Internal radiotherapy of painful bone metastases

Abstract

Internal radiotherapy is effective in the treatment of metastatic bone pain and can improve quality of life. A number of controlled studies using various agents have shown a mean response rate in pain relief of 70–80% of treated patients. Some investigators prefer radionuclides which emit low beta particles for the treatment of bone pain, because the assumption of lower bone marrow toxicity of this agents. However, neither dosimetric data for radiation absorbed dose to the bone marrow nor clinical blood count depression have shown any significant differences between these agents. Other researchers suggest enhanced antitumoral effects using high-energy beta emitters and propose aggressive first-line treatment in the early disease stage instead of using these radiopharmaceuticals only in end-stage patients suffering intractable bone pain. Another approach consists of including other treatment modalities such as autologous stem cell rescue or in combination with chemo or bisphosphonate therapy to a radionuclide treatment scheme. Future research should focus more on the curative effects of combination with radiosensitizer, for example, chemotherapy, or repeated treatments with bone seeking agents.

Introduction

Skeletal metastases occur in many patients with different kinds of solid malignant tumors, especially in advance stage of prostate-, breast- and lung cancer. Resulting bone pain interferes with the patient’s quality of life and requires effective treatment. The incidence of bone metastases in patients with cancer is mainly derived from autopsy studies [1], and is most commonly associated with advanced stage of breast cancer (in 47–85% of patients), prostate cancer (33–85%) and lung cancer (32–60%) [2], [3]. The typical sites of bone metastases are the thoracolumbar spine, pelvis, lower and upper limbs and the skull [1]. Patients with bone metastasis commonly endure severe bone pain and this symptom has the most impact on quality of life. The mechanisms involved in bone pain are poorly understood [4], but are likely to be a consequence of osteolysis (bone breakdown) [5]. Infiltration of the bone trabeculae and matrix by tumor osteolysis is one of the physical factors. Other factors included micro-fractures and stretching to the periost by tumor growth [6]. Biochemical mechanisms of pain include the stimulation of nerve endings in the endosteum by variety of chemical mediators which include bradykinin, prostaglandin, histamine, interleukin and tumor necrosis factor produced by the osteolytic process [6], [7].

The development of metastases in bone is a multifactorial process. Primary tumor cells invade the surrounding tissue by producing proteolytic enzymes, thereby traversing the wall of small blood vessels and entering the circulation [8]. Although most tumor cells do not survive the protective host-surveillance mechanism in this initial stage [9], [10], the surviving cells enter the bone marrow cavity [5] and are believed to adhere to the endothelium [11]. Tumor cells can then enter the bone and potentially form bone metastases, or the bone provides chemotactic factors to adhere the tumor cells [12], [13]. Direct and indirect effects of the tumor on the vascular system ultimately cause necrosis and bone destruction [14]. The necrosis and subsequent pain may also result from tumor products [15], osteoclast activating factors [16], alpha transforming growth factor [17], parathyroid hormone-like substances [18], tumor necrosis factor [19], and perhaps from other unidentified agents [11], [20].

Bone metastases are traditionally classified as osteolytic or osteoblastic [5]. Osteolytic metastases are believed to be caused by osteoclast-related peptides, which are induced by tumor cells in the bone microenvironment. In contrast, osteoblastic metastases are believed to be caused by osteoblastic proliferation, differentiation and bone formation stimulated by the production of factors (e.g. endothelin-1 and tumor growth factor β) by cancer cells. However, this is more a theoretical point of view and reflects two extremes. Morphological analysis suggest that most bone metastases have both osteolytic and osteoblastic elements [5]. If an osteolytic component predominates, destruction of both trabecular and cortical bone can occur, and the risk of fracture in weight-bearing areas increase [21].

Prostate and breast cancer patients are commonly candidates for palliative treatment with bone seeking radionuclide agents because their use can often result in a relatively long survival time in patients with a high incidence of bone metastases. In prostate cancer the balance between resorption and mineralization is impaired resulting in the overall formation of an osteoblastic lesion [12], but the resorption by osteoclast is not completely lost [11] since increased systemic markers of both bone formation and resorption have been observed in patients with prostate cancer [11]. Bone metastases caused by breast cancer are more mixed, comprising both osteolytic and osteoblastic elements. PTHrP and procathepsin D, both mediators of osteoclast activation, are expressed by breast cancer cells [5], [22].

Standardized measurement tools are necessary to control the effect of bone pain treatments. Standardized pain measurement is necessary using pain relief as a response criterion. But pain is a multidimensional experiences with numerous domains, including the physiological, sensory, affective, cognitive, behavioral, and sociocultural [23]. Unfortunately, there is a lack of one standardized valid methodology to assess the pain status in cancer patients [24].

The available scales for measurement of pain can be divided into the two broad categories of one-dimensional scales, most often used to measure pain intensity, and multidimensional scales. One-dimensional scales include the three main types of visual analogue (VAS), categorical verbal (VRS), and categorical numerical scales (NRS). All of these approaches are commonly used to measure pain intensity and are well validated in the cancer population [25], [26], [27]. The VAS divides the pain level in 10 steps, from a level of no-pain (scale 0) to the most severe pain imaginable [28], [29]. The VRS use a variety of choice from 4-grade scales (none, slight, moderate and severe) to 6-grade scales (none, very mild, mild, moderate, severe, and very severe) [25], [27] or 15-grade scales [29]. NRS are a 0–10 scale using as the standard solution suggested by sound psychometric data [30]. VAS are valid and reliable in acute and chronic pain, and are frequently use for estimation of the therapeutic effect in bone pain treatment with bone-seeking radiopharmaceuticals [31], [32], [33], [34], [35], [36]. This scale also shows a good sensitivity for treatment effects in short-term analgesic studies [25], [37]. But this method depends on the appropriateness of administration method and of the instructions given to the study subjects [38].

The Expert Working Group of the European Association of Palliative Care recognized that a simple intensity scale of “none, mild, moderate, and severe” is the most widely used in the clinical context, but also that scales with a larger numbers of intervals are more desirable, both in research and clinical practice, because of higher sensitivity to treatment effects [27].

Several pain questionnaires have been designed to capture the multidimensional nature of chronic pain, some of which are applied to the cancer patients pain population and can be useful for clinical or research purposes. However, some of the measuring properties and validity aspects are yet to be fully clarified in this patient population. Among several tools, the Brief Pain inventory (BPI) is probably the most used tool in the cancer pain population and the McGill Pain Questionnaire (MPQ) the most popular among chronic non-cancer pain patients [24].

The BPI is a simple and easy tool to capture information about the history, intensity, location, and quality of pain [39]. Numeric scales (range 0–10) indicate the intensity of pain in general and a percentage scale quantifies the pain relief induced by the treatment. In addition, there are seven questions to determine the degree to which pain interferes with function, mood, and enjoyment of life. This tool is self-administered and easily understood and available in different languages [28], [29], [40], [41], [42], [43], [44]. The MPQ reflects the sensor, affective, and evaluative dimensions of chronic pain [45] and has been validated in cancer pain [46]. The SF-MPQ is a short form of the MPQ and was developed for use in research settings [45], [47]. The SF-MPQ consists of 15 representative words from the sensory (n = 11) and affective (n = 4) categories of MPQ. The Present Pain Index, verbal rating scale, and visual analogue scale measuring pain intensity are included. The 15 words are scored using a four-point verbal rating scale, ranging from none, mild, moderate, to severe pain. The SF-MPQ correlates highly with the MPQ. Whereas the MPQ is available in many languages, the SF-MPQ is only available in English [27].

Another universally valid tool for estimation for quality of life is the Karnofsky performance status, which measure the ability of a person to perform usual activities, evaluating a patient’s progress after a therapeutic procedure, and determining a patient’s suitability for therapy. It is used most commonly in the prognosis of cancer therapy, usually after chemotherapy and customarily administered before and after therapy [48], [49].