Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive soft-tissue sarcoma arising from cells of the nerve

sheath, most notably the Schwann cells or perineural cells.1 It can develop de novo from peripheral nerves or from preexisting benign neurofibromas.2,3 MPNST are relatively rare, with a reported incidence of 1 per 106 people per year.1,4 Neurofibromatosis type 1 (NF1) and radiation exposure are the most important risk factors, with 50% to 60% of MPNST occurring in patients with NF1 and 10% of MPNST occurring in patients with prior radiation exposure.1,2,5,6 The rates of successful treatment of MPNST are generally low, and the available literature provides only limited guidance regarding the management of this disease. As with most soft-tissue sarcomas, surgical resection is typically the primary treatment modality for MPNST.1 Depending on the tumor's location though, anywhere from 5% to 80% of MPNST will be unresectable because of involvement of critical neurovascular structures.1,7 Complete wide resection can therefore be a serious challenge, and can carry the additional risk of significant functional loss. Radiotherapy is generally recommended for all MPNST, but the role of chemotherapy remains controversial as a result of the rarity of the disease and subsequent paucity of data. 1,8Several chemotherapeutic agents have been used against MPNST, but the clinical benefits have been variable and inconclusive. 2,3,7,925 Part of this inconsistency, no doubt, arises from the fact that most large studies on MPNST span long periods and use a variety of chemotherapeutic agents sporadically in their series.1,2,11,12,14,1618,2022,25 There have been no controlled studies looking at the effect of chemotherapy on MPNST alone. To contribute additional information on the clinical management of MPNST, we therefore report a series of patients seen at our musculoskeletal tumor center over 5 consecutive years and treated with a similar chemotherapeutic regimen. Specifically, this study investigates short-term outcomes in MPNST patients treated with aggressive surgical intervention, radiation therapy, and chemotherapy using doxorubicin and ifosfamide. It aims to test the hypothesis that multimodality therapy including doxorubicin and ifosfamide leads to improved disease-free survival (DFS) and overall survival (OS) in patients with MPNST, versus comparative rates currently published in the literature.

MATERIALS AND METHODS

Pathology records at our musculoskeletal tumor center were searched for all patients with a new diagnosis of MPNST between 2003 and 2008. Inclusion criteria for this study were confirmed pathologic diagnosis of MPNST, primary treatment involving doxorubicin and ifosfamide chemotherapy, complete clinical records, and minimum follow-up of 12 months or until death of the patient. Eighteen patients were identified from pathology records. Four patients were excluded because they did not receive doxorubicin and ifosfamide chemotherapy. Two patients were excluded because doxorubicin and ifosfamide were only given as secondary treatment for recurrent disease. Two patients were excluded because they were primarily treated elsewhere and/or had incomplete clinical records. The remaining 10 patients (6 male, 4 female) are the subjects of this study. The clinical data for these patients are listed in Table 1.

The mean age at presentation was 40 years (range, 2070). Four patients had known NF1. The MPNST were located in the hip/pelvis (3 patients), upper arm (2 patients), thigh (2 patients), ankle (1 patient), jaw (1 patient), and chest wall (1 patient). Nine of the 10 tumors were described as high-grade and 9 were at least 5 cm in largest dimension. Six patients had only local disease at presentation. Four patients had metastatic disease at presentation. The lungs were the most common site of metastasis (3 patients), but regional nodes were involved in 1 patient. Patients were treated mainly using multimodality therapeutic approaches, including surgery, chemotherapy, and radiotherapy. Overall strategies did not change substantially during the study period, although decisions about neoadjuvant versus adjuvant chemotherapy, total cycles of chemotherapy, and use of radiotherapy were customized depending on the patient's and physician's preferences. All patients were treated with surgical excision of resectable disease. Five patients received at least 1 cycle of neoadjuvant chemotherapy. All patients in this study received doxorubicin and ifosfamide as part of their primary treatment. Etoposide was added in 4 patients and camptothecin added for 1 additional patient. Seven patients received radiation therapy. Outcome measures were disease status at last follow-up, DFS, and OS. DFS was measured from the date of definitive surgery or disease remission to the date of local recurrence or metastasis. If the patient did not have local recurrence or metastasis, DFS was measured to the date of last follow-up. OS was measured from the date of diagnosis to the date of last follow-up or patient death. One- and 2-year DFS and OS rates were calculated using Kaplan-Meier methodology. Survival distributions were statistically compared using the Mantel-Cox log-rank test.