Bone scintigrams: their clinical usefulness in patients with breast carcinoma.

A comparison of bone scintigrams and roentgenographic skeletal surveys, obtained on 170 patients with breast carcinoma, was made to evaluate the diagnostic efficacy of these techniques in detecting metastatic bone lesions. The bone scans were abnormal in 81 patients, while the roentgenograms were abnormal in only 51. In 34 of the 81 (42%) patients with abnormal bone scans, there was no radiographic evidence of a benign lesion to account for the increased ratiotracer uptake; and the abnormalities noted on the bone scans were proven to be bony metastases on follow-up examinations. In the remaining 47 patients with positive bone scintigrams, both the scans and the roentgenograms were abnormal; however, in 23 patients the bone scan demonstrated significantly more lesions than what the roentgenograms had revealed. This study confirms that bone scan is superior to roentgen surveys in detecting skeletal metastases in patients with breast carcinoma. It was noted that the metastatic lesions can be visualized on the scans earlier than they are apparent on the X-rays by a mean interval of 4 months.     

Radiofrequency ablation of hepatic metastases

The liver is one of the most common sites for cancer metastases that result in significant morbidity and mortality. Although surgical resection is associated with improvements in local control and survival, only a minority of patients are candidates for this approach. Radiofrequency ablation (RFA) is an important alternative/complementary tool in the treatment of metastatic disease to the liver and can lead to palliation as well as increased survival in selected patients. RFA has been shown to be safer and better tolerated than other ablative techniques and has been associated with a low rate of local recurrence when performed properly. RFA also has shown some promise in combination with surgical resection and other therapies. Patients who undergo RFA still suffer from progressive metastatic disease, reinforcing the premise that local therapies have little impact on the natural history of aggressive cancers. Trials combining RFA with surgical resection and regional and systemic chemotherapy are ongoing and it is the hope that RFA combined with multimodality adjuvant therapy will reduce the development of both local disease and progressive metastatic disease, leading to improved overall survival.     

The radiocolloid bone marrow scan in malignant disease

The radiocolloid bone marrow scans in 107 patients with malignant disease were reviewed. The observed scan patterns were classified into five groups: normal (type 1), moderately expanded (type 2), greatly expanded (type 3), peripheral expansion with central depression (type 4), and greatly reduced to absent intramedullary marrow (type 5). Correlation was made between scan pattern and clinical status of the patient for each disease category. In polycythemia vera, there was progressive expansion of the marrow organ that correlated well with the patient's course but not duration of disease. Type 3 or 4 marrow scans were associated with failure of effective marrow function. In myelofibrosis, regardless of associated cause, the scan pattern was predominantly type 4 or 5. Among the 42 patients with leukemia, 41 had abnormal scans. Type 4 was the characteristic scan pattern in untreated acute leukemia, and the scan became more normal with favorable treatment response. Patients with chronic myelogenous leukemia, either with myelofibrosis or blast crisis, had a type 4 or 5 marrow pattern. Scan patterns in the 30 patients with Hodgkin's disease were influenced by stage of disease and prior therapy. In untreated patients of stage I-II, the scan pattern was always normal. Among the 17 stage III or IV patients, scan patterns of type 4 or 5 were frequently observed regardless of previous therapy. Focal defects were common in this group and were of two types: (1) a small irregular defect due to infiltration of tumor (two cases), and (2) a sharply circumscribed defect due to radiation therapy (seven cases). Patients with metastatic malignancy and lymphosarcoma involving bone marrow had abnormal scans showing peripheral expansion or focal defects. Some of the clinical applications for radiocolloid marrow scanning that were suggested for these observations include determining optimal bone marrow biopsy site, aiding staging and the evaluation of treatment response for hematologic malignancies, screening patients for metastatic involvement of bone as an adjunct to the strontium-85 bone scan, and evaluating extent of bone marrow injury following radiation therapy. It is concluded that the radiocolloid scan of the bone marrow organ can be an important aid in management of patients with malignant disease.     

The importance of complete screening for amyloid fibril type and systemic disease in patients with amyloidosis in the respiratory tract

BACKGROUND: Patients with symptomatic thoracic involvement by amyloidosis are virtually all of AL-type, and have historically been divided into systemic and localised disease, a subdivision that helps predict outcome and aids management. Assessment and classification of amyloid has evolved in recent years to include a variety of tests, including radiolabelling of the serum amyloid P component (SAP scan) to assess anatomical distribution and immunohistochemical studies to assess fibril subtypes. Furthermore, CT scanning is now a frequent investigation for the diagnosis of thoracic disease. We wished to determine the value of these investigations on the management of such patients with amyloidosis. METHODS: Clinicopathological data, including immunohistochemical analysis, CT scans and SAP scan results, were retrospectively reviewed from patients presenting with amyloidosis in the respiratory tract. These were then analysed to determine their impact on classification and prognosis. RESULTS: Seventeen patients over ten years were identified, one case being related to metastatic medullary carcinoma of the thyroid. Of the remaining 16 cases, one was shown to have hereditary amyloid of transthyretin-type (TTR) on immunohistochemistry, altering management. The remaining 15 cases were AL-type, with 6 cases being classified as localised and 9 cases as systemic, after evaluation for serum and/or urine monoclonal products, cardiac involvement via echocardiography, plasma cell abnormalities on bone marrow examination, CT scan and SAP scan. 3/3 patients with localised AL-type disease had a negative SAP scan, whilst 3/5 patients with systemic AL-type disease had a positive scan. SAP scan of the patient with TTR-type disease provided information on extent of disease and supported the diagnosis by the pattern of distribution. Using CT scans to discriminate between localised and systemic disease showed a significant association with mortality at 2 years (p = 0.03). CONCLUSION: Although the majority of symptomatic patients with pulmonary amyloidosis have AL-type disease, immunohistochemical confirmation is necessary in order not to miss rarer subtypes with completely different treatment regimes. Furthermore, a comprehensive evaluation, including SAP scan and CT scan of the thorax, in conjunction with echocardiography, bone marrow, serum and urine studies, needs to be undertaken in order to achieve maximum accuracy with regard to localised and systemic disease.     

Intravenous Bisphosphonate Therapy Does Not Acutely Alter Nuclear Bone Scan Results

IntroductionTheoretically, the bisphosphonates used to treat metastatic bone disease could influence the results of nuclear bone scans which use the structurally similar technetium 99m methylene diphosphonate (99mTc MDP). A prospective clinical study was designed to explore this hypothesis.Patients and MethodsPatients with metastatic breast cancer receiving intravenous bisphosphonate (IVBP) therapy who had ≥3 osseous lesions on nuclear bone scan were eligible. A baseline bone scan (number 1) was performed as clinically indicated and IVBP with zoledronic acid was administered within 72 hours. A second bone scan (number 2) was performed within 72 hours of zoledronic acid dosing. Both bone scans were reviewed in a blinded fashion and assessed for changes in the number and intensity of osseous lesions. Ten patients were planned to yield at least 30 lesions.ResultsTen patients were enrolled. One patient withdrew consent and 1 was excluded due to protocol deviation. Among the 8 patients were 163 assessable osseous lesions. The median time from bone scan number 1 to IVBP was 1 day (range, 1-2 days). The median time from IVBP to bone scan number 2 was 2 days (range, 1-3 days). The paired imaging showed no changes in the total number of bone metastases. One hundred sixty-one lesions were identical in both scans; in 1 patient there were 2 lesions that were discordant, one more intense, the other less intense.ConclusionThese data do not support the hypothesis that IVBP therapy interferes with bone scan results.     

Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

The CNS is a common site of metastasis in patients with malignant melanoma. Locoregional control either with surgery or radiotherapy is first-line treatment for patients with brain metastasis should they be suitable candidates. For those patients who are not and those who progress after previous treatment, there is an unmet clinical need for effective systemic therapies. Systemic cytotoxics, such as temozolamide and fotemustine, have only modest activity, resulting in a median progression-free survival ranging from 1–2 months, in patients with metastatic melanoma to the brain. Newer systemic treatments such as vemurafenib and ipilimumab have been approved for the treatment of melanoma, but evidence regarding their activity in brain metastases is inconclusive due to the limited access of patients to clinical trials. This is now being revised and more data are emerging supporting the inclusion of patients with brain metastasis in trials. In this review, the authors present data regarding the efficacy of systemically administered therapies in patients with metastatic melanoma to the brain.     

Metastatic Prostatic Adenocarcinoma Mimicking Inflammatory Breast Carcinoma: A Case Report

Prostate adenocarcinoma can manifest as a fairly indolent tumor or as a very aggressive cancer with significant invasive and metastatic potential. Common metastatic sites include bone, liver, lymph nodes, and adrenal glands. Dermatologic manifestations are rare. We present a case of a man who presented with breast skin changes that mimicked inflammatory breast carcinoma with specialized testing ultimately giving a diagnosis of metastatic prostatic adenocarcinoma. A 78-year-old man presented with left breast redness and swelling. Examination revealed an erythematous rash with subcutaneous edema over the left hemithoracic area. A breast ultrasound showed no focal mass, and a breast core biopsy had no evidence of tumor. A skin biopsy showed metastatic carcinoma in dermal lymphatics, and the tumor was found to have no estrogen or progesterone receptors or HER2 expression. Computed tomography scans, positron emission tomography, and a nuclear bone scan revealed widespread skeletal metastases. The patient received a 3-month course of capecitabine and cyclophosphamide with no improvement in his skin lesions. Subsequent immunohistochemical staining on the tumor specimen was positive for prostate-specific antigen (PSA) and α-methyl-CoA-racemase, confirming a diagnosis of metastatic prostatic adenocarcinoma. He received leuprolide and bicalutamide and demonstrated significant improvement with near-complete resolution of his skin lesions and a decrease in his PSA level. Prostatic adenocarcinoma presenting initially as a breast malignancy is a rarely recognizable clinical event. Undoubtedly, increased awareness and recognition of the rare entity described herein will allow for the prompt initiation of specific therapies, which might be of benefit to many patients.     

Renal cell carcinoma bone metastases: clinical advances

Bone is a common site of metastatic spread in patients with advanced renal cell carcinoma (RCC) occurring in around one-third of patients enrolled in clinical trials evaluating modern systemic therapies for this disease. Until recently, limited systemic therapeutic options were available for advanced RCC. Nowadays, a quiver of agents have demonstrated activity, including compounds targeting the vascular endothelial growth factor (VEGF) axis and those targeting the mammalian target of rapamycin (mTOR). Despite a detailed biological understanding of how these drugs work, their effect on bony metastases is less clear. Data suggesting that bisphosphonates (namely zoledronic acid) benefit patients with bone metastases from advanced RCC was gathered prior to the targeted therapy era; therefore, there is some uncertainty about their role in patients on modern RCC therapies. This review summarizes the current targeted therapies registered for use in advanced RCC and postulates how some of them might affect the behavior of bone metastases. It also explores the data available on the role of bisphosphonates for bone metastases from RCC, describes methods of assessing response to therapy for bone metastases and delineates future expectations for the treatment of bone metastases from advanced RCC.     

Myeloma bone disease and treatment options

Multiple myeloma (MM) is a B-cell malignancy characterized by enhanced bone loss commonly associated with a diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Recent characterization of osteoclast-activating factors (OAFs), receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL)-osteoprotegerin-RANK system, and inhibitors of Wnt signaling have provided a better understanding of myeloma bone disease in molecular level. The development of minimally invasive surgical procedures such as kyphoplasty and vertebroplasty allows myeloma patients with vertebral compression fractures to have immediate improvement in quality of life and shorter hospital stays. Monthly intravenous infusion of either pamidronate or zoledronic acid have reduced the skeletal complications among MM patients and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although pre-clinical studies suggest nitrogen-containing bisphosphonates have potent anti-tumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible anti-tumor effects clinically. As our understanding of the pathophysiology of myeloma bone disease continues to increase, new target therapies will continue to emerge offering new and more advanced options for the management of myeloma bone disease.     

Focal progression in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: a three-center-based study of 38 patients

BACKGROUND: This study aimed to investigate the outcome of patients with advanced gastrointestinal stromal tumors (GISTs) exhibiting focal disease progression during imatinib therapy, treated by surgical resection and imatinib continuation. METHODS: A consecutive series of 38 patients with metastatic GISTs who underwent treatment with imatinib at our centers during a defined period of time was evaluated. Patients were evaluated for demographics including tumor-related features, initial response, disease recurrence, and salvage treatment modalities, and were classified as having either focal or generalized progression upon presentation prior to salvage therapy. RESULTS: After a median follow-up of 31.8 months, 25 of the 38 (65.8%) patients had progressed. Nine (36%) patients were classified as having focal and 16 (64%) as having generalized progression. Salvage therapies were: surgical resection and imatinib dose escalation in patients exhibiting focal progression and imatinib dose escalation alone in the majority of patients exhibiting generalized progression. Focal progression was associated with prolonged progression-free survival (PFS) and overall survival (OS) after salvage therapy as compared with generalized progression (median PFS and OS, 11.3 months and not attained, versus 2.5 and 22.8 months, respectively). Six-month PFS was 89% and 39% in patients exhibiting focal and generalized progression, respectively. KIT mutation analysis of controlled and progressive lesions was performed in 4 patients with focal progression. Secondary KIT mutations affected progressive lesions, whereas nonprogressive lesions harbored the original mutations only. CONCLUSION: Patients with advanced GIST exhibiting focal disease progression during imatinib therapy may benefit from surgical resection and imatinib continuation. Imatinib resistance seems to be partial in these patients.     

Lack of Correlation Between Prostate-Specific Antigen and the Presence of Measurable Soft Tissue Metastases in Hormone-Refractory Prostate Cancer

Appropriate staging procedures for patients with hormone-refractory prostate cancer are poorly defined. In particular, there are no studies correlating prostate-specific antigen (PSA) with more traditional methods of staging. We have evaluated the abdominal/pelvic CT scan, bone scan, and PSA results following initial diagnosis of hot-nione-refractory prostate cancer in 177 consecutive patients (median age = 63.1 years, range 45-80). Thirty-four patients (19.2%) had nteasurable lesions (≥ 2 cm) on CT scan cotnpatible with inetastatic disease. Of the patients with measurable lesions, 29/34 (85.3%) had iztroperitoneal and/or- pelvic adenopathy; 5 patients (14.7%) had measurable lesions in the liver. Other- sites of metastatic disease were detected in less tkari 1% of the patients receiving scans. All patients had bone scan abriormalities compatible with metastatic disease. Results of these imaging studies were then compared to PSA serum concentration (Abbott IMx). The mean PSA concentration was not direrent in those patients with soft tissue disease as compared to those without soft tissue involvement and there was no correlation between PSA concentration and the presence or absence of measurable soft tissue disease. In contrast to previously published studies in hormone-naile prostate cancer patients, these studies in hormone-refractory patients indicate that the detection of metastatic disease by standard radiological procedures camot be predicted by measurement of serum PSA.     

Bone disease in testicular and extragonadal germ cell tumours

Of 297 patients with metastatic testicular and extragonadal germ cell tumours (GCT), bone involvement was detected clinically in 3% (7/251) of those at first presentation and in 9% (4/46) of relapsed cases. This difference was not statistically significant (95% confidence limits -2%; +14%). Concurrent systemic metastases, commonly involving lung (7/11 cases) and para-aortic lymph nodes (6/11), were present in all patients with bone disease. All affected patients had localized bone pain and lumbar spine was the most frequent site involved (9/11). Spinal cord compression occurred in two patients while a third developed progressive vertebral collapse after chemotherapy and required extensive surgical reconstruction. At median follow-up of 4 years, survival among patients presenting with bone disease (6/7) was similar to overall survival in the whole group (84%) and appeared better than in those with liver (18/26, 69%) or central nervous system (6/9) metastases at presentation. Back pain in metastatic germ cell tumours is often due to retroperitoneal lymphadenopathy but lumbar spine osseus metastases must be recognized early if severe potential complications, such as spinal cord compression, are to be avoided. In this series, bone metastases were not seen in the absence of widespread systemic disease suggesting all solitary bony lesions in GCT patients should be biopsied.     

Predictive value of bone scans in an adjuvant breast cancer program

Technetium 99m phosphate-complex bone scans were performed in 43 women within two months of mastectomy for stage I (1 patient), stage II (28 patients), and stage III (14 patients) breast cancer. Twelve (28%) initial bone scans were interpreted as either equivocally abnormal (6 scans) or definitely abnormal (6 scans). Radiographs confirmed metastatic disease in 2 patients who were then considered ineligible for adjuvant therapy (adriamycin-cyclophosphamide with or without local radiotherapy). Of the remaining 41 eligible patients, all have received adjuvant therapy and 36 have had at least one additional bone scan at 6-month intervals. Among 20 patients whose serial bone scans were unchanged, there has been no clinical recurrence with a mean followup of 20 months. In contrast, among 16 patients whose serial bone scans have changed (e.g., appearance of new focal lesions, disappearance of old lesions), there have been 6 clinical recurrences (p = 0.01) with a mean followup of 43 months. We conclude that carefully performed technetium pyrophosphate bone scans are helpful in the accurate initial staging of patients being considered for adjuvant breat cancer treatment, and that serial changes in the bone scan identify a group of patients at high risk for early recurrence.     

Clinical features and managements of breast cancer patients with pulmonary metastasis

One hundred-thirty-nine patients with advanced breast cancer were treated during five years since 1977 in our Department. Treatments consisted of chemotherapy (ACF and ACFM), hormone therapy (tamoxifen) and their combination (ACFT). Seventy patients had lung metastases at the initiation of these therapies. An overall response rate was 41%, whereas a response rate for metastatic lung lesions was 26% (18/69). Breast cancer is known as a systemic disease, thus other therapies such as pulmonary resection or irradiation had a limited indication to control the lung metastasis. Our result indicates that favorable responses to advanced breast cancer with systemic therapies will improve the prognosis of breast cancer patients with lung metastasis.     

Whole‐body magnetic resonance imaging in the detection of skeletal metastases in patients with prostate cancer

Whole‐body MRI is an effective method for evaluating the entire skeletal system in patients with metastatic disease. This study aimed to compare whole‐body MRI and radionuclide bone scintigraph in the detection of skeletal metastases in patients with prostate cancer. Patients with prostate cancer at high risk of skeletal metastasis with (i) prostate‐specific antigen of ≥50 ng/mL; (ii) composite Gleason score of ≥8 with prostate‐specific antigen of >20 ng/mL; or (iii) node‐positive disease were enrolled in this prospective study before systemic treatment was initiated. Whole‐body MR images and bone scans of 39 patients were analysed. Seven patients had bone metastases on bone scans, while seven patients had skeletal metastases by whole‐body MRI, with concordant findings only in four patients. Compared with the ‘gold standard’, derived from clinical and radiological follow‐up, the sensitivity for both bone scans and MRI was 70%, and the specificity for both was 100%. Magnetic resonance imaging detected 26 individual lesions compared with 18 lesions on bone scans. Only eight lesions were positive on both. Bone scans detected more rib metastases, while MRI identified more metastatic lesions in the spine. Whole‐body MRI and radionuclide bone scintigraphy have similar specificity and sensitivity and may be used as complementary investigations to detect skeletal metastases from prostate cancer.     

Lobular carcinoma of the breast metastatic to bone with unusual clinical, radiologic, and pathologic features mimicking osteopoikilosis

A 55-year-old woman who underwent a right radical mastectomy for infiltrating lobular carcinoma was found to have multiple diffuse osteoblastic bone lesions. Since she was asymptomatic, had no elevation of alkaline phosphatase, and the lesions did not take up technetium pyrophosphate on bone scan, she was thought to have osteopoikilosis. An iliac bone biopsy was performed that showed greatly thickened bony trabeculae with diffuse delicate marrow fibrosis entrapping easily overlooked short strands of small malignant cells. The histologic picture also closely resembled osteopoikilosis. Although infiltrating lobular carcinoma has been recognized as separate from ductal carcinoma in the primary site, its recognition in metastatic foci is still vague. Attention is drawn to its histologic appearance in skeletal metastases so that such lesions will be more recognizable in the future.     

Management of Colon Cancer and Liver Metastases: Is There a Role for Molecularly Targeted Agents?

Recent advances in caring for metastatic colorectal patients have yielded significantly longer survival times. When metastasis is confined to one or even two organs and is amenable to resection, 20–40 % of patients may be free of disease after 5 years. Surgery is not always possible mainly because of the tumor size or location, the number of metastatic nodules, or inadequate organ reserve. Borderline resectable disease and even clearly inoperable disease may still, though not always, become candidates for R0 resection after successful systemic treatment. There is mounting evidence that regimens that result in greater tumor reductions may have greater impact on resection rates, and the advent of newer, more effective therapies raises the hope that a greater number of patients may eventually be candidates for curative surgical treatments. This article discusses the use of molecularly targeted agents in this context, as well as their risk and benefits related to the surgical procedure.     

Molecular pathogenesis of bone metastases in breast cancer: Proven and emerging therapeutic targets

Metastatic occurrence is the principal cause of death in breast cancer patients. The high osteotropism makes breast cancer the most common primary tumor type associated with metastatic bone disease. The peculiar clinical aspects associated with metastases limited to the skeletal system suggest considering these cases as a distinctive subset of metastatic patients with a better prognosis. Because bone is frequently the first metastatic site in disease relapse, it is feasible that the next improvement in therapeutic options for bone metastatic disease could be associated with an improvement of survival expectation and quality of life in breast cancer patients. Study of the molecular basis of bone remodeling and breast cancer osteotropism has allowed identification of several therapeutic candidates involved in formation and progression of bone metastases. These targets are frequently the determinants of positive feedback between the tumor and bone cells whose clinical outcome is osteolytic lesions. In this review, we discuss the physiopathologic features underlying targeted therapeutic strategies aimed at interfering with the aberrant bone remodeling associated with breast cancer metastases.     

New developments in the treatment of gastrointestinal neuroendocrine tumors

Patients with metastatic gastrointestinal neuroendocrine tumors have traditionally been faced with few effective treatment options. Somatostatin analogs often successfully control symptoms of hormonal hypersecretion but seldom result in tumor regression. Some patients with hepatic metastases are also candidates for ablative therapies such as surgical debulking or embolization. The role of systemic agents such as interferon alfa or cytotoxic chemotherapy remains ill defined. The more prevalent use of these modalities has been restricted by low tumor response rates and the potential for toxicity. Novel agents, including radiolabeled somatostatin analogs, inhibitors of the vascular endothelial growth factor pathway, and inhibitors of mammalian target of rapamycin, have shown promising activity in recent clinical studies. Continued investigation of these agents should render a better understanding of their efficacy in patients with advanced neuroendocrine tumors.     

American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel.

PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition. METHODS: An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. 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 in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected physicians, members of the American Society of Clinical Oncology (ASCO) Health Services Research Committee, and the ASCO Board of Directors. RESULTS: Bisphosphonates have not had an impact on the most reliable cancer end point: overall survival. The benefits have been reductions in skeletal complications, ie, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. Intravenous (IV) pamidronate 90 mg delivered over 1 to 2 hours every 3 to 4 weeks is recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. For women with only an abnormal bone scan but without bony destruction by imaging studies or localized pain, there is insufficient evidence to suggest starting bisphosphonates. Starting bisphosphonates in patients without evidence of bony metastasis, even in the presence of other extraskeletal metastases, is not recommended. Studies of bisphosphonates in the adjuvant setting have yielded inconsistent results. Starting bisphosphonates in patients at any stage of their nonosseous disease, outside of clinical trials, despite a high risk for future bone metastasis, is currently not recommended. Oral bisphosphonates are one of several options which can be used for preservation of bone density in premenopausal patients with treatment-induced menopause. The panel suggests that, once initiated, IV bisphosphonates be continued until evidence of substantial decline in a patient's general performance status. The panel stresses that clinical judgment must guide what is a substantial decline. There is no evidence addressing the consequences of stopping bisphosphonates after one or more adverse skeletal events. Symptoms in the spine, pelvis, or femur require careful evaluation for spinal cord compression and pathologic fracture before bisphosphonate use and if symptoms recur, persist, or worsen during therapy. The panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy, not be displaced by bisphosphonates. IV pamidronate is recommended in women with pain caused by osteolytic metastasis to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, since it was associated with a modest pain control benefit in controlled trials. CONCLUSION: Bisphosphonates provide a meaningful supportive but not life-prolonging benefit to many patients with bone metastases from cancer. Further research is warranted to identify clinical predictors of when to start and stop therapy, to integrate their use with other treatments for bone metastases, to identify their role in the adjuvant setting in preventing bone metastases, and to better determine their cost-benefit consequences.