Osteosarcoma is the most common malignant bone tumor in childhood and adolescence, and the application of neoadjuvant chemotherapy as well as high-dose chemotherapy has effectively improved the 5-year survival rate of patients and promoted the development of limb-preserving techniques. Late studies have challenged the role of Rosen neoadjuvant chemotherapy on limb preservation and 5-year survival in osteosarcoma, arguing that timely surgery (including limb preservation and amputation) for patients without metastases, followed by adjuvant chemotherapy The prognosis is no different from that of neoadjuvant chemotherapy; studies of chemotherapy resistance have led to the recognition that multidrug resistance is the most important cause of chemotherapy failure in osteosarcoma.
Limb preservation surgery has become the standard of care in the surgical treatment of osteosarcoma of the limb, with the emergence of inactivated replantation of tumor segments, allograft bone, fibula grafts with vascular tips, tumor-based prostheses, composite prostheses, and lengthenable prostheses, replacing traditional amputation; children’s limb preservation also faces great challenges, with the main surgical challenge being limb reconstruction after tumor resection in children, and addressing limb inequality after limb preservation surgery has been a hot topic in recent years. The main surgical challenge is limb reconstruction after tumor resection in children.
Osteosarcoma occurs in adolescents, with high malignancy and mortality. The dramatic increase in 5-year survival rate is attributed to the improved efficacy of chemotherapy, and nowadays, in bone tumor centers, the cure rate of osteosarcoma is 60%-70% with preoperative and postoperative chemotherapy combined with surgery, and more than 90% of osteosarcoma patients can have limb preservation, and statistics show that 78% of patients have satisfactory limb function after limb preservation.
1.Neoadjuvant chemotherapy and adjuvant chemotherapy
Rosen proposed the concept of neoadjuvant chemotherapy in 1982, and Rosen’s early neoadjuvant chemotherapy regimen included high-dose aminoglutethimide (HDMTX), vincristine (VCR), cyclophosphamide (CTX), and adriamycin (ADM). CDP) and adriamycin (DOX) neoadjuvant chemotherapy with initial treatment with IFO 15 g/O, MTX 12 g/O, CDP 120 J/O, ADM 75 J/O, 2 cycles of ADM 90 J/O and 3 cycles of high-dose IFO, MTX (aminoglutethimide) or CDP (120-150) J/O after surgery, with no progression of disease after initial treatment, 5-year tumor-free survival rate of 64%, overall survival rate of 77%, and limb preservation in more than 90% of patients.
The newer regimens of Bacci et al [6], both of which included IFO, were shown to improve survival, and a controlled study of the Coss82 regimen found that 57% of patients who applied IFO + MTX preoperatively achieved tumor necrosis of more than 90%, and only 27% of patients who applied MTX + BCD (actinomycin D) preoperatively achieved tumor necrosis of more than 90%, and the efficacy was positively correlated with the dose of IFO Today, IFO is used in the protocols of the Rixxoli Institute of Orthopaedic Surgery in Italy, the Osteosarcoma Collaborative Group in Germany, and Harvard University Hospital Massachusetts General Hospital.
Patel et al. gave patients IFO, DOX, and CDP preoperatively and achieved a 5-year survival rate of 57% in 66% of patients with tumor necrosis >90%, followed by the addition of MTX (total dose 15 g/O) to postoperative chemotherapy in patients with tumor necrosis <90%; Bacci et al [8] treated 1148 metastasis-free limbs with four different chemotherapy regimens and seven different neoadjuvant chemotherapy regimens Osteosarcoma, the limb preservation rate increased from 20% to 71%, the 5-year survival and overall survival rates were 52% and 66%, respectively, and the 10-year tumor-free survival and overall survival rates were 52% and 57%, respectively.
Wilking [9] reported that in 62 patients with osteosarcoma treated with high-dose cisplatin (DDP) arterial infusion neoadjuvant chemotherapy, 54 achieved good histological response, reduced tumor angiogenesis by 90%, and improved tumor necrosis rate. Bacci [11] et al. concluded that the tissue necrosis rate of preoperative chemotherapy was significantly correlated with survival, and the 5-year tumor-free survival and overall survival rates were 67.9% versus 51.3% and 78.4% versus 63.7% in the good and poor histological response groups, respectively, and the degree of tissue necrosis of preoperative chemotherapy was significantly correlated with prognosis.
2. Challenges of neoadjuvant chemotherapy and high-dose chemotherapy
Later studies have challenged the role of Rosen neoadjuvant chemotherapy on limb preservation and 5-year survival in osteosarcoma. goorin questioned the rationale for neoadjuvant chemotherapy, arguing that the prognosis for patients without metastases who underwent timely surgery (including limb preservation and amputation) followed by adjuvant chemotherapy was not different from neoadjuvant chemotherapy, (5-year tumor-free survival rates of 69% and 61%), goorin’s study shook the notion that neoadjuvant chemotherapy is superior to adjuvant chemotherapy as described by Rosen since 1979. Although many scholars believe that preoperative chemotherapy helps to determine tumor response to treatment and to predict high-risk patient populations, it does not improve the prognosis of patients with unmetastatic osteosarcoma.
Bacci et al. concluded that increasing the dose of preoperative chemotherapy did not improve tissue necrosis and survival, and that the degree of tissue necrosis with preoperative chemotherapy may be influenced by the genetic sensitivity of tumor tissue to chemotherapy and is not altered by increasing the dose of chemotherapy; Bacci et al. concluded that there was no correlation between MTX dose and tumor tissue response, and that the rate of tumor tissue necrosis had little relationship with chemotherapy dose and was related to tissue type.
Eselgrim’s analysis of 917 consecutive Coss Collaborative Group patients, all of whom received regular combination chemotherapy and surgery, did not provide a correlation between high dose intensity and good outcomes.Lewis et al. found that increasing DOX/CDDP dose intensity improved histologic response rates, but increasing DOX/CDDP intensity was not significantly associated with patient survival correlation. Postoperative salvage chemotherapy administered to osteosarcoma with a poor response to preoperative chemotherapy was not effective with different agents than those used preoperatively.
Today, at Rizzoli and other institutes, four chemotherapeutic agents (MTX, CDP, ADM, and IFO) are administered simultaneously to osteosarcoma regardless of the histologic response of the tumor, and it is believed that increasing the dose intensity of the agents does not increase the tumor necrosis rate or improve the final treatment outcome. In fact, histologically poor chemotherapy response in osteosarcoma accounts for about 30% of patients, and if neoadjuvant chemotherapy is administered to this group of patients, it will undoubtedly increase the toxic side effects of chemotherapy while increasing the length of hospital stay and costs, as well as delaying the surgical resection of the tumor and risking metastatic dissemination.
Research on chemoresistance has led to the recognition that multidrug resistance is the most important cause of chemotherapy failure in osteosarcoma. The expression of the multidrug resistance gene (MDR) product P-glycoprotein (Pgp, abbreviated as p170) is significantly correlated with chemotherapy failure, and high expression of Pgp is the main mechanism of MDR. Pgp can bind to hydrophobic antitumor drugs through its hydrophobic site, and supply energy through ATP hydrolysis and reverse Baldini et al. performed immunohistochemical staining of osteosarcoma sections without metastasis and postoperatively treated with adriamycin as the only chemotherapeutic agent and found that tumors with Pgp expression had a poor prognosis due to resistance to adriamycin.
Serra et al [18] showed that high levels of Pgp expression combined with large tumor size and low age of onset suggested a high rate of tumor recurrence. A recent study found that osteosarcoma with co-expression of Pgp and Rb genes had poor prognosis [19]. mutation and inactivation of P53 gene affects not only the occurrence, development, and prognosis of osteosarcoma, but also the effectiveness of chemotherapy for osteosarcoma.
Some studies have shown that P53 gene deletion is a useful indicator of chemotherapy resistance in osteosarcoma, and other studies have shown that P53 gene and wtp53 de novo deletion are associated with cisplatin resistance in human osteosarcoma [20]. High-dose MTX plays an important role in osteosarcoma chemotherapy, MTX resistance is a major factor in poor prognosis of osteosarcoma, and reduced folate carriers (RFC) that transport MTX across the membrane into cells have become a new point of view for tumor resistance, Hattinger et al. found in a study of Saos-2 MTX-resistant variant cell lines that RFC gene expression was significantly decreased and correlated with the degree of MTX resistance.
Meschini et al [22] found that the binary alkaloid (Voacamine) significantly induced intracellular retention of adriamycin and concentrated its distribution in the nucleus, suggesting the value of the use of the natural substance Voacamine in multidrug-resistant osteosarcoma. The phenomenon of multidrug resistance mediated by proteins such as glycoprotein (Pgp), multidrug resistance-associated protein (MRP), lung resistance protein (LRP), DNA topoisomerase II (TOPO II), heat shock protein (HSP) and breast resistance protein (BCRP) and their mechanisms are gradually being recognized, and it is hoped that detection or modulation of these proteins can guide individualized chemotherapy for osteosarcoma, however However, due to the large number of multidrug resistance proteins and unclear interactions, the above purpose is obviously not fully achieved.
3.Limb preservation therapy for osteosarcoma
With the improvement of chemotherapy efficacy, limb preservation surgery has become the standard treatment of limb osteosarcoma surgery. The emergence of tumor segment inactivation and replantation, allogeneic bone, fibula graft with vascular tip, tumor-based prosthesis, composite prosthesis, and extendable prosthesis has replaced the traditional amputation; with the continuous improvement and development of treatment end, the adaptive scope of limb preservation surgery is expanding, and the treatment of stage IIB osteosarcoma, pediatric osteosarcoma, and Limb preservation for patients with pathological fracture of osteosarcoma has also been studied by some scholars, but limb preservation should be considered carefully.
3 .1 Limb preservation method
Suk et al. soaked the resected tumor bone in saline at 65oC for 30 min and reconstructed the affected limb with bone cement and metal prosthesis after inactivation, resulting in inactivated bone fracture in 2 out of 12 cases and bone discontinuity in only 1 case without local recurrence. patients, 3 of them had inactivated bone fractures, 2 had bone resorption, and no local recurrence.
Allogeneic frozen bone has been used to repair bone defects and reconstruct joint function after the amputation of tumor segments because of its good natural bone tissue structure, morphology, strength, osteoconductivity, very low immunoreactivity, and strong healing ability with the host bone. However, the activation and replacement process of allograft bone graft reconstruction in patients with osteosarcoma is slow, and it is difficult to achieve complete replacement of large segments of allograft cortical bone, and postoperative joint surface degeneration and resorption can occur, and the strength of bone and healing with natural bone are limited. or the proximal end of the donor tibia relying on bone cement and artificial prosthesis rod stem fixed together, the entire composite prosthesis mainly through the medullary stem to obtain stability.
The advantages of the allograft composite prosthesis include the ability of the allograft bone to heal with the host bone, thus reducing rotational stresses at the attachment to the prosthesis, and the allograft bone providing good tissue attachment for knee stability. Disadvantages include potential fractures, infections, infectious disease infections, bone nonunion, malunion, and resorption of the allograft bone.
Customized phased prosthesis has a standardized component system that allows the surgeon to select the right size component for the specific situation without having to be concerned about the extent of bone tumor resection due to the limitations of the prosthesis size. The prosthesis can be divided into distal femoral and proximal tibial types and includes designs such as polyethylene tibial plateau and extensor device attachment points. This prosthesis has the advantages of good stability and early postoperative weight bearing.
Malo et al [29] conducted a comparative study between non-cemented and cemented rotary hinge prostheses, where the tumor site was distal femur and 31 patients were implanted with non-cemented rotary hinge prostheses and 25 patients with cemented rotary hinge prostheses. Postoperative function was much higher in the cemented rotary hinge prosthesis group than in the non-cemented rotary hinge prosthesis group.
The early prostheses were fixed-hinged, but the later emergence of rotating-hinged prostheses proved to be superior to the earlier fixed-hinged prostheses; the earlier functional exercise with cemented prostheses may have contributed to the higher functional scores in the cemented rotating-hinged prosthesis group. In terms of survival follow-up studies, Zeegen et al. followed up 141 patients who applied a modified prosthesis and found that 88% did not require revision at 3 years and 76% did not require revision at 5 years, with local tumor recurrence, infection, and loosening as independent risk factors for prosthesis failure.
Springer et al. reported 69 patients treated with a rotating hinge type prosthesis (75.2 months follow-up), of which 23 (33%) had at least one complication and 9 knees underwent a second surgery, with the most common complication being deep infection (14.5%), followed by knee extension dysfunction (13%), and prosthetic dysfunction (10%), despite the presence of complications. patient satisfaction rates were generally high (81% more or very satisfied).
Brickels et al [32] followed up 110 patients with this prosthesis in a multicenter combined study and showed a 5-year survival rate of 93% and a 10-year survival rate of 88%, with no significant difference in survival rates compared to those of conventional total knee replacement prostheses. There was a high incidence of complications caused by mechanical factors, all of which could be resolved by further surgery.
Fan et al. treated 176 patients with malignant bone tumors of the limb with insertional microwave antenna arrays to induce high-temperature in situ inactivation, and chemotherapy was administered before and after surgery, with a mean follow-up of 49 (24-96) months after surgery and an overall survival rate of 73.9%, indicating that this method can be used as one of the limb preservation methods for malignant tumors of the limb.Chen et al. used free fibula with blood vessels to reconstruct the tumor after resection of a complex long bone defects with low infection rates, high bone healing rates and good functional outcomes compared to conventional allografts, and Gebert et al [35] used a fibula graft with vessels as a biologic reconstruction to repair a large segmental bone defect with 31% hypertrophy of the fibula, and the main complications were fracture, pseudarthrosis, delayed healing of the incision, and transient nerve injury, with acceptable complication and reoperation rates.
The choice of limb preservation method depends mainly on the extent of the tumor, the patient’s age, the surgeon’s experience, the patient’s economic status, the follow-up treatment, and the patient’s wishes. Mastering the indications and contraindications of surgery is the key to success. For example, tumor invasion of important vascular nerves, tumor cannot be completely removed, immature bones, pathological fracture, distant metastasis of tumor, poor skin condition, infection, etc. are all contraindications of limb preservation surgery.
3.2 Limb preservation in children.
Limb preservation treatment for osteosarcoma of the extremities in children is bound to bring about a series of complications such as limb inequality that affects normal walking, causing pelvic tilt, scoliosis, joint damage due to abnormal stress, etc. Whether to perform limb preservation treatment for pediatric malignant bone tumors is still controversial [36], and limb preservation treatment in children is a major problem in limb preservation treatment for bone tumors, and solving limb inequality after limb preservation surgery is a hot spot in limb preservation treatment in recent years.
Kunta et al [37] followed up 43 children aged 4 months to 13 years for an average of 6 years, and 81% of them were suitable for limb preservation, and the suitability of limb preservation depends on the extent of tumor invasion, stage, and response to neoadjuvant chemotherapy. In the management of the epiphysis, Manfrini et al [38] concluded that limb preservation with preservation of the epiphysis is feasible if preoperative MRI examination does not reveal epiphyseal invasion, whereas Jesus-Garcia et al [39] found in a study of 25 children (14 males and 11 females) aged 4 to 17 years with unresolved osteosarcoma of the epiphyseal plate that radiological examination showed tumor invasion of the epiphyseal plate in only 11 cases and histological examination This proves that the epiphyseal plate is not a barrier to tumor growth and emphasizes the need for caution in preserving the epiphyseal plate during limb preservation surgery.
The placement of lengthenable prosthesis to repair bone defects after resection of malignant bone tumors in children can prevent later occurrence of limb inequality. The indications for lengthenable prosthesis are osteosarcoma or other malignant bone tumors without distant metastases, expected bradykinesia >2 cm, and children aged 5-15 years (too young for complications), who can undergo tumor resection prosthesis replacement in one stage.
The lengthenable prosthesis can be broadly divided into invasive lengthenable prosthesis and non-invasive lengthenable prosthesis, the former requires multiple surgeries to lengthen the prosthesis, the latter such as phenix prosthesis, whose main components include titanium prosthetic stem, composite tube structure, compression spring three parts, the lengthening mechanism of the prosthesis is in vitro magnetic field, release the compression spring, relying on its potential energy reserve will be the prosthetic stem from the composite tube top, so that The length of extension depends on the compliance of soft tissues and the pressure stored in the spring inside the prosthesis. In order to avoid nerve and blood vessel damage, the length of each extension should be less than 2 cm.
Gitelis et al. reported a mean follow-up of 24.8 months for 14 patients, with 58 lengthenings of the prosthesis, a mean of 8.5 mm per lengthening, and a mean lengthening of 38 mm per patient; Neel et al. performed a 21.5-month follow-up of 15 children undergoing phenix limb-preserving reconstruction after osteosarcoma resection, with 60 lengthenings, a mean of 8.5 mm per lengthening. according to the latest osteosarcoma postoperative scoring system, knee function was 90%.
The major complications of the lengthenable prosthesis were infection, postoperative arterial embolism, prosthesis fracture, aseptic loosening, lengthening failure, subsidence, and damage to internal components. It has been reported that 25% of lengthenable prostheses require revision after 5 years, and the main reasons for revision are infection, tumor recurrence, failure of prosthesis function, and aseptic loosening. In addition, scholars have also reported that secondary growth plate destruction can occur after limb preservation surgery for extendable prostheses. Taking the distal femur as an example, prosthesis placement may cause damage to the growth plate of the distal tibia, which in turn has growth imbalance leading to limb angulation and eventual loosening of the prosthesis.
With the deepening of clinical and basic research, the treatment of osteosarcoma will break through the current plateau, and new gene therapy, targeted therapy, anti-tumor angiogenesis therapy, and the solution of tumor drug resistance problem will provide new and more effective methods for the treatment of tumor, which will ultimately benefit mankind.