Targeted radionuclide therapy in bone cancer

Intended figures

• 1.

  PSMA PET/CT-illustrating scan of both skeletal and local recurrence

• 2.

  “Dual-alpha technology”

Introduction

When treating patients with primary bone cancers and bone metastatic disease, clinicians need to consider best combinations of the various treatments available. Optimal management requires a multidisciplinary team approach with expertise in bone complications from cancer, medical and radiation oncologists, orthopedic surgeons, interventional radiologists, nuclear medicine physicians, and palliative medicine clinicians [ ]. Metastatic bone disease most frequently affects the axial skeleton and proximal part of appendicular bones. It is a major clinical challenge in patients with breast, prostate, lung, follicular thyroid, and renal cell carcinomas, as well as multiple myeloma [ ]. This often leads to pain and skeletal complications referred to as skeletal-related events (SREs): pathological fracture, need for radiotherapy (RT) to bone or surgical interventions, spinal cord compression, and hypercalcemia. In prostate cancer fractures and spinal cord compression are still very common, despite the osteoblastic/sclerotic phenotype of bone metastases.

The aim of this chapter is to briefly review the rationale and clinical experiences with targeted radionuclide therapies in patients with bone cancers. In this context, focus will be on the use of bone-seeking radiopharmaceuticals (BSRs) in patients with osteoblastic skeletal metastases from castration-resistant prostate cancer (mCRPC) and in patients with osteosarcoma (OS) metastases. Also, recent developments in prostate-specific membrane antigen (PSMA)-targeted therapy of mCRPC will be presented.

Theranostic bone-seeking radionuclide therapies

There is a close balance between osteoclastic and osteoblastic activity within normal bone maintaining normal skeletal homeostasis. Activation of these cells by tumor-secreted factors will disturb this balance and promote tumor cell proliferation [ , ]. Bone metastases can present as lytic lesions, such as those of multiple myeloma, lung, and renal cell cancer or as relatively osteoblastic metastases, such as those present in prostate cancer and OS. Mixed lytic/blastic lesions are often encountered in breast cancer. It is mainly the tumor-induced osteoblastic activity that promotes new bone formation but also an epithelial–mesenchymal transition may occur. Here the prostate cancer cells per se may acquire an osteoblastic phenotype [ , ]. The resulting stromal phenotype of such metastases allows avid incorporation of the BSRs used both diagnostically and therapeutically.

The available radiological tools for diagnosis and monitoring of bone metastasis have improved considerably during recent years [see Chapter 47 ]. Imaging technologies involve plain structural modalities such as planar radiographs, computed tomography (CT), magnetic resonance imaging (MRI), and metabolic or molecular imaging tools such as diffusion-weighted MRI (DW-MRI), positron emission tomography (PET) with various radiolabeled tracers, and single-photon emission computed tomography (SPECT) employing a diagnostic BSR [ , ]. The latter modality can be used to provide a theranostic selection of patients deemed to benefit from BSR therapies [ ]. Nuclear medicine technologies use radiotracers that allow imaging of both metabolic and molecular characteristics of bone metastatic disease [ ]. These can be classified as osteotropic agents that image the osteoblastic reaction induced around and in the stromal phenotype in bone metastasis (bone-scan with technetium-99m methyl diphosphonate ( ^99m Tc-MDP) for SPECT or bone-PET with fluorine-18 ( ¹⁸ F), as well as a metabolic agent ¹⁸ F-fluoro-2-deoxyglucose ( ¹⁸ FDG)-PET). More recently direct oncotropic tumor imaging has become available in prostate cancer; e.g., PSMA-PET [ , ]. PET, although not specific for skeletal metastasis, has advantages over bone scintigraphy with its superior spatial resolution and shorter imaging times. However, CT or MRI is often required to rule out degenerative and/or inflammatory differential diagnoses.