5ALA
General
- Gliolan is brand name for 5 Aminolevulinic Acid Hydrochloride
- Ewelt et al., 2011: may also help with intraoperative identification of the anaplastic hotspot(s) demonstrated on preoperative PET
Mechanism
- Prodrug that is metabolised intracellularly to form the fluorescent molecule Protoporphyrin IX (PPIX).
- As the production of PpIX occurs in situ in mitochondria, fluorescence is limited to cells.
- Exogenous administration of 5 ALA leads to a highly selective accumulation of PPIX in
- Tumour cells
- In tumours there is a deficiency of the ferrochelatase enzyme that leads to the accumulation of the fluorophore protoporphyrin IX that fluoresces under blue light.
- Epithelial tissues.
- 5- ALA is taken up and is converted in the normal haem biosynthesis pathway.
- Following excitation with blue light (400 nm) from a microscope, the PPIX (640-710 nm), which has predominantly accumulated in the malignant tissue, emits a red- violet lights, which gives rise to the pink colour seen in tumour tissue.
Excitation | Emission | |
5ALA | 400 | 640-710 |
Fluorescein | 494 | 521 |
ICG | 778 | 700-850 |
Caution
- Photosensitivity: avoid sunlight exposure 48hrs post op
- Increased risk in patients with sensitive skin due to dermatological condition
- Failure of Fluorescence
- Optimal 4hrs after administration
- Blood will obscure the blue-light exciting the tumour cells with accumulated PPIX
- Brain tissue overhang is also an issue in deep seated tumours
- Surgicel and Patties will also block absorption of light
- Learning curve
- Photobleaching
- The fluorescence emitted diminishes continuously but to photochemical decomposition of PPIX (light duration, intensity of light - a closer microscope will speed up photobleaching)
- Under blue light 36% in 25 minutes
- Under white light 36% in 87 minutes
- ❌ Phototoxicity
- Is limited with 5-ALA, since fluorescent microscopes do not produce sufficient energy for significant ROS production.
- Increased risk of Neurological deficit
- Blue light prevents normal tissue visualisation of surrounding tissue sulci/blood vessels can be inadvertently damaged.
- Avoid "radical resection" in tumours that have caused irreversible eloquent neurological deficit with ALA In eloquent regions use awake craniotomy to maximise surgical resection rather than 5 ALA
- Overloading this pathway with exogenous 5-ALA causes the collection of PpIX to fluorescently detectable levels in cells.
Side effects
- Photosensitivity
- N/V
- Liver dysfunction
Anecdotal advice
- Do not use for partial debulk of tumours that extend deep into brain
- Do not use with awake craniotomy
Indications
- High Grade Glioma — Grade 3 and 4
- LGG Transforming Glioma
- Biopsy for instant diagnosis?
- Fluorescence seen in abscesses, metastases (epithelial tissues), inflammatory tissue
- Peritumoral white matter where there is reactive gliosis may also fluorescence
Dosage
- The recommended dose is 20 mg 5-ALA HCl per kilogram body weight.
- The total number of bottles needed to achieve the intended dose for the individual patient can be determined according to the equation below (rounded up to the nearest whole bottle):
- The administration volume needed to achieve the intended dose for the individual patient can be calculated according to the equation below:
- Renal or hepatic impairment
- No trials have been performed in patients with clinically relevant hepatic or renal impairment. Therefore, this medicinal product should be used with caution in such patients.
- Elderly
- There are no special instructions for use in elderly patients with regular organ function.
- Paediatric population
- The safety and efficacy of Gliolan in children and adolescents aged 0 to 18 years have not yet been established. No data are available.
- The solution should be administered orally three hours (range 2-4 hours) before anaesthesia. Use of 5-ALA under conditions other than the ones used in the clinical trials entail an undetermined risk.
- Peak six hours after administration and remain elevated for 12 hours
- If the surgery is postponed by more than 12 hours, surgery should be re-scheduled for the next day or later. Another dose of this medicine can be taken 2 - 4 hours before anaesthesia.
- Precautions to be taken before handling or administering the medicinal product
Outcome
- 5- ALA enables more complete resections of contrast enhancing tumour → improved progression- free survival in patients with malignant glioma.
- Stummer et al 2006 RCT phase 3 n=322
- Showed a 29% increase in complete resections rates in the 5-ALA group as opposed to the white light group.
- Overall survival
- 13·5 months (White light) vs 15·2 months (5ALA); hazard ratio 0·82: Difference of 1.7 months
- The 5- ALA group also had a higher 6- month progression- free survival than the white light group (41% vs. 21.1%)
- 5ALA increase deficit
- Aldave 2013
Features | Non-residual fluorescence | Residual fluorescence |
Median overall survival | 27.0 months | 17.5 months |
Neurological deficit | 18.5% | 8% |
Fluorescein sodium
- Mechanism
- Has an excitation maximum of 494 nm and an emission maximum of 521 nm.
- Readily crosses capillaries, provides fluorescent contrast in the extracellular matrix
- The amount of fluorescein delivered to a tumour site is increased by the breakdown of the BBB.
- Excretion
- A urine clearance of 24-36 h after intravenous injection.
- Indication
- Cerebral angiography to
- Detect arteriovenous malformations,
- Assess superficial temporal artery-MCA anastomoses patency
- Aid in treating cerebral aneurysms.
- Fluorescein is not a tumor-specific agent, but it is excellent for visualizing regions of compromised neurovasculature.
- The presumption in its use for neuro-oncology is that these areas correspond to the enhancing regions, which also correspond to bulk tumor.
- Rates of 100% GTR have been achieved for non-eloquent tumors using microscope was developed equipped with dichroic mirrors specific for fluorescein-guided resection of malignant gliomas.
- Fluorescein-guided laser scanning confocal microscopy in humans had been able to provide assessment of tumor grade, tumor histology, and tumor margins for a variety of tumor subtypes.
- Fluorescein is FDA approved and is widely used in the field of ophthalmology as well as in GI studies.
- Side effects
- Most fluorescein clinical studies in neurosurgery report no serious adverse effects with use of the fluorophore.
- Cons
- Reduce background light
- Need to wait for the fluorescent to work
ICG
Is a near-infrared fluorescent agent with
- Maximal excitation at 778 nm
- Emission spectra range of 700-850 nm
ICG characterisitic
- ICG has a greater tissue penetrance than visible-wavelength fluorophores, such as 5-ALA and fluorescein.
- In contrast to visible wavelength fluorophores, ICG provides visualization of deeper tissue structures due to its infrared excitation and emission spectra.
- However, depth of imaging still remains limited to a few hundred microns deep to the imaging surface.
- Anionic
- Amphiphilic
- Water-soluble and fat soluble
- Can be given IV
- Cleared through renal and bile excretion.
- Tricarbocyanine probe
- Allows it to have a high affinity for proteins, such as albumin, and allows visualization of solid tumors, but may also cause higher levels of nonspecific binding.
- ICG concentration within a tumor site is enhanced by breakdown of the BBB.
- ICG provides nonspecific contrast in areas of permeable neurovasculature.
- Similar to fluorescein,
- With constant imaging, demonstrating limited photobleaching and clearance.
Uses
- IV
- Blood vessel angiography
- Tumour contrast
- ICG was able to contrast the fluorescent glioma tumor tissue within 1 mm of the histological tumor margins in an animal model.
- However, this technique is not effective in distinguishing between malignant cells and other areas of the brain that may incidentally uptake the injected dye.
- The delivery of the dye to the site of the tumor relies on
- Binding to serum proteins
- Damaged vasculature of the tumor.
- However, with time the dye will diffuse into surrounding tissue.
- Intravenously administered ICG is immediately localized to a tumor site,
- Fluorescent signal remains in the tumor up to 1 h after injection
- Identifying extrahepatic bile ducts
- Detecting liver metastases.
- Subcutaneously
- Sentinel lymph node mapping for breast, anal, and GI cancer
- Assessing lymphatic drainage for lymphedema.
Side effects
- ICG is considered to have fewer risks than other FDA approved intravenous fluorophores
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