Local Management of Bone Metastases

J. Sybil Biermann

Albert J. Aboulafia

James A. Hayman

Historically, published information and clinical trials relating to the skeletal complications of malignancy combined data that included a variety of different primary sites. Many of the diagnostic and treatment strategies that were recommended for patients with metastatic bone disease as a whole are not applicable today for the unique group of patients with metastases secondary to breast cancer. It is only recently, and not widely, appreciated that skeletal metastases that result from breast primary differ dramatically from the other primary sites with respect to clinical presentation, prognosis, and treatment. Additionally, the introduction of bisphosphonates and more recently denosumab has dramatically changed the treatment strategy for patients with metastatic breast cancer to the skeleton, rendering much of the prior literature less useful. Only a few have published articles relating to the treatment of skeletal metastases focused on the cohort of patients with primary breast cancer rather than combining data with patients with skeletal metastases from any primary site. Table 83-1 presents web site resources for patients.

Although there has been an increasing appreciation for the differences in treatment among patients with metastatic bone disease from breast and other primary sites, the goals of treatment remain the same. They include relief of pain, restoration or maintenance of function, and avoiding hypercalcemia, metabolic derangements, bone marrow invasion, spinal cord compression, and pathological fracture.

More widespread use of sensitive imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) has created the ability to detect bone metastases at an earlier stage, often identifying asymptomatic disease. Although in general the number of patients coming to surgery for skeletal stabilization has decreased, carefully selected patients will reap major benefits from surgical intervention in terms of pain control and function.

INCIDENCE

It is estimated that there were 1.66 million new cases of cancer diagnosed in the United States in 2013. Half of those cancers will include breast, kidney, lung, thyroid, and prostate, which have a proclivity for skeletal metastases. This number far exceeds the estimated number of primary sarcomas of bone (3,010 per year), with many occurring in patients under the age of 40 years. Breast cancer is the most common cancer and the second leading cause of cancer-related morbidity among women in North America and Western Europe. In those patients who develop metastases, the skeleton is the most frequently involved site. Radiographic studies have demonstrated skeletal metastases in 70% to 80%, and autopsy studies as high as 85%, of patients who die of their disease. The most common sites of skeletal involvement include the spine and long bones (i.e., femur and humerus) (1). In part, due to the long survival of patients with breast cancer, bone metastases are common, and their potential impact on quality of life, morbidity, and mortality is significant. Certainly not all skeletal metastases will require treatment. Although the spine is the most common site of metastases from breast to bone, it is estimated that only one-third of spinal metastases will become symptomatic during the course of the patients’ life. The treatment of a given skeletal lesion depends on a variety of factors including the clinical presentation. In a group of 115 cases of orthopaedic surgical management of breast cancer to bone, patients with solitary bone metastasis had a median 65-month survival, while those with visceral disease also had a median survival of 13 months (2).

TABLE 83-1 Relevant Patient Information Web sites

Entity	Description	Web site
American Cancer Society	General overview of bone metastasis for patients including symptoms, diagnosis, and treatments from the American Cancer Society	http://www.cancer.org/docroot/CRI/content/ CRI_2_4_1X_What_Is_bone_metastasis_66. asp
Novartis	Commercial site with general information on symptoms, diagnosis, and imaging studies	http://www.us.novartisoncology.com/info/ coping/bone_metastasis.jsp?usertrack. filter_applied=true& NovaId=3350119511325999391
American Academy of Orthopaedic Surgeons	Physician-authored site with general information on bone metastases for patients	http://www.orthoinfo.org/topic. cfm?topic=A00093
National Cancer Institute	Overview of metastatic cancer, including to bone	http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic
University of Michigan	General information on bone metastasis including symptoms, diagnosis, treatments, and glossary of terms	http://www.cancer.med.umich.edu/cancertreat/tissue_bone/bonegeneral. shtml

CLINICAL PRESENTATION

The clinical presentation of a patient with skeletal metastases will depend on a variety of factors. For the majority of patients with metastatic breast cancer, the primary is known before skeletal metastases become symptomatic. The clinical presentation of a patient with skeletal metastases from breast cancer may be initiated due to the onset of a symptomatic bone lesion (i.e., pain, radiculopathy, or pathological fracture) or the result of an imaging study that was performed as part of a staging evaluation (at the time of initial diagnosis or routine follow-up), or less commonly for unrelated reasons. The diagnostic workup and treatment for these conditions will depend greatly on whether the scenario takes place in the setting of a known history of breast cancer or not and whether the bone lesion is solitary or not. It is fundamentally important that in evaluating a patient with a destructive lesion of bone, a logical, thorough, and meticulous algorithm be followed in order to avoid major errors in diagnosis and treatment and minimize potential complications (3).

The majority of patients presenting with bone metastases report pain as an initial symptom, although there may be asymptomatic identification if the patient has a subsequent bone scan. In evaluating the treatment choices for patients with long bone (humerus, femur, tibia) metastasis it is particularly important to identify whether the pain is associated with weight bearing and relieved by rest, as this is one prognostic indicator of the likelihood of pathologic fracture (4). Careful assessment of the patient’s analgesic use relative to pain reporting is important, as large doses of narcotics may obfuscate the severity of the symptoms and lead to undertreatment locally.

The various clinical presentations that a patient with suspected metastatic breast cancer to bone may present include the following:

1. New onset of skeletal pain with a known history of breast cancer (symptomatic)
2. New onset of skeletal pain without a known history of breast cancer (symptomatic)
3. Discovery of an asymptomatic lesion in a patient with a known history of breast cancer (as part of routine staging or follow-up or less likely an incidental finding)
4. Discovery of an asymptomatic lesion in a patient without a known history of breast (cancer as part of routine staging or follow-up or less likely an incidental finding)

DIAGNOSIS AND IMAGING OF BONE METASTASIS

Diagnostic Evaluation

Although it is true that for any patient over age 40 with a destructive bone lesion the most likely diagnosis is metastatic tumor or myeloma, the presumptive diagnosis of metastatic disease is strengthened if the patient has a history of breast cancer. However, all too often the assumption is made that a bone lesion is metastatic in a patient with a history of breast cancer and the assumption proves to be wrong. Conversely, a patient with a very remote history of breast cancer (20 years or more) and bone pain is not suspected of having potential metastases due to the lack of appreciation of the potential delayed presentation of skeletal metastases in breast cancer. As with any patient with a potentially malignant bone lesion, the patient with breast cancer requires a logical and systematic approach to evaluation in order to optimize outcomes, avoid unnecessary procedures and expenses, and expedite medical and emotional support.

The first step in evaluating a patient with a skeletal lesion requires a careful history and physical examination. The history should include the presence or absence of prior cancer diagnosis, the stage of disease, the histology, and accounting of any prior imaging studies and treatment to date. Although generally nonspecific, the presence or absence of pain, the character of pain, the onset, severity, duration, aggravating, and alleviating factors, and response to analgesics should be noted. These aspects of pain can be quantified using such tools as a 0 to 10 pain scale or the Brief Pain Index (5) pain related to skeletal metastases is usually described as a dull, aching pain that may be exacerbated with activity or weightbearing when the lower extremities are involved. Night pain is more common in metastatic disease than in conditions such as arthritis, mechanical low back pain, or tendonitis.
A general history regarding risk factors for other cancers should also be elicited such as smoking, alcohol abuse, sun or toxin exposure, obesity, and family history.

Plain Radiographs

Plain films are the initial study to be obtained in the patient with suspected bone metastasis. Bone metastases from breast cancer may be lytic, blastic, or mixed. Use of bisphosphonates may result in a shift of the spectrum to a higher incidence of sclerotic metastases (6).

Typically lesions are poorly marginated, originate within the medullary space but cause some adjacent cortical destruction, with a characteristic “moth-eaten” appearance. Especially in the setting of pathologic fracture or insufficiency of bone, there may be adjacent periosteal reaction. Soft-tissue masses extending outside the bone may be present, particularly in deposits of long-standing.

Approximately 30% to 50% of the bone must be destroyed prior to the lesion being evident on the plain film. Generally surgical intervention is not considered in cases with less bone destruction. Although plain films are arguably the best modality for determining necessity of surgical intervention, they are not as sensitive as other modalities, particularly MRI, for determining the presence or absence of metastases.

Bone Scan

Bone scans remain relatively nonspecific as indicators of metastatic disease, with positive findings present on bone scans with unrelated causation, including arthritis, occult insufficiency fractures, and prior bone trauma. Additionally, bone scan, being a test of metabolic function, does not indicate the degree of structural damage, information important in determining which treatment modality might be most appropriate. Most skeletal metastases from breast cancer show increase radiotracer uptake at the site of involvement. Exceptions to this generalization include extremely aggressive lytic metastases (that would like be apparent on plain radiographs) and some estrogen-receptor-negative metastases, particularly those involving the cervical spine (7).

Computed Tomography Scanning

In patients with known metastatic breast cancer being followed with chest, abdomen, and pelvis computed tomography (CT) scanning, CT detected metastatic bone lesions in 43 of 44 (98%) patients with bone metastases. The remaining patient had a solitary, asymptomatic bony metastasis in shaft of femur. Bone scan was positive in all patients with bone metastases. There were 11 cases of false-positive findings on bone scan. These findings suggest that in patients with known metastases, CT scanning alone is likely sufficient to evaluate bone metastases and, in fact, bone scanning is more likely to lead to findings of false positivity (8).

Magnetic Resonance Imaging

MRI is the single best imaging modality to assess bone marrow. However, changes within the bone marrow due to skeletal metastases may be difficult to distinguish from marrow changes from nonneoplastic conditions. Benign conditions that may alter the appearance of the bone marrow on MRI include trauma, infection, radiation, the administration of growth factors (i.e., pegfilgrastim [Neulasta], filgrastim [Neupogen], granulocyte colony-stimulating factor), and osteoporosis.

With regard to decision making for intervention for symptomatic metastases, however, MRI is less useful. MRI signals are determined by paramagnetic qualities and on vascularity, depending on the sequences used, rather than structural factors. Cortical bone is relatively poorly imaged by MRI. In fact, MRI may artifactually indicate or overstate cortical erosions or bone destruction. Although MRI plays an important role in the assessment of etiology of local bone pain, it is of minimal utility in determining which patients may benefit from surgery.

Positron Emission Tomography, with or without Computed Tomography

PET scan and PET-CT are indicated for evaluating the response to treatment for patients with metastatic breast cancer. As a result, PET scans and PET-CT scans that have been performed for patients being followed with visceral metastases are discovering asymptomatic skeletal lesions. Both the PET scan and the CT scan portion of the PET are capable of discovering bone metastases prior to their becoming symptomatic. The sensitivity of PET and PET-CT compared with other imaging modalities such as the bone scan have not been well studied. Siggelkow et al. (9) in a study involving 57 patients with breast cancer found that PET scan had a relatively low positive predictive value of 74.5% and a relatively high predictive value of 98.3%. It is likely that the combination of the PET and CT will prove to be sensitive and specific when read by an experienced clinician.

EXTERNAL BEAM RADIATION THERAPY

Because bone metastases are so prevalent among women with metastatic breast cancer, treatment with external beam radiation in such patients is not uncommon. Although a number of systemic options are now available for treating diffuse bony metastatic disease, such as bisphosphonates and radionuclides, external beam radiation remains the least invasive and most effective established local therapy for the treatment of localized bony metastases. The most common reason for its use in this setting is pain control, but it can also be used to prevent progression of lesions that if left untreated could lead to fracture or spinal cord or cauda equina compression. Accordingly, the primary objective of such treatment should be to improve or maintain patients’ quality of life and physical function for the duration of their lives with the least toxicity and inconvenience.

There are a surprising number of issues to consider when assessing whether such treatment has been successful. Not only is there the degree of pain relief but also the rapidity of its onset as well as its durability. One must also take into account potential acute (e.g., nausea and vomiting) and late toxicities (e.g., fracture or spinal cord damage), the possible need for retreatment, the potential to reduce dependence on narcotics thereby reducing any associated side effects, how well such treatment results in the ability of patients to maintain or improve their physical function, and the convenience of treatment. When surveyed, patients with bone metastases ranked from most to least important the duration of pain relief, likelihood of complications, degree of pain relief, mobility, dependence on narcotics, and last, the length of treatment (10).

When making decisions about whom to treat and how best to treat them, there are a number of issues to consider. One important factor is the natural history of the patient’s disease. In the case of metastatic breast cancer, survival is typically longer than for the average patient with bone metastases, with median survival on the order of 2 to 3 years. Although physicians are not very good at estimating patients’ life expectancies (11), it still needs to
be taken into account when deciding how best to manage these patients. The number of bony lesions and the presence of visceral metastases are also relevant, as are the extent of bone destruction and the presence of an associated soft-tissue mass. The site of the lesion can also influence the likelihood of toxicity (e.g., spine vs. extremity). Other issues to consider include the patients’ performance status, any comorbidities, prior treatment with adjuvant or palliative radiation, and their ability and willingness to come for daily treatment. At the societal level, there are also the direct medical costs of treatment, the burden on family and friends, and the ability to access a nearby treatment facility in a timely fashion to consider.

When making decisions about where to treat, it is necessary to pay particular attention to patients’ symptoms and any recent imaging studies, including plain x-ray images, CT scans, MRI scans, bone scans, or fluorodeoxyglucose (FDG)-PET scans. CT and MRI are especially helpful in defining the extent of any associated soft-tissue mass. Typically, the field arrangements used to treat patients with bone metastases are relatively straightforward and often consist of two opposed treatment fields or sometimes even a single rectangular field.

Conventional External Beam Radiation

Although there is general consensus regarding its efficacy, there is controversy about how best to deliver external beam radiation for the treatment of painful bone metastases. Numerous studies have reported overall response rates in the range of 60% to 70%, with complete response rates between 20% to 30% (12). The onset of pain relief usually occurs within 3 weeks of the completion of treatment, and the duration of pain relief is typically on the order of 3 to 5 months (13). The likelihood and severity of acute toxicity depends on the site and size of the field being treated, but is generally tolerable. The likelihood of patients developing significant late complications is also very low, with pathologic fracture and spinal cord compression rates in the range of only 2% to 3%.

When it comes to treatment with radiation, higher doses typically result in improved outcomes. However, this does not necessarily appear to be the case for palliative radiation for bony metastases. In a study completed over 20 years ago, the Radiation Therapy Oncology Group (RTOG) randomized 266 patients with solitary bone metastases to 40.5 Gy in 15 fractions or 20 Gy in 5 fractions and 750 patients with multiple bone metastases to 30 Gy in 10 fractions, 15 Gy in 5 fractions, 20 Gy in 5 fractions, or 25 Gy in 5 fractions and initially reported no differences in outcomes (14). Of note, in this trial pain was assessed by the treating physician, not the patient. Interestingly, these results did not lead to the use of short-course radiation. Instead, practice patterns in the United States over the past several decades have been heavily influenced by an unplanned reanalysis of these data in which patients with both solitary and multiple bone metastases were combined into a single group and the primary end point was redefined; it reported longer-course radiation (e.g., 30 Gy in 10 fractions) to be more effective (15).

Over the past decade, evidence has been mounting in patients with uncomplicated bony metastases, typically defined as lesions that have not been previously irradiated and have or will not soon result in fracture or spinal cord compression or require surgical intervention, that singledose radiation treatment is just as effective as fractionated radiation therapy. In the Bone Pain Working Group trial 765 patients with painful bone metastases, 36% of whom had breast cancer, were randomized to 8 Gy in 1 fraction or either 20 Gy in 5 or 30 Gy in 10 fractions (16). They found no differences in terms of patient-reported time to improvement in pain, maximal pain relief, time to progression of pain, analgesics used, acute toxicity, pathologic fracture, or spinal cord compression. Patients treated with single fractions were retreated at a rate of 23% versus 10% for those receiving multiple fractions, although it was unclear whether this represented lower efficacy of single fractions or just a lower threshold to retreat patients after a single fraction.

The Dutch Bone Metastasis Study randomized 1,171 patients, 39% of whom had breast cancer, to either a single 8 Gy fraction or 24 Gy in 6 fractions and reported nearly identical results (17). Again, differences in patient-reported response rates, duration of response, use of pain medication, side effects, and quality of life were nonexistent between the two arms, while the retreatment rate was higher in the single-fraction group (25% vs. 7%). One difference in this study was that the rate of pathologic fractures was twice as high as in the single-fraction group; however, the absolute rates were still extremely low (4% vs. 2%). In a follow-up study, these investigators found that single-fraction patients who did not respond or who had progressive pain were much more likely to be retreated than multiple-fraction patients (35% vs. 8% and 22% vs. 10%, respectively), supporting the assertion that physicians are more willing to retreat patients with single fractions (18). They also reported that retreatment with radiation is highly effective in both patients without either an initial response (66% response rate after single fractions and 33% after multiple fractions) or progressive pain after an initial response (70% for single fractions and 57% after multiple fractions). Another issue especially relevant to patients with breast cancer, who, as noted above, often have prolonged survival, is whether single fractions provide pain relief that is as durable as fractionated radiation. To address this issue, the Dutch investigators looked specifically at 320 patients enrolled in their study who survived for greater than 52 weeks, 63% of whom had breast cancer (19). The mean duration of response and progression rates in this subgroup were similar between single- and multiple-fraction patients, 29 versus 30 weeks and 55% and 53%, respectively, again with high response rates following retreatment. Therefore, while the rates of progression among patients with prolonged survival are relatively high, these data suggest that it may be preferable to retreat those patients who progress rather than initially treating all patients with longer treatment courses. These investigators also examined cost and quality-of-life issues associated with single- versus multiple-fraction radiation using data from their trial and concluded that single fractions are less costly, associated with comparable quality-adjusted survival, and therefore are more cost-effective (20).

More recently the RTOG conducted another bone metastases trial limited to patients with either breast (50%) or prostate cancer and randomized 898 such patients to either a single 8 Gy fraction or 30 Gy in 10 fractions (21). Again the response rates were similar, while the retreatment rate was higher in the patients treated with single fractions (18% vs. 9%). Interestingly, the rate of acute toxicity was greater in the multiple-fraction arm than in the single-fraction arm (17% vs. 10%). Data from a Canadian trial confirmed this result and also found that the prophylactic use of antiemetics reduced the likelihood of nausea and vomiting when treating the lumbar or pelvic region (22).

In addition to the studies mentioned above, at least 12 other randomized trials have been performed examining this issue. The results of these trials have been summarized in several systematic reviews (12, 23), and meta-analyses
(13, 24), all of which fail to demonstrate a difference between single and multiple fractions. These data led Cancer Care Ontario to develop evidence-based guidelines on fractionation for palliation of bone metastases that recommended the use of single fractions for symptomatic uncomplicated bone metastases (25). More recently, the American Society for Radiation Oncology (ASTRO) developed a guideline that came to a similar conclusion (26). It is therefore interesting to note that when radiation oncologists are surveyed regarding the use of single fractions in this setting many are reluctant to use them (27, 28) and these results have been confirmed by several studies of actual treatment records (29, 30, 31 and 32). When patients are surveyed, some have expressed a preference for single fractions, while others favor multiple fractions (27).

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