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© 1997 The Journal of Bone and Joint Surgery, Inc.
Current Concepts Review - Treatment of Metastatic Adenocarcinoma of the Pelvis and the Extremities* , WASHINGTON, D.C.*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.
Cancer is the second leading cause of death in the United States; in 1991, 23.7 per cent (514,657) of the total number of deaths were cancer-related126. The rate of survival has improved over the last three decades; the five-year rate of survival from the time of diagnosis has increased by 20 and 30 per cent for breast and prostate carcinoma, respectively, since 1963126. Bone is the third most common site for distant metastases from adenocarcinoma, second only to the lung and the liver. Bone metastases were the first presentation of carcinoma in 23 per cent of 429 previously undiagnosed patients19. Although not always clinically evident, there is bone involvement at the time of autopsy in as many as 85 per cent of patients who die from carcinoma of the breast, prostate, or lung66,114. Breast (32 per cent), prostate (36 per cent), and lung carcinoma (14 per cent) are the most commonly reported types in the United States126. Of these adenocarcinomas, lung cancer contributes to 33 per cent of the deaths of men and to 24 per cent of those of women126. Radionuclide imaging demonstrated bone metastases in 590 (63 per cent) of 933 patients diagnosed with a primary adenocarcinoma, with 789 (85 per cent) of these patients having metastases secondary to breast, lung, or prostate carcinoma115. The most frequent sites of bone metastases are the vertebrae, pelvis, ribs, femora, and skull. The duration of survival after the diagnosis of metastatic bone disease often depends on the histological characteristics of the primary carcinoma. Patients who have metastatic bone disease secondary to breast carcinoma have a better prognosis for survival (thirty-four months) than do those who have metastatic bone disease secondary to carcinoma of the prostate (twenty-four months), cervix (eighteen months), colon and rectum (thirteen months), or lung (less then twelve months) or those who have it secondary to melanoma (three and one-half months)60,80. These numbers are only estimates; the duration of survival can vary quite widely among individual types and grades of tumors. The duration of survival of patients who had metastatic breast carcinoma ranged from one to ninety months in one study60, whereas that of patients who had metastatic prostate carcinoma was more than sixty months in 20 per cent of patients in two other reports7,81. Orthopaedic surgeons may be the first physicians to establish the diagnosis of metastatic adenocarcinoma, as the initial presentation is osseous involvement in 23 per cent of patients19. Orthopaedic surgeons also often are involved in the assessment and operative management of patients who have either an impending or an actual pathological fracture secondary to metastatic adenocarcinoma. Therefore, orthopaedic surgeons need to familiarize themselves with the clinical presentation, proper workup, and diagnosis of suspicious lesions; the biomechanical effects on bone; and the methods of treatment for metastatic adenocarcinoma.
Pain is the most frequent clinical symptom of metastatic bone disease, ranking second only to death as the most feared aspect of cancer for patients118,119. In a study of eighty-seven patients who had breast cancer, Winchester et al. found that recurrent or metastatic disease was associated with pain in seventy-nine patients and that osseous metastases were symptomatic in thirty-two of thirty-three patients125. An extensive review of fifty-four studies revealed pain secondary to cancer in 7067 of 9007 patients12. The etiology of cancer-related pain is not fully understood, but it may include the stimulation of nerve endings in the endosteum resulting from the release of chemical agents from destroyed bone tissue, stretching of the periosteum due to the increasing size of the tumor, fracture, and growth of the tumor causing inflammation in the surrounding soft-tissue envelope82. Metastases in bone also may activate both nociceptors and mechanoreceptors in the endosteum and the periosteum14,31,37. It has been hypothesized that direct pressure from the tumor results in the release of several chemical mediators of pain, including substance P, prostaglandins, growth factors, bradykinin, and histamine37,104. The clinical presentation of pain ranges from a dull ache to a deep, intense pain that is exacerbated by weight-bearing. Occasionally, the pain is worse at night and is not relieved by rest. It often is difficult to assess the source of pain in elderly patients who also have degenerative conditions of the spine and the hips or in patients who have an infection or an inflammatory disease. In patients who have cancer, pain is not always related directly to the malignant tumor, and sometimes all of the symptoms of pain have a non-malignant origin120. Galasko and Sylvester identified a non-malignant origin for back pain in eleven of thirty-one patients who had a primary carcinoma38. Heim and Oei reported that 34 per cent of patients who had prostate cancer had pain in the absence of metastatic bone disease47. Other clinical parameters, such as swelling or localized tenderness, often are not specific indicators and are not always present except when there is a pathological fracture. Pathological fractures have been reported to occur in 9 per cent48 to 29 per cent106 of patients who have bone metastases, depending on the location of the lesion3,48,106,110. In a study of 1800 patients who had cancer that metastasized to bone, 165 sustained a pathological fracture48. In another study, by Schurman and Amstutz, sixty-three of 700 patients who had breast cancer had femoral metastases; of these sixty-three, eighteen had progression to fracture106. Five types of primary carcinoma account for approximately 80 per cent of all pathological fractures. Breast carcinoma accounts for 50 per cent; kidney carcinoma, for 10 per cent; lung carcinoma, for 10 per cent; thyroid carcinoma, for 5 per cent; and other, less common adenocarcinomas, for 5 per cent84. Most of these lesions appear to be osteolytic on plain radiographs. Breast carcinoma appeared to be osteoblastic in seventy-eight (15 per cent) of 516 metastatic bone lesions in two studies58,124. There is a strong relationship between the presence of an osteolytic lesion and the risk of fracture, whereas the primarily osteoblastic metastatic deposits found in patients who have prostate carcinoma rarely result in pathological fracture. In a study of 306 primary carcinomas that metastasized to the femur, leading to an actual or impending fracture, only eleven (4 per cent) were prostate carcinomas40. Higinbotham and Marcove reported that only four (3 per cent) of 150 pathological fractures secondary to metastatic bone disease were the result of a primary prostate carcinoma48. The most common sites of pathological fractures are the proximal ends of the long bones. Harrington reported that 258 (65 per cent) of 399 fractures occurred in the femur, whereas only sixty-eight (17 per cent) were in the humerus41.
As most of these patients initially are seen by clinicians because of pain, this often will direct the diagnostic workup. Plain radiographs generally are made of the affected region, often leading to the identification of local lesions. Metastatic lesions generally are radiolucent, with minimum periosteal reaction. The epicenter often is located within the intramedullary canal; intracortical or juxtacortical locations are uncommon. Axial and proximal appendicular locations are common sites for metastases; metastatic lesions rarely are located in the foot or the hand. In a review of 41,833 malignant tumors, it was found that only three (0.007 per cent) had metastasized to the bones of the hand127. Extensive review of the literature showed that only fifty-five osseous metastases had been reported in the hand as of 198317. Lesions in the distal part of the extremity often are secondary to primary carcinoma of the lung or the kidney or are associated with the terminal stages of widespread metastatic disease from other primary carcinomas46. Bone lesions in patients who are more than forty years old are most likely to be secondary to either metastatic adenocarcinoma or myeloma. The likelihood of a metastatic adenocarcinoma decreases in patients who are less than forty years old, whereas there is an associated increase in bone infections and primary sarcomas of bone. After a skeletal lesion has been identified, a bone scan should be performed to determine whether the lesion is isolated or whether multiple bones are involved. Radionuclide scanning with technetium-99m methylene diphosphonate is an extremely sensitive modality for the identification of associated lesions. It has been estimated that a tumor must reach a size of one centimeter and must destroy from 30 to 50 per cent of the bone before it can be detected on a plain radiograph2,25,32,39. Radionuclide scans have been reported to demonstrate lesions an average of three months earlier than plain radiographs, and the minimum size of tumor detectable with radionuclide scanning has been estimated to be two millimeters35,124. Galasko studied fifty women who had breast carcinoma and found that only twenty-five (50 per cent) had a lesion that was apparent on plain radiographs, whereas forty-two (84 per cent) had a lesion that was identified on radionuclide scanning35. In a later study, Galasko reported that a period of two to eighteen months was necessary before a lesion identified on radionuclide scanning could be visualized on plain radiographs36. Although sensitive, radionuclide scanning is not specific, especially for the detection of a solitary lesion. Of 273 patients who had a known primary carcinoma and had been found to have metastatic disease on radionuclide scanning, only 55 per cent actually had metastasis68. The benign causes for the radionuclide uptake in the remaining 45 per cent included trauma (25 per cent), infection (10 per cent), and miscellaneous factors (10 per cent). The anatomical site was noted to be important, with most metastatic lesions (80 per cent) occurring in the vertebral bodies68. Correlation of known tumor markers with the results of radionuclide imaging can be helpful for determining the need for additional evaluation. This is especially true for patients who have prostate carcinoma and may have abnormal uptake on radionuclide imaging. Of 107 patients who had prostate carcinoma, sixteen had confirmed metastatic bone disease, thirty had benign bone disease, and sixty-one had normal scans33. Correlation of the level of serum prostate-specific antigen with the presence of bone metastases was undertaken with use of a chi-square two-by-two contingency table. When a patient was seen to have focal abnormalities on bone scans, the diagnosis of bone metastasis could be ruled out, with a high degree of accuracy (predictive value of a negative test, 98.5 per cent), if the level of serum prostate-specific antigen was eight nanograms per milliliter or less33. Because lesions identified on radionuclide scanning may be secondary to either degenerative disease or trauma, a biopsy, to assist in staging and treatment, should be considered for most patients who have at least one osseous site. After the diagnosis of metastatic bone disease has been established, biopsy of subsequent sites is not necessary before treatment. The use of serum assays to diagnose and monitor patients who have metastatic bone disease is currently under investigation. Although lacking specificity, the level of serum alkaline phosphatase was reported by Schaffer and Pendergrass to be elevated in 77 per cent of 158 patients who had bone metastases secondary to prostate carcinoma102. An elevated level of serum alkaline phosphatase also was reported in 32 per cent of forty-seven patients and in 53 per cent of 167 patients who had breast cancer that had metastasized to bone20,91. The level of serum acid phosphatase often is elevated in patients who have prostate cancer that has metastasized to bone, although the increase may be due only to local extension of the disease. Of ninety-five patients who had prostate cancer that had metastasized to bone, 61 per cent had an elevated level of serum acid phosphatase; of seventy-three patients who did not have evidence of metastasis to bone, 11 per cent had an elevated level102. Although costly and relatively insensitive, urinary calcium and hydroxyproline have been used as measures of bone resorption, with decreased levels being associated with a clinical response to treatment53,61. Recently, newer biochemical markers of bone metabolism have been evaluated for their specificity in monitoring metastatic bone disease. These immunoassays have included markers of osteoblastic activity (bone Gla protein and procollagen-I carboxyterminal peptide) and osteoclastic activity (deoxypyridinoline and pyridinoline-crosslinked carboxyterminal telopeptide)61. Bone Gla protein is a non-collagenous protein that is produced by osteoblasts, deposited in bone matrix, and measurable in the circulation. Its serum level is considered to be a measure of osteoblastic function61. Procollagen-I carboxyterminal peptide is a trimetric, globular protein cleaved from type-I collagen molecules before their assembly into fibers. Its serum concentration is directly related to bone formation73. Deoxypridinoline is associated with collagen cross-links, found exclusively in bone, and excreted in the urine, with urine levels reflecting bone resorption18,27. Pyridinoline-crosslinked carboxyterminal telopeptide, another degradation peptide of type-I collagen, also is considered to reflect bone resorption96. In a prospective study, 150 patients who had bone metastasis were compared with 233 patients who did not. The patients were evaluated with respect to the predictability of bone involvement on the basis of several bone-metabolic markers (bone-Gla protein, procollagen-I carboxyterminal peptide, deoxypridinoline, and pyridinoline-crosslinked carboxyterminal telopeptide)61. Osteoblastic markers were elevated mainly in osteoblastic lesions, whereas most osteolytic or mixed lesions demonstrated elevated levels of osteoclastic markers61. Identification of a bone-alkaline-phosphatase isozyme has enabled researchers to quantitate bone metastasis more accurately. In a recent study that included forty-four patients, the specificity of the bone-alkaline-phosphatase isozyme for predicting bone metastases was 90.5 per cent as compared with 57.2 per cent for total alkaline phosphatase129. In another recent study, use of an immunoradiometric assay of serum bone alkaline phosphatase was associated with a high specificity (86.5 per cent) and sensitivity (78.6 per cent) for demonstrating the early progression of bone metastases94. In patients who have prostate carcinoma, prostate-specific antigen has proved to be a valuable tool both for diagnosis and for gauging of the response to treatment in the presence of metastatic bone disease after radical prostatectomy. The level of prostate-specific antigen, a 34,000-kilodalton serum protease produced by normal and malignant prostate epithelial cells, was found to be elevated in eight of ten patients who had recurrent prostate carcinoma57. The usefulness of measuring levels of this antigen for the purposes of initially diagnosing and then following the progression of the disease was explored in several studies, with prostatic acid phosphatase being found to be less specific6. In a large series of 852 patients who had newly diagnosed and untreated prostate carcinoma, Oesterling et al. found levels of serum prostate-specific antigen to be strongly predictive of the onset of bone metastasis85. In patients who were followed with monitoring of levels of serum prostate-specific antigen, the false-negative rate for a level of 10.0 micrograms per liter was only 0.5 per cent when correlated with a radionuclide scan that was indicative of metastasis85. However, in a recent study of 212 patients, 15 per cent who had bone metastases at the time of presentation had a level of serum prostate-specific antigen of less then twenty nanograms per milliliter76. While monitoring of the levels of prostate-specific antigen may be more cost-effective and at least as sensitive as radionuclide scanning for the diagnosis of metastatic prostate carcinoma, its role in predicting bone metastases in a prospective, controlled study of patients who have biopsy-proved disease has yet to be determined. When a metastatic lesion develops in a patient who has a known primary carcinoma and no previous history of bone metastasis, biopsy is indicated for restaging to determine whether medical or radiation treatment is needed. Patients who have evidence of multiple sites of involvement on radionuclide scanning without an impending pathological fracture should have biopsy of the most accessible lesions. Needle biopsy generally is preferred to open techniques. In patients who have monostotic disease, additional workup of the lesion is necessary before biopsy. Given the possibility that a sarcoma might be identified, computerized axial tomography or magnetic resonance imaging should be considered before biopsy. A more difficult problem arises in patients who have an occult primary neoplasm and skeletal metastases. Identification of the primary neoplasm in the presence of metastasis has proved difficult. In a series reported by Nystrom et al., additional diagnostic studies identified the primary carcinoma in only 129 (48 per cent) of 266 patients83. Rougraff et al. recently described a diagnostic approach with which the location of the primary adenocarcinoma was identified successfully in thirty-four of forty patients who had a bone lesion at the time of presentation98. A careful history and physical examination, followed by a routine chest radiograph and, when indicated, a computerized axial tomography scan of the chest, yielded a 66 per cent rate of successful diagnoses98. Computerized axial tomography of the abdomen and the pelvis established the diagnosis in an additional 13 per cent of the patients. It is interesting that skeletal biopsy was diagnostic in only 8 per cent of the patients, although it was confirmatory in an additional 28 per cent98. This type of standardized approach to the diagnosis of such lesions provides the clinician with reliable information and allows unnecessary tests or operative procedures to be avoided. The development of an algorithm that encompasses benign lesions, primary malignant bone tumors, and metastatic bone disease can be of assistance in the workup of patients who have bone lesions (Fig. 1).
Open or needle biopsy of the metastatic lesion may be performed depending on the experience of the surgeon and the pathologist. Both procedures should be performed with adherence to the principles of proper biopsy of musculoskeletal lesions111. It is preferred that the treating surgeon perform the biopsy, in the event that a sarcoma is identified and a wide resection is necessary. A conference with the radiologist and the pathologist before the biopsy can help to identify the most representative region within a heterogeneous lesion. If an open biopsy is performed, care must be taken not to contaminate adjacent tissue, thereby making limb salvage more difficult. Complications of biopsy can have profound effects on the outcome69,70. The biopsy should violate only a single compartment, to prevent contamination of uninvolved muscle and bone compartments, and the biopsy track should be resected at the time of the definitive limb-salvage procedure. Longitudinal incisions are preferable to transverse incisions because, in most extensile exposures that are necessary for limb-sparing, longitudinal incisions are used to resect primary malignant lesions of both bone and soft tissue. The surgeon should try to avoid exposing adjacent major neurovascular structures or raising large tissue flaps so that resection of large portions of soft tissue will not be necessary to achieve tumor-free tissue margins. Meticulous hemostasis is mandatory and prevents the spread of tumor cells during the operative exposure; a tourniquet is optional, provided that it is released and hemostasis is achieved before closure. Drains may be used, but they should be brought directly out of the incision rather than being allowed to exit from a separate site and thus to create a track from the tumor to the skin that must be excised during the definitive resection. Culture specimens should be obtained at the time of the biopsy in the event that osteomyelitis may be masquerading as a neoplastic process. Mycobacterial and fungal cultures should be performed in addition to routine cultures and gram stains. The pathologist must be presented with enough tissue in order to make a diagnosis. Frozen sections frequently can be examined to determine whether a representative portion of the tissue was obtained with the biopsy. Portions of the pseudocapsule are preferable to those from the central regions of the tumor, as the latter may be necrotic and devoid of diagnostic material. Biopsy of a soft-tissue mass associated with a bone lesion is preferable to actually entering the bone, as this tissue often reflects the most aggressive portion of the tumor111.
Operative treatment is indicated primarily to alleviate pain, to prevent neurological compromise secondary to compression of the spinal cord by collapsed bone, and to maintain the patient's ability to walk. The decision as to whether to intervene operatively is clear for medically stable patients who have a pathological fracture. For patients who have an impending pathological fracture, decision-making can be more difficult. The orthopaedic surgeon often must predict, on the basis of the radiographic characteristics of the metastatic lesion, whether the patient should be treated with radiation therapy only or with an operation combined with radiation therapy. Operative treatment should be performed only when necessary as it is associated with a higher risk of complications in these patients because of their weakened medical condition. In addition, operative treatment may delay the chemotherapeutic or hormonal intervention that is necessary to treat the systemic spread of metastatic disease. The biomechanical implications of osteolytic metastasis are profound, even with small cortical defects. Cortical perforations are divided into two categories: stress-risers and open-section defects93. Stress-risers are perforations that are smaller than the cross-sectional diameter of the bone, whereas open-section defects are larger than the cross-sectional diameter. Stress-risers decrease torsional rigidity by 60 per cent, and open-section defects decrease bone strength by almost 90 per cent93. These results have been confirmed by in vitro studies51,52,67. In one study, canine femora with small cortical defects had a 62 per cent reduction in bending strength, and open-section defects that resulted in a 50 per cent reduction in cross-sectional area reduced cortical strength by 87 per cent67. Endosteal defects, which do not involve the entire cortex, also have been evaluated in vitro and with computer models52. Endosteal defects centered within the femoral diaphysis that reduced the cross-sectional area by 50 per cent resulted in a 60 per cent reduction in strength52. Endosteal defects situated at the point of maximum bending stress reduced strength by more than 90 per cent52. A cortical perforation results in a concentration of forces at the edge of the defect because of an asymmetrical redistribution of the stresses experienced during loading. A pathological fracture results if these forces overcome the fatigue strength of the cortex93. Available data suggest that lytic defects reduce both the stiffness and the strength of bone, whereas osteoblastic metastases reduce the stiffness but not the strength49. However, these observations may not be related directly to what occurs in a clinical setting. Other factors may play a role in the reduction of bone strength. Patients who have osteolytic bone metastases may be at greater risk of fracture than those who have osteoblastic metastases. The presence of viable tumor may impede the body's ability to repair bone defects. The bone surrounding osteolytic lesions may be weaker in older patients, who may have either osteomalacia or osteoporosis. In addition, patients who have a higher level of activity may have an increased risk of injury. Adjuvant therapy for cancer, such as local irradiation or systemic chemotherapy, may slow bone repair of osteolytic lesions or may adversely affect the surrounding bone. Tong et al. reported the effect of adjuvant treatment on the risk of fracture in 1016 patients who had metastatic adenocarcinoma116. These authors compared two groups of patients who were managed with fractionated radiation therapy and found a higher rate of fracture in those who received doses of forty gray than in those who received doses of twenty gray (18 compared with 4 per cent). The clinical radiographic criteria for the operative treatment of impending fractures have been generated largely from retrospective studies. These often-quoted criteria are based on studies of lesions that involved more than 50 per cent of the cortex, were larger than 2.5 centimeters, were in the peritrochanteric region, and had not responded to radiation therapy. The hypothesis that 50 per cent cortical involvement is associated with a high risk of pathological fracture was originally proposed by Parrish and Murray, but only four of the ninety-six patients in their series were seen before the fracture and were managed with prophylactic fixation; the remaining ninety-two patients first were seen after the fracture, and the radiographs were not reviewed with respect to the size of the lesion87. Fidler evaluated the notes and radiographs of sixty-six patients (100 bone metastases) to determine whether the percentage of cortical destruction could be used to predict the risk of a pathological fracture28. Fidler concluded that the risk of fracture was low (2 per cent; one of forty-three metastatic lesions) when cortical destruction was less than 50 per cent and the risk was high (79 per cent; nineteen of twenty-four metastatic lesions) when cortical destruction was more than 75 per cent. However, the radio-graphic parameter of 50 per cent cortical destruction is questionable: of the thirty-three lesions causing 50 to 75 per cent cortical destruction, twenty (61 per cent) led to a fracture but thirteen (39 per cent) did not. The hypothesis that bone lesions that are larger than 2.5 centimeters are predictive of pathological fracture originally was proposed in a study of 338 patients, ninety-four of whom were initially seen with femoral metastases9. However, eight of the nineteen patients who had a fracture had a lesion that was smaller than 2.5 centimeters, resulting in a false-negative rate of 42 per cent. In a retrospective analysis of fifty-nine patients (ninety-seven bone lesions) who were receiving radiation therapy, Cheng et al. did not find any association between the radiographic criterion just mentioned and the risk of fracture15. Application of a specific measurement as opposed to a percentage has inherent inaccuracy, as such a measurement can be used to assess only a specific region or bone. Variability among patients with respect to cortical diameter and osseous quality in a specific region of bone is high and may explain the discrepancies in the prevalence of fracture reported by different investigators. More recently, Keene et al. attempted to evaluate these criteria objectively in a study of patients with breast cancer who had a lesion in the proximal part of the femur58. However, fractures could not be predicted on the basis of the size of the lesion or the percentage of cortical involvement because the ranges for these values were similar between patients who had a fracture and those who did not. The reliability of radiographic evaluation was questioned because the size of the lesion could vary on any two radiographs of the same patient. Bone pain that was unresponsive to radiation therapy also was found not to be associated with the risk of fracture58. In an attempt to address these inconsistencies, Mirels proposed a scoring system for quantitating the risk of pathological fracture77. With use of this system, a numerical score is assigned to four variables: the location of the lesion, the degree of pain, the radiographic appearance, and the size of the lesion. In a study of seventy-eight lesions in thirty-eight patients who had had irradiation without a previous fracture, the average score was 7 points (range, 4 to 9 points) for the fifty-one lesions that were not associated with a pathological fracture and 10 points (range, 7 to 12 points) for the twenty-seven that were associated with a pathological fracture77. Twenty-two of the twenty-five lesions for which the score was 9 points or more were associated with a fracture, compared with only one of the forty-one lesions for which the score was 7 points or less. Four of the twelve lesions for which the score was 8 points were associated with a fracture. On the basis of these data, Mirels recommended irradiation and observation of lesions with a score of 7 points or less and operative treatment of those with a score of 8 points or more. The central problem in the clinical evaluation of patients who have an impending pathological fracture stems from the inaccuracy of radiographic assessment. It has been estimated that bone destruction of as much as 50 per cent must occur before a lesion can be identified35. Computerized axial tomography, although providing better cortical resolution, has not proved to be any better than other methods for the radiographic assessment of osseous lesions. In a recent study of human cadavera in which ten pairs of specimens consisting of the proximal part of the femur with a simulated intertrochanteric metastatic bone defect were used, three orthopaedic oncology surgeons evaluated bone strength on the basis of plain radiographs and computerized axial tomography scans50. Their estimates of the size of the lesion and the bone strength were then compared for intraobserver error and with the results of biomechanical testing. Even though the radiographic resolution for both imaging studies was better than could be achieved in the actual clinical setting, there was only modest agreement among the surgeons with regard to the maximum size of the lesions. No relationship was found between the measured load-bearing capacity of the femora and the capacity estimated by the surgeons with use of the radiographic studies50. Estimates of the risk of fracture that are based on radiographic criteria can be highly inaccurate. More qualitative methods of measurement, such as that proposed by Mirels77, which are easy to apply and incorporate several variables, may provide orthopaedic surgeons with the means to predict better which patients are at risk for pathological fracture.
The treatment of metastatic bone disease consists of either systemic or local therapy. Systemic treatment can be chemotherapy, hormonal therapy, administration of radionuclides, or bisphosphonate therapy. The type of chemotherapy varies depending on the type of carcinoma; however, specific discussion of this topic is outside the scope of the current review. It should be noted that patients who have either metastatic bone disease or myeloma and bone lesions and are not at risk for fracture may have regression of the metastatic bone disease without the need for local adjuvant therapy or local operative intervention. Bone lesions that progress during chemotherapy should be treated either with local irradiation or both operatively and with irradiation. Local modalities include radiation therapy or operative treatment, or both.
Systemic Therapy
Radionuclides Strontium-89 is a beta-emitting, bone-seeking radionuclide that can remain in the bone for as long as 100 days10. The results of therapy with strontium-89 are variable; most authors have reported an average rate of response of 75 per cent in association with doses of between 1.11 and 1.48 maximum beta energy per kilogram82,103. Although promising, the results of treatment have been difficult to interpret because of discrepancies in the criteria used to evaluate pain. In a multi-center study of eighty-three patients who had prostate cancer, there was a dramatic or substantial decrease in bone pain in forty-five patients (54 per cent); however, twenty-one patients (25 per cent) did not benefit or had worsening of the pain during the study period62. In another series, at least partial relief of pain was reported by 80 per cent of 202 patients who had either metastatic prostate or breast cancer; however, these results may be skewed, as fifty-seven patients were dropped from the study because they were "not evaluable" at its completion97. Although the rates of response have varied, strontium-89 has been shown to be superior to a placebo in clinical trials for the alleviation of bone pain65. The toxicity of strontium-89 is low; as much as a 30 per cent reversible decrease in the platelet count is expected in association with the usual recommended dose of four millicuries (148 megabecquerels) per patient103. The treatment can be repeated as often as every three months, provided that the platelet count is maintained. In a study of 284 patients who had metastatic adenocarcinoma, comparison of strontium-89 therapy with localized radiation therapy showed no appreciable difference in the initial response to pain11. Patients who had a solitary lesion received either strontium-89 or twenty gray of radiation in five fractions, whereas those who had diffuse disease received hemibody irradiation (eight gray, in a single fraction) or strontium-89. Some improvement was reported in 61 per cent of patients who had received strontium-89 as compared with 66 per cent who had received irradiation; this response was dramatic in 44 and 36 per cent, respectively. The long-term effects may be better with strontium-89 therapy; 65 per cent of patients who had received it did not have radiographic progression and needed less additional radiation therapy as compared with 47 per cent of those who had received local radiation therapy11. Although the clinical results are encouraging, the mechanism of alleviation of pain remains unclear, and actual regression of the tumor has not been clearly demonstrated. Rhenium-186 and samarium-153 emit both gamma and beta energies and are complexed with bisphosphonates, making them bone-seeking agents. Rhenium-186 was reported to decrease the intensity of pain in twelve of eighteen patients22; however, in a follow-up study of twenty-seven patients, relief of pain was noted in only eight patients (30 per cent) and was not durable in the absence of a decrease in the level of serum prostate-specific antigen105. Phase-I evaluation of samarium-153 demonstrated measurable relief of pain in seventeen of nineteen patients, with a decrease in prostate-specific antigen in seven of twenty patients117. Hematological toxicity, measured as a decrease in the platelet and white blood-cell counts, occurs two weeks after the injection and can last for four weeks before recovery8. Additional clinical investigation is needed for both of these agents.
Bisphosphonates Because of their down-regulation of bone resorption, bisphosphonates have become attractive adjuvants for the reduction of the risk of pathological fracture stemming from osteolytic lesions and for the treatment of bone pain. Studies of patients being managed for hypercalcemia have demonstrated a decrease in bone pain with attainment of normal levels of calcium. In a study of thirty-four patients who had osteolytic breast cancer and had been randomly assigned to treatment with either dichloromethylene diphosphonate or a placebo, the requirements for analgesia were decreased in fifteen of the seventeen patients who had received dichloromethylene diphosphonate as compared with three of the seventeen controls26. However, a more recent randomized study, consisting of fifty-seven patients who had metastatic prostate cancer, demonstrated no major analgesic effect from intravenous or oral administration of etidronate as compared with the effect in the controls113. Because of these results and the potential problems with delayed bone mineralization associated with etidronate, other bisphosphonates, such as clodronate and pamidronate, have gained in popularity. Clodronate can be administered intravenously or orally, and although it affects bone resorption it does not alter bone mineralization. In several studies, clodronate was found to reduce bone pain; the need for palliative radiation therapy; and, potentially, the risk of pathological fracture1,4,88. In a study of sixty-eight patients who had painful metastatic bone disease or hypercalcemia, thirty-five patients were assigned to treatment with clodronate and thirty-three, to treatment with a placebo4. Only four patients who received clodronate reported progressive bone pain, whereas twenty patients in the control group were symptomatic. In a study of ninety-two patients who had metastatic prostate carcinoma, eighty patients had a dramatic decrease in pain after intravenous administration of clodronate1. Paterson et al. reported on 173 patients who had breast cancer that metastasized to bone; eighty-five patients were managed with oral administration of clodronate and eighty-eight received a placebo88. Clodronate was associated with a 32 per cent decrease in the rate of fracture; there were eighty-four fractures per 100 patient-years in the group that had received clodronate as compared with 124 in the control group. The analgesic effect of clodronate appears to be delayed, with several months of administration being necessary to achieve the desired effect. Studies concentrating on the metabolic effects of clodronate over short periods (two to four weeks) did not show any decrease in bone pain1,86. Intravenously administered clodronate, although short-acting, can be given to patients who have severe hypercalcemia or bone pain, with oral administration being substituted at two weeks. Gastrointestinal symptoms, including nausea and vomiting, have been reported but are infrequent and generally respond to antiemetic medications. Pamidronate, another bisphosphonate that does not interfere with bone mineralization appreciably while preventing bone resorption, is administered primarily intravenously, as the gastrointestinal side effects of the orally administered preparation often are severe29,123. In one study, 25 per cent of patients had to withdraw because of gastrointestinal symptoms associated with orally administered pamidronate123. In a randomized study of 131 patients who had metastatic bone cancer, pamidronate was associated with a substantial decrease in fracture, hypercalcemia, and bone pain as compared with the rates for controls122. These results were supported in a recent study of 380 women who had stage-IV breast cancer and at least one lytic bone lesion54. The patients were randomized to receive either intravenously administered pamidronate (185 patients) or a placebo (195 patients) while they were having cytotoxic chemotherapy. Skeletal complications were assessed monthly and included pathological fracture, the need for radiation therapy or operative intervention because of bone lesions, compression of the spinal cord, and hypercalcemia. Bone pain and quality of life also were assessed. The results were encouraging; in patients who had received pamidronate, the first skeletal complication occurred later (at an average of 13.1 months as compared with 7.0 months in the control group). In addition, a lower rate of skeletal complications was reported in the group that had received pamidronate (seventy-nine [43 per cent] of 185 patients as compared with 110 [56 per cent] of 195 patients). There was also a significantly lower increase in bone pain (p = 0.046) and a significantly lower decrease in functional status (p = 0.027) in the group that had received pamidronate than in the group that had received the placebo. The rate of non-vertebral pathological fractures was reduced, but the rate of vertebral fractures was similar between the two groups. The rate of survival also was not altered by treatment with pamidronate54. Bisphosphonates, primarily clodronate and pamidronate, are promising adjuvants for the systemic treatment of bone metastases. Although bisphosphonates act quickly to reduce hypercalcemia, long-term administration is necessary to treat widespread osteolytic disease. As tumor growth is not altered by use of these drugs at sites of bone metastases, the drugs should be used in conjunction with other types of therapy to control the progression of the disease.
Local Therapy
Radiation Therapy Radiation therapy can be given as a single dose or in fractionated doses over a period of several days. The advantage of single-dose therapy is its lower cost and its greater ease of delivery for patients. Comparison of the results of several retrospective studies demonstrated no appreciable difference in relief of pain or rates of recurrence between the two modalities. These findings were confirmed in a prospective, randomized study comparing the results, in 288 patients, of a single dose of eight gray with those of fractionated doses of three gray over a two-week interval (total dose, thirty gray)92. When a single dose is used, administration of between six and eight gray has been recommended by some authors55,56. In a recent prospective, randomized study of 270 patients who had bone pain secondary to metastasis, the results of a single dose of four gray (137 patients) were compared with those of a single dose of eight gray (133 patients)56. At four weeks, there was no difference in the rate of complete relief of pain or in the duration of the response between the two groups; twenty-five of ninety-eight patients surveyed reported no pain in response to a dose of four gray as compared with twenty-two of ninety-six in response to a dose of eight gray. Even though the authors recommended administration of eight gray when a single-dose regimen is used, patients who had reduced tolerance had adequate control of the pain with a single dose of four gray. Patients who have recurrence of pain because of biomechanical weakness should be managed with operative stabilization. In patients who have recurrent tumor growth without a decrease in bone strength, repeat radiation has proved to be effective. In a study encompassing 280 skeletal sites in 105 patients, radiation was repeated once for fifty-seven sites and twice for eight78. Although several schedules of fractionation were used, forty-nine (86 per cent) of fifty-seven patients had measurable relief of pain after repeat treatment. Multiple lesions necessitate a different approach, which generally includes multiple-site or hemibody irradiation. These modalities have been reported to be effective in controlling pain related to widespread metastases101,116. Tong et al., in a study of 1016 patients, effectively treated multiple lesions with multiple separate fields in doses ranging from fifteen to thirty gray116. Rapid relief of pain was reported in patients who were managed with fifteen gray over a period of one week; patients who received twenty-five to thirty gray over a period of two weeks had reduced benefit. Hemibody irradiation usually is given as a single dose ranging from six to ten gray, with 60 to 80 per cent of patients having relief of pain within two days after treatment101. Acute toxicity (nausea, vomiting, or diarrhea) is common but transient, disappearing within a few days after treatment. Hematological toxicity peaks after two to three weeks, with normal function being restored in most patients after four to six weeks. Doses of more than eight gray increase toxicity considerably, but lower doses are well tolerated. The concomitant administration of chemotherapy can increase these side effects. Hospitalization is necessary for patients who are to have hemibody irradiation of the upper torso, as hydration, antiemetics, and corticosteroids must be administered to minimize side effects. Hemibody irradiation of the lower torso is more easily tolerated and does not necessitate hospitalization. There have been no studies, to my knowledge, comparing the results of separate multiple-site treatment with those of hemibody irradiation in a prospective, randomized manner101.
Operative Treatment A rapid return to walking has been reported by several authors. Ryan et al. reported that fifteen of eighteen patients regained the ability to walk within four days after treatment of a femoral fracture with intramedullary fixation100. Relief of pain and increased mobility after operative treatment were clearly demonstrated in a study of 366 patients who had a pathological fracture45. Three hundred and forty-six patients (95 per cent) who had been able to walk before the fracture also were able to do so postoperatively, and 160 (86 per cent) of 186 had excellent or good relief of pain45. In deciding whether to select internal fixation or prosthetic reconstruction for the treatment of a pathological fracture in a patient who has metastatic bone disease, the surgeon must consider several factors. First, as these patients often have a limited life expectancy, rapid recovery is imperative both for maintaining the quality of life and for adjuvant treatment. Second, successful fracture-healing often is unpredictable for reasons such as continued local tumor growth, poor bone quality, poor nutritional status, and the effects of chemotherapy and radiation therapy. Gainor and Buchert found that a pathological fracture was less likely to heal in patients who survived for less than six months, whereas the fracture united in twenty-two (88 per cent) of twenty-five patients who survived for more than six months after operative stabilization and a dose of radiation of thirty gray or less34. The use of methylmethacrylate to reconstitute large bone defects permits most patients to bear weight immediately. Methylmethacrylate maintains excellent rigidity, especially when compressively loaded, and it is not adversely affected by radiation79. Biomechanical data supporting the use of methylmethacrylate were reported by Ryan and Begeman, who created 2.5-centimeter defects in the femoral shafts of cadavera and either filled the defects with methylmethacrylate or left them open99. Axial load and torsional strength increased by 50 and 70 per cent, respectively, in the defects that had been treated with methylmethacrylate. The results of a retrospective study of the operative treatment of 166 metastatic lesions of the humerus and the femur in 147 patients, by Yazawa et al., illustrate the difficulty in dealing with pathological fractures128. Proximal femoral implants included endoprostheses (twenty-eight patients), total joint prostheses (thirteen patients), screws and side-plates (nine patients), and intramedullary devices (eighteen patients). Failure of fixation or prosthetic replacement was reported in eleven (9 per cent) of 119 patients who had a femoral lesion as compared with only two (4 per cent) of forty-six who had a fracture of an upper extremity. The rate of failure was high (three of nine patients) for fractures of the proximal part of the femur that were treated with a compression screw. Intramedullary fixation and prosthetic replacement augmented with methylmethacrylate were the most successful methods. Common reasons for failure included poor initial fixation, improper selection of the implant, and progression of tumor-induced bone destruction around the implant128. Although the results of clinical studies are not yet available, the introduction of reconstruction nails for the fixation of fractures of the proximal part of the femur has enabled the orthopaedic surgeon to treat pathological subtrochanteric fractures of the femur more reliably with an intramedullary device. However, as fixation with a locking nail depends on the quality of the surrounding bone, pathological intertrochanteric and femoral neck fractures still are best treated with prosthetic replacement. In contrast to similar lesions in the lower extremity, isolated lesions in the upper extremity that are not associated with fracture may be amenable to treatment with a brace, and operative treatment often can be avoided. However, for patients who depend on support of the arms (as with use of a walker) for walking, or for those who have bilateral involvement of the upper or lower extremities, operative stabilization should be seriously considered after a pathological fracture has occurred. The poor results of non-operative treatment of pathological fractures of the humerus have been reported previously24,30. In a study of twenty-nine such fractures in twenty-seven patients, nine fractures were treated with radiation, eight were treated with internal fixation, and twelve were treated with other means24. Of the extremities treated with radiation, five had relief of pain but four were left without function. In contrast, internal fixation both decreased the pain in and improved the function of seven of the eight extremities. Flemming and Beals reported on eight pathological fractures of the humerus that had been treated non-operatively, with very poor results30. Four fractures went on to a non-union, and relief of pain was rated as poor or fair after the treatment of seven fractures. The operative choices for the treatment of pathological fractures of the upper extremity include use of a compression plate, a flexible intramedullary nail augmented with methylmethacrylate, a rigid intramedullary nail with or without methylmethacrylate, and a prosthetic replacement. In a retrospective study of fifty-four patients who had an established or impending pathological fracture of the humerus and were managed with intramedullary Rush-rod fixation with and without methylmethacrylate, all patients had relief of the pain initially after the procedure64,108. However, pain was a problem for four patients secondary to acromial impingement from protrusion of the rod and for three who had loosening of the rod64,108. In a more recent study of twenty-two pathological fractures of the humerus in twenty-one patients, nineteen fractures were treated with intramedullary fixation121. Postoperatively, fourteen patients had only mild or moderate pain. Complications included failure of the fixation in five (24 per cent) of the twenty-one patients. A compression plate had been used in two patients, and it failed in both. In a recent report on pathological lesions of the humeral diaphysis that had been treated with a locking intramedullary nail, union was radiographically apparent in all seven of eleven patients who survived at least three months and had radiographs available95. It was recommended that this technique be reserved for fractures between the proximal one-sixth and the distal one-fourth of the humerus in order that there be sufficient bone for fixation with interlocking screws95. Use of a compression plate, although not recommended for diaphyseal fractures, proved superior to intramedullary fixation for supracondylar fixation of cadaveric humeri23. In a comparative study of posterior fixation with one plate, double plating, and fixation with Rush rods and methylmethacrylate, a 50 per cent lateral, semicylindrical cortical defect was created in the distal one-third of twenty-four matched pairs of fresh-frozen humeri from human cadavera23. The values for peak torque to failure and for total energy absorbed were lower for specimens treated with Rush rods or a single plate as compared with those for specimens treated with double plating. Prosthetic reconstruction is recommended for lesions of the proximal part of the humerus that involve the humeral head or for those that have substantial segmental diaphyseal involvement16,109. A long-stemmed humeral prosthesis, with or without use of an allograft when there is substantial bone loss, has been suggested for reconstruction of the proximal part of the humerus109. Intercalary segmental replacement109 was used in a series of four patients, with good results16; all patients reported excellent function of the upper extremity without evidence of prosthetic loosening or local progression of the tumor. The primary indications for this technique are extensive diaphyseal involvement, failure of other methods of internal fixation, and recurrence of the tumor in patients in whom a wide resection is needed because of a lack of response to radiation therapy. Reconstruction of the proximal part of the femur and the acetabulum is often the most technically demanding procedure; the implant is at risk of failure because the forces about the hip are extremely high for most normal activities. Forces on the proximal part of the femur have been estimated to be 3.5 times body weight during the mid-stance phase of gait, and these forces increase to 7.7 times body weight during stairclimbing21,89. Options for operative reconstruction of the diseased proximal part of the femur include internal fixation with a sliding hip-screw and a side-plate or with a Zickel or reconstruction nail, prosthetic replacement with a long-stemmed femoral component, or replacement of the proximal part of the femur. Most authors have recommended prosthetic reconstruction with either an endoprosthesis or a total hip replacement for fractures of the femoral neck. Intertrochanteric fractures of the femur can be treated with either internal fixation or prosthetic replacement. Although reported to be associated with the highest rate of complications, internal fixation is still advocated by some authors44,75,128,130. Use of a Zickel nail for the treatment of pathological fractures of the proximal part of the femur was reported in two studies75,130. In one of these studies, femoral shortening secondary to progression of the disease occurred in 24 per cent of twenty-one patients75. In the other study, which included fifty patients, a maximum of four centimeters of shortening was reported130. Although methylmethacrylate was not used to augment internal fixation in either study, these results underscore the problems associated with internal fixation in the presence of continued bone destruction. A reconstruction nail, with proximal and distal interlocking capability, theoretically can prevent shortening in patients who have continued destruction of diaphyseal bone. The options for prosthetic replacement include use of a long-stemmed standard or calcar-replacing femoral component and use of a proximal femoral replacement. The advantages of these implants include ease of insertion and maintenance of both the flexor and the abductor muscle attachments of the hip. The disadvantages include the dependence on distal femoral fixation and the possibility of progression of the disease, which could destabilize the femoral component. For this reason, the indications for proximal femoral replacement include either failure of internal fixation or continued progression of the disease in a patient who is unable to have radiation therapy. Because resection of the proximal part of the femur in order to insert a proximal femoral endoprosthesis results in sacrifice of the abductor and flexor muscle attachments of the hip to bone, a walker or cane usually is needed for efficient walking. Prosthetic replacement for the treatment of proximal femoral lesions has been proposed. Lane et al. reported on a series of 167 consecutive actual or impending pathological fractures of the hip that had been treated with either a long-stemmed femoral endoprosthesis or a total hip arthroplasty63. The patients were followed for a maximum of one year or until death; the median duration of survival was 5.6 months. Of the seventy-eight patients who had been able to walk preoperatively, fifty-six (72 per cent) were able to walk independently or with use of a walker after the prosthetic replacement. Of the eighty-five patients who had been unable to walk for two weeks or more before treatment, forty (47 per cent) were able to walk independently or with use of assistive devices postoperatively. Systemic progression of the disease was the main factor that limited walking. Complications were infrequent and included wound infection (four patients) and pulmonary embolus (two patients). Additional complications that must be anticipated are hypotension and possible cardiac arrest during hip arthroplasty when a long-stemmed femoral component is inserted with cement. In a series of seven patients who had a long-stemmed component inserted with cement, four died in the operating room and three were successfully resuscitated90. All seven patients were elderly, had osteoporotic bone, and had a previously undisturbed intramedullary canal, and several batches of methylmethacrylate had been used in all procedures. As patients who have metastatic bone disease characteristically are older, with women accounting for a large percentage of patients, cardiopulmonary compromise must be anticipated during insertion of the femoral implant. Decompression of the femoral canal with a distal venting hole, retrograde insertion of cement, and hand-packing of the cement about the proximal metaphysis were recommended90, but these methods have not been clinically proved to reduce the morbidity of this procedure. Adequate volume replacement, invasive hemodynamic monitoring, and ready-mixed vasopressor solutions are useful adjuvants in the management of patients who are at risk for cardiac arrest90. Several small series have focused on proximal femoral replacement for the treatment of pathological fractures. Sim and Chao reported on eighty-two patients who had either metastatic disease (thirty-three patients) or a primary malignant bone tumor (forty-nine patients) and were managed with segmental replacement of the proximal part of the femur107. Of this combined group of eighty-two patients, thirty-eight (46 per cent) had at least one complication. The most common complication was overlengthening of the extremity secondary to use of an oversized implant (eleven patients; 13 per cent), followed by instability of the hip (ten patients; 12 per cent). Additional complications included temporary sciatic neurapraxia due to overlengthening (four patients; 5 per cent), deep infection (four patients; 5 per cent), perforation of the femoral shaft (two patients; 2 per cent), and the need for amputation due to infection (two patients; 2 per cent). Problems with limb length and neurapraxia decreased after the introduction of a modular-component system. All but one of the dislocations were in patients who had had replacement of the acetabular component. Eleven patients had radio-graphic evidence of loosening of the acetabular component, but none needed a revision. Twenty per cent of the bipolar cups demonstrated wear on radiographs, and 43 per cent of the patients had evidence of stress-shielding of the implant107. Acetabular insufficiency secondary to bone metastasis has been classified by Harrington according to the location and extent of the tumor and the amount of bone destruction42. Class-I lesions are those in which the lateral cortex and the superior and medial acetabular walls are structurally intact; class-II, those that have deficiencies in the medial wall; and class-III, those that have deficiencies in both the medial and the superior wall. Class-I lesions can be treated successfully with conventional total hip arthroplasty with cement; class-II lesions, with a technique that transfers the stress of weight-bearing away from the deficient wall and onto the intact acetabular rim with use of a protrusio ring; and class-III lesions, with reconstruction of the acetabular columns with implants and methylmethacrylate to fix the protrusio ring into place. In a recent series reported by Harrington, fifty-eight patients (including thirty-seven who had a class-III lesion) had a total joint replacement for the treatment of periacetabular fracture due to metastasis44. Thirty-seven patients who survived for more than six months described the pain as slight or none, and all twenty-four patients who survived for more than two years had slight or no pain. Thirty-nine of the fifty-one patients who survived for more than six months were able to walk either without use of walking aids (twenty patients) or with a cane (nineteen patients). Complications included loosening of the acetabular component in four patients because of progressive bone destruction; in two of these patients, the component was successfully revised44.
In summary, although the clinical presentation may vary among patients, there are well established protocols for the diagnosis and workup of metastatic adenocarcinoma. Most bone lesions can be successfully treated non-operatively; however, the determination of which patients are at risk for a pathological fracture still poses a dilemma for the orthopaedic surgeon. Because of the relative inaccuracy of skeletal imaging in predicting substantial bone loss, scoring systems that incorporate other variables are needed to determine the risk of pathological fracture. Successful operative treatment for impending or actual pathological fractures depends on achieving rigid fixation with either internal fixation or a prosthetic device. Adjuvant systemic and local treatment to achieve local tumor control is imperative in order for the operation to be successful. Although operative treatment can restore the ability to walk and improve the quality of life, future medical advances hold the most promise for patients who have metastatic bone disease.
Department of Orthopaedic Surgery, Georgetown University, 3800 Reservoir Road, N.W., Washington, D.C. 20007.
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Introduction
Clinical Presentation