Weight gain in menopause: systematic review of adverse events in women treated with black cohosh.

Weight gain is a frequent problem in perimenopausal and postmenopausal women. Cimicifuga racemosa (CR) is a popular treatment option for menopausal symptoms. The aim of this review was to investigate whether there is scientific evidence that CR causes weight gain. We searched our database for medically confirmed, spontaneous adverse events regarding weight gain, literature for case reports and randomized controlled trials. Thirty cases in total were spontaneously reported in 15 years. The causality was not considered certain/likely in any of the cases. A nurse (consumer) assessed the causality as possible. Only one case was published in the literature. However, no change in body fat composition was reported, and the causality seems unlikely. Of the 31 identified studies, 17 were double-blind placebo-controlled, five were double-blind reference-controlled and nine were open reference-controlled. In total, 1839 women were treated with CR for up to 12 months. Two studies reported weight gain as an adverse event; however, no significant differences in weight changes were observed between the groups. One case of weight gain (about 2 kg) was reported, but the authors did not specify in which treatment group. In conclusion, this study provides no scientific evidence that the use of Cimicifuga racemosa causes weight gain in menopausal women.

Isopropanolic black cohosh extract and recurrence-free survival after breast cancer.

OBJECTIVE: To investigate the influence of an isopropanolic Cimicifuga racemosa extract (iCR) on recurrence-free survival after breast cancer, including estrogen-dependent tumors. METHODS: This pharmacoepidemiologic observational retrospective cohort study examined breast cancer patients treated at general, gynecological and internal facilities linked to a medical database in Germany. The main endpoint was disease-free survival following a diagnosis of breast cancer. The impact of treatment with iCR following diagnosis was analyzed by Cox-proportional hazards models, controlling for age and other confounders. RESULTS: Of 18,861 patients, a total of 1,102 had received an iCR therapy. The mean overall observation time was 3.6 years. Results showed that iCR was not associated with an increase in the risk of recurrence but associated with prolonged disease-free survival. After 2 years following initial diagnosis, 14% of the control group had developed a recurrence, while the iCR group reached this proportion after 6.5 years. The primary Cox regression model controlling for age, tamoxifen use and other confounders demonstrated a protractive effect of iCR on the rate of recurrence (hazard ratio 0.83, 95% confidence interval 0.69 0.99). This effect remained consistent throughout all variations of the statistical model, including subgroup analyses. TNM status was unknown but did not bias the iCR treatment decision as investigated separately. Hence, it was assumed to be equally distributed between treatment groups. Correlation analyses showed good internal and external validity of the database. CONCLUSION: An increase in the risk of breast cancer recurrence for women having had iCR treatment, compared to women not treated with iCR is unlikely.

Treosulfan in the treatment of advanced ovarian cancer: a randomised co-operative multicentre phase III-study.

BACKGROUND: In August 1988 a randomised phase III multicenter trial was started in order to compare cisplatinum/treosulfan (PT) with standard cisplatinum/cyclophosphamide (PC) in advanced ovarian carcinoma, aiming at lower toxicity and maintained efficiency. PATIENTS AND METHODS: Five hundred and nineteen patients were enrolled into the protocol. Final evaluation after a median observation time of more than five years was made in July 1996 and included 398 eligible patients, of whom 366 were evaluable regarding efficiency and 290 in respect of toxicity. The tumour stages were classified as FIGO II in 53, FIGO III in 244 and FIGO IV in 68 patients. The patients were stratified regarding post-operative tumour burden. RESULTS: Hematological and gastrointestinal toxicity WHO > = 3 were comparable between the two study arms though a significant difference could be demonstrated regarding alopecia (PT 8% vs. PC 47% after six cycles). The median time to progression as the main efficiency item was in favour of the study schedule (PT 20.6 vs. PC 15.1 months) while significant differences were neither observed in the whole study group nor in the analysed subgroups (R0, < 2 cm, > = 2 cm). The same held true for overall survival. CONCLUSION: PT may be recommended as a less toxic substitute for the former standard PC. After the acceptance of paclitaxel/cisplatin as a new standard, the role of treosulfan should be investigated regarding adjuvant therapy in patients without residual tumor, as a potential partner in triple or sequential treatment and in second-line treatment.

Weekly intravenous recombinant humanized anti-P185HER2 monoclonal antibody (herceptin) plus docetaxel in patients with metastatic breast cancer: a pilot study.

BACKGROUND: In patients with HER2-positive metastatic breast cancer (MBC), combined treatment of herceptin (H) and chemotherapy (CT) improves time to progression, response rates and survival compared with CT alone. MATERIALS AND METHODS: We evaluated the safety and efficacy of weekly Docetaxel combined with weekly H as treatment in HER2 overexpressing MBC. RESULTS: Preliminary toxicity data from 12 patients and 76 cycles of D and 80 cycles of H were analysed. No G3/4 toxicity was observed. The most frequent non-hematologic toxicities were fatigue (2 patients G2, 2 patients G1), dyspepsia (1 patients G2, 3 patients G1), diarrhea (1 patient G2, 3 patients G1), and nausea (1 patient G2, 3 patients G1). Six partial responses have been observed in 12 patients (ORR 50%). CONCLUSIONS: The combination of weekly Docetaxel and Herceptin is well tolerated with significant anti-tumor activity.

Detection of serum autoantibodies to tumor suppressor gene p53 with a new enzyme-linked immunosorbent assay in patients with ovarian cancer.

Sera from 99 ovarian cancer patients were assayed for serum autoantibodies to p53 using a newly developed enzyme-linked immunosorbent assay (ELISA). Results were compared to the investigation using the former ELISA. The incidence of autoantibodies (25%) was lower using the newly developed ELISA as compared to the previous results (41%). The results were consistent in 79% of patients (P < .001). The incidence of autoantibodies was lower in patients with complete remission (19%) as compared to that of patients with recurrence (30%) and before primary surgery (26%). No statistically significant correlation was found among p53 serum autoantibody status and tumor stage, degree of malignancy, histologic subtype, and residual tumor after primary surgery. Use of the newly developed ELISA resulted in a higher consensus between immunohistochemically negative and autoantibody negative cases. Owing to further purifying of the prepared human recombinant p53. the newly developed ELISA seems to be of higher specificity as compared to the former ELISA.

ELISA-Based Quantification of p105 (c-erbB-2, HER2/neu) in Serum of Ovarian Carcinoma.

The most important prognostic parameters for gynecologic malignancies are tumor stage, residual tumor after surgical treatment, histological subtype, and degree of malignancy (1-2). However, these factors present an incomplete picture of the tumor biology. Therefore, investigation of other prognostic factors is of special clinical relevance, particularly in view of the unexpectedly progressive course of the disease and frequent relapses in some cases.

Differential Expression of Apoptosis-Associated Genes bax and bcl-2 in Ovarian Cancer.

The deregulation of the balance between proliferation and programmed cell death is considered one of the most important features of malignant tumors. The search for new markers, which may reflect the tumor progress and response to various therapy regimens, has recently focused on alterations of genes involved in regulation of programmed cell death and apoptosis. The bcl-2-family is a still growing family of genes, which play a major role in regulation of cell suicide, acting either as inhibitors (e.g., bcl-2, bcl-xl, mcl-1) or promoters (e.g., bcl-xs, bax, bak, bad) of apoptosis (1-3). The chromosomal translocation t(14;18), leading to overexpression of the Bcl-2 protein was first described in human B-cell lymphoma (4). Later on, Bcl-2-overexpression without chromosomal translocations was also detected in various epithelial tumors (5-12). It has been suggested that Bcl-2 as the major inhibitor of apoptosis plays a role in tumor development and progress by prolonging the survival of malignant cells. Unexpectedly, expression of Bcl-2 has been shown to be connected with parameters of favorable prognosis and prolonged survival in nonsmall-cell lung cancer (6), breast (7-9), and, recently, in ovarian cancer (10-12). Bax-expression, in contrast, was associated with an unfavorable outcome, as well as negative histopathological features in breast (13) and ovarian cancer (12). Moreover, the association of Bax-expression with predictors of poor clinical outcome was strongly connected with concomitant downregulation of Bcl-2-expression (12,13). The unexpected effect of Bcl-2- and Bax-expression on prognosis of ovarian cancer patients is underlined by the survival curves of patients. Especially, patients with exclusively Bax-positive tumors had a statistically significantly reduced survival as compared to patients with exclusively Bcl-2-positive tumors (12). This difference could be observed for patients with tumors of different stage and grade, as well as for patients with no evidence of disease or residual tumor after primary surgery (12). One explanation for these observations is that the apoptosis inhibiting or promoting effect of these homologous proteins depends partly on protein-protein interactions. Bax, for example, the main antagonist of Bcl-2, heterodimerizes with Bcl-2 or Bcl-Xl and homodimerizes with itself (1-3). The ratio of Bax-heterodimers to Bax-homodimers seems to be the critical determinant for regulating cell death (2,3). In cells in which 80% of Bax is found in homodimers, an apoptotic signal results in cell death (2,3), suggesting a crucial role of the Bax/Bcl-2 balance for the regulation of proliferation or cell suicide.

nm23-H1 expression defines a high-risk subpopulation of patients with early-stage epithelial ovarian carcinoma.

The role of the nm23 gene in human ovarian cancer is still controversial. We studied the expression of the nm23-H1 gene in 247 human epithelial ovarian carcinomas. The patients were followed-up until their death, or for a minimum of 5 years if they survived. The expression of the gene was studied by means of immunohistochemistry and a semiquantitative scoring system considering the staining intensity and the number of reactive tumour cells. Patients carrying tumours with higher expression scores (4-6 on a scale from 0 to 6) had a significantly lower survival (P = 0.01) than the rest. Further stratified statistical analysis revealed that this effect was mainly attributable to the subgroup of patients with early-stage (I and II), well- and moderately differentiated tumours. In fact, a multivariate analysis carried out for this subset of patients showed nm23-overexpression to be the only significant independent predictor of an ominous prognosis. The association of nm23-overexpression with a worse prognosis was most probably not due to mutation of the nm23 gene, since mutational analysis in 60 tumours by means of single-strand conformational polymorphism and direct sequencing disclosed only one mutation, which was located outside the open reading frame. Our results seem to indicate that nm23 expression is associated with a significantly worse prognosis in early-stage, well-differentiated epithelial ovarian carcinoma, a finding with important clinical implications, considering that many patients with ovarian cancers showing these features do not undergo any further treatment beyond surgical staging. If confirmed, they could help in tailoring the treatment of these patients in the future.

Expression of the mismatch repair protein hMSH2 in carcinoma in situ and invasive cancer of the breast.

BACKGROUND: Dysregulations in the mechanism of DNA-repair are contributed to tumorgenesis and tumorprogression in human cancer. The mismatch repair gene hMSH2 encodes a protein, which recognizes and binds to mismatch-sequences of the DNA. METHODS: Using immunohistochemical techniques hMSH2 expression was analyzed in invasive cancer (n = 85) and in situ carcinoma (n = 34) of the breast. RESULTS: The percentage of hMSH2 positive cases was significantly (p = 0.0001) decreased in invasive cancer as compared to in situ carcinomas. There was an association of hMSH2 expression with parameters of unfavorable prognosis, such as lymph node involvement (p = 0.03), higher degree of malignancy (p = 0.05) and higher proliferative activity (p = 0.05). CONCLUSIONS: During development from in situ to invasive cancer of the breast, hMSH2 expression seems to be downregulated. However, in invasive cancer, hMSH2 expression seems to be associated with tumor progression. This could be explained by the fact that enhanced proliferation of tumor cells results in increased mistakes within DNA replication procedures.

Long term results of definitive radiotherapy for cervical carcinoma using four applications of high dose rate afterloading.

BACKGROUND: In definitive radiotherapy for cervical carcinoma, combined modality treatment using external beam radiotherapy and brachytherapy is standard. Although the optimal number of afterloading applications is controversial, the majority of authors recommend three applications. METHODS: In this study, the authors investigated the use of 4 applications with iridium-192 afterloading with a dose of 7.5 grays (Gy). Standardized radiotherapy doses were adapted to the individual tumor anatomy using a prospective schedule. RESULTS: In the 73 study patients, actuarial and tumor-related 5-year survival rates by T classification were: T1b: 30% (100% cause specific survival); T2a: 55% (76% cause specific survival); T2b: 50% (60% cause specific survival); T3a: 50% (67% cause specific survival); T3b: 39% (50% cause specific survival); and T4a: 40% (40% cause specific survival). Morbidity, graded according to the National Cancer Institute's Common Toxicity Criteria (CTC) were low: CTC Grade 1: 7 patients (7.6%); CTC Grade 2: 7 patients (7.6%); CTC Grade 3: 1 patient (1.4%); and CTC Grade 4: 1 patient (1.4%). In a multivariate analysis, the T classification was the only significant independent prognostic factor for actuarial survival, tumor related (cause specific) survival, local tumor control and freedom of metastatic disease. The number of afterloading applications was an independent prognostic factor for local tumor control. CONCLUSIONS: Based on the long term results of the current study, external beam radiotherapy combined with 4 afterloading high dose rate applications (total of 30 Gy) appears to be clinically feasible and results in satisfactory survival rates and few side effects.

[Efficiency, safety and tolerability of recombinant human interleukin-3 (rhIL-3) as supportive therapy accompanying dose-intensive carboplatin containing chemotherapy in ovarian cancer with special regard to thrombocytopenia]. / Effizienz, Sicherheit und Verträglichkeit von rekombinantem humanen Interleukin-3 (rhIL-3) als supportive Therapie begleitend zur dosisintensivierten Carboplatin-haltigen Chemotherapie bei Patientinnen mit Ovarialkarzinom unter besonderer Berücksichtigung der Thrombozytopenie.

OBJECTIVE: In a prospective, randomized, placebo-controlled double-blind trial we evaluated to what extent a dose-intensification of adjuvant chemotherapy is possible with the help of Interleukin-3 (rhIL-3). MATERIAL AND METHODS: Following initial surgery, 12 patients with primary ovarian cancer have been treated with Carboplatin and Cyclophosphamide (dosage: AUC 4 according to Calvert). After randomisation, a group of 6 patients prophylacticly received rhIL-3 against myelosuppression on days 3-12 of the cycle, in contrast to a group of 6 patients who received placebo-injections. RESULTS: The patients treated with rhIL-3 showed less hematologic side-effects. Adherence to 4-weekly chemotherapy courses was more frequent in the rhIL-3-group (73% vs. 44%, p = 0.005). An intensification of the chemotherapy with 3-weekly courses did not succeed significantly. Observed side-effects of rhIL-3-therapy were headaches, fever, flu-like symptoms, rashes and blisters at the site of injection which excluded 2 of 6 patients from the study. CONCLUSIONS: Supportive rhIL-3 to adjuvant Carboplatin-based chemotherapy enables a better keeping of 4-weekly courses in contrast to the placebo-group due to faster recovery of hematologic parameters. Due to the side-effects, of IL-3, this cytokine cannot be recommended for routine clinical use.

Immunohistochemical detection of HSP60-expression in human ovarian cancer. Correlation with survival in a series of 247 patients.

PURPOSE: In a previous pilot study, HSP60 expression at the transcriptional (mRNA) level was shown to be a negative prognostic factor in ovarian cancer. The aim of this study was to determine HSP60-expression by means of immunohistochemistry and to correlate the results with survival in a large series of ovarian carcinoma patients with a closed follow-up. MATERIALS AND METHODS: Slides from routinely processed, paraffin-embedded tumor blocks belonging to 247 patients with epithelial ovarian carcinoma were studied for the overexpression of HSP60 using the Lk2 monoclonal antibody and the strepatvidin-biotin-peroxidase technique. HSP60-expression was correlated with overall survival by means of life-table analysis and the Kaplan-Meier method. RESULTS: 47 tumors (19%) expressed HSP60. Of them, 12/29 (41.4% positivity) were stage I tumors, whereas only 35 out of the remaining 218 tumors in more advanced surgical stage (16.1%) showed HSP60 staining. This difference was statistically significant (Fisher s exact test; p = 0.004). Even when stratifying stage for stage, the difference between groups still remained statistically significant (Chi square test; p = 0.0095). The survival curve analysis showed a significant difference in favor of those tumors expressing HSP60 (median survival 28 vs. 37 months; log-rank test, p = 0.02). CONCLUSION: Immunohistochemical detection of HSP60-expression in human epithelial ovarian carcinoma is significantly more frequent in tumors from patients with initial stages of the disease. Therefore, HSP60-expression determined by this method is associated with a significantly better prognosis.

Effects of paclitaxel in combination with radiation on human head and neck cancer cells (ZMK-1), cervical squamous cell carcinoma (CaSki), and breast adenocarcinoma cells (MCF-7).

BACKGROUND AND PURPOSE: The anticancer drug paclitaxel, a natural product from Taxus brevifolia, is a microtubule-stabilising agent, which has been shown to block different cells in the G2/M phase of the cell cycle and so modulate their radioresponsiveness. We investigated the radiosensitizing potential of paclitaxel in human head and neck cancer cells (ZMK-1), in cervical squamous cell carcinoma cells (CaSki) and in breast adenocarcinoma cells (MCF-7). METHODS: ZMK-1 cells were incubated with paclitaxel for 3, 9, or 24 h before irradiation. ZMK-1-, CaSki- and MCF-7 cells were incubated with paclitaxel for 24 h after irradiation. The paclitaxel concentration (70 nM, 7 nM, 0.7 nM) was chosen to obtain equivalent toxicity at the different incubation times (3 h, 9 h, 24 h respectively). Radiation doses were from 0 to 8 Gy. Cell survival was measured by a standard clonogenic assay after a 9-day incubation. Flow cytometry was used to measure the capacity of paclitaxel to cause accumulation of cells in the G2/M phase of the cell cycle. RESULTS: Paclitaxel alone was cytotoxic in a time- and concentration-dependent manner. Up to 36% of the ZMK-1 cells accumulated in G2/M after treatment for 24-36 h. If the cells were incubated with paclitaxel before irradiation the isoeffect enhancement ratios for ZMK-1 cells, determined at the 37% survival level, were 0.81, 1.48 and 1.15 for 3-h, 9-h, and 24-h pre-incubations respectively. For a paclitaxel incubation of 24 h after irradiation, the isoeffect enhancement ratios, determined at the 37% survival level, were 0.72, 0.76 and 1.2 for the ZMK-1. CaSki, and MCF-7 cells respectively. CONCLUSION: In the three cell lines no radiosensitizing effect of paclitaxel could be demonstrated unambiguously. The use of asynchronized cells or the support of cellular repair mechanisms while the cells are blocked in G2/M could partly explain the results.

Docetaxel is effective in the treatment of metastatic endometrial cancer.

BACKGROUND: Systemic treatment of endometrial carcinoma with distant metastases is currently performed, inter alia, with anthracyclines, platinum, paclitaxel, if osfamid or progestins. This is the first report presenting experience in treatment of metastatic endometrial carcinoma with docetaxel. CASE REPORT: A 69-year-old women with adenocarcinoma of the endometrium was treated with primary combined radiotherapy. Two years later disseminated bilateral pulmonary metastases were detected and the patient was submitted to chemotherapy with epirubicin. After three cycles of chemotherapy with epirubicin examinations revealed metastatic progression. Thus, chemotherapy was changed to docetaxel. RESULTS: After three cycles of chemotherapy with docetaxel examinations revealed remission of the described pulmonary metastases more than 50%. A further three cycles of chemotherapy with docetaxel lead to continuing shrinkage of the detectable metastases to less than 25% of the original size. Because of various side effects, like increasing fatigue and asthenia, uncomfortable acral paresthesia and allergic skin reactions, the patient refused to continue chemotherapy. CONCLUSION: We conclude that docetaxel may be an active agent in patients with metastatic endometrial cancer, but care should be taken to minimize side-effects.

Expression of the p53 tumour suppressor gene as a prognostic marker in platinum-treated patients with ovarian cancer.

Drug resistance is one of the most important clinical problems in the treatment of ovarian cancer. This study was designed to determine whether expression of p53 could be used as a marker for predicting the response to chemotherapy of ovarian cancer. Tissue blocks were obtained from 187 patients with diagnosed untreated ovarian cancer. Paraffin sections from the primaries were immunohistochemically analysed for p53 expression. All patients underwent platinum-based chemotherapy after surgery. We analysed whether the number of chemotherapy cycles was related to survival in women with p53 positive and p53 negative ovarian cancer. 27/187 cases were p53 positive. Expression of p53 was associated with other factors of unfavourable prognosis. Patients with p53 positive tumours had a significantly worse prognosis compared with patients with p53 negative tumours (P = 0.037). There was a statistically significant dose-response effect of platinum-based chemotherapy in patients with p53 negative tumours, which could not be seen in patients with p53 positive tumours (P = 0.01 versus P = 0.553). This could also be observed in patients with residual tumour after surgery (P = 0.0001 versus P = 0.8866). Expression of p53 may be an additional useful marker in predicting response to chemotherapy. Thus, it is possible to identify a subgroup of patients who may benefit from alternative therapy regimens.

Randomized trial of recombinant human interleukin-3 versus placebo in prevention of bone marrow depression during first-line chemotherapy for ovarian carcinoma.

PURPOSE: To determine whether recombinant human interleukin-3 (rhIL-3) reduces bone marrow depression and improves chemotherapeutic schedule adherence in ovarian cancer patients receiving first-line combination chemotherapy. PATIENTS AND METHODS: In a randomized multicenter study, 185 patients received carboplatin (dose based on projected area under the concentration-time curve [AUC]=4) and cyclophosphamide (750 mg/m2) day 1, every 3 weeks for six cycles. Patients were randomized to receive rhIL-3 (5 microg/kg) or placebo once daily subcutaneously on days 3 to 12. RESULTS: Adherence to chemotherapeutic regimen, mean chemotherapy cycle length, tumor response rate, and median survival at 24 months did not differ between groups. The number of side effects-primarily allergic reactions, flu-like symptoms and fever-were higher in the rhIL-3 group, which resulted in 21 discontinuations compared with one in the placebo group. Compared with placebo, the rhIL-3 group had higher platelet counts day 1 of cycles 2 to 6. The number of patients with World Health Organization (WHO) grade IV thrombocytopenia or number of platelet transfusions did not differ. Leukocyte counts differed only in cycles 1 and 2 between groups. The leukocyte nadir occurred earlier in the rhIL-3 (day 12) than in the placebo group (day 15, P=.006). Leukocytes and neutrophils were only higher in the rhIL-3 group day 1 of cycle 2. In cycles 4 and 5, more patients with WHO grade IV neutropenia received rhIL-3 (P < .005). Eosinophil counts were higher day 1 of cycles 2 to 6 in the rhIL-3 group (P < .0001). CONCLUSION: rhIL-3 had stimulatory hematopoietic effects. This did not result either in reduction of platelet transfusions or in improvement of chemotherapeutic schedule adherence. There were more side effects in the rhIL-3 group than in the placebo group. rhIL-3 at 5 microg/kg/d is, therefore, not of clinical benefit in this chemotherapeutic regimen.

Breast preserving surgery decision making.

Mammography, and in special cases MRT, allow the detection of DCIS and microcarcinomas. Breast preserving surgery needs intraoperative care for tumor free margins. Decision making under favourable and unfavourable conditions is discussed. Tumor grading is important with respect to locoregional recurrences. Improvements in breast cancer diagnosis are discussed in a separate paper in the same volume. The significance of c-erbB2 in pT1N0M0 stage has been determined in 472 cases. Within the c-erbB family, c-erbB2 has highest significance. p53 should also be evaluated with respect to tumor progress. In a few cases of malignant cystosarcoma phyllodes, p53 reaction was found in epithelial and mesenchymal cell systems. These results correspond to the results of Domagala et al (90) which show that vimentin positivity correlates with high proliferation, a high degree of malignancy and c-erbB2 positivity. Finally, the significance of angiogenesis with respect to the ineffective knot-formation for tumor cell transport and detachment of epithelia with apoptosis are discussed. The significance of proteolytic activity of cancer according to the results of Schmitt et al (89) is included in the discussion. Biochemical analysis seems to be much more effective for prediction of metastatic process as compared with immunohistochemical evaluations.

Early intensive and myeloablative adjuvant chemotherapy in women with high-risk breast cancer.

BACKGROUND: Women with breast cancer and > 10 positive lymph nodes have an unfavorable prognosis. The optimal combination and intensity of adjuvant chemotherapy is uncertain. Between July 1994 and December 1996 we treated 19 patients with early intensive followed by high-dose chemotherapy and autologous peripheral blood stem cell transplantation. PATIENTS AND METHODS: Patients were initially diagnosed with breast cancer and multiple positive lymph nodes. Induction chemotherapy consisted of two courses VP16, ifosphamide, cisplatin and epirubicin (VIPE) and one course of mitoxantrone, cyclophosphamide and thiotepa (MCT). Peripheral blood stem cells were mobilized after the first or second course of VIPE and retransfused two days after high dose chemotherapy. RESULTS: Stem cells were successfully collected in all patients. Major toxicities (WHO grade III and IV) were neutropenia, thrombocytopenia, alopecia, nausea, infections and mucositis. Hematopoietic recovery occurred in all patients with a median of 10 days for leukocytes and 13 days for platelets. No patient died of therapy-induced complications. The median observation time is 24 months. Two patients have relapsed, one with locoregional disease. The projected rate of patients with disease-free survival after three years is 88%. CONCLUSIONS: Early intensive and myeloablative chemotherapy followed by peripheral blood stem cell transplantation is a highly efficient and feasible protocol for high risk patients with breast cancer.