Biomedical subjects

Allan Lipton

Publications and source records attributed to Allan Lipton.

At least 37 records · Page 2Linked to original sources

PubMed2004

Monitoring the circulating levels of the HER2/neu oncoprotein in breast cancer.

The HER2/neu oncoprotein is a major target for the development of new cancer therapies and is similar to the estrogen receptor, which guides hormone therapy. The HER2/neu status is used to guide therapy decisions in patients with HER2/neu-overexpressing breast cancer tumors. The HER2/neu oncogene, or c-erbB-2, encodes a transmembrane receptor protein that is expressed on normal epithelial cells and can be overexpressed in breast cancer cells. Studies have shown that the extracellular domain (ECD) of the HER2/neu oncoprotein is released from the cell and can be measured in the circulation of women with breast cancer. Enzyme-linked immunosorbent assay methods used to measure the circulating HER2/neu ECD have shown that the prevalence of elevated ECD levels is approximately 18.1% in women with primary breast cancer and approximately 45.6% in women with metastatic breast cancer (MBC). Many studies have monitored the circulating ECD levels after surgery and indicate that increasing ECD levels can indicate recurrence of breast cancer earlier than clinical diagnosis. Studies in women with MBC showed that serial changes in circulating HER2/neu ECD levels paralleled the clinical course of disease, regardless of the treatment regimen. Several studies identified a subgroup of patients with MBC who had HER2/neu-negative disease by tissue testing but developed elevated ECD levels with MBC. In contrast to tissue testing, which is a one-time event, monitoring the circulating levels of the HER2/neu ECD in patients with breast cancer provides a real-time assessment of the HER2/neu status and provides important information for managing the therapy of patients with MBC.

Adult↗

PubMed2004

Combining flavopiridol with various signal transduction inhibitors.

Treatment of human tumors with a combination of chemotherapeutic agents results in improved response as well as the ability to use less toxic concentrations of the drugs. Recent phase I clinical trials with the cyclin-dependent kinase inhibitor, flavopiridol, have shown some promise in the treatment of a variety of human tumors. Because of the severe toxicity, however, the use of less toxic doses in combination with other antiproliferative agents would be desirable. The purpose of this study was to examine the effects of combining flavopiridol with several signal transduction inhibitors: the SC236 COX-2 inhibitor, a PKC kinase inhibitor and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor in a control vector transfected MCF-7 human breast cancer cell line (MCF/neo) and a HER-2/neu transfected MCF-7 cell line (MCF/18). Enhanced (better than that seen with either agent alone but not additive) growth inhibition was observed in both cell lines with the combination of flavopiridol and the PKC kinase inhibitor. The combination of flavopiridol and the SC236 COX-2 inhibitor resulted in an enhanced effect in the MCF/18 cell line and a synergistic effect in the MCF/neo cells. The combination of flavopiridol and LY294002 resulted in a synergistic effect in the MCF/18 cell line and an additive effect in the MCF/neo cells. These data suggest that combinations of flavopiridol and signal transduction inhibitors warrant further studies as treatments for breast tumors, and that HER-2/neu expression may influence the choice of inhibitor to combine with flavopiridol.

Antineoplastic Agents↗

PubMed2004

Gemcitabine/Irinotecan/celecoxib in pancreatic cancer.

Unresectable pancreatic cancer has few therapeutic options and a dismal prognosis. Cyclooxygenase-2 (COX-2) expression is increased at the RNA and protein levels in most human pancreatic cancers. The purpose of this trial was to determine whether the addition of a COX-2 inhibitor to chemotherapy was beneficial. To date, 11 patients with inoperable pancreatic cancer have been treated with the combination of gemcitabine (Gemzar), irinotecan (Camptosar), and celecoxib (Celebrex) at 400 mg orally twice daily. Encouraging pain relief, improvement in performance status, and decreases in CA 19-9 and carcinoembryonic antigen levels have been observed.

Aged↗

PubMed2003

American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer.

PURPOSE: To update the 2000 ASCO guidelines on the role of bisphosphonates in women with breast cancer and address the subject of bone health in these women. RESULTS: For patients with plain radiographic evidence of bone destruction, intravenous pamidronate 90 mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence supporting the efficacy of one bisphosphonate over the other. Starting bisphosphonates in women who demonstrate bone destruction through imaging but who have normal plain radiographs is considered reasonable treatment. Starting bisphosphonates in women with only an abnormal bone scan but without evidence of bone destruction is not recommended. The presence or absence of bone pain should not be a factor in initiating bisphosphonates. In patients with a serum creatinine less than 3.0 mg/dL (265 mumol/L), no change in dosage, infusion time, or interval is required. Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided. Creatinine should be monitored before each dose of either agent in accordance with US Food and Drug Administration (FDA) labeling. Oncology professionals, especially medical oncologists, need to take an expanded role in the routine and regular assessment of the osteoporosis risk in women with breast cancer. The panel recommends an algorithm for patient management to maintain bone health. CONCLUSION: Bisphosphonates provide a supportive, albeit expensive and non-life-prolonging, benefit to many patients with bone metastases. Current research is focusing on bisphosphonates as adjuvant therapy. Although new data addressing when to stop therapy, alternative doses or schedules for administration, and how to best coordinate bisphosphonates with other palliative therapies are needed, they are not currently being investigated.

Bone Density↗

PubMed2003

Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma.

BACKGROUND: The objective of this study was to assess the efficacy and safety of zoledronic acid in patients with bone metastases secondary to renal cell carcinoma (RCC). METHODS: A retrospective subset analysis of patients with RCC enrolled in a multicenter, randomized, placebo-controlled study of zoledronic acid was performed. Patients were randomized to receive zoledronic acid (4 or 8 mg as a 15-minute infusion) or placebo with concomitant antineoplastic therapy every 3 weeks for 9 months. The primary efficacy analysis was the proportion of patients with one or more skeletal-related events (SREs), which were defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate (events per year), disease progression, and multiple event analysis. RESULTS: In this subset of 74 patients with RCC, zoledronic acid (4 mg) was found to significantly reduce the proportion of patients with an SRE (37% vs. 74% for placebo; P = 0.015). Similarly, zoledronic acid significantly reduced the mean skeletal morbidity rate (2.68 vs. 3.38 for placebo; P = 0.014) and extended the time to the first event (median not reached vs. 72 days for placebo; P = 0.006). A multiple event analysis demonstrated that the risk of developing an SRE was reduced by 61% compared with placebo (hazard ratio of 0.394; P = 0.008). The median time to progression of bone lesions was significantly longer for patients who were treated with zoledronic acid (P = 0.014 vs. placebo). Zoledronic acid appeared to be well tolerated; the most common adverse events in all treatment groups included bone pain, nausea, anemia, and emesis. CONCLUSIONS: Zoledronic acid (4 mg as a 15-minute infusion) demonstrated significant clinical benefit in patients with bone metastases from RCC, suggesting that further investigation of zoledronic acid in this patient population is warranted.

Aged↗

PubMed2003

Bisphosphonates and metastatic breast carcinoma.

BACKGROUND: Metastasis to the skeleton occurs in approximately 75% of patients with advanced breast cancer. It is the cause of much morbidity and decreased quality of life in these patients. METHODS: Zoledronic acid (Zoledronate) is a new, potent third-generation bisphosphonate that has recently been approved by the U.S. Food and Drug Administration for the treatment of both osteolytic and osteoblastic bone metastases. A Phase 3 clinical trial comparing the efficacy of Zoledronic acid 4 and 8 mg compared with Pamidronate 90 mg every 3-4 weeks has been completed. RESULTS: A 15 minute infusion of 4 mg of zoledronic acid is at least as effective as 90 mg of pamidronate in preventing skeletal complications in patients with metastatic breast cancer. CONCLUSIONS: Bisphosphonate treatment can delay skeletal events in patients with breast carcinoma that is metastatic to bone. Future trials will build on the results achieved with bisphosphonate treatment.

Administration, Oral↗

PubMed2003

A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases.

BACKGROUND: Osteoprotegerin (OPG) is a decoy receptor for OPG ligand (OPGL), or receptor activator of NF-kappaB ligand (RANKL). RANKL/RANK interaction is important in terminal differentiation and activation of osteoclasts. In binding to RANKL, OPG blocks differentiation and activation of osteoclasts. AMGN-0007 is a recombinant OPG construct developed as a potential therapeutic agent in the treatment of bone disease. METHODS: A randomized, double-blind, double-dummy, active-controlled, single-dose, dose escalation study was conducted to determine the safety and effect on bone resorption of AMGN-0007 in patients with multiple myeloma (n = 28) or breast carcinoma (n = 26) with radiologically confirmed lytic bone lesions. Patients were randomized (3:1 ratio) to receive a single dose of either AMGN-0007 (subcutaneously [SC]) or pamidronate (90 mg intravenously) and were followed for 56 days. Medications or other diseases affecting bone metabolism and chemotherapy within 28 days of dosing were exclusion criteria. Biologic activity of AMGN-0007 was assessed by measurement of the surrogate marker of bone resorption, urinary N-telopeptide of collagen (NTX). RESULTS: AMGN-0007 caused a rapid, sustained, dose-dependent decrease in NTX/creatinine levels, which was at least comparable to the profile observed with pamidronate. Four serious adverse events were reported, three in breast carcinoma patients: a fracture in the left femur (pamidronate, considered unrelated), extreme fatigue (0.3 mg/kg AMGN-0007, considered unrelated), and congestive heart failure (1.0 mg/kg AMGN-0007, considered by the investigator to be probably related to doxorubicin and radiation therapy); one event occurred in a multiple myeloma patient: Herpes zoster (pamidronate, considered unrelated). Two multiple myeloma patients (1.0 mg/kg AMGN-0007) had albumin-adjusted serum calcium levels of 1.9 mmol/L on Day 8 but without clinical symptoms. CONCLUSIONS: A single SC dose of AMGN-0007 suppressed bone resorption as indicated by a rapid, sustained, and profound decrease of urinary NTX/creatinine in multiple myeloma and breast carcinoma patients. Changes were comparable to those with pamidronate. AMGN-0007 was well tolerated.

Antineoplastic Agents↗

PubMed2003

Bone metastases in breast cancer.

Patients with advanced breast cancer who develop bone metastases suffer from long-term skeletal morbidity. Complications of bone metastases include pain, pathologic fractures, and spinal cord compression, which have a significant impact on the quality of life of patients. Treatment options for patients with bone metastases include surgery, radiation, and analgesics to reduce bone pain and to prevent or repair fractures. Intravenous bisphosphonates can delay the onset of bone metastasis and reduce the percentage of patients who experience skeletal complications of bone metastasis, thus reducing skeletal morbidity. For the past 6 years, pamidronate disodium (90 mg administered by 2-hour intravenous infusion) has been the treatment of choice for the prevention of skeletal complications of bone metastases in patients with breast cancer. However, a more potent bisphosphonate, zoledronic acid (4 mg administered by 15-minute intravenous infusion), was approved for use and has improved efficacy in patients with bone metastases. Because of the increased efficacy and more convenient infusion time, zoledronic acid may become the new standard of care for the treatment and prevention of skeletal complications secondary to bone metastases in patients with breast cancer. Phase III clinical trials have shown that patients with an existing skeletal complication are more likely to develop subsequent complications compared with patients who have not experienced a complication. Therefore, zoledronic acid therapy should be initiated when the patient is diagnosed with bone metastasis.

Antineoplastic Agents↗

PubMed2003

Decreased response to paclitaxel versus docetaxel in HER-2/neu transfected human breast cancer cells.

Taxanes are effective in the treatment of metastatic breast cancer. Docetaxel has been shown to be more potent than paclitaxel in inducing bcl-2 phosphorylation and apoptosis and is clinically active in some paclitaxel-resistant breast tumors. HER-2/neu overexpression has been shown to correlate with resistance to hormonal therapy as well as chemotherapy. Using a HER-2/neu transfected MCF-7 human breast cancer cell line, we investigated the role of HER-2/neu overexpression on resistance to paclitaxel and docetaxel treatment. A control vector transfected MCF-7 human breast cancer cell line (MCF/neo) and a HER-2/neu transfected MCF-7 line (MCF/18) were treated with various concentrations of docetaxel or paclitaxel. Cell number was assessed using the MTT tetrazolium dye assay. In the control vector transfected MCF/neo cell line, paclitaxel and docetaxel gave similar dose-dependent growth inhibition ( p = 0.175). In HER-2/neu transfected MCF/18 cells, docetaxel treatment resulted in a dose-dependent inhibition similar to that seen in MCF/neo cells. Paclitaxel, however, gave significantly less growth inhibition than docetaxel in the HER-2/neu overexpressing MCF/18 cells (p = 0.0003). These data suggest that HER-2/neu overexpression may contribute to paclitaxel resistance. In contrast, the cytotoxic effects of docetaxel in these breast carcinoma cells are not affected by HER-2/neu expression. Therefore, docetaxel may be the preferred taxane therapy in HER-2/neu overexpressing breast tumors.

Antineoplastic Agents, Phytogenic↗

PubMed2003

Biochemical markers and skeletal metastases.

Bisphosphonate therapy for the treatment of skeletal complications from osteolytic metastases has become standard care in patients with cancer who have metastatic bone disease. The ability to assess patient response to bisphosphonate therapy has been helped by the availability of immunoassays that can measure bone collagen breakdown products that are increased in the blood and urine of patients with osteolytic metastases. Measurements of the carboxy and amino terminal telopeptides in blood and urine particularly have been helpful as adjunct methods to facilitate the treatment of patients with skeletal metastases. These biochemical bone markers have been shown to correlate with the extent of skeletal involvement and seem to provide a means of monitoring the dose and scheduling of bisphosphonate therapy of patients with cancer who have bony metastases.

Alkaline Phosphatase↗

PubMed2003

Metastatic breast cancer: overview of treatment.

Patients with metastatic breast cancer have a median survival of 2 to 3 years. Twenty percent of the patients who present with bone-only metastasis will be alive at 5 years from diagnosis. Current therapies are aimed at improving the quality of life, symptom control, and prolongation of survival. Newer endocrine and chemotherapeutic drugs are available to the medical oncologist for care of patients with metastatic breast cancer. We will briefly review the new advances in the treatment of metastatic breast cancer.

Antibodies, Monoclonal↗

PubMed2003

Effect of the combination of docetaxel, zoledronic acid, and a COX-2 inhibitor on the growth of human breast cancer cell lines.

Current trends in the treatment of human tumors are with drug combinations that result in improved responses as well as the ability to use less toxic concentrations of the drugs. Recent reports have shown that COX-2 inhibitors and taxanes are effective in the suppression of human tumor growth. The bisphosphonate, zoledronic acid, primarily used in the treatment of bone metastases, also inhibits proliferation and induces apoptosis in human breast and prostate carcinoma and multiple myeloma. HER-2/neu overexpression has been suggested as a mechanism for resistance to both hormonal therapy as well as chemotherapy. This study examines the effects of combining a cyclooxygenase-2 inhibitor with zoledronic acid and/or docetaxel in a HER-2/neu transfected and control human breast cancer cell line. All three compounds produced dose-dependent growth inhibition in both cell lines. The HER-2/neu transfected MCF/18 cells, however, were less sensitive to zoledronic acid than the control MCF/neo cells, 9% to 53% inhibition and 18% to 67%, respectively. Enhanced growth inhibition was observed in both cell lines with the combination of docetaxel and SC236 and the combination of docetaxel and zoledronic acid. The combination of SC236 with zoledronic acid also gave an enhanced inhibitory effect in the MCF/neo line. This combination, however, was additive in the HER-2/neu transfected MCF/18 cell line. The triple combination of SC236, zoledronic acid and/or docetaxel resulted in a small increase in growth inhibition compared to that seen with the double combinations.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Potential clinical utility of serum HER-2/neu oncoprotein concentrations in patients with breast cancer.

BACKGROUND: The HER-2/neu oncogene and its p185 receptor protein are indicators of a more aggressive form of breast cancer. HER-2/neu status guides Herceptin therapy, specifically directed to the extracellular domain (ECD) of the HER-2/neu oncoprotein. The HER-2/neu ECD is shed from cancer cells into the circulation and is measurable by immunoassay. METHODS: We performed a systematic review of the peer-reviewed literature on circulating ECD with respect to prevalence, prognosis, prediction of response to therapy, and monitoring of breast cancer. RESULTS: The prevalence of increased ECD in patients with primary breast cancer varied between 0% and 38% (mean, 18.5%), whereas in metastatic disease the range was from 23% to 80% (mean, 43%). Some women with HER-2/neu-negative tumors by tissue testing develop increased ECD concentrations in metastatic disease. Increased ECD has been correlated with indicators of poor prognosis, e.g., overall survival and disease-free survival. Increased ECD predicts a poor response to hormone therapy and some chemotherapy regimens but can predict improved response to combinations of Herceptin and chemotherapy. Many studies support the value of monitoring ECD during breast cancer progression because serial increases precede the appearance of metastases and longitudinal ECD changes parallel the clinical course of disease. CONCLUSIONS: The monitoring of circulating HER-2/neu ECD provides a tool for assessing prognosis, for predicting response to therapy, and for earlier detection of disease progression and timely intervention with appropriate therapy.

Biomarkers, Tumor↗

PubMed2003

Bisphosphonate therapy in the oncology setting.

Patients with metastatic cancer and bone involvement are at chronic risk of skeletal complications, including bone pain, fractures, spinal cord compression and hypercalcaemia of malignancy. Therapies targeting the primary malignancy are often unable to prevent skeletal complications, which often require orthopaedic surgery, radiation therapy and analgesics. Intravenous bisphosphonates can reduce the risk of skeletal complications and the requirement for palliative radiation therapy. Since its broad regulatory approval, zoledronic acid (ZOMETA, Novartis Pharma AG/Novartis Pharmaceuticals Corporation) 4 mg by 15-minute intravenous infusion has become widely used to treat bone metastases from all solid tumours and is becoming the standard of care for advanced breast cancer and multiple myeloma. Additionally, cancer treatment-induced bone loss is an emerging problem in clinical oncology, and bisphosphonates -- particularly intravenous bisphosphonates -- may provide benefits even before bone lesions develop. Further investigations of bisphosphonates in these and other indications are ongoing.

Administration, Oral↗

PubMed2003

Epidermal growth factor receptor mRNA in peripheral blood of patients with pancreatic, lung, and colon carcinomas detected by RT-PCR.

The epidermal growth factor receptor (EGFR) is overexpressed in many solid tumors. An RT-PCR assay was used to detect EGFR mRNA in the blood of 43 patients with pancreatic, lung (NSCLC), colon, and renal carcinomas. After an initial serum tube was drawn to clear the line of detached epithelial cells, a 3 ml sample of EDTA-anticoagulated blood was collected from each cancer patient and healthy control. Total RNA was isolated from each sample and from cancer cell lines. After reverse transcription using specific priming, outer and nested primers for EGFR were employed for cDNA amplification. RNA integrity was confirmed with RT-PCR amplification using beta2-microglobulin primers. PCR products were electrophoresed on agarose gels containing ethidium bromide and visualized. The assay was validated using Southern blotting and was capable of detecting a lower limit of 100 fg of total RNA from the A431 cell line. EGFR-positive cells were detected in 3/10 (30%) non-small cell lung cancer patients, 2/11 (18%) pancreatic cancer patients, and 2/16 (12.5%) colon cancer patients, but in 0/6 (0%) patients with renal carcinoma (16% of solid tumor patients overall). All 23 healthy controls were negative. This study is the first to apply RT-PCR for the detection of EGFR mRNA in the peripheral blood of patients with pancreatic and renal carcinomas, and it lends further support for the use of EGFR mRNA as a marker of CTCs in the blood of patients with certain types of solid tumors.

Adenocarcinoma↗

PubMed2002

American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma.

PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of lytic bone disease in multiple myeloma and to determine their respective role relative to other conventional therapies for this condition. METHODS: An expert multidisciplinary Panel reviewed pertinent information from the published literature through January 2002. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the Panel. Expert consensus was used if there were insufficient published data. The Panel addressed which patients to treat and when to treat them in the course of their disease. Additionally, specific drug delivery issues, duration of therapy, initiation of treatment and management of treatment of lytic bone disease was reviewed and compared with other forms of therapy for lytic bone lesions. Finally, the Panel discussed patient and physician expectations associated with this therapy for bony metastases, as well as public policy implications related to the use of bisphosphonates. The guidelines underwent external review by selected physicians, by the Health Services Research Committee members, and by the ASCO Board of Directors. RESULTS: The available evidence involving randomized controlled trials is modest but supports that oral clodronate, intravenous pamidronate, and intravenous zoledronic acid are superior to placebo in reducing skeletal complications. A reduction in vertebral fractures has consistently been seen across all studies. No agent has shown a definitive survival benefit. Intravenous zoledronic acid has recently been shown to be as effective as intravenous pamidronate. Because there are no direct comparisons between clodronate and pamidronate or zoledronic acid, the superiority of one agent cannot be definitively established. However, the panel recommends only intravenous pamidronate or zoledronic acid in light of the use of the time to first skeletal event as the primary end point and more complete assessment of bony complications in studies evaluating it. Additionally, clodronate is not available in the United States. The choice between pamidronate and zoledronic acid will depend on choosing between the higher drug cost of zoledronic acid, with its shorter, more convenient infusion time (15 minutes), versus the less expensive drug, pamidronate, with its longer infusion time (2 hours). CONCLUSION: Bisphosphonates provide a meaningful supportive benefit to multiple myeloma patients with lytic bone disease. However, further research on bisphosphonates is warranted, including the following: (1) when to start and stop therapy, (2) how to integrate their use with other treatments for lytic bone disease, (3) how to evaluate their role in myeloma patients without lytic bone involvement, (4) how to distinguish between symptomatic and asymptomatic bony events, and (5) how to better determine their cost-benefit consequence.

Clodronic Acid↗

PubMed2002

Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer.

PURPOSE: To determine the effect of elevation of serum HER-2/neu on response to hormone therapy. PATIENTS AND METHODS: Seven hundred nineteen metastatic patients with estrogen receptor-positive (ER(+)), progesterone receptor-positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels. RESULTS: Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with non-elevated and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with non-elevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P <.0001). CONCLUSION: Patients with ER(+) and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER(+) and serum HER-2/neu-negative patients. Their survival duration is also shorter.

Aged↗

PubMed2002

Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status.

PURPOSE: The objective assessment of bone metastases is currently based on serial changes in skeletal survey. We performed a prospective study to determine whether a correlation exists between the biochemical markers of bone turnover and x-ray evaluation of bone metastases in patients with or without bisphosphonate therapy, and whether bone markers are influenced by extraskeletal disease. PATIENTS AND METHODS: Patients with either bone or extraskeletal metastases were consecutively enrolled and World Health Organization response criteria were applied for both bone and extraosseous disease every 3 to 4 months. Serum levels of bone-specific alkaline phosphatase (B-AP) and C-telopeptide (ICTP) and urine levels of N-telopeptide (NTX) were measured monthly. The data were analyzed by generalized estimation equation regression. RESULTS: We studied 97 patients with bone metastases (52 also with extraskeletal metastases) and 26 with extraosseous disease only. Median time on study was 153 days, and 281 objective evaluations (171 in bone) were performed. With bisphosphonates (49 patients receiving pamidronate and three receiving clodronate), percent change from levels without therapy was 47% for NTX (P <.001) and 69% for B-AP (P =.008). With disease progression in bone, percent change from mean levels during stable disease was 152% for NTX (P <.001) and 144% for ICTP (P <.001) regardless of bisphosphonate therapy. NTX had the highest positive predictive value (71%) for the diagnosis of bone metastases progression. Extraskeletal disease had no significant effect on bone markers. CONCLUSION: Urinary NTX may be a valuable bone marker to assess the antiresorptive effect of bisphosphonate therapy and to evaluate the progression of bone metastases.

Adult↗