Photodynamic therapy (PDT) is hardly a mainstream cancer treatment, but new photosensitizers, new light sources and delivery devices, and a plethora of laboratory findings attempting to explain precisely how PDT kills tumor cells are expanding the understanding and use of the therapy.
The concept is relatively simple: Inject into a patient a light-sensitive drug that concentrates primarily in tumor cells, and 2 or 3 days later activate the drug with a light source (usually some kind of laser) directed at the tumor. The drug reacts with the oxygen in the tissue and produces singlet oxygen, which is cytotoxic to tumor cells. For PDT to work, the cancer must be accessible either directly (including in an operative bed) or endoscopically.
Thomas Dougherty, Ph.D., director of the Photodynamic Therapy Center at Roswell Park Cancer Institute (RPCI) in Buffalo, N.Y., first developed photodynamic therapy some 3 decades ago. In addition to many centers in Europe and Japan, he estimates that some 100 centers in the United States are now using PDT.
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Exactly how Photofrin and the various other photosensitizers under investigation cause cell death is unclear, said Barbara Henderson, Ph.D., professor of cellular and molecular biophysics at Roswell Park Cancer Institute. Some photosensitizers appear to induce necrosis while others induce apoptosis, but this may also depend on the photosensitizers subcellular target. "Weve been able to make photosensitizers that localize in almost every compartment of the cell except maybe the nucleus," said Henderson. "Those that localize in the mitochondria may be the most effective." Whether the exact mechanism of cell death is important is somewhat unclear, although it may govern whether PDT induces an adaptive immune response (conceivably resulting in decreased metastases) and/or an inflammatory response.
Studies of mechanisms of action have, for example, shown that PDT induces transcription factors likely to activate vascular endothelial growth factor (VEGF). Charles Gomer, Ph.D., professor of pediatrics and radiation oncology at the University of Southern California, Los Angeles, and his colleagues combined PDT in animal tumor models with an anti-VEGF therapy, which resulted in better cure rates, he said. After later finding that PDT induces COX-2, which may have a role in angiogenesis, they then added COX-2 inhibitors to PDT. "Not only did we see enhanced tumor response by the combined modality but no enhanced skin response," said Gomer.
The skin response is a particular concern with Photofrin because the drug seems to accumulate in the skin, causing skin photosensitivity sometimes for weeks. For this and other reasons, three new photosensitizers are in clinical trials, one under the auspices of the National Institutes of Health and the other two sponsored by Light Sciences Corp. of Seattle. Light Sciences has a license and research agreement with Roswell Park Cancer Institute, giving them the exclusive rights to develop many photodynamic compounds and technologies discovered and tested at the institute.
Additional light sources are under study as well. Most of the light used is produced by lasers and is in the red part of the spectrum where tissue penetration is greatest. Other wavelengths are being studied for use, and the newer solid-state lasers will be useful and easier to maintain. Still, noted Eli Glatstein, M.D., professor of radiation oncology at the University of Pennsylvania, Philadelphia, more attention should be paid to dosimetry, or the amount, rate, and distribution of the light in tissues. "It isnt always what comes out of the laser but what hits the tissue that counts," he said.
Light Sciences Corp. also has developed an innovative light source for oncologya microarray of light-emitting diodes that delivers light at a low energy and that can be implanted directly into a tumor. The device is being used in one of the companys clinical trials of photosensitizers.
Most physicians who are using PDT get referrals from all over the country, and sometimes from abroad, from both physicians and patients. Patients with premalignant or superficial types of cancer who want, for example, to try to avoid losing their esophagi, larynxes, or bladders, or perhaps live a little longer with a malignant brain tumor, may seek out PDT. Because of the interest in the therapy, a number of investigational studies of PDT are well under way.
Gastrointestinal Cancers
Patients with premalignant conditions in the esophagus such as high-grade dysplasia or superficial cancers appearing in Barretts esophagus are candidates for esophagectomy, noted Kenneth Wang, M.D., associate professor at the Mayo Clinic, Rochester, Minn. To avoid the morbidity and possible mortality associated with esophagectomy, Wang has used PDT on these patients. In many patients, the Barretts and dysplasia improve considerably or disappear. He is trying to learn if certain genetic or biological factors, such as lack of the p53 mutation, play a role in determining who responds best. Roswell Park Cancer Institute gastrointestinal surgeon Hector Nava, M.D., is doing these studies as well. There is also work on a balloon device that would separate folds in the esophagus for more even treatment.
One problem in treating the esophagus with PDT is pain, which can be severe and last for days. On the other hand, if there are local recurrences after radiation therapy or chemotherapy, PDT often can be used effectively to treat the recurrence.
A less well-known GI application of PDT is in bile duct cancers. Using the technique of endoscopic retrograde cholangiopancreatography, an endoscopist inserts optical fibers into the bile duct obstructed by tumor. The light activates Photofrin that has been previously injected into the patient. "This seems to allow very small branches of the bile ducts to open up, even in areas where you didnt shine the light, and relieves the patients jaundice," said Wang.
Brain Tumors
Neurosurgeon Paul Muller, M.D., professor of surgery at the University of Toronto, and Andrew Kaye, M.D., a neurosurgeon in Melbourne, have probably the most extensive experience with PDT in brain tumors. Using an optical fiber in a light-diffusing medium, Muller applies PDT to the surgical bed immediately following resection to treat patients with malignant glial tumors, particularly glioblastoma and anaplastic astrocytoma. He has seen occasional dramatic results and long-term survival, but he added that, of course, "this is not scientific certitude."
Two multi-institutional phase III studies, both begun about 4 years ago, are under way in the United States and Canada. The first, a randomized controlled trial at two institutions, focuses on newly diagnosed patients and is an attempt to see whether Photofrin PDT (cavitary photoillumination) increases survival when added to standard care, which is surgical resection of as much tumor as possible followed by radiotherapy and sometimes chemotherapy. The second phase III trial, being carried out at four centers, focuses on patients who already have failed radiotherapy, have undergone previous surgery or biopsy, and are candidates for "palliative reoperation" in an effort to extend survival. In this trial, the question is whether a low or higher light dose has an effect on survival.
Muller noted that these may be the only trials of PDT that have had patient survival as an end point. "PDT is an evolving discipline," Mueller added.
Head and Neck Cancer
For years, Merrill Biel, M.D., has been treating several types of head and neck cancers with PDT. "In treatment of early cancer of the larynxeither a primary cancer or a radiation failurewith more than 10 years of follow-up in some patients, our cure rate has been 88%, which is very consistent with the standard cure rates with radiotherapy or surgery, which typically will involve laryngeal resection," said Biel, who is a head and neck oncologist at Ear, Nose and Throat SpecialtyCare of Minnesota, located in Minneapolis, and a clinical professor at the University of Minnesota. Similarly, treatment of superficial oral, oral/pharyngeal, or nasal cavity tumors has yielded a cure rate of 88% to 90%.
Biel has also treated stage 3 and 4 head and neck tumors by giving PDT after surgery to the resection bed in an attempt to eradicate microscopic disease. "I think there is a place for PDT intraoperatively in all advanced tumors," said Biel, "but a clinical trial is needed. We had one all set to go but there was no funding for it."
Bladder Cancers
PDT as a treatment for noninvasive bladder cancers had a bad reputation because of reports of toxic effects such as bladder contraction, bladder irritation, and other problemsoccasionally permanentafter the treatment. "It turns out, though, that the toxicity was dose-related," said Unyime Nseyo, M.D., professor and chairman of the division of urology at Virginia Commonwealth University School of Medicine, Richmond. "The higher the light or drug dose, the more toxicity."
This led Nseyo and colleagues to try PDT as sequential therapy. "Rather than deliver a whopping dose to kill the cancer, we decided to fractionate, much as is done with radiotherapy," Nseyo said.
Nseyo has treated about 20 patients with sequential therapy, delivered every 6 months so as to make sure all skin sensitivity has subsided. Because tumors can regrow in the meantime, he said he is looking for "an ideal photosensitizer" that will work well in bladder cancers and can be given in sequential doses. "Some new ones are coming out, but they have not been thoroughly enough investigated to put them into our clinical practice yet," he said.
Intraperitoneal and Pleural Disease
Photofrin PDT is already approved by the FDA for use in certain lung cancers. However, intraperitoneal treatment using PDT has been somewhat problematic. "We either need a new photosensitizer, a different way of handling the distribution of light, possibly by altering the light sources or the light-diffusing medium that we place into the peritoneum, or a way of getting more oxygen to the area," said Pennsylvanias Glatstein.
The Philadelphia group is also investigating what they call "interstitial PDT," beginning with prostate cancer that has recurred after radiotherapy. They are using an experimental photosensitizer called lutetium texaphyrin. The technique resembles brachytherapy but, instead of radioactive seeds, physicians place fiberoptic light sources in the prostate in conjunction with a photosensitizer. "We put a template over the perineum and through that template, using ultrasound, we insert the fiberoptics into the prostate," Glatstein said.
PDT has faced some challenges since Dougerty developed it in the 1970s, and some clinicians have backed off from using PDT because of its complexity. But the development of new sensitizers, the search for new indications for PDT, and the sheer number of centers throughout the world that now use PDT has left Dougherty optimistic. "So things are not so gloomy," Dougherty said.
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