Immunotherapy for Colon Cancer

This year it’s estimated that more than 100,000 new cases of colon cancer and an estimated 44,180 new cases of rectal cancer will be diagnosed in the U.S., according to the American Cancer Society. Combined, colorectal cancer — one of the most deadly malignancies — is expected to kill more than 50,000 Americans this year alone.

For those with the most advanced form of colorectal cancer, which has spread well beyond the last section of large intestine or rectum to distant parts of the body like the liver and lungs, the prognosis is bleak. Only around 1 in 8 people with stage 4, or metastatic, colorectal cancer survives 5 years, and many live only months after the cancer has spread that far.

Given the dire reality, there’s been a push to provide treatment options that give patients a better chance at living a longer, fuller life. One of those options are immunotherapy drugs, which in recent years have been approved by the Food and Drug Administration. Immunotherapy drugs — which essentially enlist the body’s own defenses to fight cancer — may greatly improve chances of survival for a small fraction of patients with metastatic colorectal cancer. For those who are candidates for immunotherapy, drugs such as pembrolizumab (Keytruda) and nivolumab (Opdivo) and the combination of nivolumab and ipilimumab (Yervoy) may be given intravenously to stimulate the immune system to fight the cancer.

While the number eligible for this treatment is limited, the results are promising. Initial research shows that upwards of half the patients who are candidates for immunotherapy respond to the treatment. Some patients only live longer, but some see lasting results and have their cancer put into remission — where “you can’t even find any cancer,” says Dr. Boone Goodgame, medical director of oncology at Texas-based health care system Ascension Seton and an assistant professor of oncology at Dell Medical School at the University of Texas at Austin.

[See: 10 Innovations in Cancer Therapy. ]

Picking Patients Who Could Benefit

While immunotherapy is used much more extensively to treat other types of cancer, like the deadly skin cancer melanoma and a type of lung cancer (non-small cell), it’s only recently been introduced as a secondary treatment option for a limited group of patients with metastatic colorectal cancer.

“Right now it really is limited to 5% or less of patients with metastatic disease,” explains Dr. Dung Thi Le, an associate professor of oncology at Johns Hopkins University School of Medicine. Le serves on advisory boards for Bristol-Myers Squibb and Merck, which make immunotherapy drugs that are approved for treatment of colorectal cancer. She’s studied immunotherapy for colorectal cancer patients and receives research funds from both pharmaceutical companies.

This smaller group of patients has a genetic abnormality called mismatch repair deficiency. In tissue that’s normal, mismatch repair proteins fix errors that are made when DNA is replicated in cells. However, in tumors that have mismatch repair deficiency, one or more of the repair proteins is missing, leading to lots of mutations.

These mistakes become apparent in repetitive sequences of DNA called microsatellites. These strands of DNA can be longer or shorter than they normally would be as a result of the DNA errors, which makes the errors easier to identify, explain Li and Cara Wilt, a senior nurse practitioner at the Johns Hopkins University School of Medicine, in a paper they co-authored.

Patients who have this mismatch repair deficiency have a high level of microsatellite instability in the tumor, referred to as MSI-high. Because the tumor has such a high level of genetic mutations, the immune system is able to recognize it as a threat. That means in metastatic colorectal cancer that’s MSI-high the approach may effectively be a lifesaver.

“So while there’s a lot of hope, we certainly don’t want to give false hope to the 95% of patients that don’t have this abnormality in their tumor,” Li says. “However, we also do not want to miss those patients — although not common — who will really benefit from this therapy.”

As such, National Comprehensive Cancer Network guidelines now recommend MSI testing for all patients who have metastatic colorectal cancer, Li notes. Methods for doing this include immunohistochemistry, a lab test that involves evaluating mismatch repair proteins. For the vast majority with colorectal cancer, all those proteins are intact; they have microsatellite stable tumors and aren’t currently candidates for immunotherapy.

[See: Facts You Should Know About Lung Cancer.]

Treatment Options

Immunotherapy isn’t what’s called a first-line therapy yet. Rather it’s recommended for that select group of patients who haven’t responded to traditional treatment like chemotherapy — or who need an additional therapy to fight MSI-high metastatic colorectal cancer.

Generally speaking, treatment options depend on how advanced colorectal cancer is. When caught early — where the abnormal growth of cells is still limited to the lining of the colon, for example — surgery may be all that’s needed to eradicate the cancer. However, chemotherapy is commonly also employed to ensure cancer cells are killed.

For some with rectal cancer in the earliest stages, surgery alone may be sufficient to remove a tumor. If it’s still mainly confined to the rectum and surrounding tissue, or what’s referred to as locally advanced, a couple different treatment approaches may be recommended.

“For patients who have what’s called locally advanced rectal cancer, the approach is to give a combination of chemotherapy and radiation therapy upfront to try to reduce the size of the rectal cancer (and then) have the surgeon do the surgery, hopefully sparing the anal sphincter — so that bowel function can be preserved,” says Dr. Edward Chu, chief of the division of hematology/oncology and deputy director of the UPMC Hillman Cancer Center at the University of Pittsburgh School of Medicine.

For those patients with metastatic colorectal cancer, a combination of those treatment options is often tried. Sometimes targeted therapies are recommended as well. That may include, for example, drugs that target a protein called VEGF (vascular endothelial growth factor) that’s involved in the formation of new blood vessels, which help tumors grow.

For those who are candidates for immunotherapy, how long the course of treatment lasts varies greatly. It could be several months or a couple years, depending on how well patients respond to it and tolerate the drugs.

Additionally, new immunotherapy drugs are being developed and studied in an effort to extend this option to more patients with colon cancer. And experts suggest those with microsatellite-stable colorectal cancer, who aren’t candidates for the currently-approved immunotherapy drugs, consider joining clinical trials for experimental immunotherapy drugs.

Side Effects

Most patients are able to tolerate immunotherapy and many do very well on it. Still, while side effects differ from chemo, they may be serious and even fatal, as the immune system can attack healthy parts of the body as well. “Just like these immunotherapies are activating the immune system at the tumor site, they also can rev up the immune system in normal tissues,” Chu says.

“The side effects of immunotherapy are all sorts of autoimmune problems,” Goodgame adds. He notes that among the most serious is an autoimmune colitis — inflammation of the colon — that can cause severe diarrhea and even life-threatening colon problems.

It can lead to major organ problems, as well, including inflammation of the kidneys ( nephritis), which can affect kidney function, hepatitis (inflammation of the liver) and myocarditis (inflammation of the heart muscle), which can lead to sudden death.

Experts say it’s key to manage patients closely and keep tabs on changes and any possible side effects from immunotherapy drugs. Medications like steroids may be used to treat milder side effects like rash during immunotherapy; for more severe side effects, the therapy may be suspended or stopped, as the focus shifts to solely treating the side effect.

Early Detection

The U.S. Preventive Services Task Force recommends those of average risk beginning routine screening for colorectal cancer at age 50, while the American Cancer Society suggests starting screening at age 45 — something many clinicians now suggest as well.

“In terms of screening and early detection, it’s critical that anyone who is now age 45 or older should be screened for colon cancer,” Chu says. While there are a number of screening methods, he says the gold standard is colonoscopy. This screening can detect polyps, or abnormal growths, so they can be removed; and suspicious tissue can be biopsied to confirm whether or not it’s colon cancer.

[See: 6 Options for People Who Don’t Want a Colonoscopy.]

Depending on a person’s family history — whether close relatives developed colon cancer, especially at a younger age — earlier screening may be recommended. Talk with you doctor if you’re not sure when to get screened for colorectal cancer.

A person’s colon cancer risk and findings from the initial screening (the presence or absence of polyps, for example) will also dictate how often a person gets screened after they’re first checked.

The point, experts say, is not to put off getting checked. That’s because even with a push to develop new treatments for colorectal cancer, it’s much more difficult to treat — and far deadlier — when it’s advanced, and it can usually be effectively treated when detected early.

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