Aggressive Treatment Approaches Expected to Move Dial in Metastatic Colon Cancer

Michael J. Cavnar, MD

The management of patients with liver metastases from colorectal cancer (CRC) is complex and requires careful assessment from a multidisciplinary tumor board— especially in light of recent advances made with chemotherapy, according to Michael J. Cavnar, MD. Now, researchers are seeking to confirm the benefit of using hepatic artery infusion pumps to further improve outcomes.

“With the increasing efficacy of chemotherapy, more patients who once would have strictly received palliative therapy can now undergo surgery,” said Cavnar. “I also believe that we’re going to have level-1 evidence illustrating the benefits of hepatic artery infusion pumps in the not-sodistant future. I have seen patients start off with high disease burden and, over time, become disease free. Of course, this isn’t the case for everyone; some may progress on this or experience complications. However, I truly believe aggressive treatments such as this one are going to move the dial in metastatic colon cancer.”

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Cavnar, an assistant professor of surgery at the University of Kentucky Markey Cancer Center, highlighted the role of surgery in CRC, the role of tumor sidedness in informing surgical decisions, and research efforts that are being done to evaluate the utility of hepatic artery infusion pumps.

OncLive^®: What are the key components of surgical care in CRC that medical oncologists should be aware of?

Cavnar: I’m a surgical oncologist, so the treatments I provide generally focus on surgery. However, for this disease process, we need to look at much more than surgery. When treating patients with colon cancer, we must collaborate with colleagues across many specialties, particularly those in medical oncology.

It’s also important to be aware of the historical aspects of liver metastases, which are largely surgical. Notably, several advances have also been made with chemotherapy, which is used around the time of surgery after resection of liver metastases. We also [consider] palliative chemotherapy, which is given to [those with] unresectable disease.

In addition, [another topic of interest has to do with] the hepatic artery infusion pump, which is among my areas of specialty. At the University of Kentucky, we have a clinical trial that has been ongoing for about 6 months now; this is an effort that I am actively working on.

Tumor sidedness is another key component to consider when selecting the appropriate treatment for these patients. What factors do you use to inform surgical decisions?

The right side of the colon is the easiest to remove surgically. As such, if someone has a right-sided cancer, unless it’s very bulky or advanced, we typically perform the surgery laparoscopically. A hospital stay for that type of operation could be several days, and recovery is typically quick. Left-sided disease, depending on where it is, can be more complicated. If the tumor is in the upper part of the left colon, we call this a descending or sigmoid colon. Those [cases], surgically, are fairly straightforward and usually don’t involve a diverting ileostomy. As you get down into rectal cancer, which technically would fall under a left-sided disease, the surgical management is much more complicated and often involves neoadjuvant radiation. The anastomosis is much higher risk and is frequently protected with a diverting ileostomy, which later requires another surgery to reverse.

If a patient just has a primary tumor, the surgical aspects are the dominant factor because up-front surgery for primary colon cancer is the standard of care. If the patient has synchronous metastatic disease, meaning they have metastatic disease that is diagnosed at the same time as their primary tumor, then the left- versus right-sidedness helps guide the selection of chemotherapy; that is an evolving practice.

A typical first-line chemotherapy regimen for either a left- or right-sided colon cancer would be something like FOLFOX/ bevacizumab [Avastin], which both should respond to. If you get into a situation where a patient could not receive bevacizumab, maybe due to some cardiovascular issues, then we consider adding other biologics. If [we are dealing with] a KRAS mutant left-sided tumor, then that patient would not receive an EGFR inhibitor.

What is your approach for treating liver metastases in practice? How has this evolved in recent years?

The standard of care largely depends on the burden of the disease. A patient with confined liver metastases and only 1 or 2 small lesions can be managed with a minimally invasive procedure. In my practice, smaller lesions are typically done with a laparoscopic or robotic approach, which consists of small incisions and a 1- to 2-day hospital stay. Almost all patients with metastatic colon cancer receive some type of perioperative chemotherapy. Although there are some variations to this, giving 6 months of chemotherapy both before and after surgery is fairly standard. As the number and the complexity of the metastases increases, things become more complicated.

Notably, there is this concept of a future liver remnant, which I believe is a major advancement in liver surgery. We used to be under the impression that, in order to do surgery on the liver, we had to do a major hepatectomy—either a left hepatectomy, which involves removing about 40% of the liver, or a right hepatectomy, which involves removing about 60% of the liver. These are major operations, and about 5 years ago, they carried over a 5-year mortality rate. As the understanding of liver surgery and the biology of colon cancer has evolved, it’s now understood that [the goal is focused] not so much about getting a wide margin but about taking out the metastasis and leaving as much healthy liver as possible. Historically, major hepatectomies accounted for most surgeries performed; however, now they are the minority.

What are the most intriguing data regarding the utility of hepatic artery infusion pumps?

Hepatic artery infusion pumps have been around since the 1970s. They basically capitalize on the fact that liver metastases obtain their blood supply from the artery that feeds the liver. Ultimately, the liver has a dual inflow of blood; about one-third is from the hepatic artery and about twothirds is from the portal vein. For whatever reason, colorectal liver metastases only obtain blood flow from the artery, which has been demonstrated for many years.

In the 1970s, they started infusing chemotherapy directly into the liver. The dose that you would need to put into [a patient’s] veins to achieve that level would be incredibly toxic to the body. Instead, we can achieve a dramatic response by [infusing] a small amount [of chemotherapy] at a high concentration directly into the liver. Although this sounds great conceptually, we need to prove this. To this end, so much work has been conducted at Memorial Sloan Kettering Cancer Center; this is where I did all of my training and learned about the artery pump. It’s truly one of the biggest programs in the country and in the world.

Could you expand on some of these efforts?

Many clinical trials have been conducted over the years, with the early trials focused on how this [approach] could be [used] safely. [Investigators] generally started with patients who had high disease burden, along with those who had unresectable disease. These patients were initially given hepatic artery chemotherapy through the pump. However, early on, it was learned that although this controlled liver disease, patients could still develop lung metastases. They learned that you could safely give regular chemotherapy, along with pump chemotherapy; as such, this became the standard. They then played around with different regimens, determining which would be the best to give.

The [most] data are focused on adjuvant pumps; this means that patients who undergo complete resection of liver metastases have a pump implantation at the same time of their surgery, so they leave their operating room with a pump. Then, a few weeks after surgery, they start chemotherapy into the liver remnant.

This process has been studied in a randomized trial, which was first [published] in 1999 in the New England Journal of Medicine; there was follow-up [information that was released] later on. [The approach was found to] unequivocally lower recurrence within the liver. The randomized study compared patients who had resection and just received adjuvant f luorouracil versus that plus a hepatic artery pump. The study showed that, initially, the overall survival was significantly longer in patients who received the pump. At the 10-year follow-up, that statistical difference drifted a little bit. If you look at the graph, the curves are still different, but the P value is .1, which led many to believe that the pump did not work.

What is being done to settle the debate of whether the pump should be used in practice?

A trial examining today’s modern chemotherapy, with or without the pump, has not been done.

This is a very difficult study to set up because those who believe in the pump, like myself, believe in it strongly, whereas others really do not. That being said, I’m actually involved in a multinational consortium on the hepatic artery pump, which just started. We recently had a Zoom call with about 50 surgeons from all over the world; it was impressive to see these people all together. We’re in the early stages of developing [such a] clinical trial, [and] we believe we could prove [the effectiveness of] this [approach].

In the meantime, the group at Memorial Sloan Kettering Cancer Center has come out with really powerful support of this [approach in the form of] retrospective data. They had a paper published in 2016 in the Journal of Clinical Oncology that included about 2000 patients who had liver resection [as a] result of CRC liver metastases.

All patients received modern chemotherapy, typically FOLFOX. They looked at the patients who received pumps and compared them with those who did not. They used propensity matching, which basically compares apples to apples and oranges to oranges, and the survival difference was dramatic. A 10-year survival of approximately 40% was reported [with the pump], which is essentially a cure, versus about 23% [in those without it]—almost a doubling of survival. We, in this consortium, mark that date as the time when the game started to change again.