The Role of Estrogens, Including Its Sources, Tissue Distribution, Metabolism, and Mechanism

The role of estrogens, including its sources, tissue distribution, metabolism, and mechanism of action, is discussed in this review. The ER alpha and beta are functioning separately, and there is a physiological balance between their activity. Whenever this balance is overthrown due to endogenous or exogenous carcinogenic factors, malignancy develops. Risk factors of breast cancer are listed and evaluated individually. It should be stressed however, that their carcinogenic effect sums up. The knowledge of established risk factors rises the possibility of chemoprevention, which might be highly desirable in case of gene carriers. Special emphasis is attached to the SERM molecules which act as antiestrogens. Their antitumour effect is largely used in the treatment of hormone sensitive advanced breast cancer patients, and their efficacy has been proved in adjuvant therapy as well. Their preventive use might also be justified, especially in gene carriers. Aromatase inhibitors form a special class among the SERM molecules. In Hungary, anastrozole, letrozole and exemestane are widely applied for the therapy of breast cancer patients, while raloxifene has only been introduced recently, mainly in order to prevent osteoporosis. The therapeutic value of fulvestrant is unknown yet and its antitumour effect has to be explored. The therapeutic significance of these molecules lies in the fact that they might be effective after the development of tamoxifen resistance. There are several explanations for this phenomenon offering new targets for the further development of a succesful antitumour chemotherapy. Eckhardt S. Perspectives for the hormonal therapy of breast cancer. Hungarian Oncology 47:133–140, 2003

Aim: The authors present the Hungarian interim analysis and experience with the BCIRG 001 randomized, multicentric, phase III clinical trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) and FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer patients. The results are presented according to international data. Patients and methods: Three Hungarian centers – St. Margit Hospital, Budapest, National Institute of Oncology, Budapest, Petz Aladár Hospital, Gyôr – participated in the international trial. Between June 1997 and June 1999, 61 patients with node positive breast cancer were enrolled in the study after the surgery. Thirty-four patients were randomized to TAC (75/50/500 mg/m2 6x q3wk) and 27 patients were randomized to FAC (500/50/500 mg/m2 6x q3wk) chemotherapy, with prospective stratification by node (1–3, 4+). In the case of patients with ER and/or PR positive tumours 5 years tamoxifen treatment was started. Radiotherapy was performed after the 6th cycle of chemotherapy. Results: 36 months of follow up was performed. In both arms the hematological toxicity was more frequent. The TAC group showed a higher incidence of neutropenia (76%) compared to the FAC (22%), as well as a higher incidence of febrile neutropenia (26%), without grade 3–4 infection and there were no cases of septic death. Regarding non-hematological toxicity more grade 3–4 nausea and vomiting was observed in the FAC group. At three years follow up, the international results show statistically significant improvement in disease-free survival (82% vs. 74%, p=0.0011) in favour of TAC, and similar tendency was observed in the case of overall survival (92% vs. 87%, p=0.11). This benefit with TAC was seen regardless of hormone receptor status. Due to the low number of Hungarian patients we cannot declare the same results. Conclusions: Based on the international analysis TAC was superior to FAC chemotherapy. Additional follow up data will evaluate the role of TAC in the adjuvant setting of early breast cancer treatment. The results indicate that TAC has the potential to be incorporated in the new strategies of adjuvant breast cancer treatments. Boér K, Láng I, Juhos É, Pintér T, Szántó J. Hungarian experience with docetaxel combination (TAC) in the adjuvant treatment of breast cancer. Results of BCIRG 001 randomized, multicentric, phase III trial. Hungarian Oncology 47:141–148, 2003

Introduction: The organized breast cancer screening programme has started in Hungary at the end of 2001. Aim: To assess the screening rate, the cost of screening and treatment and to calculate the expected epidemiological and economic gain and cost-effectiveness of mass-screening programme. Methods: The data derive from the financial database of the National Health Insurance Fund of Hungary from 2001. To assess the screening rate the authors used the code „No. 42400 mammography screening” of outpatient care. The cost of treatment includes the cost of outpatient care, the acute and chronic inpatient care, the subsidies of the prices of medicines and the expenditure on disability to work (including sickness-pay). The expected benefits of the screening programme were modeled with changing mortality decrease for a 10 years interval. Results: The screening rates of women aged 45–65 for 2001 and 2002 were 7% and 21.7%, respectively. The cost of treatment of breast cancer was around 8.6 billion Hungarian forints (29,939,868 USD, 33,426,321 Eur) in 2001. In the age-group 45–65 with 10% mortality decline 509 lives (net present value, NPV: 365), with 20% mortality decline 1.074 (NPV: 772) lives and with 30% mortality decline 1.582 (NPV: 1.139) lives can be saved during a 10 years screening programme. The cost of one life saved varies between 5.7 million forints (19,876 USD, 22,190 Eur)/life saved and 17.8 million forints (62,047 USD, 69,273 Eur)/life saved according to the mortality decline. The cost of one life year saved varies between 271,000 forints (946 USD, 1057 EUR)/life year saved and 847,000 forints (2955 USD, 3299 EUR)/life years saved. Conclusion: The implementation of organized breast cancer screening can lead to cost savings in Hungary. The cost-effectiveness of breast cancer screening seems to be acceptable for purchaser. Boncz I, Sebestyén A, Gulácsi L, Pál M, Dózsa Cs. Health economics analysis of breast cancer screening. Hungarian Oncology 47:149–154, 2003

Objective of the study: to investigate the clinical outcome of HNSCC patients, and their hormonal status. Method: The liver function (GGT), hypophysis gonadotrop hormone (FSH, LH, prolactin) and sex-steroid hormone serum levels were examined in 130 male HNSCC patients. Clinical parameters for age, primary tumor site and clinical tumor stage were also recorded. Results: The survival was disadvantageously influenced by the following parameters: age, the presence of lymph node metastasis, advanced tumor stage, the lower than normal testosterone and the higher than normal FSH serum levels. Conclusion: Elevated FSH and decreased testosterone serum levels showed significant correlation with the survival of head and neck cancer patients. The better understanding of their exact role in the biology of HNSCC requires further investigations. Remenár É, Számel I, Budai B, Orosz Z, Gaudi I, Kásler M, Gundy S. Hormonal influence in head and neck cancer. Hungarian Oncology 47:155–159, 2003

Aim: To present a unique case of an early (T1N0M0) adenocarcinoma of the head of the pancreas, which was successfully treated with radiotherapy alone. Material and method: After the computer tomography operated histological verification the combination of interstitial high dose rate after-loading brachytherapy (18 Gy, 6 Gy/die) and percutan irradiation (46 Gy) was applied. Result: Fifty-two months after completion of the treatment the patient is alive with no evidence of disease. Conclusion: The combination of these therapeutic modalities may be an effective tool to deliver curative dose without any significant sequelae in the treatment of operable pancreatic carcinoma, when the patient’s condition contraindicates surgery. Takácsi-Nagy Z, Varga J, Poller I, Fodor J, Major T, Németh G. Successful treatment of a localised pancreatic cancer with radiotherapy alone: a case report. Hungarian Oncology, 47:161–163, 2003

The authors determined serum PSA levels in combination with digital rectal examination (DRE) and evaluated their role in the differential diagnosis of prostate diseases with special reference to cancer. The possible causes of differences between the observed cut-off level of PSA and the standard level PSA were analyzed. In the last few years the PSA determination found its clinical role in the diagnosis of prostate cancer. Bánfi G, Kiss F, Kádár A, Romics I. Summary of our clinical experiences with the determination of serum prostate-specific antigen level in the first 5-year period. Hungarian Oncology 47:165–168, 2003

In the second half of 2002, IARC for Central and Eastern European countries targeted studies on the relationship between chromosomal aberrations (CAs) and cancer risk. For these purposes we preliminarily investigated, under identical methodological circumstances, the base-line level of CAs in peripheral blood lymphocytes of 1414 healthy Hungarian persons between 1986 and 2001. The age and sex as biological, and smoking habit and residency (Budapest, industrial- and agricultural settlements) as environmental confounding factors were evaluated. Previously, people were not exposed to any known potential mutagens. The overall frequencies of aberrant cells (1.60±0.05%) were not influenced by sex, age and residency, but the smoking habits (1.84±0.09%) had significant impact on the elevation of aberrant cells. Aneuploidy, exchange-type dicentric chromosomes and the total of aberrations increased significantly with the age of the donors. The individual frequency of aberrant cells ranged between 0–12%. No aberrant cells were detected in 35% of individuals, and 1 aberrant cell was found in 23% of the total population, while 42% of the examined persons were characterized with aberrant cell rates between 2–12%. The initial value of 0.85% of aberrant cells doubled by the end of the examined 16-year period, following 2–4-fold fluctuations. None of the investigated biological or environmental factors was responsible for the elevation of the CAs. The causes of the elevation of CA-level can be explained more precisely when these data will be compared to cancer registry database of these persons. Kelecsényi Zs, Székely G, Gundy S. Sporadic chromosomal aberrations in healthy individuals studied between 1986-2001. Hungarian Oncology, 47:169–176, 2003

Background: The environment is source of carcinogen effects, which cannot be monitored as precisely as it would be required. Due to this fact, it is worth to screen for areas with higher than expected number of cancers that is for clusters. The significance of cluster suspicion is highly variable and the investigations for clusters could need significant resources. Therefore step-wise protocols are recommended, which evaluate before proceedings the possibility of exclusion of cluster existence, or of requirement for further epidemiological investigations. Sometimes, the results establish actions to reorganise the environmental control. Objectives: The relationship between cancer incidence and dangerous waste disposal sites was investigated in Tolna county (Hungary) and the usefulness of cluster studies was demonstrated by the results. Methods: The incidence data based on histological investigations and the location of 7 dangerous waste disposal sites were analysed by geographical information system. Results: The incidences were not elevated around 6 sites. The cancer risk seemed to be high by site in settlement S., because of high standardised incidence ratio (SIH=1.41) and empirical Bayes adjusted SIH (SIHEB=1.38). The risk increase proved to be significant in z-test and mid-p test by 10% and 15% type I error. Since the risks showed non-homogeneous spatial distribution in the county and the number of high-risk settlements was 2.3 to 6.6, the cluster in S. cannot be rejected as false positive observation. The chromium contaminated wastes have been stored in S. for several decades at river-side. Assuming that the exposure was spred by the river and the villages in the 5-km vicinity of the river were exposed, the SIHs were aggregated for every 15-km intervals. The distance from S. was inversely related to the aggregated SIHs. Conclusions: The sites proved to be non-carcinogenic sources apart from the site S. for which the results suggested the high-risk status. The environmental pollution by site in S. could explain the increased incidence. Consequently, additional studies are indicated in S. to improve the reliability of cluster evaluation. The study also demonstrated that the cluster investigation can be inserted into public health practise to improve the efficiency of cancer control. Sándor J, Szerencse P, Szücs M, Németh Á, Kiss I, Ember I. Investigation of spatial cluster for environmental related cancers. Hungarian Oncology 47:177–183, 2003

120 chemotherapy naive patients were treated with gemcitabine 1250 mg/m2 iv. days 1 and 8 and cisplatin 70 mg/m2 iv. on day 1 between May 1999 and June 2001. The treatments were administered in 21 cycles. The median age of the patients was 53.1 years, the male/female ratio 65%-35%. Performance status was: WHO 0: 26%, WHO 1: 74%. The staging of patients were: IIIA-N2 23%, IIIB 37%, IV 40%. By histology the tumors were: 53.3% adenocarcinoma, 40% squamous cell carcinoma, 2.5% adenosquamous carcinoma, 0.8% macrocellular carcinoma and 3% non-small cell carcinoma (not categorised). We evaluated 413 cycles of chemotherapy. The median number of cycles was 3.44. The primary endpoint of the study was the median survival and time to progression, and the response rate. The results are the following: RR 40% (PR 37.5%, CR 2.5%), MR 13.3%, SD 25%, PD 22%. The time to progression (TTP) in the SD+MR group: 29.8 weeks, in the RR group: 34.1 weeks, mean of all patients: 28.1 weeks. The survival time was estimated by Kaplan-Meier curves. The median survival (MS) of all treated patients was: 54.9 weeks, in the PD group: 34.4 weeks, in the SD+MR group: 59.1 weeks, in the PR+CR group: 62.1 weeks. Conclusion: gemcitabine and cisplatin combination is a very well tolerated therapeutic regimen in the 1st line treatment of NSCLC. Furthermore, this treatment improves the RR and the survival of the patients as well. Ostoros Gy, Kovács G, Gergely-Farnos E, Magyar P, Szondy K, Strausz J, Ferenczi E. Efficacy of Gemzar-Cisplatine treatment in stage IIIA-N2, IIIB and IV non-small cell lung cancer. Hungarian Oncology 47:185–188, 2003

In our Department we have studied the first line treatment of 90 stage IIIA-IV non-small cell lung cancer patients using gemcitabine/cisplatin combination. Thirteen cases have been unevaluable for various reasons. At the time of evaluation the planned 4 cycles have been delivered to 38% of patients (34/90). The PR was 39% (30/77), the CR was 2.6% (2/77) while the ORR was found to be 41% (32/77). 226 treatment cycles have been evaluated for side effects. There was no treatment-induced death in this series. CTC grade 3–4 neutropenia occurred in 5.7% of the cycles and only in 2 cases combined with fever. CTC grade 3–4 thrombocytopenia occurred in 4.4% of the cycles but only one patient required platelet suspension administration. Grade 3-4 anaemia developed in 3.5% of the cycles where 5 cases have been treated with RBC concentrate while 3 cases with erythropoetin. Complete alopecia occurred in 6 patients but 3 of them received brain irradiation as well. CTC grade 3–4 nausea and vomiting occurred in 4.4 and 3% of the cycles, respectively, but rehydration was only necessary in 3% of the cycles. Delay of the therapy due to hematological toxicity or vomiting occurred in 8% of the cycles but did not last longer than 2 weeks. Severe CTC grade 3-4 nephrotoxicity did not occur in this study while grade 1–2 elevation of serum creatinin level was found in 1.7% of the cycles. We have concluded that the gemcitabine/cisplatin combination is a safe outpatient modality for the first line treatment of advanced non-small cell lung cancer patients. Sárosi V, Lénárt T. Gemcitabine-cisplatine combination in the first line treatment of non-small cell lung cancer. Analysis of the safety of the regime. Hungarian Oncology 47:189–193, 2003.

In the first phase of this study 34 patients with advanced pancreatic cancer have been treated either with gemcitabine/cisplatin or gemcitabine/5-fluorouracil (5FU)/leucovorin combination. (Gemzar: 900 mg/m2, Cisplatin: 20 mg/m2, 5-FU: 750 mg/m2). Treatments were continued till tumor progression. There was no difference observed between the two protocols in the clinical response rates (PR=65%). On the other hand, a significant difference was found between the two protocols regarding the side effects. In the case of gemcitabine/5-FU neutropenia, thrombocytopenia and anaemia (as well as nausea and vomiting) were much less frequent compared to gemcitabine/cisplatin combination. Based on these data the efficacy of gemcitabine/5-FU combination was evaluated in 99 stage III, T1-4, N1 and stage IV, T1-4, N0-1, M1 pancreatic cancer patients throughout 364 treatment cycles. OR was achieved in 10% while stable disease in 52% of the cases. The average survival period was 8.33 months while the time to progression was 5.75 months. Based on these data we recommend gemcitabine/5-FU/leucovorin combination for the treatment of advanced pancreatic cancer. Bodoky Gy. Experiences with the treatment of advanced pancreatic cancer in Hungary. Hungarian Oncology 47:194–197, 2003

M-VAC combination chemotherapy was considered as the „gold standard” of the treatment of advanced and metastatic bladder cancers. Arrival of gemcitabine or taxanes in the 90s attracted attention since their efficacy was combined with low toxicity profiles. Gemcitabine/cisplatin combination became the most frequently studied treatment modality in the past 3 years. Multicentric, multinational randomized phase-III study indicated that in bladder cancer the gemcitabine/cisplatin combination is equal to M-VAC while in the case of the former the risk to benefit ratio is lower. Accordingly, gemcitabine/cisplatin combination is a safer treatment option in advanced and metastatic bladder cancer and is a real alternative to M-VAC. In the case of patients where cisplatin cannot be administered due to poor renal function, the new drugs with better toxicity profiles provide further treatment options. Bodrogi I. Role of gemcitabine/cisplatin in the treatment of advanced and metastatic bladder cancer. Hungarian Oncology 47:198–203, 2003