5-Aminolevulinic Acid Protoporphyrin IX Fluorescence- Guided Surgery for CNS Tumors. First 41 cases in Latin America

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1 13 5-Aminolevulinic Acid Protoporphyrin IX Fluorescence- Guided Surgery for CNS Tumors. First 41 cases in Latin America Cirurgia Guiada por Fluorescência com 5-ALA em Tumores do SNC. Primeiros 41 casos na América Latina Ricardo Ramina 1 Erasmo Barros da Silva Júnior 2 Maurício Coelho Neto 3 Leonardo Gilmone Ruschel 4 Felipe Andrés Constanzo Navarrette 4 ABSTRACT Introduction: In the last two decades the 5-aminolevulinic acid (5-ALA) has been utilized in primary brain lesions and metastases surgery to aid the identification of tumor limits and infiltration. Objectives: In this retrospective study, we demonstrate our experience with the first 41 cases Latin America of surgical resection of central nervous system (CNS) lesions with 5-ALA. Methods: In 41 consecutive patients, we recorded age, sex, histopathological diagnosis, intraoperative 5-ALA fluorescence tumor response, 5-ALA post-resection resection grade through magnetic resonance image (MRI) and other concomitant intra-operative techniques utilized (transoperative imaging, awake surgery, electrophysiological stimulation and monitoring). Results: Twenty seven high-grade gliomas and 4 non-glial lesions were 5-ALA fluorescence positive; 6 low-grade gliomas, 1 high-grade glioma and a hippocampal gliosis were 5-ALA fluorescence negative. In one case of a low-grade glioma, the patient developed a cardiac arrhythmia, probably not related to 5-ALA administration, but the surgery was suspended. Conclusions: 5-ALA fluorescence-guided surgery is a safe and easy technique to be used, increasing tumor total gross resection in glioma cases, proving to be an invaluable neurosurgical tool for intracranial tumor surgery. There was no serious side effect in this series. This dye should be utilized in all cases of high-grade gliomas. Key words: 5-aminolevulinic acid; Glioma; Brain cancer; Metastasis; Extent of resection; Fluorescence-guided resection RESUMO Introdução: Nas últimas duas décadas, o ácido 5-aminolevulínico (5-ALA) vem sendo utilizado em cirurgia de lesões cerebrais primárias e metástases para auxiliar na identificação dos limites do tumor e da infiltração. Objetivos: Com este estudo retrospectivo demonstramos nossa experiência com os primeiros 41 casos de ressecção cirúrgica com 5-ALA de lesões do sistema nervoso central (SNC) na América Latina. Métodos: Em 41 pacientes consecutivos foram registrados dados de idade, sexo, diagnóstico histopatológico, resposta intraoperatória da fluorescência de tumor com 5-ALA, grau de ressecção com 5-ALA através da imagem de ressonância magnética (MRI) pós-ressecção e outras técnicas intraoperatórias concomitantes utilizadas (imagem intraoperatórias, cirurgia acordada, estimulação eletrofisiológica e monitorização). Resultados: Vinte e sete casos de gliomas de alto grau e 4 lesões não-gliais obtiveram fluorescência positiva com 5-ALA; 6 casos de gliomas de baixo grau, 1 caso de glioma de alto grau e 1 gliose hippocampal obtiveram fluorescência negativa com 5-ALA. Em um caso de glioma de baixo grau, o paciente desenvolveu uma arritmia cardíaca, provavelmente não relacionada com administração de 5-ALA, mas a cirurgia foi suspensa. Conclusões: A cirurgia guiada por fluorescência de 5-ALA é uma técnica segura e fácil de ser utilizada, aumentando a ressecção total de tumor em casos de glioma e provando ser uma ferramenta inestimável para a neurocirurgia em cirurgias de tumor intracraniano. Não ocorreu nenhum efeito colateral grave nesta série. Este corante deve ser utilizado em todos os casos de gliomas de alto grau. Palavras-chave: Ácido 5-aminolevulínico; Glioma; Câncer no cérebro; Metástase; Extensão da ressecção; Ressecção guiada por fluorescência 1 MD, PhD, Neurosurgeon, Chairman of Neurosurgery Department, Neurological Institute of Curitiba (INC) 2 MD, MSc, Neurosurgeon, Neurosurgery Department, Neurological Institute of Curitiba (INC) 3 MD, Neurosurgeon, Neurosurgery Department, Neurological Institute of Curitiba (INC) 4 MD, Medical Resident, Neurosurgery Program, Neurological Institute of Curitiba Received Mar 10, Accepted May 16, 2017.

2 14 Introduction 5-ALA is a natural biochemical precursor of haemoglobin that evokes production and accumulation of protoporphyrin IX (PpIX), a fluorescent compound in appropriately filtered light 1. The PpIX stored in malignant brain tumors helps to discriminate neoplastic and normal brain tissues during tumor resection. A xenon light source with a switch between white and violet-blue light coupled to the surgical microscope excites the PpIX and allows the visualization of tumor fluorescence, in red, and normal tissue, non-fluorescent, in blue 2. Since the beginning of 2000 s 5-ALA was widely described as a reliable adjuvant tool for malignant gliomas and metastatic brain tumors removal 3-5. Although routinely used in Europe, Asia and Australia, in the USA the 5-ALA is considered a drug, rather than a dye, and is not yet approved by the US Food and Drug Administration (FDA) for use in humans 6. In Brazil, the salt 5-ALA is approved by ANVISA - the Brazilian Patent Office and National Sanitary Vigilance Agency - under registry number According to the ANVISA it is not considered a drug but a correlate. It has been used in dermatology and urology. The purpose of this article is to evaluate our initial patient population who underwent CNS lesions surgery using 5-ALA to investigate the indications, safety and feasibility of the method, comparing with the neurosurgical literature. Intraoperative care: Image-guidance with neuronavigation was utilized in all intracranial cases to aid optimal craniotomy and subcortical orientation. Electrophysiological stimulation and monitoring or awake surgery was an addition for tumors in eloquent areas. The Zeiss PENTERO 800 was the surgical microscope in all cases. During the corticotomy, switching white to blue excitation light was used to reveal cortical and/or subcortical tumor infiltration and limits (Fig. 1). During the tumor resection, a few zones were identified: a non-fluorescent necrotic tissue (Fig. 2A) a strong red fluorescence solid lesion, corresponding to contrast-enhanced MRI (Fig. 2B); a pink fluorescence infiltrating tumor, visualized only under blue light (Fig. 2C); and a non-fluorescent normal tissue (Fig. 2D). The tumor removal usually was performed from the core to periphery and the decision for a 5-ALA free removal was based according to the risks for post-operative deficits versus the attempting to achieve maximum surgical efficiency. Intraoperative MRI (imri) was also available to aid tumor removal evaluation. Post-operative care: All patients underwent post-operative MRI in the first 24 hours. Total gross (TGR) or partial resections were defined according to the RANO-criteria. Histopathological diagnosis, Ki-67 and IDH1 were performed for tumor classification. Methods Between November 2015 and May 2017, at our institution, 41 consecutive adult patients with diagnosed nervous system tumor underwent 5-ALA fluorescence-guided surgery. This study has Ethics Committee approval and informed consent by the patients. Preoperative care: Every patient underwent imaging evaluation with MRI, spectroscopy and perfusion. Tractography and functional MRI were performed for tumors in eloquent regions. Three hours before surgery, the 5-ALA was administered orally after dissolving it in 50 ml of drinking water, with a dosage of 20 mg/kg. Patient care (anesthesia induction, positioning, etc.) were all performed as routine. Figure 1. Corticotomy without (left) and with (right) blue light, with subcortical 5-ALA fluorescence in red. Figure 2A. Tumor without (left) and with (right) blue light, with non-fluorescent necrotic tissue in the markers.

3 15 Results A total of 41 patients were included. Mean age was 51.5 years and 12 were female and 29 male. A male patient with history of drug addiction presented cardiac arrhythmia probably not related to 5-ALA administration, the surgery was suspended and performed a week later, after clinical investigation, without additional use of 5-ALA. From 40 surgeries (Table 1), there were 5 cases of awake surgery and 14 cases of electrophysiological monitoring with tumors in eloquent area. Intraoperative 31 cases were 5-ALA positive and 9 were negative. There was one case of intramedullary tumor (melanoma) 5-ALA positive. Figure 2B. MRI showing the contrast enhancement tumor area (upper) and, during surgery, the red fluorescent tumor (5-ALA positive) in the markers (lower). Figure 2C. Tumor and infiltrating borders without (left) and with (right) blue light. From the 31 positive cases, 5-ALA free removal was achieved in 22. In 19 cases, there was residual 5-ALA positive tissue not resected to avoid postoperative neurological deficits. In 23 cases, imri was performed. One case (5-ALA negative) required additional tumor resection based on the image findings. In postoperative MRI, 26 from the 40 cases had a total gross resection. Six from these 26 cases were 5-ALA negative. Histopathological examination revealed 35 glial (24 grade IV and 3 grade III) and 5 non-glial tumors. All eight cases of recurrent tumors (all high-grade gliomas: 7 grade IV and 1 grade III) were 5-ALA positive. The histology of 5 non-glial tumors was: one case of radionecrosis after stereotaxic radiosurgery for a pulmonary adenocarcinoma metastasis (5-ALA positive with 5-ALA free removal); one case of inflammatory disease (5-ALA positive with 5-ALA free removal); one case of hippocampal gliosis (5-ALA negative); one case of intramedullary C5-C6 metastatic melanoma (5-ALA positive with 5-ALA free removal; and one curious case of cysticercosis (5-ALA positive with 5-ALA free removal. Mild cutaneous rash was observed in one patient. Figure 2D. Non-fluorescent tissue without (left) and with (right) blue light.

4 16 Discussion The aim of surgical resection of brain glioma is not only tumor mass removal but maximal resection of invaded brain tissue with functional preservation. The extent of tumor resection is the most important prognostic factor and technologies for better identifying glioma tissue intraoperatively, other than the conventional surgical microscope are needed. Over the past 20 years, 5-ALA fluorescence-guided surgery for malignant intracranial tumor resection has been undergoing full development, especially for high-grade gliomas, demonstrating an increase rate of total gross resection and progression free survival (PFS) 3-5. In 1995, at the neurosurgical department of the grosshadern university in Munich, Germany the first patient with a glioma was submitted to surgical resection with 5-ALA. In 1998, a randomized study including 270 patients was reported 2. In this study, gross-total resection was obtained in 65% of patients using 5-ALA and only 35% in patients without 5-ALA. This dye is the only agent tested in a multi-center randomized controlled trial approved for clinical use in Europe, Asia and Australia 6,8. The highest visible fluorescence was yielded by 20 mg/kg without relevant collateral effects or clinical complications. No fluorescence was elicited at 0.2 mg/kg and doses higher than 20 mg/kg do not elicit increases fluorescence 9. 5-ALA intensity fluorescence is a strong predictor for degree of tumor cellularity. Tumor infiltrated tissue may not illuminate, and, conversely, areas without tumor cells may exhibit ALA fluorescence, due to reactive changes as inflammation 10. In the present article, there were three cases of inflammatory/ infectious disease, all of them 5-ALA positive. surgeon that weak fluorescence (pink zones) represents tissue with infiltrating tumor. It is correlated with residual tumor on imri, giving useful intraoperative information 13. In nonenhancing low-grade gliomas, 5-ALA fluorescence may be observed in approximately 20% of cases, especially in tumors with a volume exceeding 10.6 cm (about 2.8 cm of diameter), and the estimated fluorescence of 46% 14. imri and 5-ALA is very useful in these cases. In our experience with 8 low-grade gliomas, 2 cases (25%) were 5-ALA positive. In the 24 cases of grade IV glioblastoma (GBM), only one case was 5-ALA negative and the TGR was achieved with imri confirmation. In 7 cases, a subtotal/partial resection was carried out due to infiltration of eloquent areas. In the 17 cases of GBM with TGR, 2 cases of 5-ALA residual weak fluorescence (pink) were found with imri demonstrating complete tumor removal, as confirmed in post-operative MRI. Possibly its occurrence was due to reactive local changes or low tumor cellularity in these infiltrated borders. Serial biopsies in these zones were also performed, and negative for malignancy. In our 3 cases of grade III tumors, all were 5-ALA positive. Comparing with imri alone, 5-ALA was less sensitive, more specific and a faster intraoperative tool, and possibly decreasing surgical time. Both techniques were used in 23 cases of our series, increasing safety of 5-ALA-guided resection close to eloquent areas and improving GTR. We previously reported a series of imri aiming better tumor removal 15, and the benefits of the combination of these tools (5-ALA, imri, neuronavigation) seems essential for overall survival and PFS improvement Transient neurological deficits seem justified by long-term benefits for the patients when applying these adjuvant techniques, especially 5-ALA 19. The diagnostic accuracy of 5-ALA in high grade gliomas appears to be >80%, with high sensitivity and positive predictive value and low specificity and negative predictive value 11. Also, the recurrent status of tumors, despite adjuvant treatment (radiation, chemotherapy) does not seem to interfere in fluorescence. Histopathological features of high grade gliomas such as Ki 67 index and vascular proliferations are significantly correlated with 5-ALA fluorescence. However, in brain metastasis about 27% of lesions are 5-ALA negative 12. The 5-ALA usefulness in the extent of resection also warns the

5 17 Table 1. List of 40 surgeries with 5-ALA with age, sex, diagnosis/tumor grade, awake surgery (Y: yes/n: no), electrophysiological monitoring/stimulation (EFMS), 5-ALA fluorescence, imri and grade of resection.

6 18 Conclusions 5-ALA fluorescence-guided surgery is a reliable and safe adjuvant tool for malignant intracranial surgery, increasing GTR rates. In glioma surgery, especially in high-grade and even large low-grade tumors, 5-ALA should be associated with other modern adjuvant tools (neuronavigation, imri) improving results and benefits for the patient. Long-term follow-up of patients undergoing 5-ALA free-resection is needed to evaluate prognosis of this group of patients. According to our experience and a large number of articles reported in the literature the use of 5-ALA is recommended for all patients with high-grade gliomas and brain metastases. References 1. Stummer W, Stepp H, Möller G, Ehrhardt A, Leonhard M, Reulen HJ. Technical principles for protoporphyrin-ix-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir (Wien). 1998;140(10): Stummer W, Stocker S, Wagner S, Stepp H, Fritsch C, Goetz C, et al. Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery. 1998;42(3):518-25; discussion Ewelt C, Nemes A, Senner V, Wölfer J, Brokinkel B, Stummer W et al. Fluorescence in neurosurgery: Its diagnostic and therapeutic use. Review of the literature. J Photochem Photobiol B. 2015;148: doi: /j.jphotobiol Ferraro N, Barbarite E, Albert TR, Berchmans E, Shah A, Bregy A. et al. The role of 5-aminolevulinic acid in brain tumor surgery: a systematic review. Neurosurg Rev. 2016;39(4): doi: /s Senders J, Muskens I, Schnoor R, Karhade A, Cote D, Smith TR, et al. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017;159(1): doi: /s Halani SH, Adamson D. Clinical utility of 5-aminolevulinic acid HCl to better visualize and more completely remove gliomas. Onco Targets Ther. 2016;9: doi: /OTT. S Brasil. Suplemento Anvisa Nº Retificação de Publicação em Produtos para Saúde ANVISA. Diario Oficial da União 10 jun 2014; (109 Suppl) Seção 1:16. Disponível em 8. Senders JT, Muskens IS, Schnoor R, Karhade A, Cote D, Smith TR, et al. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017;159(1): doi: /s Stummer W, Stepp H, Wiestler O, Pichlmeier U. Randomized, Prospective Double-Blinded Study Comparing 3 Different Doses of 5-Aminolevulinic Acid for Fluorescence-Guided Resections of Malignant Gliomas. Neurosurgery Apr 1. doi: /neuros/nyx074. [Epub ahead of print]. 10. Lau D, Hervey-Jumper SL, Chang S, Molinaro AM, McDermott MW, Phillips JJ, et al. A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas. J Neurosurg. 2016;124(5): doi: / JNS Mansouri A, Mansouri S, Hachem LD, Klironomos G, Vogelbaum MA, Bernstein M, et al. The role of 5-aminolevulinic acid in enhancing surgery for high-grade glioma, its current boundaries, and future perspectives: A systematic review. Cancer. 2016;122(16): doi: /cncr Hickmann AK, Nadji-Ohl M, Hopf NJ. Feasibility of fluorescence-guided resection of recurrent gliomas using five-aminolevulinic acid: retrospective analysis of surgical and neurological outcome in 58 patients. J Neurooncol. 2015;122(1): doi: /s Stummer W, Tonn JC, Goetz C, Ullrich W, Stepp H, Bink A et al. 5-Aminolevulinic Acid-derived Tumor Fluorescence. Neurosurgery. 2014;74(3): doi: / NEU Jaber M, Wölfer J, Ewelt C, Holling M, Hasselblatt M, Niederstadt T et al. The Value of 5-Aminolevulinic Acid in Lowgrade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features. Neurosurgery. 2016;78(3): doi: /NEU Ramina R, Coelho Neto M, Giacomelli A, Barros E Jr, Vosgerau R, Nascimento A et al. Optimizing costs of intraoperative magnetic resonance imaging. A series of 29 glioma cases. Acta Neurochir (Wien). 2010;152(1): doi: /s Schatlo B, Fandino J, Smoll NR, Wetzel O, Remonda L, Marbacher S et al. Outcomes after combined use of intraoperative MRI and 5-aminolevulinic acid in high-grade glioma surgery. Neuro Oncol. 2015;17(12): doi: /neuonc/ nov Coburger J, Engelke J, Scheuerle A, Thal D, Hlavac M, Wirtz C et al. Tumor detection with 5-aminolevulinic acid fluorescence and Gd-DTPA enhanced intraoperative MRI at the border of contrast-enhancing lesions: a prospective study based on histopathological assessment. Neurosurg Focus. 2014;36(2):E3. doi: / FOCUS Hauser SB, Kockro RA, Actor B, Sarnthein J, Bernays RL. Combining 5-Aminolevulinic Acid Fluorescence and Intraoperative Magnetic Resonance Imaging in Glioblastoma Surgery. Neurosurgery. 2016;78(4): doi: / NEU Stummer W, Tonn JC, Mehdorn HM, Nestler U, Franz K, Goetz C et al. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis

7 19 from the randomized 5-aminolevulinic acid glioma resection study. Clinical article. J Neurosurg. 2011;114(3): doi: / JNS097. Corresponding Author Ricardo Ramina, MD,PhD Chairman of Neurosurgery Department Neurological Institute of Curitiba 300, Jeremias Maciel Perretto St Curitiba, Brazil ramina@inc-neuro.com.br