If decades and decades of cancer research have shown anything, it is that there is no magic bullet to defeat cancer. he scientific community is increasingly certain that the success of the fight against the most aggressive tumors lies in attacking multiple fronts simultaneously to prevent the escape of tumor cells that enable disease progression. Two new, independent studies published on Wednesday in The Lancet explore this strategy in the context of liver cancer and confirm that combining two targeted therapies with a traditional treatment that disrupts the tumor’s nutrient supply can delay disease progression. Both studies, which are phase III trials, evaluate different drug combinations, but share a common strategy: attacking the tumor from different fronts to maximize efficacy.

One of the studies, called LEAP-012, employed a three-pronged therapeutic approach against an intermediate-stage tumor that, while not yet spread to other parts of the body, is too large for surgical removal: non-metastatic, non-resectable hepatocellular carcinoma. In a clinical trial, researchers from Idibaps-Clínic in Barcelona, showed that adding slenvatinib (a molecular therapy) and pembrolizumab (an immunotherapy) to traditional chemoembolization (which blocks the tumor’s blood supply) improves progression-free survival — the time a patient lives without tumor progression. Although the results of the clinical trial are modest — the progression-free survival increased from 10 months with chemoembolization alone to 14.6 months with the three-pronged approach — the findings mark a breakthrough in a tumor type that has seen no significant therapeutic advances in two decades. Nearly 500 patients participated in the research.

In the other study (EMERALD-1), led by the Clínica Universidad de Navarra (CUN), researchers also tested a three-pronged strategy for inoperable liver cancer. In a trial with 616 patients, they added a combination of durvalumab (an immunotherapy) and bevacizumab (a drug that blocks blood vessel growth) to conventional chemoembolic therapy, and found that it slowed disease progression. The combination of the two targeted therapies delayed cancer progression by 6.8 months compared to the participants who received a placebo.

Every year, around 6,000 cases of liver cancer are diagnosed in Spain. In the vast majority of cases (90%), patients have a history of cirrhosis, often due to hepatitis B or C, alcohol abuse, or metabolic diseases. Josep Maria Llovet, a professor of Medicine and Hepatology at the University of Barcelona and ICREA professor at Idibaps, notes that 30% of tumors are diagnosed at early stages, when the typical treatment involves removal of the tumor, liver transplant, or radioembolization (microwaves used to eliminate small tumors).

However, other cases are diagnosed when the cancer is more advanced: “Between 40% and 50% of tumors are detected at advanced stages, when there is invasion of blood vessels or lymph nodes, or when metastasis has occurred. But there’s also another 25% of tumors detected at intermediate stages, for which chemoembolization is the standard treatment.” The new therapeutic approaches recently tested are aimed at these intermediate-stage cases.

“After 20 years of mechanical treatment, where we prevented the tumor from feeding by blocking its feeding artery and releasing regional chemotherapy [delivered to the area], we transitioned to a combined treatment with systemic therapy,” explains Llovet, the international lead investigator of the LEAP-012 study. Indeed, the same team from Idibaps-Clínic developed chemoembolization two decades ago, which has since become the standard treatment.

This intervention was a game-changer in clinical practice, but its effects were limited, and patients continued to have a poor prognosis in the medium term. The new approach outlined in the trial published in The Lancet marks a significant step forward for a group of patients who urgently needed better therapeutic outcomes, according to Llovet.

“With the standard treatment, we achieved an average survival of about 25 months, but after eight months, the tumor would progress,” he explains. “With this new treatment, progression-free survival has increased to 15 months, and we have reduced the probability of progression by 34% overall in more than a third of patients. These results are expected to change clinical practice for 25% of patients with this cancer worldwide.”

Triple action

The new strategy developed by the Idibaps team targets the tumor on three fronts simultaneously. First, with chemoembolization, the tumor is starved by blocking its nutrient artery, the pathway through which the nutrients that fuel its growth enter, while chemotherapy is directly released into the tumor mass to more efficiently destroy malignant cells. Next, lenvatinib, a multikinase inhibitor, blocks the pathways that enable the tumor to revascularize (develop blood vessels), helping to halt the progression of tumor cells. Finally, pembrolizumab lifts the molecular brakes the tumor has placed on the immune system, allowing it to be attacked.

“Seventy-five percent of treated patients achieved an objective response [a reduction of at least 30% in the tumor’s diameter]. Previously, with chemoembolization alone, this was seen in 50% of patients,” explains Llovet. While the impact on overall survival showed a trend that was not yet statistically significant, the results suggest that the findings will be further studied with a longer follow-up of the patients included in the study. So far, they have been followed for approximately 26 months.

In the case of the EMERALD-1 trial, the authors claim that the risk of disease progression or death was reduced by 23%, although they acknowledge that the study is still ongoing to further analyze the overall survival of patients in the future. Bruno Sangro, Director of Hepatology at the CUN and lead author of the study, stated that the results represent “an important advance” for a group of patients for whom “there had been no progress in more than 20 years,” adding that “it is a realistic therapeutic alternative for those who cannot undergo surgery.”

These synergies between different therapeutic approaches follow the scientific trend of advancing precision medicine, such as immunotherapy and molecular therapy, to earlier stages of the disease. Regarding the Idibaps study, María José Safont, spokesperson for the Spanish Society of Medical Oncology (SEOM) and oncologist at the Consortium of the General University Hospital of Valencia, noted that this new therapeutic approach “represents a significant innovation in attempting to improve outcomes for a patient population with limited treatment options.”

Safont, who was not involved in the research, contextualized the five-month improvement in progression-free survival achieved by one of the new drug combinations: “It is a clinically relevant advance in the context of hepatocellular carcinoma, as it is a disease with generally unfavorable prognosis. This increase in survival represents a delay in tumor progression and could improve the quality of life for patients. Although a five-month difference may seem modest at first, in oncology, it is a significant advance, especially in diseases with limited therapeutic options.”

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32-year-old Bianca Perea has been thankfully declared cancer-free following the UK’s first liver transplant for advanced bowel cancer.

This pioneering procedure offers a beacon of hope to others facing similarly dire prognoses.

Bianca Perea was diagnosed with stage four bowel cancer In November 2021

Bianca Perea, a trainee lawyer from Manchester, was diagnosed with stage four bowel cancer, the most severe form, and was told that it had spread extensively to all segments of her liver.

Initially visiting her GP in Wigan due to constipation and bloating, Perea was subsequently referred for a colonoscopy and biopsy that confirmed the devastating diagnosis. Doctors informed her that the aim was to prolong her life, not cure her condition.

Perea kept faith. “I don’t want to sound kind of ignorant or arrogant or anything like that, but I just didn’t feel in my gut that that was going to be it,” she said.

Cancer treatment

Over the next two and a half years, Perea underwent an aggressive treatment regime at Christie NHS Foundation Trust, including 37 rounds of chemotherapy combined with the targeted drug panitumumab. The treatment successfully eradicated cancer from her bowels, enabling surgeons to remove the tumour in May 2023. However, the tumours in her liver remained inoperable.

Recognising her exceptional response to treatment, doctors explored the possibility of a liver transplant – a treatment previously deemed unfeasible for bowel cancer patients. In February 2024, she was added to the transplant list and received a donor liver last summer at Leeds Teaching Hospitals NHS Trust.

Remarkably, within weeks of the transplant, Perea was back on her feet. She said: “Within four weeks of going under the knife, I was able to drive and walk the family dogs, it was really quite incredible. To go from being told I’d only have a short time to live to now being cancer-free is the greatest gift. I’ve been given a second chance at life and I’m going to grab it with both hands. I am so grateful to the family who agreed to donate their loved one’s liver.”

Organ donation

Dr Ian Rowe, honorary consultant hepatologist at Leeds Teaching Hospitals NHS Trust, emphasised the role of organ donation in saving lives. “We are indebted to the family of the organ donor. Organ donation saves lives,” he said. He encouraged people to register their decision on the NHS Organ Donor Register and communicate their wishes to loved ones.

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View all articles by Letara Draghia.