INTRODUCTION
The reconstruction of defects caused by bony tumor resection can be a significant undertaking with multiple options available.1 En bloc resection of tumors is typically performed for primary bone sarcomas, but may be necessary in benign aggressive tumors as well.1,2 Multiple reports also describe improved prognosis and survival when complete metastasectomy is performed for malignancies such as renal cell and thyroid carcinoma.3–7 Although multiple surgical options are available for joint-preservation after intercalary tumor resection, the complications are not insignificant.8 The increase in indications for en bloc resection of tumors with resultant intercalary defects necessitates that newer technologies and techniques be used.
The use of distraction osteogenesis after tumor resection is limited in the literature and was initially only used to correct limb-length discrepancies that would occur after tumor resection.9–13 More recently, use of a magnetic intramedullary nail (Precice, NuVasive Specialized Orthopedics, Inc., Aliso Viejo, CA) has been used for both the correction of limb-length discrepancy and to aid in the incorporation of intercalary allografts after tumor resection.14,15 This technology has also been used to perform plate-assisted bone segment transport (PABST) to reconstruct segmental bony defects.16,17
This report describes the utilization of the Precice Bone Transport Nail (BTN) after tumor resection. This technique allows for noninvasive biologic reconstruction after tumor resection with the possibility of allowing the patient to weight bear and not delay chemotherapy.
TECHNIQUE
Preoperative planning is essential and requires multiple steps for the patient undergoing bone transport. After identification of a patient that is a candidate for bone transport, templating should occur to identify the proper nail size, whether antegrade or retrograde transport is indicated, and whether the transport can occur with a single transport or whether it will require a screw exchange or a “pit stop” for the nail to be “recharged.” The PBT Nail is indicated for defects up to 100 mm. Treating defects beyond 100 mm are off-label. Recharging the nail involves removal of the intercalary screws and reversing the direction of transport to mobilize the screw holes as close to the regenerate as possible. For example, in Fig. 1, a minimum of 13.3 cm will need to be resected to obtain negative margins. This would be considered the minimum distance of the transport, and a significantly longer transport should be considered as a wider resection of the normal bone on either side of the tumor would be desirable as a margin. Without a recharge, this nail can transport 10 cm. To maximize the amount of the bone that can be transported with a recharge, the proximal osteotomy should occur just distal to the proximal locking screws. Measurements should then be taken to determine the number of recharges that can occur and whether transport should begin in the 3 cm proximal window or the 7 cm distal window. This initial templating can also determine whether the BTN is the best option or whether PABST should be considered.
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FIGURE 1.: An example of templating with the bone transport nail. The minimum resection in this case is 133 mm. Note: Treating defects beyond 100 mm are off-label. This would require the proximal osteotomy to be performed no more than 69 mm from the top of the nail to provide enough proximal bone for the recharge. If the initial intercalary screw is placed in the distal window, 70 mm of transport could be performed followed by a 63 mm recharge to bridge this gap.
The timing of both the initial surgery and screw exchanges should be determined in conjunction with the patient's chemotherapy regimen. For example, if a screw exchange is planned from the proximal slot to the distal slot in Fig. 1, the timing of the surgery to the start of transport, along with the rate of transport, should be calculated to determine the date that the screw docks at the distal portion of the proximal window. If transport were to begin 7 days after surgery at a rate of 1 mm/d, then docking would occur 37 days after surgery for a 3 cm window. An estimation of when the patient will start adjuvant chemotherapy and when they will have a window of recovery should be coordinated with the docking date. As the patient's chemotherapy regimen takes precedence and recovery can vary, there should be some flexibility in the timing of the screw exchange. As the screw exchange can be performed through a small incision, chemotherapy does not need to be delayed postoperatively as the risk of infection and wound dehiscence is low (Fig. 2). If preparation of the docking sites is planned just before docking, this should also be calculated and coordinated with the patient's oncologist to minimize delay in their chemotherapy.
FIGURE 2.: The screw exchange can be performed percutaneously or through a small incision. The proximal screw is initially placed through the proximal hole to allow the distal hole to enter the distal window after initial transport. The distal locking screw is then drilled (A) and placed (B) before removal of the proximal screw (C).
Surgery should be performed with a goal of negative margins and ideally without the need for adjuvant radiation. Intraoperative frozen sections are taken of the marrow margins to help confirm this. Biologic reconstruction with bone transport would offer little for the patient if an early local recurrence were to occur. The use of neoadjuvant radiation may be considered, although the use of distraction osteogenesis in the setting of prior radiation is not extensively described, and has been mostly limited to craniofacial reconstruction with mostly satisfactory results.18–20 Matsubara et al21 described a case of femoral reconstruction with distraction osteogenesis after radiation. Although consolidation occurred, the regenerate was delayed, and multiple complications occurred. Targeted neoadjuvant radiation could enable the resection to be performed to the healthy bone and limit the complications with distraction osteogenesis.
Care should be taken during the resection to minimize osteonecrosis of the bone ends, particularly if preparation of the docking site is not planned. After resection of the tumor, preliminary nail placement is beneficial to determine the optimal placement of the locking screws and the location that the osteotomy for the bone transport segment will be performed. This osteotomy can typically be made through a small incision with multiple drill holes and osteotome completion to minimize the trauma to this area. The nail is then replaced and stabilized with locking screws proximally and distally. Blocking screws may be considered for additional stability and to ensure proper alignment is maintained. Once proximal and distal fixation is obtained, only one intercalary screw should be placed if a screw exchange is planned or if the transport distance needs to be maximized.
If immediate bone grafting of the defect is considered, then this can be performed after the nail is in place. The author has used this technique when the defect is larger than one nail can bridge or when significant metaphyseal bone has been resected to restore bone stock. The author's technique is to place the bone graft into AlloDerm Regenerative Tissue Matrix (Allergan plc, Dublin, Ireland), which is sutured to the tissues surrounding the defect, and secured both proximal and distal to the bone ends, without securing it to the bone being transported (Fig. 3). AlloDerm is an acellular dermal allograft, with the potential for incorporation into the surrounding tissues and neovascularization, without a significant inflammatory response.22 The author has dubbed this as the transplanted membrane technique (TMT). A nonabsorbable monofilament polypropylene suture is used to suture the AlloDerm to the surrounding tissues and to itself. A combination of both autograft and allograft bone is then placed into the AlloDerm through a small window just before closing the AlloDerm to itself with the suture. A running stitch is used to close the AlloDerm to prevent the bone graft from extravasating. Suturing the AlloDerm to the surrounding tissue and making sure there is enough space for the bone to be transported through the AlloDerm is essential to prevent the AlloDerm from becoming interposed between the bone ends.
FIGURE 3.: Demonstration of the transplanted membrane technique with immediate bone grafting of the resection site during the initial surgery. The AlloDerm (Allergan plc, Dublin, Ireland) is sutured proximal and distal to the bone ends (A) and tacked to the surrounding tissues to prevent it from moving with bone transport. The AlloDerm is then sutured to itself (B) after the bone graft is placed to prevent extravasation of the graft. The distal femur (C) can also be reconstructed using this technique by providing bone stock as with the patient discussed in
Fig. 5.
Transport may begin 7–10 days after surgery and is typically performed at 1 mm/d divided into 3 sessions for the femur and 0.75 mm/d divided into 3 sessions for the humerus and tibia. The patient should be monitored every 2–3 weeks with radiographs to assess the regenerate and to ensure that the patient is being compliant with transport. The regenerate may be affected by radiation and by the type of chemotherapy. Unfortunately, the literature on the effect of chemotherapy on distraction osteogenesis is very limited. Cytotoxic chemotherapy, such as cisplatin, has been shown to inhibit healing during bone transport in mice.23 The effects of cytotoxic chemotherapy on distraction osteogenesis in humans is less clear, with some series noting a delay in regenerate, whereas others note no effect.16,24,25 Regardless, the chemotherapy did not outright prevent regenerate from forming. Of note, there have been no reports of local recurrence with distraction osteogenesis after tumor resection, and the concern of causing tumor growth with bone transport is only theoretical.
Bisphosphonates and denosumab are also used in the treatment of both primary bone tumors and metastatic disease.26–30 It is possible that these medications may increase the regenerate formation. Both pamidronate and zoledronic acid have been used to increase the regenerate when it was noted to be poor.31 If the patient is not on these medications as part of their standard chemotherapy regimen, they should not be routinely used to promote the regenerate. Zoledronic acid has been shown to have an increased complication rate when used with standard chemotherapy in osteosarcoma in 2 separate Phase 3 trials.32,33 The uncertainty of the effect of chemotherapy on the regenerate demonstrates the need for close follow-up to adjust the transport cadence on an individual basis. The transport may also be reversed with the BTN if there is significant concern regarding the regenerate and then restarted when there is more consolidation.
Preparation of the docking site has been used to improve the union rates when compared to compression alone.17,34 Open curettage of the site as well as percutaneous methods have been described with placement of autologous bone, bone marrow aspirate, and allograft including demineralized bone matrix. Autograft and bone marrow aspirate should be used with caution in patients with metastatic disease or primary bone tumors that may involve the marrow, such as Ewing’s sarcoma, to ensure that tumor cells are not transferred to the docking site. The use of demineralized bone matrix raises the concern for promoting tumor growth because of it containing bone morphogenetic protein (BMP). Although in vitro studies of BMP-2 in osteosarcoma have shown an increase in the proliferation of tumor cells, animal studies have not demonstrated an increase in the recurrence of the primary tumor or the risk of metastatic disease.35–37 The risk of inducing tumor growth with using BMPs after tumor resection seems theoretical, but the literature is significantly limited.38
The author has used bone grafting at the time of resection using the TMT noted above in 6 patients who underwent treatment with either the BTN or with PABST. Five of the 6 patients have had consolidation of the bone graft with bridging bone and remodeling of the osteotomy sites at an average of 5 months after completion of transport with no failures of fixation noted. No secondary grafting procedures have been performed. Although the results are promising, longer term follow-up is needed to ensure this is a viable treatment option.
CLINICAL CASES
A 69-year-old man with isolated metastatic renal cell carcinoma to the right femur underwent treatment with the BTN (Fig. 4). The patient had a 17 cm defect after tumor resection with negative margins. Because of the large defect, he underwent bone grafting using the TMT at the time of surgery. He also had blocking screws placed distally to provide more stability and prevent angular deformity with placement of the nail. An anteroposterior screw was not placed as it was directly behind the patella and would not have been able to be placed percutaneously. He received adjuvant therapy with nivolumab, ipilimumab, and denosumab. The patient began bone transport 7 days after surgery at a rate of 0.33 mm performed 3 times daily for a total of 1 mm/d. The patient developed abundant regenerate, and his rate was increased by performing the transport 4 times daily for a total of 1.33 mm/d. The patient underwent a screw exchange and recharging of the nail to maximize the transport. At 1-year follow-up, the patient was fully weight-bearing without pain, had significant regenerate, evidence of healing at the bone grafting site, and no evidence of local recurrence.
FIGURE 4.: Preoperative radiographs (A) of a 69-year-old man with isolated metastatic renal cell carcinoma. After initial resection (B), a 17-cm defect was created. Note: Treating defects beyond 100 mm are off-label. After 3 cm of transport (C), a screw was exchanged and placed into the distal window. To maximize the transport, the nail was transported 5.5 cm, recharged (D), and transported another 5.5 cm for a total transport of 14 cm. At most recent follow-up, the patient had abundant regenerate proximally (E), and consolidation of the bone graft with bridging bone distally (F) from the transplanted membrane technique.
A 16-year-old male with primary, nonmetastatic osteosarcoma, underwent joint-preservation surgery and reconstruction with the BTN after 3 cycles of neoadjuvant chemotherapy (Fig. 5). The resection was performed just distal to the physis with 2 locking screws placed. A fracture of the medial condyle occurred during resection and was repaired. Bone grafting with the TMT was performed during the surgery to help restore the bone stock in the metaphyseal region. He was kept non–weight bearing and in a knee immobilizer because of the minimal bone remaining after resection. The patient began lengthening 7 days after surgery at a rate of 1 mm/d divided into 3 sessions. He restarted chemotherapy with doxorubicin, cisplatin, and methotrexate 2 weeks after surgery. Transport started in the proximal window, and he underwent a screw exchange to bridge the 9 cm defect that resulted with resection. He was unable to follow-up for a month during his transport, and his regenerate was minimal. A progressive improvement in the regenerate was noted after he completed his chemotherapy (Fig. 6). He also continued transport after developing pain during transport and had a partial backing out of his distal locking screw and migration of the nail which was likely because of over compression with docking (Fig. 7). Eight months after resection, the patient has no pain with evidence of healing of the docking site and continued improvement in the regenerate. He is toe-touch weight bearing but has knee range of motion from only 0–30 degrees because of prolonged use of the knee immobilizer.
FIGURE 5.: T1-gadolinium enhanced coronal MRI (A) of a 16-year-old male with an osteosarcoma of the distal femur that spared the epiphysis. The patient underwent resection just distal to the physis and had good regenerate proximally after 7 mm of initial transport (B) with some bone graft noted distally on AP and lateral radiographs from the TMT. At the most recent follow-up (C), there is increasing regenerate proximally and evidence of healing distally with consolidation of the bone graft from the TMT.
FIGURE 6.: A 16-year-old male after osteosarcoma resection demonstrating minimal regenerate (A) at the completion of transport and just before completing adjuvant chemotherapy. Two months after completing chemotherapy (B), the regenerate has significantly increased and is bridging the defect.
FIGURE 7.: A 16-year-old male after osteosarcoma resection just before docking (A) and after docking had completed (B). The patient continued transport despite having pain, which resulted in backing out of the distal locking screw, migration of the nail, and valgus angulation of the distal fragment.
DISCUSSION
Noninvasive distraction osteogenesis using the BTN after tumor resection is promising. It avoids the prolonged use of an external fixator and associated pin-tract infections which could be significant for a patient on chemotherapy.39 The literature is limited regarding protocols for bone transport in tumor patients, but even with cytotoxic chemotherapy, regenerate forms and seems to recover after chemotherapy has stopped as in the case above.
Multiple factors should be considered when using the BTN in cancer patients. Preoperative templating and planning is essential to a successful treatment. Chemotherapy schedule and regimen, as well as the history of or need for radiation, should be factored into all decisions, and the treatment should be individualized to the patient. Bone grafting, either at the time of surgery, or before docking, also needs to be considered in the setting of the type of tumor resected, and type of bone grafting considered.
Although the current literature is positive, further studies are necessary to help confirm whether chemotherapy or radiation affects healing and whether there is an increased risk for local recurrence or not. The functional results of this procedure will also need to be compared with other treatment modalities. The promising results of the available literature, in addition to the cases described above, provide a foundation for further study. Distraction osteogenesis using the BTN after tumor resection should be considered as an option for biologic reconstruction.
REFERENCES
1. Gutowski CJ, Basu-Mallick A, Abraham JA. Management of bone
sarcoma. Surg Clin North Am. 2016;96:1077–1106.2.
2. Zou C, Lin T, Wang B, et al. Managements of giant cell tumor within the distal radius: a retrospective study of 58 cases from a single center. J Bone Oncol. 2018;14:100211.
3. Higuchi T, Yamamoto N, Hayashi K, et al. Long-term patient survival after the surgical treatment of bone and soft-tissue metastases from renal cell carcinoma. Bone Joint J. 2018;100B:1241–1248.
4. Higuchi T, Yamamoto N, Hayashi K, et al. The efficacy of wide resection for musculoskeletal metastatic lesions of renal cell carcinoma. Anticancer Res. 2018;38:577–582.
5. Kato S, Murakami H, Demura S, et al. The impact of complete surgical resection of spinal metastases on the survival of patients with thyroid cancer. Cancer Med. 2016;5:2343–2349.
6. You D, Lee C, Jeong IG, et al. Impact of metastasectomy on prognosis in patients treated with targeted therapy for metastatic renal cell carcinoma. J Cancer Res Clin Oncol. 2016;142:2331–2338.
7. Zaid HB, Parker WP, Safdar NS, et al. Outcomes following complete surgical metastasectomy for patients with metastatic renal cell carcinoma: a systematic review and meta-analysis. J Urol. 2017;197:44–49.
8. Takeuchi A, Yamamoto N, Hayashi K, et al. Joint-preservation surgery for pediatric osteosarcoma of the knee joint. Cancer Metastasis Rev. 2019;38:709–722.
9. Sato W, Okazaki H, Goto T. Leg lengthening as a means of improving ambulation following an internal hemipelvectomy. Case Rep Orthop. 2016;2016:7089142.
10. Singhania AK, Lovisetti L, Maguire J, et al. Use of the Ilizarov technique to improve limb function following hemipelvectomy. Eur J Surg Oncol. 2003;29:64–68.
11. Catagani MA, Ottaviani G. Ilizarov method to correct limb length discrepancy after limb-sparing hemipelvectomy. J Pediatr Orthop B. 2008;17:293–298.
12. Kang S, Lee JS, Park J, et al. Staged lengthening and reconstruction for children with a leg-length discrepancy after excision of an osteosarcoma around the knee. Bone Joint J. 2017;99B:401–408.
13. Pilge H, Ruppert M, Bittersohl B, et al. Lengthening of newly formed humerus after autologous fibula graft transplantation following intercalary tumor resection. J Pediatr Orthop B. 2018;27:322–325.
14. Muratori F, Scoccianti G, Beltrami G, et al. Is an intramedullary nail a valid treatment for limb-length discrepancy after bone tumor resection? Case descriptions. Surg Technol Int. 2018;33:281–288.
15. Vercio RC, Shields TG, Zuckerman LM. Use of magnetic growing intramedullary nails in compression during intercalary allograft reconstruction. Orthopedics. 2018;41:330–335.
16. Lesensky J, Prince DE. Distraction osteogenesis reconstruction of large segmental bone defects after primary tumor resection: pitfalls and benefits. Eur J Orthop Surg Traumatol. 2017;27:715–727.
17. Olesen UK, Nygaard T, Prince DE, et al. Plate-assisted bone segment transport with motorized lengthening nails and locking plates: a technique to treat femoral and tibial bone defects. J Am Acad Orthop Surg Glob Res Rev. 2019;3:e064.
18. Momeni A, Januszyk M, Wan DC. Is distraction osteogenesis of the irradiated craniofacial skeleton contraindicated? J Craniofac Surg. 2017;28:1236–1241.
19. Kashiwa K, Kobayashi S, Nohara T, et al. Efficacy of distraction osteogenesis for mandibular reconstruction in previously irradiated areas: clinical experiences. J Craniofac Surg. 2008;19:1571–1576.
20. Kashiwa K, Kobayashi S, Honda T, et al. Alveolar reconstruction by distraction osteogenesis under unfavorable conditions. J Craniofac Surg. 2010;21:1810–1812.
21. Matsubara H, Tsuchiya H, Sakurakichi K, et al. Distraction osteogenesis of a previously irradiated femur with malignant lymphoma: a case report. J Orthop Sci. 2005;10:430–435.
22. Gabriel A, Maxwell GP. AlloDerm RTU integration and clinical outcomes when used for reconstructive breast surgery. Plast Reconstr Surg Glob Open. 2018;6:e1744.
23. Stine KC, Wahl EC, Liu L, et al. Cisplatin inhibits bone healing during distraction osteogenesis. J Orthop Res. 2014;32:464–470.
24. He X, Zhang HL, Hu YC. Limb salvage by distraction osteogenesis for distal tibial osteosarcoma in a young child: a case report. Orthop Surg. 2016;8:253–256.
25. Yang Z, Tao H, Ye Z, et al. Bone transport for reconstruction of large bone defects after tibial tumor resection: a report of five cases. J Int Med Res. 2018;46:3219–3225.
26. Omae K, Tsujimoto Y, Honda M, et al. Comparative efficacy and safety of bone-modifying agents for the treatment of bone metastases in patients with advanced renal cell carcinoma: a systematic review and meta-analysis. Oncotarget. 2017;8:68890–68898.
27. Cui X, Li S, Gu J, et al. Retrospective study on the efficacy of bisphosphonates in tyrosine kinase inhibitor-treated patients with non-small cell lung cancer exhibiting bone metastasis. Oncol Lett. 2019;18:5437–5447.
28. Wong ECL, Kapoor A. Does bone-targeted therapy benefit patients with metastatic renal cell carcinoma? Transl Oncol. 2019;13:241–244.
29. Gnant M, Pfeiler G, Steger GG, et al. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:339–351.
30. Savvidou OD, Bolia IK, Chloros GD. Denosumab: current use in the treatment of primary bone tumors. Orthopedics. 2017;40:204–210.
31. Kiely P, Ward K, Bellemore CM, et al. Bisphosphonate rescue in distraction osteogenesis: a case series. J Pediatr Orthop. 2007;27:467–471.
32. Piperno-Neumann S, Le Deley MC, Rédini F, et al. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17:1070–1080.
33. Li S, Chen P, Pei Y, et al. Addition of Zoledronate to chemotherapy in patients with osteosarcoma treated with limb-sparing surgery: a phase III clinical trial. Med Sci Monit. 2019;25:1429–1438.
34. Hatzokos I, Stavridis SI, Iosifidou E, et al. Autologous bone marrow grafting combined with demineralized bone matrix improves consolidation of docking site after distraction osteogenesis. J Bone Joint Surg Am. 2011;93:671–678.
35. Geller DS, Singh MY, Zhang W, et al. Development of a model system to evaluate local recurrence in osteosarcoma and assessment of the effects of bone morphogenetic protein-2. Clin Cancer Res. 2015;21:3003–3012.
36. Gill J, Connolly P, Roth M, et al. The effect of bone morphogenetic protein-2 on osteosarcoma metastasis. PLoS One. 2017;12:e0173322.
37. Tian H, Zhou T, Chen H, et al. Bone morphogenetic protein-2 promotes osteosarcoma growth by promoting epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin signaling pathway. J Orthop Res. 2019;37:1638–1648.
38. Delloye C, Suratwala SJ, Cornu O, et al. Treatment of allograft nonunions with recombinant human bone morphogenetic proteins (rhBMP). Acta Orthop Belg. 2004;70:591–597.
39. Matsubara H, Tsuchiya H. Treatment of bone tumor using external fixator. J Orthop Sci. 2019;24:1–8.
