The effect of ovarian dysfunction on bone mineral density in breast cancer patients 10 years after adjuvant chemotherapy.

BACKGROUND: Premenopausal patients treated with adjuvant chemotherapy often develop early menopause and thus, may encounter significant bone loss. We studied the long-term effects of chemotherapy-induced ovarian dysfunction on bone mineral density in breast cancer patients. MATERIAL AND METHODS: The effect of menstrual status after adjuvant chemotherapy on bone mineral density (BMD) was examined in 29 premenopausal breast cancer patients. RESULTS: During 10 years of follow-up, nearly 90% of women developed menstrual irregularities or amenorrhea. The total bone loss at the lumbar spine was -5.4% in women with preserved menstruation, -15.3% in those with irregular menses and -13.2% in amenorrheic women 10 years after adjuvant chemotherapy. The changes in lumbar spine BMD correlated significantly with menstrual function. Both amenorrhea and menstrual irregularities shortly after chemotherapy increased the risk of osteoporosis later on: one third of women with ovarian dysfunction developed osteoporosis of the lumbar spine during the follow-up. Osteopenia before adjuvant therapy predicted an increased risk for osteoporosis. CONCLUSION: The present study with a unique follow-up period of 10 years shows that ovarian dysfunction leads to long-term deleterious BMD changes and predisposes breast cancer survivors to osteoporosis.

Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.

BACKGROUND: We compared docetaxel with vinorelbine for the adjuvant treatment of early breast cancer. Women with tumors that overexpressed HER2/neu were also assigned to receive concomitant treatment with trastuzumab or no such treatment. METHODS: We randomly assigned 1010 women with axillary-node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions. The primary end point was recurrence-free survival. RESULTS: Recurrence-free survival at three years was better with docetaxel than with vinorelbine (91 percent vs. 86 percent; hazard ratio for recurrence or death, 0.58; 95 percent confidence interval, 0.40 to 0.85; P=0.005), but overall survival did not differ between the groups (P=0.15). Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody (89 percent vs. 78 percent; hazard ratio for recurrence or death, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01). Docetaxel was associated with more adverse effects than was vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure. CONCLUSIONS: Adjuvant treatment with docetaxel, as compared with vinorelbine, improves recurrence-free survival in women with early breast cancer. A short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER2/neu gene. (International Standard Randomised Controlled Trial number, ISRCTN76560285.).

Malignant fibrous histiocytoma of bone: analysis of genomic imbalances by comparative genomic hybridisation and C-MYC expression by immunohistochemistry.

Malignant fibrous histiocytoma (MFH) of bone is a rare, highly malignant tumour. As very little is known about its genetic alterations, 26 bone MFHs were analysed by comparative genomic hybridisation (CGH). Twenty-three tumours (89%) had DNA sequence copy number changes (mean, 7.2 changes per sample). Gains were more frequent than losses (gains:losses=2.5:1). Minimal common regions for the most frequent gains were 8q21.3-qter (35%), 9q32-qter (35%), 7q22-q31 (35%), 1q21-q23 (31%), 7p12-pter (31%), 7cen-q11.2 (31%) and 15q21 (31%). Minimal common regions for the most frequent losses were 13q21-q22 (42%) and 18q12-q22 (27%). High-level amplifications were detected in 8 out of the 26 tumours (31%). The only recurrent amplifications, 1q21-q23 and 8q21.2-q22, were present in two samples (8%). As copy number increase at 8q24 (the locus of C-MYC) was frequent, the expression of C-MYC was studied by immunohistochemistry. Increased levels of c-myc protein were detected in 7 out of 21 tumours studied (33%). 81% of the samples studied both by CGH and immunohistochemistry showed concordant results. Furthermore, the findings of the present study were compared to previous publications on osteosarcoma, soft tissue MFH and fibrosarcoma of bone. Clear differences were detected in CGH aberration patterns, further supporting the concept of bone MFH as an individual bone tumour entity. Finally, the findings of the present study reflect well the high malignancy and aggressive nature of bone MFH.

A high serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma.

PURPOSE: The aim of this study was to determine whether serum matrix metalloproteinase (MMP) -2 and MMP-9 levels could predict overall and disease-free survival in primary node-positive breast cancer. EXPERIMENTAL DESIGN: MMP-2 and MMP-9 levels were quantitatively measured in serum after surgery from 133 patients with primary node-positive breast cancer using enzyme-linked immunoassays. All of the patients received adjuvant therapy, postmenopausal endocrine treatment (tamoxifen or toremifen for 3 years) and premenopausal six cycles of CMF chemotherapy. The follow-up time for all of the patients was 5 years. RESULTS: Overall survival (OS) and disease-free survival (DFS) rates were better among patients with low MMP-2 levels than in patients with high levels (OS, 91% versus 75%, P = 0.020; DFS, 82% versus 58%, P = 0.005). The appearance of bone and visceral metastases was also significantly lower in patients with low serum MMP-2 levels (bone metastases, 10% versus 23%, P = 0.050; visceral metastases, 12% versus 34%, P = 0.018). The prognostic value of MMP-2 levels was most pronounced among a subgroup of estrogen receptor-positive patients (OS, 96% versus 78%, P = 0.052; DFS, 85% versus 58%, P = 0.014), whereas no significant difference was found among estrogen receptor-negative patients (OS, 73% versus 69%, P = 0.25; DFS, 73% versus 63%, P = 0.32). In multivariate analysis, MMP-2 level together with nodal status (NS), progesterone receptor (PgR), and tumor size (T) remained independent predictors for DFS (NS, P = 0.002; PgR, P = 0.004; T, P = 0.023; MMP2, P = 0.039) and OS (NS, P = 0.0002; PgR, P = 0.004; T, P = 0.004; MMP2, P = 0.032). MMP-9 levels did not correlate with survival. CONCLUSIONS: The results suggest that serum postoperative MMP-2 level is a predictor of DFS and OS, and could help to stratify breast cancer patients with primary node-positive disease into low- and high-risk groups.

Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer.

PURPOSE: Define the maximum tolerated dose (MTD), tolerability, and efficacy of gemcitabine given concomitantly with radiotherapy in patients with locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients were required to have locally advanced T1-T3 resectable pancreatic cancer. Gemcitabine, given twice weekly before irradiation as a 30-min infusion, was tested at 3 dose levels: 20, 50, and 100 mg/m(2). The radiation dose was 50.4 Gy (ICRU) in 28 fractions. The targeted irradiation volume included the tumor, edema, and a 1-cm margin. RESULTS: Twenty-eight of 34 patients was eligible for analysis of the treatment. The median age was 67 years (range 38-82). Six patients had T1, 9 had T2, and 19 had T3 diseases (AJCC). Dose-limiting toxicities were Grade 4, fatigue and nausea; Grade 3, thrombocytopenia, diarrhea, and infection. The MTD established was at the 50-mg/m(2) gemcitabine dose. A total of 21 of 28 patients underwent surgery: 18 had pancreaticoduodenectomy, 2 had total pancreatectomy, and 1 for palliative surgery. At the time of analysis, 13 of 28 (46%) were disease-free. The estimated median survival was 25 months and overall survival rate at 2 years (Kaplan-Meier) was 55%. CONCLUSION: Gemcitabine 50 mg/m(2) given twice weekly with concomitant irradiation induces acceptable and manageable toxicity and might prolong survival.

PET imaging of blood flow and glucose metabolism in localized musculoskeletal tumors of the extremities.

INTRODUCTION: Little is known about blood flow in sarcomas. Our purpose was to study glucose metabolism and blood flow in untreated localized musculoskeletal tumors of the extremities using [(18)F]fluorodeoxyglucose (FDG), oxygen-15 labeled water ([15O]H(2)O) and positron emission tomography (PET). METHODS: Six patients with high-grade osteosarcoma (OS), two with soft-tissue sarcoma (STS) and one with aneurysmal bone cyst had PET studies with [15O]H(2)O and FDG. Arterial blood sampling and autoradiography calculation method were used to define blood flow as milliliters per 100 g times minutes. Tumor FDG uptake was measured as standardized uptake values (SUVs) and regional metabolic rates for FDG (rMRFDG). Two patients also had FDG PET studies during (one patient) and after (two patients) preoperative chemotherapy. All patients underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The PET findings were compared with the clinical follow-up data and results of DCE-MRI. RESULTS: Blood flow in bone tumors was 31.7-75.2 ml/(100 g×min) and in STS 9.0-45.9 ml/(100 g×min). [(18)F]-Fluorodeoxyglucose uptake and rMRFDG in untreated bone tumors were 5.4-18.4 and 10.9-57.4 µmol/100 g/min, respectively. [(18)F]-Fluorodeoxyglucose uptake and rMRFDG in STS were 2.6-11.5 and 5.6-32.2 µmol/100 g/min, respectively. Four of five sarcomas with SUV>9.0 have already relapsed. High blood flow in untreated OS was related to long overall survival, while the predictive power of glucose metabolism was less apparent. Good histopathological response to therapy was not associated with long survival. CONCLUSIONS: Measurement of blood flow in musculoskeletal tumors appears to be feasible by PET and [(15)O]H(2)O. The influence of tumor blood flow and glucose metabolism on the final outcome in sarcoma is variable and needs further research.

Ten-year follow-up of 3 years of oral adjuvant clodronate therapy shows significant prevention of osteoporosis in early-stage breast cancer.

PURPOSE: We have previously reported that 3-year adjuvant clodronate treatment prevents bone loss in breast cancer patients. Here we report the 10-year follow-up data of clodronate in the prevention of treatment-related osteoporosis in women with early-stage breast cancer. PATIENTS AND METHODS: Two hundred sixty-eight pre- and postmenopausal, node-positive breast cancer patients were randomly assigned to clodronate, 1.6 g orally administered daily, or to control groups for 3 years. Premenopausal women were treated with adjuvant CMF chemotherapy; and postmenopausal women were treated with antiestrogens, either 20 mg tamoxifen or 60 mg toremifene, for 3 years. The bone mineral density (BMD) of the lumbar spine and hip was measured before treatment and at 1, 2, 3, 5, and 10 years after therapy. RESULTS: Eighty-nine disease-free patients were included in the analyses of osteoporosis-free survival. During the 10-year period, 24 of 89 patients were diagnosed with osteoporosis. Fourteen patients developed spinal osteoporosis (three of 41 in the clodronate group, and 11 of 48 in the control group), and 14 of 89 patients were diagnosed with hip osteoporosis (seven of 41 in the clodronate group, and seven of 48 in the control group). The 10-year spinal, osteoporosis-free survival rate was 92.7% in the clodronate group, and 77.0% in the control group (P = .035). No difference was seen in the frequency of hip osteoporosis (85.4% v 82.9%; P = .92). Baseline BMD measurement had a predictive value of 18 of 24 patients (75%) who developed osteoporosis had osteopenia of the lumbar spine at baseline. CONCLUSION: Three years of clodronate therapy significantly reduces the incidence of lumbar spine osteoporosis. Patients at risk of developing osteoporosis are among those who have pretreatment osteopenia, that is, baseline BMD measurement has predictive value.

Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status.

PURPOSE: Adjuvant chemotherapy followed by tamoxifen is a standard treatment option for women with intermediate or high-risk hormone receptor-positive breast cancer. Premenopausal women treated with chemotherapy often develop early menopause and thus, enter a period of accelerated bone loss. We conducted a prospective study of the effect of sequential adjuvant therapy with chemotherapy followed by tamoxifen on bone mineral density (BMD) in premenopausal patients. PATIENTS AND METHODS: One hundred eleven premenopausal women with early breast cancer were treated with adjuvant chemotherapy. Patients with hormone receptor-positive tumors went on to tamoxifen 6 months after the beginning of the chemotherapy (tamoxifen group), while those with hormone receptor-negative tumors received no further therapy (control group). The effect of tamoxifen and menstrual status on BMD was studied. RESULTS: Tamoxifen treatment and menopausal status correlated significantly with the changes in lumbar spine BMD (P < .0001). A significant bone loss was noted in those tamoxifen-treated patients who continued to menstruate after chemotherapy. At 3 years of follow-up, menstruating patients on tamoxifen had lost -4.6% of their baseline BMD values, while a modest gain of +0.6% was noted in the control group. In contrast, bone loss was reduced among tamoxifen-treated women as compared with controls in patients who developed chemotherapy-induced early menopause. In amenorrheic patients, the lumbar spine BMD values decreased -6.8% in tamoxifen users and -9.5% in the controls, respectively. CONCLUSION: We conclude that tamoxifen usage was associated with bone loss in patients who continued to menstruate after adjuvant chemotherapy. On the contrary, tamoxifen decreased bone loss in those women who developed chemotherapy-induced amenorrhea.

Vinorelbine, epirubicin and fluorouracil as first-line therapy in metastatic breast cancer--a phase II trial.

A phase II study was conducted to assess the toxicity and response rate of vinorelbine (NavelbineR) combined with epirubicin and fluorouracil (NEF) in metastatic breast cancer. Vinorelbine was delivered at a dose of 25 mg/m2 on days 1 and 8, epirubicin at 60 mg/m2 on day 1 and fluorouracil at 600 mg/m2 on day 1, at 3-week intervals. Forty consecutive ambulant patients with breast cancer with measurable metastases were treated with a total of 310 cycles (median 8) as first-line therapy. The objective response rate was 83% (95% CI 71-95) (6/40 CR 15%, 27140 PR 68%). In 3 patients, CNS metastases were detected during NEF therapy those who had a partial response in their visceral metastases. Median time to progression was 13 months (95% CI 7-19) and estimated median survival time was 32 months. The main dose-limiting adverse effect, grade III-IV haematological toxicity, was reported in 92% of patients. One patient died of neutropenic sepsis. Grade III infections requiring hospitalization were observed in 8 patients (20%). Half of the patients complained of mild constipation, nausea or stomatitis, which were easily managed. Almost all patients had grade III alopecia. One patient with previous adjuvant anthracycline therapy (CEF x 9 two years earlier) developed fatal grade IV cardiac failure associated with pulmonary emboli 2 months after completion of NEF therapy (PR with 6 cycles). In line with the observations of others conducting phase II first-line trials combining vinorelbine and epirubicin, it is concluded that the NEF regimen is effective in metastatic breast cancer. Haematological toxicity, however, requires dose reductions in many patients. Furthermore, careful monitoring of cardiac function is necessary, particularly in patients who received prior adjuvant anthracycline therapy.

Short-term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy-induced ovarian failure.

Chemotherapy-induced ovarian failure causes rapid bone loss in premenopausal women with early breast cancer. The aim of the present study was to investigate the effect of intravenous intermittent clodronate during adjuvant chemotherapy in prevention of this rapid bone loss. 45 premenopausal women with early stage breast cancer were treated with adjuvant chemotherapy. In addition, all women were randomly allocated to receive either seven cycles of intravenous clodronate infusions (1500 mg each) parallel to the chemotherapy or no further therapy. The mean bone loss in the lumbar spine at 6 months was -0.5% in the clodronate group and -1.4% in the control group (p = 0.22) and, at 12 months, -3.9% and -3.6%, respectively (p = 0.62). Type I collagen metabolite PINP levels at six months were significantly lower in the clodronate group than in the control group: 22.6 microg/l (range 15.7-55.8 microg/l) and 44.0 microg/l (range 12.5-91.9 microg/l), respectively (p = 0.0001). At 12 months, no difference between the PINP levels in clodronate and control groups were seen. In conclusion, in this small study a short-term intermittent intravenous clodronate treatment did not seem to prevent clinically significantly the bone loss related to chemotherapy-induced ovarian failure in premenopausal women with early stage breast cancer, even though a significant reduction of a biochemical marker of bone turnover (PINP) was seen during the therapy.

Lactose intolerance associated with adjuvant 5-fluorouracil-based chemotherapy for colorectal cancer.

BACKGROUND & AIMS: Bowel mucosal injury associated with 5-fluorouracil (5-FU) treatment might result in secondary lactose intolerance. The frequency and clinical significance of 5-FU-related hypolactasia are unknown. METHODS: One hundred fifty patients randomly assigned to receive 1 of 2 adjuvant 5-FU-based chemotherapy regimens, the Mayo regimen or the simplified de Gramont regimen, were studied for lactose tolerance by using an oral lactose absorption test, a symptom questionnaire, treatment-related toxicity, and Subjective Global Assessment of Nutritional Status questionnaire before, during, and 2 and 6 months after chemotherapy for colorectal cancer. RESULTS: The frequency of hypolactasia increased from 24% before treatment to 35% during treatment (P < 0.0001). Therapy-related hypolactasia was reversible on discontinuation of chemotherapy. Symptoms compatible with lactose intolerance occurred in 94% of patients with an abnormal lactose absorption test result during chemotherapy. The frequency of hypolactasia increased during chemotherapy in both treatment groups, but was detected more commonly in those for whom therapy included continuous 5-FU infusions (the de Gramont regimen; 45% vs. 25%; P = 0.006). The presence of hypolactasia during chemotherapy was associated with flatulence, diarrhea, and poor nutritional status. CONCLUSIONS: Reversible chemotherapy-related hypolactasia and lactose intolerance are not infrequent in patients treated with 5-FU-based adjuvant chemotherapy for colorectal cancer. Avoidance of lactose during chemotherapy may improve treatment tolerability in these patients.