5-Aminolevulinic Acid and Brain Metastases

7 5-Aminolevulinic Acid and Brain Metastases

Marcel A. Kamp, Marion Rapp, Jan Frederick Cornelius, Hans-Jakob Steiger, and Michael Sabel

Abstract
Cerebral metastases are one of the most common intracerebral neoplasms. It was questioned if the 5-aminolevulinic acid (5-ALA) technique is feasible to visualize cerebral metastases and metastatic infiltration, subsequently improves the degree of surgical resection, and lowers the high local recurrence rates. However, only about half of cerebral metastases reveal 5-ALA-derived tumor fluorescence. A very limited number of retrospective studies have suggested that the 5-ALA technique does not allow a reliable visualization of residual parts or the infiltration zone after metastasis resection. Predictors for 5-ALA-induced fluorescence of cerebral metastases have not yet been identified. However, the dichotomized 5-ALA fluorescence behavior might be an indicator for a more aggressive behavior of cerebral metastases.

Keywords: cerebral metastases, cerebral metastasis, 5-ALA, fluorescence-guided resection, recurrence, protoporphyrin IX

7.1 Introduction

Cerebral metastases are neoplasms that originate from malignant tumors outside the central nervous system (CNS), spread secondarily to the brain, and are not connected with the primary tumor. About 50% of cerebral metastases originate from non–small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), about 20% from breast cancer, and 5 to 20% from melanoma.1,2 Metastases are the most common cerebral neoplasms with an estimated incidence of about 200,000 patients in the United States each year.^3,4 Approximately 20 to 40% of cancer patients develop cerebral metastases, about 20% dural metastases, and 8% leptomeningeal metastases.⁵ However, the incidence of occult cerebral metastases might even be higher based on autopsy studies.⁶ Modern targeted cancer therapies further alter the incidence and behavior of cerebral metastases. For example, the introduction of human epidermal growth factor receptor 2 (HER2) targeted therapies in HER2-positive breast cancer patients led to a clinically observed increase in the incidence of cerebral metastases over historical estimates.⁷ Similarly, the CNS is the first site of tumor progression in 46% of patients with an anaplastic lymphoma kinase (ALK) rearranged NSCLC treated with crizotinib.⁸ On the other hand, subtyping of different tumor entities, development of new chemotherapies, and induction of targeted therapies have dramatically improved systemic control and patient outcomes. As the outcome of cancer patients is improving and cerebral metastases are observed more frequently, the adequate therapy of cerebral metastases is an increasing challenge in modern neuro-oncology. Achieving long-lasting local tumor control with low morbidity and mortality and providing patients with favorable quality of life (QOL) should be major goals in the treatment of cerebral metastases.

7.2 Evidence for the Surgical Resection of Cerebral Metastases

Treatment options for cerebral metastases include surgery, single-fraction stereotactic radiosurgery (SRS), radiation therapy, and chemotherapy. Different factors, such as the patient’s clinical and neurological condition, number and location of the metastases, and—if applicable—the histopathological diagnosis of the primary tumor, influence the choice of the favored therapy. Therefore, treatment of cerebral metastases is multimodal and interdisciplinary.

Surgical resection of cerebral metastases is still a key modality in the treatment of oligometastatic patients. Its impact has been evaluated in a series of prospective, randomized, and controlled studies comparing resection of single cerebral metastases combined with a whole-brain radiation therapy (WBRT) in comparison to WBRT alone: The key study by Patchell et al and a later Dutch study provided evidence for a significant benefit of a combined treatment as compared to WBRT alone, resulting in an improved progression-free, functionally independent progression-free, and improved overall survival of patients.^9,10,11,12 Even after induction of other therapy modalities such as SRS, surgery for single cerebral metastases is one of the major therapeutic approaches and included in the common recommendations and international guidelines (level I evidence).^{13,14,15,16,17} In practice, surgery should be considered for large tumors with a diameter of more than 2 to 3 cm, for surgically accessible metastases, and for symptomatic patients who are otherwise healthy.

7.3 Standard Surgical Technique and Associated Problems

The aim of surgery is to completely remove the cerebral metastasis as safely as possible and to achieve long-lasting tumor control.¹⁸ The surgical standard procedure is a microsurgical, white-light-assisted, circumferential resection from the surrounding brain tissue assuming that the cerebral metastasis is well circumscribed. A gliotic pseudocapsule might facilitate complete en bloc resection of cerebral metastases. In contrast to a piecemeal resection, en bloc resections were considered to lower the risk of neurological complications, local recurrence, and leptomeningeal dissemination.^19,20 Frequently, modern neurosurgical techniques are integrated during metastasis resection. A neuronavigation system may help plan the craniotomy, while the intraoperative use of ultrasound may help with the surgical approach for localizing the cerebral metastases. Surgical associated neurological deficits might be prevented by preoperative functional imaging (e.g., by functional MRI or transcortical magnet stimulation) or intraoperative neurophysiologic mapping (e.g., by intraoperative neurophysiological monitoring and awake surgery) to determine location of eloquent cortical tissue and white fiber connections.

The standard technique of metastasis resection results in up to 30% incomplete surgical resections and, without any additional adjuvant therapy, up to 60% local tumor progression.21,22,23,24 The local recurrence rate after surgery alone was 46% after 1 year in a prospective, randomized American multicenter study and after 2 years 53 and 59% in a retrospective Korean and the prospective, randomized EORTC 22952–26001 trail, respectively.^22,23,24 One explanation for the high local recurrence rate is an irregular tumor–brain interface or an infiltrative growth pattern of cerebral metastases.²⁵ Another explanation for the high local recurrence rate might be unintended residual tumor tissue after assumed gross total resection.²¹ In fact, residual tumor tissue was observed in up to 20% after intended complete surgical resection of cerebral metastases.^21,26 A supramarginal resection with extension of the surgical resection after complete gross total resection to a depth of additional 5 mm might address infiltrative tumor tissue or residual parts and might subsequently result in a lower local recurrence rate.^27,28

7.4 A Rationale for 5-ALA-Derived Fluorescence Detection of Cerebral Metastases

5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) of high-grade glioma maximizes the extent of surgical resection and improves progression-free survival.²⁹ 5-ALA-derived fluorescence is also observed in culture with several malignancies outside the CNS such as lung adenocarcinoma, pleural carcinoma, breast carcinoma, colon carcinoma, and malignant melanoma cells.^{30,31,32,33,34,35} Apart from these experimental results, various diagnostic and therapeutic approaches utilize 5-ALA-derived fluorescence including multiple prospective, randomized, and controlled studies that have provided evidence for the use of 5-ALA (and hexylaminolevulinate) for detection of bladder cancer.^{36,37,38,39,40,41,42,43} This technique was shown to increase detection of bladder malignancies and to lower their recurrence rates.⁴⁴ Additional phase I or II studies evaluating the value of 5-ALA-derived fluorescence for intraoperative diagnosis or resection were conducted in patients suffering from breast, gastrointestinal, renal, prostate, or ovarian cancer.⁴⁵ An interesting phase I study showed 95% sensitivity and 94% specificity in 5-ALA fluorescence-based detection of residual tumor tissue during laparoscopic partial nephrectomies.^45,46

We therefore questioned whether 5-ALA FGS will visualize cerebral metastases and metastatic infiltration, subsequently improving the degree of surgical resection and lowering local recurrence rates.

7.5 5-ALA Fluorescence of Metastatic Brain Tumors

Utsuki et al first described 5-ALA-induced fluorescence in 9 of 11 cerebral metastases (81.8%).⁴⁷ Since that first study, 12 additional studies reported 5-ALA fluorescence of cerebral metastases, of which 6 studies had ≥ 10 patients. For these six studies with more than nine patients, the proportion of 5-ALA-positive metastases ranged from 30 to 81.8%.^{47,48,49,50,51,52} In all, they included 233 patients with a total of 120 5-ALA fluorescent metastases (51.5%). Therefore, more than half of cerebral metastases exhibit either faint or strong 5-ALA-induced fluorescence ( Fig. 7.1).