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The Journal of Bone and Joint Surgery (American). 2007;89:1399-1407. doi:10.2106/JBJS.G.00075 © 2007 The Journal of Bone and Joint Surgery, Inc. What's New in Musculoskeletal Oncology1 MD Anderson Cancer Center, P.O. Box 301402, Unit 408, Houston, TX 77230-1402
Specialty Update has been developed in collaboration with the Council
of Musculoskeletal Specialty Societies (COMSS) of the American Academy of
Orthopaedic Surgeons.
This update will focus on the material in the field of musculoskeletal oncology that was published or presented over the past year. However, it should be noted that because musculoskeletal tumors are rare, the majority of the new articles and published research tends to be composed of retrospective or nonrandomized studies.
Osteosarcoma The survival of patients with osteosarcoma has plateaued in the last ten years. In an attempt to improve the overall survival rate associated with the current chemotherapy agents, Wilkins et al. investigated a dose-intensified neoadjuvant intra-arterial chemotherapy regimen in a study of sixty-two pediatric patients with nonmetastatic osteosarcoma1. Intravenous doxorubicin and intra-arterial cisplatin were administered repetitively at three-week intervals until  90% reduction in tumor
vasculature was seen with angiography. Chemotherapy was discontinued once one
of four criteria was met: (1) 90% reduction in tumor vasculature, (2) a
plateau in arteriographic change, (3) no response or progressive disease, or
(4) completion of five neoadjuvant cycles. Patients received an average of
four cycles of chemotherapy. There were no deaths due to chemotherapy
toxicity, but six patients had development of cisplatin burns. Limb-salvage
surgery was performed for 93.5% of the patients. The cisplatin burns were
excised at the time of resection. Eighty-seven percent of the patients had a
good histologic response (90% necrosis). The ten-year Kaplan-Meier
estimate of the overall survival rate was 93.2%, and the event-free survival
rate was 86.4%. The authors acknowledged that an explanation of the improved
survival seen with this protocol is purely speculative. However, these results
offer a new treatment regimen with the available chemotherapeutic agents. This
is particularly promising given the results of both the Italian and
Scandinavian Sarcoma Group and the Cooperative Osteosarcoma Study Group
(COSS), which demonstrated that dose escalation or the addition of different
chemotherapeutic agents does not correlate with better oncologic
outcomes2,3. Most osteosarcoma patients are adolescents; however, it has been noted that the prevalence of osteosarcoma in older patients is increasing4. Several authors have examined the features of osteosarcoma in older patients as well as the outcomes of treatment for such patients. Lee et al. found different radiographic characteristics of osteosarcoma in older patients as compared with adolescents5. The typical features of classic osteosarcoma were not present. Although the location was found to be the same, osteosarcomas in the older population tended to lack periosteal reaction and were associated with small extraskeletal soft-tissue masses. Although significantly lower on the differential than metastatic disease, clinicians should be aware of this varied radiographic appearance of osteosarcoma in the older patient population and should include primary sarcoma of bone in the differential of solitary osseous lesions in adults. Peter Anderson summarized the reaction of medical oncologists to osteosarcoma relapse as "Expect the worst, but hope for the best"6. This sentiment has been reinforced by the studies of several investigators7-9. Chou et al. reported the results for forty-three patients with recurrent and metastatic osteosarcoma8. The median time from the initial diagnosis to the recurrence was 21.7 months. Of the thirty-one patients who received chemotherapy and surgery, 71% were rendered disease-free. However, most patients had an additional recurrence, and only nine of the thirty-one patients remained in long-term remission. Bacci et al. performed a retrospective analysis of the management of and results for forty-four patients who had local recurrence after treatment of osteosarcoma of the extremities with neoadjuvant chemotherapy7. Of the forty-four patients, thirty-seven died of the disease and two were alive with uncontrolled disease at the time of the most recent follow-up. The five-year disease-free survival rate after the last recurrence was 15.9%. These results confirm that patients with osteosarcoma of the extremities who have a local recurrence are at a very high risk of having metastatic disease and dying of the tumor. Grimer et al. reported the outcomes for ninety-six patients who had local recurrence after definitive surgery and chemotherapy9. Treatment of the recurrence varied depending on the disease status of the patient and included surgery, chemotherapy, radiation, or a combination of the three. In the patients without metastases, the overall five-year survival rate was 41%. The presence of metastases at the time of development of the local recurrence conferred a poor prognosis. The optimal treatment for patients with recurrent disease remains an unanswered question. In order to determine whether inappropriate surgical procedures that are based on an initial misdiagnosis affect the recurrence and survival rates among patients with osteosarcoma, several authors examined the outcomes for patients with osteosarcoma who underwent unplanned or erroneous procedures. Ayerza et al. retrospectively identified nine patients who had intralesional curettage on the basis of an erroneous diagnosis of a benign lesion10. These patients had an increased risk of local recurrence (p < 0.0026) and decreased mean five and ten-year survival rates. Jeon et al., in a study of twenty-five patients who underwent intralesional curettage of a primary malignant tumor of bone, found an increased rate of recurrence and reported that the overall disease-free survival rate was 65%11. In both of those studies, the survival and local recurrence rates were adversely affected by a previous incorrect surgical procedure. The authors concluded that careful evaluation of previous surgical intervention and the amount of soft-tissue manipulation should be performed before deciding on limb salvage and the definitive surgical treatment. Platinum-based chemotherapy is an essential component of the current treatment regimen for osteosarcoma in children. Although it is very effective, cisplatin can have major side effects. Knight et al. proposed that the frequency and severity of ototoxicity have been underreported12. After serial audiologic examinations in sixty-seven patients ranging in age from eight months to twenty-three years, those authors reported bilateral hearing loss in 61% of the patients. In addition, they found that toxicity studies have traditionally underreported ototoxicity and minimized the significance of hearing loss in children. The authors argued that hearing loss at frequencies above 2000 Hz is very important in young children and that even minimal losses at these frequencies considerably increase a child's risk for academic difficulties and social and emotional problems. That study further reinforced the need for new treatment options for osteosarcoma. Considerable research has been performed to develop chemotherapy agents that are able to circumvent the mechanisms that are responsible for drug resistance. PNU-159548 is a prototype of a novel class of anthracyclines that has both intercalating and alkylating activities without the cardiotoxic side effects seen with doxorubicin. A recent study has shown it to be effective in both drug-sensitive and drug-resistant osteosarcoma cell lines13. Simultaneous exposure of PNU-159548 and doxorubicin, methotrexate, or cisplatin to drug-sensitive osteosarcoma cell lines resulted in additive or synergistic interactions. The highest in vitro efficacy was seen with sequential administration of the agents. These data suggest that PNU-159548, used alone or in combination with current chemotherapeutic agents, may provide a new treatment option. Several studies have examined the outcome of osteosarcoma treatment to discern prognostic indicators. Alkaline phosphatase has been specifically identified as a prognostic factor by several authors. Bramer et al. examined the prechemotherapy, postchemotherapy, and postoperative values of alkaline phosphatase levels in eighty-nine adult patients with osteosarcoma to determine value for predicting the chemotherapy response and survival14. In accordance with previous studies, the investigators showed that elevated pretreatment alkaline phosphatase levels that are more than twice the normal level are predictive of a worse survival rate. However, the study also showed that the alkaline phosphatase levels after chemotherapy but before surgery were more prognostic. An elevated postchemotherapy alkaline phosphatase level was 100% predictive of a poor response, but a decrease in alkaline phosphatase levels after chemotherapy did not correlate with improved survival unless the levels returned to normal. The data concerning the prognostic significance of HER-2 expression in osteosarcoma patients are rather controversial. Recently, Scotlandi and colleagues assessed the expression of HER-2 in a study of eighty-four osteosarcoma patients and found that overexpression was present in 32% of the patients15. This overexpression was independent of gene amplification. Immunohistochemical analysis also revealed a positive correlation between HER-2 and P-glycoprotein (p < 0.0001). Overexpression of HER-2 and P-glycoprotein at the time of diagnosis was associated with a higher relapse rate and a worse prognosis. Immunotherapy trials were conducted for osteosarcoma during the 1970s. Unfortunately, few trials were successful, suggesting that osteosarcoma cells escape immune surveillance. Tumor cells can lose HLA class-I molecules from their surface and thereby escape recognition by CD8+ T cells. Such a loss has been demonstrated in a number of solid malignant lesions. Tsukahara and colleagues investigated the status of the HLA class-I expression in osteosarcoma specimens16. Thirty-three osteosarcomas were stained with the anti-HLA class-I monoclonal antibody EMR8-5. Loss or downregulation of HLA class-I expression was seen in 52% of twenty-five primary tumors and 88% of metastatic tumors. When HLA class-I expression was correlated with outcome, the patients with osteosarcomas highly expressing HLA class I showed significantly improved overall and event-free survival rates than did those with an HLA class-I-negative osteosarcoma.
Increasing numbers of patients are surviving the diagnosis of cancer. As the number of long-term survivors increases, the prevalence of secondary cancers is increasing. Koshy et al. evaluated the results for 109 pediatric patients with postradiation sarcoma and found that the type of treatment was the most significant factor for overall survival17. The overall five-year survival rate for all patients in the study was 40.2%; however, the overall five-year survival rate for patients who had received both chemotherapy and surgery was 68.3% (p < 0.0001). Shaheen et al. examined the outcomes for twenty-four patients with postradiation sarcoma after a mean duration of follow-up of seventy months18. Of the ten patients with localized disease at the time of diagnosis who were managed with both surgery and chemotherapy, six remained alive with no evidence of disease, three had died of the disease, and one had died of an unrelated cancer after a mean duration of follow-up of seventy months. The estimated five-year disease-free and overall survival rates were 58% and 69%, respectively. The outcome for six patients with localized tumors who were managed with surgery alone was poor. Factors associated with an improved outcome were localized disease, completion of a full course of neoadjuvant chemotherapy, and tumor necrosis.
Another group of investigators evaluated the necrosis rate and oncologic
outcomes for adult and pediatric patients with postradiation osteosarcoma who
had been managed with chemotherapy and surgical resection in the era of
contemporary
chemotherapy19. The
mean amount of tumor necrosis was 63.5%, with seven patients having
Chondrosarcoma remains a challenging tumor to diagnose accurately and treat effectively. Siedel et al. confirmed that the analysis of biopsy specimens of chondrosarcomas is fraught with difficulty and inaccuracy. The greatest utility of the biopsy was found not to be its ability to accurately diagnose the grade of the tumor but to confirm the existence of a cartilage tumor. This finding was also confirmed in the studies by Dodd20 and Rinas et al. 21 Dodd reviewed the institutional experience with the use of fine-needle aspiration as a diagnostic tool for the diagnosis of chondrosarcoma20. The investigator found that the diagnostic accuracy was 67% for primary chondrosarcoma and 86% for recurrent or metastatic lesions. The investigator concluded that fine-needle aspiration is a reliable means of diagnosis of recurrent and/or metastatic chondrosarcoma only in patients with a documented history of chondrosarcoma. Rinas et al. retrospectively reviewed cytology samples from patients with dedifferentiated chondrosarcoma21. In none of the fine-needle aspiration or core-needle specimens were both the low-grade and high-grade components of dedifferentiated chondrosarcoma identified. The authors concluded that sampling error may make the diagnosis of dedifferentiated chondrosarcoma difficult to establish on the basis of cytologic examination alone. Both of those studies confirm that in the diagnosis of chondrosarcoma, clinical and radiographic correlation is essential. The treating physician must be able to use the biopsy information in the context of the radiographs and clinical presentation to manage patients appropriately. To help to delineate radiographically between benign and malignant cartilage lesions, Feldman et al. investigated the role of 18-fluorodeoxyglucose positron emission tomography (FDG-PET)22. They evaluated twenty-nine cartilage lesions and found that a maximum standard uptake value cutoff of 2.0 correlated with the postoperative histopathologic findings and could distinguish benign from malignant cartilage neoplasms. No distinction between chondrosarcoma subtypes nor grade was noted. Although a relationship between outcome and the grade of chondrosarcoma has been well established, controversy still remains with regard to what type of surgical treatment should be performed. There is a trend toward conservative (intralesional) treatment of low-grade lesions within the extremities. Etchebehere et al. demonstrated good oncologic results in a study of twenty-three patients who underwent intralesional resection of a grade-I medullary chondrosarcoma23. Clear-cell chondrosarcoma is a rare neoplasm with a slow clinical course and infrequent metastases. Itala et al. reviewed their experience with sixteen patients with clear-cell chondrosarcomas who were managed at one institution and who had long-term clinical follow-up24. Patients were managed with either resection (ten patients) or intralesional curettage (six patients). The overall ten-year survival rate was 89%, and the ten-year disease-free survival rate was 68%. As with conventional chondrosarcoma, the authors found that inadequate surgical margins increased the risk of local recurrence and metastases. In addition, they noted that clear-cell chondrosarcoma has a tendency to metastasize relatively late; therefore, prolonged follow-up of these patients is necessary. Chondrosarcomas are not considered to be radiosensitive; however, the basis for this resistance is not known. Moussavi-Harami et al. previously identified immortalized human chondrosarcoma cell lines that lacked p16(INK4a), a major tumor-suppressor protein that regulates the cell cycle25. By studying the effects of ectopic p16(INK4a) expression on chondrosarcoma cell resistance to low-dose gamma irradiation (1 to 5 Gy), they found that p16(INK4a) expression significantly increased radiation sensitivity in clonogenic assays. These results suggest that the absence of p16 expression may contribute to the radiation resistance of chondrosarcomas and that the restoration of p16 expression may improve the radiation sensitivity of chondrosarcoma. In an effort to increase the radiosensitivity of chondrosarcomas, Rhomberg et al. investigated the radioresponsiveness of chondrosarcoma after the administration of the radiation-sensitizing agent, razoxane26. Thirteen chondrosarcomas were irradiated with a median tumor dose of 60 Gy. Razoxane was given at a dose of 125 mg twice daily, starting five days before the irradiation. Among the eight patients who had unresectable or recurrent disease, there was one complete response, five partial responses, and two tumors that remained unchanged. The study was limited by the fact that there was no control group with which to compare the response; however, the results suggested that a prospective, randomized trial would be beneficial to further evaluate the possible role of razoxane as a chondrosarcoma radiosensitizer. The optimal treatment for dedifferentiated chondrosarcoma is still under discussion. Adjuvant chemotherapy and surgical resection of the tumor with wide margins is recommended; however, several authors have questioned whether this approach is effective. Bruns et al., in a report on thirteen patients with dedifferentiated chondrosarcoma, pointed out that it is unclear whether a radical resection improves long-term results as the mean survival time in their study, similar to those previously reported in the literature, was 9.7 months27. In addition, Staals et al., in a retrospective study of 123 patients with dedifferentiated chondrosarcoma, found that there was no beneficial effect from adjuvant chemotherapy28. The two and five-year survival rates were 34% and 24%, respectively. Although these results are similar to those reported by Dickey et al.29, the study by Staals et al. was limited by the fact that it was retrospective and included a relatively small group of patients who actually received chemotherapy. In addition, the chemotherapeutic regimens were not standardized. Therefore, further investigation is needed to define the exact role of chemotherapy in the treatment of these rare sarcomas.
The development of therapeutic strategies that exploit tumor-specific biological mechanisms is at the frontier of cancer medicine. In the Ewing family of tumors, many investigators have concentrated on understanding the mechanisms through which EWS/FLI-1 possesses transforming activity and its role in tumorigenesis. Therapeutic approaches that target EWS/FLI-1 proteins may be valuable strategies for the treatment of Ewing sarcoma. Investigators have hypothesized that treatments that combine an mRNA-targeting strategy, such as using antisense oligonucleotides, with another approach that targets the protein product of the same gene not only would result in the suppression of gene expression but also would circumvent the need for high dosages with either individual treatment, thus minimizing the possible toxicity to normal cells. Mateo-Lozano et al. found that the concurrent administration of EWS/FLI-1 antisense oligonucleotides and rapamycin, a macrolide antibiotic that inhibits mTOR (a serine/threonine kinase that regulates translation and cell division) induced the apoptotic death of Ewing cells in culture and the combined in vivo treatment caused a significant inhibition of tumor growth in mice. These results provide the basis for a novel strategy for the treatment of Ewing sarcoma30. Although it is known that the fusion proteins EWS/FLI-1 are responsible for the malignant phenotype of Ewing sarcoma, only a few of their transcriptional targets are known. Using a variety of methods, investigators have shown that caveolin-1 (CAV1) is overexpressed in Ewing sarcoma cell lines and tumor specimens, is a new direct target of EWS/FLI-1, and is necessary for ESFT tumorigenesis31. Loss of CAV1 expression inhibited the anchorage-independent growth of Ewing sarcoma cells and markedly reduced the growth of Ewing sarcoma cell-derived tumors in nude mice xenografts. In addition, the reexpression of CAV1 knockdown Ewing sarcoma cells rescued the oncogenic phenotype of the original Ewing sarcoma cells. These results indicated that CAV1 is a factor in promoting the malignant phenotype in Ewing sarcoma. CAV1 may be a candidate for the development of targeted therapy for these patients.
Soft-tissue sarcomas are a rare and heterogeneous group of neoplasms that are often difficult to definitively classify. In addition to, and complementing, the traditional diagnostic methods of examination of hematoxylin-eosin stained slides and immunohistochemistry, additional cytogenetic and molecular biologic methods are being increasingly utilized and relied upon in sarcoma pathology. A current review of these methods is available32. Understanding the basis of these methods and their application is critical to providing more accurate and validated specific diagnoses of soft-tissue sarcomas. The recently developed technique of DNA microarray analysis permits simultaneous measurement of the expression level of thousands of genes. It has the ability to highlight important pathways and to potentially identify diagnostic markers and therapeutic targets. Recently, this technology has been applied to soft-tissue sarcomas. Subramanian et al. examined the gene expression profile of extraskeletal myxoid chondrosarcoma and identified eighty-six genes that distinguished extraskeletal myxoid chondrosarcoma from other sarcomas33. The five top genes in their analysis were NMB, DKK1, DNER, CLCN3, and DEF6. In situ hybridization for NMB gene expression on tissue microarrays showed that it was highly expressed in seventeen of twenty-two cases of extraskeletal myxoid chondrosarcoma and was very rarely expressed in other tumors. Thus, the authors hypothesized that NMB could function as a novel diagnostic marker for this particular tumor. High levels of expression of PPAR  and the gene
encoding its interacting protein, PPAR C1A, were also identified. This
finding suggests that the activation of lipid metabolism pathways is present
in extraskeletal myxoid chondrosarcoma and that small-molecule inhibitors for
PPAR may be a treatment option. Despite advances in the treatment of local disease, distant metastases remain the predominant cause of death in patients with synovial sarcoma. In an attempt to find a candidate for targeted therapy, Thomas et al. assessed thirty-eight synovial sarcoma specimens for epidermal growth factor receptor (EGFR) and HER-2/neu protein expression with use of standard immunohistochemical techniques34. EGFR and HER-2/neu protein were detected by means of immunohistochemistry in 55.3% and 52.6% of the synovial tissue specimens, respectively. Coexpression was observed in 34.2% of specimens. The authors concluded not only that EGFR and HER-2/neu expression may be an important molecular event in the oncogenesis of synovial sarcoma but also that the receptors may represent viable candidates for targeted therapy. Radiation therapy is a common adjuvant for the treatment of soft-tissue sarcomas. Intraoperative radiation is often given immediately before or after limb-sparing surgery to treat locations that potentially harbor residual disease. Preoperative and postoperative radiation and the complications associated with their administration have been well studied. However, the ramifications of single-fraction, high-dose intraoperative radiation have only been recently examined. Two groups recently evaluated these effects after limb salvage35,36. Oertel and colleagues, in a retrospective study, examined the effects of intraoperative radiation after limb salvage followed by postoperative external beam therapy36. Acute toxicity was observed in 23% of the patients and included wound-healing problems (prevalence, 17%), severe skin reactions (4%), and perioperative thrombosis (2%). Late toxicity occurred in 17% of the patients and included neuropathy (prevalence, 5%), joint contracture/fibrosis (5%), radiation necrosis/ulcer/fistula (3%), and severe chronic lymphedema (4%). Tumor size, patient age, and external beam radiation dose did not significantly affect outcome. Resection status and grade were significant prognostic factors for survival, and resection status and intraoperative radiation dose were significant prognostic factors for local control. Kunos et al., in a retrospective study, evaluated whether single-fraction, high-dose intraoperative radiation at the time of surgery affected the surgical outcome in patients who also had preoperative or postoperative radiation35. There was no significant difference between the groups with respect to the frequency of early wound complications (defined as those occurring less than ninety days postoperatively) or late wound complications (defined as those occurring more than ninety days postoperatively). Both of those studies support single-fraction, high-dose intraoperative radiation as a viable adjuvant treatment to limb-salvage surgery and external beam radiation.
Giant-cell tumor of bone accounts for 5% of all primary tumors of bone. The current standard treatment for giant-cell tumor of bone is curettage and cementation or bone-grafting. Adjuvant therapies have been shown to decrease the rate of recurrence of giant-cell tumors. In a recently published study evaluating the efficacy of argon beam coagulation as an adjuvant for the treatment of giant-cell tumors, the authors found that the patients had a good to excellent functional outcome after a mean duration of follow-up of seventy-three months37. The five-year recurrence-free survival rate was 87.2%. Several authors have suggested that, in terms of recurrence, it does not matter which adjuvant is employed38,39. That study showed that argon beam coagulation can be another adjuvant option. Giant-cell tumor of bone is a locally aggressive lesion that has the propensity to metastasize. At the present time, there are no reliable predictors of recurrent or metastatic disease in cases of giant-cell tumor. In an attempt to identify a clinically relevant molecular marker, investigators performed array comparative genomic hybridization on twenty frozen tumors and showed that 20q11.1 is frequently amplified in giant-cell tumor. They also correlated the presence of 20q11.1 with the development of metastatic disease. Thus, 20q11.1 may serve as a prognostic marker of adverse events associated with giant-cell tumors. The clinical presentation of polyostotic fibrous dysplasia is extremely varied. There is substantial variation between patients in terms of orthopaedic manifestations, including the number of fractures, the degree of deformity of the limbs, and the presence of scoliosis. There are no clear treatment guidelines, and thus the orthopaedic surgeon has to make treatment decisions on a case-by-case basis. Leet et al. evaluated a group of young patients with polyostotic fibrous dysplasia to see if there was any correlation between function, disease burden, and deformity40. With use of the Pediatric Outcomes Data Collection Instrument, the authors found that the loss of the normal femoral neck-shaft angle and the disease burden in the lower extremities had the greatest effect on functional activity. Preserving the neck-shaft angle may improve the functional outcome for these patients. Osteogenesis imperfecta is caused by a defect in collagen-I synthesis. Otherwise known as brittle bone disease, osteoporosis is a common sequela. In an attempt to combat the osteoporosis and decrease the risk of fracture, many children have been managed with bisphosphonate therapy. The effect of an oral bisphosphonate in children was evaluated in a randomized, double-blind, placebo-controlled trial41. Thirty-four children with osteogenesis imperfecta were randomized to receive olpadronate or placebo and were followed for two years. Children were assessed with regard to the number of fractures, bone mineral content, bone density, and function. Compared with the placebo group, children in the olpadronate group had a reduction in the risk of fracture of the long bones as well as a greater increase in bone mineral content and bone density. However, there were no detectable effects on functional outcome or vertebral height. Although that study showed that the use of bisphosphonates will decrease the risk of fracture, how its use will affect osteogenesis imperfecta in the long term remains to be investigated. Investigators also evaluated the use of bisphosphonates to prevent early collapse in patients with osteonecrosis of the femoral head. Many young adult and pediatric survivors of solid tumors and hematopoietic malignancy have development of osteonecrosis as a sequela of the disease and its treatment. Lai et al. identified forty patients with Steinberg stage-II or III nontraumatic osteonecrosis of the femoral head42. Patients were randomly divided into a bisphosphonate treatment group (alendronate) and a control group (no treatment). Patients were evaluated radiographically every ten weeks. In the control group, twenty patients had progression of disease, with nineteen hips having collapse of the femoral head; however, in the bisphosphonate group, only four hips had progression, with two of the four having collapse of the femoral head. That was not the first study to conclude that use of a bisphosphonate will retard osteonecrosis, but as a prospective, randomized study it served to confirm the results of an earlier prospective open-label trial43. However, long-term follow-up is needed to ascertain whether bisphosphonate therapy prevents or simply retards the progression of osteonecrosis.
The five most common carcinomas that metastasize to the bone are breast, kidney, lung, thyroid, and prostate. A considerable amount of work is being done to combat skeletal metastases. In order to decrease skeletal events and improve patient outcomes, investigators are exploring both clinical and preclinical strategies to inhibit the growth of bone metastases. Bone metastases in non-small-cell lung cancer are associated with a worse prognosis. Unfortunately, there are no predictive or diagnostic markers to identify the patients who are at high risk for metastatic bone disease. In an attempt to identify prognostic markers, Papotti et al. compared the clinicopathologic parameters for thirty patients with resected non-small-cell lung cancer who had subsequent development of bone metastases with those for thirty control patients with resected non-small-cell lung cancer who did not have any metastases and twenty-six patients with resected non-small-cell lung cancer and non-bone metastatic lesions44. Primary tumors were investigated with immunohistochemistry studies for ten markers involved in bone resorption or the development of metastases. The presence of bone sialoprotein was strongly associated with the development of bone metastases and, independently, with worse survival outcome. To allow for the evaluation of bone sialoprotein expression in non-small-cell lung cancer as a whole, a series of 120 consecutive resected lung carcinomas was added to the study, and the bone sialoprotein prevalence reached 40%. The authors concluded that bone sialoprotein expression in non-small-cell lung cancer could be useful for identifying high-risk patients and thus alerting the clinician to the need for careful surveillance and preventive treatment. Similarly, Brown et al. investigated whether alkaline phosphatase and N-telopeptide (markers of bone formation and the bone resorption, respectively) had prognostic significance for bone metastases secondary to prostate cancer and non-small-cell lung cancer45,46. With use of patients from the placebo arm of two phase-III trials on zoledronic acid, the levels of urine N-telopeptide and serum alkaline phosphatase were assessed every three months. Patients were monitored for skeletal events, bone disease progression, and death. In each disease group and in the overall group, high levels of each marker at the beginning of the study were significantly associated with an increased risk of negative outcomes. After long-term follow-up, high N-telopeptide levels were associated with an increased risk of skeletal events and were a better predictor of negative outcomes than alkaline phosphatase levels were. This study45 suggests that N-telopeptide can be used as a prognostic indicator. The monitoring of N-telopeptide urine levels may provide a method for alerting the physician to which patients are at risk for the development and progression of osseous metastases. The early diagnosis and treatment of bone loss and bone metastases with bisphosphonates has become common in patients with metastatic carcinoma. Clemons et al. prospectively evaluated the efficacy of zoledronic acid as a second-line agent in patients who had already received first-line therapy for metastatic breast cancer with another bisphosphonate (pamidronate or clodronate)47. By the eighth week of treatment, patients experienced a significant decrease in pain. That study was the first to demonstrate that patients with either progressive bone metastases or skeletal events while receiving clodronate or pamidronate can obtain palliative benefits with a switch to the more potent bisphosphonate, zoledronic acid. Although the question would benefit from examination in a prospective, randomized trial, these findings have significant implications related to the use of bisphosphonates in the cancer population. Radiation therapy is an effective way to palliate symptoms resulting from osseous metastatic disease. A wide variety of dose schedules have been used, varying from one fraction of 6 to10 Gy to multiple fractions, most often 30 Gy delivered in ten fractions. Several groups have performed prospective, randomized, controlled studies to investigate whether single-fraction radiation therapy is equal to multiple fractions for the treatment of painful metastases. In a study by Kaasa et al., 376 patients were prospectively randomized to single or multiple-fraction radiation therapy48. The treatment groups had similar outcomes. Both groups experienced similar pain relief within the first four months, and this was maintained throughout the follow-up period. No differences were found in terms of fatigue or global quality of life, and the rate of survival was similar in both groups. The conclusion of that study was confirmed by the findings of the Dutch Bone Metastasis Study, in which 320 prospectively enrolled patients were randomized to receive a single fraction of 8 Gy or a total of 24 Gy in six fractions for painful bone metastases49. The investigators concluded that single-fraction radiation therapy should be the standard dose schedule for all patients with painful bone metastases, including patients with an expected favorable survival49. They based their conclusion on the fact that among the 320 patients surviving more than fifty-two weeks, the duration of the response and the rate of progression were similar between the two groups. Sze et al. performed a systemic review and meta-analysis of the randomized trials comparing single fraction and multiple-fraction radiation therapy for the palliation of metastatic bone pain50. They identified eleven trials involving 3435 patients; the two trials discussed above were not included in their analysis. The study revealed that there was no significant difference between single-fraction radiation therapy and multiple-fraction radiation therapy in reducing the overall pain response; however, there were higher percentages of pathological fracture and the need for retreatment in the group of patients who received single-fraction dosing. Thus, although single-fraction therapy may be as effective for relieving pain as multiple-fraction therapy, the increased incidence of pathological fracture and need for retreatment may render it less economically feasible in term of health-care dollars and patient outcome.
Allograft Reconstruction The use of structural cadaveric allografts for reconstruction of large bone defects after tumor resection is a common treatment option. However, for clinicians who do not have a ready supply of allografts, there is the option of reimplanting the autoclaved tumor-bearing bone. Khattak et al. recently investigated whether these autografts would provide a viable reconstructive option51. The investigators examined the outcomes for nineteen patients who had had wide excision followed by reimplantation of the resected bone after it had been autoclaved at 120° for ten minutes. The most common complication was infection. The autoclaved osseous segment united with the normal bone in eleven of the twelve patients at a median of 24.2 months. No patient had fracture or resorption of the autoclaved fragment. The authors concluded that reimplantation after autoclaving resected bone is a cost-effective alternative when allografts are not readily available. Careful patient selection is required, however, so as not to reimplant structurally unsound bone. Alloprosthetic composite reconstruction has become a valuable option after resection of the proximal part of the femur, the proximal part of the tibia, and the proximal part of the humerus. Not only does it restore bone stock, but it provides a biologic anchor for attachment of the host tendons. Thus, these reconstructions have the potential for improved functional outcome when compared with reconstruction with an endoprosthesis. In a recent study in which fifty-two patients who had a proximal femoral endoprosthetic reconstruction were compared with twenty patients who had an alloprosthetic composite reconstruction, the median abduction strength was better for the patients who had the allograft-prosthetic composite reconstruction52. Furthermore, more patients who had the alloprosthetic composite could walk without assistance and without a limp.
Curettage and cementation with polymethylmethacrylate is the mainstay of treatment for giant-cell tumor. Often, thorough curettage results in a large defect and the polymethylmethacrylate reconstruction is augmented with Steinmann pins or screws. A cadaveric biomechanical study was performed to determine whether augmenting the cement with crossed screws would result in a stronger reconstruction than one in which the cement was augmented with Steinmann pins53. The specimens were subjected to 2000 compressive cycles and were subsequently monotonically loaded to failure under a controlled displacement rate. The authors found that the femora that were reconstructed with crossed screws and cement failed at higher loads and had greater stiffness than those that were reconstructed with cement alone (p = 0.025 and p = 0.0007) or cement augmented with intramedullary Steinmann pins (p = 0.019). In addition, the fracture geometry was different. The femora that were reconstructed with cement and crossed screws fractured through the extra-articular segment, whereas the femora that were reconstructed with cement alone or with cement with Steinmann pins fractured through an intra-articular portion of the bone. Thus, augmentation of the polymethylmethacrylate with crossed screws may provide a better reconstructive option for large cavitary lesions of the distal part of the femur than cementation or cementation with Steinmann pins.
Endoprosthetic reconstruction is a reliable method for the treatment of skeletally mature individuals who have undergone resection of a juxta-articular tumor. It provides an anatomic cosmetic appearance, rapid restoration of function, and good-to-excellent functional results. However, cemented megaprostheses have been associated with the intermediate to long-term problems of infection, mechanical breakage, and aseptic loosening, which ultimately lead to failure. Technology has been developed in an attempt to eliminate the problem of aseptic loosening associated with massive endoprosthetic reconstruction. The Compress prosthesis (CPS; Biomet, Warsaw, Indiana) achieves immediate, high-compression fixation at the host-prosthesis junction that not only induces bone hypertrophy and thus avoids stress shielding but that also seals the medullary canal from particulate debris, thus potentially decreasing the risk of aseptic loosening. Bhangu et al. compared twenty-six distal femoral Compress prostheses with twenty-six matched cemented distal femoral endoprostheses54. At two years of follow-up, no significant difference could be found between the two groups with regard to infection, implant failure, or aseptic loosening. These results, although preliminary, suggest that the Compress press-fit prosthesis implant, in the short-term, is safe and effective when compared with conventional stems. However, long-term follow-up is needed to assess whether it meets its objective and is truly associated with a decrease in aseptic loosening and late device failure. In another study, forty-four consecutive patients who had uncemented proximal tibial prostheses were evaluated to determine the risk of aseptic loosening55. Twelve patients had fourteen complications leading to prosthetic failure; however, after a mean duration of follow-up of sixty months, there were no cases of aseptic loosening. Thus, that study indicates that the use of an uncemented proximal tibial prosthesis may decrease the risk of aseptic loosening and ease revision if needed for the treatment of infection. A recent study examined the prevalence of patellar complications following distal femoral resection and endoprosthetic reconstruction56. The authors retrospectively examined the results for forty-three patients who had had reconstruction of the knee with use of a rotating-hinge endoprosthesis after resection of the distal part of the femur. Sixty-three percent of the patients had patellar complications. The two most common patellar complications were patella baja and patellar impingement; however, patella alta, osteonecrosis, fracture, dislocation, loosening of the patellar component, patellar pain requiring revision, and avulsion of the patellar tendon were also documented. The authors suggested that restoration of the normal anatomic joint line may help to prevent abnormalities of the patella and patellar tendon. To do this, they recommended careful measurement of both the resected specimen and the tibial plateau resection. In addition, the calculation of the length of the prosthetic reconstruction must include the length of the tibial tray and polyethylene as well as the distal femoral prosthesis. Intensive physical therapy and surveillance of the patellar tendon length may help to prevent patellar tendon contracture postoperatively, and this may in turn prevent patella baja, a relatively common complication.
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Introduction
Malignant Bone Tumors
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