Five-year follow-up results of aerobic and impact training on bone mineral density in early breast cancer patients.

A 12-month exercise program reversibly prevented hip bone loss in premenopausal women with early breast cancer. The bone-protective effect was maintained for 2 years after the end of the program but was lost thereafter. PURPOSE: Breast cancer survivors are at an increased risk for osteoporosis and fracture. This 5-year follow-up of a randomized impact exercise intervention trial evaluated the maintenance of training effects on bone among breast cancer patients. METHODS: Five hundred seventy-three early breast cancer patients aged 35-68 years and treated with adjuvant therapy were allocated into a 12-month exercise program or a control group. Four hundred forty-four patients (77%) were included in the 5-year analysis. The exercise intervention comprised weekly supervised step aerobics, circuit exercises, and home training. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry. Physical activity was estimated in metabolic equivalent (MET) hours per week and physical performance assessed by 2-km walking and figure-8 running tests. RESULTS: In premenopausal patients, the 12-month exercise program maintained femoral neck (FN) and total hip (TH) aBMD for 3 years, but the protective effect was lost thereafter. The mean FN aBMD change in the exercise and control groups was - 0.2% and - 1.5% 1 year, - 1.1% and - 2.1% 3 years and - 3.3% versus - 2.4% 5 years after the beginning of the intervention, respectively. Lumbar spine (LS) bone loss was not prevented in premenopausal women and no training effects on aBMD were seen in postmenopausal women. The main confounding element of the study was the unexpected rise in physical activity among patients in the control group. The physical performance improved among premenopausal women in the exercise group compared with the controls. CONCLUSION: The 12-month exercise program prevented FN and TH bone loss in premenopausal breast cancer patients for 3 years. The bone-protective effect was reversible and lost thereafter.

A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1).

STUDY AIM: Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). METHODS: Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0-2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75-90 mg/m2, C 900-1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3-4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). RESULTS: The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3-4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67-1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57-1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. CONCLUSIONS: The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.

Effect of exercise on bone structural traits, physical performance and body composition in breast cancer patients--a 12-month RCT.

In this 12-month RCT, we examined whether aerobic impact exercise training (3x/week) could facilitate breast cancer survivors' recovery by enhancing their bone structural strength, physical performance and body composition. After the adjuvant chemo- and/ or radiotherapy, 86 patients were randomly assigned into the training or control group. Structural bone traits were assessed with pQCT at the tibia and with DXA at the femoral neck. Agility (figure-8 running), jump force and power (force platform), grip strength and cardiovascular fitness (2-km walk test) were also assessed. Training effects on outcome variables were estimated by two-way factorial ANCOVA using the study group and menopausal status as fixed factors. Bone structural strength was better maintained among the trainees. At the femoral neck, there was a small but significant 2% training effect in the bone mass distribution (p=0.05). At the tibial diaphysis, slight 1% to 2% training effects (p=0.03) in total cross-sectional area and bone structural strength were observed (p=0.03) among the postmenopausal trainees. Also, 3% to 4% training effects were observed in the figure-8 running time (p=0.03) and grip strength (p=0.01). In conclusion, vigorous aerobic impact exercise training has potential to maintain bone structural strength and improve physical performance among breast cancer survivors.

Effect of supervised and home exercise training on bone mineral density among breast cancer patients. A 12-month randomised controlled trial.

UNLABELLED: The ability of combined step aerobic- and circuit-training to prevent bone loss after breast cancer treatments was related to skeletal site and patients' menopausal status. Among premenopausal breast cancer survivors, a 12-month exercise intervention completely prevented bone loss at the femoral neck, whereas no exercise effect was seen at lumbar spine or at neither site in postmenopausal women. INTRODUCTION: The primary objective of this randomised clinical trial was to determine the preventive effect of supervised weight-bearing jumping exercises and circuit training on bone loss among breast cancer patients. METHODS: Of 573 breast cancer survivors aged 35-68 years randomly allocated into exercise or control group after adjuvant treatments, 498 (87%) were included in the final analysis. The 12-month exercise intervention comprised weekly supervised step aerobic- and circuit-exercises and similar home training. Bone mineral density (BMD) at lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry. Physical performance was assessed by 2-km walking and figure-8 running tests, and the amount of physical activity was estimated in metabolic equivalent-hours/week. RESULTS: In premenopausal women, bone loss at the femoral neck was prevented by exercise, the mean BMD changes being -0.2% among the trainees vs. -1.4% among the controls (p = 0.01). Lumbar bone loss could not be prevented (-1.9% vs. -2.2%). In postmenopausal women, no significant exercise-effect on BMD was found either at the lumbar spine (-1.6% vs. -2.1%) or femoral neck (-1.1% vs. -1.1%). CONCLUSIONS: This 12-month aerobic jumping and circuit training intervention completely prevented femoral neck bone loss in premenopausal breast cancer patients, whereas no effect on BMD was seen in postmenopausal women.

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.

Three-year oral clodronate treatment does not impair mineralization of newly formed bone--a histomorphometric study.

Bisphosphonates have been used successfully in the treatment of malignant hypercalcemia and skeletal metastases. Recently, clodronate has been studied in adjuvant settings in primary breast cancer. However, long-term effect of adjuvant clodronate on bone histology has not been reported, whereas bone mineral density studies have been published. The aim of this study was to examine the effect and safety of long-term clodronate treatment on bone quality as measured by histomorphometric techniques from bone biopsies. A total of 299 patients with early stage breast cancer were randomized to receive adjuvant oral clodronate (1.6 g/day) or to a control group for 3 years. All patients had adjuvant treatment: premenopausal women had six cycles of chemotherapy and postmenopausal women had antiestrogen for 3 years. Trabecular bone quality was examined in transiliac bone biopsy specimens by using histomorphometric techniques in 28 clodronate treated and 35 control patients who were disease-free at 3 years and who allowed the biopsy specimen to be obtained. No statistically significant differences were found in the values of osteoid, mineral apposition rate, or mineralization lag time in bone biopsies between the clodronate and the control groups. Postmenopausal women who received two antiresorptive drugs, antiestrogen and clodronate, developed features of secondary hyperparathyroidism with increased eroded surface and osteoclast number. In premenopausal, women clodronate with adjuvant chemotherapy, which induced early menopause and rapid bone loss in most of the patients, seemed to conduct slight depression in bone formation. Three-year oral clodronate treatment does not impair mineralization of newly formed bone: however, clodronate with different adjuvant breast cancer treatments has a diverse impact on bone histomorphometry depending on the type of therapy.

Tamoxifen treatment reverses the adverse effects of chemotherapy-induced ovarian failure on serum lipids.

In all, 146 premenopausal women with early stage breast cancer were treated with adjuvant chemotherapy. In addition, 5-year tamoxifen treatment was started after chemotherapy to those 112 patients with hormone-receptor-positive tumours while those with hormone-receptor-negative tumours received no further therapy. The serum lipid levels were followed in both groups. The levels of serum total and low-density lipoprotein (LDL) cholesterol increased significantly after chemotherapy only in patients who developed ovarian dysfunction. Total cholesterol increased +9.5% and LDL cholesterol +16.6% in patients who developed amenorrhoea (P<0.00001 and 0.00001, respectively). The cholesterol levels did not change in patients who preserved regular menstruation after chemotherapy. After 6 months of tamoxifen therapy, the total cholesterol decreased -9.7% and the LDL cholesterol -16.7% from levels after the chemotherapy, while the cholesterol concentrations remained at increased levels in the control group (P=0.001 and P<0.0001, respectively). The high-density lipoprotein cholesterol levels did not change significantly in either tamoxifen or control group. The effects of tamoxifen treatment on serum lipids after chemotherapy have not been studied before. Our current study suggests that adjuvant tamoxifen therapy reverses the adverse effects of chemotherapy-induced ovarian failure on total and LDL cholesterol and even lowers their serum levels below the baseline.

C-erbB-2 expression does not predict response to docetaxel or sequential methotrexate and 5-fluorouracil in advanced breast cancer.

Breast cancer patients with c-erbB-2-positive tumours seem to benefit from anthracycline-based adjuvant chemotherapy. The predictive value of c-erbB-2 for taxane sensitivity is not yet clear. The purpose of this study was to assess whether c-erbB-2 expression is associated with clinical sensitivity to docetaxel (T) or sequential methotrexate and 5-fluorouracil (MF). A total of 283 patients with metastatic breast cancer were initially enrolled in a randomised multicentre trial comparing docetaxel with sequential MF in advanced breast cancer. Paraffin-embedded blocks of the primary tumour were available for 131 patients (46%). c-erbB-2 status was determined by immunohistochemistry using a polyclonal antibody to the c-erbB-2 protein. C-erbB-2 expression was scored in a semi-quantitative fashion using a 0 to 3+ scale. Staining scores 2+ or greater were considered positive. Response evaluation was performed according to World Health Organization (WHO) recommendations. Overall 54 (42%) patients had c-erbB-2-positive tumours. There was no association between treatment outcome and c-erbB-2 overexpression. The overall response rates (RR) (n=128) among c-erbB-2-negative and -positive patients were 35 and 44%, respectively (P=0.359). In the MF arm (n=62), the RR was somewhat higher in the c-erbB-2 overexpressors (33% versus 18%, P=0.18). In the docetaxel arm the RRs were very similar, regardless of the c-erbB-2 expression (53% versus 53%). While several studies have suggested a prognostic and putative predictive significance of c-erbB-2 overexpression in early breast cancer, the significance of c-erbB-2 expression as a predictive factor for response to various cytotoxic treatments in advanced breast cancer is still controversial. In this study, c-erbB-2 expression could not predict response to either MF or T. Thus, tumours over-expressing c-erbB-2 are not uniformly more sensitive to taxanes and c-erbB-2 expression cannot yet be applied clinically as a predictive factor for response in advanced breast cancer.

Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment.

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and -1.3% in the menstruating group and -7.5 and -10.4% in the amenorrhoeic group (P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and -0.3%, and -3.5 and -5.8% (P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine -3.0% compared with controls -7.4% at three years (P=0.003), but no significant difference was found in the femoral neck: -1.7% versus -2.8%, respectively (P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine -5.8% versus -9.7% (P=0.008) and femoral neck -3.5% versus -5.1% (P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

Effect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area.

Chemotherapy doses are sometimes reduced because of obesity in patients. This study examines the effect of parameters reflecting the body size, body weight and height, body mass index (BMI), and body surface area (BSA) on the depth of the blood leukocyte nadir in breast cancer patients receiving adjuvant chemotherapy, when drug dosing was based on the BSA. Three hundred and forty patients with node positive breast cancer without distant metastases were treated with 6 cycles of adjuvant postoperative CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and 5-fluorouracil 600 mg/m2 i.v. every 3 weeks). Patients within the highest BMI had the highest leukocyte nadir values (Spearman correlation coefficient 0.3, p < 0.001). A high body weight and a large BSA were also associated with high leukocyte nadirs. We conclude that when the blood leukocyte nadir is used as a surrogate marker for the drug effect, obese patients receiving intravenous CMF have higher leukocyte nadirs than the lean ones. Therefore, the drug doses should not be reduced because of obesity, and even when obese patients are treated according to the scheduled doses they may remain slightly underdosed.

The effect of clodronate and antioestrogens on bone loss associated with oestrogen withdrawal in postmenopausal women with breast cancer.

In this study we report bone mineral density (BMD) changes during clodronate and antioestrogen treatment in women with breast cancer having discontinued hormone replacement therapy (HRT) at the time of operation compared to women who had not used HRT immediately before the operation. 61 postmenopausal women with operable breast cancer were treated with the adjuvant antioestrogen tamoxifen 20 mg or toremifene 60 mg daily for 3 years. All patients were randomized to clodronate (1.6 g daily orally) or control groups for 3 years. 23 patients had recently (recent users) and 38 never or not for at least 1 year before operation used HRT (non-users). BMD of lumbar spine and femoral neck were measured before antiresorptive therapy (antioestrogens and clodronate) and at 1, 2, 3 and 5 years thereafter. All patients were disease-free at the time of BMD measurements. Patients who had recently used HRT had more significant bone loss as compared to HRT non-users at 3 years in lumbar spine - 3.0% vs. + 1.2% (P< 0.001), but not in femoral neck - 0.4% vs. + 1.7% (P = 0.27). Adding 3-year clodronate treatment to antioestrogen therapy improved BMD marginally at 3 years: lumbar spine + 1.0% vs. -1.7% (P = 0.01) and femoral neck + 2.4% vs. -0.4% (P = 0.12). This was also seen at 5 years of follow-up, 2 years after termination of the antiresorptive therapy: HRT recent users vs. HRT non-users in lumbar spine -6.5% vs. +0.5% (P< 0.0001) and in femoral neck -4.8% vs. -1.5% (P = 0.38); and clodronate vs. controls in lumbar spine -1.0% vs. -3.2% (P = 0.06) and in femoral neck -0.1% vs. -5.2% (P = 0.001, respectively). The type of endocrine therapy (tamoxifen and toremifene) had no significant influence on BMD changes. We conclude from this study that postmenopausal women who have recently discontinued HRT experience more rapid bone loss than HRT non-users. Neither 3-year antioestrogen therapy alone nor antioestrogen together with clodronate could totally prevent the bone loss related to HRT withdrawal in lumbar spine, even though clodronate seemed to retard it.

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.

Subclinical cardiotoxicity following adjuvant dose-escalated FEC, high-dose chemotherapy, or CMF in breast cancer.

We compared adjuvant chemotherapy-related myocardial damage by antimyosin scintigraphy in patients who received either nine cycles of FEC (fluorouracil, epirubicin and cyclophosphamide) where the doses of epirubicin and cyclophosphamide were escalated according to the leucocyte nadir (group I, n = 14), three cycles of FEC followed by high-dose chemotherapy with alkylating agents (CTCb) given with the support of peripheral blood stem cell transplantation (group II, n = 14), or six cycles of standard intravenous CMF (cyclophosphamide, methotrexate and fluorouracil; group III, n = 8). The cardiac uptake of In-111-antimyosin-Fab (R11D10) antibody was measured and the heart-to-lung ratio (HLR) calculated 8-36 months after the last dose of chemotherapy. Cardiac antimyosin antibody uptake was considerably higher among patients treated with nine cycles of dose-escalated FEC than among those who were treated with three cycles of FEC and high-dose CTCb (HLR, median 1.98; range 1.36-2.24 vs median 1.51; range 1.20-1.82; P < 0.001), or those treated with CMF (median 1.44; range 1.15-1.68; P < 0.001). The difference between groups II and III was not significant (P > 0.1). A linear association was found between the cumulative dose of epirubicin and the cardiac antimyosin uptake (P < 0.001). We conclude that subclinical cardiac damage caused by three cycles of conventional-dose FEC followed by one cycle of high-dose CTCb chemotherapy is small as compared with the damage caused by dose-escalated FEC.

Leucocyte nadir as a marker for chemotherapy efficacy in node-positive breast cancer treated with adjuvant CMF.

The purpose of this study was to examine the association between the leucocyte nadir and prognosis in breast cancer patients receiving adjuvant chemotherapy consisting of cyclophosphamide, methotrexate and fluorouracil (CMF). Three hundred and sixty-eight patients with node-positive breast cancer without distant metastases were treated with six cycles of adjuvant CMF. Some patients (n = 60) also received tamoxifen. All patients underwent surgery and received radiotherapy to the axillary and supraclavicular lymph nodes and the chest wall. The effect of leucopenia caused by CMF on distant disease-free survival (DDFS) and overall survival (OS) was assessed. A low leucocyte nadir during the chemotherapy was associated with a long DDFS in univariate analysis when tested as a continuous variable (the relative risk (RR) 1.3, 95% confidence interval (CI) 1.04-1.06, P = 0.02). Similarly, when the leucocyte nadir count was divided into tertiles, the patients who had the highest nadir values during the six-cycle treatment had worst outcome (RR 1.6, 95% CI 1.07-2.5, P = 0.02). However, in a multivariate analysis only the number of affected lymph nodes, tumour size, progesterone receptor status, surgical procedure, age and adjuvant tamoxifen therapy retained prognostic significance, whereas the leucocyte nadir count did not. A low leucocyte nadir during the adjuvant CMF chemotherapy is associated with favourable DDFS and it may be a useful biological marker for chemotherapy efficacy.

FEC mobilized stem cells for high-dose therapy in breast cancer patients. SB6 9401 Study Group.

The feasibility of mobilizing peripheral blood stem cells (PBSC) using anthracycline containing polychemotherapy and G-CSF on the first 50 patients randomized to the high-dose arm in the adjuvant SBG 9401 is investigated. The patients were treated with standard FEC (5-fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2) for two courses followed by a modified third FEC course with a C dose of 1200 mg/m2 supported with subcutaneous G-CSF (filgrastim) at 5 mg/kg followed by harvest around day 11. The mean yield of CD34+ cells per patient was 10.6x10(6)/kg (range 2.6-29.1). The side effects after the third course were low and only one patient developed an uncomplicated granulopenic fever. Our data indicated a correlation between number of transfused CD34+ cells and days to neutrophil and platelet recovery. In conclusion, the modified FEC regimen followed by G-CSF is a feasible method for PBSC mobilization in the adjuvant setting.

Aminoterminal propeptide of type I procollagen (PINP) correlates to bone loss and predicts the efficacy of antiresorptive therapy in pre- and post-menopausal non-metastatic breast cancer patients.

The aim of this study was to determine the correlation between changes in collagen metabolites (ICTP, mature cross-linked carboxy-terminal telopeptide of type I collagen; PINP, the amino-terminal propeptide of type I procollagen) and bone mineral density (BMD) in 206 pre- and post-menopausal breast cancer patients with non-metastatic disease. All patients received adjuvant cancer treatment--premenopausal patients chemotherapy and post-menopausal patients anti-oestrogens. In addition, the patients were also randomized to receive oral clodronate 1600 mg daily for 3 years. BMD was measured at baseline and at 1 and 2 years, the collagen metabolites at baseline and at 1 year. There was a highly significant negative correlation between the changes in PINP and BMD in lumbar spine and femoral neck from baseline to 12 months in all patients (r(s) = -0.68, P < 0.0001, and -0.45, P < 0.0001, respectively), and in pre- and post-menopausal patients separately. The changes in PINP levels at 12 months predict further changes in BMD at 24 months (r = -0.70, P < 0.0001, and -0.51, P < 0.0001, respectively). ICTP and BMD changes correlated significantly only in lumbar spine of premenopausal patients who developed rapid bone loss due to chemotherapy-induced amenorrhoea (r(s) = -0.34, P = 0.0003). The PINP levels at 12 months were significantly lower in the clodronate group than in the control group (P < 0.0001). Our results indicate that PINP is a sensitive marker of bone turnover rate. Changes in PINP levels significantly predicted changes in BMD and correlated with the antiresorptive efficacy of clodronate treatment.

Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients.

PURPOSE: In the majority of premenopausal breast cancer patients, an adjuvant chemotherapy-induced early menopause occurs, which is known to be a strong predictor of osteoporosis. We present data on the effect of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy on bone mineral density (BMD) and the efficacy of clodronate on the prevention of bone loss in 148 premenopausal breast cancer patients without skeletal metastases. MATERIALS AND METHODS: Patients were randomized to receive oral clodronate 1,600 mg/d or to a control group. In addition, patients were treated with six cycles of CMF therapy. BMD of the lumbar spine and femoral neck was measured by dual-energy x-ray absorptiometry (DEXA) before therapy and at 1 and 2 years. RESULTS: Changes in the BMD of lumbar spine and femoral neck were -5.9% and -2.0% without clodronate and -2.2% and +0.9% with clodronate at 2 years (P = .0005 and .017, respectively). Patients who developed amenorrhea after chemotherapy had a rapid bone loss, which was significantly reduced by clodronate. In controls, bone loss was 9.5% in the lumbar spine and 4.6% in the femoral neck, while in the clodronate group, bone loss was 5.9% and 0.4%, respectively, at 2 years. Patients with preserved menstruation had only marginal changes in BMD. CONCLUSION: Chemotherapy-induced ovarian failure causes rapid bone loss in premenopausal breast cancer patients. Women older than 40 years are at particularly high risk. Clodronate significantly reduces this bone loss.

Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antioestrogens.

The effect of clodronate on bone mineral density (BMD) was studied in 121 post-menopausal breast cancer women without skeletal metastases. In addition, two antioestrogens, tamoxifen and toremifene, were compared in their action on bone mineral density. Patients were randomized to have an adjuvant antioestrogen treatment either 20 mg of tamoxifen or 60 mg of toremifene daily for 3 years. In addition all patients were randomized to have 1600 mg of oral clodronate daily or to act as control subjects. BMD of the lumbar spine and femoral neck were measured by dual-energy radiographic absorptiometry before therapy and at 1 and 2 years. At 2 years, clodronate with antioestrogens markedly increased BMD in the lumbar spine and femoral neck by 2.9% and 3.7% (P = 0.001 and 0.006 respectively). There were no significant changes in BMD in the patients given antioestrogens only. No significant differences were found between tamoxifen and toremifene on bone mineral density. Clodronate with antioestrogens significantly increased bone mass in the lumbar spine and femoral neck. Both antioestrogens, tamoxifen and toremifene, similarly prevented bone loss in the lumbar spine and femoral neck.

The prognosis of stage III breast cancer treated with postoperative radiotherapy and adriamycin-based chemotherapy with and without tamoxifen. Eight year follow-up results of a randomized trial.

Sixty-one patients with primary node positive stage III breast cancers were randomized to receive postoperative radiotherapy and doxorubicin-based chemotherapy (eight cycles of CAFt: cyclophosphamide, adriamycin, oral ftorafur) with or without tamoxifen as adjuvant treatment. The five-year overall survival for all patients was 49% (with tamoxifen 48% and without tamoxifen 50%) and disease-free survival 33% (with tamoxifen 27% and without 39%). Local control for all patients was only 64% despite the postoperative radiotherapy. There was no significant difference between these two treatment groups in overall and disease-free survival or local control. The prognosis of stage III breast cancer remains grim despite modern adjuvant therapy. In addition to more effective systemic treatment more effective local therapy is also needed in order to obtain satisfactory local control. The most important studies in stage III breast cancer with 5-year survival results are reviewed here.

Passive leg raising does not produce a significant or sustained autotransfusion effect.

Passive leg raising is widely used to treat hypotension associated with hypovolemia. Presumably gravity causes a central translocation of leg venous blood and an increase in filling pressure, cardiac output, and arterial pressure. Ten healthy volunteers, 25 to 35 years old, had measurements of heart rate, blood pressure, and cardiac output in the supine position after 20 sec and 7 min of 60 degrees passive leg elevation. The protocol was performed 3 and 45 min after the subjects changed from an ambulatory upright to a supine position. Stroke volume and cardiac output increased transiently (8-10%) when the legs were raised after 3 min rest in the supine position. By 7 min of leg elevation, these beneficial effects disappeared. After 45 min supine, leg raising had no effect on stroke volume or cardiac output but increased blood pressure (4 mm Hg) by increasing peripheral resistance (15%). Thus, leg raising, like application of the MAST trousers, fails to produce any sustained increase in cardiac output or stroke volume. Small venous leg volumes and time-dependent changes in the distribution of venous volume and compliance may explain the absence of any sustained 'autotransfusion' effect.