Continuing Education Activity

Osteogenic sarcoma is the most common primary malignant bone tumor with an annual incidence of 900 cases in the United States. This activity reviews the role of the interprofessional team in history and physical examination, laboratory evaluation, and management. It also includes a review of the recent advances in the management of this condition.

Objectives:

• Summarize the etiological factors of osteogenic sarcoma.
• Review the evaluation of osteogenic sarcoma.
• Outline the management of osteosarcoma.

Introduction

Osteogenic sarcoma (osteosarcoma) is the most common primary tumor of the bone, found most commonly in the extremities, with a bimodal age distribution.[1] Approximately 75% of cases present before the age of 25 years and are majorly primary (without attributing risk factor). A late peak is seen after the age of 50 years (peaking at 70 years), secondary to Paget’s disease and irradiation.[2] 

High-grade conventional intramedullary osteosarcoma is the most common subtype.[3] It is a biologically complex and aggressive tumor with a propensity to involve the growing metaphysis of the extremity bones, usually adjacent to the physes with the greatest growth (lower femur, upper tibia, and the upper end of the humerus).[4]

Complete surgical extirpation is usually the treatment of choice if localized.[5] Around 10% to 20% have evidence of metastases at presentation, the most common site being the lungs.[6] Occult micrometastasis at diagnosis are presumed to be more frequent, considering that over 80% patients present with metastasis despite local control before the advent of chemotherapy. With the routine use of chemotherapy, approximately two-thirds of children and adolescents will achieve long-term cure.[7]

Etiology

Risk factors for the development of osteosarcoma include previous irradiation, Paget’s disease of the bone, and inherited syndromes caused by abnormalities in DNA repair mechanisms such as Li-Fraumeni syndrome (LFS), Wermer’s syndrome, Rothmund Thompson syndrome, and familial retinoblastoma syndrome.[8] Retinoblastoma (associated with familial retinoblastoma syndrome) and p53 (associated with LFS) tumor suppressor genes are reported to be mutated in 67 and 90 percent of the cases, respectively.[9]

Mutations in RAS associated family member 1a, which is a major downstream effector molecule of K-ras, has been shown to be hypermethylated in tumor cell lines.[10] PI3K/mTOR pathway, a downstream effector of the Ras pathway, has also been shown to be mutated in osteosarcoma.[11] 

Additionally, pathways such as Notch signaling via Notch 1-4 phenotype involved in morphogenesis and proliferation have been implicated in the pathogenesis.[12][13] Epigenetic changes involving the inhibition of histone deacetylases have also been reported.[14] Inhibitors of aurora kinases and DNA methyltransferases have also shown some promise as potential treatment options.[15]

Epidemiology

Approximately 900 cases of osteosarcoma are diagnosed in the United States of America every year.[14] Osteosarcomas constitute less than 1% of all newly diagnosed tumors in adults, and close to 4% of all newly diagnosed cases in children.[4] It is the most common tumor in the adolescent age group, after the exclusion of haematolymphoid malignancies, with a predilection for males.[6] 

About 20 percent of the cases present with metastatic disease at presentation. The most common site of distant spread is the lung (60-70 percent), followed by bone (either skip or distant) in 20-30 percent cases.

Amongst osteosarcomas, which originate along the cortex or the periosteum, parosteal osteosarcoma is the most common juxtacortical lesion, constituting 1 to 6 percent of the cases.[16] The Ilium is the most common bone in the pelvis to be involved by osteosarcoma.[17]

Vertebral osteosarcomas comprise 4 to 15 percent of primary spinal tumors and 1 to 3 percent of osteosarcomas.[18] High-grade craniofacial osteosarcomas develop in older age, in contrast to conventional osteosarcomas.[19]

Pathophysiology

Rapid bone growth has been shown to predispose to the development of this tumor, as is evidenced by the involvement of the bone in proximity to the growing physes and the fact that it is seen to occur more commonly at the time of the pubertal growth spurt.[4]

Histopathology

The most common type of osteosarcoma is high-grade, intramedullary, conventional osteosarcoma. This is further divided into histological subtypes are osteoblastic, chondroblastic, and fibroblastic varieties depending on the predominant cellular component.[20] In addition to these three subcategories, there exist variants of conventional osteosarcoma that confer worse prognosis – telangiectatic, small cell, multifocal, and undifferentiated high-grade pleomorphic sarcoma.[4]

In contrast to the conventional osteosarcomas (high grade) that are intramedullary, two indolent variants arising from the surface of the cortex include periosteal osteosarcomas (intermediate grade) that arise from the inner cambial layer and parosteal osteosarcomas (low-grade) that arise from the outer fibrous layer of the periosteum, respectively.[21][22]

Osteosarcoma is a mesenchymal neoplasm that produces osteoid as well as the woven bone matrix.[23] Production of the osteoid matrix is the "sina qua non" for diagnosis.[24] The amount of matrix may vary from well-formed trabeculae (which point towards a benign process), dense osteoid (seen in the sclerotic variant of osteoblastic OGS) to inconspicuous amounts of the matrix (seen in fibroblastic or small cell variant of osteogenic sarcoma).[25]

Osteoid is characterized histologically as being glassy, densely eosinophilic, and homogenous. Osteoid deposition by malignant cells may be described by the following patterns – filigree or lacelike (delicate and anastomosing), sclerotic (dense confluent sheets of the matrix), and thick trabeculae (which may mimic dense bone).[26]

The most common histologic subtype is the osteoblastic variant of conventional osteosarcoma, which shows a preponderance of a lacelike osteoid matrix without the presence of significant chondroid or fibrous matrix.[27] Epithelioid tumor cells may be seen growing in clusters surrounded by osteoid.[28]

Parosteal osteosarcomas have a stuck-on appearance. Histopathological examination demonstrates a well-differentiated fibrous tissue with osseous components, hypocellular spindle cell stroma with well-differentiated trabeculae. These may undergo dedifferentiation into dedifferentiated parosteal osteosarcoma (DPOS), which may demonstrate the presence of high-grade spindle cell sarcoma along with the primary tumor.[22]

History and Physical

Presenting Complaints

Pain and swelling at the local site, usually at the growing ends of an extremity (long bone), are the common presenting symptoms.[29] Absence of signs of infection (local signs and symptoms mimicking osteomyelitis - usually considered to be more common with Ewing's sarcoma), history of antecedent trauma, or history of receiving irradiation to the site may also offer a clue to the diagnosis.[30]

Many patients present with pathological fracture due to primary tumor or bony metastases (bone to bone spread).[31] Others with metastasis present with symptoms pertaining to the organ, frequent cough, and hemoptysis with pulmonary metastases.[32]

Signs

Palpable mass, restriction of joint movement, pain on weight-bearing, localized warmth, and inflammatory erythema at the site of involvement are common signs.[4]

Constitutional signs and symptoms may be absent until the advanced stage of the disease.[29]

The preoperative neurological deficit in vertebral osteosarcoma can be assessed according to the Bradford and Mac bride modification of the Frankel grading system.[33] The classification given by Tomita et al can be used to classify the location and grade of spinal tumors.[33][34]

Evaluation

Initial investigations include the following:

Imaging: A radiograph of the local site (in two planes) will show periosteal reaction (sunburst appearance, Codman's triangle) with osteoid deposition on the radiograph.[35] A normal X-ray might not rule out the existence of a sarcoma conclusively, and MRI might be indicated in the event of continuing bone pain to rule out a bony pathology.[36]

In craniofacial osteosarcomas, a radiograph may not always show the typical sunburst appearance, and may instead show radiolucent to radioopaque lesions depending upon the degree of calcification or osteoid formation.[37][38]

Areas of bony cortical destruction, microcalcifications, and periosteal bone formations may be better visualized on a Computed Tomographic scan, which may be performed in cases of diagnostic uncertainty, or when an MRI is contraindicated.[39][40]

Tc 99 whole-body bone scanning or F 18 - FDG PETmay be indicated for ruling out other sites of bone to bone metastasis, "skip lesions."[39][35]

Blood tests: This includes complete blood count and biochemistry, serum ALP, ESR.

Biopsy: USG, MRI, or CT guided core needle biopsy might prove to be adequate in most cases. The histopathological specimen should be sent for molecular, genetic, microbiological studies. While there is some evidence to support the assumption that not all needle tracts need to be resected, all open biopsy tracts should be resected.[41]

The role of liquid biopsy in osteosarcoma is still in flux. However, this may be considered if the results of tissue biopsy are unconvincing. It detects circulating tumor cells, circulating tumor DNA, and micro RNA.[42]

Pre chemotherapy evaluation: Chemotherapy may result in auditory, renal, and cardiac toxicity, making baseline assessment of these parameters extremely important. Pure tone audiometry, baseline renal function testing, and echocardiographic evaluation might be warranted.[43]

Treatment / Management

Overview of the Treatment of Osteosarcoma

Multimodality therapy consisting of neoadjuvant chemotherapy, followed by surgery and chemotherapy in the adjuvant setting, is considered the treatment of choice.[44][45] The combination of chemotherapy, surgical procedures, and advanced imaging modalities has led to an increase in limb salvage rates from 53% in the 1980s to greater than 90% in recent times.[46] Along with an improvement in psychological and cosmetic outcomes, limb salvage procedures have comparable overall survival and local recurrence rates to amputation.[9] The utility of neoadjuvant chemotherapy has been attributed to the presence of subclinical micrometastatic disease.[6]

Enrollment in a clinical trial should be considered in all cases. General principles of management include,

• Localized, low-grade osteosarcoma
  • Wide excision is the treatment of choice.
  • Neoadjuvant chemotherapy is usually not recommended, except when it is a periosteal lesion.
  • If high-grade on the surgical specimen, adjuvant chemotherapy is warranted.

• Localized, high-grade osteosarcoma
  • Neoadjuvant chemotherapy followed by surgery is the standard of care.
    • Limb sparing surgery is considered in those with a good histologic response to chemotherapy. 
  • Depending on margins and response to neoadjuvant chemotherapy at the time of surgery, postoperative treatment involves chemotherapy with or without local therapy (radiation and/or re-resection).
    • Assessment of histological response to neoadjuvant treatment is of paramount importance in deciding the choice of chemotherapy.
  • If unresectable, chemoradiation is preferred. 

• Metastatic osteosarcomas
  • Neoadjuvant chemotherapy followed by wide excision of the primary tumor, along with metastasectomy, is indicated in pulmonary, visceral, or skeletal metastases if deemed resectable.
  • Chemotherapy, with or without radiation therapy, followed by reassessment of the primary site for local control, is indicated in unresectable metastatic disease.

• Relapsed or refractory osteosarcoma
  • Resection or second-line chemotherapy or a combination of the two is preferred.
    • Metastatectomy of bony metastases may be associated with poorer survival when compared to those who undergo resection of pulmonary only metastases.
  • If disease progression is evidenced, palliative radiation or best supportive treatment can be offered.[47][48]

Response Assessment following Neoadjuvant Chemotherapy 

The degree of histological necrosis has been shown to correlate with the disease-free survival in patients who have received neoadjuvant chemotherapy.[49] Less than <10% of viable cells on the biopsy specimen correlates with a favorable response and an improvement in disease-free survival.

Huvos was the first to describe the grade of histological necrosis in biopsy specimens from patients who had been treated with Von Rosen's protocol. These were classified from grade I to IV, with grade II and IV corresponding to complete response to therapy.[50] Rosen observed that those with grade III-IV responses had improved disease-free survival.[51]

Relapsed/Recurrent Osteosarcoma With or Without Metastasis

Treatment options include,

• If possible, surgical resection is preferred. Mostly, adjuvant chemotherapy is given.
  • A 5-year survival rate of 33% may be obtained in patients in whom a second surgical remission can be achieved.[41][48]
  • Recommended chemotherapy regimens have been listed in the 'medical oncology' section.
• If not candidates for surgery,
  • Chemotherapy with or without radiation is preferred.

In those with metastasis, dismal 5-year survival rates of 20%, which has remained unchanged over the past 25 years, underline the need to explore newer approaches.

Supportive Management/Palliative Medicine

The management of chemotherapy-related complications such as nausea and vomiting, anemia, neutropenic fever, fatigue, neuropathy,  and cardiotoxicity, provision of symptom directed therapy, and counseling regarding goals of care discussions, has shown improvement in the quality of life. Provision of continuity of care through home care and round the clock telephonic liaison might assume special significance, given the existing circumstances (ongoing SARS -COV -2 pandemic). Hospice should be considered early.[52][53]

Special Situations

Surface osteosarcomas[22][21]

Surface osteosarcomas are variants with comparatively lower malignant potential. Management is as following,

• Curative surgery remains the treatment of choice.
  • While local resection may be recommended for conventional parosteal osteosarcoma, wider margins are recommended in patients undergoing curative resections for high-grade surface osteosarcomas (dedifferentiated parosteal osteosarcomas and high-grade osteosarcomas).
• Chemotherapy is usually not recommended in the treatment of conventional parosteal osteosarcoma after a retrospective analysis failed to demonstrate any benefit in survival.
  • If high-grade areas are visualized on the histopathology specimen, treatment with adjuvant chemotherapy is advised. Though the exact benefits of chemotherapy have not been earmarked, there is a consensus that standard chemotherapy regimens be used in high-grade surface osteosarcomas.

Differential Diagnosis

Osteoblastic osteosarcoma can be confused with an osteoblastoma or a fracture callus.[26]

While, osteoblastic osteosarcoma, originates in the meta-diaphysis of the bony appendicular skeleton, consists of sheets of atypical cells within an osteoid matrix, may demonstrate entrapment of pre-existing bone with a permeative growth pattern often with extension into the soft tissue and presence of atypical mitoses with a high rate of replicating cells, osteoblastoma is usually well-circumscribed, with a peripheral rim of reactive bone, consisting of a loose fibrous stroma with a vascular component, rimming of bone trabeculae and absence of atypical mitoses. Callus formation is usually associated with a history of accompanying trauma, organized matrix deposition, presence of granulation tissue-like stroma, presence of hyaline cartilage with woven lamellar bone, and presence of transition area from immature osteoid to that of osteoblasts lined bony spicules.

While conventional skeletal chondrosarcoma and dedifferentiated chondrosarcoma are the closest differentials of chondroblastic osteosarcoma, fibrosarcoma/undifferentiated pleomorphic sarcoma and desmoplastic fibroma may mimic fibroblastic osteosarcoma. Among the list of differentials for morphologic variants, an aneurysmal bone cyst might be considered a close differential for telangiectatic osteosarcoma. At the same time, Ewing sarcoma/ primitive neuroectodermal tumor may resemble a small cell variant of osteogenic sarcoma. Fibrous dysplasia and desmoplastic fibroma mimic low-grade intraosseous osteosarcoma. Giant cell-rich osteosarcoma needs to be differentiated from a giant cell tumor of the bone (osteoclastoma).

Among surface osteosarcomas, low-grade parosteal osteosarcoma needs to be differentiated from osteochondroma, heterotropic ossification, and surface osteoma. Chondroblastic osteosarcoma and periosteal chondrosarcoma form the closest differentials for periosteal osteosarcoma (intermediate grade surface osteosarcoma), while reactive surface lesions need to be considered in the differential of high-grade surface osteosarcoma.

Surgical Oncology

Surgery [41][48][54][55]

Surgical resection is the treatment modality of choice. Limb salvage surgery has grown in importance over the past few decades. The goals of surgery are manifold, primarily removal of the tumor with clear microscopic margins in addition to the preservation of the functional status.

The definition of a clear margin needs to be interpreted in the context of certain developments which have allowed better scrutiny of the survival – tumors that are localized to only a part of the bone may be cleared in an intercalated fashion, avoiding resection at the articular surface and normal bone in order to obtain a better functional outcome. The choice of the operative procedure may be changed from a salvage surgery to a rotationplasty or amputation in those with a poor response to neoadjuvant chemotherapy. A wider margin of uninvolved fat would be preferred to the fascia, as the tumor is more likely to invade fat than bone.

A higher risk of local recurrence has come to be associated with local salvage when compared to amputation. However, this has not been shown to correlate with poorer overall survival.

Amputation may be preferred in cases where the achievement of disease-free margins will lead to a non-functional limb or when the patient preference is for a bioprosthesis with the potential to provide a greater degree of functionality (over the cosmetic advantages that might accompany a limb salvage.

Rotationplasty, which involves an intercalary resection of the bone followed by rotation up to 180 degrees craniocaudally with the rotated ankle serving as the knee joint, has the potential to provide excellent oncological, functional, and psychological outcomes.

Compressive osteointegration, allograft bone reconstruction, and a hybrid approach that utilizes side plates in developing an augmented cemented intramedullary fixation constitute advances with the potential to improve post-surgical rehabilitation and quality of life.

Local ablative therapies such as stereotactic radiosurgery, cryotherapy, or radiofrequency may be indicated in the management of solitary pulmonary metastasis.[56][57][58][59][5]

Radiation Oncology

Radiotherapy [41][60][61][62][48]

Radiation therapy is indicated in the management of tumors that are deemed inoperable at initial presentation, pulmonary metastases that have been proven to be resistant to chemotherapy, and palliation of spinal cord compression and bone pain.

Radiotherapy may have a role in whom complete surgical resection cannot be achieved due to the anatomical location (pelvis, vertebrae, and the base of the skull) involved or in case of patient refusal for undergoing surgery. The multimodality treatment in such cases involves chemotherapy in addition to high dose photon radiotherapy (50-70 Gray). RT may have a role in such cases and may lead to an increase in the progression-free interval.

RT has also been postulated to have a role in the management of low-grade parosteal osteosarcomas when surgery is not deemed to be feasible, although this needs to be subjected to further scrutiny through clinical trials. Hypofractionation and accelerated radiotherapy are two approaches that have been used to overcome radioresistance.

Newer RT techniques such as Proton beam radiotherapy and carbon ion beam radiotherapy should be considered in the treatment of primary unresectable tumors. Intraoperative extracorporeal irradiation, which involves primary tumor resection with limb salvage involving the removal of the affected bony segment and subjecting it to a single dose of extracorporeal irradiation (50 Gray), before re-implanting it, has shown favorable results and needs to be evaluated further.

Pertinent Studies and Ongoing Trials

European and American Osteosarcoma Study (EURAMOS) [63][64][63]

The European and American osteosarcoma study is a collaborative trial with the involvement of four study groups, who have come together with an aim to improve treatment outcomes in the study population. Patients aged less than 40 years, with or without metastasis and high-grade osteosarcoma, were enrolled in this trial and received standard chemotherapy in the form of methotrexate, doxorubicin, and cisplatin in the adjuvant setting. Good response to treatment was defined as the presence of viable tumor less than 10%.

The addition of pegylated interferon-alpha 2 b, in addition to standard chemotherapy in the good response group, was studied. The addition of pegylated interferon-alpha 2 b did not affect the disease-free survival or the overall survival.

Ifosfamide and etoposide (IE) were used in addition to the standard chemotherapy protocol in those with a poor histological response to neoadjuvant chemotherapy at resection. The addition of IE failed to demonstrate an improvement in DFS or OS. Standard therapy with the MAC regimen has been advised as the chemotherapeutic regimen of choice in high-grade osteosarcoma.

INTERGROUP 0133 Study [65][66]

The Intergroup 0133 study is a phase III randomized control trial with a two by two factorial study design, which was designed to study the effect of the addition of ifosfamide to the existing standardized chemotherapy, and assess whether the addition of mifamurtide had any impact on the survival in patients with newly diagnosed osteosarcoma. The addition of ifosfamide to the standard regimen did not lead to an improvement in EFS. The study showed that the addition of mifamurtide improved overall survival, but there was no change in EFS when added to standard chemotherapy. However, this difference is OS was later noted to be statistically insignificant.

Medical Oncology

Chemotherapy for Osteosarcoma

• Chemotherapy is the standard of care. It can be given either neoadjuvant and/or adjuvant setting. The ideal timing of chemotherapy (i.e., preoperative versus postoperative) is not clear.
  • Von Rosen was the first to introduce the concept of neoadjuvant chemotherapy in the management of osteosarcoma.[9][67] The objective was to provide ample time for the development of customized prostheses and reduction in the tumor load.
    • Besides, the advantages of neoadjuvant chemotherapy include an improvement in the quality of life brought about the amelioration of symptoms, treatment of micrometastatic disease, to increase chances of complete resection, and assessment of response to chemotherapy (degree of necrosis).[68][69] The extent of the response to neoadjuvant chemotherapy has been used to predict survival.[70] Neoadjuvant chemotherapy has increased the proportion of patients qualifying for limb-salvage surgery; however, chemotherapy should not be considered a substitute for adequate surgery.
  • In those who receive neoadjuvant chemotherapy, if the tumor at the surgery has ≥ 10% residual cancer, a change in the chemotherapeutic regimen might be beneficial (MD Anderson approach).[71] Although this is a debatable area.

• Regimens for nonmetastatic, resectable disease:
  • The standard of care is
    • Cisplatin and doxorubicin,
    • MAP (high-dose methotrexate (HD-MTX), doxorubicin, and cisplatin), or
    • MAP + Ifosfamide per the AOST 0331 (EURAMOS-1) trial[63][67]
      • Three and four-drug combinations are preferred for young patients (<40 years old), with good performance status
      • 10 weeks of neoadjuvant chemotherapy
      • 19 weeks of adjuvant chemotherapy (starting one week postoperatively)
      • Caution should be exercised with high-dose methotrexate in adults. 
  • For those intolerant to HD-MTX, 
    • Carboplatin, ifosfamide, and doxorubicin is a reasonable approach. However, this has a higher risk of secondary malignancies.

• Regimens for relapsed/refractory disease:
  • Etoposide plus ifosfamide is the most commonly used second-line regimen.
  • Other options include[47][72][73][48][74][75][76]
    • regorafenib,
    • high dose ifosfamide ± etoposide,
    • sorafenib (alone or in combination with everolimus),
    • cyclophosphamide and topotecan,
    • docetaxel and gemcitabine, or
    • gemcitabine alone.
  • The following combinatorial regimens may be considered useful in specific circumstances - cyclophosphamide and etoposide; ifosfamide, carboplatin, and etoposide; HD-MTX, etoposide, and ifosfamide.[48][77][73]
  • Samarium 153 – ethylene diamine tetramethylene diphosphonate is indicated in the management of relapsed or refractory disease after progression on second-line therapy.[78]

• Regimens for metastatic disease at diagnosis: 
  • If not a candidate for surgery, there is no consensus. Common options include
    • AOST 0331 protocol (HDMTX, doxorubicin, and cisplatin), or
    • AOST 06P1 protocol (HDMTX plus doxorubicin, cisplatin, ifosfamide, and etoposide)
  • Other treatment approaches that have been evaluated in the metastatic setting - concomitant use of HD-MTX and ifosfamide; etoposide and ifosfamide in the maximum tolerated doses along with the use of haematopoetic stem cell factors; carboplatin and etoposide; gemcitabine and docetaxel, and use of liposomal and aerosolized preparations.[79][41][48][80][48]

Radiopharmaceuticals

Intratumoral heterogeneity limits the use of radiopharmaceuticals such as 153-Sm-EDTMP and 153-Sm-DOTA. Radium 223, in combination with chemotherapeutic approaches, may be used.[81] Combinatorial approaches are being evaluated in ongoing trials (NCT 03478462)

Immunotherapy

A higher percentage of CD 8 positive T lymphocytes within the tumor has been shown to correlate positively with the prognosis. A higher degree of genomic instability and PD-L1 expression also point towards the possibility of heightened sensitivity to immune checkpoint blockade. Multiple cell-surface proteins have also been exploited as possible targets of treatment. 

Three specific approaches involving targeted antibodies have been suggested – monoclonal antibodies targeting cell surface proteins, bispecific T cell engagers, and antibodies coupled cytotoxic agents.[82]

Monoclonal antibodies that have been explored for exploring a potentially beneficial role include trastuzumab against HER 2, cixutumumab, which targets insulin-like growth factor 1, and the monoclonal antibody against glycoprotein nonmetastatic B - glembatumumab vedotin. Monoclonal antibodies targeting disialoganglioside GM 2 (found in both primary and recurrent tumors) alone or in combination with other immunoadjuvants such as sargramostim or interleukin two have also been used.

Other immunotherapy approaches include dendritic cell vaccines in combination with chemotherapeutic agents such as decitabine (to upregulate antigen expression) and gemcitabine (to increase cytotoxicity directed against tumor cells and decrease myeloid stem cells). A trial combining the first viral oncolytic therapy T-Vec (Talimogene laherparepvec) along with PD 1 blockade in the management of sarcomas is underway.

While Chimeric antigen receptor T cells Insulin-like growth factor 1 receptor and tyrosine kinase-like orphan receptor one have demonstrated prolongation of survival in preclinical studies, CART cells targeting HER-2 are being studied in the adult osteosarcoma population. Future adoptive therapies involving the use of gamma delta T cells, unmodified CD 8 T cells, and T cells engineered with high-affinity receptors are in the pipeline.  A pediatric phase II trial of ipilimumab in the pediatric age group demonstrated a similar toxicity profile along with an increase in activated CD 8 lymphocytes. The absence of absolute anti-tumor responses has not deterred the exploration of various combination immunotherapy approaches directed against CTLA – 4, PD -1, and PD – L1.   

Strategies that target the tumor microenvironment have also been developed for use in the clinical trial setting.

Bone Targeted Therapies 

Osteosarcomas are unique in that bone-targeted therapies such as bisphosphonates and anti RANK ligand monoclonal antibody (denosumab) have been evaluated in trials, which were aimed at re-positioning these approaches, which are otherwise supportive, as curative.  The use of bisphosphonates in osteosarcomas is only recommended in the setting of a clinical trial after a recent study evaluating the role of zoledronic acid in combination with chemotherapy failed to demonstrate an improvement in the overall survival, relapse-free survival, or the histological response.[83][84]

Staging

The two staging systems used in the classification of osteosarcomas include

• Enneking system, and
• TNM system - proposed by the American Joint Committee of Cancer (AJCC)/International Union against Cancer.

While the TNM staging is based upon the size, nodal involvement, and metastatic extent of the tumor, the Enneking system uses the histological grade and extent in relation to the histological compartment. The histological grade is divided into low and high grade. The anatomical compartmentalization of the tumor may be intra-compartmental or extra-compartmental.[41][48]

Prognosis

Prior to the advent of chemotherapy, the 5-year overall survival rate was between 10% to 20% only[46]. While the five-year survival of localized extremity osteosarcomas approaches 70%, pelvic osteosarcomas have a relatively poorer prognosis with a five-year survival of 30%.[17] The failure to obtain a positive margin (intralesional resections), lack of response to neoadjuvant chemotherapy (denoted by the poorer percentage of necrosis), and pathological fracture are associated with a poor prognosis (with higher rates of local recurrence).[85]

The presence of metastatic disease at presentation has the worst impact on prognosis, with overall survival ranging between 20 to 30%.[86] Bone metastases and non-pulmonary metastases fare poorer than those with only pulmonary involvement.[87]

Male sex, non-caucasian race, elevated ALP, and LDH levels have also been associated with a poor prognosis.[88] Osteosarcomas arising in diseased bones such as those with Paget’s disease and irradiated bone have also been shown to be associated with a poorer prognosis.[89][90]

The histological subtype of the tumor, which may also prove to be crucial in determining the response to treatment may also be a determinant of prognosis.[26] It has been shown that telangiectatic and fibroblastic tumors have a better prognosis (and a better response to chemotherapy) as compared to chondroblastic and osteoblastic subtypes.[26]

Craniofacial osteosarcomas are usually low-grade tumors and have been considered to have a favorable prognosis when compared to extremity osteosarcomas.[91] Radiotherapy related craniofacial osteosarcomas are generally considered to be more aggressive than primary craniofacial osteosarcomas.[92]

Naples prognostic score that includes four parameters namely serum albumin level, serum cholesterol, neutrophil to lymphocyte ratio, and monocyte to lymphocyte ratio, has also been proposed for preoperative prognostication and has been shown to correlate with Enneking stage, presence of pathological fracture, local recurrence, and presence of metastasis.[93] A preoperative prognostic model that uses ESR and CRP has also been proposed.[94]

Complications

Pathological Fracture [95][96][97][98][99]

Treatment may include a conservative or surgical approach. Structurally significant bone destruction, a sudden change in character and intensity of pain, presence of incident pain, uncertainty about the degree of destruction, presence of solitary bone metastasis to exclude a different primary tumor are considered indications which should invite a discussion at a site-specific interdisciplinary disease management group.

Referral to an orthopedic surgeon is indicated when prophylactic fixation is indicated, risk of impending pathological fracture is high (Mirel's score greater than equal to 8 or presence of features which have been included in Harrington's classic criteria), reconstruction or stabilization following a pathological fracture or stabilization of spinal cord instability (in vertebral fractures/metastatic spinal cord compression) is required.

The following criteria have been included in the Harrington's criteria to determine the risk of a pathological fracture in the proximal femur,

• Destruction of 50% of the circumference of the cortical bone,
• persistent pain on weight-bearing despite appropriate local irradiation,
• proximal femoral lesions in excess of 2.5 cm in size, and
• proximal femoral lesions with avulsion of the greater trochanter. 

An interventional radiology review for radiofrequency ablation of metastatic bone disease may be indicated. Percutaneous kyphoplasty and cement vertebroplasty are minimally invasive approaches that may be indicated in cases of painful vertebral fractures.

Secondary Malignancies

The development of secondary malignant neoplasms has been seen to have increased in incidence, by a factor of 2.5% to 4% in those who receive chemotherapy. While, haematolymphoid malignancies are the most commonly observed secondary neoplasms, breast cancer, thyroid cancer, soft tissue tumors have also been observed to occur with an increased incidence in this patient population.[100][101]

Pearls and Other Issues

Areas for Future Research[102][103]

Reasons behind the preferential spread of osteosarcoma to the bone, as well as the mechanisms underlying manipulation of the tumor stroma, need to be studied further. The mechanism underlying intertumoral and intratumoral heterogeneity also needs to be evaluated, with an emphasis on identifying actionable targets. While multiple studies are in the process of evaluating the role of receptor tyrosine kinase inhibitors, their role in combination with other strategies needs to be evaluated further.

Improved modes of delivery of chemotherapy, such as aerosolized cisplatin, are also being evaluated for the management of pulmonary metastases.

Novel formulations such as liposomal, lipoproteins, and microspheres may be especially effective in overcoming drug resistance and ameliorating the toxic effects of high-dose chemotherapy on local tissues. A combination of chemotherapy with stem cell therapies is also a potential future area of study.

Enhancing Healthcare Team Outcomes

While the 5-year survival was close to 20% in the early 1970s, it has increased to 67% with the advent of combination chemotherapy and limb-salvage surgery.[104] NCCN recommends enrollment in a clinical trial, when available. Discussion in a multidisciplinary disease management group with expertise in sarcoma should be initiated as soon as the diagnosis has been made.[105] 

Discussion about the chosen modality of surgery should involve a core multidisciplinary team consisting of specialists from medical oncology, surgical oncology, radiation oncology, radiology. interventional radiology and nursing.[106] Specialists from nuclear medicine, oncology pharmacy, psychology, and palliative medicine form a part of the extended multidisciplinary team.

The tumor board discussion might involve a recapitulation of certain important points that might prove to be invaluable in deciding the type of resection – Tumor size and extent of involvement of adjacent tissues, response to neoadjuvant therapies, and personal preferences of the patient and their family members. There should be an emphasis on the challenges that are expected to follow reconstruction strategies following curative resection involving growing bones.[41] 

Effective symptom directed treatment, efficient communication, good end of life care, discontinuation of life-sustaining treatment in the event of physiological futility, and provision of palliative sedation for refractory symptoms are seminal interventions to be considered within the purview of specialist palliative medicine.