.
Anatomic distribution and site-specific histologic subtypes of 1,708 consecutive patients with soft tissue sarcomas seen at The University of Texas M.D. Anderson Cancer Center Sarcoma Center (MDACC Sarcoma Database, June 1996 – December 1998).
 |
Sarcomas of nonosseous tissues, also known traditionally as “soft-tissue” sarcomas, comprise a group of relatively rare malignancies that exhibit tremendous diversity of anatomic site and histopathologic characteristics. These tumors share a common embryologic origin, arising primarily from tissues derived from the mesoderm. The notable exceptions are sarcomas of neural tissues and possibly the Ewing’s sarcoma/primitive neuroectodermal tumor (PNET) family of tumors, which are believed to arise from tissues of ectodermal origin. Despite the fact that the somatic nonosseous tissues account for as much as 75% of total body weight, primary neoplasms of these connective tissues are comparatively rare, accounting for 1% of adult malignancies and 15% of pediatric malignancies. The annual incidence of softtissue sarcomas in the United States is about 7,800 new cases, with 4,400 deaths annually.1 Nonetheless, despite their rarity, these tumors are important to understand completely, since clinical outcomes might be compromised if initial management is anything less than ideal. Additionally, biologic insights derived from sarcomas are providing new strategies to the detection, treatment, and prevention of other more common malignancies.
This chapter will review current concepts in the diagnosis, staging, and multidisciplinary management of patients with sarcomas of nonosseous tissues. The evolving contributions of molecular biology and basic scientific principles underlying the varied differentiation and clinical behavior of these tumors will also be reviewed. Although clinicopathologic aspects of sarcomas are increasingly important in categorizing these tumors, anatomic site of primary disease remains an important variable on which treatment and outcomes may depend. Localized extremity sarcoma, which accounts for approximately 50% of all sarcomas (and is therefore the anatomic site with the largest literature base), will be the focus of the first section of the chapter. Retroperitoneal sarcomas (RPSs) will be addressed separately later in the chapter. The remaining anatomic sites will not be discussed directly because of their rarity but the principles of local management are based on the knowledge gained from the randomized trials performed in extremity lesions. Sarcomas arising in visceral sites are the exception since they often are found in mobile structures that are not contained by tissue planes or anatomic barriers to tumor spread and pose unique challenges. These are briefly mentioned later in the section on adjuvant radiotherapy (RT). The important contributions of multidisciplinary care, including RT and systemic treatments such as chemotherapy, will also be discussed at length. Throughout, the emphasis will be on identifying what is known from definitive data and what questions in sarcoma management require additional research to address more fully.
The causes of sarcoma development remain obscure in the vast majority of cases. The conceptual frameworks that address the neoplastic transformation of mesenchymal stem cells are in rapid evolution based on new insights from the molecular analyses of sarcoma tissue and other normal tissues from the affected patient and family members. Genetics and environmental factors each appear to play a role in the neoplastic transformation of soft tissue into sarcomas.
It has been recognized for more than 30 years that sarcomas can arise in the context of certain genetic predispositions to cancer development. One of the earliest observations of familial cancer development (i.e., genetically transmitted predisposition to malignancy) was the development of sarcomas and other tumor types (such as breast cancer) in certain kindreds.2–4 This autosomal dominant genetic predisposition has now become known as the Li-Fraumeni syndrome and it has been characterized at the molecular level as a germline mutation of the p53 gene which presumably acts in this context as a faulty tumor suppressor.5,6 The actual molecular pathways that lead to development of sarcoma are still poorly understood and are the subject of much basic scientific inquiry.
Other genetic disorders are also associated with increased risk of sarcoma development, occasionally along specific histopathologic lines of differentiation. The best studied example of this is the predilection of patients with neurofibromatoses to develop malignant peripheral nerve sheath tumors (MPNST, also referred to variably in the literature as neurofibrosarcomas or malignant schwannomas).7 Type 1 neurofibromatosis (von Recklinghausen’s disease) is an autosomal dominant disease that can disrupt the function of the NF1 gene, located on chromosome 17q11.2. The endogenous function of the NF1 gene product (neurofibronin) is incompletely understood, but it appears to act as a tumor suppressor gene via stimulation of guanosine triphosphatase (GTPase) activity. This, in turn, may control ras oncogene signaling pathways. Common mutations in NF1 include truncations, with loss of function, which lead to uncontrolled signaling through ras pathways.8–10 This may be a fundamental process that facilitates the development of MPNST over time in patients with neurofibromatoses. There is up to a 10% cumulative lifetime risk of developing sarcoma (usually MPNST) in patients with type 1 neurofibromatosis.11
Survivors of childhood retinoblastoma have also been noted to have an increased risk of sarcoma development later in life. This provides yet another molecular model of a dysfunctional or deleted tumor suppressor genetic element (in this case, the product of the Rb gene on chromosome 13q14).12–17 The risk of soft-tissue sarcoma in retinoblastoma patients and families is accompanied by the risk of development of several other types of neoplasms, including osteosarcomas, breast cancer, and lung cancer. No reasons have been convincingly posited for the development of one type of malignancy over another in patients with Rb mutations, and this remains an important question to be addressed by future research on mechanisms of neoplastic transformation.
Gardner’s syndrome represents an important genetic connection between dysfunctional regulation of epithelium as well as of mesenchymal cells. Gardner’s syndrome represents one subset of patients with familial adenomatous polyposis disorders of the bowel (usually the colon) who also have extracolonic abnormalities such as epidermoid cysts and osteomas. The molecular lesion has been identified as a defect within the APC (adenomatous polyposis coli) gene on chromosome 5q21. Patients with Gardner’s syndrome are at much increased risk to develop mesenteric and intraperitoneal desmoid tumors. Desmoid tumors are mesenchymal cells proliferating in a pattern of aggressive fibromatosis, characterized by bland cells that—although histologically benign—act in a malignant fashion with uncontrolled proliferation and infiltration of vital structures. It remains poorly understood why some patients with Gardner’s syndrome develop desmoid tumors whereas others do not, and the lifetime risk of developing desmoid tumors has been estimated at approximately 10 to 20%, representing an increase in risk nearly 1000 times greater than the general population for development of these tumors.
Besides genetic predisposing conditions, environmental exposures have been associated with the development of sarcomas. One of the most important exposures to recognize is ionizing radiation. Sadly, this is most often a late effect of radiation therapy given to treat another condition (often a different prior malignancy). Sarcomas have been noted as a late effect of radiation therapy for breast cancer, Hodgkin’s disease, non–Hodgkin’s lymphomas, and other tumor types.13 Dose of radiation appears to be correlated with later development of sarcoma, with a very low risk in patients who received < 10 Gy.13 However, the molecular mechanisms may be complex, since it has been noted clinically that sarcomas appear at the margins of prior RT treatment fields. This suggests that the mutagenic effect may be maximal at the edges of prior RT where scatter radiation leads to dose sufficient to induce mutations but insufficient to kill the mutated cells. Traditionally, radiation-associated sarcomas were thought to arise several years following prior radiotherapy, although newer data indicate that a shorter latency period of 2 to 4 years may also be possible.18–21 Malignant peripheral nerve sheath tumors, angiosarcomas, and other high-grade unclassifiable histopathologic subtypes comprise the majority of radiation-associated sarcomas. Although aggressive, it is not clear that radiation-associated sarcomas truly behave differently from other high-grade sarcomas. Clinical outcomes have been reported to be poor in patients with such secondary radiation-associated sarcomas, perhaps due to the lack of ability to use full multi-modality treatment (e.g., due to having reached prior radiation tolerance to tissues or prior doxorubicin exposure). Radiation-associated sarcomas should be approached as new primary disease and treated appropriately to optimize the patient’s outcomes (as discussed later).
Certain chemical exposures have also been documented to induce sarcomas, and chemical-induced development of sarcomas in animal models has been one of the more widely employed models of studying neoplastic transformation in the laboratory. Hepatic angiosarcomas have been associated with exposure to several classes of chemicals,22 including polyvinyl chloride,23–25 arsenicals,26,27 and a colloid consisting of thorium dioxide (“thorotrast,” an antiquated contrast agent).28–30 The relationship between exposure and development of sarcoma is quite a bit less clear for other possible compounds, including dioxin (such as Agent Orange and other phenoxyacetic acid-based herbicides) or chlorophenols used in wood preservatives,31–36 although definitive data do not exist to resolve this point of possible causality.
Chronic irritation of tissues is a controversial point in the development of sarcomas. Certainly, there is an increased risk of sarcoma development in lymphedematous arms of women who have undergone radical mastectomy, often with the additional complicating variable of prior RT (the Stewart-Treves syndrome).37,38 Limited data also suggest that other sources of chronic tissue irritation and inflammation might be associated with development of sarcoma.39 Although a history of prior trauma is not infrequently elicited from patients with soft-tissue sarcomas, the causative impact of any such trauma on sarcoma development is in doubt.
Severe and chronic immunosuppression following solid organ transplantation represents yet another risk factor for development of sarcomas. Sarcomas represent a disproportionate percentage of tumors (10%) in patients following solid organ transplantation, although Kaposi’s sarcoma comprises the majority of these.40
Given the rare incidence of sarcomas in the general population, no general screening is indicated beyond routine health care surveillance. However, it is important for physicians to be aware of the predisposing genetic tendencies and environmental exposures that might increase the risk of sarcoma development. Complete family history should reveal clues as to genetic predispositions, including a family history of polyposis, neurofibromatosis, retinoblastoma, any cancer at young age in first-degree relatives, or prior sarcomas. Genetic counseling would be appropriate to discuss issues relating to these predispositions. In appropriate patients, a more detailed clinical evaluation might be required at a lower threshold of intervention than one might use for general health care. Rapidly growing masses, especially symptomatic ones, in patients with neurofibromatosis should be considered for surgical removal to rule out the potential of sarcomatous transformation within a neurofibroma. Similarly, any superficial or deep abnormalities of skin or soft tissues in patients with a history of prior RT should be evaluated very thoroughly, given the known increased risk of sarcoma development.
Anatomic distribution and site-specific histologic subtypes of 1,708 consecutive patients with soft tissue sarcomas seen at The University of Texas M.D. Anderson Cancer Center Sarcoma Center (MDACC Sarcoma Database, June 1996 – December 1998).
. Approximately one-third to one-half of all sarcomas of nonosseous tissues occur in the lower extremities, where the most common histopathologic subtypes have traditionally been noted to include liposarcomas as well as the vaguely defined entity of “malignant fibrous histiocytoma” (MFH). With improved pathologic tools to categorize sarcomas (e.g., immunohistochemistry, molecular analyses), it is increasingly recognized that sarcomas previously referred to as MFH are often more accurately categorized as poorly differentiated liposarcomas or leiomyosarcomas, as well as other histologic subtypes. RPSs comprise 15 to 20% of all soft-tissue sarcomas, with liposarcoma and leiomyosarcoma being the predominant histologic subtypes. The visceral sarcomas make up an additional 24%, whereas the head and neck sarcomas comprise approximately 4% of all sarcomas seen at a tertiary care cancer center (see Fig. 122.1).
The majority of patients with nonosseous sarcomas present with a painless mass, although pain is noted at presentation in up to a third of cases.41 Delay in diagnosis of sarcomas is common, with the most common incorrect diagnosis for extremity and trunk lesions being hematoma or “pulled muscle.” Delayed diagnosis of RPSs is extremely common, since most of the tumors in this area can grow to massive size before causing any symptoms (such as abdominal distention or psoas irritation with back or groin discomfort).
Physical examination should include an assessment of the size and mobility of the mass. Its relationship to the fascia (superficial versus deep) and nearby neurovascular and bony structures should be noted. A site-specific neurovascular examination and assessment of regional lymph nodes should also be performed.
In broad terms, sarcomas can be classified as neoplasms arising in bone versus those arising from the nonosseous or periosseous “soft” tissues. Sarcomas of nonosseous tissues can be further grouped into those that arise from viscera (e.g., gastrointestinal or gynecologic organs) and those that originate in nonvisceral soft tissues such as muscle, tendon, adipose tissue, pleura, synovium, and other connective tissues.
The most universally applied classification scheme for soft-tissue sarcoma is based on histogenesis, as outlined in the recent World Health Organization classification system for sarcomas.42,43 This classification system is reproducible between pathologists for the better differentiated tumors. However, as the degree of histologic differentiation declines, the determination of cellular origin becomes increasingly difficult. In particular, despite advanced immunohistochemical techniques44 and electron microscopy, determining the cellular origin for many spindle cell and round cell soft-tissue tumors is difficult, occasionally arbitrary, and sometimes impossible. This leads to significant disparity in diagnosis among pathologists. A discrepancy between the original histologic assessment and that of a subsequent expert review has been noted in as many as 25% of cases.45,46
| Histologic Subtype | Cytogenetic Finding | Genes |
|---|---|---|
| Myxoid liposarcoma | t(12;16) | TLS / CHOP |
| Well-differentiated | Rings and giant | Amplified 12q13-15 |
| liposarcoma | markers | HMG1-C |
| CDK4 | ||
| MDM2 | ||
| Lipoma (minimal atypia) | 12q abnormalities | Amplified 12q13-15 |
| Lipoma | 12q14-15 abnormalities | |
| 6p abnormalities | ||
| Synovial sarcoma | t(X;18) | SYT/SSX1 or SSX2 |
| Ewing’s family/ | t(11;22) and others | EWS/FLI1(and others) |
| PNET | ||
| Rhabdomyosarcoma (alveolar) | t(2;13) or t(1;13) | PAX3 (or 7)/FKHR |
| Clear cell sarcoma | t(12;22) | EWS/ATF1 |
| Extraskeletal myxoid | ||
| chondrosarcomas | t(9;22) | EWS/CHN |
| t(9;17) | RPB56 / CHN | |
| Dermatofibrosarcoma | t(17;22) | Collagen type I alpha1 |
| protuberans | ring(17;22) | PDGF-B |
| Endometrial stromal sarcoma | t(7;17) | |
| Uterine leiomyosarcoma | t(12;14) | |
| 7q- | ||
| Desmoplastic small | t(11;22) | EWS/WT1 |
| round-cell tumor | ||
| Alveolar sarcoma of | t(X;17) | |
| soft parts |
PNET = peripheral neuroectodermal tumors.
The spectrum of grades observed among histologic subtypes of soft-tissue sarcoma. (From Enzinger FN and Weiss SW, editors. Soft Tissue Tumors. 3rd ed. Mosby-Year Book Inc; 1995. With permission.)
). In careful comparative multivariate analyses, histologic grade has been the most important prognostic factor in assessing the risk for distant metastasis and tumor-related mortality.49,50 Several grading systems have been proposed, but there is no consensus regarding the specific morphologic criteria that should be employed in the grading of soft-tissue sarcomas.
Two of the most commonly employed grading systems are the U.S. National Cancer Institute (NCI) system developed by Costa and colleagues51 and the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system developed by the French Federation of Cancer Centers Sarcoma Group.52 The NCI system is based on the tumor’s histologic subtype, location, and amount of tumor necrosis, but cellularity, nuclear pleomorphism, and mitosis count are also to be considered in certain situations. The FNCLCC system employs a score generated by the evaluation of three parameters: tumor differentiation, mitotic rate, and amount of tumor necrosis. The prognostic values of these two grading systems were retrospectively compared in a population of 410 adult patients with nonmetastatic soft-tissue sarcoma.53 Univariate and multivariate analyses suggested that the FNCLCC system has a slightly better ability to predict distant metastasis development and tumor-related mortality. Significant discrepancies were observed in one-third of cases. An increased number of grade 3 tumors, reduced number of grade 2 tumors, and better correlation with overall and metastasis-free survival were observed in favor of the FNCLCC system.53 Thus, in the absence of other comparative data, the FNCLCC system may be the best presently available grading system.
In discussing grade, it is important to note two well-described characteristics of sarcomas. First, there is often tremendous intratumoral heterogeneity within individual sarcomas, leading to sampling artifact, which could render inaccurate diagnoses based on very limited amounts of tumor (e.g., diagnoses based on only needle-based sampling). This is true, for example, for common histopathologic subtypes such as de-differentiated liposarcomas, where one area of the tumor might have a relatively low-to-intermediate grade appearance and another area at some distance within the same tumor might have more evident high-grade components. Any discussion of the clinical relevance of grading must take into account this variability inherent in the diagnostic process, which will add to the clinical variability in outcomes among patients with any given grade of sarcomas.
Second, grade of tumors may indeed change over time. This process is best described in the evolution of de-differentiated liposarcomas arising in conjunction with well-differentiated liposarcoma in the same patient. Additional examples include the fibrosarcomatous degeneration that can accompany multiple recurrent dermatofibrosarcoma protuberans.
A, Fast-spin echo T2 fat-saturated magnetic resonance image of a TNM T2b high-grade sarcoma in the posterior thigh compartment of a 55-year-old woman. Note the containment by the superficial fascia overlying the posterior thigh muscles where there is a “strip” of peritumoral edema. Anteriorly the lesion can be seen to be separate from the femur but the edge of the tumor is less clearly defined than its superficial component presumably because of muscle infiltration.B, Sagital magnetic resonance image view of the same patient shown in A, The main lesion manifests a well defined border. However a clear zone of peritumoral edema is evident tracking proximally toward the head of the femur, seen at the top of the figure. Inferiorly the edema seems to be even more pronounced as evidenced by the triangular shaped signal enhancement pointing inferiorly. Whether or not the zone of edema harbors microscopic disease is uncertain and can pose uncertainties for accurate treatment planning (see text).
A 57-year-old male with T2 pelvic leiomyosarcoma. Top, Axial T2-weighted fast-spin echo MR image reveals heterogeneous mass involving the rectum (note air in rectal lumen - arrow). Bottom, Note abutment of mass to right seminal vesicle (arrow).
A, Coronal view fat-saturated postgadolinium enhanced magnetic resonance image showing an 8.3 cm by 6.6 cm solid liposarcoma adjacent to and compressing the upper pole of the left kidney. The mass lies below the spleen and is separate from the kidney (see line of demarcation with arrow) but is part of a larger fatty tumor (see Fig. 5B and 5C). The midline vessels are well visualized postgadolinium. B, A computerized tomography (CT) image of the same lesion as in figure A. The mass can be seen adjacent to the kidney as before. An additional mass of fatty attenuation with grey areas of edema, inflammation, or increased cellularity can be seen bounded by a rim anteriorly (arrow). This mass has the appearance of abnormal fat which must be considered in treatment planning. Note the displacement of bowel containing contrast. C, Sagital view magnetic resonance image of the case in A and B but in different sequence without gadolinium. The potential advantage of MRI in separating the anterior edge of the retroperitoneal sarcoma (long arrow) from the normal fat anteriorly is seen. The more solid component can also be seen (arrowhead) inferior to the spleen. In addition these images can be exported digitally to a three dimensional radiotherapy treatment planning work station or CT simulator work station where the MRI images can be fused to the CT planning slices. This can provide more accurate demonstration of tumor in selected cases for contouring the gross tumor volume (GTV) and clinical target volume (CTV) than may be possible with CT images alone. This is particularly helpful in situations where CT does not show tumor as well as MRI.
and 122.4). 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.54,55 However, a recent study by the Radiation Diagnostic Oncology Group that compared 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.56 On the other hand, although it may be true that the diagnostic evaluation may be equally served by both modalities, the treatment planning requirements (e.g., for both surgery and RT) may require additional information provided by the multiplanar capability of MRI and the ability to perform MRI/CT image fusion.57,58 For pelvic lesions, the multiplanar capability of MRI may provide superior single-modality imaging (see Fig. 122.4). In the retroperitoneum and abdomen, CT usually provides satisfactory anatomic definition of the lesion. Occasionally, MRI with gradient sequence imaging can better delineate the relationship of the tumor to midline vascular structures, particularly the inferior vena cava and aorta (Fig. 122.5). More invasive studies such as angiography or cavography are almost never required for the evaluation of soft-tissue sarcomas.
Cost-effective imaging to exclude the possibility of distant metastatic disease is dependent on the size, grade, and anatomic location of the primary tumor. In general, patients with low- and intermediate-grade tumors or high-grade tumors less than 5 cm in diameter require only a chest radiograph for satisfactory staging of the chest. This directly reflects the comparatively low risk for presentation with pulmonary metastases in these patients.59 However, patients with high-grade tumors larger than 5 cm (T2) in size should undergo more thorough staging of the chest by CT due to the increased risk of presentation with established metastatic disease in this group. Patients with retroperitoneal and intra-abdominal visceral sarcomas should undergo imaging of the liver to exclude the possibility of synchronous hepatic metastases; the liver is a more common site for first metastasis for these lesions. CT scanning is usually adequate in these patients to assess the liver, although the increased sensitivity of MRI scanning of the liver may be valuable if any questionable findings are noted on initial CT.
Biopsy of the primary tumor is essential for most patients presenting with soft-tissue masses. In general, any soft-tissue mass in an adult that is enlarging (even if asymptomatic), 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 diagnosis60–62 and has been demonstrated to result in substantial cost savings compared to open surgical biopsy.62 Incisional biopsy may yet be required to yield optimal amounts of tissue to assess histopathology over a larger area of tumor volume, given the known heterogeneity of many sarcomas, as well as to provide sufficient material for detailed molecular and cytogenetic assays. Direct palpation can be used to guide needle biopsy of most superficial lesions, but less accessible sarcomas often require imaging-guided biopsy for safe percutaneous sampling of the most heterogeneous component of the mass. Tumor recurrences within the needle tract after percutaneous biopsy are rare but have been reported,63 leading some physicians to advocate tattooing the biopsy site for subsequent excision. In some centers, fineneedle aspiration may be an acceptable biopsy technique for primary soft-tissue masses provided that an experienced sarcoma cytopathologist is available.64–67 However, because of the frequent difficulty in accurately diagnosing these lesions even when adequate tissue is available, the major utility of fine-needle aspiration in most centers is in the diagnosis of suspected recurrences of sarcoma.
Incisional or excisional biopsy is not routinely 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 following careful planning of the orientation of resection and with expert microscopic assessment of surgical margins. Incisional and excisional biopsies should be performed with the incision oriented to facilitate subsequent wide local excision or its inclusion in a preoperative RT volume (i.e., longitudinal orientation for extremity soft-tissue masses). The incision should be centered over the mass at its most superficial point. Care should be taken not to raise tissue flaps. Meticulous hemostasis should be ensured to prevent dissemination of tumor cells into adjacent tissue planes by hematoma. All excisional biopsy specimens should be sent fresh, sterile, and anatomically oriented for pathologic analysis. The pathology report needs to comment specifically on all margins of resection in three dimensions. At definitive resection of a previously biopsied sarcoma, the previous surgical biopsy scar should be excised en bloc with the tumor.
Approach for pretreatment evaluation and staging of the patient presenting with a primary extremity soft-tissue mass. AJCC, American Joint Commission on Cancer. (From Pisters PWT Ann Surg Oncol 1998;5:464-472, with permission)
. Small superficial lesions in locations on the extremity where the morbidity of excisional biopsy is minimal (i.e., remote from joints, tendons, and neurovascular structures that would compromise the surgical margin) are easily biopsied by excisional biopsy with assessment of microscopic surgical margins. T2 lesions, T1 lesions located deep to the investing fascia of the extremity, or superficial T1 lesions situated in proximity to joints, tendons, or neurovascular structures are best biopsied by percutaneous core needle biopsy.
| T1 | < 5 cm | |||
| T1a | Superficial to muscular fascia | |||
| T1b | Deep to muscular fascia | |||
| T2 | ≥ 5 cm | |||
| T2a | Superficial to muscular fascia | |||
| T2b | Deep to muscular fascia | |||
| N1 | Regional nodal involvement | |||
| G1 | Well differentiated | |||
| G2 | Moderately differentiated | |||
| G3 | Poorly differentiated | |||
| G4 | Undifferentiated | |||
| Stage IA | G1, 2 | T1a, b | N0 | M0 |
| Stage IB | G1, 2 | T2a | N0 | M0 |
| Stage IIA | G1, 2 | T2b | N0 | M0 |
| Stage IIB | G3, 4 | T1a, b | N0 | M0 |
| Stage IIC | G3, 4 | T2a | N0 | M0 |
| Stage III | G3, 4 | T2b | N0 | M0 |
| Stage IV | Any G | Any T | N1 | M0 |
| Any G | Any T | Any N | M1 | |
From Fleming ID, Cooper JS, Henson DE, eds. American Joint Commission on Cancer AJCC cancer staging manual. 5th Ed. Philadelphia: Lippincott-Raven; 1997. Reprinted with permission from Lippincott-Raven.
A major limitation of the present staging system is that it does not take into account the anatomic site of soft-tissue sarcomas. Anatomic site, however, has been recognized as an important determinant of outcome. Patients with retroperitoneal and visceral sarcomas have a worse overall prognosis than do patients with extremity tumors. Although site is not incorporated as a specific component of any present staging system, outcome data should be reported on a site-specific basis.
Thorough understanding of the clinicopathologic factors known to impact outcome is essential in formulating a treatment plan for the patient with soft-tissue sarcoma. Over the past decade, more than a dozen multivariate analyses of prognostic factors for patients with localized sarcoma have been reported.52,69–83 With few exceptions,49A,50,69,75 most studies have analyzed fewer than 300 patients (range, 82–297 patients).
| Endpoint | Adverse Prognostic Factor | Relative Risk |
|---|---|---|
| Local recurrence | Fibrosarcoma | 2.5 |
| Local recurrence at presentation | 2.0 | |
| Microscopically positive margin | 1.8 | |
| Malignant peripheral nerve sheath tumor | 1.8 | |
| Age > 50 years | 1.6 | |
| Distant recurrence | High grade | 4.3 |
| Deep location | 2.5 | |
| Size 5.0–9.9 cm | 1.9 | |
| Leiomyosarcoma | 1.7 | |
| Nonliposarcoma histology | 1.6 | |
| Local recurrence at presentation | 1.5 | |
| Size ≥ 10.0 cm | 1.5 | |
| Disease-specific | High Grade | 4.0 |
| survival | Deep location | 2.8 |
| Size ≥ 10.0 cm | 2.1 | |
| Malignant peripheral nerve sheath tumor | 1.9 | |
| Leiomyosarcoma | 1.9 | |
| Microscopically positive margin | 1.7 | |
| Lower extremity site | 1.6 | |
| Local recurrence at presentation | 1.5 |
Adverse prognostic factors identified are independent by Cox regression analysis. From Pisters et al,49A with permission from Journal of Clinical Oncology.
Attention has recently been focused on the evaluation of molecular pathologic prognostic factors. Specific molecular parameters evaluated for prognostic significance have included p53,84 mdm2,84 Ki-67,84 altered expression of the retinoblastoma gene product (pRb)17,85 in high-grade sarcomas, and the presence of specific molecular subtypes of the SYT-SSX fusion transcripts in synovial sarcoma86 or EWS-FL11 fusion transcripts in Ewing’s sarcoma.87,88 Complete discussion of the extensive literature on molecular prognostic factors in sarcoma is beyond the scope of this chapter. Readers are referred to recent detailed reviews.89,90 Data evaluating the prognostic significance of the most widely studied molecular factor, Ki-67, are summarized below.
Ki-67, an antigen expressed throughout the majority of the cell cycle, is used as a measure of the fraction of cells undergoing division.91 Preliminary reports of series of heterogeneous sarcomas in adults suggested that the proliferation index as measured by Ki-67 nuclear staining correlated with histologic grade but was not of independent prognostic significance when histologic grade was taken into account.92,93 However, additional studies in larger numbers of patients have demonstrated that Ki-67 status is an independent prognostic factor.84,94,95 An initial immunohistochemical analysis of a cohort of 65 soft-tissue sarcomas and a subsequent analysis of 132 soft-tissue sarcomas from the French Federation of Cancer Centers Sarcoma Group demonstrated the adverse prognostic significance of increased Ki-67 activity.94,95
Recently, Heslin and colleagues evaluated the potential prognostic significance of pRb, p53, mdm2, and Ki-67 by immunohistochemical techniques in a population of 121 patients with primary, high-grade extremity sarcomas and compared these factors to conventional clinicopathologic prognostic factors (median follow-up, 64 months).84 Clinicopathologic and molecular factors 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 T2 tumor size, microscopically positive surgical margin, and a Ki-67 score greater than 20 (> 20% nuclear staining). Overexpression of p53 or mdm2 or deletion of pRb did not correlate with an increased risk of distant metastasis or tumor-related mortality.
Although specific cellular and molecular parameters have been identified as having independent prognostic significance, there is presently no consensus on how these prognostic factors should be used in clinical practice. Until more data are available, molecular prognostic factors proven to be of prognostic significance (e.g., Ki-67) should be considered for inclusion as stratification criteria in clinical trials.
Surgical resection remains the cornerstone of therapy for localized primary soft-tissue sarcoma. The discussion that follows focuses primarily on soft-tissue sarcomas in the limbs, the most common site of origin, and emphasizes conservation management with preservation of function where possible. Limb sarcomas are also the site where a significant negative outcome may be experienced by patients if amputation is needed. Nevertheless, the principles of conservation surgery described below are equally applicable to sarcomas in other anatomic sites. Over the past 20 years, there has been a marked decline in the rate of amputation as the primary therapy for extremity soft-tissue sarcoma. With the widespread application of multi-modality treatment strategies, less than 10% of patients presently undergo amputation.96,97 Instead, limb-sparing treatment is possible in the vast majority of patients with localized soft-tissue sarcomas of the extremities. In selected patients, limb sparing can be approached with surgery alone. These approaches will now be discussed.
Most surgeons consider definite major vascular, bony, or nerve involvement as relative indications for amputation. Complex en bloc bone, vascular, and nerve resections with interposition grafting can be undertaken, but the associated morbidity is high. Therefore, for a few patients with critical involvement of major bony or neurovascular structures, amputation remains the only surgical option but offers the prospect of prompt rehabilitation with excellent local control and survival.98
Currently, at least 90% of patients with localized extremity sarcomas can undergo limb-sparing procedures.96,99 The current use of limb-sparing multi-modality treatment approaches for patients with extremity sarcoma is largely based on a phase III trial from the NCI, in which patients with extremity sarcomas amenable to limb-sparing surgery were randomly assigned to receive amputation or limb-sparing surgery with postoperative RT.98,100 Both arms of this trial included postoperative chemotherapy with doxorubicin, cyclophosphamide, and methotrexate. With greater than 9 years of follow-up evaluation, 5 (19%) of 27 patients randomly assigned to receive limb-sparing surgery and postoperative radiation with chemotherapy had local recurrences, as compared to 1 (6%) of 17 patients in the amputation plus chemotherapy arm (p = .22).98 The overall survival rate was 63% for limb-sparing surgery versus 71% for amputation (p = .52), and the overall survival rate was 70% for limb-sparing surgery versus 71% for amputation (p = .97). This study established that for patients for whom limb-sparing surgery is an option, a multi-modality approach employing limb-sparing surgery combined with postoperative RT yields disease-related survival rates comparable to those for amputation while simultaneously preserving a functional extremity.
Satisfactory local resection involves resection of the primary tumor with a margin of normal tissue around the lesion. It is clear that dissection along the tumor pseudocapsule (enucleation) is associated with local recurrence rates ranging between 33 and 63%.101–103 In contrast, 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 noted in the control arms (surgery alone) of the randomized trials evaluating postoperative RT49B,104 and in single-institution reports.105 Thus, in the modern era, a discussion of limb preservation approaches must also be linked to a discussion of the role of adjuvant therapies, most commonly RT. Several randomized controlled trials have addressed different issues surrounding the use of local adjuvant approaches and collectively have established important milestones in the evolution of the local management of soft-tissue sarcomas. With one exception, these trials have focused on extremity lesions and around the themes of surgery and adjuvant RT.
| Histologic Grade | First Author/Institution | Treatment Group | Radiation Dose, Gy | No. Patients | No. Local Failure (%) | LRFS, % | OS, % |
|---|---|---|---|---|---|---|---|
| High grade | Pisters49B/MSKCC | Surgery + BRT | 42–45 | 56 | 5 (9) | 89 | 27 |
| Surgery | — | 63 | 19 (30) | 66 | 67 | ||
| Yang104/NCI | Surgery + XRT | 45 + 18 (boost) | 47 | 0 (0) | 100 | 75 | |
| Surgery | — | 44 | 9 (20) | 78 | 74 | ||
| Low grade | Pisters49B/MSKCC | Surgery + BRT | 42–45 | 22 | 8 (36) | 73 | 96 |
| Surgery | — | 23 | 6 (26) | 73 | 95 | ||
| Yang104/NCI | Surgery + XRT | 45 + 18 (boost) | 26 | 1 (4) | 96 | NR | |
| Surgery | — | 24 | 8 (33) | 63 | NR |
MSKCC = Memorial Sloan-Kettering Cancer Center; BRT = brachytherapy; LRFS = local recurrence-free survival; OS = overall survival; NCI = National Cancer Institute; XRT = external-beam radiation therapy; NR = not reported.
Unlike for malignant melanoma, a disease for which there are randomized data to address adequate margin size, there are no comparable data available to define what constitutes a satisfactory gross resection margin for a sarcoma. In general, every effort should be made to achieve a wide margin (2 cm is often an 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. Technical details of the surgical approach to extremity sarcomas are beyond the scope of this chapter but are reviewed in a recent surgical atlas.106 However, the principle remains that adequate clearance of potential tumor-bearing tissues can be achieved if there is sufficient distance between the surgical margin and the edge of any gross tumor (e.g., at least 2 cm for the closest margin) or where an intact barrier to tumor spread is excised en bloc with the tumor. In such cases, there is little evidence that RT is required despite the presence of potential adverse prognostic factors such as size or grade of tumor. The exception to this is the “unplanned excision,” where significant contamination of surrounding tissues may have taken place and the precise extent of potential microscopic tumor is essentially unknown. This problem is discussed later.
Given the low (2–3%) prevalence of lymph node metastasis in adults with sarcomas,47,48 there is no role for routine regional lymph node dissection. Patients with angiosarcoma, embryonal rhabdomyosarcoma, and epithelioid histiotypes have an increased incidence of lymph node metastasis and should be carefully examined for lymphadenopathy. Therapeutic lymph node dissection results in a 34% actuarial survival rate,47 and thus the rare patients with regional nodal involvement who have no evidence of extranodal disease should undergo therapeutic lymphadenectomy.
In contrast, visceral sarcomas are not ordinarily managed with RT because of the mobile nature of these structures within the pelvic, abdominal, or thoracic compartments. After resection of visceral sarcomas, accurate identification of the field at risk is particularly problematic. Contaminated loops of bowel or mesentery may relocate remotely within the abdominal cavity after surgery, and pleural contamination and mediastinal shift may occur following intrathoracic resections. However, fixed tumors in the pelvis or attached to internal trunkal walls may occasionally be suited to pre- or postoperative RT. Typically, however, the vast size of the radiation fields needed to cover entire body cavities, coupled with the limited RT doses that can be safely administered to organs in these situations, and the overwhelming risk of distant rather than local recurrence, confines such approaches to the investigational setting.
Sarcomas of nonosseous tissues generally respect barriers to tumor spread in the axial plane of the extremity such as bone, interosseous membrane, major fascial planes, etc. Consequently, they tend to spread in a longitudinal direction within the muscle groups of the extremity. Therefore, the margins of the RT volume must be wide in the cephalocaudal direction but in the cross-section, there may be much greater security in defining nontarget structures, especially those delimited by an intact barrier to tumor spread. For nonextremity lesions, the preferred direction is also along the direction of the involved musculature, but care must be taken to ensure that the fascial planes are appropriately recognized and encompassed in the radiation target volume.
).57,58 Further essential information is obtained from the pathology and operative reports, and metallic clips placed at the time of surgery may also help define the tumor bed.
It is often helpful to secure the treated area to minimize set-up variation and eliminate movement during treatment. Simple maneuvers such as comfortable limb positioning or fashioning customized thermoplastic molds for immobilization will facilitate reliable and consistent treatment set-ups. Treatment of superficial tissues, including the scar following definitive resection, with appropriate application of tissuelike bolus material should be considered but recognizing that this may affect ultimate skin cosmesis if fibrosis, atrophy, and telangiectasis result. Dose uniformity within irregular volumes can be optimized using beam segmentation, compensators, or wedge filters. The entire limb circumference, whole joints, or pressure areas (e.g., elbow, heel, etc.), where possible, should not be treated for the whole course as this may adversely effect limb function and distal edema in the long term.
It is also prudent to assess baseline function before initiating treatment. This is especially important when treating paired organs, such as a contralateral eye or a kidney, if functional ablation of a unilateral organ by RT is expected.
Complex anatomic plans with critical organ sparing require three-dimensional volume reconstruction and beam’s eye view planning to permit adequate protection of normal tissue and inclusion of the target volume.109,112 Very complex modulation of the beam is becoming available in many centers with the introduction of intensity modulated RT (IMRT),113,114 but ordinarily these are confined to RT plans where the target volume is immediately adjacent to critical normal tissues as found at the skull base or within the abdomen.
Treatment of sarcomas often requires large volumes of normal tissue to be irradiated, frequently to high doses. Fortunately, because most sarcomas arise in the limbs, the likelihood of life-threatening sequelae from RT damage to critical organs is low. However, the potential for serious damage to neurologic tissues in the head and neck or intra-abdominal organs including liver and small bowel remains for tumors adjacent to these structures. Because the tolerance of many normal tissues to radiation depends on the irradiated volume, the development of three-dimensional treatment planning has provided tools to quantify the relationships between dose, volume, and normal-tissue complications. Models permit normal-tissue complication probability (NTCP) to be determined for different irradiated volumes of organs or tissues to varying dose levels.115,116
These concepts are helpful when treating certain tumors in the retroperitoneum. If right sided or of great size, a tumor may infiltrate the liver capsule or be “hooded” by the liver, rendering access to an appropriate volume surrounding the tumor extremely difficult. Fortunately, although the tolerance of the entire liver to radiation is low, the NTCP model has shown that part of the liver may be treated to much higher doses safely.117 The “volume effect” can be exploited, and cases may be planned more readily and safely using dose-volume histograms.109 In these instances, if a subsequent liver resection is needed because of tumor infiltration or adherence to the capsule, detailed consultation between the surgical and radiation oncology teams is needed to ensure that an adequate volume of liver spared from the irradiation volume is left in situ.
Radiation dosages administered in postoperative RT generally depend on the tumor grade and involvement of the surgical margin.104,118,119 At the University of Texas M.D. Anderson Cancer Center (MDACC), the postoperative dose was reduced from 70 Gy for all grades to 60 Gy and 65 Gy for low- and high-grade tumors, respectively, with no increase in local relapse.120 The preoperative dose used in most institutions is approximately 50 Gy in daily fractions over approximately 5 weeks.119,121
Data regarding radiation dose response are very limited and based on underpowered retrospective studies. Fein et al. reviewed 67 patients and noted a significant improvement in local control in those treated with doses > 62.5 Gy.122 One study with few cases reported improvement in overall survival with increasing dose, particularly for larger tumors. This may reflect case selection.123 A recent study from the Institut Gustave Roussy, Villejuif, France may be more informative.124 Although retrospective and comprised of a small number of patients (n = 62), the study attempted to evaluate two postoperative RT schedules in terms of dose, fractionation, and overall treatment time in extremity sarcomas of nonosseous tissues treated between January 1984 and December 1993. Forty-five patients received 50 Gy with conventional fractionation plus a boost dose (5 to 20 Gy) following maximal conservative surgery. Seventeen patients had hyperfractionated accelerated RT to a dose of 45 Gy in 3 weeks. The 3-year local relapse rate was 16% in the conventional RT group and 36% in the lower dose hyperfractionated group. Overall survival for both groups was similar. Although the statistical power for any comparison between the two groups is too low to draw definitive conclusions, one must also be cautious in advising low doses postoperatively. The postoperative accelerated dose used in the study (45 Gy in 3 weeks) may be too low, compared to a more conventional courses of 50 Gy in 5 weeks, even when a radiobiologic conversion is undertaken.124 The approach appeared to provide results inferior to those achieved with preoperative approaches with moderate-dose twice-daily hyperfractionation125 or with conventional daily fractionation.119,126,127 Thus, the ability to treat with modest doses for many patients seems substantiated for preoperative treatment, but supportive evidence for lower dose, postoperative management is less available. Consequently, higher doses of RT following surgery are probably more appropriate in the postoperative setting, based on current data, but the search for an alternative lower dose postoperative schedule seems desirable.
The fraction size used in conventional fractionation varies (1.8 Gy vs. 2 Gy).119,128 Sparing of late effects can be expected with smaller fraction size and is particularly important when critical structures are irradiated. Several altered fractionations have been described including hyperfractionated125,129 and hypofractionated schedules130 and the accelerated regimen described above.124 No improvement in therapeutic gain is evident from these various strategies over conventional RT.49,104,119,128
Earlier, this chapter summarized principles concerning anatomic planes and the preferential pathways for sarcomas to spread within tissues. In turn, this information facilitates the design of target areas for irradiation. The basic elements in RT planning are to first define a gross tumor volume (GTV)131 and then place a margin around it to encompass tissues at risk of harboring microscopic disease (clinical target volume [CTV]). Generally, treatment is phased so that an initial volume (phase I) will treat generously around the risk zone to doses that are capable of sterilizing microscopic amounts of tumor cells (e.g., 50 Gy in 1.8 to 2 Gy fractions). Subsequently, it is customary to have at least one field reduction to permit an augmented dose to a smaller volume surrounding the highest risk zone (i.e., phase II). Usually, this dose is approximately 15 to 16 Gy, or higher if there is concern about the presence of overt gross residual disease. Typically, the subsequent phases are administered to all patients receiving postoperative RT, but the postoperative “boost” is generally restricted to margin-positive disease in the preoperative RT approach. This is because the local control rate for margin negative cases is in excess of 90% even when a subsequent boost is not provided.119,126,127 In these situations, a positive margin is declared when tumor reaches the inked surface of the specimen and clear margins can be declared if not reaching the ink irrespective of how close this is.119
Planning films for the case of retroperitoneal sarcoma shown in Figure 5 A to 5C. In figure 7A the gross tumor volume (GTV) has been contoured on a CT simulator work station (red outline). This includes the anterior located abnormal fat shown earlier (figure 5 B and 5 C). This process is performed for many thin CT slices to permit reconstruction of the image later for three dimensional treatment planning. The clinical target volume (CTV) is outlined in yellow to account for potential microscopic spread beyond the GTV. Additional margin will also be added to account for set-up variation and organ motion. Note the displacement of bowel loops by the tumor mass. The straight lines show the path of the beam for a conventional set up with opposed anterior and posterior fields.
Figure 7B shows the contoured GTV and CTV information displayed in a beam’s eye view (BEV) using a digitally reconstructed radiograph (DRR) created by the CT simulator. Shielding (Pb) can be placed once the path of the beam with the target areas defined is seen on the BEV. One can also discern the opaque tumor partially displacing bowel from target area.
In 7C a three dimensional reconstruction of the same case is shown with the GTV, CTV and areas to be shielded (Pb) shown and abdominal wall and anterior stuctures cut away. Generally these “cut-away” images are most useful for visualizing the edge of the target volume adjacent to critical anatomy which must be protected and the spatial relationship cannot be verified precisely with conventional imaging.
, B).
When postoperative RT is administered, there is no GTV if one strictly follows the conventions of the International Commission on Radiation Units and Measurements.131 However, for RT planning, it is still helpful to represent a theoretic GTV as the surgical field that includes all of the tissues handled during the surgical procedure, including undermined skin flaps, drain sites, and scars. Again, a putative zone of potential disease beyond this comprises the CTV.
A small retrospective study (n = 64 cases) suggested a dramatically inferior 5-year local control of 30% when the postoperative RT radiation field margin surrounding the tumor bed and scar were < 5 cm, compared to 93% for larger fields.134 Bone, interosseous membranes, and fascial planes are considered barriers to tumor spread in the axial directions, and, therefore, descriptions of radiation margins employed are principally in the craniocaudal direction. The RT protocol in the recently completed NCI of Canada Clinical Trial performed by the Canadian Sarcoma Group (SR2), which compared preoperative against postoperative radiotherapy (see below), required a field margin of 5 cm around the GTV for the initial phase of treatment (i.e., treatment to 50 Gy in 25 fractions).135 Generally, the GTV included any peritumoral edema seen on MRI, irrespective of 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 where the resection margins were involved. However, not all centers may use MRI scanning, and the information obtained from CT scanning is likely to be different so that some variation can be expected. At Massachusetts General Hospital (MGH), the following initial treatment phase RT margins are recommended: < 5 cm for small grade 1, 5 to 10 cm for larger grade 1, and small grade 2 to 3, and 10 to 15 cm for large grade 2 to 3 sarcomas.128 Lindberg and colleagues advocated a 5-cm and 7-cm margin for low- and high-grade lesions, respectively, at the MDACC120 and Tepper advocated margins of 10 cm beyond tumor at the NCI.136
In contrast, BRT uses significantly smaller margins compared to external-beam RT (EBRT). The BRT protocol at MSKCC used margins of only 2 cm around the surgical bed.49 Despite these marked differences, the local control rates reported are approximately 90% if low-grade lesions are excluded from the BRT data. This suggests that the zone of microscopic involvement may be less than was previously realized. Recent improvements in surgical technique may lessen the degree of intraoperative tumor dissemination and the need to irradiate all surgically handled tissues, scars, and drain sites may be unnecessary. This seems particularly relevant for major centers where surgery is performed by teams with extensive experience in sarcoma management.
Earlier, issues concerning dose of RT and how RT target volumes are chosen were discussed. The former highlights the important concept that preoperative RT is delivered to an undisturbed and potentially better oxygenated tumor site,137 which may be one reason why lower preoperative radiation doses do not appear to compromise local control.138 Nielsen et al.139 repeated the RT simulation planning in postoperative patients in a “sham” setting following preoperative RT and surgery and observed that the field size and number of joints irradiated in preoperative RT were significantly less than if the treatment had been administered postoperatively. As discussed below, this observation has recently been validated in a prospective randomized trial,140 and there is evidence that smaller treatment volumes may result in improved limb function.129,141
,122.6, 122.7A–C).143 In addition, preoperatively, bowel is much less likely to be tethered in the abdomen than following the development of postsurgical adhesions and therefore less vulnerable to the repeated treatment of isolated loops throughout the multi-fraction course. Also, the local tumor can be irradiated in situ without concern for treatment of wider areas of the abdominal cavity, which may need to be considered postoperatively because of microscopic seeding during surgery.
However, preoperative RT has certain disadvantages. One important issue concerns the almost complete reliance on the imaging characteristics of the tumor to define the target volume, and this may underestimate the true extent of the tumor detected at the time of surgery. In addition, preoperative RT is delivered on a partially representative biopsy and may interfere with future histopathologic analysis. These two concerns are more academic and theoretic than practical, however. One clinical concern with delivery of preoperative RT remains the increased risk of serious wound complications following definitive resection, discussed below.
The judgment about which approach (preoperative or postoperative RT) is more “correct” is controversial and was recently debated.144 Many competing issues are at stake, and the decision algorithm is therefore complex. It is also important to appreciate that conclusions from the current available evidence are liable to bias because of the nonrandomized fashion in which treatment was allocated. Generally, preoperative RT has tended to be chosen for more adverse presentations of disease and therefore in need of more extensive surgery.138 Because of the problems of case selection, it is hoped that the major issues will be resolved by the NCI of Canada/Canadian Sarcoma Group SR2 clinical trial.135 This is the only prospective, randomized comparison between pre- and postoperative RT and has several end points: wound complications, survival, and local control. In addition, quality of life, physical function, economic cost, RT planning parameters (field size and number of joints irradiated), and the incidence of acute and late radiation effects will be evaluated. The preliminary results of the trial have indicated that serious wound complications are twice as commonly associated with preoperative RT compared to postoperative RT (35 vs. 17%).135 As anticipated, field sizes are also significantly larger in the postoperative arm of this prospective study.140
It is clearly too soon for data to support definitive recommendations concerning the optimal sequencing of RT and surgery. More time is required for the data from the SR2 trial to mature. Thus, important outcomes such as local control, disease-free survival, long-term function, and late RT toxicity are awaited. Late RT effects are likely to be significantly greater with postoperative RT given the higher RT and larger volumes that are conventionally employed in that schedule. However, the decision to accept increased short-term surgical toxicities in the form of wound-healing complications must be balanced by improvements in some important clinical outcome measures. Nonetheless, even with this caveat, it is likely that decisions for any individual patient may be best served on a case-by-case basis, taking into account specific details of anatomic location, tumor size, RT field size, other morbidities, and risks.
A digitally reconstructed radiograph (DRR) of the head and neck of a young woman with a soft tissue sarcoma of the right cheek. Because of the proximity to the right eye, pre-operative radiotherapy has been chosen because of its ability to permit maximal restriction of the clinical target volume (CTV) to the local environment of the tumor. The same process was followed using CT simulator as described in Fig 7. The gross tumor volume (GTV) on the cheek can be seen with the surrounding CTV. Shielding is also evident (Pb). A hair clip, which the patient was wearing during the CT slice acquisition, is evident in the right parietal area; one can also see her necklace. The smaller insert shows a three dimensional image of the patient with potential beams applied.
| Treatment Context/Sarcoma Site | Issues of Concern | Comments |
|---|---|---|
| Head and neck | ||
| Paranasal sinus | Proximity to optic apparatus (eye, orbit, chiasma) | Major visual functional deficit can be minimized |
| Skull base | Proximity to spinal cord, brain stem | Other “lesser” morbidities (dental, xerostomia) may also be less due to reduced doses and volumes |
| Cheek and face | ||
| Split thickness skin graft | Skin graft breakdown and consequent infection reconstruction (especially lower limb) | Many months to years of recreational and/or vocational disability may occur during healing (rare) |
| Large volume GTV or CTV occupying coelomic cavities | ||
| Retroperitoneal | Proximity to bowel, liver, kidney | Critical organs may be displaced by tumor or not fixed or adherent as is likely in postoperative setting |
| Entire tumor treated prior to possible contamination of cavity | ||
| Some small bowel lesions with side wall adherence | Proximity to critical anatomy, especially intestine | Contamination of abdominal cavity renders postoperative RT unsuitable |
| Thoracic wall/pleura | Proximity to lung or cardiac structures | Lung may be displaced by chest wall or pleural tumor and can be avoided with preoperative, or permits GTV to be treated prior to operative contamination |
| Abdominal trunk walls | Proximity to kidney, bowel, liver, ovaries | Avoid CTV encroachment on vulnerable anatomy pelvic side wall |
| GTV adjacent to dose limiting critical anatomy | ||
| Thoracic inlet/upper chest wall low neck. | Proximity to brachial plexus | Dose limitation of critical anatomy lends itself to preoperative RT. Additional volume considerations |
| Medial thigh (young male) | Proximity to testes | Permanent infertility may be avoided |
| Central limb tumor | Proximity to other compartments | Permits partial circumferential sparing, which would not be feasible in postoperative setting |
GTV = gross tumor volume; CTV = clinical target volume.
Reproduced with permission from Seminars in Radiation Oncology 1999;9(4):335.
), (2) the desire to minimize RT dose in some situations (e.g., where critical neurologic tissues are in close proximity), and (3) a desire to not irradiate new tissues, especially skin grafts, which are vulnerable to the effects of high-dose postoperative RT once transposed into the target area at the time of surgery.145 In general, preoperative RT provides an advantage over postoperative RT in regard to these issues but also exposes the patient to significantly increased risks of serious postoperative wound complications. Even so, additional features are helpful to consider such as the anatomic location of tumor. The analysis of SR2 has indicated that the risk of preoperative RT for upper extremity lesions is extremely low, with the major occurrence of wound morbidity being evident in the lower limb. Therefore, for example, significant benefit may result from using preoperative treatment for a lesion in the shoulder girdle where lower dose and volume to the brachial plexus and adjacent lung would be a distinct advantage. A summary of the relative indications that can be used to select patients for preoperative RT is provided, notwithstanding the trade-off required between the potential benefits and the risk of wound morbidity (Table 122.5).
Two methods of RT delivery are commonly employed: EBRT in the ambulatory setting, and BRT. No randomized data compare these modalities directly. However, both have been compared with surgery alone. The 5-year local control achieved with BRT was 89% (high-grade lesions only) compared with 80 to 98% with EBRT (all grades) in these trials.49B,104
BRT has several advantages over EBRT including a shorter overall treatment time (4–6 days vs. 5–6.5 weeks), and treatment can be initiated sooner following surgery when clonogen numbers are at a minimum. The brevity of the treatment also lends itself to integration with protocols for systemic chemotherapy more readily than protracted courses of external beam. The irradiated volume is also smaller, which may confer functional advantages. Savings of $1,000 U.S. per patient treated with BRT compared to EBRT may be realized.146
The MSKCC approach requires the tumor bed to be evaluated intraoperatively and the target volume is then defined by a 2-cm margin superiorly and inferiorly and a 1.5- to 2-cm margin medially and laterally. The area is implanted with after-loading catheters placed percutaneously, spaced at approximately 1-cm increments, and sutured in place. BRT is given after the sixth postoperative day using an iridium-192 implant delivering 42 to 45 Gy over 4 to 6 days.148 For some some centers, BRT is the preferred approach, provided that the implant is technically possible and the patient is fit for the procedure. Historically, the BRT experience has been with low-dose rate BRT. More recently pulsed dose rate (PDR) techniques have become available. PDR relies on sources that migrate with different dwell times to provide the necessary dose optimization. Provided that the dwell times of PDR are short relative to the rest times, the radiobiologic effect of the two techniques should be equivalent.149 Although BRT is less common compared to EBT, most brachytherapy protocols are used in the regular management of soft-tissue sarcomas where tissue tolerance is not especially compromised.
BRT may also have advantages in situations where normal-tissue tolerance to RT is compromised. One such scenario would be the augmentation of RT dose to the operative bed following surgery in anatomic sites where this may confer a therapeutic advantage. For example, one experimental protocol for RPSs uses BRT following preoperative EBRT, which exploits the anatomic advantage of tumor mass excluding bowel from the treatment volume. The dose of preoperative RT is 45 Gy or 50 Gy in 25 fractions over 5 weeks, depending on the critical structures in the treatment volume. This is followed with a postoperative BRT boost to a total combined dose of 70 Gy. The BRT is given through a single plane of afterloading catheters placed 1 cm apart over the tumor bed at the time of resection to areas at high risk of margin involvement.150 Treatment is given with an afterloading PDR BRT unit that uses a single stepping iridium source. The dose rate is 50 cGy/hour, prescribed at 0.5 cm from the plane of the catheters. Such protocols should be considered experimental and, apart from the advantage of preoperative RT, the precise role and safety of BRT in this protocol remains to be confirmed. The use of BRT with surgery for limb salvage in previously irradiated tissues comprises another situation where normal-tissue tolerance is compromised and BRT has a significant role in selected patients.151–153
EBRT may include photons or particle beam (electrons, protons, pions, or neutrons). Protons have similar radiobiologic effects to photons and are both classified in the low linear energy transfer (LET) group. For most anatomic sites, there will be a lesser dose to nontarget tissues using protons compared to conventional radiation beams with photons and electrons. This is largely because protons have a finite range in matter that can provide a zero dose deep to the target. Their main advantage is when tumors lie in direct proximity to critical structures due to the ability to achieve more accurate targeting.154
Neutrons differ from photons and protons in that they deposit energy in tissue through collisions with nuclei, especially hydrogen, instead of with electrons on the perimeter of the atom. As a consequence, they produce a very dense column of ionization by ejection of the proton from the nucleus, in contrast to the weaker ionization produced by electrons directly or by photons indirectly ejecting an electron (the latter being the typical mechanism by which radiation interacts with tissue). Because of the density of the free radicals produced, neutron irradiation is more likely than x-irradiation to cause irreparable injury to double-strand DNA.
Due to their mode of interaction with matter, high LET radiation such as neutrons confer radiobiologic advantages over photons, which include reduced repair of radiation damage in tumor cells, sensitivity of cancer cells to RT throughout the cell cycle, and less protection offered to hypoxic cancer cells. However, any such advantages are tempered by potential late damage, and their use remains experimental. Recent reports have continued to claim promising results from the standpoint of tumor,155,156 and, in some situations, the suggestion is that the results may be superior to photons.155 As before, the problems of selection bias need to be considered in small series where the claims for the superiority of one treament over another exist if these were not randomly assigned. Also, whereas Prott and colleagues reported a modest risk of severe side effects (11%),155 others have reported a higher rate, albeit with enhanced tumor control, which complicates the decision about best management.157
The majority of interest for intraoperative RT (IORT) has been in RPS. IORT usually involves the use of electron-beam treatments, but there has been experience with high dose rate afterloading to deliver a dose of 15 Gy at the time of surgery followed by 45 Gy postoperatively in RPS.158 Willett and colleagues detailed 20 patients treated with preoperative RT, resection and then intraoperative electron-beam therapy and reported a 70% complete resection rate and an 81% 4-year local relapse free rate.143
Other approaches have used IORT boosts to the tumor bed with subsequent postoperative EBRT. IORT (20 Gy followed by 35 to 40 Gy postoperatively) was compared to conventional postoperative RT (50 to 55 Gy) in a randomized study of 35 patients. The incidence of locoregional recurrence was lower in the experimental treatment arm but no survival benefit was demonstrated.159 IORT was associated with a high rate of peripheral neuropathy when large, sometimes overlapping, RT portals were used to cover the sacral plexus region. However, gastrointestinal complications were more common in the control group where higher doses were delivered to the bowel.
Some reports also describe IORT for extremity sarcomas.160,161 It is difficult to determine the precise place of this modality, especially in extremity lesions where the use of conventional approaches such as EBRT is not associated with significant local control problems.
Hyperthermia as a local adjuvant treatment has been used, although most usually in combination with RT.162 The rationale for this approach relates to the effects of radiotherapy and hyperthermia on soft-tissue sarcoma oxygenation with a potential relationship between treatment-induced changes in oxygenation and clinical treatment outcome. However, the exact place of this approach remains experimental, and the results to date do not appear different to those achieved with conventional approaches. In addition a recent detailed description of this approach by the same authors suggests that a high complication rate and morbidity including limb loss may result.163
With the advances 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 soft-tissue sarcomas. Concurrent doxorubicin-based chemoradiation has been employed extensively by Eilber and colleagues at the University of California, Los Angeles.164,165 The intra-arterial route delivers chemotherapy more directly to the tumor and was initially favored. However, intra-arterial therapy is more complex, expensive, and prone to complications when compared to the intravenous route.166 The initial chemoradiation treatment protocol involved intra-arterial doxorubicin with unusually high dose per fraction RT (35 Gy of external-beam radiation 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 compared preoperative intra-arterial doxorubicin to intravenous doxorubicin, both followed by 28 Gy of radiation delivered over 8 days followed by surgical resection.167 No differences in local recurrence or survival were noted.
The combination of regional chemotherapy and concurrent RT originally pioneered by Eilber et al has been modified and used by other groups.168–170 Investigators from the University of Illinois treated 55 patients with a 10-day preoperative regimen of intra-arterial doxorubicin (10 mg/m2/day) and concomitant RT (25 Gy; 2.5 Gy/fraction × 10 fractions).170 With a mean follow-up of 94 months, the local control rate was 85%. Complications related to the therapy occurred in 26% of patients and required 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 infused intra-arterially or intravenously over a 3-day period followed by sequential RT (30 Gy; 3 Gy/fraction × 10 fractions).169 Resection of the residual post-treatment mass was performed 4 to 6 weeks later. At a median follow-up of 6 years, local control was achieved in 39 (98%) of 40 patients; curiously, 2 patients were excluded from this analysis because clear margins were not obtained at the time of surgery. Intra-arterial infusion-related complications occurred in 4 (11%) of 35 patients. Objective radiologic and pathologic response rates were not reported; thus, the efficacy of concurrent chemoradiation therapy in achieving cytoreduction to an extent sufficient to convert lesions resectable only by amputation to lesions amenable to a limb-sparing approach remains largely anecdotal. Moreover, whether preoperative chemoradiation approaches offer local control advantages over conventional treatment approaches employing surgery with pre- or postoperative RT is also unknown.
Actinomycin D has also been combined with external-beam radiation. Abbatucci and colleagues at the Centre Francois Baclesse, France have employed actinomycin D combined with RT.171 Their unusual protocol comprised two fractions of 6.5 Gy administered preoperatively 48 hours apart, followed by a variable protocol of 2 Gy per fraction postoperatively depending on the resection status. The postoperative RT was accompanied by intravenous actinomycin D (0.3 mg/m2) given 30 minutes prior to each of the first five postoperative RT sessions. The overall results appear similar to approaches without chemotherapy.49B,104,119,128 Alternative chemoradiation sequencing has been employed by investigators from the MGH, who have investigated a novel sequential chemoradiation strategy in the treatment of patients with localized, high-grade, large (> 8 cm) extremity soft-tissue sarcomas).172 This treatment protocol involved alternating courses of chemotherapy and RT: three courses of doxorubicin, ifosfamide, mesna, and dacarbazine and two 22-Gy courses of radiation (11 fractions each) for a total preoperative radiation dose of 44 Gy. This was followed by surgical resection with careful microscopic assessment of surgical margins. An additional 16-Gy (8 fractions) boost dose was delivered for microscopically positive surgical margins. The outcomes of 47 patients treated with this regimen have been compared to those of matched historic controls. With a median follow-up of 36 months, 5-year actuarial local control, distant metastasisfree survival, and overall survival rates for the sequential chemoradiation group are 94, 73, and 95, respectively. For the matched historic controls, these rates are 87, 46, and 57, respectively. These encouraging results will require longer follow-up, and additional prospective comparative studies will be needed for confirmation. An ongoing phase II trial from the Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group (RTOG, ECOG protocol 95-14) is further investigating sequential chemoradiation for patients with localized sarcomas. The results of this phase II study will help to better define the toxiocities and response rates associated with sequential chemoradiation. As noted before, early results from the phase III randomized multicenter Canadian SR2 study have shown that preoperative RT increases the risk of major surgical complications.135 No data have indicated any major benefits in clinical outcomes from this study, although the trial was not powered to detect such differences and the follow-up is still too short. Nonetheless, given the increased risks of preoperative radiation treatment, it seems reasonable to conclude that until more data are available, concurrent use of chemoradiation, or preoperative RT “sandwiched” with chemotherapy, is generally to be given only in restricted situations at specialty centers.
As noted above, primary surgical resection with or without adjuvant RT is the mainstay of management of sarcomas. However, although local or locoregional recurrence remains a problem for an unfortunate subset of patients following primary therapy, the truth remains that the major risk to life in sarcoma patients is uncontrolled systemic disease. Additionally, the availability of systemic therapy with proven, albeit often limited, ability to induce shrinkage of advanced sarcomas has offered the question of whether the use of systemic treatment early might affect micrometastatic disease and yield improvements in significant clinical outcomes such as overall survival and disease-free survival.
Unfortunately, given the relative rarity of sarcomas, it has proven difficult to assess this question with clinical studies of sufficient size or statistical power to answer the question definitively. Additionally, the development of systemic treatments for sarcomas is a field in rapid evolution, so that treatments may not be comparable over time. Finally, based on small underpowered studies and extrapolation from limited clinical experience, many clinicians have nonetheless developed strongly ingrained biases regarding the worth of adjuvant systemic treatments for sarcomas. It is most fair to say that the data generated to date support the need for large-scale studies to address this application of systemic treatment more definitively.
The history of studying adjuvant systemic therapy for sarcomas is plagued by underpowered studies that reveal tantalizing clinical benefits, even with older chemotherapy regimens. It is clear that nonrandomized studies are of little benefit in studying this question, since variables in patient selection, tumor definition and grade, and surgical and radiation techniques can drive outcomes significantly. Despite this, much data from the late 1970s and the early 1980s were based on single-arm, nonrandomized studies of adjuvant chemotherapy. Comparison of these patients with historic controls suggested clinical benefits,173–177 including putative survival benefits and prolongation of the time to metastatic spread of disease. From this experience has arisen a multitude of randomized trial data generated over more than a decade. With more than a dozen prospective, randomized clinical trials, the utility of systemic adjuvant chemotherapy remains controversial.164,178–191 In most trials, the use of adjuvant systemic chemotherapy was associated with decreased local recurrence rates and, therefore, a prolongation in disease-free survival. However, this did not in general translate into survival benefits in all studies. In particular, one of the larger adjuvant studies by the European Organization for the Research and Treatment of Cancer (EORTC) found no overall survival benefit when using doxorubicin-based multi-agent chemotherapy in the adjuvant setting.178 This finding, along with the toxicities of combination chemotherapy, has led some to question the value of routine use of chemotherapy in the adjuvant setting.
Actuarial curves from individual patient data meta-analysis. Local recurrence-free interval (RFI); distant recurrence-free interval; overall recurrence-free survival; and overall survival. Reproduced with permission of The Lancet Ltd. from Tierney JF, and The Sarcoma Meta-Analysis Collaboration.192
| Outcome | Hazard Ratio | 95% Confidence Inatervals | p Value |
|---|---|---|---|
| Local RFI | 0.73 | 0.56–0.94 | .016 |
| Distant RFI | 0.70 | 0.57–0.85 | .0003 |
| Overall recurrence-free survival | 0.75 | 0.64–0.87 | .0001 |
| Overall survival | 0.89 | 0.76–1.03 | .12 |
RFI = recurrence-free interval.
Data from the Sarcoma Data Base Meta-Analysis Collaboration.192 Reproduced with permission from Verweij and Seyance, Seminars in Radiation Oncology, 1999;9(4): 352–359 by W.B. Saunders Company.
| Study* | Accrual Period | Disease Sites and Comments | Number of Patients |
|---|---|---|---|
| GOG | 1973–1982 | Uterus. Dose of doxorubicin low. Mixed histologies (including leiomyosarcomas, mixed mesodermal tumors); high ineligible rate; no influence of chemotherapy on survival | 225 |
| DFCI/MGH | 1978–1983 | Extremities, trunk, head, neck, retroperitoneum; no difference in local control, RFS, or OS | 46 |
| ECOG | 1978–1982 | Extremities, trunk, head, neck, retroperitoneum | 47 |
| SSG | 1981–1986 | Extremities, trunk, head, neck, breast, throat, abdomen; high ineligibility rate; no survival difference | 240 |
| Rizzoli | 1981–1986 | Extremities; complex protocol with imbalance. Poorer than expected outcome among controls | 77 |
| IGSC | 1983–1986 | Extremities, trunk, head, neck, retroperitoneum. No survival effect seen at last report | 92 |
Study order in table according to accrual from the earliest to latest period.
GOG = Gynecologic Oncology Group; DFCI/MGH = Dana-Farber Cancer Institute/Massachusetts General Hospital; ECOG = Eastern Cooperative Oncology Group; SSG = Scandinavian Sarcoma Group; Rizzoli = Istituti Ortopedici Rizzoli; IGSC = Intergroup Sarcoma Committee; RFS = relapse-free survival; OS = overall survival.
Data from the Sarcoma Data Base Meta-Analysis Collaboration.192 Reproduced with permission from Verweij and Seyance, Seminars in Radiation Oncology, 1999; 9(4):352–359 by W.B. Saunders Company.
| Study* | Accrual Period | Disease Sites and Comments | Number of Patients |
|---|---|---|---|
| MDA | 1973–1976 | Extremities, trunk. Study terminated early because of toxicity. No effect on survival | 59† |
| Mayo | 1975–1981 | Extremities, trunk. Poor local control (no radiotherapy given). No survival benefit | 76 |
| NCI | 1977–1981 | Extremities; imbalanced randomization. Improved RFS but not OS | 67 |
| NCI | 1977–1989 | Trunk, head, neck, breast, retroperitoneum. OS and RFS not different | 80 |
| EORTC | 1977–1988 | Extremities, trunk, head, neck; high ineligibility rate; suboptimal chemotherapy compliance Improved RFS and local control but not OS SAKK (57/87) | 468 |
| Bergonie | 1981–1988 | Extremities, trunk, head, neck, retroperitoneum, pelvic. Improved RFS and OS for chemotherapy | 65 |
| SAKK (57/87) | 1987–1990 | Extremities, trunk; unpublished study | 29 |
Study order in table according to accrual from the earliest to latest period.
Data not available on three patients.
MDA = M.D. Anderson Cancer Center; Mayo = Mayo Clinic; NCI = National Cancer Institute; EORTC = European Organisation for Research and Treatment of Cancer; Bergonie - Institut Bergonie; SAKK = Swiss Group for Clinical Cancer Research; RFS = relapse-free survival; OS = overall survival.
Data from the Sarcoma Data Base Meta-Analysis Collaboration.192 Reproduced with permission from Verweij and Seynaeve, Seminars in Radiation Oncology, 1999;9(4):352–359 by W.B. Saunders Company.
and the hazard ratios (Table 122.6). A brief description of the trials in the meta-analysis including anatomic sites, accrual periods, and comments about the studies is also provided (Tables 122.7 and 122.8). These depictions separately describe the trials of doxorubicin alone versus control (see Table 122.7) and those comparing doxorubicin combination chemotherapy versus control (see Table 122.8). Although certain aspects of the methodology from the meta-analysis can be questioned,194 the results are not dissimilar from trends noted in prior individual studies, with no overall survival benefit associated with adjuvant chemotherapy in unselected sarcoma patients. However, it remains possible that the meta-analysis could still underestimate significantly the possible benefits of chemotherapy in appropriately responsive subsets of patients.193 Additionally, the relevance of these older data to more modern practice is somewhat questionable, since most of the adjuvant studies had been performed before the widespread availability of current techniques of classifying sarcomas and also before one of the more active chemotherapy agents, ifosfamide, became available.
In fact, only two agents to date are viewed as consistently offering some hope of clinical benefit to a wide range of sarcoma subtypes: doxorubicin (or the anthracycline analogue epirubicin) and ifosfamide. Only a single small randomized clinical trial has tested the use of a combination chemotherapy regimen containing both of these active agents in a postoperative adjuvant setting. This trial, performed by the Italian Sarcoma Group, was powered to detect a benefit in disease-free survival and in fact was stopped early once this end point was reached in an interim analysis.195 This trial was cleverly designed to take only very high-risk patients, usually with very bulky disease or recurrent disease. Early analysis has revealed benefits in both disease-free survival and overall survival in the first 104 patients treated in the study. Nonetheless, given the small size of this trial and the early follow-up, there remains a possibility that the results will change somewhat over time. Therefore, additional randomized trials would still be reasonable to confirm or refute this important observation. For the moment, one can make a conclusion that postoperative adjuvant chemotherapy should be discussed with patients as a possible option, but that there is no single standard of care that dictates this to be a necessity for patients with resected soft-tissue sarcomas. Further research will be required to estimate the magnitude of any clinical benefit from combination chemotherapy in the adjuvant setting and whether the benefits outweigh the toxicities of the current aggressive regimens. Histologic subtypes of sarcomas may also reveal different degrees of benefit with adjuvant chemotherapy based on endogenous chemosensitivity patterns, and this remains an important area to understand more completely. Additionally, as new approaches and newer active agents are developed, it will be important to be neither nihilistic nor dogmatic about the value of adjuvant chemotherapy. This remains an area of active uncertainty requiring high-quality studies sufficiently sized to generate firm answers to guide patient care decisions.
Preoperative chemotherapy has specific theoretic advantages over postoperative treatment. First, preoperative chemotherapy provides an in vivo test of chemosensitivity. Patients whose tumors show objective evidence of response are presumed to be the subset who will benefit most from further postoperative systemic treatment. In contrast, it is assumed that the population of nonresponding patients defined by this in vivo assessment will derive minimal or no benefit from further chemopostoperative therapy and can therefore be spared its toxicity. On the other hand, it is conceivable that the patients whose tumors respond to chemotherapy may not be those who would derive the most from chemotherapy, since these lesions with favorable biology might be those destined to do well irrespective of any systemic treatment. In contrast, those who do not respond may be the unfavorable cases who could derive the greatest benefit from the discovery of highly effective systemic treatments.
A second theoretic advantage of preoperative chemotherapy is that it treats occult micrometastatic disease as soon after the cancer diagnosis as possible. This may prevent the development of chemoresistance by isolated clones of metastatic cells or prevent the postoperative growth of micrometastases. Finally, chemotherapy-induced cytoreduction may permit a less radical and consequently less morbid surgical resection than would have been required initially. In patients with large soft-tissue sarcomas of the extremities, cytoreduction may reduce the morbidity of limb-salvage surgical procedures and possibly even allow patients who might otherwise have required an amputation to undergo limb-salvage surgery.
Investigators from the MDACC have reported long-term results with doxorubicin-based preoperative chemotherapy for AJCC/UICC stages IIC and III (formerly AJCC stage IIIB) extremity soft-tissue sarcomas.196 In a series of 76 patients treated with doxorubicin-based preoperative chemotherapy, radiologic response rates were complete response, 9%; partial response, 19%; minor response, 13%; stable disease, 30%; and disease progression, 30%. The overall objective major response rate (complete plus partial responses) was 27%. At a median follow-up of 85 months, 5-year actuarial rates of local recurrence-free survival, distant metastasis-free survival, disease-free survival, and overall survival were 83, 52, 46, and 59, respectively. The event-free outcomes reported from MDACC are comparable to those observed with chemotherapy in the phase III postoperative chemotherapy trials. Furthermore, comparison of responding patients (complete and partial responses) and nonresponding patients did not reveal any significant differences in event-free outcome.196
In a prospective study from MSKCC, 29 patients with AJCC stage IIIB (AJCC, 4th edition) soft-tissue sarcomas larger than 10 cm were treated with two cycles of a doxorubicin-based regimen prior to local therapy.197 Subjective changes in the degree of primary tumor firmness and in imaging characteristics of the tumor (intratumoral necrosis and hemorrhage) were observed in many patients but were not quantifiable. Only one patient met the standard criteria for a partial response. Survival results in this population of high-risk patients were similar to those in historic controls treated with postoperative doxorubicin or patients treated with local therapy alone. The reasons for the apparent discrepancy in response rates between the reports from MDACC and MSKCC remain unclear. Possible explanations include the fact that the population treated at MSKCC appears to be a higher risk population, with all patients having high-grade lesions larger than 10 cm. Moreover, the patients treated at MSKCC received a lower doxorubicin dose (60 mg/m2) for a fewer number of cycles (two). This may be important given the known dose-response relationship for doxorubicin.198
Recently, ifosfamide-containing combinations have been used in the preoperative setting. Selected patients treated with aggressive doxorubicin- and ifosfamide-based regimens have had major responses, and preliminary results suggest that response rates may be higher than in historic controls treated with non–ifosfamide-containing regimens.199 A randomized trial of preoperative chemotherapy (50 mg/m2 doxorubicin and 5 mg/m2 ifosfamide) versus local therapy alone has recently been completed by the EORTC Bone and Soft Tissue Sarcoma Group (EORTC protocol 62874). Toxicity results of this trial have been presented,200 but event-free outcome has not yet been formally reported.
Most studies, including one EORTC study178 and the large single-patient data meta-analysis discussed earlier,192 have reported improved local control with adjuvant chemotherapy. The benefit in the EORTC study was greatest in those not receiving RT (about 50% of cases), and the overall local control rates achieved are inferior to those expected using modern-day RT and surgery. The interpretation of these results should, therefore, be considered in the light of contemporary practice. The value of disease-free survival restricted to improved local control may not be clinically relevant or worthy of the systemic toxicities of adjuvant chemotherapy. On the other hand, in the modern era of chemotherapy with more active agents (such as ifosfamide, which was not used in the EORTC adjuvant study or in any of the trials in the meta-analysis), studies need to be powered to evaluate potential benefits of treatment on overall survival rates. Appropriately powered, prospective studies are still desperately needed in this field to prove the worth of more modern adjuvant chemotherapy in well-defined populations of patients at high risk of systemic recurrence.
It has been theorized that the antisarcoma action of adjuvant chemotherapy might be improved by modifying factors related to drug delivery. To a great extent, the rationale for this work is based in other malignancies that spread predominately within one segment of the body, such as the known predilection of ovarian cancer to remain within the peritoneal cavity. Certain sarcomas, such as gastrointestinal stromal sarcomas and certain gastrointestinal leiomyosarcomas, may recur repeatedly within the peritoneum without developing widespread hepatic or lung metastases. For such patients, it has been considered by some investigators a reasonable option to offer intraperitoneal chemotherapy. Limited single-institution data have shown this to be feasible, although the efficacy cannot be rigorously assessed, since only comparisons to historic controls are available.201 Decreases in locoregional recurrence rates have been suggested, but since there is not expected to be any impact of such therapy on possible development of hepatic metastases, the possible impact of such treatment on overall survival, if any, may be quite limited. The use of intraperitoneal chemotherapy requires large-scale randomized studies before it can be accepted as a required aspect of care for patients with resected intraperitoneal sarcomas.
Another variable is also occasionally added into the mixture of variables in this field in the form of heat. Certain investigators have promulgated the utility of heated chemotherapy instilled into the peritoneal region following resection based on hyperthermic perfusion of extremity lesions.201,202 However, no clinical data have been generated to assess objectively the potential contribution of heat in this setting. At a more systemic level, others have evaluated the potential of whole-body hyperthermia to contribute to the efficacy of combination chemotherapy, using methods to increase the temperature of the entire body or a specific region to > 41°C.203–205 Despite some limited data regarding clinical responses, this remains highly investigational. Given the expected toxicities, including hypotension and nephrotoxicity,206 the clinical outcomes associated with this investigational approach would have to represent significant improvements over conventional treatments in order to be widely accepted. At this time, this has no role in the management of sarcomas in the adjuvant setting.
Hyperthermic isolated limb perfusion (HILP) is an investigational technique in the U.S. (although recently approved by regulatory agencies in other parts of the world) that has received considerable attention in the treatment of locally advanced, unresectable sarcomas of nonosseous tissues. HILP is an experimental technique that has been evaluated for the treatment of extremity soft-tissue sarcomas in the setting of (1) locally advanced extremity lesions amenable only to amputation used in an attempt to preserve the limb and (2) locally advanced extremity lesions with synchronous pulmonary metastases, for which HILP is employed in an effort to preserve a functional extremity for the short survival anticipated in the setting of stage IV disease. A multi-center phase II trial has evaluated a series of 55 patients with radiologically unresectable extremity soft-tissue sarcomas treated with HILP using high-dose tumor necrosis factor-α, interferon-γ, and melphalan.207 A major tumor response was seen in 87% of patients: complete responses in 20 (36%) and partial responses in 28 (51%). Limb salvage was achieved in 84% of patients. Regional toxicity was limited, and systemic toxicity was minimal to moderate. There were no treatment-related deaths. This approach is presently being further evaluated in ongoing trials in Europe.
Apart from some very radiosensitive subtypes of sarcomas, most patients who undergo RT as the sole treatment modality have probably been deemed unresectable. This is a rare scenario at centers skilled in the management of sarcomas; medically fit patients with gross and “unresectable” disease should always be referred to a specialty center for multi-disciplinary management, which may combine surgery, RT, and possibly chemotherapy. For example, proximal inguinal or axillary tumors may present with disease encircling the major vascular structures in the proximal extremity. Such lesions may be resected with the involved vasculature and reconstructed. Adjuvant RT is generally used. Rarely, a patient with truly inoperable disease may require RT alone, either with photons208 or particle beams. For the latter, this includes protons, neutrons, and pions.154,157,209,210 No formal clinical trials have been performed to compare these strategies among each other, and they are generally administered in an adverse clinical context. Local control has been reported in 40 to 70% of cases with neutrons.157 Photons in such cases are reported to produce local control in approximately 30% of cases.208 As noted earlier, advocates for neutron treatments continue to report their results.155,156
Goffman et al. at the NCI treated 36 patients with large unresectable sarcomas with IdUrd and aggressive twice-daily RT.211 Further investigation may be warranted because local control was achieved in 20 patients despite approximately half of the tumors being ≥ 15 cm. The overall local control was 60% with a minimum follow-up of 1 year and was 4 or more years in 50%. The morbidity of this approach seemed modest in these high-risk cases.
The diagnosis of recurrent or metastatic disease in patients with soft-tissue sarcomas is a devastating one. Patients and physicians are aware that, in general, such a diagnosis significantly worsens the expected outcomes. The role of the multi-disciplinary sarcoma team in management of patients with metastatic sarcoma is to recognize opportunities in which multi-modality care might still be able to improve important outcomes such as survival or quality of life. Both surgery and systemic chemotherapy can play an important role to improve these outcomes significantly in selected patients. Judicious use of chemotherapy is a key part of sarcoma management, and improved understanding of the histopathologic differences between soft-tissue sarcomas will allow increased sensitivity in the study of drug therapy against sarcomas. Overall, it is important to recognize that unresectable metastatic sarcomas of soft tissues are—with rare exceptions—fatal over time, and that chemotherapy is given with the palliative aim of prolonging life and improving quality of life as much as possible.
Postmetastasis survival (from time of diagnosis of M1 disease) in a cohort of 230 patients with primary soft-tissue sarcomas of the extremities. The median postmetastasis survival was 11.6 months. From Billingsley et al.,214 by permission of Cancer.
).214 Optimal treatment of patients with metastatic soft-tissue sarcoma requires an understanding of the natural history of the disease and individualized selection of treatment options based on specific patient factors, disease factors, and limitations imposed by prior treatment.
The approach to patients with advanced or metastatic sarcomas is changing over time. We are recognizing that clinical trials must be stratified rationally in order for data of value to be derived. Studies of “sarcomas” without stratification will soon seem as naive as studies of “cancer” without further qualification: these mesenchymally derived diseases lumped under the heading of “sarcomas” can be quite different, and studies need to take that into account. In order to do that, and to generate studies of sufficient size and power, large-scale collaborations will be required on a national and an international level. Such collaborations are already in place among the nations of Europe (the Soft Tissue and Bone Sarcoma Group of the EORTC), Scandinavia, Italy, and Canada, and new collaborations are beginning in the U.S.A. under the auspices of the American College of Surgeons Oncology Group. With these collaborations, it is hoped that further research will rapidly translate research findings into the novel therapeutics that are so desperately required by patients with sarcomas.
| No. of Patients | ||||||
|---|---|---|---|---|---|---|
| First Author(s)/ Institution (yr) | Total | Pulmonary Metastases | Surgical Treatment | Complete Resection, % | Median Survival, Mo | 3-Year Survival, % |
| Creagan215/Mayo | 112 | 112 | 112 | 64 (57) | 18 | 29 |
| Putnam, Roth225/NCI | 487 | 93 | 68 | 51 (75) | 23 | 32 |
| Jablons226/NCI | 74 | 57 | 57 | 49 (86) | 27 | 35 |
| Casson216/MDACC | 68 | 68 | 68 | 58 (85) | 25 | 42 |
| Verazin235/Roswell | 78 | 78 | 78 | 61 (78) | 21 | 21.5 (5 yr) |
| Gadd217/MSKCC | 716 | 135 | 78 | 65 (83) | 19 | 23 |
| van Geel224/EORTC | 255 | 255 | 255 | 255 (100) | NR | 54 |
Mayo = Mayo Clinic; Roswell = Roswell Park Cancer Institute; NCI = U.S. National Cancer Institute; MDACC = The University of Texas M.D. Anderson Cancer Center; MSKCC = Memorial Sloan-Kettering Cancer Center; EORTC =European Organization for Research and Treatment of Cancer.
Many investigators believe that repeat thoracotomy to render patients free of disease from pulmonary soft-tissue sarcoma metastases is justified in the absence of effective systemic therapy. Several series of repeat pulmonary metastasectomy have been published.228,229 In a series of 43 such patients treated at the NCI, 72% of patients could be rendered free of disease at the second thoracotomy, with a median survival duration from the time of second thoracotomy of 25 months.228 In a report from the MDACC of a series of 39 patients undergoing reoperation for a second pulmonary metastasis after successful initial metastasectomy, factors predicting long-term survival included the presence of a solitary metastasis and the ability to perform a complete resection.229 This study also illustrates the significant survival duration many of these patients enjoy; the median survival in the 19 patients who had complete resection of unifocal recurrent metastatic disease was 65 months as compared to 14 months in the 15 patients with complete resection of two or more sites of recurrent disease.
Postmetastasis survival stratified by resection of pulmonary metastatic disease. The median survival among patients undergoing complete resection of metastatic disease was 20 months. From Billingsley et al.,214 by permission of Cancer.
).214 In summary, the clinical criteria (disease-free interval, tumor doubling time, and number of nodules) serve as general prognostic indicators, and no single criterion should be used to exclude patients from surgery. Postoperatively, the ability to achieve complete resection and the number of pulmonary nodules present appear to best define the prognosis for these patients.
Risk for and subsequent management of pulmonary metastases in 716 patients with primary or locally recurrent extremity soft-tissue sarcoma. From Brennan MF,212 by permission of Journal of the American College of Surgeons.
).212 Of the initial cohort of 716 patients, 148 patients (21%) developed pulmonary metastases. Isolated pulmonary metastases occurred in 135 (91%) of these 148 patients. Of the 135 patients with pulmonary-only metastases, 78 (58%) were considered to have operable disease, and 65 (83%) of those taken to thoracotomy were able to undergo complete resection of all of their pulmonary metastatic disease. Thus, 44% of all patients with pulmonary metastases were able to undergo complete metastasectomy. The median survival from the time of complete resection was 19 months, and the 3-year survival rate was 23%. All patients who did not undergo thoracotomy died within 3 years. For the entire cohort of 135 patients developing pulmonary-only metastases, the 3-year survival rate was only 11% (see Fig. 122.11).
The rather disappointing overall results of treatment for metastatic disease underscore the importance of careful patient selection for resection of pulmonary metastases. The following criteria are generally agreed upon: (1) the primary tumor is controlled or is controllable, (2) there is no extrathoracic disease, (3) the patient is a medical candidate for thoracotomy and pulmonary resection, and (4) complete resection of all disease appears possible.236 With careful patient selection, the morbidity of thoracotomy (or repeated thoracotomies) can be limited to the subset of patients who are most likely to benefit from this aggressive treatment approach. Finally, the potential role of systemic adjuvant chemotherapy following complete metastasectomy is discussed below in the section on individualizing the treatment of metastases.
Perhaps the most important place to begin in the approach to patients with unresectable metastatic sarcoma is the expected natural history of the disease. In this regard, the EORTC has made a major contribution recently by publishing their large series of more than 2,000 patients with advanced sarcomas of soft tissues to describe prognostic features and the natural history when treated with anthracycline-based chemotherapy.237 In this study, reviewing more than 20 years of experience, the median overall survival was approximately 1 year for the group as a whole. However, a subset of patients had more favorable expected outcomes with longer median survival. Such patients were typically those with younger age, improved performance status, sarcoma of low grade, without liver metastases, and who had developed metastatic disease following a longer duration from initial diagnosis. Importantly, this study concluded that these variables predicting improved survival were actually different than variables that would predict objective responsiveness to chemotherapy (the latter variables including such items as high-grade tumor and liposarcoma subset).237 Thus, one interpretation that is reasonable is that the most important predictor of survival with metastatic sarcoma are variables dependent on the tumor biology itself, as well as certain patient-specific factors such as age and co-morbid disease. These data are critical to understand as well so that new information regarding the impact of new drugs and treatments in development can be interpreted appropriately, based on a comparison with the correct expectations for the natural or treated history of the disease in past clinical trials.
Thus, the approach to chemotherapy in patients with sarcomas of soft tissue must be individualized based on several factors, including the biology of the disease, health status of the patient, and preferences of the patient. For patients with low-grade, asymptomatic though unresectable disease (e.g., intra-abdominal liposarcoma of low grade), it might be perfectly reasonable to follow the patient without active antisarcoma chemotherapy or to offer novel biologic treatments of low toxicity. Conversely, for patients with high-grade tumors such as synovial sarcoma, which would be expected to be sensitive to chemotherapy, early use of chemotherapy to control disease and prevent further clinical deterioration would be reasonable. Such decisions required individual physicians and patients to discuss the potential risks and benefits of different management options.
A question that arises after the resection of pulmonary metastasis is whether chemotherapy should be considered to eradicate occult microscopic disease. Although the principle is sound and reasonable for these high-risk cases, no randomized trial addressing this issue has been reported and any evidence remains anecdotal. A multi-center trial by the EORTC, in collaboration with ECOG and the Scandinavian Sarcoma Group, is attempting to address this question. Patients with potentially resectable metastases are randomized either to no chemotherapy or to receive doxorubicin/ifosfamide for three cycles preoperatively, with two additional cycles given postoperatively if there has been objective response with the preoperative treatment.238
It is increasingly recognized that different histologic subtypes of sarcomas may exhibit variable patterns of chemosensitivity. This variability complicates the interpretation of different studies between institutions and investigators in this field. For example, it is widely accepted that synovial sarcomas are among the more chemotherapy-sensitive histologic subtypes of soft-tissue sarcomas239 and that leiomyosarcomas in general have relatively lower rates of response to chemotherapy.237 It stands to reason that response rates from any study will therefore be heavily weighted by the population of patients in the trial and the distribution of histologic subtypes. Certain studies have recognized that conventional doxorubicin plus ifosfamide-based chemotherapy is suboptimal for gastrointestinal leiomyosarcomas and have excluded these from study. However, when this is done, it is impossible to tell whether high rates of response are due to the treatment under study or due to the exclusion of groups of patients that have traditionally lowered response rates in other trials.199 It is also important to recognize that response rates per se are increasingly being criticized as possibly poor surrogates for clinical benefit. It is recognized that many sarcomas have densely hyalinized desmoplastic stromal tissues associated with them. Even in cases where chemotherapy successfully induces massive tumor cell kill in vivo, such hyalinized tissue remains unchanged, leading to a falsely negative assessment of antisarcoma response to chemotherapy. Thus, objective response rates may actually underestimate the antitumor efficacy of chemotherapy. Conversely, simply shrinking a tumor and achieving a nondurable response may not be worth the toxicities of aggressive multi-agent chemotherapy. Thus, from both standpoints, “objective response” seems a suboptimal arbiter of antitumor efficacy in sarcoma management. Increasing attention in the field of drug development for sarcomas is being paid to other important indicators of clinical outcomes, such as progression-free survival, percentage survival at a given time point, and overall survival rates. Drugs may be active at slowing progression and prolonging survival even if objective response rates are low, although the clinical data to support those claims must be generated with rigor and careful attention to consistency of follow-up.
A wide spectrum of other chemotherapy drugs has been tested in sarcomas, with the expected variable response rates. Occasional small studies will suggest great benefit, with later larger studies failing to confirm initial promising results. Does this mean that chemotherapy is useless in sarcomas? Nothing could be further from the truth. It does accentuate the problems in using response rates as the arbiter of utility in assessing new agents in this field. Stabilization of disease is increasingly viewed as a realistic end point for this set of diseases, in which median survival of patients with advanced disease is so poor overall. Other potentially useful agents for soft-tissue sarcomas include gemcitabine,240,241 navelbine,242 DTIC (dacarbazine),243,244 carboplatin,245 and cisplatin.246 Certain small series have indicated a particularly useful role of taxanes in angiosarcomas of the scalp,247 and others have suggested that topotecan may induce responses in leiomyosarcomas.248
The sensitivity of sarcomas to chemotherapy was first convincingly demonstrated with doxorubicin in the early 1970s.249–251 Subsequent studies of doxorubicin in sarcomas have widely been viewed as supporting a dose-response relationship, with doses ≤ 50 mg/m2/cycle showing far less antitumor activity than dose rates of 60 mg/m2/cycle or higher.198,252–254 Although a dose response may in fact exist, it is also important to recognize that other variables affect the interpretation of dose on antitumor efficacy in these small studies with heterogeneous subsets of sarcomas. Most importantly again, in small studies, the actual histopathologic subtype of sarcoma may significantly impact on response rates. Such histologic factors have never been adequately controlled in the literature from which conclusions of dose response have been based, which limits the strength of evidence supporting this conclusion. Nonetheless, since a dose response (at least a dose threshold for optimal activity) has been documented with doxorubicin in another chemotherapy-sensitive solid tumor (breast cancer255), it seems reasonable to state that conventional doxorubicin is best used at doses > 60 mg/m2/cycle. It is nonetheless important to recognize the variability in response rates with doxorubicin as a single agent. These response rates range from < 10% (even in a modern multi-institutional study using doxorubicin at the dose of 75 mg/m2/cycle)256 to > 30% in some older single-institution studies.257 Given this variability, it is difficult to assume that a clinically meaningful dose response has been proven for sarcomas using this agent at doses higher than the conventional range of 60 to 75 mg/m2/cycle.
Many other studies of several other chemotherapy agents have been performed over the past 25 or so years. In general, rates of response to nearly all agents are < 20%. However, it is important to note that even the most active, standard agent (doxorubicin) can occasionally exhibit response rates < 20% in some large studies.256 Thus, caution must be exercised in study interpretation in both directions, so that inactive, though toxic, agents are not inappropriately viewed as useful, and so that false-negative results for potentially useful agents do not impede further study of drug application in this field. Having said this, one other chemotherapy agent, ifosfamide, stands out as potentially useful in most studies, with response rates consistently in the range of ≥ 20%. This puts ifosfamide into a category of response induction similar to that noted with doxorubicin. Ifosfamide has separate toxicities from doxorubicin, with urothelial toxicity, including hemorrhagic cystitis, distal renal tubular acidoses, and salt-wasting nephropathy among the potential problems with this agent. Ifosfamide also requires delivery over several sequential days, limiting patient convenience. Nonetheless, for certain patients, ifosfamide can be truly life saving. This has been particularly well shown for the subset of Ewing’s sarcoma patients treated on a large cooperative group clinical trial, in which the patients who received ifosfamide alternating with cyclophosphamide had significantly improved overall and disease-free survival.258 The judicious use of ifosfamide for appropriate patients can be a challenge to clinical judgment, especially considering the wide variety of dose- and schedule-ranging studies that have been performed with this agent.199,259 At this point, it seems clear that antitumor response is improved by higher doses of ifosfamide. This point has been made most convincingly by the induction of responses by high-dose ifosfamide (>10 g/m2/cycle) in patients who had previously failed the same drug at lower doses (e.g., doses of ifosfamide in the range < 6 g/m2/cycle).260,261 However, given the potential toxicities of this regimen at high doses, this approach is best reserved for a small subset of patients with disease that is expected to be highly chemotherapy sensitive to achieve meaningful responses (e.g., prior to planned surgical extirpation of metastases).
One critical controversy continues to smolder around whether the optimal approach to patients with advanced sarcomas is with combination chemotherapy regimens or with sequential single agents. Again, the shifts in management of other common solid tumors such as breast cancer are potentially applicable to sarcomas. Increasing data support the utility of sequential chemotherapy used as single agents with optimal dosing, in order both to minimize toxicity and to stretch out responses to sequential agents over a longer period of time than if the active agents were used together. There are no data to support the necessity of using chemotherapy in combination for patients with advanced metastatic sarcomas to obtain optimal outcomes. In fact, although combination chemotherapy is quite accepted as practice standard in the U.S.A., it is not necessarily the first-line approach to management of patients with advanced sarcomas with metastases in other parts of the world.
The best randomized prospective data testing the addition of an active chemotherapy agent to a chemotherapy regimen in the setting of advanced disease come from the large U.S. Intergroup study in which ifosfamide was or was not given to previously untreated patients with metastatic or advanced soft-tissue sarcomas receiving doxorubicin plus dacarbazine chemotherapy (MAID vs. AD).262 This study demonstrated no survival advantage for the group receiving the ifosfamide in combination with doxorubicin plus dacarbazine, although there was a statistically significant increase in objective response rate for the group receiving MAID.262 The role of combination chemotherapy is further called into question for broad use given the statistically significant increase in toxicities when the ifosfamide was added. Thus, despite the increased anticancer activity as evidenced by the marginally (though statistically significantly) improved response rates, no survival benefit was obtained. These data are widely interpreted as supporting aggressive combination chemotherapy for patients with bulky advanced disease who may be candidates for optimal limb-sparing surgery with preoperative chemotherapy. However, for patients with widespread advanced disease, such combination chemotherapy may only be appropriate if a rapid induction of response is required for control of acute symptoms such as tumor-related pain or obstruction. Future studies should evaluate the role of combinations versus sequential single agents with respect to impact on both disease control (disease-free survival and overall survival) as well as indicators of quality of life and treatment-associated toxicities and inconvenience.263
Advances in pharmacology and other supportive care technology have allowed great advances in the delivery of active chemotherapy for sarcoma patients. The impact of these advances may yet not have been recognized in widespread practice. One of the first strategies to advance the field of chemotherapy was in modifying the chemical structure of the most potent agent, doxorubicin, into another anthracycline, epirubicin. Epirubicin has diminished cardiotoxicity on a milligram for milligram basis, compared with doxorubicin, allowing the delivery of higher doses overall more safely. However, the efficacy differences, if any, between these agents remain unclear, and certain data from large-scale studies suggest that doxorubicin may, in fact, have a somewhat more favorable therapeutic index than high doses of epirubicin.264 Given the noted heterogeneity in sarcomas, however, larger studies stratified by histology would appear to be required before any definitive conclusions could be made concerning the relative worth of these two potent anthracyclines.
An obvious strategy, used in many other malignancies, has been to attempt delivery of dose-escalated chemotherapy. This was initially attempted solely with provision of autologous bone marrow support,245,265 and in the past decade has been significantly facilitated by the availability of hematopoietic cytokines to improve hematologic tolerance to myelosuppressive chemotherapy.266 It is also clear that peripheral blood progenitor cells can be mobilized and harvested following standard chemotherapy for sarcoma supported by granulocyte colony– stimulating factor (G-CSF).267 Many clinicians have chosen to use these peripheral blood progenitor cell harvests to support dose-intensified chemotherapy. However, simply making a therapeutic technique safer and more generally feasible does not necessarily imply that it leads to improved anticancer outcomes. Many studies of modestly dose-intensified chemotherapy have suggested the possibility of superior outcomes for patients,199,268 but to date no large-scale prospective randomized studies have been performed to confirm this compared to conventional-dose regimens. The use of high-dose chemotherapy for sarcomas with stem cell and cytokine support must be considered investigational and worthy of being performed only in the context of appropriately controlled phase III clinical trials to define the comparative worth of this approach in different types of sarcomas.
Another strategy to increase the therapeutic index of anthracyclines is to encapsulate the drug within a liposomal vehicle. At least three liposomal preparations of anthracyclines have been tested, and all have shown some efficacy in sarcomas.269 The most widely used preparation (known as Doxil in the U.S. and Caelyx in Europe) is a large liposome with polyethylene glycol anchored within the lipid bilayer, acting as a hydrophilic coating to preserve the circulating half-life of the liposome and prevent degradation within the reticuloendothelial system. This preparation, given at a dose rate less than that of unencapsulated doxorubicin, appears to be very well tolerated and approximately as effective as the nonliposomal drug.256 Whether this improved tolerability is worthy of the increased cost of the liposomal drug is a matter for future research and policy decisions. Other studies have explored the ability to deliver higher doses of liposome-encapsulated anthracyclines with acceptable tolerability, often using the support of hematopoietic cytokines such as G-CSF.269,270 The definition of increased utility of such higher doses of encapsulated anthracyclines, compared with conventional doses of these drugs, will require further investigation.
It has also been suggested that the membrane-anchored efflux pumps, such as the P-glycoprotein encoded by the MDR-1 gene, might be responsible for primary or acquired resistance of sarcomas to anthracyclines and other chemotherapy agents.271–273 Agents that might selectively block such efflux pumps, such as P-glycoprotein and the multi-drug resistance protein, could restore or convey chemosensitivity on otherwise resistant sarcoma cells. Indications of such activity using biricodar (VX-710), a small molecule inhibitor of the efflux pumps, have been observed in a subset of patients with clinically resistant sarcomas progressing on doxorubicin, in whom treatment with doxorubicin plus biricodar led to occasional responses and stabilization of disease.274 This strategy will require further confirmatory large studies but, if confirmed, would provide a novel approach not only for progressive chemorefractory disease but also for initial management of patients.
Finally, it is increasingly recognized that sarcomas represent a fertile ground for the field of drug development. Doxorubicin was first recognized as an effective agent in sarcomas and then subsequently was developed into one of the most widely used anticancer agents ever discovered. Other agents in clinical trials, such as the novel marine-derived alkaloid Ecteinascidin 743 (ET-743),275 now show promise for sarcomas, and the signal effects noted in sarcoma patients may be extrapolated into activity against other, more common malignancies in the future.
Giuiliano and Eilber originally coined the term “unplanned resection” for the operation performed for gross removal of a sarcoma without regard for preoperative imaging or the necessity to remove a margin of normal tissue covering the cancer.276 About one-third of new patients referred to a specialized center have undergone such an unplanned excision, and residual microscopic sarcoma can be detected in the wound at re-resection in 40 to 80% of cases.277 Therefore, in the unplanned resection, there is likely to be a substantial amount of residual tumour in the wound and potentially widespread local seeding of cancer cells, although this is rarely detectable by CT scan or MRI. This differs from the positive microscopic resection margin following a planned attempt at complete resection preceded by careful local staging. In patients referred to Princess Margaret Hospital following unplanned resection, if adjuvant radiation without further surgery was the only management undertaken, 50% recurred locally.80 However, Karakousis and Driscoll have recently reported conflicting information.278
The management of the unplanned excision should comprise re-excision of the tumor bed. Detailed knowledge of the first surgical approach and the potentially contaminated structures should be obtained. Where possible, all contaminated tissues should be removed without sacrificing critical structures. If microscopic evidence of sarcoma is identified in the re-excision specimen, RT should be considered unless particularly wide surgery has been undertaken.278
A substantial number of patients present with localized, small (T1) sarcomas. Management strategies for these patients have largely been based on extrapolation from existing limb-salvage approaches used for larger, locally advanced lesions. Recently, stage-specific long-term outcome data have improved our understanding of the relative risks (for local recurrence, distant recurrence, and death) imposed by smaller lesions. In addition, analysis of outcome for patients treated by surgery alone has led to the understanding that not all patients with sarcoma need local therapy consisting of surgery with pre- or postoperative RT.
A recent report from the MDACC outlined long-term outcome of a group of 122 patients presenting with T1 high-grade sarcomas. With a median follow-up of 76 months, the 5-year local recurrence-free, distant recurrence-free, disease-free, and overall survivals were 82, 83, 68, and 83%, respectively. Of note, patients who underwent maximal surgical resection with a microscopically positive surgical margin had a significantly worse disease-free survival than patients with microscopically negative surgical margins (p = .02). This group of patients had an overall outcome similar to that traditionally associated with high-risk T2 extremity sarcomas and therefore appears to represent a higher risk subset of T1 patients. A second important observation from this report was the fact that a substantial minority of recurrences (15%) was observed after 5 years of follow-up. These observations emphasize the fact that patients with sarcoma need to be followed for an extended period of time following completion of therapy.
| First Author | Institution | No. of Patients | Selection Criteria | No. with Adjuvant Radiation | Local Recurrence, % | Distant Recurrence, % |
|---|---|---|---|---|---|---|
| Geer279 | MSKCC | 174 | T1 size, primary tumor | 117 | 10 | 5 |
| Rydholm280 | Lund, Sweden | 56 | G/M margin negative | 0 | 7 | NR |
| Karakousis286 | RPCI | 116 | 2 cm G margin | 0 | 10 | NR |
| Respondek282 | MDACC | 40 | T1 size, primary tumor, G/M margin negative | 8 | NR | |
| Baldini283 | Harvard | 74 | Clinical not specified | 0 | 7 | 12 |
MSKCC = Memorial Sloan-Kettering Cancer Center; G/M = gross/microscopic; NR = not reported; Hospital; RPCI = Roswell Park Cancer Institute; MDACC = The University of Texas M.D. Anderson Cancer Center.
Rydholm and colleagues have reported their experience with 70 patients with subcutaneous or intramuscular extremity sarcomas treated with wide surgical resection and microscopic assessment of surgical margins.280 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 RT, yet only 4 (7%) developed local recurrence. A study from Brigham and Women’s Hospital reported similar results for 74 patients treated with surgical resection without RT.283 The 10-year actuarial local control rate was 93 ± 4%. Resection margins of less than 1 cm were associated with a lower local control rate than observed for patients with margins greater than 1 cm (87 vs. 100%). Karakousis and colleagues have reported results of 152 patients with extremity sarcoma, 116 of whom were managed by surgical resection without RT (with or without chemotherapy).105 Twelve local recurrences (10%) were observed. The favorable local recurrence rates reported in these series are comparable to local recurrence rates observed with conventional multi-modality therapy incorporating pre- or postoperative RT.49,104,120,125,142,148,284–286 These data support the hypothesis that selected patients with small, primary soft-tissue sarcomas can be treated with surgical resection alone without pre- or postoperative RT.
RPSs comprise about 15% of soft-tissue sarcomas. They present late and are located in regions where the administration of both surgery and RT is often compromised (e.g. adjacent to small bowel and liver). Consequently, the local control rates of extremity soft-tissue sarcomas with combined-modality treatment are not seen in RPS. In a series of 104 RPS patients treated at Princess Margaret Hospital, complete excision was achieved in only 45, macroscopic disease remained in 29, and only a biopsy was possible in 28. The overall locoregional relapse-free rate was 28 and 9% at 5 and 10 years, respectively. RT did not improve survival but appeared to significantly lengthen the time to locoregional relapse, especially with higher doses. Complete tumor resection was the only significant prognostic variable for survival and locoregional and distant failure.287 These results are similar to those reported from MSKCC.288
RPS should be evaluated prior to resection in a multi-disciplinary clinic with access to specific surgical opinions that may permit newer approaches to be developed. For example, Willet and colleagues289 detailed 20 patients treated with preoperative RT, resection, and then intraoperative electron-beam therapy and reported a 70% complete resection rate and 81% 4-year local relapse-free rate. Previously, we noted the advantages to the preoperative RT approach in RPS because (1) the tumor bulk often displaces dose-limiting small bowel from the high-dose region, (2) bowel is unlikely to be fixed by surgical adhesions characteristic of the postoperative setting, (3) optimum knowledge of the gross tumor location is possible, and (4) the risk of intraperitoneal tumor dissemination at the time of the operation may be reduced after RT pretreatment. We also noted that considerable complexicity in RT treatment planning may be encountered, but the use of conformal techniques usually permits dosage to be administered safely to critical organ regions preoperatively. It is then imperative that members of both the surgical and radiation oncology teams attend the operating room in circumstances where a significant amount of liver may have been irradiated preoperatively. Again, we cannot overemphasize that detailed evaluation of dosimetry and treatment planning films is needed to be certain that a sufficient volume of unirradiated liver is not resected at the time of surgery.109
Some centers use additional strategies to boost the area at greatest risk to a higher dose, but these strategies remain to be evaluated. These trials are warranted because of the disappointing results of the treatment of RPS with current approaches. One such approach is to use IORT or postoperative BRT boosts to the tumor bed. As noted earlier, IORT (20 Gy followed by 35 to 40 Gy postoperatively) was compared to conventional postoperative RT (50 to 55 Gy) in a randomized study of 35 patients. The incidence of locoregional recurrences was lower in the experimental treatment arm, but no survival benefit was demonstrated.159
Schema for approaching the patient with local recurrence in soft-tissue sarcoma. The schema is oriented toward extremity lesions but is equally applicable to other anatomic sites (e.g., head and neck and retroperitoneum). See text. BRT = branchytherapy; EBT = external = Beam Radiotherapy. Reproduced with permission from Catton CN, et al. Seminars in Radiation Oncology 1999;9(4):378–388.
. The initial evaluation must include a full review of previous therapy because this will have a bearing on the therapeutic options available. Therefore, all prior surgery and pathology reports should be examined: previous RT, especially volume treated, dose, and energy of radiation; and any chemotherapy given in the past.
A biopsy is necessary both to confirm the diagnosis and to determine any change in tumor grade from the original. It is also required to evaluate if the problem is indeed a recurrence or potentially a second primary arising in a radiation field. Sometimes, these are difficult to distinguish. Previous specimens also should be retrieved for comparison.
The local and systemic staging and examination should be performed in the same way as for new cases. However, perhaps more than for primary cases, the adjacent areas potentially contaminated by previous surgical interventions should be scrutinized carefully. Both the recurrent tumor, with its adjacent tissues containing potential tumor extensions and the previously contaminated tissues, should be considered at risk and candidates for resection and/or inclusion in irradiation fields at recurrence.
Several distinct groupings are evident under the rubric of the “locally recurrent” case. These include (1) those where prior treatment did not include RT, (2) patients who have been treated with previous RT in the past, (3) patients in both situations but who have distant metastases, and (4) cases where recurrence versus secondary irradiated induced tumor is difficult to distinguish.
Most patients with local relapse following surgery alone should be considered for salvage with combined-modality therapy with RT and surgery, especially since these can generally be administered safely and are probably at eventual risk of metastasis if local disease is not controlled. The need for RT in most cases in part relates to the fact that the surgery is usually more complex than it is for primary presentation cases. It may also be compromised from the standpoint of achieving good anatomic plane clearance around a well-defined mass because of the presence of multi-focal disease. Since wide-field surgery to resect such disease is required, the preoperative RT approach probably has an advantage. The use of adequate postoperative fields and doses following further surgery again could be problematic in the long term since the fields have to be large to encompass the new resection.
Amputation must occasionally be considered for patients with extremity sarcoma, as this may still be the best option for acceptable function in the face of multiple recurrences, multi-compartment disease, or encasement of critical anatomy such as neurovascular structures. The presenting function must also be considered, since there is no value to preserving an already painful and poorly functioning limb. Another consideration in managing the recurrent extremity lesion is to avoid prolongation of pain in a limb that will come to amputation. Although the precise underlying processes involved in the causation of phantom limb pain remain uncertain,290–292 it is preferable not to prolong the pain of a poorly functioning limb indefinitely since this may increase the risk of phantom limb pain.
Alternatives to amputation include limb perfusion followed by salvage surgery.207 In Eggermont and colleagues pooled results from eight centers following isolated limb perfusion with tumor necrosis factor and melphalan, 43% had locally recurrent disease. Limb salvage was attained in 82% of the total group.207 This novel approach to treating locally advanced disease requires further investigation, but shows promise for patients who might otherwise require an amputation. Except for recurrent RPS, 5-year survival is in the range of 60 to 75%, and 60 to 80% of patients achieve local control with salvage therapy.152
Recurrent RPS has a much worse prognosis than sarcoma at other sites, with a 5-year survival of about 20%. Some patients will attain a long disease-free period following treatment of a local recurrence. Unfortunately, with successive recurrences, the disease-free interval progressively diminishes, eventually mitigating against resection at the first appearance of asymptomatic re-recurrence. When complete gross resection appears technically feasible, aggressive treatment in asymptomatic patients who are otherwise well should be considered, at least for the first recurrence.
The second group, those who have received RT in the past, are the most difficult to re-treat. The previous radiation complicates the decision to re-treat with combined therapy, and a significant proportion of such patients will not be candidates for limb-sparing surgery. In one series of patients treated for an isolated extremity recurrence after combined therapy, 7 of 23 (30%) required amputation.151 In the same series, wide local excision without re-radiation was associated with a 63% (7/11) local re-recurrence rate, since the majority did not achieve clear resection margins. This finding suggests that most of these patients require local adjuvant therapy when limb-sparing surgery is contemplated.
Re-irradiation for extremity sarcoma includes the use of BRT, and EBRT, with or without intra-arterial chemotherapy. The local control rates with this approach are very acceptable, although the serious late toxicity is substantial, particularly from re-treatment with EBRT. Catton et al.151 reported prospective functional assessments after combined re-treatment in 10 patients, and 70% retained good or excellent limb function. The observation that combined re-treatment with limb-sparing surgery and BRT can be an effective method of controlling disease, and preserving a functional limb is also supported by others.153 BRT, in doses of 45 Gy or less, appears to be associated with the least toxicity.293 A cumulative dose not exceeding 95 Gy that includes the prior radiation is appropriate.152
Concurrent metastases are not infrequently identified with a local relapse. These patients are usually those who presented originally with the most adverse risk factors, and the treatment approach will reflect the anticipated prognosis. Patients who recur with multiple symptomatic metastases after a short disease-free interval are more likely to be better served using palliative systemic therapy. The management of the local recurrence will generally be directed toward symptom control and can include palliative chemotherapy, RT, or both. Aggressive surgical palliation is rarely indicated in this situation, but local excision of a small or superficial recurrence may delay or prevent the development of local complications.
The occasional patient presenting with local recurrence and limited systemic disease may benefit from aggressive treatment, especially after a long disease-free interval. A policy to consider metastatectomy for limited disease followed by treatment of the local recurrence provided that they can be rendered clinically disease-free is appropriate. The modalities chosen for the local treatment will be dictated by the prior therapy and have been discussed. The role of adjuvant chemotherapy in this setting is unknown.
A related problem that is occasionally seen is the patient with a radiation-induced soft-tissue sarcoma. In some instances, it may relate to a new sarcoma after irradiation of a previous sarcoma remotely, in others to the development of a soft-tissue sarcoma after RT for a different disease. For the former, differentiation from a recurrence may be problematic. This may be resolved by attention to the pattern of the new tumor occurrence, and the new histology may provide evidence that the tumor is different from the one for which RT was previously given. There is very little information concerning the optimal local treatment of these tumors, and they should generally be approached like new tumors other than for the limitations presented by prior therapy.
Evolution in soft-tissue sarcoma management has occurred in part through the development of multi-disciplinary groups that combine subspecialty expertise in diagnostic imaging, pathology, and surgical, radiation, and medical oncology. Coupled with a better understanding of tumor growth characteristics and availability of new imaging capability with CT and MRI, there is no reason why patients should not benefit from available expertise in this rare disease. Gustafson et al. compared patients referred to a specialty center before surgery (195 cases), following surgery (102 cases), and those not referred for specialty consultation (78 cases). This work examined a Swedish population-based series of primary soft-tissue sarcoma of extremity (329 cases) or trunk (46 cases).294 The combined number of primary tumor operations was 1.4 times higher in patients not referred and 1.7 times higher in patients referred after surgery compared to patients referred to a specialty center prior to any surgery. Moreover, the local recurrence was 2.4 times higher in the group not referred and 1.3 times higher in the group only referred to the specialty center following an initial surgery. Clasby and colleagues reporting from a single large health region in the United Kingdom, also noted inappropriate surgery, including unnecessary amputation. In addition, much of the surgery was performed by trainees, and in two-thirds of cases the resection margins were unsatisfactory.295 In another U.K. study, disappointing results were obtained in a region during a period of time devoid of a dedicated sarcoma unit, which prompted recommendation to introduce multi-disciplinary care.296 Such a recommendation has been suggested by others also.297–299
The functional result of extremity sarcoma management has become a new frontier in outcome assessment for these patients. This assessment is difficult as it requires instruments that are valid and reproducible. Many centers have yet to become experienced in the development and use of these methods, and much of the literature contains significant heterogeneity in patient samples.
Thus far, the variables associated with poorer functional outcome include large tumor size, higher doses of radiation and larger volumes, nerve sacrifice, postoperative fractures, and wound-healing complication.141,300–302 In order to evaluate and compare functional outcome, it is imperative that functional data be reported consistently. Three disease-specific scoring scales have been reported as useful in assessing soft-tissue sarcoma outcome.303 This area is discussed in detail by Davis, who observes that “function” has assumed many meanings in the literature.303 The concepts of impairment, disability, and handicap following extremity soft-tissue sarcoma are likely misunderstood and certainly not used consistently. Davis notes that impairment is a disorder of structure or function whereas disability is a restriction or lack of ability to perform an activity. Handicap results from impairment and disability and prevents or restricts an individual from performing in a role that is normal for the individual. For the population of sarcoma patients within the dimension of physical health, impairments can be manifested as soft-tissue fibrosis, loss of motion at a joint, and decreased muscle strength. Disability is manifested as limited mobility and difficulty performing routine self-care and activities of daily living. Handicap is evident in limitation in family roles, social functioning, and the capacity for employment. Unfortunately, there is a lack of consistency in the application of these definitions and concepts and assessment of outcome is therefore confusing.
Impairments are the most frequently reported outcomes following limb preservation for extremity soft-tissue sarcoma, and up to 50% of patients appear to experience significant deficits.303 Disability appears less frequent, but the reports are contradictory. It seems likely that many sarcoma patients can accommodate despite their impairments. Handicap has received little attention in the literature. However, the limited data suggest that up to 50% of patients may experience changes in their employment and vocation status post-treatment for extremity sarcoma of nonosseous tissues.303
The future challenge in treating sarcomas is to define the therapeutic ratio for the patient with sarcoma of the extremity. Specifically, the aim of the multi-disciplinary team is to minimize the amount of treatment, while maintaining or improving current standards of disease control, such that treatment morbidity is reduced and patient outcome is enhanced.303
Considerable variability exists in the literature about the reports of wound-healing complications. They have been reported in up to 40% of patients undergoing extremity sarcoma surgery.125,304–306 Differences in the definition of wound complications probably account for some of the variability in reporting. The retrospective data suggested that factors associated with compromised wound healing include patient age and nutritional status, lower extremity location and large tumor size, and preoperative adjuvant treatment, especially RT.307–310 Particularly high complication rates were noted recently with a protocol using RT and hyperthermia.163 Although most authors have reported the association with preoperative RT, reports of high rates of surgical complications without radiation or chemotherapy also exist.311 Most likely, these relate to the risk associated with extensive tumor resection in the lower extremities particularly. The use of vascularized tissue transfers may decrease the risk.307,312,313 As noted earlier, the SR2 trial results have confirmed the adverse affect of preoperative RT on wound healing in a prospective manner.135 However, the contribution of tissue transfer for wound reconstruction is unlikely to be resolved by SR2 as its use in the trial was determined on an individual basis at the surgeon’s discretion.
It is being recognized that management of sarcomas is increasingly driven by the specific nature of the disease entity, most importantly the pathophysiologic subtype. The work of Pasteur and Koch was fundamental for the recognition and definition of pathogenic microbes. Similarly, many laboratories today are identifying the molecular and cellular lesions that will redefine the field of sarcomas into more rational entities than can be elucidated by simple light microscopy. The first example of this work has been in the recognition of the Ewing’s sarcoma/PNET family of tumors. These tumors are increasingly recognized as extraosseous soft-tissue sarcomas, rather than a sarcoma of bone. Management should be an aggressive, multi-modality approach with curative intent, starting with multi-agent chemotherapy. If primary surgery has removed measurable disease, adjuvant chemotherapy is definitely indicated, with consideration of adjuvant local RT if surgical margins were suboptimal. By adopting similar strategies for PNET and Askin’s tumor314 as for conventional Ewing’s sarcoma, outcomes have improved.315 The molecular similarities between tumors of this family have led to the current convention of considering them simply morphologic and clinicopathologic variants of the same underlying molecular disease process.88,316
Another example of rapid evolution in clinicopathologic definitions is that of gastrointestinal stromal tumors (GIST). The most rigorous definition would be to classify these based upon mutation and overexpression of the c-kit membrane-anchored tyrosine kinase receptor.317 Prior to the recognition that c-kit was overexpressed and mutated, the field of spindle cell sarcomas of the gastrointestinal tract included a mixture of true GIST and gastrointestinal leiomyosarcomas, as well as de-differentiatied liposarcomas in which the adipogenic elements were obscure. The importance of identifying GIST patients is to spare them the toxicity of conventional chemotherapy, since the rates of response in GIST with standard doxorubicin or ifosfamide-based chemotherapy are unacceptably low to justify use in all patients.318 New treatment approaches are needed for these tumors. The identification of this novel molecular pathology opens new avenues for specific diagnostic tools as well as perhaps the chance to intervene therapeutically.
Molecular diagnostics are also becoming very relevant in synovial sarcomas. Synovial sarcomas have been identified in most series as a very chemotherapy responsive subset of sarcomas.199,239 Of note is the fact that clinically relevant histologic differences appear to exist even within this subclass of sarcomas, with poorly differentiated synovial sarcomas typically having a far worse prognosis than synovial sarcomas, which exhibit a more well-differentiated histologic profile. Most importantly, the specific breakpoint and rearrangement appears to have important prognostic significance for clinical behavior of the tumor, with the rearrangement in the SSX1 gene conveying a worse prognosis.86,319 The mechanisms by which these translocations transform cells via the chimeric fusion proteins is an area of important fundamental scientific inquiry, with translatable therapeutic potential.
Finally, liposarcomas are becoming increasingly well researched and well understood, with multiple histopathologic subsets.320 Myxoid and round cell liposarcomas exhibit the characteristic t(12;16) chromosomal rearrangement. These liposarcomas tend to be quite sensitive to doxorubicin-based chemotherapy in general. Well-differentiated liposarcomas exhibit ring and giant marker chromosomes on cytogenetic analysis, and these karyotypic abnormalities carry through even in de-differentiated liposarcomas, which arise in association with well-differentiated liposarcomas. Targeting the PPAR-gamma nuclear receptor is a particularly promising therapeutic strategy to force differentiation of the sarcoma cells and to decrease the proliferative thrust.321 Initial proof-of-concept data have been published in a clinical trial using this strategy,322 and larger randomized trials are planned to assess the clinical worth of this approach.
It is clear that soft-tissue sarcoma management has come a long way in a very short period of time. In less than three decades, the standard of care has shifted toward coordination of multi-modality care in specialty centers, with increased rates of function-sparing surgery and better outcomes for patients. Judicious use of aggressive multi-modality approaches shows promise to decrease relapse rates and improve survival. New scientific approaches are furthering the fundamental understanding of these unusual diseases and providing novel approaches for diagnostic techniques, which will banish the vagaries and lack of consistency that have plagued this field of clinical investigation. From such definitional changes will spring new therapeutic initiatives with promise to attack the basic mechanisms of sarcomatous transformation of cells and, it is hoped, improve outcomes for patients with less morbidity than current treatments entail. Large-scale collaborations will further this work tremendously.
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