5-ALA: an aid for identifying the infiltrative margins of malignant glioma By Professor Walter Stummer, MD, PhD, Chairman of Neurosurgery, Münster University Hospital, Münster, Germany
PROF Stummer is a world leader in the introduction and implementation of advanced fluorescence-based diagnostic methods in the operation microscope and microneurosurgery, and a key scientific developer of 5-ALA. Here, he writes about some of the challenges facing neurosurgeons in identifying the margins of infiltrative brain tumours. IN malignant glioma therapy surgery plays a major role. The last decades have demonstrated that the role of the surgeon is not simply to debulk the tumor and to establish histological diagnosis. It is well accepted that the greatest achievable degree of resection will benefit the patient and will set the stage for additional therapies to be as effective as possible, provided resections are safe. The surgeon is thereby faced with a challenge, to identify unclear margins of the tumor infiltrating the brain and, at the same time, to identify brain regions crucial for function, which are not simply evident from anatomy or tissue texture alone. Regarding safety, a number of methods have come into widespread use for locating brain function, some based on pre-operative imaging, such as functional MRI, MRI tractography or transcranial magnetic stimulation, mostly used in conjunction with neuronavigation. Even more importantly, intra-operative neurophysiological techniques, including brain mapping during awake craniotomies have now been adopted by many centers. Regarding tumor identification, neuronavigation also plays an important role. Due to the shift of brain tissue during resection however, identification of tumor or function using neuronavigation alone 42
Brain Tumour
becomes uncertain during the later stages of surgery, when it is most needed. Aids to this problem are available, such as the intra-operative MRI. However, the intra-operative MRI is expensive and only accessible to selected centers and certainly not to every patient. Fluorescence-guided resections using 5-ALA (5-aminolevulinic acid) are a far more simple method for identifying malignant glioma tissue intra-operatively. The method requires standard surgical microscopes adopted for fluorescence which are offered by the major microscope manufacturers, and 5-ALA, a pharmaceutical compound which is dissolved in water and administered orally to the patient several hours prior to surgery. 5-ALA is taken up by malignant brain tumor cells where it is converted into a fluorescent dye (protoporphyrin IX). Using a special light this fluorescence can be made visible to the surgeon and thus will reveal malignant cells invading the brain. In Europe and other countries around the world, including Japan, Australia, Korea, Taiwan and Hong Kong, 5-ALA is officially approved and available to surgeons and patients. In other countries, including the United States, regulatory approval has not been granted so far with the Food and Drug Administration (FDA) not willing to follow EMA’s 2007 ruling for the approval of 5-ALA, EMA (European Medicines Agency) being the responsible health authority corresponding to the FDA in Europe. The FDA requires more complex, randomized trials in the USA, the costs of which are prohibitive to any company willing to follow this path. From the point of view of the neurosurgeon the position of the FDA is difficult to understand for not
approving this simple (diagnostic) imaging compound, which has proven safe and helpful for tens of thousands of malignant glioma patients outside the USA and other countries so far. Non-withstanding, several USA centers are actively involved in protocols for further exploring the value of 5-ALA in malignant brain tumor surgery in the scientific setting. Due to the well accepted usefulness of tumor fluorescence induced by 5-ALA, the term “fluorescence” has become tantamount to a useful tool for brain tumor surgery. This has prompted research into other paths for making tumors fluoresce, most of which are at a preclinical stage. Ongoing research is required and necessary of course, because methods might always be improved upon. Admittedly, 5-ALA is not the final solution to the problems the neurosurgeon is faced with when operating on patients with malignant gliomas. It is only a small part of the therapeutic armamentarium against this devastating disease, not only from the surgical point of view. Yet, for the moment it is certainly meaningful to be used during surgery in conjunction with many of the other tools neurosurgeons now have, and should be made available to as many brain tumor patients as possible in the setting of structured neurooncological care. n
Professor Walter Stummer is a key scientific developer of 5-ALA (Gliolan®) and has received consultant fees from Medac and Photonamic, its distributors.