5-Aminolevulinic Acid-Guided Glioma Resection During Awake Craniotomy: Systematic Review of Functional Safety and Oncologic Benefit

The human brain is a landscape of delicate, interconnected networks that govern everything from speech to movement. When a tumor grows within these vital zones, surgeons face a profound dilemma: how much of the dangerous tissue can be removed without destroying the person's ability to function? For decades, the gold standard for navigating this tightrope has been the awake craniotomy. In this procedure, the patient is kept conscious during the operation, allowing surgeons to test language and motor skills in real time. By stimulating tiny areas of the brain and asking the patient to speak or move, the surgical team maps out the "no-go" zones, ensuring that the tumor is stripped away only up to the very edge of what is safe.

Parallel to this, another tool has emerged to help surgeons see the invisible. A substance called 5-aminolevulinic acid, or 5-ALA, is given to the patient before surgery. The tumor cells absorb this substance and, when viewed under a special blue light, glow with a distinct pinkish-red color. This fluorescence acts like a beacon, highlighting the malignant tissue that often looks identical to healthy brain under normal white light. While this glowing guide has been proven effective when patients are asleep under general anesthesia, a new question arose: could it be safely and effectively used while the patient is awake, working alongside the live mapping tests?

A recent systematic review by researchers at Queen's University Belfast set out to answer this question by gathering every available study on the subject. They analyzed data from ten different studies involving 108 patients who underwent this combined approach. The researchers looked at whether the glowing substance helped surgeons remove more tumor, whether it caused any new harm to the patient's brain function, and how the surgeons decided when to stop cutting. The findings suggest that the two methods work well together, offering a powerful way to see the tumor while strictly respecting the brain's functional limits.

The review found that the glowing substance was highly effective at identifying the most aggressive tumors. In cases of high-grade gliomas, which are the most malignant and fast-growing types, the tumor glowed in roughly three out of every four patients. However, for lower-grade, slower-growing tumors, the substance was much less reliable, lighting up in only about one out of every six cases. This distinction is crucial because it tells surgeons exactly when this tool will be most useful. When the tumor did glow, it provided a clear visual map of the cancerous tissue, often revealing residual disease that would have been missed under normal light.

Perhaps the most significant finding was how the surgeons used this information. The glowing tumor did not override the patient's safety. In many instances, the blue light showed that tumor tissue remained, but the awake mapping tests indicated that removing it would cause permanent damage to speech or movement. In these moments, the surgeons consistently chose to stop the operation, preserving the patient's function even though the tumor still glowed. This confirmed that the live mapping tests remain the ultimate authority on where the surgery must end. The glowing substance did not force a dangerous removal; instead, it gave the surgeon the confidence to remove as much as safely possible up to that functional boundary.

The safety profile of combining these techniques was reassuring. Across all 108 patients, the rate of permanent neurological damage, such as lasting speech loss or weakness, remained within the expected range for this type of difficult surgery. Temporary speech difficulties occurred in about a quarter of patients, which is common in awake brain surgery and often improves over time. Notably, no patient needed to be put fully to sleep during the procedure because of the use of the glowing substance, and the workflow of the awake surgery was not disrupted. The data suggests that the glowing guide adds a layer of visual clarity without introducing new risks.

The extent of tumor removal was also promising. Overall, surgeons achieved a complete removal of the visible tumor in more than half of the patients, with the rate rising to two-thirds in the largest group studied. The researchers noted that when the surgical cavity was free of any glowing tissue, it was strongly associated with a complete removal. This indicates that the substance helps surgeons identify and clear out the remaining cancer cells that are otherwise hidden, pushing the boundaries of resection right up to the point where the brain's function must be protected.

While the results are encouraging, the researchers are careful to note the limitations of the current data. The studies reviewed were mostly small case reports or retrospective reviews, meaning they looked back at past surgeries rather than testing the method in a controlled, forward-looking trial. There was also variation in how different hospitals measured the success of the surgery and how long they followed the patients. Because of this, the review cannot yet prove that the glowing substance leads to longer survival times or better long-term outcomes compared to mapping alone. The evidence is strong enough to show that the method is feasible and safe, but more rigorous studies are needed to quantify exactly how much extra benefit it provides.

The review concludes that using 5-aminolevulinic acid during awake brain surgery is a practical and valuable addition to the surgeon's toolkit. It does not replace the critical role of testing the patient's brain function in real time, but it complements it by making the tumor visible. This combination allows surgeons to pursue the most aggressive removal possible while maintaining a strict commitment to preserving the patient's quality of life. As the field moves forward, the hope is that larger, standardized studies will refine who benefits most from this approach, potentially turning a promising technique into a standard of care for treating complex brain tumors in vital areas.