosis in children aged 0-4 years and also to examine gender specific effects. Children born in South Hungary during 1981-1997 were analysed. Registrations of first malignancies for children, diagnosed under age 5 years before the end of 2002 were obtained from the Hungarian Paediatric Oncology Group providing a representative sample of Hungarian children over a 17 year period of time. Data were available on the corresponding numbers of births for each month of the study period were obtained. Statistical analyses were performed using logistic regression with harmonic components. The study analysed 121 cases of children, aged under 5 years, who were diagnosed with ALL. We found no seasonal effect related to date of diagnosis. However, there was seasonal variability for ALL related to date of birth. Maximal rates were seen in children born in February and August in the simple harmonic regression model for all children diagnosed with ALL. Analysis by gender found evidence of seasonality related to month of birth with peaks in February and August in boys, but different seasonal effects were seen for girls (peak in November, nadir in May). Our study provides some evidence that male specific immune responses to infections around the time of birth could explain the male predominance in the incidence of ALL.

Tumor characteristics in screen-detected and symptomatic breast cancers.

The natural course of early breast cancer has changed as a result of the introduction of mammographic screening. The present aim was a prospective analysis of screen-detected and symptomatic operable breast cancers in the era of mammographic service screening. The mode of detection (screen-detected, symptomatic or interval cancer), the type of mammographic image and other characteristics (the invasive tumor size, histological tumor type, grade, nodal, hormone receptor and HER2 status and the presence of lymphovascular invasion) of 569 invasive breast cancers were studied. Screen-detected cancers were significantly more frequently of grade I, < 10 mm of size and node-negative (p < 0.001, respectively). Symptomatic/interval cancers were significantly more frequently of grade 3, >20 mm of size (p < 0.001), and exhibited lymphovascular invasion (p = 0.001). Screening-detection of the tumor favored breast-conserving surgery, sentinel lymph node biopsy and the avoidance of chemotherapy (p < 0.001). Cancers associated with casting-type calcifications on the mammogram were typically of ductal type (p = 0.043), of grade 2-3, estrogen receptor and progesterone receptor-negative and HER2-positive (p < 0.001). Interval cancers occurred significantly more often at a younger age and remained mammographically occult as compared with other cancers. Mammographic screen-detected cancers demonstrate more favorable prognostic features, and need less extensive treatment than symptomatic or interval cancers. The mammographic appearance of the tumor reflects its biological behavior, and this should be considered in the management optimization.

The risk of early and late lung sequelae after conformal radiotherapy in breast cancer patients.

PURPOSE: To study the risks of early and late radiogenic lung damage in breast cancer patients after conformal radiotherapy. METHODS AND MATERIALS: Radiogenic lung sequelae were assessed prospectively in 119 patients by means of clinical signs, radiologic abnormalities, and the mean density change (MDC) of the irradiated lung on CT. RESULTS: Significant positive associations were detected between the development of lung abnormalities 3 months or 1 year after the radiotherapy and the age of the patient, the ipsilateral mean lung dose (MLD), the radiation dose to 25% of the ipsilateral lung (D(25%)) and the volume of the ipsilateral lung receiving 20 Gy (V(20 Gy)). The irradiation of the axillary and supraclavicular lymph nodes favored the development of pneumonitis but not that of fibrosis. No relation was found between the preradiotherapy plasma TGF-beta level and the presence of radiogenic lung damage. At both time points, MDC was strongly related to age. Significant positive associations were demonstrated between the risks of pneumonitis or fibrosis and the age of the patient, MLD, D(25%), and V(20 Gy). A synergistic effect of MLD, D(25%), and V(20 Gy) with age in patients older than 59 years is suggested. CONCLUSION: Our analyses indicate that the risks of early and late radiogenic lung sequelae are strongly related to the age of the patient, the volume of the irradiated lung, and the dose to it.

[Approaches to individual radiotherapy in breast cancer: individual risk estimation and individualized techniques]. / Törekvés a sugárterápia individualizálására emlorákban: egyéni rizikóbecslés és egyénileg alkalmazott technikák.

INTRODUCTION: Radiotherapy comprises an integral part of the curative therapy of breast cancer by improving the locoregional control and survival when given on an individualized basis. Conformal radiotherapy and three-dimensional radiation treatment planning enhance the safety of radiotherapy by adjusting the irradiated volume to the shape of the target volume, and providing control of the radiation dose to the organs at risk (OARs). PATIENTS AND METHODS: The methods introduced at the authors' institute in 2002 are demonstrated. The breast/chest wall and lymph node areas were irradiated provided that there was a minimum risk of local or locoregional relapse of 10%. CT-based 3D radiotherapy treatment planning and individual patient-positioning were applied, with thermoplastic mask-fixation in the second part of the study. The dose constraints of the OARs were given in accordance with the literature recommendations. In the first group of patients, individually shaped blocks, in the second group, multileaf collimator, and in the third group, with the aim of a more homogenous dose-distribution in the target volume, intensity-modulated beams were applied. RESULTS: During the study, 737 breast cancer patients received conformal radiotherapy based on individual risk estimation. In 372 cases only local, while in 365 cases locoregional radiotherapy was delivered. The dose-homogeneity in the target volume was significantly improved in the second period of the study, when segments were superposed on the radiotherapy fields. The proportions of the target volumes irradiated with +/-10% of the planned dose in the breast/chest wall, axillary and supraclavicular lymph nodes and internal mammary lymph nodes varied between 90.5-94.2%, 84.1-93.8% and 86.7-91.6%, respectively, depending on the radiation technique used. The parameters indicating the dose to the ipsilateral lung or to the heart were significantly higher when locoregional radiotherapy was applied compared to that in case of local radiotherapy. Radiation dose to the ipsilateral lung and the heart was significantly reduced in the second part of the study when locoregional, but not when local radiotherapy was delivered. The introduction of individual immobilization by means of thermoplastic mask-fixation resulted in a relevant decrease in the uncertainty due to breathing motion and daily positioning errors, and also in a significant reduction of the dose to the contralateral breast. CONCLUSIONS: Adjuvant radiotherapy should be based on individual risk-benefit features. The need of the introduction of special techniques may be decided after the dose-volume analysis of the conformal radiotherapy plan based on 3D radiation treatment planning.

Nuclear ß-catenin positivity as a predictive marker of long-term survival in advanced epithelial ovarian cancer.

BACKGROUND: Classical features as histomorphology, grade, FIGO stage, and residual tumour mass have strong prognostic value in advanced epithelial ovarian carcinomas (AEOC). Most AEOCs are associated with early recurrence and poor overall survival (OS). Despite of early recurrence, general poor outcome, both high grade tumours or tumours with advanced FIGO stage at the time of diagnosis, in some of such cases, long-term survival (LTS) has been recorded . The aim of this study was to compare the utility of "classical" prognostic factors to molecular factors such as ß-catenin- E-cadherin-, mutated TP53-, and MiB-1 (Ki-67) labelling index determination in predicting long-term survival. METHODS: The expression of ß-catenin, E-cadherin, Ki-67, and p53 was determined by immunohistochemistry (IHC) in AEOC. Correlation was sought for between expression of these proteins and the status of classical features vis-á-vis overall survival of patients. Statistical evaluation of the data included Kaplan-Meier analysis, the log-rank test and Cox proportional hazards model. RESULTS: As expected, residual tumour size was an independent adverse prognostic factor for OS (univariate analysis: p=0.003, multivariate analysis: p=0.005). Nuclear expression of ß-catenin in advanced ovarian cancer of LTS patients proved to be not only an independent favourable predictor of OS (univariate analysis: p=0.025, multivariate analysis: p=0.041) but also showed strong correlation with platinum sensitivity and platinum re-induction. CONCLUSIONS: Translocation of stabilized ß-catenin from cytoplasm to the nucleus plays an important role in predicting platinum sensitivity. It also seems to support the chance for platinum re-induction in AEOC and thus enhances long-term survival.

Elevated levels of circulating insulin-like growth factor-I, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: a case-control study.

There is increasing evidence that different types of breast cancers are related to distinct risk factors. We analyzed the risk of breast cancer with respect to circulating insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3, 17beta-estradiol, estrone, testosterone, androstenedione and sex hormone-binding globulin (SHBG), taking into consideration the characteristics of the tumors. Plasma hormone levels of 102 postmenopausal patients with breast cancer detected by mammography screening, and 102 matched controls were analyzed in relation to the histological type, the status of the estrogen receptor (ER), the progesterone receptor (PR) and the HER2 in the tumors. Significant positive associations were revealed between the IGF-I concentration and the overall risk of breast cancer (OR=3.1, 95% CI: 1.5-6.2), ER+PR+ breast cancer (OR=2.4, 95% CI: 1.1-5.4) and ER+PR- breast cancer (OR=4.3, 95% CI: 1.2-14.3) when the highest and the lowest ranges of IGF-I were compared. Significant associations were also found between the highest and the lowest quartiles of testosterone, resulting in OR=4.1 (95% CI: 1.8-9.4) for the risks of breast cancer and OR=5.8 (96% CI: 2.1-16.2) of ER+PR+ breast cancer. A synergy was seen between IGF-I and testosterone levels. When both plasma IGF-I and testosterone were in the highest quartile ranges, an OR=26.4 (95% CI: 1.6-426.5, p=0.021) was computed for breast cancer overall. No significant synergistic effects could be demonstrated with other parameters. There were significant, 2.5-fold (95% CI: 1.2-5.6), and 16-fold (95% CI: 2.0-133.5) increases in the overall risks of breast cancer and of ER+PR- breast cancer, respectively, when the highest and the lowest quartiles of IGFBP-3 were compared. No associations were found between any of the hormones and the risk of ER-PR- tumors. The increased prevalence of ER+ breast cancers in patients with higher levels of IGF-I, IGFBP-3 or testosterone implicate these hormones in the etiology of hormone-dependent breast cancer. Additional analyses specific for breast cancer subtypes may shed light on the value of hormone determinations for tailored chemoprevention.

Collaborative/active participation per se does not decrease anxiety in breast cancer.

The information needs of breast cancer patients on their disease, its treatment, the prognosis, and their attitude to decision-making concerning treatment were assessed. One hundred and fifty early and 45 metastatic breast cancer patients were recruited into the study. The amount of information and role in the treatment decision-making process preferred by the patient were independently estimated by the patient and the oncologist, using questionnaires. Information was provided in accordance with the wishes of the patient as perceived by the physician. Test of anxiety was performed before, and one week after the consultation. Most of the patients claimed to anticipate the provision of extensive information and an active role in the decision-making, but real interest during the consultation was found less frequently. The post-consultation anxiety test revealed a significant decrease in situational anxiety; this was not related to the patient's information needs or her attitude to the decision-making concerning treatment. Our study demonstrates that a significant decrease in anxiety may be achieved via a consultation tailored to the needs of the patient. Loading the patient with information and involvement in the decision regarding therapy as much as the patient seems comfortable with lowers distress.

Human papillomavirus infection and cervical intraepithelial neoplasia in a cohort of low-risk women.

OBJECTIVE: This study was a prospective examination of the incidence of human papillomavirus (HPV) infection in a low-risk female population and an assessment of the risk of development of LSIL with HPV infection. STUDY DESIGN: In a longitudinal study, women aged 19-60 years--non-smokers, and married or living with a constant partner, who presented for cervical cancer screening at an outpatient clinic--were invited to participate in a prospective study of cervical HPV infection, and were examined every 3 months. RESULTS: Of the 464 women at risk, 20 presented with HPV infections during the follow-up. Low-grade squamous intraepithelial lesions (LSIL) event developed in 18 women. Among these women, 13 were HPV-positive (10 high-risk and 3 low-risk types). The average duration of new LSIL was 20.1 months (95% CI: 13.9-26.3) and 55.3 months (95% CI: 45.7-64.9) in the HPV-positive and negative groups, respectively, the difference was statistically significant (p<0.001). With the use of Cox proportional hazard regression, we estimated the relative risk as 90.0 for a first instance of LSIL among women testing positive for HPV as compared with women testing negative for HPV. CONCLUSION: This study has provided evidence that HPV infection is associated with an increased risk of LSIL.

[Breast Center--a virtual unit for the multidisciplinary care of breast patients]. / Emlocentrum--virtuális klinika az emlo1betegek multidiszciplináris ellátásáira.

Breast cancer, the most prevalent female malignancy represents a major health problem. Breast cancer mortality may be halved by high quality mammography screening and care. The most efficient screening and the best treatment of patients are available at the breast centers that are equipped with special facilities, expertise and significant experience via the treatment of a high number of patients. Breast center is a virtual unit based on the collaboration of various professionals; a tight institutional frame is not a must. In these comprehensive centers, 150 breast cancer patients per year at a minimum are treated, and the most efficient special treatment methods are available. The core members of the staff are the breast pathologists, the mammographists, the breast surgeons, the oncologists/oncoradiologists, the breast nurses, the technicians and the data managers. An easy access to the service of the non-core members, the plastic surgeons, the psychologists, the psychiatrists and the clinical geneticists is necessary. An optimal collaboration of the various experts may be achieved by a training of the members, regular multidisciplinary meetings and guidelines developed and accepted by all. The requirements of a breast center have been published by the European Society of Mastology (EUSOMA), and a directory of the accredited European breast centers is maintained. The Breast Unit of the University of Szeged has been found eligible by EUSOMA to be included in the directory of the European breast units. Two mammographists do screening-mammography and clinical examination, 2 pathologists perform cytopathological, histopathological and immunohistochemical examinations. Three surgeons operate on more than 250 breast cancer patients per year, and apply wire or isotope (ROLL) localisation in case of non-palpable lesion. A plastic surgeon is available if necessary. In a half of all cases, sentinel mapping is performed with isotope- and blue dye-labelling. Two radiotherapists apply conformal radiotherapy in 250 cases per year, and 2 oncologists perform modern chemotherapies in 200 cases as a yearly average; 50 new advanced/metastatic cases per year require oncological treatments. Breast nurses, a psycho-oncologist and a mental hygienist nurse assist the team. There is access to lymphedema treatment and physiotherapy. The final goal of the program is to provide all women with high quality mammography screening and care, if necessary.

[The results of ovarian cancer therapy in the Hungarian Centers in 2002-2003]. / Petefészekrákos betegek kezelési eredményei a hazai centrumokban 2002-2003-ban.

UNLABELLED: Authors presented data of treatment results and course of disease in 487 ovarian cancer patients treated by primary surgery and paclitaxel-carboplatin combination chemotherapy between July 1, 2002 and December 31, 2003. PATIENTS: Most of our patients (87.8%) belonged to the age-group between 40-70 years. Distribution of their histological diagnosis was as 69.6% serous, 10.7% mucinous, 5.1% endometrial and 4.7% undifferentiated carcinoma. The grade distribution was found as 8.4% grade 1, 40.9% grade 2 and 35.9% grade 3. RESULTS: The primary surgery was evaluated as optimal in 41.7%, suboptimal in 37.3% and exploration was performed in 21.1%. Most patients started chemotherapy 20 days after surgery and 74.2% of them got six courses. During the evaluation period 61 intervallum laparotomies were performed, and resulted on 55.7% optimal debulking. Complete remission was found in 58.9%, and partial remission in 14.7% of patients. This treatment resulted on a complete remission in 40.9% at the follow-up of 12 months.

[Thymidylate synthase gene promoter polymorphism in patients with advanced head and neck cancer treated by radio- and 5-fluorouracil chemotherapy]. / A timidilátszintáz gén promoterpolimorfizmusának vizsgálata kis dózisú 5-fluorouracil kemoterápiával és sugárterápiával kezelt elôrehaladott stádiumú fej-nyaki rákos betegeken.

AIM: Thymidylate synthase (TS) is a rate-limiting enzyme in the DNA synthetic pathway, and represents a cellular target of antimetabolite drug 5-fluorouracil. It catalyzes the reductive methylation of deoxyuridine-5'-monophosphate to deoxythymidine-5'-monophosphate. Inhibition of TS will result in depletion of both dTMP and, subsequently, dTTP. As a consequence, dUTP is misincorporated into DNA, resulting in DNA breakage and cell death. Developing resistance against 5-fluorouracil (FURA) based drugs might be due to the failure of inhibition of thymidylate synthase enzyme function. In the promoter region of the TS gene there is a tandem repeat sequence (2R or 3R), which was found to be polymorphic and influences the gene expression. Effectiveness and tolerability of Tegafur treatment might be influenced by expression of the TS gene. Our purpose was to determine the effectiveness and tolerability of concomitant radiotherapy and low-dose chemotherapy using Tegafur in respect of promoter polymorphism of thymidilate synthase gene. MATERIAL AND METHODS: TS promoter polymorphism (2R/2R, 2R/3R, 3R/3R) was determined by polymerase chain reaction using genomic DNA, in 47 patients with advanced head and neck cancer. RESULTS: Thirty patients out of 47 showed complete response, and genotyping of these patients revealed 2R/2R in 22 (73.3%), 2R/3R in 2 (6.7%) and 3R/3R in 6 (20%). Seventeen out of 47 patients reacted with partial response, and 2R/2R or 2R/3R were revealed in 5 (29.4%) and 3 (17.6%) patients, respectively, and 3R/3R genotype was identified in 9 patients (53%). CONCLUSION: We did not find any correlation between patient's data and response to therapy, but strong correlation was found between the latter and the patient's genotype. This facts indicate that the analysis of promoter polymorphism of thymidylate synthase gene might be a useful target to examine before FURA-based chemotherapy, and might allow to go into the direction of individualized treatment of head and neck cancer. We suppose that tumor response depends on genomic features of the patients.

[Hormone resistance and its modulation in breast cancer]. / Hormonrezisztencia emlorákban--a befolyásolás lehetoségei.

Acquired hormone resistance is a reversible adaptative change of hormone-sensitive breast tumors promoting survival by changes in the balance and communication between estrogen receptor and growth factor signaling. The mechanisms of hormone resistance induced by various hormone therapies are different, however, their common feature is the dominance of growth factor signaling with the consequences of enhanced proliferation and decreased apoptosis. In case of tamoxifen or selective estrogen receptor modulator resistance, the agents' enhanced agonistic activity occurs. The increased expression of certain estrogen receptor coactivators may play an important role. The essential of hormone resistance after estrogen deprivation is estrogen hypersensitivity, which is a consequence of the enhanced activity of the membrane-associated estrogen receptor and its influence on the growth factor signaling. The integration of cell surface growth factor receptor or growth factor signal transduction blocking agents like tyrosine kinase, MAPK, mTOR, PI3K or farnesyl transferase inhibitors into hormone therapies may prevent or treat hormone resistance. The other possibility is to use the hormone therapies sequentially. A new promising agent is the pure antiestrogen fulvestrant which targets the estrogen receptor located in both the membrane or the nucleus. Also, estrogen therapy may revert hormone resistance. The use of predictive markers may promote treatment choice and indicate application of targeted therapies.

[Results of docetaxel therapy in patients with relapsed ovarian cancer]. / A kiújult petefészekrákos betegekben alkalmazott docetaxel kezelés eredményei.

UNLABELLED: Successful treatment of relapsed ovarian cancer has not been solved. Docetaxel, being one of the medicines of special interest in Hungary from 2002, has been ranked with the other well known treatment forms. In this study the authors evaluated the results of the docetaxel-carboplatin combination treatment in two oncological centers. MATERIAL AND METHODS: Sixteen patients with relapsed ovarian cancer, premedicated with steroids, were given docetaxel-carboplatin chemotherapy at a dose of 75 mg/m2 and AUC 5 in 94 courses at the Gynecological Dept., National Institute of Oncology and Oncotherapeutic Clinic of Szeged University. Median of courses was 6 (range: 2 to 15). RESULTS: CR was found in 1, PR in 4 and PD in 5 patients. Six patients showed stable disease. There was no need for dose reduction. The authors observed no extreme side effects (this evaluation does not contain the data of a patient who refused chemotherapy because of the development of hypersensitivity reaction). Almost all patients developed reversible alopecia. The probability of freedom from progression dropped to 50% 5 months after the beginning of treatment. CONCLUSION: Docetaxel has expanded the chemotherapeutic arsenal in relapsed ovarian cancer. Our results are in harmony with those reported in the literature on other drugs or combination treatments. Further trials are required to improve the effectiveness of chemotherapy.

Combined effect of cisplatin and 5-fluorouracil with irradiation on tumor cells in vitro.

The concomitant administration of chemotherapy and radiation is an alternative tool in cancer therapy. The antiproliferative and the radiosensitizing effect of Cisplatin and 5-Fluorouracil (5-FU) were studied on mouse lymphoma cells transfected with human MDR1 gene (mdr) and its parent cell line (par) combined with and without radiation. HEp2 radioresistant cell culture was used in our experiments as a model of radioresistance. The growth rate and antiproliferative effect was measured by the MTT method. Significant inhibition of tumor cell growth was observed at a low concentration of Cisplatin and 5-FU combined with radiation on the mouse lymphoma cell lines. However an extremely high dose of Cisplatin and 5-FU resulted in moderate growth inhibition in the case of the HEp2 cell line. We assume that the radiosensitizing effect of 5-FU and Cisplatin can be considered as a synergistic antitumor effect at low doses of chemotherapy and radiation in a radiosensitive cell line. In the case of a radio-and chemoresistant cell line, high doses of radiation and chemotherapeutic agent achieved moderate tumour growth inhibition without significant synergistic effect. In addition the simultaneous application of both treatments can result in remarkable toxicity.

Effective chemoradiotherapy without additive toxicity in locoregionally advanced head and neck cancer.

A previous preclinical study revealed that the maximum additive effect between chemotherapy (CT) and irradiation (RT) occurred at a low level of CT. Therapy was therefore designed with an oral drug daily given in combination with RT in order to determine the efficacy and toxicity. Locoregionally advanced head and neck tumor patients were treated with simultaneous RT and CT. RT was administered 5 times per week at 2 Gy per fraction to a total dose of 70 Gy. Throughout the treatment 30 mg/kg Tegafur was given daily orally. In the period between 2000 and 2002, 50 patients were enrolled. In 60%, complete remission was attained with an overall response rate of 94%. Acute mucositis of grade 2 or 3 was observed in 56% (28 patients), while gastrointestinal and hematological toxicity of grade 2 or 3 occured in 8% (4 patients). Because of side-effects, the duration of treatment was at most 2 weeks long. Toxicity was eliminated quickly by careful supportive therapy. In conclusion, it is considered that oral low-dose CT in combination with RT is an efficient and simple mode of treatment for locally advanced head and neck tumor patients with a poor prognosis.