As radiotherapy for bone metastases is a palliative treatment, the dose required to achieve the palliative effect is typically lower than in the definitive setting. Therefore, any bone in the body is a candidate for palliative radiotherapy because adjacent organ damage is unlikely to occur. The pathophysiology of pain relief after radiotherapy for bony metastatic disease remains somewhat unclear. Some hypothesize that relief is secondary to tumor cell killing, while others suspect radiotherapy causes a change in the local environment of the bone affecting osteoclasts, osteoblasts, and other cells activated in the region [13]. Table 17.4 outlines possible mechanisms for pain relief after radiotherapy.

For decades, tumor cell kill was thought to be the mechanism behind pain relief following radiotherapy for bone metastases. In the 1980s, a randomized trial of radiation with a single fraction compared to multiple fractions did not demonstrate a difference in pain relief between histologies [14]. Classically radiosensitive tumors, such as lymphoma, were no more sensitive to the treatment than other putative radioresistant histologies, and the authors hypothesized that factors other than tumor cell kill played a role in pain control, such as cytotoxic effect on cells secreting pain response mediators [14]. The Bone Pain trial Working Party similarly saw no difference in pain relief between different histologic subtypes, and hypothesized that pain relief may be secondary to death of radiosensitive host cells such as macrophages, which release mediators of pain response such as prostaglandin E2 [15]. There has not been a consistent dose response relationship for treatment of bone metastases in the literature [14, 16], suggesting that pain relief is not due to tumoricidal properties of radiotherapy but rather some other mechanism. Another proposed mechanism differentiates between short term and long term relief and describes the cause of pain from bone metastases as secondary to nerve stimulation in the endosteum due to release of chemical agents from destroyed bone, stretching of the periosteum by tumor growth, fracture, and growth of tumor into surrounding nerves [17]. Thus, in the short term, pain relief may be secondary to a cytotoxic effect on normal bone cells and inhibition of release of chemical pain mediators in the first 48 h following treatment, whereas pain relief achieved 2–8 weeks after treatment may be secondary to tumor cell kill [17]. Clinically, pain relief depends on the anatomy and stressors to the involved site, the histology of the primary tumor, as well as dose of radiation.

After consultation with a radiation oncologist, patients are scheduled for a “simulation” appointment. The simulation involves a non-contrast CT scan of the patient in the treatment position, determined by the treating physician. Permanent tattoos are placed on the patient’s skin for alignment purposes when the patient is to receive multiple fractions. Immobilization devices are used to ensure the patient is in the same position at the time of simulation and when they return for their treatments. After simulation, the patient returns a few days later for the start of radiotherapy. In cases where an extreme degree of precision or dose escalation is required, additional imaging techniques, such as MRI, may be used to help discern the target anatomy from the avoidance structures.

The treating radiation oncologist works with a dosimetrist and physicist to plan the treatments. This entails outlining, or contouring, structures on the cross-sectional image sets obtained at the time of simulation, delineating the tumor volume, as well as normal structures, or “organs at risk,” that would ideally be spared from radiation dose. The dosimetrist, working with the radiation oncologist, then creates a treatment plan using a computer program to model dose delivery to the target lesion and organs at risk. Once the plan is approved by the treating physician, it is transferred to the linear accelerator for treatment delivery. A medical physicist will ensure that the treatment plan modeled in the computer and the actual treatment delivered by the treatment machine are consistent by performing various quality assurance checks and calibrations prior to initiating actual treatment. Prior to the first treatment, an image guidance method, usually X-ray in nature, assures that the alignment of the patient on the treatment table is acceptable compared to the alignment at simulation. Other forms of image guidance can also be used, which include CT scans and ultrasound.

During treatment, patients are unlikely to experience any significant side effects. Acute side effects following treatment depend on the location irradiated, the total dose and the number of fractions. In some cases, however, patients can develop acute skin erythema, moist or dry desquamation of the skin, fatigue, esophagitis, diarrhea, or nausea. Incidence and severity of side effects are dependent on the normal tissues within the irradiation field, the total dose, as well as dose per fraction. Most patients treated for bone metastases experience little to none of these stated side effects, as the dose is quite low compared to curative radiation doses, and organs at risk are usually spared from the field.

Spinal cord compression is a common diagnosis seen in the Radiation Oncology clinic, and is usually caused by a bony tumor in the vertebral body growing into the epidural space and compressing the spinal cord. Radiotherapy and surgery have both been utilized as definitive management in such cases, although due to the anterior location of most tumors causing cord compression, a laminectomy with a posterior approach does not always result in immediate decompression of the tumor. In 1992, Patchell et al. enrolled patients with spinal cord compression secondary to metastatic disease in a randomized trial comparing radiation therapy alone versus direct decompressive surgery with an anterior approach followed by postoperative radiation (PORT) within 14 days [18]. Patients in the surgery and PORT arm had better outcomes than those in the RT only arm, and thus the trial was stopped early. Patients who received combined modality treatment retained the ability to walk after surgery more often than those treated with RT alone, 84 % versus 57 %, and were able to walk longer, 122 days versus 13 days [18]. These results prompted the adoption of upfront surgery with PORT for cord compression, and provide a basis for the same sequence of therapy for patients with bone metastases in other locations.

Since the early 1920s, case reports of patients treated with radiation for painful bone metastases reported good analgesic outcomes [3, 5, 7]. Historically radiation portals were designed using plain film X-rays and typically directed at the target volume, or tumor, from one or two angles. With the invention of three-dimensional imaging, radiotherapy has become more conformal and the term “three dimensional conformal radiation therapy” (3DCRT) is commonly used to describe these techniques. 3DCRT is used for all sites of disease, and involves multiple photon beams targeted at the tumor from different angles. A computer system is used to block areas containing organs at risk, to create a conformal cloud of dose targeted at the involved site, allowing for dose sparing of organs at risk. Figure 17.1 shows an example of a 3DCRT treatment plan.

Randomized trials of treatment with conventional radiotherapy have shown complete pain relief rates ranging from 15 to 54 %, and partial pain relief rates ranging from 28 to 89 % [14–16, 19–28]. The Bone Pain Trial Working Party Group showed a median time to pain relief in all patients of approximately 1 month, and a median time to complete pain response of 3–4 months, whereas median time to first increase in pain was approximately 12 months or longer [15]. In the Radiation Therapy Oncology Group (RTOG) Trial 9702, time to pain relief ranged from 3 to 7 weeks and time to pain relief was slower when metastases were irradiated in the pelvis compared to the long bones and spine, and the outcome was not dependent on histology of the primary tumor nor on the initial pain score [27]. Median duration of pain control was reported anywhere from 12 to 29 months [27]. For both single and multiple fraction treatments, Price et al. [14] demonstrated a median time to onset of pain relief of approximately 1–2 months, and for patients who achieved pain control in 1 month up to 49 % of patients reported pain control over 24 weeks. In a randomized trial of single fraction treatment compared to four fractions, approximately 20 % of patients in each cohort did not achieve pain relief [25]. Although the time to onset of pain control and the duration of pain response varies in the literature, patients should typically experience pain relief within 4 weeks of treatment, and be aware that if pain returns they may discuss retreatment with their physicians.

Complications following radiotherapy can include fracture, with an incidence ranging from 2 to 18 % depending on the total dose and fractionation scheme of treatment, although there has been controversy in the literature with regard to the incidence of fracture between treatment regimens [14–16, 19–28]. A randomized study from Berlin showed improved recalcification in patients after 30 Gy in ten fractions compared to a single fraction treatment, and recommended if there is concern about stabilization of the bone to choose a more fractionated regimen [26]. The RTOG trial 7402 showed a significantly higher fracture rate in those that received 4050 rads in 3 weeks compared to 2000 rads in 1 week [27]. In a typical practice, many factors play a role in deciding how many fractions to deliver treatment in, such as the site of disease, histology, surrounding organs, patient discomfort level, and the role of surgery.

Although radiotherapy has been used for almost a century to treat bone metastases, the dose and fractionation has been an area of controversy. One of the first randomized trials comparing dose and fractionation for treatment of bone metastases started enrollment in 1974 by the RTOG. Patients with solitary or multiple osseous metastases were eligible and were randomized to different total doses and fractionation schemes depending on if they had solitary or multiple metastases [27]. Overall, 90 % of patients received some pain relief, and those with initial pain scores less than 9 out of 10 on the visual analog pain scale, and those with breast or prostate primary tumors were more likely to achieve pain relief. For patients with solitary metastases, there was a higher risk of fracture in patients who received a higher total dose of radiotherapy, although there was no difference in the courses of radiotherapy for symptomatic response. A reanalysis of this data by Blitzer, with different response definitions, showed that highly fractionated treatments to higher total dose (4050 cGy and 3000 cGy for solitary or multiple metastases respectively) were superior in all endpoints and outcomes [19]. In 1983 a randomized trial comparing two fractionation schemes showed equivalent pain control of 48 % after either 20 Gy in 2 fractions or 24 Gy in 6 fractions [24]. A randomized trial from Germany also showed equivalence in all pain outcomes and survival with 20 Gy in 5 fractions compared to 30 Gy in 15 fractions, and the authors favored the shorter course therapy due to the poor prognosis of most patients with metastatic disease [28].

Many patients with painful bone metastases cannot tolerate a long course of treatment due to a poor performance status and inability to lie on the treatment table daily due to pain, and therefore single fraction treatment has been explored extensively, as shown in Table 17.5. A trial comparing 8 Gy in a single fraction to 30 Gy in 10 fractions showed equivalent duration and speed to onset of pain relief across all histologies [14]. Patients treated with a single fraction received retreatment more commonly, but there was no difference in toxicity and the authors hypothesized that treating physicians were more prone to deliver a second fraction to patients who had only received one treatment as opposed to those who had received ten [14]. A Danish trial showed equivalent pain relief with 8 Gy in a single fraction and 20 Gy in 5 fractions, with over half of patients reporting some pain relief at up to 6 months [25]. The Bone Pain Trail Working Party examined a single fraction of 8 Gy compared to multiple fractions; 20 Gy in 5 fractions or 30 Gy in 10 fractions, with the goal of examining long term outcomes and acute side effects [15]. In both groups, 78 % of patients had some pain relief, and 57 % experienced complete pain relief, with no difference between the regimens. After 12 months of follow up, the authors concluded that a single fraction regimen was no different in efficacy or toxicity to multi-fraction regimen, and the single fraction provided adequate durability of pain control. Jeremic & Hoskin [29, 30] both showed superior outcomes with single doses of 8 Gy compared to 4 Gy, and Gaze et al. [21] showed equivalence in all outcomes with a single fraction of 10 Gy compared to 22.5 Gy in 5 fractions. Three randomized trials showed equivalence in pain relief with 8 Gy compared to 30 Gy in 10 fractions [22, 23, 26]. Although one study reported higher rates of fracture with 8 Gy, they also found higher toxicity with the 30 Gy regimen [22]. A meta-analysis of multiple randomized trials demonstrated that when comparing single versus multiple fraction treatment, the complete response rate is 23 and 24 % respectively [20]. Using international consensus criteria to define response end points a study showed that 72 % of patient had an overall (or partial) response, and 14 % a complete response [31]. Overall, it appears radiotherapy for bone metastases results in a 60–70 % response [20]. The authors of many randomized trials urge the adoption of single fraction radiotherapy for pain relief from bony metastases as standard of care as it is more convenient for patients, provides similar outcomes, and is cost effective.

Meta-analyses of randomized trials have also shown equivalent outcomes with single and multi-fraction regimens, and no difference in outcomes when examined by biologic effective dose (BED) [16, 20]. A recent meta-analysis of 16 randomized controlled trials showed no difference in overall or complete response rates in single fraction compared to multi-fraction radiotherapy, with complete response rates of 23 % versus 24 % for single or multiple fractions respectively. There were significantly more re-treatments in the single fraction group (20 % versus 8 %), but no difference in fracture rates. The authors stress the higher retreatment in the single fraction group may be due to the fact physicians are more prepared to retreat after a single fraction than multiple fractions [20].

In 2004, Wu et al. published an evidence based guideline for radiotherapy fractionation recommending a single dose of 8 Gy for patients when the goal of therapy is pain relief for symptomatic and uncomplicated metastases [32]. The American Society for Radiation Oncology (ASTRO) recently published a list of treatments to question as part of a national “Choosing Wisely” campaign, and recommended against the use of fractionation schemes with more than 10 fractions for bone metastases [33]. A single fraction course is more commonly used for patients with uncomplicated bone metastases, whether in the postoperative setting or for those treated for intact tumors. The National Comprehensive Cancer Network (NCCN) Treatment Guideline for Prostate Cancer specifically recommends that a single fraction should be used to palliate a painful prostate cancer bone metastasis [34]. Despite these recommendations and numerous randomized trials, radiation oncologists have been reluctant to adopt the single fraction methods. In an patterns of care analysis published in the Journal of the American Medical Association in 2013, fewer than 5 % of patients received a single fraction treatment, and about 30 % of patients received more than 10 fractions [35]. A cynical view of this practice pattern indicates that increased reimbursement for additional fractions may be driving this overutilization.

Stereotactic body radiation therapy (SBRT) is a technique used to deliver high doses of radiation with high precision in a limited number of fractions. Immobilization devices are used that are more restrictive than those used for 3DCRT, and image guidance is used prior to each treatment to ensure precision of treatment delivery with accuracy to the millimeter. SBRT allows for delivery of a higher dose of radiation in a shorter course and at the same time normal tissues can be spared due to the rapid dose fall off compared to 3DCRT [36]. This rapid dose fall off is displayed in Fig. 17.2, an example of an SBRT treatment plan to a vertebral body metastasis, as compared to the dose distribution in a 3DCRT treatment plan, shown in Fig. 17.1.

It has been hypothesized that since SBRT allows for significant dose-escalation, the time to pain control may be shorter and durability may be longer compared to 3DCRT [36]. In recent years, patients with primary tumors of histologic types thought to be “radioresistant,” such as melanoma and renal cell carcinoma, have been treated with SBRT and higher doses per fraction in an attempt to improve treatment response and durability of pain control [36–39]. The disadvantages of SBRT include increased cost due to the additional quality assurance measures that must be performed to ensure patient safety, as well as longer total time on the treatment machine for positioning and image guidance. This can be difficult for patients with painful bony disease. The volume of disease can also be limiting, as it is preferable to treat smaller sized tumors with SBRT and therefore many times patients are not candidates for this modality.

There has been less experience with SBRT for bone metastases, and unlike 3DCRT, mature randomized trials comparing dose and fractionation with this technique have not yet been reported. Currently, the RTOG is enrolling patients with painful vertebral body metastases to a randomized trial of a single fraction of 3DCRT to a dose of 8 Gy, compared to SBRT in a single fraction, either 16 Gy or 18 Gy [38]. There is no outcome data published to date, although a recent publication showed safety and feasibility to proceed with the phase III component of the trial [40]. Many institutions have published phase I data as well as retrospective series of their own experience using SBRT to treat bony metastases, with good pain control and minimal toxicity [36]. Table 17.6 summarizes much of the retrospective data published with regard to SBRT for bone metastases.