Michael Parry

Current status and unanswered questions on the use of Denosumab in giant cell tumor of bone

Denosumab is a monoclonal antibody to RANK ligand approved for use in giant cell tumour (GCT) of bone. Due to its efficacy, Denosumab is recommended as the first option in inoperable or metastatic GCT. Denosumab has also been used pre-operatively to downstage tumours with large soft tissue extension to allow for less morbid surgery. The role of Denosumab for conventional limb GCT of bone is yet to be defined. Further studies are required to determine whether local recurrence rates will be decreased with the adjuvant use of Denosumab along with surgery. The long term use and toxicity of this agent is unknown as is the proportion of patients with primary or secondary resistance. It is advised that complicated cases of GCT requiring Denosumab treatment should be referred and followed up at expert centres. Collaborative studies involving further clinical trials and rigorous data collection are strongly recommended to identify the optimum use of this drug.

Very long-term outcomes after endoprosthetic replacement for malignant tumours of bone.

AIMS The aim of this study was to establish what happens to patients in the long term after endoprosthetic replacement for a primary malignant tumour of bone. PATIENTS AND METHODS We conducted a retrospective analysis of a prospectively maintained database to identify all patients who had undergone an endoprosthetic replacement more than 25 years ago and who were still alive. Their outcomes were investigated with reference to their complications and need for further surgery. A total of 230 patients were identified. Their mean age at diagnosis was 20.7 years (five to 62). The most common diagnosis was osteosarcoma (132). The most common site was the distal femur (102). RESULTS The mean follow-up was 29.4 years (25 to 43). A total of 610 further operations were undertaken, an average of 2.7 further operations per patient. A total of 42 patients (18%) still had the original prosthesis in place. The risk of amputation was 16% at 30 years (31 patients). Those without infection had a mean of 2.1 further operations (one to nine) while those with infection had a mean of 4.6 further operations (two to 11). The risk of infection persisted throughout the life of the prosthesis with a mean of 1% per year becoming infected. Of the 60 patients who developed an infection, 21 (35%) developed this following the primary procedure at a mean of 50 months, but another 19 developed this within a year of another surgical procedure. The risk of infection after any further surgery was 2.7%. The site with the highest risk of infection was the proximal tibia (43.3%). TAKE HOME MESSAGE This study highlights the inevitable need for further surgery following first-generation endoprosthetic reconstruction, although in most cases, limb salvage is maintained. Late complications, especially infection, continue for the lifetime of the implant. Cite this article: Bone Joint J 2016;98-B:857-64.

A Novel System for the Surgical Staging of Primary High-grade Osteosarcoma: The Birmingham Classification

BackgroundChemotherapy response and surgical margins have been shown to be associated with the risk of local recurrence in patients with osteosarcoma. However, existing surgical staging systems fail to reflect the response to chemotherapy or define an appropriate safe metric distance from the tumor that will allow complete excision and closely predict the chance of disease recurrence. We therefore sought to review a group of patients with primary high-grade osteosarcoma treated with neoadjuvant chemotherapy and surgical resection and analyzed margins and chemotherapy response in terms of local recurrence.Questions/purposes(1) What predictor or combination of predictors available to the clinician can be assessed that more reliably predict the likelihood of local recurrence? (2) Can we determine a better predictor of local recurrence-free survival than the currently applied system of surgical margins? (3) Can we determine a better predictor of overall survival than the currently applied system of surgical margins?MethodsThis retrospective study included all patients with high-grade conventional osteosarcomas without metastasis at diagnosis treated at one center between 1997 and 2012 with preoperative chemotherapy followed by resection or amputation of the primary tumor who were younger than age 50 years with minimum 24-month followup for those still alive. A total of 389 participants matched the inclusion criteria. Univariate log-rank test and multivariate Cox analyses were undertaken to identify predictors of local recurrence-free survival (LRFS). The Birmingham classification was devised on the basis of two stems: the response to chemotherapy (good response = ≥ 90% necrosis; poor response = < 90% necrosis) and margins (< 2 mm or ≥ 2 mm). The 5-year overall survival rate was 67% (95% confidence interval [CI], 61%–71%) and 47 patients developed local recurrence (12%).ResultsIntralesional margins (hazard ratio [HR], 9.9; 95% CI, 1.2–82; p = 0.03 versus radical margin HR, 1) and a poor response to neoadjuvant chemotherapy (HR, 3.8; 95% CI, 1.7–8.4; p = 0.001 versus good response HR, 1) were independent risk factors for local recurrence (LR). The best predictor of LR, however, was a combination of margins ≤ 2 mm and a less than 90% necrosis response to chemotherapy (Birmingham 2b HR, 19.6; 95% CI, 2.6-144; p = 0.003 versus Birmingham 1a; margin >2 mm and more than 90% necrosis HR, 1). Two-stage Cox regression model and higher Harrell’s C statistic demonstrate that the Birmingham classification was superior to the Musculoskeletal Tumor Society (MSTS) margin classification for predicting LR (Harrell’s C statistic Birmingham classification 0.68, MSTS criteria 0.59). A difference in overall survival was seen between groups of the Birmingham classification (log-rank test p < 0.0001), whereas the MSTS margin system was not discriminatory (log-rank test p = 0.14).ConclusionsBased on these observations, we believe that a combination of the recording of surgical margins in millimeters and the response to neoadjuvant chemotherapy can more accurately predict the risk of local recurrence than the current MSTS system. A multicenter collaboration study initiated by the International Society of Limb Salvage is recommended to test the validity of the proposed classification and if these findings are confirmed, this classification system might be considered the standard practice in oncology centers treating patients with osteosarcomas and allow more effective communication of margin status for research.Level of EvidenceLevel IV, prognostic study.

Survival and complications of skeletal reconstructions after surgical treatment of bony metastatic renal cell carcinoma

Improvements in survival for patients with renal cell carcinoma have resulted in an increase in the burden of disease due to skeletal metastases, which are often solitary and resistant to radiotherapy. Surgical intervention remains a valid treatment to improve function and relieve pain, and replacement is able to achieve this and improve disease free implant survival. The aim of this study was identify prognostic factors for reconstruction survival of skeletal metastases in renal cell carcinoma and to characterise the nature of the reconstruction related complications. A retrospective analysis of all patients treated for metastatic renal cell carcinoma in three international bone tumour units between 2000 and 2014 identified 268 surgical interventions suitable for inclusion. Reconstruction survivorship was calculated using the Kaplan-Meier method whilst factors affecting reconstruction survival were assessed using Cox-regression multivariate analysis. Differences in proportions were assessed using Fishers exact test. The overall rate of complications was 17%, which were classified as structural failure (7.1%), infection (4.9%) and tumour progression (3.7%). Endoprosthetic replacement when performed as the primary procedure demonstrate the best survivorship whilst factors associated with compromised reconstruction survival included previous surgical intervention and pre operative radiotherapy, and intralesional resection margins. We conclude that endoprosthetic replacement be considered as the index surgical intervention for skeletal metastases from renal cell carcinoma in certain locations as this carries the lowest incidence of complications. Revision of previous skeletal stabilisation, especially when combined with radiotherapy carries a high risk of complication, including infection, which often necessitates amputation.

Outcome of Pelvic Bone Sarcomas in Children

Background: Malignant bone tumors of the pelvis in children are rare and knowledge of their behavior is limited. Methods: A total of 113 skeletally immature patients under 16 years of age, comprising 58 females and 55 males were treated between 1983 and 2014. Tumors comprised Ewing’s sarcoma (ES) in 88 (77.9%) or osteosarcoma (OS) in 25 (22.1%). Metastases at diagnosis were present in 36 (31.9%). The mean follow-up was 5.2 years (2 to 16). Results: For patients with ES, the overall survival was 37.1% at 5-years and 33.5% at 10-years and 31.7% at 5- and 10-years in patients with OS. Local recurrence occurred in 24 patients with ES (27.3%) and 7 patients with OS (43.7%). Chemotherapy response was a predictor of local recurrence in ES with the lowest incidence seen in those with a good response to chemotherapy treated with a combination of radiotherapy and surgery. In patients with OS, both surgical margin and chemotherapy response influenced local control. Conclusions: Attaining a wide surgical margin should be the aim of treatment for all children with primary bone tumors of the pelvis. In ES, chemotherapy response has a greater influence on disease free and overall survival. Patients who demonstrate a poor response to chemotherapy should be considered for subsequent radiotherapy. Effort should be directed toward identifying nonhistologic methods of assessing chemotherapy response. Level of Evidence: Level IV—retrospective case study.

Surgical Innovation in Sarcoma Surgery

The field of orthopaedic oncology relies on innovative techniques to resect and reconstruct a bone or soft tissue tumour. This article reviews some of the most recent and important innovations in the field, including biological and implant reconstructions, together with computer-assisted surgery. It also looks at innovations in other fields of oncology to assess the impact and change that has been required by surgeons; topics including surgical margins, preoperative radiotherapy and future advances are discussed.

The prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma

The aim of this study was to evaluate the prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma. A total of 80 patients with a primary parosteal osteosarcoma were included in this retrospective study. There were 51 females and 29 males with a mean age of 29.9 years (11 to 78). The mean follow-up was 11.2 years (1 to 40). Overall survival was 91.8% at five years and 87.8% at ten years. Local recurrence occurred in 14 (17.5%) patients and was associated with intralesional surgery and a large volume of tumour. On histological examination, 80% of the local recurrences were dedifferentiated high-grade tumours. A total of 12 (14.8%) patients developed pulmonary metastases, of whom half had either a dedifferentiated tumour or a local recurrence. Female gender and young age were good prognostic factors. Local recurrence was a poor prognostic factor for survival. Medullary involvement or the use of chemotherapy had no impact on survival. The main goal in treating a parosteal osteosarcoma must be to achieve a wide surgical margin, as inadequate margins are associated with local recurrence. Local recurrence has a significant negative effect on survival, as 80% of the local recurrences are high-grade dedifferentiated tumours, and half of these patients develop metastases. The role of chemotherapy in the treatment of parosteal osteosarcoma is not as obvious as it is in the treatment of conventional osteosarcoma. The mainstay of treatment is wide local excision.

Is endoprosthetic replacement of the proximal femur appropriate in the comorbid patient

Introduction: Patients with failed hip arthroplasty requiring extensive femoral reconstruction often present with a multitude of comorbidities. Many treatment options limit initial mobilisation relying on bone graft incorporation. The use of endoprosthetic replacement (EPR), despite often being a “last resort”, offers an expeditious solution with early mobilisation that is crucial in the comorbid individual. Many perceive that the surgical insult of EPR is associated with an increased mortality. The aim of this study was to report our experience of proximal femoral EPR as the treatment for failed arthroplasty or fracture fixation. Primary outcomes included mortality, complications, revision and function. Methods: Retrospective review of proximal femoral EPR undertaken at our institution for non-oncological indications between 2007 and 2015 identified 37 patients with a mean follow-up of 33 months. Patient case notes, demographics and radiographs were studied. Results: The 90-day mortality following proximal femoral EPR was 2.7%. 9 patients had died at the time of final follow-up (mean time to death was 33 months). The mean preoperative and postoperative Oxford Hip Score improved from 8 to 31 respectively (p<0.05). When considering revision for any cause, 5-year survival was 94.6%. 2 patients suffered periprosthetic joint infection and 1 patient required revision for prosthesis dislocation. Conclusions: We report a relatively low incidence of perioperative complications, with a mortality rate similar to other revision options in this high-risk cohort. Whilst further revision may not always be possible, this “last resort” technique is safe in the comorbid population presenting with significant proximal femoral bone deficiency.

Is Arthrodesis a Reliable Salvage Option following Two-Stage Revision for Suspected Infection in Proximal Tibial Replacements? A Multi-Institutional Study

The aim of this multicentric retrospective study was to verify whether knee arthrodesis (KA) is a viable reconstructive option after two-stage revision for infection of proximal tibia (PT) endoprosthetic reconstruction (EPR). Sixty patients who underwent a two-stage revision were included. Definitive EPR or a KA with a modular system was performed following consideration of soft tissue and extensor mechanism conditions. Patients were evaluated with Musculoskeletal Tumor Society Score and Oxford Knee Score. Implant survival was assessed on the basis of recurrence of infection. Five patients did not receive any reconstruction after the first stage. In 14 cases, a KA was performed, and in 41, an EPR was implanted. At 5 years follow-up, reinfection rate in the KA group was lower (10 vs. 17.5% in KA and EPR groups, respectively). In reinfected patients, the KA group had a reduced rate of amputation when compared with those with EPR (50 vs. 88%). Functional evaluation did not show any significant differences between the two groups. A successful KA using a modular implant can eradicate infection and allow preservation of the limb with good function and good pain relief in after two-stage revision for an infected PT EPR.

Vascularized fibular epiphyseal transfer for proximal humeral reconstruction in children with a primary sarcoma of bone

Aims Preserving growth following limb‐salvage surgery of the upper limb in children remains a challenge. Vascularized autografts may provide rapid biological incorporation with the potential for growth and longevity. In this study, we aimed to describe the outcomes following proximal humeral reconstruction with a vascularized fibular epiphyseal transfer in children with a primary sarcoma of bone. We also aimed to quantify the hypertrophy of the graft and the annual growth, and to determine the functional outcomes of the neoglenofibular joint. Patients and Methods We retrospectively analyzed 11 patients who underwent this procedure for a primary bone tumour of the proximal humerus between 2004 and 2015. Six had Ewings sarcoma and five had osteosarcoma. Their mean age at the time of surgery was five years (two to eight). The mean follow‐up was 5.2 years (1 to 12.2). Results The overall survival at five and ten years was 91% (confidence interval (CI) 95% 75% to 100%). At the time of the final review, ten patients were alive. One with local recurrence and metastasis died one‐year post‐operatively. Complications included seven fractures, four transient nerve palsies, and two patients developed avascular necrosis of the graft. All the fractures presented within the first postoperative year and united with conservative management. One patient had two further operations for a slipped fibular epiphysis of the autograft, and a hemi‐epiphysiodesis for lateral tibial physeal arrest. Hypertrophy and axial growth were evident in nine patients who did not have avascular necrosis of the graft. The mean hypertrophy index was 65% (55% to 82%), and the mean growth was 4.6 mm per annum (2.4 to 7.6) in these nine grafts. At final follow‐up, the mean modified functional Musculoskeletal Tumour Society score was 77% (63% to 83%) and the mean Toronto Extremity Salvage Score (TESS) was 84% (65% to 94%). Conclusion Vascularized fibular epiphyseal transfer preserves function and growth in young children following excision of the proximal humerus for a malignant bone tumour. Function compares favourably to other limb‐salvage procedures in children. Longer term analysis is required to determine if this technique proves to be durable into adulthood.