Advanced Bone Metastases Research Articles

Role of osteoclast inhibitors in prostate cancer bone metastasis; a narrative review.

To study the role of Osteoclast inhibitors in advanced prostate cancer metastasis treatment and their efficacy in reducing skeletal related events. A comprehensive search was done using search terms as "osteoclast inhibitors" "Bisphosphonates" "Zoledronic acid" " pamidronate" " Alendronate" "Denosumab" " Prostate cancer metastasis" in pubmed and Google scholar. Relevant articles were screened and collected . The collected articles were used to frame the review and data showing use of Osteoclast inhibitors In prostate cancer bone metastasis was collected. Prostate cancer metastasizes most commonly to the skeleton thus leading to significant morbidity ranging from pain, pathological fractures to spinal cord compression and are the primary cause of patient disability and reduced quality of life.Initially, radiation therapy and radiopharmaceuticals were the mainstay of treatment however the role of Bisphosphonates and denosumab has become an integral part of therapy to manage metastatic prostate cancer. These agents significantly decrease skeletal related events and enhance patients quality of life. Emerging therapies like Radium-223 have also shown promise in reducing skeletal related events and also improving survival rates in patients with bone metastasis. Other treatment options which are being used are systemic agents like Docetaxel, cabazitaxel, hormonal therapies like abiraterone and enzalutamide. Immunotherapy with sipuleucel-T has demonstrated a reduction in mortality among prostate cancer patients with metastasis, highlighting the need for further research in this area. Ongoing studies are investigating novel agents that target both tumor cells and the bone microenvironment. Osteoclast inhibitors are effective in reducing skeletal related events in advanced bone metastasis and improve the quality of life of patients.

Biodistribution and dosimetry of 177Lu-DOTA-IBA for therapy of bone metastases

BackgroundWe designed and synthesized a novel bisphosphonate radiopharmaceutical (68 Ga- or 177Lu-labeled DOTA-ibandronate [68 Ga/177Lu-DOTA-IBA]) for the targeted diagnosis and treatment of bone metastases. The biodistribution and internal dosimetry of a single therapeutic dose of 177Lu-DOTA-IBA were evaluated using a series of single-photon emission computerized tomography (SPECT) images and blood samples. Five patients with multiple bone metastases were included in this prospective study. After receiving 1110 MBq 177Lu-DOTA-IBA, patients underwent whole-body planar, SPECT/CT imaging and venous blood sampling over 7 days. Dosimetric evaluation was performed for the main organs and tumor lesions. Safety was assessed using blood biomarkers.Results177Lu-DOTA-IBA showed fast uptake, high retention in bone lesions, and rapid clearance from the bloodstream in all patients. In this cohort, the average absorbed doses (ADs) in the bone tumor lesions, kidneys, liver, spleen, red marrow, bladder-wall, and osteogenic cells were 5.740, 0.114, 0.095, 0.121, 0.095, and 0.333 Gy/GBq, respectively. Although no patient reached the predetermined dose thresholds, the red marrow will be the dose-limiting organ. There were no adverse reactions recorded after the administration of 1110 MBq 177Lu-DOTA-IBA.ConclusionDosimetric results show that the ADs for critical organs and total body are within the safety limit and with high bone retention. It is a promising radiopharmaceutical alternative for the targeted treatment of bone metastases, controlling its progression, and improving the survival and quality of life of patients with advanced bone metastasis.

Lutetium177-Labeled DOTA-Ibandronate: A Novel Radiopharmaceutical for Targeted Treatment of Bone Metastases.

Bone metastases of malignant tumors significantly threaten the patient survival and quality of life. We designed and synthesized a novel bisphosphonate radiopharmaceutical [68Ga- or 177Lu-labeled DOTA-Ibandronate(68Ga/177Lu-DOTA-IBA)] for targeted diagnosis and treatment of bone metastases. This study explored the basic biological characteristics of 177Lu-DOTA-IBA, guiding clinical translation and providing evidence for future clinical applications. The control variable method was used to optimize the optimal labeling conditions. The in vitro properties, biological distribution, and toxicity of 177Lu-DOTA-IBA were studied. Normal mice and tumor-bearing mice were imaged using micro SPECT/CT. With Ethics Committee approval, five volunteers were recruited for a preliminary clinical translation study. 177Lu-DOTA-IBA has a radiochemical purity of more than 98%, with good biological properties and safety. Blood clearance is fast and soft tissue uptake is low. Tracers are excreted mainly through the urinary system, targeting and continuously concentrating in the bones. Three patients experienced significant pain relief within 3 days after 177Lu-DOTA-IBA treatment (740-1110 MBq), lasting more than 2 months, with no toxic side effects. 177Lu-DOTA-IBA is easy to prepare and exhibits good pharmacokinetic characteristics. Low-dose 177Lu-DOTA-IBA is effective, well tolerated, and was associated with no significant adverse reactions. It is a promising radiopharmaceutical for the targeted treatment of bone metastases, controlling the progress of bone metastasis and improving survival and quality of life of patients with advanced bone metastasis.

Outcomes of palliative surgery for bone metastasis of metastatic renal cell carcinoma in the era of targeted therapy

IntroductionThe introduction of tyrosine kinase inhibitors has revolutionized treatment strategies for metastatic renal cell carcinoma (RCC) and has improved survival rates. The number of patients with bone metastases from RCC requiring surgery will increase as survival rates improve. However, there is insufficient evidence to standardize the treatment of bone metastases after the introduction of targeted therapy for metastatic RCC. We aimed to determine the outcomes of palliative surgical treatment of bone metastases in the extremities of patients with metastatic RCC. Materials and methodsWe retrospectively reviewed 26 lesions from 17 patients who underwent surgery for extremity and acetabular bone metastases and were treated with targeted therapies for advanced RCC between 2008 and 2020. The median follow-up duration was 19 months (range, 4–76). We assessed the patients’ activities of daily living, quality of life, and pain and analyzed their postoperative values relative to preoperative values. Postoperative overall survival (OS), local progression-free survival (LPFS), and the factors affecting them were evaluated using the Kaplan-Meier method and log-rank test. ResultsThe 5-year OS and LPFS rates were 39.5% and 65.6%, respectively. The factors affecting OS were sex, Katagiri score, visceral metastases, and preoperative targeted therapy, while the factors affecting LPFS were pathologic fractures and surgical technique. ConclusionIn this study, the postoperative outcomes of palliative surgery for bone metastases from metastatic RCC were good. We suggest that systemic treatment should be prioritized over local control for advanced bone metastasis in RCC and surgery before pathological fracture should be performed for local control.

Two cases of nivolumab plus ipilimumab therapy for dialysis patients with advanced bone metastasis from renal cell carcinoma

Nivolumab and ipilimumab are immune checkpoint inhibitors. Combination therapy with these two drugs has been shown to improve the outcome of advanced renal cell carcinoma. However, data about the safety and the efficacy of combination therapy with these two drugs in hemodialysis patients are small. A 59-year-old male hemodialysis patient presented with bone metastasis from renal cell carcinoma, which was located at the right femur. He received nivolumab plus ipilimumab therapy. At 7 months after treatment, he was diagnosed with diabetes as an immune-related adverse event. He was managed with insulin therapy. At 11 months after treatment, CT revealed cytoreduction of metastasis. A 74-year-old male hemodialysis patient presented with bone metastasis of renal cell carcinoma located at the sacrum and left scapula. He received nivolumab plus ipilimumab therapy. At 6 months after treatment, CT showed no progression of metastasis. Nivolumab and ipilimumab therapy might be a viable treatment for hemodialysis patients with bone metastasis from renal cell carcinoma. However, close attention should be paid immune-related adverse events in such patients.

A Novel, Circulating Tumor Cell Enrichment Method Reduces ARv7 False Positivity in Patients with Castration-Resistant Prostate Cancer.

Background: The AR-V7 splice variant is a cause of castration-resistant prostate cancer (CRPC). However, testing for the presence of AR-V7 by real-time polymerase chain reaction (RT-PCR) shows AR-V7 positivity in healthy individuals. We hypothesized that the positivity reflects contamination by hematopoietic cells. We tried a novel circulating tumor cell (CTC) enrichment instrument, using Celsee, to clear hematopoietic cells. Methods: We tested whole blood or Celsee-enriched samples for AR-V7 by RT-PCR, and included samples from 41 CRPC patients undergoing sequential therapy. We evaluated the associations between AR-V7 status and clinical factors. We evaluated factors affecting AR-V7 positivity. Results: AR-V7 positivity was lower in Celsee-enriched than in whole blood specimens. AR-V7 and clinical factors did not predict the therapy effectiveness. We found no significant differences in the effectiveness of enzalutamide/abiraterone (Enz/Abi) upon AR-V7 evaluation. All AR-V7 positive patients had resistance to Enz/Abi. Docetaxel (DTX), cabazitaxel (CBZ), and Radium223 treatment showed no significant difference in the treatment effectiveness, regardless of AR-V7 presence. AR-V7 was more frequently positive than Extent of disease (EOD) 2 in cases with bone metastases. Conclusion: Celsee CTC enrichment suppresses AR-V7 false positivity. All AR-V7 positive patients presented resistance to Enz/Abi. DTX, CBZ, and Radium223 were effective and remain treatment options. AR-V7 positivity should progressively appear in patients with advanced bone metastases.

The prevalence, associated factors for bone metastases development and prognosis in newly diagnosed ovarian cancer: a large population based real-world study.

Background: Ovarian cancer (OC) is one of the most common malignancies in women. Advanced bone metastases (BM) commonly result in the poor prognosis. We aim to evaluate the prevalence and associated factors for the de novo BM development and prognosis in OC.Materials and methods: The present study was a cohort study that used the United States based National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. SEER documented OC patients, diagnosed between 2010 and 2015, were included in the present study. Univariable and multivariable logistic regression analyses were employed to identify associated factors for BM development. Kaplan-Meier analysis was used to estimate the overall survival and multivariable proportional hazard regression was used to identify the prognostic factors for OC patients with BM.Results: A total of 32,178 eligible OC patients were included in the present study, the prevalence of de novo BM was 1.09% (N=352). Non-serous histology [Odds Ratio (OR)=3.05; 95% CI: 1.63-5.72; P=0.001], T2/T1 stage (OR=3.39; 95% CI: 1.11-10.33; P=0.03), N1/N0 stage (OR=3.17; 95% CI: 1.72-5.84; P<0.001), and the presence of lung (OR=8.57; 95% CI: 4.37-16.80; P<0.001) and liver metastases (OR=4.95; 95% CI: 2.50-9.82; P<0.001) were all significantly associated with de novo BM development. Median survival for OC with BM was 5.00 (95% CI: 3.76-6.24) months. Multivariable Cox regression showed serous histology [Hazard ratio (HR)=1.44; 95% CI: 1.01-2.06; P=0.046] was positively associated with overall death, while surgery of the primary site (HR=0.42; 95% CI: 0.29-0.61; P<0.001) was negatively associated with overall death.Conclusion: Bone metastasis is rare in ovarian cancer patients. The factors associated with BM development and prognosis can be potentially used for BM early screening and individualized treatment.

(99m)Tc-MDP wholebody bone imaging in evaluation of the characteristics of bone metastasis of primary lung cancer

To explore the image characteristics of bone metastasis of primary lung carcinoma. Whole-body bone imaging ((99)Tc(m)-MDP) was performed in 258 patients with pathologically proven lung carcinoma. The rate of bone metastasis, distribution of the metastatic lesions and their characteristics were analyzed. Among the 258 cases, 142 patients developed bone metastasis. The overall rate of bone metastasis was 55.0%. The metastases located in axial skeleton were 49.6%, appendicular skeleton 36.0%, trunk bones of the axial skeleton 48.4%, and appendicular girdle skeleton 31.4%. Ribs, thoracic vertebrae, ilium and lumbar vertebrae had a higher rate of bone metastasis, higher than 20%, respectively. 1252 lesions were detected including 406 at the left side of the body, 387 in the axial skeleton and 459 at the right side of the body. There was no significant difference in terms of number of lesions between left side and right side (chi(2) = 3.3, P = 0.072). 1224 bone metastatic foci (97.8%) were presented as strong radioactive, 26 (2.1%) mixed lesion, and 2 (0.2%) low radioactive. According to the shape of the lesions, there were 810 punctate lesions (71.5%), 159 (14.0%) lump form, 108 (9.5%) strip form and 56 (4.9%) lamellar form. The accumulative bone metastasis rate was 28.7% for the patients with one to three lesions. The metastasis rate decreased gradually with the increasing number of metastatic lesions. Bone metastasis is very common in patients with lung cancer. Most bone metastases are characterized by strong radioactive and earlier punctate form, often occurs in the trunk bones of axial skeleton or appendicular girdles. The distribution of earlier metastases has not obvious regularity, and advanced bone metastases are often concurrent, multiple and multiform, widely and randomly distributed in the body.

Dickkopf‐1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis

Prostate cancer (PCa) frequently metastasizes to the bone and induces osteoblastic lesions. We previously demonstrated through over-expression of the Wnt inhibitor dickkopf-1 (DKK-1) that Wnts contribute to the osteoblastic component of PCa osseous lesions in vivo. To test the clinical significance of DKK-1 expression during PCa progression, tissue microarrays were stained for DKK-1 protein by immunohistochemistry. DKK-1 expression index (EI) was found to increase in PIN and primary lesions compared to non-neoplastic tissue (106 +/- 10 vs. 19 +/- 6, respectively, where the EI is the product of the percent expression and staining intensity). DKK-1 expression was also found to be higher in all PCa metastatic lesions (56 +/- 21 EI) compared to non-neoplastic tissues but was significantly decreased versus primary PCa lesions (P < 0.008). The decline in DKK-1 correlated with a shift of beta-catenin staining from the nucleus to the cytoplasm suggesting possible mechanism for the observed decrease in DKK-1 levels during PCa progression. Within metastatic lesions, DKK-1 expression was least abundant in PCa bone metastases relative to all soft tissue PCa metastatic lesions except lymph node metastases. High DKK-1 expression within PCa metastases was further associated with shorter over-all patient survival. Taken together, these data demonstrate that elevated DKK-1 expression is an early event in PCa and that as PCa progresses DKK-1 expression declines, particularly in advanced bone metastases. The decline of DKK-1 in bone metastases can unmask Wnts' osteoblastic activity. These data support a model in which DKK-1 is a molecular switch that transitions the phenotype of PCa osseous lesions from osteolytic to osteoblastic.

Prostate carcinoma bone-stroma interaction and its biologic and therapeutic implications.

The homing of prostate carcinoma to bone is a nonrandom, multistep process. Previous studies have revealed significant insights into how tumor cells can interact with the host microenvironment. In this communication, the author summarizes recent studies from his institution and draws conclusions from data published by others pertaining to the biologic and therapeutic implications of bone metastasis from prostate carcinoma. Tumor models have been established to study cellular interaction between human prostate carcinoma cells and bone stroma under two-dimensional and three-dimensional conditions. At the author's institution, experiments were conducted to show that prostate carcinoma cell growth and survival are enhanced in coculture with pleuripotent bone stromal cells. A cotargeting concept for the treatment of patients with prostate carcinoma bone metastasis is introduced. Both genotypical and phenotypical responses were observed to tumor epithelium when it was cocultured under three-dimensional conditions. A "vicious cycle" that was mediated by soluble and insoluble molecules secreted by tumor and bone may be the key to supporting and sustaining tumor colonization in bone. Cotargeting tumor and stroma has yielded promising results, both in preclinical models of prostate carcinoma bone metastasis and in the clinic with patients who were treated with a dual tumor-targeting and bone-targeting strategy. Understanding and targeting the interaction of tumor cells and bone stroma may improve the prognosis, reduce the suffering, and increase the survival of patients with advanced bone metastasis as a consequence of prostate carcinoma.

Complete androgen blockade versus monotherapy

In a comparative analysis of 29 studies, maximal androgen deprivation (MAD) was not found to be superior to partial androgen deprivation. Thus, MAD cannot be regarded as the new gold standard. Most trials focus on quality of life which--given the palliative aim of the treatment--deserves special attention. This aspect has not yet been evaluated, however, in the largest multicenter study, intergroup study 0105. In patients with advanced bone metastasis or severe pain, MAD treatment should be begun because of the flare phenomenon. The synergistic effects of LHRH agonists on the prostate are currently being investigated. Since no clear prognostic factors exist and reduction of serum-PSA levels under MAD does not delay progression, the patient must help to make the decision of whether or not MAD should be begun.

30. A randomized phase 11 evaluation of oral pamidronate for advanced bone metastases from breast cancer

30. A randomized phase 11 evaluation of oral pamidronate for advanced bone metastases from breast cancer

Chemotherapy of skeletal metastases

INTRODUCTION Metastatic cancer to bone is the most common bone cancer,23 unlike primary bone tumors, occurs at multiple sites 90% of the time.13 The axial skeleton is most often affected; the extremities rarely. Neoplasms of the breast, lung, prostate, kidney and thyroid account for nearly 80% of bone metastases. Skeletal metastases from the colon, pancreas and stomach are uncommon, occurring in less than 10% of patients with these tumors.‘.‘333 Radiographic appearance of the bone metastases aids in the identification of the primary source. Osteoblastic lesions in males most frequently will be of prostatic origin, rarely from pancreas, colon, lung, carcinoid tumor, Hodgkin’s disease, or myeloma. _41though the majority of skeletal breast lesions are lytic, the most common source of blastic bony metastases in women is breast cancer. Lytic bone lesions generally are without characteristic identifying features which would help in the identification of the primary cancer, with the exception of kidney, which often presents as a solitary radiolucent expansile bone lesion. Radiotherapy is the treatment of choice for skeletal metastases which are painful and few in number or located in strategic areas of skeletal support. However, many bone lesions, can be expected to respond favorably to chemotherapy. The effectiveness of chemotherapy on various skeletal metastases is reviewed. THYROID Thyroid carcinomas characteristically have many long term survivors following surgical therapy, 80-90% live 10 years or greater. The small number that succumb to ‘their disease often have bone or pulmonary metastases or both.1%1834 Papillary carcinoma occurs in approximately 66% of patients and tends to metastasize to local lymph nodes. Follicular carcinoma occurs in 20% of patients with a predilection for vessel invasion and subsequent bone and lung metastases. Treatment other than surgery has resided consistently with oral 13’1 administration. The dose is generally lOO-300mCi given repeatedly over 2 years for a total dose of 500 mCi.” I31 I has been documented to accumulate in bone metastases and to have a favorable effect on survival. In one study, all of 10 patients lived 5 years, with 3 patients living 6, 15 and 25 years after ‘9 therapy.” There is even documentation of roentgenograms returning to normal in 5 of 30 patients, with total regression of pain in all patients.” Other chemotherapeutic agents used in metastatic thyroid cancer without success are 5-fluorouracil, methotrexate, actinomycin D, cyclophosphamide, phenylaline mustard, and others.” The use of bleomycin has had conflicting reports.‘6 Adriamycin (75 mglm’ q3 week) achieved 4 partial remissions in 12 patients with bone involvement, it was documented as 50% radiographic regression for 1 month. One patient had relief of pain.‘O 13’1 appears to be the agent of choice when metastases are small and capable of concentrating 1311. Thus far, adriamycin is the only chemotherapeutic agent shown to be effective in advanced bone metastases.