This is the current release of the guideline.

This guideline updates a previous version: Janjan NA, Lutz ST, Bedwinek JM, Hartsell WF, Ng A, Pieters RS Jr, Ratanatharathorn V, Silberstein EB, Taub RJ, Yasko AW, Expert Panel on Radiation Oncology--Bone Metastases. ACR Appropriateness Criteria® bone metastasis. [online publication]. Reston (VA): American College of Radiology (ACR); 2008. 26 p. [108 references]

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Non-spine bone metastases with cancer (e.g., multiple myeloma, melanoma, breast, lung, or prostate cancer)

To evaluate the appropriateness of radiologic procedures for treatment of non-spine bone metastases

Patients with non-spine bone metastases

Literature Search Procedure

The Medline literature search is based on keywords provided by the topic author. The two general classes of keywords are those related to the condition (e.g., ankle pain, fever) and those that describe the diagnostic or therapeutic intervention of interest (e.g., mammography, MRI).

The search terms and parameters are manipulated to produce the most relevant, current evidence to address the American College of Radiology Appropriateness Criteria (ACR AC) topic being reviewed or developed. Combining the clinical conditions and diagnostic modalities or therapeutic procedures narrows the search to be relevant to the topic. Exploding the term "diagnostic imaging" captures relevant results for diagnostic topics.

The following criteria/limits are used in the searches.

1. Articles that have abstracts available and are concerned with humans.
2. Restrict the search to the year prior to the last topic update or in some cases the author of the topic may specify which year range to use in the search. For new topics, the year range is restricted to the last 5 years unless the topic author provides other instructions.
3. May restrict the search to Adults only or Pediatrics only.
4. Articles consisting of only summaries or case reports are often excluded from final results.

The search strategy may be revised to improve the output as needed.

The total number of source documents identified as the result of the literature search is not known.

Strength of Evidence Key

Category 1 - The conclusions of the study are valid and strongly supported by study design, analysis, and results.

Category 2 - The conclusions of the study are likely valid, but study design does not permit certainty.

Category 3 - The conclusions of the study may be valid, but the evidence supporting the conclusions is inconclusive or equivocal.

Category 4 - The conclusions of the study may not be valid because the evidence may not be reliable given the study design or analysis.

The topic author drafts or revises the narrative text summarizing the evidence found in the literature. American College of Radiology (ACR) staff draft an evidence table based on the analysis of the selected literature. These tables rate the strength of the evidence for all articles included in the narrative text.

The expert panel reviews the narrative text, evidence table, and the supporting literature for each of the topic-variant combinations and assigns an appropriateness rating for each procedure listed in the table. Each individual panel member forms his/her own opinion based on his/her interpretation of the available evidence.

More information about the evidence table development process can be found in the ACR Appropriateness Criteria® Evidence Table Development document (see the "Availability of Companion Documents" field).

Modified Delphi Technique

The appropriateness ratings for each of the procedures included in the Appropriateness Criteria topics are determined using a modified Delphi methodology. A series of surveys are conducted to elicit each panelist's expert interpretation of the evidence, based on the available data, regarding the appropriateness of an imaging or therapeutic procedure for a specific clinical scenario. American College of Radiology (ACR) staff distributes surveys to the panelists along with the evidence table and narrative. Each panelist interprets the available evidence and rates each procedure. The surveys are completed by panelists without consulting other panelists. The ratings are a scale between 1 and 9, which is further divided into three categories: 1, 2, or 3 is defined as "usually not appropriate"; 4, 5, or 6 is defined as "may be appropriate"; and 7, 8, or 9 is defined as "usually appropriate." Each panel member assigns one rating for each procedure per survey round. The surveys are collected and the results are tabulated, de-identified and redistributed after each round. A maximum of three rounds are conducted. The modified Delphi technique enables each panelist to express individual interpretations of the evidence and his or her expert opinion without excessive bias from fellow panelists in a simple, standardized and economical process.

Consensus among the panel members must be achieved to determine the final rating for each procedure. Consensus is defined as eighty percent (80%) agreement within a rating category. The final rating is determined by the median of all the ratings once consensus has been reached. Up to three rating rounds are conducted to achieve consensus.

If consensus is not reached, the panel is convened by conference call. The strengths and weaknesses of each imaging procedure that has not reached consensus are discussed and a final rating is proposed. If the panelists on the call agree, the rating is accepted as the panel's consensus. The document is circulated to all the panelists to make the final determination. If consensus cannot be reached on the call or when the document is circulated, "No consensus" appears in the rating column and the reasons for this decision are added to the comment sections.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

ACR Appropriateness Criteria®

Clinical Condition: Non-Spine Bone Metastases

Variant 1: 62-year-old man with prostate cancer. Two years after surgical resection of prostate and adjuvant HT, rising PSA level found in routine follow-up. Asymptomatic bone metastasis in right femoral neck; lesion 1.5 cm in size; minimal invasion of bone cortex. Low fracture risk per orthopaedic consult. Karnofsky performance status (KPS) 90. No other metastatic disease. No previous HT, chemotherapy, or OI have been given.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: 42-year-old woman with estrogen receptor (ER) negative/progesterone receptor (PR) negative breast cancer which overexpresses Her-2-neu. Patient developed a symptomatic lytic bone metastasis in right femoral neck; the metastasis was 1.5 cm in size; minimal invasion of bone cortex. Low fracture risk per orthopaedic consult. KPS 90. Diffuse asymptomatic bone metastases noted on bone scan with rising CEA. No previous HT, chemotherapy, or OI have been given.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 3: 54-year-old man with multiple myeloma. He suffers a pathologic fracture of the diaphysis of the right femur and is now status post a surgical pinning procedure with minimal residual pain and good progress in physical rehabilitation. KPS 70. Skeletal survey reveals several other sites of asymptomatic lytic metastases. Has received Bortezomib, dexamethasone, and OI for the 18 months since diagnosis.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field

Variant 4: 66-year-old man with metastatic non-small-cell lung cancer. Seven months status post palliative radiotherapy to the proximal right humerus to 30 Gy in 10 fractions with good pain relief until the past two weeks. Now has recurrent pain at the previously treated site, though the humerus is not considered to be at risk for pathologic fracture. KPS 60. Stable brain metastases and progressive lung metastases. Has received carboplatin and paclitaxel for the past 6 months.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 5: 47-year-old man with metastatic malignant melanoma. Unrelenting pain due to a lytic metastasis in the pubic ramus. KPS 30. Marked cachexia with progressive disease in the liver and para-aortic lymph nodes.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

Bone is one of the most common sites of metastatic spread of malignancy, and the presence of tumor in the bone can lead to pain, hypercalcemia, and pathologic fracture. The treatment of bone metastases is multidimensional and depends on many factors, including sites of metastases and extent of disease. Both osteocytes and osteoplastic lesions may be associated with pain and risk of fracture. Decisions on management frequently involve interdisciplinary care among several types of specialists, including radiologists, radiation oncologists, medical oncologists, orthopaedic surgeons or neurosurgeons, pain medicine specialists, physiatrists, and palliative care professionals. When considering treatment options, one should weigh the risks and benefit profile of radiation therapy for any particular patient's circumstance, including performance status, comorbidities, and life expectancy. Similar to the approaches used with curative therapies combining chemotherapy and radiation, studies are needed that evaluate the combination, or sequencing, of localized therapies such as surgery and external beam radiotherapy (EBRT) with systemic therapies including chemotherapy, hormonal therapy (HT), osteoclast inhibitors (OI), and radiopharmaceuticals.

Under current practice, systemic chemotherapy and/or HT and osteoclast inhibition are frequently administered when asymptomatic bone metastases are first diagnosed. EBRT is usually delayed until the metastatic disease progresses and causes significant pain or creates a risk for pathological fracture or spinal cord compression. The use of radiopharmaceuticals is generally considered in a small fraction of patients with persistent multifocal sites of pain or recurrence of pain in a previously irradiated site.

Variant 1 Discussion

This patient has a good performance status, a life expectancy that may be estimated in years, and a single site of asymptomatic bone metastasis that does not pose an immediate risk for pathologic fracture. The most useful means of predicting the risk for pathologic fracture include evaluation by a published scoring system.

The optimal management of oligometastases is an active area of research. Investigations comparing site-specific localized therapy to a more systemic approach with or without localized therapy are ongoing. Some have argued that patients with minimal sites of bone-only metastatic disease (deemed "oligometastatic") may be treated with curative intent, though the data to confirm that stance are still to be accrued.

Outside of a clinical trial, there is no frank indication to treat this femoral neck lesion with EBRT as it is not causing symptoms and there is no impending fracture. The use of an osteoclast inhibitor is considered a standard approach in this setting, though the optimal timing of treatment initiation has not been investigated. In light of the slight risk of jaw osteonecrosis associated with OI administration, a pretreatment dental evaluation to assess dentition and potential risk prior to OI use might be warranted. (See Variant 1 above.)

Variant 2 Discussion

This patient has a good performance status but has a symptomatic lesion in a weight-bearing bone. Aside from the importance of optimizing pain control in the palliative setting, the pain associated with the right femoral neck lesion is a feature associated with an increased risk of fracture. This patient (as all patients) should receive appropriate analgesic therapy as first line of treatment to provide expeditious relief. An assessment should be performed for risk of pathologic fracture and consideration for surgery, with some surgeons employing grading systems for impending fractures that measure variables such as age, pain score, location of the lesion, radiographic characteristics, and biochemical markers of bone metabolism. If the patient does not require surgery and will be treated only with EBRT, she should undergo simulation and treatment planning, with radiation delivery through parallel opposed anterior and posterior fields. As large a strip of skin and soft tissue possible should be spared to reduce the risk of long-term lower-extremity lymphedema which can be associated with full circumference extremity radiation.

In general, the setup and prescription points for treatment should follow those outlined by the International Consensus on Palliative Radiotherapy Endpoints for future clinical trials, which were updated recently. Fluoroscopic simulation, computed tomography (CT) simulation, and clinical simulation are all acceptable methods for planning radiation fields. There are no data to suggest that highly conformal therapy with intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), or proton therapy would improve the outcome for this patient.

EBRT would be expected to palliate pain in this patient at a rate of 50% to 80%, and the data suggest a rate of complete pain relief in about one-third of patients. While a recent international survey showed 101 different dose schedules in common use for treating painful bone metastases with EBRT, the rates of pain relief are equivalent for fractionation schemes including 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, and a single 8 Gy fraction. Single-fraction treatment optimizes patient convenience and reduces acute side effects but is associated with about a 20% rate of retreatment to the same site compared to an 8% retreatment rate with the more prolonged courses. For patients with femoral metastases not suitable for prophylactic fixation, a multiple-fraction regimen is more appropriate than a single 8 Gy fraction to reduce the risk of pathological facture.

Due to the presence of multifocal disease, systemic chemotherapy options should be explored, and current practice patterns also would include consideration of the use of OI. If both palliative radiotherapy and palliative systemic chemotherapy are to be delivered to this patient, they should be given sequentially rather than concurrently. OI have the ability to decrease the risk of skeletal related events (fracture, need for surgery or radiation to bone, spinal cord compression, and hypercalcemia of malignancy) as well as decrease pain from bone metastases and improve quality of life in patients with certain disease histologies. Osteoclast-inhibiting therapy is an adjunctive therapy to radiation, and analgesics for metastatic bone pain and is routinely administered indefinitely. Inhibiting osteoclast activity does not appear to impart a survival advantage. Recognized effects of the toxicities of potent OI include renal dysfunction (with intravenous bisphosphonates), hypocalcemia, and osteonecrosis of the jaw. (See Variant 2 above.)

Variant 3 Discussion

This patient presented with lytic disease in a weight-bearing bone which led to pathologic fracture and necessitated surgical stabilization. He has minimal residual pain following surgery but should receive postoperative EBRT with the dual goals of pain relief and local tumor control to limit the risk of future fracture. While there are no definitive data to suggest the most appropriate radiotherapy dose, 30 Gy in 10 fractions seems to be a reasonable option with the goal of eradicating microscopic residual disease. No reports exist regarding the use of single-fraction palliative EBRT in the postoperative setting. Treatment should be planned with initial simulation with radiation delivered through anterior and posterior fields with as large as possible skin and soft tissue strip spared to minimize the risk of long-term lower-extremity lymphedema. Fluoroscopic simulation, CT simulation, and clinical simulation are all acceptable methods for planning radiation fields. There are no data to suggest that highly conformal therapy with IMRT, SBRT, or proton therapy would improve the outcome for this patient. The presence of systemic disease coupled with his reasonably good performance status suggests that systemic treatment should be considered. (See Variant 3 above.)

Variant 4 Discussion

This patient has recurrent pain at a site that previously received palliative radiotherapy with good initial pain relief following treatment. The available data from several smaller, retrospective studies suggest that retreatment with EBRT may provide a reasonable chance for pain relief of 33% to 84%, though the most appropriate dose fractionation scheme has not been determined. Available studies reviewed provide little information about toxicity following reirradiation, so care should be taken to avoid combined doses greater than the normal tissue tolerances of structures within the retreated volumes. The tolerance of the brachial plexus must be taken into account in treating this patient. The recurrence of pain in any long bone necessitates a reassessment of pathologic fracture risk before delivering reirradiation. Treatment should be planned with initial simulation, with radiation delivered through anterior and posterior fields with as large as possible skin and soft tissue strip spared to minimize the risk of late chronic upper extremity lymphedema. Fluoroscopic simulation, CT simulation, and clinical simulation are all acceptable methods for planning radiation fields. There are no data to suggest that highly conformal therapy with IMRT, SBRT, or proton therapy would improve the outcome for this patient. Systemic chemotherapy can be considered depending on the patient's previous exposure to chemotherapy and his tolerance of further dosing, though the presence of brain metastases and progressive lung metastases make palliative care or hospice admission reasonable options. A clinical trial that investigates reirradiation is available and should be considered to further define the appropriate use of radiotherapy in the setting of recurrent painful metastasis at a previously treated site (RTOG 0433 A Phase III International Randomized Trial of Single Verses Multiple Fractions For Re-irradiation of Painful Bone Metastases. Available at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0433 .) (See Variant 4 above.)

Variant 5 Discussion

This patient has severe pain from a single site of bone metastases with poor performance status and progressive visceral disease that suggests a very limited prognosis. This patient (as with all patients) should receive appropriate analgesic therapy as first line of treatment to provide expeditious relief. He should be treated with a hypofractionated course of radiotherapy to 8 Gy in a single fraction through anterior and posterior opposed fields. Skin and soft tissue sparing techniques should be considered, though the chances of survival long enough to manifest late toxicity is minimal. The single treatment minimizes his time commitment, transportation requirements, and discomfort from being transferred on and off the treatment table. Fluoroscopic simulation, CT simulation, and clinical simulation are all acceptable methods for planning radiation fields. A single 8 Gy fraction might be more likely to cause a temporary pain flare, but anti-inflammatory medications are capable of minimizing this effect. There is no data to suggest that highly conformal therapy with IMRT, SBRT, or proton therapy would improve the outcome for this patient. He would benefit from direct hospice placement as well. (See Variant 5 above.)

Summary

• EBRT successfully provides rapid palliative relief from painful bone metastases in most cases.
• The acute side effects of palliative EBRT are usually minimal and self-limiting, while long-term side effects are uncommon and often irrelevant in a patient group with limited life expectancy.
• Radiotherapy is not commonly recommended for asymptomatic bone metastases that are not associated with a risk of pathologic fracture.
• Prospective randomized trials have proven equivalent pain relief with varied fractionation schemes, including 8 Gy in one fraction, 20 Gy in 5 fractions, 24 Gy in 6 fractions, or 30 Gy in 10 fractions. Prolonged courses are associated with a lower incidence of retreatment, while shorter courses maximize patient and caregiver convenience by reducing the number of trips to the radiation department.
• Patients who undergo surgical stabilization for impending or completed pathologic fracture of a long bone may be treated with postoperative radiotherapy to 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions or 8 Gy in a single fraction.
• Reirradiation with EBRT may be feasible and effective, though retreatment to sites including radiation-sensitive critical structures may prove risky and should be performed only as part of a clinical trial if retreatment would lead to cumulative radiation doses in excess of normal tissue tolerance.
• Management of metastatic bone disease is palliative. A multidisciplinary team of care providers should be available to the patient, including the palliative care team. Goals of care should be defined with the patient. Hospice referral should be considered if the prognosis is 6 months or less, but this does not preclude the use of radiation for pain control.

Abbreviations

• CEA, carcinoembryonic antigen
• CT, computed tomography
• EBRT, external beam radiation therapy
• HT, hormonal therapy
• IMRT, intensity-modulated radiation therapy
• KPS, Karnofsky performance status
• OI, osteoclast inhibitor
• PSA, prostate-specific antigen
• SBRT, stereotactic body radiation therapy

Algorithms were not developed from criteria guidelines.

The recommendations are based on analysis of the current literature and expert panel consensus.

Selection of appropriate radiologic treatments for patients with non-spine bone metastases

An American College of Radiology (ACR) Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists, and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient's clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient's condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the U.S. Food and Drug Administration (FDA) have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Committee on Appropriateness Criteria, Expert Panel on Radiation Oncology–Bone Metastases

Panel Members: Stephen T. Lutz MD, MS (Principal Author and Panel Chair); Simon Shek-Man Lo, MB, ChB (Co-Author and Panel Vice-chair); David D. Howell, MD (Co-author); Eric L. Chang, MD; Nicholas Galanopoulos, MD; Edward Y. Kim, MD; Andre A. Konski, MD; Neeta D. Pandit-Taskar, MD; Samuel Ryu, MD; Larry N. Silverman, MD; Catherine Van Poznak, MD; Kristy Weber, MD

Not stated

This is the current release of the guideline.

This guideline updates a previous version: Janjan NA, Lutz ST, Bedwinek JM, Hartsell WF, Ng A, Pieters RS Jr, Ratanatharathorn V, Silberstein EB, Taub RJ, Yasko AW, Expert Panel on Radiation Oncology--Bone Metastases. ACR Appropriateness Criteria® bone metastasis. [online publication]. Reston (VA): American College of Radiology (ACR); 2008. 26 p. [108 references]

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.

Print copies: Available from the American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

The following are available:

• ACR Appropriateness Criteria®. Overview. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.
• ACR Appropriateness Criteria®. Literature search process. Reston (VA): American College of Radiology; 1 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.
• ACR Appropriateness Criteria®. Evidence table development. Reston (VA): American College of Radiology; 4 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.
• ACR Appropriateness Criteria®. Radiation dose assessment introduction. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.

None available

This summary was completed by ECRI on March 25, 1999. The information was verified by the guideline developer on September 9, 1999. The summary was updated on February 12, 2002. The information was verified again by the guideline developer on March 25, 2002. This NGC summary was updated by ECRI most recently on November 12, 2004. The information was verified by the guideline developer on December 21, 2004. This NGC summary was updated by ECRI Institute on August 13, 2009. This NGC summary was updated by ECRI Institute on March 20, 2012.

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site .