Fluorescence-Guided Surgery Postpones Relapse in Patients with Malignant GliomaKey Words
Brain tumor, malignant glioma, fluorescence-guided surgery, 5-aminolevulinic acid. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
Brain surgeons in Germany using a technique that lights up tumor tissue with a fluorescent marker were about twice as successful at completely removing malignant glioma tumors (a form of brain cancer) compared to other surgeons using conventional surgery. While this advantage persisted in better progression-free survival for patients who underwent fluorescence-guided surgery, they didn’t end up living any longer than other patients in the study.
Source
The Lancet Oncology, published online April 13, 2006; in print May 2006 (see the journal abstract)
(Lancet Oncol. 2006 May; 7(5): 392-401)
Background
Malignant gliomas are the most common primary brain tumor. They will likely account for about half of the nearly 19,000 primary malignant brain tumors expected to be diagnosed in the United States in 2006.
Nearly all patients have surgery, where doctors try to determine the edges of the tumor in order to remove as much of it as safely possible. Regardless of the extent of surgery, some tumor cells remain within the brain adjacent to the area of primary tumor removal. Nonetheless, how long patients survive may depend in part on how completely their tumor is removed and thus how likely the cancer is to recur locally.
Several advanced surgical tools and imaging techniques have been developed and are becoming widely used to guide surgeons in major cancer centers. Whether these surgical approaches make surgery safer or more effective hasn’t been proven, however.
One such technique that has been developed primarily in Europe involves lighting up the brain tumor tissue with fluorescence. Before surgery, patients drink a glass of water in which 5-aminolevulinic acid (ALA) has been dissolved. When it arrives at the brain, certain molecules in the tumor become fluorescent. Surgeons wear a modified neurosurgical microscope and use violet-blue light to see the glowing tissue.
The Study
This phase III trial was designed to test the value of fluorescence-guided surgery. Beginning in October 1999, researchers at 17 sites in Germany enrolled 322 patients with suspected malignant glioma. Half of the patients were randomly assigned to conventional brain surgery using white light and the other half to fluorescence-guided surgery.
All patients had tumors that surgeons predicted could be completely removed, and during surgery they tried to remove as much tumor from all patients as was safely possible to do. The patients ranged in age from 23 to 73 years old, and had similar neurocognitive function.
Those in the fluorescence-guided surgery group drank a solution with ALA about three hours before undergoing anesthesia, and their surgeons used the fluorescence to identify brain tumor cells. Patients receiving standard surgery did not drink a placebo. After surgery, patients in both groups received standard adjuvant radiation and/or chemotherapy, as called for in the trial design. Once disease had progressed, there were no restrictions on treatment.
All patients received magnetic resonance imaging (MRI) within three days of surgery to detect and measure any remaining tumor, and again every three months for a year and a half. The researchers recorded the time before a patient’s tumor recurred, the kind and severity of any effects on their brain function, and toxic effects.
In July 2004, a planned interim analysis after 35.4 months median follow-up showed that the fluorescence-guided surgery technique was providing patients with statistically significant better progression-free survival. The trial was stopped and all patients were offered the new surgical approach, as needed. The study’s results are based on the 270 randomly assigned patients who had undergone surgery at the time of the interim analysis: 139 in the fluorescence-guided surgery group and 131 in the standard group.
The trial was conducted by the ALA-Glioma Study Group from Germany, and its lead author is Walter Stummer, M.D., of Heinrich-Heine University in Dusseldorf, Germany.
Results
Nearly twice as many patients (90 of 139, or 65 percent ) receiving fluorescence-guided surgery had their tumors completely removed as assessed by the post-operative MRI scan, compared to those who received conventional surgery using white light (47 of 131, or 36 percent).
Six months after surgery, 41 percent of those in the fluorescence-guided surgery group had no progression of their tumor, compared to 21 percent of those receiving conventional surgery. The average time to recurrence was 5.1 months for the fluorescence-guided surgery group, compared to 3.6 months for the conventional surgery group.
Though the trial was not designed to reliably measure overall survival, there was not a statistically significant difference between the two groups – patients lived about as long regardless of what surgical procedure they received.
There was no significant difference in adverse events or serious adverse events between the two groups. Tests for performance and brain function also showed no significant differences attributable to surgical technique, when measured seven days, six weeks and six months after surgery.
Limitations
For several reasons, these results should be cautiously applied to patients with newly diagnosed glioblastoma in the Untied States, said Howard A. Fine, M.D., chief of the Neuro-Oncology Branch of the National Cancer Institute’s Center for Cancer Research. “It is important for patients to realize that glioblastoma treated with surgery alone is usually rapidly fatal,” he said, “and that even the most successful surgery is not likely to make them live longer.”
“Currently we provide radiotherapy and Temodar® (temozolomide) after surgery, which has been proven to extend patients’ lives by more than two months.” It’s difficult to attribute better outcomes to surgery, he explained, because the more significant threat to glioblastoma patients comes from undetectable infiltrating tumor cells that have already moved throughout the brain at the time of primary surgery.
Thus, he said, “postoperative images showing so-called complete resection are often not clinically meaningful to overall survival,” though they may provide a short-term advantage in delaying progression of the local tumor.
Even so, he interprets the progression-free survival advantage in this study with caution. Patients enrolled were chosen for characteristics that make them better candidates for surgery than the average glioblastoma patient, he said. Also, the nature of the trial design could not prevent surgeons from knowing which group they were operating on, which might have biased the results to some degree.
Another aspect of current practice should also be kept in mind, added Fine: only 36 percent of those receiving the standard surgery had their primary tumors completely removed. “This is far less than we usually see in cancer centers in the United States, most of which use some form of guided imagery to help surgeons locate the edges of the primary tumor.”
Thus, the superior results for the fluorescence-guided surgery patients in the trial are being compared to results from standard surgical patients that do not reflect current practice, at least in the United States.
Comments
In an accompanying comment, Dr. Fred G. Barker, M.D., of the Harvard Medical School and Dr. Susan M. Chang, M.D., of the University of California–San Francisco wrote that these results represent “a step forward in the study of surgery for malignant glioma,” because there has been little hard evidence from prospective trials on surgical technique.
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