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Volum 04 Numarul 1-2, 1998


The importance of the subject presented at the symposium „Hormonotherapy in Breast Cancer”, Oradea, 1998, for the oncologists, have determined us to publish this special issue of our Journal.

The first paper, signed by N. Ghile:lan, is a real presentation of the Romanian Oncology. The author proposes a model for the Oncologycal network in our country, following the exemple of the European Com- munity ahd of the USA. He stresses the necessity of the Government involvement in elaboration and imple- mentation of a long term National Cancer Control Plan.

The second work, signed by N. Ghilezan too, is a short history of hormonotherapy of breast cancer, starting from Beatson, 1896.

  1. Cupceancu deals with the role of hormones in ontogenesis, morphology and physiology of the mammary gland.
  2. Ghilezan emphasized in his article „The molecular biology of breast cancerogenesis” those aspects which allow new strategies for treatment and prevention of breast cancer.

MOena Duma and Mlhaela Galatir show the experience of the IOCN in deteremining hormonal recep- tors related to breast cancer, using an immunohistochemical technique.

Tamoxifen appears to be the therapy of choice for the initial treatment of metastatic breast cancer in both premenopausal and postmenopausal women. The paper signed by V. Pacurar and M. Untch et al., report the role oftamoxifen in breast cancer: history, indications, results and side effects. The success oftamoxifen in reducing the risk of contralateral breast cancer has led to further use in chemoprevention of breast cancer in women at high risk.

The new antiestrogens deprived of estrogen-agonist activity try to replace tamoxifen in treatment of breast cancer. So, the second generation of antiestrogens are presented by Dana Grecea, who emphasizes its advantages in breast cancer therapy.

  1. Tănăseseu’s article deals with progestins and LH-RH agonists in breast cancer therapy. Historically, second line hormonotherapy for metastatic disease has been with progestin; due to the troubling side effects of weight and dyspnea, progestins were replaced by aromatase inhibitors. A thoroughly description of aro- matase inhibitors (AI), ranging from history to action mechanisms, indications, results and side effects, can be found in Cristina Vitoc’s preserttation. The evaluation of their role in hormonal manipulation attest the progress in endocrine therapy with the development of potent selective endocrine agents to provide physi- cians and patients with more effective and less toxic treatment options.

Menopausal breast cancer patients respond well to hormonal therapy and this aspects are presented by N. Ghilezan. Many controv~rsies ar~ related to hormonal replacement therapy in menopausal breast cancer patients and some of them are detail~d in the paper signed by N. Ghilezan..

Cristina Vitoc comments on posters, revealing the experience of other centers from Romania in hor- monotherapy field.

We hope that this new issue of the „Radiotherapy & Medical Oncology” would be of real interest for all oncologists as well as for their patients.

Maria Retegan- Turdean

1 Romania: cancer care, present and future

Prof. Dr. N. Ghilezan

Member of the Academy of Medical Sciences President of the National Oncology Comission

Director of the Institute of Oncology „I. Chiricula” Cluj-Napoca

The cancer morbidity and mortality in Romania are in a continuos increase with no trend to improve which clearly shows the lack of efficacy of the present structures. The analysis of the circuit of the cancer patient reveals the following main negative aspects:

. very advanced stage at diagnosis (60 to 80% in stage III & IV); . a lack of consensus on therapeutic strategies;

. reduced accessibility to specialized treatments especially for radiotherapy (less than 50%!) . no performant information system;

. no national coordinating organism to evaluate the professional performances of the cancer network and to develop the strategies for the future.

The pressures and constraints from the increased demands of the patients and the limited availability of resources ask for a reform of the cancer management. A proposal, after a successful model in the EC countries and the USA, is presented for Romania. The reference unit should be a departmental specialized center, organized around a radiotherapy service due to the importance of the initial investments. This specialized center should provide all facilities and resources for the curative treatment of most frequent tumors and it will integrate into a network with all the units which are treated cancer patients in the region, as well GP and organ specialists involved in cancer care. For the less frequent tumors or special techniques, the treatment will be provided by highly specialized centers, organized at regional or interdepartmental level, according to the particularities of the patient load and diversity in the corresponding territory. The main objectives for each level of cancer care and structure are presented.

The responsibility of the reform of the cancer care belong to the government which should be actively involved in elaboration and implementation of a long term National Cancer Control Plan and most important, in the permanent evaluation of the results.

Key words: cancer care, managed care, comprehensive cancer center.

11 A century of hormonal treatment! What next?

  1. Ghilezan

UMF „I. Haţieganu” Cluj-Napoca

Oncological Institute „Prof I . Chiricuţă” Cluj-Napoca

During the last 100 years, the hormonal therapy of breast cancer improved continously with more active and less toxic compounds. Due to the availability of the new molecules, the present indications have been extended over the treatment to the prevention of breast cancer, cardiovascular disease and osteoporosis. The main steps in the development of hormonal treatment and the available drugs are presented.

Key words: breast cancer, hormones, new compunds, classification

Radioterapie & Oncologie Medicală, 1998. 1-2: 11-14

15 The hormonal control of the female breast

Bogdan Cupceancu

„C.I.Parhon” Institute of Endocrinology, Bucharest

Breast is responding to hormonal action in all stages of woman’s life. As a component of the reproductive system, its development and functionality depends on the ovaries development and functionality as the strict correlation to the brain structures controlling their activity. Main hormones with direct action over the breast are oestregon and progesterone and secondly prolactin, androgens, a. s. o. the hormonal action is mediated by receptors with a similar structural organi- zation, through a common mechanism which activates cell nucleus proteins. It is also higlighted by enzymes with spe- cific hormonal action. The ovary represents the main source of oestrogens and progesterone that guarantee rise and development of breast components as well as their cyclical change during woman reproductive life. As a result of the progressive reduction of the ovarian activity in post menopause the adrenal is mainly ensuring the needs in oestrogen. But in pre as in post menopause the fatty tissue and even the mammary one itself can be more or less important steroids source. Each one of the above mentioned hormones is acting on specific breast srtuctures in well-defined periods of the menstrual cycle, during pregnancy, lactation or in post menopause. For the time being it is a well-known f~ct that the classical mechanisms of hormonal action are completed by nonhormonal structures acting at cellular and subcellular level in order to modulate the hormonal action. Those actions during the life periods are leading to morphological aspects corresponding to a specific stage in the evolution and development of the mammary gland. Even minor devia- tions from the normal hormonal succesion, or a prolonged action as in the usual „oestrogenic windows” during puberty and per-menopause when progesterone insufficiency may occur, can open the way of structural changes and the patho- logic evolution by hormonal causes or in combination with other cause-related factors.

Key words: mammary gland, hormonal control, hormonal receptors, growth factors

Radioterapie & Oncologie Medicală. I 998, 1-2.. 15-22

23 The molecular biology of breast cancerogenesis

  1. Ghilezan

Oncological Institute „I. Chiricuţă” Cluj-Napoca

The growth and differentiation of mammary gland is the result of the interaction of steroids hormones with local polypep- tides produced by the main types of the existing cells. The same proteins are involved in cancerogenesis. The mechanism of tumour proliferation and progression are described as well the main genetic lesions. The knowledge of these mecha- nisms provided the possibilities to identify new targets for developing new strategies for treatment and prevention, many of them with already very promising results.

Key words: breast cancer, cancerogenesis, therapeutic targets, prevention

Radioterapie & Oncologie Medicală, 1998, 1-2: 23-29

30 Immunohistochemical assement of estrogen and progesteron receptor in breast cancer

Milena Duma, Mihaela Galatar

Oncological Institute „I. Chiricuţă” Cluj-Napoca

We present our method for the immunohistochemical assement of estrogen receptor (ER) and progesteron receptor (PR), status on romtinely processed formalin fixed tissue ising a recently developed commercially available monoclonal antibody (DAKO RE ID5) with microwave antigen retrival techni\ue. Aseries of 715 breast carcinoma was analysed for the immunohistological staining and the assesement of total percentage of nuclei showing positive staining was made.

Key words: estrogen receptor, progesterone receptor, breast carcinoma.

Radioterapie & Oncologie Medicală, 1998, 1-2: 30-35

36 Tamoxifen in the hormonal treatment of breast cancer

  1. Păcurar

Faculty of Medecine and Pharmacy, Oradea

Honnontherapy in breast cancer has a history of more than 100 years when Beatson lets us know the remission of breast cancer after bilateral oophorectomy in 1896. In 1970 they introduce in breast cancer treatment Trifeniletilena a medicine with anti estrogenic effects called tamoxifen. Tamoxifen inhibates the action of estrogenes by a competitive binding of Estrogenic receptors, increases the inhibitive factors of celIe growth, diminishes the concentration of growth factors TGF, increases the antitumoral imune activity of killer K cells. The toxicity of tamoxifen is acceptable, some autors stressing out the risk of a second cancer of endometrium with tamoxifen treated breast cancer pacients. Tamoxifen is more efficient with pacients in menopause. In adjuvant administration tamoxifen diminishes the risk oflocal relapse and bilateral brest cancer. Tamoxifen proved its efficency in other honnonal malignant neoplasm: endometrium cancer, cancer of the ovaries, liver cancer, cancer of the pancreate, malignant melanome and kidney cancer.

Key words: breast cancer, Tamoxifen

Radioterapie & Oncologie Medicală, 1998, 1-2, 36-42

43 Non Steroidal Antiestrogens IInd generation

Dana Grecea

Institutul Oncologic „I. Chiricuţă” Cluj-Napoca

A large number of non-steroidal anti-oestrogens ( NSAEs ),like TOREMIFENE, DROLOXIFENE, RALOXIFENE,

TAT-59, IDOXIFENE, have been synthesized and their properties were evaluated. TOR is a triphenylethylene with similar effects with Tam. In preclinical studies, evidence of superiority over Tam may be sought in the following areas: receptor binding,antitumor activity, peripheral antagonist /agonist ratio, activity against Tam-resistant cell lines. The clinical studies have been tested: activity as first line therapy and in Tam resistant tumors, side effect profile utility of peripheral antagonist/agonist ratio, pharmacokinetics. The aims of modem endocrine therapy for breast cancer include: increased efficacy, decreased toxicity, improved general health.

Key words: breast cancer,hormonotherapy,non-steroidal anti estrogens (NSAEs)

Radioterapie & On cologie Medicala, 1998, 1-2: 43-47

48 Progestins and LH-RH agonists in stage IV breast cancer

  1. Tănăsescu

Oncological Institute „I. Chiricuţă” Cluj-Napoca

The honnonotherapy (HT) for the metastatic breast cancer has now a well established place and role, considering the biological arguments, the natural history of the disease, the protocolar therapeutic sequencies and, not at the last, the toxic reactions. Up to date, HT is gathered on cronologicallines of administration, progestins (PO) are reserved to the third line, after the failure of the antiestrogens and aromatase inhibitors. Regarding the LH-RH agonists, they are mainly adressing to the premenopausal pacients. PO have been shown to induce response in metastatic breast cancer, although their mechanism of action is still unknown. Suggested mechanisms are the interaction with the progesteron receptors with direct growth inhibition or indirect action by increasing the content of the honnonal receptors. Medroxyprogesterone acetate (MPA) and megestrol acetate (MA) are the best known agents. The efficacy of these drugs is similar, the response rate is up to 40-50% for the patients with no prior HT. For the pre-treated patients, the response rate is decreasing to 10%. The treatment with PO is reserved to the postmenopausal women. The LH-RH agonists action is based on the supression of estradiol production by the ovary. The administration of these agents initially stimulates gonadotropin production but subsequently blocks the release ofFSH and LH with a complete endo- crine blockade. The most known drugs are goserelin (Zoladex.) and busereline. The effectiveness of these drugs is optimal in premenopausal women when the response rate is 32-45% and is decreasing in postmenopausal women, with minimal or no ovarian function. In conclusion, the HT for the metastatic breast cancer has to be seen as a dinamic action of the different therapeutical agents, each one beeing used when the anterior line failes. PO appears as an adequate solution for the postmenopausal women, after the failure of the first two lines of HT and LH-RH agonists offer a promising option for the premenopausal patients.

Key words: breast cancer, honnonotherapy, progestins, LH-RH agonists.

Radioterapie & Oncologie Medicală, 1998, 1-2: 48-52

53 Aromatase inhibitors

Cristina Vitoc

Oncological Institute „I. Chiricuţă” Cluj-Napoca

Aromatase inhibitors (AI) have been introduce in practice 25 years ago, with the first compound beeing aminogluthetimide (AG). They opened the age of the medical alternative to adrenalectomy for menopausal women with metastatic breast cancer. Initially. AG was used as 3-rd line hormonotherapy, following tamoxifen and progestatives. Today, new genera- tion aromatase inhibitors are suitable candidates for 2-nd line or even I-st line hormonotherapy. AI are classifed in two major groups: 1) Nonsteroidal inhibitors of first generation: AG; second generation: rogletimide, fadrozolul; and third generation: anastrozolul, letrozolul, and vorozolul; 2) Steroidal inhibitors of first generation: formestan and second generation: plomestanul, exemestanul. The main products are presented, considering mechanism of action, therapeutic response, dose-response relationship, tolerance, comparative clinical trials, new indications and clinical settings. Until now, AI demonstrated: I) high aromatase selective inhibition; 2) high efficacy with marked plasma oestrogen decrease; 3) over 30% objective response rates for postmenopausal women previosly treated with TAM; 4) good tolerance; 5) convenient adminstration once daily p.o. In conclusion, new generation AI with high efficacy and tolerability trend to become a new standard in the hormonotherapy for postmenopausal breast cancer women.

Key words: breast cancer, postmenopausal, hormonotherapy, aromatase inhibitor steroidal and nonsteroidal.

Radioterapie & Oncologie Medicală, 1998, 1-2: 53-70

70 Hormonal replacement therapy: risks and alternatives

  1. Ghilezan

UMF Cluj-Napoca. Oncological Institute „Prof I.Chiricuţă”

Honnonal replacement therapy (HRT) is generally accepted for the control of menopausal effects but for breast cancer patients are controversial. The pro and cons arguments are presented. The published date suggest that the risk is accept- able and controllable. The HRT objectives are the control of the early symptoms of menopause, mainly vasomotor and genital, and the prevention of late sequels including cancer recurrence. The indications and recommendations used at the Cancer Institute Cluj are presented.

Key words: honnonal replacement therapy, breast cancer

Radioterapie & Oncologie Medicală, 1998, 1-2: 71-75

76 Endocrine treatment for early breast cancer. Overview of current standards and perspectives

  1. Untch, S. Kahlert, G. Konecny, H. Hepp

Department of OB/GYN, Klinikum Grosshadenn

Ludwing-Maximilians-Universitaet, Munich

Endocrine therapy for breast cancer is now an accepted and widespread method in both, the palliative and the adjuvant situation. Together with surgery, radiotherapy and cytotoxic therapy the use of endocrine agent in a multimodal approach to adjuvant treatment is a slow but constant process of charge. Tamoxifen is one of the most succesful endocrine agents and it proved efficacy and low toxicity. A similar benefit of treatment with Tamoxifen was seen in both, advanced and early breast cancer, node negative and node positive patients. Response to Tamoxifen is signifi- cantly influenced by age, estrogen receptor status and duration. Combination of chemotherapy and Tamoxifen should be used for patients at high risk of reccurence. Endocrine therapy rarely is intrerrupted for adverse reactions. The data are insufficient to determine the risk of endometrial cancer after therpy with Tamoxifen. New endocrine agents are currently evaluated and they have show promising results.

Key words: breast cancer, endocrine therapy

Radioterapie & Oncologie Medicală, 1998. 1-2: 76-84

85 Hormonal therapy for post menopausal breast cancer

  1. Ghilezan

Oncological Institute „I. Chiricuţă” – UMF „I. Haţieganu” Cluj-Napoca

The hormonal therapy is especially beneficial for the post menopausal breast patients. The classic indication, as first line honnonal therapy in post menopausal locally advanced or metastatic breast cancer remains tamoxifen. in adjuvant setting due to secondary effects, the hormonal therapy rise the following questions: the optimal duration oftamoxifen treatment, the role for antiestrogens and aromatase inhibitors of 2nd and 3rd generation, and the value of chemohormonal therapy. The results of the latest trials demonstrate the superiority of longer treatments – 5 years oftamoxifen vs. shorter time and the interest for the new antiestrogens and aromatase inhibitors due to a more favourable toxicity profile. A sequential combination oftamoxifen 3 years and AI 2 years is recommended by a recent published study. Chemohormonal therapy, especially with antracyclines, is very efficacious, for all patients groups/ pre- or post menopausal, N+ or N- and should be a routine indication for all breast cancer patients at risk.

Key words: post menopausal breast cancer, hormonotherapy, combinations.

Radioterapie & Oncologie Medicală, 1998, 1-2: 85-89




Cristina VITOC

96 Chestionar EMC