Breast-conservative surgery with and without radiotherapy in patients aged 55-75 years with early-stage breast cancer: a prospective, randomized, multicenter trial analysis after 108 months of median follow-up.

OBJECTIVES: Breast-conserving therapy (BCT), including postoperative whole breast irradiation (WBI), is generally accepted as the treatment of choice for most patients with early-stage breast cancer. The question whether WBI is mandatory in all patients remains one of the most controversial issues in BCT. To answer this question, a randomized, prospective, multicentre study was launched in January 2001. Primary endpoints of the study were to assess the cumulative incidence of in-breast-recurrences (IBR) and overall survival (OAS) after conservative surgery (BCS) with or without WBI. METHODS: From January 2001 until December 2005, 749 patients with unifocal infiltrating breast cancer up to 25 mm, 0-3 positive axillary lymph nodes, no extensive intraductal component or lymphvascular invasion from 11 centres in Italy, were randomly assigned to BCS+WBI (arm 1:373 patients) or BCS alone (arm 2:376 patients). Treatment arms were well balanced in terms of baseline characteristics. Systemic adjuvant therapy was administered according to the institutional policies. Kaplan-Meier method was used for survival analysis and log-rank test to evaluate the difference between the two arms. RESULTS (Last analysis 31.12.2012): After median follow-up of 108 months, 12 (3.4%) IBR were observed in arm 1 and 16 (4.4%) in arm 2. OAS was 81.4% in arm 1 and 83.7% in arm 2. There was no statistically significant difference regarding IBR and death in the two treatment groups. CONCLUSIONS: These data are promising and suggest that WBI after BCS can be omitted in selected patients with early stage breast cancer without exposing them to an increased risk of local recurrence and death. Longer follow-up is needed to further consolidate these results.

Eight-year results of a prospective non-randomised study on therapy of small breast cancer. The German Breast Cancer Study Group (GBSG).

In this report, the results of the first controlled clinical trial on breast cancer in Germany, begun in 1983, are presented after a median follow-up of 8 years. Four-year results have been previously published. In pT1 N0 M0 breast cancer, mastectomy as the standard treatment was to be compared with tumorectomy plus radiotherapy to the remaining breast tissue. The study design, originally planned as a comprehensive cohort study including randomised and non-randomised patients, had to be changed into a prospective observation study due to the low randomisation rate. 1036 out of 1119 recruited patients were evaluable. After a median follow-up of 97 months, 237 events (local recurrence, regional recurrence, distant metastases, contralateral breast cancer or death of the patient without previous recurrence) occurred. With the exception of death without recurrence, the events were evenly distributed among the two treatment groups. The 8-year local recurrence rate of the whole patient population is 8.8%. Out of all prognostic factors examined, only tumour size and grade had a significant influence on recurrent disease. Event-free survival decreased in cases with 'uncertain' tumour margins, whereas the width of the margin has no influence on disease recurrence. Based on 151 deaths observed so far, there was no significant difference in overall survival between the two treatment groups. The 8-year results of this study are in accordance with the 4-year results reported previously and with those of other breast-conserving treatment trials. There was no significant difference between the two treatment groups with regard to event-free and overall survival. Incomplete tumorectomy had a negative influence on recurrence.

Therapy of small breast cancer: a prospective study on 1036 patients with special emphasis on prognostic factors.

In 1983, The German Breast Cancer Study Group, sponsored by the Federal Ministry of Research and Technology, started a prospective multicenter trial on the treatment of early breast cancer pT1 pN0 M0. Treatment consisted of initial tumorectomy with microscopically free margins and lower axillary dissection. After conformation of a pT1 pN0-stage, additional treatment was either mastectomy or adjuvant radiotherapy (50 Gy in 25 fractions to the entire breast plus 12 Gy electron boost). In medially located tumors, the parasternal and supraclavicular area was also irradiated with 50 Gy. A randomization between both treatment modalities was initially planned but was not feasible and abandoned. Nearly all patients were treated according to their own choice. From November 1983 through December 1989, 1119 patients were recruited. Eighty-three were excluded from the protocol. Out of the remaining 1036 patients, 733 (71%) underwent breast preservation and 303 (29%) mastectomy. A detailed pathohistological examination of all tumorectomy specimens was performed in a pathologic reference center. Oncogen overexpression was evaluated by immunohistological detection of the transmembrane protein p-185 (corresponding to c-erb-B2) in 425 cases. After a median follow-up of 48 months, the frequency of local recurrences (4.7%), regional recurrences (1%), and distant metastases (5.4%) was the same in the breast preservation group and the mastectomy group. The 3-year disease-free survival was 90% after breast preservation and 88% after mastectomy (p = 0.21). In the breast preserving group, 24 patients with microscopically involved margins had a poorer disease-free survival than the study group (75% vs 90% after 3 years). The width of the margins had no impact on prognosis. Other prognostic factors in an univariate and multivariate analysis were tumor size and tumor grade. Age, menopausal status, hormone receptor status, histological tumor type, and treatment (mastectomy vs breast preservation) were not significant. P-185-expression was dependent on tumor grade and was the strongest prognostic factor in an univariate and multivariate analysis (p less than 0.001). The results emphasize the central role of tumor grade for prognosis and suggest the independent prognostic significance of the c-erb-B2 oncogen (corresponding to p-185) in pN0-patients.

Reverse transcriptase/polymerase chain reaction analysis of parathyroid hormone-related protein for the detection of tumor cell dissemination in the peripheral blood and bone marrow of patients with breast cancer.

Tumor cell dissemination in the bone marrow is an independent prognostic marker for relapse and survival for patients with primary breast cancer. Parathyroid-hormone-related protein (PTHrP) is expressed in most primary tumors and bone metastases of patients with breast cancer. PTHrP acts as an autocrine growth factor for breast cancer cells in vitro and there is evidence that it is especially important for osseous metastasis. For a sensitive detection of PTHrP-positive disseminated tumor cells a reverse transcriptase/polymerase chain reaction (RT/PCR) assay for PTHrP transcripts in the peripheral blood (PB) and in the bone marrow (BM) has been established. In mixing studies, the sensitivity of the reverse transcriptase/polymerase chain reaction (RT/PCR) for PTHrP was one tumor cell in 1 x 10(6) mononuclear cells. At this level of sensitivity, transcripts of PTHrP were detected in none of 30 PB samples and in 3 of 25 BM samples of healthy volunteers; there were also no transcripts of PTHrP in the PB and BM of 6 patients with benign breast lesions. The PB samples of 31 patients and the BM samples of 34 patients with predominantly early-stage breast cancer were tested for PTHrP expression along with immunocytology against cytokeratin 18 (CK18) as a standard immunological detection technique. PTHrP expression was shown in 9 of 31 patients in the PB and in 9 of 34 patients in the BM. In 30 patients, PB and BM samples were available simultaneously. There were cases of combined positive findings in the PB and the BM (4/30) and of isolated positivity in the PB (5/30) or in the BM (4/30). Compared to immunocytology, RT/PCR assay of PTHrP assay was significantly more sensitive in the peripheral blood (8/30 by RT/PCR compared to 1/30 by immunocytology). In the bone marrow there were cases of positivity for both markers (2/34), cases of isolated positivity by immunocytology for CK18 (3/34) and cases of isolated positivity for PTHrP transcripts (7/34). In conclusion the RT/PCR assay for PTHrP transcripts is a feasible and very sensitive technique for the detection of tumor cell dissemination in the PB, even in patients with early-stage breast cancer. The specificity of detection of PTHrP transcripts in the bone marrow is limited, possibly because of autochthonous expression of PTHrP in osteoblastic cells. The clinical follow-up of the subgroups of patients at risk, as defined by this assay, will show its prognostic significance for patients with breast cancer.

Kinetics of melphalan leakage during hyperthermic isolation perfusion in melanoma of the limb.

The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 micrograms/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 micrograms/ml (with cisplatin) in lower extremity perfusion. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been terminated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.

European School of Oncology: 20 years of cancer education and a contribution to European Guidelines of Oncology.

Since its creation in 1982, the European School of Oncology (ESO) not only looks back on two successful decades of cancer education and active promotion of knowledge and provision of oncology training in almost all parts of the world, but also the establishment of the State-of-the-Art (START) European oncology guidelines, a free, Internet-based, and readily accessible program of evidence-based medicine. In addition, ESO has been at the forefront of various activities which have led to the evolution of a common Continuing Medical Education system in Europe. A special framework to support the training of health care providers in underdeveloped countries was also launched by ESO. On the occasion of its 20th anniversary, ESO reflects on the past, defines the status quo and presents its future prospects.

Systemic therapy for treating locoregional recurrence in women with breast cancer.

BACKGROUND: Between 10% and 35% of women with operable breast cancer will experience an isolated locoregional recurrence following their primary treatment. There is currently no good evidence that adjuvant systemic treatment is effective in this situation and there is no standard treatment for women who have such a recurrence. OBJECTIVES: To investigate whether additional systemic treatment will improve the result of local therapy in regard to relapse-free and overall survival in women with potentially curatively resected loco-regional recurrence following breast cancer, who have not had a previous or synchronous distant metastases. SEARCH STRATEGY: Searches were done, in the first half of 2001, of the specialised register of the Cochrane Breast Cancer Collaborative Review Group, The Cochrane Library, MEDLINE and EMBASE. In addition, the records of the Early Breast Cancer Trialists' Collaborative Group were checked for any relevant trials. The citations in articles reviewing the treatment of locoregional recurrence of breast cancer were checked. SELECTION CRITERIA: Randomised controlled trials or trials in which women were allocated to treatment or observation by a quasi-random process (such as alternation or date of birth) were eligible. Our aim was to consider separately women with a first incidence of isolated loco-regional recurrence in the treated breast, the chest wall or the regional lymphnode areas (except clavicular nodes) which can be resected without (R0) or with (R1) microscopically demonstrable residual disease. Women with previous or synchronous distant metastases were to be excluded from this part of the review. The second part of the review was to consider women with inoperable loco-regional recurrence and / or clavicular lymphnode involvement, regardless of previous or synchronous metastases. DATA COLLECTION AND ANALYSIS: We identified three closed studies in which there were a total of four randomised comparisons of systemic therapy versus observation for women who have received radiotherapy for loco-regional recurrence of breast cancer. One trial assessed Actinomyicin-D and randomised 32 patients in the 1960s and another randomised the same number of women to alpha-interferon versus observation in the early 1980s. The Swiss SAKK trial assessed tamoxifen for "good risk" patients and combination chemotherapy (Vincristine, Doxorubicin and Cyclophosphamide) for "poor risk" patients. It randomised 178 and 50 women respectively during 1982-1991. Where possible, data on relapse-free and overall survival were extracted for these trials and analysed using RevMan 4.1. No attempt was made to pool the results of the studies because of clinical heterogeneity and the small number of randomised patients. Three ongoing trials of chemotherapy versus observation have been identified. MAIN RESULTS: The trial of 32 women who received either radiotherapy alone or in combination with systemic administration of Actinomycin-D found that chemotherapy improved the local control rate but had no apparent effect on overall survival. The interferon trial, which also included a total of only 32 patients, showed that the addition of alpha-Interferon to local treatment of locoregional recurrent breast cancer had no apparent effect on the further course of the disease. The Swiss SAKK trial of tamoxifen (178 women randomized) found an improvement in disease-free survival but not in overall survival and no results are available for the 50 women randomized into the concurrent trial of chemotherapy. The three ongoing trials of chemotherapy have a total target accrual of nearly 2000 patients. REVIEWER'S CONCLUSIONS: This systematic review of randomised trials provides insufficient evidence to do other than conclude that the most appropriate form of practice for women with loco-regional recurrence of breast cancer is participation in randomised trials of systemic treatment versus observation.

[Preoperative MR mammography in breast carcinoma. Effect on operative treatment from the surgical viewpoint]. / Präoperative MR-Mammographie beim Mammacarcinom. Einfluss auf die operative Behandlung aus chirurgischer Sicht.

INTRODUCTION: In a prospective study the diagnostic validity of magnetic resonance mammography (MRM) as well as its impact on the choice of the operative procedure in the treatment of breast cancer was examined. In 125 patients who were suspected of having breast cancer by clinical examination, ultrasound, and X-ray mammography, additional bilateral MRM was performed. Of special interest was the diagnostic potential of MRM with regard to multifocal, multicentric and contralateral lesions. METHODS: After a complete resection all lesions diagnosed by the various conventional methods were examined patho-histologically. In 112 patients, complete data were available to calculate the sensitivity and the specificity of each method as well as to correlate its results with the pathohistological findings. RESULTS: In 91 cases, a breast carcinoma was diagnosed by conventional methods, with a sensitivity/specificity of 73%/67% for clinical examination, of 58%/86% for ultrasound, and of 89%/20% for X-ray mammography. In this preselected series of patients with a prevalence of 81.25% the diagnosis established by the various methods was confirmed by MRM with sensitivity of 96.7% and specificity of 19%. Forty-six additional suspicious lesions were found only by MRM, of which 28 were malignant (25 multifocal or multicentric and 3 contralateral carcinomas), and 18 benign. The rate of false-positive MRM results was 18%. Due to the MRM findings, the therapeutic procedure was changed from breast preservation to mastectomy in 14.3%. CONCLUSION: Not only for the differential diagnosis of discrepant findings between X-ray mammography and ultrasound, but especially for the diagnosis of multifocal or multicentric lesions, MRM seems to be the method of choice. Consequently, MRM plays an important role in planning the operative procedure in breast cancer patients, especially in the context of breast preservation. To ensure optimal use of this new diagnostic tool high technical standards, proper expertise on the part of the examining radiologist, and effective cooperation among the involved disciplines (radiology, pathology, surgery) must be guaranteed.

[Initial results of the Project of the German Breast Cancer Study Group on "Breast saving therapy of the small breast cancer"]. / Erste Ergebnisse des Projekts der Deutschen Brustkrebs-Studiengruppe (GBSG) zur "Brusterhaltenden Therapie des kleinen Mammacarcinoms".

In the German Breast Cancer Study Group (GBSG) multicenter trial "Breast preservation in small breast cancer" 1119 patients were accrued over a period of six years. The study was originally designed as a randomized trial which had to be changed into a prospective observation study. A high therapeutic standard was guaranteed by quality control. The univariate analysis of prognostic variables was the first step to a valid treatment comparison. Those factors determined as being significant were combined with the treatment effects in a multivariate analysis. The published results were obtained after a median observation time of four years.

Potential impact of the 70-gene signature in the choice of adjuvant systemic treatment for ER positive, HER2 negative tumors: a single institution experience.

PURPOSE: We investigated in a single institution series of 124 women with operable breast cancer whether tumor clinicopathological features could predict the 70-gene signature (Mammaprint, MP) results, and whether MP results could help to make decisions for the use of chemotherapy (CT) in patients (pts) with ER positive breast cancer beyond recommendations of international guidelines. RESULTS: Among the 68 ER/PgR positive, HER2 negative tumors, Ki-67 ≥ 20% was the only significant predictor of a high risk-MP among standard clinicopathological features. In candidates for endocrine therapy with undetermined benefit from CT according to international guidelines, MP results would have led to different treatment decisions in 13/46 (28%) and in 20/68 (29%) pts according to NCCN and St. Gallen recommendations, respectively. CONCLUSIONS: Ki-67 independently predicted high risk-MP in ER/PgR positive, HER2 negative tumors. MP results would have led to discordant treatment recommendations in about 30% of cases, generally increasing indication rate for CT. The results of large randomized trials are warranted in order to understand whether we should rely on multigene assays rather than on standard clinicopathological features for treatment decisions.

Continuing medical education in Europe: towards a harmonised system.

One of the first reports on the state of medical education was published in 1910 in North America, with the support of the Carnegie Foundation, showing that the interest for this issue dates back at least a century. Doctors (and nurses) are among the few professionals who managed to avoid for a long time any sort of evaluation of their knowledge and competence after the achievement of their diploma. But concern has been rising in society about the fast obsolescence of medical knowledge, particularly in the last 50 years when the development of research and technology in the field has been so fast. The concept of Continuing Medical Education gained growing interest after the Second World War as a necessity for health professionals, but also as a form of protection of patients, who have the right to be treated by competent and knowledgeable doctors and nurses. The United States (US)-based Josiah Macy Foundation recently sponsored a conference exploring the state of continuing education and the result is 'a picture of a disorganised system of education with obvious foci of excellence (most in universities) but with most commercially supported events shading more towards product promotion and the welfare of doctors than prioritised dedication to enhancing the care of patients'. Despite the fact that there is a lot to be learned from the US experience, Europe has to find its own way. Considerable progress was made since 1995 when UEMS (Union Européenne des Médecins Spécialistes) started to structure CME activities in Europe at translational level. A workshop on the issue was jointly organised by the European School of Oncology (ESO) and the Accreditation Council of Oncology in Europe (ACOE) in Berlin in September 2009.

The masterclass of the european school of oncology: the 'key educational event' of the school.

The European School of Oncology (ESO) Clinical Masterclass is a one-week, full-immersion course, where students and teachers intensively interact with each other. This educational event is designed for medical or clinical oncologists who are defining and orientating their professional careers. Since 2002 nine Masterclasses have been organised in different European cities in which more than 500 oncologists have participated. In this paper, we are presenting data derived from the analysis of the questionnaire distributed to all participants.

Conservative surgery with and without radiotherapy in elderly patients with early-stage breast cancer: a prospective randomised multicentre trial.

Breast conserving therapy (BCT) including postoperative irradiation of the remaining breast tissue is generally accepted as the best treatment for the majority of patients with early-stage breast cancer. The question is whether there is a necessity for irradiating all patients. Between 2001 and 2005, 749 women aged 55-75 years with infiltrating breast carcinoma were randomly assigned to breast conservative surgery, with or without radiotherapy (RT), to evaluate the incidence of in-breast recurrence (IBR). After 5 years of median follow-up, the cumulative incidence of IBR was 2.5% in the surgery-only arm and 0.7% in the surgery plus RT arm. There are no differences in terms of overall survival and distant disease-free survival. The preliminary evaluation suggests that breast irradiation after conservative surgery can be avoided without exposing these patients to an increased risk of distant-disease recurrence. Prolonged follow-up will further clarify the possible risks and late sequelae potentially induced by breast RT.

[Indications, technique, results and value of breast saving surgery in breast cancer]. / Indikation, Technik, Ergebnisse und Stellenwert der brusterhaltenden Chirurgie beim Mammakarzinom.

Breast preservation is by no means a standard treatment modality for breast cancer. An increasing number of unsatisfactory results have been observed despite the fulfillment of requirements necessary for adequate treatment. Excellent surgical technique is a solid basis for good cosmetic result. According to the interim analysis of the German breast preservation study a tumor biopsy with a small margin of healthy tissue together with a lower axillary dissection can be considered a sufficient surgical procedure. The relationship between tumor size and size of the breast is one of the most important factors determining contraindications for breast preservation. Adequate instruction of the patient still remains a major problem for most doctors. If the patient is properly informed about the operation quality of life is not substantially altered after mastectomy and breast reconstruction compared with breast preservation therapy.

Inhibition of glycemic and hormonal responses after repetitive sucrose and starch loads by different doses of the alpha-glucosidase inhibitor miglitol (BAY m 1099) in man.

In two randomized, placebo-controlled, double-blind studies, the efficacy, duration of action and tolerability of a single morning dose of 25, 50, and 100 mg miglitol (BAY m 1099), an absorbable inhibitor of intestinal alpha-glucosidases, were assessed after repetitive sucrose or maize-starch loads (50 g of carbohydrates in 400 ml of water each at 08.00, 12.00, and 17.00 h). With sucrose, miglitol reduced the postprandial rise in blood glucose, serum insulin and serum gastric inhibitory polypeptide concentrations at any dosage. This effect was dose-dependent and confined to the first carbohydrate load in the morning, thus indicating the duration of alpha-glucosidase inhibition of less than 4 h. Sucrose malabsorption, indicated by breath hydrogen responses, occurred dose-dependently with 50 and 100 mg, but not with 25 mg of miglitol. Similarly, symptoms of carbohydrate malabsorption were absent with 25 mg of the inhibitor and mild to moderate after 50 and 100 mg of miglitol. With starch as the substrate, BAY m 1099 led to a significant amelioration of glycemic and hormonal rises after the first meal, but not thereafter. A numerical dose dependency was recognized, but this was not significant at the 5% level. Symptoms of carbohydrate malabsorption were absent with 25 mg and negligible with 50 mg BAY m 1099, but occurred almost regularly with the 100-mg dose. Breath hydrogen concentrations increased gradually with the dose of miglitol administered. A single morning dose of 25-100 mg of miglitol thus may be useful for the control of postprandial hyperglycemia after breakfast. Due to the duration of action of less than 4 h, this substance should be given with the three main meals.

The prognostic effect of histological tumor grade in node-negative breast cancer patients.

The prognostic effect of histological tumor grade was evaluated in 1036 patients with early breast cancer (pT1 pN0 M0) entered into a trial comparing mastectomy and breast preserving treatment. All analyses were adjusted for the factors treatment, patients' age, and tumor size. Tumor grade was defined according to Bloom and Richardson based on the sum of scores assigned to each of three histological features: 1) degree of differentiation, 2) pleomorphism, and 3) mitotic index. The relative importance of these factors with regard to disease-free survival was evaluated. In univariate as well as in multivariate analyses the pleomorphism was the only factor showing a significant effect (univariate: p = 0.0024, multivariate: p = 0.015). It was investigated how the factors should be combined to define a histological grading score which yields the best possible classification of the patients with respect to prognosis. A new grading system was defined splitting the patients into three groups: 1) pleomorphism 1; 2) pleomorphism 2 or pleomorphism 3 and mitotic index 1; 3) pleomorphism 3 and mitotic index 2 or 3. This yields a good classification of the patients with respect to prognosis (p = 0.0004). The prognostic effect of this score was compared with the effects of the grading systems proposed in the literature. According to Bloom and Richardson and in the modified version by Schauer and Weiss, grading is based on the sum of scores of the various histological factors. Therefore, the strong effect of the pleomorphism was diluted in these grading definitions (Bloom and Richardson: p = 0.03, Schauer and Weiss: p = 0.028). The grading system proposed by Le Doussal et al. consists only of the scores of pleomorphism and mitotic index (p = 0.014). In summary, the factor pleomorphism showed a stronger effect on disease-free survival by itself than the grading systems proposed in the literature.

[Effect of MR mammography on surgical procedure in operative treatment of breast cancer]. / Einfluss der MR-Mammographie auf das chirurgische Vorgehen bei der operativen Behandlung des Mammakarzinoms.

In addition to conventional imaging techniques, magnetic resonance (MR) mammography is an important tool in the diagnosis of breast cancer. It has proved to be the method of choice especially for the differential diagnosis of discrepant findings between mammography and ultrasound as well as the detection of multifocal and multicentric disease. In this context MR mammography is a meaningful method for the planning of breast preserving surgery and seems likely to become routine practice as long as the preconditions for high quality performance are guaranteed.

[Intraoperative radiotherapy (IORT) in treatment of breast carcinoma--a new therapeutic alternative within the scope of breast-saving therapy? Current status and future prospects. Report of experiences from the European Institute of Oncology (EIO), Mailand]. / Intraoperative Strahlentherapie (IORT) in der Behandlung des Mammakarzinoms--eine neue therapeutische Alternative im Rahmen der brusterhaltenden Therapie? Stellenwert und Zukunftsperspektiven. Erfahrungsbericht aus dem European Institute of Oncology (EIO), Mailand.

BACKGROUND: External beam radiation therapy (EBRT) represents an integral component of breast-conserving treatment. In published series it has been demonstrated that the external boost can be replaced by intraoperative radiotherapy (IORT) where irradiation at a single dose from 10 up to 15 Gy was safely delivered directly to the tumor bed. PATIENTS AND METHODS: At the European Institute of Oncology, Milan, we initiated a dose escalation study to investigate the feasibility of applying single doses of IORT from 10 Gy up to 22 Gy. A portable IORT equipment with different electron energies was used. From July to December 1999, a total of 65 patients with T1-2 (max. 2.5 cm) No-1 breast cancer, median age 58 years (range 33-80 years) was treated. Ten patients received 10 Gy, eight patients were treated with an IORT of 15 Gy, eight received 17 Gy, six had 19 Gy, and 33 were treated with 21-22 Gy. Patients with 10 and 15 Gy received an additional EBRT of 44 and 40 Gy, respectively. In all other patients IORT was the sole radiation treatment. RESULTS: No acute side effects or intermediate untoward effects after a follow-up from three to nine months related to IORT were observed. CONCLUSIONS: Since the applicator can be safely placed under the control of the surgeon and radiotherapist IORT has the potential of accurately treating the tumor bed. Skin and subcutaneous tissue are not irradiated thus decreasing the potential risk of fibrosis and eventually obtaining a better cosmesis. With IORT single doses of 22 Gy being equivalent to a 60 Gy EBRT can safely be delivered. Even so the average time of operation was prolonged by around 20 minutes IORT application ultimately improves the quality of life of the patients in shortening overall treatment. Long-term follow-up is necessary to demonstrate whether large single doses of IORT might have the potential of sufficient local tumor control without major side effects. As a future perspective a randomized trial comparing EBRT with IORT as sole treatment will be performed.