Management of bone metastases

Metastatic bone disease develops as a result of the many interactions between tumor cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signaling mechanisms involved in cancer-induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and its use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.     

Re-irradiation for painful bone metastases – A systematic review

The purpose of this review was to determine the efficacy of re-irradiation in patients with bone metastases. A literature search was conducted in Ovid Medline, OldMedline, Embase, Embase Classic, and Cochrane Central Register of Controlled Trials using relevant subject headings and keywords such as bone metastases, radiotherapy and palliative care. The resulting articles were sorted for inclusion for palliative external beam radiation retreatment response rate data. The literature search produced 2164 references and 15 articles were included in the final selection. Complete, partial and overall response rates were calculated to be 20%, 50% and 68%, respectively. Information on treatment toxicities was scarce. The efficacy of re-irradiation is comparable to initial radiation treatment. However, aspects of re-irradiation treatment including dose fractionation, related adverse events and toxicities require further corroboration.     

Stereotactic body radiotherapy in the management of painful bone metastases

More than 100,000 new cases of bone metastases are diagnosed each year, and they present an important clinical problem. They cause significant morbidity and quality-of-life issues in cancer patients. Conventional external-beam radiotherapy is currently the most common method to treat these metastases, with several randomized controlled trials showing no difference in effectiveness between multiple- and single-dosing treatment regimens. A newer technology to treat bone metastases is stereotactic body radiotherapy (SBRT), a radiation delivery method that allows for a large ablative dose to be accurately given to the target over one to a few fractions. This review details the role of SBRT in painful bone metastases, primarily in the vertebral column, but in other bony sites as well, its unique advantages and disadvantages, and its role in the treatment of tumors traditionally deemed radioresistant. Toxicity to surrounding normal tissues and patterns of local failures are also addressed.     

Cementoplasty for painful bone metastases: a series of 42 cases

The aim of this study is to assess the interest of cementoplasty in the management of bone metastases, based on a retrospective study involving 42 cementoplasty procedures. The median age of the patients is 59 years, with 24 women (57%) and 18 men, all of them presenting with an advanced disease. The cementoplasty was situated in long bones (ten patients), dorsal or lumbar vertebrae (13) and flat bones (20). The principal indication was pain, sometimes with consolidation. The intensity of pain decreases between the day before and the month following the treatment (P = 0.04) among the 25 patients who had pain assessment before and after the procedure. We note 57% good results (24 patients), 9.5% failures (4 patients), and 31% with partial results (13 patients), that is, a total of 88% with “partial or full” alleviation. 16 patients out of 22 (73%) who were no longer able to walk (because of the pain or risk of fracture) were able to resume walking. We observed in this series 40.5% of complications, all of them benign. Cementoplasty improves the quality of life of patients with bone metastases, by decreasing the pain in 88% of cases and allowing the resumption of walking in almost three-quarters of the patients who had lost the ability to walk.     

Percutaneous image‐guided cryoablation of painful metastases involving bone

BACKGROUND:

This study sought to describe the results of a single‐arm multicenter clinical trial using image‐guided percutaneous cryoablation for the palliation of painful metastatic tumors involving bone.

METHODS:

Over a 44‐month period, 61 adult patients with 1 or 2 painful bone metastases with a score of 4 or more on a scale of 0 to 10 (≥4/10) worst pain in a 24‐hour period who had failed or refused conventional treatment were treated with percutaneous image‐guided cryoablation. Patient pain and quality of life was measured using the Brief Pain Inventory prior to treatment, 1 and 4 days after the procedure, weekly for 4 weeks, and every 2 weeks thereafter for a total of 6 months. Patient analgesic use was also recorded at these same follow‐up intervals. Complications were monitored. Analysis of the primary endpoint was undertaken via paired comparison procedures.

RESULTS:

A total of 69 treated tumors ranged in size from 1 to 11 cm. Prior to cryoablation, the mean score for worst pain in a 24‐hour period was 7.1/10 with a range of 4/10 to 10/10. At 1, 4, 8, and 24 weeks after treatment, the mean score for worst pain in a 24‐hour period decreased to 5.1/10 (P < .0001), 4.0/10 (P < .0001), 3.6/10 (P < .0001), and 1.4/10 (P < .0001), respectively. One of 61 (2%) patients had a major complication with osteomyelitis at the site of ablation.

CONCLUSIONS:

Percutaneous cryoablation is a safe, effective, and durable method for palliation of pain due to metastatic disease involving bone. Cancer 2013. © 2012 American Cancer Society.     

Comparative evaluation of two hypofractionated radiotherapy regimens for painful bone metastases

AIMS AND BACKGROUND: In 75% of the patients with bone metastases (BM) pain is the dominant symptom. Radiotherapy (XRT) plays a major role in the palliation of pain in patients with BM. Several schedules of short and long fractionation XRT are used in clinical practice, with hypofractionated treatments being even more attractive for practical reasons. A considerable body of evidence supports the clinical use of short schedules and single-dose XRT. We retrospectively evaluated the efficacy of two short fractionated schedules of 8 Gy as a single dose and 20 Gy in 5 fractions in relieving pain in patients with multiple uncomplicated BM. METHOD: From January to December 2001, 130 patients with 146 painful BM were treated with palliative localized XRT. There were 42 males and 88 females with a median age of 58 years (range 28-84). The commonest sites of treatment were the spine (59.6%) and pelvis (14.4%). The primary endpoint was clinically significant pain relief in the first six months of follow-up evaluated with the IAEA (International Atomic Energy Agency) pain measurement score measuring pain severity and pain frequency. Analgesic use was also recorded before and after treatment as drug frequency and drug severity. Patients with painful BM from any primary tumor site were irradiated. Treatment schedules consisted of a course of XRT with 4 Gy/fraction/day (total dose: 20 Gy/5 fractions) (group A, 59 lesions) or with a single dose of 8 Gy (group B, 87 lesions). RESULTS: There was no significant difference in complete response (CR) rates between treatment schedules: complete pain relief was achieved in 17/59 lesions (29%) in the fractionated group and in 29/87 lesions (33%) in the single-dose group. Also the overall response (complete + partial) was similar: 35/59 lesions (60%) in group A and 60/87 (69%) in group B. The minimum, maximum and median follow-up was 3, 23, and 9 months, respectively, for group A and 3, 20, and 11 months for group B. The actuarial median duration of pain relief was similar: 4.5 months in group A and 4 months in group B. No particular side effects were recorded in either group. CONCLUSIONS: There were no differences between the two fractionation schedules used in our study with regard to pain relief and use of analgesics. Palliation of pain was obtained in approximately two thirds of patients with both schedules, providing further evidence of the similar efficacy between single and multiple fractions. With regard to pain response these data justify a recommendation for the use of a more simple and convenient 8 Gy single fraction for the palliation of uncomplicated BM.     

Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases

PURPOSE: To compare pain relief among various dose-fractionation schedules of localized radiotherapy (RT) in the treatment of painful bone metastases. METHODS AND MATERIALS: A systematic search for randomized trials of localized RT on bone metastases using different dose fractionations was performed using Medline (1966 to February 2001) and other sources. The primary outcomes of interest were complete and overall pain relief. The studies were divided into three groups: comparisons of doses given as a single fraction, single vs. multiple fractions, and comparisons of doses given as multiple fractions. The complete and overall pain responses for studies comparing single vs. multiple fractions were pooled. Exploratory analyses of the dose-response relationship, using the biologic effective dose (alpha/beta = 10), were performed using results from all three groups of trials. RESULTS: Two trials comparing single vs. single, eight trials comparing single vs. multiple, and six trials comparing multiple vs. multiple fractions were included. The complete and overall response rates from studies comparing single-fraction RT (median 8 Gy, range 8-10 Gy) against multifraction RT (median 20 Gy in 5 fractions, range 20 Gy in 5 fractions to 30 Gy in 10 fractions) were homogeneous and allowed pooling of data. Of 3260 randomized patients in seven studies, 539 (33.4%) of 1613 and 523 (32.3%) of 1618 patients achieved a complete response after single and multifraction RT, respectively, giving a risk ratio of 1.03 (95% confidence interval 0.94-1.14; p = 0.5). The overall response rate was in favor of single-fraction RT (1011 [62.1%] of 1629) compared with multifraction (958 [58.7%] of 1631; risk ratio 1.05, 95% confidence interval 1.00-1.11, p = 0.04), reaching statistical significance. However, when the analysis was restricted to evaluated patients alone, the overall response rates were similar for single fraction and multifraction RT, at 1011 (72.7%) of 1391 and 958 (72.5%) of 1321, respectively (risk ratio 1.00; p = 0.9). Exploratory analyses by biologic effective dose did not reveal any dose-response relationship among the fractionation schedules used (single 8 Gy to 40 Gy in 15 fractions). Of the other results and observations reported in the trials, only the re-irradiation rates were consistently different between the treatment arms (more frequent re-irradiation in lower dose arms among trials reporting re-irradiation rates). CONCLUSION: Meta-analysis of reported randomized trials shows no significant difference in complete and overall pain relief between single and multifraction palliative RT for bone metastases. No dose-response relationship could be detected by including data from the multifraction vs. multifraction trials. Additional data are needed to evaluate the role of re-irradiation and the impact of RT on other treatment end points such as quality of life.     

Palliative treatment of painful bone metastases from non-Hodgkin lymphoma with disodium pamidronate

We report a case of a 72-year-old male, with a known history of non-Hodgkin lymphoma of the left tonsil for two years, histologically proved and successfully treated by radical surgical excision in combination with external radiotherapy. He presented with diffuse bone pain the last month, especially at the lower left ribs, which was found to be due to multiple osseous metastases by bone scintigraphy. The patient was initially treated by common analgesics and when the pain deteriorated he was administered 180 mg i.v. disodium pamidronate (AREDIA, Novartis Inc.). The patient showed excellent pain relief as well as dramatically improvement of WHO status and stopped the analgesics. An interesting point of our case was that the pain deteriorated again after a month and reduced soon after the re-administration of pamidronate, which was continued every month. So far, 10 months after the first pamidronate injection, our patient remains stable with excellent pain relief. Despite the absence of related data in the current literature, we consider the use of high dose pamidronate intravenous therapy safe and an effective method of palliative management of painful osseous metastases from non-Hodgkin lymphoma.     

Management of bone metastases from breast cancer

Bone is the most common of breast cancer metastasis. Bone metastasis causes skeletal-related events(SREs), including pain, bone fractures, spinal cord compression, and hypercalcemia. SREs significantly impair patients' quality of life. The main purpose of treatment for bone metastasis is to prevent or delay SREs and to improve patients' quality of life. Accurate diagnosis of bone metastases is important in order to choose an appropriate treatment. Treatment of bone metastasis requires a multidisciplinary approach. Analgesic medication with NSAIDs and opioids is the first choice for pain control. In addition to bisphosphonate, the receptor activator of the nuclear factor κB ligand(RANKL)inhibitor, denosumab is a novel bone-targeting agent effective in preventing SREs. Prophylactic stabilization of impending fractures provides several advantages compared with fixation of an acute fracture, in terms of short hospitalization and a quick return to baseline. In general, radiation therapy is indicated for patients for whom surgery is suitable. Radiation therapy to palliate pain from bone metastasis can reduce the intake of analgesic medications. Local radiation therapy is indicated for a limited number of bone metastases, and systemic radionuclide therapy is appropriate for multiple lesions. In summary, treatment using these modalities for bone metastasis from breast cancer should be stratified, considering the symptoms, site of bone metastasis, and patients' life expectancy and performance status.     

Management of bone metastases in breast cancer

Opinion statement Patients with advanced breast cancer who develop bone metastases suffer an ongoing risk of skeletal complications that can have a significant impact on their quality of life (QoL). These complications include bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM), a potentially life-threatening condition. Treatment options include radiotherapy to palliate bone pain and/ or prevent impending fracture, orthopedic surgery to prevent or repair fractures, analgesics, and bisphosphonates, which can significantly reduce the risk of skeletal complications and delay their onset. Of the known bisphosphonates, zoledronic acid is the most potent. Since its regulatory approval in the United States and Europe in 2001, zoledronic acid (4 mg by 15-minute infusion) has become widely used and has replaced pamidronate (90 mg by 2-hour infusion) as the standard of care for treating bone metastases from breast cancer and bone lesions from multiple myeloma. Zoledronic acid has also demonstrated significant long-term benefits in randomized trials in prostate cancer and other solid tumors, whereas other bisphosphonates have failed. In long-term, phase III clinical testing, zoledronic acid provided significant treatment benefits beyond those of pamidronate in patients with breast cancer and demonstrated a safety profile comparable with pamidronate. Therefore, zoledronic acid is now recommended from the first diagnosis of bone metastasis. Other intravenous bisphosphonates include clodronate and ibandronate. Both are approved in Europe, but their efficacy relative to pamidronate and zoledronic acid is not known.     

Efficacy of radiotherapy for painful bone metastases during the last 12 weeks of life

BACKGROUND:

Radiotherapy is an effective treatment for painful bone metastases. Whether this applies also in patients with limited survival remains to be investigated. This study analyzed the effect of radiotherapy for painful bone metastases in patients with a survival ≤12 weeks.

METHODS:

In the Dutch Bone Metastasis Study, 1157 patients with painful bone metastases were randomized to single fraction (1 × 8 grays [Gy]) or multiple fraction (6 × 4 Gy) radiotherapy. Patients who died within 12 weeks after randomization were included in this analysis. Patients were classified as responders or nonresponders, based on their pain response to radiotherapy. This response was calculated considering changes in pain intensity (measured with an 11‐point numeric rating scale) and analgesic usage. Cox proportional hazards models were used to analyze pain response and survival.

RESULTS:

Two hundred seventy‐4 patients were included in this analysis. At randomization, the mean pain intensity score (±standard deviation) was 7 (±2). The proportion showing a pain response did not differ between the single fraction and multiple fraction groups. Toward death, pain intensity score decreased to 5 (±3) in responders (45%), whereas in nonresponders (55%) no change was observed. Despite the benefit in responders, in 60% of all patients pain intensity remained 5 after randomization.

CONCLUSIONS:

Pain responded in about half of the patients who survived ≤12 weeks after randomization into the Dutch Bone Metastasis Study. When considering radiotherapy, single fraction should be preferred. Additional palliative measures remain essential for adequate pain control. Cancer 2010. © 2010 American Cancer Society.     

Patient preference for radiotherapy fractionation schedule in the palliation of painful bone metastases.

PURPOSE: The radiotherapeutic management of painful bone metastases is controversial, with several institutional and national guidelines advocating use of single-fraction radiotherapy. We aimed to determine patient choice of fractionation schedule after involvement in the decision-making process by use of a decision board. PATIENTS AND METHODS: Advantages and disadvantages of two fractionation schedules (24 Gy in six fractions v 8 Gy in one fraction) used in the randomized Dutch Bone Metastasis Study were discussed with patients using a decision board. Patients were asked to choose a fractionation schedule, to give reasons for their choice, and to indicate level of satisfaction with being involved in decision making. RESULTS: Sixty-two patients were entered. Eighty-five percent (95% confidence interval, 74% to 93%) chose 24 Gy in six fractions over 8 Gy in one fraction (P <.0005). Variables including age, sex, performance status, tumor type, pain score, and paying class were not significantly related to patient choice. Multiple fractionation was chosen for lower re-treatment rates (92%) and fewer fractures (32%). Single-fraction treatment was chosen for cost (11%) and convenience (89%). Eighty-four percent of patients expressed positive opinions about being involved in the decision-making process. CONCLUSION: Decision board instruments are feasible and acceptable in an Asian population. The vast majority of patients preferred 24 Gy fractionated radiotherapy compared with a single fraction of 8 Gy. These results indicate the need for further research in this important area and serve to remind both clinicians and national or institutional policy makers of the importance of individual patient preference in treatment decision making.     

Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study.

PURPOSE: Few options are available for pain relief in patients with bone metastases who fail standard treatments. We sought to determine the benefit of radiofrequency ablation (RFA) in providing pain relief for patients with refractory pain secondary to metastases involving bone. PATIENTS AND METHODS: Thirty-one US and 12 European patients with painful osteolytic metastases involving bone were treated with image-guided RFA using a multitip needle. Treated patients had > or = 4/10 pain and had either failed or were poor candidates for standard treatments such as radiation or opioid analgesics. Using the Brief Pain Inventory-Short Form, worst pain intensity was the primary end point, with a 2-unit drop considered clinically significant. RESULTS: Forty-three patients were treated (median follow-up, 16 weeks). Before RFA, the mean score for worst pain was 7.9 (range, 4/10 to 10/10). Four, 12, and 24 weeks following treatment, worst pain decreased to 4.5 (P <.0001), 3.0 (P <.0001), and 1.4 (P =.0005), respectively. Ninety-five percent (41 of 43 patients) experienced a decrease in pain that was considered clinically significant. Opioid usage significantly decreased at weeks 8 and 12. Adverse events were seen in 3 patients and included (1) a second-degree skin burn at the grounding pad site, (2) transient bowel and bladder incontinence following treatment of a metastasis involving the sacrum, and (3) a fracture of the acetabulum following RFA of an acetabular lesion. CONCLUSION: RFA of painful osteolytic metastases provides significant pain relief for cancer patients who have failed standard treatments.