Sarcomas of Soft Tissue: Brian A. Van Tine

Sarcomas of Soft Tissue 90
Brian A. Van Tine
S UMMARY OF K EY P OI NT S
Incidence and Epidemiology • Presentation with recurrent disease chemotherapy sensitivity,
• Annually, 12,390 new cases occur in and positive surgical margins (gross preoperatively when possible.
the United States—fewer than or microscopic) are independent • In addition to surgery, 3 years of
1%–2% of cancer diagnoses. adverse prognostic factors for local adjuvant imatinib is the standard of
• No specific etiologic agent is recurrence. care for high-risk gastrointestinal
identifiable in the majority of • Individual patient prognosis may be stromal tumor (GIST).
cases. estimated with use of a nomogram Recurrent Disease
• Occasional cases are related to or newer techniques. • Local recurrence rates vary
previous radiation, chemical Staging Systems depending on the anatomic primary
exposure, alkylating • The American Joint Committee on site and the adequacy of local
chemotherapeutic agents, or chronic Cancer (Union for International therapy. For extremity lesions,
lymphedema. Cancer Control) system uses criteria approximately 20% of patients
• Genetic conditions related to soft that include grade, size, and location develop locally recurrent disease.
tissue sarcoma include Li-Fraumeni relative to the investing muscular • Systemic cytotoxic chemotherapy
syndrome, neurofibromatosis, fascia, nodal status, and distant with selective use of surgery is the
tuberous sclerosis, basal cell nevus metastases. Other means to mainstay of therapy for patients with
syndrome, Gardner syndrome, and characterize risk of recurrence of metastatic disease.
retinoblastoma. soft tissue sarcomas include • Correct histologic diagnosis is
Diagnosis and Evaluation of nomograms and bayesian belief important for the selection of
Extent of Disease networks. palliative chemotherapy—for
• Core needle biopsy (large lesions) or Primary Therapy instance, eribulin for liposarcoma.
excisional biopsy (small lesions) is • Primary therapy includes surgical • Kinase-directed therapy is clinically
performed. resection with an adequate margin of beneficial for patients with specific
• Pathologic review of histologic normal tissue. For extremity lesions, sarcoma diagnoses (e.g., GIST).
subtype, grade, and assessment of a limb-sparing approach is possible Pazopanib was shown to be active
margins (excisional biopsies) is in more than 90% of patients and in patients with other types of
undertaken. offers survival comparable to that of sarcoma failing other systemic
• Imaging includes magnetic amputation without the associated therapy, but has comparatively
resonance imaging (MRI) or morbidity. limited benefit.
computed tomography (CT) of the • For most patients, local control is • For the small subset of patients who
primary site. improved with preoperative or develop isolated (solitary) lung
• Chest radiography or chest CT postoperative radiotherapy. Size and metastases, 20% to 50% 3-year
(preferred) is also performed. primary site also affecting its use. survival rates have been reported
Prognostic Factors • The role of chemotherapy for with metastasis resection.
• High-grade histologic type, deep high-risk patients remains • Trabectedin, eribulin, and olaratumab
location, and T2 tumor size are controversial, but chemotherapy is have been approved by the US Food
independent adverse prognostic used at several major centers for and Drug Administration since the
factors for distant metastasis and high-risk patients, especially for last edition of this book was
survival. extremity tumors with known published.
Soft tissue sarcomas (STSs) comprise a group of relatively rare, anatomi- neoplasms of the soft tissues are comparatively rare, accounting for
cally and histologically diverse neoplasms. Most STSs share a common less than 1% of adult malignancies and 15% of pediatric malignancies.
embryologic origin, arising primarily from tissues derived from the The relative rarity of these tumors, coupled with the histologic diversity
mesodermal or ectodermal germ layers, distinct from carcinomas, of tumors, has led to studies that include diverse STS subtypes in a
which arise from the endodermal germ layer, although some sarcomas single study group, making it difficult to develop specific therapies
such as angiosarcomas also have an endodermal origin. Although the for specific tumor types, especially in adult STSs. The annual incidence
somatic soft tissues account for as much as 75% of total body weight, of STSs in the United States is about 12,390 new cases, comparable
1655
1656 Part III: Specific Malignancies
to the incidence of testicular cancer.1 However, an estimated 4990 of a variety of cancers. A dose-response relationship was found between
patients die annually of STS—a rate nearly 10-fold greater than is the radiation dose and the subsequent development of osteosarcoma,
seen with testicular cancer—emphasizing the comparatively high overall with a relative risk ranging from 0.6-fold in patients who received
mortality rate that is seen with this type of tumor. less than 10 Gy to 38.3-fold in those who received more than 60 Gy.15
The first portion of this chapter reviews the available literature on A complete understanding of the underlying biology of radiation-
the evaluation and treatment of extremity sarcomas (which account induced malignancy remains elusive. Host-related factors (especially
for half of all STS). Other specific anatomic sites are reviewed at the young age) and treatment (especially its intensity) both seem to play
end of the chapter. a role in a complex relationship.16 Underlying genetic susceptibility
is also important and is governed by factors such as deletion or mutation
of tumor suppressor and DNA repair genes, which likely means that
ETIOLOGY AND EPIDEMIOLOGY subgroups of the populations have more vastly enhanced risk than
Environmental Factors had previously been anticipated, and others are at lower risk than was
appreciated in the past. The identification of osteosarcoma as a common
No specific etiologic agent may be identified in the majority of patients second malignancy following radiation therapy for retinoblastoma is
with STS. There are a number of recognized associations between an example of a high-risk scenario. It is probable that the greater
environmental factors and the subsequent development of sarcoma; intensity of multimodality treatments for cancer that have been
these are summarized in Table 90.1. The development of sarcoma has introduced over recent years with the goal of improving cancer control
been reported after the use of ionizing radiation for the treatment of and survival will result in an increase in the rate of radiation-induced
lymphoma2; solid tumors of the head and neck,3 breast,4,5 gynecologic malignancies. For example, the use of radiation after lumpectomy for
organs, and skin; and benign conditions including endometriosis, ductal carcinoma in situ may result in unnecessary second cancers,
tuberculous arthritis,6 and benign thymic enlargement. The vast majority which are avoidable in over 95% of patients with the use of mastectomy
of radiation-associated sarcomas are high grade (87%), and the pre- and reconstruction. The most common postradiation cancer appears
dominant histologic types include undifferentiated pleomorphic sarcoma to be sarcoma, especially considering its baseline incidence rates.16
(UPS; formerly termed malignant fibrous histiocytoma [MFH]), Sarcomas have also been weakly associated with exposure to various
angiosarcoma, malignant peripheral nerve sheath tumor (MPNST), chemical agents. A number of conflicting reports have emerged that
osteosarcoma, and others; translocation-associated sarcomas are rare, suggest a relationship between occupational exposure to phenoxyacetic
in comparison, and teleologically it is difficult to understand how acids (found in some herbicides) and chlorophenols (found in some
random DNA damage leads to a specific chromosomal translocation.7–10 wood preservatives). Studies from Sweden demonstrated a link between
By criteria that were described initially by Cahan and colleagues,11 phenoxy herbicide exposure in forestry workers and the subsequent
radiation-induced sarcomas arise no sooner than 4 years after the development of sarcoma.17–20 However, additional investigations in
therapeutic radiation12,13 and often arise decades later. More recently, the United States, New Zealand, and Finland have not confirmed this
however, a shorter 2-year period after diagnosis has been used to relationship.21–23 Similarly, there has been no demonstrable increase
define radiation-related disease, and the median time from radiation in the risk of sarcoma in Vietnam veterans exposed to Agent Orange
to development of a secondary sarcoma is 8 to 10 years, but it can (dioxin or TCDD [2,3,7,8-tetrachlorodibenzo-p-dioxin]).24 Hepatic
arise even later. Contrary to early theories, recent studies have suggested angiosarcomas have been associated with exposure to a number
that both orthovoltage and megavoltage treatments are sarcomagenic9,14 of compounds, including Thorotrast (a colloidal suspension of
at doses from 8.8 to 70 Gy. In a carefully conducted case-control thorium dioxide that was formerly used as an intravenous contrast
analysis, the Late Effects Study Group found 64 cases of osteosarcoma agent in radiologic imaging procedures),25–27 vinyl chloride,28–30 and
in 9170 patients who had survived more than 2 years after the diagnosis arsenic.31,32
Table 90.1 Soft Tissue Sarcoma: Predisposing Environmental Factors

Factor Agent Patient Population Comment
Radiotherapy Orthovoltage and megavoltage radiation Therapeutic radiation patients Most commonly undifferentiated
pleomorphic sarcoma and
osteosarcoma; dose-response
relationship
Chemotherapy Alkylating agents: cyclophosphamide, melphalan, Pediatric cancer patients Relative risk of bone sarcoma
procarbazine, nitrosourea, and chlorambucil increased with cumulative drug
exposure
Chemical Phenoxyacetic acids: 2,4-dichlorophenoxyacetic acid Forestry and agricultural workers Phenoxy herbicide and defoliant
exposure (2,4-D); 2,4,5 trichlorophenoxy acetic acid (2,4,5-T); 2 exposure
methyl-4 chlorophenoxyacetic acid (MCPA)
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); dioxin Vietnam veterans No clear link demonstrable for dioxin
(Agent Orange)
Chlorophenols Sawmill workers
Thorotrast Diagnostic x-ray patients Hepatic angiosarcoma
Vinyl chloride Vinyl chloride workers Hepatic angiosarcoma
Arsenic Vineyard workers Hepatic angiosarcoma after exposure
to arsenical herbicides
Chronic Postsurgery patients Stewart-Treves syndrome
lymphedema Postradiation patients (lymphangiosarcoma)
Patients with congenital
lymphedema or filariasis
Sarcomas of Soft Tissue • CHAPTER 90 1657
Studies have suggested a relationship between exposure to alkylating secondary mutations in the TP53 gene allow the transformation into
chemotherapeutic agents and the subsequent development of sarcomas. MPNST. Because mutations in TP53 lead to an inability to control
Osteosarcomas have been reported after cyclophosphamide treatment DNA damage via the cell cycle, they also enable rapid accumulation
for pediatric acute lymphoblastic leukemia.33,34 In the report from of other mutations, which encode mutant proteins that undoubtedly
the Late Effects Study Group, prior chemotherapy, particularly with play an important role in sarcomagenesis.
melphalan, procarbazine, nitrosoureas, or chlorambucil, was found Li-Fraumeni syndrome was identified when relatives of pediatric
to be an independent risk factor for the development of sarcoma.15 STS patients were noted to have an increased frequency of diverse
The relative risk of sarcoma increased with cumulative drug exposure. and often multiple primary cancers.40 The neoplasms that were noted
Chronic lymphedema may be a factor in the development of in relatives included some STSs, premenopausal breast cancers, brain
angiosarcoma. These neoplasms have been noted to arise in the tumors, adrenocortical carcinomas, leukemias, and occasional germ
chronically lymphedematous arms of women who were treated for cell tumors.49 Follow-up of Li-Fraumeni kindreds over two decades
breast cancer with radical mastectomy (Stewart-Treves syndrome).35,36 has revealed that the majority of individuals develop cancer at young
Lower extremity angiosarcomas have also been observed in patients ages, with 79% of those affected being younger than 45 years at the
with congenital lymphedema or filariasis complicated by chronic time of diagnosis of malignancy.50 The observed cancer distribution
lymphedema.37 in families is believed to fit a rare autosomal dominant mode of genetic
A recent history of trauma is often elicited from sarcoma patients, transmission with high penetrance.205 Molecular genetic studies have
particularly those with extremity sarcoma. Usually, the interval between identified germline TP53 mutations in the majority of patients with
the traumatic event and the diagnosis of sarcoma is short, making a Li-Fraumeni syndrome.52 Germline mutations in CHK2, another
causal relationship unlikely. Some reports have suggested, however, component of the cell cycle checkpoint machinery encoded by a gene
that chronic inflammatory processes may be a risk factor for sarcoma. located on 22q11, are responsible for another subgroup of patients
Shrapnel, bullets, intramuscular iron injections, and foreign body with Li-Fraumeni syndrome, and other Li-Fraumeni–like patient
implants have been implicated.38 This effect has been modeled in an kindreds without TP53 alteration have been described.53
acute mouse model of tissue injury.39 Pediatric patients with familial retinoblastoma have a 13q chro-
mosomal deletion54 and an increased incidence of osteosarcoma and
Genetic Predisposition other neoplasms, including STS.15,54,55 The retinoblastoma (Rb1)
protein is expressed ubiquitously in normal cells and is a well-known
Germline mutations can play an important role in the development tumor suppressor, involved in maintaining the integrity of the genome
of STSs (Table 90.2). These genetic changes are identified with or through control of the cell cycle. Interesting to note, not only is the
similar to the genetic changes that are seen in corresponding sporadic Rb1 gene that is mutated in osteosarcomas associated with retinoblas-
sarcomas (Table 90.3). Mechanistically, the proteins encoded by the toma, but abnormality or absence of the Rb1 gene product has also
altered genes are involved in maintenance of the genome through been observed in multiple other malignancies, including sporadic
DNA repair and the cell cycle. osteosarcomas, breast cancer,56 small cell lung cancer,57 and STSs.58
The epidemiologic relationship between the development of STS Familial adenomatous polyposis (FAP), a subset of which includes
and inherited syndromes associated with a predisposition to neoplasia Gardner syndrome with its desmoid tumors, is caused by germline
(e.g., neurofibromatosis and Li-Fraumeni syndrome) has been appreci- mutations in the APC gene.59–61 Patients with Gardner syndrome
ated for decades.40,41 For example, patients with neurofibromatosis develop desmoid fibromatosis at a younger age than do patients with
have a 7% to 10% lifetime risk of developing an MPNST.42 A sudden sporadic desmoids.62 With the use of prophylactic colectomy, progressive
increase in the size of any neurofibroma suggests malignant transforma- mesenteric desmoid tumor is now a significant cause of death of
tion.43,44 The mechanisms underlying the transformation from a benign patients who have FAP,63 as are second neoplasms such as ampullary
neurofibroma to MPNST are not well understood. and duodenal cancers. The APC gene is involved in the Wnt cell-
However, loss-of-function mutations in the NF1 gene, which are signaling pathway. One of the normal functions of the APC protein
found in patients with neurofibromatosis, result in activation of one is to bind β-catenin.64 Thus loss-of-function mutations of APC result
of the ras signaling pathways, a well-known mechanism that has been in the activation of transcription of oncogenes by β-catenin. Consistent
identified in a variety of cancers.45 It has been observed that secondary with the importance of this pathway in desmoid tumors, loss of APC
MPNSTs (arising from a prior neurofibroma) have deletions of 17p and mutations in CTNNB1 (encoding β-catenin) are also identified
(particularly 17p12–17p13.1) and mutations at the region of the in sporadic desmoid fibromatosis.65–67
TP53 tumor suppressor gene.46–48 Therefore it is postulated that an Rhabdoid predisposition syndrome is due to inactivating germline
initial alteration in the NF1 gene contributes to the formation of a mutations in the INI1 gene.68 Patients with this syndrome develop
benign neurofibroma through activation of the ras pathway and that one or more extrarenal and/or renal rhabdoid tumors. INI1 is a member
Table 90.2 Germline Mutations Associated With Soft Tissue Sarcoma

Inheritance
Syndrome Pattern Locus Gene Associated Soft Tissue Sarcomas
Familial gastrointestinal stromal tumor syndrome AD 4q12 KIT Gastrointestinal stromal tumor
Familial desmoid fibromatosis (Gardner syndrome) AD 5q21 APC Desmoid fibromatosis
Li-Fraumeni syndrome AD 17p13,22q11 TP53, CHK2 Multiple types
Neurofibromatosis type I (von Recklinghausen disease) AD 17q11 NF1 Malignant peripheral nerve sheath tumors
Retinoblastoma AD 13q14 RB1 Multiple types
Rhabdoid predisposition syndrome AD 22q11 SNF5/INII Malignant rhabdoid tumors
Werner syndrome AR 8p11–12 WRN Multiple types
AD, Autosomal dominant; AR, autosomal recessive.

Table 90.3 Selected Molecular Alterations Identified in Sarcoma

Characteristic Cytogenetic Frequency Diagnostically
Tumor Type Events Molecular Events (%) Useful?
Alveolar soft part sarcoma t(X;17)(p 11;q25) ASPL-TFE3 fusion >90 Yes
Extraskeletal myxoid t(9;22)(q22;q12) EWSR1-NR4A3 fusion >75 Yes
chondrosarcoma
Clear cell sarcoma t(12;22)(q13;q12) EWSR1-ATF1 fusion >75 Yes
Desmoplastic small round cell t(11;22)(q13;q12) EWSR1-WT1 fusion >75 Yes
tumor
Dermatofibrosarcoma Ring form of chromosomes 17 and 22 COLIA1-PDGFB fusion >75 Yes
protuberans
t(17;22)(q21;q13) COLIA1-PDGFB fusion 10 Yes
Ewing sarcoma, peripheral t(11;12)(q24;q12) EWSR1-FLII fusion >80 Yes
primitive neuroectodermal t(21;22)(q12;q12) EWSR1-ERG fusion 5–10 Yes
tumor t(2;22)(q33;q12) EWSR1-FEV fusion <5 Yes
Fibrosarcoma, infantile t(12;15)(q13;q26) ETV6-NTRK3 fusion >75 Yes
Trisomies 8,11,17 and 20 >75 Yes
Gastrointestinal stromal tumor Monosomies 14 and 22 >75 Yes
Deletion of 1p KIT or PDGFRA mutation >25 No
>90 Yes
Inflammatory myofibroblastic 2p23 rearrangement ALK fusion genes 50 Yes
tumor
Leiomyosarcoma Deletion of 1p >50 No
Liposarcoma
Well-differentiated Ring form involving chromosome 12q >75 Yes
Myxoid–round cell t(12;16)(q13;p11) FUS-DDIT3 fusion >75 Yes
Pleomorphic Complex EWSR1-DDIT3 fusion <5 Yes
Undifferentiated pleomorphic Complex >90 No
sarcoma
Malignant peripheral nerve Complex; NF1 loss >90 No
sheath tumor
Rhabdoid tumor Deletion of 22q INI1 inactivation >90 Yes
Rhabdomyosarcoma
Alveolar t(2;13)(q35;q14) PAX3-FOXO1 fusion >75 Yes
t(1;13)(p26;q14), double minutes PAX7-FOXO1 fusion 10–20 Yes
Embryonal Trisomies 2q, 8, and 20 >75 Yes
Loss of heterozygosity >75 Yes
at 11p15
Synovial sarcoma
Monophasic t(X;18)(p11;q11) SS18-SSX1 or SS18- >90 Yes
Biphasic t(X;18)(p11;q11) SSX2 fusion >90 Yes
SS18-SSX1 fusion
of the SWI/SNF protein complex, which controls gene expression varying degrees, skin hyperpigmentation, urticaria pigmentosa, and
globally through its ability to alter chromatin structure.69 Thus loss cutaneous mast cell disease in addition to one or more GISTs.76 Activat-
of INI1 gene expression results in other changes in gene expression, ing KIT mutations have been shown to lead to ligand-independent
specifically activation of oncogenes. Rhabdoid tumors have loss-of- activation of the KIT receptor tyrosine kinase pathway, which results
function mutations in both copies of the INI1 gene.70 in dysregulated cell growth, and are thought to be the first step in
Werner syndrome is a rare genetic instability syndrome caused by the pathogenesis of GISTs.74 Interesting to note, the identification
mutations in the WRN gene.71,72 Affected patients age prematurely of the important role of KIT in the pathogenesis of GISTs has led
and are at greatly increased risk for a variety of cancers, including to treatment with imatinib,77 the oral multitargeted receptor tyrosine
STSs. The WRN gene encodes a protein involved in DNA repair73 kinase inhibitor (see Prognostic Factors as Therapeutic Targets, and
and loss of WRN protein function leads to genetic instability, accumula- Gastrointestinal Stromal Tumors).
tion of genetic mutations, and ultimately predisposition to rapid aging CStratakis and Carney reported a syndrome with paraganglioma
and cancer. and wild-type GIST called Carney Stratakis syndrome78 that arises
Germline mutations in the KIT oncogene are found in patients with from germline mutations in the mitochondrial succinate dehydrogenase
familial gastrointestinal stromal tumor (GIST) syndrome.74 Activating (SDH) subunit B, C, or D.79 This trial also included pulmonary
mutations in KIT or PDGFRA are also identified in over 90% of chondroma mutations in SDH subunits B.80 Interesting to note, these
sporadic GISTs.75 Patients with the familial syndrome develop, to GISTs arise without mutation in KIT or PDGFRA.
Genetics of Sporadic Soft Tissue Sarcomas blue cell tumor supports the diagnosis of Ewing sarcoma or primitive
neuroectodermal tumor (PNET).91 By the same token, a morphologic
Sarcomas tend to fall into two major subsets. One group has a sarcoma subtype without an expected translocation may suggest a
complex karyotype that is associated with aneuploidy. In the other variant translocation, as has been observed in Ewing sarcoma–like
group, tumors are cytogenetically simple and are characterized by near small round blue cell tumors that lack the EWSR1-FLI1 translocation
diploid karyotypes with few chromosomal rearrangements, resulting but rather contain CIC-DUX4 or a pericentric X chromosome.92–94
in the formation of fusion proteins. These translocations are highly Translocations may be identified through a variety of genetic
diagnostic of specific histologic subtypes of STSs. Also, included within analyses, spanning older techniques such as cytogenetic analysis to
the cytogenetically simple STSs are GISTs, which are characterized fluorescence in situ hybridization (FISH), reverse transcriptase
by a specific activating mutation of the KIT or PDGFRA gene, but polymerase chain reaction, and RNA sequencing. A detailed description
otherwise relatively limited genetic abnormalities. Finally, other than of these techniques is beyond the scope of this chapter, but each
the common loss of expression of the metabolic enzyme ASS1 that technique has its advantages and disadvantages. Cytogenetic analysis
occurs in 88% of sarcomas,81 most sarcoma subtypes demonstrate requires fresh (living) tissue, because the cells need to be cultured
their own underlying biology because sarcomas are as diverse a set of before karyotypic analysis, and largely has been supplanted by newer
tumors as carcinomas. techniques. FISH does not require fresh or frozen tissue and frequently
may be performed with paraffin-embedded material; it is a standard
Chromosomal Rearrangements diagnostic tool in many pathology laboratories. It is noted that evidence
of a translocation from FISH is not absolutely diagnostic of a sarcoma
A large number of sarcomas have been found to have consistent subtype, because one gene such as EWSR1 may be involved in many
chromosomal abnormalities (see Table 90.3).82 These chromosomal different types of sarcomas, and such data must be incorporated with
rearrangements are important diagnostically, may be important other data regarding the tumor sample. Reverse transcriptase polymerase
prognostically (see Potential Molecular Prognostic Factors), and have chain reaction is a more sensitive technique that may be performed
shed light on the pathogenesis of sarcomas. Some of the specific on fresh, frozen, or paraffin-embedded tissues. The major drawback
translocations, such as those seen in dermatofibrosarcoma protuberans of reverse transcriptase polymerase chain reaction is the relatively high
(DFSP) or tenosynovial giant cell tumor (TGCT), provide targets for false-positive rate, which results from its sensitivity. Meticulous care
pharmacologic therapy. Benign soft tissue neoplasms also harbor is required to prevent problems from contamination. Sequencing of
chromosomal rearrangements. the RNA complement of the genome allows for detection of mutations,
Chromosomal translocations are the most common cytogenetic translocations, and to some degree gene amplification, and is expected
abnormality in soft tissue neoplasms and are likely responsible for the to be used more frequently over time.95
initiation of tumorigenesis in most cases.82 Deletions and trisomies Many sarcomas are characterized by several different translocations,
have also been reported and are thought to represent secondary changes most of which are mutually exclusive (see Table 90.3). For instance,
involved in tumor progression. Deletions tend to represent loss of alveolar rhabdomyosarcoma is characterized by a translocation involving
tumor suppressor genes, whereas trisomies suggest the presence of an chromosomes 2 and 13, which results in fusion of the PAX3 and
oncogene. Although we know much about the principal tumorigenic FOXO1 genes, or by a translocation involving chromosomes 1 and
events in many sarcomas, defining the secondary changes has been 13, which results in fusion of the PAX7 and FOXO1 genes.96–98 Sarcomas
much more problematic and is an area of intense study with the within a subtype may also have differences in the specific exons that
advent of large-scale tumor DNA and RNA sequencing and related are involved in each of these different translocations. It has been
genomic techniques. The Sarcoma Tumor Cancer Genome Project proposed that this heterogeneity may result in differences in prognosis
provides large comprehensive data set on sarcomas.584 (see Potential Molecular Prognostic Factors). For example, Ewing
Cloning and molecular analysis of the various genetic aberrations sarcoma or PNET and synovial sarcoma possess genetic variations
that characterize different sarcomas have revealed the different patho- that have been suggested to have prognostic significance, further
genetic mechanisms that underlie these tumors. Translocations typically underscored by the Ewing-like sarcomas that lack EWSR1 fusions but
create chimeric transcription factors or growth factors that result in contain other translocations.92–94,99–102 Future research, it is hoped,
deregulation of transcription or growth control. A typical example of will establish whether cytogenetic and molecular factors may be used
a chimeric transcription factor is the PAX3-FOXO1 fusion protein, as a basis for therapeutic decisions and the prediction and evaluation
which has been shown to activate a complex myogenic transcriptional of response to treatment.
program when the protein is expressed in a fibroblast cell line.83 Infantile The identification of genetic alterations with high specificity for
fibrosarcoma is characterized by a translocation involving chromosomes different sarcomas will also enable identification of specific therapeutic
12 and 15 that encodes a chimeric ETV6-NTRK3 constitutively targets. This has already resulted in the successful treatment of a
activated growth factor receptor, which remarkably is found in other variety of sarcomas—for example, GISTs, DFSP, and TGCT/pigmented
cancers such as secretory breast cancer, a subset of acute myelogenous villonodular synovitis (PVNS), and to a lesser degree angiosarcoma,
leukemia (AML), and a form of salivary gland carcinoma.84 Additional desmoid tumor, and Ewing sarcoma.77,103–105 About 90% of GISTs
NTRK fusions have been identified in other STSs, with therapeutic harbor activating mutations in the KIT oncogene, which result in
potential.85 Other oncogenic proteins appear to act by a mechanism ligand-independent activation of the KIT receptor tyrosine kinase
that remodels chromatin structure, which is known to have a profound pathway.75 Imatinib, a small-molecule drug that is administered orally
influence on gene expression (e.g., INI1 mutations in rhabdoid and inhibits the KIT receptor tyrosine kinase, is highly efficacious in
tumors).70 the treatment of GIST (see later). Ninety percent of DFSP is character-
Specific chromosomal rearrangements are very useful in the diagnosis ized by translocations involving the COL1A1 and PDGFB genes,
of STSs. Beyond the obvious benefit of providing further objective which result in activation of the platelet-derived growth factor-β
proof of a diagnosis in morphologically typical cases, the detection (PDGFβ) pathway in what is believed to be an autocrine fashion.106
of chromosomal aberrations may facilitate the diagnosis of lesions Imatinib is active against the PDGFβ pathway and has been shown
that are difficult to characterize with standard histopathologic, to be effective in the treatment of a small number of DFSPs. In a
ultrastructural, and immunohistochemical techniques.86,87 For example, similar way, TGCT/PVNS with its t(1;2) involving COL6A3-CSF1
the presence of the translocation t(X;18)(p11;q11) has been used to is responsive to imatinib or PLX3397107 by virtue of its inhibition of
confirm the diagnosis of synovial sarcoma in poorly differentiated the CSF1 receptor.365
cases that were diagnostically very challenging.88–90 Similarly, the finding It is noteworthy to mention two common benign soft tissue
of the characteristic translocation t(11;22)(q24;q12) in a small round tumors—leiomyomas and lipomas—that have a high frequency of
chromosomal rearrangements of chromosome 12q that involves the PATHOLOGY

high-mobility protein group gene HMGIC/HMGA2.109,110 These
translocations are not seen in the corresponding leiomyosarcomas or Prospectively collected databases of STS patients, some of which
liposarcomas, indicating that in these tumors, the benign form is not contain data on over 10,000 patients, demonstrated that STSs are
a precursor of the malignant counterpart. Other benign soft tissue described in essentially all anatomic sites. The anatomic sites and
neoplasms contain specific translocations, such as nodular fasciitis site-specific histologic subtypes of 4207 sarcomas treated at a single
(t[17;22][p13;q13] MYH9-USP6) or angiomatoid fibrous histiocytoma referral institution are outlined in Fig. 90.1. Approximately half of all
(t[12;22][q13;q12] EWSR1-ATF1), underscoring the idea that transloca- STSs occur in the extremities (lower, 34%; upper, 14%), where the most
tions can occur in tumors anywhere in the spectrum of connective common histopathologic subtypes are well-differentiated, myxoid–round
tissue tumors from benign to malignant.111,112
Sarcomas With Complex Karyotypes Table 90.4 Sarcomas With Complex Karyotypes
A second major subset of STSs is characterized by aneuploidy and Type of Sarcoma Resembles
the lack of specific fusion genes. This group of sarcomas includes such
Fibrosarcoma (other than congenital) Fibrous tissue
tumors as leiomyosarcomas, MPNST, and fibrosarcomas (see Tables
90.3 and 90.4). These tumors tend to occur in older patients and Leiomyosarcoma Smooth muscle
appear to have a relatively high frequency of mutations in the p53 Undifferentiated pleomorphic sarcoma Poorly differentiated
and retinoblastoma (Rb) signaling pathways.113,114 These tumors are Osteosarcoma Bone
characterized by chromosomal gains and losses that presumably target Chondrosarcoma (types other than Cartilage
tumor suppressor genes (in the event of losses) and oncogenes (in the extraskeletal myxoid)
event of gains). A special case appears to be well-differentiated or
Liposarcoma (types other than myxoid) Fat
dedifferentiated liposarcoma, with amplifications of cell cycle regulatory
genes CDK4 and HDM2 and others on chromosome 12q. The Embryonal rhabdomyosarcoma Skeletal muscle
cooperation of these genes to create a unique type of aneuploid sarcoma Malignant peripheral nerve sheath tumora Nerve sheath
remains a current challenge in the field. Supporting the clinical data Angiosarcoma Endothelium
from syndromic sarcomas, alterations disrupting chromosomal mechan-
ics and DNA repair appear to be involved in sarcomagenesis. a
Some have NF1 mutations.
N = 460 Upper extremity

(14%)
N = 141 32%
Head and neck
(4%) 8%
12%
15%
5% 14%
12%
37% 16%
18% 6%
16% N = 491 Visceral

9% (14%)
3%
59%
Retroperitoneal/ N = 489
Intraabdominal (15%)
28%
17%
3% 8%
42% 6% 3%
N = 1098
6% Lower extremity
(34%)
26%
19%
13%
8%
28%
Other MFH 24%
ERMS Leiomyosarcoma
Synovial MPNT 7%
Fibrosarcoma Liposarcoma
Figure 90.1 • Anatomic distribution and site-specific histologic types in 4207 adult patients with soft tissue sarcomas seen at the University of Texas MD
Anderson Cancer Center, 1996–2003. ERMS, embryonal rhabdomyosarcoma; MFH, malignant fibrous histiocytoma; MPNT, malignant peripheral nerve
sheath tumor; UPS, malignant fibrous histiocytoma.
cell liposarcoma (28%), and UPS (formerly termed malignant fibrous

histiocytoma [MFH]) (24%). Retroperitoneal sarcomas make up 15% Table 90.5 Histologic Classification of Soft
of all STSs, well-differentiated or dedifferentiated liposarcoma being Tissue Sarcoma
the predominant histologic subtype (42%). Visceral sarcomas make ADIPOCYTIC SARCOMAS
up an additional 14%, and the head and neck sarcomas make up
approximately 4%. Atypical lipomatous tumor/well-differentiated liposarcoma
Dedifferentiated liposarcoma
Myxoid liposarcoma
Classification Pleomorphic liposarcoma
In broad terms, sarcomas may be classified into neoplasms that arise FIBROBLASTIC AND MYOFIBROBLASTIC SARCOMAS
in bone and those that arise from the soft tissues. However, even this Malignant solitary fibrous tumor
seemingly simple distinction is fraught with difficulty, as is illustrated Inflammatory myofibroblastic tumor
by Ewing sarcoma. In childhood, Ewing sarcomas most commonly Myxoinflammatory fibroblastic sarcoma
arise in close association with bone and are often classified as bone Infantile fibrosarcomas
sarcomas. However, it is now clear that these tumors can also arise in Adult fibrosarcomas
soft tissues, which occurs more commonly in adults. So are Ewing Myxofibrosarcoma (myxoid undifferentiated pleomorphic sarcoma)
sarcomas bone sarcomas or STSs, and does it really matter in terms Low-grade fibromyxoid sarcoma (Evans tumor)
of classification? Sarcomas of the soft tissues may be further grouped Sclerosing epithelioid fibrosarcoma
into those that arise from viscera (gastrointestinal, genitourinary, and
SO-CALLED FIBROHISTIOCYTIC SARCOMAS
gynecologic organs) and those that arise from nonvisceral soft tissues
(muscle, tendon, adipose, pleura, and connective tissue). Undifferentiated pleomorphic sarcoma (UPS)
An alternative way to index STSs is by their differentiation. SMOOTH MUSCLE SARCOMAS
Tumors may be grouped broadly into adipocytic tumors, fibroblastic
Leiomyosarcoma
or myofibroblastic tumors, so-called fibrohistiocytic tumors, smooth
muscle tumors, pericytic (perivascular) tumors, PNETs, skeletal muscle SKELETAL MUSCLE SARCOMAS
tumors, vascular tumors, osseous tumors, and tumors of uncertain dif- Embryonal rhabdomyosarcoma
ferentiation (Table 90.5).115 Classification is based on clinical, histologic, Alveolar rhabdomyosarcoma
ultrastructural, immunohistochemical, and genetic features. Electron Pleomorphic rhabdomyosarcoma
microscopic evidence of cellular substructures, neurofibrils, microfila-
ments, actin-myosin complexes, and dense bodies, has historically VASCULAR SARCOMAS
been used to define the tissue of origin.116 However, the widespread Epithelioid hemangioendothelioma
availability of commercial antibodies for immunohistochemical analysis Angiosarcoma
has all but eliminated the need for electron microscopic examination. Kaposi sarcoma
Immunohistochemical staining for proteins that are characteristic of Solitary fibrous tumor (formerly hemangiopericytoma)
smooth muscle (smooth muscle actin and desmin), skeletal muscle OSSEOUS SARCOMAS
(muscle-specific actin, desmin, and myogenin), blood vessels (factor
VIII, CD34, and CD31), and epithelial tissue (epithelial membrane Extraskeletal osteosarcoma
antigen and cytokeratins) often facilitates reliable classification, with SARCOMAS OF UNCERTAIN DIFFERENTIATION
genetic proof of a sarcoma translocation considered iron-clad evidence
Synovial sarcoma
of a specific sarcoma subtype.117,118 However, because the identical
Epithelioid sarcoma
translocation may be found in more than one type of cancer, such as Alveolar soft part sarcoma
the ASPL-TFE3 translocation of both alveolar soft part sarcoma and Clear cell sarcoma of soft tissue
papillary renal cancer, translocation data cannot be used in isolation. Extraskeletal myxoid chondrosarcoma
The tissue of origin classification scheme is the basis for the 2013 Desmoplastic small round cell tumor
World Health Organization classification system for sarcomas.119,120 Extrarenal rhabdoid tumor
The World Health Organization classification system is reproducible Extraskeletal Ewing sarcoma
for most sarcomas. As the degree of histologic differentiation declines, Intimal sarcoma
however, the determination of the tissue of origin becomes increasingly
difficult. In particular, despite advanced immunohistochemical and NOTOCHORD-DERIVED TUMOR BEHAVING–LIKE SARCOMAS
molecular analyses, determining the tissue of origin for some soft Chordoma
tissue tumors may be difficult, occasionally arbitrary, and sometimes
impossible. This leads to significant disparities in diagnoses among
pathologists. Discrepancies between the original histologic diagnosis
and the subsequent diagnosis by an expert reviewer have been noted of sarcoma presentation was under 3%; however, the rate was much
in as many as 25% of cases, although these data predate modern higher for angiosarcoma (13%), embryonal rhabdomyosarcoma (14%),
immunohistochemical and genetic analyses.121,122 Review of suspicious and epithelioid sarcoma (17%).123,124
tissue specimens at an expert center is therefore wise, because the Patterns of distant metastases also differ for subtypes of sarcoma. For
degree of expertise in correctly diagnosing some of the 50 or more example, myxoid–round cell liposarcoma tends to metastasize to soft
types of rare and unusual sarcomas is directly related to the number tissue sites, including the retroperitoneum, and to the spine and pelvis
of sarcomas that a pathologist has seen, and increasingly the specific and other bone marrow sites,125,126 and patients with myxoid–round
molecular diagnostic tools needed to identify rare sarcoma subtypes. cell liposarcoma often present with metastatic disease. If a myxoid or
It is important to classify STSs as precisely as possible because of round cell liposarcoma is identified in the abdomen, the thighs should
major differences in their clinical behavior and in their susceptibility be examined for an occult primary tumor. The majority of what had
to different therapies. For example, a few STSs, including epithelioid been suspected to be primary myxoid liposarcomas of the abdomen
sarcoma, clear cell sarcoma, angiosarcoma, and rhabdomyosarcoma and retroperitoneum are actually misdiagnosed well-differentiated or
have a greater risk of regional lymph node metastasis.123,124 In one dedifferentiated liposarcomas that have myxoid features (and usually
single-institution study, the overall rate of nodal metastasis at the time metastasize far less often than myxoid–round cell liposarcoma).127
Patterns of local spread also differ dramatically among subtypes of histologic subtype and amount of tumor necrosis, but cellularity,
sarcoma. For example, DFSP has a propensity to infiltrate subcutaneous nuclear pleomorphism, and mitotic index are considered for certain
adipose tissue in a manner that is very difficult to detect; therefore subtypes. The FNCLCC system uses a score generated by evaluation
wide surgical excision of DFSP is essential. Mohs surgery has been used of three parameters: tumor differentiation, mitotic rate, and amount
for DFSP, but the concern for recurrences 5 to 10 years after initial of tumor necrosis. The prognostic values of these two grading systems
diagnosis makes one wary about anything less than a wide excision. were retrospectively compared in a population of 410 adult patients
When planning an operation for DFSP, the surgeon should regard the with nonmetastatic STS.133 Significant discrepancies were observed
grossly observable lesion as the tip of the iceberg. Myxofibrosarcoma in one-third of cases. An increased number of grade III tumors, a
and, to an even greater extent, angiosarcoma also spread very diffusely reduced number of grade II tumors, and better correlation with overall
and may be very difficult to resect with negative margins owing to and metastasis-free survival were observed in favor of the FNCLCC
microscopic tumor insinuation 2 cm or more from the gross tumor. system.133 Thus in the absence of other comparative data, the FNCLCC
system appears to be the best presently available grading system. The
Histologic Grading FNCLCC has therefore been incorporated into the American Joint
Committee on Cancer (AJCC) version 7 STS staging system.134
Histologic classification alone does not always provide enough informa-
tion to predict the clinical behavior of STSs. For many sarcomas, CLINICAL PRESENTATION AND DIAGNOSIS
histologic grading provides additional information that can aid in
predicting biologic behavior and planning treatment. The spectrum The majority of patients with STS have a painless mass, although
of grades varies among specific histologic subtypes (Fig. 90.2). For pain is noted at presentation in up to one-third of cases135; synovial
example, liposarcomas exhibit wide variations in grade, whereas Ewing sarcoma in particular may be most associated with a painful mass,
sarcomas or PNETs are always considered high grade. In careful among the sarcomas. Delay in diagnosis of sarcomas is common; the
comparative multivariate analyses, histologic grade has been the most most common incorrect diagnosis for extremity and trunk lesions is
important prognostic factor in assessing the risk for distant metastasis lipoma or hematoma.
and tumor-related mortality.128–130 Several grading systems have been Physical examination should include an assessment of the size and
proposed, but there is no consensus regarding the specific morphologic mobility of the mass. Its relationship to the fascia (superficial versus
criteria that should be used in the grading of STSs. The two most deep) and nearby neurovascular and bony structures should be noted.
important criteria appear to be the mitotic index and the extent of A site-specific neurovascular examination and assessment of regional
tumor necrosis. lymph nodes should also be performed.
Two of the most commonly used grading systems are the US
National Cancer Institute (NCI) system developed by Costa131 and Biopsy
the FNCLCC system (Federation Nationale des Centres de Lutte
Contre le Cancer) developed by the French Federation of Cancer Biopsy of the primary tumor is essential for most patients with soft
Centers Sarcoma Group.132 The NCI system is based on the tumor’s tissue masses. In general, any biopsy should be performed on any soft
Histologic grade
Histologic type
I II III
Fibrosarcoma
Infantile fibrosarcoma
Dermatofibrosarcoma protuberans
Malignant fibrous histiocytoma
Liposarcoma
Well-differentiated liposarcoma
Myxoid liposarcoma
Round cell liposarcoma
Pleomorphic liposarcoma
Leiomyosarcoma
Rhabdomyosarcoma
Angiosarcoma
Malignant hemangiopericytoma
Synovial sarcoma
Malignant mesothelioma
Malignant schwannoma
Neuroblastoma
Ganglioneuroblastoma
Extraskeletal chondrosarcoma
Myxoid chondrosarcoma
Mesenchymal chondrosarcoma
Extraskeletal osteosarcoma
Malignant granular cell tumor
Alveolar soft part sarcoma
Epithelioid sarcoma
Clear cell sarcoma
Extraskeletal Ewing sarcoma
Figure 90.2 • The spectrum of grades observed among histologic subtypes of soft tissue sarcoma. (Modified from Weiss SW, Goldblum JR. Malignant
soft tissue tumors of uncertain type. In: Weiss SW, Goldblum JR eds. Enzinger and Weiss’s Soft Tissue Tumors. 5th ed. Philadelphia: Mosby; 2008.)
tissue mass in an adult that is asymptomatic or enlarging, is larger 90.4). This is because MRI enhances the contrast between tumor and
than 5 cm, or persists beyond 4 to 6 weeks. The preferred biopsy muscle and between tumor and adjacent blood vessels and provides
approach is generally the least invasive technique required to allow a multiplanar definition of the lesion.140,141 Despite the fact that a study
definitive histologic diagnosis and assessment of grade. In most centers, by the Radiation Diagnostic Oncology Group that compared MRI
core needle biopsy provides satisfactory tissue for diagnosis136–138 and and computed tomography (CT) in patients with malignant bone (n
has been demonstrated to result in substantial cost savings compared = 183) and soft tissue (n = 133) tumors showed no specific advantage
with open biopsy; core needle biopsy (usually with multiple passes) of MRI over CT from a diagnostic standpoint,142 the majority of
also yields adequate material for molecular testing, with fine-needle musculoskeletal radiologists and almost all surgical oncologists prefer
aspiration considered inadequate by most practitioners.138 Direct MRI for soft tissue tumors. For pelvic lesions, the multiplanar capability
palpation may be used to guide needle biopsy of most superficial of MRI may provide superior single-modality imaging (Fig. 90.5),
lesions, but less accessible sarcomas often require an image-guided although similar techniques are commonly available with CT scans.
biopsy in order to safely sample the most heterogeneous component The multiplanar capability is also helpful for visualization of disease
of the mass. Needle tract tumor recurrences after closed biopsy are in non-coplanar ways when conformal radiotherapy technique is being
rare but have been reported,139 leading some surgeons to advocate
tattooing the biopsy site for subsequent excision or for inclusion in
radiotherapy treatment volumes (Fig. 90.3). Owing to the frequent
difficulty in accurately diagnosing these lesions even when adequate
tissue is available, fine-needle aspiration is not recommended for initial
diagnosis. The major use of fine-needle aspiration in most centers is
in the diagnosis of suspected recurrent sarcoma.
Incisional or excisional biopsy is rarely required but may be per-
formed when a definitive diagnosis cannot be achieved through less
invasive means. Several technical points merit comment. Biopsy of
relatively small, superficial masses that can easily be removed should
entail complete excision with microscopic assessment of surgical
margins. Incisional and excisional biopsies should be performed with
the incision oriented longitudinally (for extremity lesions) to facilitate
subsequent wide local excision. The incision should be centered over
the mass at its most superficial point. Care should be taken not to
raise tissue flaps. Meticulous hemostasis should be ensured to prevent
dissemination of tumor cells into adjacent tissue planes by hematoma.
All excisional biopsy specimens should be sent fresh, sterile, and
anatomically oriented for pathologic analysis. At definitive resection
of a previously biopsied sarcoma, the previous surgical biopsy scar
should be excised en bloc with the tumor.
Figure 90.3 • Axial computed tomography (CT) image of a recurrent
well-differentiated (i.e., low-grade) liposarcoma of the retroperitoneum. Note
Imaging the tumor nodule (arrow) representing a tumor implant within muscle from
a previous needle biopsy that was performed through the posterior abdominal
For soft tissue masses of the extremities, magnetic resonance imaging wall. It is beneficial to consider the location of biopsy tracts so that subsequent
(MRI) has been regarded as the imaging modality of choice (Fig. surgery or radiotherapy includes the area of the biopsy (see text for details).
Figure 90.4 • A 47-year-old man with undifferentiated pleomorphic sarcoma of the left thigh. Axial contrast-enhanced T1-weighted (left) and flow sensitive
gradient (right) images reveal a large mass in the vastus intermedius muscle. A plane is identified between the mass and the profunda femoris and superficial
femoral vessels (arrows).
A B
Figure 90.5 • (A) A 48-year-old man with retroperitoneal and intraabdominal well-differentiated and dedifferentiated liposarcoma. Axial contrast-enhanced
computed tomography (CT) images show a large heterogeneous mass with foci of calcification, consistent with osteosarcoma divergent differentiation sometimes
seen with this form of sarcoma. In this situation, the finding of osteoblasts does not merit the use of chemotherapy for osteosarcoma; the risk of this tumor
recurrence rests entirely with the dedifferentiated liposarcoma portion of the diagnosis. (B) The same patient as in (A), with coronal sectioning from data
existing from the axial CT scans. This technique is now commonly used with both magnetic resonance imaging and CT.
of numerous studies and has been reviewed in detail elsewhere. The

technique uses radiolabeled glucose analogues,20 which are taken up
at increased rates by malignant tumors. Pilot studies of PET in STS
suggest that by evaluating tumor metabolic activity, PET scans may
allow for noninvasive assessment of tumor grade.143 PET may be
helpful in the assessment of locally recurrent STS144 and in the evalu-
ation of response to therapy.145,146 PET may also be useful in differentiat-
ing benign peripheral nerve sheath tumors and MPNSTs and plexiforms
in neurofibromatosis patients, although more prospective research is
needed.147 The role and cost-effectiveness of PET in the staging of
STS remain undefined; further prospective studies will be required
in order to fully define the role for FDG-PET in the diagnosis, evalu-
ation, and treatment of STS. For example, for the vast majority of
patients with metastatic GIST, PET-CT appears to add very little to
the assessment of response to tyrosine kinase inhibitors, given the
excellent image quality of contrast-enhanced CT scan.148
Figure 90.6 • Contrast-enhanced computed tomography scan of the STAGING

abdomen demonstrating a retroperitoneal undifferentiated pleomorphic sarcoma.
Note the large mass (bottom arrow) between the aorta and inferior vena cava The relative rarity of STSs, the anatomic heterogeneity of these lesions,
with abutment and displacement of celiac axis and hepatic artery (top arrows). and the presence of more than 50 recognized histologic subtypes of
The portal vein (arrowheads) is well visualized, and low-attenuation foci in variable grade have made it difficult to establish a functional system
the liver, which are unopacified hepatic veins, are incidentally visualized. that can accurately stage all forms of this family of neoplasms. The
seventh edition of the AJCC (Union for International Cancer Control
[UICC]) system is the most widely used staging system for STSs.134
used and is an especially helpful adjunct in using image fusion This staging system was first published in 1977, and incorporates
techniques or to visualize peritumoral edema that may harbor sarcoma histologic grade into the conventional TNM system (Table 90.6).
cells. In the retroperitoneum and abdomen, CT usually provides The 2010 edition classification functionally eliminated tumor depth
satisfactory anatomic definition of the lesion (Fig. 90.6) and is a very in staging, and classifies node-positive disease without metastases
useful modality for imaging metastatic disease in the lungs and (N1M0) as stage III as compared with stage IV in the sixth edition
abdomen, given the averaging of signal that occurs with normal patient of 2002. In addition, a unique staging system for GIST has been
respiration and peristalsis during the much lengthier MRI procedure. generated.134 For the detailed background of these changes, the reader
Occasionally, MRI with gradient sequence imaging may better delineate is referred to a more complete discussion.
the relationship of the tumor to midline vascular structures, particularly Three distinct histologic grades (G1–3) are recognized according
the inferior vena cava and aorta. Older and more invasive studies such to the French (FNCLCC) grading system, in the interest of consistency
as angiography or cavography are almost never used for the evaluation among institutions. Histologic grade and tumor size are the primary
of STSs. determinants of clinical stage (see Table 90.6). Tumor size is further
The usefulness of fluorine-18 (18F) fluorodeoxyglucose–positron substaged as “a” (a superficial tumor that arises outside the investing
emission tomography (FDG-PET) with CT registration images fascia) or “b” (a deep tumor that arises beneath the fascia or invades
(PET-CT) in the evaluation and treatment of STS has been a subject the fascia), although it does not affect stage in AJCC version 7.
Stage-specific survival plots based on prior versions of the AJCC criteria

Table 90.6 American Joint Committee on Cancer are outlined in Fig. 90.7.
(AJCC) Staging System, Seventh Edition A major limitation of the present staging system is that it does
not take into account the anatomic site of STS, patient age, or histologic
Stage Grade Tumor Nodes Metastasis
type, nor does it is necessarily use enough size categories—all factors
IA G1, GX T1a, T1b N0 M0 that appear to be important determinants of outcome. Patients with
IB G1, GX T2a, T2b N0 M0 retroperitoneal and visceral sarcomas have a worse overall prognosis
IIA G2, G3 T1a, T1b N0 M0 than do patients with extremity tumors. Although site is not incor-
IIB G2 T2a, T2b N0 M0
porated as a specific component of any present staging system, outcome
data should be reported on a site-specific basis when feasible, because
III G3 T2a, T2b N0 M0 this also affects survival.
Any Any N1 M0 Nomograms and newer techniques such as bayesian belief networks
IV Any G Any T Any N M1 may better help specify risk for discussion with patients.149,150 These
have been generated for both specific anatomic sites and for specific
G: PRIMARY TUMOR GRADE
sarcoma histologies. It is difficult to envision a unique staging system
The FNCLCC tumor grade is used (three-stage system). for each of the more than 50 STS histologies, which argues that a
G1 Low grade multidimensional risk assessment as may be performed with nomograms
G2 Intermediate grade should supersede traditional staging systems in the interest of accuracy,
G3 High grade
although this comes at the cost of simplicity. As the first example of
this technique being used in STSs, Kattan and colleagues constructed
GX Grade unknown and validated a nomogram to predict the probability of 12-year
T: PRIMARY TUMOR SIZE AND LOCATION sarcoma-specific death based on a prospective series of patients (Fig.
T1 Tumor ≤5 cm
90.8).149 This tool is useful for individual patient counseling, follow-up
scheduling, and clinical trial eligibility assessment and is further
T2 Tumor >5 cm facilitated by being also available for personal computers and handheld
a Superficial to investing fascia (irrelevant in devices. Nomograms have since been developed for specific anatomic
version 7) sites such as the retroperitoneum, or for specific sarcoma subtypes,
b Deep to investing fascia (irrelevant in such as liposarcoma.151–154 These useful tools may be found online at
version 7) www.nomograms.org.
N: LYMPH NODES
N0 No involved nodes PROGNOSTIC FACTORS
N1 Regional nodal involvement
Conventional Clinicopathologic Factors
M: METASTASES
A thorough understanding of the clinicopathologic factors that are
M0 No metastatic disease known to affect outcome is essential in formulating a treatment plan
M1 Metastatic disease present for the patient with STS. Since the late 1970s, multivariate analyses
of prognostic factors for patients with localized sarcoma have been
FNCLCC, Federation Nationale des Centres de Lutte Contre le Cancer. reported. Although initial studies were limited by sample size, the
From American Joint Committee on Cancer (AJCC) Cancer Staging Manual. 7th ed. largest databases from referral centers and a variety of national registries
New York: Springer; 2010.
now contain data from thousands of patients, allowing for increasingly
1.0
UICC stage I (n = 168)
UICC stage II (n = 500)
UICC stage III (n = 478)
0.8
Proportion surviving
0.6
0.4
0.2
0
0 12 24 36 48 60 72 84 96 108 120 132 144 156
Time (mo)
Figure 90.7 • Overall survival by American Joint Committee on Cancer stage in a population of 1146 patients with primary extremity sarcoma. UICC,
Union for International Cancer Control.
100 Table 90.7 Multivariate Analysis of Prognostic

Factors in Patients With Extremity Soft
90
Tissue Sarcoma
80
Relative
70 End Point Adverse Prognostic Factora Risk
Remission (%)
60 Local recurrence Age >50 years 1.6

50 Local recurrence at presentation 2.0
Microscopically positive margin 1.8
40 Fibrosarcoma 2.5
Malignant peripheral nerve tumor 1.8
30
Distant recurrence Size 5–10 cm 1.9
20 Total Fail Size >10 cm 1.5
10 17 1 Amputation High grade 4.3
27 5 Limb-sparing surgery Deep location 2.5
0 Local recurrence 1.5
0 1 2 3 4 5 6 7 8 9 10 Leiomyosarcoma 1.7
Other nonliposarcoma histology 1.6
Years
Disease-specific Size >10 cm 2.1
survival Deep location 2.8
Figure 90.8 • Local recurrence rates in patients with high-grade extremity
sarcomas randomly assigned to undergo amputation or limb-sparing surgery. Local recurrence at presentation 1.5
All patients were treated with adjuvant chemotherapy with doxorubicin, Leiomyosarcoma 1.9
cyclophosphamide, and methotrexate. Median follow-up was longer than 9 Malignant peripheral nerve 1.9
years (P = .22). (Redrawn with permission from Yang JC, Rosenberg SA. sheath tumor
Surgery for adult patients with soft tissue sarcomas. Semin Oncol. 1989;16:289.) Microscopically positive margin 1.7
Lower extremity site 1.6
a
Adverse prognostic factors identified are independent by Cox regression analysis.
sophisticated analyses of a variety of subsets of sarcoma patients. Modified from Pisters PW, Leung DH, Woodruff JM, et al. Analysis of prognostic
Nonetheless, many of the primary principles regarding patient outcomes factors in 1041 patients with localized soft tissue sarcomas of the extremities. J Clin
were made evident in those first studies. Oncol. 1996;14:1679.
The initial study of prognostic factors in extremity sarcoma from
Memorial Sloan Kettering Cancer Center evaluated clinicopathologic
prognostic factors in a series of 423 patients with localized extremity
STS seen from 1968 to 1978.145 This analysis was among the first to example, the AJCC staging system for STSs of retroperitoneum or
discriminate between specific clinical end points, and clearly established viscera is nonsensical with respect to primary tumor depth (indicated
the clinical profile of what is now accepted as the high-risk patient as superficial or deep), because all tumors from this anatomic site are
with extremity STS: the patient with a large (in this case >5 cm), deep tumors, and staging systems specific for each clinical scenario
high-grade, deep lesion. The adverse prognostic significance of a high may be more appropriate means to estimate clinical outcomes. Separate
tumor grade, deep tumor location, and tumor size over 5 cm was also reviews of prognostic factors for sarcomas of the retroperitoneum,136,155
noted in the report of the French Federation of Cancer Centers study head and neck,156–159 gastrointestinal tract,160,161 colon and rectum,162
of 546 patients with sarcomas of the extremities, head and neck, trunk and uterus,163 synovial sarcomas,164,165 UPS (formerly termed malignant
wall, retroperitoneum, and pelvis.129 fibrous histiocytoma [MFH]),166–168 and Ewing sarcoma169–172 also have
A follow-up report evaluated clinicopathologic prognostic factors been reported.
that had been documented prospectively in a population of 1041
patients with extremity STS.128 The end points for the multivariate Potential Molecular Prognostic Factors
analyses were local recurrence, distant recurrence (metastasis), and
disease-specific survival. Results of the regression analyses for each of As clinicopathologic factors affecting patient outcomes were being
these end points are summarized in Table 90.7 as an example of the identified, examination of the tissue itself for factors predicting outcome
key prognostic factors that are ascertained in such studies. These results, became another topic of interest, and continues to this day in the
using prospectively acquired data, confirm the initial observations form of more detailed molecular profiling of RNA expression, compara-
made at that institution using an independent data set.8 In addition, tive genomic hybridization, tumor DNA or RNA sequencing, and
the previously unappreciated prognostic significance of specific histologic analysis of DNA modifications such as methylation patterns in specific
subtypes and the increased risk for adverse outcome associated with tumors. Some of the first parameters that were evaluated for prognostic
a microscopically positive surgical margin or locally recurrent disease significance included p53,173 HDM2 (the human version of the murine
were noted. Unlike for other solid tumors, the adverse prognostic p53 interacting protein MDM2),173 Ki-67,173 altered expression of
factors for local recurrence of STS are somewhat different from those the retinoblastoma gene product (pRb)174,175 in high-grade sarcomas,
that predict distant metastasis and tumor-related mortality (see Table and the importance of the specific type of SS18-SSX fusion transcripts
90.7).128 Therefore staging systems that are designed to stratify patients in synovial sarcoma100 or EWSR1-FLI1 fusion transcripts in Ewing
according to risk of distant metastasis and tumor-related mortality sarcoma.99,100 Notably, although many individual immunohistochemical
using these prognostic factors (such as the AJCC/UICC system) do markers have been examined as prognostic factors in outcome, data
not stratify patients according to risk of local recurrence. are generally conflicting. It is well recognized that there is variability
It should be emphasized that the prognostic factors that have been in immunohistochemistry in both technique (which may vary among
identified have been derived primarily from studies of patients with laboratories) and assessment (what may be 2+ staining to one investiga-
localized extremity sarcomas. Despite the fact that extremity sarcomas tor is 3+ or 4+ staining to another).
make up the majority of sarcomas, these results do not necessarily As one of the first examples of analyzing multiple immunohisto-
apply to the populations of patients with STS in other sites. For chemical markers with respect to outcome, Heslin and colleagues
evaluated the potential prognostic significance of pRb, p53, HDM2, mutations appear to have a lower risk of relapse compared with exon
and Ki-67 with immunohistochemical techniques in a population of 11 KIT mutation or PDGFRA mutant GISTs. Although it is conceivable
121 patients with primary, high-grade extremity sarcomas and compared that the type of mutation is a surrogate for the behavior of a GIST,
these factors with conventional clinicopathologic prognostic factors it is also plausible that the type of mutation represents the initial
(median follow-up, 64 months).173 Clinicopathologic and molecular pathogenetic mechanism, making it a true prognostic marker and
factors that were found to be statistically significant adverse prognostic target. It is apparent that the mutation in KIT is context dependent;
factors in both univariate and multivariate analyses for the separate KIT mutation and ETS transcription factor family member ETV1
end points of distant metastasis and tumor-related mortality included overexpression appear to synergize to drive GIST development.185
tumor size greater than 5 cm, microscopically positive surgical margin,
and a Ki-67 score greater than 20 (>20% nuclear staining). Overexpres- Molecular Therapeutic Targets in Sarcomas:
sion of p53 or HDM2 or deletion of pRb did not correlate with an Gastrointestinal Stromal Tumor
increased risk of distant metastasis or tumor-related mortality. Similarly,
data with respect to specific SS18-SSX translocation type (i.e., SSX1 We have just now begun to see the implications and success of targeting
or SSX2) and outcome have yielded conflicting results,100,101 and the genetic alterations in sarcomas that drive oncogenesis. GISTs were
specific EWSR1-FLI1 translocation does not appear to affect overall previously thought to be gastrointestinal leiomyosarcomas that were
outcomes for patients.99,100,177 Finally, ASS1 expression was seen to particularly resistant to cytotoxic chemotherapy. It was subsequently
inversely correlate with overall survival (OS) in osteosarcoma and demonstrated that these tumors were derived from interstitial cells of
myxofibrosarcoma.178,179 Cajal or their precursors and were frequently characterized by point
With the increasing use of genomic analyses such as RNA expression mutations in the KIT receptor tyrosine kinase and were clearly distinct
arrays, comparative genomic hybridization, or tumor RNA sequencing, from leiomyosarcomas.75,186 Subsequently, the tumors were treated
it is possible that expression or mutation-specific stratification may with imatinib, which targets the KIT kinase, with dramatic results.188
be possible within specific histologic types, in a manner analogous to Mutations in KIT were observed in exon 11 (juxtamembrane domain,
current use of this technique to stratify breast cancer.180 In addition, seen in 71% of tumors), exon 9 (the extracellular region, 13%), exon
these profiles have been applied to determining metastatic potential 13 (first lobe of the split-kinase domain, 4%), and exon 17 (phos-
of primary tumors, and this approach could clearly be applicable to photransferase domain, 4%). The subset of patients with exon 11
STSs, in which the presence or absence of metastases remains the mutations resulting in point single amino acid substitutions (i.e.,
most important prognostic factor.181 Phosphoprotein profiling could missense codon mutations) fared much better than did patients with
become useful for patient risk stratification, as has been examined in deletion or insertion mutations of exon 11 (5-year RFS rate of 89%
stage III rhabdomyosarcoma to predict outcome.182 This approach ± 11% versus 37% ± 10%, respectively).184 In addition, tumors that
also holds future promise for both prognostic and therapeutic approaches lack mutations in KIT appear to have mutations in PDGFα receptor
(see later discussion), although phosphoprotein lability and tissue gene PDGFRA, and those that have no mutation in KIT or PDGFRA
handling are concerns in the proper conduct of such studies. Specific are driven by loss of SDH expression, mutation in BRAF, or other
cellular and molecular parameters have been identified as having genetic alterations such as gene fusions involving FGFR1 and NTRK3,
independent prognostic significance, but there is currently no consensus all changes that are mutually exclusive of mutations in KIT.189–191
on how specific molecular prognostic factors should be used in clinical Finally, the type of mutation that is identified appears not only to
practice. Validated markers may affect outcome prognostication in predict response to imatinib, but also to suggest whether other kinase
the future, but for the time being remain investigational. inhibitors such as sunitinib may have beneficial effects.192 Although
to date the most common adult STSs have demonstrated few consistent
Prognostic Factors as Therapeutic Targets mutations in kinase genes that are amenable to target inhibition, new
options for treatment likely will be derived from more careful genetic
The prognosis of patients with GISTs is often poor when treated with analysis of specific sarcoma subtypes through use of newer sequencing
surgery alone,183 and these tumors do not respond to conventional techniques, comparative genomic hybridization, analysis of tumor
systemic chemotherapy. Arguably the most exciting discovery in GIST microRNA (miRNA), and DNA methylation patterns.95
research is the finding of the activity of kinase-directed therapy, which
is discussed later in the chapter. The proto-oncogene KIT is the cellular
homolog of the oncogene v-Kit (identified in a feline sarcoma virus). TREATMENT OF LOCALIZED PRIMARY SOFT
KIT (also termed CD117) encodes a transmembrane tyrosine kinase TISSUE SARCOMA
receptor that is structurally similar to PDGF and provides selective
targets of key aberrations in the molecular signaling implicated in the Surgery
pathogenesis of GISTs and other tumors (e.g., DFSP). An interesting
additional feature of KIT expression in GIST is that different types Limb-Sparing Surgery Versus Amputation
and locations of mutations in KIT are independent risk factors in Surgical resection remains the cornerstone of therapy for localized
predicting disease-free survival independent of treatment with kinase STS, and the prototypical situations concern the management of
receptor inhibitors.184 KIT expression was uniformly evident in a lesions arising in the extremity, the most common anatomic site. Since
study of GIST cases not treated with imatinib.75,184 Of interest, KIT the early 1980s, there has been a marked decline in the rate of amputa-
was highly phosphorylated in all cases, even in those samples that tion as the primary therapy for extremity STS. With the widespread
lacked demonstrable KIT mutations.75 Mutations are found in specific application of multimodality treatment strategies, fewer than 10% of
regions of the KIT gene (most commonly exon 9 and exon 11), and patients undergo amputation.193,194 The current use of limb-sparing
are associated with differing prognosis (see following discussion). In multimodality treatment approaches for patients with extremity sarcoma
the era before imatinib, the subset of patients with exon 11 KIT is largely based on a randomized prospective study from the US NCI
mutations resulting in single amino acid substitutions (i.e., missense in which patients with extremity sarcomas that were amenable to
codon mutations) fared much better than did patients with deletion limb-sparing surgery were randomized to receive amputation or limb-
or insertion mutations of exon 11 (5-year recurrence-free survival sparing surgery with postoperative radiotherapy.195,196 Both arms of
[RFS]) rate of 89% ± 11% versus 37% ± 10%, respectively). A potential this trial included postoperative chemotherapy with doxorubicin,
explanation for this finding is that exon 11 missense mutations are cyclophosphamide, and methotrexate. With more than 9 years of
detected in lower-grade, favorable-outcome GISTs.184 Against this follow-up evaluation, 5 (19%) of 27 patients randomly assigned to
explanation is the fact that the metastatic GISTs with KIT exon 9 receive limb-sparing surgery and postoperative radiation with
chemotherapy had local recurrences, as compared with 1 (6%) of 17 survival rates comparable to those for amputation while simultaneously
patients in the amputation plus chemotherapy arm (P = .22; Fig. preserving a functional extremity.
90.9).196 The disease-free survival rate was 63% for limb-sparing surgery Currently, at least 90% of patients with localized extremity sarcomas
versus 71% for amputation (P = .52; Fig. 90.10), and the OS rate can undergo limb-sparing procedures.193,197 Most surgeons consider
was 70% for limb-sparing surgery versus 71% for amputation (P = definite major vascular, bony, or nerve involvement to be a relative
.97). This study established that for patients in whom limb-sparing indication for amputation. Complex en bloc bone, vascular, and nerve
surgery is an option, a multimodality approach using limb-sparing resections with interposition grafting may be undertaken, but the
surgery combined with postoperative radiotherapy yields disease-related associated morbidity is high. Therefore for a few patients with critical
involvement of major bony or neurovascular structures, amputation
remains the only surgical option but offers the prospect of prompt
rehabilitation with excellent local control and survival.196 An approach
100 approved in Europe for selected patients with locally advanced tumors
is limb perfusion, in which a tourniquet is placed proximal to the
90
tumor on a limb, the blood is flushed out, and a perfusate of tumor
80 necrosis factor (TNF) and chemotherapy is administered through
Disease-free survival (%)
a recirculating pump. This technique has allowed for limb salvage

70
even in patients with otherwise unresectable disease; chronic edema
60 is the most common long-term complication.198–200 However, TNF
is unavailable in the United States, either for patient care or for
50
clinical trials.
40
30 Completeness of Resection
20 Total Fail Satisfactory local resection involves resection of the primary tumor
10 17 5 Amputation with a margin of normal tissue around the lesion. The width of
27 10 Limb-sparing surgery the margin should differ depending on whether or not adjuvant
0 radiotherapy is used. It is clear that dissection along the tumor
0 1 2 3 4 5 6 7 8 9 10 pseudocapsule (enucleation) is associated with local recurrence rates
ranging between 33% and 63%.201–203 Wide local excision with a
Years margin of normal tissue around the lesion is associated with local
Figure 90.9 • Disease-free survival rates for patients with high-grade recurrence rates in the range of 10% to 31%, as was noted in the control
extremity sarcomas randomly assigned to undergo amputation or limb-sparing arms (surgery alone) of the randomized trials evaluating postoperative
surgery. All patients were treated with adjuvant chemotherapy with doxorubicin, radiotherapy.204,205
cyclophosphamide, and methotrexate. Median follow-up was longer than 9 In contrast to malignant melanoma, a cancer for which there are
years (P = .52). (Redrawn with permission from Yang JC, Rosenberg SA. randomized data to address adequate margin size, no comparable data
Surgery for adult patients with soft tissue sarcomas. Semin Oncol. 1989;16:289.) are available to define what constitutes a satisfactory gross resection
margin for a sarcoma, because the anatomic situation with each STS is
unique. In general, every effort should be made to achieve a wide margin
(2 cm is a frequently cited arbitrary choice) around the tumor mass,
Overall survival except in the immediate vicinity of functionally important neurovascular
100 structures, where, in the absence of frank neoplastic involvement,
dissection is performed in the immediate perineural or perivascular
90 tissue planes. The 2-cm choice is unnecessary if radiotherapy is also
used, because substantial modification of the surgical approach with
much closer margins of resection (e.g., 1–2 mm) is made possible,
80
Event free (%)
and even large lesions may be managed conservatively in that setting.

Technical details of the surgical approach to extremity sarcomas are
60 beyond the scope of this chapter but are comprehensively reviewed
in surgical atlases.206 At the same time, it is also important to bear
40 in mind that involved (i.e., positive) resection margins remain an
Logrank P = .0481 adverse finding even when adjuvant radiotherapy is used, notwith-
standing the amelioration of risk that radiation treatment provides.
20 Preoperative RT Data from Memorial Sloan Kettering Hospital, Princess Margaret
Postoperative RT
Hospital, and Massachusetts General Hospital (MGH) suggest an
0 additional absolute reduction in local control of approximately 10%
0.0 1.0 2.0 3.0 to 15% in patients with positive margins compared with those with
microscopically negative surgical margins.206–209 As a result, radia-
Time (yr)
tion therapy should never be considered a substitute for inadequate
Patients at risk surgery.
Preoperative RT 92 87 81 51 In considering the existing outcome data, it is important to bear
Postoperative RT 94 90 74 48 in mind that these data consider the rubric “positive margins” in a
uniform way, although in reality this is unlikely to be the case. In
Figure 90.10 • Actuarial probability of overall survival for preoperative fact, positive resection margins have different causes. One is oncologi-
versus postoperative radiotherapy (RT) in extremity soft tissue sarcoma. (Data cally inadequate surgery in which positive resection margins might
redrawn with permission from O’Sullivan B, Davis AM, Turcotte R, et al. have been avoidable in another surgeon’s hands. When this is the
Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the case, microscopically positive surgical margins may be considered a
limbs: a randomised trial. Lancet. 2002;359:2235.) technical failure. Alternatively, positive resection margins may arise in
1.0
0.8
Probability of survival
0.6
0.4
P = .0003
0.2
Control (n = 48)
MAID-ON (n = 48)
0.0
0 20 40 60 80 100 120
Follow-up time (months)
48 38 30 26 17 8 Control
48 45 37 16 6 5 MAID-ON
Figure 90.11 • Actuarial probability of overall survival for mesna, doxorubicin, ifosfamide, dacarbazine (MAID) chemoradiotherapy and surgery versus
control patients. The significant difference between the groups with respect to cause of death was distant metastasis. (Data redrawn with permission from
Delaney TF, Spiro IJ, Suit HD, et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys.
2003;56:1117.)
anatomically adverse presentations in which locally advanced disease

challenges the goals of conservative resection from the outset. In a Lymph Node Dissection
study from the Princess Margaret Hospital, Gerrand and colleagues Given the low (under 3%) prevalence of lymph node metastasis in adults
evaluated the type of microscopically positive margin as a prognostic with sarcomas,121,213 there is no role for routine regional lymph node
factor and defined four groups in this setting.210 Patients with low-grade dissection. Patients with angiosarcoma, embryonal rhabdomyosarcoma,
liposarcomas and microscopically positive surgical margins (group 1) and epithelioid histologic types have an increased incidence of lymph
have a low risk of local failure, as do those in whom a positive margin node metastasis and should be carefully examined for adenopathy with
is anticipated before surgery in order to preserve critical structures physical examination, imaging, and sentinel lymph node sampling.
and in whom radiotherapy is given to sterilize the minimal residual Therapeutic lymph node dissection (curative) results in a 34% actuarial
disease (group 2). However, two categories of positive margins are survival rate123; therefore the rare patients with regional nodal involve-
associated with a higher risk of local recurrence: (1) patients who have ment who have no evidence of extranodal disease (these patients more
undergone an unplanned excision and who have a positive margin on commonly have evidence of other metastatic disease) should undergo
subsequent reexcision (group 3) and (2) patients with unanticipated therapeutic lymphadenectomy. Patients with adverse features at the time
positive margins occurring during primary sarcoma resection (group of dissection (i.e., extracapsular extension beyond the lymph nodes
4; Fig. 90.11). For group 3, an unplanned excision is defined as an into perinodal fat or positive or doubtful margins on the neurovascular
excisional biopsy or resection that is carried out without adequate bundle) or in whom treatment into the next grossly uninvolved lymph
preoperative staging or consideration of the need to remove normal node echelon is not feasible with surgery should also be considered
tissue around tumor, an adverse feature reported by the same authors for additional adjuvant nodal irradiation. The principles underlying
previously.211 These data appear to support the premise that, provided this approach have recently been outlined.214
that adjuvant radiotherapy is administered, a very small amount of
residual disease resulting from a planned positive margin at the site of Surgery Alone
a critical anatomic structure (group 2; local recurrence rates of 3.6% Although the majority of patients with extremity STS should be
and 95%; confidence interval [CI], 0%–10.4%) is not associated with treated with preoperative or postoperative radiotherapy, reports have
the same deleterious risk that occurs with a positive margin that follows suggested that concomitant radiotherapy might not be required for
major contamination due to a “shell-out” intralesional operation (group select patients with completely resected, small, primary STSs (Table
3; local recurrence rate of 32% [95% CI, 11%–53%]) or inadvertent 90.8).215–218 Rydholm and colleagues have reported their experience with
contamination of the wound (group 4; local recurrence rate of 38% 70 patients with subcutaneous or intramuscular extremity sarcomas
[95% CI, 14%–61%]).210 These data seem particularly relevant to treated with wide surgical resection and microscopic assessment of
anatomic sites where achievement of adequate resection margins is a surgical margins.217 Negative histologic margins were obtained in 32
perennial problem, such as the head and neck, as evidenced by results of 40 subcutaneous and 24 of 30 intramuscular tumors. The 56
from a prospective series in which the outcome approached those of patients with microscopically negative margins received no postoperative
extremity and body wall sarcomas.212 We caution, however, that such radiotherapy, yet only 4 (7%) developed local recurrence. A study from
results are probably not attainable without a defined management Brigham and Women’s Hospital reported similar results for a selected
protocol and joint multidisciplinary assessment before treatment is group of 74 patients with primary extremity STS treated with surgery
undertaken, because there exist issues that merit discussion at the without radiotherapy.218 The 10-year actuarial local control rate was
individual case level (e.g., the complex relationship among tissues to 93 ± 4%. The absolute gross margin was a significant predictor of
be resected and reconstructed and the radiotherapy volumes and doses, local recurrence; patients with a close gross margin of less than 1 cm
all of which can influence one another in the decision algorithm). had a 10-year local control rate of 87% ± 6% compared with 100%
Table 90.8 Selected Results of Surgery Alone for Patients With Soft Tissue Sarcoma
First Author Institution No. of Patients Selection Criteria Adjuvant Radiation (No.) Local Recurrence (%)
Geer216 MSKCC 174 T1 size, primary tumor 117 10
Rydholm217 Lund, Sweden 56 G/M margin negative 0 7
Baldini218 BWH 74 T1 size, G/M margin negative 0 7
Karakousis225 RPCI 116 2-cm G margin 0 10
Fabrizio583 Mayo 34 Not stated 0 15
BWH, Brigham and Women’s Hospital; G/M, gross/microscopic; Mayo, Mayo Clinic; MSKCC, Memorial Sloan Kettering Cancer Center; RPCI, Roswell Park Cancer Institute.
Table 90.9 Selected Studiesa Examining Local Control With Surgery and Radiotherapy for Localized Soft
Tissue Sarcoma
Radiotherapy Approach First Author Radiation Dose (Gy) Study Design No. of Patients Local Failure (%) Subset
Preoperative EBRT Suit220 50–56 Retrospective 89 17
Barkley221 50 Retrospective 110 10
Brant222 50.4 Retrospective 58 9
O’Sullivan214 50 RCT 94 7
Brachytherapy Pisters237 42–45 RCT 119 9 High grade
45 23 Low grade
Postoperative EBRT Lindberg229 60–75 Retrospective 300 22
Karakousis227 45–60 Retrospective 53 14
Suit232 60–68 Retrospective 131 12
Yang204 45 + 18 RCT 91 0 High grade
50 5 Low grade
O’Sullivan214 RCT 96 7
a
Randomized controlled trials and selected nonrandomized retrospective series.
EBRT, External beam radiotherapy; RCT, randomized controlled trial.
for patients with a closest gross margin of 1 cm or greater (P = .04). potential to treat a greater proportion of cases with radiotherapy and
The generally favorable local control rates with surgery alone that lower the 19% local recurrence rate in some of those “favorable cases”
these and other investigators206,219 reported in these series of highly that are currently treated with surgery alone by widening the indication
selected patients are comparable to local recurrence rates observed for for adjuvant radiotherapy in a proportion of these patients.227 This
more heterogeneous patient populations treated with conventional view is consistent with contemporary observations such as the local
multimodality therapy incorporating preoperative or postoperative recurrence rate of 7% in patients who received combined modality
radiotherapy (Table 90.9).67,204,220–226 These data support the hypoth- treatment, as in the Canadian randomized trial (see Preoperative or
esis that select patients with small, primary STSs may be treated Postoperative Radiotherapy).228
with surgical resection alone without preoperative or postoperative Factors other than anatomic location, tumor size, and the feasibility
radiotherapy. of achieving an R0 resection (macroscopically and microscopically
It is difficult to define the precise selection criteria that should complete) should be considered in selecting patients for treatment by
be used to identify patients with primary sarcoma who can safely surgery alone. For example, the issue of whether the patient has had
undergo treatment with surgery without radiotherapy. Most investiga- a prior “unplanned” excision (see earlier) is important. At the Princess
tors have limited this approach to patients with carefully selected T1 Margaret Hospital, a significantly higher rate of local recurrence was
tumors that may be resected with clear margins (see Table 90.8). apparent in patients who were treated after unplanned excision on
In contrast, Karakousis and colleagues did not consider absolute the outside than in patients who received their treatment at Princess
tumor size but instead used surgical resection alone for all patients Margaret Hospital (22% versus 7%; P = .03).211 It is important to
in whom a minimum intracompartmental margin of 2 cm could be remember that unplanned excision is very common in the community
maintained circumferentially, irrespective of tumor size.215 Karakousis setting, where small soft tissue lesions are often excised without image
and colleagues updated the results for high-grade STS of the policy guidance under the presumption that they are benign. Therefore
of limiting the use of postoperative radiation treatment for tumors although it is reasonable to attempt a reexcision if it is considered
resected with positive or “narrow” (<2 cm) resection margins.227 This feasible, patients who have undergone unplanned excision should also
approach has yielded useful data because the consistent application be strongly considered for adjuvant radiation.
of this treatment approach resulted in a local recurrence rate of 19%
with “wide” margin surgery alone compared with 24% after “narrow” Preoperative or Postoperative Radiotherapy
margin surgery and adjuvant radiotherapy.227 Although the results
provide some clarity about the 2 cm or greater margin benchmark, Conservative (limb-sparing) surgery and radiotherapy have been
it would be useful to also have similar data from other groups for a combined to optimize local control for patients with localized STS.
variety of margin widths to draw conclusions about when it is safe Radiotherapy may be administered preoperatively,220–222,229,230 postopera-
to withhold radiotherapy. Moreover, the authors acknowledge the tively,224,231,232 or with interstitial techniques (brachytherapy).67,223,233–237
Local Control Admitted

Data from two randomized controlled trials (RCTs)72,204 have confirmed 716
earlier retrospective reports suggesting that surgery combined with
radiotherapy results in superior local control compared with surgery
alone.221,224,226 Yang and colleagues from the NCI reported on an RCT Pulmonary metastases
of postoperative external beam radiotherapy (EBRT).204 In this trial, 148 (20%)
141 patients with localized extremity STSs amenable to limb-sparing
resection were randomly assigned to receive postoperative EBRT or
no radiotherapy. All patients with high-grade lesions received postopera- Pulmonary metastases
tive chemotherapy. In the subset of 91 patients with high-grade lesions, only: 135 (19%)
no local recurrences were noted in the 44 patients who received
postoperative radiotherapy (with chemotherapy) versus nine local
recurrences (19%) in the 47 patients who received postoperative Operation
chemotherapy alone (P < .001). In the 50 patients with low-grade 78 (58%)
sarcomas, 1 (4%) of 26 patients who received adjuvant radiotherapy
had a local recurrence versus 8 (33%) of 24 patients treated by surgical
resection alone (P = .016). However, no improvement in survival was Complete resection
noted with adjuvant radiotherapy in the entire cohort of patients or 65 (83%)
in any subgroup.
The second RCT of postoperative radiotherapy was conducted at
Memorial Sloan Kettering Cancer Center, where investigators studied 3-year survival 3-year survival
adjuvant brachytherapy for patients with extremity and superficial 15/65 (23%) 15/135 (11%)
trunk STSs.209 A total of 164 patients with extremity or superficial
trunk STSs were randomly assigned to receive adjuvant brachytherapy
(42–45 Gy with an iridium-192 implant) or no postoperative radio- Figure 90.12 • Risk for and subsequent management of pulmonary
metastases in 716 patients with primary or locally recurrent extremity soft
therapy after complete resection of their sarcomas. Randomization tissue sarcoma. (Redrawn with permission from Brennan MF. The surgeon
took place in the operating room after gross total resection, thereby as a leader in cancer care: lessons learned from the study of soft tissue sarcoma.
limiting the potential bias that might influence the extent of surgical J Am Coll Surg. 1996;182:520.)
resection in a comparative trial. Of 119 patients with high-grade
tumors, 68 also received chemotherapy. With a median follow-up of
76 months, 5-year actuarial local control rates were significantly better
in the group treated with adjuvant brachytherapy (82%) than in those
who received surgery alone (69%). Subset analysis demonstrated that
the local control advantage of brachytherapy was confined to patients because the outcome of interest (i.e., a difference in survival consequent
with high-grade lesions, in whom the 5-year local control rate was on a differential in local control) would require a prohibitively large
89% (versus 66% in the surgery-only group; Fig. 90.12). Patients sample size. Therefore it is most improbable for these trials, with their
with low-grade STSs did not appear to experience the same local modest sample sizes that were intended for evaluation of different
control benefit with adjuvant brachytherapy.209,237 As was noted in outcomes, to be capable of demonstrating an effect. Indeed, it is most
the NCI RCT,188 the improvement in local control did not translate unlikely if even a meta-analysis of the trials could demonstrate this.
into any detectable survival difference between the brachytherapy and Furthermore, data from nonrandomized studies support the concept
no-brachytherapy arms of the trial. that there is little, if any, relationship between local control and survival.
Local failure rates with combined-modality regimens incorporating In a series from Sweden, the outcome of patients who were treated
surgery and radiotherapy are generally less than 15% (see Table 90.9). with an inadequate excision was compared with that of patients who
Despite theoretical advantages that may favor preoperative radiation, had an adequate operation.241 Local recurrence was 3.5 times more
brachytherapy, or postoperative radiation, there does not appear to common after inadequate excision, but there was no difference in the
be a major difference in local control rates among these radiation incidence or timing of distant metastases. The power of the RCTs
techniques, although at present, data comparing the approaches that have been reported so far to detect a difference in survival is
are sparse. relatively small, and a large number of patients may be required to
demonstrate that prevention of local recurrence affects survival.239
Relationship Between Local Control and Survival Stotter and colleagues have argued that local recurrence is a time-
Whether local control affects OS for patients with STS remains unclear dependent variable and should be considered as such in multivariate
and highly controversial.238–242 Only an adequately powered prospective studies.238 Analysis in this fashion of the data from a nonrandomized
randomized trial can assess the precise nature of any relationship between study demonstrates a statistically significant relationship between local
local control and OS. Three RCTs have evaluated local control and control and survival. Other retrospective analyses have yielded similar
survival in the context of defining treatment approaches for STS. In conclusions.243,244
a randomized trial from the NCI of amputation versus conservative For a more detailed description of the methodological problems
surgery plus radiation, local recurrence rates were 19% in the limb- associated with time-dependent variables and the use of surrogate end
sparing arm versus 6% in the amputation arm (P = .022).195,196 Despite points that emerge after the initial sarcoma treatment, the reader is
this, OS rates were equivalent at 70% for limb-sparing surgery and 71% referred elsewhere.245 In this context, it is clearly important to distinguish
for amputation (P = .97). In the randomized trials of postoperative between the well-defined adverse prognostic impact of subsequent
radiotherapy,204,209 the improvement in local control that was noted local recurrence on survival128,242,246 and the unproved positive effect
in patients who were treated with surgery plus radiotherapy did not of improved local control (i.e., prevention of local recurrence with
translate into any detectable survival advantage. None of the cur- improved local therapy) on survival. The former phenomenon might
rently available data from prospective RCTs support the hypothesis be a manifestation of more aggressive tumor biology—that is, more
that better local control enhances survival in patients with sarcoma. biologically aggressive lesions might recur locally and metastasize more
Methodologically, the available trials are problematic for this issue frequently.
Treatment Sequencing: Preoperative Versus to a total combined dose of 66 Gy in all postoperative cases and in
those preoperative patients in whom the resection margins were
Postoperative Treatment involved.
Of further interest, an improvement in OS (a crude rate of 85% The results of this trial are complex because the primary end point
versus 72% in favor of postoperative radiotherapy; P = .048) emerged that powered the trial, and hence its sample size, was the cumulative
initially from the Canadian SR2 RCT but dissipated after longer incidence of acute wound complications 120 days after protocol surgery
follow-up (Fig. 90.13).228,247 Thus in terms of OS, it appears reasonable in both arms of the study. Nevertheless, local control rates after 3.3
to treat patients with postoperative EBRT because local control rates years of median follow-up are identical in both arms of the study
are comparable to those with preoperative techniques but major wound (7%). As might be expected, local wound complications were more
complication rates are significantly lower. On the other hand, given common in the preoperative radiation cohort, although increased late
the lower risk of late effects such as fibrosis with preoperative radiation, complications such as radiation field fibrosis were more common in
consideration of longer-term end points should be a consideration in the postoperative group, who were treated with a larger treatment
any patient in whom radiation therapy is considered.248 Also, in field with a higher total dose of EBRT.250
anatomic sites where wound complications are rarely seen (e.g., the The results of the Canadian RCT provide insight into the compara-
upper extremity), the rationale for wound complication avoidance as tive efficacy, functional outcome, economic costs, and complication
a reason to favor the use of postoperative radiotherapy is not as sound. rates of preoperative and postoperative treatment sequencing for
In particular, the obvious advantage of preoperative radiotherapy in EBRT. In the absence of a clear local control advantage to any
the proximal arm and shoulder is apparent where avoidance of large- specific radiation technique, clinicians have considered other factors
volume and higher-dose irradiation that may treat the lung or brachial in formulating standards of care. Such factors have included wound
plexus may be achieved. These principles are also reasonable in the complication rates, financial costs, patient convenience, health-related
head and neck based on data from Princess Margaret Hospital.214 quality of life and physical function, radiotherapy toxicity, and perhaps
In contrast to external beam radiation therapy, which requires 5 even OS.
to 7 weeks of treatment, with brachytherapy the patient’s entire local It is clear that although field size and radiation dose may be mini-
treatment (surgery plus radiation) may be completed in the 2 weeks mized with preoperative radiotherapy,251 major wound complications
after primary tumor resection. Brachytherapy has potential cost after preoperative radiotherapy and surgery have been reported to be
advantages249 and has implications in terms of overall patient conve- in the 20% to 35% range.252,253 In the Canadian Sarcoma Group
nience. Accordingly, where the necessary expertise is available for RCT, wound complications were defined as secondary wound surgery,
brachytherapy, brachytherapy provides an excellent, cost-effective hospital admission for wound care, deep packing, or prolonged dressings
alternative for patients with high-grade lesions, although such expertise within 120 days after tumor resection. By these criteria, preoperative
is increasingly uncommon. Brachytherapy should not be used for radiation had a significantly higher rate (35% versus 17%; P = .01)
patients with low-grade sarcomas.237 of wound complications than did postoperative EBRT. Of note, the
The only randomized study of preoperative versus postoperative risk was confined to the lower extremity.228
EBRT for patients with localized extremity STS was conducted by Taken in isolation, the wound complication fact alone may be
the National Cancer Institute of Canada Clinical Trials Group/Canadian expected to cause some groups to continue to favor postoperative
Sarcoma Group. In this trial, 190 patients with extremity STS were radiotherapy. The Canadian RCT demonstrates that late tissue
randomized to preoperative versus postoperative EBRT.228 The outcomes strongly favor the preoperative approach, with equivalent
radiotherapy parameters for this protocol required a field margin of longer-term local tumor control.228 The rates of grade 2 or higher
5 cm around the gross tumor volume for the initial phase of treatment fibrosis and edema were significantly higher in the postoperative arm
(i.e., treatment to 50 Gy in 25 fractions), and this generally included compared with preoperative radiotherapy and were independently
any peritumoral edema that was seen at MRI, irrespective of the grade associated with the larger irradiation volumes and doses used in
or size of the tumor. Subsequently, a reduced-volume field was treated postoperative radiotherapy.228 Short-term functional outcome in the
SR2 trial has also been reported, and data continue to be collected
prospectively.254 Two validated instruments—the Toronto Extremity
1.0
Salvage Score (TESS) and the 36-item Short Form quality-of-life
CR versus PR (P < .05) instrument (SF-36)—were applied, as was the observer-based
0.9 Complete (n = 67)
Partial (n = 17)
Musculoskeletal Tumor Society Rating Scale (MSTS).254 Patients who
0.8 Unres. (n = 30) were treated with postoperative radiotherapy had better function with
Proportion surviving
0.7 higher MSTS, TESS, and SF-36 bodily pain scores at 6 weeks after
surgery than did those who were treated with preoperative radiation,
0.6
but there were no differences at later time points up to 1 year. Thus
0.5 the timing of radiotherapy has minimal impact on the function
0.4 of patients with STS in the first year after surgery, but thereafter,
0.3 significant factors likely come into play. These include the apparently
deteriorating late tissue sequelae caused by larger doses and volumes.
0.2
Of interest, patients who experience wound complications appear
0.1 CR versus UR (P < .001) to continue to have some impaired function. Further follow-up
0.0 will be required in order to assess the ongoing evolution of these
0 60 120 180 competing risks.
Time (months)
Conformal Radiotherapy and Intensity-Modulated
Figure 90.13 • Proportion of patients with retroperitoneal sarcoma who Radiotherapy
survive from the date of first operation for patients undergoing complete
(gross negative margin), incomplete (gross positive margin), or no resection. STS occurs in virtually any anatomic site, and the capacity for unusual
CR, Complete resection; PR, partial resection; UR, unresected. (Data reproduced presentation is nearly limitless. This can result in circumstances in
with permission from Jaques DP, Coit DG, Hajdu SI, et al. Management of which conventionally delivered radiotherapy is impossible owing to
primary and recurrent soft-tissue sarcoma of the retroperitoneum. Ann Surg. the magnitude of the volume to be treated, uncertainty in defining
1990;212:51.) the target for radiotherapy, or, more usually, the proximity of normal
tissues to the intended target volume. Although some presentations Neutrons have been used in a number of pilot studies, primarily
are extremely problematic (e.g., uncertain targets due to organ mobility in patients with locally advanced disease, with 60% to 70% local
or imprecise anatomic issues resulting from poor definition of tumor control rates,262–264 but are more a curiosity now given the increasing
location related to imaging limitations or inadequate surgical and/or use of proton beam radiation clinically. As an example, one study
pathologic description), others may be addressed with novel methods reviewed the results of 220 patients with locally advanced sarcomas
of radiotherapy delivery. The most commonly available advance over who were treated with neutron radiotherapy. Ninety-four patients
standard external beam radiation is intensity-modulated radiotherapy, with gross residual disease after resection were treated with neutron
an advanced form of three-dimensional conformal radiotherapy in therapy alone; among these patients, 27% had major morbidity, 26%
which radiation beams are not only shaped at their perimeters, but had 5-year survival, and 56% had local control. A total of 104 patients
also include variable intensity across the profiles of the beams. This with microscopically positive margins of resection received a neutron
permits the creation of greatly improved conformation of dose to boost dose; they had 7% morbidity, 65% 5-year survival, and 78%
targets of irregular shape while generating high-dose gradients between local control rates. These results suggest that for patients with gross
tumor and normal tissues. A full discussion of the potential uses of residual disease, neutron beam radiation may provide improved local
intensity-modulated radiotherapy in STS is beyond the scope of this control compared with conventional external beam treatment, but
chapter, but the topic is discussed in detail elsewhere.255 It may be these data should continue to be interpreted with caution when one
administered preoperatively, postoperatively, or as a sole modality with considers the late tissue sequelae that appear to result from neutron
specific indications. Some applications highlight its use in lesions beam radiation use. Comparative studies are needed to define the
adjacent to the spine or critical anatomic structures of the head and precise role of particle beam–based therapy in the treatment of STS.
neck and in the retroperitoneum to permit liver avoidance (and to Apart from unresectable disease, it seems unclear where the benefit
permit spinal cord, kidney, and intestinal dose limitation), especially of proton and other particle-based therapy (e.g., carbon ion) might
in lesions involving the right upper abdominal quadrant. Avoidance accrue when one considers the exceptionally favorable results of
of late toxicity to anatomic structures such as weight-bearing bone conventional photon-based treatment combined with surgery and the
that are at risk for fracture after treatment of extremity sarcomas seems more adverse normal tissue tolerance to particle-based therapy.
also to be feasible.256 Although these approaches are promising, their As one clear situation in which the greatest possible targeting is
precise contribution and role need to be evaluated.257 desired, proton beam radiation has proved useful in rhabdomyosarcoma
in parameningeal locations, where children’s developing brains may
Conventional Radiotherapy Without Surgery be less affected by the penumbra of the radiation field265; this modality
Radiotherapy alone has been used as primary therapy for patients has also found use in unresectable sarcomas.266,267 There are no compara-
with locally advanced, inoperable STS and patients with stage IV tive data examining this newest approach for sarcoma radiation therapy,
disease. Efforts to use radiation as the primary treatment have dem- and this still relatively scarce resource seems best directed to those
onstrated that high doses (>65 Gy) are required in order to achieve clinical situations in which the most care with nearby structures (e.g.,
local control rates between 30% and 60%258,259 and that there appears brain, spinal cord) must be taken, with chondrosarcoma of the skull
to be an inverse relationship between tumor size and local control base or chordoma of the clivus serving as good examples of where
rates. In a series of 35 patients treated with high-dose (>65 Gy) primary this novel technique may be most effective relative to other options.268,269
radiotherapy for tumor sizes less than 5 cm, 5 to 10 cm, and larger
than 10 cm, the local control rates were 88%, 53%, and 33%, Chemotherapy
respectively.260 In general, local control rates with radiation alone are
inferior to those after surgery; therefore primary radiation should be Adjuvant Chemotherapy
reserved for patients who are medically unfit for surgery, have technically In the past 30 years, improvements in surgical and radiotherapy
unresectable tumors, or refuse surgery as initial therapy. However, techniques have led to impressive rates of local control, particularly
some caution is necessary in interpreting such results in a scientifically in extremity STS, with concomitant sparing of normal tissues and
valid manner. Encumbered with such adverse selection factors, the preservation of limb and/or organ function. Despite substantial efforts
outcome of radiotherapy would never be comparable to that of surgery. in the same period, much less progress has been made in finding ways
Moreover, surgery has the added advantage over radiotherapy alone to eradicate the micrometastases that are the ultimate cause of death
because its use for locally advanced cases is ordinarily also combined in many individuals with apparently localized STS. The discovery
with adjuvant radiotherapy. that doxorubicin had significant antitumor activity against adult STS
has prompted the initiation of multiple RCTs since 1973 to evaluate
Particle-Based Radiotherapy (Emphasizing Proton the benefit of doxorubicin alone or in combination with other agents
after the completion of local treatment. However, most of these trials
Beam Therapy) were too small to detect moderate treatment effects reliably. Results
The use of radiation particles (electrons, neutrons, protons, and even from most of these studies are omitted for lack of space, and readers
portions of whole atoms such as carbon ions) provides another means are directed to prior editions of this chapter for details.
to control the radiation field. Proton therapy allows for more accurate The statistical technique of meta-analysis may overcome the problem
dose administration (lower exit dose of the proton beam) compared of inadequate power of small RCTs, and meta-analyses based on
with photon-based radiotherapy but at the same time a lower area individual patient data (IPDMA) may minimize other potential biases
under the curve or integral doses than after conformal photon radiation (e.g., exclusion of unpublished trials, variable follow-up, postrandomiza-
therapy or intensity-modulated radiation therapy.261 tion exclusions, and differing definition of end points) that are inherent
Particle-based radiotherapy has been emphasized by certain groups in analyses that are limited to published results. In 1997, the Sarcoma
because of the lower oxygen enhancement ratio compared with x-rays Meta-Analysis Collaboration (SMAC) published an IPDMA of
and the consequent attractive possibility of overcoming the biologic outcomes for 1568 STS patients included in 14 RCTs that completed
phenomenon that hypoxic cells generally limit the curability of accrual by December 1992.270,271 Significant improvements were found
malignancy with x-rays. Additional differences from x-rays are the in local and distant relapse-free intervals and RFS for all patients, and
reduced repair of sublethal and potentially lethal damage. These particle these improvements did translate into a significant OS benefit in the
effects are less vulnerable to the differential radiosensitivities associated prospectively defined subgroup—almost 60% of the patients—with
with different phases of the cell cycle. It should be apparent that some extremity sarcomas, but not in all patients.
of these repair phenomena also negatively affect the tolerance of normal These data were updated in a 2008 meta-analysis that also included
tissues. newer studies that contain ifosfamide as part of their backbone, but
Table 90.10 Doxorubicin-Based and Ifosfamide-Based Chemotherapy for Localized Soft Tissue
Sarcoma: 2008 Sarcoma Meta-Analysis of Adjuvant Clinical Trials Results
LOCAL RECURRENCE DISTANT RECURRENCE OVERALL RECURRENCE SURVIVAL
RELATIVE RISK (RR) AND 95% CONFIDENCE INTERVAL (CI) FOR LOCAL RECURRENCE, DISTANT RECURRENCE, OVERALL
RECURRENCE, AND SURVIVAL
Treatment RR 95% CI RR 95% CI RR 95% CI RR 95% CI
Doxorubicin 0.75 0.56–1.01 0.69 0.56–0.86 0.69 0.56–0.86 0.84 0.68–1.03
Doxorubicin with ifosfamide 0.66 0.39–1.12 0.61 0.41–0.92 0.61 0.41–0.92 0.56 0.36–0.85
Combined 0.73 0.56–0.94 0.67 0.56–0.82 0.67 0.56–0.82 0.77 0.64–0.93
RELATIVE RISK REDUCTION AND 95% CI FOR LOCAL RECURRENCE, DISTANT RECURRENCE, OVERALL RECURRENCE,
AND SURVIVAL
Treatment ARR 95% CI ARR 95% CI ARR 95% CI ARR 95% CI
Doxorubicin 3% 1%–7% 9% 4%–14% 9% 4%–14% 5% 6%–21%
Doxorubicin with ifosfamide 5% 1%–12% 10% 1%–19% 12% 3%–21% 11% 3%–19%
Combined 4% 0%–7% 9% 5%–14% 10% 5%–15% 6% 2%–11%
ARR, Absolute risk reduction.

Modified from Pervaiz N et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer.
2008;113:573.
did not include data from the largest trial of adjuvant chemotherapy, versus 45%, P = .94 for chemotherapy versus control groups, respec-
which was a negative study for improved OS.271 For the 18 studies tively). The 4-year OS remained better for the chemotherapy group
and 1953 patients included in the meta-analysis, the odds ratio (OR) (69% versus 50%; P = .04). At the last published analysis, after a
for local recurrence was 0.73 (95% CI, 0.56–0.94; P = .02) in favor median follow-up of 90 months (range, 56 to 119 months), the
of chemotherapy. For distant and overall recurrence, the OR was 0.67 intention-to-treat analysis continued to demonstrate a trend toward
(95% CI, 0.56–0.82; P = .0001) in favor of chemotherapy. In terms improved OS (P = .07).273 The 5-year OS estimates, a reasonable end
of survival, doxorubicin alone had an OR of 0.84 (95% CI, 0.68–1.03; point for the survival analysis of adjuvant treatment in STSs, were
P = .09), which as not statistically significant. However, the OR for 66% and 46% for the treatment and the control groups, respectively
doxorubicin combined with ifosfamide was 0.56 (95% CI, 0.36–0.85; (P = .04).273
P = .01) in favor of chemotherapy. With the understanding that The authors of a second study, a prospective randomized feasibility
publication and other biases may affect interpretation of meta-analyses, trial, concluded that a regimen of six cycles of ifosfamide, doxorubicin,
these are the strongest data supporting the use of adjuvant chemotherapy and dacarbazine given concurrently with postoperative hyperfractionated
for patients with primary extremity or trunk STS, without reference radiotherapy (during cycles 3 and 4 when doxorubicin was omitted
to histology. from the regimen) was manageable and tolerable.274 It did not translate
Compounding the problem of small numbers of STS cases, STSs into significant benefits in RFS (P = .1 versus control arm), time to
as a group show marked heterogeneity in pathology and site of origin; local failure (P = .09), or OS (P = .4), but the small number of
this is much less evident in breast cancer. For example, it has been patients (31 versus 28) precludes meaningful conclusions regarding
suggested that in the 1997 SMAC meta-analysis, chemotherapy benefits benefit. A third small RCT, from another Italian center, examined
for extremity (57% of total) and high-grade STSs were obscured by patients who received either an intensive epirubicin-ifosfamide combina-
inclusion of sarcomas at other locations (head and neck, trunk, and tion (n = 19) or single-agent epirubicin (n = 16), in comparison with
visceral or retroperitoneal, including uterus) and those of low (5%) local therapy alone (n = 43); the study was closed early for poor
or unknown grade (28%). Another point of contrast with breast cancer accrual and was accordingly underpowered for efficacy end points.275
is the relative paucity of drugs that are active against STS. At the time In the largest randomized study of adjuvant chemotherapy to date,
of the SMAC meta-analysis, only two agents (doxorubicin and ifos- Woll and colleagues randomized 351 patients from 1995 to 2003
famide) produced overall response rates exceeding 20% in patients 1 : 1 between observation alone or five cycles of chemotherapy with
with advanced disease. This provides limited opportunity to exploit doxorubicin (75 mg/m2 per cycle) and ifosfamide (5 g/m2 over 24
the potential advantages of combination chemotherapy. Of the 14 hours per cycle), every 21 days, with lenograstim support after each
trials that were included in the original SMAC meta-analysis, six used cycle. In the preliminary analysis of data, 5-year RFS was 52% in
doxorubicin alone, and the remaining eight were trials of combination both arms, and 5-year OS was 69% in the observation arm versus
chemotherapy. Only one unpublished STS trial (29 patients) examined 64% in the chemotherapy arm.276
the combination of doxorubicin with ifosfamide, the addition of which Can blanket recommendations be made regarding the use of adjuvant
appears to be the more important component of adjuvant chemotherapy, chemotherapy in adult STS? In an editorial277 that accompanied the
despite what are relatively modest response rates for ifosfamide in the report of the Italian Cooperative Group Trial that still addresses many
metastatic setting in unselected patients. issues faced today,272 Bramwell concluded that a specific standard of
Full reports have been published on other phase II trials and RCTs care was not yet clear and that the situation would take some time
(Table 90.11) examining anthracycline and ifosfamide-based regimens to change. Guidelines from the United States and Canada support
supported by growth factors. In the Italian Cooperative Group study,272 the use of chemotherapy in selected patients.278 European guidelines
accrual was terminated based on an early stopping rule, after half the recommend adjuvant chemotherapy only after shared decision making
planned number of patients had been recruited. The median RFS and careful selection of patients.279 With the current state of knowledge,
and OS (see Table 90.11) were superior for the chemotherapy group, chemotherapy is a reasonable standard of care for those patients willing
but a high cumulative incidence of late distant relapses was noted to accept significant toxicity for what may be little if any improvement
(2-year incidence 28% versus 45%, P = .08; 4-year incidence 44% in OS. Observation after primary tumor control is a reasonable option
Table 90.11 Largest Randomized Controlled Trials With Ifosfamide Adjuvant Chemotherapy Versus
Observation in Soft Tissue Sarcoma
SURVIVAL
No. of
Study Chemotherapy Regimen Patients Disease Sites Follow-Up RFS OS
Italian Epirubicin + Ifosfamide + filgrastim (×5) 53 Limb (grade III >5 cm) 59 mo (median) 48 months 75 months
Cooperative288,a
Control 51 16 months 46 mo
P = .04 P = .03
Australian Ifosfamide + doxorubicin + dacarbazine 31 Limb 47, Trunk 12 41 mo (mean) 77% NR
Cooperative274,b (IFADIC) + filgrastim (×6) (grades II/III)
Control 28 57% NR
EORTC (Woll et al, Ifosfamide + doxorubicin + 175 Trojani grades II to III NR P = .1 P = .4
ASCO abstract)276 sargramostim STS at any site 52% (5 yr) 64% (5 yr)
Control 176 52% 69%
(P = NS) (P = NS)
Outcome data provided in original papers or abstracts.

a
Median RFS plus OS.
b
(1) Comparison percent RFS plus OS after mean observation period of 41 months (range, 8–84 mo). (2) Overall survival plotted but actuarial results not reported at defined
follow-up time(s).
ASCO, American Society of Clinical Oncology; EORTC, European Organisation for the Research and Treatment of Cancer; NR, not reported at defined follow-up time; NS, not
significant; OS, overall survival; RFS, recurrence-free survival.
for many people, most so in those sarcomas already known to be will or will not be beneficial may be useful when dealing with
relatively chemotherapy resistant. Those people who are most likely marginally effective chemotherapy. However, the lack of data sup-
to benefit from adjuvant chemotherapy are those who can tolerate porting regimens other than anthracycline-ifosfamide in the adjuvant
ifosfamide chemotherapy; the meta-analysis of 2008 indicated that setting presently limit the usefulness of such information.
the benefit from chemotherapy appeared to be more an issue of delivery
of ifosfamide, rather than doxorubicin.271 Numerous neoadjuvant treatment approaches and preoperative
Given the difficulty with ifosfamide in older patients, adjuvant drug regimens have been explored. Intraarterial administration of
chemotherapy is unsuitable for the substantial minority of patients drugs such as doxorubicin or cisplatin has been evaluated, in some
who are older than 60 to 65 years of age, owing to the increased cases in conjunction with radiotherapy, isolated limb perfusion, and/
toxicity observed with ifosfamide; this group has largely been excluded or hyperthermia. The intraarterial route delivers drugs more directly
from RCTs evaluating these regimens. Whether to administer adjuvant to the tumor but is more complex, expensive, and prone to complica-
chemotherapy and the regimen that is chosen will depend on a number tions than is the intravenous route. In the one small RCT on routes
of considerations, including risk of relapse, physician preferences (which of administration, there were no differences in rates of local control
may also depend on patient age and comorbid conditions), referral or overall failure between neoadjuvant chemotherapy given intraarterially
practices, and available resources. Although there are strong opinions or intravenously.280,281 In a series of nonrandomized studies reflecting
on whether or not chemotherapy has added sufficiently to local therapy the evolution of neoadjuvant treatment at their center over a 20-year
for routine use in high-risk patients, all agree on two facts: (1) High-risk period, the University of California, Los Angeles (UCLA) group treated
patients die far too often of metastatic disease, and (2) there is a need a total of 498 patients with neoadjuvant chemotherapy.282 As one
to improve on the limited benefit observed with current anthracycline- example of their studies, the combination of chemotherapy and 28 Gy
ifosfamide combinations. of radiotherapy before surgery was noted by investigators to provide
the best local control with the lowest complication rate. On the basis
Neoadjuvant Chemotherapy of results of the RCT described earlier, intraarterial doxorubicin was
Given that the role of postoperative adjuvant chemotherapy for patients replaced with intravenous doxorubicin, and cisplatin and ifosfamide
with adult STS remains controversial, it is hardly surprising that the were added in a follow-up protocol.282 In the whole group of 498
advantages of chemotherapy given before surgery (neoadjuvant therapy) patients, the overall local recurrence rates were 11% at 5 years and
are even less clear, particularly because there no adequately powered 15% at 10 years, and corresponding OS rates were 71% and 66%.
RCTs have addressed this issue. Nonetheless, neoadjuvant chemotherapy The local recurrence rate was lower and OS rate higher for patients
has theoretical benefits that include the following: who had no residual tumor (38%) or greater than 95% necrosis (14%)
after neoadjuvant chemotherapy, compared with those who had less
• Destruction of the primary tumor may reduce the risk of contamina- than 95% necrosis. In a multivariate analysis, pathologic necrosis was
tion at surgery and permit closer margins with less tissue loss and an independent predictor of local recurrence and OS. The percentage
functional disability but improved local control, which has been of patients with 95% or greater necrosis increased to 48% with the
observed consistently in randomized clinical trials. addition of ifosfamide, compared with 13% for patients in all other
• Extensive delays in initiating chemotherapy resulting from complex protocols combined.
surgery and/or radiotherapy are avoided; for rapidly growing tumors, Pisters and colleagues reviewed the long-term results of neoadjuvant
this earlier elimination of micrometastases may improve survival, chemotherapy given at the University of Texas MD Anderson Cancer
although this has not been proved. Center for stage IIIB extremity sarcomas between 1986 and 1990.283 All
• Treating with an intact tumor allows the medical oncologist to patients received doxorubicin-based regimens; at that time, ifosfamide
assess the effects of preoperative therapy and thus judge whether was rarely used (three patients). In 75 patients, the overall clinical
the chosen chemotherapeutic regimen has activity against the specific objective response rate (complete response plus partial response) was
tumor in the specific patient being treated. The importance of this 27%. At a median follow-up of 85 months, the 5-year actuarial local
opportunity to determine whether an empirically chosen regimen recurrence–free survival, overall RFS, and OS rates were 83%, 52%,
and 59%, respectively. In contrast with the UCLA group’s results282 analyzed; an increased rate of thrombocytopenia and wound complica-
for pathologic response, there were no differences in any outcomes tions was seen with concurrent radiotherapy. This is the basis for the
between responding and nonresponding patients, as defined at that time. ongoing ISG trial Localized High-Risk Soft Tissue Sarcomas of the
In a separate analysis at MD Anderson, 65 patients (42 extremity Extremities and Trunk Wall in Adults: An Integrating Approach
sarcomas and 23 retroperitoneal sarcomas) were treated at the same Comprising Standard Versus Histotype-Tailored Neoadjuvant Che-
center between 1991 and 1996 with doxorubicin- or ifosfamide-based motherapy (NCT01710176).
neoadjuvant chemotherapy; 34% achieved a radiographic partial Preoperative chemoradiotherapy, reported in a series of clinical
response and 9% a minor response.284 Patients having partial response trials as noted later, should be delivered only in centers experienced
had higher rates of negative-margin resections, local recurrence–free in these techniques, providing further rationale for referral of the
survival, and OS than did nonresponders. Postoperative morbidity was majority of patients with STSs to centers that can provide multidis-
also evaluated in a larger cohort of 105 patients (71 extremity and 34 ciplinary assessment and treatment.
retroperitoneal STS) treated at MD Anderson during the same period, of
whom 50 received ifosfamide in addition to doxorubicin.285 The authors Combined Preoperative Chemotherapy and Radiotherapy
found no evidence that preoperative chemotherapy increased surgical With the advances that have been made with combined-modality
complications (e.g., wound infections and other wound problems), treatment of other solid tumors, there has been interest in combined-
length of hospital stay, rate of readmission, or rate of reoperation. modality preoperative treatment (concurrent or sequential chemotherapy
Similar outcomes have been observed in other reported series.286 and radiation) for patients with localized STSs. Concurrent doxorubicin-
The European Organisation for the Research and Treatment of based chemoradiation has been used extensively by Eilber and colleagues
Cancer (EORTC) has performed the only RCT assessing preoperative at UCLA.289,290 This treatment protocol involved intraarterial doxo-
chemotherapy for STS (three cycles of doxorubicin and ifosfamide rubicin with a hypofractionation schedule to be coincident with
plus filgrastim) versus no preoperative chemotherapy (control).287 A intraarterial chemotherapy (35 Gy of EBRT delivered in 10 daily
total of 150 patients with high-risk STS (≥8 cm any grade, or grade fractions, which was reduced to 17.5 Gy in 5 daily fractions to minimize
II/III tumors <8 cm, or grade II/III local recurrence tumors/inadequate local toxicity). A subsequent prospective randomized trial from the
surgery) were randomized, of whom 134 were considered eligible for same group that remains unpublished compared preoperative intraarte-
outcome assessment. Radiotherapy was indicated for tumors that were rial doxorubicin and intravenous doxorubicin, both followed by 28 Gy
excised with close or microscopically positive margins and was given of radiation delivered over 8 days followed by surgical resection. No
in 46% of patients in the chemotherapy arm and 54% of patients in differences in local recurrence or survival were noted.
the control arms. Limb salvage was possible in 89% of patients, and The combination of regional chemotherapy and concurrent
chemotherapy did not affect postoperative wound healing. Grade 4 radiotherapy that was originally pioneered by Eilber and colleagues
toxicities were rare, although there was one death due to neutropenic has been modified and utilized by other groups.291–293 Investigators
fever. At a median follow-up of 7.3 years, the 5-year RFS and OS from the University of Illinois treated 55 patients with a 10-day
rates were 56% versus 52% (P = .36) and 65% versus 64% (P = .22) preoperative regimen of intraarterial doxorubicin (10 mg/m2/day) with
for the chemotherapy and control arms, respectively. Although originally concomitant radiotherapy (25 Gy; 2.5 Gy per fraction in 10 frac-
planned as a phase III trial with adequate numbers to detect a 15% tions).293 With a mean follow-up of 94 months, the local control rate
difference in 5-year OS, the study was closed after completion of the was 85%. Complications related to the therapy occurred in 26% of
phase II section because of slow accrual. Most groups have concluded patients and required further operative management in 7% of patients.
that for large high-grade tumors, preoperative chemotherapy is feasible, Temple and colleagues treated a group of 42 patients with a similar
does not increase postoperative morbidity, increases the rate of oper- regimen of 60 to 90 mg of doxorubicin that was infused intraarterially
ability, and may enhance local control. The beneficial effects on distant or intravenously over a 3-day period followed by sequential radiotherapy
metastases and OS, if any, were marginal. (30 Gy; 3 Gy per fraction in 10 fractions).292 Resection of the residual
It is impossible to determine from the results of the phase II posttreatment mass was performed 4 to 6 weeks later. At a median
retrospective or prospective series whether preoperative neoadjuvant follow-up of 6 years, local control was achieved in 39 of 40 patients,
chemotherapy reduces distant metastases and improves survival, and although two patients were excluded from this analysis because clear
the EORTC RCT was too small to illuminate this issue. Preoperative margins were not obtained at the time of surgery. Intraarterial
chemotherapy, particularly in combination with preoperative radio- infusion–related complications occurred in 4 (11%) of 35 patients.
therapy, can induce substantial rates of pathologic necrosis, may increase Objective radiographic and pathologic response rates were not reported;
operability in large high-grade tumors, and leads to impressive rates therefore the efficacy of concurrent chemoradiation therapy in achieving
of local control. It is not clear, however, that these results are better cytoreduction to an extent sufficient to convert lesions that are resectable
than would be achieved with preoperative radiotherapy alone, par- by amputation only to lesions that are amenable to a limb-sparing
ticularly if radiation is delivered by using modern intensity-modulated approach remains anecdotal. Moreover, whether preoperative chemo-
techniques; and most neoadjuvant chemotherapy regimens are associated radiation approaches offer local control advantages over conventional
with substantial toxicity. Neoadjuvant chemotherapy is considered a treatment approaches using surgery with preoperative or postoperative
standard of care for sarcomas more common in children—for example, radiotherapy is also not apparent. In fact, with current local control
Ewing sarcoma, rhabdomyosarcoma, and osteogenic sarcoma—given rates with surgery and radiation alone exceeding 90%, it is difficult
the known survival benefit of chemotherapy in those diagnoses in to appreciate how this outcome would be improved with preoperative
children. The contribution of drugs such as cisplatin and dacarbazine chemotherapy unless the strategy involved a radiotherapy dose reduction
(agents with poor activity in metastatic STS) other than increasing to ameliorate normal tissue toxicity.
toxicity may be questioned. Alternative chemotherapy-radiation sequencing has been used by
There is potential benefit according to an RCT comparing neo- investigators from MGH, who have reported mature data from a
adjuvant chemoradiotherapy with preoperative radiotherapy alone in sequential chemoradiation strategy in the treatment of patients with
patients with large high-grade STS. The Italian Sarcoma Group (ISG) large (>8 cm) localized, high-grade extremity STSs.294 The MGH
and Spanish Sarcoma Group have published the feasibility findings protocol involves interdigitating courses of chemotherapy and radio-
of a randomized clinical trial of three versus five cycles of epirubicin therapy: three courses of doxorubicin, ifosfamide, mesna, and
and ifosfamide.288 A total of 321 patients were randomized to either dacarbazine and two 22-Gy courses of radiation (11 fractions each)
three cycles of neoadjuvant therapy or three cycles neoadjuvantly and for a total preoperative radiation dose that is lower than is usually
two cycles adjuvantly; 152 of the patients also received concurrent used (44 Gy). This was followed by surgical resection with microscopic
radiotherapy to 44 to 50 Gy. Chemotheraputic dose intensity was assessment of surgical margins. An additional 16-Gy (eight fractions)
A B C
Figure 90.14 • (A) Angiosarcoma of the scalp and facial areas in an older woman. Note the infiltrative and multinodular nature of this process, characterized
by mottled discoloration and ecchymosis in a circumferential pattern around the scalp. These lesions pose a formidable challenge in achieving local control
because of their propensity to manifest out-of-field recurrences after wide-field surgical and radiotherapy interventions, in addition to a high predilection for
therapy to fail in regional lymph nodes and distant sites. (B–C) The same patient as in (A) showing the circumferential involvement and unresectable nature
of many of these tumors, which are characteristic of angiosarcoma.
boost dose was delivered for microscopically positive surgical margins. recruited 55, 35, and 41 patients, respectively, ranged from 72%
The strategy therefore simultaneously addresses the dual problems of to 91%, and limb salvage surgery was possible in 84% to 91% of
local control and metastatic risk. The outcomes of 48 patients who patients. Small numbers of patients experienced subsequent local
were treated with this regimen between June 1989 and March 1999 recurrence, and some of these patients needed later amputations. Not
were compared with those of a matched series of historic controls surprisingly, many patients ultimately developed and died of distant
(treated between January 1988 and March 1997).294 The 5-year actuarial metastases.
local control, distant metastasis–free survival, and OS rates for the Various techniques of regional or whole-body hyperthermia have
sequential chemotherapy-radiation group are 92%, 75%, and 87%, been combined with a variety of chemotherapy regimens.299–302 A
respectively. For the matched historic controls, these rates are 86%, group from Munich evaluated preoperative chemotherapy (four cycles
47%, and 58%, respectively. The protocol was toxic, with 29% of doxorubicin, ifosfamide, and etoposide) combined with regional
experiencing confluent moist skin desquamation, 25% requiring hyperthermia (RHT) followed by surgery and adjuvant treatment
hospitalization at some time for febrile neutropenia. Wound-healing (same chemotherapy with or without radiation). Median follow-up
complications evaluated with published criteria228 were apparent in times were 58 months for the RHT-91 protocol (59 patients) and 30
29% of patients and confined to the lower extremities, as was also months for the RHT-95 protocol.302 All patients had grade II/III
observed in the Canadian Sarcoma Group treatment sequencing RCT.228 tumors 5 cm or larger with extracompartmental extension. Clinical
One patient died from late marrow dysfunction attributed to chemo- response rates were 42% and 33% for the two protocols, with respective
therapy. Although the results are encouraging from a tumor standpoint local progression–free survival rates of 58% and 57%. Corresponding
(Fig. 90.14), they will require prospective comparative studies for OS rates were 42% and 48%, respectively. The possible usefulness of
confirmation and especially because of the local and systemic toxicity hyperthermia as part of local tumor control was further evaluated in
associated with this approach.295 Although a Radiation Therapy a phase III RCT (EORTC 62961/European Society of Hyperthermic
Oncology Group (RTOG) phase II study yielded similar outcomes Oncology [ESHO] RHT-95). The assumption was made that preopera-
compared with the data of DeLaney and colleagues,294,296 they too are tive chemotherapy with doxorubicin, ifosfamide, and etoposide is
characterized by concerning features of significant toxicity, including effective for patients with high-risk localized disease in this setting,
marrow dysplasia and treatment-related deaths. and patients were randomized to receive preoperative etoposide,
ifosfamide, and doxorubicin (EIA, four cycles) plus RHT (two fractions)
Hyperthermic Isolated Limb Perfusion and Whole-Body versus EIA chemotherapy alone. As a result, no difference was expected
in terms of OS; improved local control was confirmed in those patients
Hyperthermia With Chemotherapy treated with hyperthermia.303
Hyperthermic isolated limb perfusion and whole-body hyperthermia
are two investigational techniques that continue to receive considerable TREATMENT OF SARCOMA PATIENTS AT
attention, particularly in Europe. Hyperthermic isolated limb perfu- SPECIALTY CENTERS
sion (with TNF-α, interferon-α [IFN-α], and melphalan) has been
used as a neoadjuvant therapy to render tumors resectable and as a Data on other tumor types have demonstrated improved outcomes
primary therapy to avoid amputation in patients with nonresectable for patients who require complex treatment and are treated at centers
extremity STS.297,298 Overall response rates in early series, which with specific sarcoma expertise.304 More comprehensive data addressing
this issue in STS come from Sweden, where Gustafson and colleagues If no prior radiotherapy was used, adjuvant radiation should be
analyzed the quality of treatment in a population-based series of 375 administered after surgery for locally recurrent disease. Occasionally,
patients with primary STSs arising in the extremities (n = 329) or subtherapeutic or low-dose radiation was previously used, and such
the trunk (n = 46).305 Comparisons were made between patients who patients might be candidates for additional adjuvant radiation by
were referred to a specialty soft tissue tumor center before surgery (n external beam or brachytherapy approaches. Patients who have had
= 195), those who were referred after surgery (n = 102), and those a full course of prior radiation should be managed on an individual
who were not referred for treatment of the primary tumor (n = 78). basis.
The total number of operations for the primary tumor was 1.4 times In a series of 40 patients with recurrent extremity sarcoma, limb
higher in the patients who were not referred and 1.7 times higher in salvage was possible by combining limb-sparing reresection with
the patients who were referred after surgery than in patients who were adjuvant brachytherapy.311 A median dose of 45 Gy was possible with
referred before surgery. Of greatest significance, however, was the this technique, despite the fact that most patients had received prior
finding that the local recurrence rate was 2.4 times higher in the external beam radiation. The 5-year actuarial local control rate was
patients who were not referred and 1.3 times higher in the patients 68%, with satisfactory limb preservation. However, brachytherapy
who were referred after surgery than in patients who were referred to should be used with caution in patients who have locally recurrent
a specialty soft tissue tumor center before any manipulation of their low-grade sarcomas, because it appears to be ineffective against low-grade
tumor. Finally, Blay and colleges presented the findings of the NetSarc sarcomas.209,237
network on 13,454 patients seen between 2010 and 2014.306 Patients Catton and colleagues from the Princess Margaret Hospital also
managed in reference centers have a significantly higher rates of used conservative surgery and reirradiation (external beam or brachy-
management according to guidelines and R0 surgery, fewer reoperations, therapy) for treatment of local recurrences arising in a previous radiation
and better PFS.306 These findings support the principle of centralizing field in a subset of 10 patients with extremity sarcoma.312 With a
treatment of these rare tumors, which frequently require complex relatively short median follow-up of 24 months for the entire cohort,
multimodality therapy. local control in the patients treated with further surgery and reirradiation
was 100%.312 Similarly, two studies reported a local control rate of
TREATMENT OF LOCALLY RECURRENT SOFT 82.5% (33 of 40) and 65% (17 of 26), respectively, with use of conserva-
tive surgery and reirradiation with brachytherapy.311,313 However, despite
TISSUE SARCOMA these encouraging findings, amputation or, at least in Europe,
Incidence of Local Recurrence hyperthermic isolated limb perfusion297 might be the only options
for local control in some patients who were previously treated with
Despite optimal multimodality therapy, at least 20% to 30% of STS radiation and have recurrent extremity sarcoma.
patients will develop recurrent disease, with a median disease-free
interval of 18 months.128,307 Not surprisingly, local recurrence rates TREATMENT OF METASTATIC SOFT
are a function of the primary tumor site and are highest for retro- TISSUE SARCOMA
peritoneal and head and neck sarcomas. This is due in part to the
fact that adequate surgical margins are technically more difficult to The most common site of metastasis from STS of the extremity is
attain in these locations. Indeed, the earlier discussion regarding the the lung. Indeed, the lungs are the only site of recurrence in approxi-
type of positive margin notwithstanding,210 at multivariate analysis mately 20% of all patients with primary extremity and trunk STSs.303,307
an unqualified positive surgical margin is an adverse prognostic factor Primary visceral and gastrointestinal sarcomas such as GISTs also
associated with local recurrence operation for recurrent disease.128,129 commonly metastasize to the liver. Extrapulmonary metastases are
In addition, use of conventional standard-dose postoperative radio- uncommon forms of first metastasis and usually occur as a late mani-
therapy (60–65 Gy) is often limited in the retroperitoneum and the festation of widely disseminated disease.307 An obvious exception is
head and neck by the relative radiosensitivity of surrounding structures. in myxoid liposarcoma, in which unpredictable and aberrant recurrences
These factors result in local recurrence rates of 38% for high-grade to any area containing fat (the pelvis, retroperitoneum, mediastinum,
retroperitoneal sarcomas155 (and at least two-thirds for people with paraspinal and subcutaneous soft tissue, and bone marrow) are a
well-differentiated or dedifferentiated liposarcoma of the retroperito- hallmark of disease behavior.122,314 Evidence strongly suggests that
neum) and 48% for high-grade head and neck sarcomas,308 compared apparently isolated soft tissue masses that occur in the setting of this
with 5% to 25% for extremity lesions (see Table 90.9). It should also disease are metastases, sharing the same molecular lineage with the
be acknowledged, however, that the rarity of nonextremity lesions original primary tumor.315 For sarcomas in general, the median survival
probably results in a more varied approach to management, which from the time of development of metastatic disease is 8 to 12 months.
may influence the ultimate outcome and may also have influenced Exceptions include alveolar soft part sarcoma, extraskeletal myxoid
the ability to design and execute clinical trials in the past. It would chondrosarcoma, solitary fibrous tumor, and less commonly leiomyo-
seem that properly applied principles of local management can achieve sarcoma and fibrosarcoma, among other diagnoses, in which metastatic
similar results even in sites with traditionally poor results, such as the disease may persist for more than 10 years. Optimal treatment of
head and neck, where disease access is limited by proximity to critical patients with metastatic STS requires an understanding of the natural
local anatomy.212 history of the disease and individualized selection of treatment options
based on specific patient factors, disease factors, and limitations imposed
Surgery and Radiotherapy by prior treatment. For these reasons, referral to a high-volume sarcoma
center is strongly recommended.278
Locally recurrent STS generally manifests as a nodular mass or series
of nodules arising in the surgical scar or radiation port. Patients with Surgical Resection
retroperitoneal recurrences usually have nonspecific symptoms, often
after the recurrence has reached a substantial size. The current surgical approach for pulmonary metastases from STS is
Treatment approaches for patients with locally recurrent STS need based on an extrapolation of the observations of Martini, Marcove,
to be individualized on the basis of local anatomic constraints and and colleagues in a series of patients with osteosarcoma treated at
the limitations on present treatment options imposed by prior therapies. Memorial Sloan Kettering Cancer Center in the 1960s. It had been
In general, all such patients should be evaluated for reresection of observed that in a series of 184 patients who underwent amputation
their local recurrence. The results of such salvage operations are good; for osteosarcoma, 75% developed metastatic disease to the lungs within
two-thirds of patients survive long term.309,310 18 months of amputation; there were no 5-year survivors in this
Table 90.12 Selected Analyses of Survival After Complete Resection of Pulmonary Metastases From
Soft Tissue Sarcoma in Adults
NO. OF PATIENTS
First Author/ Pulmonary Surgical Complete Median Survival Three-Year
Institution Total Metastases Treatment Resection (%) (months) Survival (%)
Creagan/Mayo318 112 112 112 64 (57%) 18 29
Casson/NCI332 487 93 68 51 (75%) 23 32
Jablons/NCI320 74 57 57 49 (86%) 27 35
Casson/MDACC321 68 68 68 58 (85%) 25 42
Verazin/Roswell338 78 78 78 61 (78%) 21 21.5 (5 yr)
Gadd/MSKCC322 716 135 78 65 (83%) 19 23
Van Geel/EORTC329 255 255 255 255 (100%) NR 54
EORTC, European Organization for Research and Treatment of Cancer; Mayo, Mayo Clinic; MDACC, University of Texas MD Anderson Cancer Center; MSKCC, Memorial Sloan
Kettering Cancer Center; NCI, US National Cancer Institute; NR, not reported; Roswell, Roswell Park Cancer Institute.
group.316 In the absence of any effective systemic therapy for this The ability to completely resect all pulmonary disease is perhaps
disease, efforts were made to resect such metastatic lesions in later the most important prognostic factor affecting survival after pulmonary
patients. Martini and colleagues reported successful complete resection metastasectomy; patients with residual pulmonary disease have a median
in 22 of 28 patients, with a substantial 5-year overall disease-free survival of 9 months versus 27 months (P < .0001) for patients who
survival rate of 32%.317 are rendered completely free of disease at thoracotomy.320,322 In a series
Multiple investigators have since reported their experience with of 65 patients with metastatic pulmonary lesions from extremity
pulmonary metastasis surgery for adults.318–329 Three-year overall sarcoma from the Memorial Sloan Kettering Cancer Center, the median
disease-free survival rates after thoracotomy for pulmonary metasta- survival after complete resection was 19 months versus 10 months
sectomy have ranged from 23% to 54%, as outlined in the selected for patients who had incomplete resections and 8 months for patients
series summarized in Table 90.12.318–322,329,330 With the exception of who did not undergo surgery (P = .005).322 The 3-year OS rate after
a study that evaluated the development and treatment of pulmonary complete resection was 23% compared with 2% in those who were
metastases in patients with extremity sarcomas through use of a prospec- treated nonsurgically (P < .001). The clinical criteria of disease-free
tive sarcoma database (3-year survival rate of 23% after complete interval, tumor doubling time, and number of nodules can serve as
resection),322 most studies have been retrospective analyses of the results general prognostic indicators in patients who are being considered
of pulmonary resection in populations of carefully selected patients for pulmonary metastasectomy, but no single criterion should be used
with metastatic sarcoma from heterogeneous primary sites. This could to exclude patients from surgery.
account for some of the variability in the reported survival rates. The ability to achieve complete resection and the number of
Many investigators believe that repeated thoracotomies to render pulmonary nodules that are present appear to best define the prognosis
patients free of disease from pulmonary STS metastases are justified for patients postoperatively. Although carefully selected patients may
in the absence of effective systemic therapy. Several series of reoperative benefit from surgical resection of pulmonary metastases, this treatment
pulmonary metastasectomy have been published.331,332 In an NCI approach is feasible in only a small fraction of patients who develop
series, 72% of 43 patients were rendered free of disease at the second pulmonary metastases. This is best illustrated by data from Memorial
thoracotomy, with a median survival duration from the time of the Sloan Kettering, where a population of 716 patients with primary
second thoracotomy of 25 months.331 In a report from the MD extremity sarcoma were followed for the subsequent development and
Anderson Cancer Center of a series of 34 patients undergoing reopera- treatment of pulmonary metastases. Of the initial cohort, 148 patients
tion for a second pulmonary metastasis after successful initial metastasis (21%) developed pulmonary metastases. Isolated pulmonary metastases
resection, factors predicting long-term survival included the presence occurred in 135 (91%) of these 148 patients. Of the 135 patients
of a solitary metastasis and the ability to perform a complete resection.332 with pulmonary-only metastases, 78 (58%) were considered to have
This study also illustrated the significant survival duration of many operable disease, and 65 (83%) of those who underwent thoracotomy
of these patients; the median survival in the 19 patients who had were able to undergo complete resection of all their pulmonary meta-
unifocal recurrent metastatic disease was 65 months compared with static disease. This group represents only 44% of patients with pul-
14 months in the 15 patients with complete resection of two or more monary metastases. Median survival from the time of complete resection
sites of recurrent disease. was 19 months, and the 3-year OS rate was 23%. All patients who
It remains difficult to predict which patients will benefit from did not undergo thoracotomy died within 3 years. For the entire
pulmonary resection, owing to the selection bias inherent in choosing cohort of 135 patients who developed pulmonary-only metastases,
people for surgery. A number of different clinical criteria have been the 3-year OS rate was only 11%.
evaluated by univariate analysis, including the disease-free inter- The disappointing overall results of treatment for pulmonary
val,318,320,330,333 number of metastatic nodules,330,333–336 and tumor metastases underscore the importance of careful patient selection for
doubling time.330,336,337 Multivariate analyses from both the NCI and resection of pulmonary metastases. The following criteria are generally
Roswell Park Cancer Institute confirm that a short disease-free interval agreed on: (1) the primary tumor is controlled or is controllable;
(as a surrogate end point of adverse behavior) and incomplete pulmonary (2) there is no extrathoracic disease; (3) the patient is a medical
resection are adverse prognostic factors for survival of patients with candidate for thoracotomy and pulmonary resection; and (4) complete
pulmonary metastases.320,338 A multivariate analysis from the MD resection of all disease appears possible.339 With careful patient selec-
Anderson Cancer Center suggested that, in addition, the presence of tion, the morbidity of thoracotomy may be limited to the subset of
more than three metastatic pulmonary nodules on preoperative chest patients who are most likely to benefit from this aggressive treatment
CT is an adverse prognostic sign.320 approach.
Wedge excision with negative margins is the procedure of choice After the reports of several randomized studies documenting activity
for patients who undergo surgery for isolated pulmonary metastases. ranging from 24% to 67%,361–363 Bramwell and colleagues performed
Formal segmentectomy, lobectomy, and mediastinal lymph node an RCT comparing ifosfamide (5 g/m2 by 24-hour infusion) with
dissection are not necessary and do not contribute to improved local cyclophosphamide (1.5 g/m2).363 Respective response rates were 18%
control. Occasionally, lobectomy or even pneumonectomy is required and 8%, but the difference was not statistically significant, owing to
because of the proximity of the metastatic lesion to a pulmonary the inadequate power of the study (P = .13). Nonetheless, the authors
artery, vein, or major bronchus. Multiple ipsilateral lesions do not correctly concluded that ifosfamide was the more active drug, and all
represent a contraindication—nor, in fact, do bilateral pulmonary sarcoma medical oncologists agree with this assessment.
metastases. Bilateral lesions may be approached through staged tho- Indirect data from several RCTs in which ifosfamide and/or
racotomies, median sternotomy, or simultaneous bilateral anterior cyclophosphamide was added to doxorubicin have provided additional
thoracotomies, depending on the surgeon’s preference and the number evidence that ifosfamide is a more active analogue than is cyclophos-
and location of the pulmonary metastases. In such cases, the preferred phamide.340 Questions about the optimal scheduling of ifosfamide
approach for most thoracic surgeons is simultaneous bilateral wedge (multiple daily bolus doses versus continuous infusion) have never
resections via a sternotomy or “clamshell” anterior thoracotomy. Isolated been satisfactorily resolved and are confounded by dose differences in
lesions are amenable to thoracoscopic resection. many studies. Two consecutive phase II studies by investigators at MD
Anderson evaluated ifosfamide (14 g/m2) given as a 72-hour continuous
Chemotherapy infusion or a 2-hour infusion for 3 consecutive days. Respective response
rates were 19% and 42%.364 In an EORTC RCT comparing 5 g/m2
First-Line Chemotherapy ifosfamide over 24 hours with 3 g/m2 ifosfamide over 4 hours on days
Single agents 1 to 3, response rates were 3% and 17.5%, respectively. However,
The single-agent activity of doxorubicin against metastatic STS is well a subsequent EORTC study showed no difference in response rates
established, with response rates usually reported as being in the range for 9 g/m2 ifosfamide by continuous infusion or intermittent bolus
of 20% to 30%,340–343 but response rates as low as 10%344 and as high injection365 (see the section on high-dose ifosfamide).
as 41%345 have also been noted. The dose-response curve for doxorubicin To directly address whether OS with the combination of doxorubicin
in sarcomas was demonstrated to be steeper than that for any other and ifosfamide was superior to that with doxorubicin, Judson and
tumor in the first RCT to address a dose-response question; the response colleagues conducted a randomized phase III trial (EORTC 62012).343
rate increased from 18% at 45 mg/m2 to 37% at 75 mg/m2 (see later A total of 445 patients were randomized to either doxorubicin (75 mg/
discussion).346 m2; 25 mg/m2 per day, days 1–3) or doxorubicin with ifosfamide
Epirubicin, which was developed as an active but minimally less (10 g/m2 over 4 days with mesna and pegfilgrastim). There was no
cardiotoxic analogue of doxorubicin, produced an objective response OS difference between the arms, with median OS of 12.8 months
rate slightly lower than that of doxorubicin (18% versus 25%; P = [95.5% CI, 10.5–14.3] in the doxorubicin group and 14.3 months
.33) in an EORTC RCT of 167 patients receiving equimolar doses [95.5% CI, 12.5–16.5] in the doxorubicin and ifosfamide group
(75 mg/m2) of the drugs.347 There is some evidence of a dose-response (hazard ratio [HR], 0.83 [95.5% CI, 0.67–1.03]; stratified logrank
relationship with epirubicin as with doxorubicin; a dose escalation test P = .076). The response rate of the combination (26%) was
study showed response rates of 17%, 44%, and 100% for 140 mg/ superior to that of doxorubicin alone (14%; P < .0006). This study
m2, 160 mg/m2, and 180 mg/m2 of epirubicin, respectively.348 Only supports the use of combination therapy when the goal of palliation
three patients were entered at the maximum tolerated dose of 180 mg/ is tumor shrinkage, thus leaving single-agent doxorubicin as the frontline
m2, and 160 mg/m2 was recommended for routine clinical use. However, standard of care.
the EORTC group, in a three-arm RCT of 334 patients, was unable A phase II randomized clinical trial of the PDGF-α monoclonal
to demonstrate any benefit from either of two schedules of epirubicin antibody olaratumab given with doxorubicin compared with doxo-
(150 mg/m2) compared with doxorubicin (75 mg/m2); all regimens rubicin alone was conducted by Tap and colleagues.366 A total of 133
produced response rates of 14% to 15%.349 Furthermore, there was patients were randomized in a 1 : 1 ratio to receive either olaratumab
considerably more myelosuppression in the two epirubicin arms, with (15 mg/kg) on day 1 and day 8 plus doxorubicin (75 mg/m2) or
two toxic deaths. Nevertheless, particularly in Europe, epirubicin has doxorubicin alone (75 mg/m2) on day 1 of a 21-day cycle for up to
commonly been substituted for doxorubicin. eight cycles. This was then followed by monotherapy maintenance
A number of studies of liposomal anthracyclines have suggested with olaratumab alone. Median progression-free survival was not
that these agents have lower rates of cardiotoxicity but variable significant with olaratumab plus doxorubicin at 6.6 months (95%
activity.350–354 An EORTC phase II RCT344 demonstrated low activity CI, 4.1–8.3) and with doxorubicin at 4.1 months (95% CI, 2.8–5.4)
for both doxorubicin and PEGylated liposomal doxorubicin (Doxil, (stratified HR, 0.67 [95% CI, 0.44–1.02]; P = .0615). Olaratumab
Caelyx)—9% versus 10%—but different spectrums of toxicity, with plus doxorubicin demonstrated a median OS of 26.5 months (95%
less myelosuppression but with palmar-plantar erythrodysesthesia (grade CI, 20.9–31.7) compared with 14.7 months (95% CI, 9.2–17.1)
3: 20%) as the dose-limiting toxicity in the PEGylated liposomal with doxorubicin alone (stratified HR, 0.46 [95% CI, 0.30–0.71; P
doxorubicin arm. = .0003). The objective response rate was not significant (18.2%
Lack of response rather than cardiotoxicity is the main limiting versus 11.9%; 95% CI, 5.3–22.2) with doxorubicin (P = .3421). This
factor for anthracycline use in palliative chemotherapy of STS. None- led to frontline US Food and Drug Administration (FDA) contingent
theless, strategies to reduce anthracycline toxicity are of particular approval of olaratumab for use with doxorubicin as a standard of care
importance in the adjuvant setting.355 Some American investigators while awaiting confirmatory phase III results.
use continuous-infusion regimens with doxorubicin, which have been
shown to be equally effective but less cardiotoxic,356–358 whereas others Combination chemotherapy
give split doses via intravenous push. Dexrazoxane is undoubtedly In the 1970s and early 1980s, before the widespread availability of
cardioprotective when given with doxorubicin.359 Concerns about ifosfamide, most combination chemotherapy regimens were based on
the possibility of tumor protection are theoretical and have not doxorubicin and dacarbazine. The addition of cyclophosphamide and
been noted in ongoing studies, and in adults American Society of vincristine, which are active against childhood sarcomas, created a
Clinical Oncology (ASCO) guidelines indicate that dexrazoxane regimen called CyVADIC, for which the Southwest Oncology Group
should be added in the treatment of patients receiving anthracyclines (SWOG) reported response rates as high as 59% in patients with
when a patient reaches 300 mg/m2 cumulative lifetime dose of metastatic disease.367 Later investigators were unable to reproduce such
doxorubicin.360 high response rates with the same regimen, however, and summary
data on variants of the CyVADIC regimen revealed an overall response dose of 75 mg/m2) and a 2.4- to 2.8-fold increase of the ifosfamide
rate of 35% in 2092 patients.368 CyVADIC was the control for the dose (over a standard dose of 5 g/m2). Significant toxicities included
three-arm EORTC study discussed later.369 Despite the authors’ anemia, thrombocytopenia, nephrotoxicity, and neurotoxicity; severe
conclusions that single-agent doxorubicin should remain the standard, neutropenia and febrile neutropenia were also seen at the higher doses.
CyVADIC had the highest response rate (not statistically significant), De Pas and colleagues377 reported no nephrotoxicity or neurotoxicity
with significantly lower toxicity than either of the other arms of with ifosfamide infused over 12 days at 15 g/m2 (given with doxoru-
the trial. bicin, 75 mg/m2), although myelosuppression was dose limiting.
Most regimens now used for first-line chemotherapy are based on Although not the primary objective, response rates were reported for
the combination of doxorubicin and ifosfamide. A systematic search all these phase I studies and were in the range of 28% to 58%. In
of the literature370 found three phase III RCTs and 16 phase II trials addition, for the five phase II studies of dose-escalated doxorubicin
(excluding phase I studies and those recruiting fewer than 25 patients) and ifosfamide (only studies with more than 20 evaluable patients
in adult STS that used combination regimens including an anthracycline were included), response rates were 31% to 65%. In a phase II study
and ifosfamide. Although the response rate varied widely, from 25% that was not included in the review, a response rate of 40% in 70
to 56%, in the phase II studies, they were at the lower end of this patients was documented.378
range in the three RCTs.369,371,372 In the Eastern Cooperative Oncology Patel and colleagues were the first to maximize the doses of each drug
Group (ECOG) study352 of 178 patients, the response rate was sig- used in the combination.358 In a series of small studies in which growth
nificantly higher for doxorubicin-ifosfamide than for doxorubicin alone factors were used to support patients through the intense expected
(34% versus 20%; P = .03), although median survivals were similar. myelosuppression, these investigators delivered doxorubicin at doses of
In an EORTC study of 471 patients, however, there were no significant 75 to 90 mg/m2 together with ifosfamide at 10 g/m2 divided as 2- to
differences in response rate (28% versus 23%) or median survival for 3-hour infusions daily for 4 to 5 days. Of note, they identified that
doxorubicin-ifosfamide versus doxorubicin alone.369 In an intergroup the regimen was suitable only for patients younger than 65 years old
trial of 340 patients, the ifosfamide-containing regimen Mesna with two kidneys, normal renal function, and good performance status.
Doxorubicn (Adriamycin) Ifosfamide Dacarbazine (MAID) was shown Dose reductions were not used for myelosuppressive toxicity unless it
to produce a significantly higher response rate (32% versus 17%; P was accompanied by extreme morbidity. Patel reported a 62% response
< .002) than doxorubicin-dacarbazine, but with no OS benefit.372 rate overall with a 57% response rate, a 10-month progression-free
Bramwell and colleagues performed a meta-analysis of eight RCTs survival, and a 20-month survival in those with metastatic disease.
that compared doxorubicin-based combinations with single-agent Patel and colleagues attributed their good results to the dose-intensive
doxorubicin.341 In these eight studies with a total of 2281 patients, chemotherapy. In contrast, Worden and colleagues randomized patients
10 combination regimens were evaluated; five included ifosfamide to doxorubicin at 60 mg/m2 plus either 6 or 12 g/m2 of ifosfamide
(two) or dacarbazine (three), and the remaining five used other drugs and showed no advantage for the higher dose.379 Careful review of
with low known single-agent activity. There were no significant benefits that study reveals that the restrictive selection criteria that Patel and
in terms of response rate (OR, 0.79; P = .10) or OS (OR, 0.84; P = colleagues used were not used in the latter study. Several older patients
.13) for combination chemotherapy. Inclusion of a small RCT (106 were entered, and in fact, the disadvantage of the higher-dose regimen
patients)373 that compared epirubicin (180 mg/m2) with epirubicin might have been due to unacceptable toxicity.
(180 mg/m2) plus cisplatin (120 mg/m2) and reported respective In contrast to these promising results in phase I and II studies,
response rates of 29% and 54% (P = .025) did not significantly alter response data in the cooperative group RCTs have been disappointing.
the meta-analysis results. On the basis of single-agent doxorubicin’s In an EORTC trial involving 314 patients with metastatic STS,
lower overall toxicity compared with combination regimens, Bramwell standard-dose doxorubicin (50 mg/m2) plus ifosfamide (5 g/m2) was
and colleagues suggested that for chemotherapy given with palliative compared with higher-dose doxorubicin (75 mg/m2) with the same
intent, doxorubicin alone was a reasonable first-line option,341 a dose of ifosfamide plus lenograstim.370–380 Respective response rates
conclusion that was also reached in a commentary by Santoro.374 This were 21% and 23%, with similar median OS times (56 versus 55
leaves open the possibility of further second-line chemotherapy with weeks), but median progression-free survival was significantly longer
ifosfamide in fit patients with disease progression or relapse after a in the high-dose arm (19 versus 29 weeks; P = .03). In the other RCT
response to doxorubicin therapy. Whether patients with advanced that was included in Verma and Bramwell’s review, as yet reported
sarcomas should be treated with chemotherapy at all is also a topic only in abstract form, 162 patients were randomized to receive
of debate in Europe.375 standard-dose MAID or MAID with doses escalated 25% plus granu-
One reason for the lack of convincing evidence that standard-dose locyte colony-stimulating factor (G-CSF) support. Respective response
combination chemotherapy improves outcomes compared with single- rates were 37% versus 43% (P not significant), but no survival data
agent doxorubicin for metastatic STS might be that the doses of the were reported. There were five toxicity-related deaths, however, all in
drugs in combination regimens are often reduced below optimum the dose-escalated MAID arm. In a third RCT, 180 mg/m2 epirubicin
levels to limit toxicity. In the first RCT of different doses of doxorubicin, and 150 mg/m2 epirubicin, each combined with cisplatin but with
a steep dose-response relationship was demonstrated for doxorubicin no growth factor support, were compared in 151 patients.373 There
in sarcomas, with an increase in response rate from 18% at 45 mg/ was a higher response rate (51% versus 28%, P = .004) and a marginal
m2 to 37% at 75 mg/m2.346 A similar dose-response relationship has effect on OS (P = .06) with the higher-dose regimen. Because all
been suggested for ifosfamide; the response rate increased from 8% three RCTs were quite limited tests of dose escalation, more RCTs
to 22% with an increase from 6 to 10 g/m2 in consecutive series.376 are needed before it may be concluded that such regimens are a more
Myelosuppression, particularly neutropenia, limits the doses of these effective option than conventional-dose chemotherapy.
drugs that may be safely delivered in combination. Use of hematopoietic Verma and Bramwell reported possible reasons for the lack of a
growth factors or autologous stem cell transplantation permits sub- clear benefit of dose-escalated therapy in the RCTs370; these include
stantial dose escalation of these agents. In a systematic review, Verma tumor heterogeneity, difficulties in eradicating large tumor burdens,
and Bramwell identified seven phase I trials, five phase II trials, and and the appropriateness of the drugs, doses, and schedules used. It
two RCTs exploring dose-escalated regimens of doxorubicin and is interesting that even within the same group, results may differ
ifosfamide, with and without other agents, for metastatic STS.370 Most between phase II and phase III trials. When the EORTC performed
regimens included the growth factor filgrastim or lenograstim, but in a pilot study of doxorubicin 75 mg/m2 plus ifosfamide 5 g/m2 with
two trials, autologous stem cell transplantation was also sed. In the granulocyte-macrophage colony-stimulating factor (GM-CSF) support,
phase I studies, the maximum tolerated doses were in the range of a the response rate was 45%.381 When the group repeated the study
twofold increase of the doxorubicin or epirubicin dose (over a standard as a phase III study, the response rate was 23%.380 Finally, EORTC
62012, discussed earlier, demonstrated a response benefit but no OS of reviews.340,388,389 Dacarbazine has been used most extensively, either
benefit.343 Why is there a discrepancy, and which value is closer to as a first-line agent in combination with doxorubicin and ifosfamide
the truth? Phase III studies are supposed to be more representative (MAID) or as a second-line salvage treatment. Demetri and Elias
of the overall population than are studies of highly selected patients found an overall 16% response rate for dacarbazine in 109 patients
from referral centers. Is it not possible, on the other hand, that the from collected phase II studies.340 Although dacarbazine is commonly
pilot study was conducted by a group that was more expert at treating given in divided doses over 3 to 5 days, Buesa and colleagues showed
sarcomas? Is it not possible that negative selection bias played a role in that doses of 1.2 g/m2 over 20 minutes are feasible and active, and
the phase III trials—that is, investigators treat their younger, potentially more convenient, because effective antiemetics are more available than
curable patients with combination therapy off study and enter into in decades past.390 The current availability of portable infusion pumps
the randomized phase III studies only those who are less likely to means that prolonged infusions are also feasible. Although Rosen and
benefit? We know that referral to a specialty center improves outcomes colleagues reported a response rate of 27% lasting 2 to 18 months or
of patients with early-stage disease; why not those with metastatic longer, Reichardt and colleagues were not able to confirm this high
disease? Furthermore, all of the randomized studies (other than EORTC rate of activity when they gave 12- to 14-day infusions of 200 to
62012343) that have been reported occurred before there was effective 225 mg/m2 per day of dacarbazine, observing only disease stabilization
treatment of GISTs. Many patients with GIST were entered in frontline in 8 of 25 heavily pretreated patients.391 It is worth noting that the
chemotherapy studies as having metastatic leiomyosarcoma without majority of responses we have observed with dacarbazine (DTIC) are
attention to its primary site. Inclusion of such patients, especially when in patients with leiomyosarcoma, and the occasional patient with
they are rarely accounted for in the publications, dilutes the data and solitary fibrous tumor. As a result, those patients with liposarcoma or
makes much of the information uninterpretable. UPS should be targeted for other therapies.
There is conflicting evidence on the activity of cisplatin and car-
Second-Line Chemotherapy boplatin against metastatic STS, although most reviews have reported
High-dose ifosfamide response rates of less than 15%.340,388,389 Low response rates are also
Although ifosfamide is often used as a first-line agent, it is clearly seen for etoposide given as a single agent.340,363,392 Promising early
active as second-line therapy in patients who develop progression or data on docetaxel393 could not be reproduced in later studies,374,394–397
relapse after doxorubicin-based regimens. Early studies of ifosfamide and paclitaxel similarly has little activity except in patients with
suggested that there was a dose-response relationship,376 and several angiosarcoma.398–403
groups have documented responses to high-dose ifosfamide in patients Objective response rates were also very low (3%–5%) in three
who had not responded to lower doses of the drug.357,382 Nevertheless, phase II studies of gemcitabine,404–406 although the MD Anderson
dose escalation studies of ifosfamide have produced conflicting results. group described a response rate of 18% in 39 patients if GISTs were
Doses of 12 g/m2 without and 14 to 18 g/m2 with growth factor excluded398 (they represented the majority of patients in some of the
support seem achievable and have produced response rates of 33% other studies). The MD Anderson study also confirmed the importance
to 45%, but nephrotoxicity and neurotoxicity are considerable.364,383 of timed delivery of gemcitabine; it cannot be activated pharmacokineti-
In one dose-finding study, a 2-week continuous infusion of ifosfamide cally faster than 10 mg/m2 per minute, and the remainder of a more
at 900 mg/m2/day was reasonably well tolerated; myelosuppression rapidly administered dose is simply excreted unchanged in the urine.
was dose limiting, but there was no significant nephrotoxicity or Hensley and colleagues used timed infusion of gemcitabine at 900 mg/
neurotoxicity.384 Pharmacokinetic data reported by Cerny and colleagues m2 over 90 minutes on days 1 and 8 followed by docetaxel 100 mg/
demonstrated that ifosfamide doses greater than 14 to 16 g/m2 given m2 on day 8 with growth factor support and a 25% dose reduction
over 5 days resulted in a relative decrease of the active metabolite for patients with prior pelvic radiation in a series of patients with
iphosphoramide mustard, suggesting dose-dependent saturation or leiomyosarcoma, almost exclusively of uterine origin, and observed a
inhibition of ifosfamide metabolism.385 53% response rate, somewhat lower after internal review of the data.407
Despite the aforementioned phase II trial results, the advantages It is worth noting in a nonprotocol setting that the dose of docetaxel
of increasing the dose of ifosfamide are less clear on the basis of random- the author uses is lower. Nonetheless, Leu and colleagues confirmed
ized studies. The response rate rates for 9 g/m2 (3 g/m2 over 4 hours, the activity of the regimen at the lower dose in patients with a variety
days 1 to 3) and 5 g/m2 (24-hour continuous intravenous infusion) of other sarcomas.408 Because the response rate among patients with
were 3% and 17.5%, respectively, in an RCT of 101 patients.386 leiomyosarcoma in the MD Anderson study of gemcitabine was 4
Escalation to 12 g/m2 as a 3-day continuous intravenous infusion out of 10, it was unclear whether the activity of the gemcitabine-
produced a response rate of 16% in a phase II study of 124 patients.387 docetaxel regimen was due to the timed infusion of gemcitabine, the
In an EORTC RCT of first-line chemotherapy, the response rates large number of patients with uterine leiomyosarcoma, or the addition
were 11%, 6.5%, and 9.4% for 75 mg/m2 doxorubicin, 3 g/m2 of docetaxel. To answer this question, SARC (the Sarcoma Alliance
ifosfamide over 4 hours on days 1 to 3, and 9 g/m2 ifosfamide 24-hour for Research Through Collaboration) carried out an RCT comparing
continuous infusion, respectively. In addition to these disappointingly equimyelosuppressive doses of timed-infusion gemcitabine versus the
low and similar response rates, there were no differences in progression- combination of gemcitabine and docetaxel. The study used a bayesian
free survival among the three arms.365 adaptive randomization design with continuous feedback of data into
In the end, perhaps the most important consideration for treatment the randomization model so that more patients were entered in the
of a specific patient with doxorubicin and olaratumab or the combina- arm with greater efficacy.409 Success was defined as a RECIST (Response
tion of doxorubicin and ifosfamide is whether a response is needed Evaluation Criteria in Solid Tumors) response at any time or freedom
immediately or not. It is certainly reasonable to consider doxorubicin from progressive disease at 24 weeks, based on the assessment of the
with olaratumab chemotherapy in the asymptomatic patient, under- investigators that prolonged freedom from progression was more
standing that higher doses of specific agents may be administered; in beneficial to patients than response. Results reported by Maki showed
symptomatic patients, because there may not be an opportunity to a statistically significant superiority of the combination regimen in
use second-line therapy, combination therapy with an anthracycline terms of success rate, progression-free survival, and OS.410
and ifosfamide perhaps is the wiser first-line option in a fit patient Despite poor levels of activity as single agents, some of the preceding
who needs a tumor response. drugs have been incorporated into non–anthracycline-based salvage
regimens. On the basis of encouraging data in pediatric sarcomas,
Other marketed drugs alone or in combination etoposide has been combined with ifosfamide, although with variable
Collected response rate data for many drugs that were studied in results.397,411–413 All but one such study produced response rates in the
phase II trials for metastatic STS have been published in a number range of 38% to 46%; because ifosfamide given alone has produced
rates up to 67% in phase II studies, however, these results are difficult difficult to specify a sarcoma subtype beyond synovial sarcoma, but
to interpret. Temozolomide,414–416 raltitrexed,417 sargramostim,418 the activity was seen across multiple sarcoma subtypes in subset analysis
topotecan,419,420 and vinorelbine421 seem to have minimal activity in of the phase III data.
STS, despite their proven value in other tumor types. Topoisomerase Eribulin is an agent active against the microtubule that also appeared
inhibitors such as irinotecan and topotecan appear to have significant to have activity in phase I and phase II studies435 based on progression-
activity in Ewing sarcoma and rhabdomyosarcoma,422–425 underscoring free survival data. A randomized phase III clinical trial was performed
the histologic specificity of several of these agents, such as temozolomide of eribulin versus dacarbazine in patients with liposarcoma and
in leiomyosarcoma.414 leiomyosarcoma.435 Although the trial found an OS of eribulin versus
dacarbazine (median 13.5 months [95% CI, 10.9–15.6] versus 11.5
Newer drugs months [95% CI, 9.6–13.0]; HR, 0.77 [95% CI, 0.62–0.95]; P =
Trabectedin (ET-743, ecteinascidin 743), a DNA guanine-specific .0169), this effect was driven by the liposarcoma subset in the trial.
minor groove-binding agent, seems to have clear-cut activity against As a result, eribulin was FDA approved only for the treatment of
sarcomas, in particular myxoid and round cell liposarcoma. Hints of liposarcomas.
activity in bone and STSs were observed in phase I trials and appeared The observation that patients with growing tumor may benefit
to be confirmed in phase II trials of this agent. Garcia-Carbonero and from therapy when the growth stops is not new, but its importance
colleagues reported a response rate of 17% in 35 chemotherapy-naïve is becoming increasingly recognized. Initially described in a phase II
sarcoma patients and 8% in 34 patients who had received prior study of doxorubicin as improvement436 that included both responses
chemotherapy.426 European trials also described activity in previously that were inadequate to qualify by standard criteria and stabilization
treated sarcoma patients and translocation-related sarcomas.427,428 of previously progressive disease, improvement has traditionally been
Occasional severe toxicities, sometimes lethal, seemed to be related accepted as a “second-class” response at best. Trabectedin is the arguably
to elevated baseline liver function tests; and with careful attention to first modern drug for sarcomas for which the clinical observation
alkaline phosphatase levels, toxicity other than myelosuppression and seemed to take on added meaning. The EORTC has defined rates of
fatigue has not been a major problem. In the attempt to avoid the time to progression at 3 and 6 months for active and inactive regi-
inconvenience of a continuous-infusion schedule, weekly administration mens.437 Clinicians who treat osteosarcoma have known that standard
has been evaluated. In a randomized study, the continuous infusion responses might not exist despite a complete histologic response. The
was more toxic, but it was significantly more effective in terms of experience with GIST (see later discussion) has indicated that many
time to progression and survival.429 This study indicates that the drug patients who are clearly benefiting from therapy and have objectively
is clearly active and that either the 24-hour continuous-infusion schedule measurable responses do not qualify as responders by RECIST or
every 3 weeks is superior or the dose that was chosen for the weekly World Health Organization criteria. Therefore the activity of
schedule was too low. These data were sufficient for approval of gemcitabine-docetaxel that led to improved progression-free survival
trabectedin in Europe by the European Medicines Agency, but were and OS, the activity of trabectedin, and the extent of the activity of
insufficient for US approval. As a result, a confirmatory randomized imatinib in GIST were discovered through use of modified response
phase III trial of trabectedin versus dacarbazine was performed in criteria. It makes sense to look at new classes of drugs with similar
liposarcoma and leiomyosarcoma.430 The median PFS for trabectedin expanded criteria for drug activity and to pursue their study.
versus dacarbazine was 4.2 versus 1.5 months (HR, 0.55; P < .001), The identification of a specific molecular target (the tyrosine kinase
whereas the difference in OS was not significant (12.4 versus 12.9 receptor KIT) in a rare type of STS (GIST) and successful treatment
months; HR, 0.87; P = .37. This trial led to FDA approval in the with a drug (imatinib) that inhibits that target provide a model for
United States. future drug development in STS. Despite data indicating that there
Another interesting observation from the various studies of tra- are few specific mutations associated with the most common adult
bectedin is that it has high activity against a single subtype of sarcomas, sarcomas,95 better molecular differentiation of STSs into categories
myxoid–round cell liposarcoma, made by Grosso and colleagues at with similar molecular characteristics could facilitate future studies
the Istituto Nazionale dei Tumori in Milan.431 They noted a response of novel agents. At an NCI-sponsored “state of the science” meeting
rate of 43% by RECIST and an even higher response rate when on STS, Demetri pointed out that the ideal target would meet four
changes in tumor density were considered—a so-called tissue response. conditions: (1) a single validated molecule that is critical to STS
A variety of retrospective analyses have verified this observation,428 pathogenesis in humans, (2) expressed and active, (3) a target for
and it is clear that the responsiveness of myxoid liposarcoma to tra- which there are no alternative pathways to bypass the blockade, and
bectedin is very high. It is a subtype that is also rather responsive to (4) necessary and sufficient for sarcoma survival.257 Other potential
doxorubicin plus ifosfamide, but the second-line (and sometimes targets are discussed elsewhere in this chapter.
fifth-line) activity of trabectedin is substantial. Myxoid–round cell Complex sarcomas with diverse karyotypes and/or drug-resistance
liposarcoma is characterized by a specific translocation placing either mutations are likely to require drugs used in combination to block
FUS or less commonly EWSR1 with DDIT3 (CHOP). It is possible multiple targets. Reviews have described signal transduction pathways
that trabectedin specifically blocks transcription of the fusion DNA. in sarcoma as therapeutic targets439 and the potential use of antian-
It is also evident that trabectedin is more active against tumors with giogenesis agents.440 Early reported antiangiogenesis therapies have
an altered DNA repair mechanism. Tumors with low expression of shown limited benefit in STS,441 but many agents and combinations
BRCA1 and high expression of ERCC1 have substantially longer remain to be evaluated; the approval in many countries of pazopanib
progression-free survival than do those with high expression of BRCA1 in advanced sarcomas gives hope that newer antiangiogenic approaches
and low expression of ERCC1.432 Whether the altered DNA repair is will provide benefit in sarcoma patients.434 Finally, immunotherapy
a specific feature of myxoid liposarcoma or other translocation-related is currently being explored in STS, with pembrolizumab being studied
sarcomas or whether the altered DNA repair is an independent predictor by the Sarcoma Alliance for Collaboration and Research as their 28th
of response is to be determined. study.442 They have demonstrated activity in a subset of soft tissue
Pazopanib, a multitargeted tyrosine kinase inhibitor, demonstrated tumors. Other trials of additional immunotherapy combinations have
activity in phase I and phase II studies,433 leading to a phase III yet to be reported at the time this chapter is being updated.
placebo-controlled trial in which the agent demonstrated activity as Although the majority of patients with metastatic STS will not
measured by progression-free survival (4.6 versus 1.6 months) in have access to phase II studies of investigational agents, where these
patients in whom other lines of systemic therapy had failed; there was are available, trial entry should be encouraged. Conventional wisdom
a trend toward improved OS that was not statistically significant.434 suggested that use of an investigational agent as a first- or second-line
The mechanism by which this agent is active is unclear, making it therapy for metastatic disease should be considered, given that
investigational agents that are administered as third- or fourth-line Surgical resection with negative margins remains the standard
treatments could be doomed to failure because of acquired drug primary treatment for patients with localized retroperitoneal sarcoma.
resistance. This concept has now been proven incorrect. Whenever Unfortunately, the data are extremely difficult to interpret because in
there is an effective agent or regimen (imatinib in GIST, DFSP, and most series all patients, the majority of whom may have atypical
TGCT; ifosfamide in synovial sarcoma; trabectedin in myxoid and lipomatous tumors (also called well-differentiated liposarcoma), are
round cell liposarcomas; taxanes in angiosarcoma), activity is obvious lumped together with patients with true high-grade sarcomas. Patients
even in multiply treated patients. should be thoroughly evaluated with multidisciplinary input before
there is any attempt at surgery. Because the response rate of well-
Unique routes of delivery differentiated liposarcoma to chemotherapy is zero, and at best 10%
Some experimental studies have evaluated intraperitoneal delivery of for dedifferentiated liposarcoma, we do not recommend neoadjuvant
cytotoxic agents, usually doxorubicin, cisplatin, or mitoxantrone, chemotherapy for such patients. Conversely, radiation therapy is
sometimes with hyperthermia, in sarcomas that are confined to the preferably given preoperatively (see later discussion). If primary surgery
peritoneal cavity after resection of all visible abdominal disease.388,443,444 is chosen for the patient, all patients should undergo preoperative
Evaluation of any benefit is a major challenge in these studies, however, bowel preparation and assessment of bilateral renal function with CT,
and this technique may be less suitable for sarcomas than for epithelial because en bloc multiorgan resection might be required in order to
cancers; given the concept of repeated cycles of chemotherapy to achieve negative margins. Resectability rates in recent series combining
achieve maximum tumor kill, it is intuitive that more than a single patients with primary and recurrent lesions have ranged from 25%
application would be necessary to endeavor toward curative intent. to 96% (Table 90.13).205,450–454 Resectability rates at different institutions
As noted earlier, isolated limb perfusion with chemotherapy, typically are difficult to compare and interpret because these rates are a function
melphalan, with TNF, is now approved for use in Europe.445 Although of the referral pattern, the criteria that are used to determine which
it is a time-consuming procedure, a significant proportion of patients patients will undergo surgical exploration, and the surgeons’ skill and
have long periods of freedom from disease progression, and some experience.453,455 For patients with primary lesions, grossly complete
appear to have long-term cure of disease, when the recurrences are resection is possible in up to 78% of cases.155,453 The most common
localized and metastatic disease is not an issue. reasons for unresectability are the presence of major vascular involvement
(aorta or vena cava), peritoneal implants, or distant metastases.205
Resection of adjacent retroperitoneal or intraabdominal organs, fre-
SPECIAL SITES AND SUBTYPES OF SARCOMA quently the kidney, colon, or pancreas, is required in 50% to 80%
Retroperitoneal Sarcomas of cases to permit complete resection.205,451,456 Partial resections or
debulking procedures have been performed, but there is no evidence
Retroperitoneal sarcomas are relatively uncommon, accounting for that partial resection improves survival.205,456 Deliberate partial resection
approximately 15% of all sarcomas (see Fig. 90.1). The most common should be reserved for relief of bowel obstruction or palliation of other
histologic subtypes are well-differentiated and dedifferentiated liposar- critical manifestations of advanced disease.
coma and leiomyosarcoma, found in 42% and 26% of cases, respectively Results from published series demonstrate 5-year OS rates in the
(see Fig. 90.1). Nearly 80% of patients have an abdominal mass at range of 54% to 64% for patients with completely resected retroperi-
presentation, and 50% of patients report pain.205 Patients commonly toneal sarcoma.155,205,451,453,454 OS rates for patients with incompletely
describe nonspecific gastrointestinal symptoms. Other commonly noted resected disease range from 10% to 36%. Adequate margins are often
symptoms include neurologic symptoms (primarily sensory) in 27% difficult to obtain in retroperitoneal sarcoma surgery because of the
of patients and weight loss in 7%.205,446 These tumors often grow to proximity of critical organs, vascular structures, and the spine.
substantial size before a patient’s nonspecific complaints are evaluated Consequently, recurrent disease remains a significant problem, with
or an abdominal mass is noted at physical examination. recurrence developing alone or with systemic relapse in at least half
CT and MRI are the primary methods that are used to image and likely more patients with completely resected tumors, if they are
retroperitoneal tumors (see Figs. 90.3, 90.5, and 90.6).447–449 These followed long enough.136,205,451,453,457
modalities allow assessment of the consistency of the mass (fat, cystic A number of studies have evaluated prognostic factors for retro-
or solid components, associated necrosis), the precise anatomic location peritoneal sarcomas by univariate and multivariate analysis.136,155,446,451,457
of the mass, and the extent of any regional disease, and they confirm For patients without metastatic disease, complete surgical resection
function of the contralateral kidney. CT of the abdomen and pelvis and histologic grade were the primary determinants of survival in
usually provides images that are satisfactory for treatment planning. several multivariate analyses.155,446,451,454,457 Some investigators have also
Occasionally, MRI with gradient sequence imaging may be helpful found by multivariate analysis that large tumor size (>10 cm) and
in defining long-segment vascular anatomy for surgical planning. For fixation to adjacent retroperitoneal structures other than neurovascular
patients with an abnormal chest radiograph, chest CT should be bundles or bone were significant adverse factors for survival.451 Patients
performed to exclude the possibility of metastatic disease. who undergo a grossly complete resection have a 60% 5-year OS rate
The differential diagnosis for a retroperitoneal mass is relatively and a median survival of 64 months. These results are significantly
limited. Physical examination should include a testicular examination better than those of patients who have an incomplete resection (grossly
in men to evaluate the possibility of a primary testicular neoplasm. positive margins) or unresectable disease. For patients with low-grade
Laboratory tests should include the common serum markers for germ lesions, the median survival (80 months versus 20 months) and 5-year
cell tumors, β-human chorionic gonadotropin, and α-fetoprotein. If OS rate (70% versus 25%) are significantly better than those for
physical examination is suggestive of testicular malignancy or biochemi- patients with high-grade lesions.205
cal markers are elevated, testicular ultrasonography should be performed. The unfavorable outcomes for retroperitoneal sarcoma logically
This may obviate laparotomy for patients with metastatic testicular point to the need to investigate adjuvant approaches. The obvious
tumors and allow identification of primary retroperitoneal germ cell candidates include preoperative chemotherapy and preoperative
tumors. radiotherapy. Detailed discussions of the pertinent issues in these
In general, preoperative biopsy is not necessary when radiographic approaches are available458,459 and are summarized in the following
appearance enables the diagnosis of well-differentiated liposarcoma section.
(atypical lipomatous tumor) and surgical resection is planned for a
resectable primary retroperitoneal mass. If there is a question of diagnosis Surgery Plus Radiation Treatment
(lymphoma) or if preoperative chemotherapy or radiation is considered, Postoperative EBRT has been shown to reduce local recurrence rates
a core needle biopsy is essential. for extremity sarcomas and superficial trunk sarcomas. However,
Table 90.13 Resectability Rates for Retroperitoneal Sarcomas in Selected Series

Accrual Period Total No. of No. Completely Restability
First Author Institution (years) Patients Resected Rate (%)
Glenn471 NCI 19 50 37 74
Karakousis450 Roswell Park 24 68 27 40
Dalton451 Mayo Clinic 19 116 63 54
Jaques205 MSKCC 5 114 67 59
Alvarenga446 Royal Marsden 20 110 28 25
Karakousis453 Roswell Park 17 87 83 95
Kilkenny454 University of Florida 25 63 49 78
MSKCC, Memorial Sloan Kettering Cancer Center; NCI, US National Cancer Institute.
gastrointestinal toxicities or neurotoxicities often limit the delivery of of radiotherapy consisted of 45 Gy in 25 fractions. Although the
sufficient radiation doses to the retroperitoneum. Several retrospective median radiation volume exceeded 7 L, preoperative EBRT was
studies have suggested that postoperative EBRT might improve local associated with EORTC/RTOG acute toxicity scores of 2 or lower
control after grossly complete resection,205,236,450,457,460,461 but other small in all patients who underwent resection. Furthermore, no patient was
retrospective reports have not suggested any improvement in local hospitalized for acute toxicity, and there were no treatment interruptions
control with postoperative radiotherapy.205,236,450 or requirements for cessation of treatment because of acute toxicity.
However, these series have included small numbers of patients The remarkably low toxicity of the preoperative course with enormous
(typically up to 40 at most), no standard treatment protocol, and radiotherapy volumes in the study has been attributed to the displace-
variable details regarding histopathologic findings, extent of resection, ment of bowel outside the target volume. At the same time, brachy-
and margin status. The largest study addressing this issue was reported therapy used postoperatively in selected cases did appear to be associated
by the French Sarcoma Group with the suggestion that postoperative with toxicity and also does not appear to have contributed to enhanced
radiotherapy was associated with significantly reduced local recurrence tumor outcome. Late toxicity resulted in death in 4% (2 of 46) and
compared with surgery alone.462 In this report, 145 patients had localized with life-threatening illness in 2% (1 of 46) of patients, all of whom
nonmetastatic retroperitoneal sarcoma. As is typical for this disease, had been treated with brachytherapy to the upper abdomen. The
the tumors were large (median size, 15 cm; range, 2–70 cm), and 2-year OS and disease-free survival rates for resected retroperitoneal
only a minority (6%) were T1 lesions. As in others series, liposarcoma sarcoma were 88% and 80%, respectively. Significantly better 2-year
was unusually well represented (30%). Their patients may differ from disease-free survival was achieved in patients with primary (in contrast
those in other reports in that only 27 cases (19%) had grade 1 lesions. to recurrent) disease and in those with low-grade tumors (93% and
A significant number of patients (31%) had neurovascular or bone 95%, respectively).463 Similarly, in the MD Anderson Cancer Center
involvement. Complete resection was performed in 94 of the 145 phase I trial (N = 35), the tolerance of preoperative radiotherapy was
patients (65%), and 60 of these patients received radiotherapy to a also reported. The MD Anderson Cancer Center trial differed from
median dose of 50 Gy. Of the 94 patients who underwent complete the Princess Margaret Hospital study in that it also evaluated outcome
resection, the 5-year actuarial local recurrence-free interval was 60% after preoperative doxorubicin in addition to concurrent allocation
for those who were treated with radiotherapy and 23% for those who to one of six sequential 1.8-Gy-per-fraction escalating radiotherapy
did not receive postoperative radiotherapy (P = .0021). Clearly, the protocols (from 18 to 50.4 Gy) and used intraoperative electron beam
likely possibility of selection bias must be considered in interpreting as the boost technique in localized retroperitoneal tissue sarcoma.464
these results, because patients with large and more complex (i.e., At the highest radiation dose of 50.4 Gy, 2 (18%) of 11 patients had
unusually located or infiltrating) lesions and patients who experienced grade 3 or 4 nausea. Twenty-nine patients (83%) underwent laparotomy;
postoperative morbidity are less likely to have been treated with 6 patients had interval disease progression and did not undergo surgery.
radiotherapy. Grossly complete resection (R0 or R1) was performed in 26 (90%)
Preoperative EBRT for retroperitoneal sarcoma offers certain theo- of 29 patients who underwent operation. Intraoperative electron beam
retical and practical advantages: (1) High-dose treatment could minimize use was feasible and successfully administered in 22 patients who had
the risk of tumor implantation in the peritoneal cavity after a marginal R0 or R1 resections. This trial demonstrates that preoperative external
resection by sterilizing a large number of tumor cells; (2) partial tumor beam radiation may be safely administered to a total dose of 50.4 Gy
regression could facilitate grossly complete resection; (3) there are with continuous-infusion doxorubicin.
favorable anatomic issues, including the tumor displacement of critical The three articles with sufficient follow-up that describe the use
radiosensitive organs (bowel predominantly) away from the preoperative of preoperative radiotherapy with a brachytherapy or electron boost
radiation field, thereby reducing toxicity and improving tolerance; reported improved outcomes compared with most other series, especially
and (4) an intact peritoneum offers a mechanical barrier to tumor for primary (as opposed to recurrent) presentation cases,463,465,466 and
seeding during the time radiotherapy is being administered before presumably the MD Anderson Cancer Center trial will demonstrate
resection and division of these membranes. Moreover, postoperative similar findings with maturation of the data.464 However, we caution
radiotherapy is problematic if bowel is tethered in the radiotherapy against overinterpretation of results that could be explained by surgical
target area, making it impossible to treat some patients, at least without technique at major referral sarcoma centers or by case selection; of
unnecessary risk of complications. note, none of the four studies provides a comparison control group
Two series, from the Princess Margaret Hospital and from the from which to infer efficacy. Similarly, it remains unclear what contribu-
University of Texas MD Anderson Cancer Center, are informative tion is being provided by the use of brachytherapy or intraoperative
because acute toxicity resulting from preoperative radiotherapy was radiotherapy (IORT) (as opposed to the preoperative EBRT, common
differentiated prospectively from the effects of other treatments.463,464 to all four studies), which should probably remain protocol based in
In the Princess Margaret Hospital series, the median preoperative dose expert hands or be reserved for individual nonstandard clinical use.
risk from metastatic disease. If an effective chemotherapeutic regimen

Intraoperative Radiation Treatment could be identified early, with the primary tumor intact, and if some
IORT offers the advantage of a direct boost dose to the tumor bed, progression of disease under therapy would not render the patient
thereby allowing a reduction in the dose of relatively more toxic unresectable, it would be beneficial. Thus there is an indication for
concomitant EBRT. However, critical evaluation of its role is especially preoperative chemotherapy in appropriately selected patients. Proof
problematic because of treatment selection factors (both medical and of principle comes from the UCLA study mentioned previously,
technical) along with the fact that any observations of efficacy are in which complete responses to chemotherapy and radiation were
confounded by the frequent use of additional fractionated EBRT in demonstrated.
the “adjuvant package.” Therefore a clear demonstration of the
effectiveness of IORT is lacking, although its potential value should Gastrointestinal Stromal Tumors
continue to be evaluated in appropriate investigational protocols. The
same situation applies to the use of adjuvant brachytherapy approaches GISTs represent about 80% of sarcomas that arise from the gastro-
to dose augmentation in the retroperitoneum. intestinal tract. This group of soft tissue tumors has become increasingly
The efficacy of combined adjuvant IORT and EBRT has been recognized as a separate subtype of sarcoma defined pathologically by
evaluated in series from MGH and the Mayo Clinic,465,467 and in a expression of the receptor tyrosine kinase KIT (CD117) in about
previous report from the NCI.468 The NCI study was a prospective 95% of cases.473 The management of GIST has undergone a revolution
trial in which 30 patients with completely resected retroperitoneal with the development and availability of imatinib, an agent with
sarcomas were randomly assigned to receive IORT (11- to 15-MeV significant clinical benefit for patients with advanced GISTs. Details
electron beam to a dose of 20 Gy) with low-dose postoperative EBRT of the molecular pathology of GISTs are addressed in the sections
(35–40 Gy) or to receive high-dose postoperative EBRT (50–55 Gy) Potential Molecular Prognostic Factors and Prognostic Factors as
alone.468 IORT with low-dose EBRT was associated with a signifi- Therapeutic Targets.
cantly lower rate of gastrointestinal toxicity (7% versus 60%), but This section of the chapter covers the evaluation and treatment of
no differences were noted in local control, disease-free survival, or patients with GISTs. Consideration of these issues is often aided by
OS. The rates of 5-year disease-free survival (20%) and OS (40%) subclassification by clinical staging into patients with localized, resectable
seen in this study were comparable to those observed with surgery disease and patients with metastatic GIST.
alone.236,451 The reports from MGH and the Mayo Clinic described
preoperative high-dose EBRT (40–50 Gy), instead of postoperative Localized (Surgically Resectable) Gastrointestinal
administration, with IORT (using an electron beam to a dose of
8.75–30 Gy, depending on the series).443,444 Both articles report Stromal Tumors
on overall toxicity without differentiation between the influence of Patients with localized GISTs are best treated with surgical resection
preoperative EBRT and the boost after resection. This likely arose of the primary tumor. Surgical resection generally consists of segmental
because of retrospective toxicity data collection in the two studies, resection of the involved section of the gastrointestinal tract without
which is further confounded by the frequent use of IORT in each.465,466 local or regional lymphadenectomy. Because GISTs were only recently
The inference from our analysis of the results of both studies is that pathologically defined, there are few reports outlining the natural
much of the toxicity seems related to use of IORT and is not from history of localized GISTs (excluding other forms of mural gastro-
preoperative EBRT. intestinal neoplasms); the studies available analyzing patients from
In summary, in the management of retroperitoneal sarcoma, before the era of imatinib (after 2000) indicate tumor-specific mortality
complete surgical resection remains the standard of care. In selected in unselected patients of at least 50%.161,474 Those patients with KIT
patients with advanced disease, some disabling symptoms may be del557-558 (within exon 11) appear to have a higher risk of recurrence
palliated by low- to moderate-dose EBRT. There are no currently than those with other KIT exon 11 or exon 9 or other mutations
available data to support the use of routine neoadjuvant or adjuvant (e.g., PDGFRA, BRAF, or SDH subunits).475
chemotherapy for these patients. Given the relatively high complication Details of the natural history of patients with surgically treated
rates of high-dose external beam radiation to the retroperitoneum gastrointestinal leiomyosarcoma, the vast majority of whom might
and the lack of clear demonstrable clinical benefit, routine preoperative have what we currently would classify as GISTs, are outlined in
or postoperative EBRT is not recommended outside the setting of a prior reports.161,162,476 These reports emphasize the importance of
clinical trial, and clinicians should be encouraged to enter patients in macroscopically and microscopically complete surgical resection and
ongoing trials at referral centers.458,459,469 the adverse prognostic significance of large tumor size and high tumor
grade (as assessed with light microscopic criteria). Although surgical
Chemotherapy resection has been the mainstay of therapy for patients with local-
Retrospective studies have not demonstrated any benefit for preopera- ized GISTs, prior analyses of patients at MD Anderson and MSKCC
tive470 or postoperative155,205,450,471 doxorubicin-based chemotherapy demonstrated 50% or lower disease-specific 5-year survival rate for
for retroperitoneal sarcomas. In one study, six complete responses patients in whom a grossly complete resection of their primary GIST
were seen in 23 patients who received high-dose doxorubicin-ifosfamide- had been achieved.161,474
cisplatin with concurrent radiotherapy.280 Neoadjuvant chemotherapy The precise role of imatinib in the postoperative treatment of
has been combined with hyperthermia472 and preoperative radio- patients with localized GISTs is now well defined. The first RCT, the
therapy464 without excessive toxicity. These techniques remain experi- Z9001 trial by the American College of Surgeons Cooperative Group,
mental, however, and need further assessment, eventually in RCTs, examined 1 year of imatinib at 400 mg oral daily versus placebo, and
in order for their place in the management of retroperitoneal sarcomas was closed early owing to a clear advantage of imatinib in decreasing
to be evaluated. the recurrence rate at 1 year. This finding of improved progression-free
Most of the studies indicated previously included retroperitoneal survival (while patients were essentially still on imatinib) led to the
sarcomas as a single group without differentiating primary histologic drug’s approval in many countries in the adjuvant setting, despite lack
type or grade. Because of the preponderance of patients with atypical of a disease-specific survival advantage.477 The follow-up to the Z9001
lipomatous tumors who were included in such studies, the role of study was the SSG XVII study, which examined 1 year of imatinib
chemotherapy is questioned, given that the response rate of recurrent versus 3 years. This study was notable for both a progression-free
well-differentiated liposarcoma to chemotherapy is zero. Clearly, for survival and OS advantage for longer exposure to imatinib (92%
high-grade retroperitoneal sarcomas, the recurrence rate is unacceptably versus 82% 5-year survival), making 3 years of imatinib the new
high, and even when the local disease is controlled, patients are at standard of care for high-risk GIST.478
response and showed that they predicted for progression-free survival.492

Metastatic Gastrointestinal Stromal Tumors These changes—a 10% or greater decrease in maximum tumor diameter
The primary sites of failure for most patients with recurrent GIST or a 15% or greater decrease in tumor density, the “Choi criteria”—were
are the liver, the peritoneum, or sometimes both sites. It is very rare confirmed to have prognostic importance in an independent group
for this tumor to metastasize to the lungs. of patients with GIST.493 There is increasing evidence that similar
findings are seen in other tumors and after other treatments, suggesting
Chemotherapy that major therapeutic effects are missed when patients are evaluated
GISTs are entirely resistant to conventional cytotoxic chemotherapy only according to RECIST.188 Notably, the findings on contrast CT
agents. In the era of imatinib and other tyrosine kinase inhibitors, largely mirror those seen on PET scan, and patients who can tolerate
there is no defined role for conventional chemotherapy agents in this CT or MRI may be followed by standard imaging modalities without
disease. resorting to PET-CT scans. We generally reserve PET-CT in metastatic
The identification of mutations of KIT, which cause constitutive disease to those who have allergies or intolerance to CT contrast
activation of the KIT tyrosine kinase receptor pathway in GIST, and agents or MRI imaging.
the activity of imatinib in vitro against a GIST cell line479 prompted A variety of investigators have reported that KIT mutation type
treatment in 1996 of a Finnish patient with imatinib,480 a tyrosine affects outcome, at least in the era before imatinib.184,475 Furthermore,
kinase inhibitor that is highly effective against chronic myeloid leukemia. Heinrich and colleagues reported a higher rate of partial response to
An impressive response led to rapid initiation of phase I481 and random- imatinib (72% versus 32%; P < .004) for patients with exon 11 versus
ized phase II studies of imatinib for GISTs.482 In an EORTC study, exon 9 mutations in the initial phase II study188 with similar findings
40 patients, of whom 36 had GISTs, were treated at dose levels ranging in the North American study.487 Debiec-Rychter and colleagues have
from 400 to 1000 mg/day orally. There were 19 patients who had published details of similar findings from the EORTC study.486
partial responses (54%) and 13 with stable disease (37%). Disease A unique aspect in the treatment of GIST with imatinib or another
progressed in four of five of non-GIST patients. The most common tyrosine kinase inhibitor is that therapy should be continued even in
side effects of imatinib were nausea, vomiting, edema, and rash. In a the face of documented disease progression, a practice that is endorsed
multicenter phase II study, 147 patients were randomly assigned to by National Comprehensive Cancer Network (NCCN) guidelines.
receive 400 or 600 mg of imatinib daily. Although no patient had a In almost all cases, the progression occurs in only a portion of the
complete response during treatment, 79 (54%) had a partial response, tumor, while the majority of the tumor continues to be controlled
and 41 (28%) had stable disease. The median duration of response by imatinib. Stopping all KIT inhibition leads to more rapid, diffuse
had not been reached at a median follow-up of 24 weeks from the tumor progression and shortened survival, and thus is to be avoided
onset of response.77 There were no significant differences in response in clinical practice.
rate or toxicities between the two doses; edema, diarrhea, and fatigue Other soft tissue tumors that express activated tyrosine kinase
were the most common side effects. Gastrointestinal hemorrhage receptors include DFSP (by virtue of PDGFβ signaling) and TGCT
occurred in approximately 5% of patients. (by virtue of CSF1 signaling), whose receptors are blocked by imatinib,
Two RCTs of imatinib were completed in North America483,484 with evidence of radiologic response thereafter. Case reports and series
and in Europe and elsewhere,485 accruing 746 and 946 patients, of patients with DFSP or TGCT have documented responses to
respectively, with locally advanced or metastatic GIST. They compared imatinib.103,494 A phase I clinical trial of PLX3397 in TGCT demon-
400 and 800 mg of imatinib and assessed OS, progression-free survival, strated prolonged tumor regression.107 The phase III trial is ongoing.
and toxicity. There was no significant survival advantage for the higher
dose. Progression-free survival was significantly longer in the EORTC Surgery
study.485 A similar magnitude of improvement (4 months median and The role of surgery in patients with metastatic GIST is becoming
5% increase in 2-year progression-free survival) in the North American better defined. There is no role for surgical resection in patients with
study was not statistically significant (P = .12).484 Most oncologists multifocal recurrence. The advantage of adding surgical resection to
on both sides of the Atlantic prefer to start with the 400-mg dose, imatinib in responding patients in whom all disease may be resected
which is considerably less toxic, increasing it only if patients do not is unknown, because some patients remain on imatinib for 10 years
respond or relapse after the initial response. There are data to suggest or more without progression. Surgery in the setting of focal resistance—
that the higher dose is more effective in the subset of patients with that is, a single progressive metastatic site while other disease appears
exon 9 mutations.486,487 For patients with GISTs who are refractory to be controlled—is one means to be parsimonious with surgical
to imatinib, sunitinib, a compound that targets multiple tyrosine intervention, and most consider it a reasonable treatment strategy;
kinases (KIT, PDGFRs, FLT3, and VEGFRs), may be effective, and the role of surgery in advanced GIST is being pursued in randomized
has been approved in many countries based on a progression-free clinical trials of early (at best response) versus later (e.g., focal progres-
survival and OS advantage of sunitinib in comparison to placebo.488 sion) surgery. It is clear that imatinib must be continued in the
Regorafenib has also demonstrated a significant improvement in postoperative setting in patients with locally advanced or metastatic
progression-free survival in a randomized phase III study that allowed disease resected.161,495,496
crossover for progressing patients (and for those who had been on
regorafenib as well).489 These data from an RCT support the use of Head and Neck Sarcomas
regorafenib in third-line metastatic GIST after failure of imatinib and
sunitinib. Head and neck sarcomas are uncommon, accounting for only 4% of
One observation from the early studies of imatinib in GIST was all sarcomas and less than 1% of head and neck malignancies in adults.
that traditional responses to treatment frequently underestimated the (A detailed discussion of the current state of knowledge for adult and
obvious clinical benefit that was observed. Van den Abbeele and pediatric head and neck sarcoma is available elsewhere.497) The most
colleagues noted that responses measured with PET at 1 month common histologic subtypes in adults are ill-defined fibrosarcoma
predicted for improved progression-free survival, whereas bidimensional (18%), UPS (formerly termed malignant fibrous histiocytoma [MFH])
responses according to SWOG criteria did not.490 Choi and colleagues (16%), and rhabdomyosarcoma (15%).308 In recent large series of
noted that response on CT often included decrease in size but that 176,308 188,498 and 254499 patients with head and neck sarcomas, the
the degree of tumor shrinkage would have been classified as a minor most common anatomic sites were the neck (23%–38%) and paranasal
response in a substantial fraction of the patients.491 The tumors were sinuses (14%–30%).
also noted to have decreased in density after contrast enhancement.490 In the pediatric population, 40% of all STSs occur in the head
Choi and colleagues defined CT changes that correlated with PET and neck, where the most common histologic types are neuroblastoma
and embryonal rhabdomyosarcoma. The treatment of these lesions relapses manifested (overall control rate of 82%).212 This population
in the pediatric population is beyond the scope of this chapter and of head and neck patients included five patients with intracranial
is reviewed in Chapter 92. extension and one with spinal cord compression; more than half of
Methods of diagnosis, imaging, and biopsy for head and neck the lesions were greater than 5 cm in size (a formidable problem for
sarcomas do not differ substantially from those for other head and lesions in this anatomic location), and 85% were deep to the investing
neck tumors. Wide surgical excision with negative margins is the fascia. The series also contained four angiosarcoma patients, a group
therapeutic mainstay for head and neck sarcomas. Regional lymph of patients with sinister local control probability (see Vascular Sarcomas,
node metastases are rare, occurring in only 4% to 6% of patients in later). In fact, three of the seven local failures occurred in the angio-
large series.498,499 Therefore in the absence of clinically positive lymph sarcoma patients. If the series is confined to more usual STS, the local
nodes, regional lymphadenectomy is not routinely performed. control rate was 33 out of 36 (92%). The metastatic relapse-free rate
Series have identified prognostic factors for head and neck sarco- also exceeded 80% in this series, potentially related in part to the
mas.156,159,308,498,499 Multivariate analyses of patients with head and smaller overall dimension of sarcomas in this location compared with
neck sarcomas identified high histologic grade and positive surgical sarcomas elsewhere. The improved local control compared with a
margins as independent adverse prognostic factors for survival.158,159 previous series of patients treated at the same institution might also
Age greater than 60 years at diagnosis was also found to be an have contributed to this amelioration because the local control rate
independent adverse prognostic factor in one multivariate analysis.159 in the earlier series was substantially lower and death from concurrent
Additional data from the Mayo Clinic confirm that the presence of local and metastatic disease was evident.502
metastases is associated with a poor (25%) 5-year OS rate and that Wound complications, assessed by the Canadian trial criteria,228
certain histologic subtypes (angiosarcoma and nonorbital rhabdomyo- were also seen with less frequency in this prospective study of head
sarcoma) may have an adverse prognosis.499 and neck lesions (overall rate, 8 of 40 [20%])212 than noted earlier
Patterns of failure for head and neck sarcomas reflect the difficulty with preoperative radiotherapy in extremity lesions. This may relate
in obtaining adequate surgical margins in the head and neck region. to the greater use of flaps for head and neck reconstruction.
Local recurrence remains a significant problem, with overall rates At present, useful guidelines for administering preoperative
of local recurrence ranging from 14% to 48%,308,498,500 making it radiotherapy in the head and neck are (1) the need to maximally
important to consider appropriately applied principles of sarcoma restrict radiotherapy volumes in some anatomic sites (e.g., close to
management with combined modality approaches where appropri- critical anatomy); (2) the desire to minimize radiation dose in some
ate. As with sarcomas elsewhere in the body, biologic behavior is a situations (e.g., where critical neurologic tissues are in close proximity,
function of histologic grade, with local recurrence rates ranging from such as the optic structures); and (3) a desire not to irradiate new
22% for low-grade head and neck sarcomas to 48% for high-grade tissues, especially vascular reconstructions that are vulnerable to the
lesions.308 Systemic recurrence develops in 12% to 31% of patients effects of high-dose postoperative radiotherapy.
despite complete resection.308,500 Overall 5-year survival rates are 45% to
68%.308,498,499,501 Genitourinary Sarcomas
Radiation Treatment Although STSs of the genitourinary tract are uncommon in adults,
On the basis of experience gained in treating extremity sarcomas, they account for up to 8% of all malignant disease in children younger
adjuvant radiotherapy should be considered whenever there is doubt than 15 years.503 The management of genitourinary sarcomas in children
as to the adequacy of surgical margins or if the location of the tumor has been more successful than that in adults and is discussed in detail
precludes complete excision. Evidence for the benefit of adjuvant elsewhere in this book. In the Memorial Sloan Kettering Cancer Center
radiotherapy is less plentiful than in extremity lesions and probably adult sarcoma database, only approximately 3% were of genitourinary
relates to the rarity of these lesions and the absence of randomized origin. The paratesticular region (33%) and prostate or seminal vesicles
trials addressing the specific issues for these lesions. However, Tran (28%) are the most frequent sites of genitourinary sarcomas, followed
and colleagues from UCLA have shown that the rate of local control by the bladder (23%) and kidneys (16%). The most common histologic
was 52% with surgery alone versus 90% in head and neck patients subtypes in adults are leiomyosarcoma (44%) and rhabdomyosarcoma
who were treated with combined radiotherapy and surgery.585 Additional (33%), although a spectrum of other histologic subtypes has been
evidence from Princess Margaret Hospital reveals that head and neck reported.504
STS patients with clear surgical margins or microscopic residual disease A feature of genitourinary sarcomas that distinguishes them from
had similar local failure rates (26% and 30% failure, respectively), other sarcomas is the fact that the vast majority of these lesions are
provided that radiotherapy was administered.502 Indeed, these outcomes of high histologic grade. In a report from the Memorial Sloan Kettering
for radiotherapy after R0/R1 resections approach those achieved in Cancer Center, fully 86% of genitourinary sarcomas were high grade,
extremity sarcoma. and 56% were larger than 5 cm.504 Similar findings have been reported
One strategy to improve outcome in head and neck sarcomas is from the MD Anderson Cancer Center, where 15 (88%) of 17 primary
through the use of preoperative radiotherapy. This approach may have sarcomas of the kidney met pathologic criteria for high-grade classifica-
particular advantages in this site because of the smaller volumes of tion and tumor size ranged from 5.5 to 23 cm.505 These findings have
radiotherapy and the lower doses that may be used compared with obvious prognostic implications, and series reports have indicated
the postoperative treatment in difficult surgical access locations, relatively poor 5-year OS rates for patients with high-grade histologic
especially in the base of the skull. Obvious advantages that are provided type (48% versus 100% for low-grade lesions) or large tumor size
relate to the ability to spare critical anatomy such as the optic structures (30% for lesions ≥5 cm versus 83% for lesions <5 cm).
(globes, optic nerves, and the optic chiasm) and the brainstem and The primary treatment for genitourinary sarcomas, as with sarcomas
spinal cord. If for no other reason, the preoperative approach promotes elsewhere in the body, is complete resection with histologically negative
collaboration between the surgical and radiation oncologist, facilitates margins. There are no comparative trials specifically evaluating adjuvant
a complete management plan to be fashioned before any surgical therapy in this subgroup of sarcomas, but most investigators have
intervention, and maximizes the opportunity to achieve control even extrapolated from the lessons that have been learned with extremity
when disease may be resected with a small but planned positive margin STS and use adjuvant therapy for patients with high-risk lesions,
against critical unexpendable anatomy, as was discussed earlier.210 including those with high histologic grade, large tumor size, microscopi-
In a prospective series of 40 patients (excluding rhabdomyosarcoma) cally positive margins, gross residual disease, or unfavorable anatomic
with adverse selection criteria managed with preoperative radiotherapy site (prostate or kidney). Using preoperative chemoradiation and surgery
between 1989 and 1999 at the Princess Margaret Hospital, seven local for patients with nonbulky sarcomas of the bladder and prostate and
postoperative chemoradiation after radical surgery for patients with of prognosis, but because there are virtually no survivors among patients
bulky disease, investigators at UCLA and at the City of Hope have in whom extrauterine disease is found at the time of exploration,
reported encouraging results, with 9 of 11 patients with leiomyosar- therapeutic extrapelvic dissection has no role. In a review of 423
comas alive with no evidence of disease at a mean follow-up of 61 patients from the West Midlands Cancer Registry, 5-year survival
months.506 These promising results are similar to those reported from rates for patients with stage I, II, III, or IV (International Federation
the Mayo Clinic for a subset of seven patients with bladder sarcomas of Gynecology and Obstetrics [FIGO] staging system) uterine sarcomas
who were treated with preoperative radiotherapy and cystectomy507 were 51%, 13%, 10%, and 3%, respectively.163
and are superior to those observed in a small series of patients who A number of investigators have evaluated adjuvant therapy for
were treated with surgery alone.508 MMMT and overt sarcomas. To date, there is only one completed
Paratesticular and spermatic cord sarcomas, if managed appropriately, RCT, which evaluated pelvic radiation versus observation after resection
can provide satisfactory outcome, as was reported in small series from of FIGO stage I or II uterine MMMT and other sarcomas. This study
the Princess Margaret Hospital509 and the MD Anderson Cancer demonstrated a decreased risk of local recurrence with radiation, but
Center.510 Simple excision proved to be inadequate treatment for no effect on OS.521 A study of chemotherapy (cisplatin-ifosfamide)
sarcomas in the spermatic cord and paratesticular region. In the Princess versus whole abdominal radiation as an adjuvant to surgery for stage
Margaret Hospital report, wide repeat excision revealed microscopic I to IV uterine carcinosarcoma demonstrated modest numeric superior-
residual disease in 27% of completely excised cases. These series suggest ity of chemotherapy over radiation, but no statistically significant
that adjuvant radiation should be considered for these patients and difference in OS.522 These results parallel findings that have been
for those with narrow repeat resection margins. Definitive conclusions noted for patients with extremity sarcomas: demonstrable improvement
on multimodality therapy for genitourinary sarcomas await further in local control with adjuvant radiation but no impact on survival,
experience with larger numbers of patients. and modest benefit, if any, with chemotherapy, although the same
The comparative infrequency of these lesions and the lack of a concerns exist pertaining to the small sample size to detect an effect
uniform staging system leads to difficulties in comparison of series of this kind.204,209
and identification of prognostic factors. Prognostic factors for survival Several investigators have identified prognostic factors for survival
were analyzed in the series from the Memorial Sloan Kettering Cancer in uterine sarcoma.163,523 Multivariate analysis of 423 cases of uterine
Center, and, on univariate analysis, favorable prognostic variables sarcoma demonstrated that advanced tumor stage, poor histologic
included tumor diameter less than 5 cm, low histologic grade, para- grade, increased age, and leiomyosarcoma histologic subtype (versus
testicular or bladder (versus kidney or prostate) tumor site, and complete MMMT) are characteristics that adversely affect survival.163 A similar
surgical resection.504 No significant differences in survival were noted multivariate analysis by the Gynecologic Oncology Group of prognostic
on the basis of patient age, sex, or histologic subtype. A poor prognosis factors in 453 patients with uterine sarcomas demonstrated that factors
for patients with primary renal sarcomas has also been observed at related to progression-free interval were histologic grade, histologic
MD Anderson, with 13 of 15 evaluable patients dead of disease after type (homologous versus heterologous MMMT), adnexal spread, and
a mean of 23 months.505 Complete tumor resection was possible in lymph node metastasis.523 These prognostic factors are of importance
72% of patients in the series of 43 adult genitourinary sarcomas from for selecting adjuvant therapy for individual patients and in designing
Memorial Sloan Kettering. The 5-year OS rate was 64% for this group future clinical trials in uterine sarcoma.
of patients. No patient with an incomplete resection survived 5 years.
Unfortunately, as with head and neck rhabdomyosarcomas, the Chemotherapy
favorable results that are observed in pediatric patients with genito- There is some evidence that MMMTs respond well to cisplatin chemo-
urinary rhabdomyosarcoma treated with a multimodality approach therapy alone524 or in combination with other drugs, in keeping with
(58%–74% 5-year OS rate)511,512 have not been observed in adults; the present understanding of their biology as metaplastic carcinomas.525
in one study only 5 (36%) of 14 adults were alive at the time of Ifosfamide also seems to be active in MMMT,526 but doxorubicin
analysis (median follow-up, 32 months) despite aggressive multimodality appears of more limited value.526 In a Gynecologic Oncology Group
therapy.504 study527 in which 76 patients with completely resected MMMT were
given three cycles of adjuvant ifosfamide/cisplatin, 2-year RFS (63%)
Uterine Sarcomas and Carcinosarcomas and OS (74%) rates were better than those for historical controls.
The findings of the aforementioned adjuvant study underscore the
Uterine sarcomas are uncommon neoplasms that make up between activity of cisplatin and ifosfamide in MMMT or carcinosarcoma.
2% and 4% of uterine malignancies.513,514 The three main histologic Paclitaxel combined with topotecan produced a 29% response rate
subtypes in a recent series of 66 uterine sarcomas were as follows: in 45 patients with recurrent mullerian tumors,528 and a retrospective
mixed mesodermal (müllerian) tumors (MMMTs), which primarily analysis of MMMT of the ovary found a very high response rate
include carcinosarcoma (metaplastic carcinoma rather than sarcoma (72%) for a combination of paclitaxel and cisplatin.529 Further explora-
per se), 48%; leiomyosarcomas, 36%; and endometrial stromal sarcomas tion of agents active in epithelial ovarian cancer may be justified in
(ESSs), 15%.515 It is notable that ESSs are now differentiated between MMMT.
(low-grade) ESS, a hormonally responsive tumor with a specific In contrast, uterine leiomyosarcoma, which often metastasizes to
translocation, and undifferentiated endometrial sarcoma, formerly the lung rather than the liver, responds to doxorubicin.526 With respect
high-grade ESS, a highly lethal disease with a different set of transloca- to adjuvant chemotherapy, no significant differences in recurrence,
tions than ESS. As with patients who have adenocarcinomas of the progression-free survival, or OS rates were evident in a Gynecologic
uterus, most patients with uterine sarcomas have vaginal bleeding Oncology Group RCT of 156 patients comparing doxorubicin (60 mg/
(77%–99%) or pelvic pain (30%) at presentation.516–519 A palpable m2) with no adjuvant chemotherapy after resection of stage I uterine
pelvic mass is present in 20% to 50% of patients.519,520 The diagnostic sarcomas.530 This trial was underpowered to detect small differences
workup is similar to that for the common uterine neoplasms and in outcome, however. The combination of gemcitabine, 900 mg/m2
involves an outpatient biopsy or fractional dilation and curettage. over 90 minutes on days 1 and 8, plus docetaxel 100 mg/m2 on day
Imaging studies, including CT and MRI, are used preoperatively in 8 (75 mg/m2 in an off-protocol setting) was initially studied in uterine
patients with positive preoperative biopsy findings or those with leiomyosarcoma at Memorial Sloan Kettering Cancer Center.407 There
clinically apparent masses at examination. was a 53% response rate, and median progression-free survival was
The standard treatment approach for patients with localized disease 5.6 months. The randomized SARC002 study indicated that the
is total abdominal hysterectomy with bilateral salpingo-oophorectomy. combination provides improved progression-free survival and OS for
Complete abdominal exploration is important from the standpoint uterine and nonuterine sarcomas alike.
Desmoid Tumors (Aggressive Fibromatoses) single-institution experiences; therefore there is no clearly defined
consensus on the role of radiation therapy in the management of
Desmoid tumor is an uncommon malignancy. It is estimated that patients with desmoid tumors.
approximately 1000 new cases (three to four cases per million) occur
annually in the United States.531 The tumor arises principally from Chemotherapy
the connective tissue of muscle and the overlying fascia or muscular Patients with desmoid tumors usually are seen by a medical oncologist
aponeurosis. Clinically, the tumor manifests as a poorly circumscribed, only if the tumors have progressed after surgery and radiotherapy and
initially painless mass and is commonly located in the muscles of the are considered inoperable or are located at sites that are not amenable
shoulder and pelvic girdle and frequently in the thigh. It is most to full-dose radiotherapy. Given the activity of hormonal therapy,
common in patients between the ages of 20 and 40 years with a peak systemic chemotherapy, or multitargeted tyrosine kinase inhibitors,
incidence of 25 to 35 years. Aggressive fibromatosis, extra-abdominal systemic treatment may be a more attractive way to achieve tumor
desmoid, well-differentiated nonmetastasizing fibrosarcoma, and grade I shrinkage and control with substantially less morbidity than surgery.536
fibrosarcoma are terms that have also been used to describe this lesion Desmoid tumors are rarely life-threatening, except in the case of
in the past; the latter two have been largely discarded to prevent intraabdominal desmoids that are seen in FAP or Gardner syndrome,
confusion with sarcomas, which have the ability to metastasize, a which may kill patients via invasion of vital intraabdominal organs.
feature never observed with desmoid tumors. Rare responses have been reported to nonsteroidal antiinflammatory
drugs; antiestrogens have well-recognized activity.537–539 Desmoids also
Surgery and Radiation respond to relatively low-dose chemotherapy with methotrexate (50 mg
Surgical resection remains the mainstay of therapy for desmoid tumors, per week) and vinorelbine (25 mg/m2 per week).539 Regressions are
although observation alone is increasingly used in patients with static often slow, and toxicity sometimes requires administration to be
and largely asymptomatic lesions, owing to the slow change of many extended to 2-week intervals. Several groups have shown the activity
of these lesions and morbidity of surgery in this group of generally of a more toxic combination involving vinblastine in lieu of vinorel-
younger patients.532 Wide local resection with negative microscopic bine.540,541 A more aggressive regimen of doxorubicin and dacarba-
margins (R0) is obviously preferred over an incomplete resection. zine542,543 produced substantial regressions in desmoids secondary to
When resection is performed with positive microscopic surgical margins, Gardner syndrome, and these drugs are also active in sporadic desmoids.
local recurrence rates are substantially higher. Unfortunately, there are This regimen (or either drug as a single agent) produces greater toxicity,
relatively few large series that outline actuarial local recurrence–free however, and should be reserved for patients with aggressive, symp-
survival rates stratified by microscopic margin status for patients treated tomatic disease. A variety of single systemic chemotherapy agents have
with surgery alone. Series with margin-specific local recurrence-free activity in desmoid tumors. As outlined in one review536 and a retrospec-
rates are summarized in Table 90.14.533–535 The experience of these tive analysis, the activity of sorafenib544 was demonstrated more than
institutions suggests that the local control rates for patients who are imatinib in case series and clinical trials.545 In order to consolidate
treated with surgery alone is on the order of 50% when microscopic responses achieved with targeted agents, for at least some patients
surgical margins are positive (R1 resection), compared with approxi- systemic chemotherapy can be considered; however, in this situation
mately 75% when microscopic surgical margins are negative (R0 just the systemic therapy alone could be considered. These conjectures
resection). As a consequence of the propensity for local recurrence, can hopefully be addressed in randomized clinical trials.
many groups have used postoperative EBRT for patients undergoing
local excision (R0 or R1).533,534 Postoperative EBRT is usually given Breast Sarcomas
to patients who are thought to be at higher risk for local recurrence.
However, some groups use external beam radiation for patients who Primary sarcomas of the breast account for less than 1% of all primary
have undergone an R0 resection (because of the generally high local breast neoplasms.546 They should be distinguished from cystosarcoma
recurrence rates associated with surgical treatment alone) and for most phyllodes and sarcomatoid carcinoma of the breast (carcinosarcoma),
patients who have undergone an R1 resection. The criteria for selecting which are distinct neoplastic entities. The most common histologic
patients for postoperative radiation vary widely and are largely subtypes of breast sarcomas are UPS, liposarcoma, and angiosar-
subjective. coma.547,548 A disproportionate number of angiosarcomas appear to
Interpretation of the limited literature on the use of EBRT in the arise in the breast either de novo549 or after breast conservation surgery
management of localized desmoid tumors is hampered by the rarity of for adenocarcinoma treated with adjuvant radiation.550–552 In general,
the lesion and the absence of margin-specific actuarial local recurrence however, the etiology of most breast sarcomas is unknown. An associa-
rates for large series of consecutively treated patients. Retrospective tion between augmentation mammoplasty with silicone prostheses
comparisons stratified by margin status suggest that local recurrence rates and development of breast sarcoma was postulated, but analysis of
might be reduced for patients treated with combined-modality therapy. the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program
The data substantiating this are all retrospective, nonrandomized, database failed to demonstrate any relationship.553
Table 90.14 Local Recurrence-Free Rates After Surgery for Patients With Desmoid Tumors
LOCAL RECURRENCE–FREE
SURVIVAL
Institution No. of Patients Follow-Up (mo) Overall (%) R0 (%) R1 (%)
MGH 51 12–59 69 77 56a
MDACC 122 113 62 73b 46b
MSKCC 128 88 71 86a 49a
a
Using 5-year actuarial analysis.
b
Using 10-year actuarial analysis.
MDACC, University of Texas MD Anderson Cancer Center; MGH, Massachusetts General Hospital; MSKCC, Memorial Sloan Kettering Cancer Center; R0, microscopically negative
surgical margins; R1, microscopically positive surgical margins.
At physical examination, breast sarcomas are usually well circum- dermis of the scalp or tissues of the face.561 In the head and neck,
scribed, firm, mobile, and painless. Mammography frequently dem- cutaneous angiosarcoma may be difficult to treat with surgery because
onstrates a well-circumscribed lesion, in contrast to the irregular, stellate of the infiltrating nature of the disease and the anatomic constraints
appearance of most mammary carcinomas. With the use of core needle of the head and neck that make wide surgical margins difficult to
biopsy, an increasing number of these lesions are diagnosed preopera- achieve. Primary chemotherapy with the possible addition of radiation
tively. This is important in planning an operative approach for these is preferable.
patients. Because breast sarcomas rarely spread to regional lymph OS rates for patients with localized disease who undergo curative
nodes,554–556 axillary lymph node dissection is not indicated for patients resection are similar for angiosarcomas and malignant hemangioperi-
with a clinically negative axilla. The treatment of choice for breast cytomas (68%–72%). A clear survival advantage for patients with
sarcomas is wide local excision with histologically negative margins, low-grade lesions was not demonstrable in this study, although other
or mastectomy in the case of angiosarcoma. Depending on the relative investigators have reported such a relationship for cutaneous angio-
proportions of the tumor and the breast, other histologic types also sarcomas.562 Several investigators have suggested that tumor size might
sometimes warrant total mastectomy. Given the locoregional recurrence be an important prognostic factor for survival in patients with malignant
of angiosarcomas, it is difficult to recommend immediate reconstruction; hemangiopericytomas563,564 and angiosarcomas of the face and scalp,565,566
for other histologic types the locoregional recurrence risk is lower. although no relationship was noted in the study from Memorial Sloan
Adverse prognostic factors for survival include high histologic grade Kettering.
and an infiltrative histologic pattern.548,554,556,557 A retrospective review
of 83 patients with primary breast sarcomas treated predominantly Surgery
with surgery and selective use of adjuvant chemotherapy and/ By definition, these lesions are vascular, and this should be borne in
or radiation revealed 10-year OS and disease-free survival rates of mind in planning preoperative biopsy and surgery. In the study from
62% and 50%, respectively.550 On the basis of this report and early Memorial Sloan Kettering, perioperative bleeding was noted in 33%
reports,554–556 it appears that patients with primary breast sarcomas of patients, with 18 of 69 patients experiencing extensive blood loss
have a natural history, prognostic factors, and outcome after combined- (>1000 mL) and two deaths related to hemorrhage.559 Frozen section
modality treatment similar to those of patients with extremity control of microscopic surgical margins is advisable, given the locally
sarcomas. infiltrative nature of many angiosarcomas, particularly those that arise
Adjuvant radiotherapy has no clearly defined role in this disease, on the scalp.
although it would appear prudent to offer radiation to patients who
are at high risk for local recurrence (microscopically positive margins Adjuvant Therapy
or presentation with recurrent breast sarcoma). In addition, in a report There is no clearly defined role for adjuvant radiation or chemotherapy
of a mixed group of breast sarcomas and phyllodes tumors at the for vascular sarcomas, although it seems reasonable to extrapolate
Princess Margaret Hospital, breast conservation seemed to be attainable from data derived from extremity lesions and offer adjuvant radiotherapy
with use of conservative margin-negative excision and adjuvant to patients with high-risk lesions. Unfortunately, aggressive surgical
radiotherapy in an organ-preserving approach that is consistent with approaches might prove disappointing owing to the unusual capability
contemporary management for both breast cancer and STS.558 of this disease to exhibit edge recurrence and manifest disease relatively
remote from the initial site of presentation. Alternative radiotherapy
Vascular Sarcomas techniques such as modulated electron radiotherapy are promising
and could be applied in the future to the treatment of wide field areas
The term vascular sarcoma includes the histologic subtypes of angio- that require only superficial penetration at depth, as is the case in
sarcoma (which for many pathologists also includes lymphangiosarcoma, craniofacial angiosarcoma. Considering the proximity of the brain
given that the two cannot be distinguished), hemangioendothelioma, and eyes in these lesions, limiting the depth of penetration and
and other tumors such as Kaposi sarcoma and rarer entities. Solitary consequent reduction in dose to tissues that are deeper to tumor is
fibrous tumor, formerly termed hemangiopericytoma, is sometimes the attractive aspect of this technology.567
included with these other tumor types. Together, these lesions account Paclitaxel and other microtubule active agents appear active in
for at most 3% of all STSs.559 A minority of these lesions are associated angiosarcomas, especially those arising in the scalp or the skin of the
with well-known environmental factors, as is noted in Table 90.1. In breast.400,568 A complete remission in a patient with metastatic angio-
a national review of 99 Japanese patients with angiosarcoma, angiosarcoma was seen in the phase II study of gemcitabine at MD
sarcoma was most commonly located on the head or face (29 patients) Anderson,398 so the combination of gemcitabine and docetaxel is
and was found to be associated with several predisposing conditions, particularly appealing for these tumors. Angiosarcomas are also quite
including chronic pyothorax (six patients), use of Thorotrast in the sensitive to standard doxorubicin-ifosfamide therapy, but responses
liver (five patients), previous radiotherapy (four patients), and chronic tend to be of short duration. Such therapy should be considered
lymphedema (one patient).560 Virtually all of the literature on these initially for visceral lesions such as those arising from the heart.
rare neoplasms focuses on individual histologic and site-specific subtypes Multitargeted tyrosine kinase inhibitors that affect vascular endothelial
and includes pediatric patients. These facts, and the relative infrequency growth factor receptor and bevacizumab also have activity in angio-
of these lesions, make general estimates of survival difficult for adult sarcoma.440,569,570 The combination of bevacizumab and temozolomide
patients with vascular STSs. has activity in solitary fibrous tumors, as may inhibitors of insulin-like
In a review of 69 patients with vascular sarcomas and malignant growth factor 1 receptor, although data are limited to case reports
hemangiopericytoma (not truly a vascular tumor) from Memorial thus far.571
Sloan Kettering Cancer Center, 35 patients (51%) had angiosarcoma,
28 (41%) had malignant solitary fibrous tumor, and 6 (9%) had Chemotherapy Considerations for Specific Histologic Subtypes
lymphangiosarcoma, which is now no longer distinguished from Synovial sarcomas
angiosarcoma.559 No anatomic site was spared from involvement. The Rosen and colleagues572 were the first to suggest that synovial sarcomas
most common sites of involvement for angiosarcomas and malignant were particularly responsive to ifosfamide. They documented three
hemangiopericytomas were similar: visceral, retroperitoneum, head complete responses and nine partial responses in 13 patients (9 of
and neck, and extremities. The six tumors termed lymphangiosarcomas whom had received prior doxorubicin-based chemotherapy) with
in this series all occurred in an edematous extremity. metastatic synovial sarcomas. These investigators also reported on 14
Cutaneous angiosarcoma is a variant of angiosarcoma that often patients with localized synovial sarcomas who received adjuvant
arises in the head and neck and frequently diffusely infiltrates the doxorubicin-ifosfamide-cisplatin chemotherapy.573 There was one
patient with local recurrence, but the remaining 13 patients (93%) Progression-free survival was 88% at 6 months. For comparison, in
remained disease free at a median follow-up period of 37 (6–85) all STSs, including those with myxoid–round cell liposarcoma, the
months. In a large EORTC phase II trial of 124 patients with advanced RECIST response rate to trabectedin is about 10%, and the progression-
STS who received ifosfamide (12 g/m2), the overall response rate for free survival rate is 20% at 6 months. Therefore myxoid–round cell
all histologic subtypes was 16%,387 but 8 (44%) of 18 patients with liposarcomas are uniquely sensitive to this agent.
synovial sarcoma responded. Edmonson and colleagues described a Activation of the peroxisome proliferator-activated receptor–γ
higher response rate in synovial sarcomas for doxorubicin-ifosfamide (PPAR-γ) nuclear receptor stimulates terminal differentiation in
than for doxorubicin alone (88% versus 20%; P = .02) in the setting preadipocytes and in liposarcoma cell lines regardless of histologic
of an RCT of multiple histologic subtypes of STS.371 A subsequent subtype.576 Troglitazone, previously used in the treatment of diabetes
ECOG phase II study of doxorubicin-ifosfamide in synovial sarcomas mellitus, is an activating ligand for PPAR-γ. Biopsies before and after
showed 5 partial responses (42%) in 12 patients; however, the median troglitazone therapy were performed in 34 of 49 patients with different
survival for the whole group was only 11 months, and the trial was types of liposarcomas entering a phase II trial.577 Five of seven (71%)
closed because of poor accrual.574 In many studies evaluating ifosfamide, evaluable patients with myxoid–round cell disease exhibited histologic
including some of the RCTs, the question of response by histologic evidence of lineage-appropriate differentiation of liposarcoma cells,
subtype has not been addressed, and most of the data on histologic whereas only one of three (33%) patients with high-grade pleomorphic
variations in response come from subset analyses of larger trials. Because disease showed such changes. The clinical significance is of this finding
many of the patients with synovial sarcoma are young and fit, inclusion is limited, because a phase II study in liposarcoma demonstrated no
of ifosfamide in first-line chemotherapy for metastatic disease seems radiologic responses.578
reasonable. If the circumstances merit adjuvant chemotherapy, an Both well-differentiate and dedifferentiated liposarcomas have
anthracycline-ifosfamide combination would be a logical choice. amplification on chromosome 12 of MDM2 and CDK4 in 80% of
cases.579 Dickson and colleagues performed a nonrandomized phase
Leiomyosarcomas II clinical trial of the CDK4 inhibitor palbociclib.580 Sixty patients
Hensley and colleagues407 were the first to report the activity of the were treated. The progression-free survival rate at 12 weeks was 57.2%
gemcitabine-docetaxel combination in patients with leiomyosarcomas. (2-sided 95% CI, 42.4%–68.8%), and the median PFS was 17.9
Although clearly active in that subset, particularly in leiomyosarcomas weeks (2-sided 95% CI, 11.9–24.0 weeks). Further work targeting
arising from the uterus, this regimen is broadly active and should not MDM2 and CDK4 is needed.
be limited to leiomyosarcomas, as noted in a follow-up randomized
study of gemcitabine-docetaxel versus gemcitabine.410 Investigators in Pediatric Sarcomas in Adults
other series have questioned the activity of the combination compared
with the use of gemcitabine alone. In contrast to the increased activity Embryonal and alveolar rhabdomyosarcomas and PNETs including
of ifosfamide in synovial sarcomas, ifosfamide appears less active against extraskeletal Ewing sarcoma all appear to be chemotherapy sensitive
leiomyosarcomas than against other subtypes,363,376 even when GISTs when they occur in adults. Adult patients with these tumors should
were excluded,376 and high-dose ifosfamide had a similar lack of receive aggressive combination chemotherapy similar to that offered
efficacy.364,383,386 to children with the same disease; one caveat is that the weekly vin-
cristine used in rhabdomyosarcomas in children is intolerable in
Liposarcomas adults.581,582 The outcome appears to be poorer for adults with “pediatric
Marked clinical activity of trabectedin (ET-743) was noted in patients sarcomas” than for pediatric sarcoma patients. Greater detail on these
with myxoid–round cell liposarcoma.575 Among 51 patients who were diagnoses is available in Chapter 92.
treated at five institutions, a RECIST response rate of 51% was noted,
with objective benefit characterized by decreased postcontrast tumor
density in all of the responding patients, and an additional 29% were The complete reference list is available online at
categorized as having minor response or stable disease by RECIST. ExpertConsult.com.
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Sarcomas of Soft Tissue • CHAPTER 90 1693.e1
1693.e1
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Sarcomas of Soft Tissue 90

Brian A. Van Tine

Table 90.1 Soft Tissue Sarcoma: Predisposing Environmental Factors

Table 90.2 Germline Mutations Associated With Soft Tissue Sarcoma

AD, Autosomal dominant; AR, autosomal recessive.

Table 90.3 Selected Molecular Alterations Identified in Sarcoma

chromosomal rearrangements of chromosome 12q that involves the PATHOLOGY

N = 460 Upper extremity

16% N = 491 Visceral

cell liposarcoma (28%), and UPS (formerly termed malignant fibrous

of numerous studies and has been reviewed in detail elsewhere. The

Figure 90.6 • Contrast-enhanced computed tomography scan of the STAGING

Stage-specific survival plots based on prior versions of the AJCC criteria

100 Table 90.7 Multivariate Analysis of Prognostic

60 Local recurrence Age >50 years 1.6

a recirculating pump. This technique has allowed for limb salvage

and even large lesions may be managed conservatively in that setting.

anatomically adverse presentations in which locally advanced disease

Local Control Admitted

ARR, Absolute risk reduction.

Outcome data provided in original papers or abstracts.

Table 90.13 Resectability Rates for Retroperitoneal Sarcomas in Selected Series

risk from metastatic disease. If an effective chemotherapeutic regimen

response and showed that they predicted for progression-free survival.492

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