Modular endoprostheses today represent a standard treatment option in the management of musculoskeletal tumors of the lower extremities. Long-term results of these reconstructions, however, are often limited by the course of the underlying disease. We therefore report our experiences in cancer patients with megaprostheses of the lower limb after a minimum of 15 years. 62 patients, 34 men and 28 women, with a mean age of 26 years (median, 20; range, 6–83) were included in this investigation with a mean follow-up of 230 months (median, 228; range, 180–342). Endoprosthetic reconstructions of the proximal femur (11), the distal femur (28), the total femur (2) or the proximal tibia (21) were indicated for osteosarcoma (43), chondrosarcoma (5), malignant fibrous histiocytoma (3) or other tumors (11). All patients have received either a KMFTR (22) or a HMRS (40) modular prosthesis; 23 patients had a muscle flap, 14 had a fibular transposition osteotomy and 4 have received an artificial LARS ligament for soft-tissue reconstruction.Background
Materials and Methods
Preoperative serum CRP has been identified as an independent predictor in various malignancies. For osteosarcoma, however, the value of serological markers is unreliable. Aim of this study was to evaluate the prognostic power of preoperative CRP in patients with osteosarcoma. Out of our prospective database, 87 patients with osteosarcoma (43 female, 44 male with an average age of 20.4 years) have been identified with complete documentation of peri-operative CRP-levels, a minimum two year follow-up and after exclusion of concomitant infection, smoking-history or cardio-vascular disease. Pre-operative CRP before tumour resection was correlated with clinical and pathological factors, overall survival and infection rates in an uni- and multi-variate statistical model with and without landmark analysis.Aim
Method
Endoprosthetic replacement following oncological conditions has shown to be at higher risk of sceptical complications due to the use of implants of unusual size, major soft tissue loss and immunsupression. 373 patients have been treated at our institution for malignant tumours of the bone or soft tissue around the knee with a modular tumour-prostheses of the knee joint since their availability from 1978. Infection or septic complications were identified in 78 patients (20.9%). In 15 cases of superficial wound healing disturbances with a fistula simple excision and revision of the wound was performed. In 48 cases of deep periprosthetic infections patients underwent one-stage revision with explantation of the total prosthetic material except femoral and tibial stems, extensive debridement of the wound and replantation of the disinfected prostheses throughout one operation. In 8 patients two-stage revision of the prostheses was performed, using an antibiotic impregnated cement spacer and Steinmann nails. In 5 patients amputation of the affected limb was indicated, whereas 2 patients could be treated conservatively. Out of the patients treated by one-stage revision 16 developed recurrent infection and had to undergo consecutive surgery. After two-stage surgery 4 patients showed signs of septic recurrence. According to our results deep periprosthetic infection of tumour-prostheses primarily can be treated by one-stage revision, in recurrent infections, however, two-stage revision should be performed. We additionally suggest the use of local or pedicled muscle flaps to obtain better soft tissue coverage of the prostheses after infection.
Resection of the upper limb together with the shoulder girdle is known as forequarter amputation. In selected patients, this type of resection may have to be extended to a resection including parts of the thoracic wall in order to achieve local tumour control in advanced stages of neoplasms. Although, forequarter amputation alone is well described, reports on its combination with parts of the chest wall only consist of few case reports, while larger experiences and systematic reviews of its obstacles and complications are missing. A series of six patients, five females and one male with, average age 58 years (range 41 to74 years), undergoing forequarter amputation with partial chest wall resection has been treated for malignancies around the shoulder at the Medical University of Vienna since 1993, thereby, to our best knowledge, presenting the largest series published to date. Patient data of all departments involved were retrospectively analysed and patients were followed-up according to standard oncological protocols. The underlying disease was malignant schwannoma in two, undifferentiated sarcoma in two, osteosarcoma in one and squamous cell sarcoma in one. A vast tumour of the shoulder and axillar space, uncontrollable pain, lymphedema, partial loss of function of the affected limb and ulceration indicated treatment. All patients underwent radical amputation of the upper limb and all structures of the shoulder girdle including two to seven ribs. Chest wall reconstruction was achieved by a PTFE patch alone or in combination with a Stratos®-implant. Myo-cutaneous reconstruction was performed by a pedicled (n=3) or a free myo-cutaneous forearm flap (n=3). There were no cases of peri-operative mortality. In two patients full forearm flap necrosis occurred and indicated two revisions in each with coverage by a free flap. One patient suffered vascular complications and underwent five revisions. Average follow-up was 14 months (range 5 to 35 months). Median survival was 8.5 months, with three patients still alive at the time of this investigation. Three patients died of systematic metastatic disease between 5 and 35 months after surgery. Two patients were successfully supplied with myo-electrical prostheses. The key issues for surgical management of the resulting defect were
the restoration of mechanical chest wall stability, a sufficient myo-cutaneous flap, preferably a free pedicled flap as it seemed more efficient than the free extremity flap and the management of concomitant complications such as paralysis of the phrenic nerve, chylothorax and post-operative pain. Although forequarter amputation is a mutilating operation and in advanced stages of disease certainly can only temporarily limit disease progression, in selected cases, it may remain an option in vast tumours of the shoulder girdle.
Besides the femur and the tibia, the humerus is the third most common localisation of osteosarcoma. 78 patients with osteosarcoma of the humerus have been treated at our institution since 1934. Among these, 7 patients have been admitted before implementation of the Vienna Tumour Registry in 1968, additionally 4 patients had undergone primary surgical resection at another institution. This left 67 patients for follow-up after multi-modal therapy of humeral osteosarcoma comprising neo-adjuvant and adjuvant chemotherapy and surgical resection. (38 males and 29 females with an average age of 21.8 years, range 3.6 to 73.2 years) The subtypes of tumours observed were classic osteosarcoma in 56 patients, parostal sarcoma in 4, teleangiectatic sarcoma in 3, secondary sarcoma in 2 (one in Morbus Paget and one after radiation of a hemangioendothelioma), high-grade surface sarcoma in 1 and a humeral lesion within a multifocal osteosarcoma in 1. The localisation was foremost the proximal humerus (61) and rarely affecting the distal (5) or total bone (1). 11 patients suffered from pulmonary metastases upon primary diagnosis. In 9 cases resection alone was indicated. 9 patients underwent a resection-replantation-plasty, and in 2 patients primary amputation was performed. 46 patients were treated by resection and endoprosthetic reconstruction using ceramic prostheses (7), custom-made endoprostheses (13) or humeral HMRS modular prostheses (26). Before 1980 a non-standardised neo-adjuvant and adjuvant chemotherapy was administered in 12 patients, all patients thereafter received a chemotherapeutic regimen according to the COSS or EURAMOS-1 protocol. In 3 patients with parostal sarcoma no adjuvant therapy was indicated. The patient with multifocal osteosarcoma was treated conservatively by chemotherapy, radiation and immunotherapy by dendritic cell vaccination. The overall survival was 58% at 5 years. 23 patients died of their disease at an average of 25 months after operation (range 2 to 135 months). Average follow-up of the remaining patients was 91 months. (range 1 to 389 months). 4 patients treated before 1982 developed local tumour recurrence leading to secondary amputation in all cases, and death of disease within 12 months in 3 cases, respectively. 16 patients had to undergo one or more revisions, including secondary amputation in 2. Pulmonary metastases were observed in 15 patients, 2 patients developed skeletal metastates. After resection of metastatses, 14 patients died of disease, among them 9 patients died within 12 months after operation. Upon latest follow-up, 3 patients were alive disease-free, the patient with multifocal osteosarcoma was alive with disease 22 months after primary diagnosis. The multimodal treatment of osteosarcoma shows satisfactory oncological results. The implementation of standardised chemotherapeutic protocols has improved overall outcome.
The treatment of deep prosthetic infection in cancer patients with tumour prostheses remains the major complication to be dealt with in this population. The Vienna Bone Tumour Registry includes information of more than 6500 patients of a period of 36 years. 145 patients with malignant proximal femoral tumors had resection and limb salvage with an uncemented Kotz modular femoral and tibial reconstruction megaprosthesis (KMFTR). There were twenty osteosarcomas, thirteen Ewing’s sarcomas, six chondrosarcomas, six plasmozytomas, three fibrosarcomas, three liposacomas and others. Thirteen patients (7 males, 6 females with an average age of 45 years, range 10 to 75 years) suffered from deep prosthetic infection within an average of 44 months after primary implantation, representing an infection rate of 8,97 percent. Average follow-up was 109 months, range 7 to 339 months. Two patients with only mild signs of infection were treated by a conservative antibiotic regimen. Nine patients were treated by one-stage revision. One of the remaining two patients with severe infection underwent exarticulation of the hip as primary intervention, the other patient died due to general sepsis on the fourth post-operative day. Six patients showed no further signs of infection. Six patients, however, required one or more reoperations due to recurrent prosthetic infection. Among these four patients have successfully been treated by repeated one-stage revision, in two patients the prosthesis had to be removed permanently. Deep prosthetic infection around modular tumour prostheses of the proximal femur and hip seems to be less common compared to distal femur, knee or tibia. However, the treatment of this complication has a higher failure rate due to multiply recurrent infection.
Hyperactivation of the epidermal growth factor receptor (EGFR) by gene amplification, mutation as well as overexpression is a hallmark of multiple human carcinomas. However, in recent years data have accumulated that EGFR-mediated signals might also contribute to malignant progression and therapy resistance of human sarcomas. Consequently we have investigated if human osteosarcoma cell lines (n=9) express functional EGFR and its useability as therapeutic target. Osteosarcoma cells expressed distinctly differing level of EGFR reaching in some cases high amounts. However, even low expression levels were sufficient to activate both MAPK and PI3K pathways (determined by phosphorylation of ERK1/2 and S6, respectively) following EGF exposure of serum-starved cells. The EGFR-specific inhibitor gefitinib completely blocked EGF-mediated and attenuated serum-induced downstream signal activation. While gefitinib applied as single agent demonstrated only limited growth inhibiting activity in short term experiments (72h drug exposure), it led to reduced colony formation in long term experiments in the majority of cell lines. Importantly, gefitinb sensitized EGFR-expressing osteosarcoma cell lines against chemotherapy with doxorubicin and methotrexate, while it antagonised cisplatin-induced cell death. Summarizing, our data suggest that EGFR-mediated survival signals protect human osteosarcoma cells against the cytotoxic activity of several antineoplastic drugs. Consequently, combination approaches including EGFR inhibitors in addition to chemotherapy should be evaluated for treatment of high grade osteosarcoma patients.
Parosteal osteosarcoma is an uncommon tumour. Different methods of surgical treatment have been reported. Aim of this study was to investigate differences in outcome after biological and prosthetic reconstruction. Since August 1969, 28 patients have been treated at our institution. Average age was 26 years, range 15 to 59 years. Patient data was retrospectively reviewed within the prospective database of the Vienna Tumour Registry. Average follow-up was 133.9 months, range 8.4 to 382.6 months. Two patients died of disease 8.4 and 81.4 months after operation, respectively, another patient died due to unrelated causes 330.4 months postoperatively. All surviving patients were followed for a minimum of 3.6 months. Location of the lesion was the distal femur (19), proximal humerus (four), proximal tibia (three), mid-diaphyseal and proximal femur (one each). In 12 patients endoprosthetic reconstruction was indicated. Biological reconstruction was performed in 11 patients. Three patients underwent rotationplasty, two patients were amputated. Eight of 12 patients with endoprostheses have been revised, five have had multiple revisions. Causes for revision were bushing wear (four), aseptic loosening (four), infection (three) and periprosthetic fracture (one). There was no local recurrence in the endoprosthetic group. Two of 11 patients with biological reconstruction underwent revision due to pseudarthrosis and femoral fracture, respectively. There were two cases of local recurrence requiring secondary amputation. Two patients with rotationplasty underwent revision for wound healing disturbance and thrombectomy, respectively. Three patients developed lung metastases, leading to death of disease in two cases of amputation and rotationplasty. One patient with endoprosthetic reconstruction was alive 129.0 months after pulmonary metastasectomy. Functional outcome was satisfactory in all patients; there were no significant differences between patients with endoprosthetic or biological reconstruction. Biological reconstruction showed less revisions compared to endoprostheses, however, exact preoperative planning is required to obtain clear margins of resection.
The development of local recurrence after multimodal treatment of osteosarcoma is associated with a very poor prognosis. The importance of clear surgical margins has been demonstrated in multiple studies, however up to date there are no studies defining which margin width is safe from an oncological perspective. The purpose of this retrospective analysis was to evaluate whether margin width or other surgical and tumour-related factors influence the development of local recurrence in osteosarcoma patients. The files of 1867 consecutive patients with high-grade central osteosarcoma of the extremities, the pelvic bones and the shoulder girdle, who had achieved a complete surgical remission during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols between 1986 and 2005, were reviewed. Of those, the data required were available for 1369 patients, who were the subject of this analysis. Eighty of these patients developed a local recurrence during the course of their illness. The median surgical margin width amounted to 45 mm (range, 0 to 140 mm) in the local recurrence (LR) group and 50 mm (range, 0 to 350 mm) in the non-local recurrence (NLR) group (p=0.106). No statistically significant difference between the two groups was found regarding tumour size (mean, 10.38 cm and 9.53 cm respectively, p=0.169), T-status (p=0.225) and presence of pathological fracture (p=0.231). However infiltration of the soft tissue beyond the periosteum was documented in 58.8% of the patients with local recurrence and only in 36.9% of the rest (p=0.003). Furthermore, in 50% of the LR group the biopsy had been performed in a centre other than the one performing the definitive tumour resection, compared to 30.2% of the NRL group (p=0.001). In conclusion, the absolute metric width of surgical margins does not define oncological safety. Local recurrence is more likely to develop in patients with soft tissue infiltration beyond the periosteum or those biopsied in a centre other than the one performing the tumour resection.
Fibula autograft reconstruction, both vascularised (v) and non-vascularised (nv), has been established as a standard method in limb salvage surgery of bone and soft tissue tumours of the extremities. This study retrospectively analyses the results of fibula autograft procedures in general and in relation to vascular reconstruction or simple bone grafting. Since the implementation of the Vienna Tumour Registry in 1969, 26 vascularised and 27 non-vascularised fibula transfers have been performed at our institution in 53 patients, 26 males and 27 females with an average age of 21 years (range 4 to 62 years). Indications included osteosarcoma in 18, Ewing’s Sarcoma in 15, adamantinoma in 5, leiomyosarcoma in 3 and others in 12. Thirty patients were operated for reconstruction of the tibia (8v/22 nv), 7 for the femur (6v/1nv), 7 for defects of the forearm (4v/3nv), 5 for metarsal defects (all v), 3 for the humerus (1v/2nv) and one patient was treated for a pelvic defect (nv). Average follow-up was 63 months (range 2 to 259 months). 43 patients showed successful primary bony union of the autograft. In 12 cases pseudarthrosis indicated further surgical revision, 9 of these patients were primarily reconstructed by use of a nv autograft. 4 patients, 2 with v and 2 with nv reconstruction, suffered a fracture of the transplant and were operated for secondary osteosynthesis. 10 patients with v bone graft developed wound healing disturbances which led to surgery, 2 patients with nv grafts suffered such complications. In 2 patients recurrent infection of a nv and a v fibula transfer led to the implantation of a modular tumour prostheses or amputation, retrospectively. Function of all patients with primary bone healing was rated satisfactory. The use of fibula autograft in limb-salvage surgery under oncological conditions allows biological reconstruction with good functional outcome, especially when primary bone healing is achieved. Vascularised bone grafting seems to have a better outcome in terms of primary bone healing than simple fibula bone grafting, and thus represents a feasible choice in the reconstruction of bone defects from tumour resection.
Ten year results of 100 primary lower limb reconstruction prostheses implanted between 1982 and 1989 were analysed. In a Kaplan-Meier estimate there was a 85% three years, a 79% five years and 71% ten years survival rate. Most common reason for implant failure was aseptic loosening in 27% of patients (11 patients; range 10–121 months) after initial operation. Other reasons for revision surgery were implant failure (4) and infection (4). Early repair of prostheses-related minor complications, was polyethylene bushings destruction. After a median followup of 127.5 months after the initial surgery, 51 patients had died and eight patients were lost to followup. Forty-one patients were evaluated clinically and radiologically using the MTS score and the radiologic implant evaluation system of the International Symposium on Limb Salvage. 41 patients had a mean of 80% (range, 40%–100%) of the normal functional capability.