Genetic Predisposition

Germline mutations can play an important role in the development of STSs (Table 93-2). These genetic changes are identified with or similar to the genetic changes that are seen in corresponding sporadic sarcomas (Table 93-3). Mechanistically, the proteins encoded by the altered genes are involved in maintenance of the genome through DNA repair and the cell cycle.

The epidemiological relationship between the development of STS and inherited syndromes associated with a predisposition to neoplasia (e.g., neurofibromatosis and Li-Fraumeni syndrome) has been appreciated for decades.39,40 For example, patients with neurofibromatosis have a 7% to 10% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST).⁴¹ A sudden increase in the size of any neurofibroma suggests malignant transformation.^42,43 The mechanisms underlying the transformation from a benign neurofibroma to MPNST are not well understood.

However, loss-of-function mutations in the NF1 gene, which are found in patients with neurofibromatosis, result in activation of one of the ras signaling pathways, a well-known mechanism that has been identified in a variety of cancers.⁴⁴ It has been observed that secondary MPNSTs (arising from a prior neurofibroma) have deletions of 17p (particularly 17p12–17p13.1) and mutations at the region of the TP53 tumor suppressor gene.^47–47 Thus it is postulated that an initial alteration in the NF1 gene contributes to the formation of a benign neurofibroma through activation of the ras pathway and that secondary mutations in the TP53 gene allow the transformation into MPNST. Because mutations in TP53 lead to an inability to control DNA damage via the cell cycle, they also enable rapid accumulation of other mutations, which encode mutant proteins that undoubtedly play an important role in sarcomagenesis.

Li-Fraumeni syndrome was identified when relatives of pediatric STS patients were noted to have an increased frequency of diverse and often multiple primary cancers.39,48 The neoplasms that were noted in relatives included some STSs, premenopausal breast cancers, brain tumors, adrenocortical carcinomas, leukemias, and occasional germ cell tumors.⁴⁹ Follow-up of Li-Fraumeni kindreds over 2 decades has revealed that the majority of individuals have cancer at young ages, with 79% of those affected younger than age 45 years at the time of diagnosis of malignancy.⁵⁰ The observed cancer distribution in families is believed to fit a rare autosomal dominant mode of genetic transmission with high penetrance.⁵¹ Recent molecular genetic studies have identified germline TP53 mutations in the majority of patients with Li-Fraumeni syndrome.⁵² Germline mutations in CHK2, another component of the cell-cycle checkpoint machinery encoded by a gene located on 22q11, are responsible for another subgroup of patients with Li-Fraumeni syndrome, and other Li-Fraumeni–like patients’ kindreds without TP53 alteration have been described.⁵³

Pediatric patients with familial retinoblastoma have a 13q chromosomal deletion⁵⁴ and an increased incidence of osteosarcoma and other neoplasms, including STS.^15,55,56 The retinoblastoma (Rb1) protein is expressed ubiquitously in normal cells and is a well-known tumor suppressor, involved in maintaining the integrity of the genome through control of the cell cycle. Interestingly, not only is the Rb1 gene that is mutated in osteosarcomas associated with retinoblastoma, but abnormality or absence of the Rb1 gene product has also been observed in multiple other malignancies, including sporadic osteosarcomas, breast cancer,⁵⁷ small cell lung cancer,⁵⁸ and STSs.⁵⁹

Familial adenomatous polyposis, a subset of which includes Gardner syndrome with its desmoid tumors, is caused by germline mutations in the APC gene.62–62 Patients with Gardner syndrome experience desmoid fibromatosis at a younger age than do patients with sporadic desmoids.⁶³ With the use of prophylactic colectomy, progressive mesenteric desmoid tumor is now a significant cause of death of patients who have familial adenomatous polyposis,⁶⁴ as are second neoplasms such as ampullary and duodenal cancers. The APC gene is involved in the Wnt cell-signaling pathway. One of the normal functions of the APC protein is to bind β-catenin.⁶⁵ Thus loss-of-function mutations of APC result in the activation of transcription of oncogenes by β-catenin. Consistent with the importance of this pathway in desmoid tumors, APC loss and CTNNB1 (encoding β-catenin) mutations are also identified in sporadic desmoid fibromatosis.^68–68

Rhabdoid predisposition syndrome is due to inactivating germline mutations in the INI1 gene.⁶⁹ Patients with this syndrome experience one or more extrarenal and/or renal rhabdoid tumors. INI1 is a member of the SWI/SNF protein complex, which controls gene expression globally through its ability to alter chromatin structure.⁷⁰ Thus loss of INI1 gene expression results in other changes in gene expression, specifically activation of oncogenes. Rhabdoid tumors have loss-of-function mutations in both copies of the INI1 gene.⁷¹

Werner syndrome is a rare genetic instability syndrome caused by mutations in the WRN gene.72,73 Affected patients age prematurely and are at greatly increased risk for a variety of cancers, including STSs. The WRN gene encodes a protein involved in DNA repair⁷⁴ and loss of WRN protein function leads to genetic instability, accumulation of genetic mutations, and, ultimately, predisposition to rapid aging and cancer.

Germline mutations in the KIT oncogene are found in patients with familial gastrointestinal stromal tumor (GIST) syndrome.75,76 Activating KIT or PDGFRA mutations are also identified in over 90% of sporadic gastrointestinal stromal tumors (GISTs).⁷⁷ Patients with the familial syndrome experience, to varying degrees, skin hyperpigmentation, urticaria pigmentosa, and cutaneous mast cell disease in addition to one or more GISTs.⁷⁸ Activating KIT mutations have been shown to lead to ligand-independent activation of the KIT receptor tyrosine kinase pathway, which results in dysregulated cell growth, and are thought to be the first step in the pathogenesis of GISTs.⁷⁵ Interestingly, the identification of the important role of KIT in the pathogenesis of GISTs has led to treatment with imatinib,⁷⁹ the oral multitargeted receptor tyrosine kinase inhibitor (see “Prognostic Factors as Therapeutic Targets” and “Gastrointestinal Stromal Tumors” below).

Genetics of Sporadic Soft-Tissue Sarcomas

Sarcomas tend to fall into two major subsets. In one group, the tumors are cytogenetically simple and are characterized by near diploid karyotypes with few chromosomal rearrangements, resulting in the formation of fusion proteins. These translocations are highly diagnostic of specific histologic subtypes of STSs. Also included within the cytogenetically simple STSs are GISTs, which are characterized by a specific activating mutation of KIT or PDGFRA genes, but otherwise have relatively limited genetic abnormalities.

Chromosomal Rearrangements

A large number of sarcomas have been found to have consistent chromosomal abnormalities (see Table 93-3).⁸⁰ These chromosomal rearrangements are important diagnostically, may be important prognostically (see “Potential Molecular Prognostic Factors” below), and have shed light on the pathogenesis of sarcomas. Some of the specific translocations, such as those seen in dermatofibrosarcoma protuberans or tenosynovial giant cell tumor provide targets for pharmacologic therapy (see the section on treatment of GISTs). Benign soft-tissue neoplasms also harbor chromosomal rearrangements.

Chromosomal translocations are the most common cytogenetic abnormality in soft-tissue neoplasms and are likely responsible for the initiation of tumorigenesis in most cases.⁸⁰ Deletions and trisomies have also been reported and are thought to represent secondary changes involved in tumor progression. Deletions tend to represent loss of tumor suppressor genes, whereas trisomies suggest the presence of an oncogene. Although we know much about the principal tumorigenic events in many sarcomas, defining the secondary changes has been much more problematic and is an area of intense study with the advent of large-scale tumor DNA and RNA sequencing and related genomic techniques.

Cloning and molecular analysis of the various genetic aberrations that characterize different sarcomas have revealed the different pathogenetic mechanisms that underlie these tumors. Translocations typically create chimeric transcription factors or growth factors that result in deregulation of transcription or growth control. A typical example of a chimeric transcription factor is the PAX3-FOXO1 fusion protein, which has been shown to activate a complex myogenic transcriptional program when the protein is expressed in a fibroblast cell line.⁸¹ Infantile fibrosarcoma is characterized by a translocation involving chromosomes 12 and 15 that encodes a chimeric ETV6-NTRK3 constitutively activated growth factor receptor, which remarkably is found in other cancers such as secretory breast cancer, a subset of acute myelogenous leukemia, and a form of salivary gland carcinoma.⁸² Other oncogenic proteins appear to act by a mechanism that remodels chromatin structure, which is known to have a profound influence on gene expression (e.g., INI1 mutations in rhabdoid tumors).⁷¹ Specific chromosomal rearrangements are very useful in the diagnosis of STSs. Beyond the obvious benefit of providing further objective proof of a diagnosis in morphologically typical cases, the detection of chromosomal aberrations may facilitate the diagnosis of lesions that are difficult to characterize by standard histopathological, ultrastructural, and immunohistochemical techniques.^83,84 For example, the presence of the translocation t(X;18)(p11;q11) has been used to confirm the diagnosis of synovial sarcoma in poorly differentiated cases that were diagnostically very challenging.^87–87 Similarly, the finding of the characteristic translocation t(11;22)(q24;q12) in a small round blue cell tumor supports the diagnosis of Ewing sarcoma/primitive neuroectodermal tumor (PNET).⁸⁸ By the same token, a morphologic sarcoma subtype without an expected translocation may suggest a variant translocation, as has been observed in Ewing sarcoma–like small round blue cell tumors that lack the EWSR1-FLI1 translocation but rather contain CIC-DUX4 or a pericentric X chromosome inversion.^91–91

Translocations may be identified by a variety of genetic analyses, spanning older techniques such as cytogenetic analysis to fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and RNA sequencing. A detailed description of these techniques is beyond the scope of this chapter, but each technique has its advantages and disadvantages. Cytogenetic analysis requires fresh (living) tissue, because the cells need to be cultured before karyotypic analysis, and it largely has been supplanted by newer techniques. Fluorescence in situ hybridization does not require fresh or frozen tissue and frequently may be used with paraffin-embedded material; it is a standard diagnostic tool in many pathology laboratories. It is noted that evidence of a translocation by fluorescence in situ hybridization is not absolutely diagnostic of a sarcoma subtype, because one gene, such as EWSR1, may be involved in many different types of sarcomas, and such data must be incorporated with other data regarding the tumor sample. Reverse transcriptase polymerase chain reaction is a more sensitive technique that may be performed on fresh, frozen, or paraffin-embedded tissues. The major drawback of reverse transcriptase polymerase chain reaction is the relatively high false-positive rate, which results from its sensitivity. Meticulous care is required to prevent problems from contamination. Sequencing of the RNA complement of the genome allows for detection of mutations, translocations, and, to some degree, gene amplification, and is expected to be used more frequently over time.⁹²

Many sarcomas are characterized by several different translocations, most of which are mutually exclusive (see Table 93-3). For instance, alveolar rhabdomyosarcoma is characterized by a translocation involving chromosomes 2 and 13, which results in fusion of the PAX3 and FOXO1 genes, or by a translocation involving chromosomes 1 and 13, which results in fusion of the PAX7 and FOXO1 genes.^93–96 Sarcomas within a subtype may also have differences in the specific exons that are involved in each of these different translocations. It has been proposed that this heterogeneity may result in differences in prognosis (see “Potential Molecular Prognostic Factors” below). For example, Ewing sarcoma/PNET and synovial sarcoma possess genetic variations that have been suggested to have prognostic significance, further underscored by the Ewing-like sarcomas that lack EWSR1 fusions but contain other translocations.^{89,91,97–102} Future research will hopefully establish whether cytogenetic and molecular factors may be used as a basis for therapeutic decisions and the prediction and evaluation of response to treatment.

The identification of genetic alterations with high specificity for different sarcomas will also identify specific therapeutic targets. This has already resulted in the successful treatment of a variety of sarcomas, for example, GISTs, dermatofibrosarcoma protuberans (DFSP), and tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT/PVNS), and to a lesser degree, angiosarcoma, desmoid tumor, and Ewing sarcoma.79,103–105 Approximately 90% of GISTs harbor activating mutations in the KIT oncogene, which result in ligand-independent activation of the KIT receptor tyrosine kinase pathway.⁷⁷ Imatinib, a small molecule drug that is administered orally and inhibits the KIT receptor tyrosine kinase, is highly efficacious in the treatment of GIST (see section of treatment of GISTs). DFSP is characterized by translocations involving the COL1A1 and PDGFB genes, which result in activation of the platelet-derived growth factor-β (PDGF-β) pathway in what is believe to be an autocrine fashion. Imatinib is active against the PDGF-β pathway and has been shown to be effective in the treatment of a small number of DFSPs. In a similar way, TGCT/PVNS with its t(1;2) involving COL6A3-CSF1 is responsive to imatinib by virtue of its inhibition of the CSF1 receptor.¹⁰⁶

It is noteworthy to mention two common benign soft-tissue tumors—leiomyomas and lipomas—that have a high frequency of chromosomal rearrangements of chromosome 12q that involves the high-mobility protein group gene HMGIC/HMGA2.107,108 These translocations are not seen in the corresponding leiomyosarcomas or liposarcomas, indicating that in these tumors, the benign form is not a precursor of the malignant counterpart. Other benign soft-tissue neoplasms contain specific translocations, such as nodular fasciitis [t(17;22)(p13;q13) MYH9-USP6] or angiomatoid fibrous histiocytoma [t(12;22)(q13;q12) EWSR1-ATF1], underscoring the idea that translocations can occur in tumors anywhere in the spectrum of connective tissue tumors from benign to malignant.^109,110

Sarcomas with Complex Karyotypes

A second major subset of STSs is characterized by aneuploidy and the lack of specific fusion genes. This group of sarcomas includes such tumors as leiomyosarcomas, MPNST, and fibrosarcomas (see Tables 93-3 and 93-4). These tumors tend to occur in older patients and appear to have a relatively high frequency of mutations in the p53 and retinoblastoma (Rb) signaling pathways.^111,112 These tumors are characterized by chromosomal gains and losses that presumably target tumor suppressor genes (in the event of losses) and oncogenes (in the event of gains). A special case appears to be well-differentiated/dedifferentiated liposarcoma, with amplifications of cell-cycle regulatory genes CDK4 and HDM2 and others on chromosome 12q. The cooperation of these genes to create a unique type of aneuploid sarcoma remains a current challenge in the field. Supporting the clinical data from syndromic sarcomas, alterations disrupting chromosomal mechanics and DNA repair appear to be involved in sarcomagenesis.

Classification

In broad terms, sarcomas may be classified into neoplasms that arise in bone and those that arise from the soft tissues. However, even this seemingly simple distinction is fraught with difficulty, as is illustrated by Ewing sarcoma. In childhood, Ewing sarcomas most commonly arise in close association with bone and are often classified as bone sarcomas. However, it is now clear that these tumors can also arise in soft tissues, more commonly in adults. So are Ewing sarcomas bone sarcomas or STSs, and does it really matter in terms of classification? Sarcomas of the soft tissues may be further grouped into those that arise from viscera (gastrointestinal, genitourinary, and gynecologic organs) and those that arise from nonvisceral soft tissues (muscle, tendon, adipose, pleura, and connective tissue).

An alternative way to index STSs is by their differentiation. Tumors may be grouped broadly into adipocytic tumors, fibroblastic/myofibroblastic tumors, so-called fibrohistiocytic tumors, smooth muscle tumors, pericytic (perivascular) tumors, PNETs, skeletal muscle tumors, vascular tumors, osseous tumors, and tumors of uncertain differentiation (Table 93-5).¹¹³ Classification is based on clinical, histologic, ultrastructural, immunohistochemical, and genetic features. Electron microscopic evidence of cellular substructures, neurofibrils, microfilaments, actin-myosin complexes, and dense bodies, has historically been used to define the tissue of origin.¹¹⁴ However, the widespread availability of commercial antibodies for immunohistochemical analysis has all but eliminated the need for electron microscopic examination. Immunohistochemical staining for proteins that are characteristic of smooth muscle (smooth muscle actin and desmin), skeletal muscle (muscle-specific actin, desmin, and myogenin), blood vessels (factor VIII, CD34, and CD31), and epithelial tissue (epithelial membrane antigen and cytokeratins) often facilitates reliable classification, with genetic proof of a sarcoma translocation considered to be iron-clad evidence of a specific sarcoma subtype.^115,116 However, because the identical translocation may be found in more than one type of cancer, such as the ASPL-TFE3 translocation of both alveolar soft part sarcoma and papillary renal cancer, translocation data cannot be used in isolation.

Biopsy

Biopsy of the primary tumor is essential for most patients seen with soft-tissue masses. In general, any soft-tissue mass in an adult that is asymptomatic or enlarging, is larger than 5 cm, or persists beyond 4 to 6 weeks should be biopsied. The preferred biopsy approach is generally the least-invasive technique required to allow a definitive histologic diagnosis and assessment of grade. In most centers, core-needle biopsy provides satisfactory tissue for diagnosis135–135 and has been demonstrated to result in substantial cost savings compared with open biopsy; core-needle biopsy (usually with multiple passes) also yields adequate material for molecular testing, with fine-needle aspiration considered inadequate by most practitioners.¹³⁵ Direct palpation may be used to guide needle biopsy of most superficial lesions, but less-accessible sarcomas often require an image-guided biopsy to safely sample the most heterogeneous component of the mass. Needle tract tumor recurrences after closed biopsy are rare, but have been reported,¹³⁶ leading some surgeons to advocate tattooing the biopsy site for subsequent excision or for inclusion in radiotherapy treatment volumes (Fig. 93-3). Because of 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 utility 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 performed when a definitive diagnosis cannot be achieved by less invasive means. Several technical points merit comment. Relatively small, superficial masses that can easily be removed should be biopsied by 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 pathological analysis. At definitive resection of a previously biopsied sarcoma, the previous surgical biopsy scar should be excised en bloc with the tumor.

Imaging

For soft-tissue masses of the extremities, magnetic resonance imaging (MRI) has been regarded as the imaging modality of choice (Fig. 93-4). This is because MRI enhances the contrast between tumor and muscle and between tumor and adjacent blood vessels and provides multiplanar definition of the lesion.^137,138 Despite the fact that a study by the Radiation Diagnostic Oncology Group comparing MRI and computed tomography (CT) in patients with malignant bone (N = 183) and soft-tissue (N = 133) tumors showed no specific advantage of MRI over CT from a diagnostic standpoint,¹³⁹ the majority of musculoskeletal radiologists and almost all surgical oncologists prefer MRI for soft-tissue tumors. For pelvic lesions, the multiplanar capability of MRI may provide superior single-modality imaging, although similar techniques are now commonly available with CT scans (Fig. 93-5). The multiplanar capability is also helpful for visualization of disease in noncoplanar ways when conformal radiotherapy technique is being employed and is an especially helpful adjunct in using image fusion techniques or to visualize peritumoral edema that may harbor sarcoma cells. In the retroperitoneum and abdomen, CT usually provides satisfactory anatomic definition of the lesion (Fig. 93-6) and is a very useful modality for imaging metastatic disease in the lungs and abdomen, given the averaging of signal that occurs with normal patient respiration and peristalsis during the much lengthier MRI. Occasionally, MRI with gradient sequence imaging may better delineate the relationship of the tumor to midline vascular structures, particularly the inferior vena cava and aorta. Older and more invasive studies such as angiography or cavography are almost never used for the evaluation of STSs.

The utility of ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) with CT registration images (PET-CT) in the evaluation and treatment of STS has been a subject of numerous studies and has been reviewed in detail elsewhere. The technique uses radiolabeled glucose analogs,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.¹⁴⁰ PET may be helpful in the assessment of locally recurrent STS¹⁴¹ and in the evaluation of response to therapy.^142,143 The role and cost-effectiveness of PET in the staging of STS remain undefined; further prospective studies will be required to fully define the role for FDG-PET in the diagnosis, evaluation, 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.¹⁴⁴

Potential Molecular Prognostic Factors

As clinicopathological factors affecting patient outcomes were being identified, examination of the tissue itself for factors predicting outcome became another topic of interest, and continues to this day in the form of more detailed molecular profiling of RNA expression, comparative genomic hybridization, tumor DNA or RNA sequencing, and analysis of DNA modifications such as methylation patterns in specific tumors. Some of the first parameters that were evaluated for prognostic significance included p53,¹⁷¹ HDM2 (the human version of the murine p53 interacting protein MDM2),¹⁷¹ Ki-67,¹⁷¹ altered expression of the retinoblastoma gene product (pRb)^59,172 in high-grade sarcomas, and the importance of the specific type of SS18-SSX fusion transcripts in synovial sarcoma⁹⁹ or EWSR1-FLI1 fusion transcripts in Ewing sarcoma.⁹⁷ Notably, whereas many individual immunohistochemical markers have been examined as a prognostic factor in outcome, data are generally conflicting. It is well recognized that there is variability of immunohistochemistry with both technique, which may vary between laboratories, and assessment; what may be 2+ staining to one investigator is 3+ or 4+ staining to another.

As one of the first examples of analyzing multiple immunohistochemical markers with respect to outcome, Heslin and colleagues evaluated the potential prognostic significance of pRb, p53, HDM2, and Ki-67 by immunohistochemical techniques in a population of 121 patients with primary, high-grade extremity sarcomas, and compared these factors with conventional clinicopathological prognostic factors (median follow-up: 64 months).¹⁷¹ Clinicopathological and molecular factors that were found to be statistically significant adverse prognostic factors in both univariate and multivariate analyses for the separate end points of distant metastasis and tumor-related mortality included tumor size greater than 5 cm, microscopically positive surgical margin, and a Ki-67 score greater than 20 (>20% nuclear staining). Overexpression of p53 or HDM2 or deletion of pRb did not correlate with an increased risk of distant metastasis or tumor-related mortality. Similarly, data with respect to specific SS18-SSX translocation type (i.e., SSX1 or SSX2) and outcome have yielded conflicting results,^99,173 and the specific EWSR1-FLI1 translocation does not appear to affect overall outcomes for patients.^97,98,174

With the increasing use of genomic analyses such as RNA expression arrays, comparative genomic hybridization or tumor RNA sequencing, it is possible that expression or mutation-specific stratification may be possible within specific histologies, in a manner analogous to current use of this technique to stratify breast cancer.¹⁷⁵ Additionally, these profiles have recently been applied to determining metastatic potential of primary tumors, and this approach could clearly be applicable to STSs, in which the presence or absence of metastases remains the most important prognostic factor.¹⁷⁶ Phosphoprotein profiling could become useful for patient risk stratification, as has been examined in stage III rhabdomyosarcoma to predict outcome.¹⁷⁷ This approach also holds future promise for both prognostic and therapeutic approaches, although concerns regarding phosphoprotein lability and tissue handling are concerns in the proper conduct of such studies. Although specific cellular and molecular parameters have been identified as having independent prognostic significance, there is currently no consensus on how specific molecular prognostic factors should be used in clinical practice. Validated markers may affect outcome prognostication in the future, but for the time being remain investigational.

Prognostic Factors as Therapeutic Targets

The prognosis of GISTs is often poor when treated by surgery alone,¹⁷⁸ and these tumors do not respond to conventional systemic chemotherapy. Arguably the most exciting discovery in GIST research is the finding of the activity of kinase-directed therapy, which is discussed later in the chapter. The protooncogene KIT is the cellular homolog of the oncogene v-Kit (identified in a feline sarcoma virus). KIT (also termed CD117) encodes a transmembrane tyrosine kinase receptor that is structurally similar to platelet-derived growth factor and provides selective targets of key aberrations in the molecular signaling implicated in the pathogenesis of GISTs and other tumors (e.g., DFSP). An interesting additional feature of KIT expression in GIST is that different types and locations of mutations in KIT are independent risk factors in predicting disease-free survival independent of treatment with kinase receptor inhibitors.¹⁷⁹ KIT expression was uniformly evident in a study of GIST cases not treated with imatinib.^77,179 Of interest, KIT was highly phosphorylated in all cases, even in those samples that lacked demonstrable KIT mutations.⁷⁷ Mutations are found in specific regions of the KIT gene (most commonly exon 9 and exon 11), and are associated with differing prognosis (see the following discussion). In the era before imatinib, the subset of patients with exon 11 KIT mutations resulting in single amino acid substitutions (i.e., missense codon mutations) fared much better than patients with deletion/insertion mutations of exon 11 (5-year recurrence-free survival rate of 89% ± 11% vs. 37% ± 10%, respectively). A potential explanation for this finding is that exon 11 missense mutations are detected in lower-grade, favorable outcome GISTs.¹⁷⁹ Against this explanation is the fact that the metastatic GISTs with KIT exon 9 mutations appear to have a lower risk of relapse compared with exon 11 KIT mutation or PDGFRA mutant GISTs. Although it is conceivable that this type of mutation is a surrogate for the behavior of a GIST, it is also plausible that this type of mutation represents the initial pathogenetic mechanism, making it a true prognostic marker and target. It is apparent that the mutation in KIT is context dependent; KIT mutation and ETS transcription factor family member ETV1 overexpression appear to synergize to drive GIST development.¹⁸⁰

Molecular Therapeutic Targets in Sarcomas: Gastrointestinal Stromal Tumor

We have just now begun to see the implications and success of targeting genetic alterations in sarcomas that drive oncogenesis. GISTs were previously thought to be gastrointestinal leiomyosarcomas that were particularly resistant to cytotoxic chemotherapy. It was subsequently demonstrated that these tumors were derived from interstitial cells of Cajal or their precursors and were frequently characterized by point mutations in the KIT receptor tyrosine kinase and were clearly distinct from leiomyosarcomas.181,182 Subsequently, the tumors were treated with imatinib, which targets the KIT kinase, with dramatic results.¹⁸³ KIT mutations were observed in exon 11 (juxtamembrane domain, seen in 71% of tumors), exon 9 (the extracellular region, 13%), exon 13 (first lobe of the split-kinase domain, 4%), and exon 17 (phosphotransferase domain, 4%). The subset of patients with exon 11 mutations resulting in single-point amino acid substitutions (i.e., missense codon mutations) fared much better than did patients with deletion/insertion mutations of exon 11 (5-year recurrence-free survival rate of 89% ± 11% vs. 37% ± 10%, respectively).¹⁷⁹ In addition, tumors that lack KIT mutations appear to have mutations in platelet-derived growth factor (PDGF)-α receptor gene PDGFRA, and those that have no mutation in KIT or PDGFRA are driven by loss of succinate dehydrogenase expression, mutation in BRAF, or other genetic alterations, all changes that are mutually exclusive of KIT mutations.¹⁸⁴ Finally, the type of mutation that is identified appears not only to predict response to imatinib, but also to suggest whether other kinase inhibitors, such as sunitinib, may have beneficial effects.¹⁸⁵ Although to date the most common adult STS demonstrate few consistent mutations in kinase genes that are amenable to target inhibition, new options for treatment likely will be derived from more careful genetic analysis of specific sarcoma subtypes by using newer sequencing techniques, comparative genomic hybridization, analysis of tumor microRNA and DNA methylation patterns.⁹²

Completeness of Resection

Satisfactory local resection involves resection of the primary tumor with a margin of normal tissue around the lesion. The width of the margin should differ depending on whether or not adjuvant radiotherapy is used. It is clear that dissection along the tumor pseudocapsule (enucleation) is associated with local recurrence rates ranging between 33% and 63%.197–197 Wide local excision with a margin of normal tissue around the lesion is associated with local recurrence rates in the range of 10% to 31%, as was noted in the control arms (surgery alone) of the randomized trials evaluating postoperative radiotherapy.^198,199

In contrast to malignant melanoma, a cancer in which there are randomized data to address adequate margin size, no comparable data 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, except in the immediate vicinity of functionally important neurovascular structures, where, in the absence of frank neoplastic involvement, dissection is performed in the immediate perineural or perivascular 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 to 2 mm) is made possible, and even large lesions may be managed conservatively in that setting. Technical details of the surgical approach to extremity sarcomas are beyond the scope of this chapter, but are comprehensively reviewed in surgical atlases.²⁰⁰ At the same time, it is also important to bear in mind that involved (i.e., positive) resection margins remain an adverse finding even when adjuvant radiotherapy is used, notwithstanding the amelioration of risk that radiation treatment provides. Data from Memorial Sloan-Kettering Cancer Center, Princess Margaret Hospital, and Massachusetts General Hospital suggest an additional absolute reduction of local control of approximately 10% to 15% for patients with positive margins compared with those with microscopically negative surgical margins.^200–203 As a result, radiation therapy should never be considered adequate therapy after incomplete surgical resection.

In considering the existing outcome data, it is important to bear 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 fact, positive resection margins have different causes. One is oncologically inadequate surgery in which positive resection margins might have been avoidable in another surgeon’s hands. When this is the case, microscopically positive surgical margins may be considered a technical failure. Alternatively, positive resection margins may arise in anatomically adverse presentations in which locally advanced disease challenges the goals of conservative resection from the outset. In another study from the Princess Margaret Hospital, Gerrand and colleagues evaluated the type of microscopically positive margin as a prognostic factor and defined four groups in this setting.²⁰⁴ Patients with low-grade liposarcomas and microscopically positive surgical margins (group 1) have a low risk of local failure, as do those in whom a positive margin is anticipated before surgery to preserve critical structures and to whom radiotherapy is given to sterilize the minimal residual disease (group 2). However, two categories of patients with positive margins are associated with a higher risk of local recurrence: (a) patients who are seen after unplanned excision who have a positive margin on subsequent reexcision (group 3) and (b) patients with unanticipated positive margins occurring during primary sarcoma resection (group 4). For group 3, an “unplanned excision” is defined as an excisional biopsy or resection that is carried out without adequate preoperative staging or consideration of the need to remove normal tissue around tumor, an adverse feature reported by the same authors previously.²⁰⁵ These data appear to support the premise that, provided that adjuvant radiotherapy is administered, a very small amount of residual disease resulting from a “planned” positive margin at the site of a critical anatomic structure (group 2, local recurrence rate of 3.6% and 95% confidence interval [CI], 0% to 10.4%) is not associated with the same deleterious risk that occurs with a positive margin that follows major contamination because of a “shell out” intralesional surgery (group 3, local recurrence rate of 32%; 95% CI, 11% to 53%) or inadvertent contamination of the wound (group 4, local recurrence rate of 38%; 95% CI, 14% to 61%).²⁰⁴ These data seem particularly relevant to anatomic sites where achievement of adequate resection margins is a perennial problem, such as the head and neck, as evidenced by recent results from a prospective series where the outcome approaches that of extremity and body wall sarcomas.²⁰⁶ We caution, however, that such results are probably not attainable without a defined management protocol and joint multidisciplinary assessment before treatment is undertaken, because there exist issues that merit discussion at the individual case level (e.g., the complex relationship between tissues to be resected and reconstructed and the radiotherapy volumes and doses, all of which can influence each other in the decision algorithm).

Lymph Node Dissection

Given the low (less than 3%) prevalence of lymph node metastasis in adults with sarcomas,117,118 there is no role for routine regional lymph node dissection. Patients with angiosarcoma, embryonal rhabdomyosarcoma, and epithelioid histologies have an increased incidence of lymph node metastasis and should be carefully examined for adenopathy by physical examination, imaging, and sentinel lymph node sampling. Therapeutic lymph node dissection (curative) results in a 34% actuarial survival rate¹²⁰; therefore the rare patients (who more commonly have evidence of other metastatic disease) with regional nodal involvement who have no evidence of extranodal disease should undergo therapeutic lymphadenectomy. Patients with adverse features at the time of dissection (i.e., extracapsular extension beyond the lymph nodes into perinodal fat or positive or doubtful margins on the neurovascular bundle) or in whom treatment into the next grossly uninvolved lymph node echelon is not feasible with surgery should also be considered for additional adjuvant nodal irradiation. The principles underlying this approach have been outlined.²⁰⁷

Surgery Alone

Although the majority of patients with extremity STS should be treated with preoperative or postoperative radiotherapy, recent reports suggest that concomitant radiotherapy might not be required for selected patients with completely resected, small, primary STSs (Table 93-8).^208–211 Rydholm and colleagues reported their experience with 70 patients with subcutaneous or intramuscular extremity sarcomas treated with wide surgical resection and microscopic assessment of surgical margins.²¹⁰ Negative histologic margins were obtained for 32 of 40 subcutaneous and 24 of 30 intramuscular tumors. The 56 patients with microscopically negative margins received no postoperative radiotherapy, yet only 4 (7%) experienced local recurrence. A study from Brigham and Women’s Hospital reported similar results for a selected group of 74 patients with primary extremity STS treated by surgery without radiotherapy.²¹¹ The 10-year actuarial local control rate was 93% ± 4%. The absolute gross margin was a significant predictor of local recurrence; patients with a close gross margin of less than 1 cm had a 10-year local control rate of 87% ± 6% compared with 100% for patients with a closest gross margin of 1 cm or greater (P = 0.04). The generally favorable local control rates with surgery alone that these and other investigators^200,212 reported in these series of highly selected patients are comparable to local recurrence rates observed for more heterogeneous patient populations treated with conventional multimodality therapy incorporating preoperative or postoperative radiotherapy (Table 93-9).^{68,198,213–219} These data support the hypothesis that selected patients with small, primary STSs may be treated with surgical resection alone without preoperative or postoperative radiotherapy.

It is difficult to define the precise selection criteria that should be used to identify patients with primary sarcoma who can safely undergo treatment by surgery without radiotherapy. Most investigators have limited this approach to patients with carefully selected T1 tumors that may be resected with clear margins (see Table 93-8). In contrast, Karakousis and colleagues did not consider absolute tumor size but instead used surgical resection alone for all patients in whom a minimum intracompartmental margin of 2 cm could be maintained circumferentially, irrespective of tumor size.²⁰⁸ Karakousis and colleagues updated the results for high-grade STS of the policy of limiting the use of postoperative radiation treatment for tumors resected with positive or “narrow” (<2 cm) resection margins.²²⁰ This approach has yielded useful data because the consistent application of this treatment approach resulted in a local recurrence rate of 19% with “wide” margin surgery alone compared with 24% after “narrow” margin surgery and adjuvant radiotherapy.²²⁰ Although the results provide some clarity about the 2 cm or greater margin benchmark, it would be useful to also have similar data from other groups for a variety of margin widths to draw conclusions about when it is safe to withhold radiotherapy. Moreover, the authors acknowledge the potential to treat a greater proportion of cases with radiotherapy and lower the 19% local recurrence rate in some of those “favorable cases” that are currently treated with surgery alone by widening the indication for adjuvant radiotherapy in a proportion of these patients.²²⁰ This view is consistent with contemporary observations such as the local recurrence rate of 7% in patients who received combined modality treatment such as those in the recent Canadian randomized trial (see “Preoperative or Postoperative Radiotherapy” below).²²¹

Factors other than anatomic location, tumor size, and the feasibility of achieving an R0 resection (macroscopically and microscopically complete) should be considered in selecting patients for treatment by surgery alone. For example, the issue of whether the patient has had a prior “unplanned” excision (see earlier) is important. At the Princess Margaret Hospital, a significantly higher rate of local recurrence was apparent in patients who were treated after unplanned excision on the outside than in patients who received their treatment at their institution (22% vs. 7%, P = 0.03).²⁰⁵ It is important to remember that unplanned excision is very common in the community setting, where small soft-tissue lesions are often excised without image guidance under the presumption that they are benign. Therefore, although it is reasonable to attempt a reexcision if it is considered feasible, patients who have undergone unplanned excision should also be strongly considered for adjuvant radiation.

Preoperative or Postoperative Radiotherapy

Conservative (limb-sparing) surgery and radiotherapy have been combined to optimize local control for patients with localized STS. Radiotherapy may be administered preoperatively,213–215,222,223 postoperatively,^217,224,225 or by interstitial techniques (brachytherapy).^{68,216,226–230}

Treatment Sequencing: Preoperative Versus Postoperative Treatment

Of further interest, an improvement in overall survival (a crude rate of 85% vs. 72% in favor of postoperative radiotherapy, P = 0.048) emerged initially from the Canadian SR2 RCT, but dissipated after longer follow up (Fig. 93-10).^221,240 Thus in terms of overall survival, it appears reasonable to treat patients with postoperative EBRT, as local control rates are comparable to preoperative techniques, but major wound complication rates are significantly lower. On the other hand, given the lower risk of late effects such as fibrosis with preoperative radiation, consideration of longer-term end points should be a consideration in any patient in whom radiation therapy is to be considered.²⁴¹ Also, in anatomic sites where wound complications are rarely seen (e.g., the upper extremity), the rationale for wound complication avoidance as a reason to favor the use of postoperative radiotherapy is not as sound. In particular, the obvious advantage to preoperative radiotherapy in the proximal arm and shoulder is apparent where avoidance of large volume and higher dose irradiation that may treat the lung or brachial plexus may be achieved. These principles are also reasonable in the head and neck based on data from Princess Margaret Hospital.²⁰⁶

In contrast to EBRT, which requires 5 to 7 weeks of treatment, with brachytherapy, the patient’s entire local treatment (surgery plus radiation) may be completed in the 2 weeks following primary tumor resection. Brachytherapy has potential cost advantages²⁴² and has implications in terms of overall patient convenience. Accordingly, if the necessary expertise is available, brachytherapy provides an excellent, cost-effective alternative for patients with high-grade lesions, although such expertise is increasingly uncommon. Brachytherapy should not be used for patients with low-grade sarcomas.²³⁰

The only randomized study of preoperative versus postoperative EBRT for patients with localized extremity STS was conducted by the National Cancer Institute of Canada Clinical Trials Group/Canadian Sarcoma Group. In this trial, 190 patients with extremity STS were randomly assigned to preoperative versus postoperative EBRT.²²¹ The radiotherapy parameters for this protocol required a field margin of 5 cm around the gross tumor volume for the initial phase of treatment (i.e., treatment to 50 Gy in 25 fractions), and this generally included any peritumoral edema that was seen on MRI, irrespective of the grade or size of the tumor. Subsequently, a reduced-volume field was treated to a total combined dose of 66 Gy in all postoperative cases and in those preoperative patients in whom the resection margins were involved.

The results of this trial are complex because the primary end point that powered the trial, and hence its sample size, was the cumulative incidence of acute wound complications 120 days after protocol surgery in both arms of the study. Nevertheless, the local control rates after 3.3 years of median follow-up are identical in both arms of the study (7%). As might be expected, local wound complications were more common in the preoperative radiation cohort, whereas increased late complications such as radiation field fibrosis were more common in the postoperative group, who were treated with a larger treatment field with a higher total dose of EBRT.²⁴³

The results of the Canadian RCT provide insight into the comparative efficacy, functional outcome, economic costs, and complication rates of preoperative and postoperative treatment sequencing for EBRT. In the absence of a clear local control advantage to any specific radiation technique, clinicians have considered other factors in formulating standards of care. Such factors have included wound complication rates, financial costs, patient convenience, health-related quality of life and physical function, radiotherapy toxicity, and perhaps even overall survival.

It is clear that although field size and radiation dose may be minimized with preoperative radiotherapy,²⁴⁴ major wound complications after preoperative radiotherapy and surgery have been reported to be in the 20% to 35% range.^245,246 In the Canadian Sarcoma Group RCT, wound complications were defined as secondary wound surgery, hospital admission for wound care, deep packing, or prolonged dressings within 120 days after tumor resection. By these criteria, preoperative radiation had a significantly higher rate (35% vs.17%, P = 0.01) of wound complications than did postoperative EBRT. Of note, the risk was confined to the lower extremity.²²¹

Taken in isolation, the wound complication fact alone may be expected to cause some groups to continue to favor postoperative radiotherapy. The Canadian RCT demonstrates that late tissue outcomes strongly favor the preoperative approach, with equivalent longer-term local tumor control.²⁴⁷ The rates of grade 2 or greater fibrosis and edema were significantly higher in the postoperative arm compared with preoperative radiotherapy, and were independently associated with the larger irradiation volumes and doses used in postoperative radiotherapy.²⁴⁷ Short-term functional outcome in the SR2 trial has also been reported and continues to be collected prospectively.²⁴⁸ Two validated instruments—the Toronto Extremity Salvage Score (TESS) and the Short Form-36 quality-of-life instrument (SF-36)—were applied, as was the observer-based Musculoskeletal Tumor Society (MSTS).²⁴⁸ Patients who were treated with postoperative radiotherapy had better function with higher MSTS Rating Scale, TESS, and SF-36 bodily pain scores at 6 weeks after surgery than those who were treated with preoperative-radiation, but there were no differences at later time points up to 1 year. Thus the timing of radiotherapy has minimal impact on the function of STS patients in the first year after surgery, but thereafter, significant factors likely come into play. These include the apparently deteriorating late tissue sequelae caused by larger doses and volumes. Of interest, patients who experience wound complications appear to continue to suffer some impaired function. Further follow-up is required to assess the ongoing evolution of these competing risks.

Conformal Radiotherapy and Intensity-Modulated Radiotherapy

STS presents in virtually any anatomic site, and the capacity for unusual presentation is nearly limitless. This can result in circumstances in which conventionally delivered radiotherapy is impossible because of the magnitude of the volume to be treated, uncertainty in defining the target for radiotherapy, or, more usually, because of the proximity of normal tissues to the intended target volume. Although some presentations are extremely problematic (e.g., uncertain targets because of organ mobility or imprecise anatomic issues resulting from poor definition of tumor location related to imaging limitations or inadequate surgical and/or pathological description), others may be addressed by novel methods of radiotherapy delivery. The most commonly available advance over standard EBRT is intensity-modulated radiotherapy, an advanced form of 3D conformal radiotherapy in which radiation beams are not only shaped at their perimeters, but also include variable intensity across the profiles of the beams. This permits the creation of greatly improved conformation of dose to targets of irregular shape while generating high-dose gradients between tumor and normal tissues. A full discussion of the potential uses of intensity-modulated radiotherapy in STS is beyond the scope of this chapter but is discussed in detail elsewhere.²⁴⁹ It may be administered preoperatively, postoperatively, or as a sole modality with specific indications. Some applications highlight its use in lesions adjacent to the spine or critical anatomic structures of the head and neck and in the retroperitoneum to permit liver avoidance (as well as to permit spinal cord, kidney, and intestinal dose limitation), especially in lesions involving the right upper abdominal quadrant. Avoidance of late toxicity to anatomic structures such as weight-bearing bone that are at risk for fracture after treatment of extremity sarcomas seems also to be feasible.²⁵⁰ Although these approaches are promising, their precise contribution and role need to be evaluated.²⁵¹

Conventional Radiotherapy Without Surgery

Radiotherapy alone has been employed as primary therapy for patients with locally advanced, inoperable STS and patients who present with stage IV disease. Efforts to use radiation as the primary treatment have demonstrated that high doses (more than 65 Gy) are required to achieve local control rates between 30% and 60%,252,253 and that there appears to be an inverse relationship between tumor size and local control rates. In a series of 35 patients treated with high-dose (>65 Gy) primary 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%, respectively.²⁵⁴ In general, local control rates with radiation alone are inferior to those after surgery; therefore, primary radiation should be reserved for patients who are medically unfit for surgery, have technically unresectable tumors, or refuse surgery as initial therapy. However, some caution is necessary in interpreting such results in a scientifically valid manner. Encumbered with such adverse selection factors, the outcome of radiotherapy would never be comparable to that of surgery. Moreover, surgery has the added advantage over radiotherapy alone because its use for locally advanced cases is ordinarily also combined with adjuvant radiotherapy.

Particle-Based Radiotherapy (Emphasizing Proton Beam Therapy)

The use of radiation employing particles (electrons, neutrons, protons, and even portions of whole atoms such as carbon ions) provides another means to control the radiation field. Proton therapy allows for more accurate dose administration (lower “exit dose” of the proton beam) compared with photon based radiotherapy with more accurate discrimination between normal tissue and tumor compared with conformal photon-radiation therapy or intensity-modulated radiotherapy.²⁵⁵

Particle-based radiotherapy has been emphasized by certain groups because of the lower oxygen enhancement ratio compared with x-rays and the consequent attractive possibility of overcoming the biological phenomenon that hypoxic cells generally limit the curability of malignancy with x-rays. Additional differences from x-rays are the reduced repair of sublethal and potentially lethal damage. These particle effects are less vulnerable to the differential radiosensitivities associated with different phases of the cell cycle. It should be apparent that some of these repair phenomena also negatively affect the tolerance of normal tissues.

Neutrons have been used in a number of pilot studies, primarily in patients with locally advanced disease, with 60% to 70% local control rates,258–258 but are more a curiosity now given the increasing use of proton beam radiation clinically. As an example, one study reviewed the results of 220 patients with locally advanced sarcomas who were treated with neutron radiotherapy. Ninety-four patients with gross residual disease after resection were treated with neutron therapy alone; among these patients, 27% had major morbidity, 26% had 5-year survival, and 56% had local control. One hundred four patients with microscopically positive margins of resection received a neutron boost dose; they had 7% morbidity, 65% 5-year survival, and 78% local control rates. These results suggest that for patients with gross residual disease, neutron beam radiation may provide improved local control compared with conventional external beam treatment, but these data should continue to be interpreted with caution when one considers the late tissue sequelae that appear to result from neutron beam radiation use. Comparative studies are needed to define the precise role of particle beam-based therapy in the treatment of STS. Apart from unresectable disease, it seems unclear where the benefit of proton and other particle-based therapy (e.g., carbon ion) might accrue when one considers the exceptionally favorable results of conventional photon-based treatment combined with surgery and the more adverse normal tissue tolerance to particle-based therapy.

As one clear situation in which the greatest possible targeting is desired, proton beam radiation has proved useful in rhabdomyosarcoma in parameningeal locations, wherein children’s developing brains may be less affected by the penumbra of the radiation field,²⁵⁹ Proton beam radiation also has found use in unresectable sarcomas.^260,261 There are no comparative data examining this newest approach for sarcoma radiation therapy and this still relatively scarce resource seems best directed to clinical situations in which the most care with nearby structures (e.g., brain, spinal cord) must be taken. Chondrosarcoma of the skull base or chordoma of the clivus are good examples of situations in which novel technique may be most effective relative to other options.^262,263

Adjuvant Chemotherapy

In the past 30 years, improvements in surgical and radiotherapy techniques have led to impressive rates of local control, particularly in extremity STS, with concomitant sparing of normal tissues and preservation of limb and/or organ function. Despite substantial efforts in the same period, much less progress has been made in finding ways to eradicate the micrometastases that are the ultimate cause of death in many individuals who are seen with apparently localized STS. The discovery that doxorubicin had significant antitumor activity against adult STS prompted the initiation of multiple RCTs during the period 1973 to present to evaluate the benefit of doxorubicin alone or in combination with other agents after the completion of local treatment. However, most of these trials were too small to detect moderate treatment effects reliably. Results from most of these studies are omitted for lack of space, and readers are directed to previous editions of this chapter for details.

The statistical technique of meta-analysis may overcome the problem of inadequate power of small RCTs, and meta-analyses based on individual patient data may minimize other potential biases (e.g., exclusion of unpublished trials, variable follow-up, post randomization exclusions, and differing definition of end points) that are inherent in analyses that are limited to published results. In 1997, the Sarcoma Meta-Analysis Collaboration (SMAC) published an individual patient data meta-analysis of outcomes for 1568 STS patients included in 14 RCTs that completed accrual by December 1992.264,265 Significant improvements were found in local and distant relapse-free intervals and recurrence-free survival for all patients, and these improvements did translate into a significant overall survival benefit in the prospectively defined subgroup—almost 60% of the patients—with extremity sarcomas, but not in all patients (Table 93-10).

These data were updated in a 2008 meta-analysis that also included newer studies that contain ifosfamide as part of their backbone, but did not include data from the largest trial of adjuvant chemotherapy, which was a negative study for improved overall survival.²⁶⁵ For the 18 studies and 1953 patients included in the meta-analysis, the odds ratios (ORs) for local recurrence was 0.73 (95% CI, 0.56 to 0.94; P = 0.02) in favor of chemotherapy. For distant and overall recurrence the OR was 0.67 (95% CI; 0.56 to 0.82; P = 0.0001) in favor of chemotherapy. In terms of survival, doxorubicin alone had an OR of 0.84 (95% CI; 0.68 to 1.03; P = 0.09), which is not statistically significant. However, the OR for doxorubicin combined with ifosfamide was 0.56 (95% CI; 0.36 to 0.85; P = 0.01) in favor of chemotherapy. With the understanding that publication and other biases may affect interpretation of meta-analyses, these are the strongest data supporting the use of adjuvant chemotherapy for patients with primary extremity or trunk STS, without reference to histology.

Compounding the problem of small numbers of STS cases, STSs as a group show marked heterogeneity in pathology and site of origin; this condition is much less evident in breast cancer. For example, it has been suggested that in the 1997 SMAC meta-analysis, chemotherapy benefits for extremity (57% of total) and high-grade STSs were obscured by inclusion of sarcomas at other locations (head and neck, trunk, and visceral/retroperitoneal, including uterus) and those of low (5%) or unknown grade (28%). Another point of contrast with breast cancer is the relative paucity of drugs that are active against STS. At the time of the SMAC meta-analysis, only two agents (doxorubicin and ifosfamide) produced overall response rates exceeding 20% in patients with advanced disease. This situation provides limited opportunity to exploit the potential advantages of combination chemotherapy. Of the 14 trials that were included in the original SMAC meta-analysis, six used doxorubicin alone, and the remaining eight were trials of combination chemotherapy. Only one unpublished STS trial (29 patients) examined the combination of doxorubicin with ifosfamide, the addition of which appears to be the more important component of adjuvant chemotherapy, despite what are relatively modest response rates for ifosfamide in the metastatic setting in unselected patients.

Full reports have been published on other phase II and RCTs (Table 93-11) examining anthracycline- and ifosfamide-based regimens supported by growth factors. In the Italian Cooperative Group study,²⁶⁷ accrual was terminated based on an early stopping rule, after half the planned number of patients had been recruited. The median recurrence-free survival and overall survival (Table 93-11) were superior for the chemotherapy group, but a high cumulative incidence of late distant relapses was noted (2-year: 28% vs. 45%, P = 0.08;4-year: 44% vs. 45%, P = 0.94 for chemotherapy vs. control groups, respectively). The 4-year overall survival rate remained better for the chemotherapy group (69% vs. 50%, P = 0.04). At the last published analysis, after a median follow-up of 90 months (range: 56 months to 119 months), the intention-to-treat analysis continued to demonstrate a trend towards improved overall survival (P = 0.07).²⁶⁸ The 5-year overall survival estimates, a reasonable end point for the survival analysis of adjuvant treatment in STSs, were 66% and 46% for the treatment and the control groups, respectively (P = 0.04).²⁶⁸

The authors of a second study, a prospective randomized feasibility trial, concluded that a regimen of 6 cycles of ifosfamide, doxorubicin, and dacarbazine given concurrently with postoperative hyperfractionated radiotherapy (during cycles 3 and 4 when doxorubicin was omitted from the regimen) was manageable and tolerable.²⁶⁹ It did not translate into significant benefits in recurrence-free survival (P = 0.1 vs. control arm), time to local failure (P = 0.09), or overall survival (P = 0.4), but the small number of patients (31 vs. 28) precludes meaningful conclusions regarding benefit. A third small RCT, from another Italian center, examined 41 patients who received either an intensive epirubicin + ifosfamide combination (n = 19) versus single-agent epirubicin (n = 16), in comparison with local therapy alone (n = 43); the study was closed early for poor accrual and was accordingly underpowered for efficacy end points.²⁷⁰

In the largest randomized study of adjuvant chemotherapy to date, Woll and colleagues randomly assigned 351 patients, from 1995 to 2003, 1 : 1 between observation alone or 5 cycles of chemotherapy with doxorubicin (75 mg/m² per cycle) + ifosfamide (5 g/m² over 24 hours per cycle), every 21 days, with lenograstim (3 μg/kg SC daily for 14 days/cycle). In the preliminary analysis of data, 5-year recurrence-free survival rate was 52% in both arms, and 5-year overall survival rate was 69% on the observation arm versus 64% on the chemotherapy arm.²⁷¹

Can blanket recommendations be made regarding the use of adjuvant chemotherapy in adult STS? In an editorial²⁷² that accompanied the report of the Italian Cooperative Group Trial that still addresses many issues faced today,²⁶⁷ Bramwell concluded that a specific standard of care was not yet clear and that the situation would take some time to change. Guidelines from the United States and Canada support the use of chemotherapy in selected patients.²⁷³ European guidelines recommend adjuvant chemotherapy only after shared decision making and careful selection of patients.²⁷⁴ With the current state of knowledge, chemotherapy is a reasonable standard of care for those patients willing to accept significant toxicity for what may be little if any improvement in overall survival. Observation after primary tumor control is a reasonable option for many people, most so in those sarcomas already known to be relatively chemotherapy resistant. Those people who are most likely to benefit from adjuvant chemotherapy are those who can tolerate ifosfamide chemotherapy; the meta-analysis of 2008 indicated that the benefit from chemotherapy appeared to be more an issue of delivery of ifosfamide rather than doxorubicin.²⁶⁵

Given the difficulty of ifosfamide in older patients, adjuvant chemotherapy is unsuitable for the substantial minority of patients who are older than 60 to 65 years of age, because of the increased toxicity observed with ifosfamide; this group has largely been excluded from RCTs evaluating these regimens. The decision of whether to administer adjuvant chemotherapy and the regimen that is chosen will depend on a number of considerations, including risk of relapse, physician preferences (which may also depend on patient age and comorbid conditions), referral practices, and available resources. Although there are strong opinions on whether or not chemotherapy has added sufficiently to local therapy for routine use in high-risk patients, all agree on two facts: (a) high-risk patients die far too often of metastatic disease, and (b) there is a need to improve on the limited benefit observed with current anthracycline and ifosfamide combination therapy.

Neoadjuvant Chemotherapy

Given that the role of postoperative adjuvant chemotherapy for patients with adult STS remains controversial, it is hardly surprising that the advantages of chemotherapy given before surgery (neoadjuvant therapy) are even less clear, particularly because there have been no adequately powered RCTs addressing this issue. Nonetheless, neoadjuvant chemotherapy has theoretical benefits that include the following:

Numerous neoadjuvant treatment approaches and preoperative drug regimens have been explored. Intraarterial administration of drugs such as doxorubicin and cisplatin has been evaluated, in some cases in conjunction with radiotherapy, isolated limb perfusion, or hyperthermia. The intraarterial route delivers drugs more directly to the tumor but is more complex, expensive, and prone to complications than is the intravenous (IV) route. In the one small RCT on route of administration, there were no differences in rates of local control or overall failure between neoadjuvant chemotherapy given intraarterially or intravenously.275,276 In a series of nonrandomized studies reflecting the evolution of neoadjuvant treatment at their center over a 20-year period, the University of California, Los Angeles (UCLA) group treated a total of 498 patients with neoadjuvant chemotherapy.²⁷⁷ As one example of its studies, the combination of chemotherapy and 28 Gy of radiotherapy before surgery was noted by investigators to provide the best local control with the lowest complication rate. On the basis of results of the RCT described earlier, intraarterial doxorubicin was replaced by IV doxorubicin, and cisplatin and ifosfamide were added in a follow-up protocol.²⁷⁷ In the whole group of 498 patients, the overall local recurrence rates were 11% at 5 years and 15% at 10 years, and corresponding overall survival rates were 71% and 66%. The local recurrence rate was lower and overall survival rate higher for patients who had no residual tumor (38%) or greater than 95% necrosis (14%) after neoadjuvant chemotherapy, compared with those who had less than 95% necrosis. In a multivariate analysis, pathological necrosis was an independent predictor of local recurrence and overall survival. The percentage of patients with 95% or greater necrosis increased to 48% with the addition of ifosfamide, compared with 13% for patients in all other protocols combined.

Pisters and colleagues reviewed the long-term results of neoadjuvant chemotherapy given at the University of Texas MD Anderson Cancer Center for stage IIIB extremity sarcomas between 1986 and 1990.²⁷⁸ All patients received doxorubicin-based regimens; at that time, ifosfamide was rarely used (three patients). In 75 patients, the overall clinical objective response rate (complete response plus partial response) was 27%. At a median follow-up of 85 months, the 5-year actuarial local recurrence-free survival, overall recurrence-free survival, and overall survival rates were 83%, 52%, and 59%, respectively. In contrast with the UCLA group’s results²⁷⁷ for pathological response, there were no differences in any outcomes between responding and nonresponding patients, as defined at that time.

In a separate analysis at MD Anderson, 65 patients (42 extremity sarcomas and 23 retroperitoneal sarcomas) were treated at the same center between 1991 and 1996 with doxorubicin- or ifosfamide-based neoadjuvant chemotherapy; 34% achieved a radiographic partial response and 9% a minor response.²⁷⁹ Patients having partial response had higher rates of negative-margin resections, local recurrence-free survival, and overall survival than did nonresponders. Postoperative morbidity was also evaluated in a larger cohort of 105 patients (71 extremity and 34 retroperitoneal STS) treated at MD Anderson during the same period, of whom 50 received ifosfamide as well as doxorubicin.²⁸⁰ The authors found no evidence that preoperative chemotherapy increased surgical complications (e.g., wound infections and other wound problems), length of hospital stay, rate of readmission, or rate of reoperation. Similar outcomes have been observed in other reported series.²⁸¹

The European Organization for the Research and Treatment of Cancer (EORTC) has performed the only RCT assessing preoperative chemotherapy for STS (3 cycles of doxorubicin and ifosfamide plus filgrastim) versus no preoperative chemotherapy (control).²⁸² A total of 150 patients with high-risk STS (≥8 cm any grade, or grades II/III tumors <8 cm, or grades II/III local recurrence tumors/inadequate surgery) were randomly assigned, of whom 134 were considered eligible for outcome assessment. Radiotherapy was indicated for tumors that were excised with close or microscopically positive margins and was given in 46% of patients in the chemotherapy arm and 54% of patients in the control arms. Limb salvage was possible in 89% of patients, and chemotherapy did not affect postoperative wound healing. Grade 4 toxicities were rare, although there was one death as a consequence of neutropenic fever. At a median follow-up of 7.3 years, the 5-year recurrence-free survival and overall survival rates were 56% versus 52% (P = 0.36) and 65% versus 64% (P = 0.22) for the chemotherapy and control arms, respectively. Although originally planned as a phase III trial with adequate numbers to detect a 15% difference in 5-year overall survival, the study was closed after completion of the phase II section because of slow accrual. Most groups have concluded that for large high-grade tumors, preoperative chemotherapy is feasible, does not increase postoperative morbidity, increases the rate of operability, and may enhance local control. The beneficial effects on distant metastases and overall survival, if any, were marginal.

It is impossible to determine from the results of the phase II retrospective or prospective series whether preoperative neoadjuvant chemotherapy reduces distant metastases and improves survival, and the EORTC RCT was too small to illuminate this issue. Preoperative chemotherapy, particularly in combination with preoperative radiotherapy, can induce substantial rates of pathological necrosis, may increase operability in large high-grade tumors, and leads to impressive rates of local control. It is not clear, however, that these results are better than would be achieved with preoperative radiotherapy alone, particularly if radiation is delivered by using modern intensity-modulated techniques, and most neoadjuvant chemotherapy regimens are associated with substantial toxicity. Neoadjuvant chemotherapy is considered a standard of care for sarcomas more common in children, for example, Ewing sarcoma, rhabdomyosarcoma and osteogenic sarcoma, given the known survival benefit of chemotherapy in those diagnoses in children. The contribution of drugs such as cisplatin and dacarbazine (agents with poor activity in metastatic STS), other than increasing toxicity, may be questioned.

There is potential benefit from a RCT comparing neoadjuvant chemoradiotherapy with preoperative radiotherapy alone in patients with large high-grade STS. Because this will require international collaboration and opinions regarding the value of chemotherapy are often entrenched, this may never occur. Preoperative chemoradiotherapy, reported in a series of clinical trials as noted below, should be delivered only in centers experienced in these techniques, providing further rationale for referral of the majority of patients with STSs to centers that can provide multidisciplinary assessment and treatment.

Combined Preoperative Chemotherapy and Radiotherapy

With the advances that have been made with combined-modality treatment of other solid tumors, there has been interest in combined-modality preoperative treatment (concurrent or sequential chemotherapy and radiation) for patients with localized STSs. Concurrent doxorubicin-based chemoradiation has been employed extensively by Eilber and colleagues at UCLA.283,284 This treatment protocol involved intraarterial doxorubicin with a hypofractionation schedule to be coincident with intraarterial chemotherapy (35 Gy of EBRT delivered in 10 daily fractions, which was reduced to 17.5 Gy in 5 daily fractions to minimize local toxicity). A subsequent prospective randomized trial from the same group that remains unpublished compared preoperative intraarterial doxorubicin with IV doxorubicin, both followed by 28 Gy of radiation delivered over 8 days followed by surgical resection. No differences in local recurrence or survival were noted.

The combination of regional chemotherapy and concurrent radiotherapy that was originally pioneered by Eilber and colleagues has been modified and used by other groups.287–287 Investigators from the University of Illinois treated 55 patients with a 10-day preoperative regimen of intraarterial doxorubicin (10 mg/m² per day) with concomitant radiotherapy (25 Gy: 2.5 Gy per fraction in 10 fractions).²⁸⁷ With a mean follow-up of 94 months, local control was 85%. Complications related to the therapy occurred in 26% of patients and required further operative management in 7% of patients. Temple and colleagues treated a group of 42 patients with a similar regimen of 60 to 90 mg of doxorubicin that was infused intraarterially or intravenously over a 3-day period followed by sequential radiotherapy (30 Gy: 3 Gy per fraction in 10 fractions).²⁸⁶ Resection of the residual posttreatment mass was performed 4 to 6 weeks later. At a median follow-up of 6 years, local control was achieved in 39 of 40 patients, although two patients were excluded from this analysis because clear margins were not obtained at the time of surgery. Intraarterial infusion-related complications occurred in 4 (11%) of 35 patients. Objective radiographic and pathological response rates were not reported; therefore, the efficacy of concurrent chemoradiation therapy in achieving cytoreduction to an extent sufficient to convert lesions that are resectable by amputation only to lesions that are amenable to a limb-sparing approach remains anecdotal. Moreover, whether preoperative chemoradiation approaches offer local control advantages over conventional treatment approaches that combine surgery with preoperative or postoperative radiotherapy is also not apparent. In fact, with current local control rates with surgery and radiation alone exceeding 90%, it is difficult to appreciate how this outcome would be furthered with preoperative chemotherapy unless the strategy involved a radiotherapy dose reduction to ameliorate normal tissue toxicity.

Alternative chemotherapy-radiation sequencing has been used by investigators from Massachusetts General Hospital, who have reported mature data from a sequential chemoradiation strategy in the treatment of patients with large (>8 cm), localized, high-grade extremity STSs.²⁸⁸ The Massachusetts General Hospital protocol involves interdigitating courses of chemotherapy and radiotherapy: three courses of doxorubicin, ifosfamide, mesna, and dacarbazine and two 22-Gy courses of radiation (11 fractions each) for a total preoperative radiation dose that is lower than usual (44 Gy). This was followed by surgical resection with microscopic assessment of surgical margins. An additional 16-Gy (8 fractions) boost dose was delivered for microscopically positive surgical margins. The strategy, therefore, simultaneously addresses the dual problems of local control and metastatic risk. The outcomes of 48 patients who were treated with this regimen between June 1989 and March 1999 were compared with those of a matched series of historic controls (treated between January 1988 and March 1997).²⁸⁸ The 5-year actuarial local control, distant metastasis-free survival, and overall survival rates for the sequential chemotherapy-radiation group are 92%, 75%, and 87%, respectively. For the matched historic controls, these rates are 86%, 47%, and 58%, respectively. The protocol was toxic, with 29% experiencing confluent moist skin desquamation, 25% requiring hospitalization at some time for febrile neutropenia. Wound-healing complications evaluated by using recently described criteria²²¹ were apparent in 29% of cases and confined to the lower extremities, as was also observed in the Canadian Sarcoma Group treatment sequencing RCT.²²¹ One patient died from late marrow dysfunction attributed to chemotherapy. Although the results are encouraging from a tumor standpoint (Fig. 93-11), they require prospective comparative studies for confirmation, especially because of the local and systemic toxicity associated with this approach.²⁸⁹ Although a Radiation Therapy Oncology Group phase II study yielded similar outcomes compared with the data of DeLaney and colleagues,^288,290 they, too, are characterized by concerning features of significant toxicity, including marrow dysplasia and treatment-related deaths.

Hyperthermic Isolated Limb Perfusion and Whole-Body Hyperthermia with Chemotherapy

Hyperthermic isolated limb perfusion and whole-body hyperthermia are two investigational techniques that continue to receive considerable attention, particularly in Europe. Hyperthermic isolated limb perfusion (with TNF-α, interferon-α, and melphalan) has been used as an neoadjuvant therapy to render tumors resectable and as a primary therapy to avoid amputation for nonresectable extremity STS.291,292 Overall response rates in early series, which recruited 55, 35, and 41 patients, respectively, ranged from 72% to 91%, and limb salvage surgery was possible in 84% to 91% of cases. Small numbers of patients experienced subsequent local recurrence, and some of these patients required amputations. Not surprisingly, many patients ultimately died of distant metastases.

Various techniques of regional or whole-body hyperthermia have been combined with a variety of chemotherapy regimens.293–296 A group from Munich evaluated preoperative chemotherapy (4 cycles of doxorubicin, ifosfamide, and etoposide) combined with regional hyperthermia (RHT) followed by surgery and adjuvant treatment (same chemotherapy ± radiation). Median follow-up times were 58 months for the RHT-91 protocol (59 patients) and 30 months for the RHT-95 protocol.²⁹⁶ All patients had grades II/III tumors 5 cm or larger with extracompartmental extension. Clinical response rates were 42% and 33% for the two protocols, with respective local progression-free survival rates of 58% and 57%. Corresponding overall survival rates were 42% and 48%, respectively. The possible utility of hyperthermia as part of local tumor control was further evaluated in a phase III RCT (EORTC 62961/European Society for Hyperthermic Oncology RHT-95). The assumption was made that preoperative chemotherapy with doxorubicin, ifosfamide, and etoposide is effective for patients with high-risk localized disease in this setting, and patients were randomized to receive preoperative etoposide, ifosfamide, and doxorubicin (EIA, 4 cycles) plus RHT (2 fractions) versus EIA chemotherapy alone. As a result, no difference was expected in terms of overall survival; improved local control was confirmed in those patients treated with hyperthermia.²⁹⁷