Clinical Practice Guidelines


MANAGEMENT OF BONE PAIN SECONDARY TO METASTATIC DISEASE


Shashidhar H. Kori, MD; Jacqueline A. LaPerriere, Rph;
Maribeth Brune Kowalski, PharmD;
Carol Rodriguez, ARNP; and William Dinwoodie, MD
H. Lee Moffitt Cancer Center & Research Institute

Introduction

Metastatic involvement of the bone is one of the most common causes of pain in cancer patients.1 Of the estimated 1.4 million patients who will be newly diagnosed with cancer in the United States this year, 30% to 70% will develop skeletal metastases.2,3 The most common primary malignancies that metastasize to the bone are breast, kidney, lung, and prostate (Table 1).4 The most common sites of metastasis are the vertebrae, pelvis, and long bones (Table 2). Pain is the most frequent symptom of bone metastases and develops gradually over weeks to months, becoming progressively more severe. Pain combined with other complications (eg, hypercalcemia, pathologic fracture, nerve root compression, spinal cord compression, focal neurologic deficits, and forced immobilization) can lead to a decrease in patients’ quality of life.2 Palliation of symptoms can result in significant restoration of quality of life for these patients. Such palliation measures, when possible, should avoid additional discomfort to patients and be cost effective and simple to administer. The proposed algorithm on page 157 outlines such an approach, with special emphasis on the multidisciplinary team effort.

Etiology of Bone Pain

Although a bone scan is adequate for screening most patients with known malignancy and bone pain, additional plain radiographs of the symptomatic area are indicated since pure lytic lesions may not present as increased uptake on bone scan. If plain radiographs demonstrate a lytic lesion in spite of a negative bone scan, a full-body bone survey is recommended to determine the extent of metastasis. Vertebral body metastases are monitored more closely and are extensively compared to other bony metastases because a significant number of them have epidural extension of the tumor with potential for either spinal cord or nerve root compression. Magnetic resonance imaging (MRI) of the spine is superior to any other imaging study in detecting epidural tumor, and early use of the MRI in lieu of routine tests (eg, plain films of the spine, tomogram, bone scan, and computed tomography scans) may even be cost effective.5 However, a negative MRI does not preclude a patient from developing an epidural tumor later on in the course of disease progression; hence, patients with documented or suspected vertebral body metastasis should receive periodic neurologic examinations. A sudden increase in the intensity of back pain, requiring dose escalation of analgesic medication, may be the only presenting symptom of epidural tumor and cord compression, even in the absence of any other neurologic abnormality.6 Epidural tumor should be aggressively treated. Immediate administration of large doses of corticosteroids, 20 to 100 mg of dexamethasone, given intravenously, can result in immediate and dramatic relief in pain.7

Orthopedic consultation is considered for patients with nonvertebral metastatic lesions greater than 2.5 cm or with lesions that are located in weight-bearing areas. Early prophylactic mechanical stabilization of such lesions may provide improved pain control and better long-term ambulation when compared with the conventional approach of using mechanical stabilization only after a pathologic fracture has occurred.8 Additional orthopedic intervention may include local tumor resection for symptom relief. Challenging diagnostic areas of bony metastasis include the base of the skull and the pelvis. Metastases at the base of the skull are often difficult to diagnose because many of the imaging studies, including tomogram, computed tomography scan, and MRI, may fail to identify and demonstrate these lesions.9 Since symptomatic response, particularly pain relief, is dependent on the early institution of radiation therapy, treatment may have to be started on the basis of clinical diagnosis even when the imaging studies are negative. There are well-defined clinical syndromes that can help localize the possible area of metastasis.9 Patients with skull metastasis are carefully examined for possible intracranial extension of the tumor and, when present, are managed appropriately. Pelvic metastasis can cause intractable pain, which is resistant to standard analgesic therapy, due to tumor infiltration of surrounding structures. Involvement of the lumbar or sacral plexus, obstruction of the ureters, bowel obstruction, or a large pelvic mass can result in significant distress. Computed tomography of the pelvis may be necessary in many of these patients for appropriate treatment planning.

Treatment Approaches

Treatment options available for pain control in this patient population include analgesic drugs, radiation therapy, chemotherapy, hormonal manipulation, corticosteroids, nerve blocks, radiopharmaceutical agents (eg, strontium-89), biphosphonates, calcitonin, and surgical intervention. Analgesic therapy is effective for the majority of patients with bone metastases. Analgesic drugs include nonopioid analgesics, opioid analgesics, and adjuvant analgesics. Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for mild to moderate pain and work synergistically with opioids. NSAIDs produce no physical tolerance or psychological dependence, can be relatively inexpensive, and are widely available. They are used in all patients with painful bone metastasis if no contraindications to NSAID therapy exist. Opioids are an integral part of the analgesic regimen for cancer patients. Opioids are effective, are easy to administer, cause no damage to any major organ system, have no ceiling effect, and usually provide adequate pain relief with acceptable side effects. A detailed discussion of principles of opioid therapy is reviewed elsewhere and beyond the scope of this article.10-12

Radiation therapy is effective in the palliation of pain secondary to bone metastases and should be used where appropriate.13,14 Patients with single lesions unresponsive to simple analgesic regimens, as well as those with vertebral lesions and base of the skull lesions, are good candidates for radiation therapy. Even in patients with multiple diffuse metastasis, radiation therapy to key areas may reduce the patient’s requirement for opioids and may improve the patient’s overall quality of life. Further clinical research is needed to determine optimal fractionation and dosing schedules of radiation therapy in this patient population. Recent studies15-17 suggest that a single fraction of radiation therapy may be as effective as multiple fractions with regard to pain relief, side effect profile, and retreatment rate. Furthermore, single-fraction therapy could be less expensive and more convenient. Further studies are needed to more clearly define the patient population suitable for single-fraction therapy.

By virtue of their predictable anti-inflammatory response, corticosteroids can make a significant difference in selected patients with bone pain that is unresponsive to other therapies. Corticosteroids are particularly useful in vertebral body metastasis with epidural extension, cord compression, nerve root compression, involvement of adjacent nerve plexuses, and intracranial extension of tumor from skull metastasis. These agents also improve appetite and produce mild, beneficial euphoria. We feel corticosteroids are underused in many terminally ill patients because of undue concerns about long-term side effects.

Strontium-89 is an alternative to external beam radiation therapy in patients with widespread osteoblastic bony metastasis. Strontium-89 is safe for the for hospital staff and family members. Several studies18-20 have reported 50% to 70% pain relief in prostatic bony metastasis. The efficacy of strontium-89 in treating metastatic tumors other than prostate is not as clear. Major side effects associated with strontium-89 therapy are thrombocytopenia and neutropenia; hence, it should be used with caution in patients who are receiving chemotherapy.

Biphosphonates inhibit osteoclastic activity. They may not only induce better pain control in patients with lytic lesions of the bone, but also significantly slow the progression of bone metastasis, increase bone stability, and reduce other complications of bone metastasis such as hypercalcemia.21-24 The dosing regimen for symptom relief in patients with bony metastasis needs to be better defined. Side effects of biphosphonates include nephrotoxicity and gastrointestinal intolerance. Etidronate, clodronate, and pamidronate are available for clinical use.

Calcitonin is postulated to reduce bone resorption,24,25 increase circulating endogenous opioids, and act as an endorphin receptor agonist.24-26 Several studies27-30 have demonstrated its benefit in controlling resistant bone pain. Calcitonin is well tolerated, has minimal side effects, and is available in an injectable form and an easy-to-administer nasal spray.

Hypogastric plexus blocks and epidural blocks can help to relieve resistant pelvic pain. Paravertebral and dorsal root blocks are used for well-localized bony lesions unresponsive to radiation therapy. Intercostal blocks are useful for rib metastasis. Lumbar sympathetic and stellate ganglion blocks are essential in treating pain from bone metastasis associated with reflex sympathetic dystrophy. The efficacy of a nerve block depends on the technique used, the expertise of the person who performs it, and the use of imaging to guide the procedure. Patients need to be monitored for side effects such as motor weakness and anesthesia dolorosa.

Conclusions

Pain secondary to bone metastasis is common in the oncology patient population and, when uncontrolled, seriously impacts a patient’s quality of life. A systematic multidisciplinary approach to the diagnostic and therapeutic management of these patients can result in cost-effective, adequate pain control in the majority of these patients.

References

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