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Scientists at the Ecole Polytechnique Fédérale de Lausanne (EPFL), in collaboration with Lausanne's University Hospital and Lausanne University's Physiology Department, have invested more than ten years of research into the development of a fluorescence-inducing compound that may very well revolutionize the photodetection of superficial bladder cancer.
This substance, hexaminolevulinate, is the active substance in a new pharmaceutical product that has been developed by the Norwegian company PhotoCure ASA. The new product will be sold under the name Hexvix®. Photocure ASA won approval March 2 for market release of Hexvix® in 26 European countries.
Every year, nearly 200,000 cases of bladder cancer are reported in Europe and the United States. In the US alone, more than 2.5 million screenings take place every year. If caught early, the five-year survival rate from this disease is an encouraging 90%. This drops to 50% when the cancer is locally metastasized and to about 10% for distant metastasis. Catching and treating bladder cancer as quickly as possible is clearly critical for a favorable outcome.
In its early stages, bladder cancer is characterized by superficial tumors or lesions. In conventional screening, a cystoscope is used to visually examine the inside of the bladder, and suspected tumors are removed for biopsy. Upon positive diagnosis, the cystoscope is used again as a surgeon or physician visually identifies and cuts out the cancerous tissue. This "white light" examination and resection is quite difficult for flat lesions and the experience of the individual urologist or surgeon is a considerable variable factor in successful detection. The recurrence rate under this treatment is quite high, and is thought to be due in part to superficial lesions or small tumors that are overlooked during the initial screening and diagnosis.
The use of hexaminolevulinate (HAL) in detection of bladder cancer was initiated by Hubert van den Bergh, Georges Wagnières and colleagues at the EPFL and is part of a slightly different cystoscopy technique. First, HAL as part of Hexvix® is applied to bladder tissue where it is selectively metabolized by cancer cells into a fluorescent compound. About a half hour later, the physician examines the inside of the bladder with a cystoscope, using blue light instead of white light. With the help of a filter placed on the camera, the fluorescent tumors stand out as bright red spots, impossible to miss. Patients screened using this process are far more likely to be diagnosed correctly, and because the cancerous tissue is easy to identify, very small tumors are not likely to be overlooked. Even flat lesions, previously so difficult to detect, are easily spotted and removed. The lower recurrence rates reported with this technique in turn greatly reduce the likelihood of local or distant metastasis.
Exploiting a cellular manufacturing cycle
Van den Bergh and Wagnières' group developed this molecule by exploiting naturally occurring cellular processes. Protoporphyrine IX (PPIX), a naturally occuring photoactive porhyrine produced normally as an intermediate step in the cellular manufacture of hemoglobin, is fluorescent, albeit ephemerally. In healthy cells the effect quickly disappears as the molecule takes on an iron atom.
It turns out that cancer cells slightly overproduce photoactive porhyrins, and the enzyme responsible for the next step, adding the iron atom, is also inhibited. These two effects combine in cancerous cells to produce an accumulation of the fluorescent molecule.
Although this naturally occurring accumulation is too feeble to be exploited clinically, van den Bergh and Wagnières' group used it as a starting point in designing a substance that would increase the basic ingredients needed for its synthesis in the cell. The molecule they came up with, hexaminolevulinate (HAL) causes cells to over-manufacture photoactive porhyrins, and because its further metabolism is slowed down in cancer cells, photoactive porhyrins accumulate to the point where the fluorescent effect can be used clinically. These accumulations are harmless because within 24 hours the body naturally eliminates all traces of the molecule.
Ex vivo and clinical optimization studies using hexaminolevulinate were carried out in collaboration with Pavel Kucera from the Institute of Physiology of the University of Lausanne and Patrice Jichlinski from the department of Urology at the University Hospital in Lausanne.
The development of Hexvix® now means that a strong fluorescent signal can be obtained with short installation times in the bladder. Hexvix® has no observed systemic or local side effects.
Photodetection using Hexvix® has undergone extensive clinical trials in several European countries, including Switzerland, Germany, Sweden and Norway. Clinical studies aiming at obtaining similar marketing authorization in the US are ongoing.