Natural History Of Bone Metastases Research Articles

Establishment of a primary cell culture of bone metastasis from urothelial carcinoma.

e17030 Background: Urothelial carcinoma (UC) accounts for 90% of cases of bladder cancer. In advanced UC diagnosis, skeletal involvement is frequent. Here we report the establishment of a primary culture of bone metastasis (BM) from High Grade UC derived from 81 years-old patient with a previous diagnosis of papillary urothelial cancer in 2016. After 2 years, patient relapsed to bone and visceral sites and because of poor clinical condition, patient underwent palliative best supportive care. Methods: Patient-derived bone metastatic cell culture was obtained from a surgical specimen. Tumor cells were isolated by collagenase digestion. Cells were seeded on in vitro 2D plates or into 3D collagen scaffolds composed of bovine collagen type I. The establishment of tumor cell isolation was confirmed through the evaluation of cytomorphologic features and positive pan-citokeratin staining. Then, drug treatments was performed and cell survival was evaluated. The study was approved by Ethical Committee and patient signed an informed consent. Results: After a long-term culture, we were able to isolate from a 3D scaffold a tumor clone that successfully growth until passage 20. Stabilized cells generate spheroid-like aggregates, recreating acinar-structures typical of the primary papillary urothelial tumor. Next, we treated cells with: Gemcitabine (Gem), Carboplatin (Carbo), Docetaxel, Carbo+Gem and Bone targeted drugs (Zoledronic Acid and Denosumab). The most effective treatment was Gem+Carbo, in particular 24% of survival in 2D platform and 87% on 3D collagen scaffold. For all treatments, cells cultured on 3D scaffold were more resistant to drugs, mimicking more closely the in-vivo condition. Conclusions: We were able to isolate and establish a BM primary culture from UC using a 3D in-vitro collagen scaffold. This system can recreate microenvironmental conditions more similar to in-vivo ones and it promoted the isolation of tumor cell clones from stromal components of the heterogeneous primary culture. This cell line could be useful to investigate the molecular and genetic profile in order to identify promising molecular targets and to better understard the natural history of BM from UC.

Natural history of malignant bone disease in hepatocellular carcinoma: final results of a multicenter bone metastasis survey.

BackgroundBone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC). Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC.Patients and MethodsData on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed.ResultsThe median age was 70 years; 172 patients were male (81.5%). The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis); 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%). Most of these lesions were osteolytic (82.4%); 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (p = 0.001, HR = 1.819). The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (p = 0.005), ECOG performance status (p = 0.002) and treatment with bisphosphonate (p = 0.024) were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE) (p = 0.021) and OS (p = 0.001).ConclusionsThis study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.

The natural history of bone metastases in castrate-resistant prostate cancer.

239 Background: Previous authorities have commented on the lack of data regarding overall prevalence of Skeletal-Related Events (SREs) in Castrate Resistant Prostate Cancer (CRPC) in patients who have not received therapy for SRE prevention. We describe a cohort of 129 patients followed to death. Methods: 129 patients treated with palliative chemotherapy for CRPC at University College Hospital London between 01/01/2006 and 31/12/2010 had retrospective collection of data concerning date of prostate cancer diagnosis, date of CRPC, date of death, date of bone metastasis development, radiotherapy treatment, pathological fracture, bone surgery, and spinal cord compression up until 01/06/2013. Results: Median age at castrate resistant prostate cancer development was 70 years. Overall median time from prostate cancer diagnosis to establishment of castrate-resistant state was 33 months (range 5-223). Median time from castrate-resistant state to death was 23 months (0-99). Only 9/129 patients failed to develop bone metastases. A total of 162 palliative radiotherapy treatments were given to 74 patients. Only 10 radiotherapy treatments occurred prior to the development of castrate-resistant disease, the remaining 152 all occurred after castrate-resistance occurred. Symptomatic pathological fracture occurred 28 times in 22 (17%) patients. One or more surgical interventions for bone disease were carried out in 23 (18%) patients. 27 (21%) patients were treated for spinal cord compression. In total, 352 skeletal-related events occurred in 89 patients. Conclusions: Important skeletal-related events occurred in 69% of patients with mCRPC. It is possible that incomplete follow-up in clinical trials of agents such as bisphosphonates considerably under estimate the effect of the investigational agent. The frequency of pathological long bone fracture suggests current measures to detect prefracture and intervene are inadequate. [Table: see text]

Bone metastases in soft tissue sarcoma: a survey of natural history, prognostic value and treatment options

BackgroundWe surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS).MethodsThis multicenter retrospective observational study included 135 patients. Histological subtype, characteristics of bone metastases, treatment, skeletal related events (SREs) and disease outcome were recorded.ResultsThe most represented histological subtypes were leiomyosarcoma (27%) angiosarcoma (13%) and undifferentiated sarcoma (8%). Axial skeleton was the most common site for bone involvement (70%). In 27% of cases, bone metastases were present at the time of diagnosis. Fifty-four (40%) patients developed SREs and the median time to first SRE was 4 months (range 1–9). The most common SRE was the need for radiotherapy (28%) followed by pathological fracture (22%). Median survival after bone progression was 6 months (range 1–14). SREs were associated with decreased overall survival (OS) (P = 0.04). A subgroup analysis revealed that bisphosphonates significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002) while they did not determine an improvement in OS, although a favourable trend was identified (median: 7 versus 5 months; P = 0.105).ConclusionsThis study illustrates the burden of bone disease from STS and supports the use of bisphosphonates in this setting.

685P - Natural History of Bone Metastasis in Gastric Cancer: Results of an Italian Multicenter Survey

ABSTRACT Introduction in patients with gastric cancer, in accordance with the increase of survival, bone metastasis are an emerging problem. In scientific literature there are few data about the natural history of bone disease in gastric cancer. We report the preliminary data of a large Italian multicenter survey. Methods 142 patients with gastric cancer and with evidence of bone metastases have been included in the study. All patients were died due to cancer at the moment of the study inclusion. Clinico-pathological data, data on survival and Skeletal Related Events (SRE) have been collected in a master database and analyzed. Results 96 males and 46 females; median age: 62 (19-80); patients with bone metastases at the moment of gastric cancer diagnosis: 23.2%; patients with single bone metastasis: 11.3%, patients with multiple metastasis 88.7%; lytic type: 49.3%, mixed: 19.7%, blastic: 27.5%, no data 3.5%. Sites: spine (78%), pelvis (65.5%), long bones (54%), other (27%). Median time to bone metastases: 7 months (0-132). Patients with at least 1 SRE: 31.7%. Types of SREs: pathologic fracture (27.7%), radiotherapy (43.1%), spinal compression (9.3%), bone surgery (13.8%), hypercalcaemia (6.1%). Median time to first SRE: 1 (0-65). Median survival after bone metastasis diagnosis: 5 (0-48). Conclusions The present survey is the result of the largest Italian descriptive study concerning the natural history of bone disease in gastric cancer patients. Disclosure All authors have declared no conflicts of interest.

Natural history of bone metastasis in colorectal cancer: final results of a large Italian bone metastases study

Data are limited regarding bone metastases from colorectal cancer (CRC). The objective of this study was to survey the natural history of bone metastasis in CRC. This retrospective, multicenter, observational study of 264 patients with CRC involving bone examined cancer treatments, bone metastases characteristics, skeletal-related event (SRE) type and frequency, zoledronic acid therapy, and disease outcomes. Most patients with bone metastases had pathologic T3/4 disease at CRC diagnosis. The spine was the most common site involved (65%), followed by hip/pelvis (34%), long bones (26%), and other sites (17%). Median time from CRC diagnosis to bone metastases was 11.00 months; median time to first SRE thereafter was 2.00 months. Radiation and pathologic fractures affected 45% and 10% of patients, respectively; 32% of patients had no reported SREs. Patients survived for a median of 7.00 months after bone metastases diagnosis; SREs did not significantly affect survival. Subgroup analyses revealed that zoledronic acid significantly prolonged median time to first SRE (2.00 months versus 1.00 month, respectively, P=0.009) and produced a trend toward improved overall survival versus no zoledronic acid. This study illustrates the burden of bone metastases from CRC and supports the use of zoledronic acid in this setting.

Bone metastases in soft tissue sarcoma patients: A survey of natural, prognostic value, and treatment.

10063 Background: Given the limited data currently available, we surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS). Methods: This retrospective, multicenter, observational study evaluated data from 135 patients with STS metastatic to the bone who presented between 2001 and 2011. For all patients, we recorded the primary tumor histological subtype, bone metastases characteristics (onset, site), type of treatment received (surgery, radiotherapy, zoledronic acid), type and frequency of skeletal related events (SRE) and disease outcome. Results: The most represented histological subtypes among the enrolled patients were leiomyosarcoma (27%), angiosarcoma (13%) and spindle cell sarcoma (8%). The spine was the most common site for bone involvement (51%), followed by hip/pelvis (20%), long bones (15%) and other sites (14%). In 27% of cases, bone metastases were present at the time of diagnosis. Fiftyfour patients (40%) developed SREs and the median time to first SRE (if developed) was 4 months. The most common SRE was the need for radiotherapy occurring in 28% of patients followed by pathologic fracture (22%). Patients survived for a median of 6 months after bone metastases diagnosis. The occurrence of a SRE was associated with a decreased overall survival (P=0.04). A subgroup analysis revealed that zoledronic acid significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002). Conversely, It did not determine an improvement in terms of overall survival, even if favorable trend was identified (median, 7 versus 5 months, respectively; P = 0.105). Conclusions: This study illustrates the burden of bone disease from STS and supports the use of zoledronic acid in this setting.

Incidence and natural history of bone metastases in neuroendocrine tumors.

340 Background: Bone metastases (BM) occur in carcinoids and other neuroendocrine tumors (NET), however, a comparative analysis of the incidence and natural history of BM across different NET subtypes has not been performed. We retrospectively characterized BM incidence, complications, and management across five subtypes: carcinoid/unknown primary (CARC), pancreatic NET (PNET), pheochromocytomas/paragangliomas (PHEO), adrenal cortical carcinoma (ACC) and high grade NET (HGNET) using data collected in the context of the NCCN NET Outcomes Database. Methods: 296 NET patients (pts) presenting at UCSF from 2004 to 2007 were retrospectively identified. Eligibility criteria included presentation on or after Jan 1, 2004, continued management at UCSF within one year of consultation, age over 18, and pathological confirmation of an eligible NET subtype. BM identified radiographically and/or pathologically, and classified as symptomatic (pain, pathologic fracture, or spinal cord compression) or asymptomatic. BM treatments (tx) included radiation, surgery, bisphosphonate and/or denosumab. Results: BM identified in 36/296 (12%): 29% pts with HGNET (5/17), 10% pts with CARC (12/121), 7.4% pts with PNET (6/81), 17% pt with PHEO (11/66), 18% pt with ACC (2/11). BM occurred in 21 men/15 women; median age 54. 30/36 (83%) had stage IV disease at diagnosis (dx); 69% had BM at dx. 69% pts were eventually symptomatic: bone pain (24/25, 96%), cord compression (3/25, 12%) and/or pathologic fracture (6/25, 24%); 8/25 (32%) had more than one symptom from BM. Median survival from BM: 28 mo (21.1 mo if symptomatic; 34.3 mo if asymptomatic). Overall, 81% (29/36) pt received tx for BM: 53% XRT (19/36), 25% surgery (9/36), 39% bisphosphonate (14/36), and/or 11% denosumab (4/36). Conclusions: 12% of pts with NET in this database developed BM. Most pts with BM experienced pain. Serious complications such as cord compression and/or pathological fracture occurred in 36% (9/25) suggesting that bisphosphonate and/or denosumab tx may be of value in these patients. Accrual to the database is ongoing.

Validity of the recorded International Classification of Diseases, 10th edition diagnoses codes of bone metastases and skeletal-related events in breast and prostate cancer patients in the Danish National Registry of Patients

The clinical history of bone metastases and skeletal-related events (SREs) secondary to cancers is not well understood. In support of studies of the natural history of bone metastases and SREs in Danish prostate and breast cancer patients, we estimated the sensitivity and specificity of hospital diagnoses for bone metastases and SREs (ie, radiation therapy to the bone, pathological or osteoporotic fractures, spinal cord compression and surgery to the bone) in a nationwide medical registry in Denmark. In North Jutland County, Denmark, we randomly sampled 100 patients with primary prostate cancer and 100 patients with primary breast cancer diagnoses from the National Registry of Patients (NRP), during the period January 1st, 2000 to December 31st, 2000 and followed them for up to five years after their cancer diagnosis. We used information from medical chart reviews as the reference for estimating sensitivity, and specificity of the NRP International Classification of Diseases, 10th edition (ICD-10) coding for bone metastases and SRE diagnoses. For prostate cancer, the overall sensitivity of bone metastases or SRE coding in the NRP was 0.54 (95% confidence interval [CI]: 0.39-0.69), and the specificity was 0.96 (95% CI: 0.87-1.00). For breast cancer, the overall sensitivity of bone metastases or SRE coding in the NRP was 0.58 (95% CI: 0.34-0.80), and the specificity was 0.95 (95% CI: 0.88-0.99). We measured the validity of ICD-10 coding in the Danish NRP for bone metastases and SREs in prostate and breast cancer patients and found it has adequate sensitivity and high specificity. The NRP remains a valuable tool for clinical epidemiological studies of bone metastases and SREs.

P60. Skeletal metastases in malignant melanoma

Introduction: The incidence of malignant melanoma is increasing. Early stage disease is curable with surgery in 85% patients. However, the prognosis for patients with stage IV metastatic disease is poor, with a median survival of <1 year. Although they are common, there is very little published data describing the natural history of bone metastases in melanoma.

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.

Too Much, Too Little, Too Late to Start Again? Assessing the Efficacy of Bisphosphonates in Patients with Bone Metastases from Breast Cancer

The diagnosis of bone metastases can be a devastating occurrence for any woman with breast cancer. In this setting, bone metastases can result in skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, and hypercalcemia. Several trials have confirmed the ability of bisphosphonates to reduce or delay these skeletal complications, and they should now be considered standard care for these women. The analysis of SREs is the typical primary end point in bisphosphonate studies. While not undermining their importance, the definition of SREs does not include complications important to patients, such as pain and immobility. It is these symptoms that are most frequently reported by patients, and bone pain and quality of life (QoL) are often measured as secondary end points in these trials. Bone pain and QoL measures are not standardized and are difficult to compare among patient populations. We do not yet know the true efficacy of bisphosphonates as analgesics or how they impact QoL. This paper reviews the current efficacy measures used in recent bisphosphonate trials and discusses their benefits and limitations. It also explores the role of bone biomarkers and their potential use in monitoring treatment response.