Recent Advances in Colorectal Cancer Treatment

by Allyson J. Ocean, MD, and Emil T. Kuriakose, MD

The past 20 years have witnessed remarkable progress in the early detection and the treatment of colon cancer. As a result, the number of deaths due to colon cancer in the United States has been decreasing every year in both men and women, and there are now more than a million survivors of colon cancer in the United States.1

Much of this progress has been due to effective screening strategies (such as routine colonoscopies) that allow detection of precancerous polyps, which can be removed. Routine colonoscopies also increase the rate of finding cancers in earlier stages, thereby increasing the chance of cure. The most significant part of this progress, however, has been our increased understanding of the behavior of cancer cells at the molecular and genetic levels.

Over the past decade, the discovery of several molecular and genetic abnormalities unique to cancer cells has led to the development of novel therapeutic agents that are able to target the cancer cells while minimizing “collateral damage” to normal cells in the body. Furthermore, the unique variations of gene mutations discovered in different cancer cells help separate the more aggressive (high-grade) tumors from those that are less aggressive (low-grade). As a result, physicians are able to individualize treatment based on the unique genetic and molecular characteristics of the cancer of a particular patient.

The KRAS Oncogene

A pivotal milestone in cancer research was the discovery of a group of genes called the RAS family. RAS is an oncogene—a gene that encodes proteins that function as switches to turn on various genes for cell growth and division. These genes are intricate players in the normal cell cycle, responding to cues both outside and inside the cell that regulate how fast a cell should grow and divide. Furthermore, there are myriad proteins that interact with RAS—including receptors on the cell surface—that pass signals into the cell through complex circuits of protein interactions, with the end result being changes in gene expression. Mutations in the RAS genes result in permanently “turned on” switches that in turn result in uninhibited cell division, which can lead to cancer.

There are three types of RAS oncogenes, designated NRAS, GRAS, and KRAS. Although mutations in all three can cause cancer, KRAS is the most frequently mutated oncogene in human colorectal cancer.2 About 40 to 50 percent of human colorectal cancers have mutated KRAS genes.2 Recently developed laboratory assays are able to differentiate those tumors that have this mutation from those that have normal (also called wild-type) KRAS.

This has had several therapeutic implications. Those tumors that have nonmutated, or wild-type, KRAS are susceptible to a class of biologic agents called epidermal growth factor receptor (EGFR) inhibitors. EGFR is a receptor on the surface of the cell that binds to a growth factor called epidermal growth factor (EGF). This receptor activates cellular pathways that promote cell growth and division, with KRAS being one of the key players in the process. Blocking the EGF receptor removes this important signal for the continued growth of cancer cells. The two EGFR-targeting agents studied in colon cancer are Erbitux® (cetuximab) and panitumumab. In a recent trial of Erbitux alone versus best supportive care in 572 patients in whom all prior therapies had failed, overall survival and quality of life were significantly improved in the Erbitux arm.3 The benefit of treatment, however, was limited to those patients who had the nonmutated KRAS gene. Such findings show the increasing role of genetic assays to identify cancers that will be more susceptible to specific treatments.

Another exciting group of drugs that specifically targets the KRAS protein works by inhibiting an enzyme called farnesyltransferase. This enzyme is involved in activating the RAS proteins. As of yet these drugs are not available for use at the bedside and are currently being tested in animal models.

The BRAF Gene

Another component of the RAS signaling pathway is known as BRAF. Mutations that cause increased activation of this protein result in increased cell division. About 10 percent of colorectal cancers have a mutated BRAF gene.4 There is currently a commercially available assay to test tumors for BRAFactivating mutations.5 Studies have shown that BRAF mutations confer a poorer prognosis in colorectal cancer and also may predict a poorer response to EGFR inhibitors. In the CRYSTAL trial, which was presented at the 2010 Gastrointestinal Cancers Symposium, co-sponsored by the American Society of Clinical Oncology, BRAF mutations predicted a poorer prognosis overall, but it was unclear how much this mutation contributed to tumor resistance to EGFR inhibitors.6 Continued incorporation of more assays such as this one will help clinicians provide individualized therapy for patients based on the pattern of gene expression specific to their cancers.

The Onco type DX® Assay

The role of chemotherapy in early-stage colon cancer has long been a focal point of debate among oncologists. In those patients with Stage I and Stage II colon cancer (such as those whose cancers have not spread outside the colon and do not involve lymph nodes), it is unclear at present whether all early-stage patients benefit from additional chemotherapy after surgical removal of the tumor. Because additional chemotherapy has its own risks, the challenge has been to identify those patients who would derive the most clinical benefit from additional chemotherapy. Several large trials have sought to answer this question with conflicting results. As a result, current guidelines recommend approaching this issue on an individual patient-by-patient basis.

A promising solution to this dilemma comes from a technology called gene expression profiling, in which a panel of different genes within a cancer is analyzed to compare the patterns of gene expression of the aggressively growing tumors with the less aggressive ones. By doing this we are able to get the “signature” expression profile of a certain type of cancer.

This technique has been successfully implemented in breast cancer using an assay called Oncotype DX, which identifies high-risk tumors in patients with early-stage breast cancer and guides additional therapy decisions. Oncotype DX is now available for colon cancer as well. It looks at the expression profile of 12 genes and comes up with a recurrence score to estimate the chance of the cancer’s coming back somewhere else after it has been surgically removed.5 Using this score as a guide, clinicians are able to more accurately identify those select patients with early-stage colon cancer who would benefit from additional chemotherapy. This assay has yet to undergo validation in large prospective clinical trials, but its success with breast cancer provides hope for similar results in colon cancer.

Paradigm Shifts

Advanced-stage cancer of any type is extremely difficult to treat and is considered incurable. Aside from various combinations of conventional chemotherapy—and sometimes palliative radiation—options for these patients are usually very limited.

Animal models of different types of cancer have shown that cancer cells, like all other cells in the body, respond to positive and negative feedback signals that control their rate of growth. Interestingly, cancer cells themselves release substances that can stop the growth of other cancer cells in tissue cultures.7–11

This remarkable phenomenon has been studied extensively at the Rogosin Institute, affiliated with NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The researchers developed a cell encapsulation technology, called the macrobead. The macrobead is a capsule made of agarose (a sugar molecule) in which cancer cells can be contained and isolated. It was found that cancer cells can survive indefinitely inside these beads and, furthermore, remain isolated from the host immune system. When the macrobeads were implanted in mice with cancer, the beads inhibited growth of the cancers. Additional experiments demonstrated that the encapsulated cancer cells were releasing a cancer-suppressing material that permeated the bead. Even more intriguing was the finding that the tumor-blunting effect occurred regardless of the type of cancer cells in the beads or the species from which the cancer cells originated. This presented a novel way of treating cancer.

Today a Phase II trial is being conducted by the Rogosin Institute with macrobeads in advanced-stage colon and pancreatic cancers to test this very idea.12 The macrobeads are implanted laparoscopically into the abdominal cavity in patients with advanced colorectal or pancreatic cancers in whom all conventional therapy has failed. The major advantage of this new type of treatment is the relative lack of side effects and toxicities that are common with conventional chemotherapy.

A Promising Future

Promising developments such as these make this a very exciting time to practice oncology. We have come a long way from the days of conventional intravenous chemotherapy as the primary means of treating all forms of cancer. The average survival of patients with advanced colorectal cancer has doubled over the past few decades, and these new therapies have led to this improvement in survival time. Today’s targeted therapies and the rapid pace at which new molecular and genetic targets are being discovered make the prospect of individualized cancer therapy a reality that will soon be realized. 

Colon Cancer Survivor Profiles

Briana Stephen

Briana Stephen was 28 years old when she was diagnosed with Stage IV colon cancer on Halloween weekend 2008, just months after completing the Boston and San Diego Marathons. “I have always been active and have eaten a healthy diet, and there is no history of cancer in our family,” she says of the surprise that the diagnosis presented.

Told that unless the cancer was treated immediately she could expect to live only a few months, Briana proceeded with several surgeries and chemotherapy regimens. In December 2009 she was declared disease-free, but, she says, that celebration was short-lived: in March 2010, after many complications, a magnetic resonance imaging (MRI) scan revealed 13 brain tumors. Since that time she has undergone three pinpointed radiation treatments through the San Diego Gamma Knife Center and receives chemo treatments every other week.

A mother of four, Briana says that her life changed drastically in the wake of her diagnosis. She leaned on her faith and on neighbors, family, and friends—who came together as “Team Bri”—for support. She also realized that she would have to ration her energy: “I learned that I have only so much energy in a day. Wherever I choose to spend my reserves must be the priority for the day. If I use the morning to work, the rest of the day I struggle for energy—something I feel awful about when the children need me the most for schoolwork and dinner.”

Despite the changes the disease has brought to her life, she is determined not to allow the diagnosis to define her: “There’s no reason for me to allow the disease to be in the forefront of my life,” she says. “I cherish my time with loved ones way too much to give the cancer my attention. I do my best not to think about treatments, even as I’m getting them and feeling nauseated. If we have only one life to live on earth, I’d rather spend it in days of gratitude than sorrow.”

Kristen Fanti

Kristen Fanti already knew all about living with a debilitating illness when she was diagnosed with colon cancer in 2003 at age 21. Diagnosed with ulcerative colitis, a chronic inflammation of the large intestine, at age three, Kristen had learned to adapt to the challenges of the disease as doctors struggled to get her symptoms under control. Still, her cancer diagnosis, which followed a prophylactic colectomy surgery intended to control the ulcerative colitis, was a shock: “When the surgeon mentioned the words ‘cancer’ and ‘chemotherapy,’ I was numb and scared,” Kristen says.

A senior in college at the time, Kristen underwent six months of chemotherapy, which made her tired and dehydrated, caused peripheral neuropathy in her fingers and toes, and changed the taste of all her favorite foods. Determined to stay in school and graduate on time, Kristen continued with her studies, bolstered by her supportive family, her work in campus ministry, and by roommates and friends who called her “Chemo Girl” and helped her find humor in the difficult situation. “I could never have done it all without their support and laughter,” she says. “On my worst days, I would think about them or daydream about peaceful places.”

Despite finishing treatment and graduating on time with a degree in economics, Kristen knew the experience had changed her. “I had a nagging feeling that economics was not the right fit for me,” she says. “The medical environment had become comfortable; I saw nurses going to work and wanted that to be my job. I even started having dreams at night that I was a nurse.” Inspired, Kristen returned to school and within two years earned a nursing degree and lined up a job at NewYork-Presbyterian Hospital in the inpatient oncology unit.

Now five years out of treatment, Kristen sees her oncologist annually for follow-up testing but is healthy and living happily in New York City. She loves her job as an oncology nurse and feels that her cancer diagnosis directed her toward what she was meant to do: “I firmly believe that everything happens for a reason; and while it’s crazy, having cancer helped me realize my calling in life.”

Carol Kelly

Carol Kelly, 67, was looking forward to watching the big game in February 2010 when stomach pain and diarrhea sent her to the emergency room the night before the Super Bowl. Though she had been living with irritable bowel syndrome, she knew that these symptoms were different.

In fact, a colonoscopy led to a diagnosis of colon cancer. Though Carol lives in St. Petersburg, Florida, where she was working full-time and volunteering, she chose to travel to New York, where the majority of her family live, for the chemotherapy treatments that followed initial surgery to remove the tumors detected during the colonoscopy. Once in New York, her treatment was interrupted by the discovery of a hole in her heart, which had to be surgically repaired, and by a gall bladder attack, which required additional treatment.

Throughout the various ordeals of her cancer journey, Carol felt enormous support from her children—she is a mother of seven—and has remained positive and pragmatic about her diagnosis. “With today’s medicine I did not feel it was the end of the world,” Carol says, “and I explained as much to my children and grandchildren.” If she faces a recurrence, she says, “I will deal with it then.”

Carol hopes her own children will learn from her experience to be proactive about their health. “If men and women, including my own children, take a proactive approach and get the tests needed (such as a Pap test, colonoscopy, and mammogram), this can be a first line of defense.”

Looking to return home to Florida soon and resume her active lifestyle, Carol will not forget the truth that cancer has reaffirmed: “Life is a precious gem,” she says. “Make every day count, even the rainy ones.”

Kathleen Tevlin-Nulty

An avid runner, Kathleen Tevlin-Nulty has completed six marathons in the past eight years, so when the then-42-year-old mother of three noticed that her running speed had slowed considerably and that she was exhausted at the end of each run, she went to the doctor. The result: Stage III colon cancer.

“I had no typical symptoms,” Kathleen says. Beyond the changes in her running and fatigue level, she had noticed only some shortness of breath and acid reflux, but nothing that would lead her to think of colon cancer. Still, in November 2009 doctors removed a 3-centimeter mass from her colon, along with 20 lymph nodes, five of which were cancerous.

Kathleen underwent chemotherapy following her initial surgery, using her experience as an athlete to see her through. “I think running prepared me for my treatments: some days you have a great run and other days you feel like you can’t even make it through the first mile.”

Throughout her journey Kathleen found sustaining support from her husband, who she says was her emotional rock. “I never would have made it through this year without him.” Friends who kept her laughing and parents and in-laws who were on hand to help also buoyed her spirits and allowed her to continue to care for her children.

Having completed treatment and eager to get back to running and on with life, Kathleen does not feel that cancer offered her any particularly illuminating insights—she was aware of the blessings in her life before her diagnosis. “I already knew I had a wonderful life, an amazing family, and fantastic friends. I didn’t need to find meaning or purpose from cancer; I already had that.”

Erica Paul

In June 2007 intense pain on her right side propelled then-26-year-old Erica Paul to visit her general practitioner. Her doctor referred her to a gastroenterologist, who ordered a colonoscopy. The test revealed a large, bleeding, malignant mass in her sigmoid colon, which had metastasized to her liver—Stage IV colon cancer.

Living in Virginia at the time, Erica was far from her family in Michigan. Though they traveled back and forth to help her through treatment, it was her boyfriend, Michael, who became her primary caregiver. The experience brought the couple even closer, and they were married in October 2008. “It was the best day of my life,” Erica says of her wedding day, “and one that I didn’t think I would live to experience.”

Erica says that the challenges presented by her diagnosis have led her to “discover my inner strength and to never give up hope.” Though she is scared at times, Erica does her best to focus on the present. “I have learned that I cannot worry about things I cannot control. I try to enjoy every day despite the challenges it may bring.”

Focusing on the blessings in her life, including her friends and family—who formed the Team Fabulous Foundation to help Erica cover the cost of her treatment—and working with a counselor to cope with the “new normal” of her post-diagnosis life have helped her immensely.

Currently undergoing radioembolization treatment targeting her liver tumors, Erica is scanned every eight weeks. Her treatment schedule doesn’t allow for much advance planning, she says, but she is optimistic about the future. “Colon cancer is not a death sentence. I plan to surpass the five-year survival rate. You have to believe in yourself and you can live a long, meaningful, happy life with cancer.”

Symptoms of Colorectal Cancer

Although colorectal cancer first develops with few, if any, symptoms, if symptoms present, they may include:

Diarrhea or constipation
The feeling that your bowel does not empty completely
Blood (either bright red or very dark) in your stool
Stools that are narrower than usual
Frequent gas pains or cramps, or feeling full or bloated
Weight loss with no known reason
Feeling very tired all the time
Nausea or vomiting

These symptoms can also be associated with many other health conditions. If you have any of these symptoms, discuss them with your doctor. Only your doctor can determine why you’re having these symptoms. Usually, early cancer does not cause pain. It is important not to wait to feel pain before seeing a doctor.

Source: Colon Cancer Alliance