Researchers at Jefferson Medical College and the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, buoyed by a new five-year, $5 million grant from the National Cancer Institute, are beginning a clinical trial to determine whether a simple test for the protein that causes traveler's diarrhea will help provide surgeons and oncologists with a more accurate picture of the extent of colorectal cancer in patients. The scientists hope the test will enable them to determine whether or not cancer has spread from the colon to the lymph nodes, and at the same time, result in improved diagnoses and more appropriate treatment.
The work, led by Scott Waldman, M.D., Ph.D., Samuel M.V. Hamilton Family Professor of Medicine and director of the Division of Clinical Pharmacology at Jefferson Medical College, may ultimately result in a blood test that could tell patients whether their colorectal cancer thought cured has returned.
The test looks for evidence of a protein, guanylyl cyclase C, or GCC, which is expressed only by intestinal cells and colorectal cancer cells. Most colorectal cancers originate in the cells that line the intestine - cells that normally make GCC. When the cells become cancerous, they continue to make GCC.
According to Dr. Waldman, knowing the extent of disease is crucial to managing patients with colorectal cancer. Patients typically undergo surgery to remove the cancer and the nearby lymph nodes, which are the first place cancer usually spreads. After surgery, a pathologist examines lymph node tissue for cancer cells. If none are found, the patient is "staged" as having cancer confined to the bowel. But if cancer is found in the lymph nodes, the patient's prognosis and management changes.
"It's apparent that the further the progression of disease, the worse the prognosis of the patient," he says. If the disease is found outside of the intestine, for example, most patients are given chemotherapy.
But such a system is flawed because most pathologists examine only a thin slice of lymph node tissue, Dr. Waldman says, potentially missing a cancer. In addition, such a test lacks sensitivity, relying on a pathologist's eye to see colon cancer cells in a field of cells on a slide.
"There's clearly a problem with that system because about 20 percent of patients thought to have disease confined to the bowel show up with recurrent disease and ultimately die of the returning disease," he says. "There's thought to be micrometastases that have escaped histopathological detection."
Dr. Waldman thinks there is a better way. He uses a two-pronged approach: a powerful amplification technique called RT-PCR analysis to magnify the presence of cancer cells compared to normal cells and couples it with GCC, which he hopes will be a very specific marker for cancer. "Then you can take a lymph node and use the amplification technique to amplify the signal for cancer," he explains.
GCC appears to be very specific to colon cancer cells outside the intestine, and is only expressed in metastatic colon cancer cells that have spread there. By combining the marker with the amplification technique, which can detect one cancer cell in 10 million cells, researchers may have a very specific and sensitive way to detect metastatic colon cancer cells in the lymph nodes of patients undergoing colorectal cancer staging, he says.
"We hope to use this new molecular technique to improve the accuracy of colorectal cancer staging so that more people can receive chemotherapy and can benefit from it," he says.
The trial, for which recruitment has already begun, is looking at approximately 2000 patients at five centers: Jefferson, Fox Chase Cancer Center in Philadelphia, the University of Florida in Gainesville, McGill University in Montreal and a community hospital, Conemaugh Memorial Medical Center in Johnstown, Pa.
The trial will examine RT-PCR-GCC analysis as a method to determine if disease spread to the lymph nodes and then follow those patients to see how they do clinically during the next five years.
"We expect to find the GCC-RT-PCR analysis will identify patients who have tiny amounts of cancer in the lymph nodes that were undetected by histopathology," he says. "The pathology will be done in parallel with testing for GCC. We believe that the patients who are histopathology negative but GCC positive will do worse in terms of clinical progression - they will develop recurrent disease that was missed the first time."
In a previous trial, Dr. Waldman and his Jefferson co-workers examined 21 colorectal cancer patients. One group of 11 patients had been disease-free for at least six years and deemed "cured." The other group of 10 patients developed recurrent disease within three years after cancer surgery. The latter had been told initially that they had no signs of cancer in their lymph nodes after surgery, meaning their cancer had not spread.
When pathologists examined lymph node samples of each patient for the presence of GCC, they found the disease-free patients' lymph nodes showed no signs of the marker. Conversely, GCC was present in every patient whose cancer had returned.
"The earlier trial was on a small scale, and until you do this [larger] trial, you really can't be sure if testing for GCC is as good as it appears," he says. "This is a prospective trial in which patients are staged and then we see how they do. In the past, the study was retrospective - we knew what happened to the patient. There's no bias in this trial - we don't know what will happen."
Dr. Waldman isn't sure that one marker will necessarily catch all colorectal cancer that has spread elsewhere in the body, noting eventually, a panel of markers may be used. "We think GCC represents an order of improvement over what is done now. Perhaps adding other markers will make it even better."
To participate in the trial, a patient must have a newly diagnosed colorectal cancer and be treated by a surgeon from one of the participating institutions. To find out more about the study or to enroll, please call 1-800-JEFF-NOW.
Contact: Steve Benowitz or Phyllis Fisher 215-955-6300. After Hours: 215-955-6060