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. 2007 Dec;24(4):363–374. doi: 10.1055/s-2007-992324

Palliative Radiation Therapy in the Management of Brain Metastases, Spinal Cord Compression, and Bone Metastases

Samir V Sejpal 1, Amit Bhate 1, William Small Jr 1
PMCID: PMC3037246  PMID: 21326588

ABSTRACT

Radiation therapy plays an important role in both curative and palliative cancer treatment. Palliative radiation therapy is given to alleviate symptoms, restore function, relieve suffering caused by cancer, and improve quality of life. Pain relief, control of bleeding or ulceration, prevention of impending compression or obstruction from tumor, and shrinkage of tumor masses causing symptoms are indications for palliative radiotherapy. Palliative radiotherapy is a very effective tool in alleviating pain symptoms and generally well tolerated. Common fractionation schemes are 8 Gy delivered in one fraction and 30 Gy delivered in 10 fractions. This article discusses general principles of administering palliative radiation therapy. Site-specific treatment is addressed, divided into palliative radiotherapy for brain metastases, spinal cord compression, and bone metastases. In each of these areas, we discuss presentation, management, and therapeutic strategies.

Keywords: Palliative care, brain metastases, whole brain radiotherapy, spinal cord compression, bone metastases

Radiation therapy plays an important role in cancer treatment. It can be broadly divided into therapy delivered for curative and palliative intent. Curative therapy is delivered to eradicate tumor and hence cure the patient. Palliative radiation therapy is given to alleviate symptoms, restore function, prevent morbidity of disease progression in the area treated, relieve suffering caused by cancer, and improve quality of life. Approximately half of all patients diagnosed with cancer receive radiation therapy at some point in their life.1 In 2002, 40 to 50% of patients referred to radiation oncology clinics were treated with palliative intent.2,3 Table 1 lists the indications for use of palliative radiotherapy.1,3 Indications in the emergent setting include spinal cord compression, superior vena cava syndrome, and symptomatic brain metastases. Treatment is initiated promptly. With the exception of very radiosensitive cells such as lymphocytes, radiation therapy does not cause immediate cell death. The cells die at their next scheduled division. Hence pain relief may not be immediate, and acute toxicities manifest several days after commencement of treatment.1 Analgesics and corticosteroids (in central nervous system [CNS] metastases) play an essential role in the management of patients during radiation therapy treatment planning and concurrently with treatment as needed.

Table 1.

Indications for the Use of Palliative Radiation Therapy1

Indications Example
Alleviation of pain symptoms Bone metastases
Control of fungating or ulcerative mass Chest wall or sternum metastases after mastectomy in breast cancer patient
Control of bleeding Vaginal bleeding in patient with metastatic cervical cancer
Shrinkage of symptomatic tumor mass Brain metastases causing neurological deficits
Relief of impending obstruction Near airway obstruction due to tumor mass in a lung cancer patient
Prevention of symptoms Prophylactic treatment in a patient with impending bone fracture
Oncologic emergencies Spinal cord compression, symptomatic brain metastases, superior vena cava syndrome
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GUIDING PRINCIPLES OF PALLIATIVE RADIATION THERAPY

Total dose delivered, dose per fraction, timing of radiation therapy, and permissible side effects differ greatly between patients treated for curative versus palliative intent.

In the curative setting, doses of 45 to 50 Gy in 1.8- to 2-Gy fractions are required to control microscopic disease. For gross tumors, doses of 60 to 70 Gy or more delivered over 6 to 7 weeks may be required for optimal control. Late complications are reduced when doses are kept below 2 Gy per fraction. Timing of radiation therapy also plays a critical role in some studies. For example, for head and neck cancers treated with curative intent, radiation treatment should ideally begin within 6 weeks of surgery and should be completed within 7 to 8 weeks for maximum local tumor control. Normal tissue toxicity limits the dose of radiation that can be delivered. Moderate to severe acute side effects are sometimes inevitable in the curative setting, but they are accepted when necessary for optimal tumor control.1

The paradigm for cancers treated in the palliative setting is remarkably different. In general, patients treated with palliative radiotherapy are treated with a lower total dose of radiation, larger daily fraction, and shorter treatment times of 1 to 2 weeks when compared with patients treated with curative intent. In the United States, the most widely used palliative regimen is 30 Gy in 10 fractions given in 2 weeks.1 Length of remaining life and performance status are important factors that play a role in how dose is administered per fraction and duration of treatment. For example, many patients with spinal cord compression are debilitated and unable to ambulate. Daily visits to a radiotherapy center and positioning on the treatment couch can be a cause of discomfort. Short overall treatment time would be preferable for patient convenience and comfort. Prognostic factors influence dose schedule.

The radiobiological principles applied in the curative setting are less relevant to patients treated in the palliative setting. Lower total doses of radiation are used because the goal of treatment is relief of symptoms as opposed to eradication of tumor. Patients receive higher dose per fraction and complete treatment in a shorter period of time to expedite symptom control. Side effects are thus less intense and less prolonged due to lower total dose and shorter overall treatment time. Although it is true that larger fraction size will lead to more late effects, these take months or years to develop and are unlikely to appear in a population with a short life span. Table 2 summarizes the general differences in radiation delivery in the curative and palliative setting.

Table 2.

Differences in Radiotherapy Delivered in the Curative versus Palliative Setting

Curative Palliative
Goal Eradicate tumor Alleviate symptoms
Total dose and fraction size 45–50 Gy in 1.8- to 2-Gy fractions for microscopic disease; 60–70 Gy in 1.8- to 2-Gy fractions for control of gross tumor Multiple schemes; most commonly used are 30 Gy in 10 3-Gy fractions or 8 Gy in a single fraction
Duration 6–8 weeks for most solid tumors Single fraction to 4 weeks depending on patient performance status, life expectancy, and site involved
Side effects (acute) More intense and prolonged due to higher total dose and longer treatment times Less intense and prolonged due to smaller total dose and shorter treatment times
Side effects (late) Fraction size kept to 1.8–2 Gy to reduce late effects Fraction size and duration of treatment depends on patient performance status, life expectancy, and site involved
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BRAIN METASTASES

Epidemiology

An estimated 20 to 40% of cancer patients develop brain metastases during the course of their illness.4 Up to 170,000 cases are diagnosed each year in the United States, and the incidence is increasing due to improvements in systemic therapy, improved imaging modality techniques such as magnetic resonance imaging (MRI) that can better detect small lesions, and an aging population.5 Risk of developing brain metastases varies with primary tumor. In adults, lung cancer accounts for half of all metastases.5 Melanoma, breast, and colon cancers also have a high propensity to spread to the brain. The incidence may be rising in women with breast cancer.6 Several factors in different series are predictive for occurrence of brain metastases in breast cancer patients: lung metastases as the first site of relapse, negative hormone receptor status,7 Her-2 overexpression, number of metastatic sites,8 and younger patients with hormone receptor negative tumors.6

Pathogenesis

Brain metastases result from the hematologic spread of tumor emboli, which have a predilection to concentrate in the gray-white matter junction and in the terminal watershed areas of the brain. The distribution of metastases is proportional to the weight and relative blood supply of brain compartments with ~80% occurring in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem.9,10 Tumors more likely to go the cerebellum include small cell lung cancer and tumors arising from the prostate, uterus, and gastrointestinal tract.10

Clinical Presentation

The most common presenting symptom is headache (49%), followed by focal neurological deficits (30%), cognitive dysfunction (32%), gait ataxia (21%), seizures (18%), speech difficulty (12%), visual disturbance (6%), sensory disturbance (6%), and limb ataxia (6%).4 Patients may also present with nausea and vomiting. These symptoms reflect signs of increased intracranial pressure, and the spread of edema through the white matter influences onset and acuity of signs and symptoms. Melanoma, choriocarcinoma, and testicular carcinoma can produce hemorrhagic brain metastases, and when they bleed into a tumor, a patient may experience an acute worsening of symptoms.10

Management

It is important to identify the number of brain metastases accurately through a contrast-enhanced MRI because the treatment strategies differ between patients with one to three metastases compared with those with extensive disease. Size of metastases and histology of tumor can also play a role. Treatment decisions may also be influenced by prognostic factors, the most important ones being performance status, age, and extent of extracranial disease. The Radiation Therapy Oncology Group (RTOG) analyzed outcome based on these prognostic variables by analyzing 1200 patients enrolled in three RTOG brain metastases studies. They identified three prognostic groups based on recursive partitioning analysis (RPA) (Table 3). The best survival was seen in RPA class I, which had a medial survival of 7.1 months. Patients with Karnofsky Performance Score (KPS) < 70 had a median survival of < 3 months.11

Table 3.

Survival Based on Recursive Partitioning Analysis (RPA) of Prognostic Factors11

RPA Class Patient Characteristics Median Survival (months)
KPS, Karnofsky performance status.
I KPS > 70, primary controlled, age < 65, metastases to brain only 7.1
II KPS < 70 or primary uncontrolled or age > 65 or extracranial metastases 4.2
III KPS < 70 2.3
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The goal of treatment is rapid control of symptoms and durable symptom-free remission. Without treatment, the median survival is 1 month. With steroid treatment only, median survival approximates 2 months.10 Definitive treatment options continue to evolve and include whole brain radiotherapy (WBRT), surgery, and stereotactic radiosurgery (SRS) delivered through gamma knife or linear accelerator. In general patients who are RPA class I with single brain metastases are treated aggressively with surgery followed by WBRT. Patients with multiple metastases are treated with WBRT alone. Patients with two to three metastases and RPA class I or II are approached with single or multiple modalities (WBRT, WBRT + SRS, or SRS alone).9 Corticosteroids are administered concurrently and tapered subsequently.

WBRT Alone

WBRT alone is the modality of choice in patients who have multiple brain metastases or lesions that are too large, numerous, or inaccessible for surgery or SRS.5 Fig. 1 shows a typical WBRT port. Response rates vary from 50 to 75% in different series.12,13,14 In one study, ~75% of patients experienced neurological improvement, and of these, roughly two thirds maintained improvement for duration of their lives or for at least 9 months.13 Radiographic responses on computed tomography scans were seen in 59% of lesions when treated with 30 Gy in 10 3-Gy fractions.14 Complete remission rates were observed in 37%, 35%, 25%, and 14% from metastases from small cell carcinoma, breast cancer, squamous cell carcinoma, and nonbreast adenocarcinoma, respectively.14 Median time to improvement is 1 to 2 weeks for severe impairment and 3 weeks for moderate dysfunction.10 Short-time side effects include transient worsening of neurological symptoms and alopecia. Long-term side effects such as memory loss, dementia, and decreased concentration, although possible, are usually not expected to manifest in a population with a short life span9

Figure 1.

Figure 1

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Whole brain radiotherapy port film. Patients are treated in supine position with a custom mask for immobilization. Parallel opposed lateral fields are used with the gantry at 90 and 270 degrees. The field borders go 2 cm beyond the bony skeleton in the superior, anterior, and posterior margin, and between C1 and C2 vertebral bodies in the inferior margin. Custom blocks are designed to avoid radiation to the eye, oral cavity, and facial structures. In this example, the patient had metastatic lesions from non–small cell lung cancer near the base of skull, and the inferior margin was extended to the C2 vertebral body. He had poor performance status. A dose of 30 Gy in 10 fractions was delivered.

Three RTOG randomized controlled trials failed to show improvement in median survival time (15 to 18 weeks) when comparing difference fractionation schemes varying from 40 Gy in 20 fractions to 20 Gy in 5 fractions.10,15 RTOG randomized controlled trials evaluating accelerated fractionation schedules (54.5 Gy given twice daily in 1.6-Gy fractions versus 30 Gy in 10 fractions),16 concomitant radiosensitizers such as misonidazole and bromodeoxyuridine,17,18 and rapid-dose escalation schedules (10 Gy in 1 fraction or 15 Gy in 2 fractions)10,19 failed to shown significant benefit. The most common fractionation used is 30 Gy in 10 fractions of 3 Gy given over 2 weeks.5 Treatment should be individualized based on performance status, extent of systemic disease, severity of neurological symptoms, and life expectancy. An appropriate strategy is to treat favorable prognosis patients with longer fractionation schedules (such as 40 Gy in 20 fractions over 4 weeks) to minimize CNS toxicity. Patients with a rapid progression of intracranial disease or a short life expectancy can be approached with 30 Gy in 10 fractions over 2 weeks.

WBRT with Surgery

WBRT is also used as an adjunct treatment after surgery in patients with single brain metastases or with radiosurgery in patients with a limited number of brain metastases to prevent local recurrence or development of new brain lesions. Two of three randomized controlled trials comparing WBRT alone or WBRT with surgery showed a significant survival advantage to combined modality treatment.20,21,22 Patchell et al examined 48 patients with a single brain metastasis and reported recurrence rates of 20% in the combined modality group compared with 52% in the group receiving WBRT alone.22 Patients in the combined modality group remained functionally independent longer (median 38 weeks versus 8 weeks) and had significantly longer survival (median 40 weeks versus 15 weeks). The authors concluded that patients with single brain metastases receiving combined modality treatment lived longer, had fewer recurrences in the brain, and an improved quality of life compared with patients treated with WBRT alone (20%). Noordijk et al looked at 63 patients with single brain metastases treated with surgery and WBRT versus WBRT alone. They found an equal median survival of 5 months in patients with active extracranial disease. However, patients with inactive or controlled extracranial disease had a significant benefit with combined modality treatment (median 12 versus 7 months; p = 0.02). Age proved to be an independent prognostic factor, and the authors concluded that patients with absent or controlled extracranial disease, especially when they are younger that 60 years, should be treated with combined modality treatment; WBRT alone may be adequate treatment for patients with progressive extracranial disease.21

Patchell et al, in another randomized trial, compared the benefit of WBRT with surgery versus surgery alone in 95 patients who had undergone complete resection of single brain metastases. They were randomly assigned to 50.4 Gy WBRT versus observation. Although there was no benefit in overall survival or functionally dependent survival, the authors concluded that patients receiving postoperative radiotherapy had had significantly fewer recurrence in the brain at the site of original metastases (10% versus 46%), other sites in the brain (14% versus 37%), and they were less likely to die of neurological causes (14% versus 44%) when compared with patients who were treated with surgery alone.23

WBRT with SRS

SRS is a competing modality to neurosurgical resection. Its advantages over surgery include treatment of surgically inaccessible lesions, outpatient procedure, avoidance of craniotomy, and treatment of multiple lesions. SRS delivers a highly conformal dose to the treatment volume, usually < 4 cm in diameter, using multiple convergent beams. Treatment can be delivered with high-energy X-rays from a linear accelerator, gamma rays produced from gamma knife, or through charged particles such as protons, which are produced by cyclotrons.

SRS when used as initial therapy is delivered as a boost with WBRT or delivered solely without whole brain radiation. When used as a boost, the rationale is to improve local control. When delivered as a sole modality, the rationale is to achieve local control without the possible side effects of WBRT. Radiosurgery is also used as a salvage treatment for patients who progress after WBRT.24

Two randomized trials have shown a benefit with the addition of SRS boost to WBRT.24,25 Kondiolzka et al randomized patients with two to four brain metastases to WBRT alone (30 Gy in 12 fractions) versus WBRT with radiosurgery.25 Median time to local failure was 6 months versus 36 months (p = 0.0005) favoring the combined modality arm. Survival was not statistically significant (7.5 months WBRT versus 11 months combined modality). There was no neurological morbidity due to SRS boost.

The RTOG randomized 333 patients with one to three brain metastases to WBRT or WBRT followed by SRS boost. At 6 months, patients in the combined modality group were more likely to have a stable or improved performance status (43% versus 27%, respectively; p = 0.03). There was no improvement in overall survival between the two groups. However, combined modality did show a survival advantage in patients with single brain metastases by univariate analysis (6.5 months versus 4.9 months) and in patients with RPA class 1 by multivariate analysis. The authors concluded that WBRT and stereotactic boost treatment improved functional autonomy for all patients, and survival for patients with a single unresectable brain metastasis. They recommended that combined modality be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases.25

SRS Alone

Studies on the efficacy of SRS alone as initial therapy (with the omission of WBRT) are in progress. A recent Japanese trial that randomized 132 patients with one to four brain metastases to SRS versus SRS and WBRT showed that the combined modality did not significantly improve overall survival (7.5 months versus 8 months; p = 0.42). However, patients receiving the combined modality were less likely to have tumor recurrence at 1 year (47% with combined modality versus 76% with SRS alone), and salvage treatment was less frequently needed in the combination group (10 patients in the combined modality group versus 29 patients with SRS alone; p < 0.001).26

In 2005, the American Society for Therapeutic Radiology and Oncology (ASTRO) published an evidence-based review on the role of radiosurgery in the treatment of brain metastases.24 They concluded that use of SRS alone as initial therapy (with WBRT used as salvage) does not alter survival when compared with WBRT with or without SRS boost. Firm conclusions on the impact of neurocognition with the omission of WBRT could not be made due to lack of adequate evidence. However, omission of WBRT may affect intracranial control (failure at sites not treated with SRS). The treating physician therefore has to take these two endpoints (impact on overall survival and intracranial tumor control) into account when making a decision to include or omit WBRT.24

Ongoing trials include a phase two Eastern Cooperative Oncology Group study of patients with “radioresistant” histologies (melanoma, renal cell carcinoma, sarcoma) with one to three brain metastases treated with SRS alone. The American College of Surgeons Oncology Group is initiating a phase III randomized controlled trial of SRS delivered with or without WBRT in patients with one to three cerebral metastases.24

Future Advances

The use of radiosensitizers and new chemotherapeutic agents are areas currently under investigation for patients with brain metastases. Motexafin-gadolinium (MGd) is a radiosensitizer that demonstrates selective uptake in tumors and works by generating reactive oxygen species and depleting reducing agents necessary to repair cytotoxic damage.5 In two phase III trials, MGd when combined with WBRT has shown a benefit in patients with non–small cell lung cancer (NSCLC) in neurocognitive function and increased time to neurological progression.27,28 Efaproxiral is another radiosensitizer that has been used with WBRT. It binds to hemoglobin and exerts its effects by increasing tumor oxygen levels and thereby overcoming restrictions secondary to the blood-brain barrier.5 In phase III randomized controlled trials, WBRT plus supplemental oxygen with or without Efaproxiral showed a significant survival benefit in patients with breast cancer (8.7 versus 4.6 months; p = 0.061).29 Future randomized studies with this agent in breast cancer patients with brain metastases are pending.5 Temozolomide is a second-generation oral alkylating prodrug that readily crosses the blood-brain barrier and shows modest activity in patients with newly diagnosed or recurrent brain metastases.5 Phase II trials of temozolomide with WBRT suggest improvement in response rates30 and improvement in progression-free survival.31

Conclusions

Brain metastases occur frequently in cancer patients and they are a significant cause of morbidity and mortality. Palliative radiotherapy plays an invaluable role in the management of patients. Treatment is individualized and based on prognostic factors such as age, performance status, extent of CNS involvement, extent of systemic disease, as well as number and location of metastases. WBRT alone is the standard of care in patients who have multiple brain metastases or lesions that are too large, numerous, or inaccessible for surgery or SRS. Aggressive treatment of WBRT with surgery or SRS boost is recommended in patients with limited metastases and favorable prognosis. New directions include use of radiation sensitizers and chemotherapeutic agents to improve the survival of patients with brain metastases.

METASTATIC SPINAL CORD COMPRESSION

Epidemiology

Approximately 5 to 10% of cancer patients develop metastatic spinal cord compression (MSCC) during the course of their disease.32 More than 20,000 new cases are reported annually in the United States.33 Although MSCC has been reported with every major type of systemic cancer, the incidence for a given tumor is a function of the incidence of that tumor as well as its propensity for bony spinal involvement.34 The most common primaries are breast, lung, and prostate cancers, each accounting for ~20% of cases.35 Multiple myeloma or plasmacytoma, non-Hodgkins lymphoma, and renal cell cancers each account for 5 to 10% of cases.34 Most cord compressions are secondary to involvement of the vertebral column anterior to the spinal cord and less frequently due to tumor posterior to the cord or invasion of the epidural space.9 In children, compression is more likely to be caused by a paravertebral mass impinging on the spinal cord, and the tumor types most commonly involved are sarcoma, neuroblastoma, and Wilms' tumor.34 Route of spread is through direct arterial embolization of tumor cells.34

Clinical Presentation

MSCC is a medical emergency that requires rapid intervention with steroids and radiation therapy to preserve function and reverse established deficits. If untreated, its natural history is one of progressive pain, paralysis, sensory loss, and sphincter dysfunction.35 MSCC is defined as compression of the dural sac surrounding the spinal cord or cauda equina by an extradural tumor mass. Subclinical cord compression is the presence of radiographic features in the absence of clinical features.36 Localized back pain is the most common presenting symptom occurring in > 90% of patients.34 They may complain of radicular pain for weeks or months before the onset of neurological symptoms.9 Motor deficits are present in 65 to 85% of patients, followed by sensory deficits, which occur in 40 to 90%. Loss of bladder and bowel function, paraplegia, and paralysis are late symptoms.9,34

Talcott et al identified six risk factors for MSCC based on a multivariate analysis of imaging-, neurological-, and patient-related factors. Patients with none of the six risk factors (inability to walk, increased deep tendon reflexes, presence of bone metastases, compression fracture on spine radiographs, bone metastases diagnosed > 1 year earlier, age < 60) had a 4% risk of MSCC compared with 87% when all six risk factors were present.37 Patients with paralysis at presentation or after treatment have a shorter life expectancy than ambulatory patients.36

Management

Surgery and/or radiation therapy are the primary approaches to treat spinal cord compression. High-dose steroids are administered with radiation treatment and tapered gradually with completion of treatment. Surgical indications include the surgical candidate who can undergo decompression and fixation; spinal instability or bony compression where direct fixation and stabilization may be the only way to preserve ambulation; intraspinal bony fragment, which are less likely to respond to radiation treatment; impending sphincter dysfunction requiring rapid decompression; single site of cord compression; radioresistant tumor; neurological progression during or after radiation treatment; and a previously radiated site that had received a maximum cord tolerance dose.34,36

Radical Resection Plus Radiation Therapy

A small randomized controlled trial of 29 patients comparing laminectomy followed by radiotherapy to radiotherapy alone in the treatment of spinal epidural metastases showed no difference between the two arms in regard to pain relief, improved ambulation, or improved sphincter function.38 Laminectomy, however, may not be the optimal surgery for MSCC. Laminectomy involves removal of posterior elements of the spinal column. Most spinal metastases, however, are located in the vertebral body, anterior to the spine. Laminectomy can further destabilize the spine by removing the only elements that are intact.33

In the 1980s, surgeons developed a different procedure for MSCC using an anterior approach and decompression with total removal of the pathological vertebral body and tumor mass followed by replacement with cement (methyl 2-methacrylate) and fixation devices.34 A more recent randomized controlled trial of 101 patients evaluated direct circumferential decompressive surgery plus postoperative radiotherapy versus radiation therapy alone.33 A dose of 30 Gy in 10 fractions was delivered within 14 days after surgical resection and compared with radiotherapy alone. Patients randomized to circumferential decompression followed by postoperative radiotherapy had a higher ambulatory rate compared with radiotherapy alone (84 versus 57%; p = 0.001) and retained the ability to walk significantly longer than those treated with radiotherapy alone (122 days versus 13 days; p = 0.003). Use of steroids and opioid analgesics was significantly reduced in the surgical group. There was no difference between 30-day mortality rates between the two groups, and 30-day morbidity was substantially worse in the radiation group. The authors concluded that the optimal treatment for MSCC is surgery as the initial treatment followed by radiotherapy.

Radiation Therapy: Dose and Schedule

Various dose schedules are used worldwidel however, the most commonly used prescriptions are 8 Gy in 1 fraction and 30 Gy in 10 fraction.34 Figs. 2 and 3 show a typical port film for spinal cord compression. Three prospective studies have evaluated optimal dosing, and no one regimen has demonstrated superiority.36 In a retrospective review of 1304 patients, Rades et al evaluated five radiation therapy schedules for motor function, ambulatory status, and infield recurrence: 8 Gy in 1 fraction, 20 Gy in 5 fractions, 30 Gy in 10 fractions, 37.5 Gy in 15 fractions, and 40 Gy in 20 fractions.39 Similar functional outcome and ambulatory states were seen in all treatment groups. The three more protracted schedules (30 Gy in 10 fractions, 37.5 Gy in 15 fractions, and 40 Gy in 20 fractions) were associated with fewer infield recurrences. The authors recommended two schedules: 8 Gy in 1 fraction for patients with poor estimated survival (< 4 to 6 months) and 30 Gy in 10 fractions for other patients. Single fraction regimen is associated with good results in terms of improved functionality, and of the three protracted schedules, 30 Gy in 10 fractions offers the shortest overall treatment time and costs.32

Figure 2.

Figure 2

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Spinal cord compression port film for lumbar vertebral body lesion. For lesions in the thoracic and lumbosacral spine, parallel opposed anteroposterior to posteroanterior fields are used with the radiation port centered on the site of cord compression (L4 vertebral body in this example). The radiation port extends 6 to 8 cm wide and one or two vertebral bodies above and below the site of compression. For paraspinal extension of tumor, the radiation port may be widened.

Figure 3.

Figure 3

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Spinal cord compression port film for cervical vertebral body lesion. Cervical spine lesions are treated with opposed lateral beams to minimize dose to the oral cavity and pharynx. Side effects are usually minimal with standard treatment schedules. They include reduced blood counts, depending on the amount of spine or bone marrow in the radiation field, and diarrhea, nausea/vomiting, dysphagia, or mucositis depending on the portions of gastrointestinal tract in the radiation port.

Patients who show neurological deterioration or recompression after radiation treatment should be considered for surgery. Reirradiation may not be desirable for infield recurrences if the tumor recurs within a short time frame after completion of treatment. The tumor could be radioresistant, and there is also concern about radiation myelitis when retreating the cord within a short interval. Reirradiation may be considered if > 6 weeks have passed since the completion of treatment.36

Prognostic Factors and Response to Treatment

Prognostic factors for local control and survival after radiation therapy of MSCC were evaluated by investigating several variables in a group of 1852 patients. Table 4 shows the results. Treatment outcome depends on pretreatment function. Resolution of back pain can be expected in the majority of patients.40 In one study, 100% of ambulatory patients maintained walking function; ~50% with motor impairment regained the ability to ambulate. All patients able to void at presentation preserved their capacity, and 38% with sphincter dysfunction did not need an indwelling catheter after treatment.40 Survival ranges from 3 to 6 months and is higher in patients who are ambulatory before or after surgery.34

Table 4.

Prognostic Factors Associated with Decreased Local Control and Poor Survival in MSCC Patients (Significant by Multivariate Analysis)38

Involvement of bone metastases at time of radiation treatment
Involvement of visceral metastases at time of radiation treatment
Interval from tumor diagnosis to MSCC > 15 months
Nonambulatory status prior to start of radiation treatment
> 14 days from time to develop motor deficits and start of radiation treatment
Histology (primary tumors other than breast cancer, prostate cancer, myeloma/lymphoma)
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MSCC, metastatic spinal cord compression.

Conclusions

Spinal cord compression is a medical emergency requiring immediate intervention to prevent loss of neurological function and reverse established deficits. Surgical indication generally includes spinal instability or bony compression,36 and surgical intervention is usually limited to patients with involvement of one spinal segment with a good performance status and expected life span of > 3 months.32 For all other patients, radiation therapy alone continues to play an important role in the management of MSCC. The randomized study by Patchell, which showed a benefit for decompressive surgery followed by postoperative radiotherapy, may change the management of selected patients with MSCC.33 Reirradiation of infield recurrence may be considered if > 6 weeks have elapsed since the end of last radiation treatment.

BONE METASTASES

Epidemiology

After the liver and lung, bone is the third most common site of metastases.41 Eighty percent of all bone metastases are secondary to breast, prostate, and lung carcinomas.42 The true incidence is difficult to assess because it depends on the prevalence of cancer in a particular community, but ~50% of cancer patients who develop metastatic disease have skeletal involvement.42

Although bone metastases usually become apparent after a primary tumor is diagnosed, they can be a presenting problem in up to 20% of patients.9 Bone metastases are a significant cause of morbidity and can lead to bone pain, immobility, hypercalcemia, pathological fractures, nerve root damage, and spinal cord compression.41

Pathophysiology of Bone Metastases and Clinical Presentation

Cancer cells metastasize to bone almost exclusively via hematogenous spread, although this may also result via direct extension of tumor.9 Bone metastases are generally classified into two types.42 Osteoblastic metastases are characterized by the deposition of new bone via increased osteoblastic activity, whereas osteolytic metastases are characterized by the destruction of normal bone via increased osteoclastic activity.43,44 Metastatic lesions can contain both components, and an absolute distinction cannot always be made.44,45 Lytic skeletal metastases can cause bone pain, fractures, and hypercalcemia. Osteoblastic lesions can lead to pain, spinal cord compression, and myelosuppression. Bone necrosis secondary to vascular compromise from direct tumor involvement can also be present.46

The most common presentation is localized pain, which occurs in 75% of patients. Pathological fractures occur in 10 to 30% of patients and are more frequently seen in the femur. Hypercalcemia and spinal cord compression occur in 10% and 5% of patients, respectively. Up to 80% of bone metastases occur in the vertebra (most commonly lumbar spine followed by thoracic spine) and pelvis.42 Bone scan, positron emission tomography scan, plain radiographs, and MRI all play in a role in the detection of metastatic disease.

Management

The goals of therapy are to relieve pain, improve function, and maintain skeletal integrity. Treatment should be individualized, and consideration should be given to the overall prognosis of a patient because long-term survivors are more at risk for late toxicities and require longer lasting relief. Palliative therapies currently available include radiotherapy, radioisotopes, chemotherapy, hormonal therapy, orthopedic surgical intervention, and bisphosphonates.47 Depending on the primary lesion and site involved, analgesics, corticosteroids, hormonal therapy, chemotherapy, or bisphosphonates may be administered while patients are receiving their radiation treatments.

Radiation Therapy

Radiation therapy is an effective modality for pain control. Up to 80% of patients have improvement in pain, and up to 20 to 50% have complete pain relief.48,49 The maximal effect is noted on average 1 to 3 weeks after treatment. Fig. 4 shows a treatment port film for a lesion in the humeral head region. Although more than 40 different fractionation schedules are reported in the literature, the most common fractionation schemes adopted are 30 Gy in 10 fractions in the United States, 20 Gy in 5 fractions in Canada, and 8 Gy in 1 fraction in some European countries.48 Three recent randomized controlled trials have evaluated the efficacy of 8 Gy in single-fraction versus multifraction treatment for bone metastases.49,50,51 In 1999, the Dutch Bone Metastasis Study group evaluated 8 Gy in 1 fraction versus 24 Gy in 6 fractions in 1171 patients with bone metastases. The Bone Trial Working Party Study (BTWPG) compared 8 Gy in a single fraction versus 20 Gy in 5 fractions or 30 Gy in 10 fractions in 765 patients. RTOG 9701 reported on 898 patients randomized to 8 Gy in a single fraction versus 30 Gy in 10 fractions.

Figure 4.

Figure 4

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Bone metastases port film. This patient received 30 Gy in 10 fractions for metastatic disease to the humeral head area.

In all three randomized controlled trails, there was no difference in complete response rates between the single-fraction arm and the protracted radiation therapy arms. The overall response rates and complete response rates in the Dutch study and BPTWG were 71% and 35%, and 78% and 57%, respectively. In the RTOG trial, the overall response rate was 66%, and partial response rates (48% in the 30-Gy arm and 50% in the 8-Gy arm) and complete response rates (18% in the 30-Gy arm and 15% in the 8-Gy arm) (p = 0.06) were reported. In the RTOG study, there was no difference between the two groups at 3-month follow-up in terms of pain relief, narcotic relief, or pathological fracture incidence. Grade 2 to 4 acute toxicity was more frequent in the multifraction arm (17%) versus the 8-Gy arm (10%) (p = 0.002). Late toxicity was rare in both arms (4%).

Although single-fraction therapy appears to be as efficacious as multifraction treatment, retreatment rates were higher in the single-fraction arm in all three studies. In the Dutch study, 24% in the single-fraction arm required retreatment compared with 6% in the multiple-fraction arm (p = 0.001). The BPTWG showed a higher retreatment rate of 23% in the single-fraction arm compared with 10% in the multiple-fraction arms (p < 0.001). In the RTOG trial, retreatment rates were twice as high in the single-fraction arm (18%) compared with the protracted arm of 30 Gy in 10 fractions (9%) (p < 0.001). The authors in the RTOG study noted a potential physician bias in the decision to retreat. Patients in the multifraction arm will be less likely to receive further treatment with radiotherapy compared with those in the single-fraction arm due to higher acute toxicity to adjacent critical structures (spinal cord, lungs, and bowel) with higher-dose treatment regimens.

Based on evidence from three large randomized controlled trials, single-fraction treatment is as efficacious as multifraction treatment in providing pain relief. It remains to be seen if single-fraction treatment will become the standard of care for bone metastases in the United States.48

Surgical Intervention

Surgical fixation should be considered in patients with impending fractures or a pathological fracture. Pain exacerbated by movement is an important factor that may predict for impending fracture.43 When greater than a third of a long bone is affected and > 50% of the cortex is destroyed, the fracture rate is as high as 80%. Fractures may occur through lytic lesions on weightbearing bones and are most commonly seen in the proximal femur.43

Some general guidelines for surgical intervention include life expectancy > 3 months; procedure planned expected to expedite mobilization; quality of bone proximal and distal to metastatic lesion is adequate to support fixation device; cortical bone destruction is > 50%; pathological avulsion fracture of the lesser trochanter; lesion ≥ 2.5 cm located in the proximal femur; and stress pain that persists after radiation.9

With impending fractures, prophylactic internal fixation is followed by radiation therapy to inhibit further tumor growth and bone destruction. It is easier to stabilize bone when it is still intact. Pathological fractures are also approached with primary internal stabilization followed by radiotherapy.

Radionuclide Therapy and Hemibody Irradiation

The most common radioisotopes used in bone metastases include strontium-89 and samarium-15. Both radioisotopes localize to areas of increased osteoblastic activity. Systemic radionuclides may be considered in the following circumstances: patients with widely metastatic disease as an adjuvant to external beam radiotherapy; as first-line therapy in patients without a predominant site of pain; when external beam radiotherapy options have been exhausted and normal tissue tolerance has been reached; in patients with life expectancy > 3 months; and in patients with good marrow reserve because myelosuppression and pancytopenia are the major toxicities reported.9 Radionuclide therapy has shown efficacy in bone metastases from prostrate and breast cancer.43

Hemibody irradiation (HBI) is infrequently used in the United States because the use of radioisotopes is equally efficacious with less toxicity.9 HBI can be rapidly efficacious when multiple sites of symptomatic bone metastases are present.43 A phase III study of local-field irradiation followed by observation or HBI conducted by the RTOG revealed that the long-term benefit of HBI was small; ultimate progression rates were not statistically different between the two arms.52

Conclusions

The skeletal system is a common site of cancer metastases. Radiation therapy plays an important role in the management of these patients and provides pain relief in 80% of cases. Although 30 Gy in 10 fractions in a common scheme used in the United States, results from three large randomized controlled trials suggest that single-fraction treatment of 8 Gy is as effective as multifraction treatment in providing pain relief.48,49,50,51 Surgical intervention with internal fixation followed by radiotherapy is considered in patients with impending or pathological fractures.43

Future Directions

Palliative radiotherapy plays an important role in cancer management. As of 2002, 40 to 50% of all patients referred for radiation treatment are treated with a palliative intent.2,3 An effective tool in alleviating pain symptoms and restoring function, it is generally well tolerated. This review looked at palliative radiotherapy in the management of brain metastases, spinal cord compression, and bone metastases. Palliative radiotherapy also plays a significant role in visceral metastases.

More clinical research in palliative care is needed. Barnes et al evaluated the number of abstracts relating to symptom control and palliative care (SCPC) presented at the ASTRO annual meeting between 1993 and 2000.2 Of the 3511 abstracts presented, an average of 47, or 1.3%, were related to SCPC. Curative radiotherapy abstracts accounted for 33.5% of all abstracts presented in 2000, with the remainder divided among physics, radiobiology, treatment complications, benign diseases, and quality of life. As palliative radiotherapy continues to be an integral and significant component of a radiation oncology practice, research in this field is needed and actively encouraged.2

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