The Impact of Chemotherapy on the Survival of Patients With High-grade Primary Extremity Liposarcoma

Soft tissue sarcomas (STS) are a collection of histologically distinct neoplasms that are classified based on their type of mesenchymal tissue differentiation.1,2 Liposarcoma is the most common soft tissue sarcoma and accounts for at least 20% of all sarcomas in adults with the extremity being the most common site of primary disease.3–8 Classification of liposarcoma into 3 types, based on morphologic features and cytogenetic aberrations, is now widely accepted.9 These 3 types are: well-differentiated/de-differentiated,1 myxoid/round cell,2 and pleomorphic.3 The extent of differentiation, as reflected by histologic grade, remains the most important determinant of clinical course and of ultimate prognosis for patients with liposarcoma.9–17 Myxoid/round cell liposarcoma represents a morphologic continuum, and histologic grading is based on the extent of round cell component.10 Myxoid/round cell tumors with greater than 5% round cell component, dedifferentiated and pleomorphic liposarcoma are all considered high grade.10,11,14–19 The development of distant metastasis is the main determinant of survival for these higher grade histologic subtypes and is related to the size of the primary tumor as well as to the specific histologic subtype. For extremity liposarcoma >5 cm, distant metastasis may occur in 25% of dedifferentiated lesions, in 50% of myxoid/round cell lesions and in 75% of pleomorphic lesions.17 Although surgery and radiation therapy have achieved excellent local control and functional results for extremity liposarcoma, distant metastasis remains a difficult problem limiting survival. Over the past 2 decades neoadjuvant/adjuvant chemotherapy has been used in an attempt to improve the outcome of patients with high-risk primary extremity STS. A meta-analysis of 14 randomized trials employing adjuvant doxorubicin based chemotherapy (DOX) found that DOX was associated with a significant (10%) improvement in recurrence-free survival but not associated with an improvement in overall survival.18 Ifosfamide based chemotherapy (IF) for patients with primary STS was introduced in the early 1990s as a promising treatment based on the responses generated in the treatment of metastatic disease.19–21 The few randomized trials performed using IF have come to differing conclusions and are limited in their impact due to small sample sizes, lack of stratification for histologic subtype, and inclusion of multiple nonextremity tumor sites.22–24 All of these studies were designed to examine impact of chemotherapy on a collection of many different histologies making it difficult to assess the potential benefit to a specific histology. Chemotherapy is now standard treatment of Ewing's sarcoma and rhabdomyosarcoma given their high response rates and improved survival with systemic therapy. For patients with primary extremity sarcoma of other histologies, such as liposarcoma, the impact of chemotherapy on survival remains controversial and has not been evaluated systematically. The objective of this study is to determine if chemotherapy offers a survival benefit to patients with high-risk primary extremity liposarcoma.