As we explained in Part 1, malignant gliomas such as glioblastoma are a deadly form of brain cancer and pose many challenges to modern oncology. These invasive tumors inevitably result in death within two years, the average survival being about one year. Complete surgical removal of the main tumor mass is viewed as the key to successful treatment. Trouble is, surgeons have an extremely hard time separating the malignant glioma from the normal surrounding brain.
Numerous surgical technologies and strategies have been developed to meet this challenge. Among the more promising is the approach known as fluorescence-guided surgery, or FGS. In most studies to date, this approach has used the natural substance called 5-aminolevulinic acid. The substance is taken orally a few hours before surgery, and this leads to the selective concentration of the body’s very own photosensitizer, protoporphyrin IX or PpIX, within glioma cells. (For more details about PpIX and photosensitizers, please see the new book, The Medicine of Light.)
Since the introduction of FGS, many studies have reported that this approach can be beneficial in the treatment of malignant gliomas. Under blue-violet light conditions, the PpIX emits a reddish glow, and this enables identification of tumor tissue that would otherwise be extremely difficult to distinguish from normal brain tissue. Whereas brain tumor tissue can be identified by its deep red fluorescence, normal brain tissue appears to be colored blue.
Scientists from the First Affiliated Hospital of Harbin Medical University, in Harbin, China, recently conducted a systematic review and meta-analysis of the literature to address the value of FGS for high-grade malignant gliomas. Much of their analysis was aimed at glioblastoma multiforme (GBM), which we discussed in Part 1.
The Harbin research team compared FGS with the conventional approach to neurosurgery, known as neuronavigation-guided resection. This data analysis clearly showed that FGS had superior sensitivity and specificity compared to the standard approach, meaning that FGS made the tumor tissue much easier to detect, and malignant tumors were much easier to distinguish and separate from normal brain tissue.
In addition, the Harbin researchers reviewed survival data in a total of six clinical studies. Of these studies, three were randomized controlled clinical trials, the gold standard for “proof” of a medical treatment’s efficacy. Their conclusion: FGS led to significantly better overall survival when compared to surgery under normal white light conditions. Moreover, patients treated with FGS went significantly longer without showing any signs of a worsening of their disease within a six-month period.
For example, in a 2006 randomized clinical trial, the progression-free survival was 41% in the FGS group, compared to only 21% in the white light group. In a 2008 randomized trial, the overall survival was twice as high in the FGS group compared to the white light group; however, this trial was much smaller than the other two, and thus the findings should be considered less reliable.
The most recent randomized clinical trial was published in the March 2011 Journal of Neurosurgery. As the largest of the three trials (349 patients total), this study found that the progression-free survival rate at six months was 46% in the FGS group, versus 28% in the white light group. The researchers also noted that repeat surgery was significantly less frequent in FGS patients, and those patients with incomplete resections (i.e., residual tumor tissue) showed more rapid neurological deterioration.
Another salient point, as the Harbin research team points out, is that FGS is much simpler and less costly than other types of surgery for patients with malignant brain tumors. With the rising cost of medical care, any approach that reduces cost while improving the patient’s survival deserves serious attention.
Additional randomized clinical trials will be needed before mainstream cancer surgeons and medical policymakers are willing to embrace the power and promise of the photodynamic approach. For anyone facing a malignant glioma, however, the existing evidence would already seem too compelling to ignore.
At this writing, 5-aminolevulinic acid for fluorescence-guided brain surgery has been approved in Europe, Canada, and Japan, but not in the United States.
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Zhao S, Wu J, Wang C, Liu H, Dong X, et al. Intraoperative fluorescence-guided resection of high-grade malignant gliomas using 5-aminolevulinic acid-induced porphyrins: a systematic review and meta-analysis of prospective studies. PLoS One. 2013 May 28;8(5):e63682
Stummer W, Tonn JC, Mehdorn HM, Nestler U, Franz K, Goetz C, Bink A, Pichlmeier U; ALA-Glioma Study Group. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. J Neurosurg. 2011 Mar;114(3):613-23
Eljamel MS, Goodman C, Moseley H. ALA and Photofrin fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trial. Lasers Med Sci. 2008 Oct;23(4):361-7
Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006; 7(5):392-401
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