When John Graham’s throat cancer returned a year and a half after it was seemingly eradicated by standard radiation therapy, his doctors thought the best option for the Minneapolis salesman would be a laryngectomy-an operation that would leave him with half a voicebox. Before consenting to the radical procedure, however, Graham (not his real name) sought a second opinion from Merrill Biel, an oncologist at the Abbot-Northwestern Hospital in Minneapolis, who had reported success with an innovative cancer treatment called photodynamic therapy (PDT).
Instead of performing surgery, Biel proposed to inject Graham with an experimental photosensitive drug, Photofrin, which attaches to special proteins in the blood that accumulate in abnormal tissues such as tumor cells. (The drug also gathers to some extent in healthy tissue, though in much lower concentrations.) Two days after the injection, Biel explained, he would thread a laser-tipped tube through Graham’s throat and bathe the affected area in laser light. The light would activate the Photofrin-a synthetic version of natural, light-sensitive agents called porphyrins-which would, in turn, release toxic agents that kill cancer cells.
One of the main advantages of PDT is that Photofrin has no toxicity unless light is shined on it.
Hemotherapy drugs, by contrast, are poisonous to cancerous and healthy cells alike, though they, too, can save lives. Another benefit is that PDT, unlike radiation therapy, can be repeated as often as necessary without danger to the surrounding healthy tissue, so long as the light beam is focused squarely on the tumor. And PDT is less draconian than surgery, the other cancer stalwart. “If PDT doesn’t work, you can always do surgery,” Biel explains. “But if you take the voicebox out, you can’t put it back in.”
Graham opted for the experimental therapy. And the decision appears to have paid off. More than five years later, Graham remains cancer-free. In fact, so have most of Biel’s other patients: of some 120 patients with vocal-cord and mouth cancer that he has treated with PDT over the past eight years, 95 percent are apparently cured.
Other researchers in the United States, Canada, Japan, Europe, and Australia have reported similarly encouraging findings. As a result, PDT is finally getting some official recognition. In 1993, Canada approved Photofrin for the treatment of bladder cancer-the first light-activated drug sanctioned for use anywhere in the world. A year later, the drug received marketing approval in Japan and the Netherlands for treating early-stage lung, esophageal, and other cancers. The U.S. Food and Drug Administration approved the drug for treatment of esophageal cancer in 1995, and French health regulators granted a similar endorsement in 1996.
This progress stems largely from the efforts of Thomas Dougherty, who created Photofrin and has promoted PDT since the early 1970s. “For the longest time, hardly anyone was interested in Photofrin,” says Dougherty, head of radiation biology at the Roswell Park Cancer Institute in Buffalo. “We managed to change people’s minds not by what we said, but by making the drug available to other investigators whose clinical findings speak for themselves.”
The technique does have limitations, however. “Once you’ve found the tumor, the big question is how to get the light there,” says Thomas DeLaney, chief of radiation oncology at Boston Medical Center. Indeed, while some internal organs can be reached using flexible fiber optic catheters, the approach is unable to destroy very large tumors because of the practical difficulties of distributing light throughout the interior of a sizable mass. What’s more, PDT’s greatest strength, its photosensitivity, is also its greatest weakness. Photofrin is retained in the skin for about six weeks, during which time patients have to avoid direct sunlight or bright lights to prevent the possibility of inadvertently damaging or killing normal cells.
The good news is that some half-dozen companies, including Quadra Logic Technologies (QLT), the Vancouver, British Columbia, company that is marketing Photofrin, and PDT, Inc., in Santa Barbara, Calif., are developing second-generation drugs to avoid these problems. QLT’s new light-sensitive compound, benzoporphyrin derivative (BPD), leaves the body much more quickly, so a patient has to remain out of the sun for only a couple of days. Some researchers believe the drug will be able to attack larger and deeper tumors than Photofrin because it is activated by lower-frequency light that penetrates farther into human tissue.
Progress on the pharmaceutical front has been accompanied by corresponding advances in light-delivery technology. “In the early days, we used big, expensive lasers that had to be operated by a trained technician,” says Dan Doiron, chief scientist for PDT, Inc. “We now have cheaper, more compact laser systems that can be operated by doctors and nurses in a small hospital or office setting.” These laser and pharmaceutical advances “open up opportunities for treating a wide range of diseases in addition to cancer,” he notes, because PDT drugs selectively congregate in a variety of rapidly growing cells, not just cancerous ones.
Investigators are therefore exploring applications for treating such disorders as eye diseases, psoriasis, and rheumatoid arthritis. QLT, for instance, is testing the drug BPD for the treatment of age-related macular degeneration-the leading cause of blindness in people over the age of 50. BPD accumulates in the network of abnormal blood vessels in the eye that obscure vision; when illuminated with laser light, the compound can clear away those unwanted vessels. BPD also tends to accumulate in greater concentrations in the rapidly proliferating skin cells characteristic of psoriasis, which, too, can be destroyed by the administration of light. In preclinical trials, treatment with BPD and light also selectively killed cells that proliferate in the joints of patients suffering from rheumatoid arthritis. And more recent clinical trials have shown that the drug can suppress the activation of immune cells that cause the symptoms of psoriatic arthritis.
Although conventional cancer therapies will still be needed to treat tumors that cannot be illuminated by optical means, as well as malignancies that have spread throughout the body, PDT can complement existing techniques. Biel predicts PDT will take its place alongside surgery, radiation, and chemotherapy as a fourth weapon in the anticancer arsenal. And patients who have exhausted the usual options may have another chance.
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