Previously, intraoperative visualisation was limited by the surgeon’s ability to identify the tumour’s parameters under conventional white-light microscopy. Preoperative MRI scans can be subject to imprecise registration on the patient’s skin surface anatomy, which can potentially result in inaccurate neuro-navigation intraoperatively. Contrast enhancement on MRI is not always sensitive for tumour margins either.
The development of 5-ALA fluorescence-guided surgery (5-ALA FGS) has become an invaluable neurosurgical advancement in high-grade glioma surgery as it addresses the limitations present with the use of preoperative and even intraoperative MRI. 5-ALA produces fluorescence that allows for real-time identification of tumour borders with high precision, therefore ensuring that a ‘more complete’ resection can be undertaken [1].
5-ALA is naturally produced in humans via the haemoglobin metabolic pathway. When ingested orally prior to surgery, exogenous 5-ALA has remarkable penetration of the blood-brain barrier (BBB) and of the tumour interface. The compound accumulates with high sensitivity and specificity within malignant glial cells before metabolising into the fluorescent metabolite protoporphyrin IX (PpIX) intracellularly. The heightened PpIX production within the tumour cells emit violet-red fluorescence when stimulated by 405nm-wavelength blue-light microscopy, permitting intraoperative visualisation.
It has been evidenced that 5-ALA use allows for a closer resection to the tumour margins than when relying on preoperative MRI alone [2], and it produces superior results in terms of gross total resection (GTR) and progression-free survival (PFS) [3] [4]. Additionally, 5-ALA use is correlated with less residual tumour volumes in post-operative measurements, and patients in this cohort require repeat resections less frequently [3].
5-ALA in High Grade Glioma Surgery
High grade gliomas (HGGs) are diffuse and infiltrative tumours with poorly defined borders, and neoplastic cells can lie beyond the visible tumour bulk. 5-ALA is proposed to be a sensitive adjunct at delineating tumour parameters; its fluorescence extends beyond the gadolinium contrast-enhancing areas as mapped out on MRI because PpIX is also able to accumulate within the marginal cells [5].
A systematic review and meta-analysis were conducted to investigate the accuracy, extent of resection (EOR), and survival outcomes of the use of 5-ALA. Regarding the diagnostic accuracy of glioblastoma multiforme (GBM) with 5-ALA, overall sensitivity was reported to be 0.87 (95% CI, 0.81–0.92) with specificity of 0.89 (95% CI, 0.79–0.94). Compared to white-light resection, contrast-enhancing tumours were more likely to be completely resected in the patients assigned to 5-ALA, and this cohort demonstrated greater 6-month PFS and overall survival [6].
5-ALA-guided surgery has become an indispensable adjunct in HGG treatment for neurosurgical centres worldwide. Aside from producing consistently successful results and decreasing overall mortality, it is also relatively easy and inexpensive to use. Currently, 5-ALA is only licensed for adults for FGS of malignant gliomas, and it is generally considered safe with minimal adverse effects [7].
5-ALA in Paediatric Neurosurgery
Much the same as in adults, EOR is an important prognostic factor in paediatric HGG surgery. The Children’s Cancer Group HGG study (CCG-945) reported that the 5-year PFS was double in those who underwent a surgical resection of 90% or more compared with those who had suboptimal resection regardless of tumour histology [8]. Hence, there is great interest in maximising the likelihood of GTR in paediatric neurosurgery, which could potentially be enhanced by extending the use of 5-ALA beyond the adult population.
Though praised for its superiority over conventional white-light resection of adult glioblastomas, the use of 5-ALA in paediatrics is still unlicensed. The safety profile and presence of any adverse effects is ambiguous; no extensive clinical studies have been performed within this subpopulation. The spectrum of paediatric tumour types is more varied than in adults, and not all are appropriate for FGS with 5-ALA (even if they are intra-axial and contrast-enhancing on MRI) [9]. Aside from malignant gliomas, these tumours include primitive neuroectodermal tumours (PNET), ependymomas, pilocytic astrocytomas and medulloblastomas, and the value of fluorescence in these cell lineages is uncertain [10] [11]. With a pathobiology distinct from adult tumours [12] [13], the true benefit of using 5-ALA is still unclear alongside concerns of inconsistent fluorescence [10] [14]. For example, Beez et al. showed positive fluorescence in only 50% of paediatric HGG’s [15], and Labuschagne et al. found 5-ALA fluorescence to be useful in only 37.5% of cases [10].
The first instance of 5-ALA use in paediatrics was described in 2009 in a patient with pleomorphic xanthoastrocytoma (PXA; histologically a low-grade, WHO grade II, tumour). Intraoperative visualisation was deemed advantageous for successful resection in this case, and aside from transient nausea, the patient did not undergo any complications related to surgery or 5-ALA administration [16].
Since then, several reports have documented successful fluorescence using 5-ALA in paediatrics without any adverse effects [17] [18] [19] [20]. In these reports, 5-ALA was found to be effective in achieving a higher rate of GTR in addition to being generally safe to administer to children based on adult dosing guidelines [21].
Malignant gliomas were most likely to fluoresce according to these reports, with patchy and inconsistently non-valuable fluorescence for pilocytic astrocytomas, medulloblastomas, and gangliogliomas [9] [21] [22]. This may perhaps further restrict the application of 5-ALA depending on histology. Further investigations are warranted before integration of treatment protocols for these differing tumour types. Nonetheless, it is notable that EOR was still more favourable with suboptimal fluorescence in general, than in cases without [11].
5-ALA, Hepatotoxicity, and Coagulopathy
Authors have found a positive correlation between 5-ALA use in adult patients and transient post-operative elevations in liver enzymes (PELE) [23] [24] [25] [26]. Though 5-ALA-induced hepatotoxicity appears to be dose-dependent, the effects reported were generally temporary and benign; measurements were below threefold the upper limit of normal [23]. Because post-operative liver dysfunction can have many aetiologies and be multifactorial, 5-ALA induced PELE should be a diagnosis of exclusion especially in adults, where primary liver disease, alcohol or drug use, adiposity, and medications commonly affect liver enzymes. Asymptomatic increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) can also result from prone positioning, intra-operative hypotension and blood loss. Propofol itself inhibits the cytochrome P450 system, and the resulting accumulation of PpIX alongside its decreased elimination from the hepatobiliary system may result in hepatotoxicity manifesting as PELE as well [25].
That said, PELE has also been observed in neurosurgical patients not administered 5-ALA. It seems that the transient change in enzyme measurements is not strictly indicative of 5-ALA safety; the synergistic effects of invasive surgery, anaesthesia, antibiotics and use of anti-epileptic drugs may all have a role to play. Importantly, no sequelae of liver impairment or evidence of liver failure were reported in these adult patients [27].
A handful of cases have also demonstrated PELE in children [10] [15] [28]. It was frequently the only observed complication attributable to 5-ALA ingestion. None of these patients required further treatment of their hepatic abnormality. Interestingly, greater PELE correlated with younger age [14]. Is there a role for age-related pharmacodynamics in the metabolism of 5-ALA [11]?
Another notable side effect associated with 5-ALA ingestion in adults is post-induction hypotension with a 70% incidence reported in a single-centre retrospective study. The precise mechanism is unclear, but authors have shown that there is a greater risk in female patients, in those with low pre-operative baseline blood pressures [29], and in those prescribed with anti-hypertensive medications [23]. A separate systematic review in patients undergoing urogenital surgeries found a 25.5% incidence rate of adverse effects with 5-ALA use, with hypotension accounting for 60% of these [30]. However, all authors have concluded that 5-ALA-associated toxicity was minor, recommending a review of anti-hypertensive and hepatotoxic medications, and to consider perioperative blood pressure monitoring only [23] [26].
A report from one paediatric centre described a fatal complication in one of their patients who underwent 5-ALA-guided resection of a posterior fossa tumour with leptomeningeal disease. She developed a fulminant rash, fever, and leukocytosis of approximately 40,000/ml six days post-operatively. Extensive work-up excluded an infectious cause. Liver enzymes, however, were within normal range. The authors concluded that theirs was an exceptional case in the absence of any plausible explanation [22].
A prospective multi-centre study which examined both the efficacy and safety profile of 5-ALA use in adults established a correlation between 5-ALA and haematological abnormalities. These abnormalities, however, were generally found to be mild and self-resolving. These included primary leucocytosis, anaemia, and thrombocytopenia. None of the patients included in the study had coagulation or bleeding disorders prior to 5-ALA ingestion, and none developed any long-term haematological disorders following resolution of the peri-operative abnormality [26].
Another retrospective single-centre study conducted over five years into 5-ALA use in adult brain surgery reported that significant adverse haematological reactions were uncommon when compared to a control group. Haemoglobin and platelets were measured before, immediately post-operatively, and at 24 hours. No significant differences were demonstrated at any time between the groups. Haemoglobin and platelet counts both remained 20% above baseline at all times. There was no significant difference in transfusion requirements (3.9% in the 5-ALA groupcompared to 3.8% in the control group). Four patients in the 5-ALA group required reintervention within the first 48 hours due to bleeding. However, none of the bleeding complications were associated with thrombocytopenia; all platelet counts were > 150,000/mL. Thus, the authors concluded that side-effects of 5-ALA are rare and that changes in haematological indices are likely to be multifactorial, with the role of 5-ALA unclear or even insignificant [31].