Role of radiation therapy in patients with bone metastasis

Introduction

Bone metastasis is common and is one of the leading causes of complications in the natural history of cancer. The consequences of bone metastasis may compromise quality of life, limit day-to-day activities, threaten life expectancy, and increase medical intervention and expenses. The complications of bone metastases, usually referred to as skeletal-related events (SREs), include pain, hypercalcemia, bone fractures, and nerve compression that may require radiation therapy (RT) or surgery [ ]. The overall cumulative incidence of bone metastases 1 year after solid tumor diagnosis reaches approximately 5% and increases continually with follow-up [ ]. The risk of bone metastasis occurring depends on the type of primary tumor, with prostate cancer patients having the highest incidence, followed by lung and breast cancer patients. Patients with bone metastasis and SRE have been shown to be at higher risk of mortality [ ], indicating that managing bone metastasis and its complications is critical for cancer care. RT is recognized as a standard of care for palliation of noncomplicated painful bone metastases [ ]. Nevertheless, RT may also play a role in other aspects of bone metastasis complications, such as preventing fractures and relieving nerve compression. Moreover, using advanced radiation techniques such as stereotactic body radiation therapy (SBRT) that makes it possible to deliver high doses of radiation to the target volume with adequate protection of surrounding organs is now widely used for curative purposes for oligometastasis [ ] and may also benefit patients with advanced disease [ ]. In this chapter, after presenting the principles and mechanisms of action of irradiation, we will expose the goals and indications of RT in the management of bone metastasis, comment on the purposes and modalities of re-irradiation and SBRT, and discuss the role of RT in combination with other bone-targeting treatments.

Mechanisms of action of radiation therapy in bone metastasis

The purpose of RT is to expose tumors to ionizing radiations that cause damages to the cells. Direct damages affect DNA in the form of base deletions and single- or double-strand breaks. Indirect damages happen with the ionization of water molecules, producing free radicals that in turn impair surrounding intracellular proteins. During RT treatment, both tumor cells and surrounding normal cells are exposed to ionizing radiations. The radiation-induced damages trigger cellular mechanisms that aim to repair them. Nevertheless, the capacity for damage repair differs between tumor cells and normal cells. DNA repair functions are usually altered in tumor cells, leaving mistakes in the DNA that may affect cell function and lead to radio-induced cell death, while normal cells manage to repair ad integrum most of the damage and may survive. The differences in radiation-induced damage repair between tumor and normal cells define the differential effect and are a fundamental principle of RT treatment. RT not only affects tumor cells but also the tumor microenvironment. The tumor stroma is composed of extracellular matrix and several types of cell (immune cells, cancer-associated fibroblasts, epithelial cells, blood, and lymphatic vessels) and hosts an interactive network involving tumor cells through cell–cell interactions and chemokines. RT has an impact on tumor vasculature [ ], induces a wound healing response (with the release of inflammatory cytokines), modulation of cancer-associated fibroblasts [ ], and remodeling of the extracellular matrix [ ]. RT may facilitate the antitumoral immune response and promote immunogenic cell death [ , ].

The RT technique used most often is external beam radiotherapy, referring to ionizing radiation delivered with beams generated from outside the patient. Photons produced by a linear accelerator ( Fig. 61.1 ) are the most frequent type of ionizing radiation used for external beam radiotherapy. The dose of radiation is measured in Gray units (Gy), where 1 Gy is 1 J of absorbed energy per kilogram.

The mechanism of action of ionizing radiation on bone metastases leading to pain relief and bone healing is not fully understood. RT certainly has an antitumoral effect, resulting in metastasis shrinkage and promoting the restoration of bone homeostasis and normal bone formation [ ]. Nevertheless, this effect is only seen several weeks after the end of treatment, while pain relief may be obtained within a few hours or days. Other features of the analgesic response to RT suggest that killing tumor cells is not the only mechanism implicated in pain relief. The analgesic effect can be seen after a single low dose; furthermore, bone pain caused by tumor types commonly recognized as radioresistant usually responds favorably to palliative RT. This suggests that dose and histology are not the only key parameters ( Fig. 61.2 ).

Inflammatory cells are potentially a target for bone RT. These cells are stimulated within bone metastases to produce proinflammatory mediators such as IL-1 and tumor necrosis factor α (TNF-α) which are implicated in tumor proliferation and invasiveness and pain stimulation [ ]. Depletion or modulation of inflammatory cells by irradiation may explain the rapid pain response to RT. This phenomenon may explain the good pain relief response to RT with benign inflammatory disease. Nevertheless, there is a lack of data to support this hypothesis in the field of irradiation of metastases .

The literature on the effects of RT on osteoblasts remains conflicted. Reduced mineralization of bone after RT was found in several studies with decreased or constant osteoblast numbers [ ]. Nevertheless, osteoblasts have proven to be relatively resistant to radiation-induced apoptosis [ , , ] and may remain functional after 10 Gy. Furthermore, under certain conditions, irradiation may enhance osteoblast differentiation and activities [ ]. These results suggest that RT may not have a direct effect on the bone formation ability of osteoblasts.

Other cells known to be affected by irradiation to normal bone in preclinical studies are osteoclasts. Total body irradiation with 2 Gy on mice was shown to induce a decrease in mineral density and enhanced osteoclastogenesis [ , ], with increased expression of pro-osteoclastic chemokines such as RANKL. After a dose of 20 Gy in four fractions, focal irradiation of normal murine bone led to an early and transient increase in osteoclasts, followed by long-term depletion that may be explained by the loss of osteoclast progenitors [ ]. Osteoclasts were shown to be more sensitive to irradiation than osteoblasts with lower numbers of surviving fractions [ ]. In an in vitro study, low dose irradiation was associated with osteoclastogenesis activation, while high doses (8 Gy) induced inhibition of bone resorption through blockage of osteoclast differentiation. Osteoclasts' response to RT in the context of bone metastasis remains largely unknown. Prospective clinical data from randomized trials evaluating the analgesic efficacy of RT on bone metastases in primary treatment [ ] and in re-irradiation settings [ ] demonstrated that the biomarkers for osteoclast activity were significantly different between the groups of responder versus nonresponder patients. In patients who did not respond to RT, baseline serum concentrations of pyridinoline and deoxypyridinoline were higher than those of the responders. After RT, markers rose further in the first group whereas in responders, the value stayed relatively unchanged. Authors suggested that bone resorption inhibition, and thus osteoclast activity from local RT, is a key predictive factor for pain response.

Taking these results together suggests that response to RT in terms of bone pain and bone healing might have common physiopathological pathways. They involve the antitumoral effects of irradiation, which remain a key factor in RT response, but microenvironment and especially osteoclast modulation are also determining factors while remaining largely unknown.

The purposes of radiation therapy

Indications

The objectives of radiotherapy are pain control, bone recalcification, reduced risk of fracture, treatment of neurological complications, and improved quality of life.