Classification of failure of limb salvage after reconstructive surgery for bone tumours

SPECIALTY UPDATE: ONCOLOGY Classification of failure of limb salvage after reconstructive surgery for bone tumours A MODIFIED SYSTEM INCLUDING BIOLOGICAL AND EXPANDABLE RECONSTRUCTIONS E. R. Henderson, M. I. O Connor, P. Ruggieri, R. Windhager, P. T. Funovics, C. L. Gibbons, W. Guo, F. J. Hornicek, H. T. Temple, G. D. Letson From Norris Cotton Cancer Center, Lebanon, New Hampshire, United States Previous classification systems of failure of limb salvage focused primarily on endoprosthetic failures and lacked sufficient depth for the effective study of the causes of failure. In order to address these inadequacies, the International Society of Limb Salvage (ISOLS) formed a committee to recommend revisions of the previous systems. The purpose of this study was to report on their recommendations. The modifications were prepared using an earlier, evidence-based model with subclassification based on the existing medical literature. Subclassification for all five primary types of failure of limb salvage following endoprosthetic reconstruction were formulated and a complementary system was derived for the failure of biological reconstruction. An additional classification of failure in paediatric patients was also described. Limb salvage surgery presents a complex array of potential mechanisms of failure, and a complete and precise classification of types of failure is required. Earlier classification systems lacked specificity, and the evidence-based system outlined here is designed to correct these weaknesses and to provide a means of reporting failures of limb salvage in order to allow the interpretation of outcome following reconstructive surgery. Cite this article: Bone Joint J 2014;96-B:1436 40. E. R. Henderson, MD, Assistant Professor Norris Cotton Cancer Center, Musculoskeletal Oncology Program, One Medical Center Drive, Lebanon, PA, 03756, USA. G. D. Letson, MD, Professor Moffitt Cancer Center, Sarcoma Program, Tampa, Florida, USA. M. I. O Connor, MD, Professor Mayo Clinic, Department of Orthopaedic Surgery, Jacksonville, Florida, USA. P. Ruggieri, MD, PhD, Professor Instituto Ortopedico Rizzoli, Orthopaedic Oncology Division, Bologna, Italy. R. Windhager, MD, Professor P. T. Funovics, MD, Assistant Professor University of Vienna, Department of Orthopaedic Surgery, Vienna, Austria. C. L. Gibbons, MA FRCS, Professor Oxford University, Orthopaedic Oncology, Oxford University Hospitals, Oxford, UK. W. Guo, MD PhD, Professor People s Hospital, Musculoskeletal Tumor Center, Peking University, Beijing, China. F. J. Hornicek, MD PhD, Professor Massachusetts General Hospital, Center for Connective Tissue Oncology, Boston, Massachusetts, USA. H. T. Temple, MD, Professor University of Miami, Department of Orthopaedic Surgery, Miami, Florida, USA. Correspondence should be sent to Dr E. R. Henderson; e-mail: eric.r.henderson@gmail.com 2014 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620x.96b11. 34747 $2.00 Bone Joint J 2014;96-B:1436 40. Failures of limb-preservation surgery using endoprostheses were first classified by Wirganowicz et al 1 as either mechanical or non-mechanical. In 2011 this classification system was expanded to include three mechanical and two non-mechanical types of failure. 2 When classified by this method, significant differences were shown in the incidence and frequency of each type, and the timing of failure when various anatomical sites of endoprosthetic use were compared. This suggests that analyses of failure and efforts to improve prostheses should be specific to site. There were soon problems with this classification system. First, failures resulting from inadequate or dysfunctional soft tissues were grouped together for simplicity, despite disparate endpoints of wound dehiscence and joint instability. Secondly, this system did not allow a distinction between early and late aseptic loosening or infection. These two phenomena have been shown to have distinct, bimodal timeframes. 3,4 Thirdly, the system did not distinguish between prosthetic breakage and peri-prosthetic fracture. Lastly, the system did not distinguish between recurrent disease within the bone and that within soft tissues. In addition, the 2011 classification system omitted provision for failure of reconstruction using allograft and expandable implants. Descriptions of failure relating to expandable implants were added to the classification in 2012. 5 In an effort to address deficiencies of the current system, the International Society of Limb Salvage (ISOLS) established a committee to improve the classification for endoprostheses, and create a new system for allograft failures. The purpose of this study was to report the modifications to the 2011 classification system developed by this committee. Modified classification of limb salvage failures Endoprosthetic failures. As described previously, limb salvage with endoprosthetic failure types 1 to 5 were ordered to reflect the likelihood of limb loss. 2,6 Modifications of the previous system include subcategories of A and B for each type of failure (Table I). Type 6 failures are specific to expandable endoprostheses. Type 1 failures: soft-tissue failure. Soft-tissue failures are classified as failure of function (type 1A) and failure of cover (type 1B). Functional failures 1436 THE BONE & JOINT JOURNAL

CLASSIFICATION OF FAILURE OF LIMB SALVAGE AFTER RECONSTRUCTIVE SURGERY FOR BONE TUMOURS 1437 Table I. Classification of failure of limb salvage after endoprosthetic reconstruction General category Mode Subcategory Description Mechanical Non-mechanical Paediatric Type 1 Soft-tissue failure Dysfunctional or deficient soft tissues resulting in compromised limb function Type 2 Aseptic loosening Clinical and radiological evidence of peri-prosthetic loosening Type 3 Structural failure Breakage, fracture or wearrelated failure resulting in deficient supporting structure Type 4 Infection Infected reconstruction not amenable to retention Type 5 Tumour progression Recurrence or progression of tumour with endoprosthesis Type 6 Paediatric failures A Functional B Coverage A Implant A Soft-tissue A Physeal arrest B Joint dysplasia Limited function owing to insufficient musculoligamentous attachment Aseptic wound dehiscence Aseptic loosening < 2 years after implantation Aseptic loosening > 2 years after implantation Implant breakage or wear; expandable implant lengthening malfunction Peri-prosthetic osseous fracture Infected implant < 2 years after implantation Infected implant > 2 years after implantation Soft-tissue progression of tumour with endoprosthetic Bony progression of tumour with endoprosthetic Growth arrest resulting in longitudinal or angular deformity Dysplastic joint resulting from articulation with implant are those resulting in dysfunction as a result of instability, such as dislocation or symptomatic subluxation of a joint, excessive soft-tissue resection, tendon rupture, and poor soft-tissue ingrowth into the prosthesis. Failures of cover involve aseptic wound dehiscence. A failure of cover may lead to deep infection, but if an infection occurs secondary to inadequate soft-tissue cover, the failure should be classified as type 1B. Type 2 failures: aseptic loosening. Conventional aseptic loosening manifests as osteoclast-mediated peri-prosthetic resorption of bone, usually due to microscopic polyethylene debris, which typically presents several years post-operatively. 7 Technical issues may also play a role as, for example, in the undersizing of uncemented implants or poor cementing technique for cemented implants. Patients undergoing adjuvant treatments for oncological disease may present with an early form of aseptic loosening resulting from poor bone ingrowth and the formation of a fibrous bone implant junction. 8-11 In order to accommodate these temporal and aetiological differences, failures causing aseptic loosening have been subclassified as early (< two years, type 2A) and late (> two years, type 2B) as defined by Chao et al. 4 Type 3 failures: structural failure. Structural failures have been subclassified according to the site of dysfunction. Implant wear or breakages requiring revision are considered type 3A and peri-prosthetic fractures are considered type 3B. In order to facilitate complete data collection, wear-related exchange of a bushing or other articulating component should be reported as 3A failures even if they have reached their anticipated functional duration. Type 4 failures: infection. Failures attributable to infection were subclassified according to the work of Coventry 12 Fitzgerald et al, 13 and Jeys. 3 In 2005 Jeys 3 published the largest series of tumour endoprostheses to focus on failure due to infection. Using the classification systems of Coventry 12 and Fitzgerald et al 13 (classes I, II and III), Jeys 3 reported that most deep infections occurred within the initial two-year post-operative period or within two years of the most recent surgical intervention, after which the rate of infection decreased. Because Jeys 3 did not demonstrate a correlation with the initial four-week post-operative period (class I), the subclassification described here combines classes I and II of Coventry and Fitzgerald into early infection (< two years, type 4A), with class III infections considered late (> two years, type 4B). Type 5 failures: recurrence of disease. Because of potential differences of treatment and prognosis, failure of limb salvage due to a recurrent tumour as a consequence of at the time of the endoprosthetic reconstruction has been subclassified to differentiate between recurrence within the soft tissues (type 5A) and recurrence within bone (type 5B). Both types necessitate removal of the prosthesis, but VOL. 96-B, No. 11, NOVEMBER 2014

1438 E. R. HENDERSON, M. I. O CONNOR, P. RUGGIERI, ET AL Table II. Classification of failure of limb salvage after biological reconstruction General category Mode Subcategory Description Mechanical Non-mechanical Paediatric Type 1 Soft-tissue failure Dysfunctional or deficient soft tissues resulting in compromised limb function Type 2 Graft host nonunion Clinical and radiological evidence of graft host nonhealing Type 3 Structural failure Breakage or fracture resulting in deficient supporting structure Type 4 Infection Infected reconstruction not amenable to retention Type 5 Tumour progression Recurrence or progression of tumour with allograft Type 6 Paediatric failures A Functional B Coverage A Hypertrophic B Atrophic A Fixation B Graft A Soft tissue A Physeal arrest B Joint dysplasia Limited function due to insufficient musculo-ligamentous attachment Aseptic wound dehiscence Nonunion with abundant host-sided callus formation Nonunion without host-sided callus formation Plate and/or screw breakage leading to construct instability Fracture through allograft Infected biological implant < 6 months after implantation Infected biological implant > 6 months after implantation Soft-tissue tumour progression with allograft Bony tumour progression with allograft Growth arrest resulting in longitudinal or angular deformity Dysplastic joint resulting from articulation with graft soft-tissue recurrence may be addressed by removal of the prosthesis, wide local excision, and possible adjuvant treatment without further resection of bone. In contrast, bony recurrence necessitates the removal of further native bone, potentially requiring a total bone prosthetic replacement or amputation to be undertaken. Type 6 failures: failure of limb salvage in paediatric patients. Skeletally-immature children who undergo limb salvage surgery with an endoprosthesis are at risk of modes of failure which are not applicable to adults. 5 The lengthening mechanism of expandable implants may fail and this is considered to be a structural failure, or type 3A. However, types of failures reported in the literature that have not been included in previous classifications include physeal arrest (type 6A) and joint dysplasia (type 6B). 5,14-16 Allograft failures. Failures of allograft reconstruction were categorised according to the modes of failure described previously in the literature (Table II). 17-20 Allograft failure, types 1 to 5, was ordered in a similar fashion as endoprosthetic failure and, more importantly, sequenced to correlate with the likelihood of limb loss. 21,22 Type 1 failure: soft-tissue failure. Allograft soft-tissue failures are subclassified as functional failures and failures of cover based on precedents in the literature. Getty and Peabody 23 reported glenohumeral instability or dislocation in 11 of 16 patients who were treated with an allograft or allograft prosthesis composite for a proximal humeral tumour. Potter et al 24 reported instability in 18% and 19% proximal humeral osteo-articular allografts and allograft prosthetic composites, respectively, following resection of a tumour. Wound dehiscence requiring further surgery has also been described. Ramseier et al 25 reported significant wound complications in children undergoing allograft replacement following physeal-sparing surgery, although retention of the graft was achieved in all four patients. Type 2 failures: nonunion at the graft host junction. Nonunion of the allograft host bone junction is reported to occur in 4% to 50% of cases, making it the most common cause of failure of massive allografts used for limb salvage surgery. 18,19,26,27 Nonunion at this site has been subclassified to reflect the local biological healing capacity of the host, using the terms hypertrophic (type 2A) and atrophic non-union (type 2B), thereby indicating whether an improvement in stability is likely to result in union at the allograft host junction. Nonunion is affected by radiation therapy and chemotherapy. After the course of chemotherapy is complete, healing should occur. However, radiation has longer-term effects and may reduce healing at the allograft host junction permanently. 28 Nonunion may not only reflect local biological factors but also the intimacy of the allograft to the host bone, as gapping can prevent healing. 28 Nonunion often manifests as breakage of internal fixation devices due to repetitive micromovement at the junction site. Observations in experimental animals and human trials consistently demonstrate the importance THE BONE & JOINT JOURNAL

CLASSIFICATION OF FAILURE OF LIMB SALVAGE AFTER RECONSTRUCTIVE SURGERY FOR BONE TUMOURS 1439 of rigid fixation of the allograft host junction. 28 Others have reported significantly higher rates of allograft fractures in patients undergoing chemotherapy. 29 Type 3 failures: structural failure. Structural failures of allograft occur in 6% to 42% of cases and are usually fractures of the graft. 18,19,23,27,30 These failures have been subclassified as failure of fixation (type 3A) and fracture of the allograft (type 3B). Failures of fixation typically occur early in the post-operative period, prior to union at the allograft host junction, and may be treated by revision of the fixation. 31 These failures have been subclassified accordingly. Failures of fixation occurring with an allograft host nonunion should be considered type 2 failures because fatigue failure is an expected result of nonunion. 18,19 Allograft fractures occur both early and late. Typically early fractures occur at the allograft host junction; periarticular fractures can arise at various times. 31,32 These fractures occur in the subchondral region of the osteoarticular allograft, resulting from subchondral resorption of bone causing inadequate support of the articular surface. 33 These fractures are commonly seen in osteoarticular grafts of the tibia. 33-36 Late allograft fractures occur secondary to creeping substitution and revascularisation of the graft, typically near or around screw holes. 28 Allografts are devoid of periosteum and undergo little or no remodelling. These fractures may occur many years after the initial procedure. Not all allograft fractures require replacement of the allograft, as some may heal with revision of the fixation and autograft placement. 28 Type 4 failures: infection. Allograft infections are subclassified as early (A) and late (B), defined as within or beyond six months of implantation, as described first by Loty et al 37 and later by Donati et al. 17 Most allograft infections are early, 37,38 and caused by Staphylococcus organisms. 38,39 Donati et al 17 reported a higher rate of late infections than Loty et al. 37 However, 50% of late infections reported by Donati et al 17 occurred after re-operation for allograft fracture, and therefore cannot be considered late infections as defined by Loty et al. 37 Late infections that occur in patients undergoing revision surgery are commonly observed in those receiving adjuvant chemotherapy or radiation treatment. 22,40 Treatment of allograft infections generally requires removal of the graft and a two-stage revision procedure using another allograft, a prosthesis, a vascularised autograft or a combination of these implants. 26 Type 5 failures: recurrent disease. Failure caused by recurrent tumour is the type which is most likely to result in amputation or death and is therefore assigned type 5. 18,39 Similar to endoprostheses, failures due to recurrent tumour are subclassified according to the site of recurrence owing to differences in the treatment required for each location. Soft-tissue recurrences abutting an allograft (type 5A), which are infrequent, may be treated with revision of the graft without resection of additional bone, whereas bony recurrences, which are more common, require further resection and portend a poorer prognosis, particularly in the presence of a skip lesion. 28,41 The decision to resect and perform limb salvage or to amputate depends on a number of factors: the presence or absence of metastases, the response to chemotherapy, soft-tissue considerations, and neurovascular involvement. Type 6 failures: salvage after failure in paediatric patients. Similar to type 6 paediatric limb salvage failures for endoprostheses, paediatric allograft failures are subclassified as premature physeal arrest (type 6A) and joint dysplasia (type 6B). Allograft reconstruction in adolescent patients in whom one physis must be sacrificed offers the advantage of sparing an adjacent physis. Equal limb lengths can be maintained with contralateral epiphysiodesis. Although higher rates of non union are not necessarily increased in this patient population, short segment instrumentation around a joint can result in limitation of movement. 28 Functional limitations can occur owing to a limitation of movement at the joint and altered levels for the joint lines. Discussion Medical classification systems are intended to apply objective measurements relevant to a condition in order to bring clarity to one or more aspects of that condition s severity or management. These systems may be designed with various goals in mind, such as clarification of the aetiology, the severity of the disease, and the optimal treatment. Simplicity is often achieved at the cost of specificity. Therefore, if a classification system is to define a complex condition successfully, it may need to be complicated. The initial classification of failures of limb salvage published in 2011 stemmed from an analysis of the largest cohort of patients receiving tumour endoprostheses which had been reported at that time. The system was designed in response to general categories of observed failures. The intention was to provide a simple system which was easy to apply. However, the criticism of this system stemmed from assertions that some failures, such as recurrent tumour formation, did not directly compromise the prosthesis and were not really failures of the reconstruction. These concerns were a misunderstanding of the intent of the system, which was to classify failures of salvage, not merely failures of the prosthesis. Failures of soft-tissue infection and aseptic loosening may also be regarded in this manner. Another substantial barrier to classifying failure of limb salvage is the multimodal manner in which failures occur. Indolent infection may result in loosening which is not clinically or radiologically apparent and which ultimately manifests itself as breakage of the prosthesis or peri-prosthetic fracture, but the primary aetiology may be difficult to discern. This emphasises the importance of intra-operative evaluation when addressing a failure. Implant bone interfaces that appear intact should be assessed for the quality of the fixation and cultures should always be obtained. Despite the increasing role of endoprostheses in limb salvage, structural allografts remain useful. Although VOL. 96-B, No. 11, NOVEMBER 2014

1440 E. R. HENDERSON, M. I. O CONNOR, P. RUGGIERI, ET AL allografts are subject to some of the same types of failure as endoprostheses, the criteria for their successful incorporation are distinct and require a separate system of classification. The authors acknowledge that differing definitions of early and late infections for endoprosthetic and allograft reconstructions may prove confusing. However, these definitions are based on best evidence and will undergo further prospective inquiry. Albeit still relatively uncommon, the use of expandable endoprostheses continues to increase. These implants provide new opportunities for failure stemming both from their added mechanical complexity and the effects on their skeletally-immature hosts. Owing to the infrequency of their use, improving outcomes of these devices requires consistent reporting of their distinct types of failure. The modifications to the classification proposed here are intended to fulfil this purpose. 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