Trends and Treatment Options
Allyson J. Ocean, MD
Medical Oncologist, Jay Monahan Center for Gastrointestinal Health
Medical Oncologist, Solid Tumor Service, NewYork-Presbyterian Hospital
Assistant Professor of Clinical Medicine, Weill Medical College of Cornell University
Colorectal cancer takes the lives of more women each year than does ovarian, uterine, or cervical cancer. Now a new study by American Cancer Society (ACS) researchers has found that in sharp contrast to the overall declining rates of colon cancer in the United States, incidence rates among adults younger than 50 are increasing. The study authors suggest that these increases may be related to rising rates of obesity and changes in dietary patterns, including increased consumption of fast food. The authors say that further studies are necessary to elucidate causes for this trend and to identify potential prevention and early-detection strategies.
Overall incidence rates for colon cancer in the United States have been on the decline since the mid-1980s, with the drop accelerating in the most recent time period. Rates are now dropping 2.8 percent per year in men and 2.2 percent per year in women, largely due to an increase in screening, particularly colonoscopy, among people 50 and older. Screening can reduce colon cancer incidence by finding and removing polyps before they become cancerous.
American Cancer Society researchers led by Rebecca L. Siegel examined trends in colon cancer incidence rates between 1992 and 2005 among young adults (ages 20 to 49) by sex, race/ethnicity, age, stage at diagnosis, and tumor location. The study found that among individuals ages 20 to 49, incidence rates of colon cancer increased 1.5 percent per year in men and 1.6 percent per year in women from 1992 to 2005. Among non-Hispanic Whites, rates increased for both men and women in each 10-year age grouping (20 to 29, 30 to 39, and 40 to 49 years) and for every stage of diagnosis. They found the largest annual percentage increase in colon cancer incidence in the youngest age group (20 to 29 years), in whom incidence rates rose by 5.2 percent per year in men and 5.6 percent per year in women. They say the rises are due to an increase in left-sided tumors, particularly in the rectum.
The researchers discuss several possible causes for the rise, including rising rates of obesity, which is a risk factor for colon cancer. Dietary factors may also play a role. The researchers note that between the late 1970s and the mid-1990s, fast-food consumption in the United States increased fivefold among children and threefold among adults. A diet high in fast food is associated with both greater meat consumption and reduced milk consumption.
Increased consumption of red and processed meat has been shown to increase the risk of cancers of the distal colon and the rectum, whereas milk and calcium consumption have shown a protective effect against left-sided tumors in which the rise in incidence was most prominent. They say it is plausible that unfavorable dietary patterns in children and young adults over the past three decades may have contributed to the increase in colorectal cancer among young adults observed in the study.
The authors conclude: “The disparate increase in left-sided colorectal cancer suggests that particular attention be given to studies to elucidate the behavioral and environmental risk factors responsible for this trend and potential prevention and early detection strategies.”
The Big Picture
So what should women know about colorectal cancer to put this new information in perspective?
Risk Factors and Screening
First, both men and women are at risk of developing colorectal cancer. In most cases colorectal cancer occurs in people 50 or older, but, as the new ACS study cited above proves, younger individuals can also get this disease. In addition, there is some evidence to suggest that people of African-American or Ashkenazi Jewish descent are at increased risk of developing colorectal cancer.
Medical risk factors include a personal or family history of colorectal polyps or cancer, a personal history of inflammatory bowel disease, and a personal or family history of an inherited genetic cancer syndrome, such as familial adenomatous polyposis (FAP) or hereditary nonpolyposis colon cancer (HNPCC).
Women who do not have any of these risk factors are considered at average risk for colorectal cancer and should begin screening at age 50. Women who do have one or more of these risk factors are considered at increased risk of the disease. Although these medical factors cannot be changed, women at increased risk can protect themselves by discussing their risk factors with their physician and undergoing earlier and more frequent screening as appropriate.
Lifestyle risk factors for colorectal cancer include obesity, physical inactivity, smoking, heavy alcohol consumption, a diet high in red or processed meats, and a diet inadequate in fruits and vegetables. Fortunately, these are risk factors that can be changed. Women who have any of these lifestyle risk factors can consult their physician or nutritionist about adjusting their lifestyle to reduce their colorectal cancer risk and optimize their overall health and well-being.
Early colorectal cancer causes no symptoms, which is why screening ideally begins when an individual feels well—before any symptoms of disease develop. As the cancer grows, however, symptoms may develop; these include rectal bleeding or blood in the stool, a change in bowel habits, abdominal pain, and unexplained fatigue.
In some cases people who experience the symptoms of colorectal cancer ignore them because they are scared or embarrassed. It’s important to understand that, first, these symptoms do not necessarily indicate colorectal cancer; they could be caused by another, less serious condition. Second, if the symptoms are due to colorectal cancer, this disease is treatable. And, third, no one should die of embarrassment. Anyone who experiences the symptoms of colorectal cancer should see a physician for prompt evaluation and diagnosis—the earlier the diagnosis, the greater the chance for cure.
You’ve Been Diagnosed with Colorectal Cancer. Now What?
1. Build your colorectal cancer treatment team.
For anyone diagnosed with colorectal cancer, the first step is to gather the right people to ensure that you’ll receive the best treatment possible. Research has shown that people with colorectal cancer are more likely to get the best results if they have a good team of medical specialists taking care of them.
So who plays on the team? Ideally, your roster—or multidisciplinary team—will include doctors and other professionals who specialize in the treatment of colorectal cancer as well as family and friends who can help you navigate the treatment process.
You, of course, are the starring player. In addition, specialized physician members of your team might includegastroenterologists, surgeons, medical oncologists, radiation oncologists, interventional radiologists, pathologists, and radiologists. A patient’s disease location or unique treatment plan will determine which specialists become part of the team.
In addition, oncology nurses, oncology social workers, mental health professionals, dieticians, and patient navigators—all fulfill extremely important roles in helping patients and caregivers throughout the cancer process with supportive care and access to available resources.
The key to success in therapy is communication among all the professionals involved. Cancer centers, university clinics, and community clinics throughout the country commonly practice using this team-based approach. Some physicians practice independently, however, and may not be affiliated with a particular center. If this is the case, a patient or caregiver can bring members of the treatment team together to help get the best possible care.
2. Investigate your treatment options.
If a diagnosis of colorectal cancer is made, staging the disease is the next step in the treatment plan. The term staging refers to the local and distant extent of the disease and provides a framework for outlining treatment options and discussions regarding prognosis. An important step in this process is a review of the biopsy specimen by a pathologist. This should be done prior to making any decisions regarding the need for further studies or surgery. This is especially important for cancerous polyps, which may sometimes be fully removed with surgery. Other parts of the staging process include a physical examination by the physician; imaging studies, such as a CT [computed tomography] scan, a PET [positron emission tomography] scan, or an endoscopic ultrasound; and laboratory blood tests, including tumor markers.
The staging of colorectal cancer is based on the depth of invasion of the cancerous tumor through the colon or rectal wall, and an integral component is the determination of whether cancer cells have spread to nearby lymph nodes or to distant organs. Stage I and II colorectal cancers are considered localized early-stage tumors that do not have lymph node involvement. Stage III colorectal cancer is locally advanced and has involvement of regional lymph nodes. Stage IV colorectal cancer indicates disease that has metastasized, or spread outside the colon to distant organs. Staging is critical in determining prognosis in colorectal cancer, as earlier-stage disease indicates longer survival and a better chance for cure.
- Surgery. Surgery is the only curative treatment for localized colorectal cancer. Surgery is often required for diagnosis and staging of the disease or for bleeding or obstruction associated with the tumor. Surgery entails removal of the cancerous tumor, as well as an adequate amount of normal tissue surrounding the tumor, and removal of regional lymph nodes.
- Chemotherapy.When a disease recurrence develops after a potentially curative surgical procedure, it is believed to come from microscopic tumor cells that are present and undetectable at the time of surgery. The goal of adjuvant (postoperative) chemotherapy is to eradicate these microscopic tumor cells to decrease the likelihood of recurrence and to increase the cure rate. Data from multiple clinical trials over the past 50 years support the routine use of adjuvant systemic chemotherapy after surgical resection of colon cancer with lymph node involvement. Adjuvant chemotherapy is associated with an approximately 30 percent reduction in the risk of disease recurrence and a 22 to 32 percent reduction in mortality.
The average length of adjuvant chemotherapy treatment is six months. The routine use of adjuvant chemotherapy for Stage II colon cancer is controversial and is considered only for patients with tumors with features that may increase the rate of recurrence.
- Radiation therapy.Radiation therapy has emerged as a significant part of adjuvant treatment for rectal cancer, whereas adjuvant treatment of colon cancer that is removed by surgery includes chemotherapy alone. This is due to a higher rate of local recurrence in the pelvis in patients with rectal cancer. A series of clinical trials in the 1980s and 1990s determined that there is a survival advantage when postoperative radiation therapy is combined with chemotherapy following resection of Stage II and III rectal cancers.7,,,,,
- Chemotherapy and targeted therapies.Systemic chemotherapy and targeted antibody therapies represent newer treatment options for Stage IV colorectal cancer (disease that has spread to other sites in the body). Approximately 30 to 40 percent of patients with colon or rectal cancer have metastatic disease at the time of diagnosis. Combining chemotherapy with targeted antibody therapy has been shown to improve survival in people with metastatic disease.12,13,14 The past decade in cancer therapy has led to the development of novel targeted therapies that enable people to live longer with metastatic disease.
There is increased understanding of the biologic processes important for the survival and the growth of colorectal cancer cells, including the role of angiogenesis, the process by which a tumor makes blood vessels to support its own growth.15
Another important growth pathway in metastatic colorectal cancer is the epidermal growth factor receptor (EGFR) pathway. EGFR transmits signals through a set of proteins inside the cancer cell that instruct the cancer cell to reproduce and metastasize. Data suggest that blocking EGFR stops this growth signal. Antibodies have been developed that block the EGFR pathway (EGFR-blockers). These antibodies are used in combination with chemotherapy to slow the growth of tumors.
In 2008 significant information about the use of EGFR-blockers was presented and published. This relates to another important gene inside the cancer cell called K-ras, which also controls cancer cell growth. Some tumors have mutations in the K-ras gene; this mutation leaves the K-ras protein always turned “on,” so signaling within the cancer cell continues regardless of whether the EGFR is blocked with an antibody. Mutations in the K-ras gene occur in approximately 40 percent of metastatic colorectal cancer patients. This finding is important because it affects what therapies can be used to fight the cancer.16,17
3. Build a support network.
When an individual is facing a diagnosis of colorectal cancer, the whole family needs information and support to cope with this difficult event. People with colorectal cancer and their family members should feel comfortable asking their health professionals, including their physicians and nurses, for educational and support resources. Treatment centers often have nurses or social workers available to provide counseling and referrals to support groups and other resources.
Drawing on local and national education, support, and advocacy groups is also important. Some organizations—such as the Colon Cancer Alliance (www.ccalliance.org)—provide a colorectal cancer survivor buddy program. CancerCare (www.cancercare.org) offers professional counseling services in person, by phone, and online. Organizations such as the American Cancer Society (www.cancer.org), CancerConsultants.com (www.cancerconsultants.com), and the Jay Monahan Center for Gastrointestinal Health (http://monahancenter.org) are reliable sources of comprehensive, up-to-date information about colorectal cancer prevention, treatment, support, and clinical trials.
Finally, women often serve as the caregivers in the family, putting others’ needs before their own. When a woman is diagnosed with colorectal cancer, it is important that she reach out to her family and friends to let them know how they can help. These loved ones want to help but often don’t know how. Help with simple things—someone to drive to chemotherapy appointments, a neighbor to take out the trash each week, a different family member to bring dinner every day, or a friend to take the children out periodically—can be of tremendous support and can also alleviate the helplessness felt by family and friends.
For women who have been diagnosed with colorectal cancer, recent advances in treatment mean more hope for survival than ever before. Women need to be aware of the symptoms of colorectal cancer and should see a gastroenterologist for evaluation and diagnosis if they experience these symptoms. Remember that colorectal cancer often causes no symptoms at all. For this reason women need to speak with their primary care doctor or OB-GYN about undergoing regular screening for colorectal cancer, along with their routine screening for breast and cervical cancers. Colorectal cancer screening can result in the early detection or even prevention of colorectal cancer—and, ultimately, lives saved.
New Molecular Targets in Colorectal Cancer
Advances in metastatic colorectal cancer will require identification of other targets and pathways that contribute to colorectal cancer progression and metastasis. Inhibitors of several key molecules and pathways are currently being studied. Three candidate proteins and pathways are active areas of research in colorectal cancer: insulin-like growth factor-I receptor (IGF-IR), Src, and toll-like receptor 9 (TLR9).
IGF-IR is a cellular protein, and activation of the IGF-IR pathway results in increased cellular proliferation, malignant transformation, resistance to apoptosis (programmed cell death), tissue invasion and metastasis, and angiogenesis.18 IGF-IR is overexpressed in colon cancer, but activation rather than overexpression may play a more important role. There is substantial overlap in signaling between the IGF-IR and EGFR pathways, raising the possibility that activation of the IGF-IR pathway may be one way in which cells can escape EGFR inhibition. The first IGF-IR inhibitors to enter Phase I clinical testing have been monoclonal antibodies: CP-751871, AMG 479, and IMC-A12.
Src is a nonreceptor protein that is found on the intracellular portion of the cell membrane and was the first oncogene (a potentially cancer-inducing gene) discovered.19 Src promotes angiogenesis, the formation of new blood vessels to tumors, and is overexpressed in more than 80 percent of human colorectal cancers. Its activity increases with cancer progression, with higher levels found in metastases than in primary tumors. Src inhibitors are currently in clinical development; they are unlikely to cause shrinkage of solid tumors and are more likely to influence tumor progression, invasion, and metastasis.
TLR9 has a role in immune regulation in the gastrointestinal tract. It may also have a role in modulating cell signaling, including signaling through the EGFR pathway. Clinical evaluation of TLR9 agonists in cancer patients is under way.
People with colorectal cancer should always ask their physician if there is a clinical trial indicated for their type and stage of cancer. The recent advancements in the treatment of colorectal cancer emanate from results of large clinical trials investigating whether new drugs in combination with chemotherapy and radiation therapy improve survival. Members of the cancer healthcare team can help people with a colorectal cancer diagnosis decide whether to enroll in a clinical trial as well as help choose a trial that is right for them.