GASTROINTESTINAL CANCER PROGRAM

There are more than 225,000 cases of gastrointestinal (GI) cancer in the United States each year, accounting for more than 130,000 deaths. Although curable when detected at an early stage, colorectal cancer (CRC) remains the second leading cause of cancer mortality. For cancers of the esophagus and pancreas, mortality approaches incidence. Although relatively uncommon in the United States, gastric and liver cancers are among the most common malignancies in other parts of the world. Thus, GI cancers are a major public health problem worldwide, and improved methods of detection, prevention, and treatment are required. Many members of the Fox Chase scientific community conduct research in GI cancer and more detailed presentations by individual principal investigators can be found throughout the Scientific Report.

Given the relative resistance of GI cancers to standard chemotherapeutic agents, a major emphasis of the GI program at Fox Chase involves development of novel systemic approaches, in particular those with a potential for improved tumor selectivity. Immunotherapy trials active over the past year have included Phase I and Phase II studies of pretargeted radioimmunotherapy, immunoconjugates, and viral vector tumor vaccines (see WEINER reports). Other new drugs in early phase clinical trial include oxaliplatin and raltitrexed; both are cytotoxics with single-agent activity against CRC.

Given the clinical problems of both tumor control and distant metastases, multimodality treatment approaches that integrate systemic therapy with surgical and radiotherapy are also being developed (see EISENBERG, HANKS, SIGURDSON reports). Phase I and II neoadjuvant programs for patients with clinically localized rectal, esophageal, and pancreatic cancers are underway. These include applications of hyperfractionated external beam radiotherapy, new radio-sensitizers such as gemcitabine, and organ-sparing surgical approaches. Patients may also participate in large-scale Phase II and III post-surgical adjuvant programs of the Eastern Cooperative Oncology Group (ECOG) and Radiation Therapy Oncology Group (RTOG). In addition to the systemic therapy of metastatic disease, surgical techniques involving hepatic arterial infusional therapy, cryosurgery, and radioimmuno-guided surgery are being explored. As many GI cancer patients can look forward to long-term survival, the minimization of late treatment toxicity is of utmost importance. Conformal radiation techniques are utilized to treat the tumor and avoid the exposure of normal uninvolved tissues.

Identification of risk factors for CRC and other GI cancers permits screening strategies based upon individual patient characteristics. Influences on CRC risk include diet, family history, personal history of CRC or polyps, and inflammatory bowel disease. In addition, germline mutations in genes such as MLH1, MSH2, PMS1, PMS2, which are responsible for familial adenomatous polyposis (FAP) and hereditary non-polyposis CRC (HNPCC), have been identified and clinical testing is available for suspected affected individuals. The availability of genetic testing for cancer predisposition raises a variety of ethical, legal, and social issues for individual patients, their families and society at large. The GI Tumor Risk Assessment Program was designed with two major objectives: 1) to provide a service to patients wishing to undergo risk assessment and screening, and 2) to conduct laboratory, epidemiologic, and psychosocial studies of hereditary GI cancers. A multidisciplinary team including gastroenterologists, genetic counselors, medical oncologists, and health educators offer risk assessment, counseling, education, and recommendations regarding screening, including the appropriateness, risks, and benefits of genetic testing. A registry and tissue bank are being designed for collection of family health history information, as well as germline and tumor DNA from affected and non-affected members of `high risk' cancer families.

The primary goal of this translational research program is to develop efficacious regimens for the prevention of colon cancer. Areas of research include: 1) the identification of effective chemopreventive agents and their mechanisms of action, 2) the establishment of biomarkers of colon cancer susceptibility and surrogate endpoints of carcinogenesis, and 3) the identification of target populations at increased risk for colon cancer.

Recent studies have focused on the use of two mouse models of colon cancer. Drs. Clapper and Cooper, in collaboration with Dr. Murthy, are investigating colitis-associated colorectal dysplasia and cancer in a mouse model of dextran sulfate sodium-induced colitis (see CLAPPER report). Previous studies have identified detoxification enzyme depletion as an early event in the progression of colitis to colon cancer. An analysis of the role of b-catenin and p53 in this process is in progress. We have recently demonstrated that the Phase II detoxication inducer oltipraz can completely inhibit the formation of invasive cancers in this model. These data represent the first attempt to develop a preventive therapy for individuals with ulcerative colitis.

The recent generation of mouse strains with genetic deficiencies in the "colon cancer genes" has provided a novel opportunity to evaluate the functional relationship between the molecular and biochemical events associated with the formation of precancerous and cancerous colon lesions. The chemically induced mouse mutation called Multiple Intestinal Neoplasia (Min) produces a phenotype reminiscent of human FAP (see CLAPPER report). A bank of intestinal tissues (normal and tumor) from heterozygous Min and wild type mice has been generated and currently includes over 1400 accessions. This novel tissue resource will support the comprehensive evaluation of the pathological and molecular events, which accompany the progression of intestinal polyps to invasive carcinomas. This model provides an opportunity to further evaluate the role of APC in colon carcinogenesis in vivo and to develop preventive strategies to circumvent this aberrant pathway.

Chemoprevention is the unique strategy to reduce cancer risk through the administration of natural or synthetic compounds. The goal of the Clinical Chemoprevention Program at Fox Chase (see SZARKA report) is to develop, implement and evaluate interventions in both the community and academic settings to prevent cancers in high-risk populations. Our varied research activities in colon cancer prevention are made possible through collaboration among investigators in medical oncology, pharmacokinetics, pharmacy, molecular and genetic epidemiology, behavioral research, family risk programs and biostatistics. This multidisciplinary approach facilitates the development of clinical studies evaluating promising chemopreventive agents in individuals with significant risk for GI malignancies.

Fox Chase offers an environment rich in resources for chemoprevention trials. Fox Chase investigators have expertise in the evaluation of chemopreventive agents in both the preclinical and clinical settings, as well as a background in the Phase I evaluation of therapeutic agents. Fox Chase is a current holder of a Master Agreement for Phase I Studies of New Chemopreventive Agents, (Dr. Szarka, P.I.) and Phase II Clinical Trials of New Chemopreventive Agents, (Dr. Engstrom, P.I.). In addition to CRC prevention research performed under the master agreement mechanism, investigators at Fox Chase have been active participants in the national colon cancer chemo-prevention studies, ECOG 8292 A Phase II Double Blind Chemoprevention Trial of High Dose Folic Acid versus Placebo in Patients with Resected Polyps and ECOG C92-70 Colorectal Cancer Chemoprevention Trial Using Aspirin-A Phase III Study.

Fox Chase also holds a Master Agreement NCI-CN-25407-20 Evaluation of Chemopreventive Agents by In Vivo Screening and NCI-CN-25418-51 Preclinical Evaluation of Intermediate Endpoints and their Modulation by Chemopreventive Agents (Dr. Clapper, P.I.). By supporting preclinical investigations, the Workstatements issued under these master agreements provide an essential link between the laboratory and clinic in an effort to: 1) identify and develop biomarkers and intermediate endpoints of chemopreventive activity that might be used in future human clinical trials, 2) evaluate the effect of chemopreventive agents on select biomarker, and 3) improve biomarker sensitivity, specificity, assay methodology, and sample handling.

DNA mismatch repair (MMR) is a specialized system involved in the maintenance of genomic integrity. A germ-line defect in MMR genes, such as MLH1 and MSH2, is associated with Lynch Syndrome or HNPCC. It is estimated that HNPCC represents approximately 3-5% of all CRC cases. Due to the MMR defect, HNPCC individuals carry a generalized predisposition to cancer that is not restricted to the colon-rectum; additional target organs are endometrium, stomach, urinary and biliary tracts, brain and skin. Typically, tumors from HNPCC patients show instability of simple repetitive sequences (microsatellites), which are the hallmark of a defective MMR. Approximately 15% of sporadic CRCs also show microsatellite instability. The main interest of this group is to further characterize the genetic bases of HNPCC and obtain a deeper understanding of the function of eukaryotic MMR (see BELLACOSA report). We are currently testing the hypothesis that MED1 is a novel MMR gene and examining the possibility that MED1 mutations are relevant to the pathogenesis of human CRC.

This research program is focused on understanding the relationships of hepatitis B virus infections, environmental factors, genetic events and gene-environment interactions to the etiology and pathogenesis of hepatocellular carcinoma (HCC). The ultimate goal is to reduce the burden of HCC by developing methods of primary and secondary prevention. One aspect of that program requires identification of HCCs at an early, resectable stage.

To that end, the Liver Cancer Prevention Center (LCPC), under Dr. London's direction, began operations in 1985. Its primary purpose is to monitor individuals chronically infected with hepatitis B virus (HBV) for the development of HCC. Because of the high prevalence of HBV chronic infections among persons of Asian origin, more than 25,000 Asian Americans residing in the Delaware Valley have been tested over the past 16 years and more than 3,000 chronic carriers identified. To detect HCCs at an early, treatable stage, serum alpha-fetoprotein (AFP) levels are measured in these individuals at six month intervals. Elevated levels of AFP trigger ultrasound and other imaging examinations of the liver. Patients are followed not only at Fox Chase, but also at clinics in St. Mary Hospital in Langhorne, PA, and in the Philadelphia Health Department, as well as in the private practices of a network of 10 physicians serving Asian patient populations. Patients with chronic hepatitis B are managed and hepatitis B vaccine is offered to uninfected family members of HBV carriers.

Patients considering Phase I treatments are a particularly vulnerable population. While previous studies have described patient perceptions and the influences on these perceptions with regard to the potential benefits and toxicities of Phase I treatment, little is known about how patients weigh perceptions in deriving a treatment valuation, and hence a treatment choice. In collaboration with investigators at Georgetown University^c, we have been developing a model (Health Stock Risk Adjustment [HSRA] model) to explain the decision making of patients with life-threatening illnesses in a context of uncertainty and risk. Health stock is an individual's prediction of future quality adjusted life expectancy. The HSRA model predicts that relative health stock--the ratio of current health stock to health stock before the current illness--is the key determinant of treatment choice. In a pilot study of cancer patients entering Phase I trials, we found that patient-reported health status (quality of life) is associated with patient expectation of benefit and harm from experimental therapy. Furthermore, patients overestimated the potential benefits and toxicities of experimental therapy when compared with their physicians. A three-year multicenter trial (R01-CA82085, Dr. Meropol, P.I.) has been initiated to compare the decision making of patients who decline Phase I participation with those who enroll in early phase studies, in an effort to obtain empirical validation of the HSRA model. In addition, patient satisfaction, and the perceptions of physicians and nurses will be assessed.

This research, which currently includes three studies, focuses on the impact of cancer and cancer risk on colon or rectal cancer patients and their families (see MANNE report). Our first study examines the impact of colon cancer on patients' marital relationships. Specifically, we are looking at how spouses provide the emotional support and caregiving to colon or rectal cancer patients during the treatment process, and how the emotional and practical support (or lack of support) received from spouses assists in patient's coping and adaptation. The second study examines the impact of long-term survivorship from colon cancer on patients who completed treatment from five to ten years ago. This study asks patients about their quality of life, long-term medical problems, and colon cancer surveillance behaviors. The third study examines demographic, physician-influence, attitudinal and family relationship factors that contribute to the attitudes and colon cancer surveillance behaviors of siblings of individuals diagnosed with colon cancer prior to the age of 56 years. First degree relatives of these patients are at increased risk for colon cancer, and early initiation of colon cancer screening is recommended.

AJANI, J.A., EISENBERG, B., EMANUEL, P., FUCHS, C., HAYMAN, J., HEITMILLER, R., KURTZ, R., LEVIN, B., MEROPOL, N., MINSKY, B., MOVSAS, B., NESBITT, J., ORRINGER, M., POEN, J., PUTMNAM, J.B., SCHWARTZ, R. NCCN practice guidelines for upper gastrointestinal carcinomas. Oncology 12 (11A):179-223, 1998.

CHENG, J.D., WERNESS, B.A., BABB, J.S., MEROPOL, N.J. Paradoxical correlations of cyclindependent kinase inhibitors p21waf1/cip1 and p27kip1 in metastatic colorectal carcinoma. Clin. Cancer Res. (in press).

CHENG, J.D., COMPTON, C.C., MEROPOL, N.J. Uncommon cancers of the esophagus. In Textbook of Uncommon Cancer, 2nd Edition, edited by D. Raghavan, M.L. Brecher, D.H. Johnson, N.J. Meropol, J.T. Thigpen. John Wiley and Sons, Sussex, England (in press).

CHENG, J.D., COMPTON, C.C., MEROPOL, N.J. Uncommon cancers of the stomach. In Textbook of Uncommon Cancer, 2nd Edition, edited by D. Raghavan, M.L. Brecher, D.H. Johnson, N.J. Meropol, J.T. Thigpen. John Wiley and Sons, Sussex, England (in press).

MEROPOL, N.J. Colorectal cancer: new drugs in late-phase clinical development. ASCO Education Book Fall, pp. 45-51, 1998.

RAGHAVAN, D., BRECHER, M.L., JOHNSON, D.H., MEROPOL, N.J., THIGPEN, J.T. Editors. Textbook of Uncommon Cancer, 2nd Edition. John Wiley and Sons, Sussex, England (in press).

BUDMAN, D.R., MEROPOL, N.J., REIGNER, B., CREAVEN, P.J., LICHTMAN, S.M., BERGHORN, E., BEHR, J., GORDON, R.J., OSTERWALDER, B., GRIFFIN, T. Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J. Clin. Oncol. 16:1795-1802, 1998.

CREAVEN, P.J., PENDYALA, L, MEROPOL, N.J., CLENDENINN, N.J, WU, E.Y., LOEWEN, G.M., PROEFROCK, A. Initial clinical trial and pharmacokinetics of thymitaq (AG337) by 10 day continuous infusion in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 41:167-70, 1998.

GASKIN, D.J., KONG, J, MEROPOL, N.J., YABROFF, R.K., WEAVER, C., SCHULMAN, K.A. Treatment choices by seriously ill patients: The health stock risk adjustment model. Medical Decision Making18:84-94, 1998.

MEROPOL, N.J. Oral fluoropyrimidines in the treatment of colorectal cancer. Eur. J. Cancer 34:1509-1513, 1998.

MEROPOL, N.J., WOOD, D.E., NEMUNAITIS, J., PETRELLI, N.J., LIPMAN, B.J., AGOSTI, J.M., WHITMORE, J.B. The Leukine Surgical Prophylaxis Research Group. Randomized, placebo-controlled, multicenter trial of granulocyte-macrophage colony-stimulating factor as infection prophylaxis in oncologic surgery. J. Clin. Oncol. 16:1167-1173, 1998.

MEROPOL, N.J., BLUMENSON, L.E., CREAVEN, P.J. Octreotide does not prevent diarrhea in patients treated with weekly 5FU plus high-dose leucovorin. Am. J. Clin. Oncol. 21:135-138, 1998.

MEROPOL, N.J., BARRESI, G.M., FEHNIGER, T.A., HITT, J., FRANKLIN, M., CALIGIURI, M.A. Evaluation of natural killer cell expansion and activation in vivo with daily subcutaneous low-dose interleukin-2 plus periodic intermediate-dose pulsing. Cancer Immunol. Immunother. 46:318-326, 1998.

MEROPOL, N.J., RUSTUM, Y.M., CREAVEN, P.J., BLUMENSON, L.E., FRANK, C. Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: a potential role for growth factor as mucosal protectant. Cancer Invest. (in press).

SCHWARTZ, G.N., PENDYALA, L., KINDLER, H., MEROPOL, N., PEREZ, R., RAGHAVAN, D., CREAVEN, P. The clinical development of paclitaxel and the paclitaxel/carboplatin combination. Eur. J. Cancer 34:1543-1548, 1998.

^§   Fox Chase researcher

^a   R. Scher: Present address--Riverview Medical Center, Red Bank, NJ 07701

^b   S. Murthy: MCP/Hahnemann University, Philadelphia, PA, 19102

^c   C. Burnett, D. Gaskin, J. Kong, J. Rowland, K. Schulman, R. Yabroff: Georgetown University, Washington, DC 20057

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

Fox Chase Cancer Center

Scientific Report 1998