Management of bone metastases [Íîâîñòü äîáàâëåíà - 16.04.2008]
Management of bone metastases
André Bonneau, MD CCFP
Director of the Norman Bethune community health centre in Laval, Que
Peter, a 77-year-old engineer, has nonresectable lung cancer that has metastasized to his bones. Palliative radiotherapy to his pelvis and spine helped the pain for some time, but now he is in the last stages of his disease. He is bedridden because of weakness, fatigue, and pain. Peter wants to leave this world in the house he built with his own hands, so he receives frequent home visits.
Pain from bone metastases in his left pelvis has recurred and has not responded to increases in his opioid. Peter has had maximum radiotherapy to his pelvis. He is taking 3 80-mg oxycodone SR tablets every 12 hours and, on average, 5 20-mg oxycodone IR tablets for breakthrough pain daily. He is now having trouble swallowing his pills because of a stubborn esophageal candidiasis, which is being treated with 100 mg of fluconazole daily. He reports hip pain at 10 on a 10-point scale.
Bone metastases are a frequent complication of cancer and the most frequent type of pain related to cancer. In advanced breast and prostate cancer, they occur in up to 70% of cases.1,2 In lung, colon, stomach, bladder, uterus, rectum, or kidney cancer, the prevalence is between 15% to 30%. While most patients with bone metastases present with pain in the bones, some patients present with complications of the bone metastases, such as neurological impairment secondary to compression of nerves in the spine or base of the skull. The extent of investigation of neurological impairment or bone pain depends upon the stage of the disease, the goals of care, and the potential effect of investigation on management or outcome.
| Opioids |
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Opioids
Pain medications
The first step is to optimize the opioid dosage. Because Peter is experiencing dysphagia, his medication must be administered parenterally to get his pain under control. Dysphagia can happen in the final stage of illness with loss of consciousness or general weakness. Various conditions can cause dysphagia to temporarily occur, including esophageal candidiasis.
Figure 13,4 provides an overall guide to switching from one opioid to another. Careful calculations are needed to determine the exact dose of the new medication. By applying the guidelines in Figure 1, the calculations for Peter are as follows:
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Six 80-mg tablets of oxycodone SR every 24 hours equals 480 mg. Add 5 20-mg oxycodone IR tablets every 24 hours, which equals 100 mg. The opioid total is 580 mg of oxycodone every 24 hours.
- The morphine-equivalent dose of 580 mg of oxycodone every 24 hours is 1160 mg of morphine every 24 hours.
- Hydromorphone is chosen to minimize the subcutaneous (SC) volume. Calculation is as follows: 1160 ÷ 5 = 232. Conversion of 1160 mg of morphine is, therefore, 232 mg of hydromorphone.
- The hydromorphone dose is decreased by 25%, as Peter can be more sensitive to this opioid. The total is 174 mg of hydromorphone every 24 hours, rounded off to 180 mg every 24 hours.
- Calculation is revisited to ensure accuracy.
- The SC approach is used to adminster the hydromorphone; therefore, the 180-mg dose is halved, equaling 90 mg of hydromorphone every 24 hours. It is delivered continuously, which represents 4 mg/h of SC hydromorphone (rounded up from 3.75 mg).
- Peter’s breakthrough doses will be 4 mg of hydromorphone subcutaneously every 20 minutes as needed.
Over the next 24 hours, Peter’s pain is reduced to a 5 on a 10-point scale with the switch to SC hydromorphone; however, his optimal pain level is 1 to 2 on a 10-point scale, and he is not able to sit comfortably at this point. Radiotherapy is not an option, as further dosage can result in neurological damage. Peter needs a good adjuvant to manage the refractory pain. He is given 16 mg/d of dexamethasone subcutaneously.
| Pain medications |
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Adjuvant pain medications are indicated at this point, as they will improve pain management and reduce toxicity from only steadily increasing the opioid. A variety of adjuvant classes of medications can be helpful in bone metastases, including nonsteroidal anti-inflammatory drugs, steroids, bisphosphonates, and cannabinoids.5
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs are most useful in a patient with moderate bone pain who is able to tolerate oral medications. They should not be used by frail elderly, patients with renal failure or previous peptic ulcer disease, or those who were unable to tolerate them in the past.
Steroids
Steroids are the choice for treatment of short-term relief from bone pain, as they can be given parenterally and act within 24 to 48 hours. A dose of 4 to 16 mg of dexamethasone is typically used in palliative pain management. Because dexamethasone has a long half-life, a daily dose given in the morning is less likely to cause insomnia. If rapid pain control is needed, start with the highest dose and see if it has the desired effect. When pain is controlled, the dose can be titrated down to the lowest effective dose. The dose should be sub-stantantially reduced in older adults because of potential side effects, such as psychosis.
Bisphosphonates
If Peter had been in a palliative care unit in hospital, intravenous bisphosphonates could be considered. All oral bisphosphonates are poorly absorbed by the intestines and have little effect on established bone metastases. Bisphosphonates form a 3-dimensional structure that chelates calcium (Ca++). Consequently, they have a strong affinity for bone and are used extensively in conditions of osteoclast bone resorption, such as tumour-associated osteolysis. Bisphosphonates are concentrated at sites of active remodeling; their antiresorptive action is due to direct inhibitory effects on osteoclasts rather than strictly physiochemical effects. The antiresorptive activity is thought to involve 2 primary mechanisms: osteoclast apoptosis and inhibition of the components of the cholesterol biosynthetic pathway.
Bisphosphonates can be divided into 3 generations; the third-generation bisphosphonate (eg, zoledronic acid) is 10 000 times more potent than first-generation etidronate. Sixty to 90 mg of pamidronate (a second-generation bisphosphonate) intravenously, in 500-mL infusion solution of 5% dextrose in water (D5W) over 2 hours, can give up to 4 weeks of adjuvant pain relief. Four mg of Zolendronate intravenously in 100-mL infusion solution of D5W over 15 minutes can give pain relief for up to 4 to 8 weeks. Bisphosphonates are best used in patients who will live at least 2 weeks to benefit from the more expensive but longer-lasting relief.
Bisphosphonates are excreted by the kidneys, and modifications need to be made in cases of renal failure. In particular, zoledronate is known to be toxic to the kidneys, and their function should be monitored if this medication is given on a regular basis. When pamidronate is given for the first time, it can be accompanied by a release of cytokines, which might explain a flulike syndrome associated with mild fever and muscular aches and pains.
Cannabinoids
There are 3 cannabinoids available on the market. Only 1 has the official indication to treat pain in cancer—Sativex.6 This is a combination of 2 cannabinoids from the Cannabis sativa plant: delta-9-tetra-hydrocannabinol and cannabidiol. Sativex has recently received approval as an adjuvant medication for the treatment of cancer pain in Canada. It is initiated at 3 to 4 sprays daily and titrated up to the most effective dose. It is indicated for use in cancer pain with a neuropathic component not adequately treated with opioids.
Within 48 hours, the dexamethasone and titration of the opioid result in good pain relief for Peter. The dexamethasone is titrated to 12 mg subcutaneously once a day. Two weeks after these adjustments, Peter passes away peacefully and free of pain.
| Radiotherapy for bone metastases |
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Radiotherapy is used for bone metastases to relieve pain, prevent impending pathological fractures, and promote healing of pathological fractures.7 Radiotherapy is successful in pain relief in 60% to 70% of patients, but it takes up to 3 weeks for the full effect to be seen. Single-fraction treatments have the same response rate as multiple fractions in the management of bone metastases.
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Footnotes |
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None declared
Palliative Care Files is a quarterly series in Canadian Family Physician written by members of the Palliative Care Committee of the College of Family Physicians of Canada. The series explores common situations experienced by family physicians doing palliative care as part of their primary care practice. Please send any ideas for future articles topalliative_care@cfpc.ca .
| References |
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- Roodman DG. Mechanisms of bone metastasis. N Engl J Med 2004;350(16):1655-64.
[Free Full Text] - Coleman R, Rubens R. Bone metastases. In: Abeloff M, Armitage J, Niederhuber J, Kastan M, McKenna WG, editors. Clinical oncology. 3 ed. New York, NY: Churchill Livingstone; 2004. p. 627-38.
- Hallenbeck JL. Palliative care perspectives. New York, NY: Oxford University Press; 2003. p. 66-72.
- Harlos M, MacDonald L. Managing pain in palliative patients. In: MacDonald N, Oneschuk D, Hagen N, Doyle D, editors. Palliative medicine: a case-based manual. 2 ed. New York, NY: Oxford University Press; 2005. p. 17-38.
- MacDonald S, Hall J. Bone pain. In: MacDonald N, Oneschuk D, Hagen N, Doyle D, editors. Palliative medicine: a case-based manual. 2 ed. New York, NY: Oxford University Press; 2005. p. 47-58.
- Russo E, Guy G, Robson P. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers 2007;4(8):1729-43.[Medline]
- Barnes E, Chow E. Cancer: radiotherapy. In: Bruera E, Higginson I, Ripamonti C, von Gunten C, editors. Textbook of palliative medicine. New York, NY: Oxford University Press; 2006. p. 871-9.
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