Aminolevulinic acid (ALA)–protoporphyrin IX fluorescence guided tumour resection. Part 1: Clinical, radiological and pathological studies

doi:10.1016/j.jocn.2012.03.009

Journal of Clinical Neuroscience

Volume 19, Issue 11, November 2012, Pages 1471-1474

https://doi.org/10.1016/j.jocn.2012.03.009 Get rights and content

Abstract

The intraoperative identification and resection of glioma is a significant and important challenge in neurosurgery. Complete resection of the enhancing tumour increases the median survival time in glioblastoma compared to partial glioma resection; however, it is achieved in fewer than half of eligible patients when conventional tumour identification methods are used. Increasing the incidence of complete resection, without causing excess morbidity, requires new methods to accurately identify neoplastic tissue intraoperatively, such as use of the drug 5-amino-levulinic acid (ALA). After ALA ingestion, the fluorescent molecule protoporphyrin IX (PpIX) accumulates in high grade glioma, allowing the neurosurgeon to more easily detect and accurately resect tumour. The utility of ALA has been demonstrated in a large, multicentre phase III randomised control trial of 243 patients with high grade glioma. ALA use led to a significant increase in the incidence of complete resection (65% compared to 36%), improved progression-free survival at 6 months (41% compared to 21%), fewer reinterventions, and delayed onset of neurological deterioration. This review provides a broad assessment of ALA–PpIX fluorescence-guided resection, with Part 1 focusing on its clinical efficacy, and correlations with imaging and histology. The theoretical, biochemical and practical aspects of ALA use are reviewed in Part 2.

Section snippets

The clinical problem

The extent of resection of glioma directly and significantly affects patient median survival time independent of age, degree of disability, World Health Organization (WHO) grade, or subsequent treatment modalities.¹ Maximal survival benefit is reported when resection volume is greater than 98%² and a complete resection of all gadolinium enhancing tumour significantly improves the survival effect of adjuvant radiotherapy and chemotherapy.³

Achieving complete resection is challenging using

High grade glioma

An initial pilot study using 5-amino-levulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence to identify and guide the resection of glioblastoma demonstrated a strong correlation between intraoperative fluorescence and histological tumour, and between complete resection of fluorescence and complete resection of contrast enhancement.¹²

This lead to a multi-centre collaborative ALA-Glioma Study Group randomised controlled trial that compared conventional white light microsurgical

High grade glioma

Intraoperative PpIX fluorescence has been well validated in patients with high grade glioma suspected on preoperative imaging, and subsequently diagnosed on histology. It shows a high sensitivity and specificity for areas of confluent tumour cells. Fluorescence is observed in 91% of biopsies that contain high grade glioma on histology (91% sensitivity; Table 1).[12], [16], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28] In these patients, 85% of all the fluorescing tissue contains

Positron emission tomography and MRI

The historical gold standard for assessing surgical resection and treatment response in brain tumours is gadolinium enhanced MRI,⁴⁴ although T2-weighted/fluid-attenuated inversion recovery sequences and positron emission tomography (PET) may be more clinically important for identification of neoplastic tissue, placement of resection margins, determining the volume of residual tumour postoperatively and predicting survival.⁴⁵

There is good evidence that PpIX fluorescence correlates with areas of

Conclusion

ALA–PpIX fluorescence guided resection is a significant evidence-based advancement in the surgical management of glioma. ALA–PpIX allows the neurosurgeon to more accurately distinguish glioma margins intraoperatively, and increases the incidence of complete resection of enhancing tumour. Complete resection results in improved patient survival, greater response to adjuvant therapies, and a decreased number of reoperations.

To safely introduce ALA and fluorescence guided resection into

Conflicts of interest/disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgements

Thank you to Geoff Osborne at the University of Queensland for helpful comments on an earlier draft of the manuscript.

References (46)

M.J. McGirt et al.
Independent association of extent of resection with survival in patients with malignant brain astrocytoma
J Neurosurg
(2009)
M. Lacroix et al.
A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival
J Neurosurg
(2001)
R. Stupp et al.
Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial
Lancet Oncol
(2009)
G.E. Keles et al.
The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere
Surg Neurol
(1999)
C. Nimsky et al.
Volumetric assessment of glioma removal by intraoperative high-field magnetic resonance imaging
Neurosurgery
(2004)
W.B. Pope et al.
MR imaging correlates of survival in patients with high-grade gliomas
AJNR Am J Neuroradiol
(2005)
W. Stummer et al.
Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial
Lancet Oncol
(2006)
J.H. Sherman et al.
Neurosurgery for brain tumors: update on recent technical advances
Curr Neurol Neurosci Rep
(2011)
C. Senft et al.
Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial
Lancet Oncol
(2011)
C. Senft et al.
Influence of iMRI-guidance on the extent of resection and survival of patients with glioblastoma multiforme
Technol Cancer Res Treat
(2010)

H.M. Mehdorn et al.

High-field iMRI in glioblastoma surgery: improvement of resection radicality and survival for the patient?

Acta Neurochir Suppl

(2011)

W. Stummer et al.

Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients

J Neurosurg

(2000)

W. Stummer et al.

Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias

Neurosurgery

(2008)

C.B. Scott et al.

Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90–06

Int J Radiat Oncol Biol Phys

(1998)

U. Pichlmeier et al.

Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients

Neuro Oncol

(2008)

R. Diez Valle et al.

Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience

J Neurooncol

(2011)

W. Stummer et al.

Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article

J Neurosurg

(2011)

S.M. Chang et al.

Perioperative complications and neurological outcomes of first and second craniotomies among patients enrolled in the Glioma Outcome Project

J Neurosurg

(2003)

C. Ewelt et al.

Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence

Clin Neurol Neurosurg

(2011)

M. Hefti et al.

5-aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institutuion

Swiss Med Wkly

(2008)

R. Ishihara et al.

Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas

Neurol Med Chir (Tokyo)

(2007)

D.W. Roberts et al.

Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between delta-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article

J Neurosurg

(2011)

F. Stockhammer et al.

Association of F18-fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas

Acta Neurochir (Wien)

(2009)

Cited by (90)

Levulinic acid: a potent green chemical in sustainable agriculture
2022, New and Future Developments in Microbial Biotechnology and Bioengineering: Sustainable Agriculture: Revisiting Green Chemicals
The accelerated demand, rising cost, chaotic geopolitical situation, and detrimental environmental impact of fossil fuels have necessitated the introduction of renewable alternative candidates and some sustainable solutions for the betterment of the future of mankind. Levulinic acid (LA) has been identified as one of the platform chemicals that could be produced from starch waste and lignocellulosic biomass via cost-effective chemical conversion which may play a key role in the protection of ecological, economical, and environmental sustainability. LA and its derivatives have many commercial applications in the preparation of pharmaceuticals, fuel and food additives, solvents, specialized biopolymers, agricultural products, and many more. At present, its production is solely based on the petrochemical route but research has shown efficient chemo-enzymatic conversion of cellulose and starch-based waste to LA is an environment viable option that could improve waste management procedures in sustainable agriculture systems. A large number of natural products (cellulose, fructose glucose, inulin), left over from cereals (kernel grain, sugarcane bagasse, corn stover, rice, and paddy straw), unused plant parts (sawdust of poplar, shoot shell of bamboo, pruning of olive tree), invasive weeds (water hyacinth) could emphasize the commercially applicable synthesis of this green chemical from renewable sources. However, the commercialization of the green synthesis of LA requires calibrated energy-efficient pretreatment, appropriate source selection, removal of agricultural waste transportation bottlenecks, an innovative technical collaboration of farmer-researchers-industry, and rigorous environmental and economical assessment. In this review, we have summarized the role of LA as a potential green chemical, enlisted its original, present, and probable sources, depicted the role of LA in different industrial sectors, emphasized the agronomical and technical advancements, highlighted the commercial bottlenecks and suggested some futuristic multifaceted research and development areas which may unfold a new chapter in agricultural waste management and green chemical synthesis without altering the key undertakings of sustainable agriculture.
Patterns of multiple human papillomavirus clearance during 5-aminolevulinic acid-based photodynamic therapy in patients with genital warts
2021, Photodiagnosis and Photodynamic Therapy
Citation Excerpt :
The 5-aminolevulinic acid (5-ALA) is topically applied to the genital warts and is highly selectively absorbed by fast proliferation cells. It induces excess accumulation of the photosensitizer protoporphyrin IX [11,12] which is activated by red light and leads to excess production of cytotoxic oxygen radicals, causing cytotoxic or immunomodulatory effects [11,13–15]. Photodynamic therapy is effective for treating genital warts with a low rate of recurrence [16–18].
Multiple human papillomavirus infections are commonly encountered in genital warts. Infection can be eliminated using 5-aminolevulinic acid-based photodynamic therapy. The aim of this study was to identify the preponderant genotypes and patterns of human papillomavirus co-infection clearance during photodynamic therapy in patients with genital warts.
We conducted a retrospective study between January 2020 and February 2021 at two hospitals in Guangzhou, China. Human papillomavirus typing and quantitative detection were performed before starting treatment and after each session of photodynamic therapy.
A total of 97 patients participated in the study. Co-infections with low-risk and high-risk types were common in genital warts. Types 6 was the most common type detected, followed by types 52, 11, 58, 51 and 56. Patients with multiple infections were more likely to have high-risk human papillomavirus infection. The viral load of high-risk human papillomavirus before treatment was significantly lower than that of low-risk human papillomavirus, and decreased faster during therapy. In addition, high-risk types were cleared more readily than low-risk types, and 51.4% of high-risk types were eliminated after three rounds of therapy. A transient increase in viral load, especially low-risk types, was observed after two sessions of therapy.
Low-risk human papillomavirus was preponderant in patients co-infected with low-risk and high-risk types. Photodynamic therapy effectively eliminated multiple human papillomavirus infections. The response to photodynamic therapy was mainly determined by the low-risk types in patients infected with combinations of low-risk and high-risk types.
Predictors of human papillomavirus persistence or clearance after 5-aminolevulinic acid-based photodynamic therapy in patients with genital warts
2021, Photodiagnosis and Photodynamic Therapy
Numerous studies have confirmed that 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) is an effective treatment for human papillomavirus-associated diseases. In this study, we evaluated the variables associated with human papillomavirus (HPV) persistence or clearance after ALA-PDT in patients with genital warts.
We performed a retrospective chart review of all patients with genital warts or subclinical HPV infection who received ALA-PDT treatment between January 2019 and December 2020 at Nanfang Hospital and Dermatology Hospital of Southern Medical University and analyzed the predictors of HPV persistence or clearance. HPV genotype and viral load assays were analyzed before treatment and after each session of photodynamic therapy.
Multiple sexual partners, a history of recurrent HPV infection, and severe pain response during photodynamic therapy were associated with higher odds of viral persistence after three rounds of ALA-PDT. Infection with single strains of HPV, and mucosal and subclinical infection were more likely to be cleared after three rounds of photodynamic therapy.
Our findings suggest that patients with multiple sexual partners, a history of recurrent infections, and severe pain response during photodynamic therapy should undergo close surveillance and monitoring, and may need additional photodynamic therapy sessions. Infection with a single strain of HPV, and mucosal or subclinical infections are more likely to be cleared after three courses of ALA-PDT treatment. These findings may improve the efficiency of ALA-PDT in clinical practice.
Current and new fluorescent probes for fluorescence-guided surgery
2020, Strategies for Curative Fluorescence-Guided Surgery of Cancer
Surgical resection is an important treatment of cancer. Despite advances in preoperative imaging, surgery itself is primarily guided by the surgeon’s ability to locate pathology by direct vision and/or palpation. Fluorescence-guided surgery (FGS) is a promising technique that is increasingly used to aid surgeons in identifying sites of tumor and surgical margins. Intraoperative visualization of tumors may not only allow more complete resections but also improve safety by avoiding unnecessary damage to normal tissue, reducing operative time and decreasing the need for second-look surgeries. A number of new FGS imaging probes have recently been developed, complementing a small but useful number of existing probes. In this review, we describe current clinical and preclinical FGS techniques and new fluorescent probes that may assist FGS.
Optimization of high-grade glioma resection using 5-ALA fluorescence-guided surgery: A literature review and practical recommendations from the neuro-oncology club of the French society of neurosurgery
2019, Neurochirurgie
When feasible, the surgical resection is the standard first step of the management of high-grade gliomas. 5-ALA fluorescence-guided-surgery (5-ALA-FGS) was developed to ease the intra-operative delineation of tumor borders in order to maximize the extent of resection.
A Medline electronic database search was conducted. English language studies from January 1998 until July 2018 were included, following the PRISMA guidelines.
5-ALA can be considered as a specific tool for the detection of tumor remnant but has a weaker sensibility (level 2). 5-ALA-FGS is associated with a significant increase in the rate of gross total resection reaching more than 90% in some series (level 1). Consistently, 5-ALAFGS improves progression-free survival (level 1). However, the gain in overall survival is more debated. The use of 5-ALA-FGS in eloquent areas is feasible but requires simultaneous intraoperative electrophysiologic functional brain monitoring to precisely locate and preserve eloquent areas (level 2). 5-ALA is usable during the first resection of a glioma but also at recurrence (level 2). From a practical standpoint, 5-ALA is orally administered 3 hours before the induction of anesthesia, the recommended dose being 20 mg/kg. Intra-operatively, the procedure is performed as usually with a central debulking and a peripheral dissection during which the surgeon switches from white to blue light. Provided that some precautions are observed, the technique does not expose the patient to particular complications.
Although 5-ALA-FGS contributes to improve gliomas management, there are still some limitations. Future methods will be developed to improve the sensibility of 5-ALA-FGS.
Machine learning assisted intraoperative assessment of brain tumor margins using HRMAS NMR spectroscopy
2020, PLoS Computational Biology
Complete resection of the tumor is important for survival in glioma patients. Even if the gross total resection was achieved, left-over micro-scale tissue in the excision cavity risks recurrence. High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS NMR) technique can distinguish healthy and malign tissue efficiently using peak intensities of biomarker metabolites. The method is fast, sensitive and can work with small and unprocessed samples, which makes it a good fit for real-time analysis during surgery. However, only a targeted analysis for the existence of known tumor biomarkers can be made and this requires a technician with chemistry background, and a pathologist with knowledge on tumor metabolism to be present during surgery. Here, we show that we can accurately perform this analysis in real-time and can analyze the full spectrum in an untargeted fashion using machine learning. We work on a new and large HRMAS NMR dataset of glioma and control samples (n = 565), which are also labeled with a quantitative pathology analysis. Our results show that a random forest based approach can distinguish samples with tumor cells and controls accurately and effectively with a median AUC of 85.6% and AUPR of 93.4%. We also show that we can further distinguish benign and malignant samples with a median AUC of 87.1% and AUPR of 96.1%. We analyze the feature (peak) importance for classification to interpret the results of the classifier. We validate that known malignancy biomarkers such as creatine and 2-hydroxyglutarate play an important role in distinguishing tumor and normal cells and suggest new biomarker regions. The code is released at http://github.com/ciceklab/HRMAS_NC.

View all citing articles on Scopus

View full text

ReviewAminolevulinic acid (ALA)–protoporphyrin IX fluorescence guided tumour resection. Part 1: Clinical, radiological and pathological studies

Abstract

Section snippets

The clinical problem

High grade glioma

High grade glioma

Positron emission tomography and MRI

Conclusion

Conflicts of interest/disclosures

Acknowledgements

Independent association of extent of resection with survival in patients with malignant brain astrocytoma

J Neurosurg

A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival

J Neurosurg

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

Lancet Oncol

The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere

Surg Neurol

Volumetric assessment of glioma removal by intraoperative high-field magnetic resonance imaging

Neurosurgery

MR imaging correlates of survival in patients with high-grade gliomas

AJNR Am J Neuroradiol

Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial

Lancet Oncol

Neurosurgery for brain tumors: update on recent technical advances

Curr Neurol Neurosci Rep

Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial

Lancet Oncol

Influence of iMRI-guidance on the extent of resection and survival of patients with glioblastoma multiforme

Technol Cancer Res Treat

High-field iMRI in glioblastoma surgery: improvement of resection radicality and survival for the patient?

Acta Neurochir Suppl

Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients

J Neurosurg

Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias

Neurosurgery

Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90–06

Int J Radiat Oncol Biol Phys

Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients

Neuro Oncol

Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience

J Neurooncol

Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article

J Neurosurg

Perioperative complications and neurological outcomes of first and second craniotomies among patients enrolled in the Glioma Outcome Project

J Neurosurg

Finding the anaplastic focus in diffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET, and intraoperative, ALA-derived tissue fluorescence

Clin Neurol Neurosurg

5-aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institutuion

Swiss Med Wkly

Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas

Neurol Med Chir (Tokyo)

Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between delta-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article

J Neurosurg

Association of F18-fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas

Acta Neurochir (Wien)

Review
Aminolevulinic acid (ALA)–protoporphyrin IX fluorescence guided tumour resection. Part 1: Clinical, radiological and pathological studies