Osteosarcoma

Osteosarcoma is a bone tumor and can occur in any bone, usually in the extremities of long bones near metaphyseal growth plates. The most common sites are as follows:

• Femur (42%, 75% of which are in the distal femur)
• Tibia (19%, 80% of which are in the proximal tibia)
• Humerus (10%, 90% of which are in the proximal humerus)
• Skull and jaw (8%)
• Pelvis (8%)

A number of variants of osteosarcoma exist, including conventional types (osteoblastic, chondroblastic, and fibroblastic), telangiectatic, multifocal, parosteal, and periosteal. This article only addresses conventional osteosarcoma (often referred to simply as osteosarcoma).

The exact cause of osteosarcoma is unknown. However, a number of risk factors have been identified.[3, 4, 7, 8, 9, 10, 11, 12, 13, 14]

Rapid bone growth appears to predispose persons to osteosarcoma, as suggested by the increased incidence during the adolescent growth spurt, the high incidence among large-breed dogs (eg, Great Dane, St Bernard, German shepherd), and osteosarcoma's typical location in the metaphyseal area adjacent to the growth plate (physis) of long bones.

Genetic predisposition plays a role. Bone dysplasias, including Paget disease, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses and retinoblastoma (germline form) are risk factors. The combination of constitutional mutation of the RB gene (germline retinoblastoma) and radiation therapy is linked with a particularly high risk of developing osteosarcoma, Li-Fraumeni syndrome (germline p53 mutation), and Rothmund-Thomson syndrome (autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, and cataracts).

The only known environmental risk factor is exposure to radiation. Radiation-induced osteosarcoma is a form of secondary osteosarcoma and is not discussed further in this article.

In the United States, the incidence of osteosarcoma has been cited at 3.1 per million (4.4 per million population < 25 years).[15]  The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Pediatric Monograph 1973-2004 found the incidence to be slightly higher in Blacks than in Whites, as follows[15] :

• Blacks – 3.4 cases per million per year (5.0 per million < 25 years)
• Whites – 3.0 cases per million per year (4.2 per million < 25 years)

The incidence of osteosarcoma is slightly higher in males than in females. According to SEER data, the average male-to-female ratio is 1.22:1.[15]

Osteosarcoma is very rare in young children (0.5 cases per million per year in children < 5 years). However, the incidence increases steadily with age, rising more dramatically in adolescence in correspondence with the adolescent growth spurt, as follows[16] :

• Age 5-9 years – 2.6 (Black) or 2.1 (White) cases per million per year
• Age 10-14 years – 8.3 (Black) or 7 (White) cases per million per year
• Age 15-19 years – 8.9 (Black) or 8.2 (White) cases per million per year

A second peak of incidence exists in individuals older than 60 years.[15]

The present understanding of outcome and prognosis for osteosarcoma is driven by certain serum markers, clinical staging, and histologic response to chemotherapeutic agents.[17]

According to SEER data for 1973-2004, the overall relative 5-year survival rates were as follows[15] :

• Age < 25 years - 61.6% (females, 65.8%; males, 58.4%)
• Age 25-59 years - 58.7% (females, 64%; males, 54.6%)
• Age 60-85+ years - 24.2% (females, 27.0%; males, 19.9%), with a drastic drop with advancing age (from ~50% for patients in their 50s to 17% for those in their middle-to-late 60s and to 10.8% for those aged 80 years or older) 

Patients with an elevated ALP at diagnosis are more likely to have pulmonary metastases. In patients without metastases, those with an elevated LDH are less likely to do well than are those with a normal LDH.

Bu et al conducted a meta-analysis of eight published studies to determine whether p16(INK4a) is a prognostic factor for patients with osteosarcoma.[18]  The meta-analysis showed that a high level of expression of p16(INK4a) was significantly associated with favorable overall survival. The investigators concluded that p16(INK4a) is an effective biomarker of survival for patients with osteosarcoma.

Ma et al conducted a study to determine the diagnostic and prognostic value of circulating miR-148a in the peripheral blood of patients with osteosarcoma.[19]  Expression of miR-148a was significantly associated with tumor size and distant metastasis. High expression of miR-148a was associated with poor overall survival and poor disease-specific survival. The investigators concluded that detection of circulating miR-148a expression in the peripheral blood is useful in identifying patients with osteosarcoma who have a poor prognosis.

A study by Zhao et al found that high expression of the oncoprotein transient receptor potential melastatin member 8 (TRPM8) was predictive of a poor prognosis in patients with osteosarcoma, in that it was associated with higher clinical stage and distant metastasis, as well as with shorter overall survival and disease-free survival.[20]  TRPM8 may prove to be a useful molecular target for therapy in osteosarcoma patients.

Clinical staging as it relates to prognosis is discussed elsewhere (see Staging).

In a retrospective study by Kim et al, the records of 331 patients with stage II osteosarcoma who had undergone surgery and chemotherapy were reviewed.[21]  The authors found that initial tumor size appears to be associated with histologic response and is an important prognostic factor in osteosarcoma. Other studies have shown that patients in whom a good histopathologic response to neoadjuvant chemotherapy has been achieved (>95% tumor cell kill or necrosis) have a better prognosis than those whose tumors do not respond as favorably.

Symptoms of osteosarcoma may be present for weeks or months (occasionally longer) before patients are diagnosed. The most common presenting symptom is pain, particularly pain with activity. Patients may be concerned that their child has a sprain, arthritis, or growing pains. Often, there is a history of trauma, but the precise role of trauma in the development of osteosarcoma is unclear.

Pathologic fractures are not particularly common. The exception is the telangiectatic type of osteosarcoma, which is more commonly associated with pathologic fractures. The pain in an extremity may result in a limp. There may or may not be a history of swelling (see the image below), depending on the size of the lesion and its location. Systemic symptoms, such as fever and night sweats, are rare.

Clinical appearance of a teenager who presented with osteosarcoma of the proximal humerus (same patient as in the following images). Note the impressive swelling throughout the deltoid region, as well as the disuse atrophy of the pectoral musculature.

Tumor spread to the lungs only rarely results in respiratory symptoms and usually indicates extensive lung involvement. Metastases to other sites are extremely rare, and therefore, other symptoms are unusual.

Physical examination findings are usually limited to the site of the primary tumor, as follows:

• Mass - A palpable mass may or may not be present; the mass may be tender and warm, though these signs are indistinguishable from osteomyelitis; increased skin vascularity over the mass may be discernible; pulsations or a bruit may be detectable
• Decreased range of motion - Involvement of a joint should be obvious on physical examination
• Lymphadenopathy - Involvement of local or regional lymph nodes is unusual
• Respiratory findings - Auscultation is usually uninformative unless the disease is extensive

Most of the laboratory studies that are obtained relate to the use of chemotherapy. It is important to assess organ function before administering chemotherapy and to monitor function after chemotherapy. Important laboratory studies include the following:

• Lactic dehydrogenase (LDH)
• Alkaline phosphatase (ALP)
• Complete blood count (CBC), including differential
• Platelet count
• Liver function tests - Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and albumin
• Electrolyte levels - Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorus
• Renal function tests - Blood urea nitrogen (BUN), creatinine
• Urinalysis

The only blood tests with prognostic significance are LDH and ALP. Patients with an elevated ALP at diagnosis are more likely to have pulmonary metastases. In patients without metastases, those with an elevated LDH are less likely to do well than are those with a normal LDH.

Plain radiography

Plain radiography in primary, posteroanterior (PA), and lateral chest views is helpful (see the image below). Plain films of the suspected lesions should be obtained in two views. No single feature on a radiograph is diagnostic. Osteosarcoma lesions can be purely osteolytic (~30% of cases), purely osteoblastic (~45% of cases), or a mixture of both.

Radiographic appearance (plain radiograph) of a proximal humeral osteosarcoma (same patient as previous image). Note the radiodense matrix of the intramedullary portion of the lesion, as well as the soft-tissue extension and aggressive periosteal reaction.

Elevation of the periosteum may appear as the characteristic Codman triangle. Codman described this entity in 1909, stating, "In many cases near the junction of the healthy bone with the tumor, there is a reactive new bone formation beneath the periosteum. At the edge of the tumor, this layer of new bone ends abruptly and gives a characteristic appearance in the skiagraph [radiograph]."[22]

Extension of the tumor through the periosteum may result in a so-called sunburst appearance (~60% of cases). An image of the entire bone and the adjacent joint should be obtained to assess for skip lesions or joint involvement. Telangiectatic osteosarcomas are often very cystic and can be mistaken for an aneurysmal bone cyst.

Bone scanning

Radionuclide bone scanning with technetium-99 (99mTc)-methylene diphosphonate (MDP/MDI) is important in evaluating for the presence of metastatic or multifocal disease (see the images below). After the bone scan, an image of abnormal areas should be obtained with computed tomography (CT) or magnetic resonance imaging (MRI).

Intense radionuclide uptake of the proximal humerus is noted on a bone scan (same patient as previous 2 images).

A comparison bone scan of the involved shoulder (right image) with the uninvolved shoulder (left image) (same patient as previous 3 images).

Computed tomography

A CT scan of the primary lesion and a CT scan of the chest (high resolution) should be obtained. CT of the primary lesion helps delineate the location and extent of the tumor and is critical for surgical planning.

CT of the chest is more sensitive than plain film radiography is for assessing pulmonary metastases. Ideally, the chest CT scan of the chest should be obtained before a biopsy is performed so as to avoid the ambiguity that can arise from postanesthesia atelectasis.

Magnetic resonance imaging

MRI of the primary lesion is the best method of assessing the extent of intramedullary disease, as well as associated soft-tissue masses and skip lesions (see the image below). This imaging modality is perhaps the single most important study for accurate surgical staging of the lesion with use of the Enneking staging system. The MRI should be of the entire bone (compartment).

Magnetic resonance image appearance (T1-weighted image) of osteosarcoma of the proximal humerus (same patient as previous 4 images). Note the dramatic tumor extension into the adjacent soft-tissue regions.

In a meta-analysis of six studies including a total of 66 patients, Kupo et al found that percent slope analysis of dynamic MRI was useful for preoperative evaluation of the response of osteosarcoma patients to neoadjuvant chemotherapy.[23]

Other modalities

Echocardiography or multiple gated acquisition (MUGA) scanning may be useful. Cardiac function should be assessed before and at various intervals after treatment with doxorubicin hydrochloride.

Audiography may be considered. Hearing loss is an adverse effect of cisplatin. It typically occurs during treatment; once treatment is completed, obtaining audiograms is not typically a part of long-term follow-up care.

Two elements are important to the histologic examination of the tumor. The first, tumor type, can be assessed on the biopsy. The second, response to treatment, can be assessed on the definitive resection following chemotherapy.

In general, the characteristic feature of osteosarcoma is the presence of osteoid in the lesion, even at sites distant from bone (eg, lung). Although osteoid formation is usually obvious, electron microscopy occasionally may be required to reveal this process. Stromal cells may be spindle-shaped and atypical, with irregularly shaped nuclei.

A number of different histologic types of osteosarcoma exist, as follows:

• The conventional type is the most common in childhood and adolescence and has been subdivided according to the predominant features of the cells (osteoblastic, chondroblastic, or fibroblastic), though the subtypes are clinically indistinguishable
• The telangiectatic type contains large, blood-filled spaces and is commonly seen in adolescence and early adulthood
• The parosteal type usually arises from the bone cortex, is commonly a low grade tumor, and can be seen in childhood or adulthood; it most commonly arises on the distal posterior aspect of the femur
• The periosteal type is a low- to intermediate-grade tumor that typically arises immediately below the periosteum in children; it most frequently involves the tibia and is more common in adults.

The purpose of staging tumors is to stratify risk groups. The conventional staging used for other solid tumors is not appropriate for skeletal tumors, because these tumors rarely involve lymph nodes or regional spread.

Instead, the staging system introduced by Enneking in 1980 is based on histologic grade (low vs high), anatomic location (intracompartmental vs extracompartmental), and presence or absence of metastases.[24, 25] This system (also referred to as the staging system of the Musculoskeletal Tumor Society [MSTS]) applies to all musculoskeletal tumors (both bone and soft tissue). It has been credited with bringing order to the surgical treatment of a group of tumors for which treatment was previously approached rather haphazardly.

The Enneking staging system is typically outlined as follows:

• Low-grade tumor, intracompartmental – IA
• Low-grade tumor, extracompartmental – IB
• High-grade tumor, intracompartmental – IIA
• High-grade tumor, extracompartmental – IIB
• Any tumor (low- or high-grade, intra- or extracompartmental) with evidence of metastasis – III

The definition of a compartment is a central and crucial concept in this staging system. In general, a compartment may be defined as any individual bone (ie, each bone is a compartment unto itself), intra-articular space (ie, a purely intra-articular lesion is intracompartmental), or clearly identified fascially enclosed space (eg, the anterior compartment of the lower leg). Many of these compartments are the same ones that a surgeon would release in the setting of compartment syndrome; these relate much more to soft-tissue tumors than to bone tumors.

The Enneking staging system considers some areas of the body to be extracompartmental by definition, including the antecubital fossa, the inguinal region, the popliteal space, and intrapelvic and paraspinal lesions. Because of the unique challenges of spinal tumors, Weinstein, Boriani, and Biagin proposed an entirely separate staging system for these areas, commonly referred to as the WBB staging system.

First introduced in 1996, the WBB system focuses on the general anatomic location about the spine (conceptualizing a spinal segment as if it were the face of a clock), as well as the specific anatomic location about the spine (eg, extraosseous soft-tissue extension into muscular areas vs intradural extraosseous extension).[26, 27] Just as spinal anatomy is complex, the WBB staging system is complex, but its use is slowly increasing.

In osteosarcoma, the foremost initial question for staging is whether the tumor has metastasized. Other tumor features, though not technically used in staging, may impact the prognosis. These include the following:

• LDH and ALP measurements
• Site of primary tumor (mostly related to ease of complete resection)
• Histologic response to chemotherapy
• Cause of the disease (patients with osteosarcomas arising from Paget disease have a particularly poor prognosis)

Patients with isolated jaw lesions tend to do better and have a lower incidence of metastases.

Different primary tumor sites are associated with differing prognoses, as follows:

• Distal extremity – Best
• Distal femur – Intermediate
• Axial skeleton – Worst

In a retrospective study by Kim et al, the records of 331 patients with stage II osteosarcoma who underwent surgery and chemotherapy were reviewed.[28] The authors found that the initial tumor size appears to be associated with histologic response and is an important prognostic factor in osteosarcoma.

Patients with tumors that have a good histologic response (the definition of which is still under debate) to preoperative chemotherapy appear to have a better prognosis, though this still is under investigation.

The National Comprehensive Cancer Network (NCCN)[29]  follows both the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) and the Surgical Staging System from the Musculoskeletal Tumor Society (MTS) for staging. The European Society for Medical Oncology (ESMO), the European Reference Network for Paediatric Cancers (PaedCan), and the European Network for Rare Adult Solid Cancer (EURACAN)[30]  do not provide a specific recommendation for which system should be followed.

Before the use of chemotherapy (which began in the 1970s), osteosarcoma was treated primarily with surgical resection (usually amputation).[31]  Despite such good local control, more than 80% of patients subsequently developed recurrent disease that typically presented as pulmonary metastases. The high recurrence rate indicates that most patients have micrometastatic disease at the time of diagnosis. Therefore, the use of adjuvant (postoperative) systemic chemotherapy is critical for the treatment of patients with osteosarcoma.[32]

The orthopedic surgeon is of paramount importance in the care of patients with osteosarcoma. Often, patients thought to have osteosarcoma are referred to the orthopedic surgeon first to make the diagnosis. Moreover, because osteosarcomas are not particularly responsive to radiotherapy, surgery is the only option for definitive tumor removal (local control).[33]

In addition, an oncologic type of total joint prosthesis or complex bone reconstruction may be required following surgical resection. Therefore, close involvement of the orthopedic surgeon with the medical oncologist at the time of diagnosis, as well as during and after chemotherapy, is critical

The two main procedures performed by orthopedic surgeons in patients with osteosarcoma are biopsy and wide resection. Neither of these procedures should be undertaken unless complete tumor staging has been completed preoperatively. Such staging would typically include (but would not be limited to) the following (see Imaging Studies):

• Plain radiography of the involved bone, including the joint above and the joint below the affected region
• Total-body bone scanning
• Magnetic resonance imaging (MRI) of the primary tumor area to include the entire bone of origin
• Computed tomography (CT) of the lungs

Because osteosarcoma is a deadly form of cancer, no absolute contraindications for treatment exist. Relative contraindications would include situations in which the patient is so frail that the risks of general anesthesia outweigh any potential benefits of surgery. Another relative contraindication would be a situation in which the patient has extensive, overwhelming metastatic disease, and the benefits of comfort or hospice care outweigh the potential benefits of surgical intervention.

The genetic roots of cancer are irrefutable, and gene-focused basic science research holds tremendous promise for risk stratification, as well as for effective and innovative treatments.[34] Multidrug-resistant varieties of osteosarcoma are a case in point.[35] These cell lines have been shown to be genetically encoded with a certain membrane-bound glycoprotein that helps render these cancer cells "immune" to many chemotherapeutic agents. Early identification of such patients (perhaps at initial biopsy) would allow a tailored approach to neoadjuvant chemotherapy.

Metastatic or locally recurrent osteosarcoma presents an especially tough treatment challenge that remains incompletely answered. Patients in such cases find themselves in a particularly poor survival bracket. Future efforts must be aimed at improving chemotherapeutic and surgical treatments that can be offered to these patients.

One potential example of this is the bone-seeking radioisotope samarium (153-samarium ethylene diamine tetramethylene phosphonate), which has the potential to selectively deliver high doses of radiation to osteosarcoma cells. The safety and efficacy of this agent are being studied in patients with metastatic and locally recurrent osteosarcoma.

Guidelines for treatment of osteosarcoma have been developed by the National Comprehensive Cancer Network (NCCN)[29] ; jointly by the European Society for Medical Oncology (ESMO), the European Reference Network for Paediatric Cancers (PaedCan), and the European Network for Rare Adult Solid Cancer (EURACAN)[30] ; and by the Sarcoma European Latin-American Network (SELNET).[36] (See Guidelines.) For further information, see Bone Sarcoma Guidelines. 

So-called neoadjuvant (preoperative) chemotherapy has been found not only to facilitate subsequent surgical removal by causing tumor shrinkage but also to provide oncologists with an important risk parameter. Patients in whom there has been a good histopathologic response to neoadjuvant chemotherapy (>95% tumor cell kill or necrosis) have a better prognosis than those whose tumors do not respond as favorably. Thus, future chemotherapy trials will incorporate adjuvant tumor cell kill to provide risk-adapted treatment regimens.

Patients receiving methotrexate should not be given folate supplementation or trimethoprim-sulfamethoxazole, both of which interfere with the effects of methotrexate. Otherwise, the patient's diet is not restricted.

Xiao et al conducted a literary review intended to shed light on the clinical outcomes of various chemotherapy regimens in the treatment of metastatic, relapsed, and refractory osteosarcoma.[37] They concluded that a chemotherapy regimen comprising both a cell cycle–specific drug and a cell cycle–nonspecific drug could increase response rates.

Xiao et al found that for three-drug regimens, adding a cell cycle–specific drug to ifosfamide-etoposide therapy may result in a better response rate than adding a cell cycle–nonspecific drug or any other two-drug regimen among those in their study.[37] For patients with metastatic, relapsed, and refractory osteosarcoma, they recommended the use of second-line chemotherapy that is based on the combined ifosfamide-etoposide regimen.

In the EURAMOS-1 trial, a randomized controlled study designed to investigate whether intensified postoperative chemotherapy for patients with newly diagnosed high-grade osteosarcoma whose tumor responded poorly to preoperative chemotherapy improved event-free survival, Marina et al compared a postoperative MAP (cisplatin, doxorubicin, methotrexate) regimen (n = 310) with a regimen in which ifosfamide and etoposide were added to MAP (MAPIE; n = 308).[38]  The primary outcome measure was event-free survival in the intent-to-treat population. 

At a median follow-up of 62.1 months, 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group), and there were 193 deaths (101 in the MAP group vs 92 in the MAPIE group).[38] Event-free survival did not differ between treatment groups. The most common grade 3-4 adverse events were neutropenia, thrombocytopenia, and febrile neutropenia without documented infection. MAPIE was associated with more frequent grade 4 nonhematologic toxicity than MAP was. The study results results did not support the addition of ifosfamide and etoposide to postoperative chemotherapy in this setting.

Biopsy of malignant bone lesions is not an insignificant procedure. An improperly performed biopsy can result in the amputation of an otherwise salvageable extremity. It has also been shown repeatedly that oncologic outcomes are optimized when the biopsy is performed by the same surgeon who will be responsible for the definitive tumor resection (if one is needed).[39, 40]

Biopsy procedures include the following:

• Open biopsy (preferred to avoid sampling error and to provide adequate tissue for biologic studies)
• Trephine biopsy or core-needle biopsy (preferred for vertebral bodies and many pelvic lesions)
• Fine-needle aspiration (FNA; not recommended)

Incisional biopsy and core-needle biopsy (Craig needle biopsy; see the images below) are the most common types of biopsies performed by orthopedic surgeons.[41]  Open lines of communication between the orthopedic surgeon and the pathologist are vital to help ensure that adequate tissue is obtained for diagnostic purposes.

Core needle biopsy instruments commonly used for bony specimens. Craig needle set.

Close-up view of Craig needle biopsy instruments. Cutting cannula with T-handle attached (top) and sheath through which the cutting cannula passes (bottom).

The incision for an open biopsy must be carefully planned so as to avoid tumor contamination of the neurovascular structures and to facilitate removal of the biopsy tract en bloc during definitive surgery (see the image below).

Resected specimen of a proximal tibia osteosarcoma. The primary lesion was such that the knee joint was resected with the primary lesion. Note that the previous longitudinal biopsy tract was completely excised with the specimen.

Regardless of the technique employed, a frozen section should be examined to confirm that the tumor has been sampled accurately. If possible, extraosseous components should be sampled rather than bone to lessen the risk of fracture. Seal bone holes with Gelfoam or a similar material to decrease the risk of hematoma and tumor spread. Drains should be of the closed-suction variety, and they should be placed directly in line with the skin incision (a short distance away).

The primary aim of definitive resection is patient survival. Accordingly, margins on all sides of the tumor must contain normal tissue (wide margin). 

Wide resection is the goal for patients in whom primary tumor resection is contemplated. Simply defined, wide resection means that the entire malignant tumor has been surgically excised and that there is no remaining microscopic evidence of tumor cells at the resection margins (ie, that the margins are negative). Over the years, many authors have suggested varying and arbitrary amounts of the normal tissue cuff to remove along with the primary tumor to increase the likelihood of negative margins.

There is no universally accepted definition of the appropriate thickness of the normal cuff. Technically, a wide margin still exists even if the distance between normal tissue and tumor is onle one cell thick. Oncologically, the width achieved is less important (limb-sparing surgery vs amputation) than the achievement of a negative margin. In other words, a limb-sparing surgery without wide margins could do the patient less of a service than an amputation with wide margins. This would apply in most cases where maximal preservation of life is the primary goal.

Radical margins, defined as removal of the entire involved compartment (bone, joint to joint; muscle, origin to insertion), are usually not required for cure. A less-than-wide margin (marginal or intralesional margin) may be functionally helpful as a debulking therapy, but intrinsically, it will not be locally curative. Amputation may be the treatment of choice in some circumstances.

When limb-salvage reconstruction is possible, the following options exist, which must be chosen on the basis of individual considerations:

• Autologous bone graft
• Allograft
• Prosthesis
• Rotationplasty

Autologous bone grafts may be vascularized or nonvascularized. Rejection does not occur with these grafts, and the rate of infection is low. The growth plates of patients who are skeletally immature may limit options for stable bone fixation (osteosynthesis).

With allografts, graft healing and infection can be problematic, particularly during chemotherapy. Immunologic rejection can also occur. Allograft-prosthesis composites are also an option.

Prosthetic joint reconstruction can be solitary or expandable, though it is usually expensive. The longevity of such implants is a major concern in young children.

Rotationplasty (see the images below) is particularly suitable for patients with distal femur and proximal tibia tumors, particularly large tumors in which a high amputation is the only alternative. Lesions located in other areas of the femur or tibia may also be amenable to this treatment approach. Patients who are very young or athletic may benefit greatly from this procedure from a functional standpoint, and this procedure may also serve to minimize the number of future surgeries needed.

Intraoperative photograph of a Van Ness rotationplasty procedure. Osteosynthesis of the tibia to the residual femur is being performed. Courtesy of Alvin H. Crawford MD, FACS.

Clinical photograph taken at the conclusion of a Van Ness rotationplasty procedure (same patient as previous image). Note that the new "knee" of the operative side (left side) is purposely reconstructed distal to the normal right knee. This is in anticipation of the future growth potential of the unoperated limb. Courtesy of Alvin H. Crawford MD, FACS.

After tumor resection, vessels are usually repaired in an end-to-end fashion to optimize patency. The distal portion of the leg is rotated 180º and reattached to the thigh at the proximal edge of the resection. Other variations are also possible.[1, 28]  The rotation allows the ankle to become a functional knee joint, so the length of the leg should be adjusted to match the contralateral knee. Ideally, before rotationplasty is embarked on, patients and families should either meet or review a video recording of a patient who has had the procedure.

Metastatic lung nodules can be cured by means of complete surgical resection (most often wedge resection). Lobar resection or pneumonectomy may occasionally be required for clear margins. This procedure should be performed at the time of the primary tumor resection. Although bilateral nodules can be resected via a median sternotomy, surgical exposure is superior with a lateral thoracotomy. Therefore, bilateral thoracotomies are recommended for bilateral disease (each side separated by a few weeks).

For an osteosarcoma that recurs as one or more lung lesions only more than 1 year after the patient is off therapy, surgical resection alone can be curative; the likelihood of metastases to other sites is low. Chemotherapy is warranted if recurrence occurs earlier; in such cases, the risk of other micrometastatic disease is high.

Hearing loss is an adverse effect of cisplatin. Fever and neutropenia may occur, and if they do, patient admission is required for intravenous (IV) antibiotics and monitoring. Patients may require admission for a multitude of other medical problems during their chemotherapy treatment phase, including, but not limited to, varicella infection (for IV acyclovir and monitoring), mucositis (for narcotics), dehydration, meningitis, constipation, fungal pneumonia, and cystitis.

Restrictions on activity vary with the location of the tumor and the type of surgical procedure required for treatment.

As usual for any child with cancer, consultations should be made with an oncologist, as well as with any provider with a subspecialty related to the specific clinical circumstances. Social services, psychology, dentistry, and child life specialists are usually involved with these patients and their families throughout their treatment course.

Inpatient care

Further cycles of chemotherapy generally necessitate inpatient admission for administration and monitoring. Active drugs include methotrexate, cisplatin and doxorubicin. Patients treated with high-dose alkylating agents are at higher risk for myelodysplasia and leukemia. Therefore, a complete blood count (CBC) should be performed periodically.

Patients with fever and neutropenia should be admitted for IV antibiotic therapy and monitoring.

Admission is required perioperatively for local control (surgical resection, amputation), usually around week 10 of therapy. Resection of metastatic disease (eg, lung nodules) is typically performed at the end of therapy.

Patients may require admission for a multitude of other medical problems during their chemotherapy treatment phase, including, but not limited to, varicella infection (for IV acyclovir and monitoring), mucositis (for narcotics), dehydration, meningitis, constipation, fungal pneumonia, and cystitis.

Outpatient care

For patients on granulocyte colony-stimulating factor (G-CSF) therapy, a CBC should be performed twice weekly so that G-CSF can be discontinued when the absolute neutrophil count has reached a predetermined level (usually 1000 or 5000/μL) (see the Absolute Neutrophil Count calculator).

It is important to monitor the blood chemistries and liver function test results for patients on parenteral nutrition or who have a history of toxicity (especially if nephrotoxic or hepatotoxic antibiotics or other drugs are continued).

To monitor for recurrence, patients should continue to have blood work and radiographic scans on an outpatient basis, with the frequency decreasing over time. Generally, these visits occur every 3 months for the first 2 years; every 4 months for year 4 and every 6 months for years 4 and 5 and yearly thereafter.

When patients have been without therapy for 5 or more years, they are considered long-term survivors. These individuals should be seen annually in a late-effects clinic and monitored with appropriate studies depending on their therapy and side effects. Visits may include hormonal, psychosocial, cardiology, and neurologic evaluations.

Guidelines Contributor: Mrinal M Gounder, MD Attending Physician in Medical Oncology, Sarcoma and Developmental Therapeutics Service, Memorial Sloan-Kettering Cancer Center

Guidelines for the treatment of osteosarcoma have been published by the following organizations:

• National Comprehensive Cancer Network (NCCN) ^[29]
• European Society for Medical Oncology (ESMO), European Reference Network for Paediatric Cancers (PaedCan), and European Network for Rare Adult Solid Cancer (EURACAN) ^[30]

Treatment recommendations

The NCCN recommends that in all patients with osteosarcoma, enrollment in a clinical trial should be considered when available; in addition, whenever possible, patients should be referred to a tertiary care center with expertise in sarcoma, for treatment by a multidisciplinary team. Other guideline recommendations on treatment of osteosarcoma vary by disease stage.

Treatment recommendations for stages IA-IB (low-grade) osteosarcomas are as follows:

• Localized, low-grade osteosarcomas – The NCCN recommends wide excision alone; chemotherapy (see regimens below) prior to excision is not typically recommended but could be considered for periosteal lesions. ^[29]  ESMO-PaedCan-EURACAN recommends surgery alone for low-grade parosteal osteosarcomas and finds no benefit for chemotherapy for periosteal lesions. ^[30]
• Low-grade intramedullary and surface osteosarcoma and periosteal sarcomas with pathologic findings of high-grade disease – The NCCN recommends postoperative chemotherapy. ^[29]
• Unresectable or incompletely resected osteosarcoma –  NCCN and ESMO-PaedCan-EURACAN guidelines concur that definitive radiotherapy (RT) for local control is an option ^{[29, 30]}  for unresectable osteosarcoma. Incompletely resected osteosarcomas should be considered for RT and repeat surgery if possible.

NCCN treatment recommendations for stages IIA-IVB (high-grade) and metastatic disease include the following[29] :

• Enrollment in a clinical trial should be considered when available; in addition, whenever possible, patients should be referred to a tertiary care center with expertise in sarcoma, for treatment by a multidisciplinary team.
• Preoperative chemotherapy is recommended for all stages of high-grade disease (category 1).
• If good margins can be achieved, limb-sparing surgery is preferred for patients with good histologic response to chemotherapy; amputation may be necessary for tumors in unfavorable anatomic locations.
• Postoperative chemotherapy should continue with the preoperative regimen if there has been a good histologic response; for patients with a poor response, consider postoperative chemotherapy with a different regimen.
• Surgical re-resection with or without RT for positive margins should be performed if possible.
• For unresectable osteosarcomas following preoperative chemotherapy, consider definitive RT and chemotherapy.

ESMO-PaedCan-EURACAN guidelines recommendations for high-grade osteosarcoma include the following[30] :

• Curative treatment consists of multiagent chemotherapy and surgery.
• Chemotherapy is generally administered both before and after therapy; preoperative chemotherapy has not been shown to improve survival, but it facilitates local surgical treatment and allows assessment of histologic response.
• High-grade craniofacial osteosarcoma should be treated the same way as high-grade osteosarcoma of other sites; RT can be proposed when complete surgery is not feasible and in patients undergoing resection with positive margins.
• Heavy-particle RT and intensity-modulated RT (IMRT) can be considered, particularly for unresectable primary tumors.

NCCN treatment recommendations for metastatic disease at presentation include the following[29] :

• For resectable metastatic disease (pulmonary, visceral or skeletal), maximal chemotherapy, wide excision of primary tumor; and metastatectomy should all be considered. 
• For unresectable metastatic disease, chemotherapy should be used to control metastasis, metastatectomy should be considered if there is a good response to chemotherapy, and definitive RT should be considered for the primary site for local control.

ESMO-PaedCan-EURACAN guidelines recommend that primary metastatic osteosarcoma be treated with a curative intent, following the principles of nonmetastatic osteosarcomas.[30]

For relapsed or refractory osteosarcoma, NCCN guidelines recommend second-line chemotherapy, resection, or both. Options for disease progression after second-line therapy include the following[29] :

• Re-resection, if possible
• Clinical trial
• Palliative RT
• Second-line chemotherapy
• Best supportive treatment

ESMO-PaedCan-EURACAN guidelines advise that the treatment of recurrent osteosarcoma is primarily surgical, in the case of isolated lung metastases, though stereotactic RT, radiofrequency ablation, or cryotherapy might be alternative options in patients unfit for surgery.[30] ESMO-PaedCan-EURACAN guidelines note that there is no accepted standard regimen for second-line chemotherapy for recurrent disease, but ifosfamide with or without etoposide with or without carboplatin, or gemcitabine and docetaxel or sorafenib may be considered. RT, including samarium, may be used for palliation.

Chemotherapy regimens

ESMO-PaedCan-EURACAN guidelines note that doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide have antitumor activity in osteosarcoma.[30] In patients older than 40 years, preferred regimens often combine doxorubicin, cisplatin, and ifosfamide without high-dose methotrexate.

For first-line osteosarcoma therapy (primary/neoadjuvant/adjuvant therapy or for metastatic disease), NCCN recommendations are as follows[29] :

• Cisplatin and doxorubicin (category 1)
• MAP (high-dose methotrexate, cisplatin, and doxorubicin) (category 1)
• Doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate

For second-line therapy (relapsed/refractory or metastatic disease), NCCN recommendations are as follows[29] :

• Ifosfamide (high dose) ± etoposide
• Regorafenib (category 1)
• Sorafenib
• Sorafenib and everolimus (category 2B)
• Cyclophosphamide and topotecan
• Docetaxel and gemcitabine
• Gemcitabine

Regimens considered useful in certain circumstances are as follows:

• Cyclophosphamide and etoposide
• Ifosfamide, carboplatin, and etoposide
• High-dose methotrexate
• High-dose methotrexate, etoposide, and ifosfamide
• Samarium-153 ethylene diamine tetramethylene phosphonate (SM-EDTMP) for relapsed or refractory disease beyond second-line therapy

In 2022, the Sarcoma European Latin-American Network (SELNET) published the following clinical practice guidelines on the management of osteosarcoma.[36]

High-grade osteosarcoma

Neoadjuvant chemotherapy is recommended. The MAP regimen (doxorubicin/cisplatin/high-dose methotrexate) is most frequently used in children and young adults, whereas cisplatin plus doxorubicin is an option for patients older than 40 years.

Standard surgical therapy is wide resection (with negative margins), with limb salvage whenever possible.

Postoperative adjuvant chemotherapy, using the same drugs as in the neoadjuvant setting, should be administered for at least two further cycles.

Low-grade osteosarcoma

Wide surgical resection without systemic treatment is the standard approach. Marginal resection is acceptable in selected cases.