A computed tomography (CT) scan is the best to define the size of an osseous lesion and to evaluate the extent of cortical involvement. In the spine, CT scan is most useful to evaluate aspects of bony stability as measured by pedicle and/or posterior body wall integrity. These factors are important in establishing risk of burst fracture and for planning and assessing the safety of vertebroplasty as a treatment alternative.6 CT-guided biopsy can be used for obtaining tissue samples. Magnetic resonance imaging is valuable for evaluating marrow disease and is most sensitive in identifying metastatic deposits in the spine and pelvis. In patients with neurologic compromise, magnetic resonance imaging is best for assessing epidural disease and extent of vertebral involvement (solitary versus multifocal).
Optimal management requires a multidisciplinary team. Medical treatment, radiation therapy, surgery, and bone-targeted treatment with the bisphosphonates and denosumab are combined depending on the biology of the disease, extent of the skeletal involvement, and the life expectancy of the patient.
Systemic Therapy
Systemic therapy for bone metastases can be targeted against the tumor cell itself to reduce tumor burden or, alternatively, directed toward blocking the effect of tumor-derived growth factors and cytokines on host cells. Chemotherapy, biologically targeted agents, and endocrine treatments have direct antitumor effects, whereas agents such as the bisphosphonates and denosumab are effective by preventing host cells (primarily osteoclasts) from reacting to tumor products. Systemic therapy, therefore, has either direct or indirect actions. In general, the choice of systemic treatment for metastatic bone disease is based on the same criteria as those used for other metastatic manifestations of the malignancy.7
For breast cancer, endocrine therapy is the treatment of choice for the initial treatment of metastatic disease unless the disease is known to be estrogen receptor–negative or there is extensive and/or aggressive visceral disease. Objectively responding patients usually gain relief of symptoms (including bone pain) and might become able to resume their previous activities. Although in general the median duration of response to endocrine therapy is around 15 months, prolonged responses to first-line hormone treatments lasting several years are not uncommon in patients with bone metastases.
There have been many recent developments in cytotoxic and biologic treatments of relevance to the patient with metastatic bone disease from breast cancer. Response in bone to chemotherapy is nearly always only partial, with a median duration of response of 9 to 12 months. Chemotherapy can be more hazardous for patients with extensive bone disease, because of both poor bone marrow tolerance after replacement of functioning marrow by tumor and the effects of previous irradiation. Primary prophylaxis with hematopoietic growth factors may be required to enable chemotherapy to be administered safely.
In prostate cancer, at least 80% of prostate tumors exhibit some degree of hormone responsiveness with a median duration of response of around 2 years. Until recently, treatment to extend survival for castration-resistant prostate cancer (CRPC) was limited to docetaxel. Patients with CRPC tend to be elderly and often of too poor a performance status to receive aggressive systemic therapy. However, the recent introduction of the endocrine agents, such as abiraterone and enzalutamide, and the bone-seeking, alpha particle–emitting radioisotope alpharadin into clinical practice provides well-tolerated additional therapeutic options.
Skeletal morbidity is a major problem in multiple myeloma despite a high rate of response to chemotherapy. Despite the subjective improvement that is seen, bone healing is rare, with lytic lesions persisting despite control of the disease for months or years. Newer agents provide many more options and have transformed the clinical course of multiple myeloma in recent years into that of a chronic disease. Bone involvement in germ cell tumors and lymphoma conveys a worse prognosis, but despite this, cure with chemotherapy is frequent. For relatively chemotherapy-resistant solid tumors such as non–small-cell lung cancer or melanoma, the benefits of current chemotherapy regimens are limited and many patients with skeletal metastases from these tumors derive most benefit from local radiotherapy and bone-targeted agents. However, more effective treatments are emerging, notably the angiogenesis inhibitors in renal cell cancer, and the emergence of a range of targeted treatments for patients with specific mutations (e.g., b-raf in melanoma, epidermal growth factor receptor and alk in lung cancer) that are providing exciting new options for subsets of patients with solid tumors that also involve the skeleton.
Bisphosphonates for Metastatic Bone Disease
Over the past 15 years, bisphosphonates have become established as a valuable additional approach to the range of current treatments. Bisphosphonates are analogues of pyrophosphate, characterized by a phosphorus-carbon-phosphorus–containing central structure that binds to bone and a variable side chain that determines the relative potency, side effects, and the precise mechanism of action.8 Bisphosphonates bind avidly to exposed bone mineral, and during bone resorption, bisphosphonates are internalized by the osteoclast and subsequently cause apoptotic cell death.
After intravenous administration of a bisphosphonate, the kidney excretes approximately 25% to 40% of the injected dose, and the remainder is taken up by bone where it is retained for months or even years. All bisphosphonates suffer from poor bioavailability when given by mouth and must be taken on an empty stomach, as they bind to calcium in the diet. It is generally accepted that osteoclast activation is the key step in the establishment and growth of bone metastases. Biochemical data indicate that bone resorption is of importance not only in classic “lytic” diseases such as myeloma and breast cancer, but also in prostate cancer.5 As a result, the osteoclast is a key therapeutic target for skeletal metastases irrespective of the tissue of origin.9 Although radiotherapy is the treatment of choice for localized bone pain, the bisphosphonates provide an additional treatment approach for the relief of bone pain across a range of tumor types.9
Oral Bisphosphonates
The absorption of bisphosphonates from the gut is poor, variable, and dramatically inhibited by food intake. Nevertheless, oral clodronate and ibandronate have been shown in randomized trials to have useful efficacy in breast cancer.9,10
Intravenous Bisphosphonates
There is extensive experience with intravenous bisphosphonates in breast cancer, with zoledronic acid, pamidronate, and ibandronate all showing useful clinical activity.9,10 Comparative data are few but, in a double-blind randomized trial of 1,130 patients with advanced breast cancer, an additional 20% reduction in the risk of SREs was seen with zoledronic acid compared with pamidronate (p = 0.025).11 Ibandronate is licensed in Europe for the treatment of metastatic bone following a placebo-controlled trial of monthly infusions that showed a significant reduction in skeletal-related morbidity.12
Intravenous bisphosphonates have become routine clinical management for most patients with multiple myeloma, with zoledronic acid and pamidronate the agents of choice.11,13 Improved survival with the inclusion of zoledronic acid in first-line myeloma treatment, as well as fewer SREs, has been shown in a large randomized comparison of zoledronic acid to oral clodronate.14 In advanced CRPC, zoledronic acid was shown to reduce the overall risk of skeletal complications by 36%.15 Additionally, zoledronic acid significantly reduced the risk for SRE(s) by about 30% (p = 0.003) in the management of bone metastases from solid tumors other than breast or prostate cancer.16
Denosumab is a fully human monoclonal antibody that binds and neutralizes RANKL with high affinity and specificity to inhibit osteoclast function and bone resorption. Following a single subcutaneous dose, denosumab caused rapid and sustained suppression of bone turnover in patients with multiple myeloma and patients with breast cancer.17 A subsequent dose-finding phase 2 study defined a subcutaneous 120 mg dose every 4 weeks for phase 3 development.18 A broad development program in >5,700 patients with metastatic disease has shown superiority of denosumab over zoledronic acid in the time to first SRE in trials encompassing a broad range of solid tumors.19–21 The hazard rates for first SRE were 0.82 (95% confidence interval [CI] = 0.71 to 0.95),19 0.82 (95% CI = 0.71 to 0.95),20 and 0.84 (95% CI = 0.71 to 0.98),21 in the trials performed in breast cancer, CRPC, and other solid tumors and myeloma groups, respectively. However, no differences in overall survival or investigator-reported disease progression were found between the two treatment groups in any of the studies.
The safety profiles of denosumab and zoledronic acid are different. Denosumab does not adversely affect renal function, eliminating the need for routine monitoring of renal function. Acute-phase reactions are also less common with denosumab, but hypocalcemia is more frequent.19–21 As a result, vitamin D deficiency should be corrected and all patients should be encouraged to take calcium and vitamin D supplements throughout the course of their treatment. As with intravenous bisphosphonates, the most important adverse event associated with denosumab in the oncology setting is osteonecrosis of the jaw. This occurs with similar frequency in patients treated with denosumab or zoledronic acid, affecting 0.5% to 1% of patients per year on treatment.22
Optimum Use of Bone Targeted Agents in Metastatic Bone Disease
Despite the obvious clinical benefits of bisphosphonates and denosumab, it is clear that only a proportion of events are prevented, while some patients do not experience a skeletal event despite the presence of metastatic bone disease. It is currently impossible to predict whether an individual patient needs or will benefit from a bisphosphonate. Because of the logistics and cost of delivering monthly treatments to all patients with metastatic bone disease, certain empiric recommendations on who should receive treatment are needed. These should take into account the underlying disease type and extent, the life expectancy of the patient, the probability of the patient experiencing an SRE, and the ease with which the patient can attend for treatment (or be treated by a domiciliary service).23 The development of an SRE is not a sign of treatment failure or a signal to stop treatment; evidence is now available to confirm that bone-targeted treatments delay second and subsequent complications, not just the first event.
The recent guidelines on the management of metastatic bone disease in breast cancer from the American Society of Clinical Oncology did not recommend one bone-modifying agent (zoledronic acid, pamidronate, denosumab) over another.24 Although denosumab has some efficacy and convenience advantages, it is much more expensive than zoledronic acid and pamidronate, which are now available as generic formulations. Denosumab or zoledronic acid is appropriate for patients with endocrine-resistant metastatic bone disease from prostate cancer,25 whereas zoledronic acid or pamidronate are recommended for multiple myeloma.26 Patients with other tumors and symptomatic metastasis to bone should certainly be considered for treatment with denosumab or zoledronic acid if bone is the dominant site of metastasis, and also if bone is one of multiple involved sites when the prognosis is reasonable (life expectancy >6 months).9 Bone resorption markers such as N-telopeptide of type 1 collagen may be useful to identify patients at high risk of skeletal complications.5 Additionally, normalization of bone resorption is associated with improved clinical outcomes including fewer SREs and prolonged survival.27
NEW TARGETED THERAPIES IN THE TREATMENT OF METASTATIC BONE DISEASE
A number of targeted agents have entered clinical development. These include radium-223, inhibitors of cathepsin K, an osteoclast-derived enzyme that is essential for the resorption of bone, and Src kinase, a key molecule in osteoclastogenesis. Of all these, radium-223 shows the most promise. Radium-223 is a calcium mimetic that preferentially targets bone metastases and emits high-energy alpha particles resulting in highly localized cytotoxic effects with minimal myelosuppression. In a recent phase 3 study of radium-223 in 921 patients with CRPC and symptomatic bone metastases, radium-223 improved median overall survival by 3.6 months (hazard ratio = 0.70; 95% CI = 0.58 to 0.83; p <0.001) and significantly delayed the time to first symptomatic skeletal event (hazard ratio = 0.66; 95% CI = 0.52 to 0.83; p <0.001).28
EXTERNAL BEAM RADIATION THERAPY
Radiotherapy is effective in relieving bone pain, preventing impending fractures, and promoting healing in pathologic fractures. Hematologic or gastrointestinal side effects are usually mild and transient. Numerous randomized trials have been conducted on dose-fractionation schedules of palliative radiotherapy. Despite that, there is still no uniform consensus on the optimal dose fractionation scheme. One of the first randomized studies on bone metastases was conducted by Radiation Therapy Oncology Group (74-02).29 A total of 90% of patients experienced some relief of pain, and 54% achieved eventual complete pain relief. The trial concluded that the low-dose, short-course schedules were as effective as the high-dose protracted programs. However, this study was criticized for using physician-based pain assessment. A reanalysis of the same set of data, grouping solitary and multiple bone metastases, using the end point of pain relief and taking into account of analgesic intake and retreatment, concluded that the number of radiation fractions was statistically significant related to complete combined relief (absence of pain and use of narcotics). The conclusion was that protracted dose-fractionation schedules were more effective than short-course schedules.30 This reanalysis was contrary to the initial report, highlighting that the choice of end points are very important in defining the outcomes of clinical trials.31
Several large-scale prospective randomized trials were subsequently performed. The United Kingdom Bone Pain Trial Working Party randomized 765 patients with bone metastases to either an 8-Gy single fraction or a multifraction regimen (20 Gy in 5 fractions or 30 Gy in 10 fractions).32 There were no differences in the time to first improvement in pain, time to complete pain relief, or time to first increase in pain at any time up to 12 months from randomization. Retreatment was twice as common after 8 Gy than after multifraction radiotherapy. There were no significant differences in the incidence of nausea, vomiting, spinal cord compression, or pathologic fracture between the two groups. The study concluded that a single 8 Gy is as safe and effective as a multifraction regimen for the palliation of metastatic bone pain for at least 12 months. The Dutch Bone Metastases Study included 1,171 patients and found no difference in pain relief or the quality of life following a single 8-Gy or 24-Gy dose in six daily radiation treatments.33 However, the retreatment rates were 25% in the single 8-Gy arm and 7% in the multiple-treatment arm, respectively. In the cost-utility analysis of this randomized trial, there was no difference in life expectancy or quality-adjusted life expectancy. The estimated cost of radiotherapy, including retreatments and nonmedical costs, was statistically significantly lower for the single-fraction schedule than for the multiple-fraction schedule.34
One critical review included a systematic search for randomized trials of localized radiotherapy of bone metastases employing different dose fractionations.35 The authors suggested that protracted fractionated radiotherapy, given over 2 to 4 weeks, results in more complete and durable pain relief. However, two earlier meta-analyses showed no significant difference in complete and overall pain relief between single-fraction and multifraction palliative radiotherapy for bone metastases.36,37 The meta-analysis reported that the complete response rates (absence of pain) were 33.4% and 32.3% after single-fraction and multifraction radiation treatments, respectively, while the overall response rates were 62.1% and 58.7%, respectively. Most patients will experience pain relief in the first 2 to 4 weeks after radiotherapy, be it single or multiple fractionations.36 However, the retreatment and pathologic fracture rates were higher in single-fraction treatments.37
Since the publication of the two meta-analyses, more randomized trials on bone metastases have been reported. The Radiation Therapy Oncology Group repeated the randomized study in patients with breast or prostate cancer who had one to three sites of painful bone metastases and moderate to severe pain with patient self-assessment.38 There were 455 patients in the single 8-Gy arm and 443 in the 30-Gy in 10 fractions arm. Grade 2 to 4 acute toxicity was more frequent in the multiple arms (17%) than in the single arm (10%) (p = 0.002). Late toxicity was rare (4%) in both arms. The overall response rate was 66%. Complete and partial response rates were 15% and 50%, respectively, in the single-fraction arm compared with 18% and 48%, respectively, in the multiple-fractions arm (p = 0.6). Both regimens were equivalent in terms of pain and narcotic relief at 3 months. The single-fraction arm had a higher rate of retreatment (18% versus 9%; p <0.001). Four Norwegian and six Swedish hospitals planned to recruit 1,000 patients with painful bone metastases. Patients were randomized to single 8 Gy or 30 Gy in 10 fractions.39 The interim analysis indicated that, as in other recently published trials, the treatment groups had similar outcomes. Similar pain relief within the first 4 months was experienced in both groups and this was maintained throughout the 28-week follow-up. No differences were found for fatigue, global quality of life, and survival in both groups.
An updated meta-analysis reporting 25 randomized trials totaling 2,818 and 2,799 randomizations in single-fraction and multiple-fraction arms revealed the overall and complete response rates were 60% and 23%, respectively, in single-fraction arm versus 61% and 24%, respectively, in multiple-fraction arms, again demonstrating equal efficacy.40 However, there is some evidence that certain groups of patients would benefit from a protracted schedule. Roos et al.41 compared a single 8 Gy versus 20 Gy in five fractions for 272 patients with bone metastases causing pain with a neuropathic component. They concluded that a single dose was not as effective as multiple fractions for the treatment of neuropathic pain; however, it was also not significantly worse. They recommended that 20 Gy in five fractions be used as standard radiotherapy for patients with neuropathic pain. However, in patients with short survival, poor performance status, where the cost/inconvenience of multiple treatments was a factor, and in treatment centers with lengthy wait times, single fractions could be used instead.41
How, then, are radiation oncologists to prescribe treatment? The answer most likely resides within the clinical circumstances and individual wishes of each patient. There is no doubt that in patients with short life expectancy, protracted schedules are a burden. However, in patients with a longer expected survival, such as patients with breast cancer and patients with prostate cancer with bone metastases only, other parameters need to be taken into account. Because retreatment rates are known to be higher following a single versus multiple fractions, about 25% versus 10%, respectively, patients with good performance status may wish to share in the decision-making process.
What should be an optimal dose for single fraction treatment? A prospective randomized trial on 270 patients with painful bone metastases compared efficacy of 4-Gy or 8-Gy single doses.42 At 4 weeks, the actual response rates were 69% for 8 Gy and 44% for 4 Gy (p <0.001), but there was no difference in complete response rates at 4 weeks or duration of response between the two arms. It is concluded that 8 Gy gives a higher probability of pain relief than 4 Gy, but that 4 Gy can be an effective alternative in situations of reduced tolerance. Another randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone pain consisted of single 4 Gy, 6 Gy, or 8 Gy.43 The authors confirmed that 8 Gy could be considered as probably “lowest” optimal single-fraction radiation treatment for painful bone metastases, although single 4 Gy should not be easily discarded because of its applicability in specific cases.
Wide-Field or Half-Body External Beam Radiation
Wide-field or half-body irradiation (HBI) differs from localized external beam radiation mainly in the volume of tissues and bone metastases covered as a single treatment field. It is more useful for patients with multiple painful bone metastases. HBI is usually delivered either to the upper half or to the lower half of the body. Single-fraction HBI has been shown in retrospective and prospective phase 1 and 2 studies to provide pain relief in 70% to 80% of patients.44,45 Pain relief is apparent within 24 to 48 hours, suggesting that cells of the inflammatory response pathway may be the initial target tissue, as tumor cell activities are unlikely to be halted so quickly. Toxicities include minor bone marrow suppression and gastrointestinal side effects such as nausea and vomiting in upper abdominal radiation and may be controlled with ondansetron or dexamethasone.
Pulmonary toxicity is minimal provided the lung dose is limited to 6 Gy.46 Fractionated HBI was investigated in a randomized phase 2 study involving 29 patients, comparing a single fraction with fractionated HBI (25 to 30 Gy in multiple fractions). Pain relief was achieved in over 94% of patients. At 1 year, 70% in the fractionated and 15% in the single-fraction group had pain control, and repeat radiation was required in 71% and 13% for the single and fractionated group, respectively.47 Poulter et al.48 reported results of a randomized trial of 499 patients comparing local radiation alone versus local radiation plus a single fraction of HBI. The study documented a lower incidence of new bone metastases (50% versus 68%) and fewer patients requiring further local radiotherapy at 1 year after HBI (60% versus 76%). The choice of dose-fractionation schedule for HBI was explored by Salazar et al.49 among 156 randomized patients. Among the three trial arms of 15 Gy in five fractions over 5 days, 8 Gy in two fractions over one day, and 12 Gy in four fractions over 2 days, the 15-Gy regimen not only provided pain relief as much as the other regimens, but also a longer survival duration in prostate cancer patients.
Reirradiation
As effective systemic treatment and better supportive care result in improved survival, certain subsets of patients have longer life expectancies than before and outlive the duration of the benefits of initial palliative radiotherapy, requiring reirradiation of the previously treated sites.
Among the radiation trials comparing single- versus multiple-fractionation schemes, reirradiation rates varied from 11% to 42% following single-fraction and 0% to 24% following multiple-fraction schedules. There are at least three scenarios of “failure” where reirradiation may be considered. Response to reirradiation may be different for each of these scenarios: (1) No pain relief or pain progression after initial radiotherapy, (2) partial response with initial radiotherapy and the hope to achieve further pain reduction with more radiotherapy, and (3) partial or complete response with initial radiotherapy but subsequent recurrence of pain.
Mithal et al.50 reported a retrospective analysis of 105 patients treated with palliative radiotherapy for painful bone metastases. A total of 280 individual treatment sites were identified, of which 57 were retreated once and 8 were retreated twice. The overall response rate to initial treatment was 84% for pain relief, and at first retreatment this was 87%. Seven of the eight (88%) patients retreated a second time also achieved pain relief. A total of 17 of 23 (74%) patients responded to second radiation that used a number of single-fraction regimens, which was not significantly inferior to 31 of 34 (91%) obtained with more protracted regimens. Jeremic et al.51 investigated the effectiveness of a single 4 Gy given for retreatment of bone metastasis after previous single-fraction radiotherapy. Of 135 patients retreated, 109 patients were retreated because of pain relapsing, whereas 26 patients were reirradiated after initial nonresponse. Of the 109 patients who were reirradiated for pain relapse, 80 (74%) patients responded (complete response = 31%; partial response = 42%). Among the 26 patients who did not respond initially, there were 12 (46%) responses. The authors concluded that the lack of response to initial single-fraction radiotherapy should not deter repeat irradiation. Toxicity in their series was low and gastrointestinal only. No acute toxicity grade 3 or higher was reported. Pathologic fractures were reported in 3 of 135 (2%) patients and spinal cord compression in 3 of 135 (2%) patients in their series. The same group reported the efficacy of the second single 4 Gy reirradiation for painful bone metastases following the previous two single fractions. The overall response rate of the 25 patients (19 responders and 6 nonresponders to the two prior single fractions) was 80%, with both complete response and partial response being 40%. No acute or late high-grade toxicity (≥3) was observed in their study. No pathologic fractures or spinal cord compression were seen in any of these patients during the follow-up.52
The Dutch Bone Metastases Study Group presented the efficacy of reirradiation of painful bone metastases.53 For patients not responding to the initial radiation who were reirradiated, 66% of patients who initially received a single 8-Gy fraction responded to the retreatment versus 33% of patients who received the initial multifraction regimens. Retreatment for patients with progression was successful in 70% single-fraction patients versus 57% multifraction patients. In general, retreatment was effective in 63% of all retreated patients. A recent intergroup randomized trial on dose fractionations in repeat radiation for painful bone metastases in 850 patients concluded a single 8 Gy appears to be noninferior and less toxic than 20 Gy in multiple fractions with 2-month response rates in evaluable patients of 45% versus 51%, respectively (p = 0.17).54
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