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Radiological Review of Extremity Osteosarcoma
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 13-18 Amit Janu, Nikshita Jain, Shashikant Juvekar, Ashish Gulia.
Author: Amit Janu[1], Nikshita Jain[1], Shashikant Juvekar[1], Ashish Gulia[2].
[1]Dept of Radiodiagnosis, Tata Memorial Hospital, Parel, Mumbai. India.
[2]Orthopedic Oncology, Dept. of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, India.
Address of Correspondence
Dr Ashish Gulia, MS (Ortho), Mch (Surgical Oncology)
Associate Professor, Orthopedic Oncology, Dept. of Surgical Oncology, Tata Memorial Hospital,
Mumbai – 400012, India.
Email: aashishgulia@gmail.com
Abstract
The paradigm shift in the overall outcomes of osteosarcoma is multi factorial. Be it introduction of chemotherapy, introduction of better
imaging or advances in the technology to produce better prosthesis, the crux lies in the correct and timely diagnosis. Radiology along with
clinical evaluation and histopathological confirmation is an essential part of the three tier system which leads to an accurate diagnosis
which forms the platform to initiate an ideal treatment to have desired oncological and functional outcomes. Plain radiography has been
the age old diagnostic tool which is still as important as was in yester century. Inclusion of high end cross sectional imaging likeCT and
MRI has not only helped in early and price diagnosis but has also proved to be a boon to operative surgeons to stage the disease locally and
plan complex limb salvage strategies. In the present article we have discussed the radiological features of various sub types of osteosarcoma
to help a clinician to assess these complex varieties of lesions.
Keywords: osteosarcoma, radiological assessment.
Introduction
Osteosarcoma is the most common primary nonhematologic bone malignancy and is the most common primary bone malignancy in children. There are various subtypes of osteosarcoma, each with distinct clinical and imaging characteristics and variable survival and an incidence of 0.2 to 0.3 per 100,000/year. Osteosarcomas can be classified as intramedullary (high grade, telangiectatic, low grade, small cell, osteosarcomatosis, gnathic), juxtacortical (parosteal, periosteal, intracortical, high-grade surface), or secondary lesions [1]. Though majority of cases are of conventional high grade intramedullary osteosarcoma accounting for 75%- 90%, it is important to differentiate them from other low grade and (low grade central and parosteal osteosarcoma) and intermediate grade osteosarcoma (Periosteal osteosarcoma). An understanding of the systematic imaging approach helps to more accurately diagnose these lesions and direct effective treatment. This article provides an organized approach to analyzing and subtyping of osteosarcoma based on radiographs and guiding the referring physician if any further imaging is warranted as there is frequently overlap with other benign and malignant entities, creating substantial diagnostic challenges. For accurate diagnosis, it is important to be aware of radiographic and cross-sectional imaging features that allow differentiation of each subtype of osteogenic sarcoma from its mimics. Osteosarcoma is a malignant tumor that is characterized by production of osteoid matrix (immature bone) and variable amounts of cartilage matrix and fibrous tissue [2]. Each subtype of the osteosarcoma exhibit distinct imaging features mimicking different benign and malignant entities, however with critical evaluation of specific features a correct diagnosis can be made. Furthermore, important prognostic information, as well therapeutic options can be evaluated based on imaging.
Conventional osteosarcoma
Conventional intramedullary osteosarcoma is the most common subtype of osteosarcoma, accounting for 75% of all cases. Conventional osteosarcoma is a high-grade neoplasm produces osteoid matrix by the tumour cells centrally within the bone and eventually involves the entire width of the bone. It is often described as amorphous, fluffy, cloud-like, solid, cotton like or ivory like on the plain radiographs. It appears as homogenously increased density within bone and in soft tissues. Approximately 90 % of the osteosarcomas show some degree of osteoid matrix on radiographs [3]. Histologically osteosarcoma is pleomorphic and can produce variable amounts of cartilage, fibrous tissue, or other components. Some osteosarcomas produce more than one type of matrix and depending on the dominant cell type, they can be further subdivided into osteoblastic (50%–80%), fibroblastic-fibrohistiocytic (7%–25%), chondroblastic (5%–25%), telangiectatic (2.5%–12%), or small cell (1%) (4). Most cases of conventional osteosarcoma are seen in second and third decades of life, peaking when patients are aged 10 to 15 years, while they are unusual in patients younger than 6 years or older than 60 years [5]. The imaging characteristics of the various subtypes of osteosarcoma are summarized in Table 1.
Conventional osteosarcoma most frequently affects long bones (70%–80%), particularly near the knee, in the femur, tibia, and humerus. This lesion originates in the metaphysis, with extension to the epiphysis (seen in up to 80% of MR imaging studies) (Fig. 1C), however initial manifestation in epiphysis alone is extremely rare [6]. Patients with conventional osteosarcoma may present with pathologic fractures. Skip lesions also occur in about 5% of patients. The intraosseous and extraosseous extent of tumor seen in cross sectional imaging should be measured and documented which is vital in preoperative assessment and staging of osteosarcoma. Joint involvement is seen in 19% to 24% of cases and is diagnosed when hyaline cartilage is penetrated and synovial involvement is rarely seen [7]. Radiographic findings are characteristic, osteosarcoma tends to destroy cortex without expanding osseous contours, reflects its aggressive nature with osteoid matrix having a pattern of fluffy opacities, with aggressive periosteal reaction (laminated, hair-on-end, sunburst, or Codman triangle) and with a soft tissue mass in 80-90 % of the cases (Fig.1). Occasionally, the lesions are purely lytic (fibroblastic) or sclerotic (osteoblastic), but most common pattern seen is mixed lytic and sclerotic [8]. MR imaging is the examination of choice for local staging and for planning biopsies or surgery because of superior contrast resolution and multiplanar imaging. The entire involved bone should be scanned to evaluate for skip metastases. The lytic areas appears low signal on T1-weighted images and high signal on T2-weighted images, whereas the mineralized matrix appears low signal on both T1- weighted (see Fig.1C) and T2-weighted images. The T1- weighted images gives vital information regarding the anatomical extent of the marrow involvement, invasion into epiphysis and skip lesions. Treatment includes chemotherapy followed by wide surgical resection and limb salvage or amputation. Local recurrence is high if there has been a pathologic fracture. Staging work-up should include a non contrast chest CT and a whole-body bone scan. Approximately 15% to 20 % of patients present with radiographic metastases. Most common site for metastasis are lungs followed by other bones. All high-grade osteosarcoma are treated with a multimodality management. The standard sequence include a multiagent chemotherapy (Doxorubicin, cisplatin, high-dose methotrexate, etoposide and ifosphamide) followed by wide surgical excision of the primary tumor which is followed by adjuvant chemotherapy. Addition of chemotherapy has dramatically improved the overall outcomes of extremity osteosarcomas from a mere 20% to 60–70%.
Telangiectatic osteosarcoma
Telangiectatic osteosarcoma accounts for 2 %–7% of all osteosarcomas cases and most commonly occurs in the 1st and 2nd decades of life. Telangiectatic osteosarcomas are located in the metaphysis of long bones and show asymmetric expansion, geographic lysis of bone, with an aggressive growth pattern (ill defined margins) with cortical destruction, minimal sclerosis and soft tissue mass [9, 10]. On pathological analysis, it shows dilated cavities filled with blood and septa and a small solid mass or a rim that contains high-grade osteosarcomatous cells. Commonly it appears low attenuation mass on computed tomography (CT), low signal on T1-weighted MR imaging, and high signal on T2-weighted MR imaging with fluid-fluid levels are seen in up to 90% of these lesions (Fig. 2). The imaging and pathologic features of these lesions may be confused with those of aneurysmal bone cysts, giant cell tumor, metastases and chondroblastic conventional osteosarcoma [11, 12]. The presence of thick, nodular, solid tissue within or around the cystic spaces, best seen on contrast-enhanced MR imaging along with aggressive pattern of growth and presence of matrix mineralization, is also helpful in making the diagnosis. Matrix mineralization in these lesions may be subtle on radiographs and it is better seen on CT. Imaging also helps to guide biopsy of the viable tumour areas. It is of utmost importance that these tumors must not be confused with other differentials and a biopsy should be performed before embarking on any form of definitive surgical procedure. The staging work up and management of telangiectatic osteosarcoma is similar to that of a conventional osteosarcoma.
Small-cell osteosarcoma
Small cell osteosarcoma is a distinct but rare subtype of conventional osteosarcoma which represents approximately 1- 4% of osteosarcoma cases. It most often affects patients in the 2nd and 3rd decades of life. The pathologic characteristics may be mistaken for Ewing sarcoma or primitive neuro- ectodermal tumor because its cells are small and have round and hyperchromatic nuclei, but cells of small cell osteosarcoma lack uniformity and consistently produce osteoid [13]. These lesions are most commonly seen in the metaphysis like conventional osteosarcoma, but they can be seen purely in the diaphysis in 15% of cases [14, 15]. Small-cell osteosarcoma is an intramedullary, permeative lytic lesion that is associated with cortical destruction, aggressive periosteal reaction, and soft tissue mass (Fig. 3) [16]. Differential diagnosis includes Ewing sarcoma, lymphoma, and conventional osteosarcoma. Although osteoid matrix is typically seen, purely lytic lesions may occur in up to 40% of cases. The prognosis is poor than that of conventional osteosarcoma. Some centres modify the chemotherapy like that of Ewing sarcoma due to presence of round cells but no standard concensus exist [14]. Over all staging and management of these tumors is also similar to other high grade osteosarcoma.
Low-grade central osteosarcoma
Low-grade central osteosarcoma is uncommon variant of conventional osteosarcoma also referred to as well differentiated or sclerosing osteosarcoma [20]. The mean age of presentation is slightly older and occurs in 3rd or 4th decade of life [21]. The radiologic and pathologic findings simulates those of fibrous dysplasia and benign fibro-osseous lesions often resulting in erroneous radiographic and histologic diagnosis. The presence of aggressive features like cortical destruction, permeative pattern or a soft tissue mass is helpful in differentiation of low-grade central osteosarcoma from benign fibro-osseous lesions which are better seen on CT and MRI. These cases are usually staged with a chest radiograph only. Surgery forms the main cornerstone of the management. Chemotherapy is not warranted and these are treated with wide surgical excision. The outcomes are usually excellent with wide excision, however intra-lesional resection and curettage can result in high local recurrences and transformation of initial lesion into high grade sarcoma as well [22].
Juxtacortical osteosarcoma
Juxtacortical or surface osteosarcoma refers to originating from the surface of bone and accounts for 4% to 10% of all osteosarcomas. It is usually associated with the periosteum and cortex with variable medullary canal involvement. These lesions are further divided into parosteal, periosteal, high grade surface, and intracortical osteosarcomas because of different radiological and histological findings.
Parosteal osteosarcoma
Parosteal osteosarcoma is the most common type of juxtacortical osteosarcoma originates from the outer layer of the periosteum, accounting for 65% of juxtacortical osteosarcomas and typically manifesting in the third and fourth decades [23]. The lesion is slightly more commonly seen in women. The tumor usually occurs in the metaphysis of long bones and posterior aspect of the distal femur is the most frequent site. Pathologically, it is usually a low grade tumour with extensive osteoid matrix and minimal fibroblastic stroma with occasional areas of cartilage are seen. At radiography, the classic appearance is a lobulated, cauliflower like, juxtacortical centrally dense ossific mass, separated by radiolucent cleavage plane with adjacent normal cortex in its early stages (approximately 30% of cases at radiographs and in 65% of cases at MRI) [24, 25]. This cleavage plane refers to the periosteum interposed between the normal cortex and the tumor mass. Cortical thickening with a relative lack of aggressive periosteal reaction may also be seen (Fig.4). The ossified matrix is predominantly low in signal intensity on both T1- and T2-weighted images (Fig.4), while unmineralized soft-tissue mass larger than 1 cm3 is predominantly high in T2 signal intensity. High signal intensity indicates high grade tumour [24]. Medullary cavity invasion may be seen in 8% to 59% of cases on MR imaging, and although the prognosis of these patients of these patients is controversial, knowledge of this invasion helps in complete surgical resection. Prognosis in patients with parosteal osteosarcoma is excellent, with a 10-year survival rate of 80%. High-grade foci warrant adjuvant chemotherapy. The main differential diagnosis includes myositis ossificans, osteochondroma and periosteal chondroma. Apart from trauma history, the gradual ossification of the lesion from the periphery toward the center of the mass and no attachment to the cortex is a characteristic radiographic finding of myositis ossificans [26]. Osteochondroma have corticomedullary continuity between the tumor and the underlying medullary canal which lacks in parosteal osteosarcoma [27].
Periosteal osteosarcoma
Periosteal osteosarcoma is the second most common type of juxtacortical osteosarcoma originates from the inner germinative layer of periosteum, accounts for 25% of juxtacortical osteosarcomas and usually presents in second and third decades with slight male preponderance [28, 29]. Pathologically, it is predominantly cartilaginous with small areas of osteoid, intermediate cytologic grade distinctly lower than that of conventional osteosarcoma but higher than that of parosteal osteosarcoma. Periosteal osteosarcoma characteristically occurs in diaphysis or metadiaphysis and usually involves 50% of the osseous circumference (Fig.5). Common radiographic findings include a broad-based mass on the surface of the bone, with cortical erosions, cortical thickening and periosteal reaction. Though medullary extension can occur, it is still rare and reactive marrow changes can occur in 50% of the cases [28, 29]. Periosteal reaction is seen as perpendicular low signal intensity areas on all MR sequences arising from the inner cortex to the outer margin of the tumor (Fig.5). Pathologically tumours are chondroblastic and they usually appear low attenuation on CT and high signal on T2-weighted images. Perpendicular periosteal reaction is seen as rays of low signal intensity on all MR imaging sequences. Prognosis of patients is better than conventional osteosarcoma but worse than parosteal osteosarcoma. Treatment consists of wide local excision with limb salvage. Perisoteal osteosarcomas are intermediate grade tumors and are staged like high grade osteosarcomas. A wide surgical resection is mandatory but role of chemotherapy is controversial.
High-grade surface osteosarcoma
High-grade surface osteosarcoma is least common type of osteosarcoma and accounts for 10% of juxtacortical osteosarcomas. It usually manifests in second and third decade of life. Pathologically, it is high grade like conventional osteosarcoma. Radiologically, it affects the diaphysis or metadiaphysis of the long bones, involves the entire circumference of the bone and may invade the medullary cavity [30, 31]. These tumors are staged and treated like other high grade osteosarcoma.
Intracortical osteosarcoma
Intracortical osteosarcoma is a rare type of osteosarcoma that arises from the cortex and is most commonly seen in second decade. Radiologically, they affect diaphysis long bones and have a geographic lytic area with variable amounts of mineralized osteoid. The lesions may also have smooth margins and variable cortical thickening with common differential diagnosis for this condition includes osteoid osteoma or osteoblastoma. Medullary invasion is rare.
Secondary osteosarcoma
Although conventional osteosarcoma and secondary osteosarcoma are histologically indistinguishable, diagnosis is made on the basis of typical radiographic appearances in the pre existing lesions such as MFH or paget disease (Fig.7) or secondary to radiation. The prognosis for these patients is usually poor.
Osteosarcomatosis (multifocal osteosarcoma)
Osteosarcomatosis is a condition characterized by multiple intraosseous osteosarcomas believed to represent rapidly progressive multicentric metastatic disease. It accounts for 3% to 4% of all osteosarcomas. Most of these patients have a multiple radiographic lesions and pulmonary metastatic disease. Mean survival for these patients is less than 1 year
Conclusion
Osteosarcoma is the most common primary bony malignancy in children’s. The radiologic appearances vary over a wide spectrum and may be mimicked by various benign and malignant lesions still each subtype have often characteristic radiographic features and are suggestive of the specific diagnosis most of the time. Perhaps more important, additional cross sectional imaging modalities specifically MR imaging, provide vital information for planning biopsies or preoperative staging in surgical management. Recognition of these imaging features is an important guide for the accurate diagnosis which helps our clinical colleagues regarding the often difficult and complex multimodality treatment of patients with osteosarcoma to improve the clinical outcome.
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Emerging role of PET/CT in osteosarcoma
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 19-21 |Nilendu C Purandare1, Venkatesh Rangarajan1
Nilendu C Purandare[1], Venkatesh Rangarajan[1]
Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Parel, Mumbai 400012
Address of Correspondence
Dr.Nilendu C Purandare
Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Parel, Mumbai 400012
Email: nilpurandare@gmail.com
Abstract
The role of PET/CT in malignant tumors has grown exponentially in the past few years. Newer methods have been investigated and older methods have been refined. This article is a brief review of its current and potential utility in osteosarcoma.
Keywords: PET/CT radioisotope scans, osteosarcoma.
Introduction:
FDG PET/CT has been used to evaluate various malignancies including those of the musculoskeletal system. It is an imaging technique that provides information about the metabolic changes associated with cancer. PET imaging uses molecules that are labelled with radio nuclides. In clinical PET practice the principal radio-isotope used is the positron emitting 18 F-FDG which is a glucose analogue labelled with radionuclide 18 F. FDG is injected intravenously and is transported from the plasma to the cells by glucose transporters (GLUT 1 & GLUT 4). It then undergoes phosphorylation within the cell by the enzyme hexokinase and is converted to FDG-6-phosphate. FDG-6-phosphate does not get further metabolised and gets trapped in the cell. Cancer cells demonstrate increased anaerobic glycolysis (Warburg effect) which is believed to be due to upregulation of glucose transporters and hexokinase and reduced levels of glucose-6-phosphatase thus limiting further metabolism of the tracer in cancer cells [1]. Thus FDG PET provides unique functional information by taking advantage of the propensity of malignant tumors to demonstrate increased glucose utilization (metabolism) as compared with normal tissue. A semiquantitative measure of the metabolic activity (corrected for the amount of radiotracer injected per kilogram of body weight and for blood glucose level) is known as the standard uptake value (SUV) . Although the degree to which both benign and malignant tumors accumulate FDG can be quite variable, malignant tumors tend to have higher SUV values. In general significant difference is noted in the SUV of benign and malignant primary bone tumors. It should be noted that the interpretation of absolute SUV values can be misleading. No cutoff value of SUV can be established in clinical practice to reliably differentiate benign from malignant primary bone tumors. Osteosarcomas (OGS) and Ewings sarcomas tend to be FDG avid whereas chondrosarcomas and soft tissue sarcomas showing a wide range of uptake depending on the histology and grade of the tumor. Since OGS is FDG concentrating tumor, FDG PET can be used for staging and restaging. FDG PET can also be used to monitor response to neo-adjuvant chemotherapy and as a prognostic and predictive marker.
Use of FDG PET in staging:
Effective treatment stratification in patients with musculoskeletal malignancies requires accurate assessment of the extent of primary tumor and evaluation for the presence of metastatic disease. MRI is the modality of choice in assessing the local extent of the primary lesion for surgical planning and PET plays a limited role. However PET may allow the noninvasive estimation of the histologic grade of tumors. The SUV of bone and soft tissue sarcomas has been used as a prognostic marker to predict patient outcomes. It has been shown that the baseline SUVmax is an independent predictor of overall survival [2]. Also FDG accumulation within a large heterogeneous tumor allows identification of the areas with the highest biologic activity. This can allow targeted biopsy from the most metabolically viable portion of the tumor, which can help in ascertaining the accurate histological grade [3]. Since OGS metastasizes to multiple skeletal sites an accurate whole body bone imaging modality is important for accurate staging. Bone scanning using 99m Tc- methylene diphosphonate(MDP) has been for several years the work horse for detection of skeletal metastases in several cancers including OGS. MDP bone scan seems to be well suited to detect skeletal involvement because of the osteoblastic nature of skeletal metastases in OGS which can be detected by a conventional MDP bone scintigraphy with a high degree of sensitivity. However MDP bone scanning can suffer from limited spatial resolution due to planar imaging. In addition the high tracer uptake in the region of the growth plates can also conceal metastatic lesions. Another limitation of bone scanning is the high number of false positives and indeterminate findings which need further confirmation with anatomical imaging. Recent studies have shown a better sensitivity of FDG PET/CT than MDP bone scan primarily due to its greater ability to detect metastases in the region of the growth plate which are often masked on bone scans [4]. Addition of CT information in an integrated PET/CT scan also reduce the number of false positives leading to better accuracy compared to bone scintigraphy. Volker et al in their study in paediatric sarcomas (Ewings, OGS & RMS) showed a higher sensitivity of FDG PET (88%) over conventional imaging (37%) for skeletal metastases from Ewings sarcoma [5]. The sensitivity however was not much different (90% for PET Vs 81% for conventional imaging) for skeletal metastases in OGS. PET was superior to conventional imaging in the correct detection of lymph node involvement (sensitivity, 95% v 25% respectively). With the availability of integrated PET/CT machines, pulmonary metastases can be diagnosed using the CT component of the PET/CT study with same accuracy as that of a chest CT obviating the need for a separate CT examination of the chest. Thus an integrated FDG PET/CT can serve as a single stop shop modality for metastatic work up of OGS patients (figure 1). Various metabolic parameters can be obtained from the FDG PET/CT study that provide valuable prognostic information. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are indicators of tumor metabolism which are independent prognostic markers and can predict metastases and survival in OGS [6].
Role of FDG PET as a surrogate marker in assessing response to neoadjuvant therapy:
Since functional and biochemical changes in a tumor in response to therapy occur much earlier than morphologic changes, FDG PET has proven to be very useful in looking at tumor viability before the changes are evident on standard morphological imaging techniques. Various studies have found a strong correlation between the degree of tumor necrosis on histology following neo-adjucvant chemotherapy and reduction in FDG concentration in Osteosarcomas [7,8]. In patients classified as having a good response to chemotherapy there is significant reduction in tumor FDG concentration (figure 2). Thus PET using FDG can be potentially used as a non-invasive surrogate to predict response as well for prognostication [9]. A multiparameter analysis technique based on kinetic 18F-FDG data (dynamic PET) of a baseline study and after 2 cycles is helpful for the very early prediction of chemosensitivity in patients with soft-tissue sarcomas receiving neoadjuvant chemotherapy. This can have potential implications on management in the form of whether to change or intensify chemotherapy or to decide whether to salvage or ampute the limb in chemo non-responsive tumors.
Role of FDG PET in detection of disease recurrence:
Conventional imaging modalities such as CT and MR imaging are limited in their ability to differentiate treatment related changes from recurrent tumor. Distortion of normal anatomy, symmetry and tissue planes following surgery or radiation therapy makes detection of tumor recurrence difficult. Also degradation of image quality due to artifiacts produced by metallic prosthesis limits evaluation of local tumor recurrence. The whole body imaging capabilities of FDG PET allow detection of local as well as distant tumor recurrence. FDG PET/CT is useful in detecting recurrence at the primary site and is often complementary to other imaging modalities [9]. It is fairly accurate in detecting sites of distant failure as well. Its potential benefits and limitations compared to conventional imaging modalities will have be studied in larger homogenous patient groups.
18F Sodium fluoride (NaF) PET scan:
18F NaF is a bone seeking radiotracer which was introduced way back in 1962 for skeletal imaging [10]. The availability of integrated PET/CT systems has led to a renewed interest in the use of 18F-NaF for imaging skeletal metastases (Fig. 3). PET/CT imaging allows high-resolution functional imaging of the skeleton with greater sensitivity than that of planar scintigraphy/MDP bone scans. Integrated PET and CT system allows the interpretation of 18FNaF in conjunction with CT images. This enables better morphologic characterization and improved differentiation between benign and malignant lesions reducing the number if false positives and the indeterminate lesions. Studies have shown better accuracy and lesions detectability for 18F NaF PET scans as compared to MDP bone scans in several cancers.(11,12). 18F NaF PET/CT scan can image skeletal as well as lung metastases in a single examination and can be used for metastatic work up of OGS patients. Comparison of the diagnostic accuracy and cost effectiveness of FDG PET/CT and NaF PET/CT in OGS patients has not been investigated in detail and studies addressing the same need to be carried out.
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How important are surgical margins in Osteosarcoma?
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 22-26 |Thomas P Cloake, Lee M Jeys.
Authors: Thomas P Cloake[1], Lee M Jeys[2].
[1]The Royal Orthopaedic Hospital, Bristol Road South, Birmingham, B31 2AP, UK.
[2]School of Health and Life Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
Address of Correspondence
Professor Lee M. Jeys
Professor of Health and Life Sciences
Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
E-mail: lee.jeys@nhs.net
Abstract
Surgical resection combined with chemotherapy is the mainstay of treatment of osteosarcoma. Traditionally, surgical margins were based upon tumour grade and classified into marginal, wide or radical resection. The definition of these margins, however, remains subjective and recent research has questioned the need for wide or radical margins. Advances in surgical technique and the use of neo-adjuvant chemotherapy have led to an improvement in outcome. By reducing tumour burden, chemotherapy has provided surgeons with the option of limb salvage surgery rather than radical resection. Surgical margins and response to chemotherapy are now considered the two most important predictors of outcome in osteosarcoma. This review focuses on surgical margins with respect to limb salvage surgery and discusses the importance of response to chemotherapy.
Keywords: osteogenic sarcoma, osteosarcoma, surgical margins, chemotherapy, limb salvage surgery.
Introduction
Osteosarcoma is a high grade, primary tumour of bone in which the tumour cells produce osteoid [1]. It is the most common primary bone tumour, with an annual incidence rate of 5.0 per million [2]. Osteosarcoma is predominantly a disease of the young with a peak incidence in the second decade and displays a male predominance which is most pronounced at a younger age [3]. The treatment of osteosarcoma is challenging. The use of neo-adjuvant chemotherapy regimes combined with surgical resection has led to an improvement in outcome. Nevertheless, despite recent advances in surgical technique and chemotherapy agents, the survival rate has plateaued over the last 30 years [4]. There has been much research into prognostic factors that may help predict outcome in osteosarcoma, a number of these have been identified (see Table 1). Authors have suggested the most important, independent risk factors are the response to adjuvant chemotherapy and resection margins [5-7]. This review considers the impact of resection margins with a focus on limb salvage surgery and discusses the significance of response to chemotherapy.
Resection margins
There has been much debate around the margin of clearance required for surgical treatment of osteosarcoma. Enneking et al. were the first group to formally stage osteosarcoma into three distinct grades according to biologic aggressiveness, tumour site and distant metastases [8]. The authors suggested this system be used in surgical planning and inform the use of marginal, wide or radical resection margins. Nonetheless the definition of marginal or wide resection remains subjective and may vary between surgeons or units and has never been objectively defined (Fig 1). Kawaguchi et al. developed this concept by giving distinct numerical values for desired resection margin according to the grade to tumour suggesting a 2cm margin was required for low-grade tumours and a 3cm margin was needed for high-grade neoplasms such as osteosarcoma [9].More contemporary studies have failed to reach a consensus on a numerical value for an adequate resection margin. Li et al. reported there was no difference in local recurrence when wide (>5mm) margins and close (<5mm) margins were used [10]. Bispo et al. failed to detect a difference in local recurrence using a margin of 2mm [11]. Betrand et al. found surgical margin to be the only independent risk factor for local recurrence and suggested a margin of 1mm may be adequate [12]. These papers suggest resection does not require a strict numerical margin, however efforts should be made to ensure no margins are intralesional. However, international consensus is in equipoise regarding margins, and this has made interpreting research articles very difficult. Even within units, tumour clear margins and ‘wide’ margins have become interchangeable when in reality they may be completely different and may lead to inappropriate treatment for patients. In the oncological world, the concept of patient specific treatment or ‘personalised medicine’ is gaining popularity and what is correct for one patient, may not be suitable for another patient, even with the same tumour type.
Limb salvage surgery
Prior to the advent of effective chemotherapy, the surgical treatment for osteosarcoma involved early radical amputation or disarticulation of the affected limb. Whilst ensuring complete removal of the tumour, performing this radical surgery on young patients caused loss of function and permanent disability, without improving patient survival. Limb salvage surgery (LSS) aims to resect the tumour, whilst maintaining function of the preserved limb, all with minimal risk to the patient (Fig 2).
The emergence of efficacious chemotherapy regimes, which acted to reduce tumour burden and reduce metastatic spread, and enhanced imaging techniques such as CT and MRI have led to the increased use of LSS [13-15]. By definition, the use of LSS requires preservation of limb neurovascular structures and narrower surgical margins when compared to amputation. Preservation of tissue during tumour resection has led to the inevitable decrease in resection margins, which potentially risks causing an increase in local recurrence (Fig 3). There are conflicting reports on the rate of local recurrence in LSS with some studies reporting an increase [15-17] and others a decrease [18], when compared to amputation. Considering local recurrence is associated with poor outcome, much work has been done to examine the impact of LSS on survival. Simon et al. were one of the first groups to investigate outcomes following LSS in a multi-centre retrospective review of 227 patients. They reported LSS had a comparable survival rate with amputation at 5 years follow up [19] and provided the impetus for increased uptake of LSS amongst surgeons. A large study by Bacci et al. retrospectively compared the outcome in patients who underwent LSS to amputation. The authors report that whilst LSS was associated with reduced resection margins, local recurrence and 5-year disease free survival were comparable to amputation [20]. These results are confirmed by a number of other groups, with each describing a survival rate equal to or better than that of amputation [15,17,18,21-27].It is important to consider, however, these studies are limited by their retrospective nature. Without robust methods of randomisation, treatment decisions have been based on individual patient and tumour characteristics, local practice and patient choice, leaving them open to the influence of selection bias. Postoperative quality of life is an important outcome measure in osteosarcoma. As patients with osteosarcoma are young and can expect a prolonged period of survival following treatment, the demands put upon a salvaged limb or prosthesis can be great. It is essential, therefore to ensure there is minimal risk of technical failure, the limb provides adequate function for the individual patient and has an acceptable cosmesis for both the patient and their care givers. Measurement of quality of life in children is difficult and there have been relatively few studies assessing this outcome measure. Using objective quality of life scores, LSS and amputation groups report reduced quality of life compared to population norms [29,30]. A meta-analysis comparing quality of life in patients who underwent LSS and amputation found there was no significant difference between the 2 groups. Taking into consideration all the above evidence LSS remains a safe and effective management option and when used in combination with adjuvant chemotherapy offers a good survival outcome.
Chemotherapy/chemonecrosis
The introduction of chemotherapy regimes alongside surgical resection has led to a dramatic improvement in survival. The use of chemotherapy in the treatment of osteosarcoma began in the 1970s with the use of doxorubicin and high dose methotrexate regimens [31]. Administration of chemotherapy agents before surgical resection as neo-adjuvant therapy enhanced survival from10 – 20% to 70% [32].Current modern chemotherapy regimes are based on combination therapy using methotrexate, adriamycin/doxirubicin and cisplatin. Poor response to chemotherapy has been identified as an important independent risk factor for poor prognosis. Histological evaluation of surgical resection specimens permits the classification of response to chemotherapy as good (>90% tumour necrosis) and poor (<90% tumour necrosis). Patients who display poor response are consistently reported to have worse outcome [33,34]. A number of strategies have been employed to improve results in poor responders. Evidence suggests modification of chemotherapy regime may improve results. Several groups have showed intensification of pre-operative chemotherapy enhances tumour response [35-37] and may improve survival [38-40]. This benefit however, is limited and intensification of chemotherapy beyond a certain level does not improve outcome [36,41-43]. The use of high dose, intensive treatment to induce a good response early in the disease process has also been shown not to convey overall survival benefit [38,42-44]. Further work is therefore required to optimize tumour response and improve outcome in patients with poor chemotherapy response. A recent, large, multi-national study EURAMOS-1 investigated the effect of adding the additional agents, ifosfamide and etoposide, to salvage poor response to chemotherapy, as well as evaluating the addition of pegylated interferon for good responding tumours [45]. The published initial results suggest that the addition of interferon for good responding tumours appears beneficial, however, it was poorly tolerated and frequently refused by patients. Current practice involves assessing tumour response using resection specimens following surgery, after the completion of neo-adjuvant chemotherapy, to advise further treatment[45]. Considering tumour response to chemotherapy is such a significant prognostic factor, measuring response early in the disease process may inform further management choices. Non-invasive imaging techniques such as CT [46], MRI [47-49] and F-FDG PET [50,51] have all be used to investigate response to neo-adjuvant chemotherapy. A combination of F-FDG PET and CT (F-FDG PET-CT) scanning is widely used for the detection of many cancers. Meta-analysis of the current evidence for its use in osteosarcoma has shown F-FDG PET-CT to be a valuable modality to assess chemotherapy-induced necrosis [52]. Newer techniques for evaluating response to chemotherapy prior to surgery, such as functional MRI (fMRI) are also promising and may inform surgeon’s decisions in planning surgical margins.
Patients with poor response to chemotherapy present a complex management challenge. There have been few studies presenting evidence to guide the surgical management of these patients. Bacci et al. suggested that amputation should be considered in the setting of poor response to chemotherapy due to its significant correlation with local recurrence rates [20]. Recent work in Birmingham investigated the influence of resection margins on survival in patients with poor response to chemotherapy [28]. The authors showed there was no survival benefit gained from amputation when compared to LSS with close margins, irrespective of the risk of developing local recurrence [28]. These data demonstrate resection with preservation of the limb to be a safe surgical option even in patients with poor chemonecrosis.
Predicting outcome
The current classification systems used to grade osteosarcoma, pioneered by Enneking, incorporate tumour characteristics including the presence of metastases to guide surgical management and predict prognosis [8]. However, despite the widely accepted importance of response to chemotherapy in prognosis, the current classification fails to reflect this. In a recent presentation at International Society of Limb Salvage (ISOLS 2015), Jeys et al introduced The Birmingham Classification, which uses numerically defined tumour margins and response to chemotherapy to predict both local recurrence and survival. In this series, chemotherapy response was reported to show a significant effect on the rate of local recurrence and overall survival. It was also reported that a margin of 2mm was a statistically significant cut off value for predicting local recurrence. Furthermore, combining resection margins (greater or lesser then 2mm) with response to chemotherapy (good, >90% or poor, <90%) was more effective in predicting local recurrence and survival than other staging systems. This classification, however, requires further validation on a multi-centre basis.
Conclusion
Osteosarcoma continues to present a number to treatment challenges. Although surgical resection margins are an important predictor of outcome, limb salvage surgery with close margins has been shown to be a safe and effective surgical option. Response to chemotherapy is an important independent predictor of survival. A distinct group of poor responders exist, who despite modification to chemotherapy regimes and complete surgical excision of the tumour continue to have a poor outcome. Current classification systems have so far failed to reflect important prognostic indicators, the Birmingham Classification represents a new, robust system for classifying osteosarcoma and predicting outcome.
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Dr. Thomas P Cloake
Prof Lee M Jeys
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Chemotherapy in Osteosarcoma: Current Strategies
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 27-32 | Sandeep Jain, Gauri Kapoor.
Authers: Sandeep Jain[1], Gauri Kapoor[1]
[1]Department of Pediatric Hematology and Oncology, Rajiv Gandhi Cancer Institute & Research Centre, Delhi.
Address of Correspondence
Dr. Gauri Kapoor MD, PhD
Director Department of Pediatric Hematology and Oncology,
Rajiv Gandhi Cancer Institute & Research Centre, Delhi.
Email: kapoor.gauri@gmail.com
Abstract
Incorporation of chemotherapy to multi-modality management of high grade osteosarcoma has led to remarkable improvement in survival rates. Its use in the neoadjuvant setting is now accepted as standard of care and has the added advantage of providing important information on histologic response. Survival rates for non-metastatic disease are nearly 70%. Outcome of patients with poor histological response and those with metastatic and recurrent disease continues to be unsatisfactory and an ongoing challenge. Therefore, there is a need to develop novel agents and biologically driven strategies to target these disease subgroups. The current review focusses on evolution of chemotherapy, controversies in its use and current standard of care for osteosarcoma.
Keywords: Osteosarcoma, chemotherapy, neoadjuvant chemotherapy.
Introduction
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents accounting for 4% of all pediatric malignancies. Approximately 20% of children present with metastatic disease at diagnosis and it remains, unquestionably the most important factor affecting long term survival. Prior to 1970, the prognosis of patients with osteosarcoma was dismal, with a 10–20 % overall survival despite being treated with radical surgeries [1-3]. Outcome of patients with osteosarcoma has improved in the past three decades with the addition of effective systemic polychemotherapy and advances in surgical resection. These have led to improvements in overall survival of patients with localized disease to the tune of 70% [4-5]. Various well coordinated systemic trials by different co-operative groups in North America and Europe have identified high-dose methotrexate (HD-MTX), cisplatin, doxorubicin, ifosfamide and etoposide as active cytotoxic agents and combinations of these drugs make up the cornerstone of treatment. Chemotherapy not only takes care of micrometastatic disease at diagnosis but also facilitates limb salvage surgery. The choice of regimen and optimal schedule of chemotherapy is somewhat controversial. In this review we focus on evolution of chemotherapy, controversies in chemotherapy use and current standard of care.
Evolution of chemotherapy
Before the introduction of chemotherapy, the outcome of patients with osteosarcoma was only 15-20%, despite adequate local control. Most patients succumbed to metastatic lung disease. These findings led to the conclusion that patients with osteosarcoma have microscopic metastatic disease at the time of diagnosis and this prompted investigators to identify active agents to target it. Initial studies to demonstrate chemosensitivity of osteosarcoma were done in the early 1970s by Sutow et al [6]. He developed a regimen called “Conpadri”which included cyclophosphamide, Oncovin (vincristine), doxorubicin (adriamycin), and L-phenylalaninemustard. Later on with the inclusion of HD-MTX, the acronym was changed to “Compadri’ [6-7]. These regimes were the first rational attempt at confirming the role of adjuvant combination chemotherapy using drugs with non-overlapping toxicities in osteosarcoma. Compadri I–III yielded a 41% 18-month disease-free survival [8]. These results suggested that addition of chemotherapy improved survival in patients with osteosarcoma. However, in the absence of randomized trials, it was not clear, to what extent improvement in surgical techniques and radiological studies contributed to achieving these results. These observations were further supported by the first randomized trial from Mayo clinic wherein patients were randomized to receive adjuvant vincristine and HD-MTX versus surgery alone[9]. This trial did not show any difference between the two arms. All these concerns were put to rest by two subsequent randomized controlled trials from North America that clearly established the survival benefit of adjuvant chemotherapy. In both these trials patients receiving no adjuvant treatment had a 2 year event free survival of just 20% compared to 66% and 55% in patients who received adjuvant chemotherapy [10-11]. These trials also established adriamycin, cisplatin, HD-MTX and alkylating drugs like ifosfamide and etoposide as active agents in the treatment of osteosarcoma. The various trials showing benefit of chemotherapy in osteosarcoma are listed in Table 1[12-22].
Role of neoadjuvant chemotherapy
The concept of neoadjuvant chemotherapy (NACT) was first introduced at Memorial Sloan-Kettering Cancer Center (MSKCC) in their T-10 protocol [23]. Preoperative chemotherapy was administered in an effort to increase the number of patients who could undergo limb salvage as the surgeons needed time to order the prosthetic devices. Administration of NACT also had the theoretical advantage of treating presumed microscopic metastatic disease. The outcome of the T-10 trial was similar to that of the Multi Institutional Osteosarcoma Study (MIOS), with a 65% survival rate at 5 years. Importantly, the results of this trial laid the foundation for the subsequent important association between histologic necrosis and prognosis. However, there were concerns regarding the impact of delayed surgery among patients with chemo-resistant disease as well as the probability of development of resistant clone in those with high volume disease. To answer this concern Pediatric Oncology Group conducted a randomized clinical trial (POG 8651) between 1986 and 1993, comparing NACT with adjuvant chemotherapy. This trial compared immediate surgery followed by postoperative adjuvant chemotherapy with 10 weeks of the NACT (same drugs) followed by surgery in 100 patients under the age of 30 years with non-metastatic,high grade osteosarcoma. Chemotherapy consisted of alternating courses of HD-MTX with leucovorin rescue, cisplatin, doxorubicin, and bleomycin, cyclophosphamide,dactinomycin (BCD). The five-year relapse-free survival rates were similar between the two groups, 65% versus 61% for adjuvant and neoadjuvant arms respectively. There was also no difference in the number of patients who underwent limb salvage procedures (55% and 50 % for immediate and delayed surgery, respectively) [24]. On the basis of these results, the use of preoperative chemotherapy has become standard of care, given its advantages, as it allows sufficient time for surgical planning, potentially facilitates tumor removal, and permits evaluation of response to therapy. Several investigators in single and multi-institutional studies in the United States and across Europe, support this general strategy [13,14,16,18].
Histological response to chemotherapy
Most trials reveal that patients with greater than 90% necrosis following NACT have significantly better event free survival (EFS) compared to those with less than 90% necrosis. Several grading systems have been developed for assessing the effect of preoperative chemotherapy on the tumor. The two most commonly used classification systems are the Picci and Huvos classifications[Table 2]. The Institute of Rizzoli (IOR) reviewed data on localized extremity osteosarcoma in more than 1000 patients over the 19-year period from 1983 to 2002 [25]. Fifty-nine percent of all patients had good response to chemotherapy (Picci), and had a 5-year survival of 76%, compared to 56% for poor responders. The Cooperative Osteosarcoma Study group (COSS) database analyzed 1,700 patients between 1980 and 1998 that included all sites, ages, and presence or absence of metastases [26]. The data revealed that 55.6% of patients had good response to therapy. The 5-year survival rate for good and poor responders was 77.8% and 55.5% respectively. The European Osteosarcoma Intergroup (EOI) analyzed data of two consecutive studies between 1983 and 1986 and 1986 and 1991 [27]. A total of 570 patients were analyzed in the report. This analysis is notable for several differences compared to the COSS and IOR analyses. Only 28% of patients had a good histologic response, whereas 72% of patients had a poor histologic response. Their 5-year survival rate was 75% and 45% respectively. Interestingly, many of the patients included in the analysis did not receive HD-MTX as they were randomized to receive either doxorubicin and cisplatin or more intensive therapy including doxorubicin and HD-MTX. This data clearly established that histological response to chemotherapy is an important prognostic factor.
Intensification of neoadjuvant and adjuvant chemotherapy
As it became clear that the degree of histological necrosis after pre-operative chemotherapy predicts survival, efforts were directed to intensify chemotherapy so as to achieve maximum therapeutic response. This strategy of preoperative chemotherapy intensification has been tested in COSS-86 and MSKCC T-12 study [14,28]. Although this strategy resulted in increased proportion of good responders achieving >90% necrosis, it did not translate into improved overall survival (OS) or EFS rates. Till date only INT-0133 study has shown benefit of NACT intensification [19]. The next group of trials focused to alter or intensify chemotherapy for patients with sub-optimal response to preoperative chemotherapy. In the early 1980s at Memorial Sloan-Kettering Cancer Center, poor responders had cisplatin substituted for HD-MTX in addition to continuing BCD (bleomycin, cyclophosphamide, and dactinomycin) and doxorubicin [13]. Survival of patients with intensified adjuvant treatment was similar to others. Several other reports have also failed to demonstrate benefit of intensification of therapy for poor responders[20,29]. Thus, till date it has not been possible to improve the outcome of poor responders by altering postoperative chemotherapy. An explanation for this may be that the NACT response is a surrogate measure of chemo-sensitivity of tumor and an inherently biologic unresponsive tumor is not modifiable by currently available therapies.
Role of intra-arterial chemotherapy
The intra-arterial route was introduced in an attempt to enhance the efficacy of drugs by increasing the local concentration of chemotherapy. Alkylating agents like ifosfamide and cyclophosphamide could not be used as they required phosphorylation in liver for activation. Doxorubicin was not a suitable agent as it is associated with skin and subcutaneous necrosis. MTX achieved high tumoricidal concentrations intra-arterially but similar concentrations could also be attained via the intravenous route. Intra-arterial cisplatin was therefore, selected and found to be highly effective. Response rates with the intra-arterial route were better when compared to the intravenous route[30]. It has been used extensively at the MD Anderson Cancer Center in the TIOS pediatric trials. It was highly effective in patients with pathological fractures and neurovascular involvement. Unfortunately, intra-arterial route is labor intensive and requires general anaesthesia or conscious sedation in a radiological suite. It also requires intensive monitoring of the distal arterial vascular status during and after the infusion. Moreover, similar results could be achieved with multiple courses of combination chemotherapy administered by the intravenous route over a more prolonged period. Therefore, intra-arterial route is generally not preferred.
High Dose Methotrexate
High dose methotrexate is one of the oldest drugs used in the treatment of osteosarcoma. It is generally administered over 4-6 hours and requires aggressive hydration, leucovorin rescue, serum level monitoring and adequate infrastructure to safeguard delivery and manage toxicity. Moreover, it adds substantially to the overall cost of treatment. In addition, there are no randomized studies to compare the efficacy of higher versus intermediate doses of HD-MTX plus doxorubicin and cisplatin versus doxorubicin/cisplatin alone. Furthermore, investigators at St. Jude Children’s Research Hospital have demonstrated good outcomes with five-year EFS and OS of 66% and 75% respectively with non-methotrexate-containing chemotherapy regimen consisting of carboplatin, ifosfamide and doxorubicin [31]. All of this has led to considerable controversy regarding the optimum role of HD-MTX. Methotrexate is the only active agent that has been subjected to a comparative trial of efficacy with another active agent i.e. cisplatin. Compared to 5-20% survival of historical controls in pre-chemotherapy era, HD-MTX increased survival to 40% – 60% as a single agent. When combined with other active agents like cisplatin and doxorubicin the long term survival of 65% – 75% was reported [12-15]. Many studies have shown a favorable correlation between peak serum levels and outcome [19,32-33]. Therefore, optimum doses and administration schedule is crucial to derive optimum benefit from HD-MTX therapy. Chemotherapy regimes devoid of HD-MTX were considered, among the “major poor prognostic factors” in the treatment of osteosarcoma by Graf et al. [33]. Despite the absence of randomized trials evaluating osteosarcoma treatment with and without HD-MTX, it is generally acknowledged that methotrexate is a standard component of almost all contemporary osteosarcoma protocols in children and adolescents.
Current standard of care for patients with osteosarcoma
It is well established that chemotherapy is an integral component of osteosarcoma treatment and is essential in addition to local surgery in order to achieve a reasonable expectation of cure. Therefore, optimum treatment for osteosarcoma demands a multidisciplinary strategy. The treatment generally consists of three stages: initial cytoreduction with chemotherapy to eradicate micro metastatic disease and facilitate effective local control measures with wide negative margins; and consolidation therapy for eradication of occult residual disease to reduce the likelihood of tumor recurrence. Importantly, NACT not only helps to achieve optimal cytoreduction in facilitating limb salvage procedures but also provides a chance to assess the histologic response to chemotherapy. Most treatment protocols include cisplatin, doxorubicin and HD-MTX with or without ifosfamide plus etoposide(IE). In the recently concluded EURAMOS study, all patients received NACT: 2 blocks of MAP (methotrexate, doxorubicin and cisplatin) chemotherapy for 10 weeks followed by surgery (wide excision). Surgical excision of tumor with oncologically safe margins was the best means of local control. Post surgery, poor responders were randomized to receive MAP for 28 weeks with or without IE. All good responders continued on MAP for 28 weeks and then were randomized to no further therapy and maintenance therapy with pegylated interferon. This is the largest international trial in the history of osteosarcoma treatment and its results show that intensification of adjuvant chemotherapy by addition of IE in poor responders did not improve survival. Furthermore, in good responders addition of pegylated interferon maintenance was not useful [22]. Schema of this treatment is shown in [Figure 1] and most of the study groups endorse this strategy as current standard of care.
Non-methotrexate based chemotherapy for countries with limited resources
There is paucity of published data on osteosarcoma from India. Historically, the role of high dose methotrexate in the treatment of osteosarcoma has always been debatable. From the practical perspective, it requires rigorous pharmacokinetic monitoring and often the infrastructure required for monitoring is not available in many centers with limited resources. Therefore, most of the centers in India use cispaltin, doxorubicin and ifosfamide based chemotherapy. Pathak et al have reported relapse-free survival was 72% nonmetastatic osteogenic sarcoma of the extremities using cisplatin and doxorubicin as adjuvant therapy [35]. Recently, results from a single center study from India have revealed 2yr progression free survival of 70 % for patients with non-metastatic osteosarcoma [36]. In light of these results use of non methotrexate based therapy in resource constraint setting seems justified. In addition, it is desirable to focus on developing infrastructure to provide limb salvage procedures and direct resources to develop indigenous affordable prosthesis.
Treatment of relapsed osteosarcoma
Treatment of relapsed osteosarcoma has not been tested in randomized clinical trials, and thus, there is no single standard approach. Prognosis of patients with relapse depends on duration of off therapy and site of relapse. In a large database of 565 osteosarcoma patients who relapsed after being treated with one of three different NACT protocols within the European Osteosarcoma Intergroup, five year survival post relapse in those whose disease recurred after two years versus within two years of randomization was 35 versus 14 percent, respectively[37]. There is no reasonable chance of cure without complete surgical resection of all sites of disease. Choice of chemotherapy depends on agents used in front line therapy. In most of contemporary studies, most of the patients receive cisplatin and doxorubicin in front line therapy. Therefore, ifosfamide, etoposide and HD-MTX are the most commonly used drugs in relapse setting. In general, patients should be treated with any of the four most active agents that were not included in front line therapy. The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue has been applied to salvage therapy. However, at least two small pilot studies failed to demonstrate significant advantage of standard salvage therapy approaches [38-39].
Newer therapies
There has been significant progress in the management of patients with osteosarcoma from 1970 to 1990. However, thereafter, progress has been stalled due to limited options available for patients with poor histologic response and those with metastatic and recurrent disease. It is clear that intensification of available chemotherapeutic agents has not translated into survival benefit for these group of patients and novel agents are required. Some of the agents being tested include mTOR inhibitor (ridaforolimus), inhibitors of insulin-like growth factor I receptor, tyrosine kinase inhibitor (sorafenib), microtubule inhibitor (oferibulin), human monoclonal antibody against RANKL (Denosumab) and anti-disialoganglioside antibody (theuseofan) [40-44]. Some of these agents have demonstrated promising results in preclinical data and may offer a potential role in adjuvant therapy in the future.
Acute toxicities and Late Effects
The most frequent acute toxicities due to chemotherapy are infections secondary to myelosuppression and mucositis. Renal dysfunction may lead to hypomagnesemia and other electrolyte abnormalities from tubular and glomerular damage induced by ifosfamide and cisplatin respectively. Ototoxicity from cisplatin and cardiac dysfunction related to anthracyclines are the other commonly observed side effects. Late effects in osteosarcoma may be attributed to local therapy i.e. surgery or to systemic chemotherapy. Those related to chemotherapy are usually agent specific. Doxorubicin is known to cause chronic cardiomyopathy which is dependent on the total cumulative dose. Longhi et al reported 2% incidence of symptomatic cardiomyoathy at a median follow up of 10 years [45]. In general, cumulative dose of doxorubicin is usually limited to less than 450 mg/m2. Anthracycline and alkylating agents may also result in second malignant neoplasm (SMN). The same authors report a 10-year and 20-year cumulative incidence of SMN of 4.9% and 6.1% respectively in osteosarcoma survivors. The alkylating agent, ifosfamide is associated with infertility, especially male infertility, so sperm cryopreservation should be offered to postpubertal boys if treatment plan includes alkylating agents. In addition, ifosfamide can cause a persistent renal tubular electrolyte loss and, less commonly, a decrease in glomerular function, in a dose-dependent fashion.
Conclusion
Inclusion of chemotherapy in the multimodality treatment of osteosarcoma has undoubtedly improved survival from a dismal 20% to the present 60%. NACT has enabled limb salvage rates to the tune of 90-95% in most advanced centers. Outcome of patients with poor histological response and those with metastatic and recurrent disease continues to be unsatisfactory and an ongoing challenge. Therefore, there is a need to develop novel agents and biologically driven strategies to target these disease subgroups.
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The Current Role of Radiation Therapy for Osteogenic Sarcoma
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 33-35 Sangeeta Kakoti, Nehal Khanna, Siddhartha Laskar.
Authers: Sangeeta Kakoti[1] Nehal Khanna[1], Siddhartha Laskar[1]
[1]Department of Radiation Oncology, Tata Memorial Hospital, Mumbai. India
Address of Correspondence
Dr.Siddhartha Laskar
Professor, Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges Marg, Parel, Mumbai – 400012, India.
Email: laskars2000@yahoo.com
Abstract
Osteosarcomas are known to be relatively radio-resistant, definitive radiotherapy has a role in cases that are unresectable or have poor prognostic factors. Neo-adjuvant Chemotherapy followed by local therapy (surgery alone and/or radiotherapy) and maintenance chemotherapy remain the current standard of care for treatment of non-metastatic high grade osteosarcoma. New technologies like particle beam therapy using proton and carbon ions and use of high precision radiation therapy techniques have further improved the results of definitive radiation therapy. Current review traces the advent of radiotherapy, its current role in management of osteosarcoma and future trends in the field.
Keywords: Osteogenic Sarcoma, Radiotherapy, Management.
Introduction
Osteosarcoma (OGS), an osteoid-producing malignant mesenchymal tumour, accounts for 20-45% of all skeletal malignancies. It has a bimodal age distribution with peak incidence at 10-19 years and over 60 years (secondary to prior radiotherapy exposure, Paget’s disease etc). Male to female ratio is approximately 1.6:1. The most common sites of involvement are femur (50%), followed by tibia, humerus, pelvis, jaw, fibula and ribs. The major histological variants are conventional osteosarcoma (osteoblastic, fibroblastic or chondroblastic, according to the predominant type of matrix produced), teleangiectatic and small cell osteosarcoma. Patients commonly present with bony pain and local swelling. Patients may also present with symptoms of metastatic disease like dyspnoea, hemoptysis, or bone pain. Diagnostic investigations include Plain radiograph (characteristic ‘Sun burst’ appearance and ‘Çodman’s triangle’), MRI of local part, CT scan of chest, Bone scan (to look for skip lesions) and a histopathological examination. Tumors are staged according to either the AJCC or Enneking (MSTS) systems. Prognostic factors impacting survival [1] include presence of metastasis, response to Neoadjuvant chemotherapy (NACT), histologic type, age (each decade increases mortality rate by 7 fold), tumour location (tumours of tibia fare better than those of femur) and choice of therapy (post operative radiotherapy and amputation was associated with 92% and 76% increased relative risk of death respectively, may be confounded by advanced disease status). Prior to the extensive use of chemotherapy for treating patients with osteosarcoma, aggressive surgery was considered the treatment of choice, resulting in five year overall survival rate of 10-20% [2]. A meta-analysis by Kassir et al [3] on head and neck Osteosarcoma showed that surgical cut margin status was the sole prognostic factor and there was no survival benefit by adding radiation therapy and/or chemotherapy. But subsequently there have been great leaps in the success of osteosarcoma management. Incorporation of highly active chemotherapeutic agents resulted in significant improvement in outcomes to the tune of 60-75% [4]. The MIOS trial [5] reporting 5% versus 65% overall survival rates in patients randomised to surgery versus surgery and chemotherapy respectively, formed the basis for multimodality therapy in these tumours.
Role of Radiotherapy in management of Osteosarcoma
Osteosarcoma was always thought to be a radio-resistant tumour and hence radiotherapy was initially not included in the standard management regimens. Sir Stanford Cade a British surgeon radiotherapist in 1931 treated 133 patients with radiation therapy with an intention to avoid futile amputation in patients developing lung metastases in subsequent 6-9 months [6]. Following completion of therapy (60 Gy over six weeks) the resected specimen revealed 100% tumour necrosis in all patients.
1) Radiotherapy in definitive setting
There are no randomized trials comparing surgery versus radiotherapy (RT) as primary local therapy for osteosarcoma and is unlikely to be one in future due to ethical issues. However there are a few single arm series showing encouraging results. Machak et al [7] treated 31 patients with extremity osteosarcomas with definitive radiotherapy to a median dose of 60 Gy (range, 40–68 Gy). The 5-year local control (LC), metastasis-free and overall survival (OS) rates were 56%, 62%, and 61%, respectively. Similarly, Caceres et al [8] also noted a complete pathological response in 80% patients with limb OGS treated by chemotherapy and 60 Gy of RT. Excellent functional outcomes was noted in 86% of the patients. In 13 patients treated with definitive RT to median dose of 60 Gy, at a median follow up of 161 months, 3 year LC and OS was 70% and 75% respectively [9]. Subsequently, in the COSS registry of 175 patients [10] treated from 1980 to 2007, at a median follow up of 1.5 years (0.2-23 years), the overall survival rates after RT for treatment of primary tumors, local recurrence, and metastases were 55%, 15%, and 0% respectively. Local control rates for combined surgery and RT were significantly better than those for RT alone (48% vs. 22%). Feasibility of Stereotactic body radiotherapy (SBRT) for recurrent OGS lesions was evaluated by Brown et al [11]. Median dose delivered was 40 Gy in 5 fractions (range, 30-60 Gy in 3-10 fractions; total of 14 patients). Two grade 2 and 1 grade 3 late toxicities occurred (in the setting of concurrent chemotherapy and reirradiation); consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy [11]. Efficacy and long term toxicity are yet to be determined. Gaitan-Yanguas showed a dose-response relationship with no lesion controlled at doses of 30 Gy, and all lesions controlled with doses of >90 Gy [12].
Approximately 25% of pelvic and 10% of head and neck osteosarcomas are not resectable and hence are candidates for definitive radiotherapy. In our institute, we prescribe 70.2 Gy in 39 fractions over 8 weeks.
2) Radiotherapy in preoperative setting
Preoperative radiotherapy is gradually evolving to facilitate function preserving less mutilating surgeries. Dincsbas et al [13] treated 44 patients with preoperative RT to a dose of 35 Gy in 10 fractions followed by limb sparing surgery. The tumor necrosis rate was 90% in 87% of the patients. At a median follow-up of 44 months, the 5-year LC and OS were 97.5% and 48.4% respectively. They documented subcutaneous fibrosis in 16%, joint movement restriction in 20%, and osteo-radionecrosis and pathologic fracture in 4% patients. Chambers et al [14] reported an OS of 73% at 5 years of 33 patients treated with preoperative RT and resection for craniofacial OGS.
3) Radiotherapy in adjuvant setting
Delaney et al [15] reported 41 patients with osteosarcoma involving various sites (primary, recurrent as well as metastatic) in different settings to a dose of 10 to 80 Gy (median 66 Gy) preceded by gross total tumor resection in 65.8%, subtotal resection in 21.9% and biopsy only in 12.2%. The local control rates according to the extent of resection were 78.4%, 77.8% and 40% respectively. The overall survival rates in corresponding groups were 74.45%, 74.1% and 25% respectively. The authors concluded that adjuvant RT can help provide local control of osteosarcoma for patients in whom surgical resection with widely negative margins is not possible. Dose response relationship was not found to be significant. Caveat of the study was that the patient population as well as the treatment parameters including dose and timing of radiation (some received preoperative followed by postoperative RT) was very heterogeneous.
Guadagnolo et al [16] reported that the addition of adjuvant RT in head and neck osteosarcoma definitely improves local control for those with positive or uncertain margins. Laskar et al reported the outcomes of patients with head and neck osteosarcomas treated at the Tata Memorial Hospital, Mumbai [17]. The authors highlighted the impact of post-operative adjuvant radiotherapy, even after R0 resection or in patients with adverse prognostic factors (large tumour size, lymphovascular invasion, soft tissue infiltration etc). The patients receiving adjuvant RT at TMH were prescribed a dose of 64.8 Gy in 36 fractions over 7 weeks. The authors reported local control rate of 36%. High dose intra-operative EBRT with kV X rays or electrons is emerging as yet another experimental option. Hong et al reported outcome of extracorporeal irradiation (ECI) in the management of 16 pts with a variety of tumours (OGS being in 4 of them) to a dose of 50 Gy in single fraction. At a median follow-up of 19.5 months, there were no cases of local recurrence or graft failure. One patient required amputation due to chronic osteomyelitis [18]. Puri et al reported the outcomes of patients treated at the Tata Memorial Hospital, Mumbai, using extracorporeal irradiation [19]. Thirty-two patients (16 Ewing’s sarcoma and 16 OGS) with a mean age of 15 years (2 to 35 years) underwent this procedure. There were three local recurrences. All were associated with disseminated disease and the recurrences were in soft- tissue remote from the irradiated graft. There were no local recurrences involving the irradiated bone. The OS for patients with osteosarcoma was 65% with excellent functional outcome.
4) Radiotherapy in palliative setting
There is little data regarding dose fractionation and efficacy of radiotherapy for palliation of advanced osteosarcoma. Considering the similar mechanisms of pain and inflammation like bony metastases, data from the later are often extrapolated [20] and single fraction or protracted fractionation have both been equally used. Oligo-metastatic OGS is treated with curative intent. Metastatectomy is the gold standard as a component of the curative regimen with a documented 5 year OS of approx 22%. Stereotactic body radiotherapy (SBRT) to limited lung metastases is an equally efficacious emerging non invasive option. In a series of 46 patients with oligometastatic disease to lungs from sarcomas, at a median follow up of 22 months after median dose of 10-48 Gy in 1-5 fractions, 31% of patients survived for more than 3 years [21]. In a multicentric phase I/II trial treating 38 patients with oligometastases to a median dose of 38-60 Gy in 3 fractions, LC at two years was 96% and median survival was 19 months. Incidence of grade III-IV toxicity was 8% [22].
5) Particle therapy for osteosarcoma
Ciernik et al, treated 55 patients (42% received definitive RT) with osteosarcoma of all sites [23] using combination of photons and protons to a mean dose of 68.4 Gy. With a median follow-up of 27 months, LC at 3 and 5 years were 82% and 72% respectively. The 5-year DFS and OS was 65% and 67% respectively. Prognostic factors found to have a significant impact on disease control were grade and bulk of the tumour. The extent of surgical resection did not correlate with outcome. Grade 3 to 4 late toxicity was seen in 30.1 % of patients. In another series of 30 patients with unresectable OGS of the trunk treated with definitive Carbon ion therapy to a dose of 52.8–73.6 Gy, the 3 and 5 year LC at a median follow up of 33 months was 62% and 49% respectively. The corresponding OS was 53% and 29%. Severe skin/soft tissue reaction was reported in 5 patients [24]. With neutrons, local control rates of 55% were documented in patients with unresectable OGS of different sites [25]. A median prescribed dose of 66 Gy has been tried in a series to patients with paraspinal osteosarcomas with a resultant LC of 74%. There were no reported late toxicities [26].
6) Role of brachytherapy
There is very limited role of brachytherapy in osteosarcomas. A new treatment strategy based on direct injections of 90Y-hydroxide into the tumor bed is under preclinical trial [27].
Conclusion
Neo-adjuvant Chemotherapy followed by local therapy (surgery alone and/or radiotherapy) and maintenance chemotherapy remain the current standard of care for treatment of non-metastatic high grade osteosarcoma. Although osteosarcomas are considered to be relatively radio-resistant, definitive radiation therapy results in significant long term disease control in patients with inoperable disease and postoperatively in patients with poor prognostic factors. The outcomes of definitive treatment using radiation therapy has further been improved by the use of particle beam therapy like protons & carbon ions & escalated doses of photon therapy using modern high precision radiation therapy techniques. Hence, Radiotherapy remains an important option for local treatment of unresectable tumors, following incomplete resection, or as an effective tool for palliation of symptomatic metastases
References
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3. Osteosarcoma of the Head and Neck: Meta-analysis of Nonrandomized Studies. Laryn-goscope, 1997; 107: 56-61.
4. Dana-Farber Cancer Institute/The Children’s Hospital adjuvant chemotherapy trials for osteosarcoma: three sequential studies, A. M. Goorin, M. Delorey, and R. D. Gelber, Cancer Treatment Symposia. 1985; 3: 155–159.
5. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosar-coma of the extremity. M. P. Link, A. M. Goorin, and A. W. Miser. The New England Journal of Medicine. 1986; 314: 1513
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8. Local control of osteogenic sarcoma by radiation and chemotherapy. Caceres E, Zaharia M, Valdivia S, et al. Int J Radiat Oncol Biol Phys . 1984;10:35-39
9. Patrick Hundsdoerfer et al, European Journal of Cancer 4 5 (2009) 24 47 –2451
10. Craniofacial osteosarcoma Experience of the cooperative German–Austrian– Swiss osteosarcoma study group. Sven Jasnau, Ulrich Meyer, Jenny Potratz et al. Oral Oncology (2008) 44, 286– 294
11. Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosar-coma. Brown LC, Lester RA, Grams MP et al, Sarcoma. 2014:418270
12. A study of the response of osteogenic sarcoma and adjacent normal tissues to radiation. Gaitan-Yanguas M. IJROBP. 1981; 7: 593-595
13. The role of preoperative radiotherapy in non metastatic high-grade osteosarcoma of the extremities for limb-sparing surgery. Dincbas FO, Koca S, Mandel NM et al. Int J Radiat Oncol Biol Phys 2005;62:820-828
14. Osteogenic sarcoma of the mandible, current management. Chambers RG, Mahoney WD. Am Surg . 1970;36:463-471
15. Radiotherapy for local control of osteosarcoma. Thomas F. Delaney, Lily Park, Savelli I Goldberg et al, IJROBP, 2005; 61(2): 492-498.
16. Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Guadagnolo BA, Zagars GK, Raymond AK, et al, Cancer 2009;115: 3262-70.
17. Osteosarcoma of the head and neck region: lessons learnt from a single institutional expe-rience of 50 patients, Siddhartha Laskar, Ayan Basu, Mary Ann Muckaden et al, Head & Neck, 2008: 1020-1026.
18. Extracorporeal irradiation for malignant bone tumors. Hong A, Stevens G, Stalley P, et al. Int J Radiat Oncol Biol Phys . 2001;50:441-447
19. The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradia-tion and re-implantation of the host bone. A Puri, A Gulia, N Jambhekar, S Laskar. J Bone Joint Surg Br 2012;94-B:982–8.
20. Randomized trial of short versus long-course radiotherapy for palliation of painful bone metastases. Hartsell WF, Scott CB, Bruner DW, et al. J Natl Cancer Inst 2005;97:798–804
21. A retrospective study of SBRT of metastases in patients with primary sarcoma. Christina Linder Stragliotto, Kristin Karlsson, Ingmar Lax et al. Med Oncol. 2012; 29:3431–3439
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24. Impact of Carbon Ion Radiotherapy on Outcome in Unresectable High-grade Osteosar-coma of the Trunk, T. Kamada, R. Imai, S. Sugawara et al, I. J. Radiation Oncology d Biology d Physics Volume 75, Number 3, Supplement, 2009
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OncoMedia Sep-Dec 2015
Vol 1 | Issue 2 | Sep – Dec 2015 | page:34-35 | Dr Ashish Gulia & Dr Ashok Shyam
Author: Dr Ashish Gulia[1] & Dr Ashok Shyam[2, 3]
Dr. Ashish Gulia MS (Ortho), Mch – Surgical Oncology
[1] Fellowship – Musculoskeletal Oncology (TMH – HBNI)
Asst. Professor – Orthopaedic Oncology, Tata Memorial Hospital, Mumbai, India.
Dr Ashok Shyam MS (Ortho)
[2]Indian Orthopaedic Research Group, Thane, India
[3] Sancheti Institute for Orthopaedics &Rehabilitation, Pune, India
ONCOMEDIA will focus on News and Event related to Bone and Soft Tissue Tumors from all across the World. Specific focus will be Industry updares,New Research, Social Impactof tumors, Basic Scinece and developmentsin cytogentics and allied fields. In short OncoMedia is a place for most interesting read in this entire issue 🙂
Bone Tumors on You tube
You tube has revolutionised the information dissemination scenario. From reading text the scenario has now changed of visuals. Medical knowledge dissemination through you tube is started almost from the inceptino of the website. There are many videos and essential details that are available on the you tube website. The problem is selecting a few and finding time to watch them. The JBST Oncomedia team and gone through you tube and found some interesting vedioes that we can recommend to our readers. We will also be psoting links of these videos on jbstjournal.com too. Lets see some details of these videos.
1. Pathology of Bone tumors. Essentially meant for postgraduate students, this video gives pictures of true specimens and their description.
Link: https://www.youtube.com/watch?v=oHfozp2e8zg
2. Bone Tumor Imaging: is a video of powerpoint lecture by Dr K L Verstraete. Although made in 2012, the lecture is quite informative and will help many to update their knowledge about Bone Tumor imaging.
Link: https://www.youtube.com/watch?v=EsLIUyExEXU
3. KOC Radiology conference: This KOC talk was given by our editorial board member Dr Bhavin Jhankaria in 2014. This is a very thorough update on imaging of bone tumor and delivered in inimitable style of Dr Bhavin. We highly recommend everyone to watch this video.
Link: https://www.youtube.com/watch?v=g2TGHrYGAvA
4. MSK Imaging bone tumor: Finally we can complete the update on bone imaging by watching this detailed video. Again presented in format of voice over of a powerpoint presentation, this includes a very good visual appeal to the video.
Link: https://www.youtube.com/watch?v=VcYRoB-qRX0
We will be providing reviews of some more youtube resources in the next issue of Oncomedia. Please provide us with your comments, suggestions and criticism for this feature of JBST.
Orthopaedic Powerpoints is a new presentation of the Orthopaedic Research Group. Although PPT’s are readily available online but many of them are not recent or with medicore content. At OrthoPowerpoints.com we will assure that best quality of material is published and circulated. The website will feature peer reviewed powerpoints and to begin with includes members by invitation only. Few presentations from the editorial board of JBST are available online. Visit www.orthopowerpoints.com for more details.
IMSOS 2016:The second Annual conference of Indian Musculoskeletal Oncology Society is planned on 11-13 March 2016 and will be held in Kochi. Visit the website www.imsos2016.org for more details.
IMSOS – Surgeon’s Training Initiative: This will be a travelling fellowship open only to IMSOS members allowing them a 6-8 weeks fellowship at a centre of their choosing. Two fellowships per year will be available. Interested readers can join IMSOS and look for further announcements
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