The European Osteosarcoma Intergroup (EOI) analyzed data for two consecutive studies between 1983 and 1986 and 1986 and 199118. A total of 570 patients were analyzed in the report. This analysis is notable for several differences compared to the COSS and IOR analyses. Only 28% of patients had a good histologic response, whereas 72% of patients had a poor histologic response. Patients with a good histologic response had a 5-year survival of 75%, whereas those with a poor response had a 5-year survival of 45%. Of note, many of the patients included in the analysis did not receive HD-MTX because many were treated on a randomized study comparing two drugs, ADM and CDDP, to more intensive therapy including HD-MTX, similar to the COSS and IOR studies [Table 2]. The large randomized study failed to show an advantage of multiagent therapy compared to ADM and CDDP

**Trials No of PTS Good responders Poor responders HD-MTX used**

A factor that could possibly influence histologic response to therapy and its predictive value on survival is the histologic subtype of the tumor. In both studies, fibroblastic tumors had a higher rate of good histologic response (approximately 80% in the IOR study), whereas chondroblastic tumors had a lower rate of good responders (43% in the IOR study). Perhaps even more important, unlike other histologies, 5-year survival rates were identical for good

By knowing the histologic response to neoadjuvant therapy an exciting avenue of modifying post operative chemotherapy and hence attempting to improve survival in poor responders has opened. This has been earlier proven in hematolymphoid malignancy. In the early 1980s at Memorial Sloan-Kettering Cancer Center, poor responders had CDDP substituted for HD-MTX in addition to continuing BCD (bleomycin, cyclophosphamide, and dactinomycin) and ADM20. Patients who had adjustments in their postoperative chemotherapy based on poor

COSS 1700 56.6% 44.4% YES IOR 1000 59% 41% YES EOI 570 28% 72% NO

and for poor responders in chondroblastic histology, at 68%.

**5. Modification of chemotherapy based on necrosis**

also received ADM, CDDP, with or without IFOS.

alone19.

Table 2.

initial response did not have improvement in survival compared to those who had no modifications21. Several other reports have also failed to demonstrate an ability to rescue poor responders22,23. Although tumor necrosis correlates with outcomes, detection of this feature at such a late stage may not offer the chance to target therapy, and therefore, better methods to identify chemoresistant tumors at diagnosis are needed. Thus, to date, it has not been possible to improve the outcome of poor responders by altering postoperative chemotherapy.

#### **6. Development of chemotherapy regimens**

The choice of chemotherapeutic agents has largely been empirical with most groups using ADM, CPL or High dose methotrexate(HD-MTX).

**Role of methotrexate** — The role of HDMTX has been questioned (particularly in adults). There are no randomized studies that have shown an advantage for higher as compared to intermediate doses of methotrexate24 or for HDMTX plus doxorubicin and cisplatin versus doxorubicin/cisplatin alone25. Furthermore, investigators at St. Jude's Hospital have demonstrated good outcomes (five-year event free and overall survival rates 66 and 75 percent) with a non-methotrexate-containing chemotherapy regimen consisting of carboplatin plus ifosfamide and doxorubicin26.

On the other hand, a benefit for HDMTX is supported by at least one series that demonstrates a superior outcome with high-dose as compared to intermediate-dose methotrexate in the context of a multiagent chemotherapy regimen. Furthermore, many studies have shown a correlation between peak serum levels of methotrexate, tumor response, and outcome27-30. Thus, it is possible that determining a benefit for HDMTX has been compromised by the use of insufficient doses31 or administration schedules. The role of HDMTX in chemotherapy for osteosarcoma requires further study32.

**Benefit of ifosfamide-based therapy and mifamurtide** — The upfront addition of ifosfamide with or without etoposide to HDMTX, doxorubicin, and cisplatin improves initial tumor response rates, but the influence on overall and event-free survival is unclear33- 37. The benefit of ifosfamide and the liposomal formulation of immune stimulant muramyl tripeptide phosphatidylethanolamine (MTP-PE, mifamurtide, Junovan) were evaluated in a large phase III study involving 677 patients with nonmetastatic osteosarcoma33. All patients received doxorubicin, cisplatin, and methotrexate, and were randomized in a 2 x 2 scheme to receive or not receive ifosfamide, and then to receive or not receive liposome encapsulated mifamurtide.

The addition of ifosfamide-based therapy improved the relapse-free survival rate, but only when used in conjunction with the mifamurtide. Thus, the routine addition of ifosfamide to adjuvant chemotherapy for osteosarcoma is not recommended outside of a clinical trial However, the use of mifamurtide improved survival, which led to European regulatory approval of this agent for patients with osteosarcoma38.

**Chemotherapy for adults** - In many (but not all series, adults, especially older adults, have a worse prognosis than children with osteosarcoma. This was shown in a population-based series from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute39. Adults are most often offered doxorubicin plus cisplatin,

Chemotherapy in Osteosarcoma 99

Salvage is still possible and is more likely in patients with a longer relapse-free interval. In a large database of 565 osteosarcoma patients who relapsed after being treated on one of three different neoadjuvant chemotherapy protocols within the European Osteosarcoma Intergroup, five year survival postrelapse in those whose disease recurred after two years versus within two years of randomization was 35 versus 14 percent, respectively53. Other favorable prognostic factors in recurrent osteosarcoma include no more than one or two pulmonary nodules, the presence of unilateral pulmonary involvement, lack of pleural disruption, and achieving a second surgical remission,50,54-56. In general, patients should be treated with any of the four most active agents noted earlier if initial therapy did not include one or more of these agents. Patients who have recurrences more than 1 year after completing prior systemic therapy may benefit from reintroduction of at least some of the same drugs in a salvage regimen. The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue has been applied to salvage therapy. However, at least two small pilot studies failed to demonstrate an advantage to standard salvage therapy

A study of the mTOR inhibitor ridaforolimus in patients with metastatic sarcoma suggests potential activity for this class of compounds in patients with osteosarcoma59, raising the possibility of using these and other kinase-targeted agents in patients with metastatic disease. If activity is confirmed, it is expected that these agents will be studied in the

Among other interesting agents that may have clinical utility are inhibitors of insulin-like growth factor I receptor (IGF IR), since IGF signaling is critical for bone formation during development. Early studies with a variety of monoclonal antibodies and small molecule

**Immunotherapy** — Immune responses may influence the survival of patients with osteosarcoma. Cytotoxic lymphocytes are present in such patients60,61, and in at least one study, the degree of lymphocytic infiltration correlated with survival61. These findings have prompted investigators to explore a variety of immunotherapeutic approaches for patients

The addition of Bacille Calmette-Guerin (BCG) and interferon did not improve survival when added to multiagent chemotherapy62,63. However, encouraging preliminary results were obtained using liposomal muramyl tripeptide-phosphatidyl-ethanolamine (mifamurtide), an agent derived from BCG that activates macrophages and increases circulating cytokine levels64,65. These data led to a randomized study, described above, in which patients were assigned, using a 2 x 2 factorial design, to standard chemotherapy with or without ifosfamide and then to receive or not receive mifamurtide. The addition of mifamurtide to standard chemotherapy resulted in a statistically significant improvement in overall survival (78 versus 70 percent at six years) and a trend toward improved event-free

However, when the analysis was restricted to the 91 patients with metastatic disease at diagnosis, there was only a nonstatistically significant trend toward improved five-year

approaches57,58.

adjuvant setting as well.

inhibitors of the IGF IR are underway.

with advanced osteosarcoma.

survival (67 versus 61 percent)

**9. Newer and investigational approaches**

although the role of HDMTX remains a major unanswered question. For patients under the age of 35, we often employ all three agents, while for older patients, in whom the biology of the tumor may be somewhat different, we generally employ doxorubicin and cisplatin only, given the lack of difference between cisplatin/doxorubicin and the more complex T10-type regimen in the adjuvant setting in one study.

#### **7. Chemotherapy in metastatic disease**

Optimal management for patients who present with metastatic osteosarcoma has not been defined by randomized clinical trials, and thus, there is no single standard approach. The most active drugs in patients with measurable disease (HDMTX, doxorubicin, cisplatin, ifosfamide) have single-agent response rates between 20 and 40 percent40-45. Response rates are higher with multiagent regimens but a lower proportion of patients treated for metastatic disease show a good histological response to neoadjuvant chemotherapy as compared to those with apparently localized disease This suggests an underlying difference in the biological behavior.

In an effort to improve outcomes, the Pediatric Oncology Group and others have utilized a strategy of applying novel agents to patients with newly diagnosed metastatic disease prior to standard therapy (termed the "therapeutic window" approach)40,42,46,47. Using this approach, POG identified the combination of ifosfamide/etoposide as effective induction therapy, particularly for those with metastatic bone disease. Thus, although there is no accepted standard approach for the treatment of newly diagnosed metastatic patients, available data would suggest that such patients should be treated with currently available aggressive multiagent chemotherapy with complete surgical resection of all sites of disease if at all possible.

Nevertheless, few patients with metastatic osteosarcoma are cured, and new therapeutic approaches are needed. For patients who present with overt metastatic disease, participation in experimental trials should be encouraged.

A study evaluating the feasibility of adding trastuzumab to standard chemotherapy for patients whose tumors are HER2 positive was just completed by the Children's Oncology Group (COG)48. The results of this study are not yet available.Numerous in vitro and xenograft studies support the concept that bisphosphonates have activity against osteosarcoma alone or in combination with chemotherapy49.

#### **8. Treatment of recurrent disease**

Patients with a disease recurrence after resection alone can often be salvaged with additional surgery and chemotherapy, although their long-term survival is inferior to that of patients who received conventional multiagent chemotherapy in conjunction with surgery upfront50,51.

Treatment of relapse in patients who have already received adjuvant and/or neoadjuvant chemotherapy is a more difficult situation. Such patients usually have received most of the effective drugs, and presumably their tumors are more chemotherapy-resistant than those that have never been exposed to antineoplastic agents52.

although the role of HDMTX remains a major unanswered question. For patients under the age of 35, we often employ all three agents, while for older patients, in whom the biology of the tumor may be somewhat different, we generally employ doxorubicin and cisplatin only, given the lack of difference between cisplatin/doxorubicin and the more complex T10-type

Optimal management for patients who present with metastatic osteosarcoma has not been defined by randomized clinical trials, and thus, there is no single standard approach. The most active drugs in patients with measurable disease (HDMTX, doxorubicin, cisplatin, ifosfamide) have single-agent response rates between 20 and 40 percent40-45. Response rates are higher with multiagent regimens but a lower proportion of patients treated for metastatic disease show a good histological response to neoadjuvant chemotherapy as compared to those with apparently localized disease This suggests an underlying difference

In an effort to improve outcomes, the Pediatric Oncology Group and others have utilized a strategy of applying novel agents to patients with newly diagnosed metastatic disease prior to standard therapy (termed the "therapeutic window" approach)40,42,46,47. Using this approach, POG identified the combination of ifosfamide/etoposide as effective induction therapy, particularly for those with metastatic bone disease. Thus, although there is no accepted standard approach for the treatment of newly diagnosed metastatic patients, available data would suggest that such patients should be treated with currently available aggressive multiagent chemotherapy with complete surgical resection of all sites of disease

Nevertheless, few patients with metastatic osteosarcoma are cured, and new therapeutic approaches are needed. For patients who present with overt metastatic disease,

A study evaluating the feasibility of adding trastuzumab to standard chemotherapy for patients whose tumors are HER2 positive was just completed by the Children's Oncology Group (COG)48. The results of this study are not yet available.Numerous in vitro and xenograft studies support the concept that bisphosphonates have activity against

Patients with a disease recurrence after resection alone can often be salvaged with additional surgery and chemotherapy, although their long-term survival is inferior to that of patients who received conventional multiagent chemotherapy in conjunction with surgery

Treatment of relapse in patients who have already received adjuvant and/or neoadjuvant chemotherapy is a more difficult situation. Such patients usually have received most of the effective drugs, and presumably their tumors are more chemotherapy-resistant than those

regimen in the adjuvant setting in one study.

**7. Chemotherapy in metastatic disease**

participation in experimental trials should be encouraged.

osteosarcoma alone or in combination with chemotherapy49.

that have never been exposed to antineoplastic agents52.

**8. Treatment of recurrent disease**

in the biological behavior.

if at all possible.

upfront50,51.

Salvage is still possible and is more likely in patients with a longer relapse-free interval. In a large database of 565 osteosarcoma patients who relapsed after being treated on one of three different neoadjuvant chemotherapy protocols within the European Osteosarcoma Intergroup, five year survival postrelapse in those whose disease recurred after two years versus within two years of randomization was 35 versus 14 percent, respectively53. Other favorable prognostic factors in recurrent osteosarcoma include no more than one or two pulmonary nodules, the presence of unilateral pulmonary involvement, lack of pleural disruption, and achieving a second surgical remission,50,54-56. In general, patients should be treated with any of the four most active agents noted earlier if initial therapy did not include one or more of these agents. Patients who have recurrences more than 1 year after completing prior systemic therapy may benefit from reintroduction of at least some of the same drugs in a salvage regimen. The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue has been applied to salvage therapy. However, at least two small pilot studies failed to demonstrate an advantage to standard salvage therapy approaches57,58.

#### **9. Newer and investigational approaches**

A study of the mTOR inhibitor ridaforolimus in patients with metastatic sarcoma suggests potential activity for this class of compounds in patients with osteosarcoma59, raising the possibility of using these and other kinase-targeted agents in patients with metastatic disease. If activity is confirmed, it is expected that these agents will be studied in the adjuvant setting as well.

Among other interesting agents that may have clinical utility are inhibitors of insulin-like growth factor I receptor (IGF IR), since IGF signaling is critical for bone formation during development. Early studies with a variety of monoclonal antibodies and small molecule inhibitors of the IGF IR are underway.

**Immunotherapy** — Immune responses may influence the survival of patients with osteosarcoma. Cytotoxic lymphocytes are present in such patients60,61, and in at least one study, the degree of lymphocytic infiltration correlated with survival61. These findings have prompted investigators to explore a variety of immunotherapeutic approaches for patients with advanced osteosarcoma.

The addition of Bacille Calmette-Guerin (BCG) and interferon did not improve survival when added to multiagent chemotherapy62,63. However, encouraging preliminary results were obtained using liposomal muramyl tripeptide-phosphatidyl-ethanolamine (mifamurtide), an agent derived from BCG that activates macrophages and increases circulating cytokine levels64,65. These data led to a randomized study, described above, in which patients were assigned, using a 2 x 2 factorial design, to standard chemotherapy with or without ifosfamide and then to receive or not receive mifamurtide. The addition of mifamurtide to standard chemotherapy resulted in a statistically significant improvement in overall survival (78 versus 70 percent at six years) and a trend toward improved event-free survival (67 versus 61 percent)

However, when the analysis was restricted to the 91 patients with metastatic disease at diagnosis, there was only a nonstatistically significant trend toward improved five-year

Chemotherapy in Osteosarcoma 101

The COSS-86 study was the only prospective controlled study designed to verify whether intraarterial infusion of cisplatin was more effective than intravenous infusion in a multiagent pre-operative chemotherapy setting. In this study, intraarterial or intravenous cisplatin were given with HD-MTX, adriamycin and ifosfamide and the response rate and 10-year event free survival were also identical. The authors themselves suggested that a

In Bacci et al's study, the doses and the time infusion of cisplatin were the same for patients treated intraarterially and intravenously. When used within a three-drug regimen (HD-MTX, cisplatin, adriamycin), intraarterial cisplatin was significantly more effective on the primary tumor than the intravenous infusion. When cisplatin was delivered within a four-drug regimen (HD-MTX, cisplatin, adriamycin and ifosfamide), which significantly increased the good responses, the advantage of intraarterial cisplatin disappeared74.. Therefore, it seems that the addition of another active drug to cisplatin and adriamycin concealed the difference. The Instituto Ortopedico Rizzoli (IOR-OS) 2 and 3 studies demonstrated that the rate of histological response was significantly higher in the intraarterial cisplatin regimen than the IV regimen75. Apart from histologic necrosis, response evaluation can also be done with pre and post chemotherapy

However there is lack of randomized trials of intraarterial chemotherapy in osteogenic sarcomas to draw any definitive conclusions on this promising modality of treatment. Future endeavors should involve a multi-institutional randomized study comparing this

approach with another multiagent intravenous neoadjuvant protocol.

Fig. 2. (A) A radiogram of a man with osteosarcoma of the distal femur.

tortuous vessels and intense contrast uptake.

neovascularity.

(B) An arteriogram after the first course of chemotherapy shows viable tumor area with

(C) An arteriogram after the fourth course shows a decrease in contrast uptake with little evidence of residual tumor staining. It was estimated that there was > 90% decrease in

selection bias may have influenced outcome.

angiograms [Fig. 2].

event free survival (42 versus 26 percent) and overall survival (53 versus 40 percent) that favored mifamurtide66. The drug is not available in the United States. Thus, the role of mifamurtide in patients with metastatic osteosarcoma remains uncertain and a further randomized trial seems warranted.

Another immunotherapeutic approach that is being pursued for pulmonary metastatic disease is inhalation of aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF stimulates the proliferation and differentiation of hematopoietic progenitor cells and augments the functional activity of neutrophils, monocytes, macrophages, and dendritic cells. Recombinant GM-CSF has been used primarily to enhance neutrophil recovery after chemotherapy.

Preclinical as well as early clinical studies suggest that locally applied GM-CSF may provide antitumor effects67,68. These data form the basis for novel therapeutic vaccine approaches using irradiated tumor cells or dendritic cells that are genetically engineered to produce GM-CSF locally and provide the rationale to explore local application of GM-CSF in other diseases.

Local application to the lungs (the most common site of metastatic disease) through inhalation of GM-CSF has been studied. Early data using aerosolized GM-CSF (250 micrograms per dose, twice daily) in a variety of cancers with pulmonary metastases suggest that this approach is safe and possibly effective; in one study, a patient with metastatic Ewing sarcoma had a complete response to therapy69,70. In at least one case, upregulation of tumor-specific cytotoxic T lymphocytes has been shown.

Inhaled GM-CSF was evaluated in 43 patients with pulmonary relapse from osteosarcoma in the American Osteosarcoma Study Group [AOST] protocol 022171. Inhaled G-CSF was administered at doses from 250 to 1750 microg twice daily every other week; after four weeks, resection was performed, and G-CSF was resumed for an additional 24 weeks or until progression. Although doses as high as 1750 microg twice daily were feasible with no dose-limiting toxicity, there was no detectable immunostimulatory effect on the pulmonary metastases or suggestion of improved outcomes post relapse (three-year event-free and overall survival rates were 8 and 35 percent, respectively).

#### **10. Intra-arterial chemotherapy**

The introduction of neoadjuvant chemotherapy into the multi-modality of treatment of osteosarcoma is the most important advancement in treatment of the disease. However, for the last 10 years, there has been less significant improvement in survival with the use of multiagent neoadjuvant chemotherapy. In these patients, the extent of chemotherapyinduced tumor necrosis is strictly correlated with prognosis. To increase the rate of chemotherapy-induced tumor necrosis, delivery of larger doses of drugs to the primary tumor has been attempted using intraarterial chemotherapy. Of the drugs which are effective in osteosarcoma, cisplatin is considered the most suitable for intraarterial infusion because intraarterial cisplatin is not associated with a significant local reaction and systemic drug levels are not compromised by intraarterial infusion72,73.

event free survival (42 versus 26 percent) and overall survival (53 versus 40 percent) that favored mifamurtide66. The drug is not available in the United States. Thus, the role of mifamurtide in patients with metastatic osteosarcoma remains uncertain and a further

Another immunotherapeutic approach that is being pursued for pulmonary metastatic disease is inhalation of aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF stimulates the proliferation and differentiation of hematopoietic progenitor cells and augments the functional activity of neutrophils, monocytes, macrophages, and dendritic cells. Recombinant GM-CSF has been used primarily to enhance neutrophil

Preclinical as well as early clinical studies suggest that locally applied GM-CSF may provide antitumor effects67,68. These data form the basis for novel therapeutic vaccine approaches using irradiated tumor cells or dendritic cells that are genetically engineered to produce GM-CSF locally and provide the rationale to explore local application of GM-CSF in other

Local application to the lungs (the most common site of metastatic disease) through inhalation of GM-CSF has been studied. Early data using aerosolized GM-CSF (250 micrograms per dose, twice daily) in a variety of cancers with pulmonary metastases suggest that this approach is safe and possibly effective; in one study, a patient with metastatic Ewing sarcoma had a complete response to therapy69,70. In at least one case,

Inhaled GM-CSF was evaluated in 43 patients with pulmonary relapse from osteosarcoma in the American Osteosarcoma Study Group [AOST] protocol 022171. Inhaled G-CSF was administered at doses from 250 to 1750 microg twice daily every other week; after four weeks, resection was performed, and G-CSF was resumed for an additional 24 weeks or until progression. Although doses as high as 1750 microg twice daily were feasible with no dose-limiting toxicity, there was no detectable immunostimulatory effect on the pulmonary metastases or suggestion of improved outcomes post relapse (three-year event-free and overall survival rates were 8 and 35

The introduction of neoadjuvant chemotherapy into the multi-modality of treatment of osteosarcoma is the most important advancement in treatment of the disease. However, for the last 10 years, there has been less significant improvement in survival with the use of multiagent neoadjuvant chemotherapy. In these patients, the extent of chemotherapyinduced tumor necrosis is strictly correlated with prognosis. To increase the rate of chemotherapy-induced tumor necrosis, delivery of larger doses of drugs to the primary tumor has been attempted using intraarterial chemotherapy. Of the drugs which are effective in osteosarcoma, cisplatin is considered the most suitable for intraarterial infusion because intraarterial cisplatin is not associated with a significant local reaction and systemic

upregulation of tumor-specific cytotoxic T lymphocytes has been shown.

randomized trial seems warranted.

recovery after chemotherapy.

percent, respectively).

**10. Intra-arterial chemotherapy**

drug levels are not compromised by intraarterial infusion72,73.

diseases.

The COSS-86 study was the only prospective controlled study designed to verify whether intraarterial infusion of cisplatin was more effective than intravenous infusion in a multiagent pre-operative chemotherapy setting. In this study, intraarterial or intravenous cisplatin were given with HD-MTX, adriamycin and ifosfamide and the response rate and 10-year event free survival were also identical. The authors themselves suggested that a selection bias may have influenced outcome.

In Bacci et al's study, the doses and the time infusion of cisplatin were the same for patients treated intraarterially and intravenously. When used within a three-drug regimen (HD-MTX, cisplatin, adriamycin), intraarterial cisplatin was significantly more effective on the primary tumor than the intravenous infusion. When cisplatin was delivered within a four-drug regimen (HD-MTX, cisplatin, adriamycin and ifosfamide), which significantly increased the good responses, the advantage of intraarterial cisplatin disappeared74.. Therefore, it seems that the addition of another active drug to cisplatin and adriamycin concealed the difference. The Instituto Ortopedico Rizzoli (IOR-OS) 2 and 3 studies demonstrated that the rate of histological response was significantly higher in the intraarterial cisplatin regimen than the IV regimen75. Apart from histologic necrosis, response evaluation can also be done with pre and post chemotherapy angiograms [Fig. 2].

However there is lack of randomized trials of intraarterial chemotherapy in osteogenic sarcomas to draw any definitive conclusions on this promising modality of treatment. Future endeavors should involve a multi-institutional randomized study comparing this approach with another multiagent intravenous neoadjuvant protocol.

Fig. 2. (A) A radiogram of a man with osteosarcoma of the distal femur.

(B) An arteriogram after the first course of chemotherapy shows viable tumor area with tortuous vessels and intense contrast uptake.

(C) An arteriogram after the fourth course shows a decrease in contrast uptake with little evidence of residual tumor staining. It was estimated that there was > 90% decrease in neovascularity.

Chemotherapy in Osteosarcoma 103

[8] Francis K, Worcester JJ. Radical resection for tumors of the shoulder with preservation of

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[10] Bruland OS, Høifødt H, Saeter G, et al. Hematogenous micrometastases in

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[13] Link MP, Goorin AM, Horowitz M, et al. Adjuvant chemotherapy of high-grade

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#### **11. Conclusion**

Chemotherapy in osteogenic sarcoma has remarkable impact evident by the fact that survival has increased from dismal 20% in pre-chemotherapy era to respectable 60% in present era.The impact of chemotherapy in Limb salvage approach is tremendous with limb salvage rates around 90-95% at most referral centres. The optimal regimen and timing (Neoadjuvant vs Adjuvant) of chemotherapy needs to be defined. The strategy of chemotherapy modification based on percentage necrosis after pre-op chemotherapy needs further clarification.

Despite impressive 60% survival in most western centers, the survival data of osteogenic sarcoma is not so encouraging in developing countries. The overall 5- and 10-year survival rates in the Brazilian osteosarcoma study group were lower than the rates reported in North American and European trials. A pattern of advanced disease at diagnosis was often present, with a high proportion of patients having metastases (20.8%) and large tumor size (42.9%)76.The developing countries have low limb salvage rates secondary to non availability of costly hardware along with few referral centers with expertise to administer high dose Methotrexate. Development of indigenous, low cost and durable implants77 and less costly effective chemotherapy78 is needed to optimally treat this disease in developing countries. More patients need to be enrolled in randomized clinical trials testing optimal regimen, timing and low cost implants. Newer molecules in research pipeline provide ray of hope for metastatic and relapsed osteogenic sarcoma.

#### **12. References**

Chemotherapy in osteogenic sarcoma has remarkable impact evident by the fact that survival has increased from dismal 20% in pre-chemotherapy era to respectable 60% in present era.The impact of chemotherapy in Limb salvage approach is tremendous with limb salvage rates around 90-95% at most referral centres. The optimal regimen and timing (Neoadjuvant vs Adjuvant) of chemotherapy needs to be defined. The strategy of chemotherapy modification based on percentage necrosis after pre-op chemotherapy needs

Despite impressive 60% survival in most western centers, the survival data of osteogenic sarcoma is not so encouraging in developing countries. The overall 5- and 10-year survival rates in the Brazilian osteosarcoma study group were lower than the rates reported in North American and European trials. A pattern of advanced disease at diagnosis was often present, with a high proportion of patients having metastases (20.8%) and large tumor size (42.9%)76.The developing countries have low limb salvage rates secondary to non availability of costly hardware along with few referral centers with expertise to administer high dose Methotrexate. Development of indigenous, low cost and durable implants77 and less costly effective chemotherapy78 is needed to optimally treat this disease in developing countries. More patients need to be enrolled in randomized clinical trials testing optimal regimen, timing and low cost implants. Newer molecules in research pipeline provide ray of

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**11. Conclusion**

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patients with osteosarcoma treated with contemporary chemotherapy. Cancer

osteosarcoma of the extremities: a 27-year experience in a single institution. J Surg

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[23] Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of nonmetastatic osteosarcoma of

[24] Krailo M, Ertel I, Makley J, et al. A randomized study comparing high-dose

[25] Bramwell VH, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant

[26] Daw NC, Neel MD, Rao BN, et al. Frontline treatment of localized osteosarcoma

[27] Saeter G, Alvegård TA, Elomaa I, et al. Treatment of osteosarcoma of the extremities

[28] Bacci G, Ferrari S, Delepine N, et al. Predictive factors of histologic response to primary

[29] Delepine N, Delepine G, Jasmin C, et al. Importance of age and methotrexate dosage:

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[31] Zelcer S, Kellick M, Wexler LH, et al. Methotrexate levels and outcome in osteosarcoma.

[32] van Dalen EC, de Camargo B. Methotrexate for high-grade osteosarcoma in children

[33] Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl

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the extremity with preoperative and postoperative chemotherapy: a report from

methotrexate with moderate-dose methotrexate as components of adjuvant chemotherapy in childhood nonmetastatic osteosarcoma: a report from the

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with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study. J

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[66] Chou AJ, Kleinerman ES, Krailo MD, et al. Addition of muramyl tripeptide to

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[76] Results of the Brazilian Osteosarcoma Treatment Group Studies III and IV: Prognostic

*Filho,JCO* VOLUME 24 \_ NUMBER 7 \_ MARCH 1 2006,pg 1161-1168. [77] Limb salvage surgery for osteosarcoma: effective low-cost treatment. Agarwal M,

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Longhi A, Rimondini S, Donati D, Manfrini M, Ruggieri P, Biagini R, Bacci G. Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous cisplatin, doxorubicin and salvage chemotherapy based on histologic

Factors and Impact on Survival. *Sérgio Petrilli, Beatriz de Camargo, Vicente Odone*

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[57] Sauerbrey A, Bielack S, Kempf-Bielack B, Zoubek A, Paulussen M, Zintl F. High-dose

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[60] Trieb K, Lechleitner T, Lang S, et al. Evaluation of HLA-DR expression and Tlymphocyte infiltration in osteosarcoma. Pathol Res Pract 1998; 194:679. [61] Goorin AM, Perez-Atayde A, Gebhardt M, et al. Weekly high-dose methotrexate and

[62] Winkler K, Beron G, Kotz R, et al. Adjuvant chemotherapy in osteosarcoma - effects of

[63] Rosenburg SA, Chabner BA, Young RC, et al. Treatment of osteogenic sarcoma. I. Effect

[64] Kleinerman ES, Jia SF, Griffin J, et al. Phase II study of liposomal muramyl tripeptide in

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of adjuvant high-dose methotrexate after amputation. Cancer Treat Rep 1979;

osteosarcoma: the cytokine cascade and monocyte activation following

(CGP 19835A) in the treatment of relapsed osteosarcoma. Am J Clin Oncol 1995;

**5**

*India*

**Limb Salvage for Osteosarcoma:**

*P.D Hinduja National Hospital & Medical Research Centre*

Manish G. Agarwal\* and Prakash Nayak

*Department of Orthopaedics*

**Current Status with a Review of Literature**

Osteosarcoma is the most common primary bone tumor. These tumors have long been known to be very aggressive in their natural history and therefore for a very long time amputation was considered to be the only way to achieve local control of the tumor in the limb. Even after an amputation, only 10-20%survived1,2, the rest succumbing to systemic

In the last 30 years a sea of change has occurred in the outlook for these cancers. Chemotherapy has allowed better local and systemic control5, 6. Better imaging with CT and MRI has allowed the surgeon to accurately define the extent and therefore plan tumor resection. Advances in bioengineering have provided exciting options for reconstruction and the world has moved from amputation to limb salvage. In osteosarcoma, survival improved from dismal 10-20% to 50-70%7, 8. Long term studies showed that limb salvage operations, performed with wide margins and chemotherapy did not compromise the

Cheaper and yet effective chemotherapy protocols and low cost indigenously manufactured megaprosthesis have allowed limb salvage surgery to develop even in the poorer countries. Good surgical technique has improved functional results and made limb salvage today, the

The patient is first assessed clinically and a mental impression formed whether the limb is salvageable, borderline or non salvageable. All patients undergo an imaging workup for local extent and distant spread. This is done prior to a biopsy. An MRI of the local area helps further define the extent and relationships to vital structures like the neurovascular bundle. The MRI helps us plan the margins of resection. The commonest site of distant metastases is the chest. An xray of the chest and where limb salvage is considered a CT scan of the chest (if the x-ray is clear) helps to screen for pulmonary metastases. A bone scan is used to screen for skip lesions and osseous metastases. A PET-CT scan is now being increasingly used for staging instead of

survival or local control compared to an amputation9-14.

standard of care for osteosarcoma.

**2. Evaluation**

Corresponding Author

 \*

**1. Introduction**

disease3,4.

[78] Non-methotrexate based triple drug combination chemotherapy for untreated osteosarcoma. S. S. Hingmire, S. K. Pai, A. V. Bakshi, R. Bharath, M. Agarwal, A. Puri, U. Dangi, S. Mandhaniya, T. Maksud and P. M. Parikh. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 20512.

## **Limb Salvage for Osteosarcoma: Current Status with a Review of Literature**

Manish G. Agarwal\* and Prakash Nayak *Department of Orthopaedics P.D Hinduja National Hospital & Medical Research Centre India*

#### **1. Introduction**

108 Osteosarcoma

[78] Non-methotrexate based triple drug combination chemotherapy for untreated

No 18S (June 20 Supplement), 2007: 20512.

osteosarcoma. S. S. Hingmire, S. K. Pai, A. V. Bakshi, R. Bharath, M. Agarwal, A. Puri, U. Dangi, S. Mandhaniya, T. Maksud and P. M. Parikh. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25,

> Osteosarcoma is the most common primary bone tumor. These tumors have long been known to be very aggressive in their natural history and therefore for a very long time amputation was considered to be the only way to achieve local control of the tumor in the limb. Even after an amputation, only 10-20%survived1,2, the rest succumbing to systemic disease3,4.

> In the last 30 years a sea of change has occurred in the outlook for these cancers. Chemotherapy has allowed better local and systemic control5, 6. Better imaging with CT and MRI has allowed the surgeon to accurately define the extent and therefore plan tumor resection. Advances in bioengineering have provided exciting options for reconstruction and the world has moved from amputation to limb salvage. In osteosarcoma, survival improved from dismal 10-20% to 50-70%7, 8. Long term studies showed that limb salvage operations, performed with wide margins and chemotherapy did not compromise the survival or local control compared to an amputation9-14.

> Cheaper and yet effective chemotherapy protocols and low cost indigenously manufactured megaprosthesis have allowed limb salvage surgery to develop even in the poorer countries. Good surgical technique has improved functional results and made limb salvage today, the standard of care for osteosarcoma.

### **2. Evaluation**

The patient is first assessed clinically and a mental impression formed whether the limb is salvageable, borderline or non salvageable. All patients undergo an imaging workup for local extent and distant spread. This is done prior to a biopsy. An MRI of the local area helps further define the extent and relationships to vital structures like the neurovascular bundle. The MRI helps us plan the margins of resection. The commonest site of distant metastases is the chest. An xray of the chest and where limb salvage is considered a CT scan of the chest (if the x-ray is clear) helps to screen for pulmonary metastases. A bone scan is used to screen for skip lesions and osseous metastases. A PET-CT scan is now being increasingly used for staging instead of

<sup>\*</sup> Corresponding Author

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 111

results in an acceptably low rate of local recurrence of the tumor. An adequate margin is generally wide in most areas. It may be close in some areas for example in the case of a distal femur resection, the popliteal vessels may be on the pseudocapsule but can be easily separated and experience has shown an acceptable low rate of local recurrence. After salvage the limb should have an acceptable degree of function and cosmetic appearance with a minimal amount of pain, and should be capable of withstanding the demands of normal daily activities. It must look and function comparable or better than an artificial limb after amputation. Balancing these sometimes conflicting requirements is what makes limb

In selected cases, limb salvage can be combined with metastatectomy. For patients with uncontrollable disease, limb salvage should be considered if the surgery can be accomplished with minimum morbidity and rapid return to function. These patients can enjoy relief from pain, improved quality of life, and intact body image that limb salvage can

Barriers to limb salvage include poorly placed biopsy incisions, major vascular involvement, encasement of a major motor nerve, pathological fracture of the involved bone, infection and inadequate motors after resection. These adverse factors are barriers but not absolute contraindications. For example in pathological fractures, the fracture often heals with chemotherapy and the specimen can be removed with adequate margins. Ability to transfer motors, graft nerves and vessels and provide skin cover with microsurgical methods have allowed successful limb salvage despite many barriers. If the patient has limited financial resources, it is better to spend the money on chemotherapy and do an amputation rather

For successful local tumor control it is essential to achieve a complete resection of the tumor with an adequate margin (Fig 1). As stated earlier, an adequate margin in any particular case remains controversial25. For high grade sarcomas, a wide margin is considered adequate and will achieve successful control of the primary tumor approximately 95% of the time, whereas marginal or intralesional margins are associated with higher rate of local recurrence and poor outcomes26. For bone 3cm away from the extent on T1-MRI image is adequate27-32. The marrow is always sent from the cut end for frozen section evaluation for tumour. If positive the resection is revised. For the soft tissue 1-2cm margin is preferred wherever possible. In practice, the line between a wide and a marginal margin is sometimes difficult to define as the surgeon strives to control the tumor while still leaving the patient with a useful limb. However, when in doubt, the surgeon errs on the side of excess tissue removal. The adequacy of the margin can be judged by bivalving the specimen. If there is any doubt about margins, a frozen section can be done and a decision for an amputation can be made on table. This is the reason that any patient undergoing a limb salvage procedure is

forewarned about this possibility and a consent for amputation always obtained.

After completion of the tumor resection, the surgeon must reconstruct the resulting surgical defect. The surgeon must eliminate potential dead space and transfer tissues if necessary to

salvage surgery a complex and difficult, but rewarding process.

offer, even if they may not survive long term.

than doing limb salvage and not giving chemotherapy.

**7. Surgical resections and reconstructions**

**6. Barriers to limb salvage**

CT chest and bone scan. Presence of distant metastases decreases cure rates but with effective treatment when the metastases are resectable, cure rates of 20-40% have been reported.

#### **3. Biopsy**

Irrespective of how typical the imaging appearance, a histopathological diagnosis is a vital step in the diagnostic work up of bone tumors. Fine needle aspiration provides only cytologic material and is not the preferred method for diagnosis of primary bone tumors like osteosarcoma15. For bone tumors, the cellular architecture as well as the quality of matrix has to be studied for a proper diagnosis which FNAC cannot provide. A tissue sample may be obtained either by an open incisional biopsy or a closed core biopsy. Traditionally an open biopsy has been used. Various complications related to open biopsy like incorrect placement of incision, large scale contamination of tissues, infection and pathological fracture have often forced an amputation when otherwise a limb salvage was feasible. This happens more frequently when the open biopsy procedure is performed by individuals not experienced in managing tumors. A badly done biopsy can negatively impact overall survival16-21. We therefore recommend that open biopsy should only be performed in specialized units by surgeons experienced in managing tumors.

Percutaneous core biopsy of bone lesions provides early and definitive diagnosis. The biopsy site chosen should be such that the tract can be excised en bloc with the tumour. The periphery of the tumour is the best site and the pre biopsy MRI may help in localizing the most representative area. Necrotic or heavily calcified or ossified areas are avoided. A soft tissue mass is adequately representative for a biopsy. Where necessary an imaging C-arm or CT guidance is used.

#### **4. Patient education**

The patient and the patient's family participate in the decision making process. They are counseled in detail especially when limb salvage is considered regarding the costs, change in lifestyle and mobility and risks involved. The possibility of an amputation and other complications is explained. Amputation as an alternative is also offered in an unbiased way and the patient is encouraged to make his own decision. An attempt is made to facilitate a meeting between the prospective limb salvage candidate and a patient who has already undergone the procedure. Photographs and videos are also shown to the patients and their families.

When the patient and the family are fully informed and participate in the choice of treatment, they are much more likely to be satisfied with the ultimate outcome, even if complications and problems arise at a later stage. It is important to stress to patient and their family that limb salvage may require additional procedures either in near or distant future to manage some of the complications.

#### **5. Indications for limb salvage surgery**

Long term clinical case studies have shown that a limb salvage procedure has the same survival as an amputation9-14. Therefore every patient with a malignant tumor of the extremity is considered for limb salvage if the tumor can be removed with an adequate margin and the resulting limb has satisfactory function. An adequate margin is one that results in an acceptably low rate of local recurrence of the tumor. An adequate margin is generally wide in most areas. It may be close in some areas for example in the case of a distal femur resection, the popliteal vessels may be on the pseudocapsule but can be easily separated and experience has shown an acceptable low rate of local recurrence. After salvage the limb should have an acceptable degree of function and cosmetic appearance with a minimal amount of pain, and should be capable of withstanding the demands of normal daily activities. It must look and function comparable or better than an artificial limb after amputation. Balancing these sometimes conflicting requirements is what makes limb salvage surgery a complex and difficult, but rewarding process.

In selected cases, limb salvage can be combined with metastatectomy. For patients with uncontrollable disease, limb salvage should be considered if the surgery can be accomplished with minimum morbidity and rapid return to function. These patients can enjoy relief from pain, improved quality of life, and intact body image that limb salvage can offer, even if they may not survive long term.

#### **6. Barriers to limb salvage**

110 Osteosarcoma

CT chest and bone scan. Presence of distant metastases decreases cure rates but with effective

Irrespective of how typical the imaging appearance, a histopathological diagnosis is a vital step in the diagnostic work up of bone tumors. Fine needle aspiration provides only cytologic material and is not the preferred method for diagnosis of primary bone tumors like osteosarcoma15. For bone tumors, the cellular architecture as well as the quality of matrix has to be studied for a proper diagnosis which FNAC cannot provide. A tissue sample may be obtained either by an open incisional biopsy or a closed core biopsy. Traditionally an open biopsy has been used. Various complications related to open biopsy like incorrect placement of incision, large scale contamination of tissues, infection and pathological fracture have often forced an amputation when otherwise a limb salvage was feasible. This happens more frequently when the open biopsy procedure is performed by individuals not experienced in managing tumors. A badly done biopsy can negatively impact overall survival16-21. We therefore recommend that open biopsy should only be

Percutaneous core biopsy of bone lesions provides early and definitive diagnosis. The biopsy site chosen should be such that the tract can be excised en bloc with the tumour. The periphery of the tumour is the best site and the pre biopsy MRI may help in localizing the most representative area. Necrotic or heavily calcified or ossified areas are avoided. A soft tissue mass is adequately representative for a biopsy. Where necessary an imaging C-arm or

The patient and the patient's family participate in the decision making process. They are counseled in detail especially when limb salvage is considered regarding the costs, change in lifestyle and mobility and risks involved. The possibility of an amputation and other complications is explained. Amputation as an alternative is also offered in an unbiased way and the patient is encouraged to make his own decision. An attempt is made to facilitate a meeting between the prospective limb salvage candidate and a patient who has already undergone the procedure. Photographs and videos are also shown to the patients

When the patient and the family are fully informed and participate in the choice of treatment, they are much more likely to be satisfied with the ultimate outcome, even if complications and problems arise at a later stage. It is important to stress to patient and their family that limb salvage may require additional procedures either in near or distant future

Long term clinical case studies have shown that a limb salvage procedure has the same survival as an amputation9-14. Therefore every patient with a malignant tumor of the extremity is considered for limb salvage if the tumor can be removed with an adequate margin and the resulting limb has satisfactory function. An adequate margin is one that

treatment when the metastases are resectable, cure rates of 20-40% have been reported.

performed in specialized units by surgeons experienced in managing tumors.

**3. Biopsy**

CT guidance is used.

and their families.

to manage some of the complications.

**5. Indications for limb salvage surgery**

**4. Patient education**

Barriers to limb salvage include poorly placed biopsy incisions, major vascular involvement, encasement of a major motor nerve, pathological fracture of the involved bone, infection and inadequate motors after resection. These adverse factors are barriers but not absolute contraindications. For example in pathological fractures, the fracture often heals with chemotherapy and the specimen can be removed with adequate margins. Ability to transfer motors, graft nerves and vessels and provide skin cover with microsurgical methods have allowed successful limb salvage despite many barriers. If the patient has limited financial resources, it is better to spend the money on chemotherapy and do an amputation rather than doing limb salvage and not giving chemotherapy.

#### **7. Surgical resections and reconstructions**

For successful local tumor control it is essential to achieve a complete resection of the tumor with an adequate margin (Fig 1). As stated earlier, an adequate margin in any particular case remains controversial25. For high grade sarcomas, a wide margin is considered adequate and will achieve successful control of the primary tumor approximately 95% of the time, whereas marginal or intralesional margins are associated with higher rate of local recurrence and poor outcomes26. For bone 3cm away from the extent on T1-MRI image is adequate27-32. The marrow is always sent from the cut end for frozen section evaluation for tumour. If positive the resection is revised. For the soft tissue 1-2cm margin is preferred wherever possible. In practice, the line between a wide and a marginal margin is sometimes difficult to define as the surgeon strives to control the tumor while still leaving the patient with a useful limb. However, when in doubt, the surgeon errs on the side of excess tissue removal. The adequacy of the margin can be judged by bivalving the specimen. If there is any doubt about margins, a frozen section can be done and a decision for an amputation can be made on table. This is the reason that any patient undergoing a limb salvage procedure is forewarned about this possibility and a consent for amputation always obtained.

After completion of the tumor resection, the surgeon must reconstruct the resulting surgical defect. The surgeon must eliminate potential dead space and transfer tissues if necessary to

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 113

allograft or by fibula or iliac crest strut autograft.28 Because of the large contact area and vascularity of the bed, usual complications associated with allografts like infection, nonunion and fracture are rare. We reported our results in ten cases with complete

Fig. 2. The various kinds of bone defects resulting from an excision of an osteosarcoma.

These are a result of complete circumferential excision of bone segments. These can be intercalary or joint involving (Fig 2). Since most tumors occur around the metaphysis, joint

Megaprosthesis is a large metallic joint designed to replace the excised length of bone and the adjacent joint. These are fully constrained hinge joints. They provide an immediate return to function and are not affected by ongoing adjuvant treatment like chemotherapy

Hemicortical excision can be done for a low grade osteosarcoma like parosteal

osteosarcoma. For all others, a full segment resection is advised.

**7.2 Full segment defects**

involving defects are more common.

**7.2.1 Joint involving defects**

**<IP_ADDRESS> Megaprosthesis**

incorporation of the graft in all the cases and no local recurrence.28

allow an effective closure. Occasionally, the reconstruction or substitution of a segment of artery or nerve may be required.

Most osteosarcomas occur in the metaphyseal portion of the bone, so that the typical resection involves the whole proximal or distal part of the bone. If the joint is not contaminated by the tumor, an intraarticular resection is performed through the joint. If the joint is contaminated, then an extraarticular resection is required, taking the entire joint and joint capsule, and cutting through the uninvolved bone on the other side of the joint to achieve a wide margin. The gap remaining needs reconstruction either with metal or with bone or a composite of the two. For tumors that involve the diaphyseal portion of a bone, an intercalary resection and reconstruction can be performed that saves the joints at either end. It is now possible to save the joint even if only 1.5-2cms of condyle thickness remain27. For low grade osteosarcoma, a hemicortical excision which removes only a part of the bone circumference is effective in disease control. The reconstruction done often depends on the kind of defect (fig 2).

Fig. 1. Margins considered adequate for high grade osteosarcoma excision.The figure shows a resection specimen of the distal femur osteosarcoma. It is covered by an uninvolved muscle layer. The biopsy track has been completely excised enbloc with skin. There is 3cm margin from marrow extent of tumor at proximal end and the joint cartilage as margin for the distal end.

#### **7.1 Hemicortical defects**

These result generally from partial circumferential excision of benign or low grade tumors like a parosteal osteosarcoma. Reconstruction of these defects can be done by a shaped

allow an effective closure. Occasionally, the reconstruction or substitution of a segment of

Most osteosarcomas occur in the metaphyseal portion of the bone, so that the typical resection involves the whole proximal or distal part of the bone. If the joint is not contaminated by the tumor, an intraarticular resection is performed through the joint. If the joint is contaminated, then an extraarticular resection is required, taking the entire joint and joint capsule, and cutting through the uninvolved bone on the other side of the joint to achieve a wide margin. The gap remaining needs reconstruction either with metal or with bone or a composite of the two. For tumors that involve the diaphyseal portion of a bone, an intercalary resection and reconstruction can be performed that saves the joints at either end. It is now possible to save the joint even if only 1.5-2cms of condyle thickness remain27. For low grade osteosarcoma, a hemicortical excision which removes only a part of the bone circumference is effective in disease control. The reconstruction done often depends on the

Fig. 1. Margins considered adequate for high grade osteosarcoma excision.The figure shows a resection specimen of the distal femur osteosarcoma. It is covered by an uninvolved muscle layer. The biopsy track has been completely excised enbloc with skin. There is 3cm margin from marrow extent of tumor at proximal end and the joint cartilage as margin for

These result generally from partial circumferential excision of benign or low grade tumors like a parosteal osteosarcoma. Reconstruction of these defects can be done by a shaped

artery or nerve may be required.

kind of defect (fig 2).

the distal end.

**7.1 Hemicortical defects**

allograft or by fibula or iliac crest strut autograft.28 Because of the large contact area and vascularity of the bed, usual complications associated with allografts like infection, nonunion and fracture are rare. We reported our results in ten cases with complete incorporation of the graft in all the cases and no local recurrence.28

Fig. 2. The various kinds of bone defects resulting from an excision of an osteosarcoma. Hemicortical excision can be done for a low grade osteosarcoma like parosteal osteosarcoma. For all others, a full segment resection is advised.

#### **7.2 Full segment defects**

These are a result of complete circumferential excision of bone segments. These can be intercalary or joint involving (Fig 2). Since most tumors occur around the metaphysis, joint involving defects are more common.

#### **7.2.1 Joint involving defects**

#### **<IP_ADDRESS> Megaprosthesis**

Megaprosthesis is a large metallic joint designed to replace the excised length of bone and the adjacent joint. These are fully constrained hinge joints. They provide an immediate return to function and are not affected by ongoing adjuvant treatment like chemotherapy

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 115

Special attention is paid during closure to ensure that the prosthesis is fully covered by a healthy soft tissue envelope. Wherever possible, as in proximal tibia, tendons are reattached to the construct. In the proximal femur, wherever possible, reattachment of the abductors reduces the limp. In the shoulder, the rotator cuff is lost and the proximal humerus implant works as a mere spacer to allow function of the elbow and hand. Wherever the deltoid and axillary nerve can be preserved, a reverse shoulder implant can be used.30 This allows active flexion and abduction which was not possible with the conventional implant. Scapular endoprosthesis after a scapulectomy may provide better function than simple humeral suspension of the latissimus dorsi, trapezius, deltoid and rhomboids can be preserved with

It is now possible to reconstruct the entire humerus or femur (fig 4)with prosthesis. Though the surgery involves a massive exposure and long duration, the functional results have been

better abduction and flexion.31

superior to that after an amputation and external prosthesis.

Fig. 4. A total Femoral endoprosthetic replacement

and radiotherapy. They thus form the mainstay in limb salvage surgery for reconstruction after tumor resection.

Advances in metallurgy and fabrication have tremendously improved these joints. Joint breakage is now rare and aseptic loosening rates are also very low with the use of rotating hinges and with extracortical bridging between the bone and implant collar.29 Infection and local recurrence are the commonest cause of prosthesis failure and happen in around 15% of cases.

A customised joint has to be ordered as per individual patient's dimensions. It takes 4-6 weeks for fabrication. In contrast modular systems (Fig 3) allow for immediate availability. They also allow intraoperative flexibility. The drawback is that they are expensive and a large inventory of the components has to be kept. A customized prosthesis can be improved with every joint but this is not possible for a modular system. Currently modular systems are used for most adults and children near skeletal maturity as adequate modularity ensures a good fit into the defect for almost all patients. In children or in places where anatomy is distorted, customized implants are used to adjust for smaller or abnormal bone size and to allow expansion.

Fig. 3. Figure showing a modular megaprosthetic system for distal femur or proximal tibia resection (RESTOR, Adler Mediquip Pvt Ltd, India). Note that numerous components linked to assemble the complete prosthesis. The modularity allows the implant to be matched to the defect as well as to the bone in which it is to be implanted.

and radiotherapy. They thus form the mainstay in limb salvage surgery for reconstruction

Advances in metallurgy and fabrication have tremendously improved these joints. Joint breakage is now rare and aseptic loosening rates are also very low with the use of rotating hinges and with extracortical bridging between the bone and implant collar.29 Infection and local recurrence are the commonest cause of prosthesis failure and happen in around

A customised joint has to be ordered as per individual patient's dimensions. It takes 4-6 weeks for fabrication. In contrast modular systems (Fig 3) allow for immediate availability. They also allow intraoperative flexibility. The drawback is that they are expensive and a large inventory of the components has to be kept. A customized prosthesis can be improved with every joint but this is not possible for a modular system. Currently modular systems are used for most adults and children near skeletal maturity as adequate modularity ensures a good fit into the defect for almost all patients. In children or in places where anatomy is distorted, customized implants are used to adjust for smaller or abnormal bone size and to

Fig. 3. Figure showing a modular megaprosthetic system for distal femur or proximal tibia resection (RESTOR, Adler Mediquip Pvt Ltd, India). Note that numerous components linked to assemble the complete prosthesis. The modularity allows the implant to be

matched to the defect as well as to the bone in which it is to be implanted.

after tumor resection.

15% of cases.

allow expansion.

Special attention is paid during closure to ensure that the prosthesis is fully covered by a healthy soft tissue envelope. Wherever possible, as in proximal tibia, tendons are reattached to the construct. In the proximal femur, wherever possible, reattachment of the abductors reduces the limp. In the shoulder, the rotator cuff is lost and the proximal humerus implant works as a mere spacer to allow function of the elbow and hand. Wherever the deltoid and axillary nerve can be preserved, a reverse shoulder implant can be used.30 This allows active flexion and abduction which was not possible with the conventional implant. Scapular endoprosthesis after a scapulectomy may provide better function than simple humeral suspension of the latissimus dorsi, trapezius, deltoid and rhomboids can be preserved with better abduction and flexion.31

It is now possible to reconstruct the entire humerus or femur (fig 4)with prosthesis. Though the surgery involves a massive exposure and long duration, the functional results have been superior to that after an amputation and external prosthesis.

Fig. 4. A total Femoral endoprosthetic replacement

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 117

continues to grow while the operated leg does not. This required the child to use shoes with a thick heel to compensate for limb length discrepancy but also resulted in limp and poor function. To overcome these problems, a special prosthesis was designed which could be lengthened periodically (expandable prosthesis). The prosthesis had a wormgear mechanism which allowed a telescoping cylinder to increase the length when a screw was turned (Fig 5). This was done surgically by a small operation in which a small cut was made and a screw driver used on the prosthesis to turn a screw which allowed a tube to telescope out. This had to be done repeatedly as the child grew to keep pace with the growth of the normal side. Though surgery was involved, the fact was that now length

Even with all these advances, it means that the child has to undergo multiple surgical procedures for lengthening. It means admission to hospital, anaesthesia and surgery, all of this adding to the costs of treatment. Also, since we want to minimize the number of operations required, we lengthen more at each operation. We try to lengthen 1cm or more depending on the child and the need. Every surgery results in some stiffness, pain and time to rehabilitate to come to normal as this much growth is not easily adjusted to by the body. Each surgery also increases the risk of infection which is estimated to be about 8% in the

In order to solve some of the problems above, prostheses have been developed which can be expanded remotely without the need of any surgery. We have used the implant made by stanmore implants worldwide, U.K. The prosthesis has a very sophisticated mechanism sealed inside it which allows lengthening to happen with the help of an electromagnetic field.35 A rare earth magnet is placed along with a motor and a gear system inside the prosthesis. A coil from outside around the implant can now generate an electromagnetic field to turn the motor. Through a system of miniature gears, the movement of the motor can allow the expansion of the implant by moving the telescoping tube out just like it was done with a screw driver. The biggest advantage is that now surgery is not required for lengthening. Small amounts of lengthening are done more like normal growth. There is no pain or stiffness, no hospitalization and no risk of infection. In the long run this turns out to

Allografts offer the surgeon additional reconstructive options in bridging large bone defects after tumor excision. Osteoarticular allografts have shown a success rate of 70% at long term follow-up.42. Allografts have the advantage of providing biological bed for soft tissue anchorage. The attachment of muscle insertions is more successful in allografts than in prostheses, yielding better function in some sites. Initial enthusiasm for allografts has been tempered by a variety of problems as experience has accumulated. While it was initially hoped that massive allografts would become fully incorporated into the host, retrieval data show that only a small percentage of the allograft actually becomes revascularized, while the rest remains necrotic 43, 44. Rather than a biologic replacement for the excised bone segment, the allograft functions as a biologic spacer. Massive allografts are susceptible to infection (5-15%), fracture (15-20%), Non-union (15-20%) and osteoarthritis from collapse of the articular surface (with osteoarticular graft) 45-49. Chemotherapy and radiotherapy can

could be maintained in these children.

be cheaper than the minimally invasive implant.

**<IP_ADDRESS> Osteoarticular allografts**

current era.34

Fig. 5. An expandable distal femur megaprosthesis. This is a minimally invasive expandable system. The screwdriver drives a wormgear mechanism to drive out a telescoping cylinder resulting in lengthening.

Regardless of the method of fixation to the host bone, the prosthesis may loosen over time. Mechanical wear of the polyethylene bearing surfaces can lead to failure of the reconstruction. Rebushing is required more commonly in the fixed hinge implant and generally after five years.29, 32 Using an hydroxyapatite coated or porous coated collar to allow extracortical bone bridging between host bone and implant has reduced the rates of aseptic loosening to almost zero.29 Breakages are now rare with the use of stronger metals and superalloys like titanium and Chrome-cobalt. When these implants fail, revision procedures though complex have generally been successful after implantation of a new prosthesis.33

#### **<IP_ADDRESS> Expandable prosthesis**

Managing limb lengths is a challenge in young children treated with limb saving surgery. While they are cured of cancer, the operated leg becomes shorter as the normal leg

Fig. 5. An expandable distal femur megaprosthesis. This is a minimally invasive expandable system. The screwdriver drives a wormgear mechanism to drive out a telescoping cylinder

Regardless of the method of fixation to the host bone, the prosthesis may loosen over time. Mechanical wear of the polyethylene bearing surfaces can lead to failure of the reconstruction. Rebushing is required more commonly in the fixed hinge implant and generally after five years.29, 32 Using an hydroxyapatite coated or porous coated collar to allow extracortical bone bridging between host bone and implant has reduced the rates of aseptic loosening to almost zero.29 Breakages are now rare with the use of stronger metals and superalloys like titanium and Chrome-cobalt. When these implants fail, revision procedures though complex have generally been successful after implantation of a new

Managing limb lengths is a challenge in young children treated with limb saving surgery. While they are cured of cancer, the operated leg becomes shorter as the normal leg

resulting in lengthening.

**<IP_ADDRESS> Expandable prosthesis**

prosthesis.33

continues to grow while the operated leg does not. This required the child to use shoes with a thick heel to compensate for limb length discrepancy but also resulted in limp and poor function. To overcome these problems, a special prosthesis was designed which could be lengthened periodically (expandable prosthesis). The prosthesis had a wormgear mechanism which allowed a telescoping cylinder to increase the length when a screw was turned (Fig 5). This was done surgically by a small operation in which a small cut was made and a screw driver used on the prosthesis to turn a screw which allowed a tube to telescope out. This had to be done repeatedly as the child grew to keep pace with the growth of the normal side. Though surgery was involved, the fact was that now length could be maintained in these children.

Even with all these advances, it means that the child has to undergo multiple surgical procedures for lengthening. It means admission to hospital, anaesthesia and surgery, all of this adding to the costs of treatment. Also, since we want to minimize the number of operations required, we lengthen more at each operation. We try to lengthen 1cm or more depending on the child and the need. Every surgery results in some stiffness, pain and time to rehabilitate to come to normal as this much growth is not easily adjusted to by the body. Each surgery also increases the risk of infection which is estimated to be about 8% in the current era.34

In order to solve some of the problems above, prostheses have been developed which can be expanded remotely without the need of any surgery. We have used the implant made by stanmore implants worldwide, U.K. The prosthesis has a very sophisticated mechanism sealed inside it which allows lengthening to happen with the help of an electromagnetic field.35 A rare earth magnet is placed along with a motor and a gear system inside the prosthesis. A coil from outside around the implant can now generate an electromagnetic field to turn the motor. Through a system of miniature gears, the movement of the motor can allow the expansion of the implant by moving the telescoping tube out just like it was done with a screw driver. The biggest advantage is that now surgery is not required for lengthening. Small amounts of lengthening are done more like normal growth. There is no pain or stiffness, no hospitalization and no risk of infection. In the long run this turns out to be cheaper than the minimally invasive implant.

#### **<IP_ADDRESS> Osteoarticular allografts**

Allografts offer the surgeon additional reconstructive options in bridging large bone defects after tumor excision. Osteoarticular allografts have shown a success rate of 70% at long term follow-up.42. Allografts have the advantage of providing biological bed for soft tissue anchorage. The attachment of muscle insertions is more successful in allografts than in prostheses, yielding better function in some sites. Initial enthusiasm for allografts has been tempered by a variety of problems as experience has accumulated. While it was initially hoped that massive allografts would become fully incorporated into the host, retrieval data show that only a small percentage of the allograft actually becomes revascularized, while the rest remains necrotic 43, 44. Rather than a biologic replacement for the excised bone segment, the allograft functions as a biologic spacer. Massive allografts are susceptible to infection (5-15%), fracture (15-20%), Non-union (15-20%) and osteoarthritis from collapse of the articular surface (with osteoarticular graft) 45-49. Chemotherapy and radiotherapy can

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 119

Fig. 6. An allograft with a pedicled (vascularised) fibula for a resection arthrodesis of the knee. The allograft is hemicylindrical to avoid any compression of the pedicle or skin attached to the fibula. The xray shows the union at junctions which happened uneventfully

Rotationplasty is a procedure which allows the ankle to substitute as the knee after 1800 rotation of the limb. The original idea was conceived by Borggreve in 1927 to treat a shortened lower limb with stiff knee after tuberculosis and popularized by Van Ness for management of proximal focal femoral deficiency57. Salzer in 1974 first used it for malignant tumors around the knee58. It is essentially an intercalary limb resection preserving the

in less than 6 months.

**<IP_ADDRESS> Rotationplasty**

adversely affect the union rates48-52. An additional concern is the potential for the transmission of bacterial or viral disease.

#### **<IP_ADDRESS> Alloprosthetic composite and others**

Sometimes a composite of an allograft and an endoprosthesis is used for certain limbsalvage reconstructions. An appropriate allograft is selected and implanted to replace the **s**egment of bone resected. The articular surfaces of the graft are excised and replaced using conventional techniques of total joint arthroplasty. The allograft provides a source of bone stock and a site for tendon insertions, while the prosthesis provides a reliable and stable articulation and some support for the allograft. The surgeon can customize the implant for any particular need. An allo-prosthesis construct has a lower fracture rate than allograft alone49 and is not susceptible to osteoarthritis.

#### **<IP_ADDRESS> Resection arthrodesis**

Arthrodesis for the knee, though disabling can provide a practical low cost option for reconstruction after bone tumor resection especially if patient is likely to engage in heavy manual labour. Even in a developing country it causes difficulty with squatting, traveling in bus, etc. It is therefore not easily accepted and done only occasionally by us. The principles of surgery involve bone grafts coupled with internal fixation, very similar to those of intercalary resections. Allografts alone, unlike in intercalary resections have shown a high failure rate due to infection, fracture and non-union.53-54 Autografts vascularised or nonvascularised are used along with fixation which is either a locked long nail, or a long plate or sometimes an external fixator.55 Distraction osteogenesis has been another option used particularly in benign tumors. An intramedullary nail, double osteotomy, fewer rings and early fixator removal have reduced the complication rates.55 We have preferred to use a double barrel live fibula or an allograft combined with a live fibula and neutralized with a long plate.(fig 6)

The defect can be bridged by using autograft or an allograft or a combination. A vascularised live fibula with allograft supplementation is a good alternative and our method of choice. A non vascularised graft always has the risk of fracture. Fixation is either with a plate spanning the defect or with a long customized nail. These patient have to be immobilized for a long time till union. Besides, radiotherapy and chemotherapy can interfere with union. An intercalary long segment allograft can be used with implant fixation but has a high rate of complications45. Even with an autograft, non union and fracture rates are high and it is almost a year before arthrodesis is sound. Till this time the patient has to be protected and load bearing restricted.

Functionally, the gait of these patients with knee arthrodesis is a little awkward due to the stiff knee and sitting is difficult. However these patients are not afraid of loading their limb and can engage in strenuous activities56.

Very few of our patients opted for an arthrodesis. The ones that did, did it for reasons of cost. The low cost of the megaprosthesis made it easier for patients to opt for a mobile reconstruction. Occasionally a nail and cement arthrodesis is used in cases where long term survival is unlikely (palliative limb salvage). A long K nail is used with cement to bridge the defect. The cement provides rotational stability. In these cases patient can be ambulant immediately.

adversely affect the union rates48-52. An additional concern is the potential for the

Sometimes a composite of an allograft and an endoprosthesis is used for certain limbsalvage reconstructions. An appropriate allograft is selected and implanted to replace the **s**egment of bone resected. The articular surfaces of the graft are excised and replaced using conventional techniques of total joint arthroplasty. The allograft provides a source of bone stock and a site for tendon insertions, while the prosthesis provides a reliable and stable articulation and some support for the allograft. The surgeon can customize the implant for any particular need. An allo-prosthesis construct has a lower fracture rate than allograft

Arthrodesis for the knee, though disabling can provide a practical low cost option for reconstruction after bone tumor resection especially if patient is likely to engage in heavy manual labour. Even in a developing country it causes difficulty with squatting, traveling in bus, etc. It is therefore not easily accepted and done only occasionally by us. The principles of surgery involve bone grafts coupled with internal fixation, very similar to those of intercalary resections. Allografts alone, unlike in intercalary resections have shown a high failure rate due to infection, fracture and non-union.53-54 Autografts vascularised or nonvascularised are used along with fixation which is either a locked long nail, or a long plate or sometimes an external fixator.55 Distraction osteogenesis has been another option used particularly in benign tumors. An intramedullary nail, double osteotomy, fewer rings and early fixator removal have reduced the complication rates.55 We have preferred to use a double barrel live fibula or an allograft combined with a live fibula and neutralized with a

The defect can be bridged by using autograft or an allograft or a combination. A vascularised live fibula with allograft supplementation is a good alternative and our method of choice. A non vascularised graft always has the risk of fracture. Fixation is either with a plate spanning the defect or with a long customized nail. These patient have to be immobilized for a long time till union. Besides, radiotherapy and chemotherapy can interfere with union. An intercalary long segment allograft can be used with implant fixation but has a high rate of complications45. Even with an autograft, non union and fracture rates are high and it is almost a year before arthrodesis is sound. Till this time the

Functionally, the gait of these patients with knee arthrodesis is a little awkward due to the stiff knee and sitting is difficult. However these patients are not afraid of loading their limb

Very few of our patients opted for an arthrodesis. The ones that did, did it for reasons of cost. The low cost of the megaprosthesis made it easier for patients to opt for a mobile reconstruction. Occasionally a nail and cement arthrodesis is used in cases where long term survival is unlikely (palliative limb salvage). A long K nail is used with cement to bridge the defect. The cement provides rotational stability. In these cases patient can be ambulant

transmission of bacterial or viral disease.

**<IP_ADDRESS> Alloprosthetic composite and others**

alone49 and is not susceptible to osteoarthritis.

patient has to be protected and load bearing restricted.

and can engage in strenuous activities56.

**<IP_ADDRESS> Resection arthrodesis**

long plate.(fig 6)

immediately.

Fig. 6. An allograft with a pedicled (vascularised) fibula for a resection arthrodesis of the knee. The allograft is hemicylindrical to avoid any compression of the pedicle or skin attached to the fibula. The xray shows the union at junctions which happened uneventfully in less than 6 months.

#### **<IP_ADDRESS> Rotationplasty**

Rotationplasty is a procedure which allows the ankle to substitute as the knee after 1800 rotation of the limb. The original idea was conceived by Borggreve in 1927 to treat a shortened lower limb with stiff knee after tuberculosis and popularized by Van Ness for management of proximal focal femoral deficiency57. Salzer in 1974 first used it for malignant tumors around the knee58. It is essentially an intercalary limb resection preserving the

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 121

easily accepted alternative over amputation for the economically backward. In children one can adjust the stump length for growth and avoid all the problems and costs associated with expandable prosthesis and expansions. It also works as an excellent salvage option for a failed megaprosthesis, especially after infection.66 Another advantage is that with large tumors and extensive quadriceps involvement (common in a developing country like India), it can still provide functionally good outcome. An osteotomy of the femur early in the procedure allows limb rotation and makes dissection of the neuro-vascular bundle easier.66 A specially designed jig helps to cut the bone perfectly perpendicular to the long axis and makes osteosynthesis between tibia and femur easier.65-66. Rotationplasty can be performed in even in smaller hospital setups without need for complex instrumentation. Long term results have not shown

We have found excellent functional scores and patient satisfaction with this method. This has to be compared with an high above knee amputation or hip disarticulation where even with an artificial limb the function is inferior. Walking speeds, gait, oxygen consumption and general efficiency were better or comparable with other procedures like arthrodesis, endoprosthesis & amputation68-70. Though cosmetically unappealing, functional benefits overshadow the appearance. Prior to surgery the patient is shown photographs and videos and wherever possible meets another similar patient. The mental preparation goes a long

Intercalary defects are broadly classified as diaphyseal, metaphyseo-diaphyseal, or

Fig. 8. Various types of intercalary defects depending on the level of distal and proximal cut

any arthroses in the ankle joint proving excellent adaptation.67

way in ultimate acceptance by the patient.

**7.3 Intercalary defects**

epiphyseodiaphyseal (fig 8).68

continuity of the neurovascular bundle. The limb continuity is established by fusing the Tibia with the proximal femoral remnant after 1800 external limb rotation. This allows the ankle joint to come to the level of the knee and its axis of motion corresponding with the original knee. A special external prosthesis then is fitted allowing the patient to ambulate. Ankle movements now simulate knee movements (Fig 7). This reconstruction therefore functions like a below-knee amputation. A big advantage is that the sole being the normal weight bearing area, there is no phantom pain. The stump can be left longer in children to account for subsequent shortening with growth. These patients are able to walk normally, run, participate in leisure outdoor sporting activities, ride a bicycle and drive a car etc.

Fig. 7. Rotationplasty. A: the rhomboid incision taken. B &C : The Anteroposterior and lateral xrays of a femoral osteosarcoma after induction chemotherapy. D: postoperative xray showing the osteosynthesis between the proximal femur and proximal tibia using a plate. E: The clinical appearance of rotationplasty

Though very well described in literature with functional results comparable to an endoprosthetic reconstruction59-62, the limb disfigurement produced has been a psychological barrier to widespread acceptance especially in the developed world. Most series for functional evaluation have shown superior functional results compared to megaprostheses, but small numbers in rotationplasty group have made statistical evaluation difficult.62-63 Patients with rotationplasty are reported to have less pain and are more likely to participate in sports as compared to megaprostheses.61 Akahane et al64 in a small group of 17 patients reported better function and quality of life results with a rotationplasty than with an endoprosthesis. Rotationplasty is a low cost alternative to prosthesis in a developing country like India.65 The surgical procedure is straightforward, the external orthoses cheap and easily available and with no revisions necessary coupled with the ability to squat and load the limb make it an easily accepted alternative over amputation for the economically backward. In children one can adjust the stump length for growth and avoid all the problems and costs associated with expandable prosthesis and expansions. It also works as an excellent salvage option for a failed megaprosthesis, especially after infection.66 Another advantage is that with large tumors and extensive quadriceps involvement (common in a developing country like India), it can still provide functionally good outcome. An osteotomy of the femur early in the procedure allows limb rotation and makes dissection of the neuro-vascular bundle easier.66 A specially designed jig helps to cut the bone perfectly perpendicular to the long axis and makes osteosynthesis between tibia and femur easier.65-66. Rotationplasty can be performed in even in smaller hospital setups without need for complex instrumentation. Long term results have not shown any arthroses in the ankle joint proving excellent adaptation.67

We have found excellent functional scores and patient satisfaction with this method. This has to be compared with an high above knee amputation or hip disarticulation where even with an artificial limb the function is inferior. Walking speeds, gait, oxygen consumption and general efficiency were better or comparable with other procedures like arthrodesis, endoprosthesis & amputation68-70. Though cosmetically unappealing, functional benefits overshadow the appearance. Prior to surgery the patient is shown photographs and videos and wherever possible meets another similar patient. The mental preparation goes a long way in ultimate acceptance by the patient.

#### **7.3 Intercalary defects**

120 Osteosarcoma

continuity of the neurovascular bundle. The limb continuity is established by fusing the Tibia with the proximal femoral remnant after 1800 external limb rotation. This allows the ankle joint to come to the level of the knee and its axis of motion corresponding with the original knee. A special external prosthesis then is fitted allowing the patient to ambulate. Ankle movements now simulate knee movements (Fig 7). This reconstruction therefore functions like a below-knee amputation. A big advantage is that the sole being the normal weight bearing area, there is no phantom pain. The stump can be left longer in children to account for subsequent shortening with growth. These patients are able to walk normally, run, participate in leisure outdoor sporting activities, ride a bicycle and drive a car etc.

Fig. 7. Rotationplasty. A: the rhomboid incision taken. B &C : The Anteroposterior and lateral xrays of a femoral osteosarcoma after induction chemotherapy. D: postoperative xray showing the osteosynthesis between the proximal femur and proximal tibia using a plate. E:

Though very well described in literature with functional results comparable to an endoprosthetic reconstruction59-62, the limb disfigurement produced has been a psychological barrier to widespread acceptance especially in the developed world. Most series for functional evaluation have shown superior functional results compared to megaprostheses, but small numbers in rotationplasty group have made statistical evaluation difficult.62-63 Patients with rotationplasty are reported to have less pain and are more likely to participate in sports as compared to megaprostheses.61 Akahane et al64 in a small group of 17 patients reported better function and quality of life results with a rotationplasty than with an endoprosthesis. Rotationplasty is a low cost alternative to prosthesis in a developing country like India.65 The surgical procedure is straightforward, the external orthoses cheap and easily available and with no revisions necessary coupled with the ability to squat and load the limb make it an

The clinical appearance of rotationplasty

Intercalary defects are broadly classified as diaphyseal, metaphyseo-diaphyseal, or epiphyseodiaphyseal (fig 8).68

Fig. 8. Various types of intercalary defects depending on the level of distal and proximal cut

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 123

Non vascularised fibular autograft can be a simple low cost and yet effective alternative to Allograft or VF. Krieg et al71 reported from their experience of 31 cases using a non vascularised fibula a primary union rate of 89% in a median time of 24 weeks. 15% had a fatigue fracture with no fractures where a double or triple strut was used. Hypertrophy of

The results of allograft can be improved by combining them with a vascularised fibula either placed in the medullary canal of the allograft or as an onlay by providing vascularity in the centre of the allograft.72-73 The healing of the junctions is quick and reliable and the fibula hypertrophies over a period of time. The allograft provides the initial strength and the vascularised autograft provides speed of union. Our experience with radiated allograft alone has been rather disappointing with only about 40% grafts incorporating. Radiation and chemotherapy have probably resulted in poorer incorporation. A single fibula especially in defects over 20cm was prone to fracture. We therefore recommend an allograft combined with a live fibula rather than an allograft alone for long full segment defects. The faster incorporation results in fewer failures and earlier return to full function. For smaller defects with strong and rigid fixation, a VF

Reimplanting the tumor bearing bone after some form of treatment (autoclaving, pasteurization, freezing with liquid nitrogen, or extracorporeal radiation) to kill the tumor cells is another exciting low cost option. Though dead like an allograft, it is perfectly matched to the defect. Autoclaved bone has provided fairly good results as reported from 12 cases from Pakistan with only one non-union and no fractures with an average MSTS score of 70% at a mean follow-up of 49 months.74 Yamamoto et al75 histologically examined a specimen of autoclaved and reimplanted bone in femur retrieved after 24 months and found most of the graft not incorporated. New bone formation was thin and superficial over the graft and bone scan exaggerated the bone formation. This does not seem to match the clinical experience cited above. In future it may be possible to improve the osteoinductivity of autoclaved bone by coating with rhBMP-2.76 A combination of dehydration and thermal denaturing can prevent loss of strength and improve clinical

High temperatures associated with autoclaving are known to damage the collagen matrix leading to loss of strength as well as BMP and osteoinductivity. Pasteurisation involves heating the bone to 60 deg C for 30 min in a water bath and is an effective way of killing all tumor without affecting strength and osteoinductivity. Clinical results with pasteurized graft have shown results at least comparable to allografts.78-79 Freezing in liquid nitrogen is another way of killing the tumor and yet being able to reimplant the bone. Tsuchiya et al80 reported bony union at a mean of 6.7 months after the operation in 26/28 patients. There were three deep infections, two fractures, and two local

Extracorporeal irradiation (FIG 10) with doses of 5000rad (equivalent to 25kgy of conventional radiation) is also effective in killing all tumor.81 The rate of non union (7%) is

the graft was similar to that in VF.

alone may be adequate.

performance.77

recurrences.

**7.3.2 Reimplantation of tumor bearing bone**

#### **7.3.1 Autografts and allografts**

Although numerous problems continue to limit the success of allograft reconstructions, they remain a viable choice for selected uses, especially in the upper extremity, for intercalary resections, and for patients who will not need chemotherapy. Intercalary allografts have shown higher success than the osteoarticular ones46. Reconstruction of epiphyseodiaphyseal defects with allografts is challenging. Despite the large cancellous bony contact surface, lack of rigid fixation at the epiphyseal end delayed the average time to union to 18 months compared to 13 months at metaphyseal end.68 Vascularised fibula (VF) is a good alternative for intercalary defects especially for longer gaps.69-70 VF showed 93% union rate with only 15% delayed union as compared to allografts which have had 68-90% union rates with 51-57% delayed union rates.69 Most of VF patients could return to athletic activity. Donor site morbidity was not a serious problem with most complications resolving with conservative treatment.

Fig. 9. A: Osteosarcoma of the femur treated by an intercalary resection. The surgeon reconstructed the defect with an interlocking nail only which broke in 2 years. This was replaced by an Allograft with a vascularised fibula placed in the intramedullary canal (B). C & D show the follow up xray at one year showingthe excellent incorporation of graft and fibular hypertrophy

Although numerous problems continue to limit the success of allograft reconstructions, they remain a viable choice for selected uses, especially in the upper extremity, for intercalary resections, and for patients who will not need chemotherapy. Intercalary allografts have shown higher success than the osteoarticular ones46. Reconstruction of epiphyseodiaphyseal defects with allografts is challenging. Despite the large cancellous bony contact surface, lack of rigid fixation at the epiphyseal end delayed the average time to union to 18 months compared to 13 months at metaphyseal end.68 Vascularised fibula (VF) is a good alternative for intercalary defects especially for longer gaps.69-70 VF showed 93% union rate with only 15% delayed union as compared to allografts which have had 68-90% union rates with 51-57% delayed union rates.69 Most of VF patients could return to athletic activity. Donor site morbidity was not a serious problem with most complications resolving with

Fig. 9. A: Osteosarcoma of the femur treated by an intercalary resection. The surgeon reconstructed the defect with an interlocking nail only which broke in 2 years. This was replaced by an Allograft with a vascularised fibula placed in the intramedullary canal (B). C & D show the follow up xray at one year showingthe excellent incorporation of graft and

**7.3.1 Autografts and allografts**

conservative treatment.

fibular hypertrophy

Non vascularised fibular autograft can be a simple low cost and yet effective alternative to Allograft or VF. Krieg et al71 reported from their experience of 31 cases using a non vascularised fibula a primary union rate of 89% in a median time of 24 weeks. 15% had a fatigue fracture with no fractures where a double or triple strut was used. Hypertrophy of the graft was similar to that in VF.

The results of allograft can be improved by combining them with a vascularised fibula either placed in the medullary canal of the allograft or as an onlay by providing vascularity in the centre of the allograft.72-73 The healing of the junctions is quick and reliable and the fibula hypertrophies over a period of time. The allograft provides the initial strength and the vascularised autograft provides speed of union. Our experience with radiated allograft alone has been rather disappointing with only about 40% grafts incorporating. Radiation and chemotherapy have probably resulted in poorer incorporation. A single fibula especially in defects over 20cm was prone to fracture. We therefore recommend an allograft combined with a live fibula rather than an allograft alone for long full segment defects. The faster incorporation results in fewer failures and earlier return to full function. For smaller defects with strong and rigid fixation, a VF alone may be adequate.

#### **7.3.2 Reimplantation of tumor bearing bone**

Reimplanting the tumor bearing bone after some form of treatment (autoclaving, pasteurization, freezing with liquid nitrogen, or extracorporeal radiation) to kill the tumor cells is another exciting low cost option. Though dead like an allograft, it is perfectly matched to the defect. Autoclaved bone has provided fairly good results as reported from 12 cases from Pakistan with only one non-union and no fractures with an average MSTS score of 70% at a mean follow-up of 49 months.74 Yamamoto et al75 histologically examined a specimen of autoclaved and reimplanted bone in femur retrieved after 24 months and found most of the graft not incorporated. New bone formation was thin and superficial over the graft and bone scan exaggerated the bone formation. This does not seem to match the clinical experience cited above. In future it may be possible to improve the osteoinductivity of autoclaved bone by coating with rhBMP-2.76 A combination of dehydration and thermal denaturing can prevent loss of strength and improve clinical performance.77

High temperatures associated with autoclaving are known to damage the collagen matrix leading to loss of strength as well as BMP and osteoinductivity. Pasteurisation involves heating the bone to 60 deg C for 30 min in a water bath and is an effective way of killing all tumor without affecting strength and osteoinductivity. Clinical results with pasteurized graft have shown results at least comparable to allografts.78-79 Freezing in liquid nitrogen is another way of killing the tumor and yet being able to reimplant the bone. Tsuchiya et al80 reported bony union at a mean of 6.7 months after the operation in 26/28 patients. There were three deep infections, two fractures, and two local recurrences.

Extracorporeal irradiation (FIG 10) with doses of 5000rad (equivalent to 25kgy of conventional radiation) is also effective in killing all tumor.81 The rate of non union (7%) is

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 125

Fig. 11. A: Preoperative xray of a distal femur osteosarcoma. B: The MRI shows the extent just proximal to the distal femoral physis. Note the skip lesion proximally. C: The defect was constructed with a custom prosthesis designed to fit into the small distal and proximal fragment. The distal fixation is with an hydroxyapatite coated surface and small

extracortical plates. The proximal fixation is with a curved short intramedullary stem. This prosthesis could be lengthened with a noninvasive expansion mechanism (STANMORE

Any tumor in the pelvis is a challenge to an orthopaedic oncologist for resection and osteosarcoma being a high grade malignant tumor is even more challenging. Tumors are often large at presentation and do not always respond well to the preoperative chemotherapy. Osteosarcomas of the pelvis are rare accounting for 7-9% of all osteosarcomas.88 Prognosis has been reported to be dismal with 18% 5 year survival88,89,90 . Recent report indicates a 50% 5 year survival.91 Since osteosarcoma does not respond well to radiation, surgical resection with a tumor free margin is the only reliable method for cure.

implants, UK)

**8. Pelvis**

significantly lower with ECRT as compared to allografts (43%).82 The fracture rates were similar and there were no infections. Histological evaluation of specimens from failed ECRT cases show changes of repair and viable osteoblasts after 2-3 years.83

Fig. 10. A: Preoperative xrays of an osteosarcoma of the femur treated with extracorporeal irradiation and reimplantation(ECRT). B: schematic view showing the custom plates made to fix the construct. C: The postoperative xray showing the radiated autograft construct. Note the screws close to the distal physis. D: followup xray showing incorporation of the graft and growth from the distal femoral physis.

As in an allograft, a live fibula improves the results with pasteurized as well as radiation treated bone.71, 73, 84

#### **7.3.3 Prosthesis**

Prosthesis can be used to reconstruct non-joint defects. These can be used as physis sparing or joint saving implants.27 Endoprosthetic reconstruction of a diaphyseal defect avoids the donor site morbidity of autograft and the fracture and non-union risk of allograft especially for patients on chemotherapy. It also shortens surgical time significantly as compared to a VF. Clinical results have been at least as good as allografts.85, 86 The higher rate of loosening in the upper limb may be due to rotational stresses. The aseptic loosening may be reduced with hydroxyapatite (HA) or porous titanium bead coating.29 Customised HA coated implants have been used for epiphyseodiaphyseal defects. (fig 5) Early stability is obtained by extracortical plate fixation. No loosening or fractures were reported from 8 cases studied with a short follow up of 3 years.87 This implant can be expandable where the physis is resected to maintain limb length with growth.(fig 11) The early results are promising and this could become the method of choice for intercalary reconstruction.

Fig. 11. A: Preoperative xray of a distal femur osteosarcoma. B: The MRI shows the extent just proximal to the distal femoral physis. Note the skip lesion proximally. C: The defect was constructed with a custom prosthesis designed to fit into the small distal and proximal fragment. The distal fixation is with an hydroxyapatite coated surface and small extracortical plates. The proximal fixation is with a curved short intramedullary stem. This prosthesis could be lengthened with a noninvasive expansion mechanism (STANMORE implants, UK)

#### **8. Pelvis**

124 Osteosarcoma

significantly lower with ECRT as compared to allografts (43%).82 The fracture rates were similar and there were no infections. Histological evaluation of specimens from failed ECRT

Fig. 10. A: Preoperative xrays of an osteosarcoma of the femur treated with extracorporeal irradiation and reimplantation(ECRT). B: schematic view showing the custom plates made to fix the construct. C: The postoperative xray showing the radiated autograft construct. Note the screws close to the distal physis. D: followup xray showing incorporation of the

As in an allograft, a live fibula improves the results with pasteurized as well as radiation

Prosthesis can be used to reconstruct non-joint defects. These can be used as physis sparing or joint saving implants.27 Endoprosthetic reconstruction of a diaphyseal defect avoids the donor site morbidity of autograft and the fracture and non-union risk of allograft especially for patients on chemotherapy. It also shortens surgical time significantly as compared to a VF. Clinical results have been at least as good as allografts.85, 86 The higher rate of loosening in the upper limb may be due to rotational stresses. The aseptic loosening may be reduced with hydroxyapatite (HA) or porous titanium bead coating.29 Customised HA coated implants have been used for epiphyseodiaphyseal defects. (fig 5) Early stability is obtained by extracortical plate fixation. No loosening or fractures were reported from 8 cases studied with a short follow up of 3 years.87 This implant can be expandable where the physis is resected to maintain limb length with growth.(fig 11) The early results are promising and this could become the

graft and growth from the distal femoral physis.

method of choice for intercalary reconstruction.

treated bone.71, 73, 84

**7.3.3 Prosthesis**

cases show changes of repair and viable osteoblasts after 2-3 years.83

Any tumor in the pelvis is a challenge to an orthopaedic oncologist for resection and osteosarcoma being a high grade malignant tumor is even more challenging. Tumors are often large at presentation and do not always respond well to the preoperative chemotherapy. Osteosarcomas of the pelvis are rare accounting for 7-9% of all osteosarcomas.88 Prognosis has been reported to be dismal with 18% 5 year survival88,89,90 . Recent report indicates a 50% 5 year survival.91 Since osteosarcoma does not respond well to radiation, surgical resection with a tumor free margin is the only reliable method for cure.

Limb Salvage for Osteosarcoma: Current Status with a Review of Literature 127

Fig. 12. An Iliofemoral fusion held with a distal femur condyle buttress plate. This is

The incisions needed for each case may be different depending on the resection and reconstruction planned. A wrongly done biopsy is very likely to compromise the chance of limb salvage. It is therefore recommended that biopsy be best done by the surgeon who will

In acetabulum involving resection without reconstruction, a 2-3" shortening of the ipsilateral extremity occurs. The patient has normal function at the ankle and knee joints, but no function at the hip area. As fibrosis occurs, these patients can walk in 6-9 months with help of some support like a crutch or walking stick. The functional results could be improved by stabilising the pelvis by reconstructing. Hip transposition (mesh pseudoarthrosis) has given acceptable results with lower complication rates than other methods like prosthesis and allografts.93 Type II resections(periacetabular) have a better outcome with allograft and prosthesis composite as compared to more massive complete hemipelvic resections.94 Saddle prosthesis provides better function than a hemipelvectomy but has a considerable complication rate.95, 96 Infection (37%), dislocation (22%), fractures (22%), and heterotopic ossification (37%) were the commonest reported complications.97 Vertical migration has been noted in some cases. Pelvic allografts have been reported to give

contoured to match the bone contour.

be performing the final procedure.

The surgery is extensive and has the potential for many complications. An external hemipelvectomy has therefore been the standard of care in the past. Though it causes major disfigurement and extensive functional handicap, it was the safest way of getting a chance of cure in a pelvic osteosarcoma. With improvement in imaging as well as surgical technique and technology, limb saving resections have now become feasible and are the standard of care.

Pelvic resections for tumors are amongst the most challenging of operations for any surgeon. A detailed knowledge of anatomy and preparedness and ability to deal with large blood losses is a prerequisite. Pelvic resections are any one or the combination of the following four types. Type I (Iliac), Type II (periacetabular), Type3 (anterior arch) and type IV (sacrum). Classically, internal hemipelvectomy means resection of the entire hemipelvis from the SI joint to the pubic symphysis. Today, the term has come to include resections of the pelvis which include the acetabulum with varying portions of the Ilium & the anterior arch. Resections involving the acetabulum leave behind significantly more instability than the other types of partial pelvic resections.

Pelvic resections are extensive operations associated with the risks of major blood loss as well as wound problems from the extensive exposure and long surgical time. Resection without any reconstruction was done in the past to minimize these complications. With improvement in technique and results, reconstruction using arthodesis (iliofemoral and ischiofemoral fusion)(fig 12), surgical pseudarthrosis (mesh reconstruction), pelvic allografts, custom-made endoprostheses, the saddle prosthesis and reimplantation of the excised hemipelvis after sterilisation by radiation have been used with better cosmetic and functional results.92

It is logical to use these extensive surgical procedures only in those with a chance of cure. To minimize the incidence of local recurrence, only those patients should be selected where the extent of the tumor (judged by a preoperative workup) is such that it is possible to provide adequate margins for local control by surgery.; ie, tumors involving the innominate bone without extension into soft tissue or with minimal or moderate extension into soft tissue such that would permit an en bloc resection through clean planes and allow preservation of the major nerves and vessels for the ipsilateral extremity. Also, the general physical condition and life expectancy of the patient should justify the procedure because of the prolonged rehabilitation period (9-15mo). Involvement by the tumor of one of the major nerves, ie, sciatic or femoral, requiring its sacrifice, should revise the operative plan to that of a standard hemipelvectomy. Of course, such an eventuality should be explained beforehand to the patient, and the appropriate consent obtained.

Tumors located near the sacroiliac joints or pubic symphysis present a special problem in that positive margins of resection may occur unless the procedure is extended to the sacral ala or the contralateral side of the symphysis, respectively. Also, lesions medial to the pelvic bones may be adjacent to the neurovascular bundle and result in positive margins of excision. Induction chemotherapy may be useful to shrink these tumors prior to their surgical removal and thereby facilitate removal with more adequate resection margins.

The surgery is extensive and has the potential for many complications. An external hemipelvectomy has therefore been the standard of care in the past. Though it causes major disfigurement and extensive functional handicap, it was the safest way of getting a chance of cure in a pelvic osteosarcoma. With improvement in imaging as well as surgical technique and technology, limb saving resections have now become feasible and are the

Pelvic resections for tumors are amongst the most challenging of operations for any surgeon. A detailed knowledge of anatomy and preparedness and ability to deal with large blood losses is a prerequisite. Pelvic resections are any one or the combination of the following four types. Type I (Iliac), Type II (periacetabular), Type3 (anterior arch) and type IV (sacrum). Classically, internal hemipelvectomy means resection of the entire hemipelvis from the SI joint to the pubic symphysis. Today, the term has come to include resections of the pelvis which include the acetabulum with varying portions of the Ilium & the anterior arch. Resections involving the acetabulum leave behind significantly more instability than