Cleveland Clinic Journal of Medicine

Soft-tissue sarcomas are tumors of the mesenchymal system, and half develop in the extremities.¹ Although patients with soft-tissue sarcomas have been treated with a combination of surgery, radiation therapy, and chemotherapy, it remains unclear whether either radiation or chemotherapy improves outcomes for these patients. Soft-tissue sarcomas are therefore currently treated with surgical resection when possible, with or without chemotherapy or radiation.

Even though multimodal therapy for patients with these tumors is controversial, a multidisciplinary conference among the many providers who may be involved in the management these patients—orthopedic, medical, and radiation oncologists, as well as the referring primary care physician, plastic and reconstructive surgeons, physical therapists, and radiologists and pathologists with expertise in these tumors—is helpful.² This article presents an overview of the management of these patients, with a focus on the mainstay treatment, surgical resection. The roles of chemotherapy and radiation therapy for soft-tissue sarcomas, while touched upon here, are detailed in the final two articles in this supplement.

HISTOLOGIC GRADING AND THERAPY IMPLICATIONS

The prognosis of soft-tissue sarcomas correlates with histopathologic grade, and a three-grade system appears to be more accurate than a two-grade system.³ In general, low-grade lesions (grade 1) are unlikely to metastasize and are therefore less likely to need treatment with chemotherapy or radiation, as the risks of these therapies would most likely outweigh any benefit in terms of local control.

Specifically, the risk of radiation involves debilitation of local wound healing and the chance of dedifferentiation of low-grade lesions to higher-grade lesions with more metastatic potential. Grade 2 and 3 lesions are usually considered high-grade and are more likely to be treated with radiation and chemotherapy. Radiation is frequently used in patients with high-grade lesions when anticipated margins or actual margins are less than 1 cm.^4–6

Chemotherapy’s lack of proven efficacy for soft-tissue sarcomas likely stems from poor understanding of the pathophysiology, molecular biology, and even some aspects of the natural history of these uncommon and heterogeneous tumors. There are more than 50 subtypes of soft-tissue sarcoma,^7,8 and this heterogeneity has likely contributed to the difficulty of identifying chemotherapeutic agents that are highly active against these diseases.⁹

THE ROLE OF FAMILIAL GENETICS

Developing effective chemotherapeutic strategies may depend on grouping soft-tissue sarcomas more homogeneously. To compare like lesions with like lesions, molecular analysis and even molecular signatures may be of assistance. Along these lines, critical mutations and translocations have been described for several soft-tissue sarcoma subtypes.

Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations (ie, in every cell) in the p53 gene.¹⁰ Patients with Li-Fraumeni syndrome have an increased risk of developing soft-tissue sarcomas.^1,11

Neurofibromatosis type 1 is caused by germline mutations in the NF1 gene, and malignant peripheral nerve sheath tumors occur within neurofibromas in neurofibromatosis patients and typically have additional mutations in CDKN2A or p53.⁹ INI1 loss is seen in all cases of extrarenal rhabdoid tumors and has been reported in a subset of epithelioid sarcomas (those occurring in proximal/axial regions).^9,12 Delineation and greater understanding of these genetic abnormalities may lead to more effective medical therapy.

EVALUATION OF SUSPICIOUS SOFT-TISSUE MASSES

Figure 1 presents in flow chart form our general approach to the evaluation and management of patients with a soft-tissue mass suspicious for sarcoma—an approach detailed in the text below.

History and physical examination

Patients with soft-tissue sarcomas present with a mass that generally is increasing in size. The location and depth of the mass can be assessed on physical examination. In general, the deeper the mass, the more likely it is to be a sarcoma.¹³ Unlike bone sarcomas, soft-tissue sarcomas frequently are not associated with pain, so lack of pain does not make a mass more likely to be benign. In general, the only way to be sure that a mass is not malignant is to biopsy it. However, there are certain symptoms and signs that make a benign diagnosis much more likely. For example, very soft superficial masses that have not changed in size in years tend to be benign lipomas, and discolored lesions that go away with elevation of the affected body part tend to be hemangiomas.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is the primary imaging method for soft-tissue sarcomas. The benignity of a lesion such as a lipoma or hemangioma may be able to be determined with high certainty on MRI, in which case we call the imaging of the lesion “determinate.” Such lesions with determinate imaging (often referred to as “determinate lesions”) usually do not require a biopsy. However, the nature and identity of most lesions cannot be determined by MRI; although the MRI is still useful to help plan the biopsy in these cases, these lesions are termed “indeterminate” by MRI and should usually be biopsied.

Lesions that can be deemed determinate and usually be diagnosed as benign based on MRI findings include lipomas, hemangiomas, granuloma annulare, and ganglion cysts. However, most other soft-tissue lesions are indeterminate on MRI and, except in rare circumstances, require a biopsy to determine what they are and how they should be treated.

The primary biopsy procedures for soft-tissue sarcomas are needle or open biopsy techniques and, in general, are similar to those for bone sarcomas, as reviewed in the previous article in this supplement. Regardless of the biopsy technique, hemostasis must be meticulous and patients are generally advised to not use the affected limb for at least several days after the biopsy to reduce the risk of a cancer cell–laden hematoma. It is preferable for the biopsy to be performed by or in consultation with the surgeon who will do the resection, if required.

Avoid transverse incisions

Lymph node biopsies

Lymph node biopsies are not generally indicated in patients with soft-tissue sarcoma. However, lymph node assessment and management should be considered in cases of clear cell sarcoma, epithelioid sarcoma, angiosarcoma, and embryonal/alveolar rhabdomyosarcoma, each of which has a greater than 10% incidence of lymph node metastasis.¹⁴ In this subset of soft-tissue sarcomas, a 5-year survival rate of 46% has been reported with therapeutic lymphadenectomy with curative intent versus nearly 0% with no lymphadenectomy or noncurative lymphadenectomy.¹⁴

Our approach in these sarcomas that go to the lymph nodes with increased relative frequency has been to first resect the sarcoma and then, after the margin is determined to be negative on the permanent pathology report, to schedule a nuclear medicine radiotracer study to analyze the drainage of the surgical bed. With this information we take the patient to the operating room and assess the location of the sentinel node (ie, node with the highest level of activity) through the skin using a radioactive counter with a sterile probe. We then make an incision in this area and find the lymph node. Upon removal of the “hot” lymph node, we reassess the radioactivity of the resected node and its node bed to be sure that we have the sentinel node. If this node or any node in the dissection has tumor in it, we do a therapeutic lymphadenectomy to remove all the lymph nodes in the area. For example, in the lower leg the lymphatic drainage is to the popliteal area, the inguinal area, or both. In the lower arm the lymphatic drainage is to the epitrochlear area and the axilla.

RESECTION

The resection surgery involves careful preoperative planning, almost always with an MRI and subsequent review by musculoskeletal tumor radiologists. In the operating room, general anesthesia is preferred to avoid ineffective blocks or overly effective blocks, which prevent neurologic examination immediately after the operation. If the functional loss is not too great, resection of the entire muscle or muscles involved is performed. If neurovascular structures are not encased (ie, not more than 50% surrounded in the case of arteries or motor nerves), then these structures are spared. If arteries are encased, the vessels are bypassed and the encased structure is left with the resection specimen. If the tumor is adjacent to but not encasing the neurovascular structures, the best course is to discuss with the radiation oncology team whether they prefer preoperative or postoperative radiation therapy. In general, for a high-grade lesion with adjacent neurovascular structues and no plane between the tumor and these structures, we ask our radiation oncologist colleagues to see the patient and discuss preoperative or perioperative (brachytherapy) radiation therapy. Postoperatively, where there is less than a 1-cm margin with no fascial boundary, we generally recommend radiation.

Margins

In our experience, margins of 1 cm or greater or resections with a fascial boundary are adequate and will leave patients with a much lower than 10% risk of recurrence. Others have postulated that margins that are smaller than this can have a very low rate of recurrence if perioperative (preoperative, intraoperative, or postoperative) radiation is given (personal communication from Drs. Jeffrey Eckardt and Dempsey Springfield). However, no well-controlled study has demonstrated how close the margin can be while still achieving an acceptable recurrence rate, and such a study would be very hard to perform given the rarity and heterogeneity of soft-tissue sarcomas and the variability in their assessment and surgical treatment.

Intralesional surgery leads to recurrence

Intralesional surgery will always lead to recurrence if the lesion is truly a soft-tissue sarcoma, even in spite of radiation therapy, chemotherapy, or both. Myomectomy and compartmental resections are frequently necessary to achieve a negative margin (normal tissue around the entire resection specimen). If intralesional surgery has been performed at an outside institution, we have generally recommended resection of the tumor bed, and in our experience this has reduced the recurrence rate after intralesional surgery to levels near those obtained when we perform the biopsy. In our experience, intralesional surgery without tumor bed resection will result in recurrence in nearly every case.

Reconstruction

Postoperative reconstruction of the defect involves closure of the fascia and skin with minimal tension, if possible. If there is tension, a vacuum-assisted closure dressing is placed on the wound and the patient returns for definitive closure, usually with a muscle flap. If the flap is a straightforward rotational flap, such as a medial gastrocnemius, or if only a split-thickness skin graft is required because there is healthy muscle in the floor of the open wound, this can be performed by experienced orthopedic surgeons. If these straightforward solutions are not possible, consultation with plastic surgeons is required, and they will cover the area with a complex rotational flap or, occasionally, with a free flap. For split-thickness skin grafts, it is prudent to make certain that the width of a #15 knife blade can pass between the blade and the housing of the Padgett dermatome and to take the skin from the extremity ipsilateral to the sarcoma (even with negative margins) to ensure that skin will not be contaminated with errant sarcoma cells.

Reconstruction following sarcoma resection is discussed in further detail in the next article in this supplement.

OUTCOMES AND FOLLOW-UP

The recurrence rate for soft-tissue sarcomas resected at Cleveland Clinic over the past 15 years has been less than 10%. This rate is comparable to the rates at other institutions that perform a high volume of sarcoma resections, but at institutions without a group dedicated to these procedures or without substantial experience in them, the recurrence rate is much higher, particularly with positive margins.¹⁵

Cure for soft-tissue sarcomas depends on being disease-free not only locally but also systemically. Most metastases from soft-tissue sarcomas are to the lung and, less commonly (as noted above), the lymph nodes. We assess local recurrence and metastatic disease at 3-month intervals for the first 2 years. Among patients who are disease-free at 2 years after the definitive surgery, the cure rate is 80% to 85%. After 2 years, we assess patients for presence of disease at 6-month intervals for the next 3 years and at yearly intervals thereafter.

Patients who have a recurrence are at increased risk for metastatic disease, and it is often very hard to achieve local control, as these patients frequently have had tumor contamination of the wound. At that point, unless the entire wound is excised or an amputation is performed, recurrences will continue. A nomogram has been validated for evaluating 10-year soft-tissue sarcoma–specific survival¹⁶ and is freely available at www.nomograms.org.

FUTURE DIRECTIONS

Future research challenges in this area include breaking down soft-tissue sarcoma subgroups more homogeneously, possibly with genetic markers, to better determine which lesions might benefit from chemotherapy. The goal of improved subtyping is to decrease the metastatic rate of soft-tissue sarcomas in much the same manner that directed chemotherapy has improved the metastasis and cure rates for patients with Ewing sarcoma and osteosarcoma.

Soft-tissue sarcomas are tumors of the mesenchymal system, and half develop in the extremities.¹ Although patients with soft-tissue sarcomas have been treated with a combination of surgery, radiation therapy, and chemotherapy, it remains unclear whether either radiation or chemotherapy improves outcomes for these patients. Soft-tissue sarcomas are therefore currently treated with surgical resection when possible, with or without chemotherapy or radiation.

Even though multimodal therapy for patients with these tumors is controversial, a multidisciplinary conference among the many providers who may be involved in the management these patients—orthopedic, medical, and radiation oncologists, as well as the referring primary care physician, plastic and reconstructive surgeons, physical therapists, and radiologists and pathologists with expertise in these tumors—is helpful.² This article presents an overview of the management of these patients, with a focus on the mainstay treatment, surgical resection. The roles of chemotherapy and radiation therapy for soft-tissue sarcomas, while touched upon here, are detailed in the final two articles in this supplement.

HISTOLOGIC GRADING AND THERAPY IMPLICATIONS

The prognosis of soft-tissue sarcomas correlates with histopathologic grade, and a three-grade system appears to be more accurate than a two-grade system.³ In general, low-grade lesions (grade 1) are unlikely to metastasize and are therefore less likely to need treatment with chemotherapy or radiation, as the risks of these therapies would most likely outweigh any benefit in terms of local control.

Specifically, the risk of radiation involves debilitation of local wound healing and the chance of dedifferentiation of low-grade lesions to higher-grade lesions with more metastatic potential. Grade 2 and 3 lesions are usually considered high-grade and are more likely to be treated with radiation and chemotherapy. Radiation is frequently used in patients with high-grade lesions when anticipated margins or actual margins are less than 1 cm.^4–6

Chemotherapy’s lack of proven efficacy for soft-tissue sarcomas likely stems from poor understanding of the pathophysiology, molecular biology, and even some aspects of the natural history of these uncommon and heterogeneous tumors. There are more than 50 subtypes of soft-tissue sarcoma,^7,8 and this heterogeneity has likely contributed to the difficulty of identifying chemotherapeutic agents that are highly active against these diseases.⁹

THE ROLE OF FAMILIAL GENETICS

Developing effective chemotherapeutic strategies may depend on grouping soft-tissue sarcomas more homogeneously. To compare like lesions with like lesions, molecular analysis and even molecular signatures may be of assistance. Along these lines, critical mutations and translocations have been described for several soft-tissue sarcoma subtypes.

Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations (ie, in every cell) in the p53 gene.¹⁰ Patients with Li-Fraumeni syndrome have an increased risk of developing soft-tissue sarcomas.^1,11

Neurofibromatosis type 1 is caused by germline mutations in the NF1 gene, and malignant peripheral nerve sheath tumors occur within neurofibromas in neurofibromatosis patients and typically have additional mutations in CDKN2A or p53.⁹ INI1 loss is seen in all cases of extrarenal rhabdoid tumors and has been reported in a subset of epithelioid sarcomas (those occurring in proximal/axial regions).^9,12 Delineation and greater understanding of these genetic abnormalities may lead to more effective medical therapy.

EVALUATION OF SUSPICIOUS SOFT-TISSUE MASSES

Figure 1 presents in flow chart form our general approach to the evaluation and management of patients with a soft-tissue mass suspicious for sarcoma—an approach detailed in the text below.

History and physical examination

Patients with soft-tissue sarcomas present with a mass that generally is increasing in size. The location and depth of the mass can be assessed on physical examination. In general, the deeper the mass, the more likely it is to be a sarcoma.¹³ Unlike bone sarcomas, soft-tissue sarcomas frequently are not associated with pain, so lack of pain does not make a mass more likely to be benign. In general, the only way to be sure that a mass is not malignant is to biopsy it. However, there are certain symptoms and signs that make a benign diagnosis much more likely. For example, very soft superficial masses that have not changed in size in years tend to be benign lipomas, and discolored lesions that go away with elevation of the affected body part tend to be hemangiomas.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is the primary imaging method for soft-tissue sarcomas. The benignity of a lesion such as a lipoma or hemangioma may be able to be determined with high certainty on MRI, in which case we call the imaging of the lesion “determinate.” Such lesions with determinate imaging (often referred to as “determinate lesions”) usually do not require a biopsy. However, the nature and identity of most lesions cannot be determined by MRI; although the MRI is still useful to help plan the biopsy in these cases, these lesions are termed “indeterminate” by MRI and should usually be biopsied.

Lesions that can be deemed determinate and usually be diagnosed as benign based on MRI findings include lipomas, hemangiomas, granuloma annulare, and ganglion cysts. However, most other soft-tissue lesions are indeterminate on MRI and, except in rare circumstances, require a biopsy to determine what they are and how they should be treated.

The primary biopsy procedures for soft-tissue sarcomas are needle or open biopsy techniques and, in general, are similar to those for bone sarcomas, as reviewed in the previous article in this supplement. Regardless of the biopsy technique, hemostasis must be meticulous and patients are generally advised to not use the affected limb for at least several days after the biopsy to reduce the risk of a cancer cell–laden hematoma. It is preferable for the biopsy to be performed by or in consultation with the surgeon who will do the resection, if required.

Avoid transverse incisions

Lymph node biopsies

Lymph node biopsies are not generally indicated in patients with soft-tissue sarcoma. However, lymph node assessment and management should be considered in cases of clear cell sarcoma, epithelioid sarcoma, angiosarcoma, and embryonal/alveolar rhabdomyosarcoma, each of which has a greater than 10% incidence of lymph node metastasis.¹⁴ In this subset of soft-tissue sarcomas, a 5-year survival rate of 46% has been reported with therapeutic lymphadenectomy with curative intent versus nearly 0% with no lymphadenectomy or noncurative lymphadenectomy.¹⁴

Our approach in these sarcomas that go to the lymph nodes with increased relative frequency has been to first resect the sarcoma and then, after the margin is determined to be negative on the permanent pathology report, to schedule a nuclear medicine radiotracer study to analyze the drainage of the surgical bed. With this information we take the patient to the operating room and assess the location of the sentinel node (ie, node with the highest level of activity) through the skin using a radioactive counter with a sterile probe. We then make an incision in this area and find the lymph node. Upon removal of the “hot” lymph node, we reassess the radioactivity of the resected node and its node bed to be sure that we have the sentinel node. If this node or any node in the dissection has tumor in it, we do a therapeutic lymphadenectomy to remove all the lymph nodes in the area. For example, in the lower leg the lymphatic drainage is to the popliteal area, the inguinal area, or both. In the lower arm the lymphatic drainage is to the epitrochlear area and the axilla.

RESECTION

The resection surgery involves careful preoperative planning, almost always with an MRI and subsequent review by musculoskeletal tumor radiologists. In the operating room, general anesthesia is preferred to avoid ineffective blocks or overly effective blocks, which prevent neurologic examination immediately after the operation. If the functional loss is not too great, resection of the entire muscle or muscles involved is performed. If neurovascular structures are not encased (ie, not more than 50% surrounded in the case of arteries or motor nerves), then these structures are spared. If arteries are encased, the vessels are bypassed and the encased structure is left with the resection specimen. If the tumor is adjacent to but not encasing the neurovascular structures, the best course is to discuss with the radiation oncology team whether they prefer preoperative or postoperative radiation therapy. In general, for a high-grade lesion with adjacent neurovascular structues and no plane between the tumor and these structures, we ask our radiation oncologist colleagues to see the patient and discuss preoperative or perioperative (brachytherapy) radiation therapy. Postoperatively, where there is less than a 1-cm margin with no fascial boundary, we generally recommend radiation.

Margins

In our experience, margins of 1 cm or greater or resections with a fascial boundary are adequate and will leave patients with a much lower than 10% risk of recurrence. Others have postulated that margins that are smaller than this can have a very low rate of recurrence if perioperative (preoperative, intraoperative, or postoperative) radiation is given (personal communication from Drs. Jeffrey Eckardt and Dempsey Springfield). However, no well-controlled study has demonstrated how close the margin can be while still achieving an acceptable recurrence rate, and such a study would be very hard to perform given the rarity and heterogeneity of soft-tissue sarcomas and the variability in their assessment and surgical treatment.

Intralesional surgery leads to recurrence

Intralesional surgery will always lead to recurrence if the lesion is truly a soft-tissue sarcoma, even in spite of radiation therapy, chemotherapy, or both. Myomectomy and compartmental resections are frequently necessary to achieve a negative margin (normal tissue around the entire resection specimen). If intralesional surgery has been performed at an outside institution, we have generally recommended resection of the tumor bed, and in our experience this has reduced the recurrence rate after intralesional surgery to levels near those obtained when we perform the biopsy. In our experience, intralesional surgery without tumor bed resection will result in recurrence in nearly every case.

Reconstruction

Postoperative reconstruction of the defect involves closure of the fascia and skin with minimal tension, if possible. If there is tension, a vacuum-assisted closure dressing is placed on the wound and the patient returns for definitive closure, usually with a muscle flap. If the flap is a straightforward rotational flap, such as a medial gastrocnemius, or if only a split-thickness skin graft is required because there is healthy muscle in the floor of the open wound, this can be performed by experienced orthopedic surgeons. If these straightforward solutions are not possible, consultation with plastic surgeons is required, and they will cover the area with a complex rotational flap or, occasionally, with a free flap. For split-thickness skin grafts, it is prudent to make certain that the width of a #15 knife blade can pass between the blade and the housing of the Padgett dermatome and to take the skin from the extremity ipsilateral to the sarcoma (even with negative margins) to ensure that skin will not be contaminated with errant sarcoma cells.

Reconstruction following sarcoma resection is discussed in further detail in the next article in this supplement.

OUTCOMES AND FOLLOW-UP

The recurrence rate for soft-tissue sarcomas resected at Cleveland Clinic over the past 15 years has been less than 10%. This rate is comparable to the rates at other institutions that perform a high volume of sarcoma resections, but at institutions without a group dedicated to these procedures or without substantial experience in them, the recurrence rate is much higher, particularly with positive margins.¹⁵

Cure for soft-tissue sarcomas depends on being disease-free not only locally but also systemically. Most metastases from soft-tissue sarcomas are to the lung and, less commonly (as noted above), the lymph nodes. We assess local recurrence and metastatic disease at 3-month intervals for the first 2 years. Among patients who are disease-free at 2 years after the definitive surgery, the cure rate is 80% to 85%. After 2 years, we assess patients for presence of disease at 6-month intervals for the next 3 years and at yearly intervals thereafter.

Patients who have a recurrence are at increased risk for metastatic disease, and it is often very hard to achieve local control, as these patients frequently have had tumor contamination of the wound. At that point, unless the entire wound is excised or an amputation is performed, recurrences will continue. A nomogram has been validated for evaluating 10-year soft-tissue sarcoma–specific survival¹⁶ and is freely available at www.nomograms.org.

FUTURE DIRECTIONS

Future research challenges in this area include breaking down soft-tissue sarcoma subgroups more homogeneously, possibly with genetic markers, to better determine which lesions might benefit from chemotherapy. The goal of improved subtyping is to decrease the metastatic rate of soft-tissue sarcomas in much the same manner that directed chemotherapy has improved the metastasis and cure rates for patients with Ewing sarcoma and osteosarcoma.

Soft-tissue sarcomas are tumors of the mesenchymal system, and half develop in the extremities.¹ Although patients with soft-tissue sarcomas have been treated with a combination of surgery, radiation therapy, and chemotherapy, it remains unclear whether either radiation or chemotherapy improves outcomes for these patients. Soft-tissue sarcomas are therefore currently treated with surgical resection when possible, with or without chemotherapy or radiation.

Even though multimodal therapy for patients with these tumors is controversial, a multidisciplinary conference among the many providers who may be involved in the management these patients—orthopedic, medical, and radiation oncologists, as well as the referring primary care physician, plastic and reconstructive surgeons, physical therapists, and radiologists and pathologists with expertise in these tumors—is helpful.² This article presents an overview of the management of these patients, with a focus on the mainstay treatment, surgical resection. The roles of chemotherapy and radiation therapy for soft-tissue sarcomas, while touched upon here, are detailed in the final two articles in this supplement.

HISTOLOGIC GRADING AND THERAPY IMPLICATIONS

The prognosis of soft-tissue sarcomas correlates with histopathologic grade, and a three-grade system appears to be more accurate than a two-grade system.³ In general, low-grade lesions (grade 1) are unlikely to metastasize and are therefore less likely to need treatment with chemotherapy or radiation, as the risks of these therapies would most likely outweigh any benefit in terms of local control.

Specifically, the risk of radiation involves debilitation of local wound healing and the chance of dedifferentiation of low-grade lesions to higher-grade lesions with more metastatic potential. Grade 2 and 3 lesions are usually considered high-grade and are more likely to be treated with radiation and chemotherapy. Radiation is frequently used in patients with high-grade lesions when anticipated margins or actual margins are less than 1 cm.^4–6

Chemotherapy’s lack of proven efficacy for soft-tissue sarcomas likely stems from poor understanding of the pathophysiology, molecular biology, and even some aspects of the natural history of these uncommon and heterogeneous tumors. There are more than 50 subtypes of soft-tissue sarcoma,^7,8 and this heterogeneity has likely contributed to the difficulty of identifying chemotherapeutic agents that are highly active against these diseases.⁹

THE ROLE OF FAMILIAL GENETICS

Developing effective chemotherapeutic strategies may depend on grouping soft-tissue sarcomas more homogeneously. To compare like lesions with like lesions, molecular analysis and even molecular signatures may be of assistance. Along these lines, critical mutations and translocations have been described for several soft-tissue sarcoma subtypes.

Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations (ie, in every cell) in the p53 gene.¹⁰ Patients with Li-Fraumeni syndrome have an increased risk of developing soft-tissue sarcomas.^1,11

Neurofibromatosis type 1 is caused by germline mutations in the NF1 gene, and malignant peripheral nerve sheath tumors occur within neurofibromas in neurofibromatosis patients and typically have additional mutations in CDKN2A or p53.⁹ INI1 loss is seen in all cases of extrarenal rhabdoid tumors and has been reported in a subset of epithelioid sarcomas (those occurring in proximal/axial regions).^9,12 Delineation and greater understanding of these genetic abnormalities may lead to more effective medical therapy.

EVALUATION OF SUSPICIOUS SOFT-TISSUE MASSES

Figure 1 presents in flow chart form our general approach to the evaluation and management of patients with a soft-tissue mass suspicious for sarcoma—an approach detailed in the text below.

History and physical examination

Patients with soft-tissue sarcomas present with a mass that generally is increasing in size. The location and depth of the mass can be assessed on physical examination. In general, the deeper the mass, the more likely it is to be a sarcoma.¹³ Unlike bone sarcomas, soft-tissue sarcomas frequently are not associated with pain, so lack of pain does not make a mass more likely to be benign. In general, the only way to be sure that a mass is not malignant is to biopsy it. However, there are certain symptoms and signs that make a benign diagnosis much more likely. For example, very soft superficial masses that have not changed in size in years tend to be benign lipomas, and discolored lesions that go away with elevation of the affected body part tend to be hemangiomas.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is the primary imaging method for soft-tissue sarcomas. The benignity of a lesion such as a lipoma or hemangioma may be able to be determined with high certainty on MRI, in which case we call the imaging of the lesion “determinate.” Such lesions with determinate imaging (often referred to as “determinate lesions”) usually do not require a biopsy. However, the nature and identity of most lesions cannot be determined by MRI; although the MRI is still useful to help plan the biopsy in these cases, these lesions are termed “indeterminate” by MRI and should usually be biopsied.

Lesions that can be deemed determinate and usually be diagnosed as benign based on MRI findings include lipomas, hemangiomas, granuloma annulare, and ganglion cysts. However, most other soft-tissue lesions are indeterminate on MRI and, except in rare circumstances, require a biopsy to determine what they are and how they should be treated.

The primary biopsy procedures for soft-tissue sarcomas are needle or open biopsy techniques and, in general, are similar to those for bone sarcomas, as reviewed in the previous article in this supplement. Regardless of the biopsy technique, hemostasis must be meticulous and patients are generally advised to not use the affected limb for at least several days after the biopsy to reduce the risk of a cancer cell–laden hematoma. It is preferable for the biopsy to be performed by or in consultation with the surgeon who will do the resection, if required.

Avoid transverse incisions

Lymph node biopsies

Lymph node biopsies are not generally indicated in patients with soft-tissue sarcoma. However, lymph node assessment and management should be considered in cases of clear cell sarcoma, epithelioid sarcoma, angiosarcoma, and embryonal/alveolar rhabdomyosarcoma, each of which has a greater than 10% incidence of lymph node metastasis.¹⁴ In this subset of soft-tissue sarcomas, a 5-year survival rate of 46% has been reported with therapeutic lymphadenectomy with curative intent versus nearly 0% with no lymphadenectomy or noncurative lymphadenectomy.¹⁴

Our approach in these sarcomas that go to the lymph nodes with increased relative frequency has been to first resect the sarcoma and then, after the margin is determined to be negative on the permanent pathology report, to schedule a nuclear medicine radiotracer study to analyze the drainage of the surgical bed. With this information we take the patient to the operating room and assess the location of the sentinel node (ie, node with the highest level of activity) through the skin using a radioactive counter with a sterile probe. We then make an incision in this area and find the lymph node. Upon removal of the “hot” lymph node, we reassess the radioactivity of the resected node and its node bed to be sure that we have the sentinel node. If this node or any node in the dissection has tumor in it, we do a therapeutic lymphadenectomy to remove all the lymph nodes in the area. For example, in the lower leg the lymphatic drainage is to the popliteal area, the inguinal area, or both. In the lower arm the lymphatic drainage is to the epitrochlear area and the axilla.

RESECTION

The resection surgery involves careful preoperative planning, almost always with an MRI and subsequent review by musculoskeletal tumor radiologists. In the operating room, general anesthesia is preferred to avoid ineffective blocks or overly effective blocks, which prevent neurologic examination immediately after the operation. If the functional loss is not too great, resection of the entire muscle or muscles involved is performed. If neurovascular structures are not encased (ie, not more than 50% surrounded in the case of arteries or motor nerves), then these structures are spared. If arteries are encased, the vessels are bypassed and the encased structure is left with the resection specimen. If the tumor is adjacent to but not encasing the neurovascular structures, the best course is to discuss with the radiation oncology team whether they prefer preoperative or postoperative radiation therapy. In general, for a high-grade lesion with adjacent neurovascular structues and no plane between the tumor and these structures, we ask our radiation oncologist colleagues to see the patient and discuss preoperative or perioperative (brachytherapy) radiation therapy. Postoperatively, where there is less than a 1-cm margin with no fascial boundary, we generally recommend radiation.

Margins

In our experience, margins of 1 cm or greater or resections with a fascial boundary are adequate and will leave patients with a much lower than 10% risk of recurrence. Others have postulated that margins that are smaller than this can have a very low rate of recurrence if perioperative (preoperative, intraoperative, or postoperative) radiation is given (personal communication from Drs. Jeffrey Eckardt and Dempsey Springfield). However, no well-controlled study has demonstrated how close the margin can be while still achieving an acceptable recurrence rate, and such a study would be very hard to perform given the rarity and heterogeneity of soft-tissue sarcomas and the variability in their assessment and surgical treatment.

Intralesional surgery leads to recurrence

Intralesional surgery will always lead to recurrence if the lesion is truly a soft-tissue sarcoma, even in spite of radiation therapy, chemotherapy, or both. Myomectomy and compartmental resections are frequently necessary to achieve a negative margin (normal tissue around the entire resection specimen). If intralesional surgery has been performed at an outside institution, we have generally recommended resection of the tumor bed, and in our experience this has reduced the recurrence rate after intralesional surgery to levels near those obtained when we perform the biopsy. In our experience, intralesional surgery without tumor bed resection will result in recurrence in nearly every case.

Reconstruction

Postoperative reconstruction of the defect involves closure of the fascia and skin with minimal tension, if possible. If there is tension, a vacuum-assisted closure dressing is placed on the wound and the patient returns for definitive closure, usually with a muscle flap. If the flap is a straightforward rotational flap, such as a medial gastrocnemius, or if only a split-thickness skin graft is required because there is healthy muscle in the floor of the open wound, this can be performed by experienced orthopedic surgeons. If these straightforward solutions are not possible, consultation with plastic surgeons is required, and they will cover the area with a complex rotational flap or, occasionally, with a free flap. For split-thickness skin grafts, it is prudent to make certain that the width of a #15 knife blade can pass between the blade and the housing of the Padgett dermatome and to take the skin from the extremity ipsilateral to the sarcoma (even with negative margins) to ensure that skin will not be contaminated with errant sarcoma cells.

Reconstruction following sarcoma resection is discussed in further detail in the next article in this supplement.

OUTCOMES AND FOLLOW-UP

The recurrence rate for soft-tissue sarcomas resected at Cleveland Clinic over the past 15 years has been less than 10%. This rate is comparable to the rates at other institutions that perform a high volume of sarcoma resections, but at institutions without a group dedicated to these procedures or without substantial experience in them, the recurrence rate is much higher, particularly with positive margins.¹⁵

Cure for soft-tissue sarcomas depends on being disease-free not only locally but also systemically. Most metastases from soft-tissue sarcomas are to the lung and, less commonly (as noted above), the lymph nodes. We assess local recurrence and metastatic disease at 3-month intervals for the first 2 years. Among patients who are disease-free at 2 years after the definitive surgery, the cure rate is 80% to 85%. After 2 years, we assess patients for presence of disease at 6-month intervals for the next 3 years and at yearly intervals thereafter.

Patients who have a recurrence are at increased risk for metastatic disease, and it is often very hard to achieve local control, as these patients frequently have had tumor contamination of the wound. At that point, unless the entire wound is excised or an amputation is performed, recurrences will continue. A nomogram has been validated for evaluating 10-year soft-tissue sarcoma–specific survival¹⁶ and is freely available at www.nomograms.org.

FUTURE DIRECTIONS

Future research challenges in this area include breaking down soft-tissue sarcoma subgroups more homogeneously, possibly with genetic markers, to better determine which lesions might benefit from chemotherapy. The goal of improved subtyping is to decrease the metastatic rate of soft-tissue sarcomas in much the same manner that directed chemotherapy has improved the metastasis and cure rates for patients with Ewing sarcoma and osteosarcoma.

Advances in the management of soft-tissue and bone sarcomas—referred to collectively as “musculoskeletal sarcomas” hereafter—have resulted in significant improvements in survival and quality of life.^1–3 Several factors have likely contributed to these advances, including improved surgical technique and the development of referral centers for sarcoma treatment that have embraced a multidisciplinary approach.^1,2

The goal of treatment for musculoskeletal sarcomas is to optimize oncologic outcome and maximize functional restoration.^2,3 Surgical resection has been the mainstay of therapy,^1–7 as detailed earlier in this supplement. In patients with musculoskeletal sarcomas of the extremities, limb-sparing resection has been shown to be significantly superior to amputation.^1,7–9 Wide local excision of the tumor along with its muscle compartment, followed by adjuvant chemotherapy and radiation therapy, has allowed limb salvage without an increased risk of recurrence in many patients.³ However, wide tumor resection can leave large defects that are not amenable to coverage by mobilization of the surrounding tissues, particularly if those tissues have been irradiated. As a result, resection can expose neurovascular structures, bone without periosteum, alloplastic materials, and internal fixation devices.

GOALS OF RECONSTRUCTION

Reconstructive surgery after musculoskeletal sarcoma resection aims to provide adequate wound coverage, preserve function, and optimize the cosmetic outcome.^1–3 Tumors can be found on areas crucial to limb movement or may involve tissues vital to limb function. Reconstruction to repair these deficits can take many forms. In certain situations, amputation is still inevitable. In those cases, the reconstruction should provide stable stump coverage with durability and the ability to fit well with an external prosthesis.³

TIMING OF RECONSTRUCTION

Immediate reconstruction should be pursued if possible

Immediate reconstruction after a negative margin should always be considered and should be attempted when possible. Immediate reconstruction allows the reconstructive surgeon to benefit from better evaluation of the defect and exposed structures, as no scar tissue is present to distort the anatomy. Likewise, patients benefit from faster recovery and can receive adjuvant treatment (if necessary) sooner, as well as earlier rehabilitation. Patients may also benefit psychologically from immediate reconstruction.^1,3

Indications for delayed reconstruction

Delayed reconstruction is primarily indicated when there are wound healing problems or there is uncertainty about the tumor margins. Secondary indications for delayed reconstruction are wound dehiscence and unstable soft-tissue coverage. If hardware is exposed, the recommendation is for early intervention and wound coverage with well-vascularized tissue to protect and cover the implant or prosthesis.

What about radiation therapy?

A very important consideration in reconstruction is the need for neoadjuvant or adjuvant radiation therapy.^3,10,11 Irradiated wounds have a higher incidence of complications, including a tendency to dehisce. In patients who have been previously irradiated, the best practice is to perform immediate reconstruction with well-vascularized tissue, most likely a free tissue transfer.^4,6,11,12 This practice reduces hospital stay, costs, and morbidity and increases limb salvage and patient satisfaction.¹³

SYSTEMATIC PREOPERATIVE PLANNING NEEDED

Reconstruction after musculoskeletal sarcoma resection should be planned systematically within a process that involves preoperative anticipation of the defect size and the resulting functional and cosmetic deficits that might need to be addressed. A preoperative visit to the reconstructive surgeon can be very helpful for presurgical planning.

During surgery it is usually preferable to allow the surgeon doing the tumor resection (eg, surgical oncologist or orthopedic oncologist) to complete the resection because the dimensions of the defect are not certain until negative margins are obtained.¹⁴ If tumor margins are unclear at the time of initial resection, the surgeon should consider delaying the definitive reconstruction until the permanent sections confirm negative margins. Temporary closure can be achieved with wound dressings, skin grafts (either allograft or autograft), or negative-pressure wound therapy. In the same context, if neurovascular structures are exposed it is reasonable to use a muscle flap without “tailoring” the flap to the defect. This approach allows the flap to be advanced or repositioned in case of positive margins, and the skin graft can be applied to the muscle surface in a second procedure.³

RECONSTRUCTIVE METHODS: A BRIEF OVERVIEW

Several methods can be used to close musculoskeletal sarcoma excision defects. Smaller defects can be closed primarily, although most defects are large and not amenable to primary closure. If fascia or muscle is preserved with only the skin coverage missing, the wound can be covered with either split-thickness or full-thickness skin grafts.^1,4,6 Split-thickness skin grafts can be obtained in larger amounts and often heal faster than full-thickness skin grafts. However, most resections will require durable tissue coverage, particularly if adjuvant radiation therapy is planned.

In the case of long bone sarcoma resection, the resulting defect is usually large and complex and the traditional reconstruction is based on avascular allografts and local tissue flaps. However, allografts are associated with high rates of infection, nonunion, and fracture, leading to failure in about 50% of cases. Microvascular free flaps that contain bone, such as free fibula flaps, have been used instead of allografts with good success rates.²

Lately there has been growing interest in the use of the vacuum-assisted closure device (a form of negative-pressure wound therapy) to promote wound healing. It has been shown to improve the granulation and healing of open wounds by absorbing moisture, as well as to promote adherence after skin grafting, thereby reducing the risk of graft displacement.^1,3 This device can be used immediately after musculoskeletal sarcoma resection while definitive tumor margin results are pending. It also can be used to prepare the wound bed for grafting in high-risk patients who would not tolerate more complex reconstructions. 

Local or adjacent fascial, fasciocutaneous, and dermal flaps can also be used in lower-extremity reconstruction. However, muscle or musculocutaneous flaps are the mainstay of reconstruction after resection of musculoskeletal sarcomas. This group also includes perforator flaps, which have grown in popularity in the last few years.^1,3

Musculoskeletal sarcomas can occur in virtually any region of the body, and myriad reconstructive options are available for various body sites. Since lower-extremity musculoskeletal sarcomas represent about 75% of cases,¹ we will focus mainly on reconstruction of the lower extremity.

Factors driving choice of flap

Selection of an appropriate flap is essential to an optimal outcome. Flaps should be chosen with regard to donor site morbidity, functional requirements, length and diameter of the vascular pedicle, and aesthetic outcome.³ Usually physical examination, palpation of peripheral pulses, and Doppler ultrasonography are sufficient to evaluate the circulation. A preoperative angiogram should be considered in patients with severe peripheral vascular disease or previous trauma, which can potentially compromise the reconstructive outcome.¹⁵

Each region of the lower extremity possesses unique anatomic and functional characteristics that must be evaluated. It is useful to categorize the thigh, lower leg, and foot into separate anatomic units when planning reconstruction. We further divided these units into several subunits, as previously proposed by Sherman and Law¹⁵ and as outlined below.

Thigh

The thigh is usually well perfused and has several muscle groups, which facilitates reconstruction. Primary closure, skin grafts, or local flaps are acceptable options in most cases. The remaining musculature can be rotated or advanced to cover defects in the anterior or posterior thigh, providing bulk and adequate blood supply.

Hip and proximal/lateral thigh. Local muscle or myocutaneous flap options include tensor fascia lata, vastus lateralis, and rectus femoris flaps, all of which are based on the lateral circumflex femoral artery.

The tensor fascia lata flap is thin but has a long fascia extension that can be elevated from above the knee and can include a large skin paddle that is innervated by the lateral femoral cutaneous nerve. Some patients may experience knee instability after tensor fascia lata harvest.

The vastus lateralis muscle flap provides good bulk. Its arc of rotation reaches most of the inferior and posterior pelvis. It has little effect on ambulation.

The rectus femoris muscle flap is not so bulky, is easily mobilized, and has a wide arc of rotation. The donor site can be closed primarily. Harvest of this muscle can be associated with some strength loss during knee extension. For large defects of the upper third of the leg, a pedicled rectus abdominis muscle flap based on the deep inferior epigastric artery can be used. A vertically oriented skin island can be extended up to the costal margin, improving the reach. When the nature of the wound precludes use of pedicle flaps, free tissue transfer is indicated, with the latissimus dorsi muscle flap being used most commonly.^15,16

Mid-thigh. Wounds in this location often can be closed with skin grafts or fasciocutaneous flaps. If the femur is exposed, however, a muscle flap will be required. As above, the tensor fascia lata, vastus lateralis, and rectus femoris can be used as flap options. If the lateral circumflex artery is unavailable, other flap options include the gracilis, vastus medialis, and rectus abdominis muscles. The gracilis muscle flap is based on the medial circumflex femoral artery and is useful for covering the medial aspect of the mid-thigh. Although this is a thin muscle, it can be used to cover long defects. The vastus medialis muscle flap is supplied by perforators from the profunda femoris and superficial femoral arteries. It can be rotated medially and advanced distally to cover patellar defects.

Supracondylar knee. The knee is a location where sarcoma resection is particularly likely to leave a defect with exposed bone, tendons, or ligaments that will need coverage. The gastrocnemius muscle flap combined with a split-thickness skin graft remains a consistent and reliable reconstructive option for this area. Other options are an extended medial gastrocnemius muscle flap or myocutaneous flap, which incorporates a random fasciocutaneous extension. For larger defects, free flaps should be considered, such as the anterior thigh flap, rectus abdominis muscle flap, or latissimus dorsi muscle flap. If tendons or ligaments need to be reconstructed, we favor autologous tissue, such as the fascia lata and plantaris tendons. These are easy to harvest and provide long-lasting joint stability.

Lower leg

Proximal third of the tibia. Defects here can usually be covered with a medial or lateral gastrocnemius muscle or myocutaneous flap, or a combination of the two. These muscles have a dominant vascular pedicle—the medial and lateral sural arteries. They can be harvested as an island for better reach, and they are reliable and have minimal donor site morbidity.¹⁵ The soleus muscle flap is another option that can be used alone or in combination with the medial or lateral gastrocnemius. Defects that are not amenable to closure by these flaps will most likely require free tissue transfer. The rectus abdominis or latissimus dorsi muscles are the first options. The latter can be combined with the serratus muscle if more bulk is needed.

Middle and lower thirds of the tibia. The soleus flap is frequently used for small or medium-sized mid-tibial defects. It is based on branches of the popliteal artery and posterior tibial artery. Larger defects require a combination of soleus and gastrocnemius muscle flaps or free tissue transfer.

Foot

Ideal reconstruction of the foot should provide thin and durable skin that will tolerate mechanical stress, and achieving this can be quite difficult. Skin grafts are seldom used for the foot, and are limited to non–weight-bearing portions with good underlying soft tissue.

Proximal non–weight-bearing areas (Achilles tendon and malleolar area). Local fasciocutaneous flaps are preferred. The lateral calcaneal artery flap, which is based on the peroneal artery branch, can cover exposed Achilles tendon, providing sensate coverage (sural nerve). The dorsalis pedis flap can be mobilized to cover the malleolar region and distal Achilles tendon, but donor site morbidity limits its use. Free tissue transfer is required for larger defects, and the the main options are flaps from the radial forearm, temporoparietal fascia, or lateral arm.

Heel and midplantar area. For heel reconstruction, the medial plantar artery flap, dorsalis pedis flap, abductor myocutaneous flap, peroneal artery flap, or anterior tibial artery flap can be used. The most versatile flap of the foot is the medial plantar artery flap, which is available only when the posterior tibial artery is intact. If local flaps are not suitable, microvascular tissue transfer is indicated. The radial forearm flap, scapular flap, lateral arm flap, or anterolateral thigh flap can be used. The radial forearm flap is usually the first choice because it is thin, has a long pedicle, and is easy to harvest.

If the foot defect is associated with a large cavity, muscle flaps are the first choices, specifically the gracilis or anterior serratus. A split latissimus muscle can also be applied. The full latissimus or the rectus abdominis are often too large for the type of defects observed.

Distal plantar area and forefoot. Most wounds in this region will require free tissue transfer. Free muscle flaps with split-thickness skin grafts provide the most stable and durable coverage.

Amputation vs limb salvage

It is important to evaluate the effects of lower-extremity salvage on ambulation. Salvage of a nonfunctional limb is of little value for the patient. Likewise, patients with severe medical problems may not be good candidates for limb salvage procedures. In those situations, amputation of the lower extremity is indicated. Adequate soft-tissue coverage and good distal perfusion are necessary to ensure healing of an amputation. If possible, local tissue rearrangement may be enough to provide a good amputation stump to fit an external prosthesis. In the case of radiation damage to the tissue, a free tissue transfer is necessary. The calcaneal-plantar unit from the amputated limb is frequently used as a free flap. Other flaps from the amputated limb, called fillet flaps, are harvested immediately and converted to flaps transferred to the defect site. Studies show that they are oncologically safe and reliable.¹⁷ Other flaps that provide good coverage for amputation defects are the latissimus dorsi muscle flap, the radial forearm flap, and the anterolateral thigh flap.

Upper extremities

Postoperative care following reconstruction after sarcoma resection requires a dedicated and trained team, particularly if a free flap is used for reconstruction.

Clinical evaluation of flaps includes color, temperature, and capillary refill. In cases of microsurgical reconstruction, postoperative care should include hourly examination of audible Doppler signals, at least for the first 36 hours. Free flap complications develop primarily in the first 24 hours, but they can occur during initial mobilization of the patient after a long period of bed rest. The surgical team should be aware of the potential problems and be able to act fast if necessary to reestablish blood flow to the flap.

In addition to flap monitoring, immobilization of the patient after surgery is extremely important. Postoperative swelling to the extremity should be avoided. Patients should be placed on bed rest until the postoperative swelling has subsided and the flap has adhered to the wound bed. Our protocol includes strict bed rest for about 7 days, followed by several days of dangling the extremity for short periods to ensure that dependent positioning will not alter the blood supply. A physical therapist should be involved to assist with crutches or a wheelchair. The patient should receive prophylactic anticoagulation during the resting period, in light of the high risk of deep vein thrombosis and pulmonary embolism. A compressive garment should be used to prevent lymphedema.

COMPLICATIONS ASSOCIATED WITH FLAPS

Once the flap is raised, it can still fail as a result of tension at insetting, inadequate blood flow, twisting of the pedicle, hematoma and/or infection, or the patient’s condition (eg, coagulopathy, poor nutritional status, anemia). Failure to correctly evaluate the direction of arterial flow, whether anterograde or retrograde, can cause flap loss. Instruments such as Doppler ultrasonographic equipment can be used to help to determine the flow. Partial or complete occlusion of the vascular pedicle can occur for several reasons (eg, twisting of the pedicle), and the consequences are disastrous if not recognized in time. If a pedicle problem is suspected in the case of a free flap, the patient should be taken to the operating room immediately and the flap should be explored. Rupture of the vascular anastomosis can occur as a result of technical problems, tension, and (in rare cases) infection.

Hematomas can cause mass effect, limit the venous return, and lead to flap necrosis. Hematoma formation also releases free radicals that can contribute to flap necrosis. Prevention is achieved through meticulous hemostasis. If a hematoma is suspected, the wound should be explored and the hematoma evacuated and washed out with normal saline.

The presence of an infected wound bed can also damage a flap by increasing its metabolic demand and causing the flap to be compromised by the infection itself. It is usually best to wait until the infection is controlled before planning the reconstruction.

Partial flap losses, skin graft losses, and wound dehiscence also are possible. Most of the time these require wound care, and patients’ nutrition and general health should be optimized to help the healing process. In the case of partial or complete flap loss, a new flap is often required and should be planned at a proper time.

CONCLUSIONS

Soft-tissue reconstruction following musculoskeletal sarcoma resection can be as simple as allowing the wound to heal by itself, which is less ideal, or as complex as coverage with a microsurgical osteocutaneous free flap. Limb salvage for sarcomas of the lower extremity has demonstrated good final functional outcomes without adversely affecting the oncologic results. Moreover, patients feel better psychologically and have higher quality of life.^18,19

We believe that soft-tissue coverage after a wide resection is the most critical factor for avoiding postoperative complications of the tumor resection, such as infection or fractures. For this reason, we recommend the use of well-vascularized coverage at the time of the initial operation, if possible. Careful preoperative planning is especially important. We believe that reconstruction following musculo­skeletal sarcoma resection can be done effectively only by using a team approach. Every such team should include, at minimum, an orthopedic surgeon and a reconstructive surgeon, with the mix of other providers dictated by the individual case.

Advances in the management of soft-tissue and bone sarcomas—referred to collectively as “musculoskeletal sarcomas” hereafter—have resulted in significant improvements in survival and quality of life.^1–3 Several factors have likely contributed to these advances, including improved surgical technique and the development of referral centers for sarcoma treatment that have embraced a multidisciplinary approach.^1,2

The goal of treatment for musculoskeletal sarcomas is to optimize oncologic outcome and maximize functional restoration.^2,3 Surgical resection has been the mainstay of therapy,^1–7 as detailed earlier in this supplement. In patients with musculoskeletal sarcomas of the extremities, limb-sparing resection has been shown to be significantly superior to amputation.^1,7–9 Wide local excision of the tumor along with its muscle compartment, followed by adjuvant chemotherapy and radiation therapy, has allowed limb salvage without an increased risk of recurrence in many patients.³ However, wide tumor resection can leave large defects that are not amenable to coverage by mobilization of the surrounding tissues, particularly if those tissues have been irradiated. As a result, resection can expose neurovascular structures, bone without periosteum, alloplastic materials, and internal fixation devices.

GOALS OF RECONSTRUCTION

Reconstructive surgery after musculoskeletal sarcoma resection aims to provide adequate wound coverage, preserve function, and optimize the cosmetic outcome.^1–3 Tumors can be found on areas crucial to limb movement or may involve tissues vital to limb function. Reconstruction to repair these deficits can take many forms. In certain situations, amputation is still inevitable. In those cases, the reconstruction should provide stable stump coverage with durability and the ability to fit well with an external prosthesis.³

TIMING OF RECONSTRUCTION

Immediate reconstruction should be pursued if possible

Immediate reconstruction after a negative margin should always be considered and should be attempted when possible. Immediate reconstruction allows the reconstructive surgeon to benefit from better evaluation of the defect and exposed structures, as no scar tissue is present to distort the anatomy. Likewise, patients benefit from faster recovery and can receive adjuvant treatment (if necessary) sooner, as well as earlier rehabilitation. Patients may also benefit psychologically from immediate reconstruction.^1,3

Indications for delayed reconstruction

Delayed reconstruction is primarily indicated when there are wound healing problems or there is uncertainty about the tumor margins. Secondary indications for delayed reconstruction are wound dehiscence and unstable soft-tissue coverage. If hardware is exposed, the recommendation is for early intervention and wound coverage with well-vascularized tissue to protect and cover the implant or prosthesis.

What about radiation therapy?

A very important consideration in reconstruction is the need for neoadjuvant or adjuvant radiation therapy.^3,10,11 Irradiated wounds have a higher incidence of complications, including a tendency to dehisce. In patients who have been previously irradiated, the best practice is to perform immediate reconstruction with well-vascularized tissue, most likely a free tissue transfer.^4,6,11,12 This practice reduces hospital stay, costs, and morbidity and increases limb salvage and patient satisfaction.¹³

SYSTEMATIC PREOPERATIVE PLANNING NEEDED

Reconstruction after musculoskeletal sarcoma resection should be planned systematically within a process that involves preoperative anticipation of the defect size and the resulting functional and cosmetic deficits that might need to be addressed. A preoperative visit to the reconstructive surgeon can be very helpful for presurgical planning.

During surgery it is usually preferable to allow the surgeon doing the tumor resection (eg, surgical oncologist or orthopedic oncologist) to complete the resection because the dimensions of the defect are not certain until negative margins are obtained.¹⁴ If tumor margins are unclear at the time of initial resection, the surgeon should consider delaying the definitive reconstruction until the permanent sections confirm negative margins. Temporary closure can be achieved with wound dressings, skin grafts (either allograft or autograft), or negative-pressure wound therapy. In the same context, if neurovascular structures are exposed it is reasonable to use a muscle flap without “tailoring” the flap to the defect. This approach allows the flap to be advanced or repositioned in case of positive margins, and the skin graft can be applied to the muscle surface in a second procedure.³

RECONSTRUCTIVE METHODS: A BRIEF OVERVIEW

Several methods can be used to close musculoskeletal sarcoma excision defects. Smaller defects can be closed primarily, although most defects are large and not amenable to primary closure. If fascia or muscle is preserved with only the skin coverage missing, the wound can be covered with either split-thickness or full-thickness skin grafts.^1,4,6 Split-thickness skin grafts can be obtained in larger amounts and often heal faster than full-thickness skin grafts. However, most resections will require durable tissue coverage, particularly if adjuvant radiation therapy is planned.

In the case of long bone sarcoma resection, the resulting defect is usually large and complex and the traditional reconstruction is based on avascular allografts and local tissue flaps. However, allografts are associated with high rates of infection, nonunion, and fracture, leading to failure in about 50% of cases. Microvascular free flaps that contain bone, such as free fibula flaps, have been used instead of allografts with good success rates.²

Lately there has been growing interest in the use of the vacuum-assisted closure device (a form of negative-pressure wound therapy) to promote wound healing. It has been shown to improve the granulation and healing of open wounds by absorbing moisture, as well as to promote adherence after skin grafting, thereby reducing the risk of graft displacement.^1,3 This device can be used immediately after musculoskeletal sarcoma resection while definitive tumor margin results are pending. It also can be used to prepare the wound bed for grafting in high-risk patients who would not tolerate more complex reconstructions. 

Local or adjacent fascial, fasciocutaneous, and dermal flaps can also be used in lower-extremity reconstruction. However, muscle or musculocutaneous flaps are the mainstay of reconstruction after resection of musculoskeletal sarcomas. This group also includes perforator flaps, which have grown in popularity in the last few years.^1,3

Musculoskeletal sarcomas can occur in virtually any region of the body, and myriad reconstructive options are available for various body sites. Since lower-extremity musculoskeletal sarcomas represent about 75% of cases,¹ we will focus mainly on reconstruction of the lower extremity.

Factors driving choice of flap

Selection of an appropriate flap is essential to an optimal outcome. Flaps should be chosen with regard to donor site morbidity, functional requirements, length and diameter of the vascular pedicle, and aesthetic outcome.³ Usually physical examination, palpation of peripheral pulses, and Doppler ultrasonography are sufficient to evaluate the circulation. A preoperative angiogram should be considered in patients with severe peripheral vascular disease or previous trauma, which can potentially compromise the reconstructive outcome.¹⁵

Each region of the lower extremity possesses unique anatomic and functional characteristics that must be evaluated. It is useful to categorize the thigh, lower leg, and foot into separate anatomic units when planning reconstruction. We further divided these units into several subunits, as previously proposed by Sherman and Law¹⁵ and as outlined below.

Thigh

The thigh is usually well perfused and has several muscle groups, which facilitates reconstruction. Primary closure, skin grafts, or local flaps are acceptable options in most cases. The remaining musculature can be rotated or advanced to cover defects in the anterior or posterior thigh, providing bulk and adequate blood supply.

Hip and proximal/lateral thigh. Local muscle or myocutaneous flap options include tensor fascia lata, vastus lateralis, and rectus femoris flaps, all of which are based on the lateral circumflex femoral artery.

The tensor fascia lata flap is thin but has a long fascia extension that can be elevated from above the knee and can include a large skin paddle that is innervated by the lateral femoral cutaneous nerve. Some patients may experience knee instability after tensor fascia lata harvest.

The vastus lateralis muscle flap provides good bulk. Its arc of rotation reaches most of the inferior and posterior pelvis. It has little effect on ambulation.

The rectus femoris muscle flap is not so bulky, is easily mobilized, and has a wide arc of rotation. The donor site can be closed primarily. Harvest of this muscle can be associated with some strength loss during knee extension. For large defects of the upper third of the leg, a pedicled rectus abdominis muscle flap based on the deep inferior epigastric artery can be used. A vertically oriented skin island can be extended up to the costal margin, improving the reach. When the nature of the wound precludes use of pedicle flaps, free tissue transfer is indicated, with the latissimus dorsi muscle flap being used most commonly.^15,16

Mid-thigh. Wounds in this location often can be closed with skin grafts or fasciocutaneous flaps. If the femur is exposed, however, a muscle flap will be required. As above, the tensor fascia lata, vastus lateralis, and rectus femoris can be used as flap options. If the lateral circumflex artery is unavailable, other flap options include the gracilis, vastus medialis, and rectus abdominis muscles. The gracilis muscle flap is based on the medial circumflex femoral artery and is useful for covering the medial aspect of the mid-thigh. Although this is a thin muscle, it can be used to cover long defects. The vastus medialis muscle flap is supplied by perforators from the profunda femoris and superficial femoral arteries. It can be rotated medially and advanced distally to cover patellar defects.

Supracondylar knee. The knee is a location where sarcoma resection is particularly likely to leave a defect with exposed bone, tendons, or ligaments that will need coverage. The gastrocnemius muscle flap combined with a split-thickness skin graft remains a consistent and reliable reconstructive option for this area. Other options are an extended medial gastrocnemius muscle flap or myocutaneous flap, which incorporates a random fasciocutaneous extension. For larger defects, free flaps should be considered, such as the anterior thigh flap, rectus abdominis muscle flap, or latissimus dorsi muscle flap. If tendons or ligaments need to be reconstructed, we favor autologous tissue, such as the fascia lata and plantaris tendons. These are easy to harvest and provide long-lasting joint stability.

Lower leg

Proximal third of the tibia. Defects here can usually be covered with a medial or lateral gastrocnemius muscle or myocutaneous flap, or a combination of the two. These muscles have a dominant vascular pedicle—the medial and lateral sural arteries. They can be harvested as an island for better reach, and they are reliable and have minimal donor site morbidity.¹⁵ The soleus muscle flap is another option that can be used alone or in combination with the medial or lateral gastrocnemius. Defects that are not amenable to closure by these flaps will most likely require free tissue transfer. The rectus abdominis or latissimus dorsi muscles are the first options. The latter can be combined with the serratus muscle if more bulk is needed.

Middle and lower thirds of the tibia. The soleus flap is frequently used for small or medium-sized mid-tibial defects. It is based on branches of the popliteal artery and posterior tibial artery. Larger defects require a combination of soleus and gastrocnemius muscle flaps or free tissue transfer.

Foot

Ideal reconstruction of the foot should provide thin and durable skin that will tolerate mechanical stress, and achieving this can be quite difficult. Skin grafts are seldom used for the foot, and are limited to non–weight-bearing portions with good underlying soft tissue.

Proximal non–weight-bearing areas (Achilles tendon and malleolar area). Local fasciocutaneous flaps are preferred. The lateral calcaneal artery flap, which is based on the peroneal artery branch, can cover exposed Achilles tendon, providing sensate coverage (sural nerve). The dorsalis pedis flap can be mobilized to cover the malleolar region and distal Achilles tendon, but donor site morbidity limits its use. Free tissue transfer is required for larger defects, and the the main options are flaps from the radial forearm, temporoparietal fascia, or lateral arm.

Heel and midplantar area. For heel reconstruction, the medial plantar artery flap, dorsalis pedis flap, abductor myocutaneous flap, peroneal artery flap, or anterior tibial artery flap can be used. The most versatile flap of the foot is the medial plantar artery flap, which is available only when the posterior tibial artery is intact. If local flaps are not suitable, microvascular tissue transfer is indicated. The radial forearm flap, scapular flap, lateral arm flap, or anterolateral thigh flap can be used. The radial forearm flap is usually the first choice because it is thin, has a long pedicle, and is easy to harvest.

If the foot defect is associated with a large cavity, muscle flaps are the first choices, specifically the gracilis or anterior serratus. A split latissimus muscle can also be applied. The full latissimus or the rectus abdominis are often too large for the type of defects observed.

Distal plantar area and forefoot. Most wounds in this region will require free tissue transfer. Free muscle flaps with split-thickness skin grafts provide the most stable and durable coverage.

Amputation vs limb salvage

It is important to evaluate the effects of lower-extremity salvage on ambulation. Salvage of a nonfunctional limb is of little value for the patient. Likewise, patients with severe medical problems may not be good candidates for limb salvage procedures. In those situations, amputation of the lower extremity is indicated. Adequate soft-tissue coverage and good distal perfusion are necessary to ensure healing of an amputation. If possible, local tissue rearrangement may be enough to provide a good amputation stump to fit an external prosthesis. In the case of radiation damage to the tissue, a free tissue transfer is necessary. The calcaneal-plantar unit from the amputated limb is frequently used as a free flap. Other flaps from the amputated limb, called fillet flaps, are harvested immediately and converted to flaps transferred to the defect site. Studies show that they are oncologically safe and reliable.¹⁷ Other flaps that provide good coverage for amputation defects are the latissimus dorsi muscle flap, the radial forearm flap, and the anterolateral thigh flap.

Upper extremities

Postoperative care following reconstruction after sarcoma resection requires a dedicated and trained team, particularly if a free flap is used for reconstruction.

Clinical evaluation of flaps includes color, temperature, and capillary refill. In cases of microsurgical reconstruction, postoperative care should include hourly examination of audible Doppler signals, at least for the first 36 hours. Free flap complications develop primarily in the first 24 hours, but they can occur during initial mobilization of the patient after a long period of bed rest. The surgical team should be aware of the potential problems and be able to act fast if necessary to reestablish blood flow to the flap.

In addition to flap monitoring, immobilization of the patient after surgery is extremely important. Postoperative swelling to the extremity should be avoided. Patients should be placed on bed rest until the postoperative swelling has subsided and the flap has adhered to the wound bed. Our protocol includes strict bed rest for about 7 days, followed by several days of dangling the extremity for short periods to ensure that dependent positioning will not alter the blood supply. A physical therapist should be involved to assist with crutches or a wheelchair. The patient should receive prophylactic anticoagulation during the resting period, in light of the high risk of deep vein thrombosis and pulmonary embolism. A compressive garment should be used to prevent lymphedema.

COMPLICATIONS ASSOCIATED WITH FLAPS

Once the flap is raised, it can still fail as a result of tension at insetting, inadequate blood flow, twisting of the pedicle, hematoma and/or infection, or the patient’s condition (eg, coagulopathy, poor nutritional status, anemia). Failure to correctly evaluate the direction of arterial flow, whether anterograde or retrograde, can cause flap loss. Instruments such as Doppler ultrasonographic equipment can be used to help to determine the flow. Partial or complete occlusion of the vascular pedicle can occur for several reasons (eg, twisting of the pedicle), and the consequences are disastrous if not recognized in time. If a pedicle problem is suspected in the case of a free flap, the patient should be taken to the operating room immediately and the flap should be explored. Rupture of the vascular anastomosis can occur as a result of technical problems, tension, and (in rare cases) infection.

Hematomas can cause mass effect, limit the venous return, and lead to flap necrosis. Hematoma formation also releases free radicals that can contribute to flap necrosis. Prevention is achieved through meticulous hemostasis. If a hematoma is suspected, the wound should be explored and the hematoma evacuated and washed out with normal saline.

The presence of an infected wound bed can also damage a flap by increasing its metabolic demand and causing the flap to be compromised by the infection itself. It is usually best to wait until the infection is controlled before planning the reconstruction.

Partial flap losses, skin graft losses, and wound dehiscence also are possible. Most of the time these require wound care, and patients’ nutrition and general health should be optimized to help the healing process. In the case of partial or complete flap loss, a new flap is often required and should be planned at a proper time.

CONCLUSIONS

Soft-tissue reconstruction following musculoskeletal sarcoma resection can be as simple as allowing the wound to heal by itself, which is less ideal, or as complex as coverage with a microsurgical osteocutaneous free flap. Limb salvage for sarcomas of the lower extremity has demonstrated good final functional outcomes without adversely affecting the oncologic results. Moreover, patients feel better psychologically and have higher quality of life.^18,19

We believe that soft-tissue coverage after a wide resection is the most critical factor for avoiding postoperative complications of the tumor resection, such as infection or fractures. For this reason, we recommend the use of well-vascularized coverage at the time of the initial operation, if possible. Careful preoperative planning is especially important. We believe that reconstruction following musculo­skeletal sarcoma resection can be done effectively only by using a team approach. Every such team should include, at minimum, an orthopedic surgeon and a reconstructive surgeon, with the mix of other providers dictated by the individual case.

Advances in the management of soft-tissue and bone sarcomas—referred to collectively as “musculoskeletal sarcomas” hereafter—have resulted in significant improvements in survival and quality of life.^1–3 Several factors have likely contributed to these advances, including improved surgical technique and the development of referral centers for sarcoma treatment that have embraced a multidisciplinary approach.^1,2

The goal of treatment for musculoskeletal sarcomas is to optimize oncologic outcome and maximize functional restoration.^2,3 Surgical resection has been the mainstay of therapy,^1–7 as detailed earlier in this supplement. In patients with musculoskeletal sarcomas of the extremities, limb-sparing resection has been shown to be significantly superior to amputation.^1,7–9 Wide local excision of the tumor along with its muscle compartment, followed by adjuvant chemotherapy and radiation therapy, has allowed limb salvage without an increased risk of recurrence in many patients.³ However, wide tumor resection can leave large defects that are not amenable to coverage by mobilization of the surrounding tissues, particularly if those tissues have been irradiated. As a result, resection can expose neurovascular structures, bone without periosteum, alloplastic materials, and internal fixation devices.

GOALS OF RECONSTRUCTION

Reconstructive surgery after musculoskeletal sarcoma resection aims to provide adequate wound coverage, preserve function, and optimize the cosmetic outcome.^1–3 Tumors can be found on areas crucial to limb movement or may involve tissues vital to limb function. Reconstruction to repair these deficits can take many forms. In certain situations, amputation is still inevitable. In those cases, the reconstruction should provide stable stump coverage with durability and the ability to fit well with an external prosthesis.³

TIMING OF RECONSTRUCTION

Immediate reconstruction should be pursued if possible

Immediate reconstruction after a negative margin should always be considered and should be attempted when possible. Immediate reconstruction allows the reconstructive surgeon to benefit from better evaluation of the defect and exposed structures, as no scar tissue is present to distort the anatomy. Likewise, patients benefit from faster recovery and can receive adjuvant treatment (if necessary) sooner, as well as earlier rehabilitation. Patients may also benefit psychologically from immediate reconstruction.^1,3

Indications for delayed reconstruction

Delayed reconstruction is primarily indicated when there are wound healing problems or there is uncertainty about the tumor margins. Secondary indications for delayed reconstruction are wound dehiscence and unstable soft-tissue coverage. If hardware is exposed, the recommendation is for early intervention and wound coverage with well-vascularized tissue to protect and cover the implant or prosthesis.

What about radiation therapy?

A very important consideration in reconstruction is the need for neoadjuvant or adjuvant radiation therapy.^3,10,11 Irradiated wounds have a higher incidence of complications, including a tendency to dehisce. In patients who have been previously irradiated, the best practice is to perform immediate reconstruction with well-vascularized tissue, most likely a free tissue transfer.^4,6,11,12 This practice reduces hospital stay, costs, and morbidity and increases limb salvage and patient satisfaction.¹³

SYSTEMATIC PREOPERATIVE PLANNING NEEDED

Reconstruction after musculoskeletal sarcoma resection should be planned systematically within a process that involves preoperative anticipation of the defect size and the resulting functional and cosmetic deficits that might need to be addressed. A preoperative visit to the reconstructive surgeon can be very helpful for presurgical planning.

During surgery it is usually preferable to allow the surgeon doing the tumor resection (eg, surgical oncologist or orthopedic oncologist) to complete the resection because the dimensions of the defect are not certain until negative margins are obtained.¹⁴ If tumor margins are unclear at the time of initial resection, the surgeon should consider delaying the definitive reconstruction until the permanent sections confirm negative margins. Temporary closure can be achieved with wound dressings, skin grafts (either allograft or autograft), or negative-pressure wound therapy. In the same context, if neurovascular structures are exposed it is reasonable to use a muscle flap without “tailoring” the flap to the defect. This approach allows the flap to be advanced or repositioned in case of positive margins, and the skin graft can be applied to the muscle surface in a second procedure.³

RECONSTRUCTIVE METHODS: A BRIEF OVERVIEW

Several methods can be used to close musculoskeletal sarcoma excision defects. Smaller defects can be closed primarily, although most defects are large and not amenable to primary closure. If fascia or muscle is preserved with only the skin coverage missing, the wound can be covered with either split-thickness or full-thickness skin grafts.^1,4,6 Split-thickness skin grafts can be obtained in larger amounts and often heal faster than full-thickness skin grafts. However, most resections will require durable tissue coverage, particularly if adjuvant radiation therapy is planned.

In the case of long bone sarcoma resection, the resulting defect is usually large and complex and the traditional reconstruction is based on avascular allografts and local tissue flaps. However, allografts are associated with high rates of infection, nonunion, and fracture, leading to failure in about 50% of cases. Microvascular free flaps that contain bone, such as free fibula flaps, have been used instead of allografts with good success rates.²

Lately there has been growing interest in the use of the vacuum-assisted closure device (a form of negative-pressure wound therapy) to promote wound healing. It has been shown to improve the granulation and healing of open wounds by absorbing moisture, as well as to promote adherence after skin grafting, thereby reducing the risk of graft displacement.^1,3 This device can be used immediately after musculoskeletal sarcoma resection while definitive tumor margin results are pending. It also can be used to prepare the wound bed for grafting in high-risk patients who would not tolerate more complex reconstructions. 

Local or adjacent fascial, fasciocutaneous, and dermal flaps can also be used in lower-extremity reconstruction. However, muscle or musculocutaneous flaps are the mainstay of reconstruction after resection of musculoskeletal sarcomas. This group also includes perforator flaps, which have grown in popularity in the last few years.^1,3

Musculoskeletal sarcomas can occur in virtually any region of the body, and myriad reconstructive options are available for various body sites. Since lower-extremity musculoskeletal sarcomas represent about 75% of cases,¹ we will focus mainly on reconstruction of the lower extremity.

Factors driving choice of flap

Selection of an appropriate flap is essential to an optimal outcome. Flaps should be chosen with regard to donor site morbidity, functional requirements, length and diameter of the vascular pedicle, and aesthetic outcome.³ Usually physical examination, palpation of peripheral pulses, and Doppler ultrasonography are sufficient to evaluate the circulation. A preoperative angiogram should be considered in patients with severe peripheral vascular disease or previous trauma, which can potentially compromise the reconstructive outcome.¹⁵

Each region of the lower extremity possesses unique anatomic and functional characteristics that must be evaluated. It is useful to categorize the thigh, lower leg, and foot into separate anatomic units when planning reconstruction. We further divided these units into several subunits, as previously proposed by Sherman and Law¹⁵ and as outlined below.

Thigh

The thigh is usually well perfused and has several muscle groups, which facilitates reconstruction. Primary closure, skin grafts, or local flaps are acceptable options in most cases. The remaining musculature can be rotated or advanced to cover defects in the anterior or posterior thigh, providing bulk and adequate blood supply.

Hip and proximal/lateral thigh. Local muscle or myocutaneous flap options include tensor fascia lata, vastus lateralis, and rectus femoris flaps, all of which are based on the lateral circumflex femoral artery.

The tensor fascia lata flap is thin but has a long fascia extension that can be elevated from above the knee and can include a large skin paddle that is innervated by the lateral femoral cutaneous nerve. Some patients may experience knee instability after tensor fascia lata harvest.

The vastus lateralis muscle flap provides good bulk. Its arc of rotation reaches most of the inferior and posterior pelvis. It has little effect on ambulation.

The rectus femoris muscle flap is not so bulky, is easily mobilized, and has a wide arc of rotation. The donor site can be closed primarily. Harvest of this muscle can be associated with some strength loss during knee extension. For large defects of the upper third of the leg, a pedicled rectus abdominis muscle flap based on the deep inferior epigastric artery can be used. A vertically oriented skin island can be extended up to the costal margin, improving the reach. When the nature of the wound precludes use of pedicle flaps, free tissue transfer is indicated, with the latissimus dorsi muscle flap being used most commonly.^15,16

Mid-thigh. Wounds in this location often can be closed with skin grafts or fasciocutaneous flaps. If the femur is exposed, however, a muscle flap will be required. As above, the tensor fascia lata, vastus lateralis, and rectus femoris can be used as flap options. If the lateral circumflex artery is unavailable, other flap options include the gracilis, vastus medialis, and rectus abdominis muscles. The gracilis muscle flap is based on the medial circumflex femoral artery and is useful for covering the medial aspect of the mid-thigh. Although this is a thin muscle, it can be used to cover long defects. The vastus medialis muscle flap is supplied by perforators from the profunda femoris and superficial femoral arteries. It can be rotated medially and advanced distally to cover patellar defects.

Supracondylar knee. The knee is a location where sarcoma resection is particularly likely to leave a defect with exposed bone, tendons, or ligaments that will need coverage. The gastrocnemius muscle flap combined with a split-thickness skin graft remains a consistent and reliable reconstructive option for this area. Other options are an extended medial gastrocnemius muscle flap or myocutaneous flap, which incorporates a random fasciocutaneous extension. For larger defects, free flaps should be considered, such as the anterior thigh flap, rectus abdominis muscle flap, or latissimus dorsi muscle flap. If tendons or ligaments need to be reconstructed, we favor autologous tissue, such as the fascia lata and plantaris tendons. These are easy to harvest and provide long-lasting joint stability.

Lower leg

Proximal third of the tibia. Defects here can usually be covered with a medial or lateral gastrocnemius muscle or myocutaneous flap, or a combination of the two. These muscles have a dominant vascular pedicle—the medial and lateral sural arteries. They can be harvested as an island for better reach, and they are reliable and have minimal donor site morbidity.¹⁵ The soleus muscle flap is another option that can be used alone or in combination with the medial or lateral gastrocnemius. Defects that are not amenable to closure by these flaps will most likely require free tissue transfer. The rectus abdominis or latissimus dorsi muscles are the first options. The latter can be combined with the serratus muscle if more bulk is needed.

Middle and lower thirds of the tibia. The soleus flap is frequently used for small or medium-sized mid-tibial defects. It is based on branches of the popliteal artery and posterior tibial artery. Larger defects require a combination of soleus and gastrocnemius muscle flaps or free tissue transfer.

Foot

Ideal reconstruction of the foot should provide thin and durable skin that will tolerate mechanical stress, and achieving this can be quite difficult. Skin grafts are seldom used for the foot, and are limited to non–weight-bearing portions with good underlying soft tissue.

Proximal non–weight-bearing areas (Achilles tendon and malleolar area). Local fasciocutaneous flaps are preferred. The lateral calcaneal artery flap, which is based on the peroneal artery branch, can cover exposed Achilles tendon, providing sensate coverage (sural nerve). The dorsalis pedis flap can be mobilized to cover the malleolar region and distal Achilles tendon, but donor site morbidity limits its use. Free tissue transfer is required for larger defects, and the the main options are flaps from the radial forearm, temporoparietal fascia, or lateral arm.

Heel and midplantar area. For heel reconstruction, the medial plantar artery flap, dorsalis pedis flap, abductor myocutaneous flap, peroneal artery flap, or anterior tibial artery flap can be used. The most versatile flap of the foot is the medial plantar artery flap, which is available only when the posterior tibial artery is intact. If local flaps are not suitable, microvascular tissue transfer is indicated. The radial forearm flap, scapular flap, lateral arm flap, or anterolateral thigh flap can be used. The radial forearm flap is usually the first choice because it is thin, has a long pedicle, and is easy to harvest.

If the foot defect is associated with a large cavity, muscle flaps are the first choices, specifically the gracilis or anterior serratus. A split latissimus muscle can also be applied. The full latissimus or the rectus abdominis are often too large for the type of defects observed.

Distal plantar area and forefoot. Most wounds in this region will require free tissue transfer. Free muscle flaps with split-thickness skin grafts provide the most stable and durable coverage.

Amputation vs limb salvage

It is important to evaluate the effects of lower-extremity salvage on ambulation. Salvage of a nonfunctional limb is of little value for the patient. Likewise, patients with severe medical problems may not be good candidates for limb salvage procedures. In those situations, amputation of the lower extremity is indicated. Adequate soft-tissue coverage and good distal perfusion are necessary to ensure healing of an amputation. If possible, local tissue rearrangement may be enough to provide a good amputation stump to fit an external prosthesis. In the case of radiation damage to the tissue, a free tissue transfer is necessary. The calcaneal-plantar unit from the amputated limb is frequently used as a free flap. Other flaps from the amputated limb, called fillet flaps, are harvested immediately and converted to flaps transferred to the defect site. Studies show that they are oncologically safe and reliable.¹⁷ Other flaps that provide good coverage for amputation defects are the latissimus dorsi muscle flap, the radial forearm flap, and the anterolateral thigh flap.

Upper extremities

Postoperative care following reconstruction after sarcoma resection requires a dedicated and trained team, particularly if a free flap is used for reconstruction.

Clinical evaluation of flaps includes color, temperature, and capillary refill. In cases of microsurgical reconstruction, postoperative care should include hourly examination of audible Doppler signals, at least for the first 36 hours. Free flap complications develop primarily in the first 24 hours, but they can occur during initial mobilization of the patient after a long period of bed rest. The surgical team should be aware of the potential problems and be able to act fast if necessary to reestablish blood flow to the flap.

In addition to flap monitoring, immobilization of the patient after surgery is extremely important. Postoperative swelling to the extremity should be avoided. Patients should be placed on bed rest until the postoperative swelling has subsided and the flap has adhered to the wound bed. Our protocol includes strict bed rest for about 7 days, followed by several days of dangling the extremity for short periods to ensure that dependent positioning will not alter the blood supply. A physical therapist should be involved to assist with crutches or a wheelchair. The patient should receive prophylactic anticoagulation during the resting period, in light of the high risk of deep vein thrombosis and pulmonary embolism. A compressive garment should be used to prevent lymphedema.

COMPLICATIONS ASSOCIATED WITH FLAPS

Once the flap is raised, it can still fail as a result of tension at insetting, inadequate blood flow, twisting of the pedicle, hematoma and/or infection, or the patient’s condition (eg, coagulopathy, poor nutritional status, anemia). Failure to correctly evaluate the direction of arterial flow, whether anterograde or retrograde, can cause flap loss. Instruments such as Doppler ultrasonographic equipment can be used to help to determine the flow. Partial or complete occlusion of the vascular pedicle can occur for several reasons (eg, twisting of the pedicle), and the consequences are disastrous if not recognized in time. If a pedicle problem is suspected in the case of a free flap, the patient should be taken to the operating room immediately and the flap should be explored. Rupture of the vascular anastomosis can occur as a result of technical problems, tension, and (in rare cases) infection.

Hematomas can cause mass effect, limit the venous return, and lead to flap necrosis. Hematoma formation also releases free radicals that can contribute to flap necrosis. Prevention is achieved through meticulous hemostasis. If a hematoma is suspected, the wound should be explored and the hematoma evacuated and washed out with normal saline.

The presence of an infected wound bed can also damage a flap by increasing its metabolic demand and causing the flap to be compromised by the infection itself. It is usually best to wait until the infection is controlled before planning the reconstruction.

Partial flap losses, skin graft losses, and wound dehiscence also are possible. Most of the time these require wound care, and patients’ nutrition and general health should be optimized to help the healing process. In the case of partial or complete flap loss, a new flap is often required and should be planned at a proper time.

CONCLUSIONS

Soft-tissue reconstruction following musculoskeletal sarcoma resection can be as simple as allowing the wound to heal by itself, which is less ideal, or as complex as coverage with a microsurgical osteocutaneous free flap. Limb salvage for sarcomas of the lower extremity has demonstrated good final functional outcomes without adversely affecting the oncologic results. Moreover, patients feel better psychologically and have higher quality of life.^18,19

We believe that soft-tissue coverage after a wide resection is the most critical factor for avoiding postoperative complications of the tumor resection, such as infection or fractures. For this reason, we recommend the use of well-vascularized coverage at the time of the initial operation, if possible. Careful preoperative planning is especially important. We believe that reconstruction following musculo­skeletal sarcoma resection can be done effectively only by using a team approach. Every such team should include, at minimum, an orthopedic surgeon and a reconstructive surgeon, with the mix of other providers dictated by the individual case.

Surgical resection is the mainstay of treatment for musculoskeletal sarcomas, as detailed earlier in this supplement, but chemotherapy also has a proven role in the primary therapy of most bone sarcomas and a potential role for some patients with soft-tissue sarcomas. This article provides an overview of the roles of chemotherapy for patients with bone and soft-tissue sarcomas and addresses key considerations surrounding chemo­therapy in the context of overall patient management.

BONE SARCOMAS

Because most bone sarcomas occur in pediatric patients and young adults, studies of chemotherapy in this disease have often enrolled predominantly young subjects. As a result, very limited data are available in older adults. Single-institution experiences indicate that adults with bone sarcomas have inferior outcomes compared with their pediatric and adolescent counterparts,¹ but the literature on these tumors in adults is scant. Therefore, the following discussion on chemotherapy for bone sarcomas incorporates data from trials conducted predominantly in children and young adults (ie, generally younger than 30 years and with a very large majority younger than 20 years).

Chemotherapy for osteosarcoma

At present, neoadjuvant (preoperative) chemotherapy followed by definitive resection with subsequent adjuvant (postoperative) chemotherapy is the well-established approach to treatment of localized osteosarcomas. Chemo­therapy can eradicate the micrometastatic disease that is believed to be present in the majority of patients with clinically resectable cancer.²

Efficacy. Historically, prior to the institution of effective chemotherapy, metastatic disease developed in 80% to 90% of patients who underwent curative resection with or without radiation therapy, which resulted in a long-term survival rate of less than 20%.³ In the 1980s, clinical trials that randomized patients with resectable osteosarcoma to surgery alone or to surgery plus chemotherapy found that the addition of perioperative chemotherapy led to significant improvements in recurrence rates and survival.^4,5 More recent randomized trials have shown that treatment of such patients with modern multiagent chemotherapy regimens results in a 5-year survival rate of approximately 70%.⁶ Additionally, response to neoadjuvant (preoperative) treatment has become the most important predictor of outcome, as the median survival of osteosarcoma patients who have greater than 90% necrosis in the resected specimen following neoadjuvant chemotherapy is about 90% at 5 years.^7,8

Toxicity. Current chemotherapy regimens are based on high doses of methotrexate and leucovorin in combination with doxorubicin, ifosfamide, and platinum. Long-term effects of such regimens include the following³:

• Azospermia (in 100% of patients who received a total ifosfamide dose > 75 g/m²)
• Subclinical renal impairment (in 48% of patients treated with high doses of ifosfamide)
• Hearing impairment (in 40% of patients treated with cisplatin)
• Second malignancies (in 2.1%)
• Cardiomyopathy (in 1.7%).³

In light of this, the development of equally effective but less intensive regimens for patients whose disease carries a better prognosis is highly desirable. Ongoing clinical trials are investigating this strategy.

Metastatic disease. Metastatic osteosarcoma is found in approximately 20% of patients at the time of diagnosis. Sarcoma mainly spreads hematogenously, and the lungs are the most common initial site of metastases, being affected in more than 60% of patients who develop metastatic disease.⁹ Patients with metachronous lung lesions are initially considered for aggressive treatment with neoadjuvant chemo­therapy and subsequent resection of clinically apparent disease, which results in event-free survival rates of 20% to 30%.³

Patients with disease limited to the primary tumor and no more than one or two bone lesions fare best. The presence of multiple metastases is associated with the poorest prognosis, as few patients with this profile live past 2 years.¹⁰ In a review of 202 pediatric and adult patients with documented metastases at the time of osteosarcoma diagnosis, the presence of more than 5 metastatic lesions (which was reported in 91 patients) was associated with a 5-year overall survival rate of 19%.⁹

Chemotherapy for Ewing sarcoma

Perioperative chemotherapy in patients with localized Ewing sarcoma is believed to reduce the burden of micrometastasis that is thought to be present in most patients with early-stage disease. Five-year survival rates of 50% to 72% have been reported among patients with resectable Ewing sarcoma treated perioperatively with multiagent chemotherapy.^11,12 Notably, randomized trials that studied intense multiagent chemotherapy regimens (consisting of doxorubicin, cyclophosphamide, vincristine, and dactinomycin alternating with etoposide and ifosfamide) reported the best outcomes despite significant but acceptable toxicity. In a large randomized trial involving 398 patients with resectable disease, a 5-year survival rate of 72% was achieved with the above regimen, compared with 61% in patients treated with a less intense regimen that did not contain ifosfamide and etoposide (p = .01).¹²

Compressing these standard regimens to an every-14-day instead of every-21-day schedule improved event-free survival at 3 years from 65% to 76% (p = .028) without any significant increase in toxicity in a randomized trial involving 568 patients.¹³ Data on overall survival from this trial are not yet published.

Metastatic disease. Metastatic Ewing sarcoma is found in 15% to 35% of patients with newly diagnosed disease and is treated with multiagent chemotherapy; resection of residual disease is considered in good responders.³ This approach produces objective responses to therapy, but long-term survival is rare.

Toxicity. Myelodysplastic syndrome and acute myeloid leukemia are the most dreaded long-term complications of intensive multiagent chemotherapy for Ewing sarcoma and develop in up to 8% of patients.¹⁴ Additionally, ifosfamide can lead to hematuria (~12% incidence), encephalopathy (mild somnolence and hallucinations to coma), chronic renal impairment (6% incidence), and hemorrhagic cystitis (though administration of mesna and generous intravenous hydration can minimize this latter complication).¹⁵ Recent efforts are therefore focused on testing less-intensive regimens in patients who have good prognostic features.

Chondrosarcoma: No role for chemotherapy

Chondrosarcoma, which represents approximately 20% of all bone sarcomas and has a peak incidence in older adults (ie, in the sixth decade of life), is insensitive to chemotherapy. Radiotherapy is also of limited value and is reserved for patients treated in the palliative setting.¹⁶ Definitive management of chondrosarcoma involves adequate surgical resection alone.

Aside from recent advances in the treatment of gastrointestinal stromal tumors with the small-molecule tyrosine kinase inhibitors imatinib and sunitinib (which are beyond the scope of this article), an overall survival advantage with chemotherapy has not been demonstrated in adults with soft-tissue sarcoma.¹⁷

Resectable disease

The decision to use chemotherapy needs to be weighed against the magnitude of potential clinical benefit and the acute and chronic toxicities that can develop.

Toxicity. Chemotherapy regimens with activity against soft-tissue sarcomas often contain anthracyclines, alkylating agents, and taxanes. These agents can produce serious long-term toxicities, which is especially important in patients treated with curative intent. Doxorubicin and other anthracyclines, for example, may result in cardiomyopathy, the risk of which rises with increasing cumulative dose.¹⁸ In addition, acute myeloid leukemia may develop in 2% to 12% of patients treated with anthracyclines or alkylating agents such as ifosfamide and dacarbazine.^3,19 Renal failure and an elevated risk of bladder carcinoma are uncommonly reported in patients with a history of ifosfamide treatment.¹⁵ Sensory neuropathy associated with the use of taxanes (eg, paclitaxel and docetaxel) is dose dependent and reversible in more than half of patients. However, some patients treated with high doses of these agents can have persistent symptoms of paresthesias, burning, and decreased reflexes, which can be debilitating.²⁰

Efficacy of adjuvant chemotherapy. Because chemotherapy puts patients at risk of such serious chronic toxicities, its use can be justified only if it results in significant benefit, such as prolongation of survival. A 1997 meta-analysis of 14 clinical trials evaluating adjuvant chemotherapy in patients with resectable soft-tissue sarcomas found chemotherapy to have an absolute benefit of 10% in recurrence-free survival at 10 years (ie, from 45% survival to 55% survival), with a hazard ratio of 0.75 (95% confidence interval [CI], 0.64–0.87; p = .0001) for recurrence or death.²¹ However, when the analysis was limited to overall survival at 10 years, the survival difference between patients who received adjuvant chemotherapy and those who did not (54% vs 50%, respectively) was not statistically significant (hazard ratio = 0.89; 95% CI, 0.76–1.03, p = .12).²¹

The concept of adjuvant therapy has been revisited since the antisarcoma activity of ifosfamide was established. A large European trial randomized 351 patients with resected soft-tissue sarcoma either to placebo or to doxorubicin and ifosfamide given every 21 days.²² The preliminary results, reported in abstract form at the 2007 annual meeting of the American Society of Clinical Oncology, showed a higher 5-year survival rate in the placebo arm (69%) compared with the chemotherapy arm (64%).²² This and other trials using ifosfamide in various drug combinations showed no difference in survival, suggesting that adjuvant chemotherapy should not be considered to be standard practice outside of a clinical trial.

Efficacy of neoadjuvant chemotherapy. Neoadjuvant chemotherapy also has been studied in patients with soft-tissue sarcomas. A retrospective analysis found that the greatest benefit is derived in patients with primary tumors larger than 10 cm, in whom neoadjuvant chemotherapy increased 3-year disease-specific survival from 62% to 83%.²³ However, differing results came from a prospective multicenter trial that randomized patients with large primary and recurrent tumors to either surgery alone or surgery preceded by three cycles of neoadjuvant doxorubicin and ifosfamide (all patients could also receive adjuvant radiation therapy, depending on grade and adequacy of resection).²⁴ The trial suffered from slow accrual, and only 150 patients were enrolled. At 5 years, survival was similar between the groups with and without neoadjuvant chemotherapy.²⁴ Therefore, neoadjuvant chemotherapy is not yet recommended pending results of larger randomized trials.

No clear role for recurrent disease. Local recurrence of the primary tumor after resection occurs in 10% to 50% of cases of soft-tissue sarcoma, with the specific rate depending on the primary tumor location. The highest incidence of recurrence is found in patients with retroperitoneal and head and neck sarcoma (40% and 50%, respectively), mainly because of the difficulty of obtaining clear margins. Chemotherapy has not been well studied in this setting and is of uncertain value.³

Metastatic disease

Metastatic soft-tissue sarcomas may respond to chemotherapy, but there is a lack of evidence that chemotherapy improves overall survival. Pulmonary lesions are the most common site of distant recurrence, and resection of such metastases is sometimes undertaken in well-selected patients. However, there is no level 1 evidence supporting chemotherapy in this clinical setting despite its common preoperative use. There is a paucity of randomized phase 3 trials that compare established palliative chemotherapy regimens to best supportive care. It is believed that some groups of patients do benefit, however, including those who are young and have good performance status, low tumor grade, absence of liver metastasis or pulmonary metastasis only, and a long interval between treatment of the primary tumor and development of metastatic disease.³ Some histologies, such as uterine leiomyosarcomas and facial/scalp angiosarcomas, respond better to chemotherapy.¹⁷

Drugs found to have activity against metastatic sarcoma include doxorubicin, ifosfamide, platinum agents, gemcitabine, taxanes, and dacarbazine. Used either alone or in combinations, these drugs produce responses (ie, shrink metastatic tumors) in about 13% to 33% of patients.³ Use of chemotherapy is frequently curtailed by the acute toxicity of these agents, which includes pancytopenia, transfusion requirements, febrile neutropenia, nausea, alopecia, and significant fatigue, as well as renal failure with ifosfamide or cisplatin and peripheral neuropathy with platinum agents or taxanes. Appropriate patient selection for chemo­therapy and exclusion of those who should be managed solely with best supportive care is an important challenge that oncologists often face when managing patients with metastatic soft-tissue sarcoma.

Future directions

Trabectedin (ET-743) is a novel compound with promising activity against soft-tissue sarcomas that acts by inhibiting cell-cycle transition from the G₂ to M stages. The drug covalently binds to the minor grove of the DNA molecule, changing its three-dimensional structure and impairing transcription and possibly DNA repair.²⁵ Phase 2 studies showed durable responses to trabectedin in 3% to 8% of heavily pretreated patients^26–28 and in 17% of treatment-naïve patients with advanced soft-tissue sarcomas.²⁵ Time to progression of up to 20 months has been reported in patients who respond or develop stable disease.³

Toxic effects of trabec­tedin include myelosuppression, fever, edema, arthralgias, hepatotoxicity, and (rarely) rhabdomyolysis. To date, these toxicities have been self-limiting. Larger clinical trials and longer follow-up is needed to assess whether this agent has any significant long-term toxicities.

Trabectedin has already been approved in Europe for treatment of chemotherapy-refractory soft-tissue sarcoma when given as a 24-hour infusion every 21 days.

More broadly, an active effort is under way to better understand the molecular derangements in a variety of soft-tissue sarcoma subtypes. The hope is that this understanding will lead to improved therapies that target aberrant proliferation, angiogenesis, and other biologic processes that drive the growth and metastasis of soft-tissue and bone sarcomas.

Surgical resection is the mainstay of treatment for musculoskeletal sarcomas, as detailed earlier in this supplement, but chemotherapy also has a proven role in the primary therapy of most bone sarcomas and a potential role for some patients with soft-tissue sarcomas. This article provides an overview of the roles of chemotherapy for patients with bone and soft-tissue sarcomas and addresses key considerations surrounding chemo­therapy in the context of overall patient management.

BONE SARCOMAS

Because most bone sarcomas occur in pediatric patients and young adults, studies of chemotherapy in this disease have often enrolled predominantly young subjects. As a result, very limited data are available in older adults. Single-institution experiences indicate that adults with bone sarcomas have inferior outcomes compared with their pediatric and adolescent counterparts,¹ but the literature on these tumors in adults is scant. Therefore, the following discussion on chemotherapy for bone sarcomas incorporates data from trials conducted predominantly in children and young adults (ie, generally younger than 30 years and with a very large majority younger than 20 years).

Chemotherapy for osteosarcoma

At present, neoadjuvant (preoperative) chemotherapy followed by definitive resection with subsequent adjuvant (postoperative) chemotherapy is the well-established approach to treatment of localized osteosarcomas. Chemo­therapy can eradicate the micrometastatic disease that is believed to be present in the majority of patients with clinically resectable cancer.²

Efficacy. Historically, prior to the institution of effective chemotherapy, metastatic disease developed in 80% to 90% of patients who underwent curative resection with or without radiation therapy, which resulted in a long-term survival rate of less than 20%.³ In the 1980s, clinical trials that randomized patients with resectable osteosarcoma to surgery alone or to surgery plus chemotherapy found that the addition of perioperative chemotherapy led to significant improvements in recurrence rates and survival.^4,5 More recent randomized trials have shown that treatment of such patients with modern multiagent chemotherapy regimens results in a 5-year survival rate of approximately 70%.⁶ Additionally, response to neoadjuvant (preoperative) treatment has become the most important predictor of outcome, as the median survival of osteosarcoma patients who have greater than 90% necrosis in the resected specimen following neoadjuvant chemotherapy is about 90% at 5 years.^7,8

Toxicity. Current chemotherapy regimens are based on high doses of methotrexate and leucovorin in combination with doxorubicin, ifosfamide, and platinum. Long-term effects of such regimens include the following³:

• Azospermia (in 100% of patients who received a total ifosfamide dose > 75 g/m²)
• Subclinical renal impairment (in 48% of patients treated with high doses of ifosfamide)
• Hearing impairment (in 40% of patients treated with cisplatin)
• Second malignancies (in 2.1%)
• Cardiomyopathy (in 1.7%).³

In light of this, the development of equally effective but less intensive regimens for patients whose disease carries a better prognosis is highly desirable. Ongoing clinical trials are investigating this strategy.

Metastatic disease. Metastatic osteosarcoma is found in approximately 20% of patients at the time of diagnosis. Sarcoma mainly spreads hematogenously, and the lungs are the most common initial site of metastases, being affected in more than 60% of patients who develop metastatic disease.⁹ Patients with metachronous lung lesions are initially considered for aggressive treatment with neoadjuvant chemo­therapy and subsequent resection of clinically apparent disease, which results in event-free survival rates of 20% to 30%.³

Patients with disease limited to the primary tumor and no more than one or two bone lesions fare best. The presence of multiple metastases is associated with the poorest prognosis, as few patients with this profile live past 2 years.¹⁰ In a review of 202 pediatric and adult patients with documented metastases at the time of osteosarcoma diagnosis, the presence of more than 5 metastatic lesions (which was reported in 91 patients) was associated with a 5-year overall survival rate of 19%.⁹

Chemotherapy for Ewing sarcoma

Perioperative chemotherapy in patients with localized Ewing sarcoma is believed to reduce the burden of micrometastasis that is thought to be present in most patients with early-stage disease. Five-year survival rates of 50% to 72% have been reported among patients with resectable Ewing sarcoma treated perioperatively with multiagent chemotherapy.^11,12 Notably, randomized trials that studied intense multiagent chemotherapy regimens (consisting of doxorubicin, cyclophosphamide, vincristine, and dactinomycin alternating with etoposide and ifosfamide) reported the best outcomes despite significant but acceptable toxicity. In a large randomized trial involving 398 patients with resectable disease, a 5-year survival rate of 72% was achieved with the above regimen, compared with 61% in patients treated with a less intense regimen that did not contain ifosfamide and etoposide (p = .01).¹²

Compressing these standard regimens to an every-14-day instead of every-21-day schedule improved event-free survival at 3 years from 65% to 76% (p = .028) without any significant increase in toxicity in a randomized trial involving 568 patients.¹³ Data on overall survival from this trial are not yet published.

Metastatic disease. Metastatic Ewing sarcoma is found in 15% to 35% of patients with newly diagnosed disease and is treated with multiagent chemotherapy; resection of residual disease is considered in good responders.³ This approach produces objective responses to therapy, but long-term survival is rare.

Toxicity. Myelodysplastic syndrome and acute myeloid leukemia are the most dreaded long-term complications of intensive multiagent chemotherapy for Ewing sarcoma and develop in up to 8% of patients.¹⁴ Additionally, ifosfamide can lead to hematuria (~12% incidence), encephalopathy (mild somnolence and hallucinations to coma), chronic renal impairment (6% incidence), and hemorrhagic cystitis (though administration of mesna and generous intravenous hydration can minimize this latter complication).¹⁵ Recent efforts are therefore focused on testing less-intensive regimens in patients who have good prognostic features.

Chondrosarcoma: No role for chemotherapy

Chondrosarcoma, which represents approximately 20% of all bone sarcomas and has a peak incidence in older adults (ie, in the sixth decade of life), is insensitive to chemotherapy. Radiotherapy is also of limited value and is reserved for patients treated in the palliative setting.¹⁶ Definitive management of chondrosarcoma involves adequate surgical resection alone.

Aside from recent advances in the treatment of gastrointestinal stromal tumors with the small-molecule tyrosine kinase inhibitors imatinib and sunitinib (which are beyond the scope of this article), an overall survival advantage with chemotherapy has not been demonstrated in adults with soft-tissue sarcoma.¹⁷

Resectable disease

The decision to use chemotherapy needs to be weighed against the magnitude of potential clinical benefit and the acute and chronic toxicities that can develop.

Toxicity. Chemotherapy regimens with activity against soft-tissue sarcomas often contain anthracyclines, alkylating agents, and taxanes. These agents can produce serious long-term toxicities, which is especially important in patients treated with curative intent. Doxorubicin and other anthracyclines, for example, may result in cardiomyopathy, the risk of which rises with increasing cumulative dose.¹⁸ In addition, acute myeloid leukemia may develop in 2% to 12% of patients treated with anthracyclines or alkylating agents such as ifosfamide and dacarbazine.^3,19 Renal failure and an elevated risk of bladder carcinoma are uncommonly reported in patients with a history of ifosfamide treatment.¹⁵ Sensory neuropathy associated with the use of taxanes (eg, paclitaxel and docetaxel) is dose dependent and reversible in more than half of patients. However, some patients treated with high doses of these agents can have persistent symptoms of paresthesias, burning, and decreased reflexes, which can be debilitating.²⁰

Efficacy of adjuvant chemotherapy. Because chemotherapy puts patients at risk of such serious chronic toxicities, its use can be justified only if it results in significant benefit, such as prolongation of survival. A 1997 meta-analysis of 14 clinical trials evaluating adjuvant chemotherapy in patients with resectable soft-tissue sarcomas found chemotherapy to have an absolute benefit of 10% in recurrence-free survival at 10 years (ie, from 45% survival to 55% survival), with a hazard ratio of 0.75 (95% confidence interval [CI], 0.64–0.87; p = .0001) for recurrence or death.²¹ However, when the analysis was limited to overall survival at 10 years, the survival difference between patients who received adjuvant chemotherapy and those who did not (54% vs 50%, respectively) was not statistically significant (hazard ratio = 0.89; 95% CI, 0.76–1.03, p = .12).²¹

The concept of adjuvant therapy has been revisited since the antisarcoma activity of ifosfamide was established. A large European trial randomized 351 patients with resected soft-tissue sarcoma either to placebo or to doxorubicin and ifosfamide given every 21 days.²² The preliminary results, reported in abstract form at the 2007 annual meeting of the American Society of Clinical Oncology, showed a higher 5-year survival rate in the placebo arm (69%) compared with the chemotherapy arm (64%).²² This and other trials using ifosfamide in various drug combinations showed no difference in survival, suggesting that adjuvant chemotherapy should not be considered to be standard practice outside of a clinical trial.

Efficacy of neoadjuvant chemotherapy. Neoadjuvant chemotherapy also has been studied in patients with soft-tissue sarcomas. A retrospective analysis found that the greatest benefit is derived in patients with primary tumors larger than 10 cm, in whom neoadjuvant chemotherapy increased 3-year disease-specific survival from 62% to 83%.²³ However, differing results came from a prospective multicenter trial that randomized patients with large primary and recurrent tumors to either surgery alone or surgery preceded by three cycles of neoadjuvant doxorubicin and ifosfamide (all patients could also receive adjuvant radiation therapy, depending on grade and adequacy of resection).²⁴ The trial suffered from slow accrual, and only 150 patients were enrolled. At 5 years, survival was similar between the groups with and without neoadjuvant chemotherapy.²⁴ Therefore, neoadjuvant chemotherapy is not yet recommended pending results of larger randomized trials.

No clear role for recurrent disease. Local recurrence of the primary tumor after resection occurs in 10% to 50% of cases of soft-tissue sarcoma, with the specific rate depending on the primary tumor location. The highest incidence of recurrence is found in patients with retroperitoneal and head and neck sarcoma (40% and 50%, respectively), mainly because of the difficulty of obtaining clear margins. Chemotherapy has not been well studied in this setting and is of uncertain value.³

Metastatic disease

Metastatic soft-tissue sarcomas may respond to chemotherapy, but there is a lack of evidence that chemotherapy improves overall survival. Pulmonary lesions are the most common site of distant recurrence, and resection of such metastases is sometimes undertaken in well-selected patients. However, there is no level 1 evidence supporting chemotherapy in this clinical setting despite its common preoperative use. There is a paucity of randomized phase 3 trials that compare established palliative chemotherapy regimens to best supportive care. It is believed that some groups of patients do benefit, however, including those who are young and have good performance status, low tumor grade, absence of liver metastasis or pulmonary metastasis only, and a long interval between treatment of the primary tumor and development of metastatic disease.³ Some histologies, such as uterine leiomyosarcomas and facial/scalp angiosarcomas, respond better to chemotherapy.¹⁷

Drugs found to have activity against metastatic sarcoma include doxorubicin, ifosfamide, platinum agents, gemcitabine, taxanes, and dacarbazine. Used either alone or in combinations, these drugs produce responses (ie, shrink metastatic tumors) in about 13% to 33% of patients.³ Use of chemotherapy is frequently curtailed by the acute toxicity of these agents, which includes pancytopenia, transfusion requirements, febrile neutropenia, nausea, alopecia, and significant fatigue, as well as renal failure with ifosfamide or cisplatin and peripheral neuropathy with platinum agents or taxanes. Appropriate patient selection for chemo­therapy and exclusion of those who should be managed solely with best supportive care is an important challenge that oncologists often face when managing patients with metastatic soft-tissue sarcoma.

Future directions

Trabectedin (ET-743) is a novel compound with promising activity against soft-tissue sarcomas that acts by inhibiting cell-cycle transition from the G₂ to M stages. The drug covalently binds to the minor grove of the DNA molecule, changing its three-dimensional structure and impairing transcription and possibly DNA repair.²⁵ Phase 2 studies showed durable responses to trabectedin in 3% to 8% of heavily pretreated patients^26–28 and in 17% of treatment-naïve patients with advanced soft-tissue sarcomas.²⁵ Time to progression of up to 20 months has been reported in patients who respond or develop stable disease.³

Toxic effects of trabec­tedin include myelosuppression, fever, edema, arthralgias, hepatotoxicity, and (rarely) rhabdomyolysis. To date, these toxicities have been self-limiting. Larger clinical trials and longer follow-up is needed to assess whether this agent has any significant long-term toxicities.

Trabectedin has already been approved in Europe for treatment of chemotherapy-refractory soft-tissue sarcoma when given as a 24-hour infusion every 21 days.

More broadly, an active effort is under way to better understand the molecular derangements in a variety of soft-tissue sarcoma subtypes. The hope is that this understanding will lead to improved therapies that target aberrant proliferation, angiogenesis, and other biologic processes that drive the growth and metastasis of soft-tissue and bone sarcomas.

Surgical resection is the mainstay of treatment for musculoskeletal sarcomas, as detailed earlier in this supplement, but chemotherapy also has a proven role in the primary therapy of most bone sarcomas and a potential role for some patients with soft-tissue sarcomas. This article provides an overview of the roles of chemotherapy for patients with bone and soft-tissue sarcomas and addresses key considerations surrounding chemo­therapy in the context of overall patient management.

BONE SARCOMAS

Because most bone sarcomas occur in pediatric patients and young adults, studies of chemotherapy in this disease have often enrolled predominantly young subjects. As a result, very limited data are available in older adults. Single-institution experiences indicate that adults with bone sarcomas have inferior outcomes compared with their pediatric and adolescent counterparts,¹ but the literature on these tumors in adults is scant. Therefore, the following discussion on chemotherapy for bone sarcomas incorporates data from trials conducted predominantly in children and young adults (ie, generally younger than 30 years and with a very large majority younger than 20 years).

Chemotherapy for osteosarcoma

At present, neoadjuvant (preoperative) chemotherapy followed by definitive resection with subsequent adjuvant (postoperative) chemotherapy is the well-established approach to treatment of localized osteosarcomas. Chemo­therapy can eradicate the micrometastatic disease that is believed to be present in the majority of patients with clinically resectable cancer.²

Efficacy. Historically, prior to the institution of effective chemotherapy, metastatic disease developed in 80% to 90% of patients who underwent curative resection with or without radiation therapy, which resulted in a long-term survival rate of less than 20%.³ In the 1980s, clinical trials that randomized patients with resectable osteosarcoma to surgery alone or to surgery plus chemotherapy found that the addition of perioperative chemotherapy led to significant improvements in recurrence rates and survival.^4,5 More recent randomized trials have shown that treatment of such patients with modern multiagent chemotherapy regimens results in a 5-year survival rate of approximately 70%.⁶ Additionally, response to neoadjuvant (preoperative) treatment has become the most important predictor of outcome, as the median survival of osteosarcoma patients who have greater than 90% necrosis in the resected specimen following neoadjuvant chemotherapy is about 90% at 5 years.^7,8

Toxicity. Current chemotherapy regimens are based on high doses of methotrexate and leucovorin in combination with doxorubicin, ifosfamide, and platinum. Long-term effects of such regimens include the following³:

• Azospermia (in 100% of patients who received a total ifosfamide dose > 75 g/m²)
• Subclinical renal impairment (in 48% of patients treated with high doses of ifosfamide)
• Hearing impairment (in 40% of patients treated with cisplatin)
• Second malignancies (in 2.1%)
• Cardiomyopathy (in 1.7%).³

In light of this, the development of equally effective but less intensive regimens for patients whose disease carries a better prognosis is highly desirable. Ongoing clinical trials are investigating this strategy.

Metastatic disease. Metastatic osteosarcoma is found in approximately 20% of patients at the time of diagnosis. Sarcoma mainly spreads hematogenously, and the lungs are the most common initial site of metastases, being affected in more than 60% of patients who develop metastatic disease.⁹ Patients with metachronous lung lesions are initially considered for aggressive treatment with neoadjuvant chemo­therapy and subsequent resection of clinically apparent disease, which results in event-free survival rates of 20% to 30%.³

Patients with disease limited to the primary tumor and no more than one or two bone lesions fare best. The presence of multiple metastases is associated with the poorest prognosis, as few patients with this profile live past 2 years.¹⁰ In a review of 202 pediatric and adult patients with documented metastases at the time of osteosarcoma diagnosis, the presence of more than 5 metastatic lesions (which was reported in 91 patients) was associated with a 5-year overall survival rate of 19%.⁹

Chemotherapy for Ewing sarcoma

Perioperative chemotherapy in patients with localized Ewing sarcoma is believed to reduce the burden of micrometastasis that is thought to be present in most patients with early-stage disease. Five-year survival rates of 50% to 72% have been reported among patients with resectable Ewing sarcoma treated perioperatively with multiagent chemotherapy.^11,12 Notably, randomized trials that studied intense multiagent chemotherapy regimens (consisting of doxorubicin, cyclophosphamide, vincristine, and dactinomycin alternating with etoposide and ifosfamide) reported the best outcomes despite significant but acceptable toxicity. In a large randomized trial involving 398 patients with resectable disease, a 5-year survival rate of 72% was achieved with the above regimen, compared with 61% in patients treated with a less intense regimen that did not contain ifosfamide and etoposide (p = .01).¹²

Compressing these standard regimens to an every-14-day instead of every-21-day schedule improved event-free survival at 3 years from 65% to 76% (p = .028) without any significant increase in toxicity in a randomized trial involving 568 patients.¹³ Data on overall survival from this trial are not yet published.

Metastatic disease. Metastatic Ewing sarcoma is found in 15% to 35% of patients with newly diagnosed disease and is treated with multiagent chemotherapy; resection of residual disease is considered in good responders.³ This approach produces objective responses to therapy, but long-term survival is rare.

Toxicity. Myelodysplastic syndrome and acute myeloid leukemia are the most dreaded long-term complications of intensive multiagent chemotherapy for Ewing sarcoma and develop in up to 8% of patients.¹⁴ Additionally, ifosfamide can lead to hematuria (~12% incidence), encephalopathy (mild somnolence and hallucinations to coma), chronic renal impairment (6% incidence), and hemorrhagic cystitis (though administration of mesna and generous intravenous hydration can minimize this latter complication).¹⁵ Recent efforts are therefore focused on testing less-intensive regimens in patients who have good prognostic features.

Chondrosarcoma: No role for chemotherapy

Chondrosarcoma, which represents approximately 20% of all bone sarcomas and has a peak incidence in older adults (ie, in the sixth decade of life), is insensitive to chemotherapy. Radiotherapy is also of limited value and is reserved for patients treated in the palliative setting.¹⁶ Definitive management of chondrosarcoma involves adequate surgical resection alone.

Aside from recent advances in the treatment of gastrointestinal stromal tumors with the small-molecule tyrosine kinase inhibitors imatinib and sunitinib (which are beyond the scope of this article), an overall survival advantage with chemotherapy has not been demonstrated in adults with soft-tissue sarcoma.¹⁷

Resectable disease

The decision to use chemotherapy needs to be weighed against the magnitude of potential clinical benefit and the acute and chronic toxicities that can develop.

Toxicity. Chemotherapy regimens with activity against soft-tissue sarcomas often contain anthracyclines, alkylating agents, and taxanes. These agents can produce serious long-term toxicities, which is especially important in patients treated with curative intent. Doxorubicin and other anthracyclines, for example, may result in cardiomyopathy, the risk of which rises with increasing cumulative dose.¹⁸ In addition, acute myeloid leukemia may develop in 2% to 12% of patients treated with anthracyclines or alkylating agents such as ifosfamide and dacarbazine.^3,19 Renal failure and an elevated risk of bladder carcinoma are uncommonly reported in patients with a history of ifosfamide treatment.¹⁵ Sensory neuropathy associated with the use of taxanes (eg, paclitaxel and docetaxel) is dose dependent and reversible in more than half of patients. However, some patients treated with high doses of these agents can have persistent symptoms of paresthesias, burning, and decreased reflexes, which can be debilitating.²⁰

Efficacy of adjuvant chemotherapy. Because chemotherapy puts patients at risk of such serious chronic toxicities, its use can be justified only if it results in significant benefit, such as prolongation of survival. A 1997 meta-analysis of 14 clinical trials evaluating adjuvant chemotherapy in patients with resectable soft-tissue sarcomas found chemotherapy to have an absolute benefit of 10% in recurrence-free survival at 10 years (ie, from 45% survival to 55% survival), with a hazard ratio of 0.75 (95% confidence interval [CI], 0.64–0.87; p = .0001) for recurrence or death.²¹ However, when the analysis was limited to overall survival at 10 years, the survival difference between patients who received adjuvant chemotherapy and those who did not (54% vs 50%, respectively) was not statistically significant (hazard ratio = 0.89; 95% CI, 0.76–1.03, p = .12).²¹

The concept of adjuvant therapy has been revisited since the antisarcoma activity of ifosfamide was established. A large European trial randomized 351 patients with resected soft-tissue sarcoma either to placebo or to doxorubicin and ifosfamide given every 21 days.²² The preliminary results, reported in abstract form at the 2007 annual meeting of the American Society of Clinical Oncology, showed a higher 5-year survival rate in the placebo arm (69%) compared with the chemotherapy arm (64%).²² This and other trials using ifosfamide in various drug combinations showed no difference in survival, suggesting that adjuvant chemotherapy should not be considered to be standard practice outside of a clinical trial.

Efficacy of neoadjuvant chemotherapy. Neoadjuvant chemotherapy also has been studied in patients with soft-tissue sarcomas. A retrospective analysis found that the greatest benefit is derived in patients with primary tumors larger than 10 cm, in whom neoadjuvant chemotherapy increased 3-year disease-specific survival from 62% to 83%.²³ However, differing results came from a prospective multicenter trial that randomized patients with large primary and recurrent tumors to either surgery alone or surgery preceded by three cycles of neoadjuvant doxorubicin and ifosfamide (all patients could also receive adjuvant radiation therapy, depending on grade and adequacy of resection).²⁴ The trial suffered from slow accrual, and only 150 patients were enrolled. At 5 years, survival was similar between the groups with and without neoadjuvant chemotherapy.²⁴ Therefore, neoadjuvant chemotherapy is not yet recommended pending results of larger randomized trials.

No clear role for recurrent disease. Local recurrence of the primary tumor after resection occurs in 10% to 50% of cases of soft-tissue sarcoma, with the specific rate depending on the primary tumor location. The highest incidence of recurrence is found in patients with retroperitoneal and head and neck sarcoma (40% and 50%, respectively), mainly because of the difficulty of obtaining clear margins. Chemotherapy has not been well studied in this setting and is of uncertain value.³

Metastatic disease

Metastatic soft-tissue sarcomas may respond to chemotherapy, but there is a lack of evidence that chemotherapy improves overall survival. Pulmonary lesions are the most common site of distant recurrence, and resection of such metastases is sometimes undertaken in well-selected patients. However, there is no level 1 evidence supporting chemotherapy in this clinical setting despite its common preoperative use. There is a paucity of randomized phase 3 trials that compare established palliative chemotherapy regimens to best supportive care. It is believed that some groups of patients do benefit, however, including those who are young and have good performance status, low tumor grade, absence of liver metastasis or pulmonary metastasis only, and a long interval between treatment of the primary tumor and development of metastatic disease.³ Some histologies, such as uterine leiomyosarcomas and facial/scalp angiosarcomas, respond better to chemotherapy.¹⁷

Drugs found to have activity against metastatic sarcoma include doxorubicin, ifosfamide, platinum agents, gemcitabine, taxanes, and dacarbazine. Used either alone or in combinations, these drugs produce responses (ie, shrink metastatic tumors) in about 13% to 33% of patients.³ Use of chemotherapy is frequently curtailed by the acute toxicity of these agents, which includes pancytopenia, transfusion requirements, febrile neutropenia, nausea, alopecia, and significant fatigue, as well as renal failure with ifosfamide or cisplatin and peripheral neuropathy with platinum agents or taxanes. Appropriate patient selection for chemo­therapy and exclusion of those who should be managed solely with best supportive care is an important challenge that oncologists often face when managing patients with metastatic soft-tissue sarcoma.

Future directions

Trabectedin (ET-743) is a novel compound with promising activity against soft-tissue sarcomas that acts by inhibiting cell-cycle transition from the G₂ to M stages. The drug covalently binds to the minor grove of the DNA molecule, changing its three-dimensional structure and impairing transcription and possibly DNA repair.²⁵ Phase 2 studies showed durable responses to trabectedin in 3% to 8% of heavily pretreated patients^26–28 and in 17% of treatment-naïve patients with advanced soft-tissue sarcomas.²⁵ Time to progression of up to 20 months has been reported in patients who respond or develop stable disease.³

Toxic effects of trabec­tedin include myelosuppression, fever, edema, arthralgias, hepatotoxicity, and (rarely) rhabdomyolysis. To date, these toxicities have been self-limiting. Larger clinical trials and longer follow-up is needed to assess whether this agent has any significant long-term toxicities.

Trabectedin has already been approved in Europe for treatment of chemotherapy-refractory soft-tissue sarcoma when given as a 24-hour infusion every 21 days.

More broadly, an active effort is under way to better understand the molecular derangements in a variety of soft-tissue sarcoma subtypes. The hope is that this understanding will lead to improved therapies that target aberrant proliferation, angiogenesis, and other biologic processes that drive the growth and metastasis of soft-tissue and bone sarcomas.

While radiation therapy (RT) has an integral role in the management of soft-tissue sarcoma, it has a limited role in that of bone sarcoma, with few exceptions (ie, Ewing sarcoma). In keeping with the rarity of these tumors, it has been demonstrated that patients treated at high-volume centers have significantly better survival and functional outcomes.^1–3 Accordingly, treatment should be delivered by a multidisciplinary team including orthopedic, medical, and radiation oncologists, as well as plastic and reconstructive surgeons, physical therapy specialists, and pathologists and radiologists with expertise in musculoskeletal sarcomas.⁴ As the preceding articles in this supplement have addressed the major modalities in the treatment of sarcomas other than RT, this article will focus on how RT fits into the overall management mix, with a focus on soft-tissue sarcomas, where it figures most prominently.

BONE SARCOMAS: A LIMITED ROLE FOR RADIATION

The role of RT in the management of bone sarcomas is limited. Its primary application appears to be in Ewing sarcoma, for which curative treatment requires combined local and systemic therapy. For definitive therapy, limb-salvage surgery is preferable over amputation, but amputation may be an option for younger patients with lesions of the fibula, tibia, and foot. Based on the available data, postoperative RT is probably of benefit for all patients with Ewing sarcoma with close margins and/or those with a poor histologic response.⁵ Further discussion of Ewing sarcoma management is beyond the scope of this article (see the second and fifth articles in this supplement).

For osteosarcoma, the current standard of care is surgical resection combined with neoadjuvant and adjuvant chemotherapy. RT had been used years ago, prior to the advent of effective chemotherapy regimens, but its use for osteosarcoma has now been relegated to a few select situations. These include lesions not amenable to surgical resection and reconstruction, cases in which the patient refuses surgery, cases where there are positive margins after resection, and cases where palliation is needed for symptomatic lesions.

SOFT-TISSUE SARCOMAS: RADIATION HAS A CLEAR ADJUVANT ROLE

The primary management of localized soft-tissue sarcomas is surgical resection to achieve a negative margin when feasible. Historically, local excision of soft-tissue sarcomas resulted in local failure rates of 50% to 70%, even when a margin of normal tissue around the tumor was excised. As a result, amputation became standard treatment.⁶ In a landmark National Cancer Institute study 3 decades ago, patients were randomized to amputation or to limb-sparing surgery with the addition of RT.⁷ Notably, disease-free and overall survival were not compromised by limb-sparing surgery plus RT, demonstrating that although lesser surgery in the absence of RT may be insufficient, limb-sparing surgery with RT was equal to amputation. Consequently, limb-sparing approaches have become the favored surgery for the majority of cases of soft-tissue sarcoma, as advocated in a consensus statement from the National Institutes of Health.¹

Indications vary by lesion grade

In general, adjuvant RT is recommended for all intermediate- and high-grade soft-tissue sarcoma lesions. A potential exception is a superficial tumor smaller than 5 cm with widely negative margins after resection. For low-grade lesions, re-excision is favored over adjuvant RT for positive or close margins, and RT is avoided in the setting of negative margins.

Optimal timing of radiation remains unclear

The optimal timing of adjuvant RT—preoperative versus postoperative—remains unknown. The relative advantages of preoperative RT include smaller and well-defined treatment volume, ability to use a lower dose, lack of tissue hypoxia, increased tumor resectability (smaller surgery), and improved limb function with less late fibrosis and edema. The disadvantages include inability to precisely stage patients and higher risk of acute wound-healing complications.

The National Cancer Institute of Canada compared outcomes with preoperative versus postoperative RT among 190 patients with soft-tissue sarcoma in a prospective randomized trial.⁸ Patients were stratified by tumor size (≤ 10 cm or > 10cm) and then randomized to preoperative RT (50 Gy in 25 fractions) or postoperative RT (66 Gy in 33 fractions).⁸ There was no difference between the groups in local control, distant control, or survival rates, but a higher rate of late complications, including fibrosis and edema, was observed with postoperative RT.^8,9 On the other hand, the incidence of wound complications was higher in the preoperative group (35%) than in the postoperative group (17%).⁸

Likewise, the optimal sequencing and benefits of systemic therapy (chemotherapy) with relation to local therapy (surgery with pre- or postoperative RT) remain unclear. More than a dozen individual randomized trials of adjuvant chemotherapy, as well as a meta-analysis of 14 trials of doxorubicin-based adjuvant chemotherapy, have failed to demonstrate significant improvement in overall survival in patients with soft-tissue sarcomas.¹⁰ With regard to neoadjuvant chemotherapy for soft-tissue sarcomas, there are studies suggesting improvement in local control but no consistent survival benefit.¹¹ Chemotherapy may yield a benefit in select cases, as detailed elsewhere in this supplement.

MECHANISMS OF ACTION: DIRECT AND INDIRECT

In simplified terms, radiation kills cancer cells through two basic mechanisms: indirect and direct.

The indirect effect (the most common mechanism) results from the generation of free radicals in the intracellular medium via ionization by photons. Free radicals, in turn, deposit large amounts of energy that damage DNA or some other vital component of the cell, resulting in cell death.

The direct effect is a consequence of photons themselves interacting directly with the cell in a lethal manner.

The goal of RT is to kill tumor cells selectively, without irreversibly injuring adjacent normal tissue. This is done by exploiting two abnormal aspects of tumor behavior: decreased ability for repair and increased susceptibility to ionizing radiation damage. Tumors are generally less able than normal tissue to repair DNA damage, owing to defective repair mechanisms. Tumor cells are also comparatively more radiosensitive than normal tissues, as they are more frequently in radiosensitive cell-cycle phases. Thus, dividing the radiation dose into a number of treatment fractions provides two advantages that further exploit the biologic differences between tumor and normal tissue: it allows DNA repair to take place within the normal tissues, and it allows proliferating tumor cells to redistribute through the cell cycle and move into the more radiosensitive phases.

Treatment simulation

Following initial consultation with a radiation oncologist, the eligible patient undergoes a simulation, or a treatment planning session in which he or she is positioned so as to allow treatment to be carefully designed and subsequently delivered with precision. This typically requires fabrication of a customized immobilization device to allow for consistent positioning over the treatment course. Sarcomas require that special care be taken to properly immobilize both the proximal and distal joints. Additionally, radiopaque wires are used to delineate the anatomic boundaries of the tumor or scar. Computed tomographic (CT) scans are then obtained to enable image-based three-dimensional treatment planning. The patient setup is photographed, and setup indicators are recorded and marked on the patient’s skin, some with freckle-size tattoos and some with indelible marker.

The treatment fields are then designed on the CT-simulation data set with the aid of virtual reality–type techniques. In addition to delineation of tumor volumes, three-dimensional treatment planning is used to contour all nearby normal structures on each slice. The resulting structures can then be used to specify dose constraints and help determine the optimal beam geometries to ensure proper tumor coverage and minimize the potential for side effects by reducing the dose to organs at risk. In the case of sarcomas, several strategies for reducing the risk of side effects are especially relevant: (1) carefully sparing a portion of the circumference of uninvolved bone to minimize the risk of fractures; (2) carefully sparing a strip of normal tissue to minimize edema by permitting undisrupted lymphatic drainage from the extremity; and (3) keeping dosing to joint spaces and other adjacent organs below tissue tolerances as defined by Emami et al.¹²

Determining target volume

The target volume for RT is determined on the basis of physical examination, radiologic studies, anatomical considerations, and the natural history of the sarcoma.

In the preoperative setting, longitudinal margins of 5 cm beyond the tumor and tumor-associated edema and radial margins of 2 cm are treated to 50 Gy in 25 fractions. Surgery is undertaken approximately 4 weeks after completion of RT to allow for repair in normal tissues and minimize operative and postoperative complications. Following surgery, an RT boost may be added for positive margins (16 Gy) or gross residual disease (25 Gy).

In the postoperative setting, details on the extent of dissection or observations from the surgeons themselves must be considered. Information regarding the surgical approach must be noted and can influence the effectiveness of postoperative RT as well as the incidence of late side effects. When experienced surgeons are involved, scars and drain sites, which are at risk for subclinical disease, can be planned so that their inclusion in the RT portal allows for sparing a strip of skin to minimize complications. Surgical clip placement at the boundaries of the tumor bed also facilitates RT planning.¹³ Finally, prophylactic bone stabilization may reduce the risk of subsequent fracture in cases where circumferential bone radiation in high-risk sites is anticipated.

Recommendations on the volume that must be treated vary among different authorities. Some advocate treating the entire compartment because of the risk for microscopic seeding.¹⁴ Others recommend margins around the tumor or tumor bed ranging from less than 5 cm up to 15 cm.¹⁵ Most often the postoperative approach is to include the resection bed with a 2-cm radial margin, the incision, and any drain sites in the initial treatment volume and to base the longitudinal margin on the grade and size of the primary tumor (5–15 cm). This volume is treated to 50 Gy in 25 fractions followed by two sequential reductions in field size, with the total dose determined by the extent of resection: 60 Gy for negative margins, 66 Gy for microscopically positive margins, and 75 Gy for gross residual disease.

TREATMENT DELIVERY

Once treatment planning is completed, treatments begin and are given daily Monday through Friday. Each day, the patient is positioned in the immobilization device, the field measurements are set, and positioning is checked with measurement tools and external marking of the field borders on the skin. Daily image guidance techniques may be used to increase setup reproducibility. Typical treatment times, including set­up and actual delivery, are roughly 20 to 30 minutes daily.

While external beam RT is most commonly delivered as described above, brachytherapy, or intraoperative electron beam techniques, as well as proton or other charged-particle therapies, are also applied in selected cases.^16–18

SIDE EFFECTS

Side effects of RT in the setting of sarcomas can be divided according to their onset—ie, acute versus delayed.

Acute effects. Skin changes ranging from erythema to moist desquamation in the skin overlying the high-dose volume are common. Major wound complications (delayed wound healing or need for surgical intervention) occur in approximately 17% of patients after surgical resection with postoperative RT, and perhaps more commonly (35%) with preoperative RT,⁸ though these rates vary widely in the literature. Another frequently reported acute side effect is fatigue.

Delayed sequelae after conservative resection and RT of extremity lesions include a reduction in range of motion secondary to joint contracture, edema, and fibrosis, as well as pain and bone fractures, all of which can significantly limit function of the preserved limb. In centers treating high volumes of patients with soft-tissue sarcoma, the incidence of moderate to severe late effects is less than 10%.¹⁹ In contrast to acute wound complications, a higher rate of late complications, including fibrosis and edema, have been observed with postoperative RT relative to preoperative RT.⁹ When necessary, high-dose RT does not appear to compromise the viability of skin grafts used to repair defects after sarcoma surgery if adequate time is allowed for healing.²⁰

Regardless of the management approach, intensive rehabilitation led by physical therapy specialists is imperative in minimizing disabilities after treatment of soft-tissue sarcomas.

CONCLUSION

Outcomes of patients with musculoskeletal sarcomas are optimized at specialized sarcoma centers. For patients with soft-tissue sarcomas, effectively implementing an approach that combines conservative surgery and RT—and, in select cases, chemotherapy—achieves excellent local control rates while minimizing morbidity and maximizing long-term extremity function relative to aggressive surgery alone.

While radiation therapy (RT) has an integral role in the management of soft-tissue sarcoma, it has a limited role in that of bone sarcoma, with few exceptions (ie, Ewing sarcoma). In keeping with the rarity of these tumors, it has been demonstrated that patients treated at high-volume centers have significantly better survival and functional outcomes.^1–3 Accordingly, treatment should be delivered by a multidisciplinary team including orthopedic, medical, and radiation oncologists, as well as plastic and reconstructive surgeons, physical therapy specialists, and pathologists and radiologists with expertise in musculoskeletal sarcomas.⁴ As the preceding articles in this supplement have addressed the major modalities in the treatment of sarcomas other than RT, this article will focus on how RT fits into the overall management mix, with a focus on soft-tissue sarcomas, where it figures most prominently.

BONE SARCOMAS: A LIMITED ROLE FOR RADIATION

The role of RT in the management of bone sarcomas is limited. Its primary application appears to be in Ewing sarcoma, for which curative treatment requires combined local and systemic therapy. For definitive therapy, limb-salvage surgery is preferable over amputation, but amputation may be an option for younger patients with lesions of the fibula, tibia, and foot. Based on the available data, postoperative RT is probably of benefit for all patients with Ewing sarcoma with close margins and/or those with a poor histologic response.⁵ Further discussion of Ewing sarcoma management is beyond the scope of this article (see the second and fifth articles in this supplement).

For osteosarcoma, the current standard of care is surgical resection combined with neoadjuvant and adjuvant chemotherapy. RT had been used years ago, prior to the advent of effective chemotherapy regimens, but its use for osteosarcoma has now been relegated to a few select situations. These include lesions not amenable to surgical resection and reconstruction, cases in which the patient refuses surgery, cases where there are positive margins after resection, and cases where palliation is needed for symptomatic lesions.

SOFT-TISSUE SARCOMAS: RADIATION HAS A CLEAR ADJUVANT ROLE

The primary management of localized soft-tissue sarcomas is surgical resection to achieve a negative margin when feasible. Historically, local excision of soft-tissue sarcomas resulted in local failure rates of 50% to 70%, even when a margin of normal tissue around the tumor was excised. As a result, amputation became standard treatment.⁶ In a landmark National Cancer Institute study 3 decades ago, patients were randomized to amputation or to limb-sparing surgery with the addition of RT.⁷ Notably, disease-free and overall survival were not compromised by limb-sparing surgery plus RT, demonstrating that although lesser surgery in the absence of RT may be insufficient, limb-sparing surgery with RT was equal to amputation. Consequently, limb-sparing approaches have become the favored surgery for the majority of cases of soft-tissue sarcoma, as advocated in a consensus statement from the National Institutes of Health.¹

Indications vary by lesion grade

In general, adjuvant RT is recommended for all intermediate- and high-grade soft-tissue sarcoma lesions. A potential exception is a superficial tumor smaller than 5 cm with widely negative margins after resection. For low-grade lesions, re-excision is favored over adjuvant RT for positive or close margins, and RT is avoided in the setting of negative margins.

Optimal timing of radiation remains unclear

The optimal timing of adjuvant RT—preoperative versus postoperative—remains unknown. The relative advantages of preoperative RT include smaller and well-defined treatment volume, ability to use a lower dose, lack of tissue hypoxia, increased tumor resectability (smaller surgery), and improved limb function with less late fibrosis and edema. The disadvantages include inability to precisely stage patients and higher risk of acute wound-healing complications.

The National Cancer Institute of Canada compared outcomes with preoperative versus postoperative RT among 190 patients with soft-tissue sarcoma in a prospective randomized trial.⁸ Patients were stratified by tumor size (≤ 10 cm or > 10cm) and then randomized to preoperative RT (50 Gy in 25 fractions) or postoperative RT (66 Gy in 33 fractions).⁸ There was no difference between the groups in local control, distant control, or survival rates, but a higher rate of late complications, including fibrosis and edema, was observed with postoperative RT.^8,9 On the other hand, the incidence of wound complications was higher in the preoperative group (35%) than in the postoperative group (17%).⁸

Likewise, the optimal sequencing and benefits of systemic therapy (chemotherapy) with relation to local therapy (surgery with pre- or postoperative RT) remain unclear. More than a dozen individual randomized trials of adjuvant chemotherapy, as well as a meta-analysis of 14 trials of doxorubicin-based adjuvant chemotherapy, have failed to demonstrate significant improvement in overall survival in patients with soft-tissue sarcomas.¹⁰ With regard to neoadjuvant chemotherapy for soft-tissue sarcomas, there are studies suggesting improvement in local control but no consistent survival benefit.¹¹ Chemotherapy may yield a benefit in select cases, as detailed elsewhere in this supplement.

MECHANISMS OF ACTION: DIRECT AND INDIRECT

In simplified terms, radiation kills cancer cells through two basic mechanisms: indirect and direct.

The indirect effect (the most common mechanism) results from the generation of free radicals in the intracellular medium via ionization by photons. Free radicals, in turn, deposit large amounts of energy that damage DNA or some other vital component of the cell, resulting in cell death.

The direct effect is a consequence of photons themselves interacting directly with the cell in a lethal manner.

The goal of RT is to kill tumor cells selectively, without irreversibly injuring adjacent normal tissue. This is done by exploiting two abnormal aspects of tumor behavior: decreased ability for repair and increased susceptibility to ionizing radiation damage. Tumors are generally less able than normal tissue to repair DNA damage, owing to defective repair mechanisms. Tumor cells are also comparatively more radiosensitive than normal tissues, as they are more frequently in radiosensitive cell-cycle phases. Thus, dividing the radiation dose into a number of treatment fractions provides two advantages that further exploit the biologic differences between tumor and normal tissue: it allows DNA repair to take place within the normal tissues, and it allows proliferating tumor cells to redistribute through the cell cycle and move into the more radiosensitive phases.

Treatment simulation

Following initial consultation with a radiation oncologist, the eligible patient undergoes a simulation, or a treatment planning session in which he or she is positioned so as to allow treatment to be carefully designed and subsequently delivered with precision. This typically requires fabrication of a customized immobilization device to allow for consistent positioning over the treatment course. Sarcomas require that special care be taken to properly immobilize both the proximal and distal joints. Additionally, radiopaque wires are used to delineate the anatomic boundaries of the tumor or scar. Computed tomographic (CT) scans are then obtained to enable image-based three-dimensional treatment planning. The patient setup is photographed, and setup indicators are recorded and marked on the patient’s skin, some with freckle-size tattoos and some with indelible marker.

The treatment fields are then designed on the CT-simulation data set with the aid of virtual reality–type techniques. In addition to delineation of tumor volumes, three-dimensional treatment planning is used to contour all nearby normal structures on each slice. The resulting structures can then be used to specify dose constraints and help determine the optimal beam geometries to ensure proper tumor coverage and minimize the potential for side effects by reducing the dose to organs at risk. In the case of sarcomas, several strategies for reducing the risk of side effects are especially relevant: (1) carefully sparing a portion of the circumference of uninvolved bone to minimize the risk of fractures; (2) carefully sparing a strip of normal tissue to minimize edema by permitting undisrupted lymphatic drainage from the extremity; and (3) keeping dosing to joint spaces and other adjacent organs below tissue tolerances as defined by Emami et al.¹²

Determining target volume

The target volume for RT is determined on the basis of physical examination, radiologic studies, anatomical considerations, and the natural history of the sarcoma.

In the preoperative setting, longitudinal margins of 5 cm beyond the tumor and tumor-associated edema and radial margins of 2 cm are treated to 50 Gy in 25 fractions. Surgery is undertaken approximately 4 weeks after completion of RT to allow for repair in normal tissues and minimize operative and postoperative complications. Following surgery, an RT boost may be added for positive margins (16 Gy) or gross residual disease (25 Gy).

In the postoperative setting, details on the extent of dissection or observations from the surgeons themselves must be considered. Information regarding the surgical approach must be noted and can influence the effectiveness of postoperative RT as well as the incidence of late side effects. When experienced surgeons are involved, scars and drain sites, which are at risk for subclinical disease, can be planned so that their inclusion in the RT portal allows for sparing a strip of skin to minimize complications. Surgical clip placement at the boundaries of the tumor bed also facilitates RT planning.¹³ Finally, prophylactic bone stabilization may reduce the risk of subsequent fracture in cases where circumferential bone radiation in high-risk sites is anticipated.

Recommendations on the volume that must be treated vary among different authorities. Some advocate treating the entire compartment because of the risk for microscopic seeding.¹⁴ Others recommend margins around the tumor or tumor bed ranging from less than 5 cm up to 15 cm.¹⁵ Most often the postoperative approach is to include the resection bed with a 2-cm radial margin, the incision, and any drain sites in the initial treatment volume and to base the longitudinal margin on the grade and size of the primary tumor (5–15 cm). This volume is treated to 50 Gy in 25 fractions followed by two sequential reductions in field size, with the total dose determined by the extent of resection: 60 Gy for negative margins, 66 Gy for microscopically positive margins, and 75 Gy for gross residual disease.

TREATMENT DELIVERY

Once treatment planning is completed, treatments begin and are given daily Monday through Friday. Each day, the patient is positioned in the immobilization device, the field measurements are set, and positioning is checked with measurement tools and external marking of the field borders on the skin. Daily image guidance techniques may be used to increase setup reproducibility. Typical treatment times, including set­up and actual delivery, are roughly 20 to 30 minutes daily.

While external beam RT is most commonly delivered as described above, brachytherapy, or intraoperative electron beam techniques, as well as proton or other charged-particle therapies, are also applied in selected cases.^16–18

SIDE EFFECTS

Side effects of RT in the setting of sarcomas can be divided according to their onset—ie, acute versus delayed.

Acute effects. Skin changes ranging from erythema to moist desquamation in the skin overlying the high-dose volume are common. Major wound complications (delayed wound healing or need for surgical intervention) occur in approximately 17% of patients after surgical resection with postoperative RT, and perhaps more commonly (35%) with preoperative RT,⁸ though these rates vary widely in the literature. Another frequently reported acute side effect is fatigue.

Delayed sequelae after conservative resection and RT of extremity lesions include a reduction in range of motion secondary to joint contracture, edema, and fibrosis, as well as pain and bone fractures, all of which can significantly limit function of the preserved limb. In centers treating high volumes of patients with soft-tissue sarcoma, the incidence of moderate to severe late effects is less than 10%.¹⁹ In contrast to acute wound complications, a higher rate of late complications, including fibrosis and edema, have been observed with postoperative RT relative to preoperative RT.⁹ When necessary, high-dose RT does not appear to compromise the viability of skin grafts used to repair defects after sarcoma surgery if adequate time is allowed for healing.²⁰

Regardless of the management approach, intensive rehabilitation led by physical therapy specialists is imperative in minimizing disabilities after treatment of soft-tissue sarcomas.

CONCLUSION

Outcomes of patients with musculoskeletal sarcomas are optimized at specialized sarcoma centers. For patients with soft-tissue sarcomas, effectively implementing an approach that combines conservative surgery and RT—and, in select cases, chemotherapy—achieves excellent local control rates while minimizing morbidity and maximizing long-term extremity function relative to aggressive surgery alone.

While radiation therapy (RT) has an integral role in the management of soft-tissue sarcoma, it has a limited role in that of bone sarcoma, with few exceptions (ie, Ewing sarcoma). In keeping with the rarity of these tumors, it has been demonstrated that patients treated at high-volume centers have significantly better survival and functional outcomes.^1–3 Accordingly, treatment should be delivered by a multidisciplinary team including orthopedic, medical, and radiation oncologists, as well as plastic and reconstructive surgeons, physical therapy specialists, and pathologists and radiologists with expertise in musculoskeletal sarcomas.⁴ As the preceding articles in this supplement have addressed the major modalities in the treatment of sarcomas other than RT, this article will focus on how RT fits into the overall management mix, with a focus on soft-tissue sarcomas, where it figures most prominently.

BONE SARCOMAS: A LIMITED ROLE FOR RADIATION

The role of RT in the management of bone sarcomas is limited. Its primary application appears to be in Ewing sarcoma, for which curative treatment requires combined local and systemic therapy. For definitive therapy, limb-salvage surgery is preferable over amputation, but amputation may be an option for younger patients with lesions of the fibula, tibia, and foot. Based on the available data, postoperative RT is probably of benefit for all patients with Ewing sarcoma with close margins and/or those with a poor histologic response.⁵ Further discussion of Ewing sarcoma management is beyond the scope of this article (see the second and fifth articles in this supplement).

For osteosarcoma, the current standard of care is surgical resection combined with neoadjuvant and adjuvant chemotherapy. RT had been used years ago, prior to the advent of effective chemotherapy regimens, but its use for osteosarcoma has now been relegated to a few select situations. These include lesions not amenable to surgical resection and reconstruction, cases in which the patient refuses surgery, cases where there are positive margins after resection, and cases where palliation is needed for symptomatic lesions.

SOFT-TISSUE SARCOMAS: RADIATION HAS A CLEAR ADJUVANT ROLE

The primary management of localized soft-tissue sarcomas is surgical resection to achieve a negative margin when feasible. Historically, local excision of soft-tissue sarcomas resulted in local failure rates of 50% to 70%, even when a margin of normal tissue around the tumor was excised. As a result, amputation became standard treatment.⁶ In a landmark National Cancer Institute study 3 decades ago, patients were randomized to amputation or to limb-sparing surgery with the addition of RT.⁷ Notably, disease-free and overall survival were not compromised by limb-sparing surgery plus RT, demonstrating that although lesser surgery in the absence of RT may be insufficient, limb-sparing surgery with RT was equal to amputation. Consequently, limb-sparing approaches have become the favored surgery for the majority of cases of soft-tissue sarcoma, as advocated in a consensus statement from the National Institutes of Health.¹

Indications vary by lesion grade

In general, adjuvant RT is recommended for all intermediate- and high-grade soft-tissue sarcoma lesions. A potential exception is a superficial tumor smaller than 5 cm with widely negative margins after resection. For low-grade lesions, re-excision is favored over adjuvant RT for positive or close margins, and RT is avoided in the setting of negative margins.

Optimal timing of radiation remains unclear

The optimal timing of adjuvant RT—preoperative versus postoperative—remains unknown. The relative advantages of preoperative RT include smaller and well-defined treatment volume, ability to use a lower dose, lack of tissue hypoxia, increased tumor resectability (smaller surgery), and improved limb function with less late fibrosis and edema. The disadvantages include inability to precisely stage patients and higher risk of acute wound-healing complications.

The National Cancer Institute of Canada compared outcomes with preoperative versus postoperative RT among 190 patients with soft-tissue sarcoma in a prospective randomized trial.⁸ Patients were stratified by tumor size (≤ 10 cm or > 10cm) and then randomized to preoperative RT (50 Gy in 25 fractions) or postoperative RT (66 Gy in 33 fractions).⁸ There was no difference between the groups in local control, distant control, or survival rates, but a higher rate of late complications, including fibrosis and edema, was observed with postoperative RT.^8,9 On the other hand, the incidence of wound complications was higher in the preoperative group (35%) than in the postoperative group (17%).⁸

Likewise, the optimal sequencing and benefits of systemic therapy (chemotherapy) with relation to local therapy (surgery with pre- or postoperative RT) remain unclear. More than a dozen individual randomized trials of adjuvant chemotherapy, as well as a meta-analysis of 14 trials of doxorubicin-based adjuvant chemotherapy, have failed to demonstrate significant improvement in overall survival in patients with soft-tissue sarcomas.¹⁰ With regard to neoadjuvant chemotherapy for soft-tissue sarcomas, there are studies suggesting improvement in local control but no consistent survival benefit.¹¹ Chemotherapy may yield a benefit in select cases, as detailed elsewhere in this supplement.

MECHANISMS OF ACTION: DIRECT AND INDIRECT

In simplified terms, radiation kills cancer cells through two basic mechanisms: indirect and direct.

The indirect effect (the most common mechanism) results from the generation of free radicals in the intracellular medium via ionization by photons. Free radicals, in turn, deposit large amounts of energy that damage DNA or some other vital component of the cell, resulting in cell death.

The direct effect is a consequence of photons themselves interacting directly with the cell in a lethal manner.

The goal of RT is to kill tumor cells selectively, without irreversibly injuring adjacent normal tissue. This is done by exploiting two abnormal aspects of tumor behavior: decreased ability for repair and increased susceptibility to ionizing radiation damage. Tumors are generally less able than normal tissue to repair DNA damage, owing to defective repair mechanisms. Tumor cells are also comparatively more radiosensitive than normal tissues, as they are more frequently in radiosensitive cell-cycle phases. Thus, dividing the radiation dose into a number of treatment fractions provides two advantages that further exploit the biologic differences between tumor and normal tissue: it allows DNA repair to take place within the normal tissues, and it allows proliferating tumor cells to redistribute through the cell cycle and move into the more radiosensitive phases.

Treatment simulation

Following initial consultation with a radiation oncologist, the eligible patient undergoes a simulation, or a treatment planning session in which he or she is positioned so as to allow treatment to be carefully designed and subsequently delivered with precision. This typically requires fabrication of a customized immobilization device to allow for consistent positioning over the treatment course. Sarcomas require that special care be taken to properly immobilize both the proximal and distal joints. Additionally, radiopaque wires are used to delineate the anatomic boundaries of the tumor or scar. Computed tomographic (CT) scans are then obtained to enable image-based three-dimensional treatment planning. The patient setup is photographed, and setup indicators are recorded and marked on the patient’s skin, some with freckle-size tattoos and some with indelible marker.

The treatment fields are then designed on the CT-simulation data set with the aid of virtual reality–type techniques. In addition to delineation of tumor volumes, three-dimensional treatment planning is used to contour all nearby normal structures on each slice. The resulting structures can then be used to specify dose constraints and help determine the optimal beam geometries to ensure proper tumor coverage and minimize the potential for side effects by reducing the dose to organs at risk. In the case of sarcomas, several strategies for reducing the risk of side effects are especially relevant: (1) carefully sparing a portion of the circumference of uninvolved bone to minimize the risk of fractures; (2) carefully sparing a strip of normal tissue to minimize edema by permitting undisrupted lymphatic drainage from the extremity; and (3) keeping dosing to joint spaces and other adjacent organs below tissue tolerances as defined by Emami et al.¹²

Determining target volume

The target volume for RT is determined on the basis of physical examination, radiologic studies, anatomical considerations, and the natural history of the sarcoma.

In the preoperative setting, longitudinal margins of 5 cm beyond the tumor and tumor-associated edema and radial margins of 2 cm are treated to 50 Gy in 25 fractions. Surgery is undertaken approximately 4 weeks after completion of RT to allow for repair in normal tissues and minimize operative and postoperative complications. Following surgery, an RT boost may be added for positive margins (16 Gy) or gross residual disease (25 Gy).

In the postoperative setting, details on the extent of dissection or observations from the surgeons themselves must be considered. Information regarding the surgical approach must be noted and can influence the effectiveness of postoperative RT as well as the incidence of late side effects. When experienced surgeons are involved, scars and drain sites, which are at risk for subclinical disease, can be planned so that their inclusion in the RT portal allows for sparing a strip of skin to minimize complications. Surgical clip placement at the boundaries of the tumor bed also facilitates RT planning.¹³ Finally, prophylactic bone stabilization may reduce the risk of subsequent fracture in cases where circumferential bone radiation in high-risk sites is anticipated.

Recommendations on the volume that must be treated vary among different authorities. Some advocate treating the entire compartment because of the risk for microscopic seeding.¹⁴ Others recommend margins around the tumor or tumor bed ranging from less than 5 cm up to 15 cm.¹⁵ Most often the postoperative approach is to include the resection bed with a 2-cm radial margin, the incision, and any drain sites in the initial treatment volume and to base the longitudinal margin on the grade and size of the primary tumor (5–15 cm). This volume is treated to 50 Gy in 25 fractions followed by two sequential reductions in field size, with the total dose determined by the extent of resection: 60 Gy for negative margins, 66 Gy for microscopically positive margins, and 75 Gy for gross residual disease.

TREATMENT DELIVERY

Once treatment planning is completed, treatments begin and are given daily Monday through Friday. Each day, the patient is positioned in the immobilization device, the field measurements are set, and positioning is checked with measurement tools and external marking of the field borders on the skin. Daily image guidance techniques may be used to increase setup reproducibility. Typical treatment times, including set­up and actual delivery, are roughly 20 to 30 minutes daily.

While external beam RT is most commonly delivered as described above, brachytherapy, or intraoperative electron beam techniques, as well as proton or other charged-particle therapies, are also applied in selected cases.^16–18

SIDE EFFECTS

Side effects of RT in the setting of sarcomas can be divided according to their onset—ie, acute versus delayed.

Acute effects. Skin changes ranging from erythema to moist desquamation in the skin overlying the high-dose volume are common. Major wound complications (delayed wound healing or need for surgical intervention) occur in approximately 17% of patients after surgical resection with postoperative RT, and perhaps more commonly (35%) with preoperative RT,⁸ though these rates vary widely in the literature. Another frequently reported acute side effect is fatigue.

Delayed sequelae after conservative resection and RT of extremity lesions include a reduction in range of motion secondary to joint contracture, edema, and fibrosis, as well as pain and bone fractures, all of which can significantly limit function of the preserved limb. In centers treating high volumes of patients with soft-tissue sarcoma, the incidence of moderate to severe late effects is less than 10%.¹⁹ In contrast to acute wound complications, a higher rate of late complications, including fibrosis and edema, have been observed with postoperative RT relative to preoperative RT.⁹ When necessary, high-dose RT does not appear to compromise the viability of skin grafts used to repair defects after sarcoma surgery if adequate time is allowed for healing.²⁰

Regardless of the management approach, intensive rehabilitation led by physical therapy specialists is imperative in minimizing disabilities after treatment of soft-tissue sarcomas.

CONCLUSION

Outcomes of patients with musculoskeletal sarcomas are optimized at specialized sarcoma centers. For patients with soft-tissue sarcomas, effectively implementing an approach that combines conservative surgery and RT—and, in select cases, chemotherapy—achieves excellent local control rates while minimizing morbidity and maximizing long-term extremity function relative to aggressive surgery alone.

Q: Which is the most likely diagnosis?

• Idiopathic thrombocytopenic purpura
• Vitamin C deficiency (scurvy)
• Kaposi sarcoma not related to human immunodeficiency virus (HIV) infection
• Henoch-Schönlein purpura
• Polyarteritis nodosa

A: The correct answer is Henoch-Schönlein purpura.

Idiopathic thrombocytopenic purpura is an autoimmune disease caused by specific antibodies against platelet-membrane glycoproteins. It is characterized by thrombocytopenia not explainable by contact with toxic substances or by other causes. Along with nonpalpable purpura, other common signs are epistaxis, gingival bleeding, menorrhagia, and retinal hemorrhage.

Scurvy is an uncommon deficiency of ascorbic acid (vitamin C). The elderly and alcoholics are at higher risk, as they do not take in enough vitamin C in the diet. Patients usually show perifollicular hemorrhages of the skin and mucous membranes, typically petechial hemorrhage or ecchymosis of the gums around the upper incisors. Other cutaneous signs are follicular hyperkeratosis on the forearms, small corkscrew hairs, and sicca syndrome, which is more common in adults.

Non-HIV Kaposi sarcoma usually affects elderly patients, with pink, red, or brown papules or nodules on the legs and, less commonly, on the head and neck. Histopathologic examination shows newly formed irregular blood vessels with an inflammatory infiltrate of plasma cells and lymphocytes; immunohistochemical human herpes virus staining is usually positive.

Polyarteritis nodosa is a systemic vasculitis that affects medium or small arteries with necrotizing inflammation; renal glomeruli and arterioles, capillaries, and venules are unaffected. Skin manifestations include palpable purpura, livedo reticularis, ulcers, and distal gangrene. The condition also usually affects the kidneys, the heart, and the musculoskeletal and nervous systems.

A SYSTEMIC VASCULITIS

Henoch-Schönlein purpura is a systemic vasculitis affecting the skin, gastrointestinal tract, kidneys, and joints. Palpable purpura and joint pain are the most common and consistent presenting symptoms. The kidneys are affected in about one-third of children and in 60% of adults, and this is the major factor determining the long-term outcome.¹

In our patient, laboratory testing that included a complete blood cell count, biochemical testing (including IgA levels), urinary sediment, and coagulation studies showed no abnormalities except elevations of the erythrocyte sedimentation rate and the concentration of C-reactive protein (an acute-phase reactant). These can be normal in some patients. Renal involvement was also not present.

DIAGNOSIS

The diagnosis relies on clinical manifestations. Because Henoch-Schönlein purpura is less common in adults, biopsy plays a more important role in establishing the diagnosis in this age group, and it does this by demonstrating leukocytoclastic vasculitis with a predominance of IgA deposition under immunofluorescence. Recent studies in children showed that an elevated IgA concentration along with reduced IgM levels was associated with a higher rate of severe complications.² However, depending on the age of the biopsied lesion, IgA may not be detected.

TREATMENT DIRECTED AT SYMPTOMS

Our patient received oral corticosteroids 0.5 mg/kg per day for 20 days, and the lesions resolved by 4 weeks.

Management of Henoch-Schönlein purpura is mainly directed at the symptoms, with oral hydration and nonsteroidal anti-inflammatory drugs. For severe cases, a short course of corticosteroids (0.5–1 mg/kg) may be used.

Although no controlled clinical trial has proven that Henoch-Schönlein purpura responds to corticosteroids, colchicine, or other drugs, corticosteroids are used most often, especially in patients with renal disease. Patients with severe renal insufficiency, abdominal pain, joint involvement, or bleeding should be hospitalized. Plasmapheresis³ has been used in severe cases.

HENOCH-SCHÖNLEIN PURPURA AND MALIGNANCY

During a follow-up evaluation 1 month later, our patient was diagnosed with adenocarcinoma of the breast. This highlights the value of a workup for cancer in adults with cutaneous vasculitis.

Cutaneous vasculitis can represent a paraneoplastic syndrome associated with a malignant tumor. The pathophysiology of this association is unclear, but one proposed mechanism is the exaggerated production of antibodies that react against tumor neoantigens, leading to the formation of immune complexes, or that occasionally recognize endothelial cells because of similarities with tumor antigens. Another theory is that abnormally high levels of inflammatory cytokines are produced by neoplastic cells or in response to decreased immune complex clearance.

Yet another theory is that hyperviscosity of the blood, seen in some cancers, increases the contact time for deposition of immune complexes and causes endothelial damage. Drugs used to treat cancer have also been reported to produce Henoch-Schönlein purpura.⁴

Although hematologic malignancy is three to five times more common than solid tumors in patients with small-vessel vasculitis, the disease has been associated with solid tumors of the liver, skin, colon, and breast in adults over age 40.⁵ An evaluation for neoplasm is therefore reasonable in adults with Henoch-Schönlein purpura, as is an evaluation for tumor recurrence or metastasis if the patient has been previously treated for a malignant tumor.

Q: Which is the most likely diagnosis?

• Idiopathic thrombocytopenic purpura
• Vitamin C deficiency (scurvy)
• Kaposi sarcoma not related to human immunodeficiency virus (HIV) infection
• Henoch-Schönlein purpura
• Polyarteritis nodosa

A: The correct answer is Henoch-Schönlein purpura.

Idiopathic thrombocytopenic purpura is an autoimmune disease caused by specific antibodies against platelet-membrane glycoproteins. It is characterized by thrombocytopenia not explainable by contact with toxic substances or by other causes. Along with nonpalpable purpura, other common signs are epistaxis, gingival bleeding, menorrhagia, and retinal hemorrhage.

Scurvy is an uncommon deficiency of ascorbic acid (vitamin C). The elderly and alcoholics are at higher risk, as they do not take in enough vitamin C in the diet. Patients usually show perifollicular hemorrhages of the skin and mucous membranes, typically petechial hemorrhage or ecchymosis of the gums around the upper incisors. Other cutaneous signs are follicular hyperkeratosis on the forearms, small corkscrew hairs, and sicca syndrome, which is more common in adults.

Non-HIV Kaposi sarcoma usually affects elderly patients, with pink, red, or brown papules or nodules on the legs and, less commonly, on the head and neck. Histopathologic examination shows newly formed irregular blood vessels with an inflammatory infiltrate of plasma cells and lymphocytes; immunohistochemical human herpes virus staining is usually positive.

Polyarteritis nodosa is a systemic vasculitis that affects medium or small arteries with necrotizing inflammation; renal glomeruli and arterioles, capillaries, and venules are unaffected. Skin manifestations include palpable purpura, livedo reticularis, ulcers, and distal gangrene. The condition also usually affects the kidneys, the heart, and the musculoskeletal and nervous systems.

A SYSTEMIC VASCULITIS

Henoch-Schönlein purpura is a systemic vasculitis affecting the skin, gastrointestinal tract, kidneys, and joints. Palpable purpura and joint pain are the most common and consistent presenting symptoms. The kidneys are affected in about one-third of children and in 60% of adults, and this is the major factor determining the long-term outcome.¹

In our patient, laboratory testing that included a complete blood cell count, biochemical testing (including IgA levels), urinary sediment, and coagulation studies showed no abnormalities except elevations of the erythrocyte sedimentation rate and the concentration of C-reactive protein (an acute-phase reactant). These can be normal in some patients. Renal involvement was also not present.

DIAGNOSIS

The diagnosis relies on clinical manifestations. Because Henoch-Schönlein purpura is less common in adults, biopsy plays a more important role in establishing the diagnosis in this age group, and it does this by demonstrating leukocytoclastic vasculitis with a predominance of IgA deposition under immunofluorescence. Recent studies in children showed that an elevated IgA concentration along with reduced IgM levels was associated with a higher rate of severe complications.² However, depending on the age of the biopsied lesion, IgA may not be detected.

TREATMENT DIRECTED AT SYMPTOMS

Our patient received oral corticosteroids 0.5 mg/kg per day for 20 days, and the lesions resolved by 4 weeks.

Management of Henoch-Schönlein purpura is mainly directed at the symptoms, with oral hydration and nonsteroidal anti-inflammatory drugs. For severe cases, a short course of corticosteroids (0.5–1 mg/kg) may be used.

Although no controlled clinical trial has proven that Henoch-Schönlein purpura responds to corticosteroids, colchicine, or other drugs, corticosteroids are used most often, especially in patients with renal disease. Patients with severe renal insufficiency, abdominal pain, joint involvement, or bleeding should be hospitalized. Plasmapheresis³ has been used in severe cases.

HENOCH-SCHÖNLEIN PURPURA AND MALIGNANCY

During a follow-up evaluation 1 month later, our patient was diagnosed with adenocarcinoma of the breast. This highlights the value of a workup for cancer in adults with cutaneous vasculitis.

Cutaneous vasculitis can represent a paraneoplastic syndrome associated with a malignant tumor. The pathophysiology of this association is unclear, but one proposed mechanism is the exaggerated production of antibodies that react against tumor neoantigens, leading to the formation of immune complexes, or that occasionally recognize endothelial cells because of similarities with tumor antigens. Another theory is that abnormally high levels of inflammatory cytokines are produced by neoplastic cells or in response to decreased immune complex clearance.

Yet another theory is that hyperviscosity of the blood, seen in some cancers, increases the contact time for deposition of immune complexes and causes endothelial damage. Drugs used to treat cancer have also been reported to produce Henoch-Schönlein purpura.⁴

Although hematologic malignancy is three to five times more common than solid tumors in patients with small-vessel vasculitis, the disease has been associated with solid tumors of the liver, skin, colon, and breast in adults over age 40.⁵ An evaluation for neoplasm is therefore reasonable in adults with Henoch-Schönlein purpura, as is an evaluation for tumor recurrence or metastasis if the patient has been previously treated for a malignant tumor.

Q: Which is the most likely diagnosis?

• Idiopathic thrombocytopenic purpura
• Vitamin C deficiency (scurvy)
• Kaposi sarcoma not related to human immunodeficiency virus (HIV) infection
• Henoch-Schönlein purpura
• Polyarteritis nodosa

A: The correct answer is Henoch-Schönlein purpura.

Idiopathic thrombocytopenic purpura is an autoimmune disease caused by specific antibodies against platelet-membrane glycoproteins. It is characterized by thrombocytopenia not explainable by contact with toxic substances or by other causes. Along with nonpalpable purpura, other common signs are epistaxis, gingival bleeding, menorrhagia, and retinal hemorrhage.

Scurvy is an uncommon deficiency of ascorbic acid (vitamin C). The elderly and alcoholics are at higher risk, as they do not take in enough vitamin C in the diet. Patients usually show perifollicular hemorrhages of the skin and mucous membranes, typically petechial hemorrhage or ecchymosis of the gums around the upper incisors. Other cutaneous signs are follicular hyperkeratosis on the forearms, small corkscrew hairs, and sicca syndrome, which is more common in adults.

Non-HIV Kaposi sarcoma usually affects elderly patients, with pink, red, or brown papules or nodules on the legs and, less commonly, on the head and neck. Histopathologic examination shows newly formed irregular blood vessels with an inflammatory infiltrate of plasma cells and lymphocytes; immunohistochemical human herpes virus staining is usually positive.

Polyarteritis nodosa is a systemic vasculitis that affects medium or small arteries with necrotizing inflammation; renal glomeruli and arterioles, capillaries, and venules are unaffected. Skin manifestations include palpable purpura, livedo reticularis, ulcers, and distal gangrene. The condition also usually affects the kidneys, the heart, and the musculoskeletal and nervous systems.

A SYSTEMIC VASCULITIS

Henoch-Schönlein purpura is a systemic vasculitis affecting the skin, gastrointestinal tract, kidneys, and joints. Palpable purpura and joint pain are the most common and consistent presenting symptoms. The kidneys are affected in about one-third of children and in 60% of adults, and this is the major factor determining the long-term outcome.¹

In our patient, laboratory testing that included a complete blood cell count, biochemical testing (including IgA levels), urinary sediment, and coagulation studies showed no abnormalities except elevations of the erythrocyte sedimentation rate and the concentration of C-reactive protein (an acute-phase reactant). These can be normal in some patients. Renal involvement was also not present.

DIAGNOSIS

The diagnosis relies on clinical manifestations. Because Henoch-Schönlein purpura is less common in adults, biopsy plays a more important role in establishing the diagnosis in this age group, and it does this by demonstrating leukocytoclastic vasculitis with a predominance of IgA deposition under immunofluorescence. Recent studies in children showed that an elevated IgA concentration along with reduced IgM levels was associated with a higher rate of severe complications.² However, depending on the age of the biopsied lesion, IgA may not be detected.

TREATMENT DIRECTED AT SYMPTOMS

Our patient received oral corticosteroids 0.5 mg/kg per day for 20 days, and the lesions resolved by 4 weeks.

Management of Henoch-Schönlein purpura is mainly directed at the symptoms, with oral hydration and nonsteroidal anti-inflammatory drugs. For severe cases, a short course of corticosteroids (0.5–1 mg/kg) may be used.

Although no controlled clinical trial has proven that Henoch-Schönlein purpura responds to corticosteroids, colchicine, or other drugs, corticosteroids are used most often, especially in patients with renal disease. Patients with severe renal insufficiency, abdominal pain, joint involvement, or bleeding should be hospitalized. Plasmapheresis³ has been used in severe cases.

HENOCH-SCHÖNLEIN PURPURA AND MALIGNANCY

During a follow-up evaluation 1 month later, our patient was diagnosed with adenocarcinoma of the breast. This highlights the value of a workup for cancer in adults with cutaneous vasculitis.

Cutaneous vasculitis can represent a paraneoplastic syndrome associated with a malignant tumor. The pathophysiology of this association is unclear, but one proposed mechanism is the exaggerated production of antibodies that react against tumor neoantigens, leading to the formation of immune complexes, or that occasionally recognize endothelial cells because of similarities with tumor antigens. Another theory is that abnormally high levels of inflammatory cytokines are produced by neoplastic cells or in response to decreased immune complex clearance.

Yet another theory is that hyperviscosity of the blood, seen in some cancers, increases the contact time for deposition of immune complexes and causes endothelial damage. Drugs used to treat cancer have also been reported to produce Henoch-Schönlein purpura.⁴

Although hematologic malignancy is three to five times more common than solid tumors in patients with small-vessel vasculitis, the disease has been associated with solid tumors of the liver, skin, colon, and breast in adults over age 40.⁵ An evaluation for neoplasm is therefore reasonable in adults with Henoch-Schönlein purpura, as is an evaluation for tumor recurrence or metastasis if the patient has been previously treated for a malignant tumor.