ONCOLOGY
Internal fixation of radiation-induced pathological fractures of the femur has a high rate of failure A. Sternheim, K. Saidi, J. Lochab, P. W. O’Donnell, W. C. Eward, A. Griffin, J. S. Wunder, P. Ferguson From Mount Sinai Hospital, Toronto, Ontario, Canada A. Sternheim, MD, Orthopaedic Surgeon J. Lochab, MD, Orthopaedic Resident A. Griffin, MSc, Clinical Research Manager J. S. Wunder, MD, FRCSC, Orthopaedic Surgeon P. Ferguson, MD, FRCSC, Orthopaedic Surgeon Mount Sinai Hospital, 600 University Ave, Toronto, Ontario, M5G 1X5, Canada. K. Saidi, MD, MSc, FRCSC, Orthopaedic Surgeon, Assistant Professor Northern Ontario School Of Medicine, 2120 Regent Street South, Unit 2, Sudbury, Ontario, P3E 3Z9, Canada. P. W. O’Donnell, MD, PhD, Orthopaedic Surgeon Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA. W. C. Eward, MD, DVM, Orthopaedic Surgeon Duke Cancer Center, Duke University, Durham, North Carolina 27710, USA. Correspondence should be sent to Dr A. Sternheim; e-mail:
[email protected] ©2013 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.95B8. 31832 $2.00 Bone Joint J 2013;95-B:1144–8. Received 21 February 2013; Accepted after revision 12 April 2013
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We investigated the clinical outcome of internal fixation for pathological fracture of the femur after primary excision of a soft-tissue sarcoma that had been treated with adjuvant radiotherapy. A review of our database identified 22 radiation-induced fractures of the femur in 22 patients (seven men, 15 women). We noted the mechanism of injury, fracture pattern and any complications after internal fixation, including nonunion, hardware failure, secondary fracture or deep infection. The mean age of the patients at primary excision of the tumour was 58.3 years (39 to 86). The mean time from primary excision to fracture was 73.2 months (2 to 195). The mean follow-up after fracture fixation was 65.9 months (12 to 205). Complications occurred in 19 patients (86%). Nonunion developed in 18 patients (82%), of whom 11 had a radiological nonunion at 12 months, five a nonunion and hardware failure and two an infected nonunion. One patient developed a second radiation-associated fracture of the femur after internal fixation and union of the initial fracture. A total of 13 patients (59%) underwent 24 revision operations. Internal fixation of a pathological fracture of the femur after radiotherapy for a soft-tissue sarcoma has an extremely high rate of complication and requires specialist attention. Cite this article: Bone Joint J 2013;95-B:1144–8.
Radiotherapy is often used as an adjunct to surgical resection of a soft-tissue sarcoma of the limbs1 and can give excellent local control.2 However, early complications include wound dehiscence, increased fluid drainage and infection,1,3-5 while long-term complications include fibrosis, oedema, neurological dysfunction, impaired growth of the physes, fracture and the development of a radiation-induced sarcoma.6-8 Radiation-induced pathological fracture after the surgical resection of a sarcoma is a significant problem. Several studies have addressed the risk factors for fracture of the femur,9-12 which include female gender, increasing age, location of the sarcoma in the anterior compartment of the thigh, increasing tumour size, a high radiation dose, and periosteal stripping during resection of the tumour. Radiation-induced fractures are typically insufficiency fractures that occur from a lowenergy injury within a previously irradiated field. They commonly occur in the pubic rami, acetabulum, femur, tibia, patella and metacarpal bones.11 When they occur in the femur they represent a major clinical problem as they are painful and debilitating: complications are common despite treatment by internal fixation.10,13
The purpose of this study was to assess the clinical outcome of patients with a radiationinduced pathological fracture of the femur treated by internal fixation. Our hypothesis was that these fractures have an exceptionally low potential to heal and that many patients would develop a nonunion after internal fixation, requiring further surgery.
Patients and Methods After approval from our institutional research ethics board, we carried out a retrospective review of our prospectively-collected sarcoma database between January 1986 and July 2011. We included patients who had undergone resection of a soft-tissue sarcoma with adjuvant radiotherapy and who had sustained a radiation-induced pathological fracture of the proximal or diaphyseal portion of the femur that had been treated by internal fixation. We excluded patients if the fracture was associated with a local recurrence, if the fracture had been treated without internal fixation (e.g. with an endoprosthesis) or if fixation of the fracture had taken place within the previous 12 months. A pathological fracture was defined as one that had occurred after a low-energy injury in a THE BONE & JOINT JOURNAL
INTERNAL FIXATION OF RADIATION-INDUCED PATHOLOGICAL FRACTURES OF THE FEMUR HAS A HIGH RATE OF FAILURE
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Table I. Demographics and complications for patients with a radiation-induced fracture of the femur Factors Patients (n) Mean age at sarcoma excision (yrs) (range) Male (n, %) Tumour type (n, %) Liposarcoma Undifferentiated pleomorphic sarcoma Fibrosarcoma Synovial sarcoma Soft-tissue osteosarcoma Epitheloid sarcoma Soft-tissue Ewing sarcoma Mean tumour diameter (cm) (range) Periosteal stripping (n, %) Radiotherapy (n, %) Pre-operative Post-operative Pre- and post-operative Mean total radiation dose (cGy) (range) Chemotherapy (n, %) Tumour compartment in the thigh (n, %) Anterior Posterior Medial Mean number of operations (range) Mean time to fracture (mths) (range) Mean follow-up after fracture (mths) (range) Fracture location (n, %) Intertrochanteric Diaphyseal Internal fixation device (n, %) Intramedullary nail Dynamic hip screw Dynamic condylar srew Complications (n, %) Nonunion Hardware failure Infected nonunion Secondary fracture Total Mean revision procedures for complications (range)
previously irradiated operative field. Internal fixation was defined as treatment with an intramedullary nail (IM nail), a dynamic hip screw (DHS) or a dynamic compression screw (DCS) (both AO-Synthes, West Chester, Pennsylvania). Clinical details were obtained for each patient by review of their records. We identified 1301 patients that had undergone resection of a soft-tissue sarcoma with adjuvant radiotherapy. Of these, 61 (4.7%) sustained a radiation-induced pathological fracture. Within the cohort of 1301, there were 697 patients with a soft-tissue sarcoma of the hip and thigh who had been treated by resection with adjuvant radiotherapy. A radiation-induced fracture of the femur occurred in 31 patients (4.4%). We excluded four patients due to incomplete or missing data, two with a supracondylar fracture that entered the joint, one with a subcapital fracture treated sub-optimally VOL. 95-B, No. 8, AUGUST 2013
22 58 (39 to 86) 7 (32) 10 (45) 6 (27) 2 (9) 1 (5) 1 (5) 1 (5) 1 (5) 13.7 (4 to 24) 12 (55) 8 (36) 10 (45) 4 (18) 5945.5 (5500 to 6600) 2 (9) 14 (64) 6 (27) 2 (9) 2.1 (1 to 6) 73.2 (2 to 195) 65.9 (12 to 205) 3 (14) 19 (86) 19 (86) 2 (9) 1 (5) 18 (82) 5 (23) 2 (9) 1 (5) 19 (86) 1.1 (0 to 6)
(unreduced) with cannulated screws, and two whose fracture had been treated with an endoprosthesis. This left 22 patients in the study group (Table I). There were seven men and 15 women with a mean age of 58.3 years (39 to 86) at the time of their first sarcoma resection. The mean time to fracture after this resection was 73.2 months (2 to 195). There were 12 patients who underwent periosteal stripping during resection of the primary sarcoma. All patients received adjuvant radiotherapy at our institution with either 50 Gy pre-operatively (n = 8), 66 Gy post-operatively (n = 10), or both pre- and post-operative radiation, totalling 66 Gy (n = 4). Diaphyseal fractures occurred in 19 patients and intertrochanteric fractures in three. A simple transverse or short oblique fracture was present in all patients who fractured distal to the lesser trochanter (Fig. 1). These 19 patients underwent internal fixation with an IM nail, one of which
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Fig. 1a
Fig. 1b
Fig. 1c
Radiographs of a 53-year-old man with a pathological fracture of the femur 42 months after resection of a soft-tissue sarcoma from the anterior compartment of the thigh with periosteal stripping and pre-operative radiation, a) at presentation, and b) and c) immediately after fixation of the fracture with an antegrade proximal femoral nail.
had to be converted to a dynamic compression plate intraoperatively due to extensive comminution. Three other patients with intertrochanteric fractures underwent internal fixation, two with a DHS and one with an IM nail. The fracture surgery took place either at our hospital as a tertiary referral (13 patients) or at a community hospital (nine patients). The type of fracture treatment was recorded, as was any subsequent operative and non-operative intervention. Fractures were classified as either proximal intertrochanteric or diaphyseal shaft fractures. Patients were followed regularly for their sarcoma until there was radiological evidence of healing of their fracture. The primary outcome was the failure of internal fixation of the pathological fracture of the femur. Failure was classified as nonunion, with or without hardware failure, secondary fracture or deep infection. Nonunion was defined as the absence of bridging callus at the fracture site at least 12 months after operative intervention. Hardware failure was defined as nonunion of the fracture leading to breakage of the primary implant or a change in the implant position that required further surgery. None of the patients underwent bone grafting when their fracture was fixed.
Results The mean follow-up from fracture surgery was 65.9 months (12 to 205). At final follow up, 19 patients remained free of disease and three had died from metastases. A total of 18 patients had radiological evidence of nonunion at 12 months; two patients developed a nonunion associated with infection while five also experienced hardware failure associated with nonunion. One patient developed a second radiation-induced fracture after fixation and union of the initial fracture. Of the 19 patients who experienced a complication, 13 underwent 24 subsequent revision operations. The remaining six were managed non-operatively.
Of the 13 patients who required revision surgery, six underwent between two and six revision procedures. Four needed two, one needed three (Fig. 2) and one needed six additional procedures to manage the fracture (Table I). One patient was treated with a prophylactic intramedullary nail at the time of her primary sarcoma excision because of extensive periosteal stripping and an anticipated high risk of subsequent fracture. She went on to fracture her femur with the nail in situ and underwent revision to an endoprosthesis (Stryker GMRS; Mahwah, New Jersey). Another patient suffered an intertrochanteric fracture, which was treated with a DHS and healed but subsequently developed a second radiation-induced fracture just distal to the implant. A total of eight patients underwent revision to a tumour endoprosthesis and two of these patients developed additional complications. Further surgery was required in one of these patients due to infection and the other sustained a second fracture in the field of radiation after reconstruction with an intercalary prosthesis that was revised to a proximal femoral replacement. Of the two patients who had infected nonunions, one was treated by two-stage total hip replacement and the other by above-knee amputation. In total, four patients had their fixation revised due to nonunion (n = 2) or hardware failure (n = 2): three developed additional complications. One had a failed IM and was replaced; one a nonunion after an IM nail and vascular graft, who later underwent an amputation and one who had an IM exchange for a nonunion, followed by five further operations to exchange the nail due to infection and finally an endoprosthetic replacement once infection was eradicated.
Discussion Internal fixation of radiation-induced pathological fractures of the femur after primary resection of a soft-tissue sarcoma is associated with a very high rate of THE BONE & JOINT JOURNAL
INTERNAL FIXATION OF RADIATION-INDUCED PATHOLOGICAL FRACTURES OF THE FEMUR HAS A HIGH RATE OF FAILURE
Fig. 2a
Fig. 2b
Fig. 2c
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Fig. 2d
Radiographs of a patient aged 58 years at the time of surgical excision and radiotherapy for a soft-tissue sarcoma, who had a fracture of the femur eight years later that was fixed with an intramedullary (IM) nail (a). After three years in situ, the IM nail broke and was revised to an intercalary prosthesis (b). One year later he suffered a peri-prosthetic fracture at the proximal tip of the prosthesis (c), which was then revised to a proximal femoral endoprosthesis (d). He is now 75 years of age and four years from his last revision.
complications. The rate of nonunion in this study was 82% (18 of 22) at one year. Although intramedullary nails are typically regarded as load-sharing implants, the high rate of nonunion with this device led to implant failure in five patients. Overall, 13 patients (59%) underwent revision of their internal fixation because of complications and six (46%) required more than one revision procedure. This study highlights an important and challenging clinical problem that fractures of the irradiated femur have a very low potential to heal. This is probably related to a decrease in blood supply to the bone and to change in cellular activity. The mechanism behind this is not fully understood. Since these were all low-energy fractures located within the irradiated surgical field, altered bone biology is likely to be the cause.14 Cao et al15 reported that irradiated mouse femora had fewer mesenchymal stem cells, osteoblasts and osteoclasts, blood vessels were destroyed and the number of free radicals increased. The rates of nonunion of radiation-induced fractures stand in stark contrast to typical traumatic fractures of the femur that have a rate of nonunion < 3%.16,17 The short oblique or transverse pattern of all fractures distal to the lesser trochanter, all of which occurred after minor injury such as turning over in bed, twisting while standing or a fall from a standing height, resembled the pathological fractures associated with bisphosphonate therapy.18 However, the rate of nonunion in bisphosphonate-related atypical fractures appears to be much lower than 50%.19,20 This study clearly shows that just fixing these ‘simple’ fractures is generally unsatisfactory. Other surgical options include biological augmentation of the fracture site with iliac bone grafting, a vascularised fibula graft or application of bone morphogenetic protein, or the alternative of primary reconstruction with a prosthesis. These options all have risks and complications. The assumption is that the risk of infection is high if an implant is used in an irradiated VOL. 95-B, No. 8, AUGUST 2013
field; vascularised fibular grafting may be technically difficult in a previously irradiated operative field, and restricted weight-bearing may be prolonged in older patients. Kim et al13 reported on 36 fractures of the femur after surgical resection and radiotherapy. The authors compared 30 patients treated by internal fixation to a subgroup of six patients treated with a primary endoprosthesis; 19 of the 30 patients (63%) treated by internal fixation developed a nonunion. In the group treated with an endoprosthesis, one prosthesis loosened after two years and was revised and another developed a second fracture proximal to the tip of the prosthesis. The authors concluded that primary treatment with an endoprosthesis had a lower rate of complication and should be considered for radiation-induced fractures. In another study, Lin et al10 investigated nine patients who developed a post irradiation fracture of the femur and reported that four had developed a nonunion and three a delayed union. In our study we identified an even higher rate of nonunion (82%: 18 of 22) in patients treated by internal fixation. Patients with a sarcoma are most often treated by a multidisciplinary team at a specialised cancer centre. However, if they sustain a fracture of the femur, from our experience, they are often treated at a hospital closer to home by an orthopaedic surgeon who may not routinely deal with radiation-induced pathological fractures. In our study 41% of the patients were treated in a community hospital. It is therefore important that surgeons are aware of the difficulties in treating these fractures. Treatment should be based on the assumption that the fracture will not heal even when the fracture pattern appears simple. It is also reasonable to refer these patients to a specialist centre for treatment as it is an uncommon occurrence and one that cannot be managed conventionally on the basis of the results of our study. There are limitations to this study; its retrospective nature and the small number of patients make it difficult to
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assess the clinical scope of this problem. In addition the patients underwent surgery at several hospitals and a number of surgeons were involved in their treatment using a variety of devices for fractures located in a number of positions. Also we were obliged to exclude four patients from this study because of missing data. Finally radiographs were not available for seven patients who were treated before 2002 when our hospital radiology department changed to a digital system and previous images were lost. In those cases, we relied on radiology reports to describe the fracture patterns. In conclusion, pathological fractures of the irradiated femur after resection of a soft-tissue sarcoma of an extremity have a high rate of nonunion after internal fixation. Treatment should not rely only on the healing potential of the irradiated bone. A. Sternheim was supported by the OMEGA Medical Grants Association through the generous support of Zimmer for its oncology staff. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by A. Ross and first proof edited by G. Scott.
References 1. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy on soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235–2241. 2. Biau DJ, Ferguson PC, Chung P, et al. Local recurrence of localized soft tissue sarcoma: a new look at old predictors. Cancer 2012;118:5867–5877. 3. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–315. 4. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203.
5. Cheng EY, Dusenbery KE, Winters MR, Thompson RC. Soft tissue sarcomas: preoperative versus postoperative radiotherapy. J Surg Oncol 1996;61:90–99. 6. Paulino AC. Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 2004;60:265–274. 7. Davis AM, O’Sullivan B, Turcotte R, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75:48–53. 8. Tseng JF, Ballo MT, Langstein HN, et al. The effect of preoperative radiotherapy and reconstructive surgery on wound complications after resection of extremity softtissue sarcomas. Ann Surg Oncol 2006;13:1209–1215. 9. Cannon CP, Ballo MT, Zagars GK, et al. Complications of combined modality treatment of primary lower extremity soft-tissue sarcomas. Cancer 2006;107:2455– 2461. 10. Lin PP, Schupak KD, Boland PJ, Brennan MF, Healey JH. Pathologic femoral fracture after periosteal excision and radiation for the treatment of soft tissue sarcoma. Cancer 1998;82:2356–2365. 11. Holt GE, Griffin AM, Pintilie M, et al. Fractures following radiotherapy and limbsalvage surgery for lower extremity soft-tissue sarcomas: a comparison of high-dose and low-dose radiotherapy. J Bone Joint Surg [Am] 2005;87-A:315–319. 12. Gortzak Y, Lockwood GA, Mahendra A, et al. Prediction of pathologic fracture risk of the femur after combined modality treatment of soft tissue sarcoma of the thigh. Cancer 2010;116:1553–1559. 13. Kim HJ, Healey JH, Morris CD, Boland PJ. Site-dependent replacement or internal fixation for postradiation femur fractures after soft tissue sarcoma resection. Clin Orthop Relat Res 2010;468:3035–3040. 14. Nicholls F, Janic K, Filomeno P, et al. Effects of radiation and surgery on healing of femoral fractures in a rat model. J Orthop Res 2013:Epub. 15. Cao X, Wu X, Frassica D, et al. Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells. Proc Natl Acad Sci U S A 2011;108:1609– 1614. 16. Wolinsky PR, McCarty E, Shyr Y, Johnson K. Reamed intramedullary nailing of the femur: 551 cases. J Trauma 1999;46:392–399. 17. Winquist RA, Hansen ST Jr, Clawson DK. Closed intramedullary nailing of femoral fractures: a report of five hundred and twenty cases. J Bone Joint Surg [Am] 1984;66-A:529–539. 18. Lo JC, Huang SY, Lee GA, et al. Clinical correlates of atypical femoral fracture. Bone 2012;51:181–184. 19. Ward WG Sr, Carter CJ, Wilson SC, Emory CL. Femoral stress fractures associated with long-term bisphosphonate treatment. Clin Orthop Relat Res 2012;470:759– 765. 20. Ha YC, Cho MR, Park KH, Kim SY, Koo KH. Is surgery necessary for femoral insufficiency fractures after long-term bisphosphonate therapy? Clin Orthop Relat Res 2010;468:3393–3398.
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