CLINICAL CHEMOPREVENTION TRIALS

The Clinical Chemoprevention Program at Fox Chase develops, implements and evaluates natural or synthetic drug interventions to prevent cancers in high-risk populations. Clinical research trials in cancer prevention are made possible through collaboration of investigators in clinical medicine, basic science, pharmacokinetics, pharmacy, molecular and genetic epidemiology, behavioral research, family risk programs and biostatistics. This multidisciplinary approach facilitates the evaluation of promising chemopreventive agents in individuals with significant risk for various malignancies.

An important criterion for a clinical chemoprevention study is evidence of an non-toxic effective chemopreventive agent. Data supporting the agent's ability to prevent cancer at the target site is crucial. Sufficient prior clinical use or preclinical efficacy and pharmacodynamic data need to be available for estimation of an efficacy/safety ratio.

Premalignant intermediate biomarkers such as histological lesions (polyps, leukoplakia, dysplasia), genetic changes (DNA adducts, mutations) or enzymatic changes (ornithine decarboxylase levels, glutathione S-transferase activity) are increasingly being used as surrogate endpoint biomarkers (SEBs) for malignancy. These biomarkers may be the earliest subtle changes that may ultimately prove to be highly correlated with carcinogenesis reversal or progression.

Fox Chase has access to numerous cohorts for clinical chemoprevention studies. Patients with a history of premalignant lesions amenable to chemopreventive intervention include those with colorectal adenomas (Gastrointestinal Tumor Risk Assessment Program), cervical intraepithelial neoplasia (Psychosocial & Behavioral Medicine Program), oral leukoplakia (Head and Neck Oncology, Collaborations with Dental Services), bronchial metaplasia/dysplasia (Smoking Cessation Programs), superficial bladder lesions (Urology Clinics), ductal or lobular atypical breast hyperplasia, ductal or lobular carcinoma in situ of the breast (Breast Evaluation Center, Family Risk Assessment Program), prostatic intraepithelial neoplasia (Urology Clinics, Prostate Cancer Risk Assessment Program) and Barrett's esophagus (Gastrointestinal Tumor Risk Assessment Program).

Patients with treated, non-metastatic primary cancers who are at risk for second malignancies and suitable for chemoprevention studies include those with a cancer diagnosis of head and neck, lung, colon, breast, skin, and bladder. Patients with these diagnoses are accessible through our medical, surgical and radiation oncology clinics.

Surgical candidates may be treated with chemopreventive agents in the period between diagnostic biopsy and surgery to evaluate the effects of the agents on biomarkers. Fox Chase physicians routinely perform definitive surgery on these potential study candidates, including those with mammographically detected breast lesions requiring diagnostic and excisional biopsy, and those with early stage prostatic carcinoma. This particular patient population is more appropriate for Phase II Chemoprevention Studies that evolve from our Phase I clinical trials.

Fox Chase offers an environment rich in resources for clinical chemoprevention trials. Furthermore, Fox Chase investigators have expertise in the evaluation of chemopreventive agents in both the preclinical and clinical setting, and are highly qualified to conduct Phase I, II and III chemoprevention trials.

Prolonged exposure to mutagenic substances found in tobacco products is strongly associated with an individual's risk of developing lung cancer. Oltipraz, a potent inducer of phase II detoxification enzymes, including glutathione S-transferase (GST), is being investigated as a chemopreventive agent for lung cancer based upon its in vivo protective activity against a variety of chemically induced tumors in animal models. The GSTs catalyze the conjugation of carcinogens with glutathione, resulting in less cytotoxic complexes. The association between the expression of the M1 subclass (present in 40 to 60% of the general population) and cancer susceptibility has been investigated. Several studies have shown that cigarette smokers deficient in the expression of GST M1 are at increased risk for tobacco-related malignancies, including head and neck, bladder and lung cancers. The goals of the present study were: to determine whether oltipraz could induce GST activity and inhibit cell proliferation, metaplasia and dysplasia in human tissues; to identify an effective non-toxic dose for more extensive clinical research; and, to establish a relationship between the effects in the bronchial mucosa and those in a more readily available tissue, the blood lymphocyte.

Thus far, 61 participants with a history of surgically cured lung cancer and/or >=15 pack-per-year smoking history are enrolled. Comparable to the GST M1 expression of the general population, 39% of the 56 participants for whom GST M1 genotyping has been completed were able to express GST M1. Forty-three patients underwent baseline bronchoscopy with brushings at six distinct sites. Specimens from each brushing underwent fixation and centrifugation resulting in four cytospins that were stained by the Papanicolaou method and classified as normal, metaplasia or dysplasia. Metaplasia was reported as an index or percentage of 24 slides (4 slides per 6 sites) containing metaplasia. Dysplasia was reported as present or absent. Nineteen patients had either bronchial dysplasia or a metaplasia index of >=15 percent and were randomized to placebo or oltipraz (200mg/dose) twice weekly for six months. Subjects are monitored monthly for compliance and signs of toxicity. Side effects have included nausea, abdominal bloating, flatulence, lines in the nails and colored urine for 24 hours following drug ingestion. Only one patient required study drug modification because of side effects (bloating, flatulence and constipation). The symptoms resolved when the study drug was held. Upon reinitiation of treatment at a lower dose the symptoms decreased and were tolerable.

Six and 12 months following this treatment period, patients undergo repeat bronchoscopies with brushings to determine if oltipraz affects the bronchial mucosa and SEBs of the bronchial tissue. The SEBs being evaluated include metaplasia, dysplasia, GST activity, Mib-1 marker of epithelial cell proliferation and ploidy status.

While there has been progress in the treatment of ovarian cancer, most patients still die of this disease. High-risk individuals, by virtue of a strong family history of ovarian cancer and genetic analysis, frequently undergo a prophylactic oophorectomy in an attempt to prevent the disease. Evaluation of potential chemopreventative agents in ovarian cancer has been limited due to the difficulties identifying recognizable premalignant lesions and SEBs. Fox Chase investigators have identified histologic abnormalities (e.g., inclusion cysts, surface papillomatosis and invaginations) in ovaries removed from women during a prophylactic oophorectomy for a presumed increased risk of ovarian cancer. These may represent preneoplastic lesions and can be considered novel SEBs.

Fenretinide, a retinamide derivative of vitamin A, is a promising chemopreventative agent that induces apoptosis and decreases cell proliferation. It also has an inhibitory effect on growth of ovarian cancer cells and surface epithelial cells of the ovary. In this clinical trial, we will test the hypothesis that treatment of high-risk individuals with fenretinide will alter putative SEBs of ovarian cancer. To test our hypothesis, we will conduct a phase II clinical trial of fenretinide versus placebo in women with high-risk ovarian cancer and a desire to undergo oophorectomy for prophylaxis.

Seventy-one females of all ethnic backgrounds who are 18 years or older and who have decided to undergo a prophylactic oophorectomy because of their increased risk for ovarian cancer are eligible to participate. The decision for a woman to undergo prophylactic oophorectomy must be based on one of the following criteria: (1) increased risk for ovarian cancer secondary to evidence of a genetic defect (BRCA1 or BRCA2), (2) increased risk for ovarian cancer secondary to a family history of one or more 1st degree relatives diagnosed with ovarian cancer prior to the age of 50 years, or (3) increased risk for ovarian cancer secondary to a family history of one first degree relative diagnosed with ovarian cancer (any age) and one or more first or second degree relative diagnosed with breast or ovarian cancer (any age).

Each woman will be randomized to take placebo or fenretinde daily for 4 to 6 months (except for a monthly three day holiday). At the completion of the treatment phase of the clinical trial, all patients will undergo oophorectomy and the histologic characteristics of the ovaries from the two groups of patients will be compared, as well as the relative abundance of markers of cell proliferation and apoptosis. In addition, these results will be compared to ovaries removed from untreated individuals at no risk for ovarian cancer. This study will establish baseline values of these SEBs in high-risk and normal-risk populations, as well as evaluate the specific effect of fenretinide treatment on precursor lesions of a population prone to ovarian cancer.

CLAPPER, M.L., SZARKA, C.E. Glutathione S-transferases--Biomarkers of cancer risk and chemopreventive response. Chem.-Biol. Interact. 111-112:377-388,1998.

^§   Fox Chase researcher

^a   C.A. Garay: Present address--Rhône-Poulenc Rorer Research and Development, Collegeville, PA 19426

Illustrations or unpublished data in these reports should not be used without permission of the author.

Fox Chase Cancer Center

Scientific Report 1998