Abstract
Biologics serve a unique role in the management of musculoskeletal oncology. While most of the field of biologics in orthopedic surgery focuses on injury repair, biologics in oncology can potentially serve as life-saving and tumor-altering therapeutics. We present a brief review of some of the more exciting advances in musculoskeletal oncology using biologics, specifically in giant cell tumor and sarcoma therapy. We also focus on the use of biologic augmentation in the repair of both small, contained bone defects and massive bone defects after tumor resection.
Keywords
Benign, Biologic, Bone, Malignant, Musculoskeletal, Tumor
Targeted Therapies in Orthopedic Oncology
As we continue to learn more about the pathophysiology of bone and soft tissue neoplasms, we are presented with new molecular targets for treatment. No chapter on the use of biologics in musculoskeletal oncology would be complete without a discussion of the use of biologics to treat these tumors. Targeted therapies, which use normal biology to manipulate pathologic genes and proteins, are evolving as an alternative to traditional cytotoxic chemotherapy.
Denosumab Treatment of Giant Cell Tumor of Bone
Giant cell tumor of bone (GCTB) is characterized as a benign, yet locally aggressive, tumor that can result in significant osteolysis and destruction of bone. Previous research has demonstrated that the neoplastic cells responsible for GCTB have roots drawing from aberrant and incomplete differentiation of mesenchymal stem cells along the osteoblast lineage. The histology is characterized by layers of mononuclear cells with high Receptor activator of nuclear factor k-beta (RANK) ligand (RANKL) expression, RANK-positive mononuclear cells of myeloid lineage, and large osteoclast-like giant cells which also express RANK. Each of these histologic features of GCTB makes denosumab an ideal treatment strategy. Denosumab is a human monoclonal antibody that specifically binds to RANK ligand. This provides therapeutic benefit by targeting the two physiologic pathways responsible for the aggressive osteolytic process: (1) reducing the number of RANK-positive giant cells and (2) reducing the number of mononuclear stromal cells that overexpress RANKL, which some authors believe is the true neoplastic cell in GCTB.
Early clinically trials, although small in size, show promising results. One previous cohort study evaluating denosumab treatment for GCTB found no disease progression in 96% (163/169) patients with surgically unsalvageable disease treated only with denosumab. The same study also found that of 100 eligible patients planned for surgical intervention, 74% did not need to undergo surgery after treatment, and of those remaining, 62% underwent a significantly less morbid procedure.
Tyrosine Kinase Inhibitors for Sarcoma
Recent advances in oncologic research have identified angiogenesis as a common pathway, critical in the growth, invasion, and subsequent metastases of multiple tumor types. Multiple growth factors are implicated in both the normal physiologic as well as pathologic processes. The importance of Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) has been identified as these growth factors initiate a cascade of intracellular signaling that culminates in the stimulation of endothelial cell proliferation, migration, and inhibition of apoptosis. This signaling process occurs through binding the external component of a transmembrane receptor linked to an intercellular tyrosine kinase, which initiates the aforementioned cascade of cellular events.
In sarcomas the interaction between VEGF and its tyrosine kinase receptor has recently been shown to be critical in tumor progression. These growth factors have also demonstrated their utility as prognostic indicators, with higher serum levels of VEGF strongly correlated with the poorest differentiated soft tissue sarcomas, and specifically in leiomyosarcoma, higher levels are associated with worse prognosis and shorter survival. As a result of these findings, the VEGF tyrosine kinase receptors have emerged as a key target in the development of new anticancer agents within the “cancer cell”–specific therapies. Initial clinical studies evaluating the efficacy of pazopanib in the treatment of soft tissue sarcomas have encouraging early results. A recent phase III trial demonstrated a significant improvement in progression-free survival in patients receiving pazopanib compared with placebo, yet no difference in overall survival was detected in the study. In light of these findings, the FDA approved the use of pazopanib for treatment of patients with advanced soft tissue sarcomas who have previously received chemotherapy. Although these early medications are still in the infancy of their development, they serve to highlight the critical clinical significance of these proangiogenic tyrosine kinase receptors and their potential as therapeutic targets to impair and inhibit progression of tumor grown.
Void Fillers for Benign Bone Tumors: What Are the Clinical Results?
Management of symptomatic benign bone tumors and tumor-like lesions typically requires excision and curettage of the entire lesion. This leaves behind an often-sizable defect in the bone, which must be filled to restore mechanical integrity and structural support of the affected bone. The gold standard has long been autologous bone grafting, often from the iliac crest. However, this provides additional morbidity away from the primary surgical site, with complication rates reported from 8% up to 13% from graft harvest alone, and offers a finite, and at times, insufficient amount of graft to fill the defect.
Alternative methods to fill these defects have been developed, which include allograft bone chips, polymethylmethacrylate (PMMA) bone cement, and synthetic bone substitutes. Allograft avoids the problems associated with donor site morbidity but provides no immediate mechanical stability. Additionally, resorption of allograft bone chips can be difficult to discern from tumor recurrence. Filling defects with PMMA bone cement has the advantage of providing immediate mechanical stability while also serving as an adjuvant treatment through thermo-necrosis of remaining superficial tumor cells. However, PMMA does not preserve bone stock and does not allow for any bony ingrowth. To help overcome the shortcomings of each of these methods, the use of synthetic bone graft substitutes for defects after tumor excision has been proposed.
Multiple variations of calcium products are currently commercially available to fill bone defects after tumor surgery, including calcium hydroxyapatite (HA), calcium phosphate, and calcium sulfate. A series of 60 patients with benign bone tumors treated with curettage and grafting using calcium HA ceramic chips identified good outcomes with no local recurrences, yet three patients sustained a major complication in the form of a pathological fracture. More recently, Yamamoto et al. evaluated a series of 75 patients using calcium HA with tricalcium phosphate. The group found that HA was incorporated into the healing bone at a mean of 4.2 months. However, despite excellent incorporation, there was never resorption of the synthetic graft, and a 9% complication rate was still encountered.
In contrast to calcium HA or calcium phosphate, calcium sulfate resorbs at a rate that keeps pace with the rate of new bone formation through the process of creeping substitution. In addition, the subsequent trabecular bone that grows into the prior defect has been shown to be histologically equivalent to the trabecular bone formed from the current gold standard, autogenous bone graft. A prospective multicenter trial assessing use of calcium sulfate as a bone graft substitute found 99% resorption at 6 months, and 88% of the defect filled with trabecular bone. While this trial included patients with defects attributable to trauma, revision arthroplasty, and fusion supplementation, a subset of 46 benign bone tumors showed identical results.
For treatment of enchondromas of the hand, clinical studies have demonstrated good functional outcomes and minimal recurrence with calcium phosphate, HA, and sterile plaster of Paris. Pianta et al. evaluated the mechanical strength of different void filler substitutes using a biomechanical model for enchondromas in the hand. The study found that two separate calcium phosphate bone cements provided excellent structural support and immediate restoration of mechanical stability almost comparable to that of an intact metacarpal bone. In contrast, the demineralized bone matrix added no additional stability to an empty bone cavity, which weakened the bone to 70% of its initial strength. The authors concluded that use of calcium phosphate bone cements may allow early range of motion in the hand and prevent potential complications due to stiffness and postoperative immobilization.
Overall, although autogenous bone graft remains the gold standard, the advances in recent void filler substitutes has provided an alternative method that avoids potential donor site morbidity and complications while also bypassing difficulties encountered due to the limited quantity of available autograft. However, these potential benefits must be weighed against the disadvantages. The current synthetic fillers are osteoconductive only without the osteoinductive properties seen with autogenous bone graft and provide an added financial cost that would otherwise be spared.
Osteoarticular Allografts: Still an Option?
Osteoarticular allografts have been used since the 1970s for limb-sparing reconstructions when the tumor resection requires complete resection of the native articular surface. This technique allows for the preservation of a biologic articular surface without necessitating an endoprosthesis. Osteoarticular allografts have provided overall acceptable functional outcomes in the literature, with reported Musculoskeletal Tumor Society (MSTS) scores ranging from 70% to 91%. Advantages of this technique include the ability to directly reattach a patient’s preserved native tendons and ligaments, which may increase strength and overall stability of the joint. Furthermore, the use of osteoarticular allografts allows for bone preservation that becomes increasingly more important in younger patients, who likely require at least one to two revisions during their lifetime.
In addition, the advantages of an osteoarticular allograft are also largely impacted by the anatomic site that is reconstructed. Joints with extensive soft tissue, tendon, and ligament attachments can take advantage of the retained soft tissue attachments on the allograft for added stability and function. In particular, osteoarticular allografts of the proximal tibia allow for reconstruction of the extensor mechanism. In contrast, a location such as the distal femur with few soft tissue attachments does not derive the same benefit.
However, the risk of failure and overall complications with the use of these grafts remains high, with overall complication rates ranging from 40% to 70%. A long-term study by Toy et al. found complications in 19 of 26 patients undergoing distal femoral osteoarticular allografts, which required 30 additional surgical procedures. Of note, 73% of these secondary surgeries occurred in the first 5 years after surgery. Mankin et al. reviewed their use of osteoarticular allografts in 386 patients over 24 years, finding good-to-excellent results in 73% of patients. The study also brought out the critical period in the lifespan of an allograft replacement. If an allograft survives past the increased risk of infection in the first year after implantation of 10% and 19% risk of fracture in first 3 years, they became stable with 75% retained for more than 20 years. Stability with 5- and 10-year survival has also been reported for distal femoral, unicondylar (femur & tibia), and proximal tibial allografts as 78%, 85%, and 65%, respectively.
Unfortunately, complications are not an infrequent occurrence in allograft reconstruction, with overall complication rates in up to 52% of patients. While the risk of fracture is the most common complication, infection can be far more devastating. In one series, despite infection in only 11% of patients, graft infection accounted for 43% of overall graft failures. As the most common complication, fracture risk is highest when intramedullary nail fixation is used, and this risk may be mitigated by instead providing stability with plate fixation. Fracture risk may be further reduced with a dual plating technique to provide greater stability at the allograft-host bone interface. However, this often requires greater soft tissue dissection and may increase the risk of graft or hardware infection.
There are also concerns over the potential viability of cryopreserved articular cartilage. Enneking and Campanacci performed a histological examination of the articular cartilage in their allografts, finding that 86% had no viable chondrocytes within 5 years. A series by Toy et al. evaluating distal femoral osteoarticular allografts found that 31% of patients required further surgery as a result of joint deterioration at a mean of 7.2 years. While this is a relatively large proportion of patients requiring secondary surgery before 10 years, it is a known and expected late complication of this procedure. Similarly, Mankin et al. found that 16%–20% of the surviving osteoarticular allografts required total joint arthroplasty, and Ogilvie found 25% conversion to arthroplasty at a mean of 6.6 years.
Alternative Techniques
Articular sparing resections & implants
Recent advances in computer navigation–assisted surgical procedures have allowed surgeons to push the envelope with resection margins in ways that were previously not possible. There is little room for error with respect to surgical margins as recurrence rates are directly related to the adequacy of resection. In addition, as tumor proximity approaches even closer to the physis and articular margin, navigation can help allow for retention of maximal bone stock to allow for preservation of the native joint and even maintain ability for growth. Initial reports demonstrate excellent accuracy of the navigated resection and no major complications. However, more long-term studies are needed to further evaluate these techniques before their widespread use.
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