Osteosarcoma Treatment & Management
- Author: Charles T Mehlman, DO, MPH; Chief Editor: Harris Gellman, MD more...
Before the use of chemotherapy (which began in the 1970s), osteosarcoma was treated primarily with surgical resection (usually amputation). 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.
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 Bactrim, 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. 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. 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.
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.
Restrictions on activity vary with the location of the tumor and the type of surgical procedure required for treatment.
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).
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.
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; see the images below)
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).
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). The thickness of the margin is important only for the marrow, where an adequate margin is thought to be 5-7 cm from the edge of an abnormality depicted on magnetic resonance imaging (MRI) or bone scanning.
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.
If possible, a number of options exist for limb-salvage reconstruction, which must be chosen on the basis of individual considerations, as follows:
Autologous bone graft
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.
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, 29] 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.
Further cycles of chemotherapy generally necessitate inpatient admission for administration and monitoring. Active drugs include methotrexate, cisplatin, doxorubicin, and ifosfamide. 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 intravenous (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 also performed at this time.
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.
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 year; every 6 months for the second and, perhaps, third year; 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.
Hearing loss is an adverse effect of cisplatin. Fever and neutropenia may occur, and if they do, patient admission is required for 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.
Outcome and Prognosis
The present understanding of outcome and prognosis for osteosarcoma is driven by certain serum markers, clinical staging, and histologic response to chemotherapeutic agents.
The overall 5-year survival rate for patients diagnosed between 1974 and 1994 was 63% (59% for males, 70% for females). 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. 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. 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.
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. 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.
Future and Controversies
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. Multidrug-resistant varieties of osteosarcoma are a case in point. 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.
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