5-Aminolevulinic Acid and Recurrent High-Grade Gliomas

4 5-Aminolevulinic Acid and Recurrent High-Grade Gliomas

Ramin A. Morshed, Darryl Lau, Seunggu Jude Han, Barbara Kiesel, and Mitchel S. Berger

Abstract
Greater extent of resection has an impact on clinical outcomes in the setting of recurrent malignant gliomas. However, achieving this goal in cases with invasive tumor is difficult even with the use of neuronavigation. Furthermore, in the context of recurrence, there are other unique challenges including identification of tumor versus pseudoprogression on preoperative imaging and the impact of treatment-related tissue changes on intraoperative identification of true tumor tissue. 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery offers an aide to identify tumor tissue intraoperatively and has been associated with greater extent of resection and improved outcomes for patients with newly diagnosed high-grade gliomas. Evidence of this intraoperative technique in the context of recurrent gliomas is less robust but still encouraging. In this chapter, we review the impact that 5-ALA fluorescence-guided surgery has on extent of resection as well as morbidity and mortality. Furthermore, we discuss how fluorescence may be affected in the context of recurrent lesions and the correlation between fluorescence and histological evidence of tumor tissue.

Keywords: 5-ALA, recurrent glioma, correlation of fluorescence and histology, extent of resection

4.1 Introduction

Evidence continues to demonstrate that greater extent of surgical resection affects both progression-free survival (PFS) and overall survival (OS) in the context of high-grade gliomas.1,2,3,4 Even a subtotal resection (STR) of at least 78% of the contrast-enhancing portion of tumor in patients with newly diagnosed glioblastoma (GBM) has led to survival benefits.⁵ For recurrent glioma, surgery can be multipurpose: to aid in diagnosis of recurrent tumor, to debulk tumor adjacent to eloquent cortex to maintain quality of life, and to achieve further cytological reduction to improve survival. As evidence of the latter, there are several reports demonstrating that complete extent of resection (EOR) of the contrast-enhancing portion of tumor leads to greater survival for patients with recurrent high-grade glioma.^6,7,8 Furthermore, complete resection at first recurrence has even been found to compensate for an incomplete tumor removal at the initial surgery in terms of impact on survival.⁶ Therefore, while the goal of reoperation for patients with possible recurrence may vary, for many the purpose is still to achieve the greatest EOR possible without compromising neurological function.

Yet, achieving a high-degree of resection, or gross total resection (GTR), is challenging for many reasons. Across the board, in practice, GTR of the contrast-enhancing tumor is achieved in only 20 to 30% of patients.^1,2,3,4,9,10 Even in patients amenable to GTR based on preoperative imaging, it is achieved in only 24% despite the use of neuronavigation.¹⁰ Sometimes a complete resection of the tumor is not feasible due to the presence of functional tissue. As one approaches the invasive tumor border in cases of high-grade malignant glioma, the distinction between pathologic and normal tissue can be almost impossible to make based solely on gross visualization and tactile feedback without the aid of other tools and technologies. Thus, fluorescence-guided techniques were introduced to brain tumor resections to aide a surgeon’s ability to achieve an extensive resection when possible.

5-aminolevulinic acid (5-ALA) is a compound that has been used to improve the intraoperative visualization of malignant glioma tissue. European data on 5-ALA have shown promising results demonstrating greater EOR and improved 6-month PFS and OS in the context of newly diagnosed, untreated grade III and IV malignant gliomas.¹¹ However, class I evidence of the use of 5-ALA in the context of recurrent high-grade gliomas is not available, and ongoing work is still required to determine its utility in this disease context. Here, we review clinical outcome data and considerations for the use of 5-ALA for recurrent high-grade gliomas. Topics covered include its impact on EOR, correlation with tumor pathology, and the influence of adjuvant therapies on fluorescence.

4.2 Considerations for the Use of 5-Aminolevulinic Acid

There are many considerations when selecting patients with recurrent gliomas for 5-ALA fluorescence-guided surgery (FGS). As with an initial surgery with 5-ALA, preoperative labs are acquired to rule out organ and marrow dysfunction. This involves ensuring that the leukocyte count is greater than 3,000/µL, the absolute neutrophil count is greater than 1,500/µL, the platelet count is greater than 100,000 µL, the total bilirubin level is within normal limits, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) are less than 2.4 times the upper normal limit, and creatinine is within normal limits with a creatinine clearance greater than 60 mL/min/1.73m². Adjuvant therapies may lead to abnormalities within these values preventing a patient from being a candidate for this approach. For example, temozolomide has led to 7% of patients developing leukopenia, 7% developing neutropenia, 12% developing thrombocytopenia, and 1% developing anemia.¹² Exclusion criteria for the use of 5-ALA usually include patients who report a history of allergy to compounds of similar chemical or biological composition to 5-ALA, personal or family history of porphyria, pregnancy, and hypotension.

Prior to surgery, a single administration of ALA (20 mg/kg body weight) is given orally 3 hours before anesthesia. After administration, light precautions are undertaken to protect the patient from the effects of skin photosensitivity during surgery and the postoperative period. Fortunately, the complication rate associated with 5-ALA is low. Lau et al found a 5-ALA attributable complication rate of 3.4% with patients developing intraoperative hypotension and a rash across the torso that responded to low oral doses of diphenhydramine.¹³ Stummer et al reported minor elevations in GGT and AST/ALT at 24 hours but otherwise did not see a difference in adverse events between the 5-ALA group and the control group.11

4.3 Impact on Extent of Resection

The primary purpose of 5-ALA FGS is to provide better visualization of pathological tissue in order to achieve a greater EOR. Limitations to a more extensive resection include invasion into eloquent cortex and inability to identify pathological tissue. Typically, the goal for high-grade gliomas is to remove the contrast-enhancing component seen on imaging. Some groups, however, have noted that fluorescent tissue boundaries often extend past the contrast-enhancing component seen on neuronavigation.¹⁴ Thus, the extent of fluorescent tissue resection is becoming another important benchmark to measure tumor removal.¹⁵

There are numerous reports that demonstrate high rates of extensive resection can be achieved with 5-ALA FGS in cases of recurrent malignant gliomas. Hickmann et al examined outcomes in 58 patients undergoing reoperation with 5-ALA for recurrent gliomas. Mean EOR based on MRI was 91.1% and ranged from 17.5 to 100%. More than 98% of tumor volume resection was achieved in the majority (57.1%) of surgeries. Complete resection of all fluorescent tissue was achieved in 64.1% of all surgeries and was associated with a significantly greater contrast-enhancing EOR, demonstrating 5-ALA’s role in promoting identification of enhancing tumor.¹⁵ Within a subgroup of 33 recurrent high-grade gliomas, Della Puppa et al reported a GTR (> 98% resection) rate of 94%.¹⁴ Other smaller studies have also demonstrated high rates of complete tumor resection. Tykocki et al examined outcomes in 5-ALA-guided surgery in both primary and recurrent malignant glioma. Of the three patients with recurrent tumors, all demonstrated fluorescence and underwent GTR.¹⁶ Archavlis et al reported that GTR and STR could be achieved in 59 and 41%, respectively, of 17 patients undergoing 5-ALA-guided re-resection of a malignant glioma. However, 47% of these tumors involved at least one eloquent region, limiting the ability to achieve a GTR.¹⁷

Other groups have examined 5-ALA’s ability to improve upon other tumor-identifying methods. Quick-Weller et al examined EOR when 5-ALA guidance was used in conjunction with intraoperative MRI and demonstrated complete resection in all seven patients within the cohort.¹⁸ Coburger et al also compared EOR of GBM for patients undergoing intraoperative MRI with or without 5-ALA guidance. In contrast to the report by Quick-Weller et al, these authors found for the six patients with recurrent tumor that EOR was similar whether or not 5-ALA was used.¹⁹ However, such results have to be cautiously interpreted given the limited number of patients.

4.4 Impact on Progression Free Survival, Overall Survival, and Morbidity

There is evidence that 5-ALA FGS improves both PFS and OS when used for newly diagnosed high-grade malignant gliomas.¹¹ However, very few studies have been able to examine the impact of surgery using 5-ALA on PFS and OS in the context of recurrent disease. In Hickmann et al, the 58 patients undergoing reoperation with 5-ALA FGS for recurrent gliomas had longer OS compared to 65 patients undergoing repeat surgery without 5-ALA (when patients with long-term survival > 5 years were excluded from the control arm). However, no significant impact on PFS was observed.¹⁵ Archavlis et al compared outcomes in 17 patients undergoing 5-ALA FGS and dense-dose temozolomide, and interstitial irradiation to historical controls treated with dense-dose temozolomide alone. Although it is difficult to isolate which particular therapies may have been responsible for the benefit, the authors reported an improved PFS of 3.5 months and survival after the experimental treatment by 3 months in the multimodal treatment group.¹⁷ Aside from these few reports, there is only the indirect relationship demonstrating that surgery utilizing 5-ALA increases EOR and greater EOR leads to improved PFS and OS in patients with recurrent gliomas.

One concern with 5-ALA FGS is that if greater EOR is achieved, this may lead to higher rates of neurological deficits postoperatively if appropriate monitoring and mapping techniques are not used. In Ringel et al, re-resection (not involving 5-ALA-guided surgery) was associated with an 8% rate of new permanent neurological deficits, slightly higher than the 5% rate observed for the initial surgery.⁶ However, Stummer et al did not see an impact of the use of 5-ALA on postoperative total stroke-scale scores between the experimental and control arm, suggesting that while 5-ALA FGS can improve EOR, the increased EOR does not increase neurological impairment.¹¹ A follow-up study suggested that within 48 hours, the rate of deterioration as measured by the National Institutes of Health Stroke Scale (NIH-SS) was more frequent in a cohort of patients operated on using 5-ALA FGS compared to controls. However, by 3 months, this difference was not significant.²⁰ In the study by Hickmann et al, there was no reported increase in new focal neurologic deficit based on whether fluorescence was observed intraoperatively or not. There was also no significant correlation between greater EOR and new focal deficits.¹⁵ Overall, it appears that increased EOR using 5-ALA may lead to worsening of neurological deficits in the short-term but that the rate of deficits are comparable to conventional surgery over time.

4.5 Recurrent Tumor Fluorescence and Histological Correlation

One concern with the use of 5-ALA fluorescence is that its utility may be impacted by recurrent tumor characteristics, adjuvant therapies, and the timing of these therapies. Tissue changes such as gliosis, necrosis, and vascular hyalinization are frequently seen after adjuvant radiotherapy and chemotherapy^{21,22,23,24,25,26,27,28} and their effect on both tumor and normal tissue as well as the impact on the blood–brain barrier (BBB) could potentially change the sensitivity and specificity of 5-ALA.

One point of interest is the percentage of recurrent tumors that are 5-ALA positive. Hickmann et al reported positive fluorescence in 84.1% of reoperations. The vast majority of these patients (87.3%) had undergone adjuvant therapy before recurrence, with 49.2% receiving radiotherapy in conjunction with some type of chemotherapy. Fluorescent tumors were more frequently contrast enhancing on MRI, WHO grade IV, and isocitrate dehydrogenase (IDH) mutated. All tumors with positive MRI contrast enhancement but negative intraoperative fluorescence demonstrated oligodendroglial differentiation, and all but one MRI nonenhancing, nonfluorescent tumors were oligodendroglial tumors.15 Nabavi et al found that all 36 patients in their cohort displayed some degree of 5-ALA fluorescence. Of these, 97% had received standard radiotherapy and 67% had received some type of chemotherapy.²⁹ In Kamp et al, only 1 of 13 patients was 5-ALA negative. Interestingly, all patients had received radiotherapy except for the one 5-ALA negative patient.³⁰ Utsuki et al reported that six of seven recurrent GBMs and five of six recurrent anaplastic astrocytomas were fluorescent.³¹ Collectively, these studies demonstrate that the vast majority of recurrent gliomas are 5-ALA positive.