Over the past 20 years, several developments have been made in the surgical and therapeutic treatment of colorectal cancer, which have allowed patients to have better outcomes including survivorship, according to two experts.

According to the American Cancer Society, colorectal cancer is the third most common cancer in the United States, excluding skin cancers. The organization estimates that there will be 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer diagnosed in 2022.

In light of CURE®’s 20th anniversary, we spoke with two colorectal cancer experts from City of Hope to learn more about the developments that have significantly changed the treatment landscape in this area.

“There’s nothing the same as it was 20 years ago,” said Dr. Andreas M. Kaiser, a professor and chief of the Division of Colorectal Surgery at City of Hope, a comprehensive cancer center in Duarte, California, in an interview with CURE®. “Our understanding of the disease or treatment modalities all have totally changed. If a physician in 2000 thought he or she could just continue practicing like they did at that time, I think such an individual would be lost in the field at this point and could not keep up.”

Much of the change that has occurred in colorectal cancer over the past 20 years focuses on how to treat patients and how to categorize them by subtypes.

“In the non-surgical armamentarium of treatments for patients, we have new drugs, we have new strategies and we have new — basically — molecular markers to subgroup our patients,” Dr. Afsaneh Barzi, an associate professor of gastrointestinal oncology at City of Hope and a medical director at AccessHope, a subsidiary of City of Hope, told CURE®. “To step back, colorectal cancer was bundled as one disease. When we look back about 20 years ago, it was a disease that was all under one category. And then later came first the differentiation by anatomical site, meaning rectal is different from colon. And then later on, just over the past few years, further differentiation by anatomical site, right-sided colon cancer or left-sided colon cancer.”

‘Sophisticated Technology’ in Colorectal Cancer Surgery

Although treatment of colorectal cancer may vary depending on its location, size and potential cancer spread, it often involves some combination of surgery, radiation therapy and chemotherapy.

Surgery is one of the many areas where dramatic advances have been made over the past 20 years. In the past, surgeons typically made an incision from below the sternum to the pubic bone, Kaiser said. Nowadays, many surgeries, particularly first-time surgeries, can be performed with minimally invasive tools and techniques like laparoscopy or robotic surgery. This is when a surgeon makes several small incisions, measuring a centimeter or smaller, where instruments are inserted. This allows the surgeon to perform the procedure without inserting a hand and other tools into the patient’s body. To remove the piece of affected tissue, one of the incisions can be made a little bigger by approximately two inches.

“Sometimes, we see patients who had previously, for example, had an appendectomy in the ‘80s or ‘90s, and they have a 10- or 15-centimeter-long incision,” Kaiser said. “Now we come in and do surgery for a much bigger piece of tissue than the appendix and we have much smaller incisions. That detail sometimes very clearly illustrates to the patients how we have changed our approach.”

Laparoscopic surgery was introduced back in the ‘90s, but it did not establish itself until the mid-2000s, Kaiser said. This is also around that time that robotic surgery started to evolve. Compared with laparoscopic surgery, when a surgeon holds instruments in their hands, robotic surgery involves a robot holding the tools. This doesn’t mean that the robot itself is performing the entire surgery, but rather it translates movements that the surgeon makes inside a console and implements them inside the body.

“Because it is a very sophisticated technology, it allows (for) very precise movements inside (the body),” Kaiser said. “If there is any sort of tremor in the surgeon’s hand, it corrects so that the movements are very precise such that we can do pretty much the entire operation internally. The reconnection of the bowels, we can do internally without having to make a big incision.”

This precision has positively impacted patient care and has improved outcomes like survival. First off, surgeons have learned much more about anatomy through these minimally invasive approaches, which can also minimize a patient’s bleeding risk during the procedure. Not only that, following a patient’s anatomical planes allows surgeons to remove a “nice-looking specimen,” Kaiser said, which can reduce the risk for the tumor returning in that area.

Technology has also allowed oncologists to see a tumor before treatment starts, which can help them developing a game plan which treatment to proceed with before surgery in an attempt to shrink the tumor.

“With those new medications and protocols in up to 30% (of patients), the tumor disappears and we can’t see anything left, which creates an interesting new problem, but a good problem to have. That is, should we actually still do the surgery that we originally wanted to do, or can we watch and wait (with) those patients?”

Aiming to Reduce Overtreatment in Patients

Not only has this “watch-and-wait” approach been implemented in the surgical side of rectal cancer treatment, but also in the therapy side of treatment to an extent. This may potentially reduce the risk for overtreatment in patients and for side effects from treatments.

“Not only have we brought more (therapies) to colorectal cancer, … we have also started to decelerate the treatment for patients who don’t need too much treatment,” Barzi said. “In other words, finding the right balance is happening within this space of colorectal cancer, and it’s really fascinating. Shortening the duration of adjuvant therapy for a subset of patients from a standard of six months to three months, based on the IDEA collaboration, really happened within this 20 years’ timeframe.”

Therapeutic advancements in colorectal cancer started in 2004, when two targeted drugs were approved by the Food and Drug Administration (FDA) — Avastin (bevacizumab) and Erbitux (cetuximab). In fact, Barzi said that colon cancer was among the very first cancers to have targeted drugs approved by the FDA. There has also been growth in subsequent lines of therapy including Stivarga (regorafenib), which was approved in 2013 and was the first drug to enter this space in nearly 10 years after the last approvals. This was followed by another FDA approval in 2015 for Lonsurf (trifluridine/tipiracil).

In addition to advancements in treatments, progress has also been made in the strategies used to treat patients with colorectal cancer.

“It isn’t just about using chemotherapy,” Barzi said. “It’s how we basically utilize the multimodality treatment, how we bring the surgeon, the oncologist and the radiation oncologist all on board to better the care and the outcomes of patients with colorectal cancer. It’s among few cancers that a small minority of patients with stage 4 (disease) can actually see a cure. That is a difference between colorectal cancer and many other cancers.”

A multidisciplinary approach to treating colorectal cancer has enabled physicians to help patients select the best treatment for their particular disease. For example, genetic testing could identify patients with Lynch Syndrome or microsatellite instability-high (MSI-high) disease, which can help doctors determine whether patients would be suitable for immunotherapy, Barzi said.

Advances in both surgical techniques and treatments have led to improved outcomes including survivorship, which highlights the importance of prioritizing survivors’ quality of life during treatment and beyond.

“When we talk about survivors, we should not forget that at least within the past 10, 15 years, we have confirmed evidence that the age of colorectal cancer is migrating to a younger age,” Barzi said. “We have more and more younger patients who have been diagnosed with colorectal cancer, and if these younger patients are going to be survivors, attention to survivorship issues should be forefront and at the center of the attention because these people have 30, 40, 50 years to live after their diagnosis and treatment of colorectal cancer.”

Hope for More Progress in the Future

Even with these important advancements in colorectal cancer treatment over the last 20 years, there are already improvements in the pipeline for the next 20 years, if not sooner. Technology will play a huge role in surgical techniques beyond what has already occurred.

“We will expect to see a dramatic change in sophistication in instruments getting smaller, getting more precise, having more ability to turn, etc., so that we can do a mini-incision, whereas inside the abdomen, the instruments start to (almost have) tentacles, allowing you to employ several arms internally, not externally, and do a lot more work inside,” Kaiser said.

Robotic technology may also help surgeons perform procedures inside the colon itself. Kaiser mentioned that one of the issues with colonoscopies to remove lesions is that sometimes a lesion may be hidden. With newer technology, surgeons may be able to navigate through the colon and safely shave off the lesion from the surface without poking a hole.

“I think those (technologies) will all 100% be coming,” Kaiser said. “The question is not whether they come, but more when they come. I'm very optimistic. I think it's a really exciting field to watch where we can make a difference for many reasons, because we have innovative people who think how to improve things.”

Another area of colorectal cancer that holds a lot of promise is the assessment of minimal residual disease, meaning that a very small number of cancer cells remain in the body either during or after treatment. Highly sensitive laboratory methods and technology are needed to determine whether a patient has minimal residual disease. This tactic can also help cancer teams determine which treatment to proceed with next, to make a prognosis, to see how well a treatment may be working for a patient’s cancer or even to determine a patient’s risk for recurrence.

“At least two of the assays have FDA approval for use, and there are several large trials that are ongoing to optimize how we use (minimal residual disease), who do we hold back and not give adjuvant therapy,” Barzi said. “Maybe how do we look at these patients in terms of surveillance, how often we do the surveillance scans in them to see if the cancer comes back after they've received treatment? I think that is a major progress in terms of giving the right treatment to the right patient, not over-treating the population for few patients who actually see the benefit.”

Barzi said that further progress will also be made in the treatment of colorectal cancer outside of surgery including learning what genetic mutations to target with therapies. For example, researchers are looking into targeting the mutation KRAS G12C, for which there is a targeted therapy approved by the FDA for the treatment of certain lung cancers. Of note, the KRAS gene is mutated in approximately 50% of patients with colorectal cancer. Studies conducted have not shown same magnitude of benefit in patients with colon cancer as it does in patients with lung cancer, although there are other drugs that are currently being developed that will also target this KRAS mutation for colorectal cancer.

“I am really hopeful that in the next maybe five to 10 years, we would actually have drugs to target KRAS, which is called undruggable,” Barzi said. “That’s my real hope. That’s something that I’m really looking forward to because I think it’s going to address the need in a large population, … and it is going to be a really major step forward for this disease.”

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