CONNECTING TO NJ'S CANCER TRIALS

Breast cancer survivor Lori Gusz (left) with Deborah Toppmeyer, MD

By Mary Ann Littell

In January 2002, just six months before her wedding, 35-year-old Lori Gusz was diagnosed with breast cancer. She underwent an immediate lumpectomy, followed by surgery to remove several lymph nodes, then began a round of intensive testing—bone scans, cat scans, blood work, and more—to see if the cancer had spread. And that was the easy part.

"Deciding on a course of treatment was one of the most difficult things I’ve had to do," she says. "There is so much confusing and conflicting information out there."

After the surgery and tests, Gusz saw two oncologists. They outlined totally different treatment regimens. How could she determine which one was best for her? Like millions of other Americans, Gusz turned to the Internet for information about cancer therapies. Navigating her way through the "e-maze" proved to be an additional challenge she hadn’t expected. "The volume of cancer Web sites is overwhelming," she says. "And there is so much ambiguous information about which treatments are superior."

Gusz received a third referral from a former employer who had successful treatment at The Cancer Institute of New Jersey (CINJ). She saw Deborah Toppmeyer, MD, director of CINJ’s Breast Oncology Program, who told her she qualified to participate in a clinical trial of a promising new therapy. "Up to this point, none of the physicians I saw had mentioned clinical trials as a possibility," Gusz says. "But after doing some research, I was intrigued. It seemed very state-of-the-art and I decided to do it."

Gusz says she was fortunate to have received a personal referral that helped point her in the right direction. Now, however, other patients in the state of New Jersey won’t have to rely on luck to make such important decisions. On April 15, CINJ launched a Web site, New Jersey Cancer Trial Connect (NJCTC), to provide information about all cancer clinical trials in the state. A visitor to the site enters specific information about the cancer diagnosis and treatment history, and in turn receives a comprehensive list of clinical trial "matches."

The primary goal of the Web site is to make clinical trials more accessible to cancer patients in New Jersey. Also, recruiting patients into clinical trials will ensure that more effective therapies will be developed. This year, more than 42,000 state residents will be diagnosed with cancer, and about 18,000 of them will die. Unfortunately, few of these patients will explore clinical trials as treatment options.

Susan Goodin, PharmD, director of the Division of Pharmaceutical Sciences at CINJ, says, "Clinical trials for cancer offer some of the best treatment options available, but the percentage of patients who enter them is extremely low: only 2 to 3 percent." Why is this number so small? According to a recent Harris poll, 85 percent of cancer patients are either unaware or unsure that participation in clinical trials is an option.

Another factor limiting enrollment is the fact that many physicians are reluctant to recommend clinical trials. In a recent survey, most primary care physicians and many oncologists said they viewed trials as "treatments of last resort." Goodin says that, on the contrary, clinical trials offer some of the best treatments around: "We don’t test new therapies unless we think they can be as good or better than what’s currently available."

HOW www.njctc.org WORKS

With more than 300 cancer treatment trials going on in New Jersey alone, it is difficult, if not impossible, for physicians and patients to find out about all of them. NJCTC certainly simplifies the learning process. Say you have just been diagnosed with colon cancer. Visit www.njctc.org and type in your diagnosis and other details about your condition. You’ll receive information by putting in as little as your zip code. However, the more specific you are, the greater the chance that you will locate a clinical trial that is a match. As a registered user, you may create a personal, password-protected homepage where you can store information specific to your diagnosis and treatment. If you choose, NJCTC will email you directly with monthly updates about new trials.

NJCTC is the first and only state-specific Web site in the country for cancer clinical trials. The information on the site was compiled by researching medical facilities across New Jersey. "We’ve contacted everyone in the state who is doing cancer clinical studies, so we believe our database is comprehensive," states Goodin. It’s also well-organized and easy to navigate, unlike many other sites dealing with the complexities of cancer. Visitors to the Web site can print the information, email it to friends and family, and share it with physicians, who can help the patient learn more about the trial and whether or not they meet eligibility requirements. Patients can also contact clinical trial coordinators directly. Those who don’t have Internet access can call a toll-free telephone number (866-788-3929) for clinical trials information.

"With cancer, you have no choice," says CINJ director William N. Hait, MD, PhD. "If you want the best care, you have to go to a place where they are doing something new."

CINJ has more than 150 clinical trials underway, 14 of them for breast cancer. Here is a look at a few promising ones, including the one Lori Gusz entered. (For information on other clinical trials for breast and prostate cancer and leukemia, see Clinical trials showing promise.)

Developing Targeted Therapies

"Our approach to treating breast cancer is more streamlined than it used to be," says Toppmeyer. "We’ve moved beyond the shotgun approach. Now that we better understand the enemy, we have more selective therapies targeted to different cancers."

Toppmeyer, who is also associate professor of medicine at UMDNJ-Robert Wood Johnson Medical School (RWJMS), says a primary mission of CINJ is giving patients the best possible care within the research environment. She explains that a new understanding of the genetic differences in breast cancer—in fact, in all cancers— has led to the development of innovative and targeted treatments. "Right now, we’re seeing so many promising new therapies, but we need to perform the clinical trials to determine their role, if any in our clinical armamentarium," states the oncologist.

And for cancer patients, time is critically important. Toppmeyer points out that the drug Herceptin, which has shown promise in targeting specific cancer cells that overexpress a protein called HER2, has been under study for 15 years. Some 25 to 30 percent of breast cancers overexpress HER2; these tumors tend to be more aggressive than those that do not overexpress the protein.

Herceptin is FDA-approved for first-line use in combination with paclitaxel for the treatment of breast cancers overexpressing HER2, and is also indicated as a single agent for the treatment of these cancers in patients who have already received chemo-therapy. It is still being widely studied in clinical trials at CINJ and numerous other sites in combination with different drugs to see whether new treatments are more or less effective than the standard ones and how the side effects compare.

"We’ve been studying Heceptin for a long time—from the lab with translation to the clinical arena," says Toppmeyer. "If we can get these answers more quickly, people will benefit."

In addition to the Herceptin studies, many other breast cancer trials are currently underway at CINJ. Some are nationwide studies, others are being conducted at institutions belonging to the Eastern Cooperative Oncology Group, a large, NIH-funded network of researchers, physicians and healthcare professionals. Some trials have thousands of participants, others are new and smaller in scope.

A few trials are unique to CINJ. One of them is a Phase II study involving a sequential combination of doxorubicin (trade name Adria-mycin), so named for its ruby-red color, and vinorelbine (trade name Navalbine). It is based on Hait’s own laboratory findings, studying the role of p53, a protein that plays a major role in the transcription of DNA, in cell growth and proliferation, and in a number of metabolic processes on sensitivity to different classes of chemotherapy agents. Some 50 percent of cancer cells are mutant for p53; the other 50 percent are called "wild type." Testing tumor tissue, Hait found that wild type p53 induction by doxorubicin in breast cancer cells repressed another protein, MAP4, in the cells, which in turn increased the cells’ sensitivity to certain chemotherapeutic agents.

With NIH funding, a study was launched to evaluate whether these results can be duplicated in women with breast cancer and how the treatment would be tolerated. The first drug, doxorubicin, is administered on day one. On day three, researchers measure the changes in expression of wild type and mutant p53, and vinorelbine is administered. On day 10, vinorelbine is administered again. On day 22, the cycle is repeated. Therapy continues as long as the cancer is responding to treatment and the patient is tolerating it.

This trial is for women with locally advanced or metastatic breast cancer with a tumor accessible for biopsy. Up to 40 patients can enter. "We have good medications, but we don’t always use them optimally," explains Toppmeyer. "In this trial, we’re using drugs already established for treatment of breast cancer. By altering the schedule based on genetic profiling of cancer cells, we hope to make them more effective."

IF THE TRIAL FITS….

Lori Gusz first discovered the lump in her breast while doing a routine self-examination. It was hard and immovable, but at first, she couldn’t believe it was anything serious. "At my age, you just don’t think you’re a candidate for breast cancer," she says.

When she received her diagnosis, Gusz and her fiancé immediately canceled the large wedding they’d planned for mid-July and instead, were married in a small ceremony for family and close friends. She’d had a lumpectomy a few weeks earlier, when she received word that her tumor was malignant. "It was strange, planning a wedding while having bone scans, CAT scans and other tests," she says. "Fortunately, that news was good. The was no sign of cancer anywhere else."

Gusz and her husband had a brief, not-very-enjoyable honeymoon in Jamaica, where she coped with a sore, swollen arm, the aftermath of sentinel node biopsy and lymph node removal. In the biopsy, the first node the tumor drains into is removed and studied in an effort to find out how many nodes may be affected. (In all, nine nodes were removed.) She then began her search for treatment.

After extensive discussions, Toppmeyer recommended that Gusz enter a clinical trial for breast cancer patients with positive axillary lymph nodes. It is a Phase III trial, meaning it is in the final stage of testing, with large numbers of people enrolled at numerous sites. In this trial, patients are assigned to three treatment groups to take different combinations of the medications doxorubicin (Adriamycin), cyclophosphamide (Cytoxan) and docetaxel (Taxotere). All are commonly used chemotherapy drugs. The researchers are evaluating whether giving the drugs in different combinations will prevent recurrence of cancer. They are also comparing side effects.

Gusz took the three drugs all at once in four treatments, one every three weeks. "The first chemotherapy treatment wiped me out somewhat, and I had to go into the hospital for a few days," she says. "But I tolerated the other three much more easily." The medications were given intravenously at the CINJ clinic, located on the first floor of the facility.

She finished the chemotherapy in June 2002 and underwent radiation. She is now taking Tamoxifen for five years. The drug is widely used in the treatment of breast cancer, and more recently, is given as adjuvant, or additional, therapy following primary treatment for early stage breast cancer. Some breast cancer cells are estrogen sensitive—they are stimulated to grow when estrogen binds to them. Tamoxifen prevents or delays breast cancer recurrence by blocking the binding of estrogen to the cancer cells.

Gusz says she feels great and her prognosis is very good. To celebrate it, and her new marriage, she and her husband went on another honeymoon in June, this time to Iceland. It is unknown whether treatments will affect her fertility, but she’s not concerned with that right now. "I’m just looking forward to my two-year milestone, which is when many aggressive cancers recur," she says, "and, ultimately, my five-year anniversary, when the likelihood of recurrence diminishes."

Says Toppmeyer: "The ideal concept behind clinical trials is to translate novel discoveries in the lab to the clinic. The more efficiently we’re able to do this, the more we can help patients." Patients like Lori Gusz—who says she is confident that she found the best treatment available.

Clinical trials showing promise

Groundbreaking research in UMDNJ laboratories has led to the development of many promising therapies for cancer. Moving from the bench to the bedside, here is a look at a few that are being tested in clinical trials. The prostate cancer and leukemia studies are being conducted at The Cancer Institute of New Jersey (CINJ); the breast and cervical cancer trials are at UMDNJ-New Jersey Medical School (NJMS).

Prostate Cancer

Prostate cancer is the second most common cancer in New Jersey, afflicting some 6,600 residents each year. Among the research initiatives of oncologist Robert DiPaola, MD, executive director of the Dean and Betty Gallo Prostate Cancer Center at CINJ, is studying tumors that are resistant to hormone therapy (called hormone refractory prostate cancer or HRPC). Chemotherapy is only temporarily effective in patients with HRPC.

In laboratory studies at CINJ, researchers found that certain drugs, including retinoic acid and interferon, lower the resistance of a tumor to chemotherapy. Two clinical trials are underway at CINJ to see if these results can be duplicated in patients. One, the R.I.T.E. study, is a Phase I/II trial of retinoic acid and interferon given with two commonly used chemotherapy drugs, Taxotere and estramustine. The latter two drugs have been shown to control tumor growth in more than 60 percent of patients for a limited time period (six to eight months). Since retinoic acid and interferon can alter drug resistance to chemotherapy, their addition to the Taxotere/estramustine combination may improve response rate and duration of response. This study has been funded by the U.S. Department of Defense. Another trial, for patients with metastatic HRPC, is based on the same concept, with the inclusion of two additional chemotherapeutics: Navalbine and paclitaxel.

DiPaola, who is co-author of "A Doctor’s Guide to Herbs and Supplements," has a keen interest in alternative medications and has conducted laboratory studies of several derivatives of licorice root. One such substance, Licochalcone-A, was found to kill cancer cells in the laboratory. The researcher is now conducting a Phase II study of glycyrrhiza glabra, another derivative of licorice root in pill formulation, to treat HRPC. He plans to conduct a later study of this substance combined with chemotherapy.

Another Phase I study is evaluating the safety of PROSTVAC, a prostate cancer vaccine that targets PSA (prostate specific antigen). PSA is a protein produced only in prostate tissue, and blood levels are elevated in men with prostate cancer.

Leukemia

Several studies are underway at CINJ for the treatment of patients with leukemia, myeloma, Hodgkin’s lymphoma, and other hematologic cancers. Patients participating in these trials are cared for by the multidisciplinary CINJ Hemato-logic Malignancies Tumor Study Group. These disorders are characterized by uncontrolled growth of blood cells. In acute leukemia, immature, functionless cells build up in the bone marrow and blood, preventing the marrow from producing enough normal red and white blood cells and platelets. Acute myelogenous leu-kemia (AML) is the most common acute leukemia in adults, with some 10,000 new cases annually. CINJ, a leader in the treatment of AML, sees 60 of these patients a year, nearly one percent of all new cases in the U.S.

"AML is more prevalent in people over 65,"says Dale Schaar, MD, PhD, assistant professor of medicine at RWJMS and a member of the CINJ Hematologic Malignancies Tumor Study Group. "The older you are, the more severe the disease tends to be."

A study of 12-O-tetradecanoyl-phorbol-13-acetate (called TPA) for treatment of relapsed or refractory blood malignancies or bone marrow disorders is underway at CINJ, currently the only FDA-approved site to administer this drug in the U.S. TPA was first used in China for treatment of refractory or relapsed leukemia with good results. At CINJ, there are 26 patients in the TPA study. Schaar explains, "TPA seems to control leukemic cells by promoting their development along more normal pathways, so they behave more like functional cells." In the studies in China, TPA-containing regimens have resulted in some complete remissions among study participants, and also improved quality of life, including less need for transfusions. A different Phase I trial combining TPA with gancyclovir resulted in a response in a patient with Hodgkin’s disease.

Another Phase II trial for high risk AML is unique to CINJ. It combines Ara-C (Cytarabine), a mainstay in treatment of AML, Topotecan, and a third drug, Etoposide. The drugs, given sequentially, result in a 2-step crippling of DNA repair mechanisms that enable cancer cells to reproduce. Schaar explains that the goal of this therapy is to induce a complete remission in high-risk AML patients.

	Clockwise from top: Robert Dipaola, MD; Dale Schaar, MD, PhD; Robert Wieder, MD, PhD.

Breast and cervical cancers, other tumors

Robert Wieder, MD, PhD, associate professor of medicine at NJMS, is investigating ways of making cancer cells more sensitive to chemotherapy. "High doses of chemotherapy drugs are more effective in killing cancer cells, but are toxic to patients," he explains. "We’re looking at ways in which lower doses can be used more effectively to shrink tumors without causing harm to the patient."

Wieder is studying retinoids, which play an important role in apoptosis (cell death). Retinoids can induce apoptosis in a variety of ways, including initiation of cell death along signaling pathways. In laboratory studies at NJMS, breast cancer cells incubated with retinoic acid were found to be more sensitive to chemotherapy. Wieder says there is a synergistic response, resulting in a cascade effect and an up to 100-fold greater cell kill.

In a Phase II trial for breast cancer patients who have failed to respond to other therapies, retinoic acid is given with Taxol, a chemotherapy medication commonly used in treating breast cancer. The medications are given for four days each weekly cycle (retinoic acid for three days, and Taxol on the third day of retinoic acid) for three consecutive weeks. The researchers are still recruiting patients for the study.

Wieder is studying the effects of the retinoic acid/chemotherapy combination in treating other cancers as well. In a study published in the American Journal of Clinical Oncology last year, retinoic acid was used with the chemotherapeutic agents carboplatin and Taxol to treat patients with various squamous cell carcinomas (12 head and neck, four cervix, one esophagus and one anus). The patients were treated on a protocol that included six 28-day treatment cycles with retinoic acid daily for 14 days, and with carboplatin and Taxol sandwiched into the middle of the retinoic acid treatment on day eight.

Because a number of patients responded well to the treatment, including three of the patients with cervical cancer, a new trial is underway just for patients with squamous cell cancer of the cervix. The incidence of cervical cancer has dropped dramatically because of widespread Pap smear screening. However, it is still found, particularly among underserved populations who don’t receive regular Pap smears. These patients tend to present with an advanced stage of the cancer. "It’s particularly difficult to treat, because it often does not respond to chemotherapy," says Wieder.

Another new study was carried out in collaboration with Memorial Sloan Kettering to evaluate ILX23-7553, a non-calcemic analog of vitamin D. According to Wieder, it is the first Phase I trial ever undertaken in the oncology division at NJMS. It is for patients with advanced malignancies who have already failed standard therapies. The concept behind the study is the use of agents that induce tumor cell differentiation, an alternative to chemotherapy with potentially less toxicity, improved quality of life and survival. The vitamin D family has been shown to have such properties. The study was undertaken to determine potential doses of the drug, evaluate toxicity, and determine anti-tumor activity. Patients tolerated the treatment well. Further studies are planned for higher doses to determine the safety and efficacy of the medication.