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Oncology
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Orthopedics
Osteosarcoma is a rare malignancy arising from mesenchymal tissue, and represents the most common bone sarcoma. The management of osteosarcoma is challenging, and requires a multidisciplinary approach. In daily clinical practice, surgery, radiotherapy, and conventional chemotherapy constitute the therapeutic armamentarium against the disease.
- osteosarcoma
- chemotherapy
- targeted therapy
- immunotherapy
1. Introduction
Osteosarcoma is a rare malignancy of mesenchymal origins, which is characterized by the production of osteoid from the neoplastic cells [1,2]. It is the most common bone sarcoma, with an estimated incidence in Europe of 0.3/100,000/year [3]. The incidence of osteosarcoma demonstrates a bimodal age distribution, with an initial peak in adolescence (0.8–1.1/100,000/year in the age group of 15–19 years) that coincides with the pubertal growth spurt; a second peak in the seventh and eighth decades of life often represents a secondary malignancy, or is related to Paget disease [3,4]. Approximately two-thirds of the primary tumors are located around the knee joint, with the most common locations being the distal femur, the proximal tibia, and the proximal humerus [5,6].
The diagnosis of osteosarcoma relies on morphological characteristics, since specific molecular testing is not yet available in clinical practice [3]. According to the latest World Health Organization (WHO) classification, high grade osteosarcoma subtypes include conventional osteosarcoma, which is the most common subtype, telangiectatic osteosarcoma, and small cell osteosarcoma [7]. Periosteal osteosarcoma, which is predominantly chondroblastic, is an intermediate-grade osteosarcoma, whilst low-grade central osteosarcoma and parosteal osteosarcoma are reported as low-grade neoplasms.
Both the diagnosis and management of osteosarcoma are challenging, and require a multidisciplinary approach. Currently, surgical excision, radiotherapy, and multiagent systematic therapy constitute the armamentarium of therapies against osteosarcoma in daily clinical practice [3]. However, it has been reported that 30–40% of patients with local osteosarcoma will eventually experience local or distant recurrence, with the 5-year overall survival for recurrent disease being 23–29% [8,9]. Furthermore, 10–20% of patients originally present with macroscopic metastatic disease, whilst the lungs are the most common site of metastases [5,8].
2. Current Therapeutic Approaches
The standard of care for localized low-grade osteosarcoma, such as low-grade central osteosarcoma and parosteal osteosarcoma, involves the surgical excision of the tumor with clear margins (R0 resection) [3]. As for localized periosteal osteosarcomas, neoadjuvant or adjuvant chemotherapy is not recommended, since there is no solid evidence of benefit from its use [3,10]. In contrast, for localized high-grade osteosarcoma, curative intent treatment requires neoadjuvant multiagent chemotherapy, followed by surgical excision and adjuvant chemotherapy. The incorporation of chemotherapy for the therapeutic management of localized high-grade osteosarcoma was established in the 1980s, and has improved the disease-free survival probability from <20% to >60% [3,6]. First-line multiagent chemotherapy comprises doxorubicin, cisplatin, and high-dose methotrexate (MAP regimen) [3]. The histological response to neo-adjuvant therapy with MAP is evaluated post-surgery; however, changing the chemotherapy regimen based on this information has not been proven to improve outcomes [11,12]. Specifically, EURAMOS-1, a phase III, open-label, randomized, controlled clinical trial, investigated the addition of pegylated interferon alfa-2b (IFN-a-2b) to the MAP regimen in patients who responded to neo-adjuvant therapy (<10% viable tumor); meanwhile, in poor responders (≥10% viable tumor), the addition of ifosfamide and etoposide to MAP (MAPIE) was investigated. The results showed no improvement in event-free survival (primary end point) compared to patients who were treated with adjuvant MAP [11,12]. Furthermore, radiotherapy is indicated in selected cases where surgical resection of the tumor is not feasible, or the risk of local recurrence is high and additional surgery cannot be applied [3].
For many years, therapy in cases of unresectable metastatic or recurrent osteosarcoma relied on chemotherapy, and included ifosfamide or cyclophosphamide which is given with etoposide and/or carboplatin [3]. Moreover, a combination of gemcitabine and docetaxel has been used as further line therapy. In addition, radiotherapy may have a role in the palliative setting for symptom control, mainly pain [3]. Importantly, for patients with primary metastatic disease, the same principles as those applied in localized osteosarcoma are followed [3]. In cases of local recurrence as the first event, the treatment is primarily surgical, with no evidence of benefits from chemotherapy [3,13]. Regarding cases with recurrent osteosarcoma with isolated lung metastasis, metastasectomies are considered to be the optimal treatment [3]. However, stereotactic radiotherapy, radiofrequency ablation, or cryotherapy can be used as alternatives if patients are unfit for surgery [3].
3. Surgical Advances in the Management of Osteosarcoma
Whilst the judicious use of systemic oncological treatments has successfully improved the prognosis of patients with osteosarcoma, this therapy must be combined with appropriate local control in order to achieve a cure [57]. The surgical management of osteosarcoma will vary depending on the site and characteristics of the tumor, but the overall goal is to achieve complete resection with wide margins (R0). This involves removing the tumor as well as a layer of normal surrounding tissue. This is vitally important, as studies have shown an increased risk of local recurrence and decreased survival with positive or “marginal” margins [58]. Surgery can be offered to patients with localized osteosarcomas and to patients with metastatic disease, provided that all sites are resectable. Osteosarcoma can present in surgically challenging areas of the body, such as the pelvis, base of the skull, spine, and jaw, all of which may require specialist input from additional specialties such as neuro, spinal, general, ENT and maxillofacial surgeons.
Broadly speaking, the surgical treatment of osteosarcoma in the appendicular skeleton, where most osteosarcomas are found, falls into one of the following two categories: limb salvage (sparing) or sacrificing. Historically, amputations (limb sacrificing) formed the mainstay of surgical treatment; however, there has been a significant shift towards limb salvage options, without a detrimental effect on survival. This in part is due to the advancements in both surgical techniques and oncological therapies used in the adjuvant and neo-adjuvant setting. Studies have found an improvement in functional and psychological outcomes with the transition to limb salvage surgery, as well as a higher 5-year survival rate [59]. Developments in pre-operative (imaging) and intra-operative (surgical) techniques have allowed for better surgical planning, as well as more accurate tumor resections. Osteosarcoma tumor surgery is a delicate balance of achieving clear margins for prognostic benefit against the potential detrimental effects on function if too much tissue is resected. Surgical practices have progressed to optimize the oncological outcomes without forfeiting functional ones, provided that an attempt at limb salvage does not compromise adequate disease clearance [60].
3.1. Preoperative Imaging and Planning
As part of staging and oncological work up, a variety of different imaging modalities are used to characterize tumors. The current guidelines for osteosarcoma management recommend that each patient should have a plain radiograph, magnetic resonance imaging (MRI), computerized tomography (CT), and, in certain cases, a positron emission tomography (PET) combined with a CT scan. Where surgical planning is concerned, MRI scans have been shown to provide accurate depictions of tumor appearances, including their limits within and outside the bone, differentiating medullary disease involvement, as well as soft tissue involvement [60,61]. Resection margins can be accurately measured from high-resolution MRI scans, which can predictably inform the surgeon if a planned margin will be clear or affected by tumors. Studies have shown that MRI margin measurements with the closest predicted margin provided the smallest differences with pathology reports [62]. Although there is controversy in the literature with no defined ‘safe’ margin, it is generally accepted that a minimum soft tissue margin of >2 mm and a bony margin of >3 cm are required. The ‘barrier effects’ concept, introduced by Kawaguchi, further helps surgeon better plan and understand resection margins. This concept classified anatomical structures that provided resistance against tumor invasion (such as fascia, tendons, joint capsules, etc.) into thick (3–5 cm) and thin barriers (2 cm). Therefore, barrier effects can be considered to translate into distance equivalents; this means that at sites where barriers exist, surgeons can resect less of a margin than the true physical distance, allowing for more limb salvage options [57,63].
Intra-operative cancer detection techniques may pave the future for accurate tumor resection margins at the time of surgery. Currently, postoperative histopathology takes around two weeks to assess the success of surgery and validate the resection margins. Surgeons could benefit from a novel technique that would grant a rapid and objective determination of safe tumor margins at the time of tumor resection in theatre, in addition to classifying tumor types. Preliminary research with Raman spectroscopy has produced some promising results. When Raman spectroscopy is combined with principal component analysis (PCA) techniques, tumor types such as osteoblastic, chondroblastic, and telangiatatic osteosarcomas can be readily detected and identified in vitro [64].
3.2. Computer-Assisted Navigation
Given the complex anatomical nature of osteosarcoma resection, computer-guided technologies have been introduced to enhance intra-operative guidance in areas which require accurate osteotomies. Computer navigation incorporates all the imaging modalities used in preoperative planning, such as MRI and CT, in order to achieve a better balance between disease resection and preservation of disease-free tissue. The use of computer navigation has been particularly useful in resections of osteosarcoma from the pelvis and sacrum, as well as in difficult joint-preserving surgery [57,65]. The use of navigation devices has also been shown to potentially reduce the operating time and intra-operative blood loss. Joint-preserving surgery tries to offset the long-term failings of endoprosthesis, especially in skeletally immature patients; therefore, computerized assistance can have a role in aiding the preservation of the physis, whilst maintaining sufficient resection margins [60].
The current technology does have its limitations, and is not supported by robust literature; however, there are certainly grounds for future development. Robotic technology such as the MAKO robot (Stryker) has shown effective pedigree in arthroplasty techniques, with strong transferable principles to osteosarcoma resection. The robotic arm would allow cuts to be tracked in real-time, as well as aiding steadiness and maintenance of osteotomies in the desired plane, which should ultimately improve resection accuracy. Beyond this, technologies that involve augmented reality could be employed in the future to further build on the accuracy of tumor resection, whilst sparing important soft tissue structures [66].
3.3. Patient-Specific Instrumentation (PSI) and Three-Dimensional (3D) Printing
3D technology has revolutionized the surgical approach for osteosarcoma resections. It has aided surgeons to reconstruct and resect difficult tumor formations to preserve limb and function that would have otherwise been lost. 3D technology has both direct and indirect applications to help achieve this goal.
Indirectly, 3D-printed models of the tumor and anatomy can be used to better educate and inform patients pre-operatively in clinics, as well as help surgeons better visualize their approach and orientation before and during the procedure. Furthermore, 3D models can be used in the pre-operative planning stages, and in testing the appropriateness of implants used for reconstructions [60].
Directly, 3D technology has be used to design custom cutting templates and patient-specific instrumentation that is unique to the tumor characteristic for an individual patient. Studies have shown that PSI guides significantly improve resection accuracy as well as implant positioning. 3D printing has also enabled the use of a wider range of customizable implants, which are cheaper to produce and can be employed for reconstruction after resection. This is particularly relevant where the tumor resection involves complex anatomy, or is large in size and thus unsuitable for modular implant use. The use of custom implants offers clear advantages to both the surgeon and patient, especially when combined with computer navigation for precision resection. The concept of 3D printing in combination with computer navigation is being trailed in its early phase with the ‘just in time’ project by The Aikenhead Centre for Medical Discovery (ACMD), Australia [60,65].
The future of 3D printing may involve printed biodegradable implants as a drug delivery system. Although in its infancy, the concept is built on the principle of local delivery of pharmacological products (such as chemotherapy) or stem cells to promote implant osseointegration.
3.4. Reconstruction Options
Once the tumor is successfully excised, the surgeon’s attention turns to restoring function through effective reconstruction techniques that minimize immediate and long-term complications. A variety of reconstruction options exist, which are usually dictated by the tumor morphology and location. The options range from metallic gap spanning mega/endoprosthesis, forming the mainstay of treatment, to biological options that include autografts, allografts, and reimplantation of sterilized tumor bone. Each reconstruction method is associated with its own advantages and disadvantages.
Tumor endoprosthesis is the most commonly used technique in limb-sparing surgery. Many studies have shown reliable results with good functional outcomes and rapid restoration of weight-bearing status and mobility. Implant survival is estimated at 69–78% at 10 years, which is a significant improvement compared with previous implant designs [67]. Further advances in implant design and materials aim to offset complications that hinder implants, such as mechanical failure, loosening, and infection. Modern implants also allow for growth using non-invasive methods such as magnetic force. This becomes valuable as a tool for use in the skeletally immature population, who could be effected by issues in leg length discrepancy after tumor reaction from an affected growth plate [68].
Although less commonly performed, a variety of biological reconstruction options exist, and are usually limited to skeletally immature patients. These techniques include long segment allografts, inactivated reconstructions (reimplantation of sterilized tumor bone), allograft bone or inactivated bone combined with artificial joints, fibula transplantation, and bone transport techniques [69]. These techniques have traditionally been associated with slightly higher complication rates such as non-union, pathological fractures, and infections. With advancements in artificial prostheses, the role of biological reconstructions is likely to remain limited.
This entry is adapted from the peer-reviewed paper 10.3390/jcm12082785
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