Document 7MNmDb8y000D1z5dKJ6r1reVa

THERAPY IN PRACTICE Am J Cancer 2006; 5 (2): 81-91 1175-6357/06/0002-0081/$39.95/0 2006 Adis Data Information BV. All rights reserved. Leiomyosarcoma An Overview of Etiology, Prognosis, and Treatment Options Igor Matushansky and Martee L. Hensley Memorial Sloan-Kettering Cancer Center, New York, New York, USA Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 1. Etiology and Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 2. Diagnosis and Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 2.1 Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 2.2 Tissue Diagnosis and Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 2.3 Imaging for the Extent of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 2.4 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3. Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 4. Management Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 4.1 Uterine Leiomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 4.1.1 Local Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 4.1.2 Adjuvant Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 4.1.3 Advanced/Recurrent Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 4.2 Nonuterine Leiomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 4.2.1 Adjuvant Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 4.2.2 Advanced Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Abstract Approximately 2400 people were diagnosed with leiomyosarcoma in 2004 in the US. This rare tumor of connective tissue is clinically subdivided into uterine and nonuterine leiomyosarcoma. No predisposing factors are known, and presentation is usually related to mass involvement and intrusion of adjacent structures. Tissue obtained for the initial diagnosis should be of sufficient quantity to evaluate the grade of the tumor, and a full work-up for the extent of disease must include chest, abdomen, and pelvic imaging. For localized disease, the standard of care remains limited to surgical excision. Radiation therapy can be considered for larger tumors and/or positive margins if anatomically feasible. Adjuvant chemotherapy has not been proven to be effective and remains investigational. Treatment for metastatic disease is palliative. Active agents include doxorubicin, ifosfamide, gemcitabine, and docetaxel. The last two agents in combination have recently been shown to be highly active in uterine leiomyosarcoma in the metastatic setting and are now being further pursued at the Memorial Sloan-Kettering Cancer Center (New York, NY, USA) in both the adjuvant uterine leiomyosarcoma setting and in the nonuterine leiomyosarcoma metastatic setting. Patients diagnosed with leiomyosarcoma should be referred to specialty sarcoma centers and encouraged to participate in clinical trials. Leiomyosarcoma is a malignant tumor of smooth muscle cells that may arise anywhere smooth muscle cells exist. Common sites include the smooth muscle component of the uterus and the muscularis layers of the gastrointestinal tract and large blood vessels. Traditionally, leiomyosarcoma has been divided into uterine and nonuterine (soft-tissue) leiomyosarcoma. 82 Matushansky & Hensley Uterine sarcomas represent approximately 1% of gynecologic malignancies and <5% of all uterine corpus cancers.[1] The incidence of leiomyosarcoma amongst all uterine sarcomas is estimated to be between 30%[2] and 50%.[3] Based on US annual incidence data for 2006,[4] which included 321 000 cases of all gynecologic malignancies and 40 000 cases of uterine malignancies, there were approximately 1000 cases of uterine leiomyosarcoma. Similarly, leiomyosarcoma accounted for 15% of the approximately 6000 cases of soft-tissue sarcoma recorded in the Memorial Sloan-Kettering Cancer Center (MSKCC) sarcoma pathology database between 1982 and 2003. Based on an annual incidence of 9500 cases of soft-tissue sarcoma (according to the American Cancer Society 2006 statistics),[4] 1400 cases of soft-tissue leiomyosarcoma occurred in the US in 2004. The relatively small number of cases and the diversity in the anatomic site and biologic behavior of leiomyosarcoma makes a comprehensive understanding of this condition challenging. This article provides on overview of the etiology, prognosis, and management options for leiomyosarcoma. 1. Etiology and Risk Factors Unlike several other subtypes of sarcoma, leiomyosarcoma does not involve specific genetic alterations such as fusion genes due to reciprocal translocations and/or specific point mutations. Instead, leiomyosarcoma displays complex unbalanced karyotypes representing numerous genetic losses and gains.[5] Either causatively or consequently, alterations in the tumor suppressor genes RB1[6] and TP53[7] are detected in a substantial proportion of leiomyosarcomas. A genetic or familial predisposition to leiomyosarcoma has not been identified. Radiation has been identified as a risk factor for the development of soft-tissue and bone sarcomas;[8] however, most patients with leiomyosarcoma have no prior history of radiation exposure. Despite multiple reports linking chemical carcinogens (e.g. dioxins and pesticides) and sarcomas,[9,10] a causal relationship remains to be proven. There is sufficient evidence to link sarcomas to exposure to vinyl chlorides and arsenic; however, this relationship is limited almost exclusively to hepatic angiosarcomas.[11] Uterine leiomyosarcoma has been diagnosed in women treated with tamoxifen for breast cancer.[12] Uterine sarcoma is extremely rare in tamoxifen recipients, being estimated to occur in 0.17 per 1000 users per year. However, this represents a 10-fold increase in risk compared with women who have never been exposed to tamoxifen. One study estimated that since 1978, <200 cases of uterine sarcoma have developed worldwide in women taking tamoxifen.[13] Although women should be cautioned about the increased risk of uterine cancers (including sarcomas) with tamox- ifen use, the benefits of tamoxifen in terms of breast cancer treatment greatly outweigh the risk of uterine cancer.[14,15] 2. Diagnosis and Staging 2.1 Presentation Soft-tissue tumors may be benign or malignant; a variety of lesions of borderline malignant potential are also recognized. The ratio of benign to malignant tumors is >100 : 1,[16] and benign tumors are not believed to evolve into malignant tumors.[17] An excellent clinical example of this observation is uterine fibroids. Although uterine fibroids are very common, there is little or no risk that this histologically benign lesion will progress and/or develop into a leiomyosarcoma. However, leiomyosarcoma may co-exist in a uterus that also contains benign fibroids.[18] Imaging studies may be helpful in assessing the characteristics of uterine masses that suggest malignancy.[19] Although leiomyosarcomas may arise in any site containing smooth muscle, more than half are located in retroperitoneal or intra-abdominal sites. In these locations they often present as fairly large masses with vague, nonspecific symptoms. Uterine leiomyosarcomas may present with pelvic pain or pressure, or abnormal vaginal bleeding.[20,21] Extremity leiomyosarcoma most frequently arises in the thigh and may be associated with medium or large veins.[22] Rarely, leiomyosarcoma may arise in large vascular structures and present with symptoms of obstruction to the normal flow of blood.[23] The most common arterial site is the pulmonary artery; patients may present with symptoms of decreased pulmonary outflow. Leiomyosarcoma of the inferior vena cava may present with Budd-Chiari syndrome, with obstruction of hepatic veins. Involvement of the middle portion of the inferior vena cava may result in blockage of renal veins and renal dysfunction, whereas involvement of the lower portion may cause leg edema.[24] Cutaneous leiomyosarcomas usually appear as small, solitary, extremity nodules.[25] Accurate diagnosis requires an adequate and representative biopsy or excision of the tumor with careful histologic review for correct subtyping of soft-tissue sarcoma (see section 2.2). 2.2 Tissue Diagnosis and Pathology The objective of a biopsy in the management of soft-tissue sarcomas is to obtain adequate tissue for definitive histopathologic confirmation of the diagnosis, to evaluate the tumor grade, and to identify prognostic factors that may alter the approach to definitive treatment. For lesions that are <5cm in size and superficial, an excisional biopsy is generally preferred. 2006 Adis Data Information BV. All rights reserved. Am J Cancer 2006; 5 (2) Management of Leiomyosarcoma 83 Uterine leiomyosarcomas are often found at the time of hysterectomy performed for what may have been thought to be benign disease prior to surgery. If leiomyosarcoma is suspected intraoperatively or suggested by frozen section, an attempt should be made to excise all visible tumor; however, routine lymph node dissection is not required if the lymph nodes appear normal. There is no single standard approach for nonuterine, nonsuperficial soft-tissue sarcomas, whether the tumor is a leiomyosarcoma or of a different sarcoma histology. The utility of a TruCut biopsy versus a fine needle aspiration as a first-line diagnostic option has been studied extensively. Some studies have shown that, upon independent review, a Tru-Cut biopsy improves both diagnostic accuracy and tumor grading.[26] Fine needle aspiration is usually favored for confirmation of recurrence rather than for primary diagnosis.[27] Others have argued that no open biopsy is indicated, fearing local tumor spread which would increase both the extent of the definitive operation and the need for adjuvant radiation therapy.[28] Nevertheless, because the tumor grade influences treatment options and cannot currently be determined by fine needle aspiration, adequate tissue from a Tru-Cut, excisional or incisional biopsy is generally favored over fine needle aspiration and is the preferred approach at MSKCC. Histologically, the typical leiomyosarcoma cell is elongated and spindle-shaped and has an abundant cytoplasm. Multinucleated giant cells are common. Epithelioid changes, in which the cells become rounded, with concomitant clear cell changes in the neoplasm are commonly noted. Identification of muscle antigens by means of immunohistochemistry supports the diagnosis of leiomyosarcoma. Desmin and smooth muscle actin are the most common immunohistochemical stains. Mitotic activity has been demonstrated in multivariate analysis to be the best indicator of prognosis, along with the tumor location and size (see also section 3).[29] The grading of sarcoma, as determined by cellularity, differentiation, pleomorphism, necrosis, and number of mitoses, is an important prognostic factor (see also section 3). However, disagreement exists as to which is the best grading system. The American Joint Committee on Cancer (AJCC)[30] recommends a three-tier system (low, intermediate, and high), whereas a two-tier system (low and high) is used at MSKCC for all soft-tissue sarcomas.[31] The clinical implications of this discordance are obvious since it makes comparisons of clinical trials, and attempts at combining the results of multiple trials, difficult. In an attempt to define a practical grading system for soft-tissue sarcoma, the European Organisation for Research and Treatment of Cancer (EORTC) studied the histologic features of tumors from 282 patients who participated in an adjuvant chemotherapy trial, and correlated the pathologic findings with outcome. Although no feature was found to correlate independently with survival, in a multivariate analysis, the combination of the mitotic count, presence or absence of necrosis, and tumor size did correlate with survival.[32] Mutation of TP53, nuclear overexpression of TP53, and a high Ki-67 proliferation index have been associated with high grade and poor survival in other studies.[33] However, because biologic markers have not been consistently shown to be independent prognostic factors, they cannot at present be used to grade sarcomas. 2.3 Imaging for the Extent of Disease The imaging studies performed for soft-tissue sarcomas in general depend on the primary lesion site, the histology, and the potential sites of metastases. CT is the modality used most often. Several small studies have suggested that magnetic resonance imaging (MRI) may provide better anatomic detail for determining resectability.[34] However, a Radiology Diagnostic Oncology Group (RDOG) study comparing these modalities showed no clear benefit of MRI over CT.[35] Positron emission tomography (PET) is a metabolic scan that can detect areas of enhanced metabolism (e.g. cancer cells) but, in the absence of an anatomical mass (as visualized by CT), the significance of enhanced metabolism is currently unclear. As yet, there is no clear role for the routine use of PET in leiomyosarcoma. Although some studies support PET as a useful modality,[36] sites of known metastases may not be PET-avid. PET may, however, be useful in assessing early responses[37] in areas known to be PETavid prior to treatment, but has not yet been shown to have a clear advantage over CT. Additional imaging studies should be driven by patient symptomatology. Metastatic spread in leiomyosarcoma is mostly hematogenous, with lymph node involvement being unusual.[38,39] For patients with extremity leiomyosarcoma, 70% of distant metastases will be in the lung,[40,41] whereas patients with retroperitoneal leiomyosarcoma or uterine leiomyosarcoma seem as likely to develop intraabdominal (including parenchymal liver metastases) and pulmonary metastases.[42,43] Thus CT with contrast of the chest, abdomen, and pelvis is the standard imaging procedure for leiomyosarcoma. 2.4 Staging There have recently been significant changes in the staging of soft-tissue sarcoma. The original 1992 staging system was based on a review published in 1977,[44] which incorporated tumor size into the determination of the grade. The newest staging system, defined by the AJCC in 2002,[30] includes both the tumor size and the depth of invasion (table I). Lymph node involvement is rare in sarcoma but when it does occur the disease is considered to be 2006 Adis Data Information BV. All rights reserved. Am J Cancer 2006; 5 (2) 84 Matushansky & Hensley Table I. American Joint Committee on Cancer classification system for soft-tissue sarcomas (including leiomyosarcoma), based on tumor grade (G),a primary tumor (T),b regional lymph nodes (N),c and distant metastasis (M)d [30] Stage I Stage II Stage III Stage IV Low grade Superficial and deepe G1, T1a, N0, M0 G1, T1b, N0, M0 G1, T2a, N0, M0 G1, T2b, N0, M0 G2, T1a, N0, M0 G2, T1b, N0, M0 G2, T2a, N0, M0 G2, T2b, N0, M0 High grade Superficial and deepe G3, T1a, N0, M0 G3, T1b, N0, M0 G3, T2a, N0, M0 G4, T1a, N0, M0 G4, T1b, N0, M0 G4, T2a, N0, M0 High grade Large and deepe G3, T2b, N0, M0 G4, T2b, N0, M0 Metastasis to lymph nodes Metastasis to distant sites Any G, any T, N1,f M0 Any G, any T, N0, M1 a GX: grade cannot be assessed; G1: well differentiated; G2: moderately differentiated; G3: poorly differentiated; G4: poorly differentiated or undifferentiated. b TX: primary tumor cannot be assessed; T0: no evidence of primary tumor; T1: tumor 5cm in greatest dimension; T1a: superficial tumor; T1b: deep tumor; T2: tumor >5cm in greatest dimension; T2a: superficial tumor; T2b: deep tumor. c NX: regional lymph nodes cannot be assessed; N0: no regional lymph node metastasis; N1: regional lymph node metastasis. d MX: distant metastasis cannot be assessed; M0: no distant metastasis; M1: distant metastasis. e Superficial tumors are located exclusively above the superficial fascia without invasion of the fascia. Deep tumors are located either exclusively beneath the superficial fascia, or superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia. Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors. f The presence of positive nodes (N1) is considered stage IV. stage IV metastatic, as disease-free survival is identical to that for patients with metastases to other sites.[30] Uterine leiomyosarcoma is still frequently staged according to the International Federation of Gynecology and Obstetrics (FIGO) classification system (table II).[45] An important research question is whether staging uterine leiomyosarcoma according to soft-tissue sarcoma staging systems might improve estimations of the prognosis. Leiomyosarcomas arising from different anatomical primary sites may behave differently even when matched for stage and grade. Whether this is simply a function of the anatomy or an inherent difference in leiomyosarcomas of various anatomical primary sites remains to be elucidated. However, what is currently clear is that there are factors that impact on our ability to treat tumors at specific sites, such as the difficulty of radical resections for head and neck tumors, and the limitations of radiation therapy in intra-abdominal sites. Moreover, it is difficult to separate the site from the adequacy of treatment. Patients with retroperitoneal sarcomas commonly die due to complications caused by local recurrence[42,43] an uncommon event in extremity lesions. Distant metastatic disease is often the cause of death from intra-abdominal and pelvic visceral leiomyosarcomas.[40,41] 3. Prognosis The stage and grade are the most important prognostic factors in soft-tissue sarcoma, including leiomyosarcoma. For small, su- perficial, extremity soft-tissue sarcomas, whether high- or lowgrade, there is a relatively low chance of recurrence. For large (>5cm), high-grade lesions, the risk of metastasis is significant. The primary location may impact on the prognosis, perhaps because of issues of resectability. A computer program (nomogram) that calculates the prognosis for overall survival in soft-tissue sarcomas has been developed and is available on the MSKCC website.[46] The median survival from the time metastases are recognized is 812 months, although 2025% of patients with metastatic sarcoma are alive 2 years after diagnosis. Table II. International Federation of Gynecology and Obstetrics classification of uterine leiomyosarcoma[45] Stage IA IB IC IIA IIB IIIA IIIB IIIC IVA IVB Description of extent of uterine cancer Tumor limited to lining of uterus Invasion to <1/2 thickness of lining Invasion to 1/2 thickness of lining Invasion into cervical nodes Invasion of cervical stroma Invasion of ovaries; positive peritoneal cytology Vaginal metastases Involvement of pelvic lymph nodes Invasion of bladder or rectum Distant or abdominal metastases; or inguinal lymph node involvement 2006 Adis Data Information BV. All rights reserved. Am J Cancer 2006; 5 (2) Management of Leiomyosarcoma 85 Although disease stage is an important prognostic factor for recurrence and survival, recent data suggest that the relative importance of certain prognostic factors may vary with time. For early recurrence, it would appear that the grade is a more powerful prognostic indicator, whereas for late recurrence, tumor size assumes a progressively more important role.[47,48] 4. Management Approaches Treatment of soft-tissue sarcomas depends on the location of the primary tumor, the stage, and the grade. A multimodality approach including surgical resection, radiation therapy, and chemotherapy may be required (figure 1). The relative rarity of soft-tissue sarcomas has meant that many clinical trials have enrolled all, or most, sarcoma histologic subtypes. Although this approach improves patient accrual, it makes parsing out specific recommendations for one histologic subtype difficult. As understanding of the molecular variabilities among soft-tissue sarcoma subtypes improves, it is hoped that treatment recommendations will become more histologic-type specific. Success in conducting subtype-specific clinical trials will require a strong commitment to multi-institution cooperative efforts. 4.1 Uterine Leiomyosarcoma Uterine sarcomas are rare, accounting for approximately 1% of gynecologic malignancies, and <5% of all uterine corpus cancers.[1] The uterus is the only organ that can give rise to three different types of sarcomas: leiomyosarcoma, endometrial stromal sarcoma, and carcinosarcoma (also known as malignant mixed Mullerian tumor, or MMMT). Approximately 60% of women present with disease that is limited to the uterus or to the uterus and cervix (FIGO stages I and II), and undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy, resulting in cure rates of 2060%.[49-51] Women who present with advanced disease (FIGO stages III and IV) and women whose disease recurs after total abdominal hysterectomy and bilateral salpingo-oophorectomy have a poor prognosis and, with few exceptions, their disease is not considered curable. 4.1.1 Local Control For disease confined to the uterus, surgical resection is the appropriate treatment. Adjuvant radiation remains controversial. Most retrospective studies have suggested a decrease in local recurrence rates with adjuvant pelvic radiation but no improvement in overall survival because of the high risk of distant metastatic disease.[52] However, a study from Spain[53] did show a survival advantage with the use of radiation therapy. This trial accrued 103 patients, 41.5% of whom had a diagnosis of leiomyosarcoma. Postoperative external beam radiotherapy was adminis- tered to 55 patients (24 of whom received brachytherapy as well); 33 patients received postoperative chemotherapy and 15 patients were observed without further treatment. When compared with no postoperative radiotherapy, treatment with postoperative radiotherapy increased the 5-year locoregional disease-free interval from 36% to 76%; the 5-year disease-free interval from 53% to 68%; and overall survival from 37% to 73%. Although these numbers are impressive, it is believed that distant metastases are the main reason for disease recurrence in uterine leiomyosarcoma. Interestingly, 84% of relapses occurred locally in this study. It is hoped that the ongoing, randomized EORTC-55874 trial will determine the exact impact of adjuvant radiation in this malignancy. 4.1.2 Adjuvant Chemotherapy Similarly, there is currently a lack of robust data to support the use of adjuvant chemotherapy. The Gynecologic Oncology Group (GOG) performed a prospective randomized trial which compared adjuvant chemotherapy with doxorubicin versus no further therapy in patients with stage III uterine leiomyosarcoma or MMMT. No significant improvement was noted in the progression-free interval or overall survival for the group as a whole. There was a small improvement in progression-free survival in the subset of patients with leiomyosarcoma, but the study was neither designed nor powered to assess the impact of adjuvant doxorubicin by histologic type.[54] Since that study was designed, it has become clear that uterine leiomyosarcoma and MMMT have different chemotherapy sensitivities. Doxorubicin is not a highly active agent in MMMT but remains one of the most active agents in advanced uterine leiomyosarcoma. Appropriately designed, histology-specific trials of adjuvant therapy for completely resected uterine leiomyosarcoma are needed. Encouraging results demonstrating the activity of docetaxel plus gemcitabine in patients with measurable disease who have failed prior therapy[55] make the investigation of this regimen in the adjuvant setting attractive. A pilot study of adjuvant docetaxel plus gemcitabine in patients with completely resected leiomyosarcoma of the uterus is currently in progress at MSKCC and a multi-institution study of adjuvant therapy has recently opened. 4.1.3 Advanced/Recurrent Disease Current treatment options for advanced and/or recurrent leiomyosarcoma are somewhat limited. Phase II trials have demonstrated minimal activity with cisplatin,[56] mitoxantrone,[57] aminothiadiazole,[58] and oral etoposide.[59] Moderate activity was observed with ifosfamide (response rate 17%),[60] intravenous etoposide (response rate 10.7%),[61] and doxorubicin (response rate 25%).[62] 2006 Adis Data Information BV. All rights reserved. Am J Cancer 2006; 5 (2) 86 Matushansky & Hensley Presentation Palpable mass Signs/symptoms related to unidentified mass Initial imaging (dictated by site of presentation) CT scan (chest or abdomen/pelvis) MRI (extremity) Diagnostic biopsy Incisional, excisional, Tru-Cut Grade determination needed Pathologic identification LMS confirmed Imaging for extent of disease CT scan (chest, abdomen, pelvis) Single site of disease Multiple sites of disease Surgically resectable Not surgically resectable Multiple sites: locally confined Surgical resection Multiple sites: distant locations Radiation therapy (case-by-case basis) Adjuvant therapy Observation (routine CT scans) Clinical trials recommended Recurrence Systemic chemotherapy Gemcitabine/docetaxel Doxorubicin/ifosfamide Clinical trials Fig. 1. Outline of recommended diagnostic and treatment strategy for leiomyosarcoma (LMS). MRI = magnetic resonance imaging. In combination chemotherapy trials, the combination of hydroxycarbamide, dacarbazine, and etoposide showed a response rate of 18.4%,[63] while the combination of doxorubicin and ifosfamide showed a response rate of 30.3%.[64] No randomized clinical trials have evaluated the combination of doxorubicin and ifosfamide versus doxorubicin alone. Either approach may be reasonable as first-line therapy for advanced and/or recurrent uterine leiomyosarcoma. A phase II study of docetaxel plus doserate-based gemcitabine for patients with recurrent/persistent leio- myosarcoma who had had treatment failure with 02 prior chemotherapy regimens, conducted at MSKCC, resulted in a 53% objective response rate.[55] Seven patients had stable disease. Approximately half of these patients had failed prior doxorubicin-based therapy. Fourteen patients had received prior radiation therapy. Toxicity was moderate, with a 21% incidence rate of grade 3 or 4 neutropenia. There were only two episodes of neutropenic fever and no treatment-related deaths. Thus, the results of this phase II study make dose-rate-based gemcitabine plus docetaxel a reasona- 2006 Adis Data Information BV. All rights reserved. Am J Cancer 2006; 5 (2) Management of Leiomyosarcoma 87 ble first-line option for uterine leiomyosarcoma. Two multi-institution GOG trials of this regimen are currently under way in patients with advanced uterine leiomyosarcoma who have either had treatment failure after one cytotoxic regimen or no prior cytotoxic chemotherapy. 4.2 Nonuterine Leiomyosarcoma Approximately 1400 patients are diagnosed with soft-tissue leiomyosarcoma annually in the US; according to the MSKCC sarcoma database it is the third most common sarcoma. Very few histology-specific clinical trials have been performed. Current treatment options are derived from larger clinical trials that have encompassed many subtypes of sarcomas. The mainstay of treatment for soft-tissue sarcoma remains wide surgical excision. Adjuvant radiation therapy, using either external beam radiation or brachytherapy, has been shown to be beneficial for local control in situations where (i) negative margins were clearly obtained but the primary tumor was large (>5cm); or (ii) the edge of the resection was close to the negative margin.[65-67] However, the utility of radiation therapy in improving disease-free survival and overall survival remains unproven in both the preoperative[67] and postoperative settings.[66] 4.2.1 Adjuvant Chemotherapy The use of adjuvant chemotherapy remains unclear although it has been evaluated in >20 clinical studies. All of these studies enrolled patients with all types of soft-tissue sarcoma, not specifically leiomyosarcoma. Most of the studies were small and lacked sufficient statistical power to detect small changes in overall survival. The most rigorous meta-analysis was performed in 1997[68] and updated in 2000;[69] 23 potential studies were initially considered but only 14 were ultimately included, giving a study cohort of 1568 patients. The trials all used doxorubicin either alone (in six trials) or in combination with various other chemotherapeutic agents. Leiomyosarcoma represented 12% of all diagnoses. On the whole, disease-free survival at 10 years was found to be significantly improved with adjuvant chemotherapy compared with surgery alone (55% vs 45%; p = 0.0001). Local disease-free survival at 10 years also favored chemotherapy, improving from 75% to 81%. However, although overall survival improved from 50% to 54% at 10 years with combination therapy, the difference was not statistically significant (p = 0.12). In the Kaplan-Meier subset analysis of patients with leiomyosarcoma (n = 188; 12% of all patients), recurrence-free survival and overall survival did not differ between those who received adjuvant chemotherapy and those who did not. Specifically, events per patient (i.e. overall risk of death or recurrence) occurred in 43 of 91 (47.3%) patients in the adjuvant chemotherapy versus 42 of 88 (47.7%) patients in the control group. Since the 1997 meta-analysis,[68] two studies have been performed in which ifosfamide was incorporated into the adjuvant therapy regimen. A small randomized trial from the Italian Sarcoma Group showed adjuvant therapy with epirubicin and ifosfamide to statistically significantly improve disease-free survival and overall survival compared with no adjuvant chemotherapy.[70] However, as only 8 of the 104 patients in the trial had leiomyosarcoma (3 in the chemotherapy arm and 5 in the control arm), the applicability of these data to leiomyosarcoma is not known; most patients in the trial were classified pathologically as having malignant fibrous histiocytoma and synovial sarcoma. More importantly, in a subsequent report after a median 7 years of followup in which an intention-to-treat analysis was performed, the overall survival benefit was seen to be only a trend and was no longer statistically significant (p = 0.07).[71] Another study by Brodowicz et al.[72] enrolled 59 patients who underwent primary surgery and then were randomized to receive either radiotherapy alone or radiotherapy followed by dacarbazine, ifosfamide, and doxorubicin. There were no statistically significant differences between the two treatment groups in terms of relapse-free survival, time to local failure, time to distant failure, or overall survival. There are several reasons why these previous trials may have failed to detect a benefit with chemotherapy. Firstly, the studies, while large by sarcoma trial standards, were small in comparison with clinical trials of other cancer subtypes and therefore may not have had sufficient statistical power to detect smaller differences in outcome. Secondly, the studies did not limit enrollment to patients with high-grade, large tumors, who have the poorest prognosis and therefore the most to gain. Thus the benefit of chemotherapy may have been diluted by inclusion of patients with tumors associated with a better prognosis. Thirdly, we must accept the daunting possibility that, despite using the best study designs and inclusion criteria, current chemotherapy agents may not be `effective' for sarcomas in the adjuvant setting. The difficulty is in defining effectiveness. While the 1997 Sarcoma Meta-analysis Collaboration did not show whether doxorubicin-based chemotherapy was associated with an overall survival advantage in the adjuvant setting, it did show a benefit in disease-free survival (p = 0.0001) and local-recurrence-free survival (p = 0.016).[68] A subset analysis showed that doxorubicin-based chemotherapy was associated with a statistically significant survival advantage in patients with large (>10cm), high-grade sarcomas of the extremities. However, the study was not designed to examine this subgroup a priori.[69] 2006 Adis Data Information BV. All rights reserved. Am J Cancer 2006; 5 (2) 88 Matushansky & Hensley In summary, current data suggest that adjuvant chemotherapy with the agents studied to date is not beneficial for patients with localized soft-tissue sarcomas. In response to these issues, and recognizing the inherent difficulties of performing clinical trials in patients with sarcomas, two recent editorials addressed the design of clinical trials assessing the efficacy of chemotherapy in soft-tissue sarcomas. Bramwell[73] maintains that it is ethically acceptable to perform a study with a control arm in which patients receive no chemotherapy and expressed hope that such a trial might provide a more definitive conclusion and clarify earlier results. Judson[74] points out that the true value of aggressive chemotherapy must be clearly defined through a prospective randomized trial of sufficient size and statistical power to provide meaningful results. In an attempt to begin to address these points by using existing data, the clinical sarcoma databases of MSKCC and the M.D. Anderson Cancer Center (Houston, TX, USA) were combined to examine the efficacy of chemotherapy in the treatment of softtissue sarcomas. Of the 674 patients identified as having presented with primary, high-risk (AJCC stage III) extremity soft-tissue sarcoma from 1984 to 1999,[48] 338 patients received local therapy (surgery and/or adjuvant radiotherapy) only and 336 patients received local therapy plus chemotherapy. Surprisingly, the use of adjuvant chemotherapy was associated with shorter disease-free survival. One interpretation of these data may be that since this was a retrospective analysis, patients presenting with more aggressive primary lesions were predicted to fare worse and were therefore recommended to receive chemotherapy. Clearly, additional evidence is needed before subjecting all patients to the significant morbidity associated with chemotherapy in the adjuvant setting. 4.2.2 Advanced Disease Approximately half of all patients with adequate local control of their disease will develop distant metastasis.[30] Accordingly, multiple agents have been tested alone and in combination. Although most clinical studies performed in this setting have included all pathological subtypes of soft-tissue sarcomas, we present here selected studies in which leiomyosarcoma represented 30% of cases. Doxorubicin has consistently demonstrated a response rate of 25%.[75,76] Other less active agents include dacarbazine (response rate 17%);[77] docetaxel (response rate 17%);[78] vinorelbine (response rate 11%);[79] and gemcitabine (response rate 11%).[80] Although ifosfamide has historically been considered not particularly effective in leiomyosarcoma,[81] recent reports have indicated a response rate of 25% with this agent.[82] One possible explanation for this inconsistency is over-representation in the earlier studies by gastrointestinal stromal tumors which, until very recently, were classified as leiomyosarcomas. To further compli- cate the issue, sarcoma classification has markedly changed with extensive advances in immunohistochemistry as well as nomenclature over the last several years;[83] in fact more than half of the previously classified sarcomas were reclassified upon recent review.[83] Although disconcerting, the overall percentage of patients with leiomyosarcoma increased from 10% to 20% (with a concurrent decrease in other sarcomas, mostly malignant fibrous histiocytoma), suggesting that the previously cited studies might have had an even greater preponderance of leiomyosarcoma than originally believed, thus adding somewhat to their validity in assessing the efficacy of certain treatments for leiomyosarcoma. Building on the experience with single-agent chemotherapy, combination chemotherapy has been trialed. Once again, selective trials are discussed in which leiomyosarcoma represented 30% of cases. Although the combination of docetaxel and gemcitabine has been reported to yield a 53% response rate,[55] this occurred in a study in which 85% of the patients had uterine leiomyosarcoma, and thus its efficacy in nonuterine leiomyosarcoma and nonleiomyosarcoma soft-tissue sarcomas remains to be fully defined. Promising preliminary data on this combination in the treatment of soft-tissue sarcomas have come from the University of Michigan (Ann Arbor, MI, USA)[84] where 35 patients with various softtissue sarcomas were treated with docetaxel and dose-rate-based gemcitabine. Of the 12 patients with nonuterine leiomyosarcoma, two had a complete response and five had a partial response. An additional three patients had stable disease. Preliminary results of a randomized trial of gemcitabine versus gemcitabine plus docetaxel in soft-tissue sarcoma are due to be reported at the American Society of Clinical Oncology 2006 annual meeting by Maki et al. Doxorubicin with ifosfamide remains the most active combination, with reproducible response rates of 3436%.[81,85] Three- and four-drug combination therapy regimens have been evaluated in the setting of advanced sarcoma, with no improvement beyond the response rates reported with the combination of doxorubicin and ifosfamide.[81,86] It should be pointed out that while an increase in the objective response rate can be achieved with combination chemotherapy, an increase in median survival has not been demonstrated in trials comparing combination chemotherapy with single agents.[62,75,86] Although it might be argued that since historically nonuterine soft-tissue sarcomas have been grouped, the translational benefit from uterine leiomyosarcoma to nonuterine leiomyosarcoma may be obscured by the numerous other histological subtypes enrolled, a 1999 meta-analysis seems to indicate that this is not the case.[87] Overall, there were 2185 cases, of which 538 were classified as leiomyosarcoma. Statistical analysis showed that 1-year survival (overall 48% and leiomyosarcoma 49%), 2-year survival (overall 22% and leiomyosarcoma 20%), median survival time (overall 51 2006 Adis Data Information BV. All rights reserved. Am J Cancer 2006; 5 (2) Management of Leiomyosarcoma 89 weeks and leiomyosarcoma 52 weeks), and response rates (overall 26% and leiomyosarcoma 22%) were essentially identical when leiomyosarcoma-specific data were compared with the combined data on all soft-tissue sarcoma subtypes. This suggests that it is reasonable to extrapolate findings specifically to leiomyosarcoma from large clinical studies in which 25% of all cases were leiomyosarcoma. 5. Conclusion The management strategy for leiomyosarcoma, as used at MSKCC, involves the judicious and appropriately timed use of surgery, radiation therapy, and chemotherapy. Of these three strategies, the initial approach in the treatment of soft-tissue sarcoma, including nonuterine leiomyosarcoma, is wide surgical excision. The surgical approach for uterine leiomyosarcoma is surgical excision by hysterectomy with or without oophorectomy. Radiation therapy is administered adjuvantly for high-grade lesions, positive margins, and nonuterine soft-tissue sarcoma lesions >5cm in size. Adjuvant radiation therapy is not generally recommended for completely resected, stage I and II uterine leiomyosarcoma for which surgical resection is complete. The efficacy of adjuvant chemotherapy for uterine or nonuterine leiomyosarcoma remains unproven as a means to improve overall survival. Currently, adjuvant chemotherapy for completely resected, high-grade leiomyosarcoma is offered to patients participating in an appropriate clinical trial. Treatment for advanced, metastatic, and/or recurrent disease involves the use of chemotherapy in combination with radiotherapy and surgery. Active drugs in leiomyosarcoma include doxorubicin, ifosfamide, dose-rate-based gemcitabine plus docetaxel, and dacarbazine. Trials to assess whether single agents or combination therapy offer the best approach are in progress. Finally, all patients diagnosed with sarcomas should be referred to cancer centers with expertise in the diagnosis and treatment of sarcomas for consideration of clinical trial participation to help establish a standard of care and improve treatment strategies. Acknowledgments I Matushansky and ML Hensley have no conflicts of interest that are directly relevant to the content of this review. No sources of funding were used to assist in the preparation of this review. References 1. Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth muscle neoplasms: a clinicopathologic study of 213 cases. Am J Surg Pathol 1994; 18 (6): 535-58 2. Kelly KL, Craighead PS. Characteristics and management of uterine sarcoma patients treated at the Tom Baker Cancer Centre. Int J Gynecol Cancer 2005; 15 (1): 132-9 2006 Adis Data Information BV. All rights reserved. 3. Livi L, Paiar F, Shah N, et al. Uterine sarcoma: twenty-seven years of experience. Int J Radiat Oncol Biol Phys 2003; 57 (5): 1366-73 4. American Cancer Society. Statistics for 2006 [online]. Available from URL: http:// www.cancer.org/docroot/stt/stt_0.asp [Accessed 2006 Feb 23] 5. Wang R, Lu YJ, Fisher C, et al. Characterization of chromosome aberrations associated with soft-tissue leiomyosarcomas by twenty-four-color karyotyping and comparative genomic hybridization analysis. Genes Chromosomes Cancer 2001; 31 (1): 54-64 6. Cance WG, Brennan MF, Dudas ME, et al. Altered expression of the retinoblastoma gene product in human sarcomas. N Engl J Med 1990; 323 (21): 1457-62 7. Latres E, Drobnjak M, Pollack D, et al. Chromosome 17 abnormalities and TP53 mutations in adult soft tissue sarcomas. Am J Pathol 1994; 145 (2): 345-55 8. Brady MS, Gaynor JJ, Brennan MF. Radiation-associated sarcoma of bone and soft tissue. Arch Surg 1992; 127 (12): 1379-85 9. Wiklund K, Dich J, Holm LE. Soft tissue sarcoma risk in Swedish licensed pesticide applicators. J Occup Med 1988; 30 (10): 801-4 10. Zahm SH, Ward MH, Blair A. Pesticides and cancer. Occup Med 1997; 12 (2): 269-89 11. Bosetti C, La Vecchia C, Lipworth L, et al. Occupational exposure to vinyl chloride and cancer risk: a review of the epidemiologic literature. Eur J Cancer Prev 2003; 12 (5): 427-30 12. Silva EG, Tornos CS, Follen-Mitchell M. Malignant neoplasms of the uterine corpus in patients treated for breast carcinoma: the effects of tamoxifen. Int J Gynecol Pathol 1994; 13 (3): 248-58 13. Wickerham DL, Fisher B, Wolmark N, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol 2002; 20 (11): 2758-60 14. Chlebowski RT, Col N, Winer EP, et al. American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 2002; 20 (15): 3328-43 15. O'Regan RM, Jordan VC. The evolution of tamoxifen therapy in breast cancer: selective oestrogen-receptor modulators and downregulators. Lancet Oncol 2002; 3 (4): 207-14 16. Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990; 94 (4): 435-8 17. Quade BJ, Wang TY, Sornberger K, et al. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer 2004; 40 (2): 97-108 18. Leibsohn S, d'Ablaing G, Mishell Jr DR, et al. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol 1990; 162 (4): 968-76 19. Worthington JL, Balfe DM, Lee JK, et al. Uterine neoplasms: MR imaging. Radiology 1986; 159 (3): 725-30 20. Sutton GP, Blessing JA, Manetta A, et al. Gynecologic Oncology Group studies with ifosfamide. Semin Oncol 1992; 19 (6 Suppl. 12): 31-4 21. Brenner PF. Differential diagnosis of abnormal uterine bleeding. Am J Obstet Gynecol 1996; 175 (3 Pt 2): 766-9 22. Kevorkian J, Cento DP. Leiomyosarcoma of large arteries and veins. Surgery 1973; 73 (3): 390-400 23. Gustafson P, Willen H, Baldetorp B, et al. Soft tissue leiomyosarcoma: a population-based epidemiologic and prognostic study of 48 patients, including cellular DNA content. Cancer 1992; 70 (1): 114-9 24. Hollenbeck ST, Grobmyer SR, Kent KC, et al. Surgical treatment and outcomes of patients with primary inferior vena cava leiomyosarcoma. J Am Coll Surg 2003; 197 (4): 575-9 25. Spencer JM, Amonette RA. Tumors with smooth muscle differentiation. Dermatol Surg 1996; 22 (9): 761-8 26. Pitcher ME, Fish S, Thomas JM. Management of soft tissue sarcoma. Br J Surg 1994; 81 (8): 1136-9 27. Trovik CS, Bauer HC, Brosjo O, et al. Fine needle aspiration (FNA) cytology in the diagnosis of recurrent soft tissue sarcoma. Cytopathology 1998; 9 (5): 320-8 28. Rydholm A. Soft tissue lesions in adults: biopsy yes or no? Ann Oncol 1992; 3 Suppl. 2: S57-8 29. Fletcher C, Unni K, Mertens F. World Health Organization classification of tumours. Lyons: IARC Press, 2002 30. Greene F, Page DL, Fleming ID, et al, editors. AJCC cancer staging manual. 6th ed. New York (NY): Springer, 2002 Am J Cancer 2006; 5 (2) 90 Matushansky & Hensley 31. Hajdu S. Pathology of soft tissue tumors. Philadelphia (PA): Lea & Febiger, 1979 32. van Unnik JA, Coindre JM, Contesso C, et al. Grading of soft tissue sarcomas: experience of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 1993; 29A (15): 2089-93 33. Drobnjak M, Latres E, Pollack D, et al. Prognostic implications of p53 nuclear overexpression and high proliferation index of Ki-67 in adult soft-tissue sarcomas. J Natl Cancer Inst 1994; 86 (7): 549-54 34. Demas BE, Heelan RT, Lane J, et al. Soft-tissue sarcomas of the extremities: comparison of MR and CT in determining the extent of disease. AJR Am J Roentgenol 1988; 150 (3): 615-20 35. Panicek DM, Gatsonis C, Rosenthal DI, et al. CT and MR imaging in the local staging of primary malignant musculoskeletal neoplasms: report of the Radiology Diagnostic Oncology Group. Radiology 1997; 202 (1): 237-46 36. Umesaki N, Tanaka T, Miyama M, et al. Positron emission tomography with (18)Ffluorodeoxyglucose of uterine sarcoma: a comparison with magnetic resonance imaging and power Doppler imaging. Gynecol Oncol 2001; 80 (3): 372-7 37. Vernon CB, Eary JF, Rubin BP, et al. FDG PET imaging guided re-evaluation of histopathologic response in a patient with high-grade sarcoma. Skeletal Radiol 2003; 32 (3): 139-42 38. Fong Y, Coit DG, Woodruff JM, et al. Lymph node metastasis from soft tissue sarcoma in adults: analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg 1993; 217 (1): 72-7 39. Leitao MM, Sonoda Y, Brennan MF, et al. Incidence of lymph node and ovarian metastases in leiomyosarcoma of the uterus. Gynecol Oncol 2003; 91 (1): 209-12 40. Gadd MA, Casper ES, Woodruff JM, et al. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993; 218 (6): 705-12 41. Anraku M, Yokoi K, Nakagawa K, et al. Pulmonary metastases from uterine malignancies: results of surgical resection in 133 patients. J Thorac Cardiovasc Surg 2004; 127 (4): 1107-12 42. Youssef E, Fontanesi J, Mott M, et al. Long-term outcome of combined modality therapy in retroperitoneal and deep-trunk soft-tissue sarcoma: analysis of prognostic factors. Int J Radiat Oncol Biol Phys 2002; 54 (2): 514-9 43. Pisters PW, O'Sullivan B. Retroperitoneal sarcomas: combined modality treatment approaches. Curr Opin Oncol 2002; 14 (4): 400-5 44. Russell WO, Cohen J, Enzinger F, et al. A clinical and pathological staging system for soft tissue sarcomas. Cancer 1977; 40: 1562-70 45. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 1989; 96 (8): 889-92 46. Memorial Sloan-Kettering Cancer Center. Sarcoma nomogram [online]. Available from URL: http://www.mskcc.org/mskcc/html/6181.cfm [Accessed 2006 Feb 27] 47. Stojadinovic A, Leung DH, Allen P, et al. Primary adult soft tissue sarcoma: timedependent influence of prognostic variables. J Clin Oncol 2002; 20 (21): 4344-52 48. Cormier JN, Huang X, Xing Y, et al. Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomes. J Clin Oncol 2004; 22 (22): 4567-74 49. Major FJ, Blessing JA, Silverberg SG, et al. Prognostic factors in early-stage uterine sarcoma: a Gynecologic Oncology Group study. Cancer 1993; 71 (4 Suppl.): 1702-9 50. Nordal RR, Kristensen GB, Kaern J, et al. The prognostic significance of surgery, tumor size, malignancy grade, menopausal status, and DNA ploidy in endometrial stromal sarcoma. Gynecol Oncol 1996; 62 (2): 254-9 51. Nordal RR, Kristensen GB, Kaern J, et al. The prognostic significance of stage, tumor size, cellular atypia and DNA ploidy in uterine leiomyosarcoma. Acta Oncol 1995; 34 (6): 797-802 52. Hornback NB, Omura G, Major FJ. Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma. Int J Radiat Oncol Biol Phys 1986; 12 (12): 2127-30 53. Ferrer F, Sabater S, Farrus B, et al. Impact of radiotherapy on local control and survival in uterine sarcomas: a retrospective study from the Grup Oncologic Catala-Occita. Int J Radiat Oncol Biol Phys 1999; 44 (1): 47-52 54. Omura GA, Blessing JA, Major F, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 1985; 3 (9): 1240-5 2006 Adis Data Information BV. All rights reserved. 55. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002; 20 (12): 2824-31 56. Thigpen JT, Blessing JA, Beecham J, et al. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 1991; 9 (11): 1962-6 57. Muss HB, Bundy BN, Adcock L, et al. Mitoxantrone in the treatment of advanced uterine sarcoma: a phase II trial of the Gynecologic Oncology Group. Am J Clin Oncol 1990; 13 (1): 32-4 58. Asbury R, Blessing JA, Smith DM, et al. Aminothiadiazole in the treatment of advanced leiomyosarcoma of the uterine corpus: a Gynecologic Oncology Group study. Am J Clin Oncol 1995; 18 (5): 397-9 59. Rose PG, Blessing JA, Soper JT, et al. Prolonged oral etoposide in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 1998; 70 (2): 267-71 60. Sutton GP, Blessing JA, Barrett RJ, et al. Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Am J Obstet Gynecol 1992; 166 (2): 556-9 61. Slayton RE, Blessing JA, Angel C, et al. Phase II trial of etoposide in the management of advanced and recurrent leiomyosarcoma of the uterus: a Gynecologic Oncology Group Study. Cancer Treat Rep 1987; 71 (12): 1303-4 62. Omura GA, Major FJ, Blessing JA, et al. A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 1983; 52 (4): 626-32 63. Currie J, Blessing JA, Muss HB, et al. Combination chemotherapy with hydroxyurea, dacarbazine (DTIC), and etoposide in the treatment of uterine leiomyosarcoma: a Gynecologic Oncology Group study. Gynecol Oncol 1996; 61 (1): 27-30 64. Sutton G, Blessing JA, Malfetano JH. Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 1996; 62 (2): 226-9 65. Pisters PW, Harrison LB, Leung DH, et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996; 14 (3): 859-68 66. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998; 16 (1): 197-203 67. O'Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002; 359 (9325): 2235-41 68. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults: Sarcoma Meta-analysis Collaboration (SMAC). Cochrane Database Syst Rev 2000; (2): CD001419 69. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 1997; 350 (9092): 1647-54 70. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol 2001; 19 (5): 1238-47 71. Frustaci S, De Paoli A, Bidoli E, et al. Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology 2003; 65 Suppl. 2: 80-4 72. Brodowicz T, Schwameis E, Widder H, et al. Intensifed adjuvant IFADIC chemotherapy for adult soft tissue sarcoma: a prospective randomized feasibility trial. Sarcoma 2000; 4: 151-60 73. Bramwell VH. Adjuvant chemotherapy for adult soft tissue sarcoma: is there a standard of care? J Clin Oncol 2001; 19 (5): 1235-7 74. Judson I. Systemic therapy of soft tissue sarcoma: an improvement in outcome. Ann Oncol 2004; 15 Suppl. 4: iv193-6 75. Borden EC, Amato DA, Rosenbaum C, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987; 5 (6): 840-50 76. Mouridsen HT, Bastholt L, Somers R, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas: a randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol 1987; 23 (10): 1477-83 77. Gottlieb JA, Benjamin RS, Baker LH, et al. Role of DTIC (NSC-45388) in the chemotherapy of sarcomas. Cancer Treat Rep 1976; 60 (2): 199-203 Am J Cancer 2006; 5 (2) Management of Leiomyosarcoma 91 78. van Hoesel QG, Verweij J, Catimel G, et al. Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcomas of the adult: EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 1994; 5 (6): 539-42 79. Fidias P, Demetri GD, Harmon DC. Navelbine shows activity in previously treated sarcoma patients: phase II results from MGH/Dana-Farber/Partners Cancer Care Study [abstract]. Proc Am Soc Clin Oncol 1998; 17: A1977 80. Patel SR, Jenkins J, Papadopoulos NE, et al. Preliminary results of a two-arm phase 2 trial of gemcitabine in patients with gastroinstestinal leiomyosarcomas and other soft-tissue sarcomas (STS) [abstract]. Sarcoma 1999; 3 (1): 56 81. Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993; 11 (7): 1269-75 82. van Oosterom AT, Mouridsen HT, Nielsen OS, et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer 2002; 38 (18): 2397-406 83. Daugaard S. Current soft-tissue sarcoma classifications. Eur J Cancer 2004; 40 (4): 543-8 84. Leu KM, Ostruszka LJ, Shewach D, et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 2004; 22 (9): 1706-12 85. Loehrer Sr PJ, Sledge Jr GW, Nicaise C, et al. Ifosfamide plus doxorubicin in metastatic adult sarcomas: a multi-institutional phase II trial. J Clin Oncol 1989; 7 (11): 1655-9 86. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995; 13 (7): 1537-45 87. Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcomas: an analysis of 2,185 patients treated with anthracycline containing first-line regimens: an European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Study Group. J Clin Oncol 1999; 17 (1): 150-7 Correspondence and offprints: Dr Igor Matushansky, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C1179, New York, NY 10021, USA. E-mail: matushai@mskcc.org 2006 Adis Data Information BV. All rights reserved. Am J Cancer 2006; 5 (2)