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a The authors contributed equally to this article.
Affiliations
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science China, 100730, Beijing, China
a The authors contributed equally to this article.
L.J. Yu
Footnotes
a The authors contributed equally to this article.
Affiliations
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science China, 100730, Beijing, China
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science China, 100730, Beijing, China
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science China, 100730, Beijing, China
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science China, 100730, Beijing, China
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science China, 100730, Beijing, China
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science China, 100730, Beijing, China
The surgical choice for grade 1 chondrosarcoma has been debated for decades. Intralesional resection can minimize the damage caused by surgery and offer better functional outcome. However, controversy remains about whether it will result in higher rates of local recurrence and metastasis, fewer complications, and better functional outcome compared with resection with wide margin. This systematic review and updated meta-analysis therefore compared intralesional resection and resection with wide margin in terms of local recurrence, metastasis, complications, and functional outcome.
Methods
Medline, Embase, and the Cochrane Library were comprehensively searched in December 2016 to identify studies comparing intralesional resection and resection with wide margin for central grade 1 chondrosarcoma. Data of interest were extracted and analyzed using Review Manager 5.3.
Results
Ten studies involving 394 patients were included, with 214 patients who had intralesional resection and 180 patients who had resection with wide margin for grade 1 chondrosarcoma. Intralesional resection was associated with lower complication rates (P < 0.0001) and better Musculoskeletal Tumor Society score (MSTS). There were no significant differences in terms of overall local recurrence (P = 0.27), local recurrence based on adjuvant therapies (P = 0.22), local recurrence in studies that included lesions of the hand, foot, pelvis, and axial skeleton (P = 0.55), and metastasis (P = 0.74) between groups.
Conclusion
Intralesional resection provides lower complications and better functional outcome with no significant increase in the risk of recurrence and metastasis. We think it is a suitable treatment for central grade 1 chondrosarcoma.
Surgical treatment of chondrosarcoma aims to minimize the risk of recurrence and metastasis while maximizing patients' functional outcome and reducing the damage caused by surgery. Intralesional resection was recommended in the treatment of grade 1 chondrosarcoma to minimize local recurrence while preserving function.
Most studies reporting on this issue were retrospective studies with small cohorts. A previous meta-analysis on this subject was published in 2010, and it compared the overall local recurrence and metastasis between these two surgical techniques. However, more studies were published regarding this issue since 2010. In our current meta-analysis, we are able to evaluate the complications, metastases, functional outcome, and recurrence based on different anatomic sites and the use of adjuvant therapies with more studies and cases involved. Therefore, an updated meta-analysis and systematic review was conducted to compare the safety and efficacy of intralesional resection and resection with wide margin for patients with central grade 1 chondrosarcoma.
Material and methods
Search strategy
Medline, Embase, and the Cochrane Library were comprehensively searched by two independent researchers in December 2016. Search terms included chondrosarcoma, low grade, grade 1, surgery, and relative MeSH terms. Additional studies were identified from references of retrieved articles.
Inclusion and exclusion criteria
Clinical trials were included if they (1) involved patients undergoing surgical treatment of primary grade 1 chondrosarcoma of bone, (2) compared intralesional resection and resection with wide margin (including marginal resection, wide resection and radical resection), and (3) had a minimum follow-up period of 24 months. Studies were excluded if they were (1) conference abstracts, animal studies, cadaveric studies, in vitro studies, or articles published in a form other than clinical trials, (2) studies without quantitative data, (3) studies without specific outcomes on cases that underwent intralesional resection and resection with wide margin for central primary grade 1 chondrosarcoma, or (4) studies that included lesions of the skull.
Data extraction and quality assessment
Data collected from cases with primary grade 1 chondrosarcoma were extracted and analyzed by two researchers. The cases were reviewed and screened carefully for data of interest. The level of evidence of studies was determined based on the CEBM Level of Evidence 1 (2009), and the quality of studies was estimated according to the Newcastle–Ottawa Scale (NOS).
Statistical analysis
This meta-analysis was conducted using Review Manager 5.2 (Cochrane Collaboration, Oxford, UK). Discontinuous variables were analyzed by odds ratios (OR). Pooled analysis was performed with parameters with sufficient data, and 95% confidence intervals (CIs) were recorded. Heterogeneity among the studies was assessed using the chi-squared and I-squared (I2) tests. A fixed effect model was applied when I2<50%, whereas a random effect model was applied when I2>50%. A P value < 0.05 was considered statistically significant. Funnel plots were used to assess potential bias.
Results
Literature search
A comprehensive search of Medline, Embase, and the Cochrane Library yielded 752 articles. After careful screening, 10 studies with 214 patients who underwent intralesional resection and 180 patients who underwent resection to achieve wide margin were included in this meta-analysis (Fig. 1). Five studies were included despite the fact that they included cases with recurrent chondrosarcoma because sufficient data were acquired to exclude the individuals who were not presented with central primary grade 1 chondrosarcoma.
The basic characteristics of the studies involved in this meta-analysis are listed in Table 1. All 10 studies were retrospective with small cohorts due to the rare incidence of grade 1 chondrosarcoma. All studies compared clinical outcomes between intralesional resection and resection with wide margin for central primary central grade 1 chondrosarcoma. Quality of included studies was assessed based on the NOS quality score by two researchers, and all studies yielded moderate quality, with an average score of 5.7 (ranging from 5 to 7). Parameters including local recurrence, metastasis, and complications were analyzed.
Table 1Study characteristics.
Author
Level of evidence
Design
Matching
Patient Number
Follow-up
Quality Score
Country
Demographics
IC
WR
Aarons 2009
3b
R
1
17
15
56vs88
******
US
Bauer 1995
3b
R
NS
24
16
84
*******
Sweden
de Camargo 2010
3b
R
NS
19
4
94.8
******
Brazil
Campanacci 2013
3b
R
NS
64
21
67
*****
Italy
Chen 2016
3b
R
3
7
4
72.9vs61.3
*****
China
Donati 2010
3b
R
NS
14
13
157
******
Italy
Etchebehere 2005
3b
R
NS
11
6
71.9
*****
Brazil
Funovics 2011
3b
R
NS
33
28
81
******
Austria
Gunay 2013
3b
R
1,2
13
17
73vs75
*****
Turkey
Leerapun 2007
3b
R
1,2
13
57
102
******
US
1. Age; 2. Gender; 3. Lesion size; NS: not specified.
All studies had a minimum follow-up period of 2 years; the mean follow-up period of included studies ranges from 56 months to 102 months. The diagnosis of grade 1 chondrosarcoma was multidisciplinary and was a joint decision based on clinical, radiographical and histological features. The surgical staging was made according to Enneking et al.
The reason for surgical choice between intralesional resection and excision with wide margin was not specified in nine studies, and was discussed in one study. In this study, wide resection was performed in cases with aggressive radiologic findings, whereas the rest with intralesional resection.
Local recurrence was reported in all 10 studies; there were 21 of 214 cases that underwent intralesional resection that had local recurrence, and 9 of 180 cases that underwent resection with wide margin had local recurrence. Pooled analysis showed no significant difference with low heterogeneity (OR: 1.59, 95% CI: 0.70–3.62, P = 0.27, I2 = 0%) (Fig. 2a). Six of the 10 studies used adjuvant therapies only in all cases that underwent intralesional resection (phenol, alcohol, nitrogen PMMA packing, and electro-cauterization). Pooled analysis of these six studies also showed no significant difference in local recurrence (OR: 1.89, 95% CI: 0.69–5.00, P = 0.22, I2 = 0%) (Fig. 2b).
Figure 2a. Overall recurrence. b. Recurrence with adjuvant therapies. c. Recurrence of studies including lesions of the hand, foot, pelvis, and axial skeleton.
Local recurrence was also analyzed based on anatomic site. Pooled analysis of five studies showed no significant differences between intralesional resection and resection with wide margin in femur, tibia, and humerus (Table 2).
We also conducted a pooled analysis of studies including lesions of the hand, foot, pelvis, and axial skeleton and excluded the studies that only reported the lesions of long bones of the appendicular skeleton, which showed no significant differences in terms of local recurrence (OR: 1.44 95% CI: 0.44–4.68, P = 0.55, I2 = 0%) (Fig. 2c).
Metastasis
All 10 studies were included in the pooled analysis of metastasis, with a total of one metastasis in patients who underwent intralesional resection, and four metastases in patients who underwent resection with wide margin. Three patients developed lung metastasis within 1 year after index surgery, one after intralesional resection and two after wide resection. One patient developed multiple metastases in the lung, deltoid muscle, and abdomen 3 years after wide resection, and the histology upgraded to grade 2 chondrosarcoma. One patient developed lesion in the ipsilateral tibia 6 years after the first resection. There was no significantly difference found (OR: 0.74, 95% CI: 0.12–4.64, P = 0.74, I2 = 25%) (Fig. 3).
which showed significantly fewer complications in patients who underwent intralesional resection (OR: 0.12, 95% CI: 0.05–0.31, P < 0.0001, I2 = 27%) (Fig. 4). There were 30 major complications reported, with detailed information listed in Table 3.
Functional outcome was specifically reported in two studies using Musculoskeletal Tumor Society score (MSTS). Both showed a significant difference, in favor of the intralesional resection group.
also reported a better functional MSTS in patients treated with intralesional resection, whereas none of the 15 patients in the intralesional resection group in one study and four of the six patients in the intralesional resection group in the second study scored 50% or less.
Publication bias
One funnel plot was drawn for which we suspected potential publication bias. The overall recurrence was evaluated using a standard-error based funnel plot with fixed effect size. Outcomes from 10 studies were within the 95% CIs and were symmetrical (Fig. 5).
Sensitivity analysis was conducted by excluding studies with fewer than 20 cases and studies that applied wide resection in cases with aggressive radiologic findings. Sensitivity analysis did not have a significant impact on our results in terms of overall recurrence, recurrence with adjuvant therapies, metastasis, and complications.
Discussion
It is essential to combine radiographic interpretation and clinical evaluation with histologic findings to achieve an accurate preoperative diagnosis of central grade 1 chondrosarcoma,
which was conducted in all included studies. While histologic grading is one of the most valuable predictors of clinical course in chondrosarcoma patients, histologic diagnosis of grade 1 chondrosarcoma can be quite a challenge when differentiating it from enchondroma due to inter-observer variability, various finding in related literature and the rarity of chondrosarcoma.
We reviewed the included studies and their references on histological grading if accessible. Following characteristics were often utilized when diagnosing grade 1 chondrosarcoma: permeative growth into bony trabeculae, cellularity of the specimen, the identification of double- or multinucleated cells and increased size of nuclei.
Surgical treatment for grade 1 chondrosarcoma has been debated for decades. The damage caused by excessive resection should be avoided as much as possible on the basis that adequate surgical margin is achieved.
Local recurrence of grade 1 chondrosarcoma can progress in malignancy, which may influence patient survival.
This is a reasonable suggestion, although more evidence may be needed to prove this theory in chondrosarcoma, and the reliability of radiologic evaluation of chondrosarcoma remains questioned.
Most studies included in our analysis did not specify on what grounds they chose between intralesional resection and excision with wide margin; only one study stated that they chose resection with wide margin for patients with aggressive radiologic findings.
Sensitivity analysis showed no difference when this was excluded. More studies are needed to explore the exact indications for these two surgical techniques.
Adjuvant therapies after intralesional resection were reported to achieve local tumor control
Adjuvant therapies adopted varied: phenol, cryosurgery, and cauterization with polymethyl methacrylate (PMMA) packing are among the most common adjuvant therapies for chondrosarcoma after intralesional resection.
Our meta-analysis showed that intralesional resection does not significantly increase the risk of local recurrence with or without adjuvant therapies. Phenol plus ethanol and cryosurgery were reported to be equally effective as adjuvant therapies for low-grade chondrosarcoma.
reported no recurrence after curettage with cryosurgery in a series of 15 cases. In our meta-analysis, phenol, alcohol, nitrogen, and electro-cauterization were used as adjuvant therapies. We failed to compare different adjuvant therapies and their influence on local recurrence because the number of studies is limited and different types of adjuvant therapies were used in the same cohort in some studies. Thus far, current studies failed to demonstrate that one adjuvant therapy was superior to the others.
There were also no significant differences show when anatomical sites were taken into account. Grade 1 chondrosarcoma of axial skeleton, foot, hand, and pelvis was associated with higher biologic aggressiveness
However, lesions located in the hand, foot, pelvis, and axial skeleton were included in our meta-analysis, the results of which did not show a significant increase in the risk of local recurrence or metastasis. We also conducted a pooled analysis of studies including lesions of the hand, foot, pelvis, and axial skeleton to see whether there would be an increased risk of local recurrence when lesions of these anatomic sites are taken into account, the results of which also showed no significant difference. We were able to collect enough data to evaluate lesions of femur, tibia, and humerus, respectively. Three pooled analyses all showed no significant difference in local recurrence. Despite the fact that chondrosarcomas of the axial skeleton, pelvis, foot, and hand are different in their biologic behaviors and prognoses,
the results of our meta-analysis suggest that the application of intralesional resection is not limited by the anatomic site of chondrosarcoma (lesions of the skull were not discussed in this analysis).
The impact of local recurrence on patient survival is critical, as it may present as an aggressive phenotype and may develop to higher-grade lesions.
The mean follow-up time of included studies ranges from 56 to 102 months, which is considered reasonable by us. If the recurrence remains solitary grade 1 chondrosarcoma, a repeat intralesional curettage might be recommended
We did not conduct a pooled analysis of metastasis based on the use of adjuvant therapies or anatomic site due to the rare incidence of metastasis in included studies. All patients with metastasis included in our study developed lung metastasis. A chest radiograph may be recommended in the case of suspected metastasis. Other excessive exposure to computed tomography (CT) scans might be avoided due to the rare incidence of metastasis reported in included studies.
Complication rates after intralesional resection are significantly lower than those for resection with wide margin according to several studies.
Our study found significantly fewer complications after intralesional resection, which may significantly improve patients' satisfaction. According to our analysis, complications after wide resection were mainly prosthesis-related, and this may be the result of the frequent need for major endoprosthetic reconstruction.
Major complications like fractures, loosening, and infection were more prominent in the wide resection group, patients with these complications often need second surgical treatment, leading to poor functional outcome and prolonged hospital stay.
Functional outcome was assessed by MSTS score in most current studies.
We did not conduct a pooled analysis because of the lack of sufficient data. Resection with wide surgical margin has been associated with poor functional outcome and morbidity. Limb salvage with wide resection may be difficult, especially in the case of local recurrence.
which included five studies with 190 patients. They reported no significant difference in terms of overall local recurrence and metastasis. Our meta-analysis included 10 studies with 394 patients. With more studies and cases involved, we were able to compare the complications, functional outcomes, and recurrence based on different anatomic sites and adjuvant therapies for the first time, which showed significant fewer complications, better functional outcome in the patients who underwent intralesional resection, and no significant difference in recurrence between the two groups. In addition, our results regarding overall recurrence and metastasis are consistent with the previous meta-analysis.
Limitation
Our study has several limitations, as follows. 1. All studies included were retrospective studies, which limited the quality of this meta-analysis. 2. Patients were not randomized or standardized between or within cohorts. With respect to selection bias, some studies claimed that resection with wide margin would be preferred in the presence of radiologic aggressiveness and lager lesion size due to the potentially higher risk of recurrence. However, only one study included specified the selection process, and selection bias is almost inevitable in retrospective studies. 3. The studies included involved small cohorts due to the rare incidence of chondrosarcoma, and the sample sizes are smaller when categorized by anatomic sites, which may lead to failing to detect statistical significance if it did exist. 5. The mean follow-up time was not consistent among involved studies, and studies have reported that grade 1 chondrosarcoma can recur 10–20 years after treatment.
6. Marginal resection, wide resection and radical resection were categorized into the group of resection with wide margin due to the rare incidence of chondrosarcoma and the lack of detailed report in literature. It is possible that the surgical margin was recorded as intralesional resection based on surgical outcome whereas it was planned to be a marginal resection initially. However, our analysis aims to discover the influence of surgical margin has on patient outcome, rather than the surgical technique to achieve certain surgical margin. 7. Suffering from inter-observer variability, various finding in related literature and the rarity of chondrosarcoma, the differential histologic diagnosis between grade 1 chondrosarcoma and atypical enchondroma (or borderline chondrosarcoma) may be controversial in some circumstances despite all studies stated to have reached histological diagnosis of grade 1 chondrosarcoma. However, it has been reported that atypical enchondroma (or borderline chondrosarcoma) follows a rather malignant clinical process with local recurrence and metastasis reported,
thus we consider our analysis legitimate despite of the potential controversy on this matter.
Strengths
Our meta-analysis also had several strengths. 1. This meta-analysis further investigates the complications, metastasis, and local recurrence based on anatomic site and adjuvant therapies with more studies and cases involved and explores the potential causes for any differences. 2. Relevant articles in all languages were screened carefully by two independent researchers using a wide range of search terms. 3. Clear exclusion and inclusion criteria were used. 4. The quality of all studies was assessed by NOS quality assessment score. 5. Due to the rare incidence of grade 1 chondrosarcoma, this meta-analysis gathers valuable information to conduct a quantitative analysis with a relatively large number of cases. 6. Randomized controlled trials are not feasible in this case; therefore, this meta-analysis gathers data from retrospective studies and provides the best evidence available.
Conclusion
Today, the 10-year survival rate for chondrosarcoma has reached 79–100%.
With regard to grade 1 chondrosarcoma, we found no significant difference in local recurrence between intralesional resection and wide resection with or without adjuvant therapy. Neither was the metastasis rate higher with intralesional resection. Intralesional resection offers significantly lower complication rates and better functional outcome. Randomized trials are not feasible due to the rare incidence of this disease. Therefore, this meta-analysis provides the best evidence available, and we support intralesional resection as a safe and function-preserving treatment for central primary grade 1 chondrosarcoma.
Conflict of interest statement
We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled.
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