Angiogenic factors in relation to clinical effect in a phase II trial of weekly paclitaxel.

BACKGROUND: Several anticancer agents including paclitaxel have an inhibitory effect on angiogenesis. AIMS: To compare the overall response rate and time to progression with changes in circulating angiogenic factors during palliative treatment with weekly paclitaxel. MATERIAL AND METHODS: Patients with metastatic BC, ECOG 0-2, received weekly paclitaxel, concomitant with trastuzumab if HER2+ BC (n = 7). Circulating vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were determined at base-line and before start of new course. RESULTS: Fifty-five of 63 included patients were evaluable. The overall response rate including stable disease ≥24 weeks (CR + PD + SD) was obtained in 25 of the evaluable patients (45%). The median time to progression (TTP) was 5.3 months and overall survival (OS) 16.7 months. Patients with triple negative breast cancer (TNBC) showed a trend towards higher base-line VEGF compared with hormone receptor positive or HER2+ tumours and had shorter TTP. Significant differences in VEGF and bFGF levels at 12 weeks were found between patients with longer versus shorter TTP (VEGF: p = 0.046, bFGF: p = 0.005) and between patients gaining versus lacking clinical benefit (VEGF: p = 0.05, bFGF: p = 0.02). CONCLUSIONS: The clinical utility of circulating VEGF may be a useful tool for monitoring treatment efficacy.

Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden.

BACKGROUND: While treatment for breast cancer has been refined and overall survival has improved, there is concern that the incidence of brain metastases has increased. METHODS: We identified patients in Sweden with incident breast cancer 1998-2006 in the National Cancer Register, and matched these to the National Patient Register to obtain information on hospital admissions for distant metastases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed with Cox regression as estimates of relative risk. RESULTS: Among 50 528 breast cancer patients, 696 (1.4%) were admitted with brain metastases during median 3.5 years of follow-up. Admissions for other metastases were found in 3470 (6.9%) patients. Compared with the period 1998-2000, patients diagnosed with breast cancer 2004-2006 were at a 44% increased risk of being admitted with brain metastases (HR 1.44, 95% CI 1.13-1.85). CONCLUSION: The incidence of admissions with brain metastases in breast cancer patients was increasing in the mid-2000s in Sweden. These findings support a true increase in incidence of brain metastases among breast cancer patients.

Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial.

Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin(®)) and paclitaxel (Taxol(®)) alone (ET) or in combination with capecitabine (Xeloda(®), TEX). Starting doses for ET were epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2), and for TEX epirubicin 75 mg/m(2), paclitaxel 155 mg/m(2), and capecitabine 825 mg/m(2) BID for 14 days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8 months for patients treated with ET, and 12.4 months for those treated with TEX (HR 0.84, 95% CI 0.65-1.07, P = 0.16); median OS was 26.0 months for women in the ET versus 29.7 months in the TEX arm (HR 0.84, 95% CI 0.63-1.11, P = 0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (χ(2) 3.66, P = 0.16). TTF was significantly longer for patients treated with TEX, 6.0 months, versus 5.2 months following ET (HR 0.73, 95% CI 0.58-0.93, P = 0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.

Immediate reconstruction with implants in women with invasive breast cancer does not affect oncological safety in a matched cohort study.

Physicians are still concerned about the oncological safety regarding immediate breast reconstruction (IBR) in breast cancer patients. This study aimed to evaluate possible differences between local, regional, and distant recurrences between women having implant-based reconstruction versus women operated with mastectomy alone. Secondary aims were to evaluate time to oncological treatment as well as disease-free and breast-cancer-specific survival. In a retrospective cohort designed study, 300 reconstructed patients with invasive breast cancer were matched with 300 patients from the population-based Regional Breast Cancer Register of the Stockholm-Gotland health-care region operated with mastectomy alone. They were matched for age, tumor size, nodal stage, and year of operation. Also included were patients treated with neoadjuvant chemotherapy and postoperative radiotherapy. The median follow-up for both the groups was 11.5 years (range 2-20). There were no significant differences in the local recurrence rate, 8.2% in the IBR group and 9.0% in the control group or in the regional recurrence rate, 8.2% versus 9.7%. Distant metastases occurred more frequently in the control group (27.1%) when compared to the IBR group (20.3%). There were no significant differences in time to treatment or in complications rate. Breast cancer mortality was 17% for the IBR group and 23% in the control group during follow-up. This long-term follow-up survey with a well-matched control group demonstrates that IBR with implants is safe to offer patients with invasive breast cancer without any negative effect on the oncological safety.

Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy.

BACKGROUND: The purpose was to investigate adjuvant marrow-supportive high-dose chemotherapy compared with an equitoxicity-tailored comparator arm. PATIENTS AND METHODS: Five hundred and twenty-five women below the age of 60 years with operated high-risk primary breast cancer were randomised to nine cycles of granulocyte colony-stimulating factor supported and individually tailored FEC (5-fluorouracil, epirubicin, cyclophosphamide), (n = 251) or standard FEC followed by marrow-supported high-dose therapy with CTCb (cyclophosphamide, thiotepa, carboplatin) therapy (n = 274), followed by locoregional radiotherapy and tamoxifen for 5 years. RESULTS: There were 104 breast cancer relapses in the tailored FEC group versus 139 in the CTCb group (double triangular method by Whitehead, P = 0.046), with a median follow-up of all included patients of 60.8 months. The event-free survival demonstrated 121 and 150 events in the tailored FEC- and CTCb group, respectively [P = 0.074, hazard ratio (HR) 0.804, 95% confidence interval (CI) 0.633-1.022]. Ten patients in the tailored FEC regimen developed acute myeloid leukaemia (AML)/myelodysplasia (MDS). One hundred deaths occurred in the tailored FEC group and 121 in the CTCb group (P = 0.287, HR 0.866, 95% CI 0.665-1.129). CONCLUSION: The update of this study shows an improved outcome linked to the tailored FEC treatment in relation to breast cancer relapse, but also an increased incidence of AML/MDS.

Model describing the relationship between pharmacokinetics and hematologic toxicity of the epirubicin-docetaxel regimen in breast cancer patients.

PURPOSE: The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients. PATIENTS AND METHODS: Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m(2). Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m(2)) or reduced (minimum, 40/50 mg/m(2)). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment. RESULTS: In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data. CONCLUSION: The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.

Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study.

BACKGROUND: Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. METHODS: 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. FINDINGS: At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. INTERPRETATION: Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.

Acute quadriplegic myopathy following autologous peripheral blood stem cell transplantation for breast cancer.

Autologous peripheral blood stem cell transplantation (APSCT) is increasingly used in the treatment of breast cancer. We report a patient who experienced septic shock, and after treatment with antibiotics, high-dose corticosteroids and mechanical ventilation due to respiratory insufficiency, developed quadriplegia. Electroneurophysiological examination, as well as a muscle biopsy, showed a typical picture of acute quadriplegic myopathy with loss of thick filament proteins. This is, to the best of our knowledge, the first reported case of this complication following APSCT.

Cost-effectiveness analysis of pegylated-liposomal doxorubicin and liposomal daunorubicin treatments in patients with Kaposi's sarcoma.

Economic evaluations of new AIDS treatment drugs are important. For physicians treating patients with Kaposi's sarcoma, these issues are especially meaningful since cancer treatment costs for this group of patients are high. Kaposi's sarcoma is the most frequently occurring neoplasm in AIDS patients, affecting about 15% of this population. In our study, a retrospective economic evaluation has been made based on data from two randomized phase III clinical studies of severely immune-compromised HIV-infected individuals and which compares liposomal doxorubicin with liposomal daunorubicin. We have estimated the cost and cost effectiveness of the two drugs. The costs per complete or partial response are USS 18340 for daunorubicin and USS 8871 for doxorubicin. The incremental cost per additional responder by using liposomal doxorubicin instead of liposomal daunorubicin is USS 1910. Sensitivity analysis shows that these results hold over a wide range of assumptions.

Followup after 11 years--update of mortality results in the Stockholm mammographic screening trial.

Results from several randomised mammography screening trials have shown that it is possible to reduce mortality in breast cancer by mammographic screening at least for women above 50 years of age. The purpose of this article is to present data on mortality in breast cancer in study and control groups of the Stockholm trial after 11 years of followup, to analyse which age group benefits most from screening. In March 1981, 40,318 women in Stockholm, aged 40 through 64 years, entered a randomized trial of breast cancer screening by single view mammography alone, versus no intervention in a control group of 20,000 women. Two screening rounds were performed and the attendance rate was over 80% in the two rounds. During 1986 the control group was invited once to screening. Totally 428 and 217 cases of breast cancer were diagnosed in the study and control groups respectively. After a mean follow-up of 11.4 years a nonsignificant mortality reduction of 26% was observed for the whole study group, with a relative risk (RR) of death in breast cancer of 0.74 (CI(confidence interval) = 0.5-1.1). For women aged 50-64 years a significant 38% mortality reduction was observed with a RR of 0.62 (CI = 0.38-1.0). For women aged 40-49 years no effect on mortality was found, with a RR of death in breast cancer of 1.08 (CI = 0.54-2.17). The breakpoint for benefit in this study seemed to be at 50 years of age when 5-year age groups were analysed, but this tendency is uncertain because of the low statistical power in the analysis of the younger age groups. Long screening intervals, the use of single-view mammography, and the fact that more than 50% of the women in age group 40-49 years were still below 50 years of age when the study was closed, were all facts that could have influenced the results in age group 40-49 years. Larger studies are needed to answer the question whether mammographic screening can be successful in younger age groups.

The Stockholm Mammographic Screening Trial: Risks and benefits in age group 40-49 years.

This article presents updated data on breast cancer mortality for women under age 50 from the Stockholm Mammographic Screening Trial, as well as a review of some side effects associated with screening in this age group. Approximately 40,000 women aged 40-64 (14,842 aged 40-49 years) were randomized to a trial of breast cancer screening by single-view mammography alone; 20,000 women (7,103 aged 10-49) were randomized to a control group. In the 40-49 age group, 24 and 12 breast cancer deaths were found in the study and control groups, respectively, after 11.4 years of follow-up. The relative risk of breast cancer death in screened to nonscreened women was 1.08 (95% confidence interval: 0.54-2.17). The rates of benign surgical biopsies, false positives, and follow-up costs were higher among women under age 50. Large overview studies are needed, however, to determine whether mammography screening consistently reduces mortality in women 40-49 years of age. Side effects such as costs and public aspects of mammography screening in this age group also warrant further study.

Neglected aspects of false positive findings of mammography in breast cancer screening: analysis of false positive cases from the Stockholm trial.

OBJECTIVES: To examine the implications of false positive results of mammography in terms of the time lag from screening and complete mammography to the point when women with false positive results are declared free of cancer; the extra examinations, biopsies, and check ups required; and the cost of these extra procedures. DESIGN: Review of women with false positive results from the Stockholm mammography screening trial. SETTING: Department of Oncology, South Hospital, Stockholm. SUBJECTS: 352 and 150 women with false positive results of mammography from the first and second screening rounds of the Stockholm trial. MAIN OUTCOME MEASURES: Extra examinations and investigations required and the cost of these procedures. RESULTS: The 352 women from the first screening round made 1112 visits to the physician and had 397 fine needle aspiration biopsies, 187 mammograms, and 90 surgical biopsies before being declared free of cancer. After six months 64% of the women (219/342) were declared cancer free. The 150 women in the second round made 427 visits to the physician and had 145 fine needle aspiration biopsies, 70 mammograms, and 28 surgical biopsies, and after six months 73% (107/147) were declared cancer free. The follow up costs of the false positive screening results were Kr2.54m (250,000 pounds) in the first round and Kr0.85m (84,000 pounds) in the second round. Women under 50 accounted for about 41% of these costs. CONCLUSIONS: The examinations and investigation carried out after false positive mammography --especially in women under 50--and the cost of these procedures are a neglected but substantial problem.

Nonattendance in the Stockholm mammography screening trial: relative mortality and reasons for nonattendance.

The first objective of this study was to analyze the survival rate in a group of 69 breast cancers detected among nonattenders in a randomized mammographic screening trial in relation to 142 clinically detected cancers in a nonscreened control population. By analyzing the cancers of the nonattenders we identified two subgroups, one (A) had actively avoided mammography, had cancers in more advanced stages on diagnosis, and had significantly higher mortality from breast cancer than the control group (p = 0.003). The second subgroup (B) had mammography done outside the screening program. This subgroup had a nonsignificant, slightly better survival (p = 0.19) compared to the control group. Concerning stage the cancers in group B were similar to the cancers by the screening program. The second objective was to analyze women's reasons for nonattendance in the screening program. We interviewed 200 randomly selected nonattenders; 33% stated that they never could imaging having mammography (definite nonattenders), 29.5% that they for various reasons had missed the mammography but could imagine having it next time (possible future attenders), and 32% had been examined outside the program. Reasons for nonattendance included disinterest, medical problems, and fear of X-rays. From this interview investigation we believe that the subgroup of definite nonattenders (33%) is difficult to influence. The second subgroup classified as possible future attenders (29.5%) we believe can be influenced by more information and a new opportunity to receive mammography, i.e., a reminder letter. The third subgroup, those examined outside the screening program (32%) were aware of the benefit of mammography, taking action on their own.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-view screening mammography: psychological, endocrine and immunological effects of recalling for a complete three-view examination.

To investigate influences of a recall due to inconclusive findings on screening mammography, 45 women were examined with psychological ('mood' and 'coping'), endocrine and immunological tests immediately after complete mammography (first interview), 2-3 days after the initial screening mammography, and 3 weeks after the women had been informed of normal findings (second interview). The mood score in the first interview was significantly lower than in the second. No differences were found in the endocrine and immunological tests. The recall for complete mammography provoked a significant short-term emotional reaction not reflected in changes in the endocrine and immune functions.

The general mammography screening program in Stockholm. Organisation and first-round results.

This presentation describes the organization and first-round results of the Stockholm mass mammography screening program, and discusses ways of checking the quality of an ongoing screening program. The Stockholm mammography screening program started in 1989 at five independent screening units, and comprises more than 150,000 women aged 50 to 69 years. The first round was completed in June 1991. Compliance during the studied period was 70.6%, and the recall rate was 3.0% of the attending women. Breast cancer was diagnosed in 676 women, of whom 90 (13.3%) had a cancer in situ. The cancer prevalence rate was thus 6.3 cancers per 1,000 screened women. Surgery was performed on 925 women, of whom 249 had benign lesions, giving a benign/malignant ratio of 0.37 to 1. Fifty-two per cent of the cancer patients were operated with breast conserving surgery. The median size of the invasive cancers was 12 mm; almost 80% were node-negative. Experience from the first two years of this mass mammography screening program shows that it meets the major quality requirements. One of the main future goals is to maintain the high quality of the program. Another important goal is a further increase in compliance.

Treatment failure and dietary habits in women with breast cancer.

BACKGROUND: Epidemiological and experimental evidence suggests that breast cancer risk can be reduced by dietary measures. Study of the relationships between dietary habits and prognosis in patients with breast cancer is essential to the design of diet intervention trials. PURPOSE: Our purpose was to determine whether dietary habits are associated with disease-free survival in patients with breast cancer who have undergone treatment. METHODS: We interviewed 240 women about their dietary histories. These women were 50-65 years old and had pathological stage I-II breast cancer with subsequent follow-up for 4 years; 209 of these women were postmenopausal. Differences in dietary variables between groups of patients were analyzed with bivariate and multivariate statistical methods. RESULTS: Cancers were classified as estrogen receptor (ER) rich (> or = 0.10 fmol/micrograms of DNA) in 149 patients and as ER poor (< 0.10 fmol/micrograms of DNA) in 71 patients. Fifty-two patients had treatment failure during follow-up. The 30 patients with ER-rich tumors who had treatment failure reported higher intakes of total fat, saturated fatty acids, and polyunsaturated fatty acids than did the 119 patients with ER-rich tumors who did not have treatment failure. The multiple-odds ratio (OR) for treatment failure in these women was 1.08 for each 1% increment in percentage of total energy (E%) from total fat. For treatment failure within the first 2 years, the OR was 1.19 for each 1-mg increase in vitamin E intake per 10 megajoules of energy. In women with treatment failure 2-4 years after diagnosis, ORs were 1.13 and 1.23 for each E% increment in total fat or saturated fatty acids, respectively. No association between dietary habits and treatment failure was found for women with ER-poor cancers. There was a tendency to a dose-response relationship (in quartiles) between intake of saturated fatty acids and disease-free survival, but the observed differences were not statistically significant. CONCLUSIONS: Dietary habits at the time of diagnosis may affect prognosis, at least for patients with ER-rich breast cancers. Dietary fat may have an effect on growth or spread of breast cancer, both of which may vary according to type of fat. Total fat and saturated fatty acids were the dietary parameters most strongly associated with risk for treatment failure. IMPLICATIONS: Dietary intervention might serve as an adjuvant treatment to improve breast cancer prognosis.

Randomized study of mammography screening--preliminary report on mortality in the Stockholm trial.

In March 1981, 40,318 women in Stockholm, aged 40-64, entered a randomized trial of breast cancer screening by single-view mammography alone versus no intervention in a control group of 20,000 women. The attendance rate during the first screening round was 81 per cent and the cancer detection rate was 4.0 per 1000 women. The detection the rate fell to 3.1 per 1000 in the second round, which was completed in October 1985. During 1986 the controlled design of the study was broken and the control women were invited once to screening which was completed the same year. A total of 428 cases of breast cancer were thus diagnosed in the study group and 439 in the adjusted control group. After a mean follow-up of 7.4 years the number of breast cancer deaths in the study and control groups was 39 and 30 respectively. The relative risk of breast cancer death (screening versus control) was 0.71 (95 per cent confidence interval: 0.4-1.2). Among women older than 50 years at entry the relative risk was 0.57 (95 percent confidence interval: 0.3-1.1). Cancer deaths among women under 50 were few and perhaps because of this no mortality reduction was seen in this age group. The estimate of mortality reduction lies between the results from two earlier Swedish randomized controlled trials.