Margins should be at least wide, according to Enneking's definition [ Table 3 ],[ 32 ] meaning that the tumor, including the biopsy scar, has to be removed surrounded by an inviolate cuff of healthy tissue. Advances in imaging techniques, and in biomedical engineering, as well as the positive effects of preoperative chemotherapy have led to a major shift away from amputation toward limb salvage surgery. Rotationplasty, another well-established biological reconstruction method for tumors around the knee, can result in functional and psychological outcomes equal or even superior to endoprosthetic reconstruction[ 32 ] but is cosmetically challenging.
Surgery of sarcomas of the axial skeleton remains particularly challenging, both because local recurrence poses a great hazard and because complications after reconstruction are frequent. It is essential that surgeons should aware of all surgical techniques and implement the most appropriate one for each patient after consultation within the multidisciplinary OS team. More recent advances include total en bloc spondylectomy for vertebral tumors and hip transposition for pelvic sarcomas.
Extracorporeal irradiation ECI consists of en bloc removal of the tumor-bearing bone part, exclusion of the tumor from the bone, irradiation, and finally reimplantation back in the body. ECI can effectively prevent the growth of discrepancy frequently observed in prosthetic replacement by evading resection of the normal growth plate and interstitial bone growth from surrounding healthy bones.
The method is best suitable for an intercalary long bone defect with allograft supplementation as well as for proximal humeral osteoarticular reconstruction. OS was long considered a radioresistant tumor; thus, the experience with radiotherapy in the local treatment of OSs is limited. Retrospective studies suggest that it may be helpful in some cases, including in those with close or positive surgical margins[ 13 ] or in the palliative setting.
High doses, including those up to 80 Gy, are thought to be required to achieve some tumor kill. Localized proton beam therapy may be useful to achieve high tumor doses and spare normal surrounding tissue for unresectable lesions.
The bone-seeking isotope, samariumEDTMP, may be helpful for palliation of metastases positive on bone scan findings, but this treatment requires hematopoietic stem cell rescue due to its hematologic toxicity.
Successful treatment of OS requires the use of systemic chemotherapy. Early, nonrandomized trials suggested that systemic chemotherapy produced better outcomes in OS patients compared with historical controls. However, not all investigators were convinced that the better outcome resulted from the use of chemotherapy.
At that time, most trials were limited to patients without clinically detectable metastases, and the superior outcome could have been the result of the selection of a cohort of patients with better outcomes.
In addition, it could also be explained by earlier diagnosis resulting from the routine use of CT to assess for pulmonary metastasis or improvements in surgical techniques. In that study, following surgical resection, patients were randomly assigned to either observation or chemotherapy group. That particular study was raised substantial controversy as it suggested that historical controls were not valid and that randomized trials were essential.
Two subsequent randomized studies clarified this controversy. Rosen et al. It also provided the opportunity to examine the histologic response of the tumor to preoperative therapy and assess its effectiveness. A strong correlation between the degree of necrosis Huvos grade and subsequent DFS was observed,[ 48 ] which has been confirmed in a number of subsequent clinical trials. However, a prospective, Children's Oncology Group trial demonstrated no difference between treatment using immediate definitive surgery and treatment with neoadjuvant chemotherapy followed by definitive surgery.
An advance in the technology of histopathologic evaluation of the tumor necrosis rate has demonstrated to be a reliable prognostic tool. The Huvos necrosis grading system is extensively used for the assessment of chemotherapy in OS [ Table 4 ].
On the basis of the percentage of tumor necrosis after chemotherapy, patients can be classified as a poor responder or good responder, which is an important parameter to predict long-term prognosis.
Investigators at Memorial Sloan Kettering Cancer Center, using the T protocol, reported an improved outcome for patients with poor histologic responses following a change in postoperative therapy. However, the majority of these studies have not been able to reproduce the initial results reported by Rosen et al. For example, the role of high-dose methotrexate remains controversial, with a few randomized studies reporting it not to be an important component of therapy, while others reported that it was.
However, in spite of these pitfalls, the standard chemotherapy for the European Osteosarcoma Intergroup EOI has continued to be the two-drug combination of cisplatin and doxorubicin,[ 52 ] since there was no survival advantage to the use of more complex regimens observed in their studies. In addition, although the use of bleomycin, cyclophosphamide, and actinomycin-D was common in OS, subsequent studies have demonstrated the combination to be ineffective,[ 52 ] and these drugs are no longer included in the treatment of OS.
Intra-arterial administration of chemotherapy offers the theoretical advantage of maximizing drug delivery to the tumor vasculature,[ 53 ] and pharmacokinetic studies demonstrate high local drug concentrations with dramatic clinical responses. Ifosfamide has, relatively recently, been shown to have activity in OS,[ 54 ] and when incorporated either alone or in combination with etoposide into the treatment of patients with metastatic disease, the results appear promising.
MTP, a component of the bacillus Calmette-Guerin cell wall, is conjugated to PE and encapsulated in liposomes to improve delivery to the reticuloendothelial system. The rationale supporting the use of this immune adjuvant was the encouraging results obtained in a prospective randomized trial of this compound in canines as well as its apparent efficacy in relapsed patients. However, there appeared to be an interaction between ifosfamide and MTP-PE, and further investigations, which attempt to exploit this interaction, are ongoing.
Parallel to the North American developments in OS, the EOI conducted a series of studies based on six cycles of the two-drug regimen of cisplatin and doxorubicin. The event-free survival time for patients treated by COSS investigators was superior when ifosfamide was incorporated into the standard three-drug regimen, and a previous nonrandomized Italian trial reported that the addition of ifosfamide and etoposide to standard chemotherapy for patients with poor histologic responses resulted in an outcome for those patients that was similar to that reported for patients with good histologic responses.
In addition, although the INT trial concluded that the addition of ifosfamide did not improve outcome, this drug was administered at a lower dose than the one administered to patients with metastatic OS, and studies in those patients suggested the presence of a dose-dependent effect. Taken together, these findings suggest that the combination of ifosfamide and etoposide has significant activity and might improve the outcome for patients with poor histologic responses. Although a few studies have evaluated the role of altering postoperative therapy in poor histologic responders, the role of high-dose ifosfamide and etoposide in this setting has not been investigated in a large controlled trial.
The North American Children's Oncology Group COG has recently completed a series of three pilot studies using a backbone of cisplatin, doxorubicin, and high-dose methotrexate. The purpose of these pilots was to develop a chemotherapy regimen that could subsequently be tested in a randomized study. The pilots evaluated three different strategies. Pilot 1 was based on the premise that doxorubicin is an essential component of OS therapy,[ 56 ] and its use has been limited by the potential for cardiotoxicity.
This complication appears to be at least partially ameliorated with dexrazoxane. Hence, pilot 1 evaluated the feasibility of increasing doxorubicin dose intensity by administering dexrazoxane. Pilot 2 evaluated the feasibility of combining standard-dose ifosfamide with dose-intensive doxorubicin with dexrazoxane and pilot 3 evaluated the feasibility of increasing the dose intensity of ifosfamide and etoposide. It appears that we have reached the limit in the survival of OS patients achievable with currently available chemotherapy.
Since further improvements in outcome will depend on refinements of therapy, the impact of which will be assessable only in large patient groups, four major research groups in OS, COG, COSS, EOI, and SSG, have agreed on trying to conduct an intergroup randomized study.
The power of such collaboration lies in the ability to conduct large trials with rapid accrual, allowing investigation of new agents quickly and effectively. Acknowledging the difficulties that face the establishment of such collaboration and recognizing that there are no available new agents, the group has agreed on a relatively simple randomized study to determine whether ifosfamide and etoposide improve the outcome for patients with poor histologic responses.
Although adjuvant chemotherapy is effective in the setting of localized OS, the outcome for patients with clinically detectable metastases at diagnosis continues to be suboptimal. Unfortunately, the use of multiagent treatment for OS is associated with acute and long-term toxicities.
These include the potential for hearing loss and hypomagnesemia[ 59 ] associated with the administration of cisplatin. Therefore, it is essential to obtain baseline audiograms before initiation of treatment to monitor for hearing loss. It is also important to monitor electrolytes secondary to the potential for abnormalities even years after treatment completion.
Other treatment-related complications include anthracycline-induced cardiomyopathy,[ 60 ] which is typically observed with high cumulative doses.
Cardiac function is usually followed closely during treatment. Since doxorubicin appears to be an important component of therapy, methods to minimize the potential for this complication are under evaluation. These include the use of dexrazoxane, continuous-infusion doxorubicin, and pegylated liposomal doxorubicin. In addition, postpubertal males should be given the opportunity to carry out sperm banking since chemotherapy for OS has the potential to produce sterility. Although newer techniques for maintaining fertility in women are under development, their indications are not well established.
Patients with the periosteal type of OS have a more favorable outcome. The prognosis for patients with conventional high-grade OS primarily depends on whether metastases are detectable at diagnosis.
For patients with the initially localized disease, the prognosis depends mainly on 2 variables: Resectability and the response to chemotherapy. Those who have the completely resectable disease and those whose tumors have an excellent histologic response to neoadjuvant chemotherapy have the best likelihood for a cure. The fact that most relapses occurred at metastatic sites primarily the lung attests to the fact that most patients have the undetectable metastatic disease at diagnosis i.
With the introduction of postoperative adjuvant chemotherapy, survival rates began to improve. In a small dataset of patients younger than 5 years, the outcome appeared to be similar to that of older patients[ 4 ]. Of interest in this group were the incidence of second malignancy 5. The cohort includes a larger number of patients with amputations than would be seen in recently treated patients[ 60 ].
Improving the survival rate and functional outcome and minimizing the short- and long-term adverse effects remain goals of clinical trials for OS. Strategies currently under consideration include dose intensification e. High-dose administration of the bone-seeking radioisotope samarium is also under investigation with autologous stem-cell support for safety and efficacy in metastatic or nonresectable OS limited to bone. Finally, the role of the emerging field of oncolytic viruses for the treatment of OS is currently being explored ClinicalTrials.
The major goals of cancer biology studies are to identify prognostic factors and therapeutic targets. Gene and protein expression array data may soon provide customized information on tumor prognosis and metastatic potential as well as indications of possible tumor targets for selective therapy.
Increasing the understanding of the basic biology of OS has been a high priority in recent years. Since therapy intensification after a poor histologic response has not generally resulted in improved outcome and the prognostic factors available are limited, efforts are directed at identifying biological factors that predict the outcome.
Examples include studies of P-glycoprotein expression, DNA ploidy, human epidermal growth factor receptor 2 overexpression, cDNA expression profiling, and comparative genomic hybridization. Many molecular markers are also currently under study, but sufficient data have not yet been accrued to allow any to be recommended as prognostic factors.
Another area of active research has been the use of radiographic studies as predictors of chemotherapy response at surgical resection. Although several methods have been tested, none thus far have been sufficiently sensitive or reliable. Assessments by conventional radiographs, CT, and MRI show definite changes in response to presurgical chemotherapy, but the changes do not correlate reliably with histologic response.
Various studies suggest that three-phase bone scans and thallium scintigraphy may predict a histologic tumor response. Dynamic MRI and positron emission spectroscopy are also promising. Ultimately, if radiographic studies are effective at determining the degree of necrosis at surgical resection, serial evaluation of tumor response could be performed, and these radiographic studies could then serve as a prognostic factor or a determinant of therapeutic efficacy.
Recently, antiangiogenic therapy becomes a highly promising therapeutic approach for the treatment of cancer. Vascular endothelial growth factor VEGF and fibroblast growth factor have been recognized as the two most potent positive regulators of angiogenesis. More than forty antiangiogenic agents are being tested in cancer patients in clinical trials worldwide. It has activity in pediatric malignancies, but large multicenter trials are needed to assess the effect of the drug in childhood malignancies.
The ongoing clinical trial of bevacizumab includes evaluation against OS and malignant fibrous histiocytoma of bone. FDA approved both agents for the treatment of advanced renal cell carcinoma in adults. There is a clear need for newer effective agents for patients with OS, especially for patients who present with metastatic disease or develop disease recurrence.
Those patients are candidates for participation in clinical trials of novel agents. Monoclonal antibodies directed against OS may prove useful as treatment, either for drug delivery or as radiopharmaceuticals. Trastuzumab, which targets the epidermal growth factor receptor 2, is currently under investigation in OS.
Monoclonal antibodies specific for the ganglioside GD2, a cell surface antigen expressed by human neuroblastomas, also recognize human OSs and could be considered for therapy. Insulin-like growth factor has been found to be expressed on OS cells, suggesting growth hormone antagonists may be an effective treatment.
Bone-seeking isotopes such as samarium may allow the delivery of extremely high doses of local irradiation, perhaps providing an appropriate treatment approach for sites of mineralized disease. Investigation of new agents such as trimetrexate and imatinib is also an active area of research in OS. For patients presenting with localized OS, increasing the dose intensity may increase the efficacy of currently available agents.
Author would like to acknowledge Mr. Amit Pawar, and Dr. National Center for Biotechnology Information , U. Indian J Med Paediatr Oncol. Author information Copyright and License information Disclaimer.
Address for correspondence: Dr. E-mail: moc. This article has been cited by other articles in PMC. Abstract Osteosarcoma OS , the most common type of primary malignant bone tumor, is defined by the presence of malignant mesenchymal cells producing osteoid or immature bone.
Keywords: Bone tumor , childhood malignancy , musculoskeletal tumor , osteosarcoma , radioresistance. Introduction Malignant tumors that arise in tissues such as the bones, cartilage, and muscle are called sarcoma. Epidemiology In general, bone tumors in children are rare, with an estimated 8. Open in a separate window.
Pathology In most patients, the etiology of OS remains obscure. Figure 1. Clinical Features Most patients with OS present with pain and swelling in the involved region and usually seek medical attention following trauma or vigorous physical exercise, both of which are common in this population.
Management Surgery The goal of OS surgery must always be complete tumor removal. Table 3 Enneking's criteria for surgical margins in musculoskeletal tumors.
Radiotherapy OS was long considered a radioresistant tumor; thus, the experience with radiotherapy in the local treatment of OSs is limited. Chemotherapy Successful treatment of OS requires the use of systemic chemotherapy. Table 4 Huvos necrosis grading system. Therapy-related sequelae Unfortunately, the use of multiagent treatment for OS is associated with acute and long-term toxicities.
Prognosis Patients with the periosteal type of OS have a more favorable outcome. The cohort includes a larger number of patients with amputations than would be seen in recently treated patients[ 60 ] Improving the survival rate and functional outcome and minimizing the short- and long-term adverse effects remain goals of clinical trials for OS The major challenge is curing patients with the unresectable metastatic disease Strategies currently under consideration include dose intensification e.
Future directions The major goals of cancer biology studies are to identify prognostic factors and therapeutic targets. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgments Acknowledgement Author would like to acknowledge Mr.
References 1. Link MP, Eilber F. Paediatric oncology: Osteosarcoma. Principles and Practice of Paediatric Oncology. Philadelphia, PA: Lippincott; Cancer in Children: Clinical Management. New York: Oxford University Press; Carrle D, Bielack SS. Current strategies of chemotherapy in osteosarcoma. Int Orthop. Osteosarcoma incidence and survival rates from to Data from the surveillance, epidemiology, and end results program. Epidemiology of childhood cancer in India.
Indian J Cancer. Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2. J Pathol. Gorlick R. Current concepts on the molecular biology of osteosarcoma. Cancer Treat Res. Clinical utility of biochemical bone turnover markers in children and adolescents with osteosarcoma.
Adv Med Sci. Weber, MD , and Alexandre Arkader, MD , nationally renowned surgeons who specialize in treating bone and soft tissues tumors, limb-sparing surgery and reconstructive surgery. Treatment for osteosarcoma always involves chemotherapy. Chemotherapy refers to medicines that help fight cancer.
This medicine may be given before surgery, after surgery, or at both times. This helps target the primary tumor, as well as any cancer cells that may have already spread but not yet been detected. In most cases, chemotherapy is given to your child through an implantable venous port in his chest. This port remains in place for the duration of therapy and helps your child avoid multiple needle sticks. To remove a cancerous tumor above his knee, Liam had a unique surgical procedure.
About 90 percent of children with osteosarcoma can be treated with limb-sparing also known as limb-salvage and reconstructive surgery.
CHOP surgeons regularly perform these complex surgeries and are constantly working to improve outcomes for children with the most difficult-to-treat tumors. Limb-sparing surgery is performed under general anesthesia. It involves cutting out the tumor and a margin of healthy tissue surrounding it. In about 10 percent of cases — because of the size or location of the tumor — osteosarcoma cannot be removed with limb-sparing surgery.
In these rare situations, two surgical options exist:. After surgery for osteosarcoma, your child should expect to stay two to five days in the Hospital. Though surgery for malignant tumors is highly effective, we understand that any surgery can be a stressful experience for children and families.
At CHOP, we offer a wealth of resources about how to prepare your child for surgery and what to expect during surgery. For more details about safety protocols at Children's Hospital of Philadelphia, see safety in surgery.
In rare situations, radiation therapy may be an option to treat osteosarcoma. Radiation therapy uses high-energy waves such as X-rays to kill or shrink cancer cells. We offer pediatric proton therapy in collaboration with Penn Medicine. Proton therapy is an innovative form of radiation treatment that is only available at select hospitals across the nation.
The greatest benefit of proton therapy is that it delivers most of its energy to a very narrow field at the location of the tumor — making it less damaging to the surrounding healthy tissue. If surgery was performed, your child will be examined by the surgeon about 1 to 2 weeks after surgery, then again at three and six months post-surgery. If your child had reconstructive surgery, she may require long-term follow-up care to monitor the joint replacement, allograft or fibular grafting.
Children who had a limb amputation or rotationplasty will need to be fitted with a prosthetic and routine adjustments as they grow. Regular monitoring by trained clinicians is strongly encouraged to monitor for possible recurrence of the growth and manage any side effects of treatment.
Our team is committed to partnering with parents and referring physicians to provide the most current, comprehensive and specialized care possible for your child. If your child needs continued monitoring into adulthood, she can continue to see some of the same doctors who treated her.
For families who live farther away and need continued monitoring, our clinical professionals will help your child transition to adult care near home. Children's Hospital of Philadelphia has an excellent track record of treating children diagnosed with bone cancers like osteosarcoma. As with any cancer, prognosis and long-term survival can vary greatly from child to child, however. Prompt medical attention and aggressive therapy are important for the best prognosis.
Our referral nurse navigator can give your family timely access to world-renowned pediatric orthopaedic surgeons in every specialty. Osteosarcoma Bone Cancer in Children. Contact Us.
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