ABSTRACT: Prostate cancer is the most commonly diagnosed cancer among American men. The majority of patients with advanced disease have metastatic bone lesions, which are frequently very painful. These lesions tend to respond well to treatment with both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, although careful dose titration and individualized treatment plans may be needed to achieve maximal analgesia. Opioid side effects are often transient or well controlled with additional medication. Patients with intolerable side effects may experience fewer adverse reactions with a different opioid. Palliative radiation provides pain relief in up to 80% of prostate cancer patients with single or at most a few sites of localized bone pain. Bisphosphonates, powerful inhibitors of osteoclast-mediated bone resorption, are promising new agents for the treatment of painful bone lesions in prostate cancer patients. Radioisotopes, which deliver high-dose radiation to bone lesions without significantly affecting normal bone, are highly effective in providing some degree of pain relief in up to 80% of patients with diffuse, painful bone metastases. Also, chemotherapy shows promise in alleviating pain and possibly extending survival in patients with advanced prostate cancer.[ONCOLOGY 13(11):1537-1549, 1999]
Prostate cancer is the most commonly diagnosed cancer among American men and the second leading cause of cancer death. An estimated 179,300 men will be diagnosed with this cancer in 1999 and 37,000 men will die from complications of prostate cancer.
Approximately 70% to 85% of patients with advanced prostate cancer have associated clinically apparent bone metastases, while another 20% to 25% have metastatic liver lesions. In addition to pelvic pain associated with primary tumor extension, these metastatic lesions cause pain that ranges from mild to very severe and may require extensive, highly individualized pain management. Pain is perhaps the one aspect of cancer that patients fear most, and effective pain control is a critical issue for patients and often a challenge for clinicians.
Numerous studies have shown that pain has a significant impact on multiple dimensions of quality of life. Patients with poorly controlled pain experience significant physical effects, such as decreased strength, limited mobility, and difficulty sleeping. In terms of psychological effects, patients with pain have increases in fear, anxiety, and depression and a decrease in their overall enjoyment of life. Socially, pain has an effect on the patient’s ability to form and maintain relationships with others and also places an increased burden on caregivers.
Pain needs to be continually reassessed in the prostate cancer patient since disease progression, response to treatment, and response to pain control maneuvers all influence treatment strategies. The clinician needs to educate both patients and their families and caregivers about pain, its causes and treatments, and their active participation in pain management. Education should address pain assessment, dose titration, side effect management, and any fears and misconceptions regarding addiction and tolerance.
The majority of men with advanced prostate cancer have sclerotic bone metastases and associated bone pain. Prostate cancer is the most common source of osteoblastic metastases, and these lesions are most common in the skeleton where red bone marrow is located.[3,4]
Although bone metastases from prostate cancer are primarily osteoblastic, there is increasing evidence that osteolysis also plays a key role in these sclerotic lesions and may be crucial to invasion from marrow into bone. Tumors may secrete proteases that cause bone cell lysis, and yet osteoclastic activity is required to break down the mineralized bone matrix; also, tumor cells secrete a number of factors that enhance osteoclastic activity.
Tumor growth in bone may produce pain via multiple mechanisms. As the tumor expands outward from the marrow space, it may cause increased interosseal pressure, particularly if the growth is rapid. This may activate mechanoreceptive nociceptors in bone and stretch the highly innervated periosteum. Edema and inflammation may also contribute to pain, via both increased pressure and secreted mediators, which, in turn, activate pain receptors.
Extensive bone disease can also lead to fractures, and there is increasing evidence that tumors may synthesize prostaglandins, bradykinins, and other substances that both sensitize nociceptors and stimulate osteoclasts. Adjacent nerves, vascular structures, and soft tissue may also be compressed by expanding bone tumors.
Chronic pain due to metastatic bone lesions generally develops gradually, is often described by patients as dull and aching, and tends to be well localized. The most common sites of bone metastases from prostate cancer are the pelvis, vertebrae, ribs, femora, and skull. Unlike arthritic pain, which tends to decrease during the course of the day, cancer-related bone pain tends to increase as the day goes on and is often most intense at night.
A significant number of patients have transient and often traveling bone pain, however, which at is not necessarily related to activity. Unlike visceral or neuropathic pain, bone pain generally responds well to pharmacologic maneuvers, although inconsistent pain (ie, sporadic and/or traveling pain) is more challenging to treat effectively.
Neurologic dysfunction often is also associated with metastatic bone disease, particularly when vertebral metastases encroach on the spinal cord or spinal nerves, or when metastatic lesions in the skull impinge on cranial nerves. Neuropathic pain is generally described as burning or shooting and may be accompanied by a sensation of numbness. Neurologic involvement may present as lower extremity pain, weakness, or paresthesias in a radicular pattern; less commonly, the upper extremities may be involved.
Patients may also present with cranial nerve palsies from metastatic disease in the skull. Clival metastases, for example, may compress the hypoglossal nerve, producing unilateral tongue weakness and protrusion. Disease in the middle cranial fossa may affect the facial nerve and cause ipsilateral weakness in the upper and lower face or numbness, particularly in the lower lip and jaw area. Unilateral deafness, diplopia, and other visual disturbances may also occur as the result of cranial nerve damage from bony tumors.
Since small metastatic skull lesions may not be visible on plain film or bone scans, computed tomographic (CT) scans with bone window and “thin cuts” (5-mm sections) should be ordered to evaluate cranial neuropathies. Magnetic resonance imaging (MRI) may be necessary when CT scans fail to demonstrate an etiology for these conditions.
Neuropathic pain may also be caused by tumor growth in pelvic soft tissues near the prostate gland, particularly the psoas muscle, which contains the lumbosacral plexus. Compression of this nerve plexus can manifest as lower back pain radiating to the anterior thigh or into the posterolateral leg and buttock; the pain may be unilateral or bilateral depending on the location of the compression tumor.
Neuropathic pain often responds poorly to opioids but may be successfully treated with antidepressants or anticonvulsants. (See “Pharmacologic Management” below for a more extensive discussion of these drugs.)
Other Pain Syndromes
Enlargement and inflammation of the primary prostatic tumor may cause urethral, rectal, suprapubic, and penile pain. Less commonly, prostate cancer patients may have metastatic involvement of abdominal organs or extensive abdominal lymphadenopathy. Both can produce vague, colicky, poorly localized visceral pain, which may be referred to cutaneous areas and may also be accompanied by low-grade nausea.
Metastatic liver disease may cause right upper quadrant pain that can radiate to the right shoulder. Abdominal pain in prostate cancer patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) may also be due to gastric irritation, ulceration, or severe constipation.
Abdominal and pelvic pain from metastatic disease is often refractory to conventional opioid therapy but sometimes may be treated effectively with localized radiation therapy.
Careful assessment of pain in the prostate cancer patient is critical to an effective treatment plan. The primary source of information should be patient self-report obtained via a standardized reporting tool. The individual perception of pain involves a complex interaction of physical, psychological, and emotional processes, and pain intensity often is not proportional to the type or extent of disease.
It is important for the clinician to address the issue of pain at every visit since patients may be reluctant to initiate such conversations on their own. A belief in stoicism, a desire to be seen as a “good” patient, denial, or the fear that pain is an ominous symptom of disease progression are all possible reasons for a patient’s reluctance to discuss pain issues with his clinician. Input from family members and caregivers should also be taken into consideration whenever possible since their relationships and daily interactions with patients may provide a valuable source of information.
The initial assessment of pain should include a detailed history, including the location, intensity, frequency, temporal pattern, and specific characteristics of the pain. Knowledge of factors that aggravate and alleviate the pain is also critical to an effective treatment plan.
The patient should be asked to grade the intensity of his pain at the time of evaluation, as well as at the times when it was least and most severe during the week prior to the examination. Three commonly used assessment scales are the Simple Descriptive Pain Intensity Scale, the 0-10 Numeric Pain Intensity Scale, and the Visual Analog Scale. Pain intensity usually can be reliably measured using a numerical rating scale, where 1 to 4 corresponds to mild pain; 5 to 6, to moderate pain; and 7 to 10, to severe pain.
A thorough assessment of pain must also include psychosocial issues, such as the patient’s attitude toward his diagnosis and treatment, his mechanisms for coping with pain and stress, his psychological responses to pain (such as anxiety and depression), and his attitude regarding controlled substances. These factors often play a role in both the patient’s experience of pain and his response to treatment. In addition, information regarding the patient’s support system and insurance plans often is crucial to the success of treatment.
Diagnostic evaluations may help determine the etiology of pain, as well as the extent of disease, and are useful to obtain at baseline, when pain progresses, and during treatment to monitor response. Radionuclide scintigraphy provides the most sensitive method for detecting early bone metastases and is a useful, accurate tool for documenting disease progression.
Bone scans may detect lesions as small as 2 mm, but, due to low specificity, scintographic findings may require radiographic confirmation. The false-negative rate for bone scanning is approximately 8%, and the rate of false-positives may be as high as 40% to 50% when only a few lesions are visible.
Radiography is specific but insensitive; at least 50% of trabecular bone structure must be destroyed before bone metastases are detectable on plain films. Computed tomography provides good definition of both soft-tissue and bone disease and may be helpful in visualizing questionable areas on a bone scan.
The clinician should keep in mind that patients may need analgesia in order to endure these potentially uncomfortable evaluations.
Evaluating Acute Pain
Acute pain in the prostate cancer patient warrants immediate evaluation, as it may be due to fracture or impending spinal cord compression. Pathologic fractures are not as common in patients with prostate cancer as in those with other cancers that metastasize to bone, and generally develop in the vertebrae and the femora.
Spinal cord compression occurs as a result of extension of vertebral metastases into the epidural space. It occurs in 10% to 15% of prostate cancer patients and is one of the most severe potential sequelae of bone involvement.
Pain is the presenting symptom in over 90% of patients with cord compression and may manifest as either acute severe back pain, band-like chest or abdominal pain, or radicular pain. The pain is generally severe and unrelenting, and may increase when the patient is in a supine position. Patients with spinal cord compression generally complain of midline pain but may experience unilateral pain in the upper and/or lower extremities. Motor, sensory, and autonomic (bowel and bladder) dysfunction generally occur later.
If left untreated, the original pain will slowly increase and neurologic symptoms will develop. The mean duration from the onset of pain to the onset of neurologic deficit is 7 weeks, but this is highly variable. Failure to promptly diagnose and treat spinal cord compression may result in permanent neurologic damage and paralysis. The severity of weakness at the time of presentation is an important prognostic factor. Approximately 90% of patients who are ambulatory at diagnosis will remain so after therapy, whereas only 13% of patients who present with paraplegia will regain function, particularly if symptoms have been present for over 24 hours.
Patients with spinal suspected cord compression should be started immediately on dexamethasone (20-mg bolus immediately, followed by 4 mg every 6 hours until cord compression is ruled out), and scheduled for an urgent MRI of the spine. Since approximately 17% to 30% of prostate cancer patients who develop spinal cord compression have multiple sites of compression, the MRI should cover all known areas of the spine affected with metastatic disease.
Localized radiation therapy is the treatment of choice in most patients with epidural compression; the most common regimen is 30 Gy in 10 fractions. More aggressive treatment in an otherwise healthy patient would consist of either laminectomy followed by radiation or anterior surgical decompression. With radiation alone, the response rate is approximately 80%; improvement of presenting symptoms occurs in 49% and stabilization, in an additional 31%.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49:8-31, 1999.
2. Ferrell BR, Rhiner M, Cohen MZ, et al: Pain as a metaphor of illness. Part I: Impact of cancer pain on family caregivers. Oncol Nurs Forum 18:1303-1309, 1991.
3. Batson OV: The role of vertebral veins in the metastatic process. Ann Intern Med 16:38, 1942.
4. Goltzman D: Mechanisms of the devel-opment of osteoblastic metastases. Cancer 80(suppl):1581-1587, 1997.
5. Payne R: Pain management in the patient with prostate cancer. Cancer 71(suppl):1131-1137, 1993.
6. Nielsen O, Munro A, Tannock I: Bone metastases: Pathophysiology and management policy. J Clin Oncol 9:509-524, 1991.
7. Gilbert RW, Kim JH, Posner JB: Epidural spinal cord compression from metastatic tumor: Diagnosis and treatment. Ann Neurol 3:40-51, 1978.
8. Janjan NA: Radiation for bone metastases. Cancer 80(suppl):1628-1645, 1997.
9. Grant R, Papadopoulos SM, Greenberg HS: Metastatic epidural spinal cord compression. Neurol Clin 9:825-841, 1991.
10. Jacox A, Carr DB, Payne R, et al: Management of Cancer Pain: Clinical Practice Guideline No 9. AHCPR publication no. 94-0592. Rockville, Maryland, Agency for Health Care Policy and Research, US Department of Health and Human Services, Public Health Service, March 1994.
11. World Health Organization: Cancer Pain Relief and Palliative Care. Report of a WHO Expert Committee. World Health Organization Technical Report Series, 804, pp 1-75. Geneva, Switzerland, World Health Organization, 1990.
12. Eisenberg E, Berkey CS, Carr DR, et al: Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: A meta-analysis. J Clin Oncol 12:2756-2765, 1994.
13. Hollander D: Gastrointestinal complications of nonsteroidal antiinflammatory drugs: Prophylactic and therapeutic strategies. Am J Med 96:274-281, 1994.
14. Valentini M, Gannizzaro R, Poletti M, et al: Nonsteroidal antiinflammatory drugs for cancer pain: Comparison between misoprostol and ranitidine in prevention of upper gastrointestinal damage. J Clin Oncol 13:2637-2642, 1995.
15. Sunshine A, Olson NZ: Non-narcotic analgesics, in Wall PD, Melzack R (eds): Textbook of Pain, 2nd ed, pp 670-685. New York, Churchill Livingstone, 1989.
16. Norrish AE, Jackson RT, McRae C: Non-steroidal anti-inflammatory drugs and prostate cancer progression. Int J Cancer 77:511-515, 1998.
17. Chaudry AA, Wahle KW, McClinton S, et al: Arachidonic acid metabolism in benign and malignant prostatic tissue in vitro: Effects of fatty acids and cyclooxygenase inhibitors. Int J Cancer 57:176-180, 1994.
18. Vijoen TC, VanAswegen CH, DuPlessius DJ: Influence of acetylsalicylic acid and metabolites on DU-145 prostatic cancer cell proliferation. Oncology 52:465-469, 1995.
19. Rose DP, Connolly JM: Effects of fatty acids and eicosanoid synthesis on the growth of two prostate cancer cell lines. Prostate 18:243-254, 1991.
20. Lipman A: Clinically relevant differences among the opioid analgesics. Am J Hosp Pharm 47(suppl): S7-S13, 1990.
21. Levy MH: Pharmacologic management of cancer pain. Semin Oncol 21:718-739, 1994.
22. Thirlwell MP, Sloan PA, Maroun JA, et al: Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. Cancer 63(suppl):2275-2283, 1989.
23. Glare PA, Walsh TD: Dose-ranging study of oxycodone for chronic pain in advanced cancer. J Clin Oncol 11: 973-978, 1993.
24. Payne R: Transdermal fentanyl: Suggested recommendations for clinical use. J Pain Symptom Manage 7(suppl):540-544, 1992.
25. Payne R, Mathias SD, Pasta DJ, et al: Quality of life and cancer pain: Satisfaction and side effects with transdermal fentanyl vs oral morphine. J Clin Oncol 16:1588-1593, 1998.
26. DeConno F, Groff L, Brunelli C, et al: Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients. J Clin Oncol 14:2836-2842, 1996.
27. Fainsinger R, Schoeller T, Bruera E: Methadone in the management of cancer pain: A review. Pain 52:137-147, 1993.
28. Bruera E, Brenneis C, Paterson AH: Use of methlyphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. J Pain Symptom Manage 4:3-6, 1989.
29. American Pain Society: Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Cancer Pain: A Concise Guide to Medical Practice. Skokie, Illinois, American Pain Society, 1992.
30. Rogers M, Watts DJ, Russell RGG: Overview of bisphosphonates. Cancer 80(suppl):1652-1660, 1997.
31. Koizumi M, Yamada Y, Takiguchi T, et al: Bone metabolic markers in bone metastasis. J Cancer Res Clin Oncol 121:542-548, 1995.
32. Urwin GH, Percival RC, Harris S, et al: Generalized increase in bone resorption in carcinoma of the prostate. Eur J Urol 57:721-723,1985.
33. Clark NW, McClure J, George NJR: Morphometric evidence for bone resorption and replacement in prostate cancer. Br J Urol 68:74-80, 1991.
34. Bishop M, Fellow G: Urinary hydroxyproline excretion—a marker of bone metastases in prostatic carcinoma. Br J Urol 49:711-718, 1977.
35. Boissier S, Magnetto S, Frappart L, et al: Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 57:3890-3894, 1997.
36. Adami S: Bisphosphonates in prostate carcinoma. Cancer 80(suppl):1674-1679, 1997.
37. Bloomfield DJ: Should bisphosphonates be part of the standard therapy for patients with multiple myeloma or bone metastases from other cancers? An evidence-based review. J Clin Oncol 16:1218-1225, 1998.
38. Coleman, RE, Purohit OP, Vinholes JJ, et al: High dose pamidronate: Clinical and biochemical effects in metastatic bone disease. Cancer 80(suppl):1652-1660, 1997.
39. Lipton A, Glover D, Harvey H, et al: Pamidronate in the treatment of bone metastases: Result of two dose-ranging trials in patients with breast or prostate cancer. Ann Oncol 5(suppl):31-35, 1994.
40. Clarke NW, McClure J, George NJR: Clinical and metabolic effects of disodium pamidronate in metastatic prostate cancer, in Bijvoet OLM, Lipton A (eds): Osteoclastic Inhibition in the Management of Malignancy-Related Bone Disorders, pp 54-63. Toronto, Hogrefe and Huber, 1991.
41. Tyrrell CJ. Collinson M, Madsen EL, et al: Intravenous pamidronate: Infusion rate and safety. Ann Oncol 5(suppl):27-29, 1994.
42. Vilimovskij, A, Thuerlimann B, Berenson JR, et al: Renal safety and tolerability of Aredia (pamidronate) administered as an intravenous 1-hour infusion: Preliminary results (abstract). Proc Am Soc Clin Oncol 18:576a, 1999.
43. Pelger RC, Hamdy NA, Zwinderman AH, et al: Effects of the bisphosphonate olpadronate in patients with carcinoma of the prostate metastatic to the skeleton. Bone 22:403-408, 1998.
44. Robinson RG, Blake GE, Preston DF, et al: Strontium-89: Treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone. Radiographics 64:816-822, 1989.
45. Breen SL, Powe JE, Porter AT: Dose estimation in strontium-89 radiotherapy of metastatic prostate cancer. J Nucl Med 33:1316-1323, 1992.
46. Robinson RG, Preston D, Schiefelbein BHS, et al: Strontium-89 therapy for the palliation of pain due to osseous metastases. JAMA 274:420-424, 1995.
47. Catton C, Gospodarowicz M: Palliative radiotherapy in prostate cancer. Semin Urol Oncol 15:65-72, 1997.
48. Porter AT, McEwan AJB, Powe JE, et al: Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25:805-813, 1993.
49. Quilty P, Kirk D, Bolger J, et al: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31:33-40, 1994.
50. Dearnaley D, Bayly RJ, A’hern RP, et al: Palliation of bone metastases in prostate cancer. Hemibody radiation or strontium-89? Clin Oncol 4:101-107, 1992.
51. Ahonen A, Joensuu H, Hiltunen J, et al: Samarium-153 EDTMP in bone metastases. J Nucl Biol Med 38(suppl):123-127, 1994.