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.

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.

Quality of life and physical performance and activity of breast cancer patients after adjuvant treatments.

OBJECTIVE: The study aimed at investigating the quality of life (QoL) and physical performance and activity, and their interrelations, in Finnish female breast cancer patients shortly after adjuvant treatments. METHODS: A total of 537 disease-free breast cancer survivors aged 35-68 years were surveyed at the beginning of a one year randomized exercise intervention. The patients were interviewed using EORTC QLQ-C30, FACIT-F, RBDI, and WHQ (for vasomotor symptoms) questionnaires. Physical performance was tested by a 2 km walking test. Physical activity was measured by a questionnaire and a prospective two-week diary. Multivariate analysis was used to study the factors associated with QoL. RESULTS: About 26% of the patients were rated as depressed, 20.4% as fatigued, and 82% suffered from menopausal symptoms. The global QoL was lower than in general population (69.4 vs 74.7, p<0.001). About 62% of the walking test results were below the population average. Fatigue (p<0.001), depression (p<0.001), body mass index (p = 0.016) and comorbidity (p = 0.032) impaired, and physical activity (p = 0.003) improved QoL. Physical activity level correlated positively to physical performance (r = -0.274, p<0.0001). CONCLUSIONS: The QoL of the patients shortly after adjuvant treatments was impaired and the physical performance poor as compared to general population. In particular, depression and fatigue were related to impaired QoL. Physical performance and activity level were the only factors that correlated positively to QoL. Thus, physical exercise could be useful in rehabilitation of cancer survivors, especially for depressed and fatigued patients.

Apoptosis in toremifene-induced growth inhibition of human breast cancer cells in vivo and in vitro.

BACKGROUND: Antiestrogens inhibit the stimulative effects of estrogens on breast cancer growth, but the mechanism(s) by which they trigger tumor regression are not completely understood. Growth retardation and tumor regression can be achieved by enhanced cell death and/or arrested cell proliferation. PURPOSE: Our aim was to investigate the effect of a new antiestrogen, toremifene, on human breast cancer cells grown either in culture or as tumors in nude mice. METHODS: The growth and morphology of in vitro cultured cells of the human breast cancer cell line MCF-7 were monitored by time-lapse video. MCF-7 cells and ZR-75-1 human breast cancer cells were grown as tumors in nude mice and subsequently examined by electron microscopy. The integrity of DNA isolated from these cells was determined by standard gel electrophoretic techniques. Northern blot hybridization analysis was used to determine the steady-state levels of the mRNAs for testosterone-repressed prostatic message-2 (TRPM-2), tumor growth factor beta-1 (TGF beta 1), and pS2 (a small, cysteine-rich protein of unknown function). RESULTS: Time-lapse video microscopy of the cell cultures indicated that treatment with 7.5 microM toremifene for 3 days caused approximately 60% of the cells to exhibit morphologic characteristics typical of cells undergoing programmed death, or apoptosis. The number of mitoses gradually decreased to zero over a 3- to 4-day period. Estrogen withdrawal for the same length of time resulted in an approximately equal number of apoptoses and mitoses. These changes were not associated with the pattern of DNA fragmentation, detectable as ladders in agarose gels, that is characteristic of the DNA of cells undergoing apoptosis. Elevated levels of TRPM-2 and TGF beta 1 mRNAs were observed in in vitro or in vivo grown tumor cells treated with 5-10 microM toremifene. Elevated levels of TRPM-2, but not TGF beta 1, mRNA were observed in the tumor cells after estrogen withdrawal. The steady-state level of pS2 mRNA in the tumor cells dropped in response to either toremifene treatment or estrogen withdrawal. CONCLUSION: Toremifene causes growth inhibition of estrogen-sensitive breast cancer cells by inducing some cells to undergo apoptosis and by inhibiting other cells from entering mitosis. The higher than normal amounts of TRPM-2 and TGF beta 1 protein that would likely result from the elevated levels of TRPM-2 and TGF beta 1 mRNAs measured in these cells after toremifene treatment may have an important role in the growth inhibition process. IMPLICATION: Apoptosis as an active, targeted process provides a potential new therapeutic approach for treating breast cancer.

Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: a prospective randomized trial.

PURPOSE: We report results of a randomized prospective study that compared single agents of low toxicity given both as the first-line and second-line chemotherapy with combination chemotherapy in advanced breast cancer with distant metastases. PATIENTS AND METHODS: Patients in the single-agent arm (n = 153) received weekly epirubicin (E) 20 mg/m2 until progression or until the cumulative dose of 1,000 mg/m2, followed by mitomycin (M) 8 mg/m2 every 4 weeks, and those in the combination chemotherapy arm (n = 150) were first given cyclophosphamide 500 mg/m2, E 60 mg/m2, and fluorouracil 500 mg/m2 three times per week (CEF) followed by M 8 mg/m2 plus vinblastine (V) 6 mg/m2 every 4 weeks. Exclusion criteria included age greater than 70 years, World Health Organization (WHO) performance status greater than 2, prior chemotherapy for metastatic disease, and presence of liver metastases in patients younger than 50. RESULTS: An objective response (complete [CR] or partial [PR]) was obtained in 55%, 48%, 16%, and 7% of patients treated with CEF, E, M, and MV, respectively. A response to CEF tended to last longer than a response to E (median, 12 v 10.5 months; P = .07). Treatment-related toxicity was less in the single-agent arm and quality-of-life (QOL) analysis favored the single-agent arm. No significant difference in time to progression or survival was found between the two arms. Similarly, no difference in survival was found when the patients who received both the planned first-and second-line treatments were compared or when survival was calculated from the beginning of the second-line therapy. CONCLUSION: Patients treated with single-agent E followed by single-agent M had similar survival, but less treatment-related toxicity and better QOL as compared with those treated with CEF followed by MV.

Pharmacokinetics and metabolism of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) in mammary tumors of antiestrogen-treated rats.

Attempts are being made to evaluate 2-[18F]fluoro-2-deoxy-D-glucose (FDG) as a noninvasive marker of therapy response in malignant tumors. We studied rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinomas by measuring the differential absorption ratio (DAR) and the metabolites of FDG in tumor homogenates. Half the rats were treated with the antiestrogen toremifene for 14 days and half were untreated. The histology of the tumors was studied by morphometry. The animals were killed 15, 45 or 240 min after injection. Regardless of whether the rats received toremifene or not, the fractional change in tumor volume correlated better with the DAR at 15 min [r = 0.284 (untreated) and r = 0.721 (treated)] and at 240 min [r = 0.932 (untreated)], than at 45 min [r = -0.137 (untreated) and r = 0.265 (treated)]. Inverse relations were found for the fraction of unmetabolized FDG and change in tumor volume [r = 0.070 (45 min) and r = -0.872 (240 min) for untreated tumors and r = -0.963 (15 min) and r = -0.715 (45 min) for treated tumors]. The DAR and the fraction of unmetabolized FDG correlated also [r = -0.420 (15 min), r = -0.647 (45 min) and r = -0.976 (240 min) for untreated tumors, and r = -0.963 (15 min) and r = -0.213 (45 min) for treated tumors]. No significant therapy-induced morphometrical changes were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell loss in dimethylbenz(a)anthracene-induced rat mammary carcinoma treated with toremifene and ovariectomy.

The antiestrogen toremifene treatment results in regression or stabilization of dimethylbenz(a)anthracene(DMBA)-induced rat mammary tumors by reducing the mitotic activity and possibly by modifying the abundant spontaneous apoptosis seen in these tumors. A comparative study on the modes of cell loss was performed in untreated DMBA tumors and in tumors treated with toremifene and ovariectomy. Ovariectomy results in massive apoptotic cell death throughout the tumors with apoptotic cells exfoliating into the glandular lumina. Apoptosis accounts for most of the cell death also in the untreated tumors. The distinctly different morphology of the apoptotic cells in the untreated tumors (condensed apoptosis) and tumors treated with ovariectomy (blebbing apoptosis) may reflect the different type or schedule of the apoptotic process. Both morphologies of apoptotic cells were seen in the toremifene-treated tumors. Blebbing apoptosis is not easily examined in paraffin-embedded material but is best detectable in plastic sections and by electron microscopy.

Mitotic activity, apoptosis and TRPM-2 mRNA expression in DMBA-induced rat mammary carcinoma treated with anti-estrogen toremifene.

Anti-estrogen toremifene inhibits growth of the 7,12-dimethylbenz(a)anthracene(DMBA)-induced rat mammary carcinoma. The changes in proliferation and cell death were studied in detail. Proliferation was measured by counting mitotic figures in histologic sections, expressed by volume-corrected mitotic index (M/V INDEX). Respective volume corrected apoptotic index (A/V INDEX) was measured by counting apoptotic nuclei in the same sections. The presence of apoptotic cells was confirmed by transmission electron microscopy. In the untreated tumors, both mitosis and apoptosis were frequent. In the toremifene-treated tumors, the mean M/V INDEX was about half of the mean M/V INDEX in the untreated control tumors. The mean A/V INDEX in the toremifene-treated tumors was about 3/4 of the mean A/V INDEX in the controls. In toremifene-treated tumors, A/V INDEX was strongly correlated with TRPM-2-gene expression, which was also enhanced when compared with the controls. TRPM-2 gene has been associated with programmed cell death induced by hormonal ablation in prostate- and breast-cancer cells. No such correlation was seen in control tumors. These findings suggest that, in the DMBA-tumor model, toremifene affects the cell turnover by inhibiting mitotic activity and modifying abundant spontaneous apoptosis. In this model, the inhibition of tumor growth results mostly from reduction of mitotic activity.

Hormonal treatment of advanced breast cancer. A randomized trial of tamoxifen versus nandrolone decanoate.

The response to tamoxifen (TAM) (10 mg to 20 mg twice orally) was compared with the response to nandrolone decanoate (NAN) (50 mg every second week or 100 mg every third week intramuscularly) in this randomized study in previously untreated women with advanced breast cancer. Patients were postmenopausal or postmenopause was induced with irradiation therapy. The two treatment groups were highly similar in different patient characteristics. Of 67 evaluable patients treated with TAM, ten (15%) had a complete or partial remission, 28 (42%) had stabilized disease and 29 (43%) had progressive disease. In the 60 patients treated with NAN, the figures were ten (17%), 22 (37%) and 28 (47%) respectively. The response rates did not differ significantly. Tam was as good as NAN in osseous metastases. Four of 34 patients responded to TAM and three of 38 patients responded to NAN. NAN had a tendency for better response in the treatment of visceral metastases. Six (43%) of 14 patients responded to NAN while only three (14%) of 21 responded to TAM (P = 0.11). The median duration of remission was 24 months in the TAM arm and 17 months in NAN (insignificant). As second line treatment, NAN after TAM gave one complete remission and three partial remissions, but none responded to TAM after NAN. The side-effects of both drugs were rare and mild. These data indicate that TAM and NAN are comparable in the treatment of advanced breast cancer.

Cell proliferation in dimethylbenz(A)anthracene(DMBA)-induced rat mammary carcinoma treated with antiestrogen toremifene.

Cell proliferation during antiestrogen toremifene treatment was studied using the DMBA-induced rat mammary carcinoma model. The volume corrected mitotic index (M/V INDEX) and the S-phase fraction (SPF) determined by flow cytometry (FCM) were used as proliferation markers. Two series of rats (A and B) treated with two dose levels of toremifene were used. The two series of tumors appeared to have different growth properties. In series A the tumors were rapidly growing with high proliferation rate. In this series, toremifene (3 mg/kg for 4 weeks) reduced significantly the mean MV/INDEX, but the slight reduction of the mean SPF was not significant. In series B the tumors grew slowly and had low levels of proliferation markers. One-third of the tumors were spontaneously stable in the untreated group. Higher dose of toremifene was used in this series (12 mg/kg for 4 weeks), and the number of regressing or stable tumors was 58% compared with 31% in series A. Taking into consideration the high number of spontaneously stable tumors in series B, it may be concluded that about one-third of the tumors regressed or remained stable due to toremifene treatment in both series. The reduction of the M/V INDEX was significant only when the regressing treated tumors were compared with the growing controls. The reduction of the SPF was not significant. We think that the M/V INDEX is a more appropriate method to measure cell proliferation than is the SPF in this tumor model, where the tumors are heterogenous and, e.g., spontaneous apoptosis is known to be frequent.

Evaluating the response to antioestrogen toremifene treatment in DMBA induced rat mammary carcinoma.

Evaluation of the treatment response to hormonal therapy in experimental mammary carcinoma models usually consists of recording the changes in tumour volume or in number of tumours. We performed quantitative histology on dimethylbenz[a]anthracene(DMBA) induced rat mammary carcinoma treated with the antioestrogen toremifene. The inhibition of growth of the treated regressing tumours was not only associated with inhibition of mitosis and reduction of the neoplastic epithelium, but toremifene seemed to reduce all main tissue components. The percentual area fractions of epithelium and stroma were equal in the untreated and the treated tumours. The estimated absolute volumes of epithelium, stroma and glandular luminae as well as the mitotic index were significantly reduced during toremifene treatment in those tumours which were responding by regression to the treatment. The findings indicate growth inhibiting effect on both epithelium and stroma or on interactions between epithelium and stroma. Adding quantitative histology to the gross response analysis in experimental animal models is feasible and may elucidate the mechanisms of action of a novel hormonal treatment.

Survival and esophageal passage after radiotherapy of inoperable esophageal carcinoma. A retrospective study of 106 cases.

Survival and esophageal passage were studied retrospectively in 106 patients with inoperable esophageal carcinoma treated with radiotherapy during the years 1972 to 1983. The survival rates were 30%, 13% and 7% at one, two and three years respectively. The survival rate for the female patients was significantly better than for the males throughout these three years; 9% of the female patients lived for three years compared to only 3% of the male patients. Forty-two percent of the patients received 'radical' irradiation (greater than 50 Gy). The 3-year survival rate was 16% after a tumor dose of 50 Gy or more, and zero with a dose less than 50 Gy, but this difference might be explained by selection factors, such as patients in poor general condition not receiving 'radical' irradiation. Esophageal passage after radiotherapy could be evaluated in 62 patients, and 22 (35%) of them required feeding gastrostomy due to esophageal discontinuity, most often within one year after completion of radiotherapy. It is concluded that radiotherapy has only a slight effect on the prognosis of inoperable esophageal carcinoma.

Pancreatic cancer. Evaluation of prognostic factors and treatment results.

From 1969 to 1984, 125 patients (49 women and 76 men) with pancreatic cancer were treated at the Department of Radiotherapy at Turku University Central Hospital. The mean age of the patients was 63 years. Surgery was the only treatment in 40 cases, 22 patients received radiotherapy, 27 chemotherapy, and 13 received both radiotherapy and chemotherapy after surgery or as the only treatment; 23 patients received no active therapy. The average survival time was 7.5 months. The mean survival times of patients in the purely surgical group was 8.1 months, in the radiotherapy group 8.7 months, in the chemotherapy group 8.1 months, and in the group which received both radiotherapy and chemotherapy 9.7 months. The average survival time of patients who received neither surgical nor oncological treatment was significantly shorter (3.2 months). Statistically significant factors regarding shorter survival times were metastases at presentation (survival time 3.9 months), and poor general condition (Karnofsky index less than 60; survival time 4.4 months).

Carbon-11-methionine and PET in evaluation of treatment response of breast cancer.

Uptake of L-methyl-11C-methionine (11C-methionine) in breast cancer metastases was studied with positron emission tomography (PET). Eight patients with soft tissue metastases were studied twice: before the onset of chemotherapy (4), hormonal therapy (3) or radiotherapy (1) and 3-14 weeks later. The radioactivity concentration of the low molecular weight fraction of venous plasma samples separated by fast gel filtration was used as input function. The input corrected uptake rate of 11C-methionine (Ki) in breast cancer metastases before the treatment ranged between 0.035 and 0.186 1 min-1 and the standardised uptake value (SUV) between 2.0 and 11.4. The uptake of 11C-methionine into the metastases decreased when clinical objective stability or regression of the metastases was later obtained and increased in cases where progressive disease was seen during treatment. We conclude that metabolic changes in the amino acid metabolism detected by PET precede the clinical response, and may be of clinical value in predicting the treatment response.

[11C]methionine quantitation in cancer PET studies.

Quantitation of the uptake of positron emitting tracers in cancer patients is still unsettled. A uniform method is needed for comparison of results and for collecting a data base of tumor PET studies. We have measured the tumoral uptake of [11C]methionine in 46 cancer patients using four different methods of analysis. The accumulation of [11C]methionine at 35-40 min after the injection adjusted to the injected dose and body surface area turned out to give similar results as a more complicated method where the uptake rate of [11C]methionine from the plasma to the tumor was calculated (r = 0.92, p less than 0.0001). The results suggest that in clinical [11C]methionine PET studies, 40 min emission scanning with frequent blood sampling is unnecessary. Only a single 5 min emission scan 25-40 min after the injection is required for analysis if the accumulation is adjusted to the injected dose and body surface area.

Carboplatin and etoposide in extensive small cell lung cancer.

The combination of carboplatin and etoposide was evaluated in 61 previously untreated patients with extensive small cell lung cancer. Treatment was given at four-week intervals with 450 mg/m2 of carboplatin intravenously (i.v.) on day 1 and etoposide 100 mg/m2 i.v. on days 1-3. The response was complete in 5 (9%) and partial in 28 (50%) of the 56 evaluable patients (overall response rate 59%). The median time to progression after response as well as the median survival time in all evaluable patients was 4.6 months. WHO grade 3 and 4 leukopenia and thrombocytopenia occurred in 8% and 11% of the courses respectively. Two treatment-related deaths were registered. The combination of carboplatin and etoposide used in the present study produced acceptable response rate and toxicity, but duration of response and median survival were shorter than expected from earlier studies.

Uptake and metabolism of hydroxymatairesinol in relation to its anticarcinogenicity in DMBA-induced rat mammary carcinoma model.

The chemopreventive effects of hydroxymatairesinol (HMR), a lignan extracted from Norway spruce (Picea abies), on the development of mammary carcinoma induced by 7,12-dimethylbenz[a]anthracene (DMBA) was studied in rats. HMR administered via diet in an average daily dose of 4.7 mg/kg body wt starting before DMBA induction reduced tumor volume and tumor growth, but no significant reduction in tumor multiplicity (number of tumors/rat) was observed. The predominant histological type in the control group was type B (well-differentiated adenocarcinoma, 78%). The proportion of type B tumors decreased to 35% in the HMR group, while the type A (poorly differentiated) and type C (atrophic) tumor proportions increased. Anticarcinogenic effects of dietary HMR (4.7 mg/kg) were also evident when the administration started after DMBA induction and was seen as growth inhibition of established tumors. Dietary HMR supplementation significantly increased serum and urinary enterolactone and HMR concentrations but had no significant effect on the uterine weight, suggesting that HMR or its major metabolite enterolactone did not have an antiestrogenic effect. Further studies are warranted to further clarify and verify HMR action and the associated mechanisms in mammary tumorigenesis.