On the Verge of Understanding

CUREColorectal Cancer Special Issue
Volume 9
Issue 0

Advances in the treatment of metastatic colorectal cancer have tripled survival rates, but more profound leaps are anticipated as researchers unravel the disease's complexities.

As Rachel Lefebvre approached a certain age, she began to take heed of the advice of a few older friends. Forty, they warned—in that half-joking way—was a tipping point after which everything went downhill. She vowed to enter the decade in fighting form, and began eating better and exercising regularly. For a while she felt great, but as she crossed the threshold of her milestone year, exhaustion set in.

Soon she wound up at her doctor, wondering aloud about vitamin deficiency. Instead, some funky liver enzyme readings led to a precautionary ultrasound, which escalated to an MRI, which resulted finally in a biopsy and a diagnosis of metastatic colon cancer.

There is no whiplash like discovering stage 4 cancer at 40. “It was so surreal,” she says 18 months later, recovering from an advanced radiation treatment called Y-90 (intra-arterial yttrium-90 radioembolization) that’s gaining favor in the treatment of metastatic disease to the liver. Doctors placed radioactive beads not much larger than red blood cells into tumors in her liver. Now she’s contemplating her next medical steps.

She fired her first doctor, who told her she spent too much time on Google. “Wouldn’t you?” she countered. “You gave me two years and I have two kids. There is no way I’m not doing everything and anything I can to outlive this.”

Empowered by the engaged stage 4 patients she found in the online forums at Colon Town (chris4life.org/colontown), she found a doctor three hours away at an academic medical center in Central Florida. Now she has options.

Colorectal cancer is an interesting example of both how far cancer treatments have advanced, and how far they still need to go. Patients with stage 4 colorectal cancer used to survive an average of just nine months; that number now hovers around 30 months.

But while incremental advances in treatment have nearly tripled survival time for those with advanced disease over the last two decades, colorectal cancer is still waiting for its miracle. Drugs like Herceptin (trastuzumab) for breast cancer have turned certain subtypes of cancer from lifethreatening diseases into conditions that can be managed for years.

“We are jealous of some of the other cancers,” says oncologist John Marshall, director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer at Georgetown University.

Researchers have been refining their treatments, and that’s been a key to the improving outcomes. But: “That’s different than finding what makes the cancer tick,” he says. “Right now, we are measuring one street corner and saying that we understand the traffic. We are measuring one gene when we know that there are multiple genes involved. We need to understand more.”

But intriguing biological clues point to complexities we’re on the verge of understanding. For example, preliminary indications are that, after diagnosis, eating a non-Western diet and exercising both increase a patient’s chance of survival. More curiously, whether the cancer appears on the left or right side of someone’s body is a clue to its origin.

Colon cancers on the right side tend to be hereditary, while those on the left side tend to be sporadic. Scientists hypothesize that it may be about how intestinal bacteria help break down food, changing its chemistry as the waste passes toward the toilet.


Patients with colon cancer versus rectal cancer have very different experiences when the disease is caught early. Slicing out a piece of the colon and stitching it back together can be a relatively simple surgical procedure. But as you get closer to muscles of the rectum, surgery has a more radical impact. Strategic radiation to shrink tumors before surgery becomes an important tool as doctors try to preserve bodily functions.

Despite these differences between subtypes, doctors tend to talk about colorectal cancer as one entity because, once the disease has spread and become metastatic, there does not appear to be any difference. The treatments are the same.

Stage 1 colorectal cancer comes with the potential for an easy surgical cure. The catch: the disease tends to remain asymptomatic, and thus hidden, until later stages. The disease can be uncovered via screening tests, but people under 50 years of age are not routinely screened, and those aged 50 and older, for whom screening is recommended, don’t always comply.

Louis Diaz, associate professor of oncology at Johns Hopkins Medical School, thinks of colorectal cancer in three groups defined by their surgical possibilities. Stage 1, 2 and 3 colorectal cancer can be operated on immediately, and can be cured. About 5 percent of stage 4 colon cancers are also immediately operable—for example, those with a single metastatic growth that can be removed along with the colon resection.

Some stage 4 disease is borderline—two to four months of chemotherapy or radiation are used to shrink tumors. Because metastatic disease can be hidden, doctors need to know if they are looking at the whole iceberg or just the tip. If treatment indicates that the cancer is relatively contained, surgery can proceed with curative intent. “When you go in surgically, you don’t want to have to go back in,” says Diaz. “Get it all.”

For a stage 1 diagnosis, surgery is the only treatment. For stage 3, it’s been proved that post-operative chemotherapy composed of fluorouracil (5-FU) and Eloxatin (oxaliplatin) for six months significantly improves a patient’s chance of being disease-free in five years, and significantly improves survival from cancer.

Stage 2 is the sticking point. Current guidelines say that post-operative chemotherapy does not have an appreciable impact on the treatment outcome. Yet, says Diaz, about half of practitioners will treat patients who are higher-risk with some kind of chemotherapy. Measuring the levels of expression of multiple genes, or “gene profiling,” using tests such as Oncotype DX or MDA114, is emerging as better way to determine prognosis and decide who needs chemotherapy.

“What we’ve got to work on is to not treat all cancers the same, but figure out their different subtypes,” explains Georgetown’s Marshall. “We’re beginning to do that now with colorectal cancer.”

For example, about 5 percent of colorectal cancer patients have one or more inherited genetic mutation in any of five specific genes, a condition called Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (HNPCC). Another 15 percent have similar mutations, but didn’t inherit them. The involvement of these five genes suggests a high rate of microsatellite instability (MSI), a condition that leads DNA to malfunction as it undergoes natural repair processes in the cell.

MSI-high tumors behave differently, Marshall says, whether the mutations were inherited or developed during someone’s life. New treatment guidelines support MSI testing for all patients with colorectal cancer. “Giving chemotherapy to stage 2 patients is controversial,” he says, and a high MSI score suggests that chemotherapy would in fact be harmful. “I don’t treat stage 2 patients without knowing their MSI.”


When Jennifer Walls was 55, she had her first colonoscopy—she now wishes she’d done it sooner— and was diagnosed with stage 1 colon cancer. Doctors took a foot from her colon and prescribed lab work every six months so they could follow the levels of CEA (carcinoembryonic antigen) in her blood. CEA exists while a fetus is developing, but is typically absent in the blood of a healthy adult. It reappears in some colon cancer, allowing doctors to track cancerous activity. Walls’ CEA levels were high before surgery, so they hoped to monitor the possibility of the cancer returning via CEA.

It didn’t work. After a medically complicated couple of years, Walls developed a cough that wouldn’t go away, and pain around her liver. Ultrasound picked up a spot, then a subsequent MRI cleared the liver but caught a worrisome lesion on the lung. Finally, a CT scan in spring of 2012 revealed the cancer was back in both lungs.

For patients like Walls and Lefebvre with metastatic disease, chemotherapy treatments may vary but generally follow a well-laid path. The backbone cocktail of drugs begins with 5-FU, which has been in use since 1958. Folinic acid (leucovorin), approved in 1991, helps activate the 5-FU. Combinations using Camptosar (irinotecan), Eloxatin and Xeloda (capecitabine) began to emerge in the early 2000s, and have evolved into regimens known as FOLFOX and FOLFIRI, both given intravenously. FOLFOX is 5-FU and folinic acid with Eloxatin, while FOLFIRI replaces Eloxatin with Camptosar.

Patients typically begin with FOLFOX, though this combination can cause neuropathy in the hands and feet— weakness, numbness and pain from nerve damage. Patients who are particularly dependent on their hands, such as musicians, might want to start with FOLFIRI, which is equivalent but less likely to cause neuropathy. Still, after starting one of these regimens, patients will need to switch to the other if their disease continues to progress.

Treatment currently lasts for six months, but trials are underway to test if three months of FOLFOX will achieve the same result, with fewer side effects. In addition to neuropathy, FOLFOX side effects can include mouth sores, diarrhea and hand-foot syndrome; FOLFIRI can cause hair loss, blood disorders, gastric upset and fatigue.

Avastin (bevacizumab), an intravenous drug designed to hamper cancer’s ability to create its own blood supply, is often part of this early mix, as well, since this has been shown to delay progression compared to chemotherapy alone. Or, instead of Avastin, first-line FOLFOX or FOLFIRI could be paired with a targeted compound like Erbitux (cetuximab, approved in 2012) or Vectibix (panitumumab, approved in 2006). A patient might start treatment with FOLFIRI plus Avastin, for instance, and then, if the regimen becomes less effective, switch to FOLFOX with Erbitux or Vectibix.

In a phase 3 trial, Erbitux with chemotherapy—as compared with chemotherapy alone—improved survival by four months and progression-free survival by a month and a half in patients who didn’t have mutations in genes called KRAS or NRAS.

Vectibix, originally approved for use alone as a later-line drug due its tumor-shrinking ability, was given a second FDA approval last year as a firstline drug to be used in combination with FOLFOX. In the study that led to that approval, its benefits closely matched those offered by Erbitux in patients without KRAS mutations.

Both of these drugs interfere with the cellular signaling needed to sustain some cancers by targeting a protein on the outsides of cancer cells: the epidermal growth factor receptor, or EGFR. But because they have no benefit for patients with KRAS or NRAS mutations, they are unable to help more than half of those with colorectal cancer.

Another option in this setting is Zaltrap (ziv-aflibercept, approved in 2012)—similar to Avastin in that it prevents blood vessel growth to tumors—which is used in combination with FOLFIRI. In a study, the drug added about a month and a half to overall survival compared with the use of FOLFIRI alone.

Unlike the targeted-drug skin rash that can appear with Erbitux and Vectibix, the most common side effects with infused Zaltrap and Avastin include fatigue, hypertension, bleeding, headaches, a drop in the number of white blood cells, sores in the mouth, diarrhea and loss of appetite.

If those regimens become less effective, a potential option— depending on the sequence of treatments—is Stivarga (regorafenib, approved in 2012), a pill that ratchets down a cancer’s ability to create its own blood supply by blocking several enzymes. The drug offers about six additional weeks of survival on average, and two months free of additional disease progression, when compared to best supportive care alone.

While several of these newer targeted drugs offer modest boosts in survival, they come with steep price tags when compared with chemotherapy (5-FU costs about $30 per treatment). A study that closely followed the advent of FOLFOX estimated its monthly price at nearly $6,000.

Erbitux costs between $8,400 and $10,600 a month. Avastin, which must be taken for many months in order to generate a benefit, costs about $5,000 a month, while patients or their health insurers are charged $11,000 per month for the similarly effective but later-line Zaltrap.

The prices of targeted cancer therapies can mean different things to different patients, depending on whether they are insured and what level of coverage their plans provide. As one example, Medicare patients foot the bill for about 20 percent, or $2,000 per month, of the cost of Zaltrap.


Still more novel agents are on the horizon. Cyramza (ramucirumab), which also controls blood-vessel growth to tumors, improved survival in patients with metastatic colorectal cancer when combined with FOLFIRI in a recent study.

“We know that when patients with advanced colorectal cancer have progression of their disease on first-line chemotherapy plus (Avastin), we can either continue the (Avastin) with second-line chemotherapy or use a different angiogenesis inhibitor, Zaltrap, with chemotherapy. And now we know that (Cyramza) can be given with chemotherapy in this setting, as well,” oncologist Smitha S. Krishnamurthi told the media days before the findings were presented at the 2015 Gastrointestinal Cancers Symposium in January. “All of these approaches have had a similar increase in survival.”

Since colorectal cancer shares a family of mutations with melanoma, the successful MEK and BRAF inhibitors developed for that condition are now being tested in metastatic colorectal cancer. Immunotherapy agents that have also proved successful in melanoma, PD-1 and PD-L1 inhibitors, are also being tested for their potential in some colorectal cancers.

And TAS-102, a close relative of 5-FU, recently completed clinical trials and is expected to gain approval by mid-December.

The drug was tested in the phase 3 RECOURSE study, which compared TAS-102 to placebo in patients with colorectal cancer who had taken at least two prior kinds of therapy. For patients treated with TAS- 102, median overall survival was 7.1 months compared with 5.3 months for those who took placebo; those findings included results for those with KRAS-mutated tumors, in whom the drug was less effective. Patients taking TAS-102 also saw a slight improvement in progression-free survival compared with placebo (2 months versus 1.7 months). Moderate to severe side effects consisted mainly of blood disorders, including decreases in platelets, white blood cells, red blood cells or neutrophils.

It is not yet clear where TAS-102 will fit into the treatment sequence among the other drugs already available for metastatic colorectal cancer.

Meanwhile, there are other investigational drugs being tested, too. As of late February, more than 100 clinical trials were open and testing a wide variety of therapies.


“Twenty years ago we had 5-FU. That was it,” says Randall F. Holcombe, chief medical officer for cancer in the Mt. Sinai Health System. “We didn’t understand that we could treat patients after surgery to prevent relapse. And we now know that it works best to give a combination of 5-FU/ oxaliplatin.”

The proliferation of chemotherapy, targeted therapy and more advanced surgical and radiation techniques gives more choices to patients and doctors. “Because we can use many of these therapies sequentially, we can provide very significant benefit for our patients and really prolong their life expectancy even with metastatic disease,” Holcombe says.

Take Jennifer Walls, for example. After she finished her FOLFOX regimen, the tumor was reduced enough that doctors could operate robotically, removing the diseased portion of the lung. That paved the way for participation in several clinical trials. She tried the experimental drug dovitinib, which is thought to inhibit a number of cellular pathways involved in colorectal cancer, but she became violently ill, she says, and had to quit the trial: “I had severe nausea. It felt like my head was exploding.”

In May of last year she tried a different trial, this time of Medi-565, a vaccine that targets CEA. The side effects were minimal this time, but by September her tumor had regrown by over 20 percent. That was disappointing, except that now it was large enough to be treated with Cyberknife, a precision radiation treatment. That treatment, as do radiofrequency ablation and Y-90, allows radiologists to safely deliver radiation to liver metastases where chemotherapy has failed and surgery is impossible.

Due to the array of medical and radiation options now available in late-stage metastatic disease, “It’s no longer a disease where we have set pathways,” says Diaz. “We now have tools to intervene in a non-toxic, non-surgical way that is apparently extending life.”

Still, there is lots of work to be done. “The standard is better than it was, but it’s not good,” says Marshall. Improvement, as always, will come via clinical trials. “I don’t want to make patients feel guilty for not going on a clinical trial, but if there is one open to them, I would strongly encourage them. We’ve got to keep trying. We need our patients as partners.”

As an example, he’s nervously watching some research on patients diagnosed with stage 4 rectal cancer who are electing not to have surgery. It’s a risky decision, but these patients have decided they do not want to lose rectal function. They know that in about 20 to 30 percent of patients who have chemotherapy or radiation, and then undergo surgery, the surgeon doesn’t find any visible cancer to remove. Unfortunately, those patients have to undergo the operation—and lose the muscles of the rectum—to find that out. Now, doctors are holding off on surgery in patients who have responded well to chemo and radiation, following them very closely for signs of recurring disease.

A study at Memorial Sloan Kettering Cancer Center compared patients who were observed after chemotherapy and radiation with those who underwent surgery after those treatments. Researchers found that 75 percent of the patients in the surveillance group didn’t need surgery during the four-year follow-up period, while 25 percent did. Survival in the surveillance group nearly matched that in the surgery group (91 versus 95 percent).

Next, a phase 2 study will follow such patients at 20 institutions across the United States. Non-surgical management will be offered to participants if their tumors disappear after chemotherapy and radiation.

“Clearly, this is a case where involvement with a clinical trial is the right thing,” Marshall says. By finding out which patients are most likely to have success with this treatment, oncologists will improve their standard of care by doing less—the proverbial win-win.

“We’re all very nervous about this, honestly,” he says. “But I completely understand the push from the patients who will risk it.”

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