Individuals with neurofibromatosis type 1 (NF1) are at relatively high risk (lifetime risk 10% to 13%) of developing a cancer of the soft tissue involving the outer layers of peripheral nerves. These cancers are called malignant peripheral nerve sheath tumors (MPNST). In individuals with NF1 these tumors often develop from pre-existing noncancer tumors of the peripheral nerve called plexiform neurofibromas, which occur in approximately 25% of individuals with NF1. Only complete surgical resection of MPNSTs has been shown to be curative, and the outcome is poor for patients whose tumor cannot be completely removed by surgery. Individuals with NF1 who have MPNSTs may fare worse than those who do not have NF1, and the reasons for this are not known.
Chemotherapy has been used for the treatment of adult soft tissue cancers after surgical resection of these tumors. While clear benefit (improved survival) has not been documented using this approach, the administration of chemotherapy prior to surgical resection (called neoadjuvant) has become standard of care for soft tissue cancers in children and has resulted in improved outcome. MPNSTs are rare and the response rate of MPNSTs to chemotherapy (percent of patients who experience significant shrinkage of their tumors) is unknown. However, responses to chemotherapy in MPNSTs have been reported. High-grade (rapidly growing) MPNSTs may therefore be responsive to chemotherapy.
The purpose of this trial is to assess if chemotherapy administered prior to surgery for high-grade unresectable MPNSTs can induce tumor shrinkage (50% or more) in at least 40% of patients treated. This study will assess possible differences between MPNSTs in patients with or without NF1 by evaluating response in equal numbers from each group. The demonstration of tumor response to therapy would have a direct impact on the management of patients with MPNST, and the plan would evaluate the effect of chemotherapy prior to surgery on survival in a subsequent larger trial. Likewise, knowledge of lack of tumor shrinkage would be helpful for sarcoma treatment teams as they look to develop other, more effective protocols.
This trial will also use a number of new imaging technologies with the goal of measuring changes in tumor size more sensitively, and of assessing activity of the tumor (actively growing versus dead tumor cells). These analyses may result in better predictors of response to therapy and potential outcome. In addition, trials could be developed combining the active chemotherapy with more targeted novel treatment approaches. Tumor tissue obtained will also undergo a detailed analysis in order to increase the knowledge of the biology of these tumors and to identify novel targets for treatment. In addition, blood samples will be obtained from patients entered on this trial with the goal of identifying if a marker measurable in the blood may help identify patients with an MPNST.
Finally, this trial will be performed as a collaboration of NF and sarcoma centers, and the development of this infrastructure may serve as the platform for the conduct of future treatment studies for MPNSTs.