It is important that as many people as possible with colorectal cancer and liver metastases have the possibility to undergo surgical removal of these metastases. Undergoing this surgery often leads to longer survival and sometimes patients are even cured. Therefore, it is encouraging that a nine-year study has yielded positive experiences with a method that paves the way for more patients to reach the operating table. The study aimed to find the best systemic therapy – treatment with medications such as chemotherapy – to make surgery possible. In addition, a ‘liver expert panel’ was set up: a team comprising a radiologist and surgeons who regularly assess whether a patient might – still – be eligible for surgery.
Is the glass half full or half empty? The latest results of the CAIRO5 study, published this week in JAMA Oncology, can be explained in two ways.
Physician-researcher and trial coordinator Marinde Bond says: “We had hoped that more intensive systemic therapy would improve survival rates for patients with colorectal cancer who have metastases only in the liver. Unfortunately, this turned out not to be the case. On the other hand, we now know that more patients can undergo less burdensome treatment. Why? Treatments involving more agents and more side effects do not lead to longer survival; so we can limit ourselves to those that have fewer side effects. Moreover, we found that the involvement of a liver expert panel—comprising a radiologist and surgeons—enabled more patients to have their metastases removed through surgery or thermal ablation (heating). These treatments are associated with longer survival.”
Every year, 12,000 people in the Netherlands are diagnosed with colorectal cancer. Fifteen percent of them either have liver metastases at diagnosis or develop them later. The best-case scenario is that a surgeon removes the metastases. Unfortunately, this is often impossible because the metastases are too large or for example invaded by blood vessels. In such cases, systemic therapy can be an option. The goal is to shrink the metastases so that surgery might become possible. Systemic therapy combines two treatments: chemotherapy and targeted therapy. While chemotherapy inhibits the growth of all dividing cells, including healthy ones, targeted therapy focuses on specific cell characteristics, primarily cancer cells. Both treatments are administered via infusion.
Marinde: “There are various systemic therapies, differing in the agents used and their quantities. However, it is unknown which is the best systemic therapy for patients with liver-only colorectal cancer metastases. To address this, a study was launched in 2014. Nearly fifty medical centers, including UMC Utrecht, are participating. All these hospitals treat patients with systemic therapy, while a smaller number also perform surgical removal of liver metastases.”
Since 2014, over 500 patients have participated in the study. These were individuals diagnosed with colorectal cancer and had metastases only in the liver. In their hospital, surgeons deemed the metastases inoperable, a judgment confirmed by the CAIRO5 liver expert panel. Participants received up to 12 rounds of systemic therapy. During this period, the liver expert panel assessed whether the metastases had shrunk enough to allow surgery. If so, systemic therapy was paused, and the patient underwent surgery. After surgery, the remaining systemic therapy was administered.
Marinde: “We looked at three key outcomes. First, how long did it take for the disease to stop progressing after starting systemic therapy? Second, how many patients were eventually able to undergo surgery or thermal ablation? And third, what were the survival rates?”
There were two study groups. The first group included participants with the poorest prognosis for long-term survival. These were patients with tumors on the right side of the colon and two specific genetic mutations, which indicate poor survival and a lack of response to a specific targeted therapy. Half of this group received three-agent chemotherapy (FOLFOXIRI) combined with the targeted therapy bevacizumab, while the other half received two-agent chemotherapy (FOLFOX or FOLFIRI) with bevacizumab.
“Last year, we published the first results in The Lancet Oncology”, says Marinde. “We found that participants receiving three-agent chemotherapy experienced longer periods without disease progression compared to those receiving two-agent chemotherapy. Additionally, the group receiving more intensive systemic therapy had more patients who were eventually able to undergo surgery or thermal ablation. But the key question remains: were there differences in overall survival? Our latest research findings reveal that the survival rates are the same for both groups. It appears that, despite the disease staying controlled for longer and more surgeries or thermal ablations being feasible in one group, the overall survival ultimately does not differ from the other group.”
The second group consisted of patients with tumors on the left side of the colon and without the two genetic mutations. These patients had the best prognosis.
Marinde explains: “In this group, all participants received two-agent chemotherapy (FOLFOX or FOLFIRI), but half were treated with bevacizumab and the other half with panitumumab as the targeted therapy. From previous research we know that Panitumumab has more side effects, particularly skin-related ones. Last year, we published findings showing that the two groups had equal durations of disease-free periods and equal opportunities for surgery or thermal ablation. Now, we’ve also concluded there’s no difference in overall survival between the two therapies.”
What do these results mean for patients? Marinde: “More intensive systemic therapies do not necessarily yield better outcomes. For both groups, the recommendation is to choose two-agent chemotherapy combined with bevacizumab, which is less burdensome for patients. This insight is a significant gain from our research.”
Another positive outcome is that the liver expert panel has opened the door to surgery for more patients. “As mentioned, surgery is the best option,” says Marinde. “But in practice, surgeons often debate whether a patient is operable, depending on factors like the extent of metastases. This study showed that the liver expert panel more frequently facilitates surgery.”
How does it work? Marinde explains: “Participating hospitals could upload liver scans through a program for the panel to review. The panel included radiologists and surgeons from participating centers. Each case was evaluated by a radiologist and three surgeons. If they didn’t reach consensus, two additional surgeons were consulted, with the majority decision prevailing. This led to more thorough assessments of liver metastases than in standard care, enabling more patients to qualify for surgery.”
The researchers now aim to introduce the liver expert panel into daily clinical practice. Marinde: “Patients who undergo surgery have significantly longer survival than those who only receive systemic therapy. It shouldn’t depend on the hospital whether or not a patient gets surgery. Every patient deserves the most careful evaluation. Ensuring equal access to life-extending and sometimes curative surgery is essential. We hope to secure funding for the liver expert panel, either through grants or as part of insured care.”
The CAIRO5 study was set up in 2014 by Professor of Medical Oncology Kees Punt (UMC Utrecht, formerly at Amsterdam UMC) and Thomas van Gulik, now Emeritus Professor of Surgery at Amsterdam UMC. Van Gulik’s work was taken over by surgeon Rutger-Jan Swijnenburg of Amsterdam UMC.
Text: Gerben Stolk
