This retrospective study, led by Dr. Paul Kent and colleagues at Rush University Medical Center, evaluated whether a three-drug combination known as “triple therapy (TT)”, or “triple immunochemotherapy”, could help control advanced fibrolamellar carcinoma (FLC). This treatment combines:
- Nivolumab – an immune checkpoint inhibitor that blocks PD-1, a molecular “off switch” used by cancer cells to suppress T-cell activity. By blocking PD-1, nivolumab helps keep the immune system engaged in attacking tumor cells.
- Interferon-alpha – one of the earliest forms of cancer immunotherapy. It is a naturally occurring immune signaling protein that stimulates immune cells such as T cells and natural killer (NK) cells, while also exerting direct anti-tumor effects.
- 5-fluorouracil (5-FU) or its oral equivalent, capecitabine – a well-established chemotherapy agent that interferes with DNA and RNA production in rapidly dividing cancer cells. In addition to its direct anti-cancer effects, it may also reduce immune-suppressive cells that help tumors evade immune attack.
This is the same therapy investigated by M.D. Anderson Cancer center in a prospective clinical trial.
Study Summary
The investigators reviewed 22 patients with FLC who were treated at Rush University Medical Center with the triple therapy between 2018 and 2020. Fourteen patients were considered evaluable because they had received sufficient treatment and follow-up imaging. When they began receiving the triple therapy:
- 5 patients were in clinical remission.
- 4 patients had stable disease.
- 5 patients had progressive disease.
At the end of the study period:
Patients who began treatment in clinical remission (5):
- Two remained in clinical remission while receiving triple therapy.
- One remained in remission after undergoing multiple surgeries or ablations.
- One achieved stable disease.
- One experienced disease progression and discontinued treatment.
Patients who began treatment with stable disease (4):
- One continued treatment and was reported to have achieved a complete response.
- One changed therapy after maintaining stable disease for a period of time.
- One changed therapy after relapse, but had maintained stable disease for a period of time.
- One discontinued treatment following relapse and subsequent surgery or ablation.
Patients who began treatment with progressive disease (5):
- One achieved a partial response.
- One remained on therapy with stable disease.
- One discontinued treatment after a period of disease stabilization.
- One discontinued treatment after relapse, but had maintained stable disease for a period of time.
- One was reported to be in clinical remission but had also undergone multiple surgeries or ablations during treatment.
It is important to note that several patients underwent surgery and/or ablation during the time period analyzed. As a result, while some patients appeared to benefit clinically from triple therapy, the study design makes it difficult to determine how much of the observed benefit was attributable to the drug regimen versus local treatments such as surgery or ablation.
Treatment side effects
Overall, the triple therapy was reasonably well tolerated. The most common side effects included:
- Fever
- Fatigue
- Headache
- Nausea
- Edema (swelling)
- Hypothyroidism
Serious side effects were relatively uncommon. The investigators reported:
- Four Grade 3 toxicities (severe side effects)
- One Grade 4 toxicity (life-threatening colitis)
The patient who developed Grade 4 colitis discontinued treatment with nivolumab but was able to continue receiving 5-FU and interferon. Overall, two patients stopped part or all of treatment because of treatment-related side effects.
Key implications of effort
This study provides early evidence that a combination of nivolumab, interferon-alpha, and 5-FU (or capecitabine) may help control advanced FLC, including recurrent, metastatic, and treatment-resistant disease. However, these findings should be interpreted cautiously. The study’s retrospective, nonrandomized design and limited sample size makes it challenging to distinguish the benefit of the triple therapy from that of surgery or ablation. Larger prospective studies are needed to confirm its effectiveness and define its role in the treatment of FLC.
The abstract of the article can be read here.