• Bone metastases present a variety of unique and complex clinical challenges that demand a multidisciplinary approach for optimal management.

• Bone is the third most common site of metastases, affecting patients with a wide variety of malignancies, most commonly breast, prostate, lung, kidney, and thyroid carcinomas.

• It is estimated that 68% of bone metastases arise from breast, prostate, and lung cancer [1].

• The prevalence of bone metastases is not well understood, as bone metastases are likely underdiagnosed worldwide.

• Prognosis is varied, ranging from a few months to a few years, depending on primary tumor type, extent of disease, prior therapies, and performance status.

• Treatment recommendations must take into account the clinical symptom, the site and number of bone metastases, prior therapies, overall prognosis, and goals of care.

• Goals should include pain control, prevention of pathologic fracture or neurological deficit, local control, and improvement in quality of life (QOL).

• The pathophysiology of bone metastases is driven by disruptions in the unique bone microenvironment.

• Specifically, one of the pathways involves alterations of the OPG/RANKL/RANK signal transduction pathway promoting increased osteoclast formation, accelerating bone resorption, which in turn releases bone-derived growth factors resulting in further proliferation of tumor cells. These tumor cells then further disrupt the OPG/RANKL/RANK pathway resulting in a cycle of bone loss and tumor growth.

• Bone metastases can cause significant morbidity for patients.

• Clinical manifestations include pain, pathologic fracture, neurological deficits due to spinal cord compression or nerve root compression, and hypercalcemia.

• Most commonly, bone metastases present with pain.

• Pain can be severe requiring aggressive medical management.

• As lesions progress, they can inhibit function and mobility.

• Ultimately, they can result in a pathologic fracture causing intense pain and immobility.

• When involving the spine or sacrum, they can cause nerve root impingement and spinal cord compression with devastating neurological deficits.

• Evaluation must involve clinical assessment as well as imaging.

• On exam, bone metastases are often associated with tenderness to palpation as well as functional pain limiting mobility and range of motion.

• Patients must be evaluated for neurological deficits including weakness, paralysis, sensory abnormalities, or incontinence.

• Pathologic fracture/instability assessment

 Neurosurgical or orthopedic evaluation should be considered for bone metastases involving the spine or weight bearing bones.

 Risk of pathologic fracture is difficult to predict; most evidence comes from retrospective surgical series.

 The Randomized Dutch Bone Metastases Study showed that in patients with femoral metastases, a cortical involvement less than 30% had a 97% negative predictive value for fracture [2].

 Mirels Staging System (Table 13.1 and Appendix) [3].

– Site of lesion: Upper limb, Lower limb, Trochanteric region.

– Nature of lesion: Blastic, Mixed, Lytic.

– Cortical Involvement: <1/3, 1/3–2/3, >2/3.

– Pain: Mild, Moderate, Functional.

 Patients receive 1–3 points for each of the four categories, increasing from right to left.

 Total <8, the risk of fracture is low and radiotherapy alone is recommended.

 Total=8, the risk of fracture is moderate and best clinical judgment is recommended.

 Total >8, the risk is high and surgery should be strongly considered.

– Only applicable to long bones (not spine).

– Has been independently validated and proven superior to clinical judgment alone [4].

 Recommendation for surgical management of impending fractures should take into consideration risk of fracture, patient performance status, comorbidities, and patient wishes.

• More than one imaging modality may be required for complete evaluation depending on clinical presentation.

• X-rays are often the first imaging study obtained as they are quick and inexpensive. However, they are limited in their ability to detect small lesions.

• Bone scans are ideal for screening patients at risk for bone metastases or evaluating the extent of bone disease.

 However, bone scintigraphy only detects osteoblastic lesions, and therefore, should not be used for patients at risk for primarily osteolytic lesions as seen in multiple myeloma.

 Bone scans are nonspecific and do not definitively distinguish between metastatic disease and other common pathologies such as arthritis and trauma.

• CT scans are the best modality for defining the size of an osseous lesion/destruction and assessing the amount of cortical involvement, imperative for assessment of pathologic fracture risk. They are also often utilized to guide needle biopsies for tissue diagnosis.

• MRI scans are particularly useful for vertebral metastasis to assess for spinal cord compression and epidural extension.

• PET/CT scans are useful for whole body screening and are particularly sensitive for osteolytic lesions.

• Treatment should begin with medical pain control.

 World Health Organization Analgesic Ladder should be utilized as a framework for treating cancer pain.

 Nonsteroidal antiinflammatory medications Nonsteroidal antiinflammatory drugs (NSAIDs) are often effective.

 Steroids can provide rapid relief of pain, but should not be administered for extended courses due to side effects.

 Pain from bone metastases is often severe requiring narcotic medications.

 For neuropathic pain, medications such as gabapentin and amitriptyline can be attempted, but are unlikely to be sufficient on their own.

 Antidepressants and benzodiazepines may be effective adjuvant medications in selected patients.

 Refer Chapter 6, Pain Management, for a more detailed discussion.

• Good pain control can be achieved through medications, but QOL can be significantly impaired due to medication side effects. In order to minimize pain medication requirements, thereby, improving QOL, a number of local and systemic therapies can be utilized.

 External beam radiation is the primary treatment modality for local pain secondary to bone metastases.

 Surgical management for bone metastases is largely reserved for prevention or management of pathologic fractures and for decompression and stabilization for spinal cord compressions.

 Interventional techniques such as vertebroplasty and kyphoplasty can be utilized for relief of mechanical pain caused by compression fracture due to vertebral metastases; however, little data exists regarding the efficacy and safety of these methods. An ablative procedure such as radiofrequency ablation or cryotherapy is often combined with these interventional techniques to prolong tumor control at the site.

 A variety of systemic therapies are available including radiopharmaceuticals, chemotherapy, targeted agents, and bisphosphonates.

• External Beam Radiation Therapy (EBRT) is the standard of care for localized bone pain resulting from bone metastases.

• It is a noninvasive, well tolerated, and cost-effective treatment modality.

• Pain relief can be rapid, occurring within days to weeks of radiation.

 The Randomized Dutch Bone Metastases Study reported the mean onset of pain relief occurring at 3 weeks and full palliative effect occurring 4–6 weeks after completion of treatment [5].

 Given this delay in peak effect, medical management of pain remains critically important during and following radiation therapy.

• Pain response from EBRT ranges from 60% to 80% [6].

• Multiple prospective randomized studies have evaluated different dosing and fractionation schemes.

• However, it was not until 2000, that a consensus meeting was held to define and regulate endpoints in an attempt to improve consistency and allow accurate and meaningful comparison of future trials [7].

• Recommended dose fractionation regimens are summarized in Table 13.2.

• Radiation Therapy Oncology Group (RTOG) 74-02

 RTOG 74-02 was one of the initial randomized controlled trials comparing fractionation regimens for bone metastases [8].

– Patients with a single bone metastasis were randomly assigned to 40.5 Gy in 15 fractions or 20 Gy in 5 fractions.

– Patients with multiple metastases were randomized to 30 Gy in 10 fractions, 15 Gy in 5 fractions, 20 Gy in 5 fractions, or 25 Gy in 5 fractions.

 Initial analysis showed 90% of patients experienced some pain relief and 54% of patients received a complete response to pain with no statistically significant difference in relief rates between any of the arms [8].

 This study was criticized for using physician assessment of pain response, and reanalysis was performed with an altered definition of a complete pain response.

 The reanalysis defined a complete pain response as no pain, no analgesic use, and no re-irradiation [9]. With this change in definition, a statistically significant benefit was found in the more protracted arms (40.5 Gy in 15 and 30 Gy in 10).

 How pain response was defined dramatically altered the outcomes of this trial, illustrating the importance of definitions and end points.

• Two randomized trials compared single-fraction radiation doses.

 Hoskin et al. randomized patients to 4 Gy versus 8 Gy in a single fraction [10].

 Jeremic et al. randomized patients to 4 Gy versus 6 Gy versus 8 Gy [11].

 In both of these studies 8 Gy was superior to 4 Gy. There was no apparent benefit of 8 Gy over 6 Gy in the later trial.

• RTOG 97-14

 RTOG 97-14 compared 30 Gy in 10 fractions with 8 Gy in one fraction [12].

 Patient assessment of pain response was evaluated with the Brief Pain Inventory.

 There were no differences in complete or partial pain response between the two arm (p=0.6).

 The re-treatment rate was 18% in the 8 Gy arm and 9% in the 30 Gy arm (p< 0.001).

 However, narcotic use and progressive pain scores were similar between the two arms, suggesting that the higher re-irradiation rate was not simply a result of decreased pain response or decreased durability of pain response.

– It has been suggested that the increased re-irradiation rate in the single-fraction arm was due to patient willingness to undergo re-irradiation given the ease of this fractionation scheme.

– Furthermore, perhaps physicians are more willing to deliver re-irradiation following a total dose of 8 Gy as opposed to higher doses.

• Metaanalysis

 A recent metaanalysis of 16 randomized trials including over 2000 patients demonstrated equivalent efficacy for pain control between single fraction 8 Gy and multifraction radiotherapy [13].

 Complete pain response rate was 23% in the single-fraction arms and 24% in the multifraction arms. Rates were measured at variable time periods ranging from 3 to 8 weeks, where reported.

 Overall pain response rates were 58% and 59% in the single-fraction versus multifraction arms, respectively.

• 8 Gy in 1 fraction is the preferred treatment regimen for noncomplicated bone metastases regardless of primary tumor type, site of metastasis, or prognosis, as it has demonstrated equivalent pain relief, while maximizing patient convenience and cost-effectiveness.

• Studies have reported higher rates of re-irradiation after single-fraction radiation versus more prolonged courses [2,12].

 Whether this is due to a less prolonged pain response or patient and physician willingness to consider re-irradiation after single-fraction radiotherapy remains unclear.

• More prolonged courses are recommended for bone metastases with an extensive soft tissue component or impending pathologic fracture in order to achieve greater tumor control and induce bone remineralization.

• Single-fraction radiation has been associated with higher rates of pathologic fracture in femoral metastases treated with radiation alone without surgical stabilization [2].

• Consider 20 Gy in 5 fractions or 30 Gy in 10 fractions in these instances.

• After surgical stabilization, the optimal radiation regimen is unknown, as little data exists.

 However, similar principles of increased remineralization are applied, and more protracted courses of radiation are generally recommended.

 Consider 30 Gy in 10 fractions.

• External beam radiotherapy for bone metastases is very well tolerated regardless of fractionation used.

• General side effects could include fatigue, pain flare, skin irritation, or hair loss in the targeted area.

• Other side effects depend on the area being treated and dose to normal structures.

• In the chest, patients can experience sore throat, dysphagia, or cough.

• In the abdomen, nausea or enteritis is possible.

• In the pelvis, patients may develop loose stool/diarrhea or bladder irritation.

• Side effects are generally mild and self-limited.

• Recommendations for medical management of side effects during treatment are summarized in Table 13.3.

• Pain flare

 A definition of pain flare was defined as a 2-point increase in the maximum pain score (0–10 on the Numeric Rating Scale-11) compared to baseline with no decrease in analgesic intake, or a 25% increase in analgesic intake with no decrease in the maximum pain score [14].

 Pain flare should be distinguished from progression of pain by requiring the worst pain score and analgesic intake to return to baseline after the increase within a 10-day follow-up period [14].

 May occur in up to 40% of patients [14].

 Consider NSAID or dexamethasone administration.

 A pilot study of 33 patients treated with 8 mg dexamethasone prior to 8 Gy in 1 fraction palliative EBRT for bone metastasis [15].

– 8 (24% of patients) experienced a pain flare within the 10 day follow-up period.

– Only 1 (3% of patients) experienced a pain flare within the first 2 days (duration of action of dexamethasone).

– The authors concluded that dexamethasone may be effective in the prophylaxis of pain flare following palliative EBRT for bone metastases.

 Hird et al. published a Phase II trial evaluating the prophylactic role of prolonged dexamethasone administration [16].

– 41 patients received 8 mg of dexamethasone daily started at least 1 hour prior to delivery of EBRT (8 Gy × 1) and for three consecutive days after EBRT.

– Pain flare occurred in 9 (22% of patients).

 A double-blind, randomized, placebo-controlled Phase III trial evaluating the efficacy of dexamethasone in reducing pain flares following EBRT for painful bone metastases was reported by Chow et al. in 2015 [17].

– Dexamethasone was delivered to 148 patients at 8 mg at least 1 hour prior to radiation and then 8 mg/day for the following 4 days postradiation therapy.

– Placebo was administered in 150 patients.

– 39 (26%) patients in the dexamethasone group versus 53 (35%) patients in the placebo group experienced a pain flare (p=0.05).

– Two grade 3 and one grade 4 biochemical hyperglycemic events occurred in the dexamethasone group compared with none in the placebo group.

– Other toxicities were mild and well balanced between the two groups.

– This study supports the use of routine dexamethasone to reduce the incidence of pain flare.

 When discussing side effects of radiation, patients should be made aware of the possibility of a pain flare, and prophylactic dexamethasone therapy should be considered.

• The goal of palliative therapy goes beyond resolution of symptoms to improvement in QOL.

• As discussed earlier, pain relief is a proven benefit of palliative EBRT for bone metastases, but does this translate to an improvement in QOL?

• The international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases defined end points largely in terms of patient-assessed pain score and analgesic consumption [18].

• The 2012 update published the recommendation for the inclusion of validated QOL instruments in all future clinical trials [19].

• McDonald et al. performed a literature review of all prospective and retrospective studies investigating the QOL following palliative radiation therapy for bone metastases [20].

 Only three randomized controlled trials were found to include validated QOL tools.

 Most commonly utilized tools were the Brief Pain Inventory, Edmonton Symptom Assessment Scale, European Organization for Research and Cancer Treatment (EORTC) QOL questionnaires.

 The review confirmed that the majority of patients did experience improvement in QOL after EBRT.

• Validated QOL assessment tools should be included in all future randomized controlled trials in bone metastases. (See Appendix for further details regarding these tools.)

• Re-irradiation of bone metastases is safe and effective with response rates varying from 33% to 84% in retrospective studies using a variety of dose/fractionation regimens [21].

• Cumulative radiation doses to critical normal structures must be considered carefully, as in all re-irradiation scenarios.

• Chow et al. published results of an international Phase III randomized controlled trial comparing 8 Gy in 1 fraction versus 20 Gy in 5 fractions for re-irradiation of bone metastases [22].

 425 patients were randomly assigned to each treatment group.

 250 (48%) of all patients who received their assigned treatment had reduced pain at treatment site or reduced need for analgesia.

 Pain severity was scored with the Brief Pain Inventory.

 Primary endpoint was pain relief at 2 months after completion of re-EBRT.

 Pain relief was defined as at least a 2 point reduction in worst pain score (without increase in analgesic use) or reduction in oral analgesic intake, or both.

 The intention to treat analysis showed noninferiority of 8 Gy in 1 fraction as compared to 20 Gy in 5 fractions with less toxicity.

 However, almost one-third of patients were not assessable at 2 months due to deaths, loss to follow up, or poor documentation.

– 140 (33%) in the 8 Gy arm and 132 (31%) in the 20 Gy arm were counted as missing data in the intention to treat analysis.

 In the patients who received the protocol treatments and were available for follow up (per protocol population), analysis did not meet the prespecified noninferiority margin.

• Oliogometastatic disease is a unique clinical scenario for which ideal management options are still being investigated.

• It is hypothesized that patients with <5 metastases have potentially curable disease and should be treated aggressively with curative intent.

• Stereotactic body radiotherapy (SBRT)/Stereotactic radiosurgery (SRS) allows for ablative, potentially curative, doses while protecting critical normal structures.

• Radiation therapy for bone metastases is usually performed with 2–3 fields with either a fluoroscopy or CT simulation.

• Attention should be taken to minimize treatment time as radiation positioning can often worsen pain.

• Typically 6–15 MV photons are used; however, electron therapy can be beneficial in superficial lesions, i.e., ribs, sternum, or skull, as electrons allow adequate target coverage while minimizing dose to deeper structures.

• The use of more complex, highly conformal techniques, such as intensity-modulated radiation therapy (IMRT) or SBRT should be reserved for areas that have been heavily radiated previously or in the unique instance of oligometastatic disease in patients with good performance status and prognosis.

• When patients have diffuse bone metastases, localized therapies such as EBRT cannot address diffuse nature of pain.

• Hemibody radiation therapy techniques were utilized historically, but these have fallen out of favor due to toxicities.

• Radiopharmaceuticals are a compelling alternative.

• Calcium and phosphorous analogs are combined with a radioactive isotope with beta minus or alpha particle emission. These analogs preferentially accumulate in bone, particularly in areas of active bone turnover, allowing localized radiation delivery to these areas.

• Of particular interest, is that they can be safely combined with other therapeutic modalities including EBRT and chemotherapy.

• Efficacy of radiopharmaceuticals for pain palliation has been demonstrated in multiple RCTs.

• Strontium-89 (Sr-89)

 Sr-89 is a calcium analog approved for use in metastatic prostate cancer in 1993 [26].

 It is a pure beta minus emitter.

 Average energy is 0.58 MeV.

 Average range in soft tissue is 2.4 mm.

 Half-life is 50.5 days [27].

 The efficacy of Sr-89 for reducing pain has been shown in multiple randomized clinical trials.

– A large multicenter Canadian trial prospectively randomized patients to Sr-89 versus placebo after localized EBRT [28].

 126 patients with hormone resistant metastatic prostate cancer were randomized to either a single injection of 10.8 mCi versus placebo.

 There were no significant differences in survival or pain relief at the index site.

 However, QOL, delay of pain progression, and tumor marker levels were all improved in the Sr-89 arm.

– Oosterhof et al. reported a Phase III randomized clinical trial comparing Sr-89 versus local EBRT in castrate resistant metastatic prostate cancer [29].

 Over 200 patients were randomized to either one intravenous injection of 150 MBq of Sr-89 versus localized EBRT.

 An overall survival benefit was seen in the EBRT group, 11 months versus 7.2 months, p=0.0457.

 There was no difference in pain response, progression free survival, time to progression or toxicity.

– A systematic review evaluating the efficacy of Sr-89 in patients with metastatic prostate and breast cancer reported some pain response to Sr-89 in 80% of patients and a complete pain response in 10% of patients [30].

 Mean duration of response ranged from 3 to 6 months. As many as 10 injections every 3 months have been administered safely.

– A second review reported complete pain responses from 8% to 77% with an average complete pain response rate of 32% [31].

 Onset of treatment ranged from 4 to 28 days with mean duration of response of 15 months.

 Sr-89 can also be combined safely with chemotherapy.

 Multiple randomized clinical trials have evaluated the efficacy and safety of combination Sr-89 and chemotherapy.

– Sciuto et al. compared Sr-89 with cisplatin versus Sr-89 with placebo [32].

 70 patients were randomized to 150 MBq Sr-89 with 50 mg/m² cisplatin versus Sr-89 150 MBq plus placebo.

 Pain relief was significantly improved in the cisplatin arm compared to the placebo arm, 91% versus 63%, p< 0.01.

 Median duration of response and progression of bone disease were also improved in the cisplatin arm.

 No survival differences or hematologic toxicities were observed.

– Tu et al. reported a survival benefit with the addition of Sr-89 to doxorubicin [33].

 They randomized 72 patients to doxorubicin with or without Sr-89.

 Median survival was 27.7 months in patients who received Sr-89 and 16.8 months in patients who received doxorubicin alone, p=0.001.

• Samarian-153 (Sm-153)

 Samarian-153 (Sm-153), also a beta minus emitter, was approved in the 1990s.

– It is created by neutron bombardment in a nuclear reactor and is chelated by ethylenediaminetetra-methylenephosphate (EDTMP) to increase affinity for bone.

– Its mean energy is 0.23 MeV with average range of 0.6 mm and half-life of 1.9 days. It has 28% gamma emission [34].

– A Phase III placebo controlled trial compared 0.5 or 1.0 mCi/kg of Sm-153 to placebo in 118 patients in a variety of cancers [35].

 Sm-153 was associated with a significant improvement in pain relief (p=0.016) with complete pain relief in 31% of patients by 4 weeks.

– In another randomized Phase III trial, 152 patients with bone metastatic castrate resistant prostate cancer were randomized to receive either radioactive or nonradioactive samarium [36].

 Complete pain relief was seen in 38% versus 18% of patients in the radioactive Samarian arm versus the nonradioactive arm, respectively (p=0.008).

 Sm-153 has also been shown to be safe and efficacious when combined with docetaxel in Phase I and II trials [37,38].

• Rhenium-186 (Re-186)

 Rhenium-186 (Re-186) is another beta minus and gamma emitting radionuclide.

 Mean energy is 0.349 MeV, average range is soft tissue is 1.1 mm, and the half-life is 3.7 days.

 The PLACORHEN study was a Phase III randomized study comparing Re-186 to placebo in 111 men with bone metastases from castrate resistant prostate cancer [39].

– Mean pain response was 27% versus 13% in the treatment arm versus placebo arm, respectively (p=0.05).

• Sr-89, Sm-53, and Re-186 have all been shown to be efficacious and safe in Phase III randomized controlled trials.

• They have also been compared to each other head to head, but no significant difference in efficacy or toxicity has been described.

• These radiopharmaceuticals should be considered for patients with diffuse bone metastases for palliation of pain and expected survival >3 months.

• The addition of Sr-89 to doxorubicin has been shown to provide a significant overall survival benefit when compared to doxorubicin alone.

• Bisphosphonates are an important systemic therapy for the treatment and prevention of skeletal complications.

• Bisphosphonates are pyrophosphate analogs that bind to exposed bone mineral. During bone resorption, they are internalized by osteoclasts and induce cell apoptosis, reducing the rate of bone resorption and remodeling [41].

• They have poor oral bioavailability, and are typically administered intravenously monthly.

• They have become standard of care in the management of multiple myeloma and solid tumors with confirmed bone metastases.

• Zoledronic acid has been shown in a prospective randomized trial to be more efficacious than pamidronate in breast cancer and advanced multiple myeloma [42].

• For castrate resistant prostate cancer and other solid tumors, zoledronic acid has also been shown to reduce skeletal related events (SREs) [43,44].

• Complications related to bisphosphonate therapy include osteoradionecrosis of the mandible and renal toxicity.

• The use of bisphosphonates in combination with EBRT has been evaluated in two prospective trials.

 Vassiliou et al. evaluated 45 patients with bone metastases from a variety of solid tumors treated with EBRT (30–40 Gy over 3–4.5 weeks) with monthly ibandronate 6 mg IV for 10 cycles [45].

– A complete pain response was seen in 57% and a partial response in 43%.

– The mean pain scores (graded from 0 to 10) were reduced from 6.3 to 0.8 at 3 months.

– Opiate use also decreased significantly from 84% to 24% at 3 months.

– Bone density assessed by CT, performance status and functioning scores all significantly improved.

– Treatment was well tolerated.

 A prospective study by Kouloulias et al. evaluated 33 patients with bone metastases from breast cancer treated with EBRT (30 Gy in 10 fractions) with monthly IV pamidronate for 24 months [46].

– The therapy was well tolerated.

– 88% complete pain response and a 12% partial response.

• Denosumab is a human monoclonal antibody which binds to the RANK ligand, inhibiting the production and normal maturation process of osteoclasts.

• Two large prospective randomized studies have shown improved efficacy of denosumab when compared to zoledronic acid.

 Stopek et al. randomized over 2000 breast cancer patient to either monthly denosumab or monthly zoledronic acid.

– Denosumab was found to be more efficacious in terms of delaying time to first and subsequent SREs (p=0.001) [47].

 A second randomized controlled trial compared denosumab to zoledronic acid in castrate resistant prostate cancer [48].

– Over 1900 patients were randomized.

– Median time to first SRE was 17.1 months in the zoledronic acid arm and 20.7 months in the denosumab arm (p=0.008 for superiority).