Infected Prostheses after Lower-Extremity Bone Tumor Resection: Clinical Outcomes of 100 Patients

Patients and Methods

From 1983 to 2010, 1,161 patients underwent megaprosthesis reconstruction at the authors' institution after limb salvage surgery for a sarcoma. There were 677 male and 484 female patients with a mean age of 31.2 y (range 7–80 y). The primary diagnosis indicating limb salvage surgery was megaprosthesis reconstruction for osteogenic sarcoma (684 patients), chondrosarcoma (121 patients), Ewing sarcoma (82 patients), other sarcomas (123 patients), bone metastases (37 patients), and aggressive giant-cell tumor (114 patients). The site of reconstruction was the distal femur (743 patients), the proximal tibia (226 patients), the proximal femur (154 patients), the total femur (29 patients), and extra-articular knee resection (nine patients) (Table 1). The types of megaprostheses used differed according to the site of reconstruction and the era (Table 2); 1,067 patients had cementless megaprosthesis reconstructions, whereas the remaining 94 patients had cemented reconstructions. The mean follow-up was 9 y (range 3–20 y); all patients were included in the post-operative follow-up and gave written informed consent for their data to be included in this study. No patients were recalled specifically for this study; all data were obtained from medical records and radiographs. This study was approved by the Institutional Review Board/Ethics Committee of the authors' institution.

At the index operation, all patients received similar intravenous antibiotic prophylaxis for 5 d (Table 3). Adjuvant treatments were administered as indicated by tumor histology; 799 patients were given high-dose neo-adjuvant radiation therapy or chemotherapy. Routine follow-up evaluation was performed every 3 mos for the first 2 y, every 6 mos for the next 3 y, and then annually. Each follow-up evaluation included clinical examination and standard radiographs. All patients had additional oncologic evaluation as indicated.

Megaprosthesis infections were diagnosed by clinical examination and raised erythrocyte sedimentation rate, C-reactive protein, and white blood cell count in joint fluid analysis and documented in cultures obtained during revision surgery. Infections were classified retrospectively as acute (occurring within 4 wks after the operation), early (occurring between 4 wks and 2 y after the operation), and late (occurring thereafter) [18,19].

We evaluated the overall survival of the megaprosthesis reconstructions after definitive management of the infection and survival with respect to the type of megaprosthesis, site of reconstruction, cement or cementless fixation, type of tumor (osteogenic sarcomas/Ewing sarcoma vs. other sarcomas and sarcomas vs. bone metastases), adjuvant treatments, microbial isolates, treatment tactics, and outcome. The survival of the megaprostheses was evaluated using Kaplan-Meier analysis [20]. Differences in survival were determined with the log-rank test. The starting point was the date of implantation of the megaprosthesis and the endpoint the revision of the megaprosthesis or amputation of the leg because of infection. The data were recorded in a Microsoft^® Excel^® 2003 spreadsheet (Microsoft Corporation, Redmond, WA, USA) and analyzed using MedCalc^® Software Version 11.1 (MedCalc Software, Mariakerke, Belgium).

Results

One hundred of the 1,161 patients (8.6%) with reconstructions experienced infection at a mean time of 3.7 y (range 0.5 mo–19 y) after the implantation of the megaprosthesis. The most common microbial isolate was Staphylococcus epidermidis (47 patients) followed by S. aureus (19 patients), Pseudomonas spp. (six patients), other isolates (20 patients), and multiple isolates (eight patients; 8%) (Table 4). There were no cases of culture-negative infections. Eleven of the 100 patients experienced acute, 16 patients experienced early, and 73 patients experienced late megaprosthesis infection. The overall prevalence of infection was higher for late (6.3%) than for early (1.4%) and acute (0.9%) infections (Table 5).

The overall survival rate of the megaprosthesis devices in response to definitive management of infection was 88% at 10 y and 84% at 20 y (Fig. 1A). The Kotz Modular Femur and Tibial Reconstruction System (Stryker Global Modular Replacement System) (KMFTR^®) (Stryker, Inc., Kalamazoo, MI) became infected more commonly than other devices (18 of 160 megaprostheses; 11.3%) compared with the Howmedica Modular Resection System (HMRS^®) fixed-hinge (56 of 653; 8.6%), HMRS^® rotating-hinge (6 of 68; 8.8%), and Global Modular Replacement System (Stryker)(GMRS^®)(20 of 280; 7.1%). The survival rate after definitive management of infection of the KMFTR^® megaprostheses was 92% at 10 y and 84% at 20 y compared with 88% at 10 y and 84% at 20 y for the HMRS^® fixed-hinge, 90% at 10 y for the HMRS^® rotating-hinge, and 86% at 10 y for the GMRS^® (Fig. 1B). The difference was not statistically significant.

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FIG. 1.

Kaplan–Meier survival curves show survival from infection in patients with megaprosthesis reconstructions. (A) Overall survival. (B) Survival in patients with KMFTR^®, HMRS^® fixed-hinge, HMRS^® rotating-hinge, and GMRS^® megaprosthesis reconstructions was not different. See text for definitions. (C) Survival was not different by reconstruction site. (D) Significantly higher survival in patients having cementless megaprosthesis reconstructions than in those having cemented reconstructions.

Proximal tibia megaprosthesis reconstructions became infected more commonly (27 of 226; 11.9%) than extra-articular knee resections (one of nine; 11.1%), distal femur (61 of 743; 8.2%), proximal femur (10 of 154; 6.5%), and total femur megaprostheses (one of 29; 3.4%). Survival in response to definitive management of infection of proximal tibia megaprosthesis reconstructions was 86% at 10 y and 82% at 20 y compared with 88% at 10 y and 82% at 20 y for the distal femur, 88% at 10 and 20 y for the proximal femur, 100% at 10 y and 74% at 20 y for the total femur, and 88% at 10 and 20 y for extra-articular knee resections (Fig. 1C). The difference was not statistically significant.

Ninety-one of the 1,067 patients (8.5%) who had cementless megaprosthesis reconstructions experienced device infections compared with nine of the 94 patients (9.6%) who had cemented megaprosthesis reconstructions. The survival in response to definitive management of infection of the cementless megaprosthesis reconstructions was 90% at 10 y and 86% at 20 y compared with 78% at 10 and 20 y for the cemented megaprosthesis reconstructions (Fig. 1D). Survival was significantly higher for the cementless megaprosthesis reconstructions (p=0.0460).

Ninety-three of the 1,010 patients with sarcomas experienced infection of their megaprosthesis reconstructions compared with seven of the 37 patients with bone metastases. The survival in response to definitive management of infection of the megaprosthesis reconstructions of the patients with sarcomas was 90% at 10 y and 84% at 20 y compared with 68% at 10 y for those with bone metastases (Fig. 2A). Survival was significantly higher for the megaprosthesis reconstructions of the patients with sarcomas (p=0.0001). Seventy-one of the 766 patients with osteogenic sarcomas and Ewing sarcomas experienced infection of their megaprosthesis reconstructions compared with 29 of the 244 patients with other sarcomas. Survival in response to definitive management of infection of the megaprosthesis reconstructions of the patients with osteogenic sarcomas and Ewing sarcomas was 90% at 10 y and 86% at 20 y compared with 90% at 10 y and 84% at 20 y for those with other sarcomas (Fig. 2B). The difference was not significant.

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FIG. 2.

Kaplan–Meier survival curves show survival from infection in patients with megaprosthesis reconstructions by tumor type. (A) Significantly higher survival of patients with sarcomas compared with those with bone metastases (p=0.0001). (B) Survival of patients with osteogenic sarcoma or Ewing sarcomas was not different from that of patients with other sarcomas.

Seventy of the 799 patients (8.8%) who received high-dose neo-adjuvant radiation therapy or chemotherapy experienced infection of their megaprostheses, compared with 30 of the 362 patients (8.3%) who did not receive any adjuvant treatment. The survival rate in response to definitive management of megaprosthesis infection in the patients who were given radiation therapy or chemotherapy was 88% at 10 y and 86% at 20 y compared with 90% at 10 y and 86% at 20 y for those who did not receive adjuvant treatment (Fig. 3). The difference was borderline significant (p=0.5480).

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FIG. 3.

Kaplan–Meier survival curve shows survival from infection of megaprosthesis reconstructions was not different in patients given adjuvant treatments and those who were not (p=0.5480).

Megaprosthesis infections were treated with one-stage revision surgery in 12 patients (12%): 10 patients with acute infection and two patients with early infection. Two-stage revision surgery was undertaken for 83 patients: 14 with early and 69 with late infections (Fig. 4). Amputation was used as the first treatment for five patients with late infection. One-stage revision surgery, which included pulse lavage and replacement of the polyethylene bushes and mobile parts of the megaprostheses without removal of the stems, was used for patients with infections caused by low-virulence susceptible microorganisms, a short duration of symptoms, and a well-fixed and functional implant. Two-stage revision surgery, including pulse lavage and extensive wound debridement, complete removal of the megaprosthesis, and insertion of a temporary aminoglycoside-loaded cement spacer, followed by antibiotic administration for 3 mos and re-implantation thereafter of a megaprosthesis, was undertaken for patients with early and late megaprosthesis infections, persistent infections, extensive osteolysis/bone loss, sinus tract formation, and antibiotic-resistant pathogens. In both one- and two-stage revision procedures, meticulous saline lavage and appropriate timing of adjuvant treatments (at 3–4 wks post-operatively) was done. Amputation as the first treatment for megaprosthesis infection was performed in patients with high-grade late infections caused by antibiotic-resistant pathogens, extensive osteolysis and loosening of the megaprosthesis, and poor soft tissue envelope formation that could not be covered adequately with soft tissue flaps.

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FIG. 4.

Images of 73-year-old male with chondrosarcoma of right distal femur. (A) Coronal T₁-weighted magnetic resonance image of thigh and knee. (B) Anteroposterior (left) and lateral (right) radiographs of right knee after wide resection and distal femoral reconstruction with a GMRS^® megaprosthesis. (C) Anteroposterior (left) and lateral (right) radiographs of knee show removal of megaprosthesis and antibiotic spacer implantation for early Staphylococcus epidermidis infection. Reimplantation of a similar megaprosthesis was done 4 mo after first revision stage. Four years after second stage, patient is asymptomatic without clinical evidence of recurrence of infection. (D) Anteroposterior (left) and lateral (right) radiographs of the right knee show no evidence of megaprosthesis loosening.

Overall, infections resolved completely without evidence of recurrence at the final follow-up in 75% of the 100 patients. Acute post-operative infections resolved completely in eight of 11 patients (72.7%), early infections resolved in 11 of 16 patients (68.7%), and late infections resolved in 56 of 73 patients (76.7%). The remaining 25 patients experienced recurrent infection and were treated with repeat surgical debridements and spacers. Five of these patients experienced resolution of their infection without evidence of recurrence at the final follow-up, whereas four patients died from their tumor before resolution of the infection, and 16 patients (21%) finally underwent amputation because of persistent infection.

Discussion

Megaprosthesis infections typically are low-organism-burden, the pathogenesis of which is related to bacteria harbored by biofilms [21]. The megaprostheses may be colonized by bacteria at the time of implantation, either through direct inoculation or by airborne contamination of the incision [22], or later through hematogenous seeding or contiguous spread [23]. Our results showed an 8.6% infection rate of megaprosthesis reconstructions, which were more commonly late infections caused by S. epidermidis. The survival after definitive management of infection was significantly higher for cementless megaprosthesis reconstructions and for reconstructions in patients with sarcomas. There were no differences in survival with respect to other types of tumors, site of reconstruction, type of megaprosthesis, or adjuvant treatment. One-stage revision was effective for acute post-operative infections, whereas a two-stage revision was necessary for early and late infections. The overall rate of amputation was 21%.

We see five limitations in this study. First, it was retrospective, with the limitations inherent in such studies. Second, the sample is relatively heterogeneous; patients with variable diagnoses of malignant and aggressive benign tumors were included. To avoid confounding the statistical analysis with patients who had a megaprosthesis reconstruction after tumor resection, we excluded patients with massive bone defects after failed total joint arthroplasty who were treated with a megaprosthesis reconstruction within the period of this study. However, we opted to include all tumor patients with a megaprosthesis reconstruction to increase the sample size and the power of our analysis. Therefore, we also included patients with bone metastases treated with megaprosthesis reconstruction and performed an analysis of survival of infection compared with patients with other diagnoses. Although our analysis showed a higher survival rate with definitive management of infection in patients with sarcomas, this finding should be regarded with caution because of the small sample of patients with bone metastases. Third, we did not control for the adjuvant treatments that the tumor patients received because all patients in this series who had adjuvant treatment were given high doses of various chemotherapy agents and radiation therapy regimens. Thus, we compared the survival in response to definitive management of infection of the megaprosthesis reconstructions in patients who had adjuvant treatments and those who did not. Fourth, we found a significantly lower survival rate in response to definitive infection management in cemented than cementless reconstructions. However, the sample of cemented reconstructions was small, and selection bias may be present. Fifth, the follow-up of the HMRS^® rotating-hinge and GMRS^® megaprostheses was brief (less than a decade).

Acute and early post-operative megaprosthesis infections typically are caused by relatively virulent pathogens, whereas late prosthetic joint infections generally are low-grade [22,24]. Staphylococci are the most common pathogens involved in prosthetic joint infections, accounting for about 50% of infections overall, followed by streptococci, enterococci, Enterobacteriaceae, P. aeruginosa, and anaerobic species [14,23,25]. Multiple pathogens are found in approximately 25% of cases, with the most common combination being coagulase-negative Staphylococcus and Enterococcus [14]. However, the presence of multiple pathogens has not been associated with poorer results of treatment of the infection or reduced functional results of the surgery [14]. Patients are considered to have a deep incisional infection if they have evidence of infection and either a positive culture or peri-prosthetic pus and a histologic picture compatible with infection at operation [13]. Radiographs are not useful in early infections but may help exclude other causes of joint symptoms and signs [24]. In chronic infections, radiographs may show bone loss and evidence of loosening around an implant, although these findings are not specific for infection [24]. Magnetic resonance imaging generally is not of value because of the artifact created by the metal prosthesis [24].

Complex arthroplasty and reconstruction procedures, large implants, greater surgical exposure and soft tissue dissection or resection, lack of soft tissue coverage, malignant tumors, previous surgery, long operating times, radiation therapy and chemotherapy, malnutrition, anemia, advanced age, diabetes mellitus, obesity, skin disease, and joint disease are the major factors associated with higher infection rates of megaprostheses compared with conventional arthroplasties [11,14,24,26,27]. Surgical risk factors for infection include revision procedures such as bushing exchange, patellar resurfacing, invasive lengthening of expandable tumor prostheses in children, cemented fixation, and joint as opposed to intercalary prosthetic reconstructions [3,14,28,29]. In a series of patients undergoing limb salvage surgery and megaprosthesis reconstruction, the infection rate in the patients who did not have radiation therapy was 9.8%, compared with 20.7% in those who had pre-operative radiation and 35.3% in those who had radiation therapy post-operatively [30]. Tumor type, local recurrence, and gender of the patient have not been associated with infection risk [14]. Although no statistical relation was found with respect to the site of reconstruction, infection rates were higher at the sites of pelvic, knee, and tibial megaprostheses [14,28,29,31]. A lower risk has been reported for proximal humeral megaprosthesis reconstructions [32,33]. These results imply that adequate soft tissue coverage is essential to prevent infection of oncologic prosthetic reconstructions in these locations [31,34]. A previous study reported higher overall survival and survival in response to infection of cementless compared with cemented megaprostheses [35]. The present study concurs with these reports; cemented fixation was an important independent predictor of survival of infection. There was no difference in survival with respect to the site of reconstruction and the type of megaprosthesis. Additionally, we did not find a significant difference in the survival rate from infection between the patients who had radiation therapy or chemotherapy or both and those who did not. This may be explained by adequate soft tissue coverage and appropriate scheme and timing of adjuvant treatments in cancer patients. However, because we did not control for adjuvant treatments, this finding should be regarded with caution.

The options for management of megaprosthesis infections include no surgery and antibiotic suppression; conservative surgery [24]; amputation, joint arthrodesis, or resection; retention of the megaprosthesis with debridement, lavage, irrigation, and antibiotics; and one- or two-stage revision [24,29]. Conservative surgery involves debridement of a joint with exchange of modular components while retaining the megaprosthesis itself, combined with long-term antibiotic therapy [24]. Conservative surgery may be effective in patients with acute and early infections, a short duration of symptoms, a well-fixed and functional implant, and well-characterized microbiology demonstrating a highly susceptible pathogen [36]. Late megaprosthesis infections have been associated with poor results when treated by lavage, debridement, and prolonged antibiotic administration [37]; eradication of late infections with local treatment alone has been successful in only 6% of these patients [14]. In such cases, removal of the infected megaprosthesis should be performed as either a one- or two-stage procedure, or amputation should be carried out [1,3,11,14,28]. Successful eradication of the infection has been reported in 98% to 100% of the cases with amputation, 72% to 91% of those with two-stage revision, and 42% of those with one-stage revision [14]. In the present series, our treatment approach provided 72.7% resolution of acute, 68.7% resolution of early, and 76.7% resolution of late post-operative megaprosthesis infections. However, amputation was necessary as the first treatment or after persistence of the infection in 21% of the patients with infected megaprostheses.

Previously, we planned revision of megaprosthesis reconstructions for infection based on clinical, laboratory, and imaging findings as well as microbiologic cultures of arthrocentesis fluid. We then treated all our patients with a two-stage revision of their megaprostheses. We saw that the results were not satisfactory; the clinical and laboratory findings in tumor patients often are misleading, and microbiologic cultures from pre-operative arthrocentesis often are not diagnostic. Seeing that most failures of cultures probably were the result of incorrect arthrocentesis, we revised our protocol and performed intra-operative joint fluid analysis and white blood cell counts. Obtaining experience, we considered patients to have a deep incisional site infection if they had clinical evidence of infection with a positive culture or peri-prosthetic pus and histologic features compatible with infection at operation. We also found that one-stage revision was more effective for acute post-operative infections, whereas two-stage revision surgery or amputation was necessary for early, late, and persistent/recurrent infections. Nowadays, based on the experience gained over the years, our decision-making process considers the patients' general health, time of occurrence of the infection, duration of symptoms, and virulence and susceptibility of the pathogen. Intra-operatively, we evaluate the morphology of the site and the stability of the implant. We treat with one-stage revision surgery those patients with acute post-operative megaprosthesis infections caused by low-virulence microorganisms and patients in poor general condition, with a short duration of symptoms, a well-fixed and functional implant, and infections caused by a highly susceptible pathogen. In contrast, we treat with two-stage revision those patients with early and late megaprosthesis infections with persistent and higher-grade infections, extensive osteolysis, megaprosthesis loosening and bone loss, poor soft tissue envelope and sinus tract formation, antibiotic-resistant pathogens, and a failed one-stage procedure. Safety measures also are undertaken, including meticulous wound lavage with physiologic saline and appropriate scheme and timing of adjuvant treatments. Efforts to improve outcome also should consider the acquired knowledge and skills regarding tumor surgery with improved techniques for tumor resection, reduced operative time, adequate soft tissue coverage of the megaprostheses, and improved microbiologic techniques for the diagnosis, prophylaxis, and management of the infection.

In conclusion, megaprosthesis reconstructions may be infected in 8.6% of the cases. Infections are more commonly late, caused by S. epidermidis. The survival rate is higher for cementless megaprosthesis reconstructions and no different with respect to the type of the tumor, type of megaprosthesis, and administration of adjuvant treatments. One-stage revision is effective for acute post-operative infections; however, a two-stage revision is necessary for early and late infections. The rate of amputation because of occurrence or persistence of megaprosthesis infection is 21%.