Sirolimus for non-progressive NF1-associated plexiform neurofibromas: an NF clinical trials consortium phase II study.
BACKGROUND
Patients with Neurofibromatosis Type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. Mammalian Target of Rapamycin (mTOR) acts as a master switch of cellular catabolism and anabolism and controls protein translation, angiogenesis, cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the mTOR pathway activity. Sirolimus is a macrolide antibiotic that inhibits mTOR activity.


METHODS
We conducted a 2-stratum phase II clinical trial. In stratum 2, we sought to determine whether the mTOR inhibitor sirolimus in subjects with NF1 results in objective radiographic responses in inoperable PNs in the absence of documented radiographic progression at trial entry.


RESULTS
No subjects had better than stable disease by the end of six courses. However, the children's self-report responses on health-related quality of life questionnaires indicated a significant improvement in the mean scores of the Emotional and School domains from baseline to 6 months of sirolimus.


CONCLUSIONS
This study efficiently documented that sirolimus does not cause shrinkage of non-progressive PNs, and thus should not be considered as a treatment option for these tumors. This study also supports the inclusion of patient-reported outcome measures in clinical trials to assess areas of benefit that are not addressed by the medical outcomes.
Brian
B
Weiss
Brigitte C
BC
Widemann
Pamela
P
Wolters
Eva
E
Dombi
Alexander A
AA
Vinks
Alan
A
Cantor
Bruce
B
Korf
John
J
Perentesis
David H
DH
Gutmann
Elizabeth
E
Schorry
Roger
R
Packer
Michael J
MJ
Fisher
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea / Q000139:chemically induced; D004644:Emotions; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018318:Neurofibroma, Plexiform / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000523:psychology; D009456:Neurofibromatosis 1 / Q000188:drug therapy* / Q000523:psychology; D010147:Pain Measurement; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D011795:Surveys and Questionnaires; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus