Why This Trial Is Important

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that form in the outer layers of peripheral nerves (nerves outside the brain and spinal cord). About half of MPNSTs are found in individuals with a hereditary condition called neurofibromatosis type 1 (NF1, A rare genetic condition that causes brown spots and tumors on the skin, freckling in skin areas not exposed to the sun, tumors on the nerves, and developmental changes in the nervous system, muscles, bone, and skin). Surgery is the only curative treatment for MPNSTs. The prognosis for patients with unresectable tumors (tumors that cannot be surgically removed) is poor.

In this trial, patients with unresectable MPNSTs will be treated with neoadjuvant chemotherapy followed by surgery and/or radiation therapy and more chemotherapy. Neoadjuvant chemotherapy is given to reduce the size of the MPNSTs prior to the administration of definitive local therapy (surgery and/or radiation therapy). The choice of treatment following neoadjuvant chemotherapy will be based on tumor location and tumor response to the chemotherapy.

"We hope MPNSTs shrink in response to neoadjuvant chemotherapy with doxorubicin, ifosfamide, and etoposide, which are standard agents with proven activity in other pediatric and adult sarcomas," said Dr. Widemann.

"Furthermore, because outcomes for NF1-associated MPNST have been reported to be worse compared to sporadic tumors," Dr. Widemann said, "we will evaluate outcomes in the two groups treated with identical therapy to determine if patients with NF1-associated MPNSTs face a worse prognosis."

Outline

This is a multicenter study. Patients are stratified according to type of malignant peripheral nerve sheath tumor (MPNST) (sporadic MPNST vs neurofibromatosis type 1 [NF1]-associated MPNST). Patients receive 1 of 2 treatment regimens depending on the location of the MPNST and tumor response to chemotherapy.

·         Chemotherapy and local control by radiotherapy and surgery: Patients receive doxorubicin hydrochloride and ifosfamide (IA) chemotherapy comprising doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 and ifosfamide IV over 1 hour on days 1-5. Treatment repeats every 21 days for 2 courses in the absence of unacceptable toxicity. Patients then receive etoposide and ifosfamide (IE) chemotherapy comprising etoposide IV over 1 hour and ifosfamide IV over 1 hour on days 1-5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim (G-CSF) subcutaneously (SC) after each chemotherapy course beginning on day 6 or 7 and continuing until blood counts recover or pegfilgrastim SC once on day 6 or 7.

After recovery from chemotherapy, patients undergo radiotherapy and receive 2 more courses of IE during radiotherapy followed by 2 more courses of IA after completion of radiotherapy. Some patients may then undergo surgery.

·         Chemotherapy and local control by surgery: Patients receive 2 courses of IA followed by 2 courses of IE as above. After recovery from chemotherapy, patients undergo surgery. After recovery from surgery, patients receive 2 more courses of IA followed by 2 more courses of IE in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 5 years.

Who Can Join This Trial

Researchers will recruit 74 patients with newly diagnosed sporadic or NF1-associated high-grade stage III or IV MPNSTs.

 

Entry Criteria

Disease Characteristics:

·         Newly diagnosed sporadic or neurofibromatosis type 1 (NF1)-associated high-grade malignant peripheral nerve sheath tumors (MPNSTs)

·         Stage III or stage IV (metastatic) disease

·         Unresectable disease

·         Measurable disease, defined as at least 1 tumor that is measurable in 2 dimensions on CT scan or MRI

Prior/Concurrent Therapy:

·         No prior chemotherapy or radiotherapy for MPNST

·         Prior surgical resection of MPNST allowed provided residual or recurrent measurable disease is present

·         Recovered from toxic effects of all prior therapy

·         At least 3 weeks since prior chemotherapy or biologic therapy for treatment of a plexiform neurofibroma, optical pathway tumor, or other NF1-associated tumor (in patients with NF1)

·         No prior doxorubicin, ifosfamide, or etoposide

·         At least 6 weeks since prior radiotherapy for treatment of a plexiform neurofibroma, optical pathway tumor, or other NF1-associated tumor (in patients with NF1)

·         No prior radiotherapy to the area involved by MPNST

·         No other concurrent growth factors (e.g., sargramostim [GM-CSF] or interleukin-11)

·         Concurrent epoetin alfa allowed

Patient Characteristics:

·         Ejection fraction normal by echocardiogram or MUGA

·         Serum creatinine normal for age OR creatinine clearance > 60 mL/min

·         SGPT < 5 times upper limit of normal (ULN)

·         Bilirubin < 2.5 times ULN

·         Absolute neutrophil count = 1,500/mm³*

·         Hemoglobin = 9.0 g/dL*

·         Platelet count = 100,000/mm³*

·         ECOG performance status 0-2

·         Not pregnant or nursing

·         Negative pregnancy test

·         Fertile patients must use effective contraception during and for 6 months after completion of study treatment

 

Study Sites and Contact Information

Study sites in the United States are recruiting patients for this trial. For more information, call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) for more information. The toll-free call is confidential.