There were three main findings of this study. First, when investigating the entire cohort, and secondly, a subgroup analysis of individual primaries (breast, lung, prostate, renal cell) there were no differences in the incidence of new or progressive lung metastasis following pathological fracture fixation with IMN compared to Arthro/ORIF. Third, when fixation methods were combined, new or progressive metastasis to the lungs following surgical intervention for pathologic fracture was associated with worsened survival outcomes. Furthermore, we also found IMN fixation negatively influenced patient survival as compared to Arthro/ORIF.
The risk of iatrogenic systemic disease progression is a meaningful question to address. One-year mortality following pathological fracture fixation is historically significant, and unfortunately, we continue to appreciate a dismal prognosis for patients with metastatic bone disease requiring orthopaedic surgical intervention. Previous studies report one year overall survival between 30–40% when all primary cancers are considered [3]. The survival of patients within our study was comparable to these numbers (42.7%, 95% CI: 35.4–49.8), however our analysis revealed a significant increase in risk of mortality in the presence of new lung metastatic disease following surgery compared to the stable group. This finding, however, may represent a surrogate marker for global systemic disease progression and physiologic deterioration. While we did not demonstrate a significant association between surgical technique and progression; it is important that further investigation be performed to assess other factors related to disease progression post-operatively. The iterative process of refining survival estimation algorithms (ex. PATHFx) using techniques such as machine learning requires accurate inputs of multiple factors predicting patient outcome.[9, 10] By furthering our understanding of surgical technical factors that are related to overall patient survival, we can more accurately counsel patients on treatment goals, and modify surgical techniques accordingly.
Interestingly, while surgical technique was not statistically associated with metastatic progression in the lung in this study, we did demonstrate that those who underwent IMN fixation experience a poorer prognosis than those undergoing reconstruction with either arthroplasty or ORIF techniques. There are many possible explanations for this observation as there are many factors that go into the surgical decision making for patients with MBD. The fracture pattern may dictate the fixation strategy, but also pre-operative survival estimates, the concomitant necessity for tumour debulking or resection, the number of metastases present (solitary vs. oligometastatic vs. polymetastatic disease) and surgeon and patient preferences, to name a few.[11] In particular, the bias towards IMN fixation when feasible in those with a very short life expectancy would confound the data and bias a worse prognosis in those treated with IMN.[12] Without standardizing pre-operative survival estimates, this confounding factor would be difficult to eliminate. Although the theoretical increase in circulating tumour cells with intramedullary manipulation did not result in an increase in new or progressive lung metastasis, perhaps there is another secondary sequela that is not accounted for in this study that negatively influences prognosis. Intramedullary manipulation may also lead to a relatively increased dissemination of tumour cells in impending fractures (vs. established fractures) due to increased intramedullary pressure changes compared to established fractures.[13] In general, surgical fixation of an impending pathological fracture bears a more favorable prognosis for the patient (and economic benefits to the health care system) than stabilizing an established pathological fracture.[14, 15] It is unclear, however, if the factor of impending vs. established fracture influences clinically relevant lung disease progression after IMN fixation. Future research should stratify cohorts according to impending vs. established fractures to help delineate this relationship.
Limitations.
There are limitations to this study. The presence of a pathologic fracture itself, regardless of the fixation type, has been theorized to lead to metastatic spread to the lungs.[16] This study included patients who had undergone surgery for both impending and established pathologic fractures. Future studies should compare the results of pathological fracture fixation vs impending pathological fracture fixation and the effect on systemic tumour burden. It is possible that the timing and sensitivity of the post-operative imaging studies did not capture a change in lung tumour burden. We used both CXR and CT to detect tumour burden; standardizing the assessment method would reduce the risk of bias associated with a potentially reduced sensitivity of detection with CXR. As we believe this clinical question is important and remains relevant, future prospective studies involving surgical MBD patients should include standardized evaluations of disease progression post-op and build on the data presented here. Furthermore, the sample sizes included, and particularly within each primary tumour type may not have been of sufficient size to detect a difference in new or progressive lung metastasis. In particular, renal cell cancer, which has an affinity for lung metastasis,[17] was associated with a 50% incidence of new or progressive lung metastasis in the IMN cohort, vs. 37% in the Arthro/ORIF cohort, with 37 patients included in this subgroup. Other potential confounding factors not analyzed include use of concomitant therapies such as chemotherapy, radiation therapy and immunotherapies, as well as the presence of visceral metastasis, and overall patient systemic health and functional status. This further emphasizes the need for using large, multi-center databases to study this heterogeneous disease process, to utilize appropriate power estimates and detect differences not only amongst the entire pooled cohort, but importantly amongst the individual primary cancer types.[18]