In continuing our discussion from the previous blog regarding how the focus of a clinical trial is determined, I’d like to address the treatment and research of two distinctive features of NF that are of significant concern to patients – dermal neurofibromas and plexiform neurofibromas. A frequent question from patients related to neurofibromas is: Why do clinical trials focus on plexiform neurofibromas, while there are no clinical trials in progress for dermal neurofibromas? Many patients feel that dermal neurofibromas are an underappreciated feature of NF.
The basis for focusing on plexiform neurofibromas thus far in clinical trials centers on three issues: first, complications of plexiforms are often more serious than for dermal neurofibromas and can sometimes be life-threatening; second, the several mouse models for testing drug effectiveness in plexiform neurofibromas are better established than the model currently available for dermal neurofibromas; and the technology for measuring dermal neurofibromas is not as advanced as for plexiforms, making it more difficult to determine the effectiveness of a specific drug on tumor growth. The good news is that the UAB NF Program has worked with collaborators recently to establish the validity of a measurement technique for dermal neurofibromas, and this method will enable the development of future clinical trials focused on testing the effectiveness of drugs in slowing or reversing the growth of these types of tumors.
In providing a more thorough explanation about the future of clinical trials for dermal neurofibromas, it’s first helpful to understand the significant differences between dermal and plexiform neurofibromas. Dermal neurofibromas are soft, benign tumors that develop under the skin. These tumors typically appear after puberty and grow slowly over a period of time. While they are variable in size and number, dermal neurofibromas can be disfiguring in some patients, causing embarrassment and problems with self-esteem. In fact, the unpredictability of dermal neurofibromas can be the most daunting aspect of this NF feature; some individuals have few or none, while others’ bodies may be completely covered. Many women with NF1 experience increased growth of neurofibromas during pregnancy, suggesting that hormonal changes may be related to their development.
The treatment approach for dermal neurofibromas is dependent on the number and location of tumors, although the most common approach is to leave them alone due to their benign nature and the low risk of medical problems. The most common treatment is surgical removal of individual tumors using either conventional plastic surgery, laser treatment, or a procedure called electrodessication that uses an electrical current to remove a large number of tumors at one time. While these treatments can be effective, each can leave scarring and none of the options prevents additional tumor development.
Plexiform neurofibromas are congenital tumors that often first appear in infancy or early childhood as a soft swelling under the skin. Affecting about 50% of people with NF1, these tumors are frequently larger and usually involve multiple branches of large nerves. Depending on their location, plexiform neurofibromas can lead to abnormal bone growth or pressure on nerves, blood vessels, or organs. For example, plexiform neurofibromas along the spine can compress the spinal cord, leading to weakness, pain, and sometimes paralysis. Surgical removal can reduce the overall size of the tumor, although it will not stop the tumor from growing.
Because the symptoms of plexiforms can be urgent and potentially life-threatening, this feature has been given greater priority over dermal neurofibromas in clinical trials. Plexiform and dermal neurofibromas are similar at the cellular level, however, so the hope is that some treatments for plexiforms may also be effective for dermal neurofibromas.
Until recently, the challenge in testing the effectiveness of specific drugs for the treatment of dermal neurofibromas has centered on the difficulty of obtaining accurate measurements of these tumors. Unlike plexiforms that grow quickly and can be measured relatively easily with imaging studies, the slower growth rate and configuration of dermal neurofibromas make them difficult to measure accurately.
In collaboration with a research group in Brazil, scientists in the UAB NF Program have tested a measurement method over the past several years that recently has been validated as providing an accurate estimate of dermal neurofibromas (Publication). Using adhesive paper frames with a 10 cm x 10 cm window cut-out, a group of patients’ dermal tumors were documented and measured by attaching the paper frame to a specific region identified by a physical landmark that was photographed; this procedure allowed us to measure growth of dermal neurofibromas over a period of time.
This recently validated measurement technique for dermal neurofibromas has opened the door to conducting clinical trials focused on testing medications to treat this feature that is problematic for so many NF patients. We are now exploring the possibility of conducting a small, independent pilot trial to determine the effectiveness of a treatment for dermal neurofibromas. Also, we have plans to design a secondary arm of a clinical trial for plexiform neurofibromas that would test the effectiveness of the medication on dermal neurofibromas. As a secondary endpoint within this trial, individuals with plexiform neurofibromas would undergo measurements of dermal neurofibromas over a period of time to determine if the medication has had an effect on slowing the growth.
We still do not know when there will be effective treatments for the various aspects of neurofibromatosis. Those with dermal neurofibromas should know that this aspect of the condition is not being ignored, and I am hopeful that clinical trials for dermal tumors will become a reality soon.
Director's Blog
Measurement Technique for Dermal Neurofibromas Validated at UAB Expands Possibilities for Clinical Trials
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- Written by: Bruce Korf
