Eric Rubin, MD, director of clinical pharmacology there, explains that the search for treatments begins in the laboratory, where scientists test new ideas. When a drug is actually developed, it is tested on laboratory animals to determine its effects-good and bad-on a living being. If the treatment is relatively safe and effective, it goes into clinical trials, which are carried out in three stages, Phase I (one), II (two) and III (three). Not only are new drugs tested in this manner, but new ways to use old drugs must go through similar steps.

    Phase I establishes the best method of administering the drug - by mouth, injection or intravenously - the best dosage, and what side effects, if any, may occur. "Some of the newer drugs have few, if any, side effects, so determining the dosage can be very complex," Rubin says. "We have to monitor patients extremely closely." The physician is also an associate professor of medicine and pharmacology at UMDNJ-Robert Wood Johnson Medical School.

    Only a limited number of patients who would not be helped by other known treatments are enrolled. Usually there are between a dozen and 30 participants. Ray Greger is a veteran of Phase I clinical trials. The 59-year-old Sandy Hook resident is currently participating in his sixth. Two have worked, four have not. But Greger continues to enroll.

    Greger's story began in 1995 when physicians determined he had bladder cancer. The bladder was removed, and an artificial one, fashioned from his large intestine, was inserted. An avid angler since his youth, Greger did his share of fresh- and salt-water fishing during the subsequent three years that he was cancer free.

    But in 1998, he began experiencing a great deal of back pain. Physicians discovered it was being caused by a tumor on his sacrum - the bone between the hip bones of the pelvis - that was pressing on his continued spine. Since the cancer had metastasized and the tumor was difficult to surgically remove, Rubin recommended Greger enter a Phase I clinical trial. Besides possibly helping develop a new drug to benefit others, Greger says he was hoping it would quell his own disease.

    "Often bladder cancer spreads to the other vital organs, particularly the liver," he says. "I was very concerned that the drug wouldn't work, and I was also worried about the possible side effects. But I did well." He suffered very little, he says, having only mild flu-like symptoms and slight nausea. What made him even happier, however, was that after four cycles, or 16 weeks, the combination of taxol, the number one cancer drug used, carboplatin, also a commonly used chemotherapy drug, and a new drug Gemzar, shrank the tumor, thus relieving the pain. His disease stayed under control for five months.

    Unfortunately, the medication began to lose effectiveness and the pain returned. Greger enrolled in a second trial, but it, along with the following three trials, was not helpful. Rubin explains that the efficacy of drugs in animals is not always the same in people. "We don't know why they sometimes don't work," he says.

    During the four trials, Greger's tumor either stayed the same size or grew a little, and he suffered severe side effects, including nausea, vomiting, diarrhea and tremors. He lost his appetite and 20 pounds. There were complications, too - an infection and a blood clot - that required hospital stays. But losing all his hair, he says, was the worst.

    "It's a personal part of your makeup and you want to keep it, even if it's not the greatest," he says. "That was really the only downer. I wore a hat and tried not to dwell on it. Except for that, I never really got depressed."

    He was concerned about what the drugs might do to his mental capabilities. A former bank executive, Greger hated having to give up his job in 1998 because of his illness. But even worse, he thought, would be if he finished a trial and wasn't "still mentally sharp." That didn't happen.

    Greger says he never once felt like a guinea pig. "The risk is minimal because you are watched so carefully. The first concern is always the patient," he explains. "A physician or a nurse practitioner is always on call to answer questions or help you. And if things aren't going just right, they find out why or stop the treatment immediately."

    Currently in his sixth Phase I trial, Greger is taking a combination of the drugs taxol, retinoic acid and interferon. This cocktail was designed at CINJ, based on work done there. "We found evidence to suggest cancer can become resistant to taxol," says Rubin. "We believe this combination may reverse that process."

    If Greger's response is any indication, it may work. He is slowly getting off his pain medication, has a full head of hair, has regained much of his energy and is slowly putting on some weight. In early April, he started getting his boat ready to launch for another season of fishing. Like many with serious diseases, he takes one day at a time and rarely makes long-range plans. He does, however, plan to continue participating in clinical trials.

    "I know I'm terminal, but I'm not even close to death," he says. "And except for cancer, there's nothing wrong with me: I don't have diabetes or heart problems or the like. If these trial medications can keep the cancer in check, I could live a long time. And I may even help come up with a cure in the meantime."

    Phase I trials are of great value, Rubin explains, because of their potential. "We aren't certain how patients will react, but there can be some very dramatic responses," he says. "We're always hopeful that a new drug or new combinations of drugs will help curb or even cure the disease."

    The second phase of trials continues to test the drug's safety and begins to evaluate how well it works. Does it shrink tumors? Are test results improved? This phase also uses a small number of patients who all have the same type of cancer.

    The third and final phase generally enrolls large numbers of people at sites across the country and sometimes even abroad. They are randomly placed into one of two groups by a computer, to eliminate any possibility of bias. One group, known as the intervention group, is given the new treatment, while the other, the control group, receives the standard treatment. At the conclusion of the trial, the responses of the two groups are compared.

    Sometimes a Phase III study will be what's known as "single blind." This means the patient is not told whether he is getting the standard treatment or the new drug. Only the doctor knows. A "double blind" study - commonly used in Phase III trials - is one in which neither the physician nor the patients knows who is getting the experimental drug or the new drug. These studies are designed to eliminate the placebo effect, or the belief by patients that they are feeling better even though they are not taking the new drug.

    But that is the only fact that may be kept confidential. Participants are given a consent form that presents all the facts, in minute detail, on what will be done during the study and why, and all possible risks and benefits. The form is reviewed with the physician and patients take it home. They have up to a week to discuss it with loved ones and make a decision. And patients don't have to remain in a study if they become uncomfortable. They may drop out at any time.

    At the start of the trial, participants receive a detailed action plan, or protocol. It explains what the trial will do, what agent will be taken, the number and type of patients enrolled, when and what tests will be done, and what information will be gathered. It also contains a day-by-day treatment schedule.

    Joseph Aisner, MD, associate director for clinical sciences at CINJ, says clinical trials are reviewed at their onset for safety, and there are a number of controls in place to make sure they continue to be conducted that way. At CINJ, trials begin with tumor study groups. There is a group for each type of cancer - breast, prostate, etc. - consisting of specialists from all disciplines of cancer care. The scientist who is directly managing the study, known as the principal investigator, is never a member of the tumor group reviewing his or her trial. A physician who starts a new trial, say for a breast cancer drug, presents his or her study concept to the breast tumor study group. The members help develop the protocol and set priorities for its use. They meet weekly to discuss patients they've seen, and decide which ones are best suited for particular trials. The study groups also meet at least once a month to discuss the trials themselves.

    Once the tumor study group has formulated the trial, a proposal is submitted to the Scientific Review Board (SRB) at CINJ. The board is comprised of physicians, surgeons, radiation oncologists, biostatisticians, bioethicists, and lay people. These people have the task of deciding if the study concept is significant enough to proceed, if the methods are valid and appropriate, and if the research is statistically feasible. "The SRB also examines how the trial will impact our resources," Aisner says. Once the SRB accepts the trial proposal, the protocol is forwarded to the CINJ Institutional Review Board (IRB), which again reviews it for human safety.

    Phase I study groups add another dimension of safety. Their members help determine the correct dosages by examining the pharmacokinetics of the drug. That is the study of what happens to the drug once it's in the body. How the drug is distributed, how long it stays there and how it is eliminated are all appraised. "This helps us understand how to use the drug," Aisner says. "For example, if a pain medication lasts only 90 minutes, taking it every four hours won't do the job." This group also looks at the drug's pharmacodynamics, or the drug's effect on the body. When a drug produces a toxic effect, for instance, the dose may continued be too high. The Phase I study group also meets weekly and passes its findings onto the SRB as well.

    CINJ's research activities are monitored by outside agencies, including the National Cooperative Groups, the FDA and NIH's National Cancer Institute.

    Crucial to the development of new drugs is the research pharmacy. Susan Goodin, Pharm D, director of the pharmacy at CINJ, says her department is responsible for the tracking, preparation and dispensing of all investigational treatments. "Since many of our protocols involve drugs that are in limited supply, it's important before starting a therapy to verify that we have enough in stock to complete the course," Goodin says.

    The pharmacy sometimes improves ways of administering treatments. Since the drugs are in the early stages of development, many have been given only on a limited basis. Methods of preparation and administration haven't been established. "In those situations," she says, "we work closely with the company developing the product to establish preparation and administration guidelines."

    Verification of dosages is a critical part of the job. First the pharmacist checks that the dosage of the drug on the patient's order matches the one outlined in the protocol. Next he or she makes sure the dosage is the correct one for the patient, based on height, weight and organ function. Finally, the pharmacist makes certain that there will be no adverse interactions with other drugs being taken by the patient, including any alternative medications.

    Goodin works closely with the SRB and IRB to assure dosages on protocols are written clearly. "We want to avoid any type of nonspecific language," she explains, "particularly for multiple-day therapies." She and her department consult with physicians on pain management and other supportive patient-care issues. And Goodin is currently involved with her own clinical trial. She is testing green tea as a preventative for mouth sores in patients receiving chemotherapy and radiation.

    Most investigators at CINJ are very optimistic about finding a cure in the near future. Rubin says that's because there's been a revolution in the way cancer research is now being approached. "Years ago we didn't know what caused cancer, so scientists took a variety of plants, ground them up, purified the active ingredients and we had cancer drugs," he explains. "We now have an understanding of cancer at its molecular level, so we can target a specific mechanism within the cell and design drugs to halt or interfere with it."

    A main target is the communication of the cells with one another, which is called signal transduction. Cells send signals back and forth using "messenger" proteins. The genes provide the information on the protein. When communication lines work properly, cells perform their normal functions. But if the lines break down or send the wrong signal, problems, like cancerous tumors, develop. The goal is to disrupt or change the communications process when it's being used by the disease.

    Oncogenes - genes that can transform a cell into a tumor cell - are sometimes responsible for cell communication problems. Antioncogenes are drugs that suppress specific oncogenes. An example is herciptin, which inhibits the oncogene Her2/neu. Scientists believe it may be responsible for some breast cancer. It proved to be successful in clinical trials on women who had previously been treated for that disease. "We hope that eventually we can give it to women in the very early stages of breast cancer," Rubin says.

    Another, bcr-abl, has been shown to be a good target for chronic myelogenous leukemia. The drug STI 571 has been effective in trials against it, even in patients who did not do well on other treatments. "This is a very exciting time in cancer research," he says. "We've moved from asking if we should study the proteins in the cells, to which specific protein should we target."

    Angiogenesis inhibitors are another promising new area of research. This is a group of compounds that block the development of new blood vessels, a process known as angiogenesis. A solid cancer tumor can't grow more than about the size of a pinhead without new blood vessels to supply it with oxygen. If blood vessels can't grow, researchers believe, the tumor will die.

    Drugs that target microtubules, which are part of the architecture that lets a cell divide, are also being studied. Blocking them means cancer cells will be unable to furiously reproduce into tumors.

    Some of these types of drugs are found in nature. One, known as epothilone, is found in fungus, and another, the very common taxol, comes from Pacific yew trees.

    Vaccines, too, are under investigation as possible ways to slow down or even stunt the growth of cancer. One currently in clinical trials that looks promising attacks prostate tumor cells.

    Prevention, the best medicine of all, Rubin says, has also taken giant leaps forward. CT and PET scans and MRIs are all greatly improved. "Until recently we had to wait months sometimes, to find out if a lump was scar tissue or a tumor," he says. "Now we can find out almost immediately. And we now can see if a tumor has formed new blood vessels and if it's growing."

    Even information on the Internet, he says, has been responsible for people getting to doctors sooner, when they suspect problems. "I'm happy when people come in with printouts from the Net," the physician says. "It's so much better than comparing their disease to Aunt Nellie's."

    A cure may be right around the corner, but for now developing new therapies is still the foremost hope. To do that, however, clinical trials must go on, and it's often difficult to recruit patients.

    Pediatric cancer is more curable than adult cancer, Rubin says, yet the percentage of kids who enroll in trials is far higher, at 85 percent, than that of adults at only as high as 10 percent.

    "Now that New Jersey has passed legislation to pay for experimental drug therapy, we're hoping that will change," he says, "because future treatments are our best hope for making cancer a disease of the past."