Abstract
Background
Endoprosthetic reconstruction of massive bone defects has become the reconstruction method of choice after limb-sparing resection of primary malignant tumors of the long bones. Given the improved survival rates of patients with extremity bone sarcomas, an increasing number of patients survive but have prosthetic complications over time. Several studies have reported on the outcome of first endoprosthetic complications. However, no comprehensive data, to our knowledge, are available on the likelihood of an additional complication and the associated risk factors, despite the impact of this issue on the affected patients.
Questions/purposes
(1) What are the types and timing of complications and the implant survivorship free from revision after the first complication? (2) Does survivorship free from repeat revision for a second complication differ by anatomic sites? (3) Is the type of first complication associated with the risk or the type of a second complication? (4) Are patient-, tumor-, and treatment-related factors associated with a higher likelihood of repeat revision?
Methods
Between 1993 and 2015, 817 patients underwent megaprosthetic reconstruction after resection of a tumor in the long bones with a single design of a megaprosthetic system. No other prosthetic system was used during the study period. Of those, 75% (616 of 817) had a bone sarcoma. Seventeen patients (3%) had a follow-up of less than 6 months, 4.5% (27 of 599) died with the implant intact before 6 months and 43% (260 of 599 patients) underwent revision. Forty-three percent of patients (260 of 599) experienced a first prosthetic complication during the follow-up period. Ten percent of patients (26 of 260) underwent amputation after the first complication and were excluded from further analysis. Second complications were classified using the classification of Henderson et al. to categorize surgical results. Briefly, this system categorizes complications as wound dehiscence (Type 1); aseptic loosening (Type 2); implant fractures or breakage and periprosthetic fracture (Type 3); infection (Type 4); and tumor progression (Type 5). Implant survival curves were calculated with the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HR) were estimated with their respective 95% CIs in multivariate Cox regression models.
Results
A second complication occurred in 49% of patients (115 of 234) after a median of 17 months (interquartile range [IQR] 5 to 48) after the surgery for the first complication. The time to complication did not differ between the first (median 16 months; IQR 5 to 57) and second complication (median 17 months; IQR 5 to 48; p = 0.976). The implant survivorship free from revision surgery for a second complication was 69% (95% CI 63 to 76) at 2 years and 46% (95% CI 38 to 53) at 5 years. The most common mode of second complication was infection 39% (45 of 115), followed by structural complications with 35% (40 of 115). Total bone and total knee reconstructions had a reduced survivorship free from revision surgery for a second complication at 5 years (HR 2.072 [95% CI 1.066 to 3.856]; p = 0.031) compared with single joint replacements. With the numbers we had, we could not show a difference between the survivorship free of revision for a second complication based on the type of the first complication (HR 0.74 [95% CI 0.215 to 2.546]; p = 0.535). We did not detect an association between total reconstruction length, patient BMI, and patient age and survivorship free from revision for a second complication. Patients had a higher risk of second complications after postoperative radiotherapy (HR 1.849 [95% CI 1.092 to 3.132]; p = 0.022) but not after preoperative radiotherapy (HR 1.174 [95% CI 0.505 to 2.728]; p = 0.709). Patients with diabetes at the time of initial surgery had a reduced survivorship free from revision for a second complication (HR 4.868 [95% CI 1.497 to 15.823]; p = 0.009).
Conclusions
Patients who undergo revision to treat a first megaprosthetic complication must be counseled regarding the high risk of future complications. With second complications occurring relatively soon after the first revision, regular orthopaedic follow-up visits are advised. Preoperative rather than postoperative radiotherapy should be performed when possible. Future studies should evaluate the effectiveness of different approaches in treating complications considering implant survivorship free of revision for a second complication.
Level of Evidence
Level III, therapeutic study.
Introduction
Endoprosthetic reconstruction of massive bone defects has become the method of choice after limb-sparing resection of primary malignant tumors of the long bones [7, 17]. Modern prosthetic systems are widely available and allow modular reconstruction of bone defects in 1- to 2-cm increments with immediate stability, and postoperatively, they enable early weightbearing, shortening the duration of functional recovery [1, 8, 17]. The downside of megaprostheses is a high rate of revision surgery due to implant complications, with reported 10-year implant survivorship free from revision ranging from 58% to 72% [4, 17, 29].
Given the improved survival rates of patients with extremity bone sarcomas [6, 31], an increasing number of patients have prosthetic complications over time, partly because they are surviving longer than they have in the past [8]. Several studies have reported on the outcome of first prosthetic complication in patients with bone sarcomas and have generally shown that preserving a functional limb is possible in most patients undergoing revision surgery [9, 14, 15]. However, these patients are expected to subsequently have further complications that may result in revision operations, the management of which has recently gained importance [8, 30]. Very few studies have reported on second complications after a first prosthetic complication in oncologic patients, mainly in the context of the probability of reinfection after one- or two-step revision for infected megaprostheses [4, 9, 22, 30]. However, no comprehensive data, to our knowledge, are available on the likelihood of an additional complication and the associated risk factors, despite the impact of this issue on the affected patients. Therefore, we sought to analyze the implant survivorship free from revision for a second complication and factors that were associated with a second complication in patients who were previously revised for a first prosthetic complication.
Specifically, we asked the following questions:
(1) What are the types and timing of complications and the implant survivorship free from revision after first complication? (2) Does survivorship free from repeat revision for a second complication differ by anatomic sites? (3) Is the type of first complication associated with the risk or the type of a second complication? (4) Are patient-, tumor-, and treatment-related factors associated with a higher likelihood of repeat revision?
Patients and Methods
We retrospectively queried our institution’s database and identified 817 patients with megaprosthetic reconstruction after resection of a tumor in the upper or lower limb between 1993 and 2015 using a single modular system (MUTARS™, Implantcast GmbH, Buxtehude, Germany) (Fig. 1). In all, 75% of patients (616 of 817) had a malignant primary bone tumor, 2.7% (17 of 616) had a follow-up of less than 6 months, and 4.5% (27 of 599) patients died with the implant intact before 6 months. A total of 43% (260 of 599) of patients had a complication of the first implant at a median interval of 16 months (IQR 5 to 57) after the primary tumor surgery. Of the complications, 33% (85 of 260) were structural, 22% (58 of 260) were infections, 17% (44 of 260) were aseptic loosening, 17% (43 of 260) were soft-tissue failures, and 12% (31 of 260) were tumor progression. The survivorship free from revision for a first complication was 72% (95% CI 68 to 75) after 2 years and 59% (95% CI 55 to 64) after 5 years. Among the patients who underwent limb-sparing surgery to treat a first complication, 80% (161 of 201) who are not known to have died were seen within the last 5 years in our department.
Fig. 1.
This STROBE diagram shows the inclusion and exclusion of patients in this study.
Megaprosthetic reconstruction was generally used in all patients with planned limb-sparing resection of a primary malignant bone tumor near a joint. We did not use other megaprosthetic implant systems, allograft-prosthetic composites or allograft reconstructions.
Data regarding patient demographics, tumor characteristics, surgical and nonsurgical treatment, postoperative complications and their treatment, the development of local recurrence and metastasis (Table 1), and patient follow-up (Table 2) were retrospectively retrieved from the patients’ medical records and entered into an electronic database. We performed a survival analysis that was based on follow-up data as of July 2018. All patient data were anonymized before analysis. The study was conducted in accordance with the Declaration of Helsinki and approved by our local ethics committee.
Table 1.
Patient demographics and oncologic and surgical details
Table 2.
Demographical and surgical data for all patients, patients with a first complication and patients with a second complication
Classification of Failures
First and second complications were classified according to the system proposed by Henderson et al. [11]. This system defines complications (failures) as those leading to a revision of the prosthesis, including the surrounding bone and soft tissues, or amputation of the affected limb. This system categorizes complications as wound dehiscence (Type 1); aseptic loosening (Type 2); implant fractures or breakage and periprosthetic fracture (Type 3); infection (Type 4); and tumor progression (Type 5). We chose to use the original [11] rather a revised form of this classification, published also by Henderson et al. [12] in 2014 that additionally records pediatric complications (physeal arrest, joint dysplasia) to ensure comparability of our results with those of previous studies, the vast majority of which have used the 2011 version [3, 24].
Depending on the timing of infection (early or late), and considering several factors, such as clinical findings, stem ingrowth, soft tissue conditions and culture results, infected patients were treated either with débridement, antibiotics, irrigation, and implant retention (DAIR), one-stage, or two-stage exchanges. An amputation was performed in 8% (9 of 115) of patients with a second complication if the chance to successfully treat the complication while retaining a functional limb was deemed low or when patients explicitly requested an ablative procedure.
Statistical Analysis
We calculated the duration of follow-up and time to first complication from the date of the primary tumor surgery to the date of the last follow-up or revision surgery. The time to second complication was calculated from the date of revision surgery for the first complication to the date of revision surgery for the second complication. Contingency tables were analyzed using the chi-square test. We checked continuous variables for normality using the Shapiro-Wilk test. Medians with interquartile ranges (IQR) were calculated for non-normally distributed data. We performed nonparametric analyses using the Mann-Whitney U and Wilcoxon signed-rank tests. Implant survivorship free from revision with their respective 95% CIs were calculated with the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HR) were estimated with their respective 95% CIs in multivariate Cox-regression models.
Statistical calculations were performed with SPSS Version 25.0 (IBM Corp, Armonk, NY, USA). All p values were two-sided; a p value < 0.05 was considered significant.
Results
What are the Types and Timing of Complications and Implant Survivorship Free from Revision After the First Complication?
A second prosthetic complication occurred in 49% of patients (115 of 234) who had limb-sparing revision for the first complication after a median interval of 17 months (IQR 5 to 48). Of these complications, 39% (45 of 115) were infections, 35% (40 of 115) were structural complications, 17% (19 of 115) were due to aseptic loosening, 6% (7 of 115) were soft-tissue failures, and 3% (4 of 115) were tumor progressions (Table 3). The survivorship free from revision for a second complication was 69% (95% CI 63 to 75) at 2 years and 46% (95% CI 38 to 54) after 5 years.
Table 3.
Prosthetic complications by anatomic location after exlcusion of patients who underwent an amputation for treatment of first complication
Does Survivorship Free from Repeat Revision for a Second Complication Differ by Anatomic Site?
With the numbers available for our study there was no difference in implant survivorship free from repeat revision among the different anatomic sites of reconstruction (Fig. 2).
Fig. 2.
This graph shows implant survival curves after treatment of the first implant complication according to the anatomic site of reconstruction.
Moreover, we found no differences in the survivorship free from revision for a second complication between upper (12%, 27 of 234) and lower extremity reconstructions (88%, 207 of 234) at 5 years (upper extremity: 59% [95% CI 38 to 79]; lower extremity: 45% [95% CI 37 to 53]; p = 0.23) or between uniaxial (84%, 184 of 234) and polyaxial joints (16%, 36 of 234) at 5 years (uniaxial: 47% [95% CI 39 to 55]; polyaxial: 46% [95% CI 23 to 69]; p = 0.54).
On the other hand, total bone and total knee reconstructions had a reduced survivorship free from revision for a second complication at 5 years compared with other endoprosthetic replacements (HR 2.072 [95% CI 1.066 to 3.856]; p = 0.031) (Table 4).
Table 4.
Multivariate Cox regression analysis of risk factors for second prosthetic complication
Is the Type of First Complication Associated with the Risk or the Type of Second Complication?
The type of first complication was not associated with the implant survivorship free from revision for a second complication in our patient cohort (HR 0.740 [95% CI 0.215 to 2.546]; p = 0.535) (Table 4).
However, we found the type of first complication was associated with the type of second complication. Most patients who had a second complication after treatment for a first structural failure had also a structural failure, while most second complications after treatment for a soft tissue complication or infection were infections (p = 0.003; Table 5).
Table 5.
Association between modes of first and second complication
Are Patient-, Tumor-, and Treatment-related Factors Associated with a Higher Likelihood of Repeat Revision?
With the numbers we had available for this study, we could not show an association between patient age, sex, and current or prior smoking status and BMI and the implant survivorship free from second revision (Table 6). On the other hand, patients with diabetes mellitus at the time of the initial surgery had a higher risk of having a second complication than patients without diabetes (HR 4.868 [95% CI 1.497 to 15.823]; p = 0.009) (Table 4). Infection was the type of second complication in all four patients with diabetes (out of five patients with diabetes with a first complication) who developed a second complication.
Table 6.
Univariate analysis of possible risk factors for second complication
The development of a pathologic fracture before surgical treatment, primary unplanned intralesional excisions, and extra-articular resections was not associated with a worse implant survivorship free from revision for a second complication (Table 6). Furthermore, there were no differences regarding the total reconstruction length during the primary surgery between patients who developed a second complication (median 170 mm; IQR 135 to 220) and those who did not (median 165 mm; IQR 135 to 220; p = 0.709).
Postoperative radiotherapy was associated with a reduced implant survivorship free from revision for a second complication (HR 1.849 [95% CI 1.092 to 3.132]; p = 0.022) whereas preoperative radiotherapy was not (HR 0.953 [95% CI 0.505 to 2.728]; p = 0.709)
Finally, we found no differences in the outcome of patients who were treated before the year 2001 and patients who were treated later in 5-year periods until 2015.
Discussion
Modular megaprostheses have become the reconstructive method of choice for extensive bone defects after surgical resection of primary malignant bone tumors [8]. Many studies have shown that complications related to these implants are relatively common [4, 8, 17, 24], and in the last years a comprehensive classification system has been established, allowing for an easier comparison of the results reported by different centers [11]. However, to our knowledge, only sporadic data have been reported on the risk for a subsequent complication after treatment for a first complication [9, 10, 30]; this is despite the fact that patients today survive longer and are expected to develop more complications over time [8], the development and management of which can have a great impact on function and quality of life. Comprehensive data are necessary to adequately counsel patients and potentially identify possible risk factors. In our analysis, we found that patients treated for any type of first megaprosthetic complication have a high risk for a second complication over time, especially if they have undergone total bone or combined distal femoral and proximal tibial replacement, postoperative radiotherapy for their primary tumor, or have diabetes mellitus.
One of the limitations of our study is its retrospective design, which has several inherent disadvantages, including its reliance on patient records and the possibility for selection bias. These shortcomings would be expected to tend to de-emphasize or underestimate the frequency of complications, and so the estimates of complication frequency and severity made here, if anything, should be considered low-end estimates. Actual risk may be higher than suggested by our analyses. We attempted to minimize the impact of selection bias by analyzing the data of a single tertiary sarcoma center where reconstruction after limb-sparing resections of bone sarcomas in the long bones adjacent to a joint was performed with a single, modular megaprosthetic system.
Another major limitation of our analysis was the limited number of evaluable prostheses in some anatomic sites, such as the distal or total humerus, or patients with relevant comorbidities, such as diabetes mellitus. As a result there was some heterogeneity in our cohort and not all of our results may be applicable to all locations. On the other hand, this is rather a reflection of the anatomical distribution of primary bone sarcomas [2, 26] and of the health status of the mostly young patients, so that we believe that our main findings will be useful for patient consultation in everyday practice. Furthermore, patients were treated over a period of more than 20 years, during which surgical techniques, prosthetic design, surgical treatment of failures, surgeons’ experience, and, to a lesser extent, neoadjuvant and adjuvant treatment regimens have evolved, which might also be a cause for inhomogeneity. However, we examined whether patients treated in different time periods had a different implant survivorship free from revision and found this was not the case in our cohort. Additionally, there is some transfer bias with 10 surviving patients who did not have complications but with a follow-up of less than 2 years; it is possible that these patients might have developed complications and undergone revision surgeries that are unknown to us. On the other hand, to avoid selection bias, we included these patients in our analysis, provided they had a minimum follow-up of 6 months; a quarter of our patients developed complications in the first 5 months after surgery, which is why we felt it would be arbitrary to exclude patients with a longer follow-up but no complications until the last presentation.
Finally, in patients treated for an oncological disease, death represents a competing event when reporting implant-related complications. As a result, a Kaplan-Meier analysis may overestimate the cumulative incidence of complications if many patients in a cohort die before they develop a complication [20]. While we acknowledge the advantages of a competing risk analysis in such a setting, only 13% (31 of 234) of the patients with a first complication died of disease before developing a second complication in our cohort, compared with 49% of patients (115 of 234) who developed a second complication as the event of interest. Furthermore, even in this setting, the Kaplan-Meier method is still considered useful for counseling individual patients on their risk of developing a complication, while the estimates produced with the competing-risk method are more appropriate to inform healthcare planning and policy decisions [20]. Considering these points, we opted for a Kaplan-Meier analysis to make this study more comparable to the existing reports on prosthetic complications [4, 24].
Our results demonstrate that the implant survivorship free from revision after a first complication in patients with bone sarcomas undergoing megaprosthetic reconstruction is less than 50% after 5 years, with 49% of patients (115 of 234) with a first complication developing a second complication after a median interval of 17 months. Most second complications in our cohort were infections, followed by structural failures. To our knowledge, ours is the first study to systematically evaluate this issue in oncological patients. In an analysis of infectious complications, Sigmund et al. [30] also found that that a high rate (46%, 38 of 83) of the oncological patients in their cohort developed a second prosthetic infection after treatment for first megaprosthetic infection, with an implant survivorship free from reinfection of 39% after one-stage revision and 48% after two-stage revision at 5 years [30]. Our results suggest that all oncological patients treated for a first megaprosthetic complication should undergo regular orthopaedic follow-up to detect a second complication early.
There were no differences in implant survivorship free from repeat revision over time among the anatomic sites we compared in our cohort (Fig. 2), nor did we find differences between upper and lower extremity reconstruction or uni- and polyaxial joints. Several studies have demonstrated that the implant survivorship from first revision varies greatly depending on the anatomic site of reconstruction [9, 11, 17, 23, 27]. Given the limited numbers of second complications in some of our anatomic site groups (Table 3), it remains unclear whether our findings are due to the small sample size or whether the impact of the anatomic site of reconstruction on second implant complications is limited compared with its effect on first complication. Given the very low incidence of sarcomas in some anatomic sites [2, 26], only large multicenter collaborative studies will likely be able to effectively address this question. On the other hand, implant survivorship free from revision for a second complication was lower for total bone and total knee (combined distal femoral and proximal tibial reconstructions) compared with other endoprosthetic replacements. These extensive reconstructions are sometimes necessary in patients with locally advanced tumors, skip lesions, pathologic fractures, or previous unplanned tumor excisions contaminating healthy structures [28, 32], and patients should be aware of the high risk of second complications when considering the treatment of first implant complication, especially if further risk factors for a complication are also present. Future analyses of patients with total bone and total knee reconstructions should evaluate the frequency of further revision procedures and the risk for secondary amputation over time after a first complication in detail, as well as possible differences in outcome after different treatment strategies.
An unexpected finding of our study was that the type of first complication in our cohort was not associated with implant survivorship free from repeat revision in uni- and multivariate analysis. On the other hand we did find an association between the type of first complication and the type of second complication (Table 5). Although previous studies have also reported that patients undergoing revision for component exchange [16], wound healing disorders [10], or implant infection [30] have a higher risk for subsequent implant infections compared with patients who had not undergone revision surgery, our study is the first, to our knowledge, to comprehensively evaluate the probability of a repeat revision for any complication after treatment of the first complication. Our results suggest that the implant survivorship from repeat revision in oncological patients may be equally poor regardless of whether the first complication was a minor revision due to a bushing wear or a two-step prosthetic revision due to infection, but, obviously, this finding should be validated in future studies evaluating different implant systems.
After controlling for relevant confounding variables, we found that diabetes mellitus and postoperative radiotherapy were associated with an increased risk for a second complication, while preoperative radiotherapy, as well as patient age and BMI at diagnosis, were not. The influence of diabetes mellitus on first megaprosthetic complications remains unclear. While it is an established risk factor in nononcologic reconstructions [21], studies on sarcoma patients undergoing megaprosthetic replacement have not demonstrated an increased risk of first prosthetic complication in patients with diabetes mellitus [22, 25]. Patients with diabetes in our series had a very poor implant survivorship free from repeat revision of 20% at 5 years and an HR of 4.87 for developing a second complication, but larger studies will need to verify its true impact on repeat revision given the low numbers of patients with diabetes in our cohort. Regarding radiation treatment, its use has been shown to have a positive influence on the prognosis of patients with Ewing’s sarcoma in particular [19, 33]; however, the most appropriate timing of treatment is still debatable. Preoperative radiation treatment is associated with a lower dose and smaller radiation field, but also with a higher rate of early wound complications. On the other hand, postoperative radiotherapy involves larger fields and higher doses, leading to a higher probability of late effects, such as fibrosis [5, 13]. Jeys et al. [18] have reported that preoperative and postoperative radiotherapy are associated with a higher risk of first prosthetic infection and that the risk appears to be higher after postoperative radiation treatment. Based on our results, we propose that preoperative rather than postoperative radiotherapy should be preferred, whenever possible, in patients with bone sarcomas undergoing endoprosthetic replacement, provided that the decision for radiation treatment is taken before surgery.
In conclusion, bone sarcoma patients who undergo revision to treat a first megaprosthetic complication should be counseled regarding the high risk for future complications, especially if they have diabetes or have had a total bone or a combined distal femoral and proximal tibia replacement. Considering that the interval between the first and second complication is relatively short, we recommend regular orthopaedic follow-up visits after the treatment of the first complication. Whenever possible, preoperative rather than postoperative radiotherapy should be performed during primary tumor treatment. Future studies should evaluate the effectiveness of different approaches in treating complications in terms of the implant survivorship free of revision for a second complication.
Acknowledgments
We thank all our patients and their families for their continuous support of our work and acknowledge the physicians, nurses, and support staff who contributed to the treatment of the patients included in this study.
Footnotes
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.
One of the authors certifies that he (JH), or a member of his immediate family, has received or may receive payments or benefits, during the study period, in an amount of USD 10,000 to USD 10,0000 from Implantcast GmbH (Buxtehude, Germany). One author certifies that he (GG), or a member of his immediate family, holds a patent for silver coating of metallic prosthesis and has or may receive payments of USD 10,000 to 100,000 from Implantcast GmbH (Buxtehude, Germany). Other authors certify that they (CT, ND, RD, DA) have received or may receive travel expenses during the study period amounting to less than USD 10,000 from Implantcast GmbH, Buxtehude, Germany.
Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.
Each author certifies that his institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
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