Induction of Malignant Bone Tumors in Radium-224 Patients: Risk Estimates Based on the Improved Dosimetry

Nekolla, E.; Kreisheimer, M.; Kellerer, Albrecht M.; Kuse-Isingschulte, M.; Gössner, W.; Spiess, H

doi:10.1667/0033-7587(2000)153[0093:iombti]2.0.co;2

Cited by 54 publications

(23 citation statements)

References 14 publications

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“…From about 1940 to 1980, several thousand German patients with noncancerous diseases have received 224 Ra against ankylosing spondylitis or bone tuberculosis (35,36). 224 …”

Section: Discussionmentioning

confidence: 99%

First Clinical Experience with α-Emitting Radium-223 in the Treatment of Skeletal Metastases

Nilsson

Larsen

Fosså

et al. 2005

Clinical Cancer Research

408

272

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Purpose: The main goals were to study the safety and tolerability of the a-emitter radium-223 ( 223 Ra) in breast and prostate cancer patients with skeletal metastases. In addition, pain palliation was evaluated. Experimental Design: Fifteen prostate and 10 breast cancer patients enrolled in a phase I trial received a single i.v. injection of 223 Ra. Five patients were included at each of the dosages: 46, 93, 163, 213, or 250 kBq/kg and followed for 8 weeks. Palliative response was evaluated according to the pain scale of the European Organization for Research andTreatment of Cancer QLQ C30 questionnaire at baseline and at 1, 4, and 8 weeks after injection. Results: Weekly blood sampling during follow-up revealed mild and reversible myelosuppression with nadir 2 to 4 weeks after the injection. Importantly, for thrombocytes only grade 1toxicity was reported. Grade 3 neutropenia and leucopenia occurred in two and three patients, respectively. Mild, transient diarrhea was observed in 10 of the 25 patients. Nausea and vomiting was more frequently observed in the highest dosage group. Serum alkaline phosphatase decreased with nadir averages of 29.5% in females and 52.1% in males. Pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4, and 8 weeks, respectively.

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“…From about 1940 to 1980, several thousand German patients with noncancerous diseases have received 224 Ra against ankylosing spondylitis or bone tuberculosis (35,36). 224 …”

Section: Discussionmentioning

confidence: 99%

First Clinical Experience with α-Emitting Radium-223 in the Treatment of Skeletal Metastases

Nilsson

Larsen

Fosså

et al. 2005

Clinical Cancer Research

408

272

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“…However, at intermediate dose levels (below 20 Gy to the bone for 226 Ra), no significant increase in cancer was observed in humans (56). For several decades, injections of 224 Ra (t 1/2 = 3.2 days) were used to treat ankylosing spondylitis (56,57). Radium-224 was recently reintroduced and reapproved for ankylosing spondylitis in Germany (41).…”

Section: Discussionmentioning

confidence: 99%

“…Radium-224 was recently reintroduced and reapproved for ankylosing spondylitis in Germany (41). For 224 Ra, long-term follow-up of patients receiving moderate levels revealed no significant difference in overall cancer incidence or life expectancy compared with a control population (56,57).…”

Section: Discussionmentioning

confidence: 99%

High-Linear Energy Transfer Irradiation Targeted to Skeletal Metastases by the α-Emitter 223Ra: Adjuvant or Alternative to Conventional Modalities?

Bruland

Nilsson²,

Fisher

et al. 2006

Clinical Cancer Research

317

224

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The bone-seeking, a-particle-emitting radiopharmaceutical Alpharadin, 223 RaCl 2 (half-life = 11.4 days), is under clinical development as a novel treatment for skeletal metastases from breast and prostate cancer. This article summarizes the current status of preclinical and clinical research on Ra dosimetry in mice and a therapeutic study in a skeletal metastases model in nude rats have indicated significant therapeutic potential of bone-seeking a-emitters. This article provides short-term and long-term results from the first clinical single dosage trial. We also present data from a repeated dosage study of five consecutive injections of 50 kBq/kg body weight, once every 3rd week, or two injections of 125 kBq/kg body weight, 6 weeks apart. Furthermore, interim results are described for a randomized phase 2 trial involving 64 patients with hormone-refractory prostate cancer and painful skeletal metastases who received four monthly injections of 223 Ra or saline as an adjuvant to external beam radiotherapy. Lastly, we present preliminary dose estimates for 223 Ra in humans. Results indicate that repeated dosing is feasible and toxicity is low, and that opportunities are available for combined treatment strategies.

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“…1,5 The risk of OS has been reported to be increased following the internal exposure to bone-seeking radioisotopes from occupational or medicinal use. [6][7][8] Interestingly, some studies have revealed the genetic and cytogenetic changes in radiation-induced OS and suggested the presence of additional tumor-associated genes. [9][10][11] However, the changes in global gene expression in radiation-induced OS remain unknown.…”

Section: Uiccmentioning

confidence: 99%

Gene expression profiling of alpha‐radiation‐induced rat osteosarcomas: Identification of dysregulated genes involved in radiation‐induced tumorigenesis of bone

Daino

Ugolin

Altmeyer-Morel

et al. 2009

Intl Journal of Cancer

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To better understand the molecular basis of radiation-induced osteosarcoma (OS), we performed global gene expression profiling of rat OS tumors induced by the bone-seeking alpha emitter 238 Pu, and the expression profiles were compared with those of normal osteoblasts (OB). The expressions of 72 genes were significantly differentially expressed in the tumors related to OB. These included genes involved in the cell adhesion (e.g., Podxl, Col18a1, Cd93, Emcn and Vcl), differentiation, developmental processes (e.g., Hhex, Gata2, P2ry6, P2rx5, Cited2, Osmr and Igsf10), tumorsuppressor function (e.g., Nme3, Blcap and Rrm1), Src tyrosine kinase signaling (e.g., Hck, Shf, Arhgap29, Cttn and Akap12), and Wnt/b-catenin signaling (e.g., Fzd6, Lzic, Dkk3 and Ctnna1) pathways. Expression changes of several genes were validated by quantitative real-time RT-PCR analysis. Notably, all of the identified genes involved in the Wnt/b-catenin signaling pathway were known or proposed to be negative regulators of this pathway and were downregulated in the tumors, suggesting the activation of bcatenin in radiation-induced OS. By using immunohistochemical and immunoblot analyses, constitutive activation of the Wnt/b-catenin signaling pathway in the tumors was confirmed by observing nuclear and/or cytoplasmic localization of b-catenin and a decrease in its inactive (phosphorylated) form. Furthermore, we found a significant reduction in the levels of glycogen synthase kinase 3b (GSK-3b) protein in the tumors relative to OB. Taken together, these findings provide new insights into the molecular basis of radiation-induced OS. ' UICCKey words: osteosarcoma; osteoblast; ionizing radiation; carcinogenesis; transcriptome Osteosarcoma (OS) is the most common primary tumor of bone in children and adolescents. The peak incidence of OS occurs in the second decade of life, with an additional smaller peak in the elderly population. This tumor is highly aggressive and is thought to arise primarily from osteoblasts (OB), boneforming cells. An increased risk for developing OS is known to be associated with some genetic disorders, such as hereditary retinoblastoma and Li-Fraumeni syndrome with germline mutations in the retinoblastoma (RB1) and TP53 genes, respectively. 1,2 In agreement with this, abnormalities of genes involved in the RB1 and TP53 tumor-suppressor pathways are often found in OS. 3,4 On the other hand, the association between ionizing radiation and the subsequent development of OS has been well documented in prior studies. For example, OS is known as one of the most frequent secondary malignant neoplasms occurring within the radiation field in patients, especially with retinoblastoma, treated with radiation therapy. 1,5 The risk of OS has been reported to be increased following the internal exposure to bone-seeking radioisotopes from occupational or medicinal use. 6-8 Interestingly, some studies have revealed the genetic and cytogenetic changes in radiation-induced OS and suggested the presence of additional tumor-associated genes. ...

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Induction of Malignant Bone Tumors in Radium-224 Patients: Risk Estimates Based on the Improved Dosimetry

Cited by 54 publications

References 14 publications

First Clinical Experience with α-Emitting Radium-223 in the Treatment of Skeletal Metastases

First Clinical Experience with α-Emitting Radium-223 in the Treatment of Skeletal Metastases

High-Linear Energy Transfer Irradiation Targeted to Skeletal Metastases by the α-Emitter 223Ra: Adjuvant or Alternative to Conventional Modalities?

Gene expression profiling of alpha‐radiation‐induced rat osteosarcomas: Identification of dysregulated genes involved in radiation‐induced tumorigenesis of bone

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