Soft-Tissue Sarcomas. Karen H. Albritton Andrea Ferrari. Michela Casanova Introduction

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1 Chapter Soft-Tissue Sarcomas Karen H. Albritton Andrea Ferrari. Michela Casanova Contents 11.1 Introduction Epidemiology/Etiology Biology/Pathology Diagnosis/Symptoms and Clinical Signs Treatment Management and Outcome Rhabdomyosarcoma Adult-Type STS Synovial Sarcoma Summary and Conclusions References Introduction Soft-tissue sarcomas (STSs) are a very heterogeneous group of nonepithelial extraskeletal malignancies that are classified on a histogenic basis according to the mature tissue they most resemble. Different histotypes with different biologies and clinical behaviors are included in this group of tumors. Usually, they are characterized by local aggressiveness and propensity to metastasize, which is correlated to the grade of malignancy. They can arise, generally as an enlarging softtissue mass, anywhere in the body (most frequently in the soft tissue of the extremities, and less usually in the trunk or head and neck region). They comprise less than 1% of all malignant tumors but account for 2% of total cancer-related mortality. In addition, they cause a relatively high burden of morbidity, due to deforming surgery, chemotherapy- and radiation-induced complications, and second cancers. They occur at any age, but a shift occurs in adolescence/early adulthood from predominantly rhabdomyosarcoma of childhood to a mixture of several adult-type STSs, with some subtypes particularly typical of adolescents and young adults [1 3] Perhaps because it occurs but is rare across all ages, and perhaps because the orthopedic surgeons and radiation oncologists who are often involved treat both children and adults, the field of STS oncology is not owned by either pediatric or medical oncology. For this reason too, it seems that STS is an adolescents and young adults cancer. Across all ages, the survival rate for STSs averages 60%, with substantial differences according to the histotype, the grade of malignancy, and the stage of the disease [1]. The treatment of patients with STSs is

2 186 Chapter 11 K. H. Albritton A. Ferrari M. Casanova complex and necessarily multidisciplinary, requiring adequate expertise. All STS patients, including adolescents and young adults, probably receive better treatment within select experienced institutions that enroll patients into clinical trials; treating patients outside of a referral center has been identified as an independent risk factor for recurrence in STS. Such a suggestion appears more relevant if one considers that the lowest proportion of patients entered onto national clinical treatment trials vs. the number of new cases occurring at age years, when it was 0.6% (Fig 11.1). Below age 10 years, it was over 30% and during adolescence it was approximately 12%. Above age 40 years it exceeded 3%. These data have been supposed to partially explain the slower rates of improvement in overall outcome observed (during the last 20- year period) in older adolescents in comparison to the younger [4, 5]. STSs of adolescents and young adults can be separated in two groups. The first includes the highly malignant tumors, characterized morphologically by small round blue cells: rhabdomyosarcoma (RMS), Ewing family of tumors (EFT), and the rare desmoplastic small round cell tumor. EFT [Ewing sarcoma, (ES) and the peripheral primitive neuroectodermal tumor (ppnet), which is cytogenetically the same neoplastic entity as ES but with a different grade of differentiation] is highly aggressive, with a high propensity to metastasize, and is typical of adolescents and young adults. Its natural history and treatment is comparable to that of the more frequent ES arising in the bone, and therefore it will not be described in this chapter, but in Chap. 12. The second group of STSs includes the classic adult-type STSs, which are generally characterized by spindle-cell histology and uncertain response to chemotherapy and radiotherapy. Although Kaposi sarcoma is a malignant STS that has historically affected young adults, its relation to the human immunodeficiency virus epidemic makes its epidemiology and management quite different. It will not be considered in this chapter and all comments about STS will pertain to non-eft, non-kaposi sarcoma. Figure 11.1 Estimated proportion of all patients diagnosed with sarcomas during who were entered onto United States national treatment trials. Values in the parentheses are the average annual accrual to the trials (numerator) and estimated average number of patients expected to have been diagnosed with the cancer in the United States during the years evaluated (denominator). Accrual data from the Cancer Therapy Evaluation Program, United States National Cancer Institute. Modified from Bleyer et al. [2] 11.2 Epidemiology/Etiology Overall, STSs are rare: with an annual incidence of around 2 3/100,000 persons of all ages. STS incidence increases exponentially with age, but peaks as a percent of all cancers in 5- to 10-year-olds. At a rate of 8.2 cases per million, STS ties as the fifth most common cancer in 15- to 19-year-olds (7.7% of all tumors); in the 20- to 24-year-olds there are 17.9 cases per million 6.6% of all tumors and the seventh most common. Although rates continue to increase with age and reach 62.3 per million in 25- to 29-year-olds, they start to become a less common proportion of all cancers with age (Fig. 11.2). In the years age period, rhabdomyosarcoma (RMS, a tumor predominantly of children and adolescents) and the spindle-cell sarcomas including fibrosarcoma, synovial sarcoma (SS), and malignant peripheral nerve sheath tumor (MPNST), are the most frequent histotypes (Figs and 11.4) [1 3]. Surveillance, Epidemiology and End Results data from the period finds dermatofibrosarcoma to be the most common non-kaposi STS among 15- to 29-year-

3 Soft Tissue Sarcomas Chapter olds, followed by leiomyosarcoma/fibrosarcoma, RMS, SS, and malignant fibrous histiocytoma (Table 11.1). Arising from immature mesenchymal cells that are committed to skeletal muscle differentiation, RMS is one of the typical cancers of childhood, as it constitutes more than 50% of STSs, with an annual incidence of 4.3 per million children younger than 20 years. On the contrary, it is seen exceedingly infrequently in adults (3% of STSs). The incidence of RMS decreases significantly with increasing age: about three out of four cases occur in children under 10 years, with a peak of incidence between 3 and Table 11.1 Soft-tissue sarcomas by histologic type in. 15- to 29-year-olds, PNET Primitive neuroectodermal tumor Histologic type % of total Kaposi Sarcoma 35.3% Dermatofibrosarcoma, including protuberans 14.9% Leiomyosarcoma, fibrosarcoma 6.3% Rhabdomyosarcoma 6.5% Synovial cell sarcoma 6.0% Ewing sarcoma/pnet 4.8% Malignant fibrous histiocytoma 4.3% Liposarcoma 4.3% Malignant peripheral nerve sheath tumor 3.8% Angiomatous/vascular sarcomas 2.3% Spindle cell sarcoma 1.5% Epithelioid sarcoma 1.4% Alveolar soft part sarcoma 1.2% Clear cell sarcoma 1.0% Small cell sarcoma 0.6% Chondrosarcoma (soft tissue) 0.5% Giant cell sarcoma 0.4% Desmoplastic small round cell tumor 0.4% Miscellaneous 4.5% Total Number 2,812 Figure 11.2 Proportion of soft-tissue sarcomas relative to all invasive cancer as a function of age in those diagnosed before age 45 years in the United States. Data from the United States SEER [1] 5 years [6]. A second smaller peak occurs in adolescence [6]. For most STS subtypes, the pathogenesis remains unknown and there are no well-established risk factors. Ionizing radiation clearly causes sarcomas, and chemical carcinogens and oncogenic viruses have been associated with the development of some type of sarcomas, but the etiological relationship remains unclear. A few genetic predispositions are well described, but cause few of all STS: neurofibromatosis type 1 (in particular increases the risk of MPNST) and Li Fraumeni syndrome (which increases the risk of RMS) are the two classic (but not the only) genetic diseases associated with soft-tissue tumors [2 3]. Those with certain genetic conditions are predisposed to have an STS at a younger age, so that the proportion of adolescents and young adults with STSs with a genetic predisposition is probably higher than in older adults Biology/Pathology The grade of malignancy describes the aggressiveness of the tumor and its natural history. It is determined by a combined assessment of histological features: degree

4 188 Chapter 11 K. H. Albritton A. Ferrari M. Casanova Figure 11.3 Types of relative incidence of soft-tissue sarcomas in adolescents and young adults in comparison to those that occur in children and older adults. LMS Leiomyosarcoma, MFH malignant fibrous histiocytoma, LPS liposarcoma, MPNST malignant peripheral nerve sheath tumor, FS fibrosarcoma, SS synovial sarcoma, ppnet peripheral primitive neuroectodermal tumor, RMS rhabdomyosarcoma Figure 11.4 Relationship of age to incidence of various types of soft-tissue sarcomas of cellularity, cellular pleomorphism or anaplasia, mitotic activity, and degree of necrosis. Different histotypes with the same grade of malignancy could display the same clinical behavior. In general, low-grade tumors may have local aggressiveness but a low tendency to metastatic spread. High-grade tumors have a more invasive behavior with a high propensity to metastasize (in particular to the lung). Some histotypes (i.e., RMS, but also SS, alveolar soft parts sarcoma, and angiosarcoma) are usually considered as being high grade independently from their mitotic index, necrosis, and cellularity. Different grading systems (generally three-grade systems) have been defined over the years by pediatric and adult oncologists for predicting clinical course and prognosis, and defining a risk-adapted treatment. The most frequently used grading systems for adult sarcomas are the National Cancer Institute (NCI) system and the French Federation of Cancer Centers (FN- CLCC) system. The Pediatric Oncology Group system is similar to the NCI system, but accounts for tumors found exclusively in childhood. Unfortunately, the use of a distinct grading system has made it difficult to compare results in pediatrics to those in adults. RMS is a distinct entity, clearly different from other STSs typical of adult age. RMS cells can be recognized by the expression of myosin and MyoD protein family antigen. Myoglobin, desmin, and muscle-specific actin are also useful as diagnostic markers. Classically, two histological subtypes of RMS have been distinguished, embryonal and alveolar [7]. The diagnosis of alveolar subtype has to be given if there is any degree of alveolar architecture or cytology. A third form, pleomorphic RMS, needs to be considered separately from other RMS subtypes: it is very rare in both the pediatric population (less than 1%) and in adolescents and young adults, occurring typically at an age older than years. It is most common in the deep soft tissues of

5 Soft Tissue Sarcomas Chapter the extremities, with a predilection for males [1, 6]. Decades ago, pleomorphic RMS was a commonly assigned subtype, then it was regarded as a variant of malignant fibrous histiocytoma and its existence put in doubt. More recently, ultrastructural, immunohistochemical and molecular techniques have refined criteria its for diagnosis. Other data suggest that pleomorphic RMS is probably biologically and clinically closer to high-grade spindle-cell sarcomas of adults than to pediatric RMS. Cytogenetic and molecular analyses may help in the diagnosis of RMS and in the definition of the subtype. Most alveolar RMSs display a specific translocation t(2;13)(q35;q14), involving the PAX3 and the FKHR genes; a variant, t(1;13)(p36;q14), has been less frequently reported. Embryonal RMS lacks a tumor-specific translocation, but generally exhibits a loss of heterozygosity at chromosome 11p, which may act by inactivating tumor-suppression genes [2, 6]. A pattern of association between histotypes and clinical features has been described (Table 11.2). The alveolar histotype is more frequently localized at the extremities and in the trunk, and it is more typical of adolescents and young adults than of children. The recent International Consensus meeting defined a new International Classification of RMS, based on the relationship between histology and prognosis. Favorable subtypes are two variants of the embryonal type, the botryoid and the spindle-cell (or leiomyomatous) variants. The classic embryonal subtype carries an intermediate prognosis and the alveolar RMS (with the recently described solid variant) has an unfavorable prognosis. Of note, spindle-cell RMS in adults appears to have a different natural history and biology from the morphologically similar spindle-cell RMS of childhood. In adults, it has a propensity to occur in the head and neck area and carries a very poor prognosis. Besides RMS, there are almost ninety subtypes of STS. Because of their relative rarity in childhood, many pediatric oncologists lump these as non-rms STSs (NRSTS). Medical oncologists find this term amusing, as this describes 98%, not 50% of the tumors they see. The naming and classification of these has been based on the normal tissue the morphology of the cancer most resembles. The classification has undergone wide alteration, and studies suggest a 25% discordance rate between pathologists for classification. However, to date, this has had little impact on clinical therapeutics, as this has been guided more by grade than classification. Clinical trials have lumped all STSs together. Recently, more advanced immunohistochemical techniques, cytogenetics (both traditional and targeted hybridization techniques), and even microarray techniques are increasing the precision of the diagnosis. Hopefully, this will allow better prognostication and development of risk-based and targeted therapeutics. Table 11.2 Translocation and fusion genes in sarcomas. Modified from Borden (2003) [8] Ewing sarcoma Clear cell sarcoma Desmoplastic small round cell tumor Extraskeletal myxoid chondrosarcoma Myxoid liposarcoma Angiomatoid fibrous histiocytoma Alveolar rhabdomyosarcoma Synovial sarcoma Dermatofibrosarcoma protuberans Congenital fibrosarcoma Inflammatory myofibroblastic tumor Alveolar soft part sarcoma Endometrial stromal sarcoma t(11;22)(q24;q12) t(21;22)(q22;q12) t(12;22)(q13;q12) t(11;22)(q13;q12) t(9;22)(q22;q12) t(9;17)(q22;q11) t(12;16)(q13;p11) t(12;16)(q13;p11) t(2;13)(q35;q14) t(1;13)(p36;q14) t(x;18)(p11;q11) t(17;22)(q22;q13) t(12;15)(p13;q25) t(2p23) t(x;17)(p11;q25) t(7;17)(p15;q21) EWS-FLI1 EWS-ERG EWS-ATF1 EWS-WT1 EWS-CHN TAF2N-CHN TLS-CHOP TLS-ATF1 PAX3-FKHR PAX7-FKHR SYT-SSX1,2 COL1A1-PDGFβ ETV6-NTRK3 various ALK fusions ASPL-TFE3 JAZF1-JJAZ1

6 190 Chapter 11 K. H. Albritton A. Ferrari M. Casanova Most pathologists feel that SS needs to be considered as a high-grade tumor, independent of mitotic index, percent of necrosis, and tumor differentiation, given its local invasiveness and propensity for metastatic spread. It is characterized by the presence of epithelial and spindle cells, probably derived from a primitive mesenchymal precursor. There are three histological subtypes: biphasic, monophasic, and poorly differentiated. In the majority of cases, tumor cells (especially the epithelial cells) display immunoreactivity for cytokeratins and epithelial membrane antigen. Immunohistochemistry is essential to differentiate the various spindle-cell sarcomas, but in some cases only the cytogenetic analysis may permit the diagnosis. Several STSs are characterized by specific chromosomal translocations (Table 11.2). The specific translocation t(x;18)(p11.2;q11.2) has been found in more than 90% of SS, with three possible transcripts, SYT-SSX1, SYT-SSX2, and SYT-SSX4 (SYT-SSX2 has recently been associated with better survival) [8] Diagnosis/Symptoms and Clinical Signs The initial signs and symptoms depend on the site of origin and tumor extension. An enlarging painless mass is the most common presentation. In 15- to 29- year olds, about one-third of STS originate in the extremities. RMS can arise anywhere in the body, including sites in which striated muscle tissue is normaly absent. The head and neck region represents the most common location, and the symptoms vary from proptosis, cranial nerve palsy, or nasal obstruction. Hematuria may be present in RMS of the genitourinary tract; ascites and intestinal obstruction can occur with retroperitoneal tumors [2, 3]. In the case of suspected lesions, three diagnostic levels need to be evaluated: (1) the histological diagnosis, for which an incisional biopsy procedure is usually preferred over fine-needle aspiration; (2) the definition of locoregional extension for which magnetic resonance imaging appears to be superior to computed tomography (CT) scan in defining soft-tissue tumor; (3) the staging of the disease for which a chest CT scan and technetium bone scan are usually required. The value of positron emission tomography scan in staging STS has not yet been determined. An adequate stratification of the patients is necessary for a risk-adapted therapy. However, as in grading, pediatric and medical oncologists have not used the same systems, making comparison of risk and prognosis difficult. The pediatric Intergroup Rhabdomyosarcoma Study (IRS) postsurgical grouping system [9] supplements the pretreatment clinical tumor-nodemetastases (TNM) classification [10], categorizing patients into four groups based on the amount and extent of residual tumor after the initial surgical procedure. Group I includes completely excised tumors with negative microscopic margins; group II indicates grossly resected tumors with microscopic residual disease and/or regional lymph nodal spread; group III includes patients with gross residual disease after incomplete resection or biopsy sampling; group IV encompasses patients with metastases at onset [9]. According to the TNM classification, T1 are those tumors confined to the organ or tissue of origin, while T2 lesions invade contiguous structures; T1 and T2 groups are further classified as A or B depending on whether tumor diameter is or >5 cm, respectively. Regional node involvement is defined as N0 or N1, and the status of distant metastases at onset as M0 or M1 [10]. However, adult oncology groups have generally utilized other systems: the Musculoskeletal Tumor Society Staging System requires the accurate definition of compartmentalization, the American Joint Committee on Cancer Staging System combines TNM definitions and histological grading [11] Treatment Management and Outcome Rhabdomyosarcoma RMS is a distinct entity and clearly differs from NRSTS in regard to its natural history and its higher sensitivity to chemotherapy and radiotherapy [6]. During the past 30 years the 5-year overall survival (OS) rates of pediatric RMS has improved dramatically from 25 30% to approximately 70% [1, 12 14]. These results are due largely to the development of

7 Soft Tissue Sarcomas Chapter Table 11.3 Rhabdomyosarcoma: the histological subtypes and their more frequent characteristics.. RMS Rhabdomyosarcoma Favorable prognosis Botryoid RMS Spindle-cell RMS 6% of all RMS; mean age 3 ears; polypoid mucosa-associated lesions of genitourinary and head-neck cavities 2%; mean age 7 years; paratesticular regions (leiomyomatous) Intermediate prognosis Embryonal RMS 60%; mean age 7 years; all sites,. in particular the head-neck regions;. Loss of heterozygosity at chromosome 11p15.5 Unfavorable prognosis Alveolar RMS Pleomorphic RMS 30%; older age (10 25 years); deep soft tissue of extremities; t(2;13)(q35;q14) translocation (variant t(1;13)(p36;q14) translocation) 2%; adults older than 45 years; extremities treatment approaches that are: (1) multidisciplinary (including surgery, radiotherapy, and in particular multiagent effective chemotherapy), (2) risk-adapted (prognostic factors are used to stratify treatment: more intensive therapy improves cure rates in those patients with less favorable disease whereas those with more favorable findings avoid overtreatment and side effects without jeopardizing survival), (3) cooperative multiinstitutional trials able to enroll a large number of patients. International cooperative multimodal treatment trials have been carried out by North-American and European groups. Historically, these trials, included subjects up to the age of 18 or 21 years. In 2001, the Children s Oncology Group STS committee raised the upper age limit of all STS protocols to 50 years. In Europe, the opportunity to enroll patients up to 30 years is now in discussion. Historically, risk stratification and therapy was usually based on the IRS [9] and TNM staging systems [10]. With the recognition of different prognostic factors (i.e., age, histology, tumor site; Table 11.3), the risk assignments has became more complex but also more careful. Table 11.4 shows the risk stratification of the new European pediatric Soft Tissue Sarcoma Study Group (EpSSG) and the Children s Oncology Group protocols for localized RMS, with the estimated survival rates and the proposed treatment for each group [15]. RMS is a markedly chemoresponsive and radiosensitive tumor. Multiagent chemotherapy has a response rate of greater than 80% in the majority of patients. The efficacy of chemotherapy permits partial modification of the aggressive surgical concepts that are essential in the management of adult-type sarcomas of uncertain chemoresponsiveness. Primary resection should be performed only when complete (i.e., histologically free margins) and nonmutilating excision is considered feasible; otherwise biopsy alone is recommended. Tumor size, local invasiveness, and especially tumor site strongly affect the feasibility of surgery, which is also influenced by the surgeon s own judgment and experience. Tumors considered unresectable at diagnosis can be completely resected in a high percentage of cases after tumor shrinkage following primary chemotherapy [16]. Due to the efficacy of adjuvant chemotherapy and radiation, local control can generally be obtained by wide resections (en bloc excisions beyond the reactive zone but within the anatomical compartment with histologically free margins), in contrast to adult NRSTS, which in general should require compartmental resection (en bloc resection of the tumor and the entire compartment of origin).

8 192 Chapter 11 K. H. Albritton A. Ferrari M. Casanova Table 11.4 Prognostic factors for RMS. IRS Intergroup Rhabdomyosarcoma Study Favorable prognostic factors Embryonal histology Initial complete resection (IRS group I) Tumor confined to the organ or tissue of origin (T1) Small tumor size (<5 cm) No regional lymph node involvement (N0) Localized disease (M0) Age between 1 and 10 years Favorable sites: non-parameningeal head-neck (orbital) non-bladder/prostate genitourinary (paratesticular, vagina) Unfavorable prognostic factors Alveolar histology incomplete resection/unresectability (IRS groups II III) Local invasiveness (T2) Large size (>5 cm) Nodal involvement (N1) Distant metastases at diagnosis (M1) Age over 10 years (and less than 1 year) Unfavorable sites: parameningeal region bladder and prostate, abdomen trunk extremities A large number of different chemotherapeutic regimens have been tested over the years within cooperative trials: today, the VAC regimen (combination of vincristine, actinomycin D, and cyclophosphamide) is still the mainstay of chemotherapy in North America [12, 13, 14], whereas the IVA regimen, which differs in the choice of the alkylating agent (ifosfamide in the place of cyclophosphamide), is the standard therapy in Europe [15, 17, 18]. The different drugs (i.e., cisplatin, etoposide, and melphalan) added over the years to these regimens have not shown clear advantage compared to the standard combinations [13]. Nevertheless, in high-risk patients it is imperative to find out more effective and intensive regimens. In IRS Study V, topotecan is currently administered in patients with less favorable outcome. In EpSSG, as shown in Table 11.5, the role of doxorubicin will be under evaluation within the IVADO regimen, with the concept of administering early the maximum dose intensity of doxorubicin (which is an effective drug, although its role as part of multidrug regimens remains controversial) [19]. In a very selected subset of patients with low-risk characteristics (completely resected small tumor, embryonal histology, paratesticular and vagina sites, age <10 years), a limited chemotherapy without an alkylating agent (VA, vincristine and actinomycin D) has been shown to be enough to maintain excellent results [15]. In adolescents and young adults, given the adverse prognostic significance of age, this regimen should probably not be recommended. At the opposite pattern of risk groups, the outcome of patients with metastatic disease at diagnosis remains poor (about 30% of survivors) despite the use of very intensive treatments, including high-dose chemotherapy followed by reconstitution with peripheral blood stem cells. New drugs are usually evaluated upfront in these patients, even if novel therapeutic approaches are needed (i.e., specific molecular targets for gene therapies). A quite new noteworthy approach may be the use of maintenance therapy with low-dose continuous chemotherapy (maybe with new antitumor mechanisms, i.e., antiangiogenic); the EpSSG trial (Table 11.5) will randomize patients with localized RMS who are in complete remission after 6 months chemotherapy to receive or not maintenance therapy with oral cyclophosphamide plus vinorelbine (that appears a promising drug in RMS) [20, 21]. If chemotherapy is a keystone in the multimodal treatment, radiotherapy also plays a relevant role because of the high radioresponsiveness of RMS. Con-

9 Soft Tissue Sarcomas Chapter Table 11.5 European Pediatric Soft-Tissue Sarcoma Study Group: risk stratification and treatment options for localized RMS. EFS Event-free survival, OS overall survival, VA vincristine-actinomycin D, IVA ifosfamide-vincristine-actinomycin D, IVADO ifosfamide-vincristine-actinomycind-doxorubicin, VNR vinorelbine, CTX cyclophosphamide, RT radiotherapy Risk group Histology a IRS b N c Site d Size & age e % f EFS OS treatment Low A B I I N0 N0 any any un 6% 6% 90% 95% 78% 90% VA, no RT Standard C D E II III II III II III N0 N0 N0 un un any un 18% 9% 27% 72% 88% 80% 85% 55% 60% IVA+VA or IVA ± RT IVADO+IVA vs. IVA + RT High F G un II III I II III N1 N0 any any any any 8% 20% 50% 60% 50% 60% ± maintenance VNR-oral CTX Very High H un I II III N1 any any 6% 40% 50% IVADO+IVA + RT + maintenance chemotherapy a Histology:...favorable, embryonal RMS (and variants); not otherwise specified, unfavorable alveolar RMS b IRS Group: group I, complete resection; group II, microscopic residual disease after initial surgery (or nodal involvement); group III, macroscopic residual tumor after surgery (or biopsy) c N (nodal involvement):..n0, no nodal involvement; N1, involvement of regional lymph nodes d Site: favorable, nonparameningeal head-neck (i.e., orbit), nonbladder/prostate genitourinary (i.e., paratesticular, vagina) e Size & age: favorable, tumor size less 5 cm AND age between 1 and 10 years f %: estimated percentage of patients g EFS OS: estimated 5-year event-free survival and overall survival (according to data from the Italian Cooperative Group, ICG)

10 194 Chapter 11 K. H. Albritton A. Ferrari M. Casanova Table 11.6 Series of 290 patients with RMS treated between 1970 and 1990 at the Memorial Sloan-Kettering Cancer Center, New York. Overall series 0 15 years years years No. of patients Histology % Embryonal % Alveolar % Pleomorphic 77% 14% 9% 84% 11% 5% 78% 17% 5% 79% 21% 30% Sites % Head-neck % Genitourinary % Extremities % Trunk 26% 35% 27% 13% 33% 38% 20% 8% 18% 39% 25% 18% 18% 16% 52% 6% Stage % T2 % >5 cm %N1 % M1 71% 68% 28% 23% 64% 63% 27% 18% 76% 76% 33% 30% 82% 68% 20% 23% sidering the risk of late radiation damage (together with the effectiveness of systemic treatment), the role of radiotherapy has partially diminished over the years and its indication is now given more carefully. With doses generally ranging between 40 and 55 Gy (depending on age, tumor size and site, response to primary chemotherapy, histology, and extent of residual tumor after surgery), radiotherapy is particularly important in those cases localized in the parameningeal region and in trunk (i.e., the pelvis), and whenever a primary or delayed complete resection is not feasible. Alveolar RMS always requires radiotherapy to improve the local control rate [22, 23]. Radiotherapy must always be administered using megavoltage equipment and allowing wide margins (2 3 cm) around the tumor volume. Careful planning is mandatory, as well as the use of modern techniques such as the three-dimensional conformal radiotherapy, to improve the therapeutic index (high dose of radiation on the tumor with reduction in the dosage to normal tissues), in particular for parameningeal RMS. Although interesting suggestions have derived from hyperfractionated and accelerated schedules, the conventional fractionation scheme currently remains the standard choice. Interstitial radiotherapy can play a role in specific situations (e.g., small tumors in the head-neck or genitourinary sites) [24]. Debate on the possible different intensities of local therapy, and indications for radiotherapy in particular (e.g., in IRS group III patients who achieve complete remission after chemotherapy, or in group II patients) implicates the concept of the total burden of therapy experienced by a given patient and the predicted sequelae; the indication for radiotherapy, in other words, can be given taking into account the probability of OS (rather than disease-free survival) and the cost of survival in terms of sequelae [18]. A different philosophy, in fact, was behind previous European studies and North American trials: in the former, the evaluation of cost pointed to a lesser use of radiotherapy, which produced higher local relapse rates than those reported elsewhere, but similar OS, since a significant number of locally relapsing patients were cured by salvage treatments; in the meanwhile, a subset of patients were cured without intensive local therapies and therefore without sequelae. This is a matter of debate, and clearly, improvements in risk stratification may lead to more suitable risk-adapted treatment choices [18].

11 Soft Tissue Sarcomas Chapter In adolescents and young adults, the frequency of alveolar RMS and of extremity tumor is clearly higher than in younger patients. A study from the Memorial Sloan-Kettering Cancer Center compared the clinical features (and the outcome) of RMS patients of years of age, with those of patients less than 16 and older than 30 years [25]. Table 11.6 shows the higher percentage of cases with large, invasive tumors and metastatic tumors in the subset of adolescents and young adults. So, with the increase of age, there is an increase in the presence of adverse prognostic clinical findings. Moreover, as shown in Table 11.3, which lists the main prognostic factors in RMS, age per se has been associated with a less satisfactory outcome (in most pediatric reported studies, the outcome of adolescents was worse than that of children) [26]. The behavior of RMS in adults needs, however, some specific comments. Adult RMS is rare and scanty information is available on its clinical and biological findings; all studies, however, highlight a largely poorer outcome than in children, with OS rates in the range of 20 50%. Apart form pleomorphic subtype, which is probably a completely different tumor, the previous unsatisfactory results raised doubts as to whether adult RMS is biologically the same as childhood RMS, and as to whether chemotherapy should be used at all to treat adults with RMS. In a recently reported large retrospective study (from the Istituto Nazionale dei Tumori of Milan, Italy, 171 patients >18 years), treatment modalities have been analyzed and patients have been stratified according to the degree to which they had been treated appropriately, based on current treatment guidelines for childhood RMS (assigning a score to each patient) [27]. Although overall results (5-year OS 40%) paralleled those of other published series, in the subset of patients whose treatment was consistent with pediatric trials guidelines, 5-year OS was 61% and increased to 72% for patients with embryonal RMS (Fig. 11.5). A high score for appropriate treatment was assigned to 39% of patients (45% of patients years old, and 29% of patients over 30 years). Moreover, the overall response to chemotherapy was 85%, substantially different from that observed in other adult sarcomas (which is definitely less than 50%) and in the same range as the rate for pediatric RMS [27]. In brief, these Figure 11.5 Rhabdomyosarcoma in adults: 5-year outcome as a function of pediatric vs. adult treatment. Data from Ferrari et al. (2003). EFS Event-free survival data suggest that chemotherapy could have the same activity in adult as in childhood RMS, and, when properly employed within a treatment strategy like that adopted for childhood patients, the outcome in adults might also fall in the same range as in children. Of course, other findings might concur with the overall unsatisfactory results of adult RMS, both clinical (i.e., higher proportion of the alveolar subtype and of large and invasive tumors) and biological factors (i.e., more pronounced expression of multidrug resistance proteins). Nevertheless, every effort should be made to improve the number of adults patients with RMS who receive fully adequate treatment: it is known that adults may tolerate intensive treatments to a lesser degree, but also that the adult medical oncologist s attitude toward a tumor so rare in adulthood may be, at least in part, important. Thereafter, young adults with RMS, as well as adolescents, should be treated within pediatric controlled trials, or at least according to the same principles that in recent decades have so dramatically improved prognosis in children Adult-Type STS This group includes a heterogeneous variety of different tumors that are found more frequently in adult age than in childhood and are generally regarded to have uncertain responsiveness to chemotherapy and radio-

12 196 Chapter 11 K. H. Albritton A. Ferrari M. Casanova therapy. These tumors are called non-rms STS by pediatric oncologists [3, 28 31]. Contrarily to RMS (and extraosseous ES), in which chemotherapy plays a crucial role, standard treatment for localized, adult-type STSs is based on surgery, often complemented by radiation therapy. Surgery remains the mainstay of treatment, but overall treatment strategy has partially changed in recent years [32, 33]. Historically, radical interventions in high-grade sarcomas of adult age have been considered: amputations and compartmental resections. Currently, functional wide resection is the goal of surgical approach, complemented by radiotherapy whenever the resection margins are narrow or the tumor is of high grade. Radiotherapy needs to be administered at higher total doses than RMS (60 65 Gy). It is usually planned as a postoperative approach, although various suggestions are in favor of using preoperative irradiation (with or without neoadjuvant chemotherapy) in locally advanced disease, to allow a delayed surgical resection. The theoretical advantages of preoperative radiotherapy are: smaller volume of irradiation with more organ preservation, more efficacy on the nonhypoxic tumor bed, and a lower risk of intraoperative contamination [34, 35]. High-grade sarcomas can recur locally, but also with distant metastases, and despite the relatively good prognosis for grossly resected patients (70 80% survival), it is generally agreed that outcome is good enough for low-grade and small tumors to be treated with surgery alone, but not for high-grade and large tumors. Therefore, in some cases, chemotherapy should be considered as part of the treatment strategy. Actually, the role of chemotherapy in these tumors continues to be controversial. To date, only a minority of the several randomized adjuvant chemotherapy trials performed in adults have shown a significant survival advantage for chemotherapy. Among those, the Italian randomized trial on high-risk patients (high grade, large, deep, extremities site) was stopped early due to evidence at an interim analysis of a significant advantage in EFS and OS for patients who received ifosfamide-doxorubicin chemotherapy versus those treated with local therapy only [36]. Moreover, 14 randomized trials comprising 1,568 adult patients were included in a meta-analysis that demonstrated a reduction in the risk of local and distant failures in the group treated with intensified doxorubicin-based chemotherapy (advantage of 10% in recurrence-free survival and of 4% in OS) [37]. Recent hints from pediatric series, moreover, suggest that chemotherapy has a more beneficial impact than is generally believed when it is given to high-risk cases, using the more effective combination (full-dose ifosfamide-doxorubicin regimen, as indicated in various adult series) [29]. These two retrospective studies, from the Istituto Nazionale Tumori of Milan [29] and from the Italian and German cooperative group [38], show that the combination of the two variables high grade and large tumor size produced a very high risk of metastatic spread (metastatic-free survival in the range of 30 40%), thus suggesting in principle the use of chemotherapy to improve the survival, and that the chances of survival clearly rise in those patients given chemotherapy. In the series from Milan, the response rate to chemotherapy in patients with measurable disease was 39% in terms of complete and partial response, but rose to 58% when minor responses were included [29]. In the absence of standard guidelines, adolescents and young adults could be included in investigational trials, or the issue of adjuvant chemotherapy (still unclear) could be considered suitable for individual clinical use. It is noteworthy that the EpSSG trial for pediatric adult-type sarcomas requires the administration of adjuvant chemotherapy for high-risk cases (G3 tumor, large than 5 cm) [31]. In addition to tumor size and tumor grade, other risk factors have been individuated: the feasibility of a complete resection, the local invasiveness, the proximal sites and deep locations, and obviously the presence of metastases at onset and the recurrent disease. The effect of histopathologic subtype on prognosis is yet unclear, although different findings suggest that some histotypes (e.g., MPNST) are associated with poor outcome, while others (e.g., leiomyosarcoma, fibrosarcoma) have been reported to have a more favorable prognosis in some series, and a poor outcome in others [39]. Different findings suggested that age is also a significant prognostic factors in STS. In various adult series, younger age (generally less than 40 years) is a

13 Soft Tissue Sarcomas Chapter favorable predictor of survival. Similarly, age has been correlated with clinical features and outcome in childhood series: in the St Jude Children s Research Hospital study (192 patients aged 1 month 22 years), the group of adolescents and young adults, with age over 15 years, had distinctive features [40]. In this age group, SS and MPNST were the most common histotypes. In comparison to younger patients, adolescents and young adults had a higher percentage of tumors that were large and invasive, with high histological grade and with metastases at onset. As a consequence, survival rates were lower (5-year OS 49%, EFS 37%) than for younger children. The tumor characteristics and outcome of this series approach those of the younger patients of adult series [40]. In the case of inoperable locally advanced disease (and moreover in patients with metastases at onset), prognosis is unsatisfactory and all therapeutic resources should be taken into consideration. Chemotherapy, eventually associated with preoperative radiotherapy, is the first option. Adult trials have shown that the combination of ifosfamide and doxorubicin constitutes the regimen with the higher response rate (with a direct relationship between response and doses). In a particular subset of patients, locoregional approaches (i.e., hyperthermic limb perfusion with intra-arterial chemotherapy or immunotherapy) could be considered. It is evident that every effort should be made to improve the therapeutic arms for advanced tumors. A recent report from the Memorial Sloan-Kettering Cancer Center commented that the outcome of localized extremity STSs has not improved over the last 20 years, suggesting that current therapy has reached the limits of efficacy [41]. New drugs and new approaches are warranted. Some data have suggested a possible role for paclitaxel in the treatment of angiosarcomas and for gemcitabine in leiomyosarcomas. New selective mechanisms, such as that of the antityrosine kinase imatinib mesylate, which dramatically modifies the clinical course of gastrointestinal stromal tumors (GIST: gastrointestinal mesenchymal tumors that are immunohistochemically positive for the product of the c-kit oncogene, CD117), must be explored for novel agents and for other histotypes. The success of imatinib mesylate in the treatment of GIST provides important lessons for the development of new therapies designated specifically for targets identified as being critical to the tumor s biology; most of the specific chromosomal translocations present in sarcomas have been cloned (with the identification of fusion genes) and may represent the ideal targets for new molecular therapies [31] Synovial Sarcoma SS probably represents the most frequent malignant tumor of soft tissues in adolescents and young adults, accounting for about 15 20% of all cases. The optimal treatment approach to SS remains to be determined. As for other STSs of adult age, the standard treatment for localized disease is surgery. Complete surgical resection of the primary tumor is the unquestionable mainstay of treatment. Extensive surgery with histologically free margins is recommended: compartment resection is the treatment of choice when feasible, otherwise wide excisions may also be accepted. A general agreement has not yet been achieved regarding the role of adjuvant treatments. Postoperative radiotherapy has a well-defined role to improve local control after less-than-compartmental resection: after wide resection, particularly in the case of a large tumor, but also after marginal and intralesional resection. In the case of locally advanced disease, the radiotherapy sandwich technique (preoperative chemotherapy and radiotherapy, then surgery followed by adjuvant chemotherapy and a possible boost of irradiation) may be useful for shrinking the tumor and making it resectable [31]. More open questions still exist regarding the role of postoperative chemotherapy, given that the rarity of the tumor hinders the adequate accrual for a randomized trial. Over the years, completely different strategies have been worked out in pediatric oncology protocols and as compared to the adult setting. Practically speaking, in European centers, a patient aged 16 years old, enrolled in pediatric trials, was treated very differently from a 22-year-old patient. Pediatricians mutated their approach from the management of RMS: due to the quite good chemotherapy response rate in the pediatric series, SS was considered as an RMS-like tumor and was treated with the same protocols designed for RMS, thus giving adjuvant chemotherapy

14 198 Chapter 11 K. H. Albritton A. Ferrari M. Casanova Table 11.7 Synovial sarcoma series from the Istituto Nazionale Tumori, Milan, Italy. Treatment and results according to the different age groups (from Ferrari et al. 2004) age 0 16 years years >30 years Overall No. of patients 46 patients Tumor >5 cm 49% 60% 73% 60% Gross resected disease 41 patients % Radiotherapy 58% 45% 49% 50% % Chemotherapy 76% 21% 15% 28% 5-year EFS 66.3% 40.5% 30.9% 40.7% to the majority of patients, even in cases of completely excised small tumors. On the contrary, adjuvant chemotherapy was employed in adult patients mainly within trials including all histotypes, with a no-therapy control arm: therefore, adjuvant chemotherapy was rarely utilized in adults and only in the recent years has it been routinely proposed for high-risk patients (local invasiveness, large size, deep localization) [42]. What would be the most adequate strategy remains unclear. Published series reported better outcome in pediatric series than in adult studies, but all the known adverse prognostic factors are more frequent in adults (large size, local invasiveness, unresectability, proximal sites), and age per se is probably a prognostic indicator. Nevertheless, the better results obtained within pediatric protocols might also be correlated with the different therapeutic strategies adopted. The most significant pediatric experience is the multicenter analysis coordinated by the University of Texas MD Anderson Cancer Center (which combined the previously published experiences of different research groups) that showed a 5-year OS of 80% and a quite high response rate to chemotherapy (60%). Of the 219 patients, 52% were adolescents (14 20 years) and the risk of event increased 0.06 times for subsequent 1 year increase in age [43]. Concerning the role of adjuvant chemotherapy, this study did not show a clear impact of chemotherapy on survival in resected patients [43]. Conversely, data from the large series of the Istituto Nazionale Tumori of Milan, Italy, showed better outcomes for patients who received adjuvant chemotherapy (5-year EFS, 55% vs. 35%) [44]. This study compared the clinical findings, the treatment modalities, and the outcome of the different age groups: as shown in Table 11.7, the EFS of grossly resected cases increased with the increase in the use of adjuvant chemotherapy. Far from a demonstration of efficacy of adjuvant chemotherapy in SS, these data would seem suggestive of a role for it [44]. By definition, SS is a high-grade sarcomas, and so this could be consistent with some suggestions regarding high-risk sarcomas coming from adult trials. SS probably stands halfway between the most typical adult STSs and pediatric small round cell sarcomas, and chemotherapy seems to play a greater role in pediatric terms compared to adult sarcomas; roughly, the response rate to chemotherapy could be estimated as around 40% for adult-type STSs, 60% for SS, and 80% for RMS and ES/pPNET. This may imply that the use of chemotherapy in all cases, regardless of prognostic stratification (as developed in previous pediatric European trials) might be considered as overtreatment: a recent pediatric Italian and German review identified a subset of patients (completely resected, tumor <5 cm) treated with adjuvant chemotherapy that showed a very low risk of metastases (48 cases, 4 local relapses, no distant relapse), suggesting that chemotherapy can be omitted in low-risk groups [45]. This will be the indication for the upcoming EpSSG protocol. Cooperative trials involving pediatric and adults patients with SS could be warranted; moreover, a large

15 Soft Tissue Sarcomas Chapter accrual of cases could permit investigation of the role of new therapies such as Bcl-2 antisense oligonucleotide, since in most cases of SS the anti-apoptotic protein Bcl-2 (overexpression of Bcl-2 correlates with tumor growth, chemoresistance, and poor outcome in various cancers) is overexpressed Summary and Conclusions STSs represent about 7% of all malignant tumors in 15- to 29-year-olds. They include a highly heterogeneous group of different histotypes, which are generally characterized by local aggressiveness and propensity to metastasize. Peculiar to childhood, RMS may occur in older age and is characterized by its high responsiveness to chemotherapy and radiotherapy. Multidisciplinary and risk-adapted treatment approaches developed by international cooperative groups have dramatically improved the prognosis of RMS during the past 30 years, improving cure rates from 30% to 70%. Young adults with RMS usually have a less favorable outcome than children, but their prognosis would be improved if fully adequate treatments derived by childhood trials are employed. Adult-type sarcomas are different tumors with various grades of malignancy, which are generally localized to the extremities. In these tumors, surgery is the mainstay of treatment, and the role of adjuvant therapies remains unclear. In particular, they are regarded to have uncertain responsiveness to chemotherapy, although recent hints would suggest a more significant beneficial impact in high-risk cases than is generally believed. The prognosis is related to the feasibility of surgical resection, and to histological grade, tumor size, local invasiveness and, clearly, the presence of metastases. SSs are typical of adolescents and young adults, and are probably positioned halfway between the pediatric small round cell tumors (such as RMS) and the most typical adult sarcomas with regard to responsiveness to chemotherapy. In conclusion, this heterogeneous group of tumors includes entities that are not so rare in adolescents and young adults. The treatment of these patients appears particularly complex and necessarily multidisciplinary, and requires adequate expertise. It is very important to emphasize that adolescents and young adults receive better treatments within selected and experienced institutions that enroll patients into clinical trails. Cooperation between pediatric oncologists and adult oncologists is needed to better define the treatment options for adolescents and young adults patients. In particular, histology as well as tumor biology and characteristics appear to be more important than the patients age. Although age per se may be considered a prognostic factor in STSs, a certain histotype would behave in the same way when arising in children, adolescents, or adults. This leads to the consideration that RMS patients, regardless of their age, would receive the better treatment when following guidelines derived from the large pediatric experience, whereas the treatment of patients with adult-type sarcomas should acquire suggestions from the body of experience gained over the years by adult oncologists. Cooperative studies are needed to investigate the role of new therapies that are specifically tailored for molecular targets, which might be the several specific chromosomal translocations identified in STSs. References 1. Bleyer WA, O Leary M, Barr R, Ries LAG (eds) (2006) Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, including SEER Incidence and Survival, National Cancer Institute, NIH Pub. No Bethesda, MD 2006, pp Wexler LH, Meyer WH, Helmann LJ. Rhabdomyosarcoma and the undifferentiated sarcomas. In Pizzo PA, Poplack DC (eds), Principles and Practice of Pediatric Oncology. 5th ed. Lippincott Williams & Wilkins, Philadelphia, pp Okcu MF, Hicks J, Merchant TE, et al: Nonrhabdomyosarcomatous soft tissue sarcomas. In Pizzo PA, Poplack DC (eds), Principles and Practice of Pediatric Oncology. 5th ed. Lippincott Williams & Wilkins, Philadelphia, 2006, pp Bleyer WA, Tejeda H, Murphy SB, et al (1997) National cancer clinical trials: children have equal access; adolescents do not. J Adolesc Health 21: Bleyer A, Montello M, Budd T, Saxman S (2005) National survival trends of young adults with sarcoma: lack of progress is associated with lack of clinical trial participation. Cancer 103: Pappo AS, Shapiro DN, Crist WM, Maurer HM (1995) Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13: