Primary osseous tumors represent 0.2% of all new cancers diagnosed in the United States. Each year, 2500 new cases of primary bone cancers are diagnosed, accounting for 6% of pediatric neoplasms.1,2 Forty-five percent of the cancers develop in children younger than 16 years, while 17% of malignancies affect children younger than 12 years. Fifty-seven percent of these cancers are located in the lower extremity,3 affecting the distal femur metaphysis (35%) and the proximal tibia (20%).2
Before 1970, amputation was the treatment of choice for cancers of the extremities. Progress in imaging modalities, operational reconstruction, and pre- or postoperative chemotherapy has permitted tumor removal with adequate margins preserving the integrity of the affected bone and leading to the improvement of overall survivorship. However, limb salvage of children's sarcomas often mandates resection of a growing physis, resulting in limb growth reduction and significant limb length discrepancy after skeletal maturity, which affects limb function and quality of life.
Expandable prostheses have been developed to manage the emerging limb length discrepancy, counterbalancing reduced growth and maintaining an adequate level of function of the limb.4–12 Absolute indications about the application of expandable prostheses have not yet been proposed, but relative indications include (1) the age of the patient at the time of surgery, which has been determined to be 11 years for girls and 13 years for boys; (2) the absence of metastatic disease; and (3) the predicted growth of more than 3 to 4 cm before skeletal maturity.13–16
Recent publications have reported that, despite the increased incidence of complications, the insertion of an expandable prosthesis is associated with satisfying results. The aim of this study was to systematically review the surgical and functional outcomes available in literature pertinent to the expandable endoprosthesis in the treatment of pediatric bony malignancies and to identify any potential trends or deficits associated with its application.
Materials and Methods
A computer-based review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.17,18 The following databases were searched: PubMed (1947 to present), Web of Science (1900 to present), Cochrane Database of Systematic Reviews (1992 to present), Embase (1974 to present), Ovid, Google Scholar (early 1900 to present), and the World Health Organization International Clinical Trials Registry platform. The search was performed using a combination of the following terms: “sarcomas [All Fields]”, “children malignancies [All Fields]”, “children cancers [All Fields]”, and “expandable/extendible/growing prostheses [All Fields]”. All databases were searched from their inception to October 15, 2018.
The titles and the abstracts of the studies were reviewed independently by 2 of the authors (O.D.S., A.K.), who used predefined criteria to select the relevant publications. For further minimization of selection bias, all articles were reviewed a third time and then assessed and discussed by all of the authors. If disagreement occurred concerning the inclusion and exclusion criteria, the senior author (P.J.P.) made the final decision. Data extraction was performed independently by all of the researchers. Data regarding study design, demographic characteristics, surgical intervention, surgical outcome, early or late complications, and treatment effectiveness and safety were recorded.
For the human studies, inclusion criteria were as follows: article was published in a peer-reviewed journal in English and included an appropriate description of the type, grade, and anatomic location of the cancer; all patients underwent salvage surgery accompanied by an expandable prosthesis because of a tumor; age at the time of surgery was up to 17 years; surveys were attempted to clarify the surgical and functional outcomes after the application of the expandable prosthesis during an adequate follow-up period; and data referring to surgical and functional outcomes were clearly rendered for each patient. Case reports and comparative studies were also considered. Exclusion criteria were as follows: article was not published in English and was a literature review, technical note, letter to the editor, or expert opinion. Articles with insufficient details about the type of intervention, the location of the malignancy, follow-up, and the clinical/functional outcome were excluded. Studies involving patients older than 17 years at the time of surgery, using a type of prosthesis other than expandable, or dealing with intercalary resections, rotationplasties, and amputations were also excluded. The search algorithm is displayed in Figure 1.
Diagram displaying the algorithm and the results of a literature search based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
All data of each study were entered into a spreadsheet and classified according to category and grade of malignancy and location and type of expandable prosthesis. Descriptive information regarding patients' demographics was analyzed. Numerical/frequency data, evidence regarding failure mode, lengthening results, number of lengthening procedures, functional scores, short- and long-term complications, and prosthesis survivorship were also examined. Averages, totals, means, and ranges were measured.
The literature search and cross-referencing resulted in a total of 513 publications. After the initial evaluation of the studies based on abstract and title, 471 publications were excluded. Further analysis of the remaining 42 articles led to the exclusion of 9 for the following reasons: failure of the article to clarify the outcome (n=1), not an original study (n=5), and not in English (n=3). Thirty-three articles were retained (Figure 1).18–46
Design and Content of the Studies
The remaining 33 articles involved 21 retrospective cohort studies, 9 prospective cohort studies, and 3 case series or reports (Table A, available in the online version of this article).11,19–50 No randomized study was identified. The included studies were published between 1995 and 2018. Four comparative studies were among them.24,27,36,40 Outcomes after the application of expandable prostheses were compared with functional results after the insertion of conventional modular prostheses in 3 of these studies.24,27,45 One of the studies compared polyethylene sleeved with unsleeved expanding prostheses.40
Summary of available data for expanding endoprostheses
After collection of all of the data, 633 patients (642 limbs) were identified for whom limb reconstruction using expandable prostheses had been performed (Table 1). A patient was excluded from the study due to the application of an expanding prosthesis for nononcological reasons (femoral fracture in Perthes disease).19 Two studies did not report the distribution of sex.11,45 The median age of the patients was 10.78 years (range, 2–18 years), but one study did not report age.45
Data From the Included Studies
Osteosarcoma was the most prevalent diagnosis, followed by Ewing's sarcoma, chondrosarcoma,19 primitive neuroectodermal tumor,41,45,46 spindle cell sarcoma,19 pleomorphic sarcoma,19 aggressive bone cyst,31 and synovial sarcoma48 (Table 1). In 3 studies,29,37,42 the type of bone sarcoma was not clarified. In 2 of these studies, among 47 patients, the most common type of cancer diagnosed was osteosarcoma.29,37 The most common anatomical location of sarcoma was the distal femur, followed by the proximal tibia, proximal femur, total femur, proximal humerus, distal tibia, and femoral diaphysis (Table 1). In 2 studies26,29 with 76 and 15 patients having femoral and tibial sarcoma, respectively, the exact location was not specified. In the study by Sevelda et al,24 the affected osseous regions were not reported.
In 3 studies, the type of expandable prosthesis was not analyzed.32,43,48 The most common type of expandable prosthesis used in the included studies was Kotz. Prostheses that were also described included Stanmore, Repiphysis, Stryker, Lewis, Howmedica, Phenix, Biomet, MUTARS, Wright, and Techmedica (Table 1).
The survivorship of prostheses was analyzed in 8 studies and was estimated based on Kaplan–Meier curves.19,21,24,29,35,41,42,45 The overall average 5-year survivorship rate was 54.65% (range, 30%–100%). The presence of a polyethylene sleeve around the tibial component of the distal femoral expandable prosthesis was associated with a reduction of survivorship (survival rate, 57.1%), as it induced lateral migration of the tibial stem.40 In the study by Ruggieri et al,29 a comparison of the Stanmore, Kotz, and Repiphysis prostheses revealed that the 5-year survivorship rates were 60%, 100%, and 90%, respectively. However, the limited number of patients prohibited drawing definite conclusions.
Twenty-five studies had data on lengthening procedures regarding the expandable prostheses.11,19–26,28–31,34–37,39,41–44,46,47,50 Per patient, the average number of expansions was 4.25 and the average gained growth was 51.85 mm. Furthermore, the average final leg length discrepancy was 19.03 mm.
Twenty-five studies evaluated functional outcomes.11,19–21,23–25,27–32,34–37,39–43,47,48,50 The Musculoskeletal Tumour Society Score questionnaire was the measure used most often and appeared to have adequate consistency across the studies.11,19–21,23–25,27–32,35,36,39,41–43,47,50 The average Musculoskeletal Tumour Society Score was 81.55%. Similarly, in the study by Henderson et al,37 in which the Paediatric Outcome Data Collection questionnaire was used, and in the study by Yashida et al,34 in which outcome was based on the International Symposium of Limb Salvage System protocol, the overall scores were 92.3% and 84%, respectively, indicating a high degree of emotional acceptance.34–37 The same results were reported in the studies by Delepine et al48 and Jaiswal et al40 when using the Société Européenne des Tumeurs Osseouses criteria and the Toronto Extremity Salvage Score, respectively. Finally, mean knee range of motion was 0° to 110° (range, 0°–130°).21,32,43,46
Despite the fact that in two comparative studies24,27 the average functional score after the insertion of conventional modular prostheses was low (70% and 69%, respectively), no significant statistical differences were noted compared with the insertion of expandable prostheses. However, the number of patients was limited and the results of the statistical analysis were not unequivocal.
Failure mode was defined as a medical emergency that may lead to prosthesis or implant revision or to an extended soft tissue reconstruction. Complications are side effects that necessitate orthopedic intervention.51 For the included studies, failure modes were categorized as described by Henderson et al.52 Among the 633 patients, 650 complications and failures were reported in 325 patients (Table 1).11,19–38,40–50 Joint stiffness affecting range of motion was usually due to contractures or to arthrofibrosis and constituted the most prevalent complication (Table 1). Surgical release restored joint function and range of motion for these patients.11,19,26,28,33,42,46–48,50 Wound dehiscence (not infectious),24,26,28,35,37,47 joint instability/subluxations/dislocations,23,24,26,29,31,35,47 superficial infections,29 skin necrosis,31,46,50 transient nerve palsies,20,26,31,35,48 and patellar maltracking26,28,33 were also detected (Table 1).
Aseptic loosening (type II failure mode) was also observed. Despite the fact that deep infection (type IV failure mode) was commonly identified (Table 1), only one study investigated the infective agents, with the following bacteria being isolated: Staphylococcus aureus, Pseudomonas species, Enterococcus species, and Escherichia coli.35 Type III failure mode was also reported, including mechanical failures, implant breakage, fatigue fractures, periprosthetic fractures,19,26–28,31,36,40,44,46,48,50 and 29 cases of structural failure with differing etiology (Table 1).
Other complications that occasionally developed included local tumor progression (type V failure),23,26,47 vascular ischemic problems,31,44,48,50 deep tissue hematomas,31,50 additional distraction osteogenesis,41 pain,41 fat embolism,47 fatal pulmonary embolism,47 and allergy to titanium.35
Overall, 312 revision surgeries were performed. The leading reason for revision was aseptic loosening of the prosthesis, followed by deep infections, soft tissue failure, mechanical failure, and periprosthetic fractures (Table A). Amputation surgeries were reported for 10 patients owing to recurrence of deep infection,19,30,31,34,41,48 local recurrence,26 and limb ischemic necrosis,44 corresponding to a rate of 1.58% (Table A).
The first expanding prosthesis was applied in Birmingham in 1976.6 In 1986, Lewis7 published the first report about its usefulness in the minimization of limb length discrepancy. Early prostheses required open procedures and were associated with increased frequency of mechanical failure and deep infections.8,9 Next-generation prostheses, such as Kotz, required minimal invasive techniques, leading to reductions in complication rates.10 However, they were linked to increased rates of lengthening mechanical failures.11 Third-generation prostheses, such as Phenix, Repiphysis, and Stanmore, are characterized by noninvasive lengthening, low complication rates, and excellent functional results, eliminating the risks of infection or muscle atrophy and enabling gradual lengthening of the soft tissues.12 The MUTARS BioXpand prosthesis is a bioexpandable endoprosthesis consisting of a mechanical growing module and a telescope actuator that stimulates the noninvasive elongation of the prosthesis. A miniaturized, mechatronic actuator is integrated into the growing module. Its elongation procedure is activated by an internal drive system that receives electric power from a high-frequency transmitter located on the overlying skin (Figure 2).
Anteroposterior (A) and lateral (B) radiographs of the right leg showing septic loosening of an expandable prosthesis of the proximal tibia after osteosarcoma resection in a 17-year-old boy. Computed tomography scan showing a leg length discrepancy of 4 cm (C). Reconstruction using a novel expandable prosthesis composed of a mechanical growing module and a telescope actuator that stimulates a noninvasive prosthesis elongation process. A miniaturized, mechatronic actuator is integrated into the growing module. The module elongation procedure is activated by an internal drive system receiving electric power from a high-frequency transmitter located on the overlying skin. Elongation is performed at a rate of 1 mm per day (D). Anteroposterior radiograph of the lower extremities showing a satisfactory outcome with leg length restoration (E).
The current review revealed the data available regarding the functional and surgical outcomes of application of expandable prostheses. Only 14 studies included more than 10 patients per type of sarcoma, anatomic region, or type of prosthesis.22,23,25,26,29–31,35,40–42,47–49 Additionally, many cases appeared to have incomplete follow-up, resulting in underestimation of local recurrences or late prosthesis failures. The insufficient number of patients prevented the drawing of definitive conclusions.
Despite these drawbacks, an initial appraisal of the outcomes of prostheses was completed. Growing endoprostheses have been used to address juvenile limb length discrepancy, with significant rates of limb growth observed and limb length equality accomplished at skeletal maturity. The average remaining limb length discrepancy (19.02 mm) after skeletal maturity was lower than 30 mm, which defines limb length discrepancy and is associated with a reduction in the quality of life.52 Although failures of the expanding mechanism have been reported,23,26,29,33,36,37 the data of the current study indicated a low rate of failure.
The overall average 5-year prosthesis survivorship rate was elevated (54.65%) and the incidence of amputation surgeries was reduced (1.58%). Thus, patients received cost-effective care, as endoprosthetic limb-preserving surgeries are more cost-effective than amputations.29 Functional outcomes data were mainly estimated by the Musculoskeletal Tumour Society Score, which ranged from 67%28,43 to 93.5%.44 Moreover, restoration of normal range of motion correlated with increased rates of mobility and functional or emotional satisfaction. These results were confirmed by studies administering different functional outcome questionnaires, including the Toronto Extremity Salvage Score,27,31 the International Symposium of Limb Salvage System,34 the Paediatric Outcome Data Collection,37 the Short Form-36,39 and the Société Européenne des Tumeurs Osseouses criteria.48 A correlation between prosthesis failure and emotional performance was not detected. However, details of children's everyday activity restrictions were not reported.
Complications of expandable prosthesis insertion were also reported. Stiffness and contractures were the most frequently encountered complications. This is largely due to the formation of a dense pseudocapsule around the prosthesis,5 resulting in restriction of joint motion and preventing lengthening interventions. Surgical release, manipulations under anesthesia, corrective cast application, and early and regular physiotherapy have been proposed as therapeutic measures.43
The studies reviewed had a significant incidence of type IV failures (deep infections) being the leading cause of revision and amputation surgeries in these patients. This increased incidence rate was due to extensive chemotherapy immunosuppression and to soft tissue loss, especially after proximal tibia reconstruction.21 Deep infections were usually a late complication and an absolute indication for revision surgery. Careful debridement, implant removal, placement of an antibiotic spacer, re-implantation, and intravenous antibiotic administration were recommended in these circumstances.23 The application of noninvasive prostheses prevented deep infections by decreasing the frequency of multiple operations,36 eliminating the risk of stretch injury to nerves and vessels and avoiding the extended resection of soft tissues. Indeed, low infection rates have been noted regarding noninvasive prostheses compared with minimally invasive prostheses.29,31,35
Aseptic loosening is another frequently reported complication, having a rate of 8% to 46%.27 Extensive loss of the bone stock in the metadiaphyseal region28 caused by the extensive stress of the cemented stem, micromotions between the polyethylene surface and bone,40 and the accumulation of metal and polyethylene implant debris triggers the osteolytic process, resulting in stem loosening. This mechanism is consistent with the observation that in cases in which a hydroxyapatite-coated collar of the proximal femoral stem was applied, aseptic loosening was not detected.19,43
Mechanical failure was also a common complication. Despite important improvements in the construction of expandable prostheses, failure of the expansion mechanism was not unusual, having a rate of 1.6% (N=13).22,23,26,29,33,36 The strength of current enhanced prostheses and increased surgical experience with the different expansion mechanisms have reduced the frequency of this complication.4
Less frequently reported were angular deformities that resulted from damage to the vascular supply of the growth plate during prosthesis insertion or the formation of a physeal bar that resulted in asymmetrical bone growth.22 Angular deformities were treated by bar resection, epiphysiodesis, and revision of the tibial component.22,37 Other complications included local tumor recurrence and transient peroneal nerve palsy, which commonly resolved after 3 to 6 months and were not related to the type of prosthesis.20 Joint instabilities or dislocations have also been reported, especially after a total femoral replacement reconstruction.24,50 Imbalance between the acetabulum and the bipolar head or the detached abductors and contracted adductors may contribute to the dislocations.24 Although pain, discomfort, and a burning sensation during the elongation process are rare, it has been suggested that lengthening be performed under general anesthesia25 or oral analgesia.11
The major limitation of this review was the heterogeneity of the data, which made accurate comparison of the studies difficult. Furthermore, it has been reported that expandable prostheses are not considered a primary surgical choice by one-third of experienced orthopedic oncologists because of the absence of definite surgical criteria, increased complication rates, and socioeconomic factors such as low implant availability,53 affecting the validity of the data. Variability in treatment protocols, selection criteria, and follow-up periods, absence of classification of disease severity, and missing statistical analysis of outcomes and recovery rates were noted. Because the factors that influence surgical outcome depend on the anatomic region, the additional separation of patients into groups based on this should be considered. Characteristically, the outcome of preservation surgery of the distal femur is defined by the sustained soft tissue and the extensor mechanism.51 Further subdividing patients into groups according to age may be necessary. For example, patients who are classified as being skeletally immature may need a future treatment approach different from those classified as being nearly skeletally mature. Prospective progress in limb-salvage techniques may also influence the overall outcome.