Reliability of Alkaline Phosphatase for Differentiating Flare Phenomenon from Disease Progression with Bone Scintigraphy

1. Introduction

Metastatic cancer commonly affects the bones. In particular, bone metastasis is clinically important in breast and prostate cancers due to their high prevalence. More than 80% of metastatic bone diseases are derived from these two cancers [1]. A previous large population-based study reported that the five-year cumulative incidence of bone metastases was 30% in patients with advanced breast cancer [2]. At postmortem examination, more than 70% of patients who died of breast cancer had evidence of bone metastases [1]. In patients with advanced prostate cancer, bone metastasis occurred in approximately 65–70% [3]. At postmortem examination, the incidence of metastatic bone disease was 90% [4].Patients with bone metastases frequently experience bone pain and skeletal-related events (SREs); that is, the development of pathologic fractures and spinal cord compression, and the need for palliative radiotherapy or orthopedic surgery [1]. Optimal treatment is aimed at delaying progression of bone metastases and reducing pain, preventing SREs, and improving quality of life. An assessment of the objective response of metastatic bone lesions to systemic therapies, such as endocrine and cytotoxic therapy, is difficult [5].Bone scintigraphy (BS) is the most widely used radionuclide technique to investigate bone metastasis, primarily due to its reasonable time and cost factor. Additionally, BS provides for visualization of the whole skeleton whereas skeletal surveys can vary in the degree of inclusion of the appendicular skeleton. Although the role of BS has been reduced due to the development of PET, it is a commonly used imaging modality for monitoring therapeutic response in patients with bone metastasis. Bone lesions with a good response to treatment will demonstrate a reduced or vanished presence compared to the high uptake visualized on a previous BS [6].However, it is important to recognize that BS to assess treatment response sometimes shows a “flare phenomenon” (FP), which can be misinterpreted as disease progression. FP is defined as an increase in the number and/or intensity of focal bone lesions after treatment in patient with bone metastases, and the metastatic lesions demonstrate improvement on later scintigraphy. Successful treatment reduces the metastatic tumor burden and induces repair processes in patients with metastatic bone lesions. In such situations, bone remodeling and formation occurs, resulting in an increased uptake on BS that can be visualized as FP [7]. Increased activity on BS may possibly indicate both FP and disease progression until the performance of subsequent BS, because a FP after successful treatment is indistinguishable from disease progression due to treatment failure [8]. Distinction between FP and disease progression could help in the decision to continue effective treatments in patients with FP and to cease ineffective treatments and consider other salvage treatment plans in patients with disease progression.Previous studies attempted to distinguish FP from disease progression using bone turnover markers, such as cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase isoform 5b (TRACP), because they were useful for accessing treatment response [9,10]. However, these markers have not yet been clinically applied or accepted. Among the various bone turnover markers, alkaline phosphatase (ALP) is the most widely used bone turnover marker. It has the advantage of being more convenient and less expensive to measure than other bone turnover markers [11]. The role of ALP has not been clearly understood, but it seems to induce a local concentration of inorganic phosphate and reduce the concentration of extracellular pyrophosphate. In addition, it is localized in the membrane of osteoblasts and, thus, represents the activity of osteoblast [12].Therefore, this retrospective study was conducted to evaluate whether ALP can differentiate FP from disease progression.

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About the Author: Tung Chi