For inoperable hepatocellular carcinoma, transcatheter arterial chemoembolization (TACE) is one of the most effective methods of palliative care available.
So what exactly is TACE? Can it be combined with sorafenib, the standard treatment for liver cancer?
Effects and drawbacks of TACE for liver cancer
TACE is the selective insertion of a catheter into the target artery of the tumor blood supply and the injection of an appropriate mixture of embolic and chemotherapeutic agents at an appropriate rate. The embolic agents occlude the target artery, thereby blocking the blood supply to the tumor and causing ischemic necrosis, and the chemotherapeutic agents are slowly released locally in the tumor, which continues to strike the tumor and can induce apoptosis with low systemic toxic effects.
However, there are still some problems with TACE for liver cancer:
- Long-term survival of patients treated with TACE is not particularly good;
- Repeated TACE treatment and chemotherapeutic agents can worsen liver damage;
- After TACE, tumor collateral circulation blood supply affects the efficacy after liver intervention;
- After TACE treatment, although tumor tissue necrosis is obvious, it also causes severe ischemia and hypoxia in the tumor adjacent tissues, and the expression of local pro-vascular growth factor increases dramatically, which accelerates tumor recurrence and metastasis.
So what is the treatment of choice for patients who have failed TACE therapy or are no longer candidates for TACE therapy? This is an important challenge for hepatocellular carcinoma that is currently not amenable to surgical resection.
The leading treatment for liver cancer: sorafenib
Sorafenib is a multi-kinase inhibitor that inhibits multiple tumor cell-associated proteases at the same time, stalling tumor growth by inhibiting signaling between these proteases and tumor tissue.
Sorafenib also effectively antagonizes the vascular endothelial growth factor receptor (VEGFR), which means it blocks the formation of new blood vessels in the tumor tissue. The tumor multiplication is naturally inhibited.
The efficacy of sorafenib in treating liver cancer has been confirmed by two clinical studies and its ability to slow the progression of progressive liver cancer and extend patient survival has kept sorafenib in the first line of treatment for unresectable liver cancer for a decade.
But in recent years, as sorafenib has been heavily used, more and more data have shown its efficacy as a single agent for hepatocellular carcinoma to be unsatisfactory. So what can be done to improve the efficacy of sorafenib? Scientists have envisioned that combining sorafenib with TACE might yield better results.
How well does TACE work in combination with sorafenib?
There is a rationale for sorafenib in combination with TACE for unresectable liver cancer.
- TACE exacerbates hypoxia in liver cancer tissue, causing upregulation of VEGFR and promoting metastasis. Sorafenib reduces VEGFR expression and inhibits angiogenesis in tumor tissue, so that sorafenib combined with TACE has a complementary effect.
- The prognosis for patients with advanced unresectable liver cancer is poor, with survival often less than a year, and the idea of combining TACE and sorafenib, both of which are important treatments for unresectable liver cancer and can prolong the survival of patients with progressive liver cancer on their own, has led investigators to explore the idea of combining the two.
Several studies suggest that sorafenib is ineffective in combination with TACE
In 2011, a joint Korean-Japanese study found that the combination of TACE and sorafenib did not significantly improve the time to tumor progression in patients (7.2 months in the sorafenib + TACE group vs 5.3 months in the placebo + TACE group).
However, there was immediate hope. the START study, a phase II study published in 2015, included 192 patients with intermediate-stage hepatocellular carcinoma and showed that TACE combined with sorafenib resulted in an overall efficacy of 69.5%, disease control of 93.7%, median progression-free survival of 384 days, and median tumor progression of 415 days. Moreover, combination sorafenib treatment prolongs the interval between TACE treatments and helps protect liver function.
But before we had time to rejoice, the SPACE study, published in early 2016, gave us another blow. This study enrolled patients with intermediate-stage multiple hepatocellular carcinoma, and two study centers in mainland China were involved.
The study found no statistical difference in median time to tumor progression between the combination therapy and placebo +TACE groups (169 days in the sorafenib +TACE group vs 166 days in the placebo +TACE group). There was also no difference in the time to tumor progression to large vessel thrombosis or intrahepatic metastasis, and no difference in overall survival between the two groups.
A multicenter phase III clinical study from the United Kingdom also showed no further improvement in efficacy with combination therapy, no difference in median progression-free survival (7.8 months in the sorafenib + TACE group vs 7.7 months in the placebo + TACE group), and no difference in median overall survival.
Based on the results of the large study, the general consensus among physicians is that the combination of sorafenib and TACE for hepatocellular carcinoma is essentially hopeless for improving outcomes.
TACTICS study offers new hope
However, the TACTICS study, reported at the 2018 American Society of Clinical Oncology Annual Meeting, brings great light to combination therapy.
The study included 156 patients and found that median progression-free survival was 13.5 months in the TACE alone group and up to 25.2 months in the TACE+ sorafenib combination group, and that combination therapy reduced the risk of disease progression by 41%. Combined sorafenib treatment significantly improved progression-free survival in patients with unresectable HCC compared with TACE alone!
There were no new toxicities during the study period, and the incidence of adverse events observed, all consistent with the known safety data for sorafenib, included hand-foot skin reactions, hypertension, elevated lipase, fatigue, diarrhea, erythema multiforme, weight loss, and hoarseness.
This newly released study is a shot in the arm for researchers who have been repeatedly frustrated. Notably, the mean duration of sorafenib after TACE in this study was 38.7 weeks, compared with a mean duration of just 17 to 21 weeks in previous combination therapy studies.
The endpoint used in the current study was treatment until patients experienced incurable progression of TACE, rather than the previously standard disease progression, so it certainly prolonged the duration of sorafenib dosing. However, this new study endpoint requires further validation to determine whether it is an appropriate surrogate for survival.
It is too early to say whether sorafenib in combination with TACE for hepatocellular carcinoma is feasible, and we need to wait for more mature findings from TACTICS and a larger sample size of multivariate validation studies before we can do so.