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The Journal of Bone and Joint Surgery (American). 2005;87:1400-1410. doi:10.2106/JBJS.E.00257 © 2005 The Journal of Bone and Joint Surgery, Inc.
What's New in Musculoskeletal Oncology1 Department of Orthopaedic Surgery, Johns Hopkins School of Medicine, JHOC #5251, 601 North Caroline Street, Baltimore, MD 21287. E-mail address: kweber6{at}jhmi.edu
Specialty Update has been developed in collaboration with the Council of
Musculoskeletal Specialty Societies (COMSS) of the American Academy of
Orthopaedic Surgeons.
This review will focus on the updates published or presented over the past year in the field of musculoskeletal oncology. Because of the rarity of musculoskeletal tumors, much of the published research in any given year is primarily composed of retrospective or nonrandomized studies. Large prospective clinical studies are usually performed in multi-institutional fashion or by orthopaedic groups at major cancer centers. Musculoskeletal oncology is one orthopaedic subspecialty, however, in which there are frequent molecular discoveries related to bone and soft-tissue sarcomas or metastatic bone disease. The update will be divided into sections addressing the advances in the diagnosis and treatment of malignant bone tumors, malignant soft-tissue tumors, benign bone and soft-tissue tumors, and metastatic disease. There will also be a section in which updates on limb-salvage options and outcomes are discussed. In addition, the upcoming tumor-related meetings and web sites will be listed along with a list of current references. Finally, the editorial staff of The Journal reviewed recently published articles in over 100 medical journals to identify high-quality research articles that received a Level of Evidence grade of I. Three level-I articles were identified that are relevant to musculoskeletal oncology, and these references are listed after the standard bibliography. A brief annotated review is provided for each of these articles.
Chondrosarcoma Chondrosarcoma remains a challenging tumor to diagnose and treat. Adequate surgical resection is the mainstay of treatment as chemotherapy and radiotherapy have not substantially improved the survival of patients with this disease. Relatively little is known about the genetic aberrations and molecular pathways associated with this tumor. Ozaki et al. used comparative genomic hybridization to identify chromosomal abnormalities in benign and malignant cartilage tumors1. They characterized gains and losses in multiple chromosomes and found that aberrations on chromosomes 2 to 11, 14, 15, and 21 only occurred in chondrosarcomas as compared with benign lesions. Better tools are necessary to diagnose and predict the biologic behavior of chondrosarcomas. Currently, the best prognostic indicator is tumor grade, which is based on light microscopy. However, even low-grade tumors can locally recur or metastasize, so a more sophisticated molecular understanding of chondrosarcoma is needed. Martin et al. evaluated the expression of telomerase reverse transcriptase in a study of sixty-one cartilage tumors ranging from benign to high grade2. Immunohistochemical staining of this enzyme was correlated with the clinical outcome. A significant correlation was noted between high expression of telomerase reverse transcriptase and subsequent metastasis with decreased disease-free survival (p < 0.01). In addition, the expression of telomerase reverse transcriptase was correlated with cartilage tumor grade on light microscopy (p = 0.006). Since the antibody clearly stains the nuclei of transformed cells, this technique may allow its routine use for the grading of chondrosarcomas. Finally, in an effort to identify molecular targets in the treatment of chondrosarcoma, researchers have discovered that the Indian hedgehog (Ihh) gene is constitutively activated (always turned "on") in chondrosarcoma3. On the basis of this finding, they implanted chondrosarcoma xenografts into immunocompromised mice and then treated the mice with triparanol, an Ihh inhibitory drug. The blockade was effective for decreasing the level of expression of Ihh target genes as well as the cellularity and proliferation of the tumors. Additional studies are necessary to determine if this method will be effective for the treatment of human chondrosarcoma. Substantial controversy exists with regard to the surgical treatment of chondrosarcoma. There is a trend toward intralesional treatment for chondrosarcoma of the extremities. With careful selection on the basis of the radiographic appearance of the lesion, patients with chondrosarcoma of an extremity can be managed with a thorough intralesional curettage, which is effective and preserves function4. However, selection of appropriate patients is crucial as some chondrosarcomas can recur locally, change to a higher-grade lesion, and even metastasize5. If the tumor recurs locally, the patient may have a poor outcome and may require radical surgery for local control5. Less controversy exists when the chondrosarcoma occurs in an axial location. The results of two recent series underscore the importance of achieving adequately wide margins in these difficult anatomic areas. The records of twenty-four patients with chondrosarcoma of the chest wall were retrospectively reviewed after a median duration of follow-up of seventy-one months6. Multivariate analysis demonstrated that only the adequacy of the surgical margin was correlated with the overall survival rate (p = 0.0029). In addition, the local recurrence rate was 10% for patients with adequate margins, compared with 75% for those with inadequate margins. Surgeons at the Rizzoli Institute recently presented their data on pelvic chondrosarcoma7. They reviewed 150 patients after a mean duration of follow-up of 104 months. The rate of local recurrence was 23% after a mean of thirty-four months, and this rate was inversely correlated with adequate margins (p = 0.016). Tumors crossing the sacroiliac joint were associated with a higher risk of inadequate margins (p = 0.02). Overall survival was correlated with tumor grade.
Dedifferentiated Sarcoma and Paget Sarcoma
Osteosarcoma Many investigators are trying to identify the molecular pathways involved in osteosarcoma progression. Recently, a discovery was made that identifies how osteoblast differentiation is disrupted in osteosarcoma12. Runt-related transcription factor 2 (RUNX2) is a transcriptional regulator of osteogenesis that creates terminally differentiated osteoblasts through Rb and p27Kip1-dependent mechanisms. Mice that are null for RUNX2 have a complete lack of ossification. In osteosarcoma, the function of RUNX2 is disrupted and p27Kip1 is not induced. This correlates with loss of differentiation rather than terminal osteoblast differentiation in a high-grade osteosarcoma. A recent study from the Rizzoli Institute involving 860 evaluable patients demonstrated a significant difference in the five-year disease-free survival rate in association with the serum lactate dehydrogenase level at the time of presentation13. The five-year disease-free survival rate was 60% for patients who had had a normal lactate dehydrogenase level at the time of presentation, compared with 39.5% for those who had had a high lactate dehydrogenase level (p < 0.0001). Patients who presented with metastatic disease had a significantly higher lactate dehydrogenase level than those who presented with localized disease. This large series lends support to the use of serum lactate dehydrogenase level as a prognostic indicator and as a way to define a group of high-risk patients who should be considered for treatment with more aggressive systemic chemotherapy. A recent comprehensive overview of the diagnosis, biology, and treatment of pediatric osteosarcoma outlines the latest chemotherapy regimens and limb-salvage procedures14.
Ewing Sarcoma
In order to test targeted therapies in vivo, immunocompromised mice are
often injected with human cancer cells. In a mouse model, human Ewing sarcoma
cells were injected into the calf and the mice were treated with different
agonists of the tumor necrosis factor-related apoptosis-inducing ligand
(TRAIL) receptor, which is known to induce apoptosis in Ewing sarcoma cell
lines16. Treatment
decreased the growth of tumors in the calf but did not cure the mice or affect
the metastasis even when doxorubicin was added to the regimen. The mice also
developed resistance to the effect of TRAIL receptor agonists. The
investigators discovered that the combination of TRAIL receptor agonists and
interferon-gamma (IFN The Children's Cancer Group and the Pediatric Oncology Group, in a cooperative study in 2003, showed that patients with nonmetastatic Ewing sarcoma had an improved outcome if ifosfamide and etoposide were added to the standard clinical regimen17. The same regimen was evaluated in a new study involving 120 patients with metastatic Ewing sarcoma18. The results of that randomized trial revealed that the addition of ifosfamide and etoposide did not improve the event-free survival or overall survival rates in patients with metastatic disease. Intensive chemotherapy regimens may adversely affect fertility in young patients. A study evaluating thirty-six teenagers and young adults who were managed with chemotherapy for the treatment of high-grade bone sarcomas showed that the fifteen patients who attempted conception were successful19. Thirteen patients had successful initial pregnancies, with uncomplicated deliveries and no birth defects. Although that study was limited by small numbers, it is encouraging to note that successful childbirth can be attained after treatment with cytotoxic chemotherapy. At a 2004 AAOS/NIH Workshop, in a report entitled "Does Sex Matter in Musculoskeletal Health? The Influence of Sex Specificity and Gender on Musculoskeletal Health," gender issues related to musculoskeletal oncology were discussed. These issues have received little attention in the literature, despite differences in both the etiology and the treatment of benign and malignant bone and soft-tissue tumors. There is a 3:2 male-to-female ratio in the prevalence of primary musculoskeletal tumors. Osteosarcoma develops in girls approximately two years earlier than in boys, and girls have a better response to chemotherapy20. Another study demonstrated fewer relapses and improved survival rates in female patients with osteosarcoma21. Similar results have been reported for soft-tissue sarcomas, but these differences have not received much attention in national studies, and the reasons for the disparities are not clear.
Patients with soft-tissue sarcomas are managed with surgical resection combined with preoperative or postoperative radiation. Such treatment results in local control of the tumor in approximately 90% of patients. However, patients generally die as a result of metastases, especially patients who present with large, deep-seated lesions. There has been no substantial progress in improving the overall rate of survival of these patients, and the effectiveness of chemotherapy has been the subject of much controversy. Molecular targeted therapy with tyrosine kinase blockade has had dramatic effects on the treatment of gastrointestinal stromal tumors, and similar break-throughs are necessary for the treatment of axial and extremity soft-tissue sarcoma. In the search for molecular targets of therapy, Ganjavi et al. recently evaluated the effect of adenoviral-mediated gene therapy with wild-type p53 (Ad-WTp53) in pediatric sarcoma cell lines22. Most sarcomas have defects in p53, a tumor-suppressor gene that regulates cell growth. Treatment of four different cell lines with Ad-WTp53 resulted in a dose-dependent decrease in cell growth and viability as well as a significant increase in chemosensitivity to cisplatin and doxorubicin. The chemotherapy agents used most commonly for patients with soft-tissue sarcoma are doxorubicin and ifosfamide. There has been a trend toward the use of higher-dose regimens to achieve better response rates and overall survival rates. Worden et al., in a prospective, randomized, phase-II study of seventy-nine patients, compared high-dose ifosfamide with standard-dose ifosfamide combined with doxorubicin as first-line therapy for the treatment of intermediate or high-grade soft-tissue sarcomas23. There was no improvement in the one-year disease-free survival rate or the overall survival rate in patients with localized or metastatic disease who received the high-dose ifosfamide. High-dose ifosfamide was associated with increased toxicity, and the final recommendation was that high-dose ifosfamide is not warranted in terms of efficacy or toxicity. Cormier et al. evaluated 674 consecutive, nonrandomized patients with primary stage-III extremity soft-tissue sarcoma who had been managed at two major cancer centers24. The goal was to evaluate the impact of adjuvant chemotherapy in patients with advanced disease. Approximately 50% of patients were managed with local therapy alone, and the other 50% were managed with local therapy and chemotherapy. Extensive statistical analyses suggested that the benefits of doxorubicin-based chemotherapy could not be sustained for more than one year. By five years, the group of patients who had received chemotherapy had worse disease-free and disease-specific survival rates compared with the group of patients who had not received chemotherapy.
Predictors of disease progression in patients with soft-tissue sarcomas are
lacking. Schuetze et al. evaluated the use of fluorodeoxy-D-glucose (FDG)
positron emission tomography (PET) scans for detecting the response to
chemotherapy and predicting the risk of progression in a study of patients
with extremity soft-tissue
sarcomas25. The
calculated standardized uptake value correlates with the rate of FDG
accumulation and was found to be a marker with which to independently identify
patients at high risk for tumor recurrence. All patients in that series were
managed with doxorubicin-based chemotherapy. There was a correlation between
the change in maximum standardized uptake values and the residual viable tumor
at the time of surgical excision (p = 0.001), although the histologic response
to chemotherapy was not correlated with patient outcome. A baseline maximum
standardized uptake value of Advances have been made in the methods used for radiation therapy in patients with soft-tissue sarcomas. Multiple modalities are available to maximize effects and minimize toxicity. An excellent recent review of these techniques and how they are integrated with surgical treatment of sarcoma is available26. One complication that has been associated with considerable morbidity in patients with soft-tissue sarcomas is a postradiation fracture. Holt et al., in a retrospective study of 364 patients with lower extremity sarcomas that had been treated with external beam radiation and surgical resection, reported twenty-seven fractures in twenty-three patients27. The likelihood of fracture was higher among female patients (p = 0.02) and among those older than fifty-five years of age (p = 0.004). Twenty-four fractures occurred in patients who had received high-dose radiation (60 or 66 Gy), whereas only three fractures occurred in patients who had received low-dose radiation (50 Gy) (p = 0.0007). The median time to fracture was forty-three months. All fractures occurred in the radiation field, and there was a higher likelihood of fracture among patients who had been managed with postoperative radiation than among those who had been managed with preoperative radiation (p = 0.008). Multivariate analysis revealed that a postradiation fracture was associated with age and the use of high-dose radiation, but no effect was associated with the amount of periosteal stripping at the time of surgery.
There have been advances in the understanding of both the diagnosis and the treatment of benign lesions over the past year. Benign bone tumors are commonly noted in children and young adults, and certain lesions require treatment while others run a self-limited disease course. Simple bone cysts occur in young children and have a low rate of healing despite treatment. The current standard of care is the injection of corticosteroid into the cyst, but alternative methods involving the use of autogenous bone marrow have been proposed. An initial study of twelve patients who were managed with marrow injection revealed promising results28. A prospective, randomized trial of eighty children is currently being performed to compare methylprednisolone acetate injections with autologous bone-marrow injections for the treatment of simple bone cysts. The early results for forty-eight children with at least two years of radiographic follow-up demonstrated no difference between the two treatments when the radiographs were evaluated in a blinded fashion. The final follow-up data may result in a different conclusion, but these early data suggest that new options for treatment should be explored. Benign bone tumors such as chondroblastoma, aneurysmal bone cyst, and nonossifying fibroma are frequently treated with intralesional curettage and bone-grafting. There has been great interest in the use of bone-graft substitutes over the past five to ten years in order to avoid the morbidity associated with autogenous graft harvest. A retrospective study of ninety-eight patients showed that a successful functional outcome can be achieved with use of calcium sulfate-based bone-graft substitutes29. There were no local recurrences in that series, and all of the lesions healed by six months. Giant-cell tumor is an aggressive benign bone tumor that is treated with intralesional curettage whenever possible. Both cement and allograft bone can be used to fill the defect, and the local recurrence rate depends primarily on the thoroughness of tumor removal. Most available series have involved patients in whom cement has been used to fill the subchondral defect. Aponte-Tinao et al., in a study of forty-three patients with a giant-cell tumor around the knee joint, compared cement filling with bone-grafting in terms of their potential effect on joint morbidity30. The defect was filled with cement in twenty-two patients and with allograft in twenty-one. The patients were evaluated clinically and radiographically after a mean duration of follow-up of seven years. There was no difference between the groups with regard to the rate of local recurrence (9%) or the rate of complications, but a significantly higher rate of articular deterioration was noted in the group that received cement (p = 0.019). Prospective series involving larger numbers of patients are needed, but this report signals a potential problem as the majority of patients with giant-cell tumors are less than fifty years old and have a normal life expectancy. If degenerative changes are extensive enough to require a total knee arthroplasty, the presence of a large amount of cement in the subchondral area will present some technical challenges. Fibrous dysplasia is a skeletal disease with a broad spectrum of severity. Patients can have a single focus or multiple sites of disease. Severe skeletal disease in childhood can lead to severe functional impairment in adulthood. Until recently, there was no objective method with which to measure the severity of the disease or to predict functional outcome. In the study by Collins et al., seventy-nine patients with varying disease severity were evaluated with use of bone scintigraphy31. A skeletal burden score was determined on the basis of the amount of fibrous dysplasia in multiple anatomical segments. This score was correlated with bone markers of metabolism to assess biological importance and with survey scores on the Short Form-36 (SF-36) and the Child Health Questionnaire-Parent Form 50 (CHQ-PF50) to assess functional outcome. After extensive analysis, the scores were correlated with the markers of bone metabolism and health-related quality of life (p < 0.001 and p = 0.001, respectively). The measurement of disease severity with use of bone scintigraphy is now a validated and reliable way to predict functional outcome. Multiple hereditary exostoses is a condition that is associated with known genetic mutations in affected patients. A prospective genotype-phenotype study was performed to evaluate the severity of disease and the risk of malignant transformation in 172 patients with this condition32. The assessment of disease severity included an evaluation of stature, the number of lesions, the number of necessary operations related to the lesions, and functional parameters. The assessment of disease severity was performed separately from the molecular evaluation of the genetic mutations. Mutations in the EXT1 and EXT2 genes have been previously described and were identified in 83% of patients in the study. Patients with EXT1 mutations had a significantly worse disease severity than those with EXT2 mutations as well as a higher likelihood of development of a sarcoma. The results of that study suggest a role for routine genetic and radiographic screening of patients with this disease. Large, deep lipomatous tumors often present a challenge to diagnosis, and local outcome depends on the biological characteristics of the lesion. Specifically, patients who have an intramuscular lipoma have a low prevalence of local recurrence compared with those who have an atypical lipomatous tumor. A recent series outlined a role for the routine use of cytogenetics in addition to standard histological analysis to more accurately diagnose and treat these tumors33. The series included fifty-five patients with an intramuscular lipoma and fifty-one patients with an atypical lipomatous tumor. A combined approach involving histological analysis and cytogenetics was performed to classify the lesions. The local recurrence rate was 4% among patients with a lipoma, compared with 27% among those with an atypical lipomatous tumor (p = 0.0006). Significant correlations included a smaller tumor size in the lipoma group (p < 0.00001) and a tendency for atypical lipomatous tumors to occur in the lower extremity (p < 0.0009).
Advances in the area of skeletal metastasis have increased our understanding of the molecular events involved in osteolytic and osteoblastic bone destruction. Research is focused on methods to decrease pain and skeletal events while maintaining function in this patient population. Our understanding of the vicious cycle of bone destruction in patients with metastatic disease has been increased by the work of Guise and Mohammad34. Recently, those investigators identified that tumor-produced endothelin-1 (ET-1) acts through receptors on the osteoblast to stimulate new-bone formation in both metastatic breast and prostate cancers. ET-1 receptor antagonists are currently being investigated in clinical trials involving men with metastatic prostate cancer. Specific downstream targets of ET-1 such as Dickkopf homolog 1 (Dkk1) have been identified to play a role in the bone destruction in patients with multiple myeloma as well as patients with osteoblastic metastases. It is now believed that both osteoblasts and osteoclasts play an important role in osteoblastic metastasis. Mice treated with inoculation of human prostate cancer into bone had a decreased osteoblastic response when treated with both ET-1 receptor antagonists and zoledronic acid (Zometa; Novartis, Basel, Switzerland), a potent inhibitor of osteoclast function.
Zhang et al. came to similar conclusions that prostate cancer metastases
induce both an osteoblastic and osteoclastic response in the
bone35. They
investigated the use of soluble murine RANK-Fc (sRANK-Fc) to block receptor
activator of nuclear factor One of the major challenges in the treatment of skeletal metastasis is the ability to predict the risk of pathologic fracture. Current guidelines are not specific or consistent and are based on plain radiographic measurements of bone destruction, location of the lesion, and pain. Hong et al. performed a biomechanical study to test the ability of quantitative computed tomography and other noninvasive radiographic methods to measure the structural rigidity of cross-sectional areas of bones containing lytic defects and to accurately predict the load-bearing capacity of the bone and the relative fracture risk36. To our knowledge, this was the first study to investigate the effect of defects in trabecular bone as opposed to cortical bone. The results indicated that the structural behavior of the trabecular section of bone was determined by its weakest cross-section. The noninvasive imaging methods used in that study were able to predict fracture risk. Ideally, these algorithms will be used clinically to measure the risk of pathologic fracture and to monitor the response of bone metastasis to systemic or local treatment. It is also difficult to predict the survival of patients with metastatic disease when contemplating surgical intervention for an impending or actual fracture. Schneiderbauer et al., in a study of 299 patients who had a total hip arthroplasty or hemiarthroplasty for the treatment of metastatic disease to the hip, identified factors associated with longer survival times37. The median duration of survival after surgery was only 8.6 months. Only 40% of the patients were alive one year after surgery. The time-interval between tumor diagnosis and surgery (median, twenty-six months) was an independent predictor of survival. Patients with metastatic breast cancer had a longer duration of survival. There was no difference in survival related to patient age at the time of surgery or the presence of postoperative complications. In addition, patients with impending fractures did not survive longer than those with actual fractures. This study provides general guidelines to determine whether the anticipated patient survival exceeds the time required for surgical recovery. It is important to perform definitive surgical stabilization for patients with pathologic fractures around the hip. Patients managed with internal fixation for the treatment of metastatic disease or multiple myeloma have a risk of hardware failure with progression of disease. Jacofsky et al. recently evaluated the results and complications of total hip arthroplasty or bipolar hemiarthroplasty when performed as a salvage procedure following failed internal fixation of a pathologic proximal femoral fracture38. Forty-two patients were reviewed, and fifteen required a proximal femoral replacement as the salvage option because of extensive bone loss or poor bone quality. Patients were followed for a mean of 5.8 years after the salvage procedure, with 90% of the implants surviving for at least five years. Patient function improved from a Harris hip score of 42 points preoperatively to 83 points postoperatively, and the majority of patients had predictable pain relief. The most concerning complication was deep infection; this complication occurred in four patients, corresponding to 21% of the patients who had received prior radiation. Aseptic loosening was not problematic in this group, possibly because of the lower activity demands of these patients. The authors described technical points of these salvage procedures in detail. There is interest in the use of minimally invasive techniques to treat metastatic bone pain. In carefully selected patients, especially those who have had a previous failure of external beam radiation, these procedures may provide an alternative to surgery and may produce long-lasting pain relief. Kyphoplasty and vertebroplasty are now commonly used techniques for patients with osteolytic metastasis to the spine without neurologic compromise. Both techniques can be performed safely, and they yield quick pain relief and an improvement in generic health outcome measures. There is a small risk of cement leakage, but the leakage is usually asymptomatic. Patients can have progressive disease involvement at other vertebral levels; thus, close observation over time is warranted. A recent small study combined the use of vertebroplasty with radiofrequency ablation to destroy the tumor tissue39. The use of radiofrequency ablation for the treatment of metastasis in multiple osseous sites was the subject of a multicenter study40. There was a significant decrease in the worst pain score for forty-one of forty-three patients, beginning four weeks after treatment. Ninety-five percent of patients in that series experienced some measure of pain relief. Another modality that is of potential benefit in the treatment of metastatic spine disease is cyberknife radiosurgery. Cyberknife treatment provides an alternative (1) for patients who are unable to have major surgery, (2) as an adjunct to surgery, (3) for patients who have had previous radiation, or (4) for patients who have radioresistant tumors41. Cyberknife radiosurgery is a minimally invasive procedure that can be performed on an outpatient basis with few side effects. The goal of cyberknife radiosurgery is to totally destroy the tissue within the target volume, so it may provide reasonable local control. This technique is not appropriate for patients with radiosensitive tumors who have not had radiation, those with cord compression and neurologic deficit, or those with spinal instability. Systemic radiation in the form of radioisotope therapy has been used for palliative relief in patients with bone metastases. Isolated series have demonstrated good pain relief, but a recent review of the available randomized, controlled, clinical trials indicated that this method had only a small effect on pain control at short and intermediate-term time-points, with no improvement in analgesic use and a significant prevalence of leukocytopenia (see discussion of the study by Roque et al. in the annotated bibliography). Nonsteroidal anti-inflammatory drugs are recommended for patients with mild to moderate pain resulting from bone metastasis. They are also recommended in combination with stronger opiates for patients with more severe pain. A multicenter randomized, double-blinded study demonstrated that dexketoprofen was safer and more effective for relieving pain than ketorolac was in patients with metastatic bone disease (see discussion of the study by Rodriguez et al. in the annotated bibliography). Finally, the use of bisphosphonates has had a major impact on the treatment of bone metastasis10. Ross et al. recently reviewed the results of thirty randomized, controlled trials to evaluate the effect of oral or intravenous bisphosphonates on skeletal morbidity in patients with metastatic bone disease (see the discussion of this study in the annotated bibliography). The review indicated that bisphosphonates were associated with a significant reduction in all skeletal morbidity end points with the exception of spinal cord compression. These drugs were found to significantly increase the time to the first skeletal event and therefore they should be started when bone metastases are first diagnosed. The findings of the review showed that bisphosphonates must be given for at least six months before an effect on skeletal morbidity is apparent and then continued until no longer clinically relevant. Of note, bisphosphonates do not affect patient survival.
Limb-salvage surgery can be performed in 85% to 90% of patients with malignant bone tumors. Often, it is used in combination with systemic chemotherapy. In this section, new techniques will be discussed and follow-up studies involving the use of existing techniques will be reviewed. The major options for limb reconstruction after bone tumor resection include the use of allografts, vascularized grafts, endoprostheses, or a combination of these materials.
Allograft Reconstruction Patients with bone tumors that require resection of the femoral or tibial diaphysis are ideal candidates for intercalary allograft reconstruction. This procedure provides a biological solution for the reconstruction of segmental defects, especially in young patients with localized disease. Muscolo et al. studied fifty-nine such patients who were managed with intercalary allografts and found that the use of chemotherapy during graft incorporation did not affect allograft survival, although it was associated with a higher rate of nonunion44. The nonunion rate was 9% overall, and the rate was significantly higher for diaphyseal junctions compared with metaphyseal junctions. Nonunions were more common when the allograft was stabilized with an intramedullary rod as compared with a plate. The rate of infection was 5%, which is lower than that in most available series. The allograft fracture rate was 7%, and all fractures occurred in areas of the graft that were not stabilized with internal fixation. The overall rate of allograft survival at five years was 79%. In a related series by the same authors, thirteen patients with a high-grade osteosarcoma underwent transepiphyseal resection of the distal part of the femur or the proximal part of the tibia followed by reconstruction with an intercalary allograft45. There were no local recurrences in the remaining epiphyseal segment after a mean duration of follow-up of sixty-three months. There were three allograft fractures, two diaphyseal nonunions, and one deep infection. This procedure is technically demanding and is associated with a high risk of complications even in the most experienced hands. However, the benefit of maintaining the native joint surface in a young patient is worth the potential complications if safe oncologic guidelines are followed. Careful preoperative imaging is necessary as removal of the malignant lesion with negative margins is of paramount importance. In the future, computer-aided surgery may allow definition of the epiphyseal margin with greater precision. It is often difficult to achieve union at the allograft-host junction because the host tissue must invade the allograft to obtain cortex-to-cortex healing. There is a lack of vascularization and remodeling within the allograft as it contains no live cells. An important study evaluated the role of vascular endothelial growth factor (VEGF) and RANKL in the regulation of angiogenesis and osteoclast-mediated bone destruction in the remodeling of structural allografts46. Intercalary femoral autografts and allografts were used in a mouse model. The authors demonstrated a deficiency of VEGF and RANKL in allografts and showed that blockade of these factors inhibited new-bone formation on the cortical surface of autografts. To evaluate the effect of exogenous VEGF and RANKL on cortical allograft healing, the grafts were coated with freeze-dried recombinant adeno-associated virus (rAAV) combined with each factor. Both resorption and new-bone formation were seen in the rAAV-VEGF and rAAV-RANKL-coated allografts. These results may have important clinical implications as new ways are devised to enhance allograft-host union in patients with large diaphyseal defects.
Vascularized Grafts
Prosthetic Reconstruction The theory of extracortical bone-bridging was evaluated in a study of 339 procedures involving the Stanmore custom rotating-hinge cemented distal femoral prosthesis48. Two hundred and twenty-five procedures were performed with use of a hydroxyapatite-coated ingrowth collar on the femoral stem, and 114 procedures were performed without this collar. The prostheses with a hydroxyapatite-coated collar were associated with a significantly lower risk of revision (p = 0.013). Only one patient who had received a hydroxyapatite-coated collar had revision for aseptic loosening, compared with thirteen patients who had not received such a collar. Examination of the retrieved implants revealed osseointegration of the hydroxyapatite-coated collars. Another study evaluated the results for ninety-nine patients who had been managed with an uncemented Kotz distal femoral or proximal tibial endoprosthesis49. Seven of twenty-five proximal tibial and eleven of seventy-four distal femoral prostheses failed as a result of infection, stem fracture, or aseptic loosening. The rates of infection (10%) and fracture (6.1%) were higher than those in previous reports. The overall actuarial five-year prosthetic survival rate was 77%. Ogilvie et al. evaluated the results of proximal femoral endoprosthetic replacement in thirty-three patients in order to assess postoperative function related to specific methods of abductor repair and the type of acetabular reconstruction50. Function was assessed with use of the Musculoskeletal Tumor Society 1987 and 1993 scores (which are clinician-recorded) and the Toronto Extremity Salvage Score (which is patient-recorded). Nine patients had the greater trochanter attached to the prosthesis, sixteen patients had an abductor soft-tissue repair, and eight patients had no abductor repair. After a mean duration of follow-up of three years, the functional scores were not significantly different among the repair groups or between patients who had a bipolar hemiarthroplasty and those who had a total hip arthroplasty. With regard to separate functional categories, the scores for strength (p = 0.03) and the use of a support (p = 0.031) were significantly better for patients with a soft-tissue abductor repair than for those with no repair. Three patients had repeated dislocations after reconstruction with a total hip arthroplasty. Improvements in soft-tissue reattachment to metal prostheses would allow better function and implant stability. Dickey et al. used a canine supraspinatus tendon model to test biomechanical end points after attachment of the tendon to a tantalum foam metal prosthesis51. Twenty-three supraspinatus tendons were detached and reattached to foam metal at the greater tuberosity. Six weeks after surgery, tendon-implant strength was 99% of normal and construct stiffness was 94% of normal. The muscle volume initially decreased, but 90% of normal volume was recovered by six weeks. These results hopefully will translate to the clinical setting for improved soft-tissue reconstruction in patients after tumor resection around major joints. One of the most exciting innovations of the last decade in the field of musculoskeletal tumor surgery is the development of a noninvasive expandable prosthesis for skeletally immature patients with juxta-articular malignant bone tumors. Gitelis et al. recently reviewed the results for sixteen patients at a minimum of twelve months after the implantation of a Repiphysis prosthesis (Wright Medical Technology, Memphis, Tennessee) in the distal part of the femur or proximal part of the tibia52. This construct uses energy stored in a compressed spring that is locked with a polyethylene sleeve. In an outpatient setting, the patient can control the lengthening while an electromagnetic field releases the locking mechanism. The average age of the patients in that series was 10.7 years. Fourteen patients had fifty-eight lengthening procedures, with an average of 8.5 mm of length being gained per expansion. Complications, which were noted in seven patients, included expansion failure, stem fracture, and infection. An alternative noninvasive expandable prosthesis from Stanmore (Middle-sex, United Kingdom) also works with use of electromagnetic induction but differs from the Repiphysis in that it does not need to be replaced with a standard endoprosthesis at the end of growth.
Future Directions
The editorial staff of The Journal reviewed a large number of recently published research studies related to the musculoskeletal system that received a Level of Evidence grade of I. Over 100 medical journals were reviewed to identify these articles, which all have high-quality study design. In addition to articles published previously in this journal or cited already in this Update, three level-I articles were identified that were relevant to musculoskeletal oncology. A list of those titles is appended to this review after the standard bibliography. We have provided a brief commentary about each of the articles to help to guide your further reading, in an evidence-based fashion, in this subspecialty area.
Upcoming meetings will provide the latest information related to the advances in clinical and basic research of primary bone and soft-tissue tumors and metastatic disease.
International Society of Limb Salvage (ISOLS)
American Society for Bone and Mineral Research (ASBMR)
International Skeletal Society (ISS)
Connective Tissue Oncology Society (CTOS)
Orthopaedic Research Society (ORS)
American Academy of Orthopaedic Surgeons (AAOS)
Rodriguez MJ, Contreras D, Galvez R, Castro A, Camba MA, Busquets C, Herrera J. Double-blind evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and ketorolac in bone cancer pain. Pain. 2003;104:103 -10.[Medline] This article describes a multicenter randomized trial comparing the efficacy and safety of dexketoprofen trometamol and ketorolac in 115 patients with metastatic bone pain. After seven days, the pain rating index was significantly lower for patients who took dexketoprofen. The adverse events were similar in both groups, but a higher percentage of patients taking ketorolac withdrew from the study. A higher percentage of patients and physicians thought that dexketoprofen was quite effective compared with ketorolac. Roque M, Martinez MJ, Alonso-Coello P, Catala E, Garcia JL, Ferrandiz M. Radioisotopes for metastatic bone pain (Cochrane Review). From The Cochrane Library. Issue 1, 2005. Chichester, UK: John Wiley and Sons. The authors reviewed the available randomized clinical trials evaluating the efficacy of radioisotopes to control metastatic bone pain as well as their effect on patient survival and complications. Only four trials met the inclusion criteria, and the results suggested that radioisotopes have a small effect on pain control from one to six months. There was no improvement in analgesic use when patients who received radioisotope treatment were compared with controls. Patients who received radioisotope treatment had a significantly decreased white blood-cell count. This treatment had no effect on spinal cord compression or patient survival. Ross JR, Saunders Y, Edmonds
PM, Patel S, Broadley KE, Johnston SR. Systematic review of role of
bisphosphonates on skeletal morbidity in metastatic cancer.
BMJ. 2003;327:469
. Erratum in:
BMJ. 2004;328:384
. This review of thirty randomized, controlled trials evaluated the effect of oral or intravenous bisphosphonates on skeletal morbidity in patients with metastatic bone disease. In studies lasting for six months or longer, bisphosphonates significantly decreased the risk of fractures, radiotherapy, and hypercalcemia. There was no effect on spinal cord compression or patient survival. Use of these compounds significantly increased the time to the first skeletal event. In studies lasting for more than one year, bisphosphonates significantly decreased the need for orthopaedic surgery. The results of specific trials are discussed, and recommendations for treatment are outlined.
The author did not receive grants or outside funding in support of her research or preparation of this manuscript. She did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.
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Introduction
Malignant Bone Tumors
) decreased both primary tumor growth and the
prevalence of metastatic disease. They described the mechanisms by which
IFN
6 was correlated with a risk of development
of metastasis (p = 0.03). Patients with a 
B ligand (RANKL), a molecule that
stimulates differentiation of osteoclast precursors to osteoclasts.
Immunocompromised mice were managed with injection of human prostate cancer
cells into a subcutaneously implanted segment of human fetal bone. The
osteoblastic response induced on the bone segment in the control group was
significantly (p < 0.05) decreased after treatment with sRANK-Fc. This
compound also decreased the number of osteoclasts, urine N-telopeptide levels,
serum prostate-specific antigen levels, and tumor volume. This molecule
inhibited both the osteoblastic and osteoclastic properties of the prostate
cancer cells, lending further support to the idea that even osteoblastic
tumors require osteoclastic activity in order to progress in bone. 
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