What’s New in Musculoskeletal Tumor Surgery

This past year, the musculoskeletal tumor surgery literature kept up with the rapidly increasing publication volume in the medical literature. Among the thousands of publications in our field, we highlight a chosen few in this Guest Editorial. We are excited to present remarkable collaborations and exciting innovations. Although the majority of research continues to be retrospective, unique approaches are being developed and international cohesion is apparent by the worldwide collaborations and sharing of prospective data sets. Molecular approaches to diagnosis and treatment have made incremental steps forward, and the use of machine learning in prognosis and diagnosis continues to make strides. Finally, surgical approaches to bone and soft-tissue tumors are becoming better understood through large case series. Soft-Tissue Sarcoma Prognostic Prediction Models Recent research has emphasized the crucial role of advanced diagnostic tools and methodologies in improving the prognosis and management of soft-tissue sarcomas. Marques et al. explored how magnetic resonance imaging (MRI) can predict the histological grade of soft-tissue sarcomas, suggesting that MRI features can provide valuable preoperative insights, potentially guiding treatment strategies1. Similarly, Kim et al. explored DNA methylation profiling as a means to classify histologic subtypes and grades in soft-tissue sarcomas2. Their findings indicate that this molecular approach can complement traditional histopathological evaluation, enhancing diagnostic accuracy and personalized treatment planning. Survival prediction models are also gaining attention. Yeramosu et al. developed a model to predict 5-year mortality in patients with soft-tissue sarcoma, emphasizing factors such as tumor size, patient age, and histological grade3. Kamalapathy et al. introduced a machine learning algorithm specifically for predicting 5-year survival in patients with soft-tissue leiomyosarcoma, highlighting the potential of artificial intelligence in clinical decision-making4. Additionally, Stauss et al. examined the impact of surgical resection margins on outcomes such as local recurrence, distant metastasis, and overall survival, underscoring the importance of achieving clear margins during the surgical procedure to improve patient prognosis5. Although the risk factors identified in these prediction model studies are not new, big data and the machine learning approach are important advancements. Specific Soft-Tissue Sarcoma Subtypes An increasing number of studies are approaching soft-tissue sarcoma subtypes as unique entities. In a Phase-2, international, open-label trial (SPEARHEAD-1), D'Angelo et al. investigated the efficacy of afamitresgene autoleucel in patients with advanced synovial sarcoma and myxoid round cell liposarcoma6. The study demonstrated promising results, with a notable percentage of patients experiencing tumor reduction and manageable safety profiles. This innovative therapy, which involves engineered T-cells targeting specific cancer antigens, showed potential in treating these aggressive sarcomas, offering hope for patients with limited treatment options, although improved survival was not proven. Atezolizumab, an immune checkpoint inhibitor, was evaluated for its effectiveness in treating advanced alveolar soft-part sarcoma in a study published in The New England Journal of Medicine7. The findings indicated that atezolizumab provided clinical benefits, including tumor shrinkage and prolonged progression-free survival for some patients. This study highlights the potential of immunotherapy in managing rare and difficult-to-treat sarcomas, underlining the importance of further research to optimize treatment protocols and patient selection. Additional studies have focused on other unique sarcoma subtypes and their management. Makris et al. provided insights into the natural history of undifferentiated pleomorphic sarcoma through the U.S. Sarcoma Collaborative, identifying factors influencing disease progression and outcomes8. Fujiwara et al. identified key survival factors in patients with clear cell sarcoma, emphasizing the importance of early detection and tailored treatment strategies9. Zhang et al. explored the optimal timing for reexcision in patients with synovial sarcoma, finding that immediate intervention postoperatively may improve outcomes compared with waiting for local recurrence10. Furthermore, Wahlig et al. assessed the clinical importance of bone marrow aspiration and biopsy in the initial staging of extraskeletal Ewing sarcoma, concluding that its routine use may not be necessary, thus potentially reducing patient burden without compromising diagnostic accuracy11. It is clear that a subtype-specific approach to the study and treatment of soft-tissue sarcoma will become increasingly more central to patient care. Wound Management Soft-tissue sarcoma surgery often results in wound complications. Therefore, ongoing research has focused on preventing and/or minimizing these complications. Mericli et al. introduced the Anderson SArcoma Risk of Complications (A-SARC) score, a novel tool designed to guide reconstructive decision-making in patients with extremity soft-tissue sarcoma12. This scoring system helps clinicians to determine when to opt for more complex reconstructive techniques over traditional methods by assessing the risk of complications. By considering various patient-specific factors, the A-SARC score emphasizes personalized treatment planning, ensuring that patients receive the most appropriate reconstructive strategy based on their individual risk profile. In another study, Gonzalez et al. analyzed the cost-effectiveness of wound vacuum-assisted closure temporization following tumor resection in patients with soft-tissue sarcoma13. By comparing propensity-score-matched patients, they demonstrated that vacuum-assisted closure temporization could be a cost-effective strategy, potentially reducing health-care expenses associated with prolonged hospital stays and additional surgical interventions, although vacuum-assisted closure temporization will not be necessary in all patients. Miwa et al. developed and validated a nomogram to predict the risk of surgical site infections after soft-tissue sarcoma resection14. This predictive tool allows clinicians to identify high-risk patients and implement targeted preventive measures, thereby minimizing the incidence of surgical site infections and improving postoperative outcomes. As further research clarifies the risks of wound complications and best practices for preventing wound complications, surgeons will be able to optimize surgical care and resource utilization in the management of soft-tissue sarcomas. Exploratory and Cutting-Edge Approaches Immunotherapy continues to be explored as a potential treatment approach for soft-tissue sarcoma. In a Phase-1 trial, Seo et al. investigated the combination of toll-like receptor 4 (TLR4) agonist injections with concurrent radiation therapy in patients with metastatic soft-tissue sarcoma15. The study demonstrated that this combination could be safe and potentially enhance the immune response against tumors. Meanwhile, Xu et al. conducted the ALTER-S006 trial, assessing anlotinib as a maintenance treatment for advanced soft-tissue sarcoma after chemotherapy16. The trial found that anlotinib could potentially prolong progression-free survival, offering a new therapeutic option for patients. Finally, a Phase-3 factorial trial of post-treatment surveillance for soft-tissue sarcoma, the Surveillance After Extremity Tumor Surgery (SAFETY) randomized controlled trial, completed the pilot study of 100 patients followed for 2 years with more or less intense clinical follow-up and thoracic imaging schedules17. The pilot phase confirmed the feasibility of enrollment, protocol adherence, and data quality. Full study enrollment was expected to be completed by the end of 2024. In support of the rationale for this trial, Priester et al. examined the utility of contrast-enhanced chest computed tomographic (CT) scans in the staging and surveillance of extremity sarcomas, finding that, although these scans can aid in detecting metastases, their routine use may not significantly impact patient outcomes18. The study suggested that a more selective approach to using contrast chest CT scans could optimize patient care and resource allocation. Tenosynovial Giant Cell Tumor (TGCT) Colony-stimulating factor 1 (CSF-1) inhibitors are a class of drugs designed to block the activity of CSF-1, a cytokine that regulates the production, differentiation, and function of macrophages. CSF-1 interacts with its receptor, CSF-1R (also known as CD115), which is expressed on the surface of macrophages and other cells of the mononuclear phagocyte system. By inhibiting the CSF-1/CSF-1R pathway, these drugs can reduce the number and activity of macrophages, which play a crucial role in various pathological processes. CSF-1 inhibitors have shown promise in the context of TGCTs. These inhibitors can decrease the recruitment and survival of tumor-associated macrophages (TAMs), which often promote tumor growth and suppress anti-tumor immune responses. Examples of CSF-1 inhibitors include pexidartinib and vimseltinib. The MOTION trial, conducted by Gelderblom et al., evaluated the efficacy of vimseltinib compared with placebo in patients with TGCTs through a multicenter, randomized, double-blinded, placebo-controlled Phase-3 study19. The trial demonstrated that vimseltinib significantly improved objective response rates in patients with TGCTs compared with placebo. Complementing this, van der Heijden et al. discussed the multimodal management of TGCTs, highlighting the integration of new druggable targets into treatment strategies20. These studies highlighted the evolving landscape of TGCT management, emphasizing the potential of targeted therapies. Prevention and Management of Thromboembolic Complications The patient population with musculoskeletal cancer is at high risk for thromboembolic and bleeding complications. Therefore, research into prevention and management is ongoing. LiBrizzi et al. used data from the PearlDiver database to evaluate the efficacy and safety of direct oral anticoagulants compared with low-molecular-weight heparin for venous thromboembolism prophylaxis in patients undergoing surgical resection of primary lower-extremity bone or soft-tissue sarcoma21. Their study concluded that direct oral anticoagulants are as effective as low-molecular-weight heparin in preventing venous thromboembolism in this patient population, with a similar safety profile with regard to bleeding complications. These findings suggested that direct oral anticoagulants could be a viable alternative to low-molecular-weight heparin for postoperative venous thromboembolism prophylaxis, potentially offering patients a more convenient oral administration route. In related research, Foster et al.22 performed a large, retrospective, single-center review that found the use of intravenous tranexamic acid during sarcoma resection to be associated with an increased risk of venous thromboembolism and pulmonary embolism. Despite the limitations of the retrospective study design, these findings nevertheless highlighted a critical consideration regarding the intraoperative management of patients with sarcoma—suggesting that, although tranexamic acid is effective in reducing blood loss, its potential risk of pulmonary embolism necessitates careful patient selection and monitoring. Additionally, in a secondary analysis of the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) randomized controlled trial23, Sabharwal et al. investigated thromboembolism incidence and risk factors after endoprosthetic reconstruction in patients with musculoskeletal cancer24. Although relatively rare in the PARITY cohort (1.8%), thromboembolic events were more likely to occur in older patients and those receiving long-term prophylactic antibiotics. In contrast to the finding by Foster et al.22, intraoperative tranexamic acid and postoperative chemical thromboprophylaxis were not associated with a greater incidence of venous thromboembolism. International Collaboration, Consensus Work, and Data-Sharing The orthopaedic oncology community is coming together more to address and answer critical research questions in the field. An example of extraordinary collaboration is the attempt at international consensus on the diagnosis and management of chondrosarcoma and the prevention and management of surgical site infections in bone tumor reconstruction. The Birmingham Orthopaedic Oncology Consensus Meeting, organized by Jeys et al., explored the associated controversies in orthopaedic oncology25. The Birmingham Orthopaedic Oncology Consensus Meeting was held in January 2024 and aimed to establish global consensus on these issues by gathering >300 delegates from >50 countries. This meeting highlighted the ongoing debates and sought to generate consensus statements based on evidence and expert opinions from various regions. Finally, data-sharing by the PARITY trial team allowed for a greater understanding of the use of opioids in the orthopaedic oncology population. Gazendam et al. explored opioid consumption patterns and predictors of chronic opioid use in patients with musculoskeletal tumors undergoing limb-salvage surgery and endoprosthetic reconstruction26. Analyzing data from the PARITY trial revealed that 33.6% of patients consumed opioids preoperatively, dropping to 6.6% at 1 year postoperatively. Chronic opioid use was significantly associated only with surgical procedures for metastatic bone disease. Other factors such as preoperative opioid use, age, sex, operative time, reoperation rates, and country of origin were not predictive of chronic use. These findings highlight the need for specific opioid-prescribing guidelines for this patient group, as addiction and chronic use were uncommon. Bone Sarcoma Chondrosarcoma Chondrosarcoma continues to be a challenging entity, and the optimal diagnosis and management is an area of controversy. As noted above, the first-ever Birmingham Orthopaedic Oncology Consensus Meeting highlighted the most pressing issues, including the management of dedifferentiated and pelvic chondrosarcoma, the diagnostic utility of imaging modalities, and the management of atypical cartilaginous tumors25. This meeting of >300 specialists from >50 countries represented an important step forward in the understanding of this challenging disease. Recent literature on differentiating among atypical cartilaginous tumors has focused on utilized imaging modalities to create predictive models. Gitto et al. created a radiomics-based machine learning model utilizing cross-sectional imaging and radiographs to accurately differentiate between atypical cartilaginous tumors and high-grade chondrosarcoma of the extremities27. Gundavda et al. developed a 9-parameter radiographic aggressiveness score utilizing radiographs and MRI to predict the grade of primary chondrosarcomas in the long bones28 The management of atypical cartilaginous tumors has also been controversial, with some groups advocating for wide resection, others for intralesional treatments, and still others for radiographic surveillance. The Leiden group reported on their experience with active radiographic surveillance for atypical cartilaginous tumors and demonstrated its safety in both the short and intermediate terms, with no malignant progression in 117 patients29. There has been an interest in the presence and implications of isocitrate dehydrogenase (IDH) mutations in patients with cartilaginous lesions. Trovarelli et al. found that the presence of IDH mutations was a negative prognostic factor in patients with chondrosarcoma30. Rey et al. examined the impact of IDH mutations in the preclinical setting and reported that, in cell lines with IDH2 mutations, enasidenib demonstrated profound antitumor effects31, although translation to clinical practice is far from ensured. Extremity Reconstruction There has been a renewed interest in the use of biologic reconstruction following extremity bone sarcoma resection. Bozzo et al. presented a prospective cohort analysis on the surgical, functional, and oncologic outcomes of distraction osteogenesis following bone sarcoma resection. They demonstrated that all patients achieved full bone-healing and independent weight-bearing at a median of 12 months postoperatively32. Bruschi et al. reported on the outcomes of an allograft-prosthetic composite (APC) reconstruction for short proximal femoral segments. They found that APC reconstruction was associated with higher functional outcomes, with no differences in complication rates33. Errani et al.34 evaluated the efficacy of resurfaced APCs for pediatric patients with proximal humeral sarcoma. They demonstrated a 25% reconstruction failure rate and recommended utilizing the technique for very young patients or older pediatric patients with preserved axillary nerve function. Fibular autografts continue to be a popular choice for long-bone reconstructions. Campanacci et al.35 reported on their experience utilizing vascularized fibular autograft for reconstruction following tibial en bloc resection. They concluded that it is a viable reconstruction option but comes with an almost 50% risk of postoperative complications including infection, fracture, and nonunion. Shahzad et al. examined the utility of combining a vascularized fibular autograft reconstruction in combination with an intercalary prosthesis in patients with a femoral diaphyseal bone tumor36. The use of a "bioprosthetic" intercalary femoral reconstruction allowed for earlier weight-bearing and quicker osseous union compared with reconstruction with an allograft and vascularized fibular autograft. Finally, Shahzad et al. reported on their experience of utilizing vascularized fibular autograft for upper-extremity reconstruction and demonstrated excellent functional outcomes and relatively low complication rates37. However, it is important to note that these studies were retrospective in nature and subject to inherent biases. Endoprosthetic reconstruction continues to be a mainstay in limb-salvage surgery, particularly after periarticular resection. Kendal et al. utilized the PARITY data set to evaluate the rates and causes of early reoperation following lower-extremity endoprosthetic reconstruction. They demonstrated a reoperation rate of >25%, with the most common causes of reoperation being infection and/or wound complications38. Mori et al. reported on the Japanese Musculoskeletal Oncology Group's experience with complications following total femoral replacement. They demonstrated that the most common serious complications were dislocations at 14% and infection rates at 15%39. Giglio et al. utilized the PARITY trial data to compare cemented and cementless fixation in lower-extremity endoprosthetic reconstruction. They demonstrated that there was no difference in complication or revision rates between the 2 groups, suggesting that both are viable options in the appropriate patient populations40. Labott et al. performed a single-center review of the utility of humeral intercalary endoprosthetic reconstruction and found that it reliably restored function but was associated with mechanical failure in 28% of patients41. Finally, Tran et al. compared functional outcomes of pediatric and adult patients undergoing lower-extremity endoprosthetic reconstruction and concluded that pediatric patients had better functional outcomes at nearly all postoperative time points, although both groups showed similar improvements from baseline to 1 year postoperatively42. Pelvic Sarcomas Pelvic sarcomas remain one of the most challenging clinical entities, with high complication rates and poor postoperative function. Evenhuis et al. provided intermediate-term results of the LUMiC acetabular prosthesis from a multicenter study43. They evaluated 166 patients who underwent periacetabular tumor resection and LUMiC reconstruction and demonstrated a reoperation rate of nearly 50%. However, most patients retained their primary implant, and the authors concluded that this remains a viable reconstruction option. Zhang et al. presented an alternative reconstruction following periacetabular tumor resection, utilizing a hip transposition with stabilization using polyethylene tape, mesh, or iliotibial graft. They found that 76% of patients were able to walk with crutches by 2 months postoperatively44. Wang et al. demonstrated that, regardless of the type of resection or reconstruction, obesity was an independent risk factor for major wound complications following pelvic sarcoma resection45. Vucicevic et al. demonstrated the steep learning curve associated with pelvic sarcoma surgery. They demonstrated a shift toward the utilization of computer navigation or 3D-printed cutting guides and multidisciplinary team care, resulting in lower rates of major blood loss and local recurrence46. The role of reconstruction following iliosacral sarcoma resection continues to be an area of controversy. Broida et al. evaluated the role of reconstruction following iliosacral resection at 2 tertiary centers47. They demonstrated that sacroiliac joint reconstruction was associated with longer operating room times, higher blood transfusion requirements, and more infections, with no improvement in function, when compared with patients who did not undergo a reconstruction. Infection Infection continues to be the leading cause of postoperative complications in patients undergoing a surgical procedure for a malignant bone tumor and was a focus of the recent Birmingham Orthopaedic Oncology Consensus Meeting25. This meeting highlighted the need for uniform definitions with respect to the surgical treatment options for periprosthetic joint infection (PJI) and the need to better define the effectiveness of antibiotic treatment regimens used to treat the unique organisms found in patients with oncological diagnoses. A number of PARITY trial secondary analyses provided valuable insights into the predictors and impact of surgical site infections following lower-extremity endoprosthetic reconstruction48. Zeitlinger et al. demonstrated that longer operative time was an independent risk factor for infection and that a prolonged course of postoperative antibiotics did not mitigate the risk of infection in this high-risk cohort49. LiBrizzi et al. demonstrated that prolonged drain duration (>14 days) was associated with infection following endoprosthetic reconstruction, whereas the use of negative-pressure wound therapy dressings did not impact infection rates50. Ray et al. highlighted the challenges of eradicating infections following endoprosthetic reconstruction, with only 28% of patients diagnosed with a surgical site infection having successful eradication of the infection51. Finally, Jackson et al. challenged the notion that postoperative infection may confer a survival benefit in patients with osteosarcoma, finding that infection was associated with increased disease progression in the subset of patients presenting with metastases at baseline52. Diagnosis Achieving an accurate diagnosis in patients with bone sarcoma is paramount, as it ensures that patients receive effective, appropriate, and timely care. Burke et al. analyzed international biopsy principles and their impact on surgical outcomes in patients with lower-extremity bone sarcoma and demonstrated that core needle biopsies are more common globally, whereas open biopsies are more frequent in the United States and Canada53. Despite longer operative times and more tissue excision with open biopsies, no differences in infection rates or oncologic outcomes were found. Low-grade central osteosarcoma often has radiographic and pathological features that mimic other bone tumors, complicating its diagnosis and treatment. Khal et al. retrospectively analyzed 49 patients with low-grade central osteosarcoma, revealing that accurate diagnosis was more common with open biopsies and that wide-margin surgical excision led to favorable outcomes, although local recurrence and distant metastasis were associated with poorer prognoses54. Extra-articular resection is commonly used to treat bone tumors with intra-articular extension around the knee, although it often results in poor functional outcomes. Kurisunkal et al. evaluated the diagnostic accuracy of MRI in predicting intra-articular involvement in 63 high-grade sarcoma cases, finding that, although MRI can sometimes overestimate joint involvement, combining imaging findings such as knee effusion with clinical signs such as disease in the Hoffa fat pad or pathological fracture improves diagnostic accuracy55. Metastatic Bone Disease Recent research in metastatic bone disease is advancing our understanding and management of this complex condition, addressing challenges in the diagnosis, treatment, and outcome predictions. Surgical Management The Musculoskeletal Tumor Society (MSTS), with the assistance of the American Academy of Orthopaedic Surgeons (AAOS), developed a Clinical Practice Guideline (CPG) for managing metastatic humeral disease56. There was evidence that the addition of cement may provide short-term improvements in pain relief and functional mobility. In patients requiring arthroplasty to reconstruct the proximal humerus, reverse total shoulder arthroplasty was recommended in order to decrease shoulder instability and improve range of motion. These findings were corroborated by Sullivan et al., who performed a retrospective review and found that reverse total shoulder arthroplasty reconstruction in the setting of metastatic bone disease allowed for better range of motion and less instability57. However, the findings of these retrospective studies remain preliminary, and shoulder reconstruction should be approached on a case-by-case basis in patients with metastatic bone disease. Two recent studies examined the optimal surgical management of skeletal metastases in the appendicular skeleton, comparing outcomes for solitary bone metastasis compared with multiple bone metastases. Ladegaard et al. conducted a retrospective study on 459 patients treated surgically between 2014 and 201958. They found that patients with a solitary osseous metastasis had a 1-year survival rate of 47%, significantly higher than the 34% for those with multiple metastases. Notably, aggressive surgical resection (R0) of solitary metastases led to a higher 1-year survival rate of 75%, compared with 42% for less complete resections. Kafchinski reviewed literature indicating that metastasectomy and reconstruction can improve survival, especially for patients with renal cell carcinoma with a solitary bone metastasis59. However, the benefits of such aggressive surgical approaches for other cancer types, such as breast and thyroid cancer metastases, remain under debate. Both studies suggested that aggressive surgical treatment of a solitary osseous metastasis can enhance patient survival, although the evidence varies by cancer type. Predictive Models Recent research in predictive models for extremity metastatic bone disease has made notable strides, as evidenced by recent studies. One study conducted in South Korea compared the performance of 5 survival prediction models among Asian patients undergoing surgery for bone metastases of the extremities. The study found that the Skeletal Oncology Research Group (SORG) model had the highest discriminatory accuracy, indicating its superior ability to predict survival postoperatively60. Vankara et al. evaluated the effectiveness of the Pathologic Fracture Mortality Index (PFMI) in predicting 30-day postoperative morbidity following fixation of pathologic fractures in patients with cancer61. The PFMI surpassed other indices in predicting all-cause morbidity, underscoring its value in risk stratification for surgical outcomes in this patient population. Furthermore, an international analysis of life expectancy trends following treatment for metastatic bone disease revealed improvements in median survival over time across various cancer types. This highlights the evolving landscape of treatment outcomes, driven by advancements in both surgical techniques and medical therapies62. Within the spinal metastasis literature, recent work has focused on enhancing predictive models, particularly the SORG machine-learning algorithm (SORG-MLA). Su et al. validated its ability to predict 6-week survival in Taiwanese patients, demonstrating good discrimination and accuracy despite slight underestimations of survival rates of <50%63. Another study investigated the algorithm's performance with missing data by intentionally removing surgical information from a larger cohort and found that, although the SORG-MLA generally performed well with up to 3 missing items, it faltered without crucial factors such as serum albumin and lymphocyte count64. An internet-based tool was developed to mitigate these challenges, enabling real-time data imputation to support more informed clinical decisions for patients with spinal metastasis, especially when timely surgical interventions are crucial.