CHEMOTHERAPY OF BREAST CANCER IN SERBIA DURING THE FIVE-YEAR PERIOD ( ) - A RETROSPECTIVE ANALYSIS

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1 Archive of Oncology 2000;8(Suppl 1):7. SESSION 1 CHEMOTHERAPY OF BREAST CANCER IN SERBIA DURING THE FIVE-YEAR PERIOD ( ) - A RETROSPECTIVE ANALYSIS 7

2 Archive of Oncology 2000;8(Suppl 1):8. 8

3 Extended abstract UDC: : Z. NE KOVI -KONSTANTINOVI INSTITUTE FOR ONCOLOGY AND RADIOLOGY OF SERBIA, BELGRADE, YUGOSLAVIA Standard treatment of breast cancer - the role of consensus recommendations Key words: Breast cancer; Standard treatment; Consensus; Clinical investigation It is not easy to define the standard treatment of breast cancer. Standard or consensus treatment should be the approach recommended for routine use, with proven benefit for particular patients group. The proven value of an approach suggests that there is no need for further investigation of its clinical use. However, there are few approaches which can be assumed as definitely proven. Proofs for the efficacy of a new drug, therapeutic regimen or therapeutic approaches come from the controlled clinical studies, and the questions to be answered by clinical studies usually come from basic science. The extensive progress in molecular biology points to the large number of topics, which should be investigated in clinical trials. A substantial number of clinical studies has been conducted during past decades, which investigated the prognostic and predictive factors in breast cancer (BC), the efficacy of various treatments, new drugs, and new combinations of drugs, optimal doses, toxicity and side effects of treatment, as well as supportive measures. However, only 3-5% of all breast cancer patients have been included in clinical studies. Thus, all other BC patients were treated according to the results obtained on a small percentage of all BC patients. The clinical investigations in advanced BC are aimed to find the efficient treatments, which then should be used in adjuvant settings. Their long duration and the need for a great number of patients characterize adjuvant clinical studies. The differences in their designs and relatively small number of patients in individual trials, made the comparison of the results difficult. To compare the results of numerous clinical studies, the panels of experts in the field were organized. They analyze the cumulative data on the efficacy of various treatments, their consistency and reproducibility, and judge whether there exists sufficient evidence for giving the recommendation for the routine use of an underlying approach. NIH Consensus Development Conference in USA (1) and St. Gallen consensus conferences on Adjuvant Address correspondence to: Dr Zora NeπkoviÊ-KonstantinoviÊ, Institute for Oncology and Radiology of Serbia, Pasterova 14, POB 228, Belgrade, Yugoslavia The manuscript was received: Accepted for publication: Archive of Oncology 2000;8(Suppl 1):9-10. Therapy of Breast Cancer in Europe, are currently giving the new consensus statements for adjuvant therapy, as well as for the new therapeutic approaches, for the use of prognostic factors, etc (2, 3). Meta-analyses of clinical investigations are currently used for the assessment of clinical value of an approach, the Early Breast Cancer Trialists Cooperative Group (EBCTCG) meta-analyses on adjuvant therapy of breast cancer being the most frequently quoted. In short, the recommendations for routine applications of ADJUVANT TREATMENT consider the following topics: PROGNOSTIC AND PREDICTIVE FACTORS. For routine selection of adjuvant treatment the only recommended prognostic and predictive factors are age, tumor size, axillary nodal involvement, tumor type, standard histologic grade and estrogen receptor (ER) and possibly progesterone receptor (PR) status (1, 3). These information are obligatory for adequate and optimal assessment of individual risk in operable breast cancer patients, as well as for optimal treatment choice. The yet unproved, but promising prognosticators, such as c-erbb-2/her2/neu receptor, p53, biological markers of angiogenesis or vascular invasion, or proteases, are not recommended for routine use, but nevertheless, they are strongly recommended for further investigation in clinical trials and basic research. ADJUVANT ENDOCRINE THERAPY. Since the steroid receptors (SR) need to be determined in an adjuvant setting, the recommendation for the consideration of endocrine adjuvant therapies comprises all SR positive patients, with the possible exception of those with tumors less than 1 cm in diameter, for whom the adjuvant treatment could be avoided. In all postemenopausal women, especially those older than 70, the adjuvant tamoxifen therapy could be recommended even though the SR status was unknown (3, 4, 5, 6). The ovarian ablation should be considered for premenopausal SR positive patients, as well as tamoxifen. Ovarian ablation produced a similar effect as certain chemotherapy regimens; thus it should be used instead, but not in addition to chemotherapy (7). Since the group of SR-negative premenopausal patients does not benefit from endocrine treatments at all, it is not justified to recommend the adjuvant endocrine therapy when the SRs are unknown. ADJUVANT CHEMOTHERAPY. Adjuvant chemotherapy is recommended as a standard treatment of high-risk operable breast cancer. The duration of treatment should not exceed 6 months. The standard regimens used are non-antracycline (CMF) and antracycline regimens (AC, FAC, FEC). Although there is evidence that the antracycline regimens produced a small but significant benefit, many earlier clinical studies used the modified CMF regimens (8). Thus, a concern of their sub-optimal dosages exists. Anyhow, the classic CMF (with oral or intravenous application of cyclophosphamide) is recommended for adjuvant setting (9). High-dose chemotherapy or the use of novel therapeutic drugs is not recommended for routine clinical use. NEOADJUVANT CHEMOTHERAPY is recommended for the purpose of down-staging the large operable tumors, or to allow the less radical surgery (3). Although these recommendations are strongly supported by evidence from clinical investigations, a lot of still open questions remain to be clarified in the future. For example, it is not still completely defined for which patients should the combination of endocrine adjuvant treatments with chemotherapy be recommended. Further, if combined, in what sequence (concomitantly, or one after the other). If postoperative irradiation is indicated, what should be the optimal sequence? It is obvious that the optimal adjuvant treatment is not yet well-defined for certain patient risk groups. Moreover, the consensus statements do not define for which patients the antracycline regimens are recommended. Obviously, consensus statements can be divided in three categories. The first refer to those suggestions that should be accepted in routine treatment. The second categories of recommendations are those treatments or actions, which should not be used in routine practice. And the third are those points for which there is 9

4 Archive of Oncology 2000;8(Suppl 1):9-10. no sufficient evidence for consensus statements on their validity. Therefore, the adjuvant treatment of operable breast cancer patients should not be considered as routine or standard in terms of no need for assessment. In the aim to contribute to the progress of clinical oncology, it would be necessary to make possible, at the national level: - to obtain the minimum of prognostic parameters for all operable breast cancer patients, including SR; - to conduct the adjuvant treatment according to the national protocols; - to register all operable BC patients in a national Registry; - to follow-up all those pts until relapse, or death, and to register the outcome; and - to analyze the results of the treatment. Thus, the routine adjuvant treatment could be judged, and the Protocol for adjuvant treatment should be changed according to our own results, rather than according to the International Concensus Recommendations only. In the meantime, the randomization of individual patients into the international adjuvant studies should be recommended, to contribute to the task of finding the optimal treatment options with the optimal quality of care. STANDARD TREATMENT OF LOCALLY ADVANCED BREAST CANCER (LABC). The standards in this field simply do not exist. On the base of clinical studies, it is usually recommended to use the systemic treatment, radiotherapy and surgery, if possible, in the routine sequence. For the current use, the National Protocol for treatment of breast cancer is accepted in 1999, which included the recommended treatment policy in sub-groups of LABC. It includes the traditionally used approaches (pre-operative breast irradiation, for example), as well as the novel treatment approaches (neo-adjuvant chemotherapy, for example). Since there are no standards, it seems to be reasonable to design the clinical study to compare those two treatment approaches in comparable sub-groups of LABC patients. STANDARD TREATMENT OF ADVANCED BREAST CANCER. Standard approaches to the advanced breast cancer treatment include the use of chemotherapy, endocrine therapy, and in a lesser extent radiotherapy and surgery, when indicated. The preferred treatment policy differs between centers, and even between experts in this field. However, the patients inclusion in clinical studies, institutional, multicentric or international, should be supported, to allow the involvement of new and better strategies in this field. REFERENCES 1. NIH Consensus Development Conference Statement: Adjuvant therapy for Breast cancer. November 2000: Goldhirsch A, Wood WC, Senn HJ et al. Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1995;87: Goldhirsch A, Glick JH, Gelber RD, Senn H-J. Meeting Highlights: International Consensus Panel on the treatment of Primary Breast Cancer. Commentary. J Natl Cancer Inst 1998;90: Early Breast Cancer Trialists Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving recurrences and deaths among women. Lancet 1992;339: Early Breast Cancer Trialists Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomized trials. Lancet 1996;348: Early Breast Cancer Trialists Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998;351: Davidson N. Adjuvant endocrine therapy for early stage breast cancer. Proc Am Soc Clin Oncol 1999;18: Early Breast Cancer Trialists Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998;352: Goldhirsch A, Coates AS, Calleoni M et al. Adjuvant chemoendocrine therapy in postmenopausal breast cancer: cyclophosphamide, methotrexate and fluorouracil dose and schedule may make a difference. J Clin Oncol 1998;16:

5 Extended abstract UDC: : : J. LAKI EVI 1 Z. NE KOVI -KONSTANTINOVI 2 D. NIKOLI -VUKOSAVLJEVI 2 S. U NJAR 2 S. VASOVI 2 S. JELI 2 L. MITROVI 2 1 CLINICAL CENTER OF MONTENEGRO, PODGORICA, YUGOSLAVIA 2 INSTITUTE FOR ONCOLOGY AND RADIOLOGY OF SERBIA, BELGRADE, YUGOSLAVIA Routine adjuvant tamoxifen treatment in postmenopausal operable node-positive breast cancer patients ABSTRACT Although tamoxifen is widely accepted as a treatment of choice in adjuvant therapy of postmenopausal, steroid receptor-positive operable breast cancer patients it is likely that all patients may not benefit equally. Therefore, the outcome (DFI and OS) was analyzed in a group of 111 postmenopausal breast cancer patients with T1-2 tumors, 1-3 involved nodes and positive ER and/or PR which were treated with adjuvant tamoxifen only, at the Institute of Oncology and Radiology of Serbia. Our results showed that the subgroups of patients existed, which benefited more than others from adjuvant tamoxifen depending on the SR content, age, duration of menopause and duration of tamoxifen treatment. The subgroup with very high ER content (~100 fmol/mg), younger than 60 and with menopause shorter than 10 years, showed the most unfavorable outcome. Patients with PR negative tumors comprised the other unfavorable subgroup. For both groups of patients some additional treatments should be considered: perhaps aromatase inhibitors for the first group, and chemotherapy for the second. Patients treated for 2-5 years with adjuvant tamoxifen, in particular those older than 60, tend to have longer OS, compared to patients who were treated for less than 2 years. In conclusion, our results suggest that the adjuvant endocrine treatment of postmenopausal receptor-positive breast cancer patients could be modified to improve the outcome, according to patients age, duration of menopause and receptor content. Archive of Oncology 2000;8(Suppl 1): therapies are aimed at controlling or eliminating subclinical residual disease. Tamoxifen is one of the most often-tested drugs in adjuvant systemic therapy (1). Adjuvant tamoxifen is a therapy of choice in steroid receptorpositive (SR+) breast cancer (BC) patients (pts), in all postmenopausal BC pts, especially SR+, and in pts older than 70, irrespective of SR status (2). It has been shown that the use of tamoxifen significantly improves 10-year survival (3), and that the treatment longer than 2 years is more beneficial than the shorter one. However, uncertainty has remained about how long the optimal treatment should last (5 years or longer, or for the lifetime). The other controversial issues concern the best way to combine chemotherapy and tamoxifen (concomitant or sequential), the use of tamoxifen in SRnegative BC pts and in premenopausal BC pts, as well as the side effects, of which the frequency of endometrial cancer being most important. The aim of this study is to estimate the effect of adjuvant tamoxifen alone in a group of postmenopausal operable node-positive (N1-3) and SRpositive BC pts, and to sort out subgroups, which would benefit more, from those who benefit less. The final goal is to estimate the requirements for additional therapy in subgroups with the more unfavorable outcome. PATIENTS AND METHODS This analysis includes 111 postmenopausal BC pts having been operated from at the Institute of Oncology and Radiology of Serbia, in Belgrade (Table 1). Table 1. Distribution of the parametars in whole group, in relation to age Key words: Breast cancer; Adjuvant treatment; Endocrine therapy INTRODUCTION Many patients relapse and die due to the metastatic disease, regardless of intensive locoregional treatment. Distant metastases may have already been present at the time of cancer diagnosis. Adjuvant systemic Address correspondence to: Dr Zora NeπkoviÊ-KonstantinoviÊ, Institute for Oncology and Radiology of Serbia, Pasterova 14, Belgrade, Yugoslavia The manuscript was received: Accepted for publication: They all had T1-T2 tumors, with histologically involved 1-3 regional lymph nodes and ER and/or PR-positive status. Modified radical mastectomy was performed in most pts, with or without postoperative irradiation and adjuvant tamoxifen was recommended for 5 years. However, some pts, for their own reasons, for the lack of the drug or rarely, for the tamoxifen intolerance, discontinued the treatment earlier than 5 years. Therefore, pts are divided in 2 groups with respect to the duration of tamoxifen therapy: the first one was treated for 6 months-2 years (33 patients), and the second group was taking tamoxifen for 2-5 years, or until 11

6 Archive of Oncology 2000;8(Suppl 1): the first relapse, no matter when it happened (78 pts). Disease outcome (DFI an OS) was analyzed in relation to classic prognostic parameters (patients age and duration of menopause, tumor size, pathologic tumor type and grade) and SR content, special attention being paid to the duration of adjuvant tamoxifen therapy. RESULTS No difference was observed in disease-free or overall survival (DFS and OS) between younger (`60 years) and older group ( 60 years) of pts. Menopausal duration significantly affected the DFS: menopause 10 years determinate the favorable prognostic group. When age and menopause duration were analyzed as related parameters, the highest significance was found in DFS and OS between the two groups (Figure 1). Figure 1. Outcome in older group ( 60 years) in relation to menopause duration The tumor size (pt1 vs. pt2), pathologic tumor grade (grade I vs. II vs. III) and pathologic tumor type (ductal vs. lobular), did not indicate the different prognostic groups, either in relation to DFS or OS, possibly due to the relatively small sample size in certain sub-groups. The analysis of SR content showed that PR+ tumors had a slightly better outcome, the difference being significant only for DFS, from 90th months up to the end of the follow-up (Figure 2). Figure 2. Outcome in relation to PR positivity Concerning the ER content, we found that very high ER level ( 100 fmol/mg), especially in pts younger than 60, was related to the significantly poor outcome, according to both DFS and OS (Figure 3). DISCUSSION Our results are in accordance with the generally accepted opinion that the effect of tamoxifen is better in older women and those with longer menopause (4). The best outcome in this study was found in pts aged 60, being menopausal longer than 10 years. No matter whether this specific subgroup had a better prognosis in itself, or whether these parameters were associated with better response to tamoxifen, probably the most appropriate treatment for these patients group should be tamoxifen. Our study confirmed that the duration of tamoxifen treatment had an influence on the outcome, and this was the only direct evidence that tamoxifen essentially changed the outcome in operable BC patients. Prognostic parameters, known as indicators of chronological age of tumor, such as tumor size, influence tamoxifen effect to a lesser extent. However, nodal status could not be assessed, since all our patients had 1-3 involved axillar nodes. It is well known that pathologic grade correlated with SR content (5, 6). In our study there was a too small number of patients with grade III tumors, which made impossible the analysis. The influence of histological type on tamoxifen therapy is controversial but it has been considered that tubular and mucinous tumors most often are ER-positive (8, 9). We analyzed two most frequent pathologic types (ductal invasive and lobular invasive carcinoma), and there were no difference observed in DFI and OS between them. All pts were ER and/or PR positive, therefore we cannot assess the use of tamoxifen in SR-negative patients. PR positivity appeared to be beneficial for the tamoxifen efficiency, but the analysis of ER gave unexpected data. It is well known that high steroid receptor levels are related to better response to tamoxifen (4), although those pts could have a poorer prognosis. Since we did not have a control group, it was impossible to assess whether, or how much tamoxifen influenced the outcome in this group. It is shown that sub-groups with different outcome exist: the group with better outcome ( 60 years, menopause 10 years) which can be treated with tamoxifen only, and that with worse outcome (PR-negative, or high content ER+), which might probably improve by the additional adjuvant treatment: in PR-negative pts the additional treatment should consist of chemotherapy, and in those with very high ER content the aromatase inhibitors should be used. In conclusion: the adjuvant hormonal therapy probably could be improved by sub-grouping the patients according to: age, duration of menopause, receptor content, and by modifying the adjuvant treatment. REFERENCES 1. Lundgren S. Review: Prospects in endocrine treatment of breast cancer. Cancer 1994;7: Goldhirsch A, Wood WC, Senn HJ et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Natl Cancer Inst 1995;87: Figure 3. Outcome in younger group (`60 years) in relation to ER level (`100 fmol/mg vs 100 fmol/mg) The analysis of the relation between the outcome and tamoxifen therapy duration showed that the outcome was better in the group with longer tamoxifen treatment (2-5 yrs), and that in older patients ( 60 yrs) there existed a trend for statistical significance in OS (Figure 4). Figure 4. Outcome in relation of adjuvant tamoxifen duration in older group ( 60years) 3. Early Breast Cancer Trialists Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: Early Breast Cancer Trialists Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving recurrences and deaths among women. Lancet 1992;339: Clark GM. Do we really need prognostic factors for breast cancer? Breast Cancer Res Treat 1994;10: Kauffman M, Von Minckwitz G, Sinn HP et al. Combination of grading and new biological factors predict relapse and survival in patients with node negative primary breast cancer. Onkologie 1994;17: Mansour EG, Ravdin PM, Dressler L. Prognostic factors in early breast cancer. Cancer 1994;74: Rosen PP, Groshen S, Saigo PE et al. Pathological prognostic factors in stage I and stage II breast carcinoma: a study of 644 patients with median follow up of 18 years. J Clin Oncol 1989;17:

7 Extended abstract UDC: : J. MLADENOVI J. A I M. DOÆI B. LUKA» N. BOROJEVI INSTITUTE FOR ONCOLOGY AND RADIOLOGY OF SERBIA, BELGRADE, YUGOSLAVIA The role of radiotherapy in postoperative treatment of early breast cancer Key words: Operable breast cancer; Adjuvant radiotherapy; Adjuvant chemotherapy; Timing Treatment of early breast cancer (stage I et II ) consists of mastectomy or breast conserving surgery with axillary dissection followed by adjuvant chemotherapy or hormonal therapy or postoperative radiotherapy in patients with increased risk for relapse. Radiotherapy, like surgery is a locoregional treatment method. The purpose of postoperative radiotherapy is to achieve local control of the disease and improve disease-free survival, but makes little difference to overall survival. Some studies on breast cancer patients who underwent radical mastectomy and received adjuvant chemotherapy, tried to find out whether the addition of irradiation treatment to the chest wall and regional lymph nodes increases survival. The hypothesis in favor of irradiation is that chemotherapy can eliminate distant micrometastasis, but is less effective against local and regional disease, which are better controlled by radiotherapy (1). Early Breast Cancer Trialists Collaborative Group showed a reduction of about two-thirds in local recurrence after postoperative radiotherapy, irrespective of whether breast surgery involved mastectomy or conservation (2). The large reduction in local recurrence corresponded to substantial reduction in the incidence of any recurrence. This Collaborative Group confirmed a reduction in breast cancer deaths, but this benefit was of only moderate size. This analysis established that local disease control eventually produce some effect on distant disease control. The favorable effect on mortality from breast cancer was offset by statistically definite increase in the annual death rate from other causes, mostly cardiovascular. The cardiac dose is somewhat greater with left-sided tumours, and the epidemiological studies found that irradiation of the left Address correspondence to: Dr Jasmina MladenoviÊ, Institute for Oncology and Radiology of Serbia, Pasterova 14, POB 228, Belgrade, Yugoslavia The manuscript was received: Accepted for publication: Archive of Oncology 2000;8(Suppl 1): breast was associated with about one-fifth more cardiac mortality than irradiation of the right breast. After mastectomy, postoperative radiotherapy include irradiation to the chest wall, including the surgical scar and regional lymph nodes ( axillary, supraclavicular and infraclavicular and internal mammary nodes ). Irradiation of the chest wall was used in selected groups of high-risk patients with angioinvasion, perineural invasion and lymphangiosis of the skin. The tumour dose for the chest wall is 50 Gy/25 fractions over a period of 5 weeks. Irradiation of the regional lymph nodes depends on finding after axillary dissection. If nodes are negative, most authors consider that there is no need to irradiate regional lymphatic. The question of whether to irradiate lymphatics in patients with positive axillary nodes is an extremely controversial issue, especially because these patients are receiving chemotherapy. However there is recommendation to selective irradiation of the axilla and supraclavicular fossa in selected patients, such as those with four or more metastatic axillary lymph nodes, involvement of the apex of the axilla, and extracapsular extension, even if these patients are receiving adjuvant chemotherapy (3). Internal mammary nodes are irradiated in patients with medial localisation of tumour and simultaneous positive axillary lymph nodes. The tumour dose for regional lymphatics is 48 Gy in 22 fractions during the four and a half weeks. After breast conserving surgery, postoperative radiotherapy of the residual breast is obligatory. The purpose is to irradiate the tumour bed, subclinical deposits in the breast and the tumour infiltrations in the lymphatics of the breast. Breast conserving surgery is associated with suspicion that in residual breast some tumour cells are falling behind, being the result of inadequate surgery or multicentricity, what necessitates postoperative irradiation. The complete ressection of primary neoplasia with a margin of adjacent normal tissue is crucial for locoregional disease control and influence in decision making about the total tumour dose of irradiation. Minimal tumour doses are Gy delivered to the entire breast in 5-6 weeks, using gamma or X-rays. Since a significant residual tumour burden may be present after the conserving surgery, with negative pathologic margins, there is a strong justification for a tumour bed boost. Boost to the tumour site can be applied by an interstitial brachytherapy or with photons or electron beams with TD l0-l6 Gy in 5-8 fractions, and recent data indicated that there were no different effects regarding local control between these two methods (4). Various series suggest that patients treated with higher doses including a boost, have a greater probability of tumour control, but higher doses are correlated with poorer cosmetics effect. Some authors indicated that in particular cases there is no need for the tumour bed boost, and those are patients with tumours less than 1 cm, with no extensive intraductal carcinoma, negative surgical margins, and those with neither necrosis nor high-grade tumours (5). To obtain optimal locoregional control of the disease, it is necessary to achieve the optimal balance between surgery, radiotherapy and adjuvant chemotherapy. Treatment decisions depend not only on differences in survival, but also on costs, side-effects and the importance of local disease recurrence to the quality of life. We analyzed postoperative irradiation treatment in one year period at the Institute for Oncology and Radiology of Serbia. The purpose was to evaluate effects of timing of postoperative radiotherapy and adjuvant chemotherapy on local control of the disease and overall survival. 161 patients with early-stage breast cancer were treated in one year period, in 1994 with radical mastectomy and postoperative radiotherapy. 40 patients received adjuvant chemotherapy, 56 received adjuvant hormonal therapy (Ro castration or/and Tamoxifen ) 4 patients receive both 13

8 Archive of Oncology 2000;8(Suppl 1):13-4. adjuvant chemo and hormonetherapy, and 61 were only irradiated. The irradiation was delivered on the regional lymphatics with TD 48 Gy in 22 fractions. Median follow-up was 48,4 months. Our results showed that relapse incidence was 31,6% with median relapse-free interval of 30,5 months. Locoregional relapse was l2,4% (only 4,3% had local recurrence as the first failure) and distant metastases occurred in 29,2% of patients. After the end of the follow-up 57% patients are alive without any signs of the disease. The five year overall survival was 80%. There is no statistically significant difference in overall survival and disease-free survival between the patients who started with radiotherapy up to 6 weeks after surgery and those over 6 weeks. In the subgroup of patients who received adjuvant chemotherapy, there is no statistically significant difference in overall survival and disease-free survival between patients who received no chemotherapy, or only one cycle of chemotherapy, and those who received two or more cycles, before starting postoperative radiotherapy. REFERENCES 1. Overgard M, Hansen S et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med l997;337: Early Breast Cancer Trialists Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355: Pierce L J, Glastein E. Postmastectomy radiotherapy in the management of operabile breast cancer. Cancer l994;74: Touboul E, Belkacemi Y et al. Early breast cancer: influence of type of boost (electrons vs iridium -192 implant) on local control and cosmesis after conservative surgery and radiation therapy. Radiother Oncol l995;34: Kuske R, Compan P et al.breast consevation therapy: 417 breast cancers with a minimum follow-up period of five years. Int J Radiat Oncol Biol Phys l989;l7: