CCO inPractice - Free Resource - Soft Tissue Sarcomas

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Oncology - Soft Tissue Sarcomas Authors: William Tap, MD () Released: 11/17/10

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Soft Tissue Sarcomas

Introduction
Sarcomas are a heterogeneous group of mesenchymal- and neural-derived malignancies that can arise in the soft tissue and bone of individuals of all ages. Soft tissue sarcomas (STS) are the most frequent sarcomas; although, even these malignancies are relatively rare. Surgery remains the mainstay of treatment for STS. The addition of radiation therapy (preoperative or postoperative) has been shown to improve local control for soft tissue sarcomas of the trunk and extremities but is of unclear benefit in retroperitoneal STS. The role of adjuvant chemotherapy is unclear, although some studies have shown a benefit with doxorubicin-based regimens, particularly for patients with STS of the extremities. New chemotherapeutic agents and targeted agents are showing activity in patients with STS, and clinical trials of these agents are ongoing. This chapter discusses current surgical, radiation therapy, and medical management options for STS. For additional CCO inPractice information on the management of bone sarcomas, click here. For additional CCO inPractice information on the management of gastrointestinal stromal tumors, click here.

Incidence and Histologies

Overall, sarcomas account for approximately 1% of all adult malignancies and 15% of pediatric malignancies. In 2009, an estimated 10,660 new cases of soft tissue sarcomas (STS) will be diagnosed in the United States and approximately 3820 individuals will die from the disease.
[Jemal 2009]

The overall 5-year survival rate of STS range from 60% to 80%, with prognosis influenced by age, tumor size,
[Mendenhall 2009]

histologic grade and subtype, and tumor location and depth. (4.0%).
[Mendenhall 2009]

STS most often arise in the lower extremities (40.5%),

followed by the thorax or trunk (17.5%), upper extremities (16.6%), retroperitoneum (13.3%), viscera (8.0%), and head and neck STS usually present as an asymptomatic mass that can vary in size depending on the locationtumors that arise in the proximal extremities and retroperitoneum are often large, whereas tumors that develop in the distal extremities tend to be small. [NCCN 2010] STS most often metastasize to the lungs, although abdominal tumors are more likely to metastasize to the liver and peritoneum. It is not surprising that STS are histologically diverse as they can be derived from mesenchymal cells in fat, muscle, blood vessels, and other connective tissues. More than 50 subtypes have been identified, with leiomyosarcomas, liposarcomas, and malignant It should be noted that several studies in the last 2 decades have fibrous histiocytomas being the most common (Table 1). shown that malignant fibrous histiocytoma is likely not a uniform subtype of STS, but that cases should be assigned to other histologies.
[Merchant 1995; Hollowood 1995; Fletcher 1992] [Toro 2006]

Molecular genetic testing is demonstrating usefulness as an ancillary diagnostic technique as

many STS subtypes have defined genetic aberrations, including deletions, amplifications, single base-pair substitutions, and translocations.
Table 1. Incidence of the Most Common Histologic Subtypes of STS

Histologic Subtype Leiomyosarcomas Malignant fibrous histiocytomas 2003-2011 Clinical Care Options, LLC. All Rights Reserved.

Percent of STS Represented 23.9 17.1

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Histologic Subtype Liposarcoma Dermatofibrosarcoma Rhabdomyosarcoma Angiosarcoma

Percent of STS Represented 11.5 10.5 4.6 4.1

The majority of sarcomas develop spontaneously, but a small percentage of them are associated with known risk factors. Radiation therapy is the strongest risk factor associated with the development of STS, and increased risk of developing sarcoma has been demonstrated in patients receiving therapeutic irradiation for breast cancer, cervical cancer, lymphoma, ovarian cancer, prostate cancer, retinoblastoma, or testicular malignancies.
[Cormier 2004; Huang 2010]

Exposure to herbicides (eg, phenoxyacetic acid) and wood

[Wong 1997; Strong 1992;

preservatives (eg, chlorophenol), and chronic lymphedema are other risk factors. In addition, the genetic disorders neurofibromatosis type 1, hereditary retinoblastoma, and Li-Fraumeni syndrome have been associated with the development of STS.
del Carmen Baena-Ocampo 2010]

Diagnosis and Staging

Because sarcomas are rare and heterogenous, they are best managed by a comprehensive, multidisciplinary team that includes pathologists, radiologists, radiation and medical/pediatric oncologists, and surgeons with specific sarcoma expertise.
Rydholm 1997; Clasby 1997; Gutierrez 2007] [Ray-Coquard 2004;

If treatment at a specialist center is not possible, consultation with a multidisciplinary team of

sarcoma experts is advised. The National Comprehensive Cancer Network guidelines highlight important principles of management for patients with sarcoma (Management Guidelines).
[NCCN 2010]

A thorough pretreatment evaluation and a diagnostic biopsy, obtained through a core needle or

incision, are essential before initiating treatment for sarcomas. A pathologist who is expert in diagnosing sarcomas should evaluate the tumor specimen because the appropriate treatment choice largely depends on the tumor histology and grade.[NCCN 2010; Clark 2005] Poor prognosis is conferred by patient age older than 60 years of age, tumor size > 5 cm, and high-grade histology. A sarcoma-specific mortality risk that includes tumor size, site, depth, grade, histology, and patient age has been derived from a prospective, prognostic analysis of 2136 patients with various sarcoma subtypes (including fibrosarcomas, leiomyosarcomas, liposarcomas, malignant fibrous histiocytomas, malignant peripheral nerve tumors, and synovial sarcomas) treated at the Memorial Sloan-Kettering Cancer Center from 1982-2001.
[Kattan 2002]

Staging of patients with soft tissue sarcomas is according to the American Joint Committee on Cancer system, commonly referred to as the tumor, node, metastasis system (TNM). conjunction with the TNM (Table 2).
[AJCC 1997]

The Musculoskeletal Tumor Society system is also used either separately or in

[Enneking 2003; Mendenhall 2009]

Table 2. Musculoskeletal Tumor Society Staging System

Stage IA IB IIA IIB III

Grade* Low (G1) Low (G1) High (G2) High (G2) Any, with metastases

Site Intracompartmental Extracompartmental Intracompartmental Extracompartmental Any

*G1, uniform cell type without atypia, few mitoses; G2, atypical nuclei, pronounced mitoses.

Surgical Treatment of Soft Tissue Sarcomas

Surgery is the mainstay of treatment of soft tissue sarcomas (STS). Low-grade STS of the extremities and trunk are managed, for the most part, with surgery alone. The rate of local recurrence following wide resection with negative margins is usually below Radiation therapy is sometimes recommended for low-grade tumors in specific situations such as locally recurrent 20%. 2003-2011 Clinical Care Options, LLC. All Rights Reserved.
[Mendenhall 2009]

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disease, positive resection margins, and/or tumor locations that would not be amenable to salvage surgery for recurrence. Optimally, tumors should be resected with 2- to 3-cm negative margins. Surgical margins should be documented by both the surgeon and the pathologist. In the case of positive margins, excluding those in bone, nerves, or major blood vessels, re-resection should be considered if the procedure would not significantly affect functionality. Treatment of select intermediate-grade and high-grade STS with surgery alone is an appealing strategy, and has been studied by a number of investigators. Several small, single-institution case series have reported excellent local control rates of 85% to 100% following the use of this approach.
[Rydholm 1991; Gibbs 1997; Baldini 1999; Fabrizio 2000; Pisters 2007]

However, appropriate criteria for selecting patients

who may be best suited to surgery alone have not been clearly defined. Patients with unequivocal wide negative margins (> 1 cm and/or bounded by an intact fascial boundary), relatively small tumors, and tumor locations where a recurrence could be resected with acceptable morbidity, are the most likely candidates for this approach. However, in the absence of rigorous prospective data, treatment of intermediate-grade and high-grade STS with surgery alone should be utilized sparingly and with caution. Complete surgical resection is the standard potentially curative treatment for retroperitoneal and intra-abdominal STS. In a singleinstitution analysis of 500 patients, median disease-specific survival was significantly longer in patients who underwent complete resection with grossly negative margins vs those who received incomplete resection (103 vs 18 months, respectively; P = .001).
1998] [Lewis

In a recent retrospective study of 382 patients with primary retroperitoneal sarcomas, Bonvalot and colleagues

[Bonvalot 2009]

reported that complete compartmental resection was associated with a 3.3-fold reduction in the rate of abdominal recurrence compared with simple complete resection. This procedure, which should be performed in a high-volume center, warrants evaluation in a prospective trial. The goal of surgery for sarcomas of the extremities should be limb preservation whenever possible. However, certain tumor characteristics warrant consideration of amputation, including extensive soft tissue mass and/or skin involvement, involvement of a major artery or nerve, extensive bony involvement, failure of preoperative chemotherapy or radiotherapy, and tumor recurrence after prior adjuvant radiation. A surgeon with expertise in STS treatment should be consulted prior to considering amputation. Postoperative rehabilitation should be continued until patients achieve maximal function.

Radiation Therapy Treatment for Soft Tissue Sarcomas of the Extremities and Trunk
The standard treatment for most intermediate-grade and high-grade soft tissue sarcomas of the extremities and trunk is conservative surgery and radiation therapy (RT). In 1982, Rosenberg and colleagues from the United States National Cancer Institute reported data on 43 patients with soft tissue sarcomas (STS) of the extremities who were randomized to receive either amputation or limb-sparing resection with adjuvant RT.
[Rosenberg 1982]

There were no differences in disease-free survival or overall survival between the 2 treatment
[Lindberg 1981; Fein 1995; Suit 1988; Singer 1994]

strategies at 5 years of follow-up. A series of subsequent reports have confirmed that this same approach of conservative surgery with RT allows for limb salvage, with excellent local disease control and good functional outcome. Furthermore, 2 additional randomized trials involving patients with STS of the extremities compared conservative surgery alone with conservative surgery plus RT.[Yang 1998; Pisters 1996] Both trials demonstrated superior local control of high-grade tumors with the addition of RT. One study employed postoperative external beam RT (and chemotherapy), brachytherapy following resection.
[Pisters 1996] [Yang 1998]

whereas the second study evaluated

For high-grade tumors, local control rates for patients in the surgery plus RT arms of

these studies were 100% and 89%, respectively. (Interestingly, neither trial demonstrated a survival benefit for surgery plus RT.) Collectively, these data support the current standard approach of conservative surgery plus RT for most intermediate-grade and high-grade STS of the extremities.

Timing of Radiation Therapy: Preoperative vs Postoperative

Sequencing of conservative surgery and radiation therapy (RT) for intermediate-grade and high-grade soft tissue sarcomas of the extremity and trunk has been well studied. There is no proven local control or survival advantage associated with either preoperative or postoperative RT, but treatment-related toxicities are clearly different. Several single-institution studies have shown excellent local control rates in the order of 80% to 85% for both sequencing approaches, that is, preoperative or postoperative.
1994; Barkley 1988; Fein 1995; Cheng 1996] [Suit 1988; Lindberg 1981; Singer

A Canadian randomized trial of preoperative vs postoperative RT provides the best available data

on this topic.

[OSullivan 2002]

This trial randomized 190 patients with localized soft tissue sarcomas of the limbs to receive 50 Gy of

preoperative RT followed by resection, or resection followed by 66 Gy of postoperative RT. The primary endpoint of the study was the 2003-2011 Clinical Care Options, LLC. All Rights Reserved.

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occurrence of wound complications within 120 days of surgery. Local control rates were similar for both treatment arms. The wound complication rate was 35% for the preoperative RT group compared with 17% for the postoperative RT group (P = .01). In addition to preoperative RT, predictors for wound complications included tumor size > 10 cm and lower extremity tumors. Late toxicities, of fibrosis and edema, were more prevalent among patients in the postoperative RT arm, although the differences between arms did not reach statistical significance.
[Davis 2005]

These late toxicities tend to be irreversible, and are most likely related to the larger treatment fields

and higher doses employed for postoperative RT. Other reports have confirmed higher wound complication rates for preoperative RT, as well as increased long-term risk of edema and fibrosis for large field size and RT doses of > 60 Gy.[Cannon 2006; Stinson 1991] The decision of whether to proceed with preoperative vs postoperative RT should be made on an individual basis. The efficacy of each approach is similar, and therefore the decision should be based on the toxicity profile for a given patient. In general, preoperative RT is the preferred approach at the Dana-Farber Cancer Institute/Brigham and Womens Hospital, given that acute wound complications are typically reversible compared with long-term edema and fibrosis, which are typically irreversible.

Radiation Therapy Technique

The design and implementation of external beam radiation treatment for soft tissue sarcomas (STS) is complex. The first step is to determine the patients optimal treatment position. For an extremity tumor, the limb should be positioned such that the path of the treatment beams can be oriented to cover the target volume, yet still spare a strip of the limb circumference. The path of the treatment beams must also avoid the opposite limb or other uninvolved parts of the body. For example, STS in the posterior thigh are often treated with the patient in a lateral decubitus position, with the involved leg straight on the table and the uninvolved leg flexed forward and anterior to the limb to be treated. To ensure accurate daily set-up, the patient should be immobilized in a custom cast. For preoperative treatment of intermediate-grade and high-grade STS, the target volume includes the gross tumor plus 5 cm proximal and distal margins, and 2-3 cm radial margins (except in the presence of an intact fascial boundary or bone where the margin can be reduced). Treatment dose is 50 Gy given in 2 Gy fractions over a period of 5 weeks. For postoperative treatment, the target volume for the first course is the larger volume of all the tissues handled at surgery including the scar and drain site plus a margin of approximately 1.5 cm, or the tumor bed plus 5-cm proximal and distal margins and 2- to 3-cm radial margins. Following the first course, 1 or 2 cone down courses are delivered to treatment volumes, which include the tumor bed plus 2- to 3-cm margins and 1- to 2-cm margins, respectively. In the postoperative setting, treatment dose is 45-50 Gy for the first course volume and 16-20 Gy for the cone down volume(s), for a total dose of 63-68 Gy. In the setting of positive margins, doses of at least 66 Gy are recommended.
[Delaney 2007]

Computerized tomography planning is essential, and to minimize long-term toxicities, at least 1 cm of the limb circumference should be spared from receiving any dose, the whole bone should receive 50 Gy, and a whole joint should receive 40-45 Gy. Three-dimensional conformal external beam radiation therapy (RT) is the most common RT technique used in the treatment of STS. Brachytherapy, in which treatment is delivered with radioactive sources instead of a beam, is another option with proven efficacy. Investigators from Memorial Sloan-Kettering Cancer Center treated patients with STS with brachytherapy delivered by iridium-192 sources that were inserted into catheters placed in the tumor bed.
[Pisters 1996]

Treatment was given over a period of 4-6 days to a dose

of 42-45 Gy. Intensity-modulated radiation therapy is a third option in this setting. This sophisticated RT technique enables more precise shaping of dose distributions to conform to complex shapes. The benefit is superior dosimetric sparing of normal tissues from the high-dose region compared with 3-dimensional conformal treatment. However, the trade-off with this approach is that a larger volume of normal tissue is exposed to a low dose of RT. Preliminary results are encouraging, but long-term data on the use of intensity-modulated RT for the treatment of STS are not yet available.
[Alektiar 2008]

Acute and Chronic Toxicities

Acute radiation therapy treatment-related toxicities are typically transient, and include fatigue, skin erythema and sometimes desquamation, muscle aches, and wound complications as described in the Timing of Radiation Therapy: Preoperative vs Postoperative section. Chronic treatment-related toxicities are usually permanent, and can include edema, fibrosis, decreased range of motion, impaired wound healing, and bone fracture. Risks of edema, fibrosis, and decreased range of motion are increased with large treatment volumes and high dose. dose (> 50 Gy).
[Stinson 1991; OSullivan 2002; Davis 2005]

Risk of bone fracture is increased with periosteal bone stripping and high

[Lin 1998; Holt 2005; Dickie 2009]

Radiation Therapy Treatment for Soft Tissue Sarcomas of the Retroperitoneum

The role of radiation therapy (RT) for the treatment of soft tissue sarcomas of the abdomen and retroperitoneum is not well defined. 2003-2011 Clinical Care Options, LLC. All Rights Reserved.

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Extrapolating from data pertaining to soft tissue sarcomas of the extremities and trunk, it is reasonable to assume that, as an adjunct to surgery, preoperative RT to 50 Gy or postoperative RT to ~ 66 Gy would be associated with improved local control. However, there are no data to support this theory. In reality, it is often difficult to deliver doses > 50 Gy to the abdomen and retroperitoneum because of the many adjacent sensitive normal structures such as kidneys, spinal cord, small bowel, and liver. In addition, tumors in these sites are frequently very large at the time of diagnosis, necessitating a large RT treatment volume which further adds to the potential for RT toxicity. The efficacy and safety of surgery alone compared with surgery and radiation for retroperitoneal sarcoma have not been evaluated in a prospective randomized trial. Several single-institution trials have been conducted, with varying results and local recurrence rates in the range of 40% to 80%.
[Sindelar 1993; Catton 1994; Stoeckle 2001; Youssef 2002; Mendenhall 2005; Pawlik 2006]

These studies generally employed

[Pawlik 2006]

postoperative external beam RT with or without intraoperative RT or brachytherapy, whereas a study reported by investigators from the University of Texas M. D. Anderson Cancer Center and Princess Margaret Hospital, Canada, employed preoperative RT. Given the small patient numbers and probable selection biases, none of these studies can be considered to provide unequivocal support for the role of RT compared to surgery alone in this setting. Significant toxicities including enteritis were seen for postoperative doses > 50 Gy, and intraoperative RT was associated with risk of peripheral neuropathies. In an effort to minimize treatment toxicity, investigators in Belgium conducted a pilot study using a provocative approach that employed preoperative intensity-modulated RT to 50 Gy to a nonconventional treatment field. The radiation target volume was limited to the area judged to be at highest risk for close or positive resection, such as the area of contact between the tumor and posterior abdominal wall.
[Bossi 2007] [Sindelar 1993]

Among 18 patients followed

for a median of 27 months, 2 developed local recurrences and toxicity was acceptable. A second report using a novel approach was reported by Tzeng and colleagues.[Tzeng 2006] Their strategy included preoperative treatment of all gross tumors plus margins to 45 Gy, with a simultaneous intensity-modulated RT boost to 57.5 Gy to the volume predicted to be at high risk for positive margins. Preliminary results showed a 2-year local recurrence rate of 20% and acceptable toxicity. The preference at the Dana-Farber Cancer Institute/Brigham and Womens Hospital is to deliver preoperative RT to 50 Gy if it can be done with a tolerable RT field. Treatment fields include all gross tumors plus 2- to 3-cm margins. Treatment in the decubitus or prone positions is considered if more of the bowel is displaced from the treatment field using these maneuvers. For patients who undergo initial surgery, unless the area at risk is relatively small and well defined, postoperative RT is not recommended. In these cases, the recommendation is close surveillance and consideration of preoperative RT at the time of local recurrence, if appropriate. Clearly, new strategies are needed to improve outcomes for soft tissue sarcomas of the retroperitoneum. These may include sequential or concurrent chemoradiation, creative radiation target volumes using intensity-modulated radiation therapy, and novel systemic agents.

Adjuvant Chemotherapy for Soft Tissue Sarcomas

The use of adjuvant chemotherapy in patients with soft tissue sarcomas (STS) remains controversial. Improved surgical techniques and wider use of perioperative radiation therapy ensure a local control rate of up to 90%, but 40% to 50% of individuals with high-grade, deep, large (> 5 cm and especially > 10 cm) STS develop distant metastasis, and the majority of these patients die of metastatic disease.
[Weitz 2003; Zagars 2003]

Multiple clinical trials have evaluated the role of adjuvant doxorubicin-based chemotherapy in this setting.

These trials have frequently enrolled a small number of patients, included a variety of STS, and have not tested standardized regimens, and therefore their findings have often been difficult to interpret. Doxorubicin has been used in the treatment of STS for a longer period than other chemotherapies. Ifosfamide is also active against many types of sarcoma. However, initial clinical trials conducted in patients with STS did not include ifosfamide. In general, most studies that addressed the use of adjuvant chemotherapy in patients with STS were inconclusive, and meta-analyses have been required to show the advantage of chemotherapy in this setting.
1997] [Sarcoma Meta-analysis

Prolongations of local recurrence-free survival, as well as distant recurrence-free survival have been observed in several studies,
[Pervaiz 2008]

but a benefit in overall survival has not been observed consistently.[Sarcoma Meta-analysis 1997; Pervaiz 2008] The most recent meta-analysis, published in 2008, included data from 18 trials and a total of 1953 patients. This study showed that the combination of ifosfamide and doxorubicin, but not doxorubicin alone, improved survival, with an absolute risk reduction of 11% related to the combination regimen. However, an analysis of pooled data from 2 phase III European trials failed to show that adjuvant doxorubicin-based chemotherapy provided any benefit in overall survival in patients who underwent complete resection of the tumor.
Cesne 2008] [Le

The benefit of the adjuvant chemotherapy is consistently more pronounced among patients with extremity sarcomas

compared to those with retroperitoneal sarcomas. The majority of sarcoma oncologists use the combination of doxorubicin (or epirubicin) and ifosfamide in the adjuvant setting, but 2003-2011 Clinical Care Options, LLC. All Rights Reserved.

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optimal doses and dose schedules have not been established. Doxorubicin has been given in doses ranging from 50-75 mg/m , either as a single bolus dose every 3-4 weeks or in divided doses given over 3 days.
1985; Rosenberg 1983; Brodowicz 2000; Frustaci 2001; Gortzak 2001] [Alvegrd 1989; Chang 1988; Gherlinzoni 1986; Glenn 1985; Omura

Studies performed in the metastatic setting showed that doses of 60-70

2

mg/m are superior to a dose of 50 mg/m

2 2

2[Antman 1993]

; therefore, the doxorubicin dose should not be lower than 60 mg/m and

should not exceed 75 mg/m because of significantly increased toxicity at this higher dose. Ifosfamide has been given in a total dose between 5 and 14 g/m , usually administered as a short, 1- to 2-hour infusion in divided doses over 5 days. Some regimens use continuous ifosfamide infusion. and impaired kidney function. An Italian study that enrolled patients with high-grade extremity and girdle sarcomas measuring > 5 cm reported a 19% improvement in overall survival at 4 years of follow-up with use of a regimen consisting of epirubicin dosed 60 mg/m on Days 1 and 2, with ifosfamide dosed 1.8 g/m on Days 1-5, infused over 1 hour, and mesna in a bolus dose (20% of the ifosfamide dose given before and 4 and 8 hours after ifosfamide infusions), with cycles repeated every 3 weeks.
[Frustaci 2001] 2 2 [Antman 1993]

The continuous infusion is associated with less risk of neurologic toxicity, and at the UCLA

Medical Center, it is frequently used in patients who are older than 55 years of age and have comorbid conditions, low albumin levels,

Because this treatment is myelosuppressive, all

patients received filgrastim. Based on these data, this regimen has been recommended for treatment of STS. With longer follow-up, a median of 89.6 months, the difference in overall survival was not significant.
[Frustaci 2003] 2

Another regimen commonly used in patients with STS consists of ifosfamide dosed 2 g/m on Days 1-5, infused over 2 hours, and doxorubicin doses 25 mg/m on Days 1-3, given as a continuous infusion.
2 [Patel 1998]

Use of this regimen was associated with a 66%

response rate in the metastatic setting, although these data were reported from a single-institution study. The decision to offer adjuvant chemotherapy for the management of STS should not be made lightly, and must be individualized for every patient. Patients who are young and do not have comorbid conditions, and who have high-grade, large (at least > 5 cm, if not > 10 cm), extremity sarcomas or recurrent sarcoma, are good candidates for adjuvant chemotherapy; however, both short-term and, more importantly, long-term adverse effects must be discussed. The list of possibly severe short-term adverse effects includes neutropenic sepsis, renal failure, neurotoxicity, alopecia, and fatigue. Long-term toxicities usually influence quality of life more significantly, and the risk of cardiotoxicity, secondary cancers, infertility, or permanent renal function impairment must be considered. In several types of sarcoma seen in adults, there is less controversy regarding the use of adjuvant chemotherapy. Ewings sarcoma, which is mainly considered to be a bone sarcoma that occurs in children, can present in soft tissues in adults, requiring aggressive management. A regimen consisting of vincristine, doxorubicin, cyclophosphamide (VDC), and dactinomycin alternated with ifosfamide and etoposide (IE) has been evaluated in a randomized trial, with significant benefit observed from the addition of ifosfamide and etoposide in patients with localized disease, but not in patients with metastatic disease, or in a subgroup analysis with Similarly, adults with rhabdomyosarcoma should receive adjuvant limited numbers, in patients 17 years of age or older. multiagent chemotherapy, the usual approach being to adopt the pediatric protocol of combining vincristine, dactinomycin, cyclophosphamide (VAC).
[Loeb 2008; Ferrari 2003] [Grier 2003]

Despite the use of the same treatment protocol, the prognosis for adults with

rhabdomyosarcoma is significantly worse than for childrenthe reported 5-year overall survival rate in adults is 27% compared with 61% in children.[Ferrari 2003; Sultan 2009] Extraosseous (extraskeletal) osteosarcoma is a rare type of sarcoma characterized by location within soft tissues without connection to the bone and typical osteosarcoma appearance under the microscope. This form of osteosarcoma is treated in a manner similar to other STS, and the same limitations of adjuvant chemotherapy apply.
[Ahmad 2002; Klein 2006]

The primary location of the sarcoma appears to be an important prognostic factor governing the use of adjuvant chemotherapy. The use of doxorubicin-based adjuvant chemotherapy may provide benefit to patients with extremity sarcomas, but has limited efficacy in patients with head and neck, retroperitoneal, and uterine sarcomas.

Neoadjuvant Chemotherapy for Soft Tissue Sarcomas

As discussed above, a low proportion of patients with soft tissue sarcomas will benefit from adjuvant chemotherapy. Hence, neoadjuvant chemotherapy appears to be an attractive strategy for these patients. Neoadjuvant chemotherapy may decrease the size of tumor and facilitate limb-sparing surgery, as well as eliminate microscopic metastasis. Moreover, microscopic assessment of the degree of necrosis can serve as an in vivo assay for sensitivity to chemotherapy. 2003-2011 Clinical Care Options, LLC. All Rights Reserved.

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Similarly to adjuvant therapy, in the neoadjuvant setting, doxorubicin and ifosfamide have been studied most extensively among chemotherapy agents. Initial studies used doxorubicin at a dose of 30 mg daily for 3 days, together with a reduced dose of radiation therapy (RT) (28 Gy in 8 fractions, or 30-35 Gy in 10 fractions, or 46 Gy in 23-25 fractions).
[Eilber 1984; Wanebo 1995]

This treatment

resulted in a low local recurrence rate, presumably because of the radiosensitizing property of doxorubicin. Doxorubicin can be given either as a short bolus infusion or as continuous infusion, either intravenously or intra-arterially.
1993; Temple 2007] [Eilber 1984; Wanebo 1995; Soulen 1992; Levine

It is likely that all methods of delivery are equivalent. The use of ifosfamide as a single agent either before or
[Eilber 2001; Eilber 2004; Cormier 2001]

concurrently with RT has resulted in similar outcomes.

[Kraybill 2006; DeLaney 2003]

Finally, the use of combination chemotherapy

consisting of mesna, doxorubicin, ifosfamide, and dacarbazine interdigitated with RT has been evaluated in a small number of These studies were not randomized but local control rates, distant metastasis-free survival, studies. disease-free survival, and overall survival were superior in the experimental group to matched historical controls. This combination treatment resulted in significant toxicity. In one study, only 59% of patients completed all scheduled chemotherapy, 83% experienced grade 4 toxicities (mainly hematologic), and 5% died of treatment-related toxicities (neutropenic sepsis and acute myelogenous leukemia).
[Kraybill 2006]

Because of its significant toxicity and lack of improved outcomes, combination chemotherapy consisting of
[Fayette 2009]

mesna, doxorubicin, ifosfamide, dacarbazine (MAID) is used infrequently.

Instead, most patients treated with neoadjuvant

[Gortzak 2001; Grobmyer 2004]

chemotherapy receive only high-dose ifosfamide and doxorubicin as single agents or in combination.

It seems sensible to assume that the benefit associated with neoadjuvant chemotherapy is of the same magnitude as the benefit derived from adjuvant chemotherapy (approximately 7%). One advantage of using neoadjuvant over adjuvant chemotherapy is the potential for identifying patients whose tumors are responsive to therapy after minimal exposure. RECIST,
[Eisenhauer 2009]

used to assess solid

tumors, are not reliable in patients with soft tissue sarcomas. For example, in the aforementioned trial of mesna, doxorubicin, ifosfamide, dacarbazine, and RT, only 22% of patients met criteria for partial response by the RECIST definition, but 64% of patients were noted to have < 25% of viable tumor in the surgical specimen.
[Eilber 2001; Lucas 2008] [Kraybill 2006]

The degree of necrosis may be a more reliable

predictive factor. It has been shown that patients with > 95% of necrosis in the resected sample have an excellent prognosis, although it is not clear if a patient with a lower degree of necrosis may still have derived some benefit from chemotherapy. Recently, encouraging results have been reported on a novel approach to response assessment, whereby changes in metabolic imaging on fluorodeoxyglucose positron emission tomography (PET) scans are used to predict the degree of necrosis on histology, although these observations require external validation.
[Benz 2008; Evilevitch 2008]

PET scans with [(18)F]fluorodeoxyglucose (FDG) have been

[Benz 2009]

shown to predict response to neoadjuvant regimens after only 1 cycle, based on changes in FDG uptake.

questioning if early treatment decisions could be made

At the UCLA Medical Center, 2 cycles of neoadjuvant chemotherapy are offered with ifosfamide or a combination of ifosfamide and doxorubicin, followed by preoperative RT, frequently adding doxorubicin as a sensitizer. Patients who had no response according to RECIST criteria, > 75% necrosis, or no decrease in the standardized uptake value on a positron emission tomography scan are followed expectantly after surgery. Responders are offered additional 2-3 cycles of adjuvant chemotherapy.

Chemotherapy for Metastatic Disease

Despite improvements in surgical techniques and greater understanding of the pathobiology of soft tissue sarcomas, according to the United States National Cancer Institutes Surveillance, Epidemiology and End Results data, the 5-year survival rate for patients diagnosed with distant metastasis is 16.8%.
[SEER 2009]

Patients with distant metastasis are usually treated with chemotherapy, mainly

with palliative intent and rarely with curative intent. Surgical resection of metastatic disease, mainly lung metastasis, can be curative in a select population of patients, particularly individuals with a limited number of metastases, but also in younger individuals with a long disease-free interval (> 2.5 years) and with low-grade tumors.
[Putnam 1995; Suzuki 2006; van Geel 1996]

Sarcomas have a very different biology as compared with the epithelioid malignancies and can frequently grow to large sizes without causing symptoms. Furthermore, there is no evidence that the decrease in the size of the tumor (response rate) or slowing of tumor growth rate (progression-free survival) translates into improved overall survival.
[Verma 2008]

There is a lack of data from randomized

clinical trials showing that systemic chemotherapy prolongs overall survival in patients with metastatic sarcoma. The majority of the available studies can be criticized because of a lack of randomization, differences in the chemotherapy regimens used, comparison to historic controls, variability in tumor types, and/or a low number of subjects. Despite these limitations, chemotherapy can frequently lead to symptomatic relief and should not be disregarded in this patient population. Large observational analyses have found that younger patients (younger than 40 years of age), patients with liposarcoma or synovial sarcoma, patients with high-grade tumors, and those without bone or liver involvement LLC. the most Reserved. 2003-2011 Clinical Care Options,derive All Rights benefit from chemotherapy.
[Karavasilis 2008; Van Glabbeke 1999]

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As with adjuvant chemotherapy, a variety of chemotherapy regimens have shown activity in the treatment of metastatic disease. It is generally believed that combination chemotherapy increases the response rate, but it most likely does not influence survival. Therefore, unless immediate control of tumor growth is important, single-agent chemotherapy is preferred. Active drugs utilized in this setting include doxorubicin, high-dose ifosfamide, gemcitabine, docetaxel, and dacarbazine. Doxorubicin is given at a dose of 70-75 mg/m every 3-4 weeks.
Borden 1987; Zalupski 1991] 2 [Santoro 1995; Borden 1987]

In the past, doxorubicin was frequently

[Santoro 1995;

combined with dacarbazine, although the superiority of this combination over doxorubicin alone has not been proven.

Ifosfamide is an important agent in the armamentarium used to treat metastatic soft tissue sarcomas. Doses used in this setting have ranged from 5-18 g/m , although the drug is most commonly given at doses between 9 and 14 g/m .
Oosterom 2002; Palumbo 1997; Buesa 1998] 2 2 [Patel 1997; Reichardt 1998; van

Although ifosfamide is an attractive treatment option, it can cause significant toxicities, including

acute renal failure, hemorrhagic cystitis, neutropenia and thrombocytopenia, and central nervous system toxicity. Adverse effects, especially neurotoxicity, are less pronounced when ifosfamide is administered as a continuous infusion rather than a bolus. Mesna should be administered together with ifosfamide to decrease the risk of hemorrhagic cystitis. Treatment with the combination of ifosfamide and doxorubicin (or epirubicin) results in higher response rates, but most likely does not influence survival. Moreover, this combination results in significantly increased toxicity. prompt symptomatic improvement. The combination of gemcitabine 675-900 mg/m on Days 1 and 8 infused at a fixed dose of 10 mg/m /min and docetaxel 75-100 mg/m on Day 8 has become an attractive second- or third-line regimen in patients with metastatic sarcoma. This regimen was initially studied in patients with uterine leiomyosarcoma, where it can be used as first-line therapy. has been expanded to include other types of soft tissue and bone sarcomas.
[Bay 2006] [Leu 2004; Hensley 2008] 2 2 2 [Patel 1998; Reichardt 1998; Verma 2008]

Hence, the use

of these 2 drugs in combination is justifiable only in younger patients with good performance status and in clinical scenarios requiring

More recently its use

This chemotherapy is quite well tolerated,

2

especially when growth factor support is provided, and docetaxel is given at a dose of 75 mg/m . Soft-tissue sarcoma chemotherapy, especially when drugs are used in combination, is myelosuppressive, and patients should receive filgrastim or pegfilgrastim to decrease the risk of neutropenic fever. Moreover, doses are frequently reduced by 20% in older patients and patients previously treated with radiation therapy. Regimens discussed here are those that are used to treat the majority of soft tissue sarcomas, but some sarcoma types require a different approach. Angiosarcoma, an aggressive sarcoma that almost always recurs even when it is resected with negative margins, responds well to single-agent paclitaxel given weekly and to doxorubicin liposomal.
[Schlemmer 2008; Skubitz 2005]

Patients with
[Grier 2003]

metastatic extraosseous Ewings sarcoma can be treated with vincristine, doxorubicin, cyclophosphamide (VDC),
2009]

whereas

the combination of vincristine, dactinomycin, cyclophosphamide (VAC) is used in patients with rhabdomyosarcoma.

[Ferrari 2003; Sultan

Trabectedin is a promising new chemotherapy agent. This antineoplastic drug is isolated from the marine tunicate Ecteinascidia turbinate and works by binding to the minor groove of DNA, thereby interfering with nucleotide excision repair machinery. 41% of patients experienced stabilization of disease. was used in patients with myxoid liposarcoma. sarcoma.
[Le Cesne 2005] [Delaloge 2001] [von Mehren 2007]

In

advanced, pretreated patients with myriad sarcoma types, use of trabectedin resulted in a response rate of 8%, although an additional A more impressive response rate of 51% was seen when trabectedin
2 [Grosso 2007]

This drug also has significant activity in leiomyosarcoma and synovial

A phase II analysis demonstrated a substantial clinical benefit with trabectedin (1.5 mg/m , 24-hour intravenous
[Demetri 2009]

infusion once every 3 weeks) in patients with liposarcoma or leiomyosarcoma after failure of standard chemotherapy when compared with historical standard therapies. In the United States, trabectedin is not currently approved for use by the US Food and Drug Administration and is available only within clinical trials or for compassionate use.

New Agents in the Treatment of Soft Tissue Sarcomas

Historically, soft tissue sarcomas have often been treated as a single entity. Improvements in our understanding of cytogenetic abnormalities and aberrations in molecular pathways have stimulated clinical scientists to use targeted therapies against specific sarcomas. In addition, new chemotherapy drugs are being developed and evaluated in patients with sarcoma. 2003-2011 Clinical Care Options, LLC. All Rights Reserved.

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Sorafenib is an oral multitargeted tyrosine kinase inhibitor, which was initially developed as a B-Raf inhibitor, although it is now believed that its main antineoplastic effect is through the inhibition of the vascular endothelial growth factor receptor. Sorafenib has been evaluated in phase II trials, where responses were seen in patients with angiosarcoma (14%) and leiomyosarcoma (6%), although no response was observed in patients with liposarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, and malignant fibrous histiocytoma.
[Ryan 2008; Maki 2008]

Occasionally, complete responses are seen with the use of sorafenib, indicating that further studies on

molecular pathways in sarcomas are required. Moreover, the use of these targeted agents in combination may possibly be more effective. Similarly, sunitinib, another tyrosine kinase inhibitor, demonstrated sporadic responses in patients with soft tissue sarcomas, although treatment with this drug resulted more frequently in stabilization of disease or in metabolic responses on positron emission tomography scanning.[George 2009] Pazopanib has also been investigated in patients with relapsed/advanced soft tissue sarcomas and demonstrated prolonged progression-free survival and overall survival when compared with chemotherapy by cross-study comparison.
[Sleijfer 2009]

Other new agents include sirolimus, which has demonstrated clinical activity in patients with malignant perivascular epithelioid cell tumors.
[Wagner 2010]

Crizotinib has shown efficacy in ALK-rearranged inflammatory myofibroblastic tumors.

[Rutkowski 2010]

[Butrynski 2010]

Imatinib has

also shown efficacy in dermatofibrosarcoma protuberans with a t17:22 translocation.

Tables and Figures

Table 1 | Table 2

Table 1. Incidence of the Most Common Histologic Subtypes of STS

Histologic Subtype Leiomyosarcomas Malignant fibrous histiocytomas Liposarcoma Dermatofibrosarcoma Rhabdomyosarcoma Angiosarcoma

Percent of STS Represented 23.9 17.1 11.5 10.5 4.6 4.1

Table 2. Musculoskeletal Tumor Society Staging System

Stage IA IB IIA IIB III

Grade* Low (G1) Low (G1) High (G2) High (G2) Any, with metastases

Site Intracompartmental Extracompartmental Intracompartmental Extracompartmental Any

*G1, uniform cell type without atypia, few mitoses; G2, atypical nuclei, pronounced mitoses.

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Keywords: Sarcoma
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