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Biomedical subjects

Robert E Coleman

Publications and source records attributed to Robert E Coleman.

At least 19 recordsLinked to original sources
PubMed2006

Effect of chemotherapy on skeletal health in male survivors from testicular cancer and lymphoma.

PURPOSE: There are concerns over the late effects of cancer therapy, including accelerated bone loss leading to increased risk of osteoporosis. Treatment-related bone loss is well recognized in breast and prostate cancer, due to overt hypogonadism, but there has been little evaluation of the skeletal effects of chemotherapy alone in adults. This study assesses the extent of bone loss due to previous chemotherapy in men. EXPERIMENTAL DESIGN: The bone mineral density (BMD) of men who had received previously chemotherapy with curative intent for lymphoma or testicular cancers was compared with that of an age-matched population of men from a cancer control population that had not received chemotherapy. BMD was measured by dual-energy X-ray scanning. Additionally, measurement of sex hormones and the bone turnover markers N-telopeptide fragment of type I collagen and bone-specific alkaline phosphatase were done. All statistical tests were two sided. RESULTS: One hundred fifteen chemotherapy-treated patients and 102 cancer controls were recruited. There was no statistical difference in BMD between the chemotherapy and control groups at either spine or hip and the mean BMD values in both groups were no lower than that of a reference population. There were no significant differences in estradiol, luteinizing hormone, and testosterone, but follicle-stimulating hormone values were significantly higher in the chemotherapy group (P=0.011). The mean values of NH2-terminal telopeptide fragment of type I collagen and bone-specific alkaline phosphatase were within the reference ranges. CONCLUSIONS: The absence of accelerated bone loss following chemotherapy is reassuring and suggests that standard dose cytotoxic chemotherapy has no lasting clinically important direct effects on bone metabolism.

Absorptiometry, Photon↗
PubMed2006

Clinical features of metastatic bone disease and risk of skeletal morbidity.

The skeleton is the most common organ to be affected by metastatic cancer and the site of disease that produces the greatest morbidity. Skeletal morbidity includes pain that requires radiotherapy, hypercalcemia, pathologic fracture, and spinal cord or nerve root compression. From randomized trials in advanced cancer, it can be seen that one of these major skeletal events occurs on average every 3 to 6 months. Additionally, metastatic disease may remain confined to the skeleton with the decline in quality of life and eventual death almost entirely due to skeletal complications and their treatment. The prognosis of metastatic bone disease is dependent on the primary site, with breast and prostate cancers associated with a survival measured in years compared with lung cancer, where the average survival is only a matter of months. Additionally, the presence of extraosseous disease and the extent and tempo of the bone disease are powerful predictors of outcome. The latter is best estimated by measurement of bone-specific markers, and recent studies have shown a strong correlation between the rate of bone resorption and clinical outcome, both in terms of skeletal morbidity and progression of the underlying disease or death. Our improved understanding of prognostic and predictive factors may enable delivery of a more personalized treatment for the individual patient and a more cost-effective use of health care resources.

Biomarkers↗
PubMed2006

Advances in treating metastatic bone cancer: summary statement for the First Cambridge Conference.

The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.

Bone Neoplasms↗
PubMed2006

Osteoprotegerin (OPG)--a potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis?

The progression of cancer depends on the establishment of a tumour blood supply, and therefore tumour angiogenesis has been identified as a major target for new anticancer agents. Recent reports have suggested that osteoprotegerin (OPG) is involved in the control of endothelial cell survival through the inhibition of the activity of tumour necrosis factor- (TNF) related apoptosis-inducing ligand (TRAIL). The role of OPG in human tumour development and angiogenesis is currently unknown. In the present study we demonstrate the ability of OPG to support endothelial cell survival, as well as the formation of cord-like structures in vitro using a matrigel tubule formation assay. Investigation of various human cancers demonstrated endothelial OPG expression in 59% of malignant tumours (n=512), but in contrast, OPG was absent in endothelial cells associated with benign tumours and normal tissues (n=178). In a series of 400 breast tumours, endothelial OPG expression was associated with high tumour grade and certain histological types. Our data show a clear separation in endothelial OPG expression between malignant tumours and nonmalignant tissues, supporting a potential biological role for this molecule in the development and/or maintenance of the tumour vasculature. This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours.

Breast Neoplasms↗
PubMed2006

A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.

PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. EXPERIMENTAL DESIGN: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. RESULTS: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. CONCLUSIONS: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.

Adult↗
PubMed2006

The role of bone markers in metastatic bone disease.

Patients with advanced cancer often develop bone metastases that lead to significant skeletal morbidity and substantially reduced functionality and autonomy [Coleman RE, Rubens RD. Bone metastases. In: Clinical Oncology, 2nd edn. New York: Churchill Livingstone. 2004, p. 1091-128]. As current methods of diagnosing bone metastases are cumbersome and not cost-effective, there is great interest in exploring the potential of biochemical assays that measure bone turnover activity. These markers may have value in measuring metastatic bone disease (MBD) progression and identifying patients at higher risk for metastases. Bone markers are also being evaluated as a possible guide to optimize treatment of bone complications. In the reports included in this supplement, experts at the frontiers of bone marker research offer insights on their progress.

Biomarkers, Tumor↗
PubMed2006

Conclusion: Bone markers in metastatic bone disease.

Bone metastases occur frequently in patients with multiple myeloma and breast, prostate, and lung cancer. Presence of metastatic bone disease (MBD) is correlated with abnormal bone remodelling, as high levels of biochemical markers of bone turnover can be detected in serum or urine from patients with these malignancies. The idea of using bone markers in the diagnosis and follow-up of patients with MBD is undergoing validation and gaining acceptance. In this conclusion, we summarise data from leading studies relating to the search for useful markers of bone resorption and bone formation in MBD.

Biomarkers↗
PubMed2006

High-dose chemotherapy with haematopoietic stem-cell support in patients with poor prognosis, relapsed or refractory germ cell tumours.

OBJECTIVE: To report our experience of high-dose chemotherapy (HDC) with haematopoietic stem-cell support (HSC) in patients with poor risk, relapsed or refractory germ cell tumours (GCTs), as this treatment might offer effective salvage for patients with disseminated GCTs. PATIENTS AND METHODS: We retrospectively reviewed the medical records and database for 33 patients with GCT who were treated with HDC with HSC in our centres. RESULTS: Thirty-three patients were treated with either one or two cycles of carboplatin and etoposide-based HDC with HSC support, between March 1990 and October 2003. Twenty-six patients (79%) had nonseminomatous GCT, six seminoma (18%), and one (3%) a combined seminoma and teratoma. Twenty patients (60%) had previously had a clinical complete response after previous chemotherapy +/- surgery for residual disease. Most patients were treated with HDC for relapsing (49%) or relative refractory disease (30%), but seven (21%) had HDC in the first partial remission. The complete response rate to HDC was 58%. There were two treatment-related deaths (6%). As of April 2005, 18 patients were alive and disease-free with a median (range) follow-up of 72 (0.5-174) months. The 5-year overall and progression-free survival probabilities were 57% and 56%, respectively. The median (range) times to absolute neutrophil count recovery (> or = 500/microL) were 13 (9-24) and 12 (10-15) days, and for platelet count recovery ( > or = 20,000/microL) were 16 (7-50) and 13 (11-17) days, in the first and second cycles, respectively. CONCLUSION: The role of HDC with HSC support in metastatic GCTs remains controversial, and data from randomized controlled trials are needed. Our experience suggests that, in selected patients, this approach might be a useful form of salvage therapy.

Adolescent↗
PubMed2006

Changes in bone resorption and vascular endothelial growth factor after a single zoledronic acid infusion in cancer patients with bone metastases from solid tumours.

Zoledronic acid (Zometa, ZOL) is increasingly used to treat tumour-induced bone disease, and is also reported to have antiangiogenic properties in vivo. In this study, we have investigated the correlations between changes in the proangiogenic cytokine, vascular endothelial growth factor (VEGF), and markers of bone resorption in a cohort of patients with metastatic bone disease, following a single infusion of ZOL. Twenty-four consecutive selected cancer patients with scintigraphic and radiographic evidence of bone metastases were treated for the first time with a single infusion of 4 mg ZOL. Patients were considered ineligible if they had received any steroid therapy, radiotherapy, chemotherapy, immunotherapy or haemopoietic growth factors in the 4 weeks before or during the study period. Circulating levels of VEGF and beta crosslinked type I collagen C-telopeptide (betaCTX) were measured at base-line and at 1, 2, 7 and 21 days following ZOL infusion. The majority of our patients (23/24) developed a significant reduction in circulating levels of betaCTX at just 1 day after the single zoledronic acid infusion, median percentage decrease 67.05% (95% CI, 52.39%; 76.27%). This reduction persisted at all following time points in almost all subjects in our patient population (day 2, 95.8%; day 7, 100%; day 21, 91.7%). The median decrease at day 2 was 85.67% (95% CI, 78.23%; 90.16%); at day 7, 67.38% (95% CI, 67.38%; 86.98); and at day 21, 76.89% (95% CI, 35.00%; 83.16%). Moreover, a linear regression model with variance analysis demonstrated a statistically significant correlation between median VEGF and betaCTX circulating levels at each of the time points (1, 2, 7 and 21 days after ZOL infusion). The present work demonstrates that a single infusion of ZOL was able to induce a rapid and long lasting decrease of betaCTX plasma levels in the majority (23/24) of the included cancer patients. Furthermore, we found that there is a correlation between the levels of VEGF and betaCTX following ZOL treatment. Future clinical trials should be designed to prospectively evaluate the prognostic role of reduction of betaCTX and VEGF in response to ZOL to predict clinical and skeletal outcome.

Adult↗
PubMed2005

Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

PURPOSE: Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. PATIENTS AND METHODS: Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. RESULTS: Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. CONCLUSION: The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Adult↗
PubMed2005

Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an anglo-celtic cooperative oncology group study.

PURPOSE To compare the clinical and pathologic response rates of doxorubicin and cyclophosphamide (AC) with doxorubicin and docetaxel (AD) as primary chemotherapy in women with primary or locally advanced breast cancer. PATIENTS AND METHODS Eligible patients with histologically proven breast cancer with primary tumors >/= 3 cm, inflammatory or locally advanced disease, and no evidence of metastases were randomly assigned to receive a maximum of six cycles of either doxorubicin (60 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) administered intravenously (IV) every 3 weeks or doxorubicin (60 mg/m(2)) plus docetaxel (75 mg/m(2)) IV every 3 weeks, followed by surgery on completion of chemotherapy. Results A total of 363 patients were randomly assigned to AC (n = 180) or AD (n = 183). A complete clinical response was observed in 17% and 20% of patients treated with AC and AD, respectively (P = .42). Overall (complete and partial) clinical response rates for AC and AD were 61% and 70%, respectively (P = .06). There was no significant difference in either the pathologic complete response rates in the breast with AC (24%) and AD (21%; P = .61) or in the number of patients with positive axillary nodes at surgery with AC (61%) and AD (66%; P = .28). At a median follow-up of 32 months, there is no significant difference between the two groups for the number of relapses. CONCLUSION In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy of breast cancer, our data do not suggest a benefit for simultaneous AD over AC.

Adult↗
PubMed2005

Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells.

We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence- and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.

Antibiotics, Antineoplastic↗
PubMed2005

Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.

BACKGROUND: Whether bone markers have prognostic value in patients with bone metastases is unknown. We investigated this question in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer (NSCLC) and other solid tumors assigned to the placebo arms of two phase III trials of zoledronic acid. METHODS: Levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were assessed every 3 months for patients with prostate cancer (n = 203) or NSCLC or other solid tumors (n = 238) and were categorized as low or high. Patients were monitored for skeletal-related events, bone disease progression, and death. The relative risks (RRs) and 95% confidence intervals (CIs) for these outcomes were estimated for patients with high versus low levels of each marker using intensity-based multiple event and Cox regression models. All statistical tests were two-sided. RESULTS: In each disease group and overall, high levels of each marker at the beginning of the study were statistically significantly associated with an increased risk of negative outcomes. Use of recent marker assessments as time-dependent covariates gave even greater prognostic significance. High N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. In recent assessments, patients with high N-telopeptide levels had an increased relative risk of skeletal-related events (prostate cancer, RR = 3.25, 95% CI = 2.26 to 4.68, P<.001; NSCLC and other solid tumors, RR = 1.79, 95% CI = 1.15 to 2.79, P = .010), disease progression (prostate cancer, RR = 2.02, 95% CI = 1.48 to 2.74, P<.001; NSCLC and other solid tumors, RR = 1.91, 95% CI = 1.16 to 3.15, P = .011), and death (prostate cancer, RR = 4.59, 95% CI = 2.82 to 7.46, P<.001; NSCLC and other solid tumors, RR = 2.67, 95% CI = 1.85 to 3.85, P<.001) compared with patients with low N-telopeptide levels. CONCLUSIONS: Baseline and recent bone marker levels were predictive of negative clinical outcomes in patients with bone metastases secondary to prostate cancer and to NSCLC and other solid tumors. N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications.

Adult↗
PubMed2005

Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo--a role in tumour cell survival?

In addition to its role in bone turnover, osteoprotegerin (OPG) has been reported to bind to and inhibit Tumour necrosis factor-related apoptosis inducing ligand (TRAIL). TRAIL is produced in tumours by invading monocytes, inducing apoptosis in neoplastic cells sensitive to this cytokine. OPG production by tumour cells would therefore be a novel mechanism whereby cancer cells evade host defences and gain a growth advantage. In this study we show that OPG produced by breast cancer cells enhances tumour cell survival by inhibiting TRAIL-induced apoptosis. OPG expression by breast cancer cells (MDA-MB 436/231) grown in vitro was examined using PCR and ELISA, and the sensitivity of these cells to TRAIL was determined. The effects of OPG on TRAIL induced apoptosis was investigated by exposing MDA-MB 436 cells to TRAIL, in the presence or absence of OPG, followed by assessment of nuclear morphology. We found that the levels of OPG produced were sufficient to inhibit TRAIL-induced apoptosis, suggesting that OPG may play a role in tumour cell survival. We also examined the expression pattern of OPG in a selection of breast tumours (n=400) by immunohistochemistry, and related OPG expression to the clinico-pathological data for each tumour. OPG expression was found to be negatively correlated with increasing tumour grade. To our knowledge these results are the first to demonstrate that OPG can act as an endocrine survival factor for breast cancer cells, as well as reporting the expression patterns of OPG in a large cohort of human breast tumours.

Apoptosis↗
PubMed2005

Preclinical evidence for the effect of bisphosphonates and cytotoxic drugs on tumor cell invasion.

Bisphosphonates (BPs) are stable pyrophosphate analogs currently used in the treatment of patients with metastatic bone disease, known to affect bone resorption by reducing osteoclast activity. Use of these drugs in adjuvant therapy is currently under investigation following reports of an effect of BPs on tumor cell apoptosis in preclinical models. Recent evidence has suggested that BPs might also affect tumor cell invasion in vitro, and the component processes of adhesion, migration and degradation, through mechanisms including inhibition of prenylation of intracellular small GTPases such as Ras and Rho. The effects potentially may be enhanced through co-administration with chemotherapy agents, as both synergistic and additive effects have been described in vitro. This review discusses the preclinical evidence for the potential use of BPs and cytotoxic drugs for inhibiting tumor cell invasion, a key process in cancer progression.

Antineoplastic Agents↗
PubMed2005

Combined effects of zoledronic acid and doxorubicin on breast cancer cell invasion in vitro.

The bisphosphonate zoledronic acid and the cytotoxic drug doxorubicin induce synergistic levels of apoptosis in breast cancer cells. As zoledronic acid and doxorubicin have been shown to reduce cell invasion and migration, we have investigated if these drugs also act synergistically on breast cancer invasion in vitro. MCF7 cells were treated with 0.05 microM doxorubicin/4 h followed by 1 or 10 microM zoledronic acid/24 h (or the reverse sequence). To study invasion, MCF7 cells were either grown on Transwell membranes coated with Matrigel or in a 24-well plate. Cells were treated sequentially using the above drug combinations, prior to starting the invasion assays for 48 h. Cell growth and death were also assessed under the same conditions. We found that invasion of MCF7 cells treated with zoledronic acid and doxorubicin was significantly reduced when compared with control, but the effect was dependent on drug sequence. At 1 microM, zoledronic acid significantly reduced invasion only if cells were pre-treated with doxorubicin, but cell growth was unaffected. For 10 microM zoledronic acid, invasion was reduced when administered before or after the doxorubicin, but this dose of zoledronic acid caused a significant reduction in MCF7 growth. Apoptosis was not induced by any of the drug doses and combinations. We conclude that pre-treatment with 0.05 microM doxorubicin followed by 1 microM zoledronic acid reduces invasion when cells were grown on Matrigel. For 10 microM zoledronic acid, pre- or post-doxorubicin also reduces invasion, but for this combination inhibition of cell growth may contribute to the reduction in invasion observed.

Antibiotics, Antineoplastic↗
PubMed2005

Economic evaluation of zoledronic acid versus pamidronate for the prevention of skeletal-related events in metastatic breast cancer and multiple myeloma.

Skeletal complications of cancer decrease health-related quality of life. Bisphosphonates can prevent skeletal-related events. We collected resource use data prospectively for 930 patients alongside a multinational trial of zoledronic acid versus pamidronate for patients with metastatic multiple myeloma or breast cancer and > or =1 bone lesion. Country-specific unit costs were assigned to counts of resource use from randomization through last trial visit. Total costs were calculated by summing costs for medical resources, plus costs of institutional care and study medications and administration. Resource use was similar for both groups. Approximately half of the patients were hospitalized at least once during the mean follow-up of 10 months (52.8% for zoledronic acid versus 52.6% for pamidronate; P = 0.9504). The average number of hospital days was 8.9 for zoledronic acid versus 9.2 for pamidronate (P = 0.728). The mean total cost was 16,434 dollars for zoledronic acid and 15,735 dollars for pamidronate, an incremental cost of 699 dollars (95% confidence interval [CI], -1047 to 2163). Mean total costs for patients with multiple myeloma were 1982 dollars (95% CI, -1491 to 5335) higher for zoledronic acid (17,958 dollars) than for pamidronate (15,976 dollars). However, among patients with breast cancer, total costs in both groups were approximately equal (15,703 dollars for zoledronic acid versus 15,680 dollars for pamidronate; 95% CI for the difference: -1875 to 2012). There were no significant cost differences between patients receiving zoledronic acid and those receiving pamidronate.

Ambulatory Care↗