Current approaches to incorporation of radium-223 in clinical practice

Parker, Chris; Heidenreich, Axel; Nilsson, Sten; Shore, Neal D.

doi:10.1038/s41391-017-0020-y

Cited by 60 publications

(52 citation statements)

References 58 publications

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“…However, the only agents specifically designed to treat bone metastases are bone-targeting agents, including the bisphosphonates zoledronate and pamidronate; the targeted alpha therapy radium-223 dichloride; and the receptor activator of NF-kB ligand (RANKL)-inhibiting antibody denosumab (9,12). Although radium-223 has been shown to prolong survival and delay time to first symptomatic skeletal event in metastatic prostate cancer, a recent phase III trial was prematurely unblinded because of an increase of fractures and deaths in patients treated with radium-223 in combination with abiraterone and prednisone (14). Bisphosphonates reduce skeletal morbidity in advanced breast cancer and can also decrease the number of bone metastases (15)(16)(17).…”

Section: Prevalence Clinical Relevance and Treatment Of Bone Metastmentioning

confidence: 99%

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Rieunier

Macaulay

et al. 2019

Clinical Cancer Research

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Bone metastases are a frequent complication of cancer that are associated with considerable morbidity. Current treatments may temporarily palliate the symptoms of bone metastases but often fail to delay their progression. Bones provide a permissive environment because they are characterized by dynamic turnover, secreting factors required for bone maintenance but also stimulating the establishment and growth of metastases. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. Via activation of the IGF-1 receptors (IGF-1R) and variant insulin receptors, IGFs promote cancer progression, aggressiveness, and treatment resistance. Of specific relevance to bone biology, IGFs contribute to the homing, dormancy, colonization, and expansion of bone metastases. Furthermore, preclinical evidence suggests that tumor cells can be primed to metastasize to bone by a high IGF-1 environment in the primary tumor, suggesting that bone metastases may reflect IGF dependency. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. Indeed, anti-IGF-1R antibodies, IGF-1R tyrosine kinase inhibitors, and anti-IGF-1/2 antibodies have demonstrated antitumor activity in preclinical models of prostate and breast cancer metastases, either alone or in combination with other agents. Several studies suggest that such treatments can inhibit bone metastases without affecting growth of the primary tumor. Although previous trials of anti-IGF-1R drugs have generated negative results in unselected patients, these considerations suggest that future clinical trials of IGF-targeted agents may be warranted in patients with bone metastases.

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Section: Prevalence Clinical Relevance and Treatment Of Bone Metastmentioning

confidence: 99%

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Rieunier

Macaulay

et al. 2019

Clinical Cancer Research

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“…Clinically, bone-targeting radiopharmaceuticals such as 153 Sm-ethylenediaminetetramethylenephosphonate and 89 Sr-chloride are widely applied β-emitters for bone palliation 11 . Currently, 223 Ra-dichloride is approved as a bone-seeking calcium-mimetic radiopharmaceutical for treatment of metastatic castration-resistant prostate cancer patients by emitting α-particles 12 . Moreover, clinical trials have been performed to combine 223 Ra treatment with additional chemotherapy to enhance therapeutic efficacy 13,14 .…”

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confidence: 99%

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Nadar

Farbod

Schilden

et al. 2020

Sci Rep

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platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195m Pt-BP) complexes to confirm preferential accumulation of these pt-based drugs in metabolically active bone. In vitro nMR studies revealed that release of pt from pt Bp complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. these pt-Bp complexes formed less pt-DnA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of pt from pt-Bp complexes proceeded relatively slow. Subsequently, radioactive 195m pt-Bp complexes were synthesized using 195m pt(no 3) 2 (en) as precursor and injected intravenously into mice. Specific accumulation of 195m pt-Bp was observed at skeletal sites with high metabolic activity using micro-Spect/ct imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195m pt Bp colocalized with calcium in the trabeculae of mice tibia. Most types of tumors, i.e. breast, prostate, lung, kidney, and thyroid, metastasize to bone since its physiological environment facilitates the formation and growth of cancer cells 1,2. These metastases affect healthy bone, which then become the primary cause of mortality 3. Distant metastases are the leading cause of death for both breast and prostate cancer patients, with 65-75% and 90% of these patients developing bone metastases in advanced stages, respectively 4,5. Bone metastases are often associated with accelerated bone resorption leading to complications such as skeletal-related events (SREs), bone pain or hypercalcemia 6,7. Unfortunately, current treatments for bone metastases are limited. Bisphosphonates (BP) and denosumab are most commonly used for palliative treatment to prevent or limit SREs 8. Although such treatments inhibit osteoclast activity and prevent the progression of metastases, they do not kill cancer cells effectively and do not improve the quality of life of patients substantially 9. Consequently, the development of effective therapies to treat bone metastases remains a major clinical challenge.

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“…Comparing our hematologic adverse events to the ALSYMPCA trial and the safety analysis by Parker et al [7,11], there are several differences in incidence. We found a higher incidence of anemia, thrombocytopenia, and leukopenia compared to both studies.…”

Section: Discussionmentioning

confidence: 82%

A Single-center Retrospective Analysis of the Effect of Radium-223 (Xofigo) on Pancytopenia in Patients with Metastatic Castration-resistant Prostate Cancer

Skelton

Dibenedetto

Pang

et al. 2020

Cureus

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Introduction Radium-223 (Xofigo, Bayer Pharmaceuticals Inc., Whippany, NJ) has been shown to increase overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC), via the phase 3 ALpharadin in SYMPtomatic Prostate CAncer (ASLYMPCA) study. Hematologic side effects of radium-223 included all-grade anemia in 31% of the patients, thrombocytopenia in 12%, and neutropenia in 5%, and persistent pancytopenia noted in 2%. However, the incidence seen in our institutional clinical practice is higher than that reported in the literature. Methods A retrospective analysis was performed by analyzing patients with mCRPC who received Xofigo at the University of Florida Health Shands Hospital (UF Health Shands) in a three-year span. Data collected included complete blood count (CBC), ECOG (Eastern Cooperative Oncology Group) functional status, kidney and liver function, evidence of bony disease on imaging, prior chemotherapy regimens, total radiation dose, and prostate-specific antigen (PSA). Results Twenty-three patients received Xofigo at UF Health, and one was lost to follow-up. Sixteen patients (73%) completed the full course (six doses) of Xofigo, while six did not. Ten patients (45%) developed pancytopenia, with two recovering counts within eight months while the other eight had persistent cytopenias (six of which were transfusion-dependent). Older age and higher ECOG score correlated with increased risk of pancytopenia. In addition, a higher percentage of patients who received prior radiation therapy were more likely to develop pancytopenia (90% vs 75%). Conclusions We found a higher rate of Xofigo-induced pancytopenia in our patient population than the 2% reported in the literature, albeit with a limited sample size, This may influence clinical decision making in the treatment of mCRPC, as pancytopenia may preclude patients from other survival-prolonging therapies. Factors such as age, functional status, and prior radiation therapy have to be considered prior to Xofigo treatment.

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Current approaches to incorporation of radium-223 in clinical practice

Cited by 60 publications

References 58 publications

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

A Single-center Retrospective Analysis of the Effect of Radium-223 (Xofigo) on Pancytopenia in Patients with Metastatic Castration-resistant Prostate Cancer

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