Photodynamic therapy—the use of light to fight cancer—is poised to take on a more prominent role in oncology 20 years after the first major studies of the treatment began. In December 1995, the U.S. Food and Drug Administration granted its first PDT approval to QLT Photo- Therapeutics of Vancouver, B.C., Canada, to market the light-sensitizing drug Photofrin (porfimer sodium) for the treatment of obstructive esophageal cancer. Like most of the settings in which researchers have studied PDT, the FDA approved use is a palliative treatment for patients with advanced cancer. But experts say PDT may prove useful in treating a wide range of cancers, from early to late stages. PDT also holds promise for treating other diseases ranging from psoriasis to macular degeneration of the retina, the most common cause of blindness in the elderly. The primary ingredients in PDT are low-energy lasers and photosensitizing drugs such as Photofrin that make cells vulnerable to damage by light. Photofrin is a semi-synthetic compound derived from the blood of cows and pigs, while some newer photosensitizers are totally synthesized. When cancer is treated with PDT, the photosensitizer is first injected intravenously. Then, after a period ranging from a few minutes to 48 hours, a laser—often attached to a fiber-optic cable to extend its reach—is used to shine light on the tumor site. The drug is retained much longer in tumor cells than in normal cells—several days versus several hours. Although no one knows precisely how PDT kills cells, the treatment creates a toxic form of oxygen that appears to damage cell membranes and other cellular components, particularly in the blood vessels that feed tumor cells. PDT's relative mildness compared with other cancer treatments is one quality that has convinced researchers of its potential. The worst side effect of Photofrin is to make the skin hypersensitive to sunburn, so patients must stay out of the sun and other bright light for weeks after treatment. But a new generation of drugs promises to solve that problem. Dr. Eli Glatstein “I've done a lot of things to patients in my career, and this is the safest thing I've ever done,” said Eli Glatstein, M.D., of the University of Pennsylvania Cancer Center in Philadelphia. “I'm quite convinced that PDT has a role to play in a number of cancers.” In a talk last year at Georgetown University's Lombardi Cancer Center in Washington, D.C., Glatstein said he recently moved to Penn to devote the final phase of his career to the development of PDT. PDT is done in only “a handful of places” in the United States, he said, but “it's used much more extensively in Japan, and is rapidly picking up speed throughout Europe.” The first-ever PDT approval was in 1992 in Canada, where it's now used to treat cancers of the bladder and esophagus. PDT with Photofrin has been approved in France and The Netherlands for esophageal and lung cancers (both early and late stage), and approvals are pending in five other European countries. In Japan, it is used to treat early stage cancers of the esophagus, lung, stomach, and cervix as well as cervical dysplasia. Thomas Dougherty, Ph.D., and his colleagues at Roswell Park Cancer Institute in Buffalo, N.Y., discovered the compound now called Photofrin, and pioneered modern PDT beginning in the mid-1970s with metastatic cancers on the skin (although its first oncologic use dates to 1903 in Germany where eosin and light were used to treat skin cancer). Roswell Park is one of the few U.S. centers performing a wide array of PDT clinical trials. Researchers there are studying PDT for skin cancer, lung cancer, and early and late esophageal cancer, among others. The Grant Hospital Laser Center in Columbus, Ohio, is another major PDT center, Dougherty said. In palliative settings, both Glatstein and Dougherty said, PDT works well for symptom relief by clearing up extensive local tumor recurrence and removing obstructions of the bronchus and esophagus. Although only the esophageal use is approved outside clinical trials, Dougherty said “off-label” uses of Photofrin may become more common because PDT “has been tried in everything” and many publications suggest its effectiveness in other cancers. But he said the technique is still rarely practiced outside academic medical centers because no photosensitizer received U.S FDA approval before late 1995. Dougherty said it's unfortunate that some patients don't get PDT earlier in the course of their disease, when it could do more good. For example, a postoperative breast cancer patient is likely to undergo radiotherapy and half a dozen different chemotherapy regimens before her physician might turn, as a last resort, to PDT. Dr. Thomas Dougherty “By the time we see them, they've been through the mill, and often there's nothing left that you could call normal tissue,” he said. “It would make a whole lot more sense to use the PDT to destroy the bulk tumor, then start chemotherapy…but you have to get into the referral line, and we haven't figured out how to do that yet” Other trials are evaluating PDT as a surgical adjuvant, including one for mesothelioma at Roswell Park and two large trials for brain tumors in Canada and Australia. In each case, the light treatment is given immediately after surgery, before the incisions are closed, to maximize the exposure of the tumor to light. More recently, researchers have begun to go beyond palliation to evaluate PDT as a means to treat and possibly cure early stage cancers. Eric Edell, M.D., at the Mayo Clinic in Rochester, Minn., is carrying out a single-arm phase I1 trial on early stage squamous cell lung cancer patients to see whether PDT can allow these patients to avoid surgery. (If cancer persists after two PDT sessions, the lung is resected.) Nine of 21 patients, with an average follow- up time of 68 months, were successfully treated with PDT and spared surgery. Planned follow-up is 5 years, and investigators at the Tokyo Medical College are doing an identical trial and will vool their results with Edell's. In Japan, a public health campaign encourages smokers to get chest x rays and sputum cytology to screen for lung cancer, which is treated in some cases with PDT. Dougherty described the (admittedly rare) case of a Japanese man who had an early stage tumor in each lung, ruling out surgery or radiation. PDT reportedly destroyed his primary tumors as well as three recurrences in later years. PDT has already improved quality of life for patients with basal cell nevus syndrome, who constantly develop basal cell skin cancers and may have 40 or 50 at a time. Allan Oseroff, M.D., chief of dermatology at Roswell Park, treats patients from far and wide with the syndrome. “We usually have to treat each patient quite frequently—once or twice a year,” Dougherty said. “But because all we're doing is shining light on them, it can be done on an outpatient basis. It's a small number, but for them it's a great benefit.” Of potential significance to a much larger number of doctors and patients are reports that PDT could prevent advanced esophageal cancer—and the radical surgery used to treat it. Hector Nava, M.D., and colleagues at Roswell Park have used Photofrin with great success to eradicate severe dysplasia and carcinoma in situ along with Barrett's esophagus (an inflammation that results from a change in esophageal tissue to resemble stomach tissue, and is often pre-malignant). The Roswell Park team expects to join a planned QLT trial aimed at securing FDA approval for this use. “The major benefit for those patients is that they avoid a horrendous surgical procedure, where mortality is about 10% and morbidity is practically 100%,” Dougherty said. “There's enough long-term data from our phase II trial indicating that [PDT] really can get rid of this stuff. “It's easy to get rid of carcinoma in situ,” he added. “The surprise was that the Barrett's also goes away. That we really had not expected. Sometimes you don't get l100%, but always 80 or 90, and you can re-treat or combine it with other treatments. And it sure beats surgery.” The Barrett's treatment is also being studied at the Mayo Clinic and at the Thompson Cancer Survival Center in Knoxville, Tenn. The most exciting prospect for PDT in the long term, its practitioners agree, is the next generation of photosensitizing drugs, now in early clinical development. Some of these drugs have advantages over Photofrin. For one thing, they are cleared from normal tissue much faster, meaning that skin photosensitivity is not a problem and treatments can be administered in closer succession. “Photodynamic therapy up until now has been a single-shot treatment,” Glatstein said. “With these new sensitizers, most of which have already completed phase I studies, we should be able to give once-a-week treatment. I think that's going to totally revolutionize this field and make it really take off.” Equally significant, he said, is the greater depth of light penetration into tissue that the new compounds may make possible. Because Photofrin absorbs light best in the red area of the spectrum, close to the light-absorption peaks for melanin and hemoglobin, those substances tend to filter out the light, limiting tissue penetration. The new sensitizers avoid this problem by absorbing light at different wavelengths, so they should be able to kill cancer cells much deeper in the tissue. Two new drugs Glatstein singled out are BPD (benzoporphyrin derivative), another product from QLT of Vancouver; and Lu-Tex (lutetium texaphyrin) from Pharmacyclics of Sunnyvale, Calif. These drugs reportedly will allow light to penetrate twice as deep into tissues as Photofrin, which allows penetration of 5 mm to 1 cm. Left: Endoscopic image of early stage lung cancer (far upper left image). Other images at left show the same tumor a few days after photodynamic therapy. Right: Image of same patient's lung 3 months after PDT, with no evidence of tumor by biopsy and brushings. Patient survived 4.5 years and died of an unrelated disease, with no tumor found at autopsy. (Courtesy of Prof. Kato, Tokyo Medical College.) Julia Levy, Ph.D., president and chief executive officer of QLT, said the company in December formed a partnership with Beaufour Ipsen of Paris to develop and market Photofrin and a second-generation sensitizer (probably BPD) in Europe. QLT earlier formed an alliance with Sanofi Winthrop, Inc., of New York to co-develop BPD for oncologic uses in the United States. In 1995, Levy and colleagues reported results of a phase 1/11 trial of BPD in patients with cutaneous metastases. They found that 47% of all patients, and 100% of those who got high BPD doses, had complete responses, and skin sensitivity was minimal. “Development of oncologic applications will be given a top priority in the new year,” said Levy. “It's a very exciting time for us; we have three or four different options for studying BPD in cancer, and we haven't decided yet exactly which direction we'll take.” Markus Renschler, M.D., director of clinical research at Pharmacyclics, said the company has completed a phase I trial of PDT with Lu-Tex on patients with skin metastases. He said more than 50% of patients responded, with half of those showing complete responses. The company plans a phase I1 trial in cutaneous metastases from breast cancer, and is also considering trials in head and neck, prostate, and brain cancers and mesothelioma. Another new photosensitizer is SnET2 (tin ethyl etiopurpurin), developed by PDT, Inc., of Santa Barbara, Calif. This synthetic compound is being tested in phase II/III clinical trials for cutaneous metastatic breast cancer in the United States and Europe, and is also in trials for AIDS-related Kaposi's sarcoma and basal cell skin cancer, said Laurens Lichty, corporate communications manager for PDT, Inc. “Metastasis to the skin occurs in 15% to 20% of breast cancer patients, and it's very difficult to manage,” Lichty said. “We've been very encouraged by the results of our earlier trials.” In a phase II trial, 96% of patients with cutaneous metastases showed complete response 3 months after treatment with SnET2 and lasers. The company has licensed the drug to Pharmacia & Upjohn of Kalamazoo, Mich., and expects to complete the breast cancer trial in 1997. PDT, Inc. is also developing lasers for PDT that are less expensive and cumbersome than those used in the past, as well as fiber optic products designed for optimal delivery of PDT to different sites in the body. Across the Atlantic, the Reuter news service reported in September that Scotia Holdings, based on the remote Isle of Lewis in Scotland, is developing a photodynamic drug known as Foscan, which the company claims will be available by 1998.
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