|Year : 2020 | Volume
| Issue : 1 | Page : 67-73
The outcome comparison of limb salvage surgery versus amputation for high-grade osteosarcoma: A systematic review and meta-analysis of the last 7-year studies
Sherly Desnita Savio, Maria Florencia Deslivia, Putu Astawa, I Gede Eka Wiratnaya
Department of Orthopaedics and Traumatology, Faculty of Medicine, Udayana University, Sanglah General Hospital, Denpasar, Bali, Indonesia
|Date of Submission||26-Nov-2019|
|Date of Acceptance||02-Mar-2020|
|Date of Web Publication||26-Jun-2020|
Dr. Sherly Desnita Savio
Department of Orthopaedics and Traumatology, Faculty of Medicine, Sanglah General Hospital, Udayana University, Jl. Diponegoro, Dauh Puri Klod, Denpasar, 80113, Bali
Source of Support: None, Conflict of Interest: None
Introduction: Until now, the decision to choose between limb salvage surgery (LSS) and amputation for high-grade osteosarcoma has been controversial. Both techniques keep on progressing, thus necessitating updated analysis of each outcome. Materials and Methods: A systematic search was conducted to identify studies through PubMed, Google Scholar, and Cochrane database to identify relevant articles. A total of four studies (173 patients) from the year 2012 were included in the analysis and for the meta-analysis of the Musculoskeletal Tumor Society (MSTS) functional score, random effect model was used to pool the result. In each study, mean difference with a 95% confidence interval (CI) was calculated for continuous outcomes using review manager. Results: Four studies containing 173 patients were included in this study. Patients' characteristics, treatment methods, and outcome were compared for each treatment option. The mean MSTS score at final follow-up for LSS group (n = 112) was 80.2, as for amputation group (n = 61) was 59.3. There was a significant difference in terms of postoperative functional outcome using MSTS score between LSS and amputation (heterogeneity, I2 = 88%; weighted mean difference, 20.64; 95% CI: 9.86–31.43; P = 0.0002). The pooled data showed that the functional outcome, as shown by the MSTS score is better in the LSS group. Conclusion: The current meta-analysis suggests that LSS procedure is superior compared to amputation in terms of the functional outcome as measured by the MSTS score. Although the metastatic and 5-year survival rate is lower in LSS, adjuvant chemotherapy should be considered in certain patients, in order to maximalize recurrence and overall outcome.
Keywords: Amputation, limb salvage surgery, osteosarcoma
|How to cite this article:|
Savio SD, Deslivia MF, Astawa P, Wiratnaya I G. The outcome comparison of limb salvage surgery versus amputation for high-grade osteosarcoma: A systematic review and meta-analysis of the last 7-year studies. J Orthop Traumatol Rehabil 2020;12:67-73
|How to cite this URL:|
Savio SD, Deslivia MF, Astawa P, Wiratnaya I G. The outcome comparison of limb salvage surgery versus amputation for high-grade osteosarcoma: A systematic review and meta-analysis of the last 7-year studies. J Orthop Traumatol Rehabil [serial online] 2020 [cited 2021 May 8];12:67-73. Available from: https://www.jotr.in/text.asp?2020/12/1/67/287718
| Introduction|| |
Osteosarcoma is the most common primary bone malignancy derived from primitive bone-forming mesenchymal cells. The epidemiology of osteosarcoma represents bimodal age distribution, where it increases with age until around puberty, and followed by a plateau between 25 and 60 years old. The second smaller peak is observed during the seventh and eighth decades of life, frequently related to Paget's disease.,, Although osteosarcoma represents only 0.2% of all malignant tumors, it is a disabling systemic disease that needs proper and wise treatment choice to enhance survival rate and patient's quality of life.,,
Few decades ago, amputation was the mainstay of treatment for osteosarcoma, but 80% of patients would still die due to metastasis even after amputation. The psychological trauma of amputation and fear of the disease should also be considered as it leads to dual mental trauma to the patient. As research and technology keep on progressing, limb-salvage procedure starts to be considered as another treatment of choice. Limb salvage itself refers to successful safe margin resection of a tumor and reconstruction of a viable, functional extremity. While this option is newer, it becomes more and more considered, as it seems to give promising functional outcome.
As for high-grade osteosarcoma, the decision to choose between limb salvage surgery (LSS) and amputation is still controversial. A meta-analysis by Han et al., was performed to compare the outcome of both treatment methods, however recent advancement of both methods necessitates an updated analysis. The Musculoskeletal Tumor Society (MSTS) score offers an objective assessment method (score range of 0%–100%) for the functional outcome of these patients, from the perspective of pain, function, emotional acceptance, manual dexterity/gait, hand positioning/use of supports, and lifting/walking ability., We performed this meta-analysis to summarize the functional outcome of the two treatment options, as measured by MSTS score, as well as a systematic review to summarize patients' characteristics and overall outcome.
| Materials and Methods|| |
The study design was a meta-analysis over numbers of randomized controlled trials (RCTs) and nonrandomized comparative studies. A systematic search was conducted based on the PRISMA guideline to identify studies through PubMed, Google Scholar, and Cochrane database to identify relevant articles, which was searched up to March 2019 using keywords included “amputation,” “limb salvage surgery,” “osteosarcoma,” and “MSTS” [Figure 1].
Those data were manually scanned and reviewed with inclusion criteria as follows: (1) the studies included a comparative design for LSS versus amputation, (2) patients with high-grade osteosarcoma in any location, (3) studies directly comparing LSS with amputation, (4) the studies reported a desirable outcome with continuous variable, as measured by MSTS score, and (5) the studies from publication year of 2012 and later. Exclusion criteria were those with bone tumor other than osteosarcoma, infection, or deformity; noncomparative studies, nonhumanin vivo andin vitro were excluded. Studies published before the year 2012 were also excluded, to ensure covering on the latest trends of treatment. [Table 1] describes the inclusion and exclusion criteria.
Due to the limitation of comparative studies in this topic, and to summarize the latest trend of treatment for the case, a total of four studies (173 patients) from the year 2012 were included in the analysis and random effect model was used to pool the result. The data extraction was collected under basic characteristics and outcome presented as the MSTS score. In each study, mean difference with a 95% confidence interval (CI) was calculated for continuous outcomes using Review Manager (RevMan) Version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).
| Results|| |
Based on the results of systematic review, there are four studies analyzed by meta-analysis. All of the studies included used cohort retrospective study design (Level III evidence), as described in [Table 2]. The sample age ranges from 3 to 78 years old. Men are slightly more often affected than women, and the most common location is the knee region (proximal tibia or distal femur). The most common histologic feature is conventional osteosarcoma, whereas the size of the tumor is mostly >8 cm, resulting in wide margin resection. Some comorbidities that might affect the outcome are poor general condition and anemia. Patients' response to chemotherapy varies, however tumor necrorsis percentage of more than 90% is considerable responsive in most literatures [Table 3]. From a total of 173 patients, 112 patients were treated with LSS, while 61 patients were treated with amputation. Resection was wide in most patients, and chemotherapy was indicated for the majority of patients [Table 4]. Within 8–268 months' follow-up, the recurrence rate is higher in LSS than amputation group. However, LSS procedure benefits in lower metastasis rate and higher survival rate. Lungs remain the most common location for metastasis. Some of the most common complications found are delayed union, nonunion, fracture, and infection [Table 5].
We performed meta-analysis to compare the functional outcome of these patients using MSTS score. As shown in [Figure 2], there was significant difference in terms of postoperative functional MSTS score between LSS and amputation procedure (heterogeneity, I2 = 88%; weighted mean difference, 20.64; 95% CI, 9.86–31.43; P = 0.0002). The mean MSTS score at final follow-up for LSS group (n = 112) was 80.2, as for amputation group (n = 61) was 59.
|Figure 2: Forest plot showing the weighted mean difference in Musculoskeletal Tumor Society score (with 95% confidence intervals) for limb salvage surgery versus amputation. DF: Degrees of freedom, IV: Inverse of variance, SD: Standard deviation|
Click here to view
| Discussion|| |
Osteosarcoma is a highly malignant primary bone tumor originating from mesenchymal cells, most probably the osteoblastic lineage of the bone. The knee area is the most common region affected, followed by proximal humerus.,, As a disabling disease affecting mostly relatively young and active patients, the mainstay of treatment method plays an important role in increasing their quality of life, one of them is by maximalizing the outcome postoperatively. While the controversies between choosing LSS or amputation have long been ongoing, the trend now has shifted as the development of technology and knowledge.,
Contrary to the 1990s era, orthopedic surgeons nowadays prefer LSS almost twice as much as amputation as the treatment of choice for high-grade osteosarcoma. This trend differs from the era before, where amputation was performed more frequently while LSS was still starting to develop in techniques. Amputation generally results in more postoperative pain, worse emotional acceptance, and increased need for assistive walking devices, whereas LSS seems to allow the survivors to return to almost normal life, though the technological feasibility was much less at that era. As the time goes, the advancement of technology enables maximalizing LSS procedures, resulting in better outcome compared to the conventional amputation method, especially in terms of functional outcome.,,,
The development of musculoskeletal imaging makes it more possible to precisely define the borders of tumor infiltrating surrounding tissues, aiding surgeon's decision for resection margin, and furthermore resulting in better overall outcome. Whereas new surgical techniques in LSS, such as compressive osseointegration, developments in endoprosthetic design, and bone graft reconstruction make LSS a more preferred method of treatment in achieving promising outcome. Therefore, LSS can be suggested as the treatment of choice for patients with high-grade osteosarcoma, especially for younger and more active patients.,, A previous meta-analysis of similar topic by Han et al., compared LSS and amputation for osteosarcoma patients, though this study did not specify on high-grade osteosarcoma. Furthermore, the literatures used vary in publication years, necessitating an updated analysis of the newer literatures. Therefore, though this study, we aim to specify the comparison as the treatment of choice for high-grade osteosarcoma, while choosing literatures from the year 2012 and beyond, to ensure updated analysis on patients' characteristics, treatments, and outcome measures.
LSS itself is generally achieved through a wide excision, where the tumor is removed en bloc with the surgical plane through a region of normal unaffected tissue. Despite the advantages of LSS, unfortunately, this procedure is not always feasible for every kind of patients. Some considerations that should be taken in account are patient's general health condition, the size of the malignancy, the location, and the possible surgical margins. Furthermore, patient's response to chemotherapy and the extent of surgery also affect postoperative functional outcome. Therefore, strict follow-up for patients receiving LSS procedure is needed considering a higher recurrence rate compared to amputation, especially in close margin resection. Whenever this happens, amputation should still be reserved as a back-up procedure.,,
Another challenge that should be taken in account in treating high-grade osteoarcoma is the so-called “localized osteosarcoma patients,” where these patients end up developing metastases within 3–6 months after, most commonly in the lungs. This arises concerns that probably almost all high-grade osteosarcoma patients actually have micrometastatic disease at presentation, which is sometimes underestimated or unnoticed. Therefore, the combined approach is often needed in curing these patients, not only the primary lesion, but also the micrometastatic disease.,,
The combined approach for high-grade osteosarcoma comprises effective surgical management and chemotherapy. As the surgical management, LSS can be performed by the use of tumor prosthesis, vascularized fibula graft, allograft, inactivated auto-osteoarticular replacement, autogenous bone replacement, rotation-plasty, and many others., The relatively higher recurrence and metastases rate in LSS may also be minimalized by the addition of chemotherapy preoperatively and/or postoperatively. Chemotherapy has been proven to markedly promote the survival rate by making the tumor shrink, edema disappear, and ossification of the tumor surface. In this modern era, advances in surgery have also made LSS more possible to perform without compromising patient's survival.
As one of the most popular measures for the functional outcome of patients with musculoskeletal tumors, MSTS score offers an objective assessment method from the perspective of pain, function, emotional acceptance, manual dexterity/gait, hand positioning/use of supports, and lifting/walking ability. However, recent study by Leopold, questioned the validity of the MSTS score as it does not seem to assess health-related quality of life adequately, considering that most of its domains include poorly defined grades. Therefore, MSTS score may have some shortcomings such as selection bias, transfer bias, and assessment bias. Furthermore, in the future, there is a need for more optimal outcome measures to evaluate functional improvement in orthopedic oncology.
This study has several limitations: (1) limited amount of studies available regarding high-grade ostosarcoma that compares LSS and amputation. Furthermore, the four studies are of level III evidence and selection bias might happen due to retrospective nature of included studies; (2) studies included are of small amount of samples; (3) no restriction regarding the location of the tumor, which may contribute to the high heterogeneity of MSTS score in analysis; and (4) there are still some possibilities that patients undergoing amputation have clinically worse initial presentation, that are not always stated in all literatures, thus resulting in amputation group being worse in terms of long-term outcome due to the progression of the disease itself. However, this study represents an important update to the current trend of treatment for high-grade osteosarcoma regarding the functional outcome of these patients being treated with LSS versus amputation. Furthermore, it is hoped that this study might be influential for future study, conducting well-designed trials with bigger amount of samples regarding this matter.
| Conclusion|| |
The current meta-analysis suggests that LSS procedure is superior compared to amputation in terms of the functional outcome as measured by MSTS score. Although the metastatic and 5-year survival rate is lower in LSS, adjuvant chemotherapy should be considered in certain patients, in order to maximalize recurrence and overall outcome. Further well-designed RCTs and cost-benefit analysis are needed to assess the two procedures in the future.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Jaffe N, Ottaviani G. Pediatric and adolescent osteosarcoma. Cancer Treat Res 2009;0:1-591.
Mirabello L, Troisi JR, Savage AS. Osteosarcoma incidence and survival improvement. Int J Cancer 2009;125:229-34. [doi: 10.1002/cncr. 24121].
Savage SA, Mirabello L. Using epidemiology and genomics to understand osteosarcoma etiology. Sarcoma 2011;2011.
Picci P. Osteosarcoma (osteogenic sarcoma). Orphanet J Rare Dis 2007;2:6.
Dhammi IK, Kumar S. Limb salvage for osteosarcoma: Current status with a review of literature. Indian J Orthop 2012;48:233-5.
Haidar R, Sagghieh S, Muwakitt S, Mumtaz G, Akel S, Kamzoul R, et al
. Limb salvage surgery for children and adolescents with malignant bone tumors in a developing country. Pediatr Blood Cancer 2008;51:787-91.
Bacci G, Ferrari S, Lari S, Mercuri M, Donati D, Longhi A, et al
. Osteosarcoma of the limb: Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br 2002;84-B:88-92.
Kamal AF, Rubiansyah P. Clinical outcome of various limb salvage surgeries in osteosarcoma around knee: Megaprosthesis, extracorporeal irradiation and resection arthrodesis. Ann Med Surg (Lond) 2019;42:14-8.
Kamal AF, Widyawarman H, Husodo K, Hutagalung EU, Rajabto W. Clinical outcome and survival of osteosarcoma patients in cipto mangunkusumo hospital: Limb salvage surgery versus amputation. Acta Med Indones 2016;48:175-83.
Yang Y, Han L, He Z, Li X, Yang S, Yang J, et al
. Advances in limb salvage treatment of osteosarcoma. J Bone Oncol 2018;10:36-40.
Mavrogenis AF, Abati CN, Romagnoli C, Ruggieri P. Similar survival but better function for patients after limb salvage versus amputation for distal tibia osteosarcoma. Clin Orthop Relat Res 2012;470:1735-48.
Han K, Dang P, Bian N, Chen X, Yang T, Fan Q, et al
. Is limb salvage with microwave-induced hyperthermia better than amputation for osteosarcoma of the distal Tibia? Clin Orthop Relat Res 2017;475:1668-77.
Yao W, Cai Q, Wang J, Gao S. Treatment of osteosarcoma around the knee in skeletally immature patients. Oncol Lett 2017;14:5241-8.
Hattinger CM, Pasello M, Ferrari S, Picci P, Serra M. Emerging drugs for high-grade osteosarcoma. Expert Opin Emerg Drugs 2010;15:615-34.
Birch JM. Epidemiology of sarcomas. Current opinion in oncology 1990;2:462-6.
Sampo M, Koivikko M, Taskinen M, Kallio P, Kivioja A, Tarkkanen M, et al
. Incidence, epidemiology and treatment results of osteosarcoma in Finland – A nationwide population-based study. Acta Oncol 2011;50:1206-14.
Deng ZP, Ding Y, Puri A, Wang EH, Gulia A, Durban C, et al
. The surgical treatment and outcome of nonmetastatic extremity osteosarcoma with pathological fractures. Chin Med J (Engl) 2015;128:2605-8.
Eiser C, Darlington AS, Stride CB, Grimer R. Quality of life implications as a consequence of surgery: Limb salvage, primary and secondary amputation. Sarcoma 2001;5:189-95.
Han G, Bi WZ, Xu M, Jia JP, Wang Y. Amputation versus limb-salvage surgery in patients with osteosarcoma: A meta-analysis. World J Surg 2016;40:2016-27.
Amankwah EK, Conley AP, Reed DR. Epidemiology and therapies for metastatic sarcoma. Clin Epidemiol 2013;5:147-62.
Gil S, Fernandez-Pineda I, Rao B, Neel MD, Baker JN, Wu H, et al
. Role of amputation in improving mobility, pain outcomes, and emotional and psychological well-being in children with metastatic osteosarcoma. Am J Hosp Palliat Care 2019;36:105-10.
Malagelada F, Tarrago LT, Tibrewal S, Ibanez AP, Jeyaseelan L, Alegria IG. Pathological fracture in osteosarcoma: Is it always an indication for amputation? Ortop Traumatol Rehabil 2014;16:67-74.
Kundu ZS. Classification, imaging, biopsy and staging of osteosarcoma. Indian J Orthop 2014;48:238-46.
] [Full text]
Harrison DJ, Geller DS, Gill JD, Lewis VO, Gorlick R. Current and future therapeutic approaches for osteosarcoma. Expert Rev Anticancer Ther 2018;18:39-50.
Miller RW, Boice JD Jr, Curtis RE. Bone cancer. In: Schottenfeld D, Fraumeni JF, eds. Cancer Epidemiology and Prevention. 2nd
ed. New York: Oxford University Press 1996;971-83.
Ayerza MA, Farfalli GL, Aponte-Tinao L, Muscolo DL. Does increased rate of limb-sparing surgery affect survival in osteosarcoma? Clin Orthop Relat Res 2010;468:2854-9.
Reddy KI, Wafa H, Gaston CL, Grimer RJ, Abudu AT, Jeys LM, et al
. Does amputation offer any survival benefit over limb salvage in osteosarcoma patients with poor chemonecrosis and close margins? Bone Joint J 2015;97-B: 115-20.
Strauss SJ, Ng T, Mendoza-Naranjo A, Whelan J, Sorensen PH. Understanding micrometastatic disease and anoikis resistance in ewing family of tumors and osteosarcoma. Oncologist 2010;15:627-35.
Bruland OS, Høifødt H, Saeter G, Smeland S, Fodstad O. Hematogenous micrometastases in osteosarcoma patients. Clin Cancer Res 2005;11:4666-73.
Wu X, Cai ZD, Chen ZR, Yao ZJ, Zhang GJ. A preliminary evaluation of limb salvage surgery for osteosarcoma around knee joint. PLoS One 2012;7:e33492.
Wang W, Yang J, Wang Y, Han G, Jia JP, Xu M, et al
. Bone transport using the Ilizarov method for osteosarcoma patients with tumor resection and neoadjuvant chemotherapy. Journal of bone oncology. 2019;16:100224.
Leopold SS. Editorial: Importance of validating the scores we use to assess patients with musculoskeletal tumors. Clin Orthop Relat Res 2019;477:669-71.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]