Colorectal cancer is a a major cause of death in many countries, and it’s one of the few cancers that can actually be prevented with screening. In 2012, a New York study showed convincingly that a colonoscopy, along with removal of polyps (growths) in the colon, resulted in a greater than 50 percent reduction in the death rate from colon cancer. This was the first study to provide evidence that detecting colorectal tumors at an earlier and more treatable stage could result in a lowering of mortality.
Nevertheless, because this landmark study did not compare colonoscopy with other ways of screening for colorectal cancer, it did not address the longstanding debate about which method is best. Even when colonoscopy is used with the intent to remove all precancerous lesions (neoplasia), colorectal cancer will occasionally be diagnosed after the procedure. It’s very likely that the lesions were missed or incompletely removed at the time of the colonoscopy. Some lesions are particularly flat or even depressed, thus hard to detect.
These limitations have spurred efforts to help doctors identify and more completely remove all neoplastic lesions at the time of colonoscopy. One of the new modalities being explored is photodynamic diagnosis (PDD), or photodiagnosis, using the light-sensitizing agent 5-aminolevulinic acid (5-ALA). This agent is converted to the natural photosensitizer, protoporphyrin IX.
After administering 5-ALA, protoporphyrin IX accumulates much more in tumor cells than in normal cells. With subsequent blue light treatment, the compound is then “excited” by the light, resulting in its emission of red light or red fluorescence. The appearance of this reddish glow can lead to an improved ability to identify the presence of cancer. At the same time, compared to most other photosensitizers, 5-ALA is much less likely to cause problems with skin photosensitivity.
Much progress has been made in recent years with the use of 5-ALA for the photodiagnosis of brain, bladder, and stomach tumors. Potentially precancerous conditions such as Barrett’s esophagus and high-grade dysplasia in inflammatory bowel disease also have been assessed with this method. Until recently, however, 5-ALA’s clinical effectiveness against colorectal tumors, particularly for flat neoplasias, was virtually unknown.
Improving the Detection of Colorectal Tumors
For decades, 5-ALA has been used either topically or intravenously. In the past few years, however, scientists have become interested in offering patients 5-ALA in an oral form in order to address diseases affecting the digestive tract, namely the stomach and colon.
This oral form of 5-ALA served as the basis for a study carried out at the National Cancer Center Hospital in Tokyo (Japan). The study’s main purpose was to test the potential for detecting adenomas (precancers), flat lesions, and early colorectal tumors using fluorescence imaging with 5-ALA. Anotherr goal was to assess the safety and acceptability of this novel imaging technique.
Over a two-year period, patients with previously diagnosed adenomas or early-stage colorectal tumors (including flat and depressed tumors) were enrolled in the study. Patients took oral 5-ALA (used as an off-label diagnostic product) dissolved in water about four hours before the flourescence imaging with blue light. All patients were instructed to avoid direct sunlight for two days after taking the 5-ALA solution.
Using a combination of endoscopy and surgery, the lesions and tumors were sampled and analayzed to determine the grade or relative aggressiveness of the cells. The grade and lesion type were then compared to the visible red fluorescence and light spectrum produced during the imaging procedure.
Red fluorescence was observed in about 82% if the lesions. Less aggressive precancerous lesions showed lower rates of red flourescence compared to higher grade lesions. Specifically, there was a 63% red flourescence in the low-grade precancerous lesions, compared to 78% in the high-grade lesions.
Thus, the key finding was that the extent of red fluorescence increased with the degree of dysplasia. In other words, the growths most likely to become cancer were also the ones to show more red fluorescence. Although flat or depressed high-grade lesions (but not low-grade lesions) showed red fluorescence, the lesions that were protruding or sticking out were more likely to show the reddish glow.
Even more important, whereas red light was not observed in the normal healthy lining of the colon, malignant tumors showed 100% fluorescence! This could have profound importance for the future screening of colorectal tumors. Imagine if this PDD technique could be integrated into standard colonoscopy procedures. It seems likely that the detection rate for malignant tumors could increase considerably, resulting in more successful treatment outcomes.
This is the first clinical study to demonstrate the impact of orally ingested 5-ALA for photodynamic diagnosis of early-stage colorectal tumors in humans. Because 5-ALA has already demonstrated benefits in both detection and treatment of other cancers,, it would seem to hold considerable promise for the detection of colorectal tumors, and and for helping to identify high-grade (high risk) precancerous lesions as well. In addition, this technique has been shown to be safe for clinical use in other cancer scenarios, suggesting a rationale for its use in detecting colorectal tumors, as reported in the January 2016 issue of Endoscopy International Open.
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