A Deadly Silence
Advances in detection and treatment of colorectal cancer may make it a topic of conversation that will save lives. by Monika Guttman Eliminating the stigma that surrounds the third most lethal cancer-first is lung and second are breast and prostate cancers-has recently become NBC News anchor Katie Couric's personal crusade. After her husband, Jay Monahan, died of the disease last year at age 42, she realized "too many Americans don't get tested because they don't want to talk about that part of their body. I think we have to use the words, say them. Colon. Rectum. Bowels. You can't be squeamish about it. It might cost you your life."
What Rock Hudson did for AIDS and General Norman Schwarzkopf did for prostate cancer, Couric's plain speaking may yet do for colon cancer: move a dreaded disease out of the darkness into the public spotlight. Others have the same idea. Actress Barbara Barrie released a book, "Second Act: Life after Colostomy and Other Adventures," two years ago about her own battle with rectal cancer. She was so reluctant to describe her symptoms to her doctors, she writes, that she suffered rectal bleeding for years before an emergency room visit diagnosed her problem. "Second Act" was such a hit that Barrie released a follow-up book, "Don't Die of Embarrassment," this winter.
Beyond Barrie and Couric, colorectal cancer needs prime-time exposure, say experts at USC and elsewhere, if only because of the numbers: more than 139,000 cases will be diagnosed this year alone, according to the American Cancer Society-about as many as ovarian, pancreatic, urinary/bladder cancers and leukemia combined. Although the death rate from colorectal cancer has been going down for the past two decades, what makes the disease so lethal is that only about a third of all cases are diagnosed in the earliest, most survivable stages. Once the cancer has spread to nearby organs or lymph nodes, the five-year survival rate drops to 50 percent. For people whose colorectal cancer has spread to other parts of the body, such as the liver or lungs, the five-year survival rate is only 5 percent.
Expanding the Arsenal
More than high-profile talking heads, what may soon push colorectal cancer into mainstream conversation is that researchers at places like the USC School of Medicine and the USC/Norris Comprehensive Cancer Center are producing newsworthy progress. Until recently, for example, the main drug used to treat colorectal cancer chemotherapeutically was the same drug used since the 1950s: 5-Fluorouracil (5-FU). In the past few years, several new drugs-either in combination with 5-FU or used alone-have been undergoing clinical trials at USC/Norris.
"We are on the brink of having a larger arsenal for colorectal cancers, along with specific information about how to use these drugs more effectively," declares Heinz-Josef Lenz, M.D., assistant professor of medicine and director of gastrointestinal oncology at USC/Norris.
Refinements and new drugs are also adding to the arsenal. For the first time in decades, several promising new drugs such as CPT-11 (Camptostar) and oxaliplatin are being tested at USC/Norris. Patients with metastatic colorectal cancer who appeared resistant to 5-FU have shown some improvement with CPT-11, for instance. With support from the National Cancer Institute at the National Institutes of Health, Lenz has developed a new protocol for treating colorectal cancer that combines oxaliplatin and a new oral drug called xeloda.
Researchers at USC are also testing substances not yet available outside the national cancer centers. One promising development: grape seed extract, known clinically as resveratrol.
Resveratrol shows potential for enhancing current colorectal cancer chemotherapy regimens, says Lenz. "Some of the early tests show resveratrol weakens tumor cells by initiating apoptosis-programmed cell death. Theoretically, if we combine resveratrol with current chemotherapy, it should make the treatment even more effective, by first making the cells more vulnerable and then by killing them with chemotherapy." Lenz and others at USC are testing this theory in the laboratory.
Another compound that USC researchers will begin investigating this spring for effectiveness in preventing colon cancer is the new class of drugs called Cox-2 inhibitors. These medications, which have been on the approval fast track at the U.S. Food and Drug Administration, are a new class of anti- inflammatory medications geared towards treating arthritis and other inflammatory conditions without the traditional side effects of drugs like aspirin. Lenz and others feel the drugs "may prove useful in preventing colon cancer." His research will try to identify specific genetic markers that would indicate when this drug could be a useful preventive therapy.
Dispelling Myths
One of the first by-products of increased information is that researchers can now dispel many of the myths that surround colorectal cancer-myths exacerbated by silence about the disease. For instance, although rectal bleeding can indeed be a sign of colon or rectal cancer, in many cases it signals something else, such as hemorrhoids or infection. Furthermore, many people rely solely on the digital rectal examination-where a physician inserts a gloved finger into the rectum and checks for abnormalities or blood - as a colorectal cancer-screening test. Current data show this is inadequate.
"The fact that you have no blood in your stool can mean you will still miss about 70 percent of cancers," warns Robert W. Beart, Jr., M.D., professor of surgery and vice chair for general surgery at USC/Norris. "That's also why home-test kits sold in pharmacies cannot be considered reliable indicators." Studies have shown that to thoroughly check for colon cancer, physicians must use "barium enemas, colonoscopy and advanced tests such as computerized tomography," says Beart.
One of the biggest myths that persists, adds Beart, is that colon and rectal cancers usually result in colostomy-where stool is collected outside the body in a plastic bag. About two-thirds of all colorectal cancers involve the colon, and those cancers are always treated with removal of the malignancy. When a piece of bowel is removed, the two remaining ends are reattached. If they cannot be reattached, colostomy is required. Colostomy is also required in rectal cancers where the sphincter must be removed. But fewer than five percent of the vast majority of colorectal cases result in colostomy, says Beart.
Instead, new surgical techniques are increasingly utilized to minimize the amount of colon that must be removed and to reattach the remaining sections. One technique for treating rectal cancer developed at USC removes the entire rectum and all the lymph nodes but saves the anal muscles and restores intestinal continence. In some cases, USC surgeons can even remove the entire colon and rectum and the attached small bowel.
New techniques are also being examined in clinical trials at the USC/Norris. Marvin L. Corman, M.D., professor of colon and rectal surgery, recently began trials of an artificial anus for patients without bowel control who are not eligible for reparative surgery. Another trial treats about 10 percent of rectal cancer cases with less radical surgery in combination with radiation therapy-thus saving the sphincter and avoiding colostomy.
Other surgical procedures have advanced treatment as well. Laparoscopic techniques, used and modified at USC for the past eight years, give patients requiring large bowel resection a newer option. Using smaller abdominal incisions instead of the conventional abdominal approach, surgeons can actually remove colon parts and reconstruct the colon with more desirable outcomes: shorter hospital stay, less requirement for pain medication and quicker recovery time. Still, notes Beart, comparisons of long-term cancer remission rates between laparoscopic and conventional surgeries are not yet available. "Most of us doing the laparoscopic surgeries for treating the cancers are doing it on a protocol-we offer it as part of research. We are comparing it to open resection, and should have data available in the next five years."
These days, chemotherapy, radiation or both almost always accompany surgery. In fact, since the government mandated this "multimodal" approach to colorectal cancer in 1988, "deaths have decreased by 30 percent," notes Beart. USC researchers took the concept a step further: a recent study found that management of colorectal cancer by a surgeon who is a specialist in colon surgery or surgical oncology (as opposed to a general surgeon) alone decreases death rates by 15 percent. However, general surgeons perform the majority of colorectal cancer surgeries-some 94 percent in Los Angeles County.
New techniques offered as part of ongoing research at USC also minimize the need for more radical surgery or colostomy. One procedure, called brachytherapy, uses small tubes to place radioactive "seeds" directly at the site of the cancer-delivering a very directed, very high dose hit as opposed to more generalized external radiation. "The concept goes back to a procedure used to treat breast cancers, sarcomas and cervical cancers," notes Beart. Among its advantages: brachytherapy can be used even in patients who have been previously treated with radiation, and it aims to preserve both continence and sexual function.
Prediction and Prevention
At USC, cutting-edge genetic research is also being put into play treating-and, hopefully, preventing-colon cancer. Treatment of colon cancer at the USC/Norris is individualized using genetic markers to help determine what drugs or combined treatments will work best for individuals with certain types of tumors. For example, in patients with stage II cancer-where it has become larger than a single tumor but hasn't yet spread beyond the colon-treatment with surgery alone currently gives favorable outcomes to 75 percent of all patients. "This still means 25 percent of patients develop tumor recurrence and need chemotherapy, but it's hard to justify treating all the patients to have some benefit for that 25 percent," says Lenz. Using markers already identified here and elsewhere, clinicians can now tell more exactly who falls into the higher risk 25 percent and definitely need chemotherapy. "Even those patients who have stage III disease-where there has been a localized spread-show increased survival rates when treated with chemotherapy," says Lenz. "These genetic markers may be very useful to decide the most effective chemotherapy regimen."
Genetic approaches are also helping identify not only which drugs may be most effective for each individual patient, but also to rule out drugs that may be toxic to a particular individual. Many Hispanic patients who have been given CPT-11, for example, do not have favorable outcomes because of metabolic differences that decrease the body's ability to detoxify the drug. Genetic research at USC is leading the search for the markers that will help establish whether or not a colorectal cancer patient will be able to detoxify CPT-11.
Beyond identifying who is at risk for developing cancer and how and when to use drugs, one of the biggest accomplishments of the genetic component of colorectal cancer is helping to determine who is at risk for a tumor coming back.
USC researchers recently published findings that suggest a physical examination every three to four months plus an annual colonoscopy will pick up the earliest recurrences almost 100 percent of the time.
What about predicting the disease even in those who have no significant history of colorectal cancer? Researchers are investigating the possible genetic markers that might flag those most at risk. Even with today's sophisticated analysis, however, only a small portion-10-15 percent of all colorectal cancers-can be explained genetically. And even those environmental factors that epidemiologic studies indicate increase an individual's risk of colorectal cancer-smoking, inactive lifestyle, high consumption of red meat, reduced consumption of fruits and vegetables-do not explain all cases of the disease.
These puzzles obviously call for more study, and USC is at the forefront: the National Institutes of Health recently awarded USC researchers a grant of more than $10 million to develop a registry of families who are at high risk of developing colorectal cancer. "The goal is to establish an international resource of families, including many different ethnic groups," says Robert Haile, Dr.P.H., professor of preventive medicine, director of the Genetic Epidemiology Program, and one of the lead researchers on the study. "We will compile a database that will help researchers around the world answer a variety of questions about the causes of colorectal cancer and effective means of prevention."
Haile, in fact, is pursuing a unique avenue of colorectal cancer research: combining genetic and epidemiologic factors to determine why, for instance, red meat increases risks in some individuals or what genetic factors work with cruciferous vegetables to be protective against the disease. Cruciferous vegetables include cabbage, turnip, broccoli, radish and horseradish.
A recent finding from a large clinical trial confirms earlier suggestions that calcium may be protective against colon cancers. In the 10-year study, an international group of investigators, including Haile and directed by John Baron at Dartmouth University, found that supplemental calcium reduced the risk of colorectal polyps (precursors of colon cancer) by as much as 25 percent.
A promising avenue for the future: gene therapy. By the middle of this year, Lenz will begin a clinical trial using the p53 gene for treating patients with liver metastasis from colon cancer. In addition, he and his colleagues are working on an existing gene therapy protocol for colon and pancreatic cancers using a retrovirus developed at USC.
"In many areas, gene therapy has proved disappointing," says Beart. "But in colon cancer, early studies show exciting possibilities. The colon is one of the few organs so accessible that it's conceivable that some kind of genetic therapy 'enema' could help prevent the disease. We are working on that, and so much more, at USC/Norris."
For more information about colorectal cancer research and treatment, or to learn about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).
