5-Aminolevulinic Acid Utility in Pediatric Brain Tumors, Other Adult Brain Tumors, and Photodynamic Therapy

9 5-Aminolevulinic Acid Utility in Pediatric Brain Tumors, Other Adult Brain Tumors, and Photodynamic Therapy


Nikita Lakomkin, Isabelle M. Germano, and Constantinos G. Hadjipanayis


Abstract
The use of 5-aminolevulinic acid (5-ALA) as an agent for fluorescence-guided surgery (FGS) of high-grade gliomas (HGGs) has been associated with significantly improved extent of tumor resection and prolonged progression-free survival relative to conventional microsurgery. These findings have led to its approval by the European Medicines Agency and, more recently, the Food and Drug Administration (FDA). This compound is currently indicated for adult patients undergoing surgical intervention for suspected HGGs. However, various studies in the literature have proposed that other brain tumor etiologies may be amenable to 5-ALA-guided resection. Based on promising results in both laboratory studies and early clinical reports, 5-ALA may facilitate improved differentiation of neoplastic tissue during the resection of pediatric brain tumors. Additionally, the accumulation of fluorescence has been observed in a variety of other adult tumor types, including primary central nervous system lymphoma, hemangioblastomas, subependymomas, and germ cell tumors. 5-ALA-mediated tumor fluorescence has also been utilized in quantitative diagnostic techniques, such as through its incorporation of spectrometry, which may augment the ability to detect tumors that exhibit reduced fluorescence accumulation. Although the primary role of 5-ALA in the management of gliomas is the identification of neoplastic tissue, this compound can also be induced to directly and selectively destroy tumors via photodynamic therapy. Studies have begun to evaluate the feasibility, effectiveness, and safety of this treatment modality. In this chapter, the evidence regarding these emerging applications of 5-ALA will be discussed, as well as potential areas that merit further investigation.


Keywords: 5-ALA, lymphoma, hemangioblastoma, germ cell tumor, subependymomas, pituitary tumor, schwannoma, pediatric brain tumor, ependymoma, photodynamic therapy


9.1 Introduction


The utility of 5-aminolevulinic acid (5-ALA) in facilitating the intraoperative visualization of tumor tissue during the resection of high-grade gliomas (HGGs) is well established.1,2,3,4,5,6 Intraoperative use of 5-ALA has been significantly associated with improved extent of tumor resection and prolonged progression-free survival for these patients.7 This led to 5-ALA approval by the European Medicines Agency in 2007. In June 2017, 5-ALA was approved by the Food and Drug Administration (FDA) for the resection of suspected HGGs as an imaging agent to facilitate the real-time detection and visualization of malignant tissue during glioma surgery (www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/MedicalImagingDrugsAdvisoryCommittee/UCM557136.pdf). Although its approval is limited to adult patients with suspected HGGs, recent studies have identified additional promising applications for 5-ALA. 5-ALA has been successfully employed in the resection of pediatric brain tumors, with very few reported adverse events.8,9,10,11 In addition, substantial 5-ALA-induced tumor fluorescence has been observed in other adult tumor types besides HGGs, such as primary central nervous system (CNS) lymphomas, and was deemed to be a useful surgical adjunct for these patients.12,13,14,15 5-ALA has been used during surgery for hemangioblastoma, subependymoma, pituitary, and germ cell tumors in addition to meningioma, ependymoma, and brain metastatic tumors, which are discussed in other chapters. Treatment modalities employing 5-ALA for applications beyond tumor visualization have been proposed as well. Under specific conditions, this agent has been demonstrated to have direct cytotoxic effects on neoplasms, and in some cases result in improved survival.16,17,18 This technique, known as photodynamic therapy (PDT), utilizes specific wavelengths of light to induce targeted damage of tumor tissue via mechanisms involving oxygen radical-mediated toxicity.19,20,21 While these applications currently represent off-label uses for 5-ALA, preliminary findings may have important implications for the management of complex cranial tumor etiologies. In this chapter, we will review the following promising new areas to be assessed for the use of 5-ALA as adjuvant to resection of other adult tumors as well as brain tumors in the pediatric population. We will also discuss 5-ALA PDT for brain tumors.


9.2 Pediatric Tumors


Pediatric brain tumors present a number of unique challenges for surgical management. As in adult patients, complete resection is important in reducing the probability of recurrence and improving long-term outcomes.22,23,24,25 Although 5-ALA has been demonstrated to be a valuable tool for the intraoperative tumor visualization in adults, literature describing the use of 5-ALA in pediatric tumors remains sparse. In the absence of large controlled trials, questions remain regarding therapeutic safety and efficacy in this patient population. The successful use of 5-ALA-enhanced visualization in the complete resection of a pediatric tumor was first reported by Ruge and Liu in 2009.10 The authors described a 9-year-old patient presenting with a right temporal lobe pleomorphic xanthoastrocytoma, who underwent 5-ALA fluorescence-guided surgery (FGS). Intraoperative fluorescence was noted to have improved the visualization of the tumor bed and no serious side effects or complications were reported. These observations have since been corroborated by several additional case reports. Bernal García et al26 reported the use of 5-ALA in the resection of a pediatric, left frontal meningeal sarcoma, while Eicker et al27 described complete tumor resection in a 15-year-old patient with medulloblastoma (image Fig. 9.1). The postoperative course was uneventful for both patients. Despite these reports, larger case series have noted distinct variations in the level of fluorescence accumulation and consequent intraoperative utility among the different tumor subtypes.9,28 As in adult patients, HGGs appear to be most likely to fluoresce.



Due to the small numbers of patients included in these series and the substantial heterogeneity between cohorts, Stummer et al performed a survey study in order to compile data regarding the use of 5-ALA during the resection of pediatric brain tumors at centers across Europe.11 Respondents were queried regarding tumor type, level of intraoperative fluorescence, 5-ALA administration practices, patient demographics, complications, and a variety of other relevant perioperative factors. Additionally, the respondents were asked to report the number of cases in which 5-ALA-induced fluorescence aided in the discrimination of high-grade tissue or informed intraoperative decision-making, which the authors used to gauge the “usefulness” of 5-ALA for these patients. Case information was collected for 78 patients, 28 of whom had fluorescence that was considered to be beneficial. Tumor fluorescence was observed most commonly in HGGs and ependymomas, representing 85 and 80% of tumors, respectively. However, 5-ALA appears to have been less effective for patients with gangliogliomas, medulloblastomas, and pilocytic astrocytomas, with evidence of tumor fluorescence to be as low as 15% for the pilocytic astrocytomas. The authors also addressed the relationship between tumor characteristics, such as location and recurrence, and the utility of 5-ALA. Although a greater percentage of patients with supratentorial tumors demonstrated useful fluorescence, this did not achieve statistical significance. The survey results also revealed distinct variations in 5-ALA administration practices between respondents where preoperative ingestion of the 5-ALA solution ranged from 2 to 6 hours. These early findings emphasize the importance of continued investigation to facilitate the development of evidence-based protocols for the use of this agent in pediatric patients.


Studies have also been carried out in vitro to describe the cellular response of pediatric brain tumors to 5-ALA. Schwake et al evaluated the 5-ALA uptake and fluorescence accumulation in the cell cultures of several pediatric tumor types.29 Cultures encompassing gliomas, medulloblastomas, ependymomas, rhabdoid tumors, and primitive neuroectodermal tumor (PNET) were included in their analysis. All cell types had some level of 5-ALA-induced fluorescence, but the strength of emissions appeared to be dependent on tumor type. Glioblastoma (GBM) and ependymoma cell lines displayed strong signals, while the two medulloblastoma lines varied in their level of fluorescence. The other test cell cultures did not demonstrate a robust response. These findings align with previously described observations in clinical cohorts.9,11,28 The timing of maximal fluorescence following exposure to 5-ALA also revealed variability. Although most cells demonstrated peak fluorescence at 3 hours, one medulloblastoma culture displayed the strongest fluorescence signals 6 hours following 5-ALA exposure. While these findings may help optimize preoperative planning for patients with these tumor types, further investigations employing in vivo models are needed.


Although the intraoperative use of 5-ALA does not appear to introduce additional risks for adult patients with gliomas, safety profiles are not as well known in children where its use in resection is more rare.30 To date, pediatric patients have not demonstrated adverse reactions following 5-ALA administration in most published reports.8,9,10,27 However, one series assessing 16 pediatric brain tumor patients reported abnormal liver function tests (LFTs) related to 5-ALA use.28 Among the overall cohort, postoperative alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) were significantly elevated compared to baseline, and were trending toward significance for aspartate aminotransferase (AST). While abnormal LFTs are known to be associated with 5-ALA administration in adults, they represent temporary changes and do not appear to have any detrimental effects on organ health.30,31 Although these laboratory results were outside the normal ranges for several patients in this pediatric series, no liver dysfunction occurred. However, the authors found a significant correlation between decreased preoperative age and higher postoperative values, commenting on the importance of continued observation for this age group in future trials. Further studies are needed to explore potential differences in the metabolism of 5-ALA in pediatric patients as well as the relationship between age and adverse events.


9.3 Other Adult Tumors Types


9.3.1 Central Nervous System Lymphoma


Although the majority of the studies in the neurosurgical literature have examined the utility of 5-ALA in glioma resection, this compound has been employed for other adult brain tumor subtypes with favorable results. For instance, several reports have highlighted the potential utility of 5-ALA-mediated fluorescence during surgical intervention for primary CNS lymphomas (image Fig. 9.2).14,32,33 Primary CNS lymphomas are rare tumors that comprise 4% of CNS tumor diagnoses.34 Since these lesions can be difficult to distinguish from other malignancies via imaging studies, a tissue biopsy is often required to make a definitive diagnosis and inform subsequent therapy.35 The success of 5-ALA guidance in the resection of gliomas has led to several studies assessing this agent in the diagnosis of primary CNS lymphomas. The first published case detailing the intraoperative response of a primary CNS lymphoma to 5-ALA was published in 2014.32 The patient was administered 5-ALA prior to open resection of a brain tumor located in the fourth ventricle. Although preoperative MRI features were suggestive of an HGG, postoperative histopathology demonstrated a large B-cell CNS lymphoma. Clear fluorescence of tumor tissue was visible during the surgery, indicating that further investigation into the role of 5-ALA for this tumor type was merited. To date, the largest case series describing the use of 5-ALA in primary CNS lymphoma was published by Yamamoto et al.36 In this cohort, 41 patients underwent 5-ALA-guided biopsy that resulted in postoperative pathological confirmation of a primary CNS lymphoma. The authors recorded that tumors in 34 of these patients demonstrated positive fluorescence, resulting in a true-positive rate of 82.9% (image Fig. 9.3). Although this rate is lower than the published values for HGGs, which have been reported to exceed 90%, it demonstrates that patients with lymphomas have the potential to benefit from fluorescence-guided visualization.37 The authors of this study suggest that 5-ALA may increase the probability of obtaining a biopsy sample that is viable for pathological diagnosis of suspected lymphomas.




Despite the relatively high rate of 5-ALA-induced fluorescence, few studies have evaluated the role of 5-ALA during the resection of primary CNS lymphomas because resection is not generally recommended for these tumors.38 Following the diagnosis of a primary CNS lymphoma, the standard of care consists of a course of chemotherapy, sometimes in conjunction with radiotherapy.35 Unlike with gliomas, the debulking of primary CNS lymphomas does not appear to be associated with improved survival,35,39,40 and the additional surgical risks introduced during partial or gross total resection are not typically considered justified due to the responsiveness of these lesions to adjuvant treatments such as methotrexate.35,41


9.3.2 Hemangioblastomas, Subependymomas, and Germ Cell Tumors


The benefits of 5-ALA guidance during resection have been reported for several other tumor types, including benign lesions and nonglial tumors. Several cases have been published describing the resection of hemangioblastomas under fluorescence guidance using 5-ALA.42,43 Hemangioblastomas are benign masses that are primarily treated via resection. However, partial resection is associated with increased risk of recurrence, and tools that can potentially improve visualization with a greater consequent likelihood of complete resection may be beneficial in improving long-term outcomes.44 Utsuki et al reported a case of strong 5-ALA-induced fluorescence in a cranial hemangioblastoma, showing that the visualization facilitated more complete resection.43 One visual benefit of 5-ALA was reported by the authors to include visible fluorescence that allowed for identification of tumor in the associated peritumoral cyst. Because these cysts often do not contain tumor, surgeons may opt not to resect this portion of the lesion in order to mitigate the risk of damaging surrounding tissue. The authors proposed that 5-ALA can be employed to intraoperatively determine whether resection of the cyst wall is indicated based on the fluorescence emissions from this structure. Utsuki et al also published a larger case series of hemangioblastomas, in which all nine tumors fluoresced following 5-ALA administration.42 In two cases, the cyst wall also had visible fluorescence, and was subsequently resected. Histopathological analysis revealed the presence of tumor in the cyst walls.


Other tumor types, including two cases of intense 5-ALA-mediated fluorescence accumulation in the resection of fourth ventricle subependymomas have been reported, with no residual lesion on postoperative MRI.12 5-ALA has also been used to facilitate the endoscopic biopsy of germ cell tumors.15 The fluorescence signal was deemed to be useful in differentiating the tumor from the surrounding tissue due to the difficulty of visualizing the mass under normal illumination. These case reports demonstrate that fluorescence can be induced for diverse tumor types, and suggest that 5-ALA may be a valuable intraoperative tool for intervention beyond the resection of gliomas. However, it is difficult to draw definitive conclusions regarding the reliability of this technique. Larger cohorts are needed in order to determine the proportion of each tumor type that accumulates sufficient fluorescence in order to provide valuable intraoperative guidance, as well as to compute the rate of false-positive fluorescence signals. Additional studies are also needed to explore the utility of 5-ALA in providing significantly meaningful advantages regarding the extent of resection and patient outcomes in these surgical populations.


9.3.3 Pituitary and Schwannoma Tumors


Marbacher et al reported a series of 458 tumors that were resected or biopsied using 5-ALA visualization, including 12 pituitary adenomas and 7 schwannomas.37 Of these, no schwannomas and only one adenoma resulted in clear fluorescence. By contrast, 99 of the 103 GBMs and 85 of the 110 meningiomas demonstrated significant fluorescence. These authors concluded that despite the benefits conferred by 5-ALA in HGG tumor visualization, this agent does not appear to be advantageous in the resection of adenomas or schwannomas. However, the presence of fluorescence in these tumors was documented based solely on observations by the surgeon, a known limitation of many 5-ALA studies.20 Subjective evaluation of fluorescence levels can introduce inter-rater variability and potentially underrepresent the true rate of positive 5-ALA response for different tumor types.


9.3.4 Objective Determination of Fluorescence


In order to augment the differentiation of neoplasm from the surrounding parenchyma, methods facilitating the direct, quantitative measurement of fluorescence levels have also been proposed, including the addition of spectrometry.45,46,47 Eljamel et al described their experiences incorporating an optical biopsy system during the resection of pituitary adenomas.13 The authors used a probe constructed from a laser and fiberoptic cables that projected light at 440 nm onto the tissue and collected the resulting fluorescence emissions. The probe was connected to a spectrometer, which can be used to generate a fluorescence spectrum. The location and intensity of the peaks were subsequently used to determine the presence of fluorescent tumor tissue based on the known spectroscopic properties of PpIX. In their series of 30 consecutive pituitary adenoma patients, the sensitivity of the optical biopsy system was 95.5% and the specificity was 100%. These results highlight the potential for spectroscopy in facilitating detection of 5-ALA-induced fluorescence. Although it has been previously reported that spectroscopic analysis of fluorescence can result in reduced specificity, no false-positive diagnoses were recorded in this case series.46 These findings are promising, particularly given the low rate of visually identified fluorescence for adenomas as reported by Marbacher et al.37 A similar probe has also been used intraoperatively by Valdés et al during surgery for low grade gliomas.48 However, rather than interpreting the fluorescence spectra, the authors used a mathematical model to estimate the actual concentration of PpIX in the sample. This model was designed to account for other fluorescence signals besides PpIX, as well as adjust for the effects on emissions as they pass through tissue prior to reaching the collection channel of the probe. The authors found that of the 20 tumor specimens without fluorescence apparent to the surgeon, 9 had detectable levels of PpIX accumulation via their approach. The sensitivity of the measurements employing the spectrometer was 58%, which compared favorably to the 21% sensitivity of direct observation by the surgeon. These studies demonstrate that incorporating quantitative diagnostic techniques has the potential to allow for broader application of 5-ALA-mediated intraoperative guidance in lower grade tumors that often exhibit reduced fluorescence accumulation.


9.4 Photodynamic Therapy


At present, the primary function of 5-ALA in neurosurgery is the intraoperative visualization of tumor tissue during biopsy or resection.2 However, it has been reported that 5-ALA can, under specific conditions, have an antitumor effect directly on tumors by PDT.18,49 The goal of PDT is to target the cancerous lesions with a nontoxic compound, followed by the trigger of its destructive properties to kill the tumor cells without harming the surrounding parenchyma.50,51 A photosensitizer is administered to the patient and subsequently activated using a specific wavelength of light, which stimulates the release of reactive oxygen species (ROS; image Fig. 9.4).19 In the case of 5-ALA-based PDT, 5-ALA is metabolized to PpIX, which is then excited by a 635-nm laser.52,53 This therapy results in the death of tumor cells via several mechanisms.54 First, the ROS can cause damage to vital cell structures, including DNA, mitochondria, and the cell membrane, with subsequent activation of apoptosis-signaling pathways.17,21 In addition, substantial necrosis coupled with damage to blood vessels has also been observed within tumors treated with PDT.19 Some therapies have also been shown to stimulate leukocyte activation and recruitment, which drives the immune response against the neoplasms.55 These techniques have been performed in the treatment of a variety of tumor types, including cervical, bladder, lung, skin, gastrointestinal, and head and neck cancers, using several classes of photosensitizers.55,56 5-ALA has already received FDA approval as a PDT agent, under the brand name Levulan, for topical use during the treatment of actinic keratosis.57 Beyond dermatological applications, 5-ALA PDT has also been considered for use in neuro-oncology due to the highly concentrated PpIX buildup in HGGs relative to normal tissue.52


Feb 12, 2020 | Posted by in NEUROSURGERY | Comments Off on 5-Aminolevulinic Acid Utility in Pediatric Brain Tumors, Other Adult Brain Tumors, and Photodynamic Therapy
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