Does reimplantation of sterilized tumor bone for reconstruction provide outcome benefits in intercalary osteosarcoma based on the potential immunogenic effect of reimplanted sterilized tumor tissue? Of 720 cases of surgically treated high-grade osteosarcoma patients treated at our institute from 2006 to 2013, 61 had predominantly diaphyseal disease. All patients were nonmetastatic at presentation. Patient and tumor characteristics, treatment details, and local recurrence-free, metastasis-free, and overall survival were compared for 24 patients who had reconstruction with sterilized tumor bone reimplantation vs 37 who did not. Both the groups were well matched in terms of baseline characteristics. Means were compared with the
Limb salvage surgery in extremity sarcoma management is the standard of care. Biologic reconstruction when possible is an attractive and durable alternative to endoprosthesis. It is widely used in diaphyseal sarcomas where saving the adjacent joints is oncologically safe. Reconstruction is usually performed using allografts with or without a live vascularised fibula, diaphyseal endoprosthesis, or reimplantation of the excised bone after sterilizing it using either external radiation [
All consecutive diaphyseal osteosarcoma patients operated between January 2006 and December 2013 at our institution were included in the study. Patient details were identified from a prospectively maintained database. Patient and tumor characteristics, treatment details, and local recurrence-free, metastasis-free, and overall survival were retrieved. Prior to surgery all patients underwent staging investigations which included plain radiographs and MRI of the limb, CT scan of the chest, and a bone scan. All patients were nonmetastatic at presentation. They received neoadjuvant and adjuvant chemotherapy as per the existing hospital protocol [
Reimplanting sterilized tumor bone is not advisable in tumor bones which are structurally weak and in bones with pathological fractures. In such cases, alternative means of reconstruction were used. In cases where the diaphyseal tumors extended very close to the articular surface and the osteoarticular part of the bone necessitated resection for oncologic reasons, endoprosthetic reconstructions were used [
Our surgical technique and method of ECRT has been documented in detail earlier [
After tumor excision, a sample of the marrow was sent for a frozen section from both residual ends of the host bone, to confirm clear margins. The resected specimen was then transferred to a separate sterile trolley, away from the main operative field to avoid any contamination of the operative field. Under aseptic precautions, all the soft tissue including the periosteum was stripped from the bone after inking the closest soft tissue margin. This inking of margins helped the pathologist report on the adequacy of resection in the final histopathology report, which otherwise would not have been possible [
The resected bone was irradiated to a dose 50 Gy/1 fraction prescribed to the midplane of the specimen using 6 MV photons or 60 Cobalt gamma rays with parallel opposing portals. On returning to the operative room, the marrow contents were reamed and the bone specimen was lavaged with a high-speed pulsatile lavage system to remove residual marrow tissue. Bone cement was packed in the medullary cavity of the radiated graft, and the specimen was realigned with the host bone and stabilised with suitable internal fixation. We thus sought to compare 24 cases of reimplanted tumor bone with 37 cases treated without reimplantation. Both the groups were well matched in terms of baseline characteristics except marked male preponderance in the reimplantation of the tumor group (Table
Baseline characteristics of reimplantation and the non-reimplantation groups.
Variables | Reimplantation group | Non-reimplantation group |
|
---|---|---|---|
|
24 | 37 | |
Female sex | 1 (4%) | 13 (35%) | 0.01 |
Median age, year (range) | 17 (8–35) | 17 (6–58) | |
Mean length of resection, cm (range) | 20 (10–45) | 22 (11–45) | 0.07 |
Proportion of tumors of size >8 cm (%) | 80 | 90 | 0.3 |
Median follow-up, month (range) | 54 (11–106) | 62 (1–131) |
Statistical analyses were completed in R version 3.2.2, including the survminer package from the Comprehensive R Archive Network. Time to local relapse, systemic relapse, and death from any cause were calculated from the date of surgery. We defined recurrence as clinical, radiological, or pathological evidence at primary or metastatic site. Patients who did not have an event at the end of study duration were censored at the date of last follow-up, death from disease, or other causes. The Kaplan‐Meier method was used to construct time to event curves. Cox proportional hazard regression modeling was employed for multivariate time to event analysis with significance set at
The median follow-up in survivors was 80 months (range 15 to 131) and in those who died of disease was 22 months (range 1 to 86). The median follow-up in the reimplantation group was 54 months (range 11–106) and in the non-reimplantation group was 62 months (range 1–131). Twenty-three patients had died at the time of evaluation (7/24 reimplantation; 16/37 non-reimplantation), 5 (2/24 reimplantation; 3/37 non-reimplantation) were alive with disease, and 33 were free of disease (15/24 reimplantation; 18/37 non-reimplantation). Thirty three (54%) remained continually disease-free with a median DFS of 80 months (range 15–131 months). In all 3 local recurrences in the reimplantation group, the recurrence was in the adjacent soft tissue and not in reimplanted bone. The oncologic outcomes of local relapse, systemic relapse, death, and actuarial survival estimates are depicted in the table and figures below (Table
Summary of outcome variables in the reimplantation and the non-reimplantation group.
Variable | Reimplantation group ( |
Non-reimplantation group ( |
|
---|---|---|---|
Local recurrence only | 1 (4%) | 1 (2.7%) | |
Metastasis only | 6 (25%) | 18 (43%) | |
Local recurrence with metastases | 2 (8%) | 0 (0%) | |
Died of disease | 7 (29%) | 16 (43%) | |
Alive with disease | 2 (8%) | 3 (8%) | |
Continually disease free | 15 (62.5%) | 18 (48.64%) | |
5 yr LRFS | 85% (range 60–90) | 97 (range 80–95) | 0.17 |
5 yr MFS | 63 (range 40–78) | 54 (range 35–70) | 0.44 |
5 yr OS | 70 (range 50–85) | 58 (range 40–70) | 0.39 |
LRFS: local recurrence-free survival; MFS: metastasis-free survival; OS: overall survival.
Kaplan‐Meier curves showing local recurrence-free survival stratified by use of reimplantation. Green line with reimplantation of tumor bone and the red without. Time is in months.
Kaplan‐Meier curves showing distant recurrence-free survival stratified by use of reimplantation. Green line with reimplantation of tumor bone and the red without. Time is in months.
Kaplan‐Meier curves showing overall survival stratified by use of reimplantation. Green line with reimplantation of tumor bone and the red without. Time is in months.
The potential advantage of tumor immunogenicity to help improve survival has not been tested as a hypothesis in human study cohorts. Nishida et al. demonstrated the induction of systemic antitumor response in malignant bone tumors following reconstruction with frozen autografts using liquid nitrogen in a murine osteosarcoma model and in a few select human cohorts with unresectable metastatic osteosarcoma combined with dendritic cell therapy [
Extracorporeal radiation and reimplantation was first reported in 1968. The single high dose ensures tumor death avoiding radiation to surrounding normal tissue. Pasteurization (heating at 60–65 degree celsius for 40 min) eradicates tumor cells as shown in both preclinical and clinical studies [
We therefore analysed our results from a subset of one of the largest series of osteosarcoma treated at a single institute to test this hypothesis in a clinical setting [
Another limitation is the fact that being a retrospective analysis, we have not measured any serum cytokine levels to objectively document an immune response.
Although unavoidable, the decision of choice of reconstruction was done in an observational fashion and was not randomized. This is inevitable as numerous factors including patient choice can influence the decision regarding choice of reconstruction modalities.
Despite these limitations, this is a reasonable comparison of survival possible in a real world scenario. The reimplantation group did not show significantly better local recurrence-free, distant relapse-free, or overall survival benefit in this series though there was a trend to superior overall survival that did not reach statistical significance. A randomised trial after propensity-matched scoring in a cohort with serum cytokine levels is ideal for answering potential causal links between sterilized tumor bone reimplantation and immune mediated survival but unlikely in a real world scenario. Our data thus failed to show a statistically superior survival benefit in the group receiving tumor bone reimplantation.
The retrospective data used to support the findings of this study are available from the corresponding author upon request.
The authors declare there are no conflicts of interest regarding the publication of this paper.