Are Pathologic Fractures in Patients With Osteosarcoma Associated With Worse Survival Outcomes? A Systematic Review and Meta-analysis

Abstract

Background Pathologic fractures occur in 5% to 10% of patients with osteosarcoma, and prior studies have suggested they are prognostically important. However, because they represent an uncommon event in the setting of an already rare disease, most studies fail to reach conclusive findings, and there is no agreement about how best to treat pathologic fractures. Questions/purposes (1) Is the occurrence of a pathologic fracture in patients with osteosarcoma associated with poorer overall survivorship? (2) Is the occurrence of a pathologic fracture in patients with osteosarcoma associated with poorer local recurrence-free survival or metastasis-free survival? (3) Is the surgical approach (amputation or limb salvage) associated with differences in local recurrence rates in patients with osteosarcoma with pathologic fractures? Methods This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Our study was registered in PROSPERO (ID: 380459). A search of the PubMed and Embase databases resulted in 625 and 747 titles, respectively. After application of the inclusion and exclusion criteria, 21 articles were finally included. Quality assessment of all studies was performed using the Newcastle-Ottawa Quality Assessment Scale. The Risk of Bias In Non-Randomized Studies of Interventions tool was used in the 11 articles that evaluated the effect of an intervention (amputation or limb salvage) on local recurrence rates. The relative risk (RR) was calculated to compare outcomes in patients with osteosarcoma with pathologic fractures and those without. Heterogeneity among studies was calculated using the I 2 statistic. The pooled RR was calculated using the fixed-effects or random-effects model depending on study heterogeneity. The fragility index and the ratio between the fragility index and the total number of participants for each outcome was additionally calculated to assess the robustness of our results. A total of 7604 patients with osteosarcoma, 12% of whom (885) had pathologic fractures, were included in our analysis. Results Pathologic fractures in patients with osteosarcoma were associated with lower 3-year (RR 1.53 [95% CI 1.29 to 1.82]; p < 0.001) and 5-year overall survival (RR 1.27 [95% CI 1.16 to 1.40]; p < 0.001). No difference in recurrence rates was found between patients with osteosarcoma with pathologic fractures and those without (RR 1.22 [95% CI 0.91 to 1.64]; p = 0.18). However, having a pathologic fracture was Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. 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.

CORR Insights®: Are Pathologic Fractures in Patients With Osteosarcoma Associated With Worse Survival Outcomes? A Systematic Review and Meta-analysis

“…Despite the reported evidence examined by Gonzalez et al [3] to the contrary, it is both surprising and counterintuitive that patients with a pathologic fracture through an osteosarcoma do not have an increased local recurrence rate. Escape of tumor cells through the fracture, accompanied by the bleeding and fracture hematoma that could disseminate those cells within the local tissue through tissue planes uncontained by the typical pseudocapsule, almost certainly results in a wider distribution of tumor cells than without fracture.…”

“…In Clinical Orthopaedics and Related Research® this month, Gonzalez et al [3] report some intuitive, some counterintuitive, some surprising, and some unsurprising findings. First, it is both intuitive and unsurprising that a patient who has a pathologic fracture through an osteosarcoma would have a worse prognosis than someone without a fracture.…”

“…Accepting the finding of adequate local control in the face of a pathologic fracture at face value requires, to some extent, that we ignore treatment bias, because local recurrence and local tumor surgery are intimately related. In Gonzalez et al [3]’s analysis, it is notable that one study showing a higher rate of local recurrence with pathologic fracture also had the lowest rate of amputation as the primary means of tumor resection. In the early evolution of osteosarcoma treatment from amputation to limb-sparing surgery, pathologic fracture was considered an absolute indication for amputation [5].…”

“…Every meta-analysis is limited by the flaws in the publications examined. Given the potential for treatment bias in the studies examined by Gonzalez et al [3], in broadest terms, we need to continue to question critically whether the oncologic outcomes of limb-sparing surgery are equivalent to amputation.…”

Oncology

“…The systematic review and meta-analysis, led by researchers from Boston (Massachusetts, USA) , aimed to fill this gap by evaluating existing studies and collating robust evidence on this issue. 1 The study followed the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in PROSPERO (ID: 380459). Searches were carried out in the PubMed and Embase databases, yielding a total of 1,372 articles.…”