²²³Ra and other bone-targeting radiopharmaceuticals—the translation of radiation biology into clinical practice

Abstract

Ra has been shown to not only have a palliative effect but also a survival prolonging effect in metastatic, castration-resistant prostate cancer with bone metastases. This article reviews the different radionuclide-based approaches for targeting bone metastases, with an emphasis on 223 Ra, and key elements of the underlying radiobiology of these that will impact their clinical effectiveness.Consideration is given to the remaining unknowns of both the basic radiobiological and applied clinical effects of 223 Ra as targets for future research.A significant burden is imposed on patients with cancer by osseous metastases; they are common in many forms of malignancy and are often highly symptomatic. In an early autopsy series of 1000 patients dying from disseminated malignancy of various primary sites, Abrams et al 1 found bone metastases present in 27.2% of their series. Metastases have biologically defined tropisms related to their site of origin. Although the biochemical determinants of these tropisms remain poorly understood, their effects are clear in the clinic and mean that certain sites of cancers have a particular preponderance for forming bone metastases. Autopsy data adapted by Coleman 2 show that 73% of patients dying of breast cancer, 68% of patients dying of prostate cancer and 36% of patients dying of lung cancer have bone metastases present at post-mortem. Of those patients with osseous metastases, a significant proportion goes on to develop skeletal-related events (SREs) in relation to their metastases. The precise definition of SREs differs between trials, but they generally refer to any of the following four clinical outcomes: the need for external beam radiotherapy (EBRT) for bone pain, development of malignant spinal cord compression, pathological fracture (symptomatic or asymptomatic) or the need for orthopaedic intervention to bone metastasis. In the context of a lifelimiting illness, any of the above is obviously of huge detriment to a patient's well-being on a number of fronts; pain by its very nature, time spent attending hospital, immobility associated with fracture/surgery etc. In their review of Phase 3 randomized trials of bone-modifying agents, Poon et al 3 show that in the placebo arms of 11 such trials, the percentage of patients with bone metastases experiencing SREs ranged from 23.47% to 67.2%. Thus bone metastases are a common finding in advanced malignancy and within the cohort of patients experiencing them; SREs are a common outcome, with obvious detriment to the quality of life of the patients affected.EBRT is a proven and well-established means of managing pain associated with bone metastases. In their systematic review of studies examining the palliative benefit of EBRT for bone metastases, Chow et al 4 found overall response rates, with regard to pain, of 58% for single fraction and 59% for multiple fraction treatments. The same authors found complete pain response rates of 23% in single fraction and of 24% in multiple fraction treatments. A large determinant of the degree...

Targeted Radionuclide Therapy: An Evolution Toward Precision Cancer Treatment

“…The alpha therapy of choice for treatment of metastatic CRPC is 223 Ra dichloride (Xofigo [previously Alpharadin], Bayer HealthCare), which was approved by the U.S. Food and Drug Administration (FDA) on May 15, 2013 [73–76]. Because it is a calcium mimetic, 223 Ra dichloride seeks the hydroxyapatite matrix in the bone naturally.…”

Estimation of human absorbed dose for 166Ho-PAM: comparison with 166Ho-DOTMP and 166Ho-TTHMP

“…Advances in knowledge: In this work, two separate points have been investigated: (1) human absorbed dose of INTRODUCTION Nowadays, radiopharmaceuticals have widespread applications in the diagnosis and treatment of various diseases. 1,2 The skeleton is one of the most common sites of metastases in several tumours such as prostate (80%), breast and lung carcinomas (50%). 3 On the other hand, multiple myeloma, as a fatal illness arising from plasma cells in the bone marrow, is an aggressive plasma cell malignancy that can entail an occurrence of progressive pain.…”

Bone-Targeted Therapies in Cancer-Induced Bone Disease

“…On the contrary, high linear energy transfer radionucleotides (particularly a-emitters) such as radium-223 have advantages in terms of relative biological effectiveness, enhanced bystander effect, reduced oxygen enhancement ratio and shorter range of radiation emission. This decreases toxicity and delivers higher energy to target tumour cells even in hypoxic sites, with lower probability to target healthy bone marrow cells [104,105]. Radionucleotides act by inducing DNA double strand breaks which when accumulated in target cells lead to cell death.…”

“…Radionucleotides act by inducing DNA double strand breaks which when accumulated in target cells lead to cell death. Due to unknown mechanisms, bystander cells not directly irradiated may also undergo apoptosis, via the formation of foci of γ-phosphorylated histone protein (γH2A) [104]. Preclinical studies demonstrated radium-223 distribution to osseous sites [106,107] and its effectiveness in decreasing osteolytic lesions in experimental models of bone metastasis [108].…”