**4. Treatment**

Currently, the treatment of localized osteogenic sarcoma is the same, independent of subtype and despite its different behaviors and genetic profiles, and includes a plan of neoadjuvant chemotherapy, followed by local treatment with

surgical resection with a subsequent round of adjuvant chemotherapy [29]. This plan was first implemented in the 1970's and improved long-term survival rates from its original 20% to the current 70%, which has remained unchanged for the past five decades [30]. The three main reasons for treatment failure are local recurrences, distant disease spread and the development of drug resistance [31].

Systemic treatment for young patients includes two cycles of 5 weeks with high dose methotrexate, doxorubicin and cisplatin (MAP) [32]. Once the neoadjuvant cycle has finalized new imaging studies are obtained and the surgical procedure is planned. The resection piece is afterwards analyzed by the pathologist who must inform the percentage of necrosis, a key factor of prognostic significance and a proxy for the tumor chemotherapy response [33]. Following local treatment, 3 to 6 cycles of the same drug regimen (MAP) are given to the patient.

Before the implementation of chemotherapy as part of the treatment plan of these patients, even the ones with localized disease, most patients underwent a limb amputation, and despite this aggressive procedure still had poor survival rates. Nowadays, the standard of care for most patients is a limb salvage procedure which has shown similar survival rates to an amputation when systemic treatment was added with a much-improved function and quality of life [34, 35]. The main goal of limb salvage procedures is to completely resect the tumor while preserving important structures for the limb survival as well as the patient's function. Several studies have addressed the importance of achieving adequate margins in a resection as a determinant factor for the feasibility of the limb salvage option [33, 36, 37]. Local recurrences, which occur in 10–15% of these patients, has been linked to the margin adequacy as a predicting factor [38].

Once a decision has been made regarding the limb salvage procedure, several options present in terms of reconstruction alternatives, all with their specific advantages and disadvantages. Resection and reconstruction with an endoprosthetic device, a non-biologic option, is the main trend worldwide currently (**Figure 6**). While the biologic alternatives include allografts, vascularized fibula, distraction osteogenesis or recycled and sterilized bone autograft [39–43]. The latter can be achieved through several different techniques such as pasteurization, irradiation, autoclave or most recently the use of liquid nitrogen [44].

Endoprosthetic reconstructions have shown good results in terms of function at short and medium-term. Among its disadvantages it is its high cost, low accessibility in some countries and limited survival (50–76% at 10 years) with a high rate of

#### **Figure 6.**

*Distal femur osteogenic sarcoma resection and reconstruction with a distal femur endoprosthetic device non-cemented.*

**79**

**Figure 7.**

*the proximal physis to be preserved.*

*Osteosarcoma*

*DOI: http://dx.doi.org/10.5772/intechopen.96765*

reoperation specially in pediatric patients, an age where primary bone malignant tumors are most frequent [45]. Allografts require a bone bank with matching bone pieces. Furthermore, allografts have the potential to transmit diseases and, in some cases, patient acceptance may be an added obstacle [46]. Bone transport is a lengthy

*Case of a 15-year-old male with an osteoblastic osteosarcoma abutting the proximal tibial physis, treated with limb salvage surgery with liquid nitrogen pretreated bone tumor autograft. Careful surgical planning allowed* 

complex treatment with multiple surgical procedures usually involved [43].

### *Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.96765*

*Recent Advances in Bone Tumours and Osteoarthritis*

adequacy as a predicting factor [38].

autoclave or most recently the use of liquid nitrogen [44].

surgical resection with a subsequent round of adjuvant chemotherapy [29]. This plan was first implemented in the 1970's and improved long-term survival rates from its original 20% to the current 70%, which has remained unchanged for the past five decades [30]. The three main reasons for treatment failure are local recur-

Systemic treatment for young patients includes two cycles of 5 weeks with high dose methotrexate, doxorubicin and cisplatin (MAP) [32]. Once the neoadjuvant cycle has finalized new imaging studies are obtained and the surgical procedure is planned. The resection piece is afterwards analyzed by the pathologist who must inform the percentage of necrosis, a key factor of prognostic significance and a proxy for the tumor chemotherapy response [33]. Following local treatment, 3 to

Before the implementation of chemotherapy as part of the treatment plan of these patients, even the ones with localized disease, most patients underwent a limb amputation, and despite this aggressive procedure still had poor survival rates. Nowadays, the standard of care for most patients is a limb salvage procedure which has shown similar survival rates to an amputation when systemic treatment was added with a much-improved function and quality of life [34, 35]. The main goal of limb salvage procedures is to completely resect the tumor while preserving important structures for the limb survival as well as the patient's function. Several studies have addressed the importance of achieving adequate margins in a resection as a determinant factor for the feasibility of the limb salvage option [33, 36, 37]. Local recurrences, which occur in 10–15% of these patients, has been linked to the margin

Once a decision has been made regarding the limb salvage procedure, several options present in terms of reconstruction alternatives, all with their specific

advantages and disadvantages. Resection and reconstruction with an endoprosthetic device, a non-biologic option, is the main trend worldwide currently (**Figure 6**). While the biologic alternatives include allografts, vascularized fibula, distraction osteogenesis or recycled and sterilized bone autograft [39–43]. The latter can be achieved through several different techniques such as pasteurization, irradiation,

Endoprosthetic reconstructions have shown good results in terms of function at short and medium-term. Among its disadvantages it is its high cost, low accessibility in some countries and limited survival (50–76% at 10 years) with a high rate of

*Distal femur osteogenic sarcoma resection and reconstruction with a distal femur endoprosthetic device* 

rences, distant disease spread and the development of drug resistance [31].

6 cycles of the same drug regimen (MAP) are given to the patient.

**78**

**Figure 6.**

*non-cemented.*

reoperation specially in pediatric patients, an age where primary bone malignant tumors are most frequent [45]. Allografts require a bone bank with matching bone pieces. Furthermore, allografts have the potential to transmit diseases and, in some cases, patient acceptance may be an added obstacle [46]. Bone transport is a lengthy complex treatment with multiple surgical procedures usually involved [43].

#### **Figure 7.**

*Case of a 15-year-old male with an osteoblastic osteosarcoma abutting the proximal tibial physis, treated with limb salvage surgery with liquid nitrogen pretreated bone tumor autograft. Careful surgical planning allowed the proximal physis to be preserved.*

#### **Figure 8.**

*Radiographic image depicting a pathological fracture through a distal femur osteosarcoma with displacement and shortening of the distal fragment.*

Frozen autografts recycled in liquid nitrogen are a biologic solution with the advantages of low cost, easy access, complete removal of viable tumor, bone morphogenic protein preservation, osteoconduction and osteoinduction properties maintained, perfect matching at the osteotomy site, does not require a bone bank, allows reattachment of tendons and ligaments, no disease transmission and no graft rejection (**Figure 7**) [47]. Among its disadvantages, the bone piece cannot be sent for full pathology analysis and thus provide the information about the percentage of necrosis obtained after systemic treatment in the indicated cases. Nonetheless, the surrounding soft tissues which are resected prior to submerging the piece in LN are sent to pathology. This technique accomplishes full necrosis of the tumoral cells and prior studies have shown that the soft tissue resection prior to the sterilization in LN is representative of the tumor response to chemotherapy [48]. Additionally, this procedure has shown no difference in terms of bone resistance to compression when compared to unfrozen bone. This allows for the initial resistance of the reconstruction, being comparable or even superior to allografts [48].

One particular scenario, the treating orthopedic oncologist should be aware of is the case of an osteosarcoma with a pathological fracture at presentation. Fractures through an osteogenic sarcoma can occur in up to 10% of the cases (**Figure 8**) [14]. In the past, this circumstance used to be a contraindication for a limb salvage procedure and patients were indisputably recommended for an amputation. Nowadays, even though those patients tend to present a worse prognosis, a limb salvage procedure is considered an option with similar recurrence rates when compared to amputations [49]. Prior studies presented the hypothesis that these patients may have a worse outcome due to a hematoma formation at the fracture site, with tumor cell dissemination [50]. Although the ideal treatment is controversial, some authors recommend stabilization of the fracture, which could be achieved by casting, external fixation or limited internal fixation followed by neoadjuvant chemotherapy, subsequent definite surgical treatment and adjuvant systemic treatment [51, 52].

Radiotherapy has a role for unresectable tumors or in cases of positive margins to help with local control. The Cooperative Osteosarcoma Study Group (COSS) has presented promising results for the case of unresectable osteosarcomas of the spine and pelvis where the treatment with radiation with a curative intent improved the 5-year survival from 0 to 29% [53, 54]. Additional studies have shown radiation is well tolerated by the patients and can achieve up to 76% local control rates [55]. These findings seem to indicate osteosarcomas do have at least a moderate response

**81**

**Author details**

Gottardo Bianchi1

Uruguay

and Ana C. Belzarena2

, Leticia Gaiero1

\*Address all correspondence to: ceciliabel@baptisthealth.net

\*

Florida, Miami, Florida, United States

provided the original work is properly cited.

, Nicolas Casales1

The authors state no conflict of interest related to the writing of this chapter.

1 Oncology Orthopedic Department, University of the Republic, Montevideo,

2 Oncology Orthopedic Service, Miami Cancer Institute, Baptist Health South

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Claudio Silveri1

*Osteosarcoma*

*DOI: http://dx.doi.org/10.5772/intechopen.96765*

case of unresectable tumors [56].

multicentre trials [58].

suffering from this cancer.

**Conflict of interest**

**5. Conclusion**

to radiotherapy, when in the past it used to be considered a radiotherapy resistant tumor. Supplementary indications for radiotherapy include symptom palliation and this treatment modality has shown to improve patients' symptoms such as pain in

Current investigation trials are in place to uncover targetable mutations that could also have prognostic implications as well studies to assess a potential role for immunotherapy in osteosarcoma patients [57]. Specifically, Cabozantinib, a tyrosine kinase inhibitor used for thyroid and renal cell cancers, has shown anti-tumor activity as well as a good tolerance and is currently under investigation through

Osteosarcoma, the most common primary bone malignancy in children and adolescents, has come a long way since its initial approach where all patients underwent an amputation prior to the 1970's. Current systemic treatment options along the myriad of reconstruction alternatives, have allowed these patients to benefit from better survival rates and improved function and quality of life. Nonetheless, the overall survival rates have remained stable for the past 50 years, a disappointing number when compared to other malignancies' statistics, suggesting more resources and research are needed to continue enhancing the outcomes of patients

#### *Osteosarcoma DOI: http://dx.doi.org/10.5772/intechopen.96765*

to radiotherapy, when in the past it used to be considered a radiotherapy resistant tumor. Supplementary indications for radiotherapy include symptom palliation and this treatment modality has shown to improve patients' symptoms such as pain in case of unresectable tumors [56].

Current investigation trials are in place to uncover targetable mutations that could also have prognostic implications as well studies to assess a potential role for immunotherapy in osteosarcoma patients [57]. Specifically, Cabozantinib, a tyrosine kinase inhibitor used for thyroid and renal cell cancers, has shown anti-tumor activity as well as a good tolerance and is currently under investigation through multicentre trials [58].
